Cardiopulmonary Resuscitation

C C2/C3 Traumatic Spondylolisthesis ▶ Hangman’s Fracture Calcium Channel Antagonist Poisoning ▶ Calcium Channel Blocker Toxicity Calcium Channel Blocker Toxicity ADEEL ABBASI, FRANCIS DEROOS Emergency Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Synonyms Calcium channel antagonist poisoning Definition Calcium channel blockers (CCBs) are widely used throughout the world and are commonly prescribed for the treatment of hypertension as well as dysrhythmias, migraine headaches, Raynaud phenomenon, esophageal spasm, and post-subarachnoid hemorrhage vasospasm. While CCBs are relatively well tolerated therapeutically, in overdose, these agents can lead to significant hemodynamic instability including hypotension and bradycardia. For the most severely poisoned patients, there is no consistently reliable treatment available. Therefore, management decisions must be individualized on a case-by-case basis and the physiologic response to each intervention should be careful monitored and considered while the treatment continues. All calcium channel blockers act by antagonizing ▶ voltage-sensitive calcium channels (L-type) which are involved in excitation-contraction coupling in both the myocardial and vascular smooth muscle as well as the spontaneous depolarization and conduction within the SA node, the AV node, and the conduction tissue in the myocardium. While these calcium channels are also present on skeletal smooth muscle cells, CCBs have little effect on these tissues function because these cells rely almost exclusively on intracellular calcium stores rather than calcium influx for their contractility needs [1]. In general, CCBs are well absorbed orally and are hepatically metabolized, predominantly by the CYP3A subgroup of the cytochrome P450 enzyme system. This metabolism can by saturated in overdose, potentially prolonging the half-life and duration of activity of these drugs. CCBs are highly protein bound and have relatively large volumes of distribution making it unlikely that hemodialysis or even hemoperfusion would be of any value in treating an overdosed patient [2]. In therapeutic doses, CCBs reduce calcium influx into vascular smooth muscle cells resulting in a decrease in the baseline contractility or tone of the peripheral vascular smooth muscle and, ultimately, a reduction in peripheral vascular resistance and blood pressure. In a typical myocardial cell, this reduction in calcium influx also results in decreased contractility. However, in the specialized conduction cells within the myocardium, this reduction in the influx of positively charged calcium both decreases the rate of spontaneous depolarization (phase 0) of the SA and AV nodes, and it reduces the electrically induced depolarization essential in cardiac conduction (Purkinje tissue). In therapeutic dosing, this reduces the resting heart rate as well as the conduction through the AV node, and may suppress spontaneous depolarizations initiated by abnormal or diseased myocardium as well as their propagation and thereby suppressing dysrhythmias [1]. Effects in Poisoned Patients In poisoned patients, the physiologic effects that have just been described for therapeutic dosing become exaggerated resulting in hypotension (most common) and Jean-Louis Vincent & Jesse B. Hall (eds.), Encyclopedia of Intensive Care Medicine, DOI 10.1007/978-3-642-00418-6, # Springer-Verlag Berlin Heidelberg 2012 444 C Calcium Channel Blocker Toxicity bradydysrhythmias. The clinical symptoms and presentation of CCB toxicity depends predominantly on the degree of cardiovascular compromise with symptoms ranging from fatigue, dizziness, and postural light-headedness, seen early and in milder cases, to confusion, syncope, and shock, seen later and in more severe cases. Myocardial chronotropy, dromotropy, and inotropy may become impaired with initially causing sinus bradycardia but progressing to AV conduction abnormalities, idioventricular rhythms, or complete heart block [2]. Although in overdose all CCBs are capable of causing severe cardiovascular compromise and death, there are some subtle differences in physiologic manifestations depending on the particular agent. The CCBs with the most significant myocardial effects, verapamil and diltiazem, have the most profound inhibitory effects on the SA and AV node. Because of this, these two agents, especially verapamil, are responsible for the majority of CCB overdose deaths. In contrast, nifedipine and the other dihydropyridines have little myocardial binding. They may initially produce a hypotensive patient with relatively normal or even increased heart rate before progressing into a bradycardic rhythm if the poisoning is severe enough. Consequences of severe cardiogenic shock such as seizures, cerebral and bowel ischemia, and renal failure are all associated with severe CCB poisoning. Notably, severe CNS depression without cardiogenic shock is uncommon. In fact, any overdose cases involving CCBs in which altered mental status is a predominant feature in the setting of relatively normal vital signs, a coingestant should be strongly considered. In addition, hyperglycemia is often seen in severely poisoned patients which is, in part, due to the impairment of calcium into the b-islet cells and insulin secretion The degree of toxicity present ultimately depends on multiple factors including which CCB is ingested, the total dose of the ingestion, the product formulation, and the patient’s underlying cardiovascular health. The timing of presentation of CCB toxicity can be as early as 2–3 h postingestion but can be significantly delayed for 8–12 h when sustained release products are involved. Sustained release formulations are particularly difficult to manage because of this potential delay in onset of hemodynamic changes combined with the continued and prolonged duration of absorption, and, often, the large amount of the CCB ingested [1]. Treatment Given the high mortality associated with CCB toxicity, patients presenting with CCB overdose should be started on treatment immediately, starting if applicable, with gastrointestinal decontamination. If the patient is able to cooperate, activated charcoal should be given orally at a recommended dose of 1g/kg to help reduce systemic absorption from the gastrointestinal tract. Multiple doses of activated charcoal (MDAC), in a reduced dose of 0.5 g/kg and without a cathartic, should be repeated every 1–2 h in ingestions involving sustained release CCBs. This is an attempt to fill the gastrointestinal tract with charcoal in an attempt to rapidly adsorb the CCB as it is slowly, but continuously, released from its formulation. Orogastric lavage should be considered if the ingestion involves a large dose of CCB, if the patient presents within 1–2 h postingestion, or if they are critically ill. Orogastric lavage may increase vagal tone and potentiate any bradydysrhythmias. ▶ Whole bowel irrigation (WBI) with polyethylene glycol in poisonings involving sustained-release formulations should also be strongly considered, even in asymptomatic patients. The dosing is 1–2 L/h via a nasogastric tube in adults and 300–500 mL/h in children and may be the most effective method of removing the large gastrointestinal reservoir of the CCB from the patient before it is systemically absorbed. This should be continued until the rectal effluent is clear. Both MDAC and WBI are important gastrointestinal decontamination methods and should be initiated as early as possible in cases involving sustained-release CCBs, even in well-appearing patients and particularly children, in an attempt to avoid progressive toxicity [3]. Pharmacotherapy should focus on improving and supporting both cardiac output as well as peripheral vascular tone. There is no single drug or regimen that has been consistently effective. A crystalloid bolus of 10–20 mL/kg of normal saline for hypotension and atropine 0.1 mg/kg for bradycardia are reasonable starting points for each manifestation respectively and may be initially stabilizing for mildly poisoned patients but are often inadequate in moderate to severe poisonings where multiple modalities are often needed simultaneously. A reasonable approach to a CCB-poisoned patient, after a fluid bolus and dose of atropine, may be to treat with a calcium bolus as well as a catecholamine infusion while you prepare to administer ▶ hyperinsulinemic euglycemia therapy (HIET). Recently, lipid emulsion therapy has been used successfully and should be strongly considered in significantly poisoned patients [1]. Drugs including glucagon and phosphodiesterase inhibitors may have limited efficacy and should be considered secondary adjuncts in the most critically ill patients. Calcium Channel Blocker Toxicity Calcium Calcium administration transiently improves myocardial inotropy and chronotropy and reverses the hypotension seen in CCB toxicity, and should be given early in bradycardic or hypotensive patients. It also improves the action of atropine if given concurrently. The exact dosing is unclear but a reasonable initial bolus is approximately 13–25 mEq of Ca2+ IV (10–20 mL of 10% calcium chloride or 30–60 mL of 10% calcium gluconate), followed either by repeat boluses every 15–20 min up to 3–4 doses or a continuous infusion of 0.5 mEq/kg/h of Ca2+ (0.2–0.4 mL/kg/h of 10% calcium chloride or 0.6–1.2 mL of 10% calcium gluconate). Although there is no difference in the efficacy of calcium chloride or calcium gluconate, the calcium salt administered should be chosen carefully as 1 g of calcium chloride contains 13.4 mEq of calcium, which is more than three times the 4.3 mEq found in 1 g of calcium gluconate. If repeat dosing or continuous infusions of calcium are used, the serum concentrations of calcium and phosphate should be monitored for hypercalcemia or hypophosphatemia. In addition, intravenous calcium may also cause nausea, vomiting, flushing, constipation, confusion, and angina. Catecholamines Catecholamines are indicated in any hypotensive CCBpoisoned patient. Mechanistically, it is logical to select an agent, such as norepinephrine, that has both b1-adrenergic effects and a1-adrenergic effects as a first line drug. Assessing the patient’s cardiac output and systemic vascular resistance will allow more refined catecholamine choices. Dopamine is not recommended as a first-line agent because it is predominantly an indirect acting pressor that acts by stimulating the release of norepinephrine from the distal nerve terminal rather than by direct a- and b-adrenergic receptor stimulation and these presynaptic catecholamines are often depleted in severely stressed patients. C Follow this by infusions of dextrose at 0.25–0.5 g/kg/h and insulin at 0.5 u/kg/h. This insulin infusion rate should be increased every 30–60 min if there is no hemodynamic improvement. Serum glucose should be monitored hourly throughout HIEG treatment [4]. Lipid-Emulsion Therapy Calcium channel blockers are highly lipophilic agents, and lipid emulsion therapy is emerging as a promising new adjunctive therapy for the management of CCB toxicity. The efficacy of this treatment is likely a pharmacokinetic one in that the highly lipophilic drugs are tightly bound to the fat emulsions and thereby lower the free serum drug levels. A recommended initial bolus infusion of a 20% lipid emulsion at 1 mL/kg over 1 min, repeated every 3–5 min to a maximum of 3 mL/kg, should be followed by a drip of 0.25/mL/kg/min [5]. This treatment has gained great favor in the anesthesiology literature for the treatment of iatrogenic bupivacaine poisoning, and many institutions have protocols that can be extrapolated to CCB-poisoned patients. Adjunctive Hemodynamic Support In a few cases of severe CCB poisonings, the bradydysrhythmias and severe hypotension can be refractory to any and all pharmacologic therapy, so successful treatment may require more invasive measures such as cardiopulmonary bypass or extracorporeal membrane oxygenation. These modalities are technically demanding and only available at tertiary care centers; however, if implemented appropriately, they have been shown to provide the hemodynamic support needed until the CCB is metabolized and eliminated, and baseline myocardial function is restored. Cardiac pacing may be attempted but is often unhelpful because patients with severe bradydysrhythmias from CCB poisoning are also like to have dramatically impaired cardiac contractility as well. Therefore, even if the heart rate is successfully improved, the cardiac output remains poor Insulin and Glucose The use of insulin and glucose, often termed hyperinsulinemic euglycemia (HIEG) therapy, has become the treatment of choice for severe CCB poisonings. The rational for this use is multifactorial and includes CCB poisoning inhibiting insulin release, forcing the normally free fatty acid–dependent myocardial tissue to become predominantly carbohydrate dependent as well as resistant to insulin [4]. In addition, insulin itself has positive inotropic effects. Dosing recommendations, based on published clinical experience, include an initial bolus of 25–50 g of dextrose (0.5–1 g/kg) and 0.1 U/kg of insulin. Evaluation and Assessment Any patient suspected of a CCB overdose should be immediately evaluated, even if there are no symptoms or signs of toxicity at the time of initial presentation. This is paramount given the seriousness and potentially fatal nature of CCB poisoning. Even with early and aggressive management, patients who present asymptomatic can deteriorate rapidly developing cardiogenic shock. This is especially true for pediatric patients who can be poisoned with very small doses [3]. Furthermore, with higher-dose and extended-release preparations available, the clinical 445 C 446 C Calcium Heparin presentation of toxicity can be significantly delayed for up to 12–15 h post ingestion. Intravenous access and continuous electrocardiographic monitoring should be initiated immediately upon arrival of the patient. In patients exhibiting any evidence of cardiovascular compromise, early central venous access and arterial catheterization is strongly recommended to allow for more accurate hemodynamic monitoring and guide therapy. Initial treatment should begin with adequate oxygenation and airway protection as clinically indicated. Given the potential for rapid deterioration of a severely poisoned patient, and the need for aggressive critical therapies, early control of the airway should be obtained. A 12-lead ECG should be obtained promptly to assess for dysrhythmias and conductional abnormalities, and repeated at least every 1–2 h for the first several hours. If the patient’s condition improves over time, ECGs can be repeated at longer intervals. Careful assessment of the degree of hypoperfusion and its sequelae, if any, may include a chest radiograph, pulse oximetry, serum chemistry analysis for metabolic acidosis and renal function, and monitoring urine output. Assays for various CCB serum concentrations are not routinely available and are not used to manage patients after overdose. If a patient presents with bradycardia of unclear origin, assessing electrolytes, particularly potassium and magnesium, renal function, and a digoxin concentration, is warranted. All patients who have overdosed with CCBs who manifest any consistent signs or symptoms should be admitted to an intensive care setting. In addition, because of the possibility of significant delayed toxicity, cases involving sustained-release formulations should be admitted for 24 h to a monitored setting, even if they are asymptomatic. This is particularly important for toddlers and small children in whom even one or a few tablets may produce significant toxicity [3]. Only patients with a reliable history involving an immediate release formulation of the CCB, who received appropriate gastrointestinal decontamination, who had a consistently normal ECG over several hours of monitoring and who are asymptomatic, can be safely referred directly for further psychiatric assessment as needed. regain their baseline neurologic function, their after-care will be limited to treating any complications from their hospital stay. Myocardial and peripheral vascular function should return to its baseline function. Patients with intentional ingestions, regardless of the degree of toxic manifestations, typically will require formal psychiatric evaluation. Prognosis While severe calcium channel blocker toxicity can cause profound cardiogenic collapse and death, if treatment is not delayed and invasive hemodynamic support is available, even severely poisoned patients can be supported for days with subsequent full recoveries. Multiple case reports document severely poisoned patients who were treated with seemingly extraordinary measures such as several days of extracorporeal membrane oxygenation or cardiopulmonary bypass despite minimal neurologic function, who make a complete recovery and regain their baseline cardiac and neurologic function. Many hypothesize that CCBs’ unique neuroprotective effects may explain these remarkable results. References 1. 2. 3. 4. 5. DeRoos F (2010) Calcium-channel blockers. In: Goldfrank’s toxicologic emergencies, 9th edn. McGraw-Hill, New York, pp 911–921 Kerns W (2007) Management of b-adrenergic blocker and calcium channel antagonist toxicity. Emerg Med Clin North Am 25:309–331 Arroyo AM, Kao LW (2009) Calcium channel blocker toxicity. Pediatr Emerg Care 25:532–538 Patel NP, Pugh ME, Goldberg S, Eiger G (2007) Hyperinsulinemic euglycemia therapy for verapamil poisoning: a review. Am J Crit Care 16:498–503 Jamaty C, Bailey B, Larocque A et al (2010) Lipid emulsions in the treatment of acute poisoning: a systematic review of human and animal studies. Clin Toxicol 48:1–27 Calcium Heparin ▶ Heparin California Valley Fever ▶ Coccidioidomycosis After-care The disposition of patients following treatment of calcium channel blocker toxicity will depend on the extent of their recovery. Patients who sustain any permanent neurologic injury will need appropriate care including rehabilitation. Otherwise, for those who make a complete recovery and Candida Infection ▶ Candidiasis Candidiasis Candidemia ▶ Candidiasis Candidiasis JOSÉ ARTUR PAIVA, J. M. PEREIRA UAG da Urgência e Cuidados Intensivos, Hospital Sao Joao and Medical School, University of Porto, Porto, Portugal Synonyms Candida infection; Candidemia; Invasive candidiasis Definition Although there are no strict definitions for nonimmunocompromised, critically ill patients, Invasive Candidiasis (▶ IC) encompasses a wide variety of severe or invasive diseases that excludes superficial or less severe diseases, like oropharyngeal and esophageal candidiasis, and includes four overlapping forms: candidemia, acute disseminated candidiasis, chronic disseminated candidiasis, and deep organ candidiasis. Essentially, all forms of IC probably begin as an episode of candidemia, but the clinical presentations of these four forms are different enough to make this classification useful. Therefore: (a) candidemia means the isolation of Candida from one or more blood specimens; given its high mortality and morbidity, essentially all patients with candidemia, even those with a single culture, should receive therapy; (b) acute disseminated candidiasis usually presents as candidemia, but the special feature of this form is that spread to several organs, namely liver, kidney, spleen, eyes, brain, and heart, is apparent; (c) chronic disseminated candidiasis (previously hepatosplenic candidiasis) occurs almost exclusively following prolonged episodes of bone marrow dysfunction and neutropenia; the liver, spleen, and sometimes kidney are prominently infected with Candida, and blood cultures are rarely positive at this point, although presumably they were positive at the time infection was initiated; (d) deep organ candidiasis in which, at the time of presentation, the blood is sterile and focal infection of the specific organ is the only manifestation, although an episode of candidemia must have led to seeding of the affected area. C 447 Treatment Epidemiology Candida spp. infections can no longer be considered as rare infections restricted to neutropenic or immunocompromised patients. All types of patients are now concerned, particularly those with severe underlying disease or critical illnesses that need aggressive diagnostic or treatment procedures. Increased survival in patients with severe diseases, more aggressive use of surgery, invasive procedures and immunosuppression, and also increased use of broad spectrum antibacterial agents led to an increasing incidence of candidemia in Europe and in the USA. Candida species are the most common cause of invasive fungal infections (70–90%) and are generally reported to be the fourth most prevalent pathogen isolated in blood cultures or deep-site infections, although this prevalence varies depending on the population surveyed [1]. ▶ ICU candidiasis represents one third of all IC. The incidence of candidemia, although rather variable from unit to unit, ranging from 0,5 to 2,22 per 10,000 patient days, is tenfold higher in the ICU than in the wards, and Candida species are responsible for around 10% of all ICU-acquired infections worldwide. In the recent SOAP study, Candida spp. accounted for 17% of all sepsis in the ICU and for 20% of all ICU-acquired sepsis. A marked increase in the proportion of non-albicans Candida isolates has been reported in several countries, usually accounting for 40–60% of cases. This observation correlated with the increasing use of azoles for prophylaxis or empirical treatment. However, the association of previous fluconazole use with the isolation of non-albicans strains has been shown in some studies but not proven in many more. The increasing incidence of non-albicans Candida species is important, as some studies show that candidemia due to non-albicans species, especially C. glabrata, C. tropicalis and C. krusei, are associated with higher mortality. The fact that C. glabrata has reduced susceptibility, and C. krusei intrinsic resistance to fluconazole, may have to do with this higher mortality and must be taken into account for the empiric therapeutic choice (Table 1). In fact, Kovacicova et al. found a significantly higher attributable mortality in patients infected with fluconazole-resistant strains [1]. However, there are important geographic and demographic variations in terms of the prevalence of species of Candida. For instance, C. glabrata is the second most prevalent species, following albicans, in North America and Northern Europe, but not in Southern Europe, Asia, and Latin America, where C. parapsilosis occupies that position. This fact may also have therapeutic implications C 448 C Candidiasis Candidiasis. Table 1 Epidemiological distribution and common susceptibility patterns of Candida species Common susceptibility patterns Species Frequency (%) Amphotericin B 5-FC Fluconazole and itraconazole Voriconazole and posaconazolea Echinocandinsb C. albicans 40–60 S S S S C. glabrata 20–30 S to I S S-DD to R S to S-DD? S C. Krusei 5–10 S to I I to R R S to S-DD? S C. lusitaniae 0–5 R S S S S C. parapsilosis 10–20 S S S S S to I? C. tropicalis 20–30 S S S S S S 5-FC 5-fluorocytosine, S susceptible, I intermediate, S-DD susceptible does-dependent (dose needs to be increased to achieve therapeutic efficacy), R resistant a Although voriconazole and posaconazole are active in vitro, in vivo, and in early clinical experience against C. glabrata and C. krusei, their efficacy against these classically azole-resistant organisms hasn’t been clearly established b Minimum inhibitory concentrations of the echinocandins are higher for C. parapsilosis than for other Candida species as C. parapsilosis may have reduced susceptibility to echinocandins and, therefore, azoles are the preferred agents (Table 1). Timing Kumar et al. showed that median time to initiation of effective antimicrobial therapy in septic shock is significantly higher for Candida (35.1 h) than for bacteria (5.5 h). He also demonstrated that survival decreased 12% per hour of delay of initiation of adequate antifungal therapy in patients with fungal sepsis and shock [2]. Morrell et al. evaluated the impact of delayed antifungal therapy in mortality. Time to initiation of empiric antifungal therapy was measured in 12-h increments, and a significant mortality benefit was observed when therapy was started within 12 h of the drawing of the first positive blood culture [2, 4]. Garey et al. showed that early – within 24 h – antifungal initiation was associated with significantly less mortality rate and that there was a progressive mortality increase with increasing delays in initiation of therapy [2, 4]. More recently, Parkins et al. found that early adequate empiric antifungal therapy was associated with a significant reduction in mortality [4]. Taur et al. subdivided time from collection of blood cultures to initiation of antifungal therapy in three periods: incubation period (time from collection to positivity), provider notification period (time from blood culture positivity to provider notification), and antifungal initiation period (from provider notification to the administration of the first dose of antifungal). In this study, in cancer patients with candidemia, the incubation period (median 32.1 h) accounted for a significant amount of time compared with the provider notification (median 0.3 h) and antifungal initiation times (median 7.5 h), and its duration was associated with inhospital mortality. Therefore, as modern blood culture systems still require around 24–48 h of incubation to positivity, new strategies are needed to shorten the incubation time. Which Antifungal Drug? “Old” (fluconazole and polyenes) and “new” (secondgeneration azoles and echinocandins) antifungals for the management of candidemia and other forms of IC differ from each other in terms of spectrum, pharmacokinetics and pharmacodynamics, efficacy, interactions, and side effects. Two main factors should be taken into account in the choice of the antifungal: the species of Candida and the host (focus, hemodynamic stability, organ dysfunction, previous use of azoles, concomitant drugs). Triazoles Triazoles exert their effects within the fungal cell membrane. The inhibition of cytochrome P450 (CYP)dependent 14-a-demethylase prevents the conversion of lanosterol to ergosterol. This mechanism results in the accumulation of toxic methylsterols and resultant inhibition of fungal cell growth and replication. Fluconazole remains one of the most prescribed triazoles because of its excellent bioavailability, tolerability, and side-effect profile. More than 80% of ingested drug is found in the circulation, and its absorption is not affected by food consumption, gastric pH, or disease state. Almost 60–70% is excreted unchanged in the urine; therefore, the dose should be adjusted in patients with a reduced clearance of creatinine. Only 10% is protein bound, and it also exhibits excellent tissue penetration, Candidiasis namely, in the central nervous system, where CSF levels are 80% of matched serum levels [4]. Fluconazole is active (fungistatic) against most Candida spp. with the exception of Candida krusei (intrinsic resistance because of an altered cytochrome P-450 isoenzyme). Candida glabrata can be resistant or dose-dependent susceptible (12 mg/kg/ day). For IC, a loading dose of 12 mg/kg followed by a daily dose 6 mg/kg should be administered since higher doses seem to be associated with a better outcome [3]. Although fluconazole has substantially fewer drug–drug interactions than other triazole compounds, it may increase serum levels of phenytoin, warfarin, rifabutin, benzodiazepines, cyclosporine, glipizide, and glyburide. On the other hand, fluconazole levels are reduced with concomitant use of rifampin [4]. Voriconazole is a low molecular weight water-soluble second-generation triazole with a chemical structure similar to fluconazole. It has a potent fungistatic activity against Candida spp. usually with lower MICs compared to fluconazole. Voriconazole is available in intravenous (▶ IV) and oral formulations. This last formulation has an excellent bioavailability which is reduced with fatty foods by 80%. Like fluconazole, CSF and vitreous penetration is excellent. In adults weighing more than 40 kg, the recommended oral dosing regimen includes a loading dose of 400 mg twice daily on day 1, followed by 200 mg twice daily. Intravenously, after a loading dose of 6 mg/kg twice daily, a maintenance dose of 3–4 mg/kg IV every 12 h is recommended [3]. In patients with a creatinine clearance lower than 50 ml/min, IV voriconazole should not be used as the risk of accumulation of cyclodextrine, to which the drug is complexed, exists. Oral voriconazole does not require dosage adjustment for renal failure, but it is the only triazole that requires dosage reduction for patients with moderate-to-severe liver failure [3]. In adults, voriconazole presents a nonlinear hepatic metabolism. Polymorphisms within CYP2C19 are responsible for interpatient serum concentrations differences. The unpredictability of patient enzymatic activity has generated an interest in the routine use of voriconazole serum-level determination. During first week of treatment, serum levels should be kept between 1 and 5.5 mg/l, not only to prevent treatment failures, but also to reduce toxicity, mainly neurotoxicity. In IC, its clinical use has been primarily for step-down oral therapy in patients with C. krusei and fluconazoleresistant but voriconazole-susceptible C. glabrata infections. Voriconazole is typically well tolerated, but some patients experience abnormal vision (up to 23%; usually transient and infusion related, without sequelae), skin rash, and transaminase elevation [5]. C Despite having in vitro activity against Candida spp. that is similar to voriconazole, posaconazole is not recommended for primary IC therapy. It is currently available only as an oral suspension with high oral bioavailability, especially when given with fatty foods [3]. Polyenes Amphotericin B and nystatin are the currently available polyenes, but nystatin is limited to topical use. Amphotericin B binds to ergosterol within the fungal cell wall membrane. This process disrupts cell-wall permeability by forming oligodendromes functioning as pores with subsequent efflux of potassium and intracellular molecules causing fungal death. Amphotericin B deoxycholate (▶ Amb-d) demonstrates a rapid fungicidal in vitro activity against almost all Candida spp. with the exception of Candida lusitaniae, but is associated with high toxicity. To avoid amphotericin B deoxycholate–induced nephrotoxicity, several lipid formulations were developed: liposomal amphotericin B (▶ L-Amb), amphotericin B lipid complex, and amphotericin B colloidal dispersion. These lipid formulations are generally less toxic but equally effective as Amb-d [5]. The peak serum level to mean inhibitory concentration ratio is the best predictor of outcome. All formulations are highly protein bound, have long halflives, and are widely distributed into tissues, but exhibit poor CSF penetration. The exact route of elimination of amphotericin B is not known and, despite its nephrotoxicity, no dose adjustment is necessary in patients with renal failure. Renal toxic effects of Amb-d are associated with a sixfold increase in mortality and a significant increase in hospital costs. Infusion-related reactions (fever, chills, hypotension, and hypoxemia) are also frequently observed [3, 5]. For most IC, the usual dosage of Amb-d is 0.5–0.7 mg/ kg/day, but dosages as high as 1 mg/kg/day should be considered for infections caused by less susceptible species such as C. glabrata or C. krusei. The typical dosage for lipid formulations is 3–5 mg/kg/day [3]. Echinocandins Echinocandins (caspofungin, anidulafungin, micafungin) are the most recently introduced class of antifungals. They inhibit the synthesis of b-1,3 glucan by inhibiting the activity of glucan synthase. This mechanism impairs cellwall integrity and leads to osmotic lysis. They are fungicidal drugs, active against albicans and non-albicans species, and susceptibility differences between the different agents in this class are minimal. C. parapsilosis and C. guilliermondii demonstrate less in vitro susceptibility to echinocandins than do most other Candida spp. related 449 C 450 C Candidiasis to amino acid polymorphism in the main subunit of glucan synthase (Fks1). However, association between ▶ MIC and treatment outcome is inconsistent [4]. Considering that echinocandin efficacy is predicted by peak to MIC ratios (five- to tenfold), they are administered once daily. Although echinocandin resistance is uncommon, it may occur during therapy. Several studies reported a decrease in microbial kill at higher doses and supraMIC concentrations: the paradoxical effect. However, its mechanism and clinical implications are unknown. This class of antifungals is only available in IV formulations due to its poor oral absorption. They are highly protein bound, have long half-lives, and their vitreal and CSF penetration is negligible [4]. Caspofungin is metabolized by both hepatic hydrolysis and N-acetylation, and inactive metabolites are then eliminated in the urine. Micafungin is metabolized by nonoxidative metabolism within the liver, and anidulafungin undergoes unique nonenzimatic degradation. All echinocandins have few side effects (phlebitis, headache, abdominal pain, diarrhea, elevated liver transaminases) and do not need dosage adjustment in patients with renal failure or dialysis. It is recommended to reduce caspofungin dosage in patients with moderate-to-severe hepatic impairment [3, 5]. No significant drug interactions were described for anidulafungin. Caspofungin has several drug interactions with agents metabolized through the cytochrome P450 system. As serum levels are reduced in the presence of rifampin, phenytoin, carbamazepine, and phenobarbital, caspofungin dosage should be increased to 70 mg/day in patients taking these medications. Tacrolimus serum levels may decrease with concomitant administration of this echinocandin [4]. Micafungin may increase levels of sirolimus, nifedipine, and cyclosporine. For IC, a loading dosage for caspofungin (70 mg/day) and anidulafungin (200 mg/day) is necessary. The maintenance dosage for caspofungin, micafungin, and anidulafungin is 50, 100, and 100 mg/day, respectively [3]. Antifungal Therapy: A Patient-Based Approach All current antifungals have been shown to be either equivalent or non-inferior to each other in several studies that included critically ill patients [3, 4]. In these clinical trials, success of therapy ranged from 60% to 83%. The high incidence of adverse events with polyene led to a higher incidence of therapy discontinuation. Due to this potential for toxicity, several international recommendations considered fluconazole and echinocandins as first-line therapy for IC, leaving polyenes as a valid alternative [2, 3]. The hemodynamic status of the patient is an important criterion for selection of empiric antifungal therapy. In hemodynamically stable patient without organ dysfunction, fluconazole is a safe choice. Alternative drugs are echinocandins or amphotericin B. In contrast, hemodynamically unstable patients with severe sepsis or septic shock should be treated with a fungicidal, broad spectrum agent with a good safety profile and, therefore, an echinocandin is the first choice. Alternatively, a lipid formulation of amphotericin B may be used [2, 3]. The likelihood of a patient being infected with an azoleresistant Candida spp. is very difficult to predict but must be taken into account. Colonization by an azole-resistant species, previous exposition to an azole or admission to an ICU with a high prevalence (>15–20%) of these species should lead the physician to prescribe an echinocandin, or as an alternative amphotericin B, and avoid azole [2]. The presence of organ dysfunctions is an important issue. Fluconazole dosage should be reduced in patients with renal dysfunction, and IV voriconazole should not be used in patients with creatinine clearance lower than 50 ml/min. Caspofungin and voriconazole dosages should be adjusted in patients with liver impairment [3]. As azoles and echinocandins, except anidulafungin, have important drug–drug interactions, concomitant therapy should also influence antifungal choice. An adequate penetration of antifungal to the source of infection is crucial. For instance, azoles penetrate well in the CNS and in the eye while echinocandins do not. Higher dosages may be necessary for the treatment of fungal endocarditis if an echinocandin is used [3]. Candida spp. ability to adhere to inert and biological surfaces is associated with virulence. Echinocandins and polyenes are the only classes of antifungals with high capacity to act in Candida biofilms. Intravenous catheter removal is strongly recommended for non-neutropenic patients with candidemia. This strategy is associated not only with shorter duration of candidemia but also with reduced mortality [2, 3]. The concept of transition or step-down is also recommended. If the patient is clinically stable and the isolate is azole-susceptible, a switch from an echinocandin or an amphotericin B formulation to fluconazole is indicated. Voriconazole is recommended as step-down oral therapy for selected cases of IC due to Candida krusei or voriconazole-susceptible Candida glabrata [2, 3]. In the management of documented IC, an echinocandin is the preferred agent for the treatment of C. glabrata infections. For infection due to C. parapsilosis, fluconazole is recommended. Yet, if the patient initially received an echinocandin, is clinically improving, and follow-up cultures are negative, continuing the use of an echinocandin is reasonable. IC by C. albicans or C. tropicalis may be Candidiasis treated with fluconazole as long as the patient is not in severe sepsis or septic shock [2, 3]. Regarding deep organ candidiasis, namely endocarditis, meningitis, osteomyelitis, and endophtalmitis, amphotericin B with or without 5-flucytosine is the preferred treatment in unstable patients. Fluconazole may be used in stable patients or for step-down therapy in these situations [3, 5]. Combination Therapy The rationale for the use of combination therapy is based on the hypothesis that efficacy can be improved when drugs with different mechanisms of action are used. The combination of antifungals may be used in forms of deep organ candidiasis as stated above. In a study recently conducted by Rex et al. comparing fluconazole with amphotericin B to fluconazole alone for patients with candidemia, combination therapy resulted in a better response rate (69% vs. 56%), especially in patients with APACHE II score between 10 and 22, and more rapid clearance of Candida from blood, but amphotericin B was associated with significant toxicity [2]. Another study has shown that combination therapy of the antibody to Heat Shock Protein (HSP) 90 with L-Amb is superior to L-Amb in monotherapy [5]. In contrast, the usefulness of adding echinocandins to fluconazole may be limited due to a possible antagonism demonstrated in an in vitro Candida biofilm model [5]. To date, the use of combination antifungal therapy in patients with IC is not recommended, and further studies are required [2]. Duration In candidemia without obvious metastatic complications, treatment should be continued for 2 weeks after the last positive blood culture and resolution of symptoms. However, the duration of antifungal therapy must be prolonged in endophtalmitis, CNS, and osteoarticular and cardiovascular Candida infections [3]. Evaluation and Assessment The diagnosis of IC is still a major challenge in the ICU, and it is often made late in the course of the infection. Clinical manifestations are often nonspecific, and, frequently, it is hard to differentiate colonization from infection. The current “gold standard” for the diagnosis of IC is either a positive culture specimen from a sterile site or characteristic histopathology. These two methods have limited sensitivity. Blood cultures are known to be negative for around 50% of patients with IC, and improvements in blood culture technique have increased the sensitivity to 70%, at the best. C The difficulties of clinically recognizing Candida infections together with the paramount importance of early initiation of treatment favored the search for predictive factors of fungal infection on which early empiric antifungal treatment should be based. Recognized risk factors for IC are: severity of illness (APACHE II score), neutropenia, colonization with Candida spp., presence of central venous catheter, parenteral nutrition, ICU length of stay 7 days, prior abdominal surgery, previous broad spectrum antibiotherapy, hemodyalisis or renal failure, and cancer chemotherapy [1]. In order to improve the risk factor–driven approach, several authors have focused on combining risk factors to develop predictive algorithms and scoring systems that may help physicians to identify patients who will benefit from early antifungal therapy. Pittet et al. in a prospective cohort study identified two independent risk factors that predicted subsequent invasive Candida infection: the severity of illness assessed by the APACHE II score and the intensity of Candida spp. colonization defined as the colonization index (threshold for intervention set at 0.5). The corrected index (product of the colonization index times the ratio of the number of distinct body sites showing heavy growth to the total of distinct body sites growing Candida spp.) with a threshold of 0.4 was associated with a 100% sensitivity and specificity [1, 4]. In a retrospective cohort analysis with prospective validation, Dupont et al. developed a predictive score for the isolation of yeast from peritoneal fluid in critically ill patients with peritonitis. In patients with three of four independent risk factors (female gender, upper GI tract origin, intraoperative cardiovascular failure, and antimicrobial therapy at least 48 h before onset of peritonitis), the positive and negative predictive values for isolation of yeast were 67% and 72%, respectively. Leon et al. based on a large prospective, cohort, observational, and multicentre study developed the bedside “Candida score”: total parenteral nutrition (1 point), surgery (1 point), multifocal colonization (1 point), and severe sepsis/septic shock (2 points). A Candida score 3 points was associated with a 7.75-fold increased likelihood of proven IC and accurately predicted (sensitivity 81% and specificity 74%) patients who could benefit from early antifungal therapy and is highly improbable if a Candida colonized non-neutropenic critically ill patient has a Candida score <3 [1, 4, 5]. Ostrosky-Zeichner et al. developed a prediction rule that can be applied to 10% of patients who stay in the ICU 4 days. The presence of at least one major risk factor (previous antibiotherapy or presence of central 451 C 452 C Candidiasis venous catheter) and at least two minor risk factors (total parenteral nutrition, dialysis, any major surgery, pancreatitis, steroids, use of other immunosuppressive agents) was associated with a low sensitivity (34%) but with a high negative predictive value (97%) [1, 4, 5]. At present, no single predictive rule provides a gold standard algorithm for IC, and further prospective validation in a clinical setting is necessary. New methods to avoid delays in appropriate antifungal therapy are therefore needed. (1,3)-b-D-glucan (▶ BG) is a cell-wall component of most fungi, except Zygomycetes and Cryptococcus, which is released during tissue invasion. BG test seems to be a promising tool for early diagnosis of IC given its high sensitivity (from 55% to 100%) and specificity (78–100%). Positive results occur not only in patients who have candidiasis, but also in aspergillosis, gastrointestinal colonization with Candida spp., endemic mycoses, and Pneumocystis jiroveci pneumonia. However, its use in the critically ill patient has two main limitations: it was not yet validated in nonneutropenic patients and there is a significant rate of false positive results (bacteremia, surgical gauze, albumin, hemodyalisis, and antibiotics such as piperacilin) [1, 4]. In addition, the cutoff for positive result is not well defined ranging from 20 to 75 pg/ml. Leon et al. showed that procalcitonin increased the predictive value of “Candida score,” as patients with multifocal colonization by Candida spp., staying more than 7 days in the ICU, that develop IC showed significantly higher values of this biomarker. The detection of Candida DNA by ▶ PCR holds great promise as a sensitive and potentially rapid diagnostic test, but, unfortunately, methodologies have not been standardized and only limited evaluations have been performed in clinical specimens. McMullan et al. conducted a prospective study of 145 consecutive non-neutropenic patients admitted to a single adult ICU. Serum was drawn twice weekly and fungal DNA amplified using a real-time PCR capable of detecting Candida spp. This assay showed a high sensitivity (71–99%) and specificity (99–100%) and an excellent positive (83–100%) and negative (99–100%) predictive value. These data suggest that this assay may perform well for the rapid diagnosis of candidemia in non-neutropenic adults, providing results on the same day [1, 4]. Since both time and distinction between albicans and non-albicans species are important new techniques are necessary. Actually, the rapid identification and differentiation of Candida albicans from Candida glabrata can be achieved within 3 h using commercial nucleic acid fluorescent in situ hybridization (PNA FISH) technique [4]. After-care Once a patient has been started on antifungal treatment, it is advisable to repeat blood cultures after 4–5 days to monitor response and breakthrough infections. All patients with candidemia should undergo funduscopic examination within the first week after initiation of therapy to rule out endophtalmitis, which occurs in about 10% of patients with candidemia and impacts on antifungal selection and duration of therapy. Patients showing suboptimal responses in spite of adequate antifungal therapy should be evaluated for several common causes of therapeutic failure, namely: lack of removal of an intravascular catheter, presence of other vascular niduses (e.g., an infected heart valve or endovascular graft), seeding of a protected site (e.g., endophtalmitis, osteomyelitis, and hepatosplenic disease) or other prosthetic devices (e.g., artificial joints and peritoneal dialysis catheters). Prognosis Invasive candidiasis is associated with a crude mortality rate of around 60%. As underlying diseases contribute to mortality, the estimated “attributable” mortality is usually reported as 40–49%. However, attributable mortality varies depending on study design: 20–50% in retrospective casecontrol studies and 5–7% in prospective clinical trials [4]. Tumbarello et al. in a retrospective analysis, identified three risk factors for mortality: inadequate antifungal therapy, infection with biofilm-forming Candida species, and APACHE III score [1]. In the study performed by Morrell et al. APACHE II score prior use of antibiotics and initiation of antifungal therapy more than 12 h after the first positive blood culture were independent determinants of hospital mortality [4]. IC and candidemia are also associated with a high ICU (12.7 days) and hospital stay (15.5 days) and with increased costs [1]. The extra cost of an episode of candidemia in adults has been estimated as 44,000 USD and 16,000€. These data underscore the need for improved means of prevention and treatment of candidemia. References 1. 2. Guery BP, Arendrup MC, Auzinger G, Azoulay E, Sá MB, Johnson EM, Müller E, Putensen C, Rotstein C, Sganga G, Venditti M, Crespo RZ, Kullberg BJ (2009) Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: part I. Epidemiology and diagnosis. Intensive Care Med 35:55–62 Guery BP, Arendrup MC, Auzinger G, Azoulay E, Sá MB, Johnson EM, Müller E, Putensen C, Rotstein C, Sganga G, Venditti M, Crespo RZ, Kullberg BJ (2009) Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: part II. Treatment. Intensive Care Med 35:206–214 Capillary Refill 3. 4. 5. Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr, Filler SG, Fisher JF, Kullberg BJ, Ostrosky-Zeichner L, Reboli AC, Rex JH, Walsh TJ, Sobel JD (2009) Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 48:503–535 Playford EG, Eggimann P, Calandra T (2008) Antifungals in the ICU. Curr Opin Infect Dis 21:610–619 Hollenbach E (2008) Invasive candidiasis in the ICU: evidence based and on the edge of evidence. Mycoses 51(2):25–45 CAP Community-acquired pneumonia: Pneumonia occurring in any patient who does not meet the criteria for HCAP, HAP, or VAP. Capillaries ▶ Microcirculation Capillary Refill BRIAN G. HARBRECHT Department of Surgery, University of Louisville, Louisville, KY, USA Synonyms Circulation; Microvascular perfusion; Perfusion Definition Capillary refill is a subjective, noninvasive assessment of peripheral cutaneous perfusion used to evaluate the adequacy of the regional or systemic circulation. A test of capillary refill involves manual compression, typically on the nailbed or distal skin of an extremity, to blanch the skin followed by rapid release of the pressure. If it takes <2 s for the skin to return to normal pink coloration, capillary refill is adequate. Delayed return of normal coloration to the area of compression (>2 s) suggests an abnormality in either the regional or systemic circulation. By definition, capillary refill measures or assesses the status of the perfusion of the skin of an extremity. In clinical practice, it is often used to evaluate the presence C or absence of shock. The ability of capillary refill to reflect the adequacy of the systemic circulation is based on the body’s compensatory responses to shock [1]. When global tissue hypoperfusion is present due to hypovolemia, cardiac dysfunction, or other causes, increased sympathetic activation leads to a1-adrenergic-mediated peripheral vasoconstriction. This peripheral vasoconstriction increases peripheral arteriolar resistance and shunts blood from the less essential peripheral vascular beds (skin, splanchnic organs) to more essential visceral organs such as the heart and the brain [1]. Increased sympathetic tone also constricts capacitance vessels in selected vascular beds to increase venous return. These responses contribute to the pale appearance of the skin and its cool, clammy consistency to the touch. Several environmental and patient factors can introduce variability into assessments of capillary refill [2, 3]. These factors include patient age, gender, and the ambient temperature the patient is exposed to. Much of the variability in capillary refill between individuals, however, appears to be due to factors that are difficult to define. Despite the subjective element in its interpretation and the relative nonspecific nature of the test, assessment of capillary refill remains a commonly performed component of the physical examination of patients. It has been reported to correlate well with hypovolemia in selected populations of patients such as infants. Capillary refill remains a component of the physical assessment of injured patients in the Advanced Trauma Life SupportR course from the American College of Surgeons and is included in guidelines for the assessment of perfusion in critically ill patients [4, 5]. Technical issues can interfere with the accuracy of using capillary refill as an index of systemic perfusion. Severe hypothermia can induce intense peripheral vasoconstriction that can interfere with capillary perfusion of peripheral tissues even though the intravascular volume may be adequate. Adequate illumination is essential to determine when normal coloration returns to the skin after compression. While generally not a problem in the Emergency Department or Intensive Care Unit, this limitation hinders applicability of capillary refill in the prehospital setting, at night, or in austere environments such as military field triage. This limitation can be significant since a technically simple, readily available test to assess perfusion may be most useful in these environments where physical examination is the only tool available to assess the patient. As mentioned above, variability between individuals can also exist independent of the status of the systemic circulation due to patient-specific factors that remain difficult to define. The assessment of 453 C 454 C Capillary Refill capillary refill is particularly useful in the field of orthopedics where casts, splints, and braces may limit access to peripheral pulses to assess perfusion. The examiner should keep in mind, however, that peripheral vascular disease, peripheral vascular injuries, or other disorders of regional blood flow can interfere with the ability of capillary refill to reflect the status of the systemic circulation. As technology has improved, a variety of modalities have been developed to assess peripheral perfusion. These technologies measure different endpoints in peripheral tissues that reflect distal tissue circulation. Their ability to measure systemic perfusion is based, in part, on the same compensatory physiologic responses that govern capillary refill. These modalities include near-infrared spectroscopy (NIRS) to measure peripheral muscle tissue oxygen saturation (StO2), microprobes, or transcutaneous sensors to measure arterial pH, arterial oxygen pressure, and arterial carbon dioxide pressure, and laser Doppler flowmetry to measure cutaneous capillary blood flow. Clinical trials on the use of NIRS to monitor StO2 as an index of the adequacy of shock resuscitation in trauma patients have been performed and the devices are commercially available for clinical use. Laser Doppler flowmetry has also been utilized clinically in selected centers, primarily to monitor microvascular perfusion of flaps in free tissue transfer operations (free flaps). One could even consider sublingual capnometry, gastric tonometry, and oxygen consumption/oxygen delivery-based goaloriented therapy as extremely sophisticated technologies designed to measure tissue or peripheral perfusion analogous to the capillary refill test [3]. Unfortunately, none of these modalities are universally accepted for assessing the adequacy of the peripheral circulation or as an index of the adequacy of resuscitation from shock in all cases. Several of these technologies continue to undergo active investigation in both the clinical and the basic science environment. Whether these tools will prove to be more useful than simple clinical assessment of the patient remains undetermined. and clammy versus warm and dry), and the appropriate clinical setting for a patient in shock. Once shock is suspected, resuscitative maneuvers should be implemented while an etiology is sought. The clinician should keep in mind that the body’s compensatory mechanisms to circulatory disturbances will act to restore intravascular volume and maintain perfusion to key visceral systems through increased heart rate, increased contractility, and activation of neuroendocrine responses. Hypotension is a relatively late development when these compensatory mechanisms have been overwhelmed. The presence of shock should not be equated with hypotension since significant hypoperfusion can occur before systemic blood pressure falls. As previously discussed, the clinician needs to be aware of potential confounders that can result in abnormal capillary refill in the face of adequate intravascular volume. Hypothermia, peripheral vascular disease, age, and poor ambient light can all interfere with the ability of capillary refill to reflect the status of the systemic circulation. One should keep in mind that constricting casts or bandages, proximal peripheral vascular injuries, or proximal vascular thromboses may produce regional abnormalities of perfusion in the face of normal systemic circulation. Assessment of the opposite extremity or a different peripheral vascular bed will prove useful in these cases. As with many other tests used to evaluate perfusion and shock resuscitation, a single measurement may provide useful information, but serial assessments over time are frequently optimal to gauge the response to therapy. Other parameters to assess perfusion and the systemic circulation are discussed in greater detail in other sections of this work. Repetitive assessment of a number of clinical endpoints (capillary refill, heart rate, urine output, base deficit, etc.) will often help the clinician to determine whether shock persists or homeostasis is being restored. References 1. Differential Diagnosis When used to assess the adequacy of peripheral perfusion as an index of the systemic circulation, a normal capillary refill test reassures the clinician that the systemic perfusion is adequate enough to perfuse the least essential part of the body. Abnormalities of capillary refill should heighten one’s suspicion for inadequate perfusion, but they are fairly nonspecific. Additional parameters of diminished perfusion should be sought such as altered mental status from decreased cerebral perfusion, location and quality of peripheral pulses, character of the skin to palpation (cool 2. 3. 4. 5. Harbrecht BG, Forsythe RM, Peitzman AB (2008) Management of shock. In: Feliciano DV, Mattox KL, Moore EE (eds) Trauma, 6th edn. McGraw-Hill, New York Anderson B, Kelly AM, Kerr D, Clooney M, Astat DJ (2008) Impact of patient and environmental factors on capillary refill time in adults. Am J Emerg Med 26:62–65 Lima A, Bakker J (2005) Noninvasive monitoring of peripheral perfusion. Intensive Care Med 31:1316–1326 Lima A, Jansen TC, van Bommel J, Ince C, Bakker J (2009) The prognostic value of the subjective assessment of peripheral perfusion in critically ill patients. Crit Care Med 37:934–938 Brierley J, Carcillo JA, Choong K et al (2009) Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock; 2007 update from the American College of Critical Care Medicine. Crit Care Med 37:666–688 Cardiac and Endovascular Infections Capnograph ▶ End-Tidal CO2 Capnography ▶ End-Tidal CO2 ▶ Pulse Oxymetry and CO2 Monitoring Capnometry ▶ End-Tidal CO2 C Definition Infective endocarditis (IE) is defined as infection involving the endocardium. Although any part of the endocardial surface may be involved, the heart valves are affected most frequently. Endocarditis may also occur at the site of a septal defect or a site where the endocardium has been disrupted by abnormal flow or intracardiac devices. The term infective endocarditis is now preferred to the older terminology, bacterial endocarditis, as it is recognized that a wide variety of pathogens may cause endocarditis. The pathologic lesion at the site of infection is the vegetation which consists of fibrin, platelets, and the offending microorganism; a paucity of inflammatory cells is present. Injury to the endothelium results either in direct infection by organisms present, even transiently, in the blood stream or may result in the formation of a platelet-fibrin thrombus that may then become secondarily infected. Treatment Capsaicin- 8-methyl-N-vanillyl-6nonenamide Capsaicin- 8-methyl-N-vanillyl-6-nonenamide, is the active component of chili peppers, plants which belong to the genus Capsicum. It is an irritant for animals and produces a sensation of burning in tissues that it contacts. Capsaicin selectively binds to a protein known as TRPV1 that is located on the membrane of heat and pain sensing neurons. Prolonged activation of these neurons depletes presynaptic substance P, one of the body’s neurotransmitters for pain and heat, and the sensation of pain is reduced. Carbonic Anhydrase Inhibitors ▶ Diuretics for Management of AKI Cardiac and Endovascular Infections DONALD P. LEVINE, PATRICIA D. BROWN Department of Medicine, Wayne State University, Detroit, MI, USA Synonyms Bacterial endocarditis; Endocarditis; Fungal endocarditis 455 Comprehensive, evidenced based guidelines for the diagnosis and management of IE are published by the American Heart Association (AHA) which were last updated in 2005 [1]. Probably the most important development impacting the initial empiric therapy of suspected IE is the emergence of Staphylococcus aureus as the most common etiology of native valve IE in most centers, reflecting the fact that a significant proportion of IE cases are now health care associated infections [2]. Methicillin resistant S. aureus (MRSA), both communityacquired and health care associated strains, must be considered a potential etiology of IE, particularly in patients whose severity of illness is sufficient to warrant admission to the intensive care unit. Because receipt of initial empiric therapy that covers the causative organism is an important predictor of favorable outcome in critically ill patients with sepsis, it is anticipated that even patients with suspected IE will receive broad-spectrum antimicrobial therapy initially. Once the diagnosis is confirmed and the causative organism identified, antibiotic therapy should be revised to a regimen known to be effective for the treatment of IE due to the isolated pathogen. The recommendations discussed below are targeted toward patients with native valve IE (NVE); the treatment of prosthetic valve infective endocarditis (PVE) is discussed separately. Viridans Group Streptococci and Streptococcus bovis The appropriate regimen for IE caused by viridans streptococci and S. bovis depends on the minimum inhibitory concentration (MIC) to penicillin for the isolate. Increasing penicillin MICs among these streptococci is C 456 C Cardiac and Endovascular Infections well described; therefore it is imperative that MIC values be available and reviewed before antibiotic therapy is adjusted. Highly susceptible isolates (MIC  0.12 mg/ml) can be treated with aqueous crystalline penicillin G sodium (12–18 million units per day, given by continuous infusion or divided into 4 or 6 equal doses) or ceftriaxone (2 g every 24 h) for 28 days. The duration of therapy may be shortened to 14 days if gentamicin (3 mg/kg every 24 h) is used; however, this “short course” regimen should not be used in patients with cardiac or extra-cardiac complication of IE or in patients at increased risk of aminoglycoside related nephrotoxicity. Vancomycin for 28 days is an alternative in patients with severe penicillin allergy. Clinicians are reminded that the strong association between S. bovis IE and colonic lesions (including malignancy) mandates an evaluation of the gastrointestinal tract once the patient’s clinical condition has stabilized. Viridans streptococci and S. bovis isolates with penicillin MIC > 0.12 to  0.5 mg/ml should be treated with penicillin or ceftriaxone for 28 days with single daily dose gentamicin for the first 14 days of therapy. Viridans streptococci with penicillin MIC > 0.5 mg/ml along with Abiotrophia, Granulicatella, and Gemella species should be managed as for enterococcal IE (discussed below). If vancomycin is used, combination with gentamicin is not necessary. IE due to S. pyogenes can be treated with 28 days of penicillin, as outlined above. Cefazolin or ceftriaxone are alternatives; vancomycin should only be utilized in cases of severe B-lactam allergy. IE due to groups B, C, or G streptococci is managed similarly; some experts do recommend the addition of gentamicin to the regimen for the first 14 days of therapy and consideration of a more prolonged (42 day) total course of treatment for these three pathogens. Although uncommon, S. pneumoniae remains an important pathogen in IE. Isolates with penicillin MICs up to 4 can be successfully treated with high dose (up to 24 million units/day) of penicillin; if the patient has concomitant meningitis, cefotaxime or ceftriaxone must be used for isolates with penicillin MICs  0.1 (provided the isolate is susceptible to these agents); penicillin and cephalosporin resistant isolates are generally managed with vancomycin in combination with cefotaxime or ceftriaxone. intrinsic property of enterococci; therefore serous infections such as IE due to enterococci are optimally managed with the addition of an aminoglycoside for synergy. IE due to strains susceptible to penicillin and gentamicin should be treated with ampicillin (12 g daily, divided into six equal doses) or aqueous crystalline penicillin G sodium (18–30 million units daily, continuously or divided into six equal doses) plus gentamicin 3 mg/kg daily in two or three divided doses (adjusted for peaks of 3–5 mg/ml with a trough of <1 mg/ml). Four weeks of therapy is sufficient for patients whose symptoms have been present less than 3 months; 6 weeks of therapy is recommended for those with symptoms more than 3 months. If the organism is sensitive, vancomycin can be substituted in patients with penicillin allergy; however, these patients should receive 6 weeks of therapy, regardless of the duration of symptoms. Streptomycin should be used for isolates that have high level resistance to gentamicin, but not to streptomycin; 15 mg/kg every 24 h divided into two doses is recommended in patients with normal renal function. Optimal therapy of isolates that demonstrate susceptibility to penicillin but high level resistance to gentamicin and streptomycin is not well established. Several studies support the use of high dose ampicillin (12 g/day) in combination with ceftriaxone (2 g every 12 h) in these cases; therapy should be given for 6 weeks. This regimen may also be a reasonable alternative for patients with aminoglycoside susceptible isolates who develop progressive nephrotoxicity during therapy. Optimal therapy for enterococcal isolates that are resistant to penicillins, vancomycin, and aminoglycosides is also unknown. For infections due to Enterococcus faecium, the AHA guidelines recommend either linezolid (1,200 mg/day in two divided doses) or quinopristindalfopristin (22.5 mg/kg per day divided into three equal doses) for a minimum of 8 weeks. Resistant E. faecalis infections may be treated with ceftriaxone plus ampicillin or imipenem-cilastatin plus ampicillin for a minimum of 8 weeks. Surgery should be a strong consideration for the management of these infections for which synergistic antimicrobial therapy is not possible. An increasing number of case reports have documented successful treatment with daptomycin in such cases, although therapeutic failures have also been reported and additional data are clearly needed. Enterococci Enterococcal isolates suspected of causing IE must undergo testing for penicillin (or ampicillin) and vancomycin MICs as well as testing for the presence of high level resistance to gentamicin and streptomycin. Relative resistance to penicillin (ampicillin) and vancomycin is an Staphylococci As discussed above, S. aureus is now the most common cause of IE in the developed world and patients critically ill with suspected IE should receive initial empiric therapy that includes coverage for this pathogen, including the Cardiac and Endovascular Infections possibility of MRSA. Although typically considered important pathogens mainly in early PVE, coagulase-negative staphylococci (CoNS) have emerged as important pathogens in NVE, causing almost 8% of such infections in noninjection drug users with IE in a recent large prospective study. Almost half of NVE due to CoNS is health care associated; medical comorbidities, long-term intravenous catheter use, and recent invasive procedures appear to be risk factors. Among the CoNS, S. lugdunensis appears to be particularly virulent, often associated with metastatic infection as well as periannular extension of the infection. Surgical treatment may be required more frequently in patients with IE due to CoNS than in patients with S. aureus infections. Patients with IE due to methicillin-susceptible S. aureus (MSSA) should be treated with nafcillin (12 g/day divided into four or six equal doses); cefazolin (6 g/day divided into three equal doses) is an alternative for patients with non-life threatening penicillin allergy. Vancomycin can be used in patients with severe B-lactam allergy. Although clinicians may be tempted to substitute vancomycin for a B-lactam, particularly in patients with reduced renal function because of the convenience of less frequent dosing, vancomycin is inferior to the B-lactams for the treatment of susceptible isolates, therefore this practice is not acceptable. It is very important to note that while the AHA guidelines recommend vancomycin dosing to achieve serum trough concentrations of 10–15 mg/ml, a more recently published consensus review recommends a vancomycin target trough of 15–20 mg/ml for serious infections such as IE [3]. The AHA guidelines list the addition of 3–5 days of gentamicin therapy as optional, noting that a clinical benefit of initial aminoglycoside therapy in S. aureus IE has not been proven. Recently, initial low dose gentamicin for S. aureus bacteremia and native valve IE was associated with significant risk of nephrotoxicity. Given the lack of data regarding benefit in this setting, we do not recommend it. Vancomycin is the recommended therapy for IE due to MRSA. However, a growing body of evidence indicates that patients with serious infections due to MRSA whose isolates have vancomycin MICs > 1 mg/ml respond less favorably to vancomycin therapy than those due to isolates with lower MICs. Daptomycin achieved clinical success rates that were non-inferior to vancomycin for bacteremia and right-sided endocarditis due to MRSA; data for the use of daptomycin in the treatment of left-sided IE is derived mainly from observational studies and case reports. There are very limited data to support the use of other agents for MRSA IE. Success has been reported with the use of trimethoprim-sulfamethoxazole, doxycycline, C minocycline, linezolid, and quinopristin-dalfopristin. Clearly, the optimal management of MRSA IE, especially infections due to isolates with higher vancomycin MICs, remains to be defined. Despite in vitro susceptibility, the addition of rifampin to the regimen for the treatment of native valve IE due to S. aureus is not recommended. In general, 6 weeks of therapy is recommended for patients with S. aureus IE; patients with uncomplicated infections can be treated with 4 weeks of therapy. Injection drug users (IDUs) with uncomplicated right-sided IE due to MSSA can be successfully managed with a 2 week course of nafcillin in combination with an aminoglycoside; the presence of septic pulmonary emboli does not preclude the use of “short course” therapy in this setting. NVE due to CoNS should be treated with regimens similar to those outlined above, based on the in vitro susceptibility data. Gram-Negative Pathogens Native valve IE due to organisms of the HACEK group (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella) should be treated with ceftriaxone (2 g daily); ampicillin-sulbactam and ciprofloxacin are alternatives. A 4 week course of antibiotic therapy is recommended. Non-HACEK Gram-negatives account for less than 2% of cases of NVE. Therapy should be based on in vitro susceptibility data; surgery is frequently required for successful management. Culture Negative Infective Endocarditis Blood cultures may be negative in patients with IE due to the presence of a fastidious bacterial pathogen, a non-bacterial pathogen or the receipt of antibiotic therapy before blood cultures are obtained. The latter reason is probably most common, particularly among patients who are critically ill on presentation. The importance of assuring that blood cultures are obtained, even in the most critically ill patient, prior to the administration of antibiotics cannot be over emphasized. Options for the empiric therapy of culture negative NVE include ampicillinsulbactam plus gentamicin or vancomycin plus gentamicin plus ciprofloxacin. A recent case series of patients with culture negative endocarditis underscored the importance of aminoglycoside therapy in the management of this infection; patients who did not receive an aminoglycoside containing regimen had a significantly higher mortality. Fungal Endocarditis The majority of cases of fungal IE are due to Candida species. C. albicans is most common in non-IDUs; non-albicans 457 C 458 C Cardiac and Endovascular Infections candida are more common in IDUs. Recommendations for management of fungal endocarditis are based mainly on expert opinion. The most current recommendations can be found in the guidelines for the management of candidiasis from the Infectious Diseases Society of America (available at www.idsociety.org). Initial therapy should consist of amphotericin B, either a standard or a liposomal preparation, with or without five flucytosine, or an echinocandin. Fungal endocarditis remains a strong indication for valve replacement. Prosthetic Valve Endocarditis PVE occurs in 1–6% of patients with a prosthetic valve. Mechanical and bioprosthetic valves have similar rates of infection overall; however, mechanical valves have a higher rate of infection during the first 3 months after implantation. S. aureus has emerged as the most common infecting agent, followed by CoNS and streptococci. Initial empiric antibiotic therapy for critically ill patients with suspected PVE will likely include broad-spectrum coverage for both Gram positive and Gram-negative pathogens; the regimen chosen should always include coverage for MRSA. If S. aureus or CoNS are confirmed, nafcillin or vancomycin should be utilized, based on susceptibility results. Rifampin (900 mg daily in three divided doses) and gentamicin should be added, although gentamicin may be discontinued after 2 weeks. Prolonged (at least 6 weeks) therapy will be required. Therapy for viridans streptococci and S. bovis isolates with penicillin MIC  0.12 mg/ml is the same as that outlined for native valve infections except that short course (2 week) regimens should not be used. The addition of gentamicin (single daily dose) to a B-lactam for the first 2 weeks of therapy is optional and the total duration of therapy should be 6 weeks. PVE due to viridans streptococci and S. bovis isolates with penicillin MIC > 0.12 mg/ml should be treated with penicillin or ceftriaxone plus gentamicin (single daily dose) for 6 weeks; vancomycin should only be utilized for patients with severe B-lactam allergy. The treatment of enterococcal PVE is the same as for native valve infections; all regimens should be given for a minimum of 6 weeks. Therapy for culture negative PVE depends on whether the onset is early (less than 1 year since valve replacement) or late. Empiric therapy for early culture negative PVE should include vancomycin, gentamicin (3 mg/kg daily in three divided doses), cefepime, and rifampin. For late PVE, the regimens outlined for native valve culture negative IE may be used, with the addition of rifampin. Anticoagulation Anticoagulation has not been shown to provide benefit in patients with native valve IE, and active IE is considered a strong contraindication to anticoagulation because of the potential risk of bleeding from unrecognized central nervous system (CNS) mycotic aneurysms. The use of anticoagulation in patients with PVE is much more controversial. The AHA guidelines recommend continuing anticoagulation in patients with PVE, except in patients with S. aureus infections who have experienced a CNS embolic event. Anticoagulation may be cautiously resumed once these patients have completed 2 weeks of appropriate antibiotic treatment. Surgery In a recently published multicenter cohort study of IE, almost 50% of patients underwent valvular surgery for the management of their infection. Despite widespread use and the belief that surgery improves outcomes in selected patients, there are virtually no data from randomized controlled clinical trials regarding appropriate indications and timing of surgery. Congestive cardiac failure (CHF) is the most common indication for surgery in IE and the clinical condition of the patient, not the duration of antibiotic therapy, dictates the timing of surgery. Surgical intervention should also be considered for infections due to resistant pathogens for which optimal bactericidal therapy cannot be devised (e.g., vancomycin resistant enterococci) and patients with left-sided IE who remain bacteremic after a week of appropriate antimicrobial therapy, provided that a metastatic focus of infection has been excluded as a cause of persistent bacteremia (4). Other generally accepted indications for surgery include one or more major embolic events in patients with left-sided IE, paravalvular extension of infection, and valve perforation or rupture. Fungal IE has long been considered a strong indication for valve replacement; however, the availability of newer and less toxic antifungal agents and the use of oral azoles for long-term suppressive therapy has resulted in clinical success. The availability of transesophageal echocardiography (TEE) has resulted in additional recommendations for surgery including persistence of a vegetation after a systemic embolic event, anterior mitral leaflet vegetations (particularly those >10 mm in size), and increase in the size of a vegetation despite appropriate antibiotic therapy. In addition to the indications listed above, surgical therapy should be considered for PVE due to S. aureus, S. lugdunensis, and early PVE due to other CoNS. Cardiac and Endovascular Infections Indications for surgical treatment are likely prevalent among patients with IE who require admission to the intensive care unit. The perception that the patient is “too sick” to undergo surgery often results in a delay of a potentially lifesaving procedure. Decisions regarding surgical intervention must be made with input from the intensivist, cardiologist, infectious diseases specialist, and the surgeon. The timing of surgical intervention in those who have had a CNS embolic event, especially if hemorrhagic, is particularly problematic. In addition to the team outlined above, input from the neurologist or neurosurgeon will be essential to optimize management for these patients. Evaluation Although it remains an uncommon infection, advances in medical technology and care have expanded the number of patients who are at risk for IE. As many as 20% of individuals with IE have no recognized preexisting cardiac condition that places them at increased risk for the infection. The diagnosis should be considered in any patient with persistent bacteremia, evidence of a systemic embolic event, or evidence of infection in the setting of a predisposing cardiac lesion. Up to 25% of IE cases are health care associated infections. The presenting features of IE may include stroke and other embolic phenomenon, evidence of metastatic infection such as musculoskeletal infection or splenic abscess, or CHF but most patients have nonspecific manifestations of infection. Elderly patients with IE are more likely to have been hospitalized for an invasive procedure before the onset of infection and have lower rates of embolic events, immune phenomena, and septic complications. Older individuals are likely to present acutely with infection due to virulent pathogens such as S. aureus; the classic peripheral stigmata of IE have become far less common as a presenting manifestation of the disease. Nevertheless, meticulous examination of the patient who presents with evidence of sepsis may reveal a conjunctival, retinal, or subungual (splinter) hemorrhage or even Janeway lesions or Osler’s nodes, findings that suggest the diagnosis even before blood cultures turn positive or the results of echocardiography are available. The majority (up to 85%) of individuals with IE will have an audible murmur. Mitral valve involvement is more common than aortic valve infection. Tricuspid valve IE is a well-recognized complication of IDU; however, in several recent series left-sided IE was more common than right-sided infections in this patient population. Tricuspid valve IE also occurs in non-IDUs with central venous catheters. Patients with right-sided IE often present with C pulmonary manifestations due to septic pulmonary emboli. The possibility of IE should be seriously considered in all patients with S. aureus bacteremia. Risk factors for valve infection in these patients include an unknown source of bacteremia, presence of a prosthetic valve, persistent fever, and persistent positive blood cultures. The risk of IE in patients with community-onset enterococcal bacteremia is also high. Because of the requirement to provide specific pathogendirected antimicrobial therapy for a prolonged course, the necessity of ensuring that a microbiologic diagnosis is confirmed cannot be overemphasized. Two sets of blood cultures should be obtained prior to the initiation of empiric antimicrobial therapy. One set of blood cultures is defined as a blood sample drawn at a single time from a single site, regardless of how many bottles or tubes are submitted from that sample. In total, 3–4 sets of blood cultures should be obtained during the first 24 h of evaluation. In patients who have no or limited peripheral venous access, cultures may be obtained via an intravascular device; however, a sample obtained in this manner represents a single set of blood cultures, even if obtained from more than one port. At least two sets of blood cultures should be obtained on each subsequent day to document the persistence or clearing of bacteremia. While blood cultures remain the single most important diagnostic test in the evaluation of patients with suspected IE, echocardiography, particularly TEE, has significantly improved both diagnosis and earlier recognition of complications of IE. The sensitivity of transthoracic echocardiography (TTE) for the diagnosis of IE is 60–65%; the sensitivity of TEE is 90–95%. Both have a specificity of greater than 90%. The superior sensitivity of TEE is even more significant in the evaluation of PVE. In patients at high risk of IE or for whom the clinical suspicion of IE is moderate to high, TEE should be the initial imaging procedure chosen; the procedure can be safely performed even in patients who are critically ill. Previously, the definite diagnosis of IE required confirmation of infection based on specimens obtained at the time of valve replacement surgery. With the advent of echocardiography, a definite diagnosis can now be made based on a constellation of clinical, microbiologic and echocardiographic findings. The modified Duke criteria are now widely accepted for the diagnosis of IE [4]. Pacemakers and Implantable CardioverterDefibrillators As the number of accepted indications for the use of permanent pacemakers and implantable cardioverter-defibrillators 459 C 460 C Cardiac Contractility has increased, cardiac device–related infections (CDIs) have become more common. CDIs may be confined to the generator pocket, or may include wire infections complicated by endocarditis. The majority of patients with CDIs present with localized findings of infection at the site of the generator pocket; however, the absence of such findings does not exclude the device as a potential source of sepsis. TTE lacks sufficient sensitivity to evaluate for device-related infection. S. aureus is implicated most often; infections due to CoNS, enterococci, Gram-negatives, and candida also occur. Successful treatment of CDIs in association with positive blood cultures requires complete removal of the device, especially in patients with IE. The mortality rate for device-related IE is as high as 66% without device removal, but is as low as 18% with complete removal and appropriate antimicrobial therapy. Emergent device removal is particularly important in the management of patients with severe sepsis. Baddour and colleagues devised an algorithm for the management of these infections that is a useful guide [5]. The device may not be safely re-implanted until the generator pocket has been adequately debrided and the blood cultures are negative. Prognosis and After-care In-hospital mortality for IE is 15–20%; the 1 year mortality may be as high as 40%. Risk factors for in-hospital death include increasing age, CHF, infection due to S. aureus or CoNS, the presence of mitral valve vegetations, paravalvular complications, surgery indicated but not performed, and PVE. Surgical treatment for IE and infection due to S. viridans is associated with a decreased risk of in-hospital mortality. For right-sided IE, there is tremendous disparity in the risk of mortality based on the risk factor for acquisition. Overall mortality is very low in IDUs, but much higher in patients with right-sided IE due to intravascular devices. IE that is health care associated is an independent predictor of both in-hospital and 1 year mortality from the infection as is IE due to S. aureus. In addition, there is a significant difference between the risk of mortality in right-sided vs. left-sided IE in IDUs. A TEE should always be performed, even in patients with clear evidence of right-sided infection (such as septic pulmonary emboli) because concomitant infection of the left-sided valves may also be present. Because a prior episode of IE is one of the strongest risk factors for subsequent episodes of IE, these patients must receive prophylactic antibiotics as recommended in the AHA guidelines for the prevention of IE. References 1. 2. 3. 4. 5. Baddour LM, Wilson WR, As B et al (2005) Infective endocarditis: diagnosis, antimicrobial therapy and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocariditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 111:394–434 Fowler VG, Miro JM, Hoen B et al (2005) Staphylococcus aureus endocarditis: a consequence of medical progress. J Am Med Assoc 293:3012–3021 Rybak M, Lomaestro B, Rotschafer JC et al (2009) Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America and the Society of Infectious Diseases Pharmacists. Am J Health Syst Ph 66:82–98 Js L, Sexton DJ, Mick N et al (2000) Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 30:633–638 Sohail MR, Uslan DZ, Khan AH et al (2007) Management and outcome of permanent pacemaker and implantable cardioverterdefibrillator infections. J Am Coll Cardiol 49:1851–1859 Cardiac Contractility LARA WIJAYASIRI1, ANDREW RHODES2, MAURIZIO CECCONI3 1 Department of Anaesthesia, St. George’s Hospital, London, UK 2 Department of Intensive Care, St. George’s Hospital, London, UK 3 Department of General Intensive Care, St. George’s Hospital, London, UK Synonyms Inotropy Definition Cardiac contractility can be defined as the tension developed and velocity of shortening (i.e., the “strength” of contraction) of myocardial fibers at a given preload and afterload. It represents a unique and intrinsic ability of cardiac muscle to generate a force that is independent of any load or stretch applied. Characteristics Factors increasing cardiac contractility – positive inotropic effect [1]: ● Sympathetic nervous system activation ● Circulating endogenous catecholamines Cardiac Contractility C ● Drugs – inotropic agents, digoxin, calcium ions (Ca2+) ● Metabolic – hyperthermia, hypercalcaemia ● Heart rate – as heart rate increases (e.g., during exercise), contractility increases (this occurs up to a certain point beyond which the tachycardia impairs normal cardiac function). This phenomenon is known as the Treppe or Bowditch effect. It is thought to be mediated by an increase in cytoplasmic Ca2+ due to reduced reuptake by the sarcoplasmic reticulum secondary to a reduction in the diastolic time. C Factors reducing cardiac contractility – negative inotropic effect [1]: ● Parasympathetic nervous system activation (e.g., vagal maneuvres) ● Drugs – b adrenoceptor antagonists ● Metabolic – hypothermia, hypoxia, hypercapnia, hyperkalemia, hypocalcemia ● Pathological states – diastolic and systolic dysfunctions Assessment It is very difficult to clinically assess cardiac contractility in vivo. One method involves measuring the rate of change of ventricular pressure with respect to time (dP/dt) and then using the maximum rate of pressure rise (peak dP/dt) to compare contractility of the heart. Another method involves the use of serial pressure – volume (PV) loops to obtain end-systolic pressure–volume relationship (ESPVR) curves (Fig. 1). These methods are quite invasive and clinically are not practical [2]. Direct, real-time visualization of myocardial wall motion and blood ejection patterns using echocardiography and Doppler allow an assessment of the functional status of the heart to be made. With echocardiography, two useful parameters are ejection fraction and shortening fraction. The left ventricle (LV) ejection fraction (normal range between 55% and 75%) is defined by (LV diastolic volume – LV systolic volume)/LV diastolic volume. The shortening fraction ratio measures the change in diameter of the LV between its contracted and relaxed states (LV end-diastolic diameter – LV end-systolic diameter)/LV end-diastolic diameter. These measurements can give an idea of heart performance, but they cannot provide objective assessments of myocardial contractility. The concept of contractility can be illustrated using force–velocity curves (where the term “force” represents the afterload to the heart and “velocity” refers to the speed of myocardial muscle shortening) (Figs. 2–4) [3]. A heart with a good contractility responds to volume loading in a different way to a heart with impaired contractility (Fig. 5). 461 Cardiac Contractility. Figure 1 Pressure volume loop for normal left ventricle. Where: EDP is end-diastolic point (when mitral valve closes), ESP is end-systolic point (when aortic valve closes), ESV is end-systolic volume and EDV is end-diastolic volume. Increasing contractility moves the ESP up and to the left, while decreasing contractility moves it down and to the right Cardiac Contractility. Figure 2 Force–velocity curve for an isolated myocardial fiber: as the force (afterload) reduces, the velocity of muscle contraction increases until a maximal velocity (Vmax) is achieved at zero afterload (in reality, Vmax cannot be obtained experimentally because the myocardium does not contract in the absence of any load, and therefore this value is obtained by extrapolation) C Cardiac Disease Cardiac Contractility. Figure 3 Effects of increasing preload on force–velocity curve for an isolated myocardial fiber. As preload gradually increases, the isometric tension within the myocardial fiber increases as dictated by the Frank–Starling mechanism of the heart (length–tension relationship). However, Vmax remains unchanged, demonstrating the fact that it does not depend on the length of the muscle fiber (i.e., preload) from which contraction is initiated Vimax ty tili Vmax c tra n Co Velocity 462 Cardiac Contractility. Figure 5 Modification of Frank– Starling curve. A heart with normal contractility (N) and a failing heart with poor contractility (F) have different abilities to respond to volume loading and hence increase their stroke volumes by different amounts affected, right ventricular end-diastolic pressures rise which can lead to an increase in right atrial pressures and venous congestion resulting in peripheral edema, ascites, and hepatomegaly. Quite often left-sided systolic dysfunction will eventually cause right-sided systolic dysfunction, and this is commonly termed biventricular failure or congestive cardiac failure. There are numerous causes of systolic dysfunction including coronary artery disease (myocardial ischemia and infarction), valvular heart disease, dilated cardiomyopathy, myocarditis, amyloidosis, drugs (e.g., ethanol excess and cocaine) and toxins (e.g., sepsis). References 1. Afterload Cardiac Contractility. Figure 4 As contractility increases, the curve is shifted up and to the right with an increase in both Vmax and isometric tension. This increase in Vmax (V’max) is of particular significance as it is a measure of cardiac contractility that is unrelated to changes in preload or afterload 2. 3. Parrillo JE, Dellinger RP (2008) Critical care medicine: principles of diagnosis and management in the adult, 3rd edn. Mosby Elsevier, Philadelphia, pp 39–52 Wigfull J, Cohen AT (2005) Critical assessment of haemodynamic data. CEACCP 5(3):84–88 Klabunde RE (2005) Cardiovascular physiology concepts, 1st edn. Lippincott Williams and Wilkins, Philadelphia, pp 81–85 Cardiac Disease Systolic Dysfunction Systolic dysfunction, often termed ventricular failure, refers to an impairment in ventricular contractility which results in a reduced stroke volume and hence inadequate cardiac output. If the left ventricle is affected, left ventricular end-diastolic pressures gradually rise which can lead to an increase in left atrial and pulmonary pressures resulting in pulmonary edema. If the right ventricle is ▶ Congenital Heart Disease in Children Cardiac Doppler ▶ Echocardiography Cardiac Magnetic Resonance Imaging Cardiac Failure in Children JONATHAN R. EGAN, MARINO S. FESTA The Children’s Hospital at Westmead, Westmead, Australia Definition Inability of the heart to meet the metabolic needs of the body as a result of an inability to sustain an effective cardiac output. Characteristics Cardiac failure can occur as a result of a myriad of cardiogenic causes in the setting of congenital cardiac disease, which can be grouped into four main categories. Cardiac failure resulting from acquired disease is discussed subsequently. Increased Pulmonary Blood Flow An atrial, ventricular, or large vessel communication (e.g., patent ductus arteriosus (PDA)) results in shunting of blood and a volume load on the systemic left ventricle. This leads to ventricular failure and pulmonary venous congestion. Left Ventricular Outflow Obstruction In the setting of aortic stenosis or coarctation there can be early myocardial failure in the neonatal, infant, or childhood age groups – depending on the degree of obstruction. Valvular Regurgitation A volume load on the ventricle leads to forward delivery failure and backward obstruction to venous inflow. Right Ventricular Failure Isolated right ventricular failure occurs in the setting of pulmonary embolism, pulmonary hypertension, or chronic respiratory failure. Management An A, B, C approach to stabilization is required – it is important to consider the effect of excessive inspired oxygen upon pulmonary vascular resistance, which can exacerbate left-to-right shunting and worsen pulmonary venous congestion. Providing positive end expiratory pressure (PEEP) via a bag and mask, with an initial FiO2 of 0.3–0.4 maximum should prove both safe and beneficial. A carefully observed trial of noninvasive ventilation C may improve oxygenation and the work of breathing. Subsequently intubation can be performed if considered necessary. Intubation of a neonate or child with cardiac failure can be risky and should be undertaken by senior trained intensivists/anesthetists. Induction drugs that can lead to pronounced reductions in systemic vascular resistance and myocardial contractility – such as thiopentone or propofol are best avoided. Ketamine is a good alternative. Apart from optimizing oxygenation and induction drugs, the hemodynamic status of the child should be preemptively stabilized with administration of fluid boluses (5–10 ml/kg of normal saline) and vasopressors (5 mcg/kg/min dopamine). Vasopressor and inodilator therapy can be modified following stabilization, full assessment, and provision of central venous and arterial lines. Initially reducing the systemic vascular resistance with either dobutamine and milrinone or levosimendan infusions – as systemic perfusion pressure permits and then transitioning to captopril will optimize myocardial performance. It is important to determine the underlying lesion(s) and any contributing factors – viral pneumonitis/bronchiolitis through careful history, examination, echocardiography, and other directed investigations. Management of fluid balance, energy requirements, and expenditure will provide a foundation on which to add diuretic, inotropic, and vasodilator therapy. Surgical repair maybe indicated and the timing of this depends on overall patient stability and local resources. Cardiac Magnetic Resonance Imaging CHADWICK D. MILLER1, DANIEL W. ENTRIKIN2, W. GREGORY HUNDLEY3 1 Department of Emergency Medicine, Wake Forest University Baptist Medical Center School of Medicine, Winston-Salem, NC, USA 2 Department of Radiology and Internal Medicine, Section on Cardiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA 3 Department of Internal Medicine, Section on Cardiology and Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA Synonyms Cardiac MR; Cardiac MRI; CMR 463 C 464 C Cardiac Magnetic Resonance Imaging Definition Cardiac magnetic resonance imaging (CMR) is the use of magnetic resonance (MR) techniques to obtain images of the heart. As with all MR technology, tissues are subjected to a strong magnetic field that orients the protons of hydrogen atoms so that they rotate, or “precess,” in a uniform manner. These hydrogen atoms are then exposed to a radio signal, commonly referred to as a pulse sequence, which transiently changes their orientation. After the radio signal, the protons revert to their original precession patterns and create a signal that is captured to create images. The time to reversion to their orderly precession is dependent on tissue composition and therefore the resulting signal patterns are specific to the tissue composition. As disease states change tissue composition, the tissues provide a different signal allowing the determination of normal and disease states. By utilizing ECG-gating, signals obtained from CMR can be processed to create both still and motion images of the heart. Further, imaging can be conducted during rest, or during cardiac stress. Finally, contrast agents can be used to exploit subtle differences in cellular and tissue composition or function. Pre-existing Condition Overview CMR has seen increased use over the past decade. Newer imaging techniques and scanner technologies have greatly enhanced the quality and diagnostic accuracy of CMR. Common indications for CMR are discussed in the section immediately below. However, in the critically ill patient, obtaining CMR testing is associated with several logistical challenges that are discussed in the Application section. Because of these challenges, other imaging modalities are often preferred over CMR. Circumstances when CMR may be strongly considered in the critically ill patient are further discussed under the heading “Clinical circumstances in which CMR would be useful in critically ill patients.” Common Indications and Appropriateness Criteria Criteria developed by a multidisciplinary panel provide guidance to determine when CMR is considered an appropriate diagnostic test [1]. These appropriate indications are summarized in the paragraphs below. Evaluation of Acute Chest Pain CMR in combination with pharmacologic vasodilator (adenosine, Persantine) perfusion imaging or inotropic stimulation (dobutamine) wall motion imaging can be used to detect inducible myocardial ischemia. Multiple studies have demonstrated that stress CMR has equal or higher accuracy compared to other stress testing modalities with sensitivity ranging from 86% to 96% and specificity from 83% to 100% for detecting 50% coronary artery luminal narrowings [2, 3]. Patients unable to exercise or who have ECGs that are not interpretable are particularly well suited for CMR imaging. CMR to evaluate acute chest pain is inappropriate in low risk patients with interpretable ECGs and the ability to exercise, as well as in patients with high pretest probability of CAD combined with positive biomarkers or ST-segment deviation. All uses of MR angiography to evaluate for CAD as a cause of acute chest pain are considered inappropriate. Evaluation of Cardiac Structure and Function CMR is well suited to provide information on cardiac anatomy and function. CMR is particularly useful when technically limited echo images have been obtained. CMR can appropriately be used to determine left ventricular function after myocardial infarction (AMI) or in patients with heart failure, assess for congenital heart disease including anomalous coronary arteries, and evaluate native and some prosthetic valves. Furthermore, CMR is useful and appropriate to evaluate for cardiomyopathies, myocarditis, pericardial disease, cardiac thrombus, cardiac masses, and aortic dissection. Although aortic dissection can be detected by cardiac MRI, the aorta is extra-cardiac and is not further discussed in this chapter. Application Equipment CMR exams are commonly performed on commercially manufactured MRI machines with specialized software to obtain cardiac images. 1.5 Tesla machines are widely used, with some institutions adopting machines with stronger magnetic fields. Power injectors are ideal if perfusion imaging is to be performed. Specialized monitoring equipment that is MRI compatible is required. Policies and Procedures Policies and procedures must be in place for patient screening and emergency response. Patients must be screened for MRI compatibility. Pacemakers, defibrillators, and ferrous implants are generally not compatible with MRI. Emergency response plans should be well delineated in the event the patient’s condition deteriorates during the exam. Cardiac Magnetic Resonance Imaging Components CMR consists of several components that must be tailored to the clinical question. Stress Agents Stress testing is commonly used to assess acute chest pain. The “stress” component can be either a vasodilator or an inotropic agent such as dobutamine. Vasodilators such as adenosine are used in conjunction with perfusion imaging techniques to capture stress myocardial perfusion images, which can then be compared with similar rest myocardial perfusion images obtained in the absence of the vasodilator and other infarct “delayed enhancement” techniques. By comparison, dobutamine stress examinations rely on the identification of a regional left ventricular wall motion abnormality that occurs when the patient has achieved target heart rate (target heart rate = [220 age]0.85) during peak pharmacologic stress. The detection of perfusion defects or wall motion abnormalities during stress is suggestive of significant coronary stenosis. Use of Gadolinium: Perfusion Imaging and Delayed Enhancement Gadolinium containing contrast agents are used to enhance the information provided from CMR. The presence of gadolinium contrast agents modifies the signal emanating from nearby protons. By exploiting differences in normal and abnormal gadolinium distribution within the myocardium both perfusion imaging and delayed enhancement imaging can aid in the diagnosis of underlying disease states. For instance, in the normal heart there should be no perceptible difference in the perfusion of a b C gadolinium through the myocardium during rest or stress perfusion imaging with vasodilators such as adenosine. The presence of a perfusion defect during adenosine stress perfusion is strongly suggestive of inducible ischemia, and the myocardial segments involved are predictive of the vascular territory affected by a high-grade flow-limiting stenosis, as demonstrated in Fig. 1. Delayed enhancement imaging exploits the fact that various disease states allow abnormal accumulation of gadolinium within myocardial tissue. Because of this, inflammation and cell death from acute myocardial infarction or acute myocarditis, scarring from old myocardial infarction or prior myocarditis, and infiltrative processes that result in myocardial scarring (such as sarcoidosis, amyloidosis, and hypertrophic cardiomyopathy) can all be identified with delayed enhancement imaging. In the setting of acute inflammation as can be seen with myocarditis or acute infarction it is the leaky basement membranes of the myocardial microvasculature, expanded extracellular space related to edema and leaky cell membranes that allow excessive accumulation of gadolinium within affected myocardial territories. In the setting of chronic scarring from prior infarct or prior myocarditis, ventricular remodeling results in the deposition of a fibro-fatty infiltrate in the area of scarring. The collagenous matrix of this infiltrate expands the extracellular space and traps gadolinium in these regions of scarring. And finally, with the various infiltrative cardiomyopathies, there is typically an abnormal accumulation of proteins and/or disordered array of myocytes also associated with regions of fibrosis and scarring that result in accumulation of gadolinium. In all of these settings, delayed enhancement imaging c Cardiac Magnetic Resonance Imaging. Figure 1 (a) Short axis image obtained through the mid-ventricle during adenosine stress perfusion. The white arrows demonstrate a large region of decreased signal intensity indicative of an area of decreased perfusion involving the lateral wall segments. (b) Catheter angiogram demonstrating injection of the left main coronary artery. The white arrow demonstrates a critical stenosis of the proximal left circumflex coronary artery, while the white arrowhead demonstrates the limited perfusion of a large obtuse marginal branch from the circumflex. (c) Repeat angiogram following percutaneous transluminal coronary intervention with stent (white asterices) placement in the proximal obtuse marginal branch. Note restoration of normal flow in the distal vessels (small white arrows) 465 C 466 C Cardiac Magnetic Resonance Imaging sequences allow clear recognition and delineation of disease regions of myocardium when compared with adjacent normal myocardium. T2-Weighted Images T2-weighted image sequences are able to detect myocardial edema. Myocardial edema is an early marker of myocardial ischemia or inflammation. The use of T2 weighted images allows the early determination of myocardial infarction, at times before chemical evidence is present in the blood. The combined use of T2-weighted imaging sequences and delayed enhancement imaging sequences can be used to discriminate between several types of myocardial injury including, acute inflammation in the setting of myocarditis, acute injury in the setting of acute myocardial infarction, and chronic scarring in the setting of remote myocardial injury. Figure 2 demonstrates features of a severe left anterior descending (LAD) territory infarction. Nephrogenic systemic fibrosis – The use of gadolinium containing contrast agents has been linked to nephrogenic systemic fibrosis, which can be a progressive fatal condition. The relationship between gadolinium containing contrast agents and nephrogenic systemic fibrosis resulted in a boxed warning from the FDA against use in patients with acute or chronic renal insufficiency (glomerular filtration rate <30 ml/min), acute renal insufficiency of any severity due to hepatorenal syndrome, or in the perioperative liver transplant period. Because this is a rapidly evolving area, readers are encouraged to consult the most recent guidance on the risk of nephrogenic systemic fibrosis. Claustrophobia – MRI is conducted in a closed environment. Therefore it may not be tolerated by patients with severe claustrophobia unless sedation is provided. Logistical Barriers to CMR Use Complications Flying objects – Metallic objects in the room or entering the room will be forcefully attracted to the magnet. This can cause severe injury or death. Burns – Unrecognized implanted metallic objects can cause tissue heating, neural stimulation, or skin burns. Implanted device malfunction – Some devices are MRI compatible, such as some ventriculo-peritoneal shunts, but require programming after the scan is completed. Others are not compatible, such as defibrillators, and can cause death if MRI is conducted. a b Ultrasound or computed tomography is often used for patients in the first 24 h of an acute illness due to their wide availability. Even in some instances where CMR may be the preferred test, CMR is less commonly used due to logistical challenges performing the procedures in critically ill patients. The logistical challenges associated with CMR include the need to have a scanner capable of CMR imaging, expertise and support to perform these examinations, and skilled readers to provide high quality expert interpretation. Critical illness adds complexity for a multitude c d Cardiac Magnetic Resonance Imaging. Figure 2 (a) Short axis T1-weighted image of the heart at the level of the mid left ventricle before the administration of IV gadolinium. (b) Similar T1-weighted image shortly after the administration of gadolinium demonstrates increased signal intensity within the anterior (A) and anterolateral (AL) wall segments, representative of early accumulation of gadolinium within the territory of the LAD coronary artery. (c) T2-weighted short axis image at the same level demonstrating increased signal intensity in the same distribution (small white arrows) representative of myocardial edema in the LAD territory. (d) Delayed enhancement image at the same level demonstrating extensive delayed enhancement in the LAD territory (small white arrows) indicative of progressive accumulation of gadolinium in the myocardium related to acute LAD territory infarction. In this particular instance the patient suffered a ST-elevation myocardial infarction (STEMI) secondary to complete occlusion of the LAD resulting in profound ischemia; the black subendocardial regions (white asterices) within this distribution are representative of regions of complete microvascular occlusion in the LAD territory Cardiac Markers for Diagnosing Acute Myocardial Infarction of reasons. First, life-sustaining equipment must be nonferrous and MRI compatible. Second, imaging times can last 30–60 min, which may be impossible in patients with hemodynamic instability. Third, patients must lie flat during the exam, which can exacerbate some disease processes. Fourth, critically ill patients commonly have renal insufficiency. Renal insufficiency increases the risk of developing nephrogenic systemic fibrosis after administration of gadolinium containing contrast agents that are commonly used in CMR. Finally, CMR may not be available emergently when it is needed. Clinical Circumstances in Which CMR Would Be Useful in Critically Ill Patients 1. Patients with new onset heart failure of uncertain etiology when echocardiography is unavailable or nondiagnostic. CMR will identify myocardial edema, inflammation, wall motion, ventricular function, and can distinguish acute from chronic myocardial infarction. This information can provide supporting or refuting evidence for AMI, myocarditis, cardiomyopathies, cardiotoxic effects of therapy, restrictive pericardial disease, and valvular dysfunction. 2. Concern of AMI or ACS in patients with a noninterpretable ECG and nondiagnostic cardiac markers. Patients with bundle branch blocks or other conditions preventing an accurate ECG assessment, or continuous unrelieved symptoms may benefit from CMR imaging. While bedside echo is often used to determine ejection fraction and to assess for regional wall motion abnormalities, CMR may also serve in similar capacity. This may be particularly useful in patients with a complicated revascularization history. CMR can be used to assess for edema, obtain resting wall motion and perfusion, and delayed enhancement. These latter features help to characterize tissue and define the etiology of left or right ventricular wall motion abnormalities. In addition, these imaging strategies have previously been shown to accurately detect MI and can do so before elevation of cardiac markers [4]. Early acquisition of this information may allow early planning of treatment strategies. 3. Clinical history concerning for a cardiac thrombus or mass. In patients with suspected intracardiac thrombus, CMR can accurately depict the presence of an intracavitary thrombus within the heart, and commonly offers superior visualization of the apical regions that may improve detection in the setting of C 467 apical thrombus. CMR is also capable of identification and characterization of mass lesions intrinsic to the heart, including not only benign lesions but also primary and metastatic neoplasms. C Conclusion CMR is able to provide a comprehensive evaluation for cardiac disease. CMR exams are able to assess for structural and functional disease of the heart with high accuracy. However, the logistical challenges associated with obtaining a CMR exam in patients with critical illness limits its use in these patients. However, there are several scenarios in which care providers, despite these logistical challenges, may choose to perform CMR imaging over other imaging modalities. References 1. 2. 3. 4. Hendel RC, Patel MR, Kramer CM, ACCF/ACR/SCCT/SCMR/ ASNC/NASCI/SCAI/SIR et al (2006) Appropriateness criteria for cardiac computed tomography and cardiac magnetic resonance imaging: a report of the American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness Criteria Working Group, American College of Radiology, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, American Society of Nuclear Cardiology, North American Society for Cardiac Imaging, Society for Cardiovascular Angiography and Interventions, and Society of Interventional Radiology. J Am Coll Cardiol 48:1475–1497 Ingkanisorn WP, Kwong RY, Bohme NS et al (2006) Prognosis of negative adenosine stress magnetic resonance in patients presenting to an emergency department with chest pain. J Am Coll Cardiol 47:1427–1432 Nagel E, Lehmkuhl HB, Bocksch W et al (1999) Noninvasive diagnosis of ischemia-induced wall motion abnormalities with the use of high-dose dobutamine stress MRI: comparison with dobutamine stress echocardiography. Circulation 99:763–770 Cury RC, Shash K, Nagurney JT et al (2008) Cardiac magnetic resonance with T2-weighted imaging improves detection of patients with acute coronary syndrome in the emergency department. Circulation 118:837–844 Cardiac Markers for Diagnosing Acute Myocardial Infarction JAMES MCCORD Henry Ford Hospital Center, Detroit, MI, USA Synonyms Cardiac troponin I; Cardiac troponin T; Creatine kinaseMB; Myoglobin 468 C Cardiac Markers for Diagnosing Acute Myocardial Infarction Definition Cardiac markers are proteins that are released from myocardial cells during acute myocardial infarction (AMI). Characteristics Cardiac Markers Creatine Kinase-MB Prior to the use of cardiac troponin I (cTnI) and cardiac troponin T (cTnT), creatine kinase-MB (CK-MB) was the most common marker used in the evaluation of individuals for possible acute myocardial infarction (AMI). Creatine (CK) is a dimer composed of two subunits, M and B. Skeletal muscle is predominantly composed of CK-MM, and CK-BB is mainly in brain and kidney. CK-MB, which comprises 20–30% of cardiac muscle, is released into the circulation during myocardial injury that occurs during AMI. Although CK-MB is predominantly located in the myocardium, 1–3% of the CK in skeletal tissue is CK-MB; smaller quantities of CK-MB are also located in other tissues such as intestine, diaphragm, uterus, and prostate. The use of CK-MB in the diagnosis of AMI is limited by low specificity in the setting of trauma or renal insufficiency. A relative index has been used, which is a function of the amount of CK-MB relative to total CK. The use of the relative index does improve specificity but decreases sensitivity in the diagnosis of AMI. In the setting of AMI, CK-MB becomes elevated in the circulation 3–6 h after symptom onset, and can remain elevated for 24–36 h. Cardiac Troponin I and T The cardiac troponins (cTn) are proteins that modulate the interaction between actin and myosin in myocardial cells. There are isoforms of cTnI and cTnT that are unique to cardiac tissue, which has allowed specific assays to be developed that measure only the cardiac forms. Most of the cTn is bound to the contractile apparatus in the myocardium but 3% of cTnI and 6% of cTnT exist free in the cytoplasm. The initial elevation of cTnI and cTnT is likely due to the free cTn, while the more prolonged elevation is secondary to the degradation of cTn bound to the contractile apparatus. The early release kinetics of cTnI and cTnT are similar becoming elevated 3–6 h after the initiation of an AMI. However, cTnI and cTnT may remain elevated for 4–7 and 10–14 days, respectively. There is a standard assay used for cTnT so there is consistent reporting of values. However, at present there is no such standardization for the different cTnI assays, and cTnI is released in various forms. Different assays detect these forms in varying degrees leading up to a 20-fold difference in measurement for the same cTnI serum concentration. These different cTnI assays, with different cut-points and measured absolute values, can lead to clinical confusion when a patient is transferred from one hospital to another. Also cTnT, as compared to cTnI, is more commonly elevated in patients with renal insufficiency. In the evaluation of patients for possible AMI, cTnI and cTnT have numerous advantages over CK-MB, and are the recognized preferred cardiac markers to be used in evaluating such patients [1]. In addition to having better specificity, the cTn have higher sensitivity detecting AMI. Patients that previously would have been diagnosed with unstable angina with normal CK-MB values may have minor myocardial necrosis that can be detected by an abnormal cTnI or cTnT. With some of the newer more sensitive assays the number of patients with ACS classified as AMI will increase further. Multiple studies have consistently shown that elevated cTn is associated with adverse events: higher mortality, recurrent MI, and need for urgent revascularization. Even minor cTn elevations are associated with high-risk angiographic findings: extensive atherosclerosis, visible thrombus, complex lesions, and slower coronary flow. Patients with ACS and an elevated cTn benefit from aggressive pharmacologic therapy and revascularization. The recommended cut-point for an elevated cTn is the 99th percentile of a normal reference population at a precision level of<10% coefficient of variation [1, 2]. The coefficient of variation is a measure of precision and defined as the standard deviation/mean when a sample is run multiple times on the same assay. In the past cTn assays where not able to meet the precision requirement at low values so only higher levels were reported as abnormal, but newer assays are more precise at low levels and guidelines recommend reporting these low levels as abnormal. Although cTn elevation is very specific for myocardial injury it does not indicate the mechanism of myocardial injury. When cardiac markers have been measured the diagnosis of AMI requires an elevated marker (preferably cTn) and at least one of the following: ischemic electrocardiographic changes, symptoms consistent with myocardial ischemia, or a new wall motion abnormality with cardiac imaging. Many acute conditions may lead to myocardial stress and damage with elevated cTn. Myoglobin Myoglobin is a protein that is found in all tissues. Myoglobin is a smaller molecule as compared to CK-MB Cardiac Markers for Diagnosing Acute Myocardial Infarction or cTn, and has been used as an early marker in the identification of AMI as it can be detected 1–2 h after symptom onset. However, the sole use of myoglobin has significant limitations in that the levels may normalize in patients that present>24 h after symptom onset, and has low specificity for AMI in the setting of renal insufficiency or muscle trauma. Considering its low specificity, and rapid rise and fall, myoglobin has usually been used in combination with either CK-MB or cTn. An elevated myoglobin is also associated with a worse prognosis in both patients with ACS and non-ACS even after adjusting for cTn elevation. The reason for this association is unclear and there is no known specific therapy that should be given to a patient based on an elevated myoglobin. Serial Measurement of Cardiac Markers The measurement of cardiac markers at presentation in the Emergency Department is not sufficiently sensitive to exclude AMI, and markers in general need to be measured serially over time. Guidelines recommend that cardiac markers, preferably cTn, should be measured over 6–9 h [1, 2]. Patients that present 8 h after their last symptoms only need one cTn to be measured. In a study of 383 consecutive patients with nondiagnostic electrocardiograms, no high-risk clinical features, and normal CK-MB values at presentation had CK-MB and cTnT measured at 0, 4, 8, and 12 h. All patients that were identified by elevated CK-MB and cTnT at 12 h had elevation of both CK-MB and cTnT at 8 h. Thus, this study suggests that measurement of cardiac markers beyond 8 h does not improve sensitivity. Another study of 773 patients who were evaluated for possible ACS had cTnI measured at presentation and at least 6 h after symptom onset. In this study there was one death and one AMI at 30 days in the 602 patients that had all normal cTnI, yielding an adverse event rate of 0.3%. Multi-marker Strategies and Dynamic Change in Markers Studies have taken advantage of the different release kinetics of various cardiac markers to be used in combination to more rapidly exclude MI. A marker that rises early during MI, such as myoglobin, combined with one that becomes elevated later, CK-MB or cTn, enables AMI to be identified earlier, and therefore more rapidly excluded. In a study of 817 patients evaluated in the Emergency Department for possible ACS had CK-MB, cTnI, and myoglobin measured at 0, 1.5, 3, and 9 h. There were 65 patients diagnosed with AMI. The combined sensitivity for myoglobin and cTnI at 90 min was 96.9% with a C negative predictive value of 99.6%. The measurement of CK-MB and sampling at 3 h did not improve sensitivity. In another study the combined sensitivity of CK-MB and myoglobin was 100% at 4 h. A dynamic change in individual cardiac markers, or a combination of markers, can identify patients with AMI earlier. In a study of 817 patients the combined sensitivity of cTnI, myoglobin, and a change in myoglobin (defined as a>than 20 ng/ml increase) had a combined sensitivity of 97.3% at 90 min. In a study of over 1,000 patients evaluated in the Emergency Department the combined sensitivity of CK-MB, cTnI, and a change in myoglobin (defined as a>25% increase), had 100% sensitivity at 90 min. In addition, a study of 975 patients demonstrated a change of CK-MB of >0.7 ng/ml over 2 h and had a higher sensitivity for MI at 93.2%, when compared to a change of myoglobin of >9.4 ng/ml over the same time period of only 77%. Most institutions employ a simple single point cut-point strategy as opposed to a change in cardiac maker strategy over time, likely because a single cut-point approach is simpler. Improved Troponin Assays: Sensitivity, Precision, and Implications for CK-MB/ Myoglobin Until recently most cTn assays did not meet the stringent precision recommendation of<10% coefficient of variation at the 99th percentile as advised in the consensus document the Universal Definition of MI in 2007 [2]. The newer more sensitive and precise assays have implications for the utility of CK-MB and myoglobin measurement, and the required time period for serial testing. Many earlier studies used a CK-MB definition of MI and/ or older cTn assays that were less sensitive and precise than assays presently available, which makes protocols based on these studies inapplicable for present practice. There have been some studies that foreshadowed how cardiac markers will be used in the era of these newer cTn assays. In a retrospective study from stored specimens of 258 patients, samples drawn at presentation and then hourly for 6 h in 1996 demonstrated that there was no significant difference between the number of AMIs identified at 3 h compared to 6 h. In a multicenter trial published in 2009, 718 patients had measurement of cardiac cTn by four more contemporary assays at 0, 1, 2, 3, and 6 h [3]. The sensitivity for AMI (using a cTnbased definition) with these four assays at presentation ranged from 85% to 95%. The overall diagnostic utility of all four assays was very high at 3 h with an area under the curve of 0.98 as measured by receiver operator characteristic curve analysis, and was not improved by blood 469 C 470 C Cardiac MR sampling at 6 h. The implication of this study is that with these newer assays sampling is adequate at 3 h and measurement at 6 h is not required. With the introduction of these new cTn assays patients with ACS that were identified as unstable angina will be reclassified as AMI. A study using a research assay that is not commercially available demonstrated that in patients with unstable angina and normal cTnI values using a contemporary cTnI assay, 44% had elevated cTnI at presentation and 82% at 8 h [4]. The advantage of myoglobin has been its early release in the setting of AMI enabling the early identification of myocardial necrosis. Several single center studies have shown that the newer more sensitive cTn assays can identify MI as early as myoglobin. This was confirmed in the Reichlin study where neither myoglobin nor CK-MB measurement improved early diagnostic utility (as measured by area under the curve) when added to sensitive cTn measurement. Presently many institutions use CK-MB in combination with cTnI, although CK-MB does not improve diagnostic accuracy when added to cTn measurement. Even when cTn is used as the sole marker evaluating patient with possible AMI, CK-MB may be helpful in identifying reinfarction in patients that have sustained a definite AMI and have recurrent symptoms several days after presentation when cTn values are still elevated and CK-MB may have normalized. However, newer studies suggest that following a change in cTn after recurrent symptoms may be able to replace CK-MB measurement to identify recurrent MI. The Universal Definition of AMI recommends a change in cTn values greater than 20% over 6 h after recurrence of symptoms to identify recurrent AMI. The role of an early change in either myoglobin or CK-MB needs to be studied further in the context of the new cTn assays, but recent studies suggest there is no use for myoglobin or CK-MB (using an absolute cut-point) in evaluating patients with possible or definite MI. Although low-level cTn detection by these new assays enable a more rapid detection of myocardial necrosis, and therefore a more rapid exclusion of AMI, these low-level elevations have lower specificity for AMI. Elevation of cTn is specific for myocardial necrosis but does not determine the mechanism of injury. Conditions that are well-known to be associated with cTn elevations with the older cTn assays (such as pulmonary embolism, sepsis, heart failure, hypertensive crisis, and many others) will find a higher frequency of cTn elevations in these conditions with the new assays. Ambulatory, asymptomatic patients with a history of chronic kidney disease, heart failure, left ventricular hypertrophy, or diabetes more commonly have cTnT elevation [5]. In this era of the new ultrasensitive cTn assays historical features, electrocardiographic changes, and cardiac imaging studies will be even more important in determining which patients have suffered an AMI. References 1. 2. 3. 4. 5. Morrow DA et al (2007) National academy of clinical biochemistry laboratory medicine practice guidelines: clinical characteristics and utilization of biochemical markers in acute coronary syndromes. Circulation 115(13):e356–e375 Thygesen K et al (2007) Universal definition of myocardial infarction. Circulation 116(22):2634–2653 Reichlin T et al (2009) Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med 361(9):858–867 Wilson SR et al (2009) Detection of myocardial injury in patients with unstable angina using a novel nanoparticle cardiac troponin I assay: observations from the PROTECT-TIMI 30 Trial. Am Heart J 158(3):386–391 Wallace TW et al (2006) Prevalence and determinants of troponin T elevation in the general population. Circulation 113(16):1958–1965 Cardiac MR ▶ Cardiac Magnetic Resonance Imaging Cardiac MRI ▶ Cardiac Magnetic Resonance Imaging Cardiac Output (CO) ▶ Cardiac Output, Measurements Cardiac Output Monitor ▶ Esophageal Doppler Cardiac Output Monitoring ▶ Cardiac Output, Measurements Cardiac Output, Measurements Cardiac Output, Measurements GIORGIO DELLA ROCCA, MARIA GABRIELLA COSTA Department of Anesthesia and Intensive Care Medicine, Medical School of the University of Udine, University of Udine, Udine, Italy Synonyms Arterial Pulse Cardiac Output (APCO); Cardiac Output (CO); Cardiac output monitoring; Continuous Cardiac Output (CCO); Pulse Contour Cardiac Output (PCCO) Definition The function of the heart is to transport blood to the cells of the body, deliver oxygen, nutrients and chemicals, and removing cellular wastes in order to ensure their survival and proper function. In certain tissues, the perfusion of blood can have additional important functions. In the kidneys, sufficient blood flow is required for maintaining proper excretory function; in the gastrointestinal tract, it is important for glandular secretion and for nutrient absorption; and in the skin, changes in blood flow play a crucial role in the control of body temperature. Thus, each tissue has a certain requirement for blood flow and the cardiac output (CO) must keep in step with these needs. In human physiology, CO represents the volume of blood expelled by the ventricles per minute. It is calculated as the product of stroke volume (SV) and the heart rate (HR), expressed as liters of blood per minute (CO = SV ∗ HR). In the healthy human adult, resting cardiac output is estimated to be slightly greater than 5 L/min. It may increase with anxiety or exercise and as much as fivefold with exercise. Pre-existing Condition The stroke volume of the left ventricle is ultimately determined by the interaction between its preload, the contractile state of the myocardium, and the afterload faced by the ventricle. Unfortunately, there is no simple measure of the “contractile state” and consequently no single equation exists that is able to describe the relationship between these three parameters. The fact that “preload” (or rather the stretch) on myocardial fibers at the end of diastole has a significant effect on the subsequent force of contraction was first recognized by Otto Frank toward the end of the nineteenth century. This fundamental relationship has since been analyzed in great detail and the adjustment of preload by blood volume transfusion or depletion remains one of the most important therapeutic maneuvers in acute C cardiovascular medicine. In practice, the adjustment of cardiac preload can be achieved via various approaches: Circulating blood volume can be increased by the administration of fluid, or reduced by the use of diuretics and/or fluid restriction. Venous return can be varied by the adoption of a headdown or head-up posture. Venous capacitance can be altered through the use of vasoconstrictor or vasodilator therapy. In its strictest sense, the term “contractility” refers to the inotropic state of the myocardium – that is, the force and velocity with which the myocardial fibers contract. This can be easily measured in an isolated muscle preparation under specified loading conditions, but it is notoriously difficult to measure in humans. In clinical practice, various contraction-phase indices are used, such as the velocity of fiber shortening, the peak rate of rise in ventricular pressure and the end-systolic pressure-to-volume ratio, but they are all affected to a greater or lesser degree by loading conditions. The “chronotropic” or “rate” state of the intact heart should also be incorporated into any clinical definition of “contractility” because variations in the pulse rate can have obvious and important effects upon CO, and manipulation of the pulse rate through the use of positive or negative chronotropes can be an important therapeutic maneuver in sick patients. It is not possible to make any precise measurements of contractility with a pulmonary artery catheter (PAC), although it is possible to make reasonable inferences about the contractile state through the use of ventricular function curves. This concept was developed by Barash and colleagues and they have described the use of a “Hemodynamic Tracking System” which defines the relationship between left ventricular stroke work index (LVSWI) and pulmonary artery occlusion pressures (PAOP) in patients with normal, slightly depressed, or severely depressed ventricular function. Adjustment of both the inotropic and chronotropic state of the heart through the use of inotropic drugs is commonly practised in critically ill medicine. In physiological terms, afterload can be defined as “the sum of all forces which oppose ventricular muscle shortening during systole” – although in a clinical sense it is probably more useful to consider systemic vascular resistance as a more appropriate definition. In isolated cardiac muscle, an inverse relationship exists between afterload and the initial velocity of muscle shortening. This would suggest a potential dependence of CO afterload. Yet, in the intact human, the output of the normal heart is relatively unaffected by changes in vascular resistance until the point when afterload becomes quite extreme. This is probably 471 C 472 C Cardiac Output, Measurements because an increase in afterload leads to an almost immediate, secondary increase in preload by the “damming up” of the blood within the left ventricle. In turn, this increases end-diastolic volume and enhances contractility according to the Frank-Starling mechanism. On the contrary, if myocardial function is severely depressed, CO may become crucially afterload-dependent. Thus, “sick” hearts can be considered as being relatively preload independent and afterload dependent, while the reverse is true for “healthy”’ hearts. As a result, “afterload reduction” (reduction of systemic vascular resistance by the use of appropriate vasoactive drugs) is of the great benefit in those whose myocardial function is most depressed. The role played by blood viscosity and, indirectly, hemoglobin concentration in determining systemic vascular resistance (SVR) is often overlooked. Although hemodilution is not commonly used as a therapeutic maneuver for reducing afterload, inadvertent hemodilution is often concomitant of serious illness. Hematocrit and fibrinogen are the most important determinants of blood viscosity and therefore make a significant contribution towards vascular resistance. As blood is a non-Newtonian fluid, no simple expression relating SVR to hematocrit and fibrinogen levels exists; however, it is easy to demonstrate the completely passive increase in venous return and CO which occur during hemodilution. Finally, it should not be forgotten that the degree of ventricular interdependence can also influence ventricular performance. The position of the interventricular septum (IVS) can alter the compliance of each ventricle under altered loading conditions with secondary effects on contractility. This effect is not usually important, but it can become so in conditions such as tension pneumothorax, cardiac tamponade, right ventricular infarction, and during mechanical ventilation in critically ill patients. The measurement of cardiac output, as first described by Fick in 1870 (although only put into practice in 1959), also makes an evaluation of respiratory exchange possible: that is, a measure of the delivery of oxygen to the tissues. The Fick principle involves calculating the oxygen consumed over a given period of time by measuring the concentration of oxygen in venous blood and in arterial blood. Cardiac output can be calculated from the following measurements: VO2 consumption per minute, using a spirometer (with the subject rebreathing the same air) and a CO2 absorber; the concentration of oxygen in blood taken from the pulmonary artery (representing mixed venous blood); the concentration of oxygen in blood taken from a cannula in a peripheral artery (representing arterial blood). We know that: VO2 ¼ ðCO  CaÞ ðCO  CvÞ where Ca is the concentration of oxygen in arterial blood and Cv is the concentration of oxygen in venous blood. Thus, rearranging the above, it is also possible to calculate cardiac output: CO ¼ ðVO2 =½Ca CvŠÞ  100: Whilst it is considered to be the most accurate method for the measurement of CO, the Fick method is invasive, requires time for analyzing the blood samples and making accurate oxygen consumption measurements is difficult. Moreover, the calculation of the arterial and venous blood oxygen concentrations is a straightforward process. Almost all oxygen in the blood is bound to hemoglobin molecules in the red blood cells. Measuring the content of hemoglobin in the blood and the percentage of saturation of hemoglobin (and therefore the oxygen saturation of the blood) is a simple process that is readily available to physicians. Using the fact that each gram of hemoglobin can carry 1.36 mL of O2, the concentration of oxygen in the blood (either arterial or venous) can be estimated using the following formula: CaO2 ¼ ðHb g=dLÞ  1:36  SatO2 =100 þð0:0032  PaO2 torrÞ CvO2 ¼ ðHb g=dLÞ  1:36  SatO2 =100 þð0:0032  PvO2 torrÞ The Fick method is considered to be the “gold standard” for measuring cardiac output, but it is not useful in clinical practice as a bedside technique. In current clinical practice, dilution technology is more commonly used. The dilution technique method was initially described using an indicator dye and assumes that the rate at which the indicator is diluted reflects the CO. The method measures the concentration of a dye at different points in the circulation. The dye is usually administered via an intravenous injection and the blood subsequently sampled at a downstream site, typically in a systemic artery. The dye dilution cardiac output measurement is based on the Stewart–Hamilton equation; more specifically, the CO is equal to the quantity of indicator dye injected divided by the area under the dilution curve measured downstream: The indicator method has been further developed with the indicator dye being replaced with cooled Cardiac Output, Measurements fluid and the change in temperature being measured at different sampling sites; this method is known as thermodilution (TD). The pulmonary artery catheter (PAC) was the first clinical device enabling the bedside measurement of cardiac output using the thermodilution technique and since its introduction in 1970 by Swan, Ganz and colleagues, it has been considered as a “clinical standard” for cardiac output assessment despite there being no true reference technique for the clinical determination of CO. The thermodilution method involves the injection of a small amount (10 mL) of cold saline at a known temperature into the pulmonary artery, the temperature of which is measured using the same catheter. The calculation of CO is again based on the Stewart–Hamilton equation: CO ¼ ðVðTb TiÞK1K2Þ=ðTbðtÞdtÞ Where: CO = cardiac output, V = volume of injectate, Tb = blood temperature, Ti = injectate temperature, K1 = catheter constant, K2 = apparatus constant, Tb(t)dt = change in blood temperature over a given time. The Stewart-Hamilton equation should theoretically be used under conditions of constant flow. Usually, the measurements are repeated three or five times and then averaged to improve accuracy. Under optimal conditions, the coefficient of variation for repeated bolus TD measurements is less than 10%. There are many sources of inaccuracy in the method: the cardiac output derived from PAC (COpa) is influenced by significant variations in respiration, and hence from the phase of the mechanical breath during which the injection is made. Mechanical ventilation was also shown to cause a high incidence of significant tricuspid insufficiency and mild to severe vena caval backward flow, which, like other valvular regurgitations, may reduce the accuracy of COpa measurements. The insertion of a PAC is a procedure associated with a number of known complications. Catheter insertion can result in arterial injury, pneumothorax, and arrhythmias. The catheter can be associated with potentially fatal pulmonary artery hemorrhage, thromboembolism, sepsis, and endocardial damage. Following its introduction into clinical practice and for the following 20 years, intermittent thermodilution was the only device available for measuring CO. Since the late 1970s, PAC monitoring of CO has expanded rapidly and broadly in clinical practice for its use in several subgroups of patients; the receiving patients include those undergoing cardiac surgery and those with sepsis and acute respiratory distress syndrome (ARDS). C The appropriate indications necessitating PAC monitoring have been debated for many years. The potential benefits of using the device are well known. For example, its use in measuring important hemodynamic indices (e.g., pulmonary artery occlusion pressure, CO, mixed venous oxygen saturation) allows for improved accuracy in the determination of the hemodynamic status of critically ill patients compared to that possible by clinical assessment alone. The additional information it provides can also be important when caring for patients with confusing clinical scenarios in whom errors in fluid management and drug therapy can result in severe consequences. In surgical patients, PAC data often help evaluate hemodynamic changes that may lead to serious perioperative complications. Preoperative PAC data are claimed to be helpful in determining whether or not it is safe for highrisk patients to proceed with surgery. Unfortunately, the impact of PAC monitoring in patients during anesthesia and intensive care upon clinical outcomes remains uncertain. The American Society of Anesthesiologists (ASA) established the Task Force on Pulmonary Artery Catheterization in 1991 in order to examine the evidence on the benefits and risks arising from the use of PAC in the various settings encountered by anesthesiologists. By the time the Society’s guidelines had been ascertained in 1992 and published in 1993, and several groups had issued statements on the appropriate indications and on competency requirements for hemodynamic monitoring. These groups included the American College of Physicians, the American College of Cardiology, the American Heart Association Task Force on Clinical Privileges in Cardiology, a panel established by the Ontario Ministry of Health, and an expert panel from the European Society of Intensive Care Medicine. In 1996, a milestone study performed by Connors and colleagues made clinicians reconsider the invasiveness and utility of PAC. The ASA therefore reconvened the Task Force on Pulmonary Artery Catheterization in 2000 in order to review its 1993 guidelines, consider the evidence and the concerns over the use of PAC that had emerged in the interim and issue an updated guideline that was subsequently published in 2003 [1]. Due to criticisms of PAC and research yielding negative judgments over its use, clinicians have started to move to less invasive, time inexpensive, easy to use, and continuous techniques. Another dilution technique is the transpulmonary indicator dilution technique (TPID). TPID is a less invasive technique developed in the 1980s and the PiCCO system is the oldest and the most studied less invasive 473 C 474 C Cardiac Output, Measurements device based on TPID technology. A central venous catheter for the injection of a thermal indicator is required, together with an arterial thermistor-tipped catheter normally placed into the femoral artery. The TPID technique works with 15–20 mL of either cold or room temperature injectate. Intermittent cardiac output is calculated from an arterial thermodilution curve in the usual way using the Stewart-Hamilton equation. Cardiac output by intermittent TPID has been widely validated against the intermittent TD [2]. Since transpulmonary thermodilution is less invasive than pulmonary artery thermodilution, the transpulmonary cardiac output (COart) technique is more often used, particularly when cardiac output monitoring is necessary over a long period of time. The TPID method is not suitable for patients with severe peripheral vascular disease, those undergoing vascular surgery, or those showing other contraindications opposing femoral artery cannulation. The LiDCO system is also based on the TPID technique and uses lithium as a tracer. The lithium dilution technique is performed using 0.3 mL of lithium injected into either a central or a peripheral vein. The resulting lithium concentration–time curve is recorded by withdrawing blood (4.5 mL/min) through a special disposable sensor, attached to the patient’s arterial line, which consists of a lithium-selective electrode in a flow-through cell. The voltage across the lithium-selective membrane is digitized online and recorded via a computer that converts the voltage signal into a lithium concentration. The Stewart-Hamilton curve allows the cardiac output (COLi) to be measured from the indicator dilution curve. COLi is calculated according to the equation: COLi ¼ LiCl  60=AUC  ð1 PCVÞ where LiCl is the concentration of lithium chloride (mmol), AUC is the area under the primary dilution curve and PCV is the packed cell volume, which can be calculated when the patient’s hematocrit is known. The lithium dilution technique is of sufficient accuracy when there is constant blood flow, homogeneous mixing of the blood, and when there is no loss of indicator between the site of injection and the detection site [3]. This technique cannot be performed in patients receiving lithium therapy. It is also difficult to use in the operating theatre, where the use of muscle relaxants containing quaternary ammonium ions can interfere with the lithium sensor and therefore the TPID should be performed with adequate time before or after muscle relaxant administration. An advantage of the lithium indicator dilution cardiac output technique is that no central venous line is necessary. This is because the indicator bolus can also be applied via a peripheral line even if, to the best of our knowledge, only one clinical study has been performed using a peripheral venous line for lithium injection. The continuous cardiac output measurement was recently introduced in order to provide a continuous or semicontinuous evaluation of cardiac output. Continuous CO measurements can be obtained using a modified PAC with an embedded heating filament (Edwards Lifesciences, Irvine, California, USA), which releases small thermal pulses every 30–60 s following a pseudorandom binary sequence. The resulting changes in pulmonary artery temperature are measured via a distal thermistor and matched with the input signal. Cross correlation of input and output signals allows for CO values to be calculated with time from the resulting TD wash-out curve. Every 60 s, a trended continuous CO (CCO) measurement is displayed, which reflects the average course of the CO over the previous 3–6 min. As relatively small quantities of heat are used to calculate CO, sudden changes in temperature or infusion of high quantities of cold infusate can influence the accuracy and reliability of the method. Hyperthermia does not influence the accuracy of CCO monitoring, although a relative increase in bias is reported for measurements taken immediately after a hypothermic cardiopulmonary bypass (CPB). (i.e., for Opti-Q, Abbott, Abbott Park, IL and Vigilance catheters, Edwards LifeSciences, Irvine, CA). Pulse contour (or wave) analysis is based upon the principle that vascular flow can be predicted by means of the arterial pressure wave form that is itself a result of an interaction between stroke volume and the systemic vascular system. Thus, resistance, compliance, and characteristic impedance at the site of signal detection have to be considered. Different models have been used to address these issues in the various pulse wave analysis devices currently available (PiCCO plus, Pulsion Medical Systems, Munich, Germany; PulseCO, LiDCO Ltd, London, UK; FloTrac/Vigileo, Edwards LifeSiences, Irvine, CA, MostCareTM, Pressure-recording-analytical-method-PRAM; Vytech HealthTM, Padova, Italy). Pulse contour analysis initially used an algorithm based on the Wesseling algorithm. Over recent years, this algorithm has been evolved in a number of steps into what is today integrated into the PiCCO monitor. For the calculation of continuous cardiac output (PCCO) the system uses a calibration factor (cal) determined by thermodilution cardiac output measurement and heart rate (HR), as well as the integrated values for the area under the systolic part of the pressure curve (P(t)/SVR), the aortic compliance (C(p)) and the shape of the pressure Cardiac Output, Measurements curve, represented by the change of pressure over time (dP/dt). This algorithm is described as follows: ð SV ¼ cal  HR  ½PðtÞ=SVR þ CðpÞ dP=dtŠdt systole This algorithm uses the TPID technique to convert the PCCO derived from the algorithm into a more accurate “calibrated” value. The calibrated algorithm is then able to track stroke volume in a continuous manner. Continuous cardiac output measured using the PiCCO monitor has been studied and compared to the TD from the PAC in different clinical fields, and these comparisons confirm the PCCO system as being accurate and precise [2]. However, it has also been shown to have some limitations, particularly during periods of hemodynamic instability. The pulse power analysis obtained from the LiDCO System (PulseCO) is different from the classic pulse contour analysis. It is based on the hypothesis that a change in the power in the vascular system (i.e., the arterial tree) during systole is due to the difference between the amount of blood entering the system (stroke volume) and the amount of blood flowing out peripherally. It is based on the principle of conservation of mass/power and the assumption that following the correction for compliance and calibration there is a linear relationship between net power and net flow. This algorithm takes the entire beat into account, thus tackling the problem of the reflected waves, and uses a so-called autocorrelation to define which part of the “change in power” is determined by the stroke volume. Autocorrelation is a mathematical function used to analyze signals that tend to be formed of repeated cycles across time (similar to a Fourier transformation), as is clearly the case for SV in human physiology. In this way, all the curve is analyzed and SV continuously recorded. When SV is established, the CO can be easily calculated by multiplying SV by HR. Initially, the algorithm transforms the arterial pressure waveform into a standardized volume waveform (in arbitrary units) using the formula: DV=DP ¼ calibration  250  e k:p where V = volume, P = blood pressure, k = curve coefficient. The number 250 represents the saturation value in mL, that is, the maximum additional value above the starting volume, at atmospheric pressure, that the aorta/arterial tree can fill to. Autocorrelation uses the volume waveform and derives the period of the beat plus a net effective beat power factor, proportional to the nominal stroke volume ejected into the aorta. This nominal stroke volume is then C calibrated in order to be equalized to a measured SV. Until the calibration is performed the system behaves as if the calibration factor is 1. Following calibration, a calibration factor of the ratio between the arbitrary CO and the measured CO can be derived. In theory, the calibration factor should be constant in the patient unless significant hemodynamic changes occur. The lithium dilution technique measures CO that is then used to calibrate the pulse pressure algorithm: the PulseCO. The continuous cardiac output of LiDCO has been validated in several studies in cardiac surgery, in major surgery and in liver transplant patients. This new algorithm has, so far, proven to be reliable in surgical and intensive care patients [3]. The Vigileo system represents the newest arterial pulse wave analysis device (Arterial Pressure Cardiac Output – APCO). This device does not use a dilution technique to calibrate the algorithm as it is an uncalibrated technique. The algorithm gets all the information it needs to calculate the arterial impedance from the analysis of the arterial pressure waveform together with the patient’s demographic (age, sex, height, and weight). The system can use any arterial line already in situ. However, the signal needs to be sampled by a specific transducer, the FloTrac. The FloTrac algorithm analyses the pressure waveform at one hundred times per second over 20 seconds, capturing 2,000 data points for analysis. According to the manufacturer, the algorithm is primarily based on the standard deviation of the pulse pressure waveform, as follows: APCO ¼ f ðcompliance; resistanceÞ  sp HR where sp is the standard deviation of the arterial pressure, HR is the heart rate, and f (compliance, resistance) is a scaled factor proportional to vascular compliance and peripheral resistance. This function is also referred to as Х. The calculation of X in the first version of the software was executed every 10 min, whereas in the second version, the software recalculates X every minute and CO is computed every 20 s. The standard deviation of the arterial pressure waveform is computed on a beat-to-beat basis using the following equation: p sp ¼ ½1=ðN 1Þ  SðN 1; k¼0Þ ðPðkÞ PavgÞ2 Š where P(k) is kth pulse pressure sample in the current beat, N is the total number of samples, and Pavg is the mean arterial pressure. Compliance and resistance are derived from the analysis of the arterial waveform. The hypothesis retains that the shape of the arterial pressure wave, in terms of its degree of kurtosis or skewness, can be used to calculate the effects of compliance and peripheral resistance upon 475 C 476 C Cardiac Output, Measurements blood flow. Additional parameters, such as the pressure dependent Windkessel compliance Cw , heart rate and the patient’s body surface area (BSA) are also included in order to take other specific patient characteristics into account. Despite the fact that the Vigileo system represents a revolution in the field of pulse pressure analysis, being a real “plug and play” tool, an assessment of the performance of the algorithms (two versions of the software have already been released in less than 3 years) is still underway. It can already be said, however, that some authors have found good agreement between the Vigileo system and intermittent thermodilution, while others have reported poor limit of agreement [4]. Beat-to-beat values of uncalibrated CO can also be obtained using the pressure recording analytical method (PRAM). This new method is based on the mathematical analysis of the arterial pressure profile changes. It allows for the continuous assessment of SV from the pressure signals recorded in the radial and femoral arteries. Based on the perturbation theory from physics, and applied to this issue of physiology, all the elements determining CO can be taken into consideration simultaneously and in a beat-to-beat manner. Sampled at 1000 Hz, the detected pressure curve it must be submitted to a form of analysis; the result is the calculation of actual (beat-to-beat) stroke volume; with no constant value of impedance and as it is derived from an external calibration neither pre-estimated in vivo nor in vitro data are required. In contrast to the bolus TD technique, PRAM is less invasive, easier to use and provides continuous data. To date, PRAM has been used in volunteers, during vascular and cardiac surgery and in patients with congestive heart failure but there have been no studies comparing PRAM with the TD technique under hyperdynamic clinical conditions. Non-invasive Techniques Nowadays, several types of Doppler techniques are commercially available for the estimation of CO by measurement of aortic blood flow (ABF) [5]. An ultrasound beam directed along the ABF is reflected, caused by the moving red blood cells, with a shift in frequency (the Doppler effect) that is proportional to the blood flow velocity according to the equation: Fd 1=4 2 f 0 ¼ C V cos u where Fd is the change in frequency (Doppler shift), f 0 is the transmitted frequency, V is the blood flow velocity, and u is the angle between the direction of the ultrasound beam and the blood flow. CO is estimated by multiplying the blood flow velocity by the cross-sectional area (CSA) of the aorta at the insonation point. The esophageal Doppler probe is introduced either orally or nasally and placed at the level of the descending aorta. This technique has some advantages over the classical suprasternal technique, the most important being a more stable positioning of the probe once the descending aorta is insonated. Three models of esophageal CO monitoring systems are commercially available and differ from each other in some important ways. Two systems use a built-in nomogram to obtain a measurement of the descending aortic diameter (CardioQ, Deltex Medical, Chicester, Sussex, UK; Medicina TECO, Berkshire, UK), whereas the other system uses M-mode echocardiography for this purpose (HemoSonic, Arrow International, Reading, PA). By rotating the esophageal Doppler probe, the best Doppler image possible can be achieved. ABF is calculated by multiplying ABF velocity by the CSA of the descending aorta and the heart rate. The limitations of this technique are turbulent flow, negotiation of blood flow to the upper part of the body, and the angle of insonating the aorta. Moreover, the technique is poorly tolerated in awake, nonintubated patients and cannot be used in patients with an esophageal disorder. Once a Doppler probe is in place, transesophageal echocardiography (TEE) cannot be performed. In summary, esophageal Doppler-derived ABF is a semi-invasive approach, which enables trend monitoring of CO. The statistical limit of agreement of this technique are greater compared to invasive technique. However, in contrast to most other techniques, it has been demonstrated in subsets of patients that hemodynamic treatment according to Doppler-derived CO measurements leads to a decrease in perioperative morbidity and length of stay in intensive care units. Doppler flow measurements obtained with transthoracic echocardiography (TTE) or TEE can also be used to estimate CO. Their accuracy depends upon image quality, sample site, angle of insonation, the profile of the blood flow velocity distribution, the signal-to-noise ratio of the blood flow velocity, and the possibility of measuring the diameter of the vessel and the shape of the cardiac valve. Most often, measurements of blood flow velocity and CSA are performed by both TTE and TEE at the level of a cardiac valve or the right ventricular (RVOT) or left ventricular outflow tract (LVOT). The best results are usually obtained by the transaortic approach using the triangular shape assumption of aortic valve opening and CO determination at the LVOT. In summary, Doppler echocardiography is technically demanding, timeconsuming, and requires a skilled operator. It is a safe, fairly reproducible and reasonably accurate method for Cardiac Output, Measurements measuring CO in selected patients, provided the signal quality is adequate during recording. The ultrasonic cardiac output monitor (USCOM Pty Ltd., Coffs Harbour, NSW, Australia) is a noninvasive transcutaneous device that provides cardiac output by continuous-wave. It was introduced for clinical use in 2001 and is based on continuous-wave Doppler ultrasound. The flow profile is obtained by using a transducer (2.0 or 3.3 MHz) placed on the patient’s chest in either the left parasternal position to measure transpulmonary blood flow or the suprasternal position to measure transaortic blood flow. A standard ultrasound conducting gel is used. This flow profile is presented as a time–velocity spectral display that shows variations of the blood flow velocity against time. Once the optimal flow profile is obtained, the trace is frozen. The CO is then calculated from the equation: CO ¼ HR
SV where the stroke volume is the product of the velocity time integral (VTI) and the cross-sectional area (CSA) of the chosen valve. The VTI represents the distance that a column of blood travels with each stroke and is calculated from the peak velocity detected. In the USCOM monitor, this is performed using a unique TouchPoint semiautomated flow profile trace which requires the operator to mark out the flow trace for a chosen stroke of the heart. This device simultaneously measures the patient’s heart rate. The CSA of the chosen valve is determined by applying height-indexed regression equations that are incorporated into the USCOM device or by using another imaging method (e.g., two-dimensional echocardiography). The regression equation used to calculate the aortic valve area is that proposed by Nidorf and colleagues. The pulmonary valve area is calculated by a separate regression equation derived from the Nidorf equation. The NICO system (Novametrix Medical Systems, Wallingford, CT, USA) uses Fick’s principle applied to carbon dioxide (CO2) for the measurement of CO. For CO2 analysis, a mainstream infrared and airflow sensor is used. CO2 production is calculated as the product of CO2 concentration and air flow during a breathing cycle and arterial CO2 content is derived from end-tidal CO2 and the CO2 dissociation curve. A disposable rebreathing loop allows an intermittent partial rebreathing state to be determined in cycles of 3 min. The rebreathing cycle induces an increase of end-tidal CO2 and mimics a drop of CO2 production. The obtained differences of these values are then used to calculate CO. Validation studies with conflicting results have been published over recent years. Fairly good CO determination was observed as long C as the NICO system was applied to intubated and mechanically ventilated patients with minor lung abnormalities and fixed ventilatory settings. However, variations in ventilatory modes, mechanically assisted spontaneous breathing or the use of this technique in patients with lung pathologies (increased shunt fraction) resulted in a decrease of CO accuracy. Thus, good accuracy can only be obtained using the partial CO2 rebreathing technique when applied in a precisely defined clinical setting to mechanically ventilated patients. Bioimpedance cardiography is based on the application of a high-frequency, low-alternating electrical current to the thorax (thoracic electrical bioimpedance). Changes in bioimpedance to this current are related to cardiac events and blood flow in the thorax. Using a mathematical conversion, changes in bioimpedance can be transformed into an estimate of stroke volume. Recently, electrical velocimetry was introduced as a new bioimpedance technique using a new algorithm: the Bernstein–Osypka equation (Aesculon, Osypka Medical, Berlin, Germany). The accuracy and reliability of the majority of thoracic bioimpedance devices have been evaluated with conflicting results. It is therefore possible that their use could lead to inappropriate clinical interventions. Common cylinder and cone-based models for bioimpedance stroke volume calculation represent oversimplifications of the complex electrical events that occur inside the thorax during the cardiac cycle; this is also the case when only the intrathoracic blood volume is used as a model. Consequently, bioimpedance CO is not currently accepted as a valid and reproducible method in clinical practice. Although some results do seem promising, this technique requires further investigation. Bioreactance technology (NICOM system, Cheetah Medical Inc., Portland, OR, USA) is the analysis of the variations in the frequency of a delivered oscillating current that occurs when the current traverses the thoracic cavity, as opposed to traditional bioimpedance that purely relies upon the analysis of changes in signal amplitude. To our knowledge, three validation studies have been conducted that compared bioreactance to intermittent (COpa) and continuous cardiac output (CCO), obtained from PAC, and to PCCO and APCO obtained respectively form PiCCO and Vigileo Systems. In each case bioreactance was found to give results comparable to those arising from the other techniques. More recently, bioreactance was also tested against intermittent and continuous CO obtained from the PiCCO System in 20 cardiac surgical patients during the postoperative period. The authors concluded that although occasional discordance may occur in CO values assessed by transthoracic bioreactance 477 C 478 C Cardiac Output, Measurements and pulse contour arterial wave analysis, the level of precision was acceptable. Applications CO is nowadays monitored in critically ill patients to assess cardiac function with the primary aim of maintaining tissue perfusion (Table 1). In addition to measurement of CO, modifications of the original PAC have allowed for continuous measurement of mixed venous oxygen saturation (SvO2), right ventricular function (RVEF), and right ventricular enddiastolic volume (RVEDV); however, the use of PAC can also cause complications. Several reports have described intrinsic morbidity and mortality arising from the use of PAC; thus its application should be restricted to highly selected patient populations. The selective use of the PAC can only be justified in patients with right ventricular failure and patients with increased pulmonary vascular resistance requiring vasodilator therapy. The use of the PAC in low-risk cardiac surgery, vascular surgery and major abdominal, orthopedic or neurosurgical procedures should not be recommended. Advocates of the PAC suggest that it is crucially important that physicians and nursing staff are familiar with the PAC technology, including the procedure of inserting, positioning and maintaining the PAC. The use of PAC requires training and education as misinterpretation of data obtained with this apparatus is common. Finally, due to its invasiveness, PAC used for the purpose of CO monitoring is no longer justified. Calibrated vs. uncalibrated wave analysis. The two available CO measurement systems, PiCCOplus and LiDCOplus, require calibration prior to the measurement of continuous CO based on the assumption that the systolic part of the arterial pressure waveform represents stroke volume. The PiCCO system requires transpulmonary thermodilution for the calibration procedure, whereas LiDCO can be calibrated using lithium dilution. Recalibration is also necessary after profound changes in arterial compliance (e.g., sepsis following CPB) and/or hemodynamics in order for subsequent measurements of CO with continuous pulse contour CO to be Cardiac Output, Measurements. Table 1 Cardiac output monitoring, different tools and clinical applications OR OR/ICU OR/ICU *Unexpected low CO *Cardiac patients undergoing major non-cardiac surgery *Heart failure Cardiac patients undergoing minor surgery Hyperdynamic CV status Patients with PHP and RV dysfunction Intraoperative time in Ltx Liver transplantation HD monitoring for ICU stay (long time) Lung transplantation Major orthopedic surgery ARDS/Septic shock/Heart failure Cardiac surgery ARDS/Septic shock Baseline approach Arterial Line Arterial Line (radial/femoral) Arterial Line Peripheral venous line or CVC CVC PAC ED ED PAC Vigileo PiCCOplus Advanced PAC (Vigilance) LiDCOplus LiDCOplus Devices Limitations Arrhythmias (Vigileo) Vascular surgery (PiCCO) PAC related complication Arterial signal quality (Vigileo) Esophageal surgery (ED) Time limited insertion Esophageal surgery (ED) Arterial signal quality (PiCCO/LiDCO) *If available and you are familiar with, first check the CV status with a TTE and or a TEE OR: operating room; ICU: intensive care unit; CO: cardiac output; Ltx: liver transplant; HD: hemodynamic; PHP: pulmonary hypertension; RV: right ventricle; CVC: central venous catheter; PAC: pulmonary artery catheter; ED: esophageal Doppler; CV: cardiovascular; TTE: transthoracic echocardiography; TEE: transesophageal echocardiography Cardiac Output, Measurements carried out with the usual accuracy. This prerequisite is mainly due to resulting changes in vasomotor tone. When these criteria are fulfilled, the accuracy of both techniques is sufficient for clinical purposes. Moreover, the PiCCO System (based on TPID technique) allows the estimation of preload index as intrathoracic blood volume index (ITBVI) and a “lung edema” index as extravascular lung water index (EVLWI). The ITBVI has been extensively investigated as a static preload index in critically ill and surgical patients (cardiac surgery, liver, and lung transplant surgery). These studies have shown that the ITBVI can predict preload better than filling pressure, particularly during the intraoperative period. The EVLWI positively correlated with survival and seems to be an independent predictor of prognosis in critically ill patients, especially in septic patients. It seems reasonable that fluid management based on EVLWI measurements can be beneficial to the critically ill. Indeed, it has been shown that fluid restriction and keeping a low EVLWI improves oxygenation, reduces the length of time that mechanical ventilation is required, and may also improve survival rates. Unfortunately no definitive data have been published so far on EVLWI and its clinical applications. Moreover, stroke volume variation (SVV) and pulse pressure variation (PPV) experimentally and clinically validated fluid responsiveness indexes in controlled mechanically ventilated patients are also continuously monitored with PiCCOplus. Together with CO, the LiDCOplus system provides information about a series of derived variables including oxygen delivery (Hb values and SaO2 need to be inserted manually) and fluid responsiveness indices such as PPV, SVV, and Systolic Pressure Variation (SPV). Recently, a protocol targeting DO2I of 600 mL/m2 in high-risk surgical patients, using the LiDCO system was proven to improve patient outcome, reduce morbidity, and length of hospital stay. Good accuracy and precision between the intermittent and continuous data obtained from LiDCO and PAC were also detected in hyperdynamic patients in the postoperative period following liver transplantation procedures. The uncalibrated Vigileo technique showed conflicting results even when the last generation algorithm was used; particularly in the hyperdynamic setting (liver transplant and septic shock patients). Together with CO, the monitor gives other derived variables such as oxygen delivery (Hb values and SaO2 together with PaO2 are inserted manually) and dynamic indices of fluid responsiveness. Based on actual references, Vigileo monitoring seems to be useful in patients with a low or normal CO level, that is, for intraoperative goal-directed therapy C (GTD). At present, its use in septic shock, liver transplant, and arrhythmic patients should not be encouraged. Doppler flow measurements for CO estimation can be performed in the descending aorta using probes that are smaller than conventional TEE probes; their correct insertion is crucial requiring highly skilled operators. Initially the esophageal Doppler technique was serially utilized in multiple prospective, randomized, controlled perioperative trials to guide hemodynamic management and it consistently demonstrated a reduction in complications and lengths of hospital stay. It has been used intraoperatively in cardiac surgical, femoral neck repair, and abdominal surgical patients, as well as postoperatively following cardiac surgery and multiple trauma; the control group in each study was randomized to standard practice either with or without the use of a central venous catheter. More recent clinical trials have, however, shown conflicting results. Limited accuracy may result from signal detection problems, the assumption of fixed regional blood flow or the use of nomograms to determine aortic cross-sectional area. The HemoSonic 100 device was developed to eliminate the latter by echocardiographic aortic diameter measurement, but optimal adjustment of both the Doppler technique and the ultrasonic signal can be challenging. Therefore, the value of the esophageal Doppler technique is limited in clinical practice. However, Doppler devices may be used in specific situations by skilled observers. Based on the ability to reliably track CO changes over time, early goal directed therapy in the intraoperative setting may be a typical indication, since different studies have demonstrated improved outcomes when using this concept. Until now, tools for continuous CO monitoring have been validated as if they were tools for snapshot measurements. Most authors have compared variations in CO between two time-points and have used Bland–Altman representations to describe the statistical agreement between these variations. The impact of time and repetitive measurements over time have not been taken into consideration. Recently Squara and coworkers proposed a conceptual framework for the validation of CO monitoring devices [6]. Four quality criteria were suggested and studied: accuracy (with a small bias), precision (with a small random error in measurements), a short response time, and an accurate amplitude response. As an amount of deviation in each of these four criteria is admitted, the authors proposed to add, as a fifth criterion, the ability to detect significant cardiac output directional changes. Other important issues regarding the designing of studies to validate cardiac output monitoring tools were also 479 C 480 C Cardiac Steroids and Glycoside Toxicity underscored: the choice of patient population to be studied, choice of reference method, the method of data acquisition, data acceptability checking, data segmentation, and the final evaluation of reliability. The application of this framework underlines the importance of precision and time response for the clinical acceptance of monitoring tools. (Nerium oleander), foxglove (Digitalis spp.), lily of the valley (Convallaria majalis), and red squill (Urginea maritima), a rodenticide of historical significance. The dried secretions of the Bufo toad, a purported aphrodisiac when topically applied, contain a cardioactive steroid and have also caused toxicity when ingested. Pathophysiology References 1. 2. 3 4. 5. 6. Practice Guidelines for Pulmonary Artery Catheterization (2003) An Update Report by the American Society of Anesthesiologists Task Force on Pulmonary artery Catheterization. Anesthesiology 99:988–1014 Della Rocca G, Costa MG, Pompei L, Coccia C, Pietropaoli P (2002) Continuous and intermittent cardiac output measurement: pulmonary artery catheter versus aortic transpulmonary technique. Br J Anaesth 88:350–356 Costa MG, Della Rocca G, Chiarandini P, Mattelig S, Pompei L, Barriga MS, Reynolds T, Cecconi M, Pietropaoli P (2008) Continuous and intermittent cardiac output measurement in hyperdynamic conditions: pulmonary artery catheter vs. lithium dilution technique. Intensive Care Med 34(2):257–263 McGee WT, Horswell JL, Calderon J, Janvier G, Van Severen T, Van den Berghe G, Kozikowski L (2007) Validation of a continuous, arterial pressure-based cardiac output measurement: a multicenter, prospective clinical trial. Crit Care 11:R105 Singer M (2009) Oesophagela doppler. Curr Opin Crit Care 15(3):244–248 Squara P, Cecconi M, Rhodes A, Singer M, Chiche JD. Intensive Care Med 2009; Jul 11 Epub ahead of print Cardiac Steroids and Glycoside Toxicity NIMA MAJLESI, DIANE P. CALELLO, RICHARD D. SHIH Department of Emergency Medicine, Morristown Memorial Hospital, Morristown, NJ, USA Synonyms Digoxin toxicity; Foxglove toxicity; Oleander toxicity Definition Cardioactive steroids are a class of animal and plantderived compounds with a steroid nucleus and a specific inotropic, chronotropic, and dromotropic effect. The term cardiac glycoside refers to a subgroup of cardioactive steroids that also contain sugar residues and include digoxin, digitalis, and ouabain. In the United States, the most common source of cardioactive steroid exposure is pharmaceutical digoxin. Plant sources include oleander Ingested cardioactive steroids (CAS) are approximately 80% bioavailable. However, toxicokinetics depends on multiple factors, including electrolyte abnormalities, medication interactions, renal dysfunction, and disruption of gastrointestinal flora. Hypokalemia, in particular, results in excessive sensitivity to CAS as less binding to skeletal Na+-K+ ATPase may result in increased effects on the myocardium. Hypomagnesemia and hypercalcemia may also potentiate CAS toxicity. Drug interactions are unfortunately common with other cardiovascular medications. Amiodarone, spironolactone, furosemide, diltiazem, carvedilol, and verapamil can all interfere with the kinetics of CAS through alteration of protein binding, inactivation of P-glycoprotein, and decreased renal perfusion. Cardioactive steroids inhibit the Na+-K+ ATPase on the membrane of the cardiac myocyte, thereby raising the intracellular Na+ content, which then prevents the Na+-Ca2+ antiporter from expelling Ca2+ in exchange for Na+. This results in an increase in intracellular Ca2+ within the myocyte and calcium-mediated Ca2+ release from the sarcoplasmic reticulum. Positive inotropy is achieved by increased available calcium to bind troponin, actin, and myosin. CAS also can affect the parasympathetic nervous system through increase of acetylcholine from the vagus nerve. The resultant effect on cardiac conduction and electrophysiology is variable. Therapeutically, CAS cause a decreased rate of depolarization and conduction through both the sinoatrial and atrioventricular nodes. A higher resting membrane potential also leads to shortened repolarization and increased automaticity of the atria and ventricles. The common ECG finding in patients on therapeutic CAS is referred to as “digitalis effect.” Digitalis effect is characterized by PR interval prolongation, QT shortening, and the ST-segment forces opposite in direction from the QRS. This is a reflection of therapeutic effect in contrast to the ECG findings in CAS toxicity. Presentation It is important to distinguish between those patients with acute and chronic CAS toxicity as clinical manifestations Cardiac Steroids and Glycoside Toxicity and management differ significantly. An assessment of the serum digoxin concentration, serum electrolytes, especially potassium and magnesium, renal function, and electrocardiogram are essential in determining the severity of toxicity and the need for treatment. In the case of plantderived CAS exposure, the serum digoxin immunoassay exhibits some cross-reactivity with these compounds and will provide qualitative assessment. These cases should be managed more by the clinical picture than the actual serum level. Digoxin toxicity, however, typically requires a concentration greater than 2 ng/mL. In acute toxicity, early nausea and vomiting are nearly universal; extracardiac manifestations may include confusion and lethargy. ECG findings vary widely, and essentially any rhythm is possible in CAS toxicity with the notable exception of rapidly conducted supraventricular tachydysrhythmias. Biventricular tachycardia, while pathognomonic, is rarely seen. The most commonly observed findings are premature ventricular contractions and atrial fibrillation or flutter with atrioventricular block [1]. Digitalis effect is not the result of CAS toxicity and represents normal therapeutic effect as mentioned earlier. An elevated serum potassium concentration as a result of Na+-K+ ATPase pump inhibition has been shown to be prognostic in adults with acute ingestion. A large observational cohort study performed before the development of digoxin-specific antibodies demonstrated a strong correlation between serum potassium and mortality [2]. A potassium concentration between 5.0 and 5.5 mEq/L was associated with a 50% mortality, and a serum potassium concentrations greater than 5.5 mEq/L was associated with 100% mortality. Though hyperkalemia may exacerbate the toxicity due to CAS, it is more a marker of severity in adults with acute ingestion rather than the primary etiology. Chronic CAS toxicity is more challenging both to diagnose and to manage. Systemic symptoms are often present, including malaise, GI symptoms, weakness, confusion, delirium, and various visual disturbances. These often include decreased visual acuity and visual color changes (xanthopsia). Unlike acute CAS toxicity, chronic toxicity is often complicated by hypokalemia due to concomitant diuretic use which as mentioned may potentiate toxicity. Hypomagnesemia, when present, will enhance the myocardial irritability these patients exhibit. However, hyperkalemia and hypermagnesemia may also be present, most commonly in the setting of new onset renal failure or insufficiency. Similar bradydysrhythmias and ventricular tachydysrhythmias which occur in acute toxicity are more common in patients presenting with chronic CAS toxicity. C 481 Treatment Digoxin-specific antibody fragments have revolutionized the treatment of CAS toxicity. The decision to administer is multifactorial and should consider the amount ingested, serum level, clinical evidence of toxicity, as well as the patient’s underlying conditions which may be exacerbated by complete removal of digoxin where clinically needed. In general, digoxin-specific Fab should be given to patients with: 1. CAS-related dysrhythmias 2. Acute ingestion with potassium greater than 5 mEq/L 3. Chronic toxicity presenting with dysrhythmias, CNS findings, or gastrointestinal symptoms 4. Serum digoxin concentration greater than 15 ng/mL at any time or greater than 10 ng/mL 6 h post-ingestion regardless of symptoms in an acute ingestion 5. Poisoning with a non-digoxin CAS The optimal dosing of digoxin-specific Fab can be determined based on the serum concentration, amount ingested, or clinical presentation [3]. 1. If the serum digoxin concentration is known, the dose is calculated as: # of vials ¼ ½serum digoxin concentration ðng=mLÞ weightŠ=100 2. If the amount ingested is known and the ingestion is acute, the dose is calculated as: # of vials ¼ ½amounted ingested ðmgÞ=0:5 ðmg=vialÞ  0:8 ðrepresents 80%bioavailability Þ 3. In the patient presenting with life-threatening toxicity requiring immediate treatment before the serum concentration can be obtained, with an unknown amount ingested, the recommended empiric dose is 10–20 vials in acute poisoning, and 5 vials in chronic poisoning. Gastrointestinal decontamination should be considered in patients with acute ingestions especially for those with non-digoxin CAS ingestions. Multiple dose– activated charcoal may be effective due to enterohepatic recirculation of CAS. Gastric lavage and emesis should be limited to the very few presenting early with non-digoxin CAS ingestions. Replacement of potassium and magnesium should occur prior to administration of digoxin-specific antibody fragments as correction often leads to abatement of the presenting cardiac dysrhythmia, and Fab administration may decrease the potassium further. In contrast, correction of hyperkalemia should begin with administration of digoxin specific antibody fragments followed by C C Cardiac Tamponade intravenous insulin, dextrose, and sodium bicarbonate, being careful not to cause hypokalemia. Intravenous calcium administration is contraindicated due to the relative intracellular hypercalcemia which exists in CAS-poisoned patients. Administration has been associated with cardiac dysfunction and arrest. Transvenous and external pacing is contraindicated in patients with CAS poisoning due to increased adverse outcomes associated with delay in digoxin-specific Fab administration and conversion to unstable ventricular dysrhythmias [4]. However, cardioversion and defibrillation is indicated in those with hemodynamic instability and ventricular dysrhythmias. Prognosis The prognosis of CAS-poisoned patients is dependent upon the complications of CAS toxicity that develop. After-care After management of acute medical consequences, patients with intentional overdoses should be referred for counseling. Patients with chronic CAS toxicity should be evaluated for alternative treatment of the underlying disorders so that unintentional toxicity will be less likely to recur. Definition Cardiac Tamponade describes the hemodynamic sequelae resulting from compression of the cardiac chambers due to accumulation of fluid (or gas) within the pericardium. Pathophysiology [1, 2] An understanding of the underlying pathophysiology is essential to fully grasp the clinical findings associated with tamponade. The pericardial sac is relatively inelastic. It can stretch to accommodate a limited volume (pericardial reserve volume) before any further increase in pericardial contents causes increased pericardial pressure and competition between the extracardiac contents and the contents of the cardiac chambers for the finite available space. As tamponade develops, the cardiac chambers are compressed and their compliance is reduced. This imposes a constraint on cardiac filling, reduces stroke volume and ultimately leads to a decrease in cardiac output. The compliance of the pericardium and the rate of fluid accumulation determine the likelihood of tamponade occurring (Fig. 1). Rapid accumulation of fluid (e.g., traumatic intrapericardial hemorrhage) will rapidly result in tamponade. Conversely, with slow fluid accumulation (e.g., as a result of inflammation), up to 2 l of fluid may be present before causing tamponade. References 1. 2. 3. 4. Bismuth C, Gaultier M, Conso F, Efthymiou ML (1973) Hyperkalemia in acute digitalis poisoning: prognostic significance and therapeutic implications. Clin Toxicol 6(2):153–162 Ma G, Brady WJ, Pollack M, Chan TC (2001) Electrocardiographic manifestations: digitalis toxicity. J Emerg Med 20(2):145–152 Antman EM, Wenger TL, Butler VP Jr, Haber E, Smith TW (1990) Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Final report of a multicenter study. Circulation 81(6):1744–1752 Taboulet P, Baud FJ, Bismuth C, Vicaut E (1993) Acute digitalis intoxication–is pacing still appropriate? J Toxicol Clin Toxicol 31(2):261–273 Acute Subacute Pressure 482 a b Volume Cardiac Tamponade DOMINIC W. K. SPRAY Anaesthetics and Intensive Care, St. George’s Hospital, London, UK Synonyms Pericardial tamponade Cardiac Tamponade. Figure 1 The effect of rapid accumulation of pericardial fluid compared to gradual accumulation. In acute tamponade, very little volume (point a) is needed before pericardial reserve volume is exhausted and a critical pressure reached. With gradual accumulation, compensatory mechanisms allow more volume (point b) to be accommodated before this critical pressure is reached. In both cases, small increments in pericardial fluid beyond this point result in rapid pressure rises Cardiac Tamponade Chronic changes in pericardial compliance allow the pericardium to accommodate this extra fluid. Compensatory mechanisms based on sympathetic stimulation (tachycardia, increased peripheral vascular resistance and increased ejection fraction due to increased contractility) with increased blood volume (upregulation of the reninangiotensin system) act to delay the decrease in cardiac output. In all cases, at the critical inflection point, very little extra fluid needs to accumulate to substantially raise pericardial pressure and cause tamponade (likewise, great benefit is seen from the initial removal of fluid during pericardiocentesis). As tamponade increases, eventually the diastolic pressures in all cardiac chambers equalize at a level similar to the pericardial pressure (15–30 mmHg). Pneumopericardium is rare but may occur after trauma, due to iatrogenic causes or secondary to gasforming infections. It can present in a similar way to fluid tamponade and is similarly a medical emergency. Hemodynamic Sequelae Venous Return Venous return usually has two peaks – one during early diastole and one during ventricular systole. Progressive tamponade causes increased pericardial pressure throughout the cardiac cycle. Since the heart chambers in total are fullest during diastole (and diastolic pressure is increased) there is effectively no space for extra blood to flow into. In contrast, the stroke volume leaving during ventricular systole makes room for venous return. Filling is therefore progressively shifted towards systole and diastolic filling diminishes. Jugular venous distension is present and the x descent of the central venous pressure trace is lost, but the y descent remains. Once tamponade is advanced enough, filling also drops during systole leading to a further fall in total venous return and cardiac output. Ventricular Interdependence and Pulsus Paradoxus Changes in pleural pressure are still transmitted to the heart during tamponade. Therefore, in spontaneous inspiration, systemic venous return increases due to the fall in intrathoracic pressure. Since the RV free wall is constricted by the pericardial effusion, the extra volume can only be accommodated by shifting the interventricular septum leftward at the expense of left ventricular volume. Therefore, during spontaneous inspiration, left ventricular cardiac output drops, manifested by an exaggerated decrease in systolic blood pressure (>10 mmHg), a phenomenon known as pulsus paradoxus (Fig. 2). Increased LV C 483 100 80 Aorta 60 C 40 20 RV 0 Inspiration Expiration Cardiac Tamponade. Figure 2 Pulsus paradoxus. Note the decreased aortic systolic pressure and narrowing of pulse pressure during spontaneous inspiration and rise again during expiration. Timings are reversed in the RV pressure trace afterload due to the decreased intrathoracic pressure may also contribute to this decrease in left ventricular stroke volume. Right ventricular output will increase during inspiration secondary to the increased venous return. Since the ventricles are in series, a few beats later, this also contributes to an increased left ventricular stroke volume during expiration. Thus the effects of ventilation during tamponade are to produce right and left sided stroke volume and pressure changes which are 180 out of phase. Note that with intermittent positive pressure ventilation (IPPV), the above findings will be reversed as intrathoracic pressure is at its highest during inspiration and decreases during expiration. Decreased Cardiac Output The end-result of the effects of tamponade is a decrease in cardiac output. The decrease in systemic venous return and reduction in end diastolic chamber volumes are the primary reasons for the low cardiac output state. End systolic volume does also decrease due to increased contractility secondary to sympathetic activation. However, this is not sufficient to maintain stroke volume, hence the reliance on tachycardia to maintain adequate cardiac output. The effects of IPPV itself on cardiac output are complicated and variable, but on the whole, IPPV tends to reduce venous return and consequently cardiac output. Therefore, IPPV should be avoided in patients who are not intubated at presentation. Corrective treatment by rapid pericardiocentesis should be the aim as this will reverse most indications for ventilation. 484 C Cardiac Tamponade Etiology and Subtypes of Tamponade shock and the differential diagnosis should include other causes for this. Classical Tamponade This presents with a spectrum of severity, from a simple effusion with few symptoms to a life-threatening emergency. It is sometimes divided on the basis of duration into acute and sub-acute. Acute tamponade is usually due to trauma, cardiovascular rupture (e.g., retrograde flow from type A aortic dissection) or iatrogenic causes (e.g., cardiac catheterization). Sub-acute tamponade develops more insidiously, usually as a result of an inflammatory process (e.g., infection, neoplasm, autoimmune, radiation or drug-induced) but sometimes due to a non-inflammatory process (e.g., hypothyroidism, amyloidosis) in which the underlying pathogenesis of the effusion remains unclear. Idiopathic pericardial effusion is also seen, often presenting with large volumes of pericardial fluid. Whatever the cause, it is important to treat any decompensation as a medical emergency and institute the appropriate management. Low Pressure Tamponade It is the trend towards pressure equalization between pericardial pressure and intracardiac pressure that gives rise to tamponade. Therefore in patients who are severely hypovolemic for whatever reason (e.g., hemorrhage, hemodialysis), with low intracardiac pressures, tamponade has been demonstrated with pericardial pressures in the range of 6–12 mmHg. Echocardiographic features are similar to patients with classic tamponade (effusion size, chamber collapse, exaggerated respiratory variation in transvalvular flow), but clinical signs such as tachycardia, jugular venous distension and pulsus paradoxus are less prevalent. Regional Tamponade Loculated or localized effusions or hematoma can occur, commonly after cardiac surgery. The hemodynamic effects of these vary widely depending on the affected chambers and the typical features of classical tamponade are often missing. Although the presentation may mimic that of heart failure, it is difficult to generalize about clinical findings and detailed imaging is often necessary to establish the diagnosis. A high index of suspicion should prevail if there is a possibility of regional tamponade given the clinical findings and a suggestive history. Evaluation and Assessment As mentioned above, tamponade manifests a continuum of symptoms with a range of clinical severity. Presentation may also include many non-specific signs and symptoms. Ultimately, the presentation will be that of cardiogenic History In cases of suspected tamponade, the usual history should be taken and predisposing factors should be sought. This may be more relevant on the ICU where patients may not be able to communicate. Symptoms Symptoms tend to relate to the degree of impairment in cardiac output. Patients may complain of tachycardia, dyspnea and fatigue as well as a central chest discomfort, often relieved by sitting forward. Clinical Signs These become all the more relevant in sedated intensive care patients who are unable to give a history or describe their symptoms. Sympathetic upregulation resulting in tachycardia is seen in virtually all cases, with exceptions being those patients in whom their underlying disease manifests bradycardia (e.g., hypothyroidism). Cardiac sounds may be muffled and the apex beat difficult to palpate in the presence of a large effusion. A pericardial rub may be present if pericarditis is the underlying etiology. Elevated jugular venous pressure is seen, with the y descent often attenuated or absent due to the absence of diastolic filling as discussed above. The x descent is usually preserved. This is usually more easily appreciated on a central venous pressure trace than by clinical examination. Pulsus paradoxus can be demonstrated in most cases of tamponade. The sphygmomanometer cuff is deflated slowly. Initially, the first Korotkoff sounds are only audible during spontaneous expiration (or IPPV inspiration), but as the cuff is deflated further, sounds are heard throughout the respiratory cycle. The difference in pressure between these two events quantifies the degree of pulsus paradoxus. There are situations in which tamponade does not give rise to pulsus paradoxus. These include any pre-existing condition where left ventricular diastolic pressure or volume are already raised (e.g., atrial septal defects, severe aortic regurgitation, chronic renal failure). Pulsus paradoxus may also occur outside the context of tamponade. It is seen in severe asthma or COPD, pulmonary embolism and in up to one third of cases of constrictive pericarditis. In intensive care patients, tamponade must always be amongst the differential diagnosis of any patient who manifests cardiogenic shock. The usual symptoms of hypotension, diaphoresis, shut down extremities and oliguria may also be used as a crude indicator of progression Cardiac Tamponade C 485 I C V3 V6 Cardiac Tamponade. Figure 3 Electrical alternans. Note the changing size of sequential QRS complexes possibly due to the heart “swinging” in the pericardial effusion of tamponade over time and the need to perform pericardiocentesis. Investigations Tamponade remains a clinical diagnosis, but certain investigations are useful to confirm suspicions. Electrocardiography This usually demonstrates tachycardia and may be of lower voltage than usual, although this is a non-specific finding. It may be possible that this finding is limited to tamponade alone rather than effusion per se. Patterns associated with acute pericarditis may also present. Electrical alternans (Fig. 3) is very specific, but insensitive for tamponade. There is a beat to beat variation in the size of electrical complexes, often, but not necessarily, restricted to the QRS. This is thought to be possibly due to the heart “swinging” in the pericardial fluid although the exact mechanism is poorly understood. Chest Radiography At least a moderate pericardial effusion (approx. 200 ml) is required before the cardiac silhouette begins to enlarge to a characteristic, round, “flask-shaped” appearance. A lateral view may show a pericardial fat pad due to separation of pericardial fat from epicardium by the pericardial fluid. Chest radiographs typically appear normal in acute tamponade, except that the lung fields usually appear oligemic. Echocardiography [3] Echocardiography remains the standard for non-invasive assessment of pericardial effusion and its hemodynamic consequences. There is a class 1 recommendation for its use in assessment of patients with suspected pericardial disease (American College of Cardiology/American Heart Association/American Society of Echocardiography Cardiac Tamponade. Figure 4 Large anterior and posterior effusion containing fibrin strands guidelines 2003). The presence of pulmonary hypertension may mask echocardiographic findings in tamponade. Typical echocardiographic findings associated with tamponade include: ● Effusion Effusion is usually well visualized (Fig. 4). It normally needs to be circumferential for classical tamponade to occur, but regional tamponade may present with loculated or localized effusions. ● Diastolic chamber collapse During atrial relaxation, the pressure in the RA is at its lowest and pericardial pressure at its highest leading 486 C Cardiac Tamponade a b Eff Eff RV LV LV RV Eff Eff RA RA LA Eff LA Cardiac Tamponade. Figure 5 Right atrial collapse as a result of tamponade. In mid diastole, the RA is seen to be full (a). After end diastole the RA collapses – this has persisted into early systole (b). Note the free wall of the RV and the LA are not well visualized in b. Eff,Effusion; RA, Right Atrium; RV, Right Ventricle; LA, Left Atrium; LV, Left Ventricle to atrial collapse (Fig. 5). If this persists for more than one third of the cardiac cycle, it is highly specific and sensitive for tamponade. Brief collapse may occur for other reasons. RV collapse occurs in early diastole when the RV is still empty (Fig. 6). This is a less sensitive, but more specific finding for tamponade than RA collapse and may not occur when diastolic pressure is raised, there is raised RV afterload, or there is RV hypertrophy (since the RV becomes less compliant). Left sided collapse occurs less often. LV collapse occurs very rarely since the wall is more muscular. LA collapse when found is very specific for tamponade. ● Ventricular interdependence and septal shift As discussed earlier, changes in right sided filling with spontaneous inspiration result in the interventricular septum shifting into the LV (Fig. 7), the cause of pulsus paradoxus. Respiratory variation in trans-mitral and transtricuspid flow is also a result of the respiratory influence on filling and ventricular interdependence. During spontaneous inspiration (or IPPV expiration), rightsided filling increases and trans-tricuspid flow is increased relative to that during spontaneous expiration (or IPPV inspiration). The reverse is true for transmitral flow. Therefore the respiratory variation in flow across the atrio-ventricular valves is 180 out of phase (Fig. 8). The presence of pulmonary hypertension can mask some of the echocardiographic signs of tamponade. ● Venous hemodynamics A plethoric IVC is often seen due to the raised central venous pressure, which may also manifest a reduced reduction in IVC diameter (<50%) during spontaneous inspiration (Fig. 9) despite the transmission of intrathoracic pressure to the RA. Doppler patterns of atrial filling will also reflect the shift towards systolic filling and the loss of the diastolic component. CT/MRI [4] These should not be used in unstable patients, but may have a role in situations where the diagnosis is unclear and the patient is relatively stable (e.g., suspected regional tamponade). Pericardial effusion may also be an incidental finding on CT. Findings suggestive of tamponade include large sized effusions, systemic venous distension, chamber deformity and interventricular shift as seen on echocardiography. Cine MRI is also capable of Cardiac Tamponade C 487 C a b RV LV Eff RA RV Eff LV Eff RA LA Eff LA Cardiac Tamponade. Figure 6 RV collapse in diastole due to tamponade (a). Note that the RV end diastolic volume is also reduced (b), contributing to the low cardiac output state. Eff,Effusion; RA, Right Atrium; RV, Right Ventricle; LA, Left Atrium; LV, Left Ventricle a b Eff LV RV IVS RV IVS Eff RA LA RA LV Eff LA Eff Cardiac Tamponade. Figure 7 Interventricular septal shift seen in tamponade with spontaneous inspiration. Note both frames are taken at the same point of the electrocardiogram. In (a), during spontaneous expiration, a normal anatomical relationship exists. In (b), the patient has inhaled, resulting in increased filling of the right side and bowing of the interventricular septum into the left ventricle as the only way to accommodate the extra RV volume. Eff,Effusion; RA, Right Atrium; RV, Right Ventricle; LA, Left Atrium; LV, Left Ventricle 488 C Cardiac Tamponade Inspiration Inspiration Expiration a Expiration b Cardiac Tamponade. Figure 8 The effect of spontaneous ventilation on atrio-ventricular valve flow velocities in tamponade. Trans-tricuspid flow (a) increases during spontaneous inspiration due to the increased systemic venous return, and decreases during expiration. During inspiration, trans-mitral flow (b) is impaired due to reduced LA filling and increased LV pressure as a result of ventricular interdependence. The reverse is true during expiration Treatment Cardiac Tamponade. Figure 9 M-mode echocardiography of the inferior vena cava during tamponade, showing a plethoric IVC with very little respiratory variation in size demonstrating all findings seen by echocardiography. Underlying pericardial pathology is better assessed by CT than echocardiography. Invasive Pressure Measurement A pulmonary artery catheter will show equalization of diastolic pressure across cardiac chambers and the respiratory changes in right and left sided pressures responsible for pulsus paradoxus. It is also useful to monitor the effects of treatment – filling pressures that remain elevated after pericardiocentesis may indicate underlying pericardial pathology. Monitoring after pericardiocentesis can help in early detection of any reaccumulation of fluid and pressure changes indicating impending tamponade. This depends on the severity of the hemodynamic disturbance. Early tamponade with minimal hemodynamic disturbance and no significant loss in cardiac output may be treated conservatively, especially since the risks associated with pericardiocentesis are increased with small effusions. Treatment should be aimed at the underlying cause (e.g., steroids for autoimmune disease, correction of clotting etc.) and monitoring must be commensurate with the clinical picture. Invasive monitoring (including consideration of a pulmonary artery catheter) is indicated and these patients should be nursed in a high dependency setting. Serial assessment is needed to ascertain the likelihood of worsening tamponade and the patient watched carefully for evidence of end organ dysfunction due to any decrease in cardiac output (e.g., oliguria, altered mental state). In patients with idiopathic effusion alone, but no tamponade, opinion is divided as to treatment. Removal of fluid should only be undertaken for treatment of possible tamponade, and not for routine diagnosis. There is conflicting evidence as to the rate of progression to tamponade, but an effusion measuring greater than 20 mm on echocardiography should be considered for drainage. This may also reduce recurrence in the future. Patients with overt tamponade represent a clinical emergency and require definitive treatment by removal of the pericardial fluid. Intravenous fluids have been used as a temporizing measure, with best effects seen in patients with a systolic blood pressure of <100 mmHg. Hydration raises pericardial pressure as well as RA pressure and LV end diastolic pressure which may explain why Cardiac Tamponade some patients do not benefit. Positive inotropes with or without vasodilators are of limited efficacy, probably because of the maximal endogenous sympathetic drive seen in most cases. Pericardiocentesis and Pericardectomy [4] Pericardial fluid is usually removed either percutaneously or by surgical pericardectomy, although balloon pericardectomy has been described in neoplastic effusions. Echocardiography allows the optimum site for pericardiocentesis to be located (the shortest route to the pericardial fluid via an intercostal approach). Echocardiography also reduces the risk of myocardial puncture and allows visualization of fluid removal and consequent hemodynamic effects. Under full asepsis, a needle is advanced into the pericardial fluid. Agitated saline may be used to confirm needle position (easily seen on echocardiography). Up to 150 ml of fluid should be removed through the needle to ameliorate the worst of the tamponade (as discussed earlier, removal of only a small volume of pericardial fluid may have great benefit). A guidewire is fed through the needle and a pigtail catheter passed over this and secured in place. This procedure in the Mayo Clinic had a success rate of 97% with complication rates of 3.5% (minor) and 1.2% (major) respectively. Complications include perforation of myocardium or coronary vessels, arrhythmias, pneumothorax, air embolism, and abdominal trauma. Pericardiocentesis should be done in the cardiac catheter laboratory unless the patient is too unwell to be moved. Fluoroscopy may be used if echocardiography is unavailable, with the sub-xiphoid route being commonest, the needle being directed towards the left shoulder. Once pericardial fluid is aspirated, a small amount of contrast is injected to confirm position and the guidewire introduced. The guidewire position is checked in two planes and the pigtail catheter passed over it. In emergency situations (e.g., during a pulseless electrical activity arrest), a sub-xiphoid entry point is used and the needle directed toward the patient’s shoulder. Aortic dissection is a major contraindication to pericardiocentesis and coagulopathy a relative one. A surgical approach is preferred where there are loculated effusions, small effusions (<1 cm) or where there is evidence of clot or adhesions. Recurrent tamponade (especially due to neoplasm) is also often best managed surgically. Pericardectomy is usually performed via a sub-xiphoid approach under general anesthesia since a small window is usually sufficient to relieve tamponade (whereas removal of the entire pericardial sac via an anterior approach is used in constrictive pericarditis). C Balloon pericardectomy allows drainage from the pericardium into the pleural cavity. The risks of general anesthesia are increased in tamponade and even partial drainage by pericardiocentesis prior to induction may help to decrease risk. Pericardial fluid samples should be sent to the laboratory for staining and culture (including mycobacteria), plus differential white cell count, specific gravity, hematocrit and protein content if the diagnosis is not known beforehand. Adenosine deaminase levels should also be requested if tuberculous effusion is a possibility. After Care and Prognosis A pericardial drain usually stays in place until drainage is less than 25 ml/day. During this time, the patient should remain fully monitored for recurrence of tamponade or possible complications. Mortality and morbidity are very low since the advent of echocardiography guided procedures, with recent studies estimating the major complication rate to be between 1.2% and 1.6%. Patients with pre-existing pulmonary hypertension complicated by tamponade seem to be at higher risk of death. Comparison between Cardiac Tamponade and Constrictive Pericarditis [5] There are some important similarities and differences between constrictive pericarditis and cardiac tamponade. Constrictive pericarditis also results in increased intracardiac pressure and equalization of left and right filling pressures. The fibrotic, scarred pericardium prevents changes in intrathoracic pressure being transmitted to the cardiac chambers (unlike tamponade). These changes are still transmitted to the pulmonary circulation. On spontaneous inspiration, the gradient from pulmonary veins to left atrium is therefore reduced and left-sided filling is impaired. This allows an increase in right sided filling during spontaneous inspiration (the same ventricular interdependence which occurs in tamponade occurs in constrictive pericarditis). The opposite occurs with spontaneous expiration. Therefore, although the mechanism is different to tamponade, pulsus paradoxus can occur in constrictive pericarditis, so cannot reliably be used to distinguish between the two (although it is more common in tamponade). Changes in transmitral and transtricuspid flows are similar between the two. In constrictive pericarditis, atrial filling occurs primarily in diastole due to raised atrial pressures driving flow. This stops abruptly around mid-diastole when the noncompliant ventricle reaches its volume limit (due to pericardial constriction). This results in the so called “square 489 C 490 C Cardiac Troponin I root sign” – the right ventricular pressure trace shows an initial dip followed by an acute rise in early diastole and then a subsequent plateau during which no more filling occurs. This is not seen in tamponade. The JVP in constrictive pericarditis is raised (also in tamponade) but contains both an x descent and a prominent, collapsing y descent (unlike tamponade where the y descent is attenuated or may be missing). Since inspiratory pressures are not transmitted to the RA, the usual increase in right heart return does not occur and so systemic venous pressure increases (or at least does not drop) during spontaneous inspiration (Kussmaul sign). The Kussmaul sign does not occur in tamponade. Pericardial effusion leading to tamponade does occur in patients with pre-existing constrictive pericarditis (effusive constrictive pericarditis). Echocardiographic findings may initially be intermediate, but pericardiocentesis unmasks the typical findings associated with constrictive pericarditis. Cardiac Ultrasound ▶ Echocardiography Cardiogenic Pulmonary Edema ▶ Heart Failure, Acute ▶ Ventricular Dysfunction and Failure Cardiogenic Shock ▶ Acute Heart Failure: Risk Stratification ▶ Heart Failure, Acute ▶ Ventricular Dysfunction and Failure References 1. 2. 3. 4. 5. Spodick DH (2003) Acute cardiac tamponade. N Engl J Med 349:684–690 Zipes DP, Libby P, Bonow RO, Braunwald E (eds) (2005) Braunwald’s heart disease: a textbook of cardiovascular medicine, 7th edn. Elsevier Saunders, Philadelphia, pp 1762–1769 Wann S, Passen E (2008) Echocardiography in pericardial disease. J Am Soc Echocadiogr 21:7–13 Restrepo CS, Lemos DF, Lemos JA et al (2007) Imaging findings in cardiac tamponade with emphasis on CT. Radiographics 27:1595–1610 Maisch B, Seferovic PM, Ristic AD et al (2004) Guidelines on the diagnosis and management of pericardial diseases. executive summary. The task force on the diagnosis and management of pericardial diseases of the European society of cardiology. Eur Heart J 25:587–610 Cardiomyopathy in Children JONATHAN R. EGAN, MARINO S. FESTA The Children’s Hospital at Westmead, Westmead, Australia Definition A disease of the heart muscle in children is typically the result of inherited conditions (consider genetic and metabolic disorders) or viral myocarditis that has become indolent – characterized by cardiogenic failure. Characteristics Cardiac Troponin I ▶ Cardiac Markers for Diagnosing Acute Myocardial Infarction Cardiac Troponin T ▶ Cardiac Markers for Diagnosing Acute Myocardial Infarction It is useful to categorize pediatric cardiomyopathy into the following four groups, the majority of which present prior to 12 months of age [1]: Hypertrophic Cardiomyopathy (HCOM) Caused as a result of hypertrophic expansion either of the left ventricular septum alone or in combination with free wall hypertrophy. This disease leads to impingement on the left ventricle cavity, impaired ventricular filling, and variable left ventricular outflow obstruction. Most commonly, this is an inherited condition and there is a strong association with Noonan’s syndrome, it is characterized by shortness of breath or syncope on exertion. It is an important cause of sudden death in young people. Cardiopulmonary Resuscitation Dilated Cardiomyopathy (DCMP) Typically as the result of burnt out viral myocarditis (40%) or idiopathic in origin. There is reduced systolic performance and global cardiac dilatation. This has a poor prognosis and apart from supportive therapies will require heart transplant where feasible and appropriate. As a result of the dilatation and resulting arrhythmic propensity there is also a risk of mural thrombus formation. Selenium deficiency also results in a dilated cardiomyopathy. Restrictive Cardiomyopathy (RCMP) RCMP is not common and results from infiltrative conditions such as hemochromatosis, amyloidosis, and glycogen storage diseases. It is increasingly prevalent with increasing age and diastolic function is primarily compromised. Arrhythmogenic Right Ventricular Dysplasia and Left Ventricular Noncompaction Right ventricular dysplasia is an inherited condition in which the right ventricle is replaced by fibrous-fatty tissue. Patients typically present with arrhythmias in early adulthood. Left ventricular noncompaction is variably inherited and associated with systemic disorders. There are coarse trabeculations of the ventricular apex, which can affect both systolic and diastolic performance of the systemic ventricle. Management Patients with HCOM have restrictions on physical activity and typically receive beta blockade prophylaxis. Partial septal myomectomy can also be considered. Given the generally guarded prognosis of the cardiomyopathies it is important to determine any (rarely) reversible causes – in particular deficiencies of thiamine, selenium or carnitine, endocrinopathies (thyroid and growth hormone abnormalities as well as phaeochromocytoma) need to be considered. Anticoagulation should be considered and maintained in those with dilated cardiomyopathy. Subsequently, supportive medical and mechanical therapies maybe indicated together with heart transplant depending on the underlying cause and overall condition of the patient. Initial supportive measures are similar to those outlined in the cardiac failure section, but about half of pediatric heart transplants are for cardiomyopathies [6]. References 1. Nugent AW, Daubeney PE, Chondros P, Carlin JB, Cheung M, Wilkinson LC, Davis AM, Kahler SG, Chow CW, Wilkinson JL, Weintraub RG (2003) The epidemiology of childhood cardiomyopathy in Australia. N Engl J Med 348(17):1639–1646 C 491 Cardioparacentesis ▶ Periocardiocentesis C Cardiopulmonary Resuscitation RAGHU R. SEETHALA1, BENJAMIN S. ABELLA2 1 Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, MA, USA 2 Department of Emergency Medicine and Department of Medicine, Pulmonary, Allergy, and Critical Care Division, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Synonyms Basic life support (BLS); Chest compression (CC) Definition Cardiopulmonary resuscitation (CPR) is a method of providing artificial (externally-generated) circulation and ventilation during cardiac arrest to achieve the return of spontaneous circulation (ROSC). The main actions performed during CPR are delivery of chest compressions (CC) and rescue breaths. In a newer form of the therapy specifically for lay public providers (“hands-only” CPR), only CCs are delivered without the provision of rescue breaths. Role of CPR Indication Cardiac arrest (CA), defined as the abrupt cessation of cardiac output usually due to sudden arrhythmia, is an exquisitely time-sensitive condition common in intensive care environments. In-hospital CA has a survival to hospital discharge rate of approximately 20%. It is critical to perform CPR as promptly as possible in all patients suspected of suffering from CA that do not have advanced directives stating a preference to eschew resuscitation efforts. It can be difficult to determine if a patient is truly in CA. Generally speaking, international resuscitation guidelines put forth by the International Liaison Committee on Resuscitation (ILCOR) recommend that rescuers begin CPR in any victim who becomes suddenly unconscious with absent or markedly 492 C Cardiopulmonary Resuscitation abnormal (gasping) respirations [1]. This definition was primarily designed for recognition of out-of-hospital CA; for in-hospital skilled providers, CA can be identified by the lack of a palpable pulse and/or measurable blood pressure. It is important to remember that CPR does not represent definitive therapy, in that correction of the underlying cause of CA must be addressed to reverse the condition (see Table 1). Epidemiology Each year over one million people in Europe and North America are afflicted with CA. Survival rates vary greatly depending on initial cardiac rhythm, location of arrest (in-hospital versus out-of-hospital, for example), and a number of other factors. Including all initial rhythms, survival rates have been documented below 10% for outof-hospital CA, and approximately 20% for in-hospital CA. During out-of-hospital CA, bystander CPR has been shown to more than double the survival rate. Unfortunately, the prevalence of CPR performed by bystanders has been documented to be as low as 25% [2]. Cardiopulmonary Resuscitation. Table 1 Potential underlying causes of cardiac arrest Category Cardiac Specific etiology Myocardial ischemia Primary arrhythmia Secondary arrhythmia from myocardial scar Cardiac tamponade Pulmonary Hyperkalemia Acidemia Hypothermia Toxins CPR is designed to maintain coronary and cerebral perfusion as well as oxygenation during CA until definitive therapy, such as defibrillation or reversal of underlying CA pathophysiology, can be performed to achieve ROSC. The commonly used acronym ABC (airway, breathing, circulation) describes the main principles that are highlighted during CPR. It must be noted that the ensuing description most aptly applies to the general case of an out-of-hospital (non-intubated) patient. For patients already in intensivecare environments, the approach to CC remains the same although clearly airway and breathing approaches will vary. See Table 2 for summary of CPR delivery recommendations. Airway and Breathing Technique The initial step in evaluating the unresponsive patient is to establish an open airway. This can be accomplished by the head-tilt, chin-lift maneuver. If obstructing material (food, emesis) is visible in the oropharynx, then the rescuer may perform a finger sweep in an attempt to clear the airway. Additionally, if airway obstruction with a foreign body is suspected, then chest thrusts, back blows, or abdominal thrusts should be performed in order to relieve the obstruction. Once an open airway has been established, and the patient is still not breathing, rescue breaths should be given. Current resuscitation guidelines recommend administering two rescue breaths for every 30 CCs for adult victims of SCA [1]. Once advanced medical support is available, endotracheal intubation should be performed. Endotracheal intubation is considered the definitive airway management in CA patients. Pulmonary embolism Hypoxic respiratory failure Metabolic Application Carbon monoxide Cardiopulmonary Resuscitation. Table 2 Summary of CPR recommendations Characteristic Parameters Chest compressions (CCs) Rate of 100 per min Depth of 5+ cm Opioid toxicity Hemorrhage Gastrointestinal bleeding Other Complete recoil between CCs Cerebral hemorrhage Drowning Minimize interruptions in CCs Ventilations Volume of 400–800 cc for most adults Hanging Penetrating or blunt trauma Common etiologies of cardiac arrest are represented here; this list is not intended to be comprehensive. Readers are encouraged to consult with reference [1] for further information Rate of 8–10 per min Employ FiO2 of 1.0 Other Call for assistance from others Obtain defibrillator Cardiopulmonary Resuscitation C Once this has been established, then a ventilation rate of 8–10 per minute is recommended, and should be performed in parallel to ongoing CCs [1]. Traditionally, performing rescue breaths was considered as important a procedure as providing CCs. The purpose of ventilation during cardiac arrest is to provide oxygenation, decrease hypercapnia, and reduce acidosis. However, recent evidence has demonstrated the detrimental effects of hyperventilation and prolonged pauses in CCs while providing ventilation. Hyperventilation increases intrathoracic pressure, thereby causing decreased venous return to the heart. This ultimately results in decreased coronary and cerebral perfusion. Additionally, interruptions in CCs to provide ventilation (in the non-intubated patient) result in decreased blood flow to the heart and brain. decompression, the intrathoracic pressure falls, resulting in passive refilling of the heart [3]. It is likely that this latter model more accurately represents the action of CPR. Circulation Adjunct CPR Techniques and Devices The most important action during CPR is to provide high quality CCs, which generate blood flow and perfusion to the brain and heart. Indeed, a more recently explored form of resuscitation care for the lay public, “hands-only” CPR, consists solely of CC delivery without rescue breaths, until the arrival of trained health-care personnel. Despite evidence demonstrating that high-quality CPR positively impacts outcomes from SCA, studies have documented that overall CPR performance is poor, both during out-of-hospital and in-hospital CA. As a result, there have been a variety of adjunctive techniques and devices developed with this in mind. Technique Active Compression-Decompression CPR (ACD-CPR) The patient should be supine on a hard surface. If the patient is on a soft surface (e.g., a mattress), a backboard should be placed under the patient. The proper technique for performing CCs in adults is to place the heel of one hand in the center of the chest over the lower portion of the sternum, with the other hand on top of the first. The rescuer should keep the elbows straight and push firmly and quickly. The sternum should be compressed to a depth of 4 to 5 cm at a rate of 100 compressions per minute. After reaching maximum depth, the chest wall should be allowed to fully recoil before the next CC is delivered [1]. Physiology of CC Currently, two models of the mechanism of blood flow during CC exist. The “cardiac pump model” postulates that the heart is compressed between the sternum and vertebra generating an artificial systole with forward blood flow from the ventricles; then during the decompression phase, the heart passively fills [3]. The “thoracic pump model” argues that direct compression of the heart is not responsible for the forward blood flow. This model suggests that CCs cause an increase in intrathoracic pressure, which creates a pressure differential for blood to flow to the lower-pressure extrathoracic arteries. During CPR Quality CA outcomes are dependent on the quality of CPR. The key components of CPR quality are CC rate, CC depth, chest-wall recoil, ventilation rate, and CC pauses. Higher CC rates have been associated with higher rates of ROSC. Increased depth of CC has been associated with greater defibrillation success for ventricular tachycardia/ventricular fibrillation. In addition, decreased interruptions in CC have been linked to improved survival. Incomplete chestwall recoil increases intrathoracic pressure, thereby decreasing the preload of the heart and decreasing coronary and cerebral blood flow. In this method of resuscitation, CPR is performed with a suction cup compression device that is attached to the middle of the sternum. The purpose of this suction cup is to convert the passive decompression phase of CC into an active decompression phase. This in turn produces a greater negative intrathoracic pressure between compressions, which enhances venous return to the heart, subsequently increasing blood flow from the heart. Evidence supporting ACD-CPR has been conflicting. While some animal and human investigations have demonstrated that ACD-CPR is capable of producing higher perfusion pressures compared to standard CPR, most have shown no overall survival benefit [3]. Mechanical CPR Devices It has been well documented in the literature that CCs are not performed to a quality consistent with guideline recommendations, partly due to rescuer fatigue. This has led to the introduction of mechanical devices that are able to deliver CCs at a consistent rate and depth. Furthermore, these devices are able to liberate rescuers from the function of CC delivery so that they can perform other important resuscitation tasks. 493 C 494 C Cardiopulmonary Resuscitation Two types of these tools are the mechanical piston device and the load-distributing band (LDB) device. The mechanical piston device compresses the sternum via a plunger mounted on a backboard. This mechanical adjunct has been shown to improve perfusion parameters like mean arterial pressure and end-tidal CO2 in both in and out-of-hospital settings [4]. The LDB uses a load-distributing compression band that is placed circumferentially around the chest and attached to a small backboard. It compresses the entire anterior chest wall resulting in increased intrathoracic pressure at a specified rate. Use of this device has shown to improve mean aortic pressure as well as coronary perfusion pressure. In 2006, two studies were published comparing an LDB device with standard CPR that yielded conflicting results. One study showed an improvement in survival to discharge with the LDB compared to standard CPR. The other study showed no improvement in survival and actually reported a significant decrease in patients with good neurological outcome. One common criticism of all mechanical CPR devices is that using these devices may lead to a clinically significant delay in the initiation of CPR. Currently, evidence supporting the use of mechanical CPR devices in lieu of standard CPR remains inconclusive but suggestive of benefit. Impedance Threshold Device (ITD) The ITD is a valve that attaches between the endotracheal tube and resuscitation ventilation bag or mechanical ventilator. It limits the flow of air into the thoracic cavity during the decompression phase of CC. In doing so, intrathoracic pressure is reduced allowing for improved venous return to the heart. Studies have suggested that the use of an ITD improves early outcome in patients with out-of-hospital SCA. As of yet, no study has shown an improvement in the victim’s long-term outcome [4]. Monitoring and Feedback Devices In an effort to improve the quality of CPR, defibrillators have been developed with CPR-sensing capabilities and the ability to provide automated feedback. In this fashion, CPR parameters such as CC rate, depth and ventilation performance can be “coached” via an automated system. Such devices still require provider action to modify errors in CPR delivery. Recent investigations in both the inhospital and out-of-hospital setting have suggested that the use of CPR-sensing defibrillators can improve both CPR delivery and initial survival rates, although these devices have not been tested in randomized controlled trials at this time. CPR-sensing and recording defibrillators may also serve an important educational role, allowing for detailed debriefing after CA events where rescuers can be shown their individual CPR performance characteristics. Cardiocerebral Resuscitation (CCR) Recent evidence has shown that interruptions in CCs during CPR results in poor hemodynamic consequence and are associated with poor outcomes. These observations have led investigators to study an alternative strategy to resuscitation, known as cardiocerebral resuscitation or CCR. This resuscitation approach involves providing a greater number of uninterrupted CCs to optimize cardiac and cerebral perfusion. One such protocol was instituted by investigators in Arizona with promising results. This protocol entailed initially providing 200 uninterrupted CCs before defibrillating a shockable cardiac rhythm, followed by 200 uninterrupted CC post-defibrillation. Further minimization of interruptions in CCs was accomplished by delaying endotracheal intubation and positive pressure ventilation by initially providing passive oxygen insufflation via an oral pharyngeal airway and non-rebreather face mask. This study demonstrated a significant improvement in survival to discharge for OHCA from 1.8% before the CCR protocol to 5.4% after the protocol [5]. Continuous Chest Compression (CCC)-CPR or “Hands-Only” CPR Recently, there has been a parallel trend in bystander CPR questioning the necessity of ventilations early during CA-resuscitation care. Some resuscitation experts have even called for the abandonment of ventilations altogether in bystander CPR for out-of-hospital CA victims. One of the major arguments for CCC-CPR is that bystanders are more likely to perform CCC-CPR than standard CPR. Also, in CA from sudden arrhythmia early ventilations are unnecessary as blood is likely to be adequately oxygenated. In fact, ventilations require pauses in CCs which decrease coronary and cerebral perfusion. CCC-CPR is also easier to learn and teach. Several animal investigations have demonstrated improved hemodynamics and outcome comparing CCC-CPR to standard CPR. Several non-randomized clinical studies have shown that there is no difference in outcome when comparing CPR with rescue breathing to CCC-CPR. In fact, one study showed that CCC-CPR led to better neurological outcome in certain population subsets. The American Heart Association issued an advisory statement in 2008 that encouraged CCC-CPR in witnessed CA, when untrained bystanders or bystanders are not willing to perform rescue breathing [2]. Cardiorenal Syndrome Complications Complications from CPR can result from providing ventilation or CCs. Victims of CA may suffer tracheal or other airway injuries during intubation attempts. Inadvertent esophageal intubation may result in increased intragastric pressures leading to vomiting and aspiration. Rib fractures and sternal fractures are uncommon but recognized complications from receiving CCs. The incidence of these fracture complications is not known; recent work has suggested that they are both uncommon, and when they do occur, they are of small clinical consequence. References 1. 2. 3. 4. 5. 2005 international consensus on cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) science with treatment recommendations, part 2: adult basic life support. Circulation 112(suppl):III-5–III-16 Sayre MR, Berg RA, Cave DM, Page RL, Potts J, White RD (2008) Hands-only (compression-only) cardiopulmonary resuscitation: a call to action for bystander response to adults who experience out-of-hospital sudden cardiac arrest: a science advisory for the public from the American Heart Association Emergency Cardiovascular Care Committee. Circulation 117:2162–2167 Ornato JP, Peberdy MA (eds) (2005) Cardiopulmonary resuscitation. Humana Press Inc., Totowa, NJ 2005 international consensus on cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) science with treatment recommendations, part 6: CPR Techniques and Devices. Circulation 112(suppl):IV-47–IV-50 Bobrow BJ, Clark LL, Ewy GA et al (2008) Minimally interrupted cardiac resuscitation by emergency medical services for out-ofhospital cardiac arrest. J Am Med Assoc 299:1158–1165 Cardiopulmonary Resuscitation (CPR) Is a constellation of maneuvers provided by bystander(s) to a person who has lost spontaneous respiration and circulation. Described by the American Heart Association (AHA), it is designed to temporarily sustain life while awaiting definitive medical care and typically involves rhythmic external compression of the chest and rescue breathing (“mouth-to-mouth”). C Cardiorenal Syndrome CLAUDIO RONCO1, MIKKO HAAPIO2, NAGESH S. ANAVEKAR3, ANDREW A. HOUSE4, RINALDO BELLOMO5 1 Department of Nephrology, St. Bortolo Hospital, Vicenza, Italy 2 Division of Nephrology, HUCH Meilahti Hospital, Helsinki, Finland 3 Department of Cardiology, The Northern Hospital, Melbourne, Australia 4 Division of Nephrology, London Health Sciences Centre, London, Canada 5 Department of Intensive Care, Austin Hospital, Melbourne, Australia Synonyms Heart–kidney interaction Definition Although generally defined as a condition characterized by the initiation and/or progression of renal insufficiency secondary to heart failure, the term cardiorenal syndrome is also often used to describe the negative effects of reduced renal function on the heart and circulation (more appropriately named ▶ reno-cardiac syndrome) (Fig. 1, Tables 1 and 2) [1–4]. A major problem with the previous terminology is that it does not allow clinicians or investigators to identify and fully characterize the relevant pathophysiological interactions. This is important because such interactions differ according to the type of combined heart/kidney disorder. For example, while a diseased heart has numerous negative effects on kidney function, renal insufficiency can also significantly impair cardiac function. Thus, a large number of direct and indirect effects of each organ dysfunction can initiate and perpetuate the combined disorder of the two organs through a complex combination of neurohumoral feedback mechanisms. For this reason a subdivision into different subtypes seems to provide a more concise and logically correct approach to this condition. We will use such a subdivision to discuss several issues of importance in relation to this syndrome. Evaluation CardioQ ▶ Esophageal Doppler 495 Cardiorenal Syndrome Type I (Acute Cardiorenal Syndrome) Type I CRS or Acute Cardiorenal Syndrome (ACRS) is characterized by a rapid worsening of cardiac function, C 496 C Cardiorenal Syndrome Chronic Acute Cardiorenal Syndrome. Table 2 Proposed definition of cardiorenal syndromes Cardiorenal syndrome (CRS) general definition C-R A pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ. CRS type I (acute cardiorenal Abrupt worsening of cardiac syndrome) function (e.g., acute cardiogenic shock or decompensated congestive heart failure) leading to acute kidney injury. R-C Cardiorenal Syndrome. Figure 1 The bidirectional nature of the cardiorenal syndrome and the acute or chronic temporal characteristics of the syndrome CRS type II (chronic cardiorenal syndrome) Chronic abnormalities in cardiac function (e.g., chronic congestive heart failure) causing progressive and permanent chronic kidney disease. CRS type III (acute reno-cardiac syndrome) Abrupt worsening of renal function (e.g., acute kidney ischemia or glomerulonephritis) causing acute cardiac disorder (e.g., heart failure, arrhythmia, ischemia). CRS type IV (chronic reno-cardiac syndrome) Chronic kidney disease (e.g., chronic glomerular disease) contributing to decreased cardiac function, cardiac hypertrophy, and/or increased risk of adverse cardiovascular events. CRS type V (secondary cardiorenal syndrome) Systemic condition (e.g., diabetes mellitus, sepsis) causing both cardiac and renal dysfunction. Cardiorenal Syndrome. Table 1 Heart and kidney interactions ● CKD secondary to HF ● AKI secondary to contrast induced nephropathy (CIN) ● AKI secondary to cardiopulmonary bypass (CPB) ● AKI secondary to heart valve replacement ● AKI secondary to HF ● Cardiovascular mortality increased by end stage kidney disease (ESKD) ● Cardiovascular risk increased by kidney dysfunction ● Chronic HF progression due to kidney dysfunction ● Uremia-related HF ● Volume-related HF ● HF due to acute kidney dysfunction ● Volume/uremia-induced HF ● Renal ischemia-induced HF ● Sepsis/cytokine induced HF which leads to acute kidney injury (Fig. 2). Acute heart failure may then be divided into four main subtypes (hypertensive pulmonary edema with preserved LV systolic function, acute decompensated chronic heart failure, cardiogenic shock, and predominant right ventricular failure). Type I cardiorenal syndrome (CRS) is common. More than one million patients in the USA alone are admitted to hospital every year with either de novo acute heart failure (AHF) or with an acute decompensation of chronic heart failure (ADCHF) [2]. Among patients with ADCHF or de novo acute heart failure (AHF), premorbid chronic renal dysfunction is common and predisposes to acute kidney injury (AKI). The mechanisms by which the onset to AHF or ADCHF leads to AKI are multiple and complex. They are broadly described in previous Cardiorenal Syndrome C 497 Cardiorenal Syndrome: Type I Hemodynamically mediated damage C Exogenous factors drugs Acute heart dysfunction Humorally mediated damage Acute kidney injury Hormonal factors Immuno-mediated damage Cardiorenal Syndrome. Figure 2 Diagram illustrating and summarizing the major pathophysiological interactions between heart and kidney in type I cardiorenal syndrome publication [1]. The clinical importance of each of these mechanisms is likely to vary from patient to patient (e.g., acute cardiogenic shock vs. hypertensive pulmonary edema) and situation to situation (AHF secondary to perforation of a mitral valve leaflet from acute bacterial endocarditis vs. worsening right heart failure secondary to noncompliance with diuretic therapy). In AHF, AKI seems to be more severe in patients with impaired left ventricular ejection fraction (LVEF) compared to those with preserved LVEF and increasingly worse when LVEF is further impaired. AKI achieves an incidence >70% in patients with cardiogenic shock. Furthermore, impaired renal function is consistently found as an independent risk factor for 1-year mortality in AHF patients with ST-elevation myocardial infarction. A plausible reason for this independent effect might be that an acute decline in renal function does not simply act as a marker of illness severity but also carries an associated acceleration in cardiovascular pathobiology leading to a higher rate of cardiovascular (CV) events, both acutely and chronically, possibly through the activation of inflammatory pathways. Cardiorenal Syndrome Type II (Chronic Cardiorenal Syndrome) Type II CRS or chronic Cardiorenal syndrome (CCRS) is characterized by chronic abnormalities in cardiac function (e.g., chronic congestive heart failure) causing progressive chronic kidney insufficiency (Fig. 3). Worsening renal function (WRF) in the context of heart failure (HF) is associated with significantly increased adverse outcomes and prolonged hospitalizations. The prevalence of renal dysfunction in chronic heart failure (CHF) has been reported to be approximately 25%. Even limited decreases in estimated GFR of >9 ml/min appears to confer a significantly increased mortality risk. Some researchers have considered WRF a marker of severity of generalized vascular disease. Independent predictors of WRF include: old age, hypertension, diabetes mellitus, and acute coronary syndromes. The mechanisms underlying WRF likely differ based on acute versus chronic HF. Chronic HF is characterized by a relatively stable long-term situation of probably reduced renal perfusion, often predisposed by both micro- and macrovascular disease in the context of the same vascular risk factors associated with cardiovascular disease. However, although a greater proportion of patients with low estimated GFR have a worse NYHA class, no evidence of association between LVEF and estimated GFR can be consistently demonstrated. Thus, patients with chronic heart failure and preserved LVEF appear to have similar estimated GFR than patients with impaired LVEF (<45%). Neurohormonal abnormalities are present with excessive production of vasoconstrictive 498 C Cardiorenal Syndrome Cardiorenal Syndrome: Type II Low cardiac output (CO) Chronic hypoperfusion Necrosis-apoptosis Chronic heart disease Low cardiac output (CO) Subclinical inflammation Endothelial dysfunction Accelerated atherosclerosis Chronic hypoperfusion Increased renal vasc. resist. Increased venous pressure Chronic kidney disease Sclerosis-fibrosis Cardiorenal Syndrome. Figure 3 Diagram illustrating and summarizing the major pathophysiological interactions between heart and kidney in type II cardiorenal syndrome mediators (epinephrine, angiotensin, endothelin) and altered sensitivity and/or release of endogenous vasodilatory factors (natriuretic peptides, nitric oxide). Cardiorenal Syndrome Type III (Acute Reno-Cardiac Syndrome) Type III CRS or acute reno-cardiac syndrome (ARCS) is characterized by an abrupt and primary worsening of renal function (e.g., acute kidney injury, ischemia, or glomerulonephritis), which then causes or contributes to acute cardiac dysfunction (e.g., heart failure, arrhythmia, ischemia). The pathophysiological aspects are summarized in Fig. 4. The development of AKI as a primary event leading to cardiac dysfunction (Type III CRS) is considered less common than type I CRS. This is partly because, unlike Type I CRS, it has not been systematically considered or studied. However, AKI is a condition with a growing incidence in hospital and ICU patients. Using the recent RIFLE consensus definitions and its Injury and Failure categories, AKI has been identified in close to 9% of hospital patients and, in a large ICU database, AKI was observed in more than 35% of critically ill patients. AKI can affect the heart through several pathways whose hierarchy is not yet established. Fluid overload can contribute to the development of pulmonary edema. Hyperkalemia can contribute to arrhythmias and may cause cardiac arrest. Untreated uremia affects myocardial contractility through the accumulation of myocardial depressant factors and can cause pericarditis. Partially corrected or uncorrected acidemia produces pulmonary vasoconstriction, which, in some patients, can significantly contribute to right-sided heart failure. Acidemia appears to have a negative inotropic effect and may, together with electrolyte imbalances, contribute to an increased risk of arrhythmias. Finally, as discussed above, renal ischemia itself may precipitate activation of inflammation and apoptosis at cardiac level. Cardiorenal Syndrome Type IV (Chronic Reno-Cardiac Syndrome) Type IV CRS or chronic reno-cardiac syndrome (CRCS) is characterized by primary chronic kidney disease (CKD) (e.g., diabetes or chronic glomerular disease) contributing to decreased cardiac function, ventricular hypertrophy, diastolic dysfunction, and/or increased risk of adverse cardiovascular events (Fig. 5). The National Kidney Cardiorenal Syndrome C 499 Cardiorenal Syndrome: Type III Volume expansion C Drop of GFR Acute kidney injury Sympathetic activation Acute heart dysfunction RAA activation, vasoconstriction Electrolyte, acid-base and coagulation imbalances Humoral signalling Cardiorenal Syndrome. Figure 4 Diagram illustrating and summarizing major pathophysiological interactions between heart and kidney in type III cardiorenal syndrome Cardiorenal Syndrome: Type IV Chronic kidney disease Glomerular/interstitial damage Acquired risk factors Primary nephropathy Anemia Uremic toxins Ca/Pi abnormalities Nutritional status, BMI Na–H2O overload Chronic inflammation Sclerosis-fibrosis Dialysis Chronic heart disease Anemia and malnutrition Ca/Pi abnormalities Na–H2O overload Unfriendly milieu Inflammation Cardiorenal Syndrome. Figure 5 Diagram illustrating and summarizing the major pathophysiological interactions between heart and kidney in type IV cardiorenal syndrome 500 C Cardiorenal Syndrome Foundation divides CKD into five stages based on a combination of severity of kidney damage and GFR. Individuals with CKD, particularly those receiving renal replacement therapies are at extremely high cardiovascular risk. Greater than 50% of deaths in CKD stage V cohorts are attributed to CV disease, namely, coronary artery disease (CAD) and its associated complications. The 2-year mortality rate following myocardial infarction (MI) in patients with CKD stage V is high and estimated to be 50%. In comparison, the 10-year mortality rate post MI for the general population is 25%. Type IV cardiorenal syndrome is becoming a major public health problem. A large population of individuals entering the transition phase towards end stage kidney disease (ESKD) is emerging. National Kidney Foundation guidelines define these individuals as having CKD. CKD, which also encompasses ESKD, is defined as persistent kidney damage (confirmed by renal biopsy or markers of kidney damage) and/or glomerular filtration rate (GFR)<60 ml/min/1.73 m2 over 3 months. This translates into a serum creatinine level of 1.3 mg/dl, which would ordinarily be dismissed as not being representative of significant renal dysfunction. Using these criteria, current estimates of CKD account for at least 11 million individuals and rising. The association between increased CV risk and renal dysfunction originally stemmed from data arising from ESKD or stage V CKD cohorts. The leading cause of death (>40%) in such patients is cardiovascular event-related. This observation is supported by Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), United States Renal Data System (USRDS), and the Wave 2 Dialysis Morbidity and Mortality Study. Based on these findings, it is now well established that CKD is a significant risk factor for cardiovascular disease, such that individuals with evidence of CKD have from 10- to 20-fold increased risk for cardiac death compared to ageand sex-matched controls without CKD. As discussed, part of this problem may be related to the fact that such individuals are also less likely to receive risk modifying interventions compared to their non-CKD counterparts. Less severe forms of CKD also appear to be associated with significant cardiovascular risk. Evidence for increasing CV morbidity and mortality tracking with mild to moderate renal dysfunction, has mainly stemmed from communitybased studies [5]. All these studies documented an inverse relationship between renal function and adverse cardiovascular outcomes. In particular, the association between reduced renal function and CV risk appears to consistently occur at estimated GFR levels below 60 ml/min/1.73 m2, the principal GFR criterion used to define CKD. Among high CV risk cohorts, baseline creatinine clearance is a significant and independent predictor of short-term outcomes (180 days follow-up), namely, death and myocardial infarction. Similar findings were also noted among patients presenting with ST-elevation myocardial infarction, an effect independent of the Thrombolysis in Myocardial Infarction (TIMI) risk score. Other large-scale studies that have examined the relationship between renal function and cardiovascular outcomes among high CV risk cohorts with left ventricular dysfunction have included the Studies of Left Ventricular Dysfunction (SOLVD), Trandolapril Cardiac Evaluation (TRACE), Survival and Ventricular Enlargement (SAVE), and Valsartan in Acute Myocardial Infarction (VALIANT) trials. These studies excluded individuals with baseline serum creatinine of 2.5 mg/dl. In all these studies, reduced renal function was associated with significantly higher mortality and adverse CV event rates. Renal insufficiency is highly prevalent among patients with heart failure and is an independent prognostic factor in both diastolic and systolic ventricular dysfunction. It is an established negative prognostic indicator in patients with severe heart failure. Cardiorenal Syndrome Type V (Secondary Cardiorenal Syndrome) Type V CRS or secondary cardiorenal syndrome (SCRS) is characterized by the presence of combined cardiac and renal dysfunction due to systemic disorders (Fig. 6). There is limited systematic information on type V CRS, where both kidneys and heart are affected by other systemic processes. Although there is an appreciation that, as more organs fail, mortality increases in critical illness, there is limited insight into how combined renal and cardiovascular failure may differently affect such an outcome compared to, for example, combined pulmonary and renal failure. Nonetheless, it is clear that several acute and chronic diseases can affect both organs simultaneously and that the disease induced in one can affect the other and vice versa. Several chronic conditions such as diabetes and hypertension are discussed as part of type II and type IV CRS. In the acute setting, severe sepsis represents the most common and serious condition, which can affect both organs. It can induce AKI while leading to profound myocardial depression. The mechanisms responsible for such changes are poorly understood but may involve the effect of tumor necrosis factor on both organs. The onset of myocardial functional depression and a state of inadequate cardiac output can further decrease renal function as discussed in type I CRS and the development of AKI can affect cardiac function as described in type III CRS. Renal Cardiorenal Syndrome C 501 Cardiorenal Syndrome: Type V Neurohumoral activation C Hemodynamic changes Systemic diseases Altered metabolism Exogenous toxins drugs Combined heart-kidney dysfunction Immunological response Cardiorenal Syndrome. Figure 6 Diagram illustrating and summarizing the major pathophysiological interactions between heart and kidney in type V cardiorenal syndrome ischemia may then induce further myocardial injury in a vicious cycle, which is injurious to both organs. Treatment Cardiorenal Syndrome Type I The salient clinical issues of type I CRS relate to how the onset of AKI (de novo or in the setting of chronic renal impairment) induced by primary cardiac dysfunction impacts on diagnosis, therapy, and prognosis and how its presence can modify the general approach to the treatment of AHF or ADCHF. The first important clinical principle is that the onset of AKI in the setting of AHF or ADCHF implies inadequate renal perfusion until proven otherwise. This should prompt clinicians to consider the diagnosis of a low cardiac output state and/or marked increase in venous pressure leading to kidney congestion and take the necessary diagnostic steps to either confirm or exclude them (careful physical examination looking for ancillary signs and laboratory findings of a low cardiac output state such as absolute or relative hypotension, cold extremities, poor post compressive capillary refill, confusion, persistent oliguria, distended jugular veins, and elevated or rising lactate). The second important consequence of the development of type I CRS is that it may decrease diuretic responsiveness. In a congestive state (peripheral edema, increased body weight, pulmonary edema, elevated central venous pressure), decreased response to diuretics can lead to failure to achieve the desired clinical goals. The physiological phenomena of diuretic breaking (diminished diuretic effectiveness secondary to post-diuretic sodium retention) and post-diuretic sodium retention may also play an enhanced part in this setting. In addition, concerns of aggravating AKI by the administration of diuretics at higher doses or in combination are common among clinicians. Such concerns can also act as an additional, iatrogenic mechanism equivalent in its effect to that of diuretic resistance (less sodium removal). Accordingly, diuretics may best be given in AHF patients with evidence of systemic fluid overload with the goal of achieving a gradual diuresis. Furosemide can be titrated according to renal function, systolic blood pressure, and history of chronic diuretic use. High doses are not recommended and a continuous diuretic infusion might be helpful. In parallel, measurement of cardiac output and venous pressure may also help ensure continued and targeted diuretic therapy. Accurate estimation of cardiac output can now be easily achieved by means of arterial pressure monitoring combined with pulse contour analysis or by Doppler ultrasound. Knowledge of cardiac output allows physicians to develop a physiologically safer and more logical approach to the simultaneous treatment of AHF or ADCHF and AKI. If diuretic-resistant fluid overload exists despite an optimized cardiac output, removal of isotonic fluid can be achieved by ultrafiltration (Fig. 7). This approach can be efficacious and clinically beneficial. The presence of AKI with or without concomitant hyperkalemia may also affect patient outcome by 502 C Cardiorenal Syndrome Extracorporeal Ultrafiltration Pre-filter pressure Filter Transmembrane pressure Post-filter pressure Pre-pump pressure TMP = Pi - π = (Pb - Pd) - π Pb π Pd Ultrafiltrate Hydrostatic Oncotic Heparin Ven. line Blood pump Art. line Cardiorenal Syndrome. Figure 7 Diagram presenting the technical features of ultrafiltration as applicable to patients with acute heart failure and diuretic-resistant fluid overload inhibiting the prescription of ACE inhibitors and aldosterone inhibitors (drugs that have been shown in large randomized controlled trials to increase survival in the setting of heart failure and myocardial infarction). This is unfortunate because, provided there is close monitoring of renal function and potassium levels, the potential benefits of these interventions likely outweigh their risks even in these patients. The acute administration of beta-blockers in the setting of type I CRS is generally not advised. Such therapy should wait until the patient has stabilized physiologically and concerns about a low cardiac output syndrome have been resolved. In some patients, stroke volume cannot be increased and relative or absolute tachycardia sustains the adequacy of cardiac output. Blockade of such compensatory tachycardia and sympathetic system-dependent inotropic compensation can precipitate cardiogenic shock and can be lethal. Particular concern applies to beta-blockers excreted by the kidney such as atenolol or sotalol, especially if combined with calcium antagonists. These considerations should not inhibit the slow, careful, and titrated introduction of appropriate treatment with beta-blockers later on, once patients are hemodynamically stable. This aspect of treatment is particularly relevant in patients with the cardiorenal syndrome where evidence suggests that undertreatment after myocardial infarction is common. Attention should be paid to preserving renal function, perhaps as much attention as is paid to preserving myocardial muscle. Worsening renal function during admission for ST-elevation myocardial infarction is a powerful and independent predictor of in-hospital and 1-year mortality. In a study involving 1,826 patients who received percutaneous coronary intervention, even a transient rise in serum creatinine (>25% compared to baseline) was associated with increased hospital stay and mortality. Similar findings have also been shown among coronary artery bypass graft cohorts. In this context, creatinine rise is not simply a marker of illness severity but it rather represents a causative factor for cardiovascular injury acceleration through the activation of hormonal, immunological, and inflammatory pathways. Given that the presence of type I CRS defines a population with high mortality, a prompt, careful, systematic, multidisciplinary approach involving invasive cardiologists, nephrologists, critical care physicians, and cardiac surgeons is both logical and desirable. Cardiorenal Syndrome Type II Pharmacotherapies used in the management of HF have been touted as contributing to WRF. Diuresis-associated hypovolemia, early introduction of renin-angiotensin-aldosterone system blockade, and drug-induced Cardiorenal Syndrome hypotension, have all been suggested as contributing factors. However, their role remains highly speculative. More recently, there has been increasing interest in the pathogenetic role of relative or absolute erythropoietin (EPO) deficiency contributing to a more pronounced anemia in these patients than might be expected for renal failure alone. EPO receptor activation in the heart may be protective from apoptosis, fibrosis, and inflammation. In keeping with such experimental data, preliminary clinical studies show that EPO administration in patients with chronic heart failure, chronic renal insufficiency, and anemia leads to improved cardiac function, reduction in left ventricular size, and lowering of B-type natriuretic peptide. Patients with type 2 CRS are more likely to receive loop diuretics and vasodilators and also to receive higher doses of such drugs compared to those with stable renal function. Treatment with these drugs may participate in the development of renal injury. However, such therapies may simply identify patients with severe hemodynamic compromise and thus a predisposition to renal dysfunction rather than being responsible for worsening renal dysfunction. Regardless of the cause, reductions in renal function in the context of heart failure are associated with increased risk for adverse outcomes. Cardiorenal Syndrome Type III The development of AKI, especially in the setting of chronic renal failure can affect the use of medications that normally would maintain clinical stability in patients with chronic heart failure. For example, an increase in serum creatinine from 1.5 mg/dl (130 mmol/l) to 2 mg/dl (177 mmol/l), with diuretic therapy and ACE inhibitors, may provoke some clinicians to decrease or even stop diuretic prescription; they may also decrease or even temporarily stop ACE inhibitors. In some, maybe many cases, this may not help the patient. An acute decompensation of CHF may occur because of such changes in medications. When this happens the patient may be unnecessarily exposed to an increased risk of acute pulmonary edema or other serious complications of undertreatment. Finally, if AKI is severe and renal replacement therapy is necessary, cardiovascular instability generated by rapid fluid and electrolyte shifts secondary to conventional dialysis can induce hypotension, arrhythmias, and myocardial ischemia. Continuous techniques of renal replacement, which minimize such cardiovascular instability, appear physiologically safer and more logical in this setting. Cardiorenal Syndrome Type IV The logical practical implications of the plethora of data linking CKD with CV disease is that more attention needs C to be paid to reducing risk factors and optimizing medications in these patients, and that undertreatment due to concerns about pharmacodynamics in this setting may have lethal consequences at individual level and huge potential adverse consequences at public health level. Nonetheless, it is also equally important to acknowledge that clinicians looking after these patients are often faced with competing therapeutic choices and that, with the exception of MERIT-HF, large randomized controlled trials that have shaped the treatment of chronic heart failure in the last two decades have consistently excluded patients with significant renal disease. Such lack of CKD population-specific treatment effect data makes therapeutic choices particularly challenging. In particular, in patients with advanced CKD, the initiation or increased dosage of ACE inhibitors can precipitate clinically significant worsening of renal function or marked hyperkalemia. The latter may be dangerously exacerbated by the use of aldosterone antagonists. Such patients, if aggressively treated, become exposed to a significant risk of developing dialysis dependence or life-threatening hyperkalemic arrhythmias. If too cautiously treated they may develop equally lifethreatening cardiovascular complications. In these patients, the judicious use of all options while taking into account patient preferences, social circumstances, other comorbidities, and applying a multidisciplinary approach to care seems to be the best approach. Cardiorenal Syndrome Type V Treatment is directed at the prompt identification, eradication, and management of the source of infection while supporting organ function with invasively guided fluid resuscitation and inotropic and vasopressor drug support. In this setting, all the principles discussed for type I and type III CRS apply. In these septic patients, preliminary data using more intensive renal replacement technology suggest that blood purification may have a role in improving myocardial performance while providing optimal small solute clearance. Despite the emergence of consensus definitions and many studies, no therapies have yet emerged to prevent or attenuate AKI in critically ill patients. On the other hand, clear evidence of the injurious effects of pentastarch fluid resuscitation in septic AKI has recently emerged. Such therapy should, therefore, be avoided in septic patients. After-care The proportion of individuals with CKD receiving appropriate risk factor modification and/or interventional strategies is lower than in the general population, a concept termed “therapeutic nihilism.” Many databases and 503 C 504 C Carukia barnesi registries have repeatedly shown that these therapeutic choices seem to parallel worsening renal function. In patients with CKD stage V, who are known to be at extreme risk, less than 50% are on the combination of aspirin, b blocker, ACE inhibitors, and statins. In a cohort involving over 140,000 patients, 1,025 with documented ESKD were less likely to receive aspirin, b blockade, or ACE inhibition post MI. Yet those ESKD patients who did receive the aspirin, b blocker, and ACE inhibitor combination had similar risk reductions in 30-day mortality when compared to non-ESKD patients who had received conventional therapy. This failure to treat is not just limited to ESKD patients. Patients with less severe forms of CKD are also less likely to receive risk modifying medications following myocardial infarction compared to their normal renal function counterparts. Potential reasons for this therapeutic failure include concerns about worsening existing renal function, and/or therapy-related toxic effects due to low clearance rates. Bleeding concerns with the use of platelet inhibitors and anticoagulants are especially important with reduced renal function and appear to contribute to the decreased likelihood of patients with severe CKD receiving aspirin and/or clopidrogrel despite the fact that such bleeding is typically minor and the benefits sustained in these patients. However, several studies have shown that when appropriately titrated and monitored, cardiovascular medications used in the general population can be safely administered to those with renal impairment and with similar benefits. Newer approaches to the treatment of cardiac failure such as cardiac resynchronization therapy (CRT) have not yet been studied in terms of their renal functional effects, although preserved renal function after CRT may predict a more favorable outcome. Vasopressin V2-receptor blockers have been reported to decrease body weight and edema in patients with chronic heart failure, but their effects in patients with the cardiorenal syndrome have not been systematically studied and a recent large randomized controlled trial showed no evidence of a survival benefit with these agents. Prognosis Considering that the presence of any type CRS defines a population with high mortality, a multidisciplinary approach involving cardiologists, nephrologists, critical care physicians, and cardiac surgeons is recommended. In both chronic and acute situations, an appreciation of the interaction between heart and kidney during dysfunction of each or both organs has practical clinical implications. The depth of knowledge and complexity of care necessary to offer best therapy to these patients demands a multidisciplinary approach. In addition, by using an agreed definition of each type of cardiorenal syndrome, physicians can describe treatments and interventions, which are focused and pathophysiologically logical. They can also conduct and compare epidemiological studies in different countries and more easily identify aspects of each syndrome, which carry a priority for improvement and further research. Randomized controlled trials can then be designed to target interventions aimed at decreasing morbidity and mortality in these increasingly common conditions. Increasing awareness, ability to identify and define, and physiological understanding will help improve the outcome of these complex patients. Acknowledgments We thank Drs. Alexandre Mebazaa, Alan Cass, and Martin Gallagher for their useful advice in the development of this manuscript. References 1. 2. 3. 4. 5. Ronco C (2008) Cardiorenal and reno-cardiac syndromes: clinical disorders in search of a systematic definition. Int J Artif Organs 31:1–2 Liang KV, Williams AW, Greene EL, Redfield MM (2008) Acute decompensated heart failure and the cardio-renal syndrome. Crit Care Med 36(Suppl):S75–S88 Ronco C, House AA, Haapio M (2008) Cardio-renal syndrome: refining the definition of a complex symbiosis gone wrong. Intensive Care Med 34(5):957–962 Ronco C, Haapio M, House AA, Anavekar N, Bellomo R (2008) Cardiorenal syndrome. J Am Coll Cardiol 52(19):1527–1539 Go AS, Chertow GM, Fan D et al (2004) Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351:1296–1305 Carukia barnesi ▶ Jellyfish Envenomation Carybdeid Jellyfish ▶ Jellyfish Envenomation Catabolism ▶ Metabolic Disorders, Other Catheter-Associated Urinary Tract Infection Catheter and Line/Tubing/ Administration Sets Change ▶ Change Catheter Port Allocation ▶ Port Designation Catheter-Associated Bloodstream Infection ▶ Catheter-Related Bloodstream Infection Catheter-Associated Urinary Tract Infection ANDREW M. MORRIS Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, ON, Canada Synonyms Foley-catheter infection; Pyelonephritis; Urinary catheter sepsis; Urosepsis Definition Catheter-associated urinary tract infection (CAUTI) is generally defined in the medical literature as bacteriuria or funguria (of at least 103 cfu/mL) in association with a urinary catheter. The definition has remained problematic, as it ignores a central tenet in the management of infections: differentiating colonization from infection. In patients without urinary catheters, pyuria is strongly associated with urinary tract infection, but some have contested using such a criterion for CAUTI. A preferred definition would be the symptoms and signs of urinary tract infection accompanied by pyuria and greater than 103 cfu/mL microorganisms in association with an urinary catheter. Epidemiology The epidemiology of CAUTI is poorly understood, owing to the problematic definition used in the literature, but C CAUTI appears to affect approximately 9% of all patients in the ICU, with a rate of 12.0 per 1,000 catheter-days. Risk factors include female sex, duration of catheterization, and duration of ICU stay. Outside of the ICU, failure to use a closed collection system has also been associated with CAUTI. Antibiotic use appears protective, but this may be because of confounding. Gram-negative bacilli and enterococci are the most common isolates, although candida species are frequently isolated in patients with prolonged ICU stay (usually in patients receiving prolonged and/or repeated courses of broad-spectrum antimicrobials). Prevention Avoiding urinary catheters and removing them when unnecessary are the best means of preventing CAUTI. Condom catheters for men have been shown to reduce CAUTI with acceptable tolerability; in-and-out catheterization is also well tolerated. Nevertheless, neither of these methods has been widely adopted in ICUs to prevent CAUTI. Use of antimicrobial catheters may reduce bacteriuria, but have not been shown to prevent CAUTI or other meaningful outcomes [1]. Treatment There are few randomized trials evaluating management of CAUTI. A small trial of catheter-associated bacteriuria in women (not in the ICU) demonstrated that asymptomatic bacteriuria frequently progressed to symptomatic CAUTI that single-dose antibiotic treatment was equivalent to a 10-day course of therapy. Another recent trial compared short-course (3 days) antibiotics and catheter change with standard care (i.e., no change, no antibiotics) for patients with asymptomatic catheter-associated bacteriuria and found no difference in meaningful outcomes, including development of pyelonephritis. Similarly, treatment of candiduria with fluconazole in immunocompetent patients temporarily eradicated the candidura, but failed to offer any long-term benefit. Evaluation As mentioned above, evaluation is problematic. At present, routine urinalyses cannot be advocated. In catheterized patients, pyuria (greater than 10 white blood cells/mL) is specific but insensitive for the presence of bacteriuria. Because it is unclear if treatment of asymptomatic patients with bacteriuria is warranted, routine cultures are also not warranted. Investigation of fever of unknown origin should include, however, urinalysis and urine culture. 505 C 506 C Catheter-Related Bloodstream Infection Prognosis When adjusted for confounding factors, CAUTI does not appear to be associated with increased mortality in critically ill patients. Economics The attributable patient cost of CAUTI in the USA ranges from $862 to $1, 007, costing US hospitals $0.39 to $0.45 billion annually [2]. References 1. 2. Lo E, Nicolle L, Classen D, Arias KM, Podgorny K, Anderson DJ et al (2008 Oct) Strategies to prevent catheter-associated urinary tract infections in acute care hospitals. Infect Control Hosp Epidemiol 29(Suppl 1):S41–50 Scott II RD (2009) The direct medical costs of healthcare-associated infections in U.S. hospitals and the benefits of prevention. In: Department of Health and Human Services, Centers for Disease Control and Prevention, 2009 Catheter-Related Bloodstream Infection ANDREW M. MORRIS Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, ON, Canada Synonyms Catheter-associated bloodstream infection; Catheterrelated infection; Central line infection; Central venous catheter infection; Line sepsis; Vascular catheter infection Definition Catheter-related bloodstream infection (CRBI) is bacteraemia or fungaemia that originate from an intravascular catheter. For the purpose of this chapter, CRBI will be limited to catheters that are usually inserted and removed in intensive care units and will not include tunneled catheters or other long-term catheters. CRBI most commonly originates from the skin-insertion site, with microorganisms traveling along the course of the vascular catheter into the bloodstream. Less often, organisms contaminate the catheter hub and travel intraluminally. Some organisms, primarily coagulase-negative staphylococci, elaborate a protective multilayered biofilm matrix preventing immune system effectors and antimicrobials from reaching the organisms. Although localized infection may occur at the site of insertion (often termed “exit site infection”), such infections are easy to diagnose, do not generally cause systemic illness, and are beyond the scope of discussion here. The study of CRBI has been complicated by the lack of a definition that is both sensitive and specific. Fever and other clinical criteria are sensitive but nonspecific, whereas repeatedly positive blood cultures drawn from the periphery and vascular catheter with identical organisms in the presence of clinical signs of infection without other primary foci are specific but insensitive. For this reason, catheter-associated bloodstream infection is often measured, which identifies bacteraemia in the presence of a vascular catheter, but may not be caused by the catheter. Epidemiology The epidemiology of CRBI is not well known, although the reported rate of CRBI in the province of Ontario, Canada (population 13 million), is 1.4 per 1,000 catheter-days. The National Nosocomial Infection Surveillance system of the CDC estimates the rate to be 1.8–5.2 per 1,000 catheter-days. There are an estimated 92,011 cases of CRBI annually in the USA [1]. Coagulase-negative staphylococci are the most common organisms responsible for CRBI, followed by (in decreasing order) Staphylococcus aureus, Candida species, and gram-negative bacilli. Prevention The Centers for Disease Control recommend five procedures that are likely to have the greatest impact on reducing CRBI with the lowest barriers to implementation: hand washing, using full-barrier precautions during the insertion of central venous catheters, cleaning the skin with chlorhexidine, avoiding the femoral site if possible, and removing unnecessary catheters. Using these very same procedures resulted in dramatic reductions across 103 ICUs in Michigan, reducing median rates of CRBI from 2.7 per 1,000 catheter-days to zero [2]. Hand Washing The evidence supporting hand-washing in preventing CRBI is not strong but is it low-cost, theoretically appealing, and, when bundled with full-barrier precautions, is proven to be effective in reducing CRBI. Full-Barrier Precautions During Insertion Sterile gloves, long-sleeved sterile gown, mask, cap, and large sterile sheet drape during insertion have been shown to dramatically reduce CRBI. Cutaneous Antisepsis Although povidone–iodine remains the most widely used skin antiseptic in hospitals, there is strong evidence that Catheter-Related Bloodstream Infection chlorhexidine is superior to povidone–iodine. Tincture of iodine also appears to be superior to povidone–iodine, but is less well studied. Site of Insertion The femoral site is unequivocally inferior to the subclavian site vis à vis infection risk. However, preference between internal jugular and subclavian veins is less clear, with colonization being greater for internal jugular venous catheters compared with subclavian venous catheters, but there is no evidence showing lower rates of CRBI with the subclavian site. Routine Changing of Lines Although most teaching (including that of the CDC) states that routine changing of lines is not advised, it is based on little evidence. One study from 1981 looked at routine changing of haemodialysis catheters in 90 patients, and showed no difference between routine changes over a wire at 7 days rather than at a new site. Another study from 1990 compared no routine changes with routine changes over a wire and routine changes at a new puncture site, and showed no difference. Treatment Treatment of CRBI begins with removal of the vascular catheter when infection is suspected. In many cases, this proves curative, with fever abating and leukocytosis resolving without the need for antimicrobials. Clearly, however, this requires further study. Optimal treatment of documented CRBI requires (a) removal of the catheter (where feasible) and (b) antimicrobial therapy [3]. Catheter Removal Catheter removal for CRBI is always preferred; however, situations do occur when this is not feasible or desired. In such situations, an option includes antibiotic lock therapy, whereby an aliquot of antibiotic is left in the catheter hub and tubing continuously. This is only likely to be beneficial for patients whose CRBI is due to an intraluminal infection, and is not supported by high-quality trials. Some experts recommend retaining the vascular catheter for CRBI due to coagulase-negative staphylococci, but the recurrence risk is high. Antimicrobial Therapy Empiric Therapy Treatment, as with all nosocomial infections, should be based on the likely organism coupled with severity of illness. For many such infections, patients will be C haemodynamically stable, and treatment of the most likely pathogens (usually staphylococci) will suffice. In centers with a high prevalence of methicillin-resistant S. aureus, vancomycin is likely an appropriate empiric therapy. However, it may be reasonable to consider a methicillinlike penicillin (e.g., cloxacillin) or first-generation cephalosporin in stable patients. Pathogen-Specific Therapy Coagulase-negative staphylococci: Removal of the catheter is often sufficient, but many authorities recommend 5–7 days therapy, unless there is no other medical hardware in situ, the vascular catheter has been removed, the patient is haemodynamically stable, and repeated blood cultures are negative. No approach has been formally evaluated with randomized controlled trials. S. lugdunensis is a coagulasenegative staphylococcus that should be treated as S. aureus. S. aureus: Treatment should be based on susceptibilities. The most effective therapy for methicillin-susceptible S. aureus is a b-lactam. However, in cases of severe allergy or resistance, vancomycin is a preferred agent. Recently, concerns have been raised regarding the effectiveness and safety of vancomycin, especially with the emergence of strains that are either resistant to or have reduced susceptibility to vancomycin. However, a recent open-label noninferiority trial comparing linezolid with vancomycin for CRBI showed a trend favoring vancomycin in intentionto-treat analysis. Optimal duration of therapy for S. aureus CRBI is unclear. Although teaching for many years has maintained the axiom “treat for 2 weeks if a removal focus of infection, and it has been removed,” recent studies have questioned this wisdom with the recognition that (a) infective endocarditis may complicate up to 13% of catheter-associated bacteraemia and (b) infective endocarditis and other complications may be seen in approximately 6% of cases of S. aureus CRBI treated with 2 weeks therapy (compared with 4 weeks). I prefer 4 weeks of therapy unless a trans-esophageal echocardiogram is performed and is negative (making endocarditis highly unlikely), which is largely consistent with recent recommendations [3]. Enterococci: The optimal treatment of enterococci is ampicillin; if unable to use ampicillin because of resistance or allergy, then vancomycin is the preferred agent. Linezolid or daptomycin are options when ampicillin or vancomycin cannot be used, although there is limited experience with these agents. The duration of treatment for enterococcal bacteraemia is unclear, although 7–14 days is usually sufficient. The risk of subsequent infective endocarditis is quite low, estimated at around 1%. Gram-negative bacilli: The optimal treatment of Gram-negative bacilli (GNB) is dependent on local 507 C 508 C Catheter-Related Infection susceptibilities. Empiric choices prior to speciation should cover the majority of possibilities, and may include combination therapy (especially if the patient is neutropaenic, severely ill, or known to be colonized with multidrugresistant organisms). However, there is weak evidence supporting combination therapy once susceptibility is known, including therapy for non-lactose-fermenting agents such as Pseudomonas aeruginosa. The optimal duration of therapy is also unknown, although 7–14 days is usually sufficient. Candida species: Candidaemia is a frequent cause of CRBI in patients who have been receiving prolonged broadspectrum antibacterial agents, as well as patients receiving total parenteral nutrition, or who have received solid organ or stem cell transplantation. Empiric therapy should be based on local data, but may include amphotericin B, fluconazole, or an echinocandin. These appear to be equally efficacious, although azole resistance has been rising in centers with high azole use. For this reason, many have recommended echinocandin therapy to be first-line treatment. Candidaemia is generally treated with 2 weeks of effective therapy, with the first negative blood culture being considered day 1. Evaluation Diagnosis is primarily a microbiological one following clinical suspicion. Where possible, cultures should come from both peripheral blood and the catheter lumen prior to antimicrobial therapy. Catheter tip cultures (using a 5 cm segment and using either a roll-plate method or sonification) are also advised; however, positive tip cultures reflect colonization, not CRBI. CRBI can be confidently diagnosed when: (a) Peripheral and catheter-drawn blood cultures are positive with the same isolate, and the catheter-drawn culture grew more quickly (i.e., with a differential time-to-positivity, or DTP, of at least 2 h) (b) A catheter-drawn blood culture and a catheter-tip culture are positive with the same isolate (c) Both peripheral and catheter-drawn blood cultures are positive, but the colony-count is threefold higher in the culture growing from the venous catheter. Prognosis CRBI has an attributable mortality of approximately 12–25%. Economics The attributable patient cost of catheter-associated bloodstream infection (not CRBI) in the USA ranges from $7,288 to $29,156, costing US hospitals $0.67–2.68 billion annually [1]. References 1. 2. 3. Scott II RD (2009) The direct medical costs of healthcare-associated infections in U.S. hospitals and the benefits of prevention. In: Department of Health and Human Services, Centers for Disease Control and Prevention, 2009 Pronovost P, Needham D, Berenholtz S, Sinopoli D, Chu H, Cosgrove S et al (2006 Dec 28) An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med 355(26):2725–2732 Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O’Grady NP et al (2009 Jul 1) Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 49(1):1–45 Catheter-Related Infection ▶ Catheter-Related Bloodstream Infection Cauda Equina Syndrome SCOTT E. BELL1, KATHRYN M. BEAUCHAMP2 1 Department of Neurosurgery, School of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA 2 Department of Neurosurgery, Denver Health Medical Center, University of Colorado School of Medicine, Denver, CO, USA Definition Cauda equina syndrome is a clinical condition arising from acute, subacute, or chronic dysfunction of nerve roots that comprise the structure known as the “cauda equina.” It is considered a spine emergency during the acute stages of neurologic deterioration from compressive lesions. Anatomically, the spinal cord ends at approximately the first to second lumbar vertebrae in normal adults. The dural sac continues as a fluid-filled structure to approximately the second sacral vertebrae. Within this sac, between levels L2 to S2, are contained the nerve roots that have emanated from the spinal cord. These nerve roots are collectively referred to as the “cauda equina,” as they exist prior to exiting the dural sac and spinal canal in pairs, through the neural foramina at each level. Cauda Equina Syndrome A variety of lesions can serve as the etiology for cauda equina syndrome, including herniated intervertebral disks, intradural, or extradural tumors, traumatic fractures, hematoma, abscess, and non-compressive causes such as neuropathy or ankylosing spondylitis [1]. The incidence of cauda equina syndrome (CES) as a true clinicopathologic entity is extremely rare; however, it is frequently over-diagnosed on initial evaluation of patients with signs and symptoms from spine or nerve dysfunction in the lower extremities. This is likely due to two reasons, (1) the highly generalized symptoms that are found at presentation, and (2) the consequences of permanent functional impairment with under-diagnosis. Because of its rarity, epidemiologic data is sparse, but historic reports place its prevalence at 1–3: 100,000 population. In patients with low back pain, the occurrence of CES is 4: 10,000. The most common etiology is herniated nucleus pulposis (HNP), still presenting as only 1–2% of those HNP cases requiring surgery [1]. Clinical Presentation The classic symptomatology of cauda equina syndrome includes perineal anesthesia, urinary or fecal retention and/or incontinence, low back and/or radicular pain, numbness in the lower extremities, weak rectal tone, or weakness in the lower extremities and associated reflexes [1]. While none of these symptoms are specific for CES individually, their presence in various combinations, frequently accompanied by certain anatomic hallmarks, can be highly sensitive for cauda equina dysfunction. The symptom with the greatest sensitivity for CES is urinary retention, found to be 90% sensitive in multiple series [2]. Without this, only 1:1,000 cases of suspected CES will be true [1]. Likewise, “saddle anesthesia,” which is absent sensation in the perineal region, has a sensitivity of 75% for CES. In the astute patient who presents early, rapid progression of clinical findings can also be an indication of CES. However, patients frequently fail to recognize the severity of their symptoms until they are more advanced. Shi et al. created a classification system to categorize severity of CES [2]. Patients fell into preclinical, early, middle, or late categorization, with no determination as to temporal progression of symptoms. The preclinical patient was considered to show only electrophysiologic changes in pudendal reflexes with imaging signs of compression; the early CES patient was considered to show slight saddle sensory disturbances and sciatica; the middle CES patients were considered to show severe saddle sensory disturbances, some bowel or bladder dysfunction, and lower extremity weakness; and late CES patients were considered to show no saddle sensation, severe bladder C and bowel dysfunction, severe sexual dysfunction. It is an important concept to attempt a categorization of severity for CES patients, as a differential response to surgery based on severity is well recognized throughout the literature [2]. The severity at presentation is as important for prognostication as timing of intervention for many patients [3]. This confounder is difficult to account for, and sometimes the distinction is minimized or ignored in level II and III analyses focusing on timing of intervention. Recognizing the difference between cauda equina dysfunction and spinal cord/conus medullaris dysfunction is important for diagnosis of CES. Asymmetry of sensory or motor disturbances can be an important finding that distinguishes cauda equina dysfunction from higher lesions affecting the spinal cord or conus medullaris [2]. For example, saddle anesthesia or lower extremity weakness can be a unilateral process in CES, but is frequently bilateral and symmetric in conus medullaris lesions. Another distinguishing finding of the saddle anesthesia resulting from CES is its lack of sensory dissociation, which is often found in spinal cord pathology. Pain can sometimes distinguish a cauda equina lesion from a spinal cord lesion. While not as sensitive for CES, if present, pain is frequently the symptom that will bring the patient to seek medical attention early. Pain from CES will be in the lumbar region or radicular in nature, radiating to lower extremities or the perineal region. The pain from CES may be quite prominent, while spinal cord lesions will usually cause only local pain (above L1 level), or little to no pain in the case of conus medullaris lesions [1]. Because of the anatomic relationship between the autonomic nervous system (ANS) and the cauda equina, symptoms relating to the function of the ANS are frequently encountered late in the course of CES, while they may be encountered relatively early with spinal cord or conus lesions due to their second degree neurons’ intramedullary location [2]. These ANS symptoms include bladder dysfunction, impotence, and sphincter disturbances. Cauda equina syndrome is considered a clinical diagnosis that is usually, but not always, accompanied by imaging findings suggesting compressive pathology. When the above-mentioned symptomatology is linked with compressive anatomic findings, urgent to emergent surgical remediation may be warranted. However, caution in diagnosis should be applied as there are many instances when imaging studies convey a compressive structural abnormality in the lumbar spine, while the patient experiences little or no symptoms. Without symptomatology, there is no indication for a diagnosis of CES. This is an important distinction when deciding if emergent surgery is needed for treatment. 509 C 510 C Cauda Equina Syndrome Evaluation Treatment is dictated by accompanying findings on full clinical evaluation. A thorough history and physical examination are paramount as a guide for proper decisionmaking in diagnosis and treatment. An appropriate physical exam will consist of the standardized format for a full neurologic examination, which consists of (1) mental status and executive function evaluation, (2) cranial nerve evaluation, (3) sensory exam, (4) motor exam, (5) central and peripheral reflex exam, (6) coordination evaluation, (7) gait evaluation. For the purpose of this discussion, focus will be placed on examination of peripheral function, i.e., sensory, motor, reflex, coordination, and gait examination, of the lower extremities. The elements of a thorough sensory exam include the dermatomal distribution of light touch, sharp-dull distinction, pain, and temperature, as well as non-segmental proprioception. Figure 1 shows the generally accepted distribution of segmental nerve root innervation for cutaneous sensation, described by Foerster in 1933 [4]. With specific nerve root impingement, one expects to find derangement in those dermatomes served by its respective lumbosacral segmental level. Frequently in CES, there is impingement of multiple roots producing a regional derangement of sensory function, which usually includes the lower sacral dermatomes, producing the saddle anesthesia in addition to more distal sensory changes. Motor function, likewise, has been well characterized with respect to the segmental innervation of the lower extremity musculature, termed myotomes. It follows a similar pattern as the innervation of cutaneous sensation. It is most valuable to describe any motor derangements by the function that is impaired or absent. The myotome served by L1 nerve roots causes hip flexion, L2-3 causes knee extension, L4 causes hip adduction, L5 causes foot inversion, eversion and dorsiflexion. The sacral nerves cause plantar flexion and knee flexion (S1-2). Strength is described as a gradient from 0 (no movement L2 S1 S2 S3 S4 L3 S5 T10 T11 L1 T12 L4 L5 L1 L2 L3 L5 L4 L5 S1 L5 L4 © 1999 Scott Bodell Cauda Equina Syndrome. Figure 1 Lower extremity dermatomes (Adapted from aafp.org) Cauda Equina Syndrome or muscle contraction) to 5 (full strength). Cauda equina syndrome may cause weakness along any point of the strength spectrum with lower motor neuron findings, which include atrophy from trophic influences, decreased tone, and reflex arc interruption. The degree of weakness found along the strength spectrum tells the story of the severity of the cauda equina lesion. Coordination and gait disturbances will occur in so much as the patient has weakness of the lower extremities. The degree of weakness will dictate the success or failure of the measures of multiple muscle coordination, such as gait. Lower sacral nerve impairment will cause weakness of rectal tone; this is always an important test to perform when evaluating for spinal cord or spinal nerve injury. Deep tendon reflexes are another element of the physical examination that will inform the examiner of the extent of injury. Reflexes become diminished in CES due to interruption of the reflex arc at the level of the lower motor neuron. It is usually the knee jerk and ankle jerk that are affected. The neurons serve an arc that communicates tendon stretch directly with alpha motor neurons and inhibitory interneurons. Interruption of this arc will cause a diminution or absence of the reflex for its respective myotome. This may be noticeable at multiple levels, reflecting the common multi-neuronal dysfunction within the cauda equina during the process of CES. In the acute stages of the disease, imaging is an important modality to help guide the clinician toward surgical treatment if appropriate pathology is seen. If trauma is suspected, initial imaging should include lumbar roentgenography or computed tomography (CT) scans, if available. The sensitivity and specificity of lumbar CTscan have been shown to be 97% and 95%, respectively, compared C with 86% and 58%, respectively, for lumbar roentgenograms (9). A CT scan has better resolution for fractures, and their relationships with the spinal canal and neural foramina can be viewed in sagittal, coronal, and axial planes. While harder to interpret due to its 2-dimensional, monoplanar depiction, roentgenograms are frequently used as a screening tool to guide decision algorithms for subsequent diagnostic maneuvers, especially in those patients in whom CT scan is contraindicated or impractical due to habitus, availability, etc. For better representation of soft tissue structures including neural elements, a magnetic resonance image (MRI) of the lumbar spine may be important in determining the nature and anatomic location of compressive pathology if surgical considerations are being made. Figure 2 shows a representation of lumbar stenosis causing neural compression. No contrast is needed in any imaging modality on evaluation of an acute process, as the diagnostic value is not improved. However, if tumor or infection is suspected, either iodinated contrast for CTscans, or gadolinium for MRI scans, is an important addition for diagnostic considerations. Another important factor in consideration of the traumatic etiology of CES is to recognize an unstable lumbar spine. With or without ongoing neural compression, treatment considerations will shift to a multimodal approach. If ongoing compressive pathology exists, surgical plans may include decompression as well as stabilization procedures. On the other hand, if CES is the result of a transient compression of neural elements that underwent closed reduction, then conservative treatment of the CES symptoms, in conjunction with a surgical stabilization procedure, may be appropriate. Cauda Equina Syndrome. Figure 2 (a and b) MRI in sagittal (a) and axial (b) planes showing a herniated disc causing cauda equine syndrome (Adapted from Chou et al. Orthopedics 200813) 511 C 512 C Cauda Equina Syndrome Treatment The timing of when to address a surgical lesion in CES is the most controversial aspect of this syndrome. It is commonly accepted as a surgical emergency. Once recognized, if appropriate compressive signs are found on imaging, surgery should be performed within 48 h from the onset of CES symptoms [3]. Some surgeons argue that evidence supports a time frame within 24 h from symptom onset. Shaprio [3] analyzed 39 cases of documented CES and described that cases operated within 24 h showed better functional recovery of lower extremity strength than cases operated within 48 h, which showed better functional recovery than cases operated after delay (two groups with mean delays of 3.4 and 9 days). Likewise, for pudendal symptoms, 24 h proved better than 48 h for urinary, bowel, and sexual function recovery, and delayed surgery showed no return of function. However, the differences in postsurgical recovery between surgery timed at <24 h versus <48 h were determined from n=2. In patients presenting after 48 h from onset of symptoms, especially if symptoms include urinary retention or incontinence, and saddle sensory changes, functional recovery is poor with or without surgery. The Shapiro study only grouped patients by timing of surgery, and did not address analysis by severity of symptoms at presentation. In a meta-analysis, Ahn et al. found that there was multivariate significance in improvement among patients presenting with CES – that based on surgery <48 h and that based on a lower degree of symptom severity at presentation. Those with worse symptom severity, including chronic low back pain, urinary symptoms, saddle anesthesia, and rectal dysfunction on presentation, tended to show worse prognosis for improvement postoperatively, even in patients operated within 48 h. Those patients with less severe symptoms, for instance, lower extremity weakness and saddle hypoesthesia, had greater chance of improvement with surgery <48 h from onset compared with surgery >48 h from onset. Other factors found to contribute to results from surgery include acuity of symptoms. Those with more acute symptom onset tend to have a better chance at improvement after surgery compared with those showing a more insidious, chronic onset. Time to recovery of symptoms has been shown to vary in small level II and III analyses [5]. Usually full extent of recovery is found within 2 years, but gradual recovery of some function has been observed for up to 5 years. The type of surgery performed also varies widely in the literature. It is a consensus that minimally invasive lesionectomy, such as semi-hemilaminotomy and microdiscectomy, is inadequate to decompress the nerve roots from the offending lesion once CES has developed. Among the procedures that produce adequate decompression exist high variability in approach. Hemilaminectomy, bilateral foraminal decompression with wide laminectomy, as well as one study that purported the need for transdural disk exploration in up to 18% of cases, have all been shown to be effective in treating CES. Rationale for the latter procedure is that it reduces the traction on injured nerves during surgery, thus improving the chances for recovery of function. When ankylosing spondylitis (AS) is found to be the etiology of CES, the pathophysiologic mechanism is not entirely clear. It is thought to be a progressive ectasia of the dura. The effectiveness of either conservative or surgical treatments has been called into question. There are some studies that advocate medical management is superior, while others that endorse surgical treatment is the most effective. This problem is classically treated conservatively, but in the last decade, a variety of surgical approaches have been employed including lumbar decompression and durotomy, and even cerebrospinal fluid shunting, to treat the ectatic lumbar dura. When there is clear lack of compressive pathology in CES, conservative management focuses on the presumed inflammatory process causing the nerve injury, similar to CES in ankylosing spondylitis. The treatment of choice for acute peripheral nerve injuries is high-dose intravenous steroids, and pain control [1]. Physical therapy early in the process of recovery, whether after conservative or operative treatment, is an important aspect of convalescence. Summary Cauda equina syndrome is a dangerous, but uncommon entity in spine pathology. If acute onset and progression are confirmed clinically, surgery should be performed without delay, within 24–48 h. While compression is the most common etiology, some inflammatory processes are found to be the cause, warranting conservative management. The prognosis for functional recovery is poor when the onset is insidious, or the presentation severe. But, under the correct circumstances, with acute onset and early symptoms, prognosis for recovery is good when treated emergently. Surgical approaches vary, but it is generally accepted that wide decompression and removal of the offending lesion are the best treatment for compressive causes of CES. Further studies, accounting for both severity on presentation and timing of treatment, are warranted to establish the best management for maximizing the patients’ ability to overcome this illness. Central Spinal Cord Syndrome References 1. 2. 3. 4. 5. Greenberg MS (ed) (2010) Handbook of neurosurgery, 7th edn. Thieme Medical Publications, New York Shi J, Jia L, Yuan W, Shi GD, Ma B, Wang B, JianFeng W (2010) Clinical classification of cauda equina syndrome for proper treatment: A retrospective analysis of 39 patients. Acta Orthopedica 81 (3):391–395 Shapiro S (2000) Medical realities of cauda equina syndrome secondary to lumbar disc herniation. Spine 25(3):348–352 Foerster O (1933) The dermatomes in man. Brain 56:1 Ahn UM, Ahn NU, Buchowski JM, Garrett ES, Seiber AN, Kostuik JP (2000) Cauda equina syndrome secondary to lumbar disc herniation: a meta-analysis of surgical outcomes. Spine 25(12):1515–1522 C-Collar C Central Spinal Cord Syndrome SARAH E. PINSKI1, ARIANNE BOYLAN2, JENS-PETER WITT3, TODD F. VANDERHEIDEN4, PHILIP F. STAHEL5 1 Department of Orthopaedic Surgery, Denver, CO, USA 2 Department of Neurosurgery, University of Colorado Denver, School of Medicine, Denver, CO, USA 3 Neuro Spine Program, Department of Neurosurgery, University of Colorado Hospital, Colorado, CO, USA 4 Department of Orthopaedic Surgery, Center for Complex Fractures and Limb Restoration, Denver Health Medical Center, University of Colorado School of Medicine, Denver, CO, USA 5 Department of Orthopaedic Surgery and Department of Neurosurgery, Denver Health Medical Center, University of Colorado School of Medicine, Denver, CO, USA This is the cervical collar that is used for stabilizing the neck in the neutral position. Synonyms “Burning Hands” syndrome; CCS; Central cord injury syndrome CCS ▶ Central Spinal Cord Syndrome Celiotomy Definition A syndrome associated with ischemia, hemorrhage, or necrosis involving the central portions of the spinal cord due to traumatic injury sustained in the cervical or upper thoracic regions of the spine, characterized by weakness in the arms with relative sparing of the leg strength associated with variable sensory loss. ▶ Laparotomy Dorsal columns Lateral corticospinal tract Central Cord Injury Syndrome ▶ Central Spinal Cord Syndrome Central Cord Syndrome ▶ Spinal Cord Injury Syndromes Central Line Infection ▶ Catheter-Related Bloodstream Infection 513 Lateral spinothalamic tract Central Spinal Cord Syndrome. Figure 1 Illustration of the affected area (red color) of central cord syndrome (CCS) in a schematic axial drawing through the spinal cord. Note that the sacral structures are more peripheral in the dorsal columns and the lateral corticospinal tract. These structures are therefore preferentially spared in patients with CCS C 514 C Central Spinal Cord Syndrome a b c Central Spinal Cord Syndrome. Figure 2 (Continued) Central Spinal Cord Syndrome Anatomy The main descending motor pathway is the lateral corticospinal tract. The tract is arranged with the cervical (cranial) nerve paths more centrally located and the sacral (caudal) nerve paths more peripherally located. The major ascending sensory pathway is the dorsal column (fasciculus gracilis, fasciculus cuneatus). Similar to the lateral corticospinal tract, the dorsal columns are arranged such that cervical structures are centrally located and sacral structures are more peripherally located (Fig. 1) [1]. Central cord syndrome (CCS) originates from a vascular compromise in the distribution area of the anterior spinal artery, which supplies the central portions of the spinal cord. Epidemiology CCS is the most common type of incomplete spinal cord injury (SCI), comprising 15–25% of all cases [1]. The “classic” mechanism leading to CCS is represented in elderly patients with underlying degenerative spinal changes, who sustain a hyperextension injury the cervical spine (C-spine), with or without evidence of acute spinal injury on plain X-rays. Susceptibility to CCS is represented by a preexisting narrowing of the cervical spinal canal due to spondylosis, osteophyte formation, stenosis and ossification of the posterior longitudinal ligament. The cervical cord may be injured by direct compression from buckling of the ligamentum flavum into a narrowed, stenotic spinal canal [1]. CCS may also occur in younger individuals sustaining high-energy trauma that results in unstable spinal fractures, ligamentous instability, or fracture-dislocations [2]. Young patients with congenital cervical stenosis are also at particular risk for sustaining a CCS after trauma. This entity presents with a wide spectrum of neurological symptoms, ranging from preserved sensation with burning dysesthesia and allodynia in the hands, to motor weakness to the upper extremities, to a complete quadriparesis with sacral sparing. As a general rule, the upper extremities are more affected than the lower extremities. The classic paradigm is represented by a patient who walks around but can’t move the arms. Return of motor function follows a characteristic pattern, with the C 515 lower extremities recovering first, bladder function next, and the proximal upper extremities and hands last [3]. Application Diagnosis is made based upon clinical and radiographic examination. Initial radiographic evaluation consists of anteroposterior, lateral, and open-mouth odontoid X-rays. CT scans may also be obtained to gain a better understanding of fractures and dislocations. The MRI represents the “gold standard” for evaluating injuries to the soft tissues (discs, ligaments), to quantify the extent of spinal stenosis and cord compression, and to asses for presence of epidural hematoma, spinal edema, and spinal contusions. At the time of initial evaluation, sacral sparing may be the only neurologic function present to differentiate incomplete from complete SCI. Most cases of CCS are successfully managed non-operatively, with the likelihood of considerable neurologic recovery [1, 3]. Medical management of CCS consists of admission to intensive care for close monitoring of neurologic status and hemodynamics. Maintenance of blood pressure (mean arterial pressure of >85 mmHg) by volume resuscitation supplemented by vasopressors, if needed, has been shown to improve neurologic outcome by presumably maximizing spinal cord perfusion and limiting secondary injury [1, 3]. Intravenous methylprednisolone is the most commonly used pharmacologic treatment for SCI. The established standard dosing is 30 mg/kg bolus followed by 5.4 mg/kg/h for 24 h if the infusion is started within 3 h of injury, and for 48 h if the infusion is started between 3 and 8 h from the time of injury. This is a controversial treatment that recent literature reviews showed no evidence for the use of corticosteroids as a neuroprotective agent. Additionally, corticosteroids may adversely affect patient outcome due to the side effects related to immunosuppression, including pulmonary infections [4]. Any patient with suspected CCS should be immobilized in a hard cervical orthosis to prevent further motion and potential injury. The cervical collar is typically used for an additional 6 weeks or until neck pain has resolved and neurologic improvement is noted. Once the patient is medically stable, early mobilization and Central Spinal Cord Syndrome. Figure 2 Case example of a 21-year old man who sustained a fall while snowboarding. He presented with bilateral upper extremity motor weakness and subjectively “burning” hands. Imaging with plain X-rays, CT scan, and MRI reveals an unstable C5/C6 flexion/distraction injury with a three-column fracture at C5, and a spinal cord contusion on MRI (arrows in panels A and B). This patient was managed surgically by posterior fusion due to the inherent instability of the injury (panel C). No decompression was performed. The patient recovered well within 3 months of surgery, with a full resolution of dysethestesia and allodynia and improved upper extremity function. The patient was able to return to work without restrictions as a pizza delivery courier C 516 C Central Venous Access Catheter (CVC) rehabilitation with physical and occupational therapy is essential. Gait and hand function training are the main goals. Surgery is indicated in those cases with spinal instability [2, 5], as outlined in the case example shown in Fig. 2. Surgical intervention for CCS without spinal instability is controversial. However, in the setting of persistent cord compression, failure of motor recovery, or neurologic decline, surgical intervention may be warranted. These symptoms may be due to a herniated disk, an epidural hematoma, or bony fragments in the spinal canal. In such cases, the early spinal decompression may prevent the progression of neurologic impairment and may lead to improved recovery and function [1, 5]. References 1. 2. 3. 4. 5. Nowak DD, Lee JK, Gelb DE, Poelstra KA, Ludwig SC (2009) Central Cord Syndrome. J Am Acad Orthop Surg 17:756–765 Stahel PF, Flierl MA, Matava B (2011) Traumatic spondylolisthesis. In: Vincent JL, Hall J (eds) Encyclopedia of intensive care medicine. Springer, Heidelberg Aarabi B, Alexander M, Mirvis SE, Shanmuganathan K, Chesler D, Maulucci C, Iguchi M, Aresco C, Blacklock T (2011) Predictors of outcome in acute traumatic central cord syndrome due to spinal stenosis. J Neurosurg Spine 14:122–130 Hurlbert RJ, Hamilton MG (2008) Methylprednisolone for acute spinal cord injury: 5-year practice reversal. Can J Neurol Sci 35:41–45 Fehlings MG, Rabin D, Sears W, Cadotte DW, Aarabi B (2010) Current practice in the timing of surgical intervention in spinal cord injury. Spine 35(suppl 21):S166–S173 Central Venous Access Catheter (CVC) ▶ Vascular Access for RRT Definition Central venous pressure (CVP) is the pressure of blood in the thoracic vena cava at the point where the superior vena cava meets the inferior vena cava prior to entry into the right atrium (RA) of the heart. Characteristics Normal values of CVP in spontaneously breathing patients are 5–10 cm of water and can be up to 5 cm of water higher in patients mechanically ventilated with positive inspiratory pressure. The normal CVP waveform consists of three upward deflections (“a”, “c”, “v” waves) and two downward deflections (“x” and “y” descents) (Fig. 1). The “a” wave reflects right atrial contraction and occurs just after the “P” wave on the ECG. It is followed by “c” wave, which is the result of tricuspid valve bulging into RA during isovolumic ventricular contraction. The third positive deflection is “v” wave and represents the filling of the RA during late ventricular systole. The “x” descent occurs during right ventricular ejection when the tricuspid valve is pulled away from the atrium and the “y” descent represents rapid blood flow from the RA into right ventricle (RV) during early diastole. Clinical Estimation of CVP Physical assessment of jugular venous distension and pressure in patients sitting up at 45–60% angle allows CVP estimation. The level of internal jugular veins filling can be determined and pulsations can be clearly seen. The vertical distance from the filling level and sternal angle is measured. Five centimeters (the approximate distance from sternal angle and RA) is added to the measured distance in order to get the CVP estimation. The external jugular veins are observed in the 20 angle of the upper part of the body against horizontal line. In patients with normal CVP values, the veins are filled to one third of the distance Central Venous Catheter Infection ▶ Catheter-Related Bloodstream Infection Central Venous Pressure ECG a CVP tracing c GORAZD VOGA Medical ICU, General Hospital Celje, Celje, Slovenia Synonyms Right atrial pressure X v Y Central Venous Pressure. Figure 1 Simultaneous ECG and CVP tracing Central Venous Pressure between clavicle and mandible. Unfortunately, considerable disagreement and inaccuracy exists in the clinical assessment of CVP in critically ill patients and therefore measurement is mandatory. Zeroing and reference level of the transducer Central venous blood volume Venous return The CVP is usually measured by placing a catheter in one of the veins and then threading it to the superior vena cava. Internal jugular and subclavian veins are most suitable for cannulation, since the catheter is easily advanced to the proper position. Antecubital veins can be also used, if catheter is long enough to reach the superior vena cava. The CVP is measured using a manometer filled with intravenous fluid and attached to the central venous catheter. Zero point, approximately the mid-axillary line in the fourth intercostal space in supine position, must be determined. Catheter should not be blocked or kinked to allow free flow of the fluid. The manometer is filled with fluid and then three-way stopcock is open to the catheter. Fluid level steadily drops to the level of the CVP, which is measured in centimeters of water. Fluid level should fluctuate slightly with breathing and may slightly pulsate. On the other hand, prominent pulsations are due to significant tricuspid regurgitation or improper position of the catheter tip in the right ventricle, which usually requires reposition of the catheter. In the ICU setting, catheters are usually connected with transducers, and the CVP waveform is continuously displayed in the monitor. Transducers also have to be zeroing and put at the standard reference level for hemodynamic measurements, which is usually 5 cm below the sternal angle. The electronically measured values are displayed in the monitor and expressed in mmHg (10 cm H2O is 7.5 mm Hg). Besides proper levelling and zeroing, changes of intrathoracic pressure should be considered in the interpretation of CVP values. Increased intrathoracic pressure is commonly seen in patients with high levels of PEEP or forced expiration, on the other hand, highly negative intrathoracic pressure frequently results from vigorous inspiratory efforts. Both conditions can markedly change CVP. Therefore, CVP waveform should be always observed in order to assess proper CVP values. Factors that affect CVP measurement are summarized in the table (Table 1). Blood volume Nonivasive estimation of CVP is possible by transthoracic echocardiography. In the subcostal view, inferior vena cava (IVC) is visualized and the diameter during inspiration and expiration is measured. The IVC collapsibility index (IVCCI) is defined as difference between maximum 517 Central Venous Pressure. Table 1 Factors affecting CVP measurement Invasive CVP Measurement Nonivasive CVP Estimation C C Vascular tone Right ventricular compliance Intrathoracic pressure Tricuspid regurgitation and stenosis Central Venous Pressure. Table 2 Estimation of CVP from measurement and respiratory variation of IVC diameter Inspiratory IVC diameter (cm) decrease Estimated CVP (mm Hg) <1.5 Collapse <5 1.5–2.5 >50% 5–10 >2.5 <50% 10–15 >2.5 No >20 and minimum IVC diameter, expressed in percent. The estimation of CVP by IVC measurement is showed in the table and is reliable in the spontaneously breathing patients (Table 2). The IVC size of 2 cm and the IVC collapsibility of 40% discriminates CVP below or above 10 mm Hg with 73% sensitivity and 85% specificity [1]. Clinical Value of CVP CVP is a static pressure variable, which is frequently used for preload assessment. CVP measurement is the essential part of hemodynamic assessment in critically ill patients and is frequently performed during surgery to estimate cardiac preload and circulating blood volume, also. CVP reflects the amount of blood returning to the heart and the ability of the heart to pump the blood into the arterial system. Measurement of the “c” wave value at the end expiration reflects end-diastolic pressure in the right ventricle and can be used as an index RV preload. At the same time CVP represents the back pressure for venous return and gives an estimate of the intravascular volume status. It predominantly depends on circulating blood volume, venous tone, and right ventricular function. In patients with normal cardiac function increased venous return is associated with increased cardiac output, without major change in CVP. On the other hand, CVP is elevated in 518 C Central Venous, Arterial, and PA Catheters patients with poor right ventricular contractility and/or obstruction to the inflow in right atrium (tamponade, tension pneumothorax) or to the outflow in pulmonary circulation (pulmonary embolism). Unfortunately, CVP poorly reflects left ventricular preload and is of little value for hemodynamic assessment in patients with heart failure and cardiogenic shock. Very poor relationship between CVP and blood volume and poor prediction of CVP changes for fluid responsiveness was found [2]. CVP values lower than 5 mm Hg have only 47% positive predictive value for fluid responsiveness in mechanically ventilated septic patients [3]. Nevertheless, CVP values in septic shock are significantly different in survivors and nonsurvivors 6–48 h after admission and CVP values 8–12 mm Hg are proposed as an early resuscitation goal of the initial hemodynamic stabilization in patients with septic shock [4]. CVP is only a part of hemodynamic assessment and must be interpreted together with other hemodynamic variables and clinical state of patient. It is clear that very high and low CVP values must be considered as abnormal, but they are not conclusive for any specific hemodynamic situation. Therefore, such findings require further diagnostic workup. Normal CVP values also can be associated with different hemodynamic disturbances in critically ill patients. Examination of the CVP waveforms gives some additional information regarding tricuspid regurgitation, cardiac tamponade, cardiac restriction, decreased thoracic compliance, and arrhythmias. Patients with tricuspid regurgitation have prominent “v” waves, on the other hand restrictive RV filling is associated with large and deep “y” descent. In patients with cardiac tamponade “x” and “y” descent usually disappear. Large inspiratory rise in the CVP during mechanical ventilation suggests decreased thoracic wall compliance. In patients with atrial fibrillation “a” wave is absent, and in presence of atrioventricular dissociation high and tall (cannon) “a” wave can be seen due to atrial contraction against closed tricuspid valve [5]. References 1. 2. 3. Brennan JM, Blair JE, Goonewardena S, Ronan A, Shah D, Vasaiwala S, Kirkpatrick JN (2007) Spencer KT reappraisal of the use of inferior vena cava for estimating right atrial pressure. J Am Soc Echocardiogr 20:857–861 Marik PE, Baram M, Vahid B (2008) Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares. Chest 134:172–178 Osman D, Ridel C, Ray P, Monnet X, Anguel N, Richard C, Teboul JL (2007) Cardiac filling pressures are not appropriate to predict hemodynamic response to volume challenge. Crit Care Med 35:64–68 4. 5. Dellinger RP, Levy MM, Carlet JM et al (2008) Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock. Crit Care Med 36:296–327 Magder S (2006) Central venous pressure monitoring. Curr Opin Crit Care 12:219–227 Central Venous, Arterial, and PA Catheters JOSÉ RODOLFO ROCCO Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Introduction Vascular cannulation is an essential tool for fluid and drug administration, accurate monitoring of hemodynamic parameters, and blood sampling in critically ill patients. Preparation, indications, contraindications, clinical utility, and techniques for vascular cannulation are reviewed in this chapter. The sites of catheterization and complications of arterial, central venous, and pulmonary artery catheterization are also presented. Central Venous Catheterization The main indications for central venous catheterization (CVC) are: (1) monitoring of hemodynamic and tecidual perfusion, and (2) therapeutic (Table 1). Central Venous, Arterial, and PA Catheters. Table 1 Indications for central venous catheterization 1 – Monitoring of hemodynamic and tecidual perfusion 1.1 – Measurement of central venous pressure 1.2 – Placement of pulmonary (Swan-Ganz) catheter and Presep® 1.3 – Placement of jugular bulb catheter 2 – Therapeutic 2.1 – Fluid therapy in general 2.2 – Fluid therapy of irritant solutions (concentrated potassium chloride, parenteral nutrition, hypertonic saline) and vasopressor amines 2.3 – Hemodyalisis and plamapheresis 2.4 – Placement of transvenous pacemaker 2.5 – When peripherical venous access is impossible Central Venous, Arterial, and PA Catheters Volemic resuscitation is not an indication for CVC. However, in a hypovolemic patient if the peripheral vein cannulation is difficult, it would be necessary to access a central vein. During cardiac arrest, there is an urgency to access a vein (peripheral or central) for drug administration. In this case, femoral vein is the first option. Cannulation of femoral vein can be done without stopping the cardiac massage. Sites of Catheterization In general, the site of catheterization is selected based on doctor’s experience. However, for some procedures, there are preferential sites (Table 2). If the patient had a pleural catheter, the venous cannulation must be done at the same side of the thoracic drain. Preparation Patient and operator preparation is a crucial component of the vascular cannulation procedure. If possible, it is advisable to obtain informed consent from the patient or surrogate whenever an invasive procedure is to be performed. Hand washing is mandatory (and often overlooked) before the insertion of vascular devices. Scrubbing with antimicrobial cleansing solutions does not reduce the C incidence of catheter-related sepsis, so a simple soapand-water scrub is sufficient. A CVC is a sterile procedure. If there is a contamination, the procedure must be interrupted and the contaminated material must be replaced. If a patient is cannulated in an emergency situation (e.g., during cardiac arrest), the venous catheter must be replaced as soon as possible. The insertion site is prepped and povidone-iodine or alcoholic solution of chlorhexidine is most commonly used, although chlorexidine appears to be more efficient. After skin preparation, the insertion site should be draped with a sterile field. The sterile field must be big enough to cover the head and the body of the patient (maximum barrier). This procedure reduced the incidence of catheterrelated sepsis six times compared to the use of sterile gloves and a small camp (Fig. 1). To avoid patient discomfort, local anesthesia, analgesia, and/or sedation need to be performed. Most vascular cannulations are done percutaneously because of the facility to insert the catheter and reduced risk of infection. Cannulation over direct vision through a surgical cut down may be performed in very difficult situations. Most of the central venous and arterial catheters are inserted passing a guidewire through the needle (the Seldinger technique) (Fig. 2). In Fig. 3, steps of the right internal jugular vein cannulation are depicted. Central Venous, Arterial, and PA Catheters. Table 2 Sites of catheterization in diverse clinical conditions Indication First choice Second choice Third choice Venous access in general SCV IJV or EJV FV Placement of (Swan-Ganz) catheter RIJV LSCV LIJV or RSCV Coagulopathy EJV IJV FV Pulmonary disease or elevated PEEP RIJV LIJV EJV Total parenteral nutrition SCV IJV – Hemodyalisis/plasmapheresis IJV FV SCV Cardiac arrest SCV IJV FV Transvenous pacemaker RIJV SCV – Hypovolemic patient SCV or FV IJV – Urgent access to airway FV SCV IJV Monitoring of venous saturation SCV IJV EJV CVP monitoring IJV EJV SCV SCV – subclavian vein; IJV – internal jugular vein; EJV – external jugular vein; FV – femoral vein; RIJV – right internal jugular vein; LSCV – left subclavian vein; LIJV – left internal jugular vein; RSCV – right subclavian vein; PEEP – positive end expiratory pressure; CVP central venous pressure 519 C 520 C Central Venous, Arterial, and PA Catheters Central Venous, Arterial, and PA Catheters. Figure 1 Vascular cannulation of right internal jugular vein in an intensive care unit setting. Note the use of sterile field covering the face and body of patient (maximum barrier) The use of Doppler or ultrasound-guided vascular access increase the success of cannulation, reducing the risk of complications related to the insertion. In the future, the use of ultrasound equipment associated with a trained team will improve this technique. Figure 4 demonstrate the collapse sign, useful to differentiate arterial from venous vessels. Catheter Tip Position After cannulation, the catheter placement in jugular or subclavian veins must be checked with a thoracic radiography. Ideally, the tip of the catheter need to be positioned 3–5 cm above the junction of the superior vena cava and right atrium or 1 cm below the right tracheobronchial angle (never below the main carina) or outside cardiac silhouette (Fig. 5). The catheter length position must be 16–18 cm at right-side cannulation and 19–21 cm at the left-side cannulation, independently of the gender or patient biotype. Subclavian Vein Catheterization The access to the subclavian vein may be gained by the supraclavicular or infraclavicular approach. The angle of insertion for all infraclavicular approaches is parallel to the coronal plane. Initially, the patient is positioned in Trendelenburg (15–30 ) in order to increase venous return (37%) with a small rolled towel between the scapulae to increase the distance between the clavicle and the first rib. However, Trendelenburg position is not well tolerated in cardiac patients. In these cases, legs are elevated to increase venous return filling subclavian vein, facilitating the cannulation. The head is slightly rotated to the opposite side and the arms are located along the body. After skin preparation and local anesthesia with lidocaine (1% or 2%), the needle is advanced 2–3 cm caudal to clavicle in the delto-peitoral angle. The insertion point can be performed lateral to the midclavicular line at the junction of the lateral and middle thirds of the clavicle, in the mid-clavicle, or at the junction of the middle and medial thirds of the clavicle (Fig. 6). When blood comes into the syringe (because a slight negative pressure is applied), the needle is fixed with fingers and the syringe is removed, and the guidewire is introduced 15 cm with the J-tip turned lower. If resistance is met when advancing the guidewire, both the guidewire and needle should be withdrawn simultaneously. It is always important to control the guidewire. The tip of guidewire is flexible to avoid vascular lesion (J-tip) during the introduction. Never try to introduce the other tip because of the risk of vascular lesion. The catheter should be introduced over the guidewire without resistance. This approach has a success rate of 70–99% and is easier to maintain, and is preferably used when airway control is necessary. Disadvantages include difficulty in controlling bleeding, higher risk of pneumothorax, and Central Venous, Arterial, and PA Catheters C 521 C A small-bore needle is used to probe for the target vessel A thin wire with a flexible tip (called a J-tip because of its shape) is passed through the needle and into the vessel lumen The needle is then removed, leaving the wire in place to serve as guide for cannulation of the vessel Vascular catheter is passed over wire-guide. In deep vessels a rigid dilator is first threaded and removed Finally the wire is removed and the catheter is advanced Central Venous, Arterial, and PA Catheters. Figure 2 Vascular cannulation with a guidewire (the Seldinger technique) interference with chest compressions during cardiopulmonary resuscitation. One study shows that the strongest predictor of a complication is a failed catheterization attempt. Many clinicians feel that three attempts are enough, and then it is time to ask another clinician to attempt catheterization from another site. The use of Doppler guidance to reduce the complications related to subclavian vein catheterization needs to be better elucidated. 522 C Central Venous, Arterial, and PA Catheters a b d e g h c f i Central Venous, Arterial, and PA Catheters. Figure 3 Steps for right internal jugular vein cannulation: (a) preparation of skin with chlorexidine and collocation of fields, (b) local anesthesia, (c) needle vein cannulation and guidewire is advanced through needle, (d) cutdown the skin with a blade (to facilitate the introduction of catheter), (e) the guidewire in place and compression of the site to avoid bleeding, (f) introduction of dilator, (g) introduction of vascular catheter is passed over guidewire, (h) the guidewire is retired, and (i) the catheter is fixed Internal Jugular Vein Catheterization The internal jugular vein has been cannulated with success rate similar to that of the subclavian vein (58–99% success rate). Three different approaches have been described (Fig. 7): (a) anterior to the sternocleidomatoid (SCM); (b) central between the two heads of the SCM, and (c) posterior to the SCM. The carotid artery lies posterior and medial to the vein. The operator must maintain a minimum pressure in internal carotid artery with the left hand and using the (b) technique previously described (Fig. 7), the vessel is cannulated at an angle of 45 pointing the needle to the ipsilateral nipple. The puncture is achieved by introducing the needle at about 1–5 cm. The rest of the procedure is same as that of a cannulation of subclavian vein. Internal jugular vein catheterization has a lower risk of pneumothorax and is easier to compress the insertion site if bleeding occurs. However, it may be more difficult to cannulate in patients with volume depletion or shock. Dressing and maintaining are also difficult. External Jugular Vein Catheterization The cannulation of the external jugular vein has reduced incidence of complications, but a higher incidence of failure (60–90% success rate). The patient is placed in the Trendelenburg position with the head turned away Central Venous, Arterial, and PA Catheters Internal jugular vein C Because catheters inserted through the neck are more difficult to dress and maintain than those in other sites, this approach is not suitable for prolonged venous access. Femoral Vein Catheterization Carotid artery a Internal jugular vein Carotid artery b Central Venous, Arterial, and PA Catheters. Figure 4 Transversal axis ultrasound view of cervical region. In (a) carotid artery is located at the left side (smaller circle) and internal jugular vein is at the right side (larger circle). In (b) there is a collapse of internal jugular vein with transducer compression from the insertion site. If necessary, the vein can be occluded just above the clavicle (with forefinger of the nondominant hand) to engorge the entry side. The recommended insertion point is midway between the angle of the jaw and the clavicle. The external jugular vein has little support from the surrounding structures, thus the vein should be anchored between the thumb and forefinger when the needle is inserted. Sometimes it is difficult to advance the guidewire or the catheter. If the catheter does not advance easily, do not force it, as this may result in vascular perforation. However, as many as 15% of patients do not have an identifiable external jugular vein. It is ideal for coagulopathy patients, because any significant bleeding can be easily recognized and treated with local pressure. The risk of pneumothorax is also avoided. 523 The femoral vein is the easiest, large vein to be cannulated and does not lead to pneumothorax. The vein is located just medial to the femoral artery 2 cm below the inguinal ligament. The needle is directed cephalad at a 45 angle. The distal tip of needle should not traverse the inguinal ligament to minimize the risk of retroperitoneal hematoma. The risk of infection and thrombosis limit its general acceptance for long-term use in critically ill patients. Other disadvantages associated with this route are the femoral artery puncture (5%) and limited ability to flex the hip (which can be bothersome for awake patients). Figure 8 shows the anatomy of the femoral sheath. Table 3 shows the advantages, disadvantages, and main contraindications of central vein cannulation. Complications Related to Vein Catheterization Complications occurring during catheter placement include catheter malposition, arrhythmias, embolization, and vascular, cardiac, pleural, mediastinal, and neurologic injuries. Pneumothorax is the most frequently reported immediate complication of subclavian vein catheterization, and arterial (carotid) puncture is the most common immediate complication of internal jugular vein cannulation. When a carotid artery puncture is performed (2–10% of attempted cannulations), the needle should be removed and pressure should be applied to the site for at least 5 min (10 min if the patient has coagulopathy). If the carotid artery has been inadvertently cannulated, the catheter should not be removed, as this could provoke serious hemorrhage. In this situation, a vascular surgeon should be consulted immediately. Pneumothorax can be detected in the postinsertion chest films in upright position and during expiration (if possible). Expiratory films facilitate the detection of small pneumothoraxes because expiration decreases the volume of air in the lungs, but not the volume of air in the pleural space. Pneumothorax can be life threatening in ventilated patients. In minutes, the patient can develop hypertensive pneumothorax and evolution to cardiopulmonary arrest. Sometimes the physical examination (hyperresonance at thoracic percussion) can be the tip for diagnosis. Pneumothorax may not be radiographically evident until 24–48 h after central venous cannulation C 524 C Central Venous, Arterial, and PA Catheters Central Venous, Arterial, and PA Catheters. Figure 5 Thoracic radiography showing the correct placement of catheter tip (arrow) Internal jugular vein Internal jugular vein Sternocleidomastoid muscle a c Anterior scalene muscle Subclavian vein b a b c Subclavian vein Central Venous, Arterial, and PA Catheters. Figure 6 Three approaches for infraclavicular access to the subclavian vein. a – Junction of the lateral and medial thirds of the clavicle; b – mid-clavicle; c – junction of the middle and medial thirds of the clavicle (delayed pneumothorax). Therefore, the absence of a pneumothorax on an immediate postinsertion chest film does not absolutely exclude the possibility of a catheter-induced pneumothorax. This is an important consideration in patients who develop dyspnea or other Central Venous, Arterial, and PA Catheters. Figure 7 Three approaches to access the internal jugular vein. a – Anterior to the sternocleidomastoid; b – central between the clavicular and sternal heads of sternocleidomastoid, and c – posterior to the sternocleidomastoid signs of pneumothorax in the first few days after central venous cannulation. Venous air embolism is one of the most feared complications of central venous cannulation. Prevention is the hallmark of reducing the morbidity and mortality of venous air embolism. Placing patient in Trendelenburg position with the head 15 below the horizontal plane C Central Venous, Arterial, and PA Catheters 525 Central Venous, Arterial, and PA Catheters. Table 3 Advantages, disadvantages, and main contraindications of central vein cannulation Femoral nerve Vein Advantages Disadvantages Contraindications EJV Secure Difficult access in obese or short neck patients IJV Low risk of Difficult view in pneumothorax obese and skin flaccidity. High risk of infection Coagulopathy, previous surgery, short neck, or obese patients SCV Constant anatomy Coagulopathy, clavicle deformity, low functional respiratory reserve, cifoescoliosis FV No interference Difficult to of thoracic progress the masses guidewire in ascitis patients, difficult hygiene, more risk of infection Femoral artery Femoral vein Inguinal ligament . sm riu r to Sa More risk of pneumothorax, difficult to compress Central Venous, Arterial, and PA Catheters. Figure 8 The anatomy of the femoral sheath can facilitate the elevation of venous pressure above the atmospheric pressure. Special care must be employed during changing connections in a central venous line. Long-term complications related to the length of time that the catheter remains in place include infection and thrombosis. Surface-modified central venous catheters have been developed to reduce catheter-related infection (e.g., minocycline and rifampin impregnated cook spectrum glide® central venous catheter). The complications observed in a study of over 4,000 cannulations of central veins are shown in Table 4. Previous surgery, difficult view Obese, urinary incontinence, infection, or local venous thrombosis EJV – external jugular vein; IJV – internal jugular vein; SCV – subclavian vein; FV – femoral vein Central Venous, Arterial, and PA Catheters. Table 4 Comparison between the incidence of complication in SCV and IJV SCV (%) IJV (%) Risk of arterial puncture 0.5 3.0 Catheter malposition 9.3 5.0 Hemo- or pneumothorax 1.3 1.5 Bloodstream infection 4.0 8.6 Vessel occlusion/thrombosis 1.2 0 Swan-Ganz Catheter SCV – subclavian vein; IJV – internal jugular vein The use of Swan-Ganz (pulmonary artery) catheter is not just important for the specialty of critical care, but it is also responsible for the specialty of critical care. This catheter is so much a part of patient care that it is impossible to function properly in the ICU without a clear understanding of this catheter and the information it provides. It is indicated whenever the data obtained improves therapeutic decision making. Although no carefully designed study has definitely established the benefit of hemodynamic monitoring to the individual patient, it is reasonable to assume that more precise bedside knowledge of cardiovascular parameters would allow earlier diagnosis and guide therapy. Table 5 shows the indications for pulmonary artery catheterization most often noted in the literature. The Swan-Ganz catheter is a multilumen catheter 110 cm long and has an outside diameter of 2.3 mm C 526 C Central Venous, Arterial, and PA Catheters (7 French gauge). There are two internal channels: proximal (right atrium) and distal (pulmonary artery). The tip of the catheter is equipped with a balloon with 1.5 mL capacity. Finally, there is a thermistor (i.e., a transducer Central Venous, Arterial, and PA Catheters. Table 5 Recommendations of pulmonary artery catheterization I. Surgical Perioperative management of high-risk patients undergoing extensive surgical procedures Postoperative cardiovascular complications Multisystem trauma Severe burns Shock despite perceived adequate fluid therapy Oliguria despite perceived adequate fluid therapy II. Cardiac Myocardial infarction complicated with pump failure Congestive heart failure unresponsive to conventional therapy Pulmonary hypertension (for diagnosis and monitoring during acute drug therapy) III. Pulmonary To differentiate noncardiogenic (acute respiratory distress syndrome) from cardiogenic pulmonary edema To evaluate effects of high levels of ventilatory support on cardiovascular status device that senses changes in temperature) located on the outer surface of the catheter 4 cm from the catheter tip. The thermistor measures the flow of a cold fluid that is injected through the proximal port of the catheter, and this flow rate is equivalent to the cardiac output. An example of this catheter is illustrated in Fig. 9. Other accessories are available on specially designed Swan-Ganz catheter: (1) an extra channel that can be used as infusion channel or for passing temporary pacemaker that leads into the right ventricule; (2) a fiberoptic system that allows continuous monitoring of mixed venous oxygen saturation; (3) a rapid-response thermistor that can measure the ejection fraction of right ventricle, and (4) a thermal filament that generates low-energy heat pulses and allow continuous thermodilution measurement of the cardiac output. It is essential to prepare the electronic equipment and test the catheter component before insertion. The access to central venous circulation for insertion of Swan-Ganz catheter is the same for placement of a central venous catheter in subclavian or internal jugular positions. The procedure has been facilitated by the use of introducer assemblies. Once an introducer sheath is in place, the pulmonary catheter is inserted and advanced until the tip reaches an intrathoracic vein (as evidenced by respiratory variations on the pressure tracing). The balloon is then inflated with 1.5 mL of air and the catheter is advanced while the pressure waveform and Valve for inflation the balloon Socket of distal lumen Socket of thermistor Proximal (RA) lumen Thermistor Extra socket Socket of proximal lumen Distal (PA) lumen Inflated balloon Swan-Ganz Catheter Central Venous, Arterial, and PA Catheters. Figure 9 The Swan-Ganz catheter. PA – pulmonary artery; RA – right atrium Central Venous, Arterial, and PA Catheters The Swan-Ganz catheter provides a significant amount of physiologic information that can guide therapy in critically ill patients. This information includes central venous pressure; pulmonary artery: diastolic, systolic, and mean pressures; pulmonary artery occlusion “wedge” pressure, cardiac output by bolus or continuous thermodilution techniques; mixed venous blood gasses by intermittent sampling; and continuous mixed venous oximetry. A multitude of derived parameters can also be obtained. 30 20 10 RA (1) Right atrium 527 Data Collected for Swan-Ganz Catheter the electrocardiogram tracing are monitored. The catheter is advanced through the right atrium and into right ventricle where a sudden increase in the systolic pressure appears on the tracing. The catheter is subsequently advanced through pulmonic valve and into the pulmonary artery where a sudden increase in the diastolic pressure is recorded. The catheter is gently advanced until a pulmonary artery occlusion or “wedge” tracing is obtained (Fig. 10). The balloon is deflated, a pulmonary artery tracing is confirmed, the catheter is secured, and a chest radiograph is obtained (Fig. 11). 0 mmHg C RV (2) Right ventricle PA (3) Pulmonary artery PCW (4) Pulmonary artery branch 4 3 1 2 Central Venous, Arterial, and PA Catheters. Figure 10 Pressure tracing recordings with corresponding locations as the pulmonary catheter is passed into the “wedge” position C 528 C Central Venous, Arterial, and PA Catheters Sc SVC MPA RLL PA RA RV Central Venous, Arterial, and PA Catheters. Figure 11 Normal course of a Swan-Ganz catheter. A Swan-Ganz catheter inserted on the right goes into the subclavian vein (Sc), into the superior vena cava (SVC), right atrium (RA), right ventricle (RV), main pulmonary artery (MPA), and in this case, the right lower lobe pulmonary artery (RLL PA) Hemodynamic variables are often expressed in relation to body size. A simple equation can replace the use of normograms: BSA (m2) = [Ht(cm) + Wt(kg) 60]/100 The parameters of cardiovascular performance directly measured (and normal values) are shown below: Central venous pressure (CVP) = 1–6 mmHg CVP is equal to pressure in right atrium. The right atrium pressure (RAP) should be equivalent to rightventricular end-diastolic pressure (RVEDP); then CVP = RAP = RVEDP Pulmonary capillary wedge pressure (PCWP) = 6–12 mmHg PCWP should be the same as the left-atrial pressure (LAP). The LAP should also be equivalent to the leftventricular end-diastolic pressure (LVEDP) when there is no obstruction between left atrium and ventricle. PCWP = LAP = LVEDP Cardiac index (CI) = 2.4–4.0 L/min/m2 CI = cardiac output/BSA Stroke volume index (SVI) = CI/heart rate (HR) (N = 40–70 mL/beat/m2) Right ventricular ejection fraction (RVEF) = SV/ RVEDP (= CVP) (N = 46–50%) Right ventricular end-diastolic volume (RVEDV) = SV/RVEF (N = 80–150 mL/m2) Left ventricular stroke work index (LVSWI) = (MAP PCWP)  SVI ( 0.0136) (N = 40–60 g.m/m2) where MAP = medium arterial pressure and 0.0136 is the factor that converts pressure and volume to units to work Right ventricular stroke work index (RVSWI) = (PAP CVP)  SVI ( 0.0136) (N = 4–8 g.m/m2) where PAP = medium pulmonary arterial pressure Systemic vascular resistance index (SVRI) = (MAP RAP)  80/CI (N = 1,600–2,400 dynes.s.m2/cm5) Pulmonary vascular resistance index (PVRI) = (PAP PCWP)  80/CI (N = 200–400 dynes.s.m2/cm5) The parameters of systemic oxygen transport are shown below (Hb = hemoglobin). Mixed venous oxygen saturation (SvO2) = 70–75% Oxygen delivery (DO2) = CI  13.4  Hb  SaO2 (N = 520–570 mL/min.m2) Oxygen uptake (VO2) = CI  13.4  Hb  (SaO2 SvO2) (N = 110–160 mL/min.m2) Oxygen extraction ratio (O2ER) = VO2/ DO2 ( 100) (N = 20–30%) Complications of Swan-Ganz Catheter The most common complication during the passage of pulmonary catheter is the development of arrhythmias. If an arrhythmia is noted, withdraw the catheter into the vena cava, and the arrhythmia should disappear. Rarely, treatment of arrhythmias is necessary, except complete heart block (which should be treated with a temporary transvenous pacemaker) and sustained ventricular tachycardia (which should be treated with lidocaine or other suitable antiarrhythmic agent). Coiling, looping, or knotting in the right ventricle may occur during catheter insertion. This can be avoided if no more than 10 cm of catheter is inserted after a ventricular tracing is visualized and before a pulmonary artery tracing appears. Aberrant catheter locations such pleural, pericardial, peritoneal, aortic, vertebral artery, renal vein, and inferior vena cava have also been reported. After catheter insertion, the complications include infection, thromboembolism, pulmonary infarction, pulmonary artery rupture, hemorrhage, pseudo aneurysm formation, thrombocytopenia, cardiac valve injuries, catheter fracture, and balloon rupture. Finally, complications can result from delay in treatment because of time-consuming insertion problems and from inappropriate treatment based on erroneous information or erroneous data interpretation. Central Venous, Arterial, and PA Catheters Arterial Catheterization Arterial catheterization is indicated whenever continuous monitoring of blood pressure or frequent sampling of arterial blood is required. Patients with shock, hypertensive crisis, major surgical interventions, and high levels of respiratory support require precise and continuous blood pressure monitoring, particularly when vasoactive or inotropic drugs are being administered. In shock patients, the difference between direct blood pressure and cuff blood pressure could be more than 30 mmHg in 50% of patients. The radial, ulnar, axillary, brachial, femoral, dorsalis pedis, and superficial temporal arteries have been used to access the arterial circulation for continuous monitoring. The radial artery of nondominant hand should be attempted first. The dual blood supply to the hand and the superficial location of the vessel make the radial artery the most commonly used site for arterial catheterization. The Allen test is frequently used to test the adequacy of collateral circulation before cannulation (Fig. 12). Ultrasonic Doppler technique, plethysmography, and pulse oximetry have also been used to assess the adequacy of the collateral arterial supply. The puncture site is slightly proximal (2 cm) to the flexion skin fold with a small catheter at 30–45 angle to the skin. For cannulation in the direct threading technique, the anterior wall of the artery is penetrated (A). When blood return is noted (B), the catheter is advanced farther up the arterial lumen as the needle is withdrawn (C) (Fig. 13). The cannula is then connected to a pressure monitoring system. a b C The axillary artery has been recommended for longterm direct arterial pressure monitoring because of its larger size, freedom for the patient’s hand, and close proximity to the central circulation. Pulsation and pressure are maintained even in the presence of shock with marked vasoconstriction. Thrombosis does not result in compromised flow in the distal arm because of the extensive collateral circulation. The major disadvantages are its low accessibility, visibility, and location within the neurovascular sheath, which may increase the risk of neurologic compromise if a hematoma develops. The major advantages of using femoral artery are its superficial location and large size, which allow easier localization and cannulation when the pulses are absent over more distal vessels. The major disadvantages are the decreased mobility of the patient, contamination from ostomies or draining abdominal wounds, and the possibility of occult bleeding into the abdomen or thigh. Both axillary and femoral arteries are cannulated by using the modified Seldinger technique. The dorsalis pedis artery may be absent in up to 12% of feet. Assessment of collateral flow to the remainder of the foot through the posterior tibial artery should precede cannulation. This can be done by occluding the dorsalis pedis artery, blanching the great toe by compressing the toenail for several seconds, and then releasing the toenail while observing the return of color. The major disadvantages of using the dorsalis pedis artery are its relatively small size and overestimation of systolic pressure (5–20 mmHg higher than the radial artery). c Central Venous, Arterial, and PA Catheters. Figure 12 Allen test: In (a) occlusion of both ulnar and radial arteries while patient makes a fist; (b) radial and ulnar arteries occluded after hand is opened; and (c) release of pressure on ulnar artery and observation for color return to hand within 5–10 s. This is a demonstration of patency of ulnar artery 529 C 530 C Cerebral Abscess a b c Central Venous, Arterial, and PA Catheters. Figure 13 Direct approach to cannulation of the radial artery The superficial temporal artery has been extensively used in infants and in some adults for continuous pressure monitoring. Because of its small size and tortuousity, surgical exposure is required for cannulation. A small incidence of neurologic complications resulting from cerebral embolization has been reported in infants. The brachial artery is not used often because of high complication rate associated with arteriography. Although this artery has been successfully used for short-term monitoring, there are little data to support prolonged brachial artery monitoring, and its use has been discouraged. Disadvantages include difficulty in maintaining the site and the possibility of hematoma formation in anticoagulated patients. The latter may lead to median nerve compression neuropathy and Volkmann’s contracture. Compartment syndrome of the forearm and hand has also been reported. Complications of Arterial Catheterization Major complications for all sites of arterial line insertion include: bleeding, ischemia, distal embolization, sepsis, neuropathy, arteriovenous fistula, and pseudoaneurysm formation. Inadvertent injection of vasoactive drugs or other agents into an artery can cause severe pain, distal ischemia, and tissue necrosis. Minor complications are: thrombosis, skin ischemia and local inflammation, infection, and hematoma. Infections are more frequent: (a) after 4 days of catheter placement, (b) when insertion is made by surgical cut down, and (c) presence of local inflammation. References 1. 2. 3. Irwin RS, Rippe JM (eds) (2007) Intensive care medicine, 6th edn. Wolkers Kluwer/Lippincott, Williams & Wilkins, Philadelphia, PA Marino PL (1998) The ICU book, 2nd edn. Williams & Wilkins, Baltimore, MD O’Donnell JM, Nácul FE (eds) (2001) Surgical intensive care medicine. Kluwer, Boston, MA/Dordrecht/London Cerebral Abscess ▶ Post-neurosurgical Empyema Brain Abscess and Subdural Cerebral Concussion Cerebral Concussion DANIEL B. CRAIG1, KATHRYN M. BEAUCHAMP2 1 Denver, CO, USA 2 Department of Neurosurgery, Denver Health Medical Center, University of Colorado School of Medicine, Denver, CO, USA Synonyms The term “cerebral concussion” is often used interchangeably with “minor traumatic brain injury” or MTBI. Other less common synonyms are: mild head injury, minor head trauma, mild brain injury. Definition Cerebral concussion can be defined as a post-traumatic, immediate, and transient change in neural function. The roots of “concussion” come from two Latin words – concutere (to shake violently) and concussus (the act of striking together). It is the most common type of head injury and has been recognized as a group of symptoms for centuries. The diagnosis of concussion is almost entirely clinical, and the range of symptoms is broad. The specific clinical definition of concussion has been contested over the years. The Vienna conference in 2001 set out to offer a comprehensive current definition resulting in a broad definition with highlights including: “an impulsive force transmitted to the head. . .rapid onset of short-lived impairment. . .resolves spontaneously. . .symptoms largely reflect a functional disturbance rather than structural injury. . .may or may not involve loss of consciousness. . .sequential resolution of symptoms. . .associated with grossly normal structural imaging studies.” The Debate Concussion amongst athletes is increasingly common and therefore it is important to have a common definition amongst practitioners from which to guide treatment. Many consider loss of consciousness at the time of injury or some minimal period of peri-traumatic amnesia as necessary symptoms. Others have searched for a clear structural brain injury – especially as imaging modalities improved to complement the physiological definition. In general, neurological and cognitive concussion symptoms are immediate, transient, caused by blunt-force trauma, and generally exist without a clear structural anatomic lesion. Historically, several evaluation systems evolved to categorize injuries based on initial symptoms, and many C recovery guidelines still use this grading system to determine return to activity protocol. At the Prague International Conference on Concussion in Sport (2004) [1], the authors supported the trend toward abandoning the classic concussion grading scale as true severity of injury has shown limited correlation to the number and duration of acute concussion signs/symptoms. Instead, they argued for a division based on management needs into simple or complex concussion. Progressive resolution of symptoms within 7–10 days defines simple concussion and represents the vast majority of injuries without the need for formal intervention or extensive neuropsychological screening. Complex concussion indicates persistent symptoms, prolonged loss of consciousness (>1 min), or prolonged cognitive impairment and requires more formal medical management with consideration of imaging, and multi-disciplinary follow-up. One final area of current debate is that of concussion being a linear spectrum of severity or a group of distinct subtypes. The spectrum ideology has been the classic model, but the variations in clinical outcome with the same impact force suggest discreet differences in pathology. This complements the progress in understanding the mechanism of injury, and may help explain why a clear common pathway in concussion remains somewhat elusive. Mechanism The blunt forward or oblique force with impact causes a rapid acceleration/deceleration of the head and a resulting anterior/posterior movement of the brain within the cranial vault. Several theories about the resulting neuronal dysfunction involve ionic shifts, altered metabolism, impaired connectivity, and changes in neurotransmission. Reticular theory suggests a temporary paralyzation of the brainstem reticular formation. Centripetal hypothesis involves a mechanical disruption of neuronal tracts. The pontine cholinergic scheme describes an activation of cholinergic neurons causing a suppressed behavioral response. The convulsive response theory is based on induction of generalized neuronal firing. No conclusive human studies have confirmed a specific mechanism, and the underlying pathophysiology is likely multifactorial. Giza and Hovda [2] describe in an animal model a train of biochemical activity in response to blunt trauma. The initial insult causes a neurochemical cascade and membrane/axon dysfunction leading to: increased extracellular potassium ! depolarization ! excitatory neurotransmitter release ! neurotransmitter storm ! generalized post-storm suppression. This series ultimately causes increased glucose use and lactate production, 531 C 532 C Cerebral Concussion decreased cerebral blood flow, NMDA receptor activation, calcium influx, and impaired oxidative metabolism. This theory is limited with respect to neuro/cognitive evaluation in an animal model, but it does offer a hypothesis on the biochemical basis of the generalized post-concussion syndrome. Overall, concussion can be viewed as a combination of mechanical changes from shearing or torsional forces in addition to a related cascade of neurochemical events. This is characterized in an animal model by massive initial depolarization and ultimate decrease in cerebral perfusion leading to metabolic depression. The real-time progression of physiologic events helps explain the later onset of some symptoms of concussion, and the cascade has been shown to render brain tissue more vulnerable to further injury. Recent studies have shown persistent metabolic alterations long after initial injury, and further studies may one day explain or even predict long-term postconcussion syndrome. Presentation The injured patient will present after a non-penetrating blunt impact to the head with a range of neurologic and cognitive symptoms. Common presentations include: brief loss of consciousness, period of retro and anterograde amnesia, visual disturbances, and disorientation. He or she may also experience dizziness, nausea and vomiting, balance problems, emotional lability, sleep disturbances, sensitivity to light or sound, fatigue, numbness/tingling, and loss of concentration. Autonomic signs include pallor, bradycardia, mild hypotension, and sluggish pupillary reaction. Less common are brief convulsions and specific neurologic deficits. Assessment of these symptoms may depend on witnesses to the event (loss of consciousness may be very brief and often missed), and availability of immediate evaluation (symptoms may be transient). This need for rapid assessment of mental status and neurologic changes encourages the use and standardization of the initial survey by the first responder (coach, trainer, doctor, EMT). Treatment In the majority of cases, the symptoms of concussion resolve spontaneously – usually in 7–10 days. Thorough serial neurologic examinations are crucial to monitor resolution of symptoms and to rule out more serious injury. At a molecular and anatomic level, the pathophysiology of the brain injury and its progression remains loosely defined and thus resists development of medical/surgical intervention to hasten recovery. As our ability to evaluate concussion has grown, the need for and length of hospitalization has decreased. Several overlapping and competing theories for the proper rehabilitative steps to return to play will be discussed in more detail later. A handful of studies have examined the importance of intentional supervised rehabilitation post concussion. Original trials in the late 1970s showed the benefit of early ambulation, activity, and education [3]. More recently, there is focus on outpatient rehab as hospital stays decrease. A randomized controlled trial in 2007 showed that early active rehabilitation did not change the outcomes of post-concussive symptom resolution and life satisfaction after 1 year between intervention and control groups [4]. Treatment is primarily tailored to the individual while determining the extent of injury. One of the most important factors in recovery remains the time from the initial injury. The pharmacologic management of the specific symptoms of concussion lacks high-level evidence. Antidepressants are the most commonly prescribed treatment for post-concussion syndrome, specifically SSRI’s and newer heterocyclics. Trazodone can be an effective choice for insomnia, although its anticholinergic side effect profile may limit its use. Acetylcholinesterase inhibitors (physostigmine, donepezil), and choline precursors (lecithin, CDP-choline) have been shown to improve neuropsychological test performance, but are limited by short half-life, side effects, and route of administration. Evaluation At the Scene Initial survey at the scene of the head injury is crucial. Primary trauma survey should be the first step (airway, breathing, circulation, disability, exposure). After vital signs have been stabilized, a more detailed examination may be performed. A neurologic exam assessing cranial nerves, coordination, motor function, and cognitive function should be performed based on the severity of injury. Questionnaires such as the mini-mental-status exam and the Maddocks questions can be quite useful for quick evaluation of a patient’s cognition and orientation and can be learned and used effectively by nonmedical personnel. At the Hospital Patient’s arriving at the hospital after concussion should be evaluated similar to the initial screen but with more thorough neurologic exam. A non-contrast head CT may be considered. Indications of a more serious injury Cerebral Concussion include: focal neurologic deficit; seizures; prolonged altered level of consciousness; oto-rhinorrhea; diplopia; anisocoria; and progressive symptoms. Concussion is classically characterized as immediate onset of symptoms, but this is not always the case. Symptoms may arise up to hours after the initial injury. However, progressive worsening of an established symptom is a red flag for possible structural injury and indicates the need for further workup. Patients presenting with a mild concussion generally do not require hospital admission, but it is important to verify that they go home with another adult capable of following their symptoms. For outpatient treatment of pain, acetaminophen is the drug of choice and narcotics and NSAIDS should be avoided due to the risks of increased intra-cranial pressure and hemorrhage respectively. If the presence of a more serious injury is suspected based on previously mentioned criteria, a more thorough evaluation is warranted. These patients should be admitted for close observation. In these instances, CT or MRI imaging is useful to rule out epidural/subdural hematoma, cerebral contusion, or possible skull fracture. Length of inpatient stay depends on individual recovery and diagnosis of more serious injury. The Acute Concussion Evaluation (ACE) provides a thorough initial medical evaluation of the patient presenting with concussion. This questionnaire evaluates the specifics of the injury and assessment of symptoms and risk factors. The Sport Concussion Assessment Tool (SCAT) developed by the Prague International Conference in 2004 is another tool for thorough graded assessment combining elements of the sideline tests with more exhaustive neuro-physical exam. The use of a standardized form is especially helpful to provide a baseline for future evaluations. It can also be an effective means of standardizing communication between various levels of medical personnel (PA, EMT, nurse, trainer, MD). C consistently demonstrate frontal and/or temporal hypometabolism following concussion both at rest and during tasks, but have had limited clinical applicability. Several newer modalities show promise in both diagnosis and assessment of recovery, specifically functional MRI (fMRI), event-related potentials (ERP’s), and magnetic source imaging (MSI) [5]. fMRI studies demonstrate increased overall brain activation during memory and sensorimotor tasks in postconcussion patients, and note a discernible difference in prefrontal cortex usage between injured and non-injured subjects with an inverse relationship between prefrontal working memory area (mid-dorsolateral) usage and symptom severity. The symptomatic subjects included in these studies had no abnormalities on T2 MRI, thus functional impairment can be observed in the absence of clinical imaging abnormalities. ERP’s represent the average electroencephalogram (EEG) signal in response to stimulus, and response time and amplitude have both proven to consistently vary with symptom severity where EEG and evoked potential (EP) testing results have been largely mixed and inconclusive. MSI integrates MRI anatomic data with magnetoencephalography which measures electrical signal parallel to skull surface detecting real-time brain activity without distortion from tissue connectivity variance between brain, bone, and skin. MSI sensitivity surpasses that of MRI or EEG alone. The clinical utility of these more complex imaging techniques is in its infancy, but they show potential for a quantifiable method of diagnosis, assessment of recovery, and further explanation of underlying pathophysiology [5]. Effectiveness The effectiveness of mTBI evaluation is best measured by the ability to rule out more serious injury and ensure safe return to normal activity. As discussed in the previous section, consistent clinical exams, proper use of imaging, and patience ensure high sensitivity and specificity of diagnosis. Role of Imaging Indications for CT and MRI to rule out more serious injury have classically been controversial and subjective, and there have been efforts to standardize these practices (Canadian Head CT Rule, New Orleans Criteria). In addition to ruling out anatomic injury, the role of imaging in evaluation of concussion has progressed significantly with the advent of more sophisticated techniques. Thus far, studies have demonstrated inability to correlate postconcussive MRI findings with symptoms or long-term outcome. Positron emission tomography (PET) scans Tolerance The cautious approach to returning to high risk activity comes in large part from the vulnerability of the postconcussion patient to a second injury more severe than the first. The Second Impact Syndrome (SIS) is a controversial term introduced in the 1980s describing repeat head injury within a few weeks of a concussion causing diffuse cerebral swelling, brain herniation, and death. Controversy stems from the paucity of case data with most examples coming from disputed cases primarily in children [6]. 533 C 534 C Cerebral Concussion Despite the low incidence, the extreme morbidity of SIS makes it hard to ignore and encourages lengthening recovery time especially in children. While the SIS debate continues, the increased risk for subsequent traumatic brain injury (TBI) in patients who have sustained at least one previous TBI is much less contested. The significance of this increased risk encompasses more than just multiple mTBI recoveries as a history of repeated concussions over an extended period of months to years can result in cumulative neurologic and cognitive deficits. This has been studied especially in boxers and football players and is a major concern regarding long-term management. This cumulative risk as well as the fear of SIS explains the previous concussion as a factor in return to play guidelines. Pharmacoeconomics The CDC estimates the incidence of mTBI at 1.1 million per year including 300,000 sports-related concussions. This translates to roughly $17 billion spent on concussion evaluation and treatment each year. These figures likely underestimate actual disease burden due to variance in assessment and reporting. Costs include both direct evaluation and treatment and time lost at work or on the field. After-care At Home Patients sent home with a mild concussion require observation and frequent reassessment, noting any continuation and/or deterioration of symptoms. Mental status changes and potential amnesia in the patient make it important to clearly explain red flag symptoms and serial evaluation instructions to the accompanying adult as well as the patient. There has been no documented evidence regarding the common practice of waking the patient every 3–4 h to assess, but in patients experiencing loss of consciousness, prolonged amnesia, or other persistent significant symptoms this is still recommended. Decisions regarding day to day activities such as driving and return to work or school should reflect the individual patient’s rate of recovery. A follow-up visit to and outpatient provider is appropriate to confirm symptom resolution. Medical Society Guidelines (CMSG) emerged in response to several deaths due to head injury, and, along with algorithms by Cantu (1986), the American Academy of Neurology (AAN) and others, their structure reflects the initial symptom milieu of the injury (specifically presence and duration of loss of consciousness and amnesia) and number of previous concussions. These guidelines express the need for longer asymptomatic waiting periods based on injury severity. The Vienna Summary and Agreement Statement from 2001 emphasizes a medically supervised, stepwise process for return to play, moving from no activity to light aerobic exercise, sport-specific training, non-contact drills, fullcontact training, and finally game play with minimum stage duration of 24 h. This system depends first on the complete lack of symptoms before starting any activity. These two schools of thought lend themselves to a combination approach with the guidelines of the CMSG, Cantu, AAN et al. determining when to begin activity and the Vienna statement clarifying a stepwise method of return to full-speed, full-contact participation. Prognosis Most concussions fall into the “simple” category as outlined earlier. In these cases the prognosis is very good, with symptoms resolving completely in 7–10 days in 90% of cases. In more complex injuries, the duration and severity of symptoms increase, but a full recovery is common. Up to one-third of patients report increased headaches 1 year after trauma. Multiple concussions over time increase the risk of permanent neurologic damage, and up to 15% of patients may experience long-term symptoms after a single event. References 1. 2. 3. 4. 5. Return to Play Many sets of guidelines offer rational and clinical approaches for return to activity, and it is important to clearly communicate these recommendations amongst patients, families, and providers. In 1991, the Colorado 6. 7. McCrory P, Johnston K, Meeuwisse W et al (2005) Summary and agreement statement of the 2nd international conference on concussion in sport. Clin J Sport Med 15(2):48–55 Giza C, Hovda D (2001) The neurometabolic cascade of concussion. J Athletic Train 36(3):228–235 Relander M, Troupp H, Bjorkesten G (1972) Controlled trial of treatment of cerebral concussion. Br Med J 4:777–779 Andersson E, Emanuelson I, Bjorklund R et al (2007) Mild traumatic brain injuries: the impact of early intervention on late sequelae, a randomized control trial. Acta Neurochir 149(2):151–160 Mendez C, Hurley R, Lassonde M et al (2005) Mild traumatic brain injury: neuroimaging of sports-related concussion. J Neuropsychiatry Clin Neurosci 17:297–303 McCrory P (2001) Does second impact syndrome exist? Clin J Sport Med 11(3):144–149 Aubry M, Cantu R, Dvorak J et al (2001) Summary and agreement statement of the first international conference on concussion in sport, Vienna 2002. Br J Sports Med 36:6–7 Cerebral Malaria Cerebral Malaria SUZANNE M. SHEPHERD, WILLIAM H. SHOFF Department of Emergency Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Synonyms Paludism Definition Cerebral malaria has been strictly defined by the World Health Organization (WHO, 2000) as a patient with confirmed plasmodium infection, usually P.falciparum, who is unarousable (Glascow Coma Scale score </= 9), and has had other potential causes of coma excluded. Many metabolic and infectious processes may cause the types of neurologic signs and symptoms associated with malaria, and the presence of malaria parasite may be incidental in endemic areas. This rather strict definition was developed for research, as such many individuals with cerebral malaria have less severe impairment of consciousness. In practice, the diagnosis of cerebral malaria is difficult with a high sensitivity but a low specificity. The diagnosis of falciparum malaria should be considered in any patient with a febrile illness including neurological symptoms, who has visited or lived in a malaria-endemic area in the past 3 months. Cerebral malaria is an acute, widespread infection of the brain with features of diffuse encephalopathy. The neurological manifestations of malaria develop rapidly and include acute severe headache, irritability, agitation, delirium, psychosis, seizures, and the hallmarks of impaired consciousness and coma. Cerebral malaria is the most serious complication of falciparum infection and the most common cause of death. Cerebral malaria is also reported in individuals infected with P.vivax and more recently P. knowlesi. Treatment If left untreated, cerebral malaria is fatal within days of infection. Severe malaria is considered a medical emergency and institution of immediate treatment is crucial. Patients should be managed at the highest level of care at the best available health care facility. ICU facilities are limited in malarial areas; therefore, patient triage to these scarce resources must identify those at greatest risk of complications. Misra et al. developed a simple but specific triage tool for adults, the malaria severity C assessment (MSA) score; however, this tool requires information that is not available at the time of hospitalization. Hanson et al., using logistic regression, developed a five-point scoring system which was validated in patient series from Vietnam and Bangladesh. The level of acidosis (base deficit) and the Glascow Coma Scale were the two main independent predictors of outcome and the coma acidosis malaria (CAM) score was derived from these variables. Mortality was found to increase with increasing score. A CAM score <2 predicted survival (PPV 95.8%, CI 93–97.7%) and safe treatment on a general ward if renal function could be carefully monitored [1]. Treatment involves administration of parenteral antimalarials, close patient monitoring to ensure early recognition and management of common complications, and the use of adjunctive treatment measures. Common complications include hypoglycemia, seizures, fluid and electrolyte imbalances, anemia, coagulation disorders, acidosis and respiratory distress and renal dysfunction. Serum glucose, sodium, lactate, urine output, and renal function should be monitored frequently. Hypoglycemia may occur with minimal to no clinical signs; therefore, serum glucose should be monitored at frequent intervals. Pharmacologic Management Use of antimalarials is the only treatment that clearly reduces mortality. Antimalarials are administered intravenously for 48 h and then orally if the patient is able to take oral medications. Even fast acting antimalarials often require 12–18 h to kill plasmodia. Treatment response is assessed by daily parasite count until clearance of all P.falciparum trophozoites is achieved from the blood. Parasitemia may increase during the initial 12–24 h because available antimalarials do not inhibit schizont rupture with release of merozoites. Rising parasitemia beyond 36–48 h after the initiation of antimalarials indicates treatment failure, usually because of high-level drug resistance. Because nonimmune hosts may have a high pretreatment total parasite burden (1,000 parasites), it may take up to 6 days to achieve complete elimination. Treatment duration depends on the sensitivity of the parasite and parasite burden, but usually lasts 7 days. Parenteral quinine has been the traditional treatment of choice for cerebral malaria, as patients with severe malaria are assumed to have chloroquine resistance. Artemisinin derivatives are now recommended by the World Health Organization (WHO) as the drugs of choice for severe malaria. Both drugs are used in combination with other 535 C 536 C Cerebral Malaria antimalarial drugs, such as doxycycline (100 mg bid PO or IV x7d) with quinine, to shorten therapy duration and prevent the emergence of resistance. Quinine is one of four main alkaloids derived from the bark of the Cinchona tree. Quinine kills plasmodia in the late stages of their erythrocyte cycle via inhibition of hemazoin biocrystallization, facilitating aggregation of cytotoxic heme products. A loading dose of quinine is recommended to rapidly develop anti-parasitic levels. 20 mg/kg body weight (salt), in normal saline or dextrose saline solution, is infused over 4 hours, preferably via infusion pump. Maintenance dosing is 10 mg/kg body weight (salt) infused every 8 h until the patient is able to take oral medication. Quinine has a narrow therapeutic window. Quinine can produce hypoglycemia via promotion of insulin secretion. Quinine causes hypotension with rapid intravenous infusion. It slows ventricular repolarization, with resultant QT prolongation. Quinine also produces cinchonism and dizziness. Quinidine has been used preferentially in the USA, given in a loading dose of 6.25 mg/kg base (=10 mg/kg salt) infused intravenously over 1–2 h, and then as a continuous infusion of 0.0125 mg/kg/min base (=0.02 mg/kg/min base). If continuous infusion is not feasible, 15 mg/kg base (=24 mg/kg salt) loading dose is infused intravenously over 4 hrs, then 7.5 mg/kg base (=12 mg/kg salt) infused over 4 h every 8 h, beginning 8 h after the loading dose. Cinchonism is a symptom complex characterized by tinnitus, hearing impairment, postural hypotension and vertigo or dizziness that occurs in a high percentage of individuals treated with quinine for malaria. Newer studies demonstrate artemisinin derivative superiority in both rapidity of parasite clearance and fever defervescence, but they have not demonstrated improved effect on mortality rates [2]. Currently, two derivatives, artesunate and artemether, are the most widely used due to efficacy and low cost. Artemisinin, was developed as a traditional treatment for fever and malaria in China (Qinghaosu). Artemisinin is a sesquiterpene lactone derived from the sweet wormwood, Artemesia annua. Artemisinin derivatives kill all stages of the parasite within the erythrocyte and also kill gametocytes. Artemisinin derivatives can also be administered intramuscularly or rectally and have few local or systemic adverse effects. Artesunate is given as two 2.4 mg/kg doses intravenously 12 h apart on day 1, and then is administered as 2.4 mg/kg daily for 6 days or given orally if the patient is awake and able to swallow. Artesunate is used in combination with Amodiaquine 10 mg/kg once a day for 3 days. These derivatives are not fully licensed in many countries; however, intravenous artesunate is available as an investigational new drug in the USA for management of severe malaria. A number of adjunctive treatments have been studied in cerebral malaria. Fluid balance is critical. Children are often hypovolemic and require fluid administration; however, there is no consensus with regard to the optimal type and amount of fluid replacement. In patients with cerebral malaria who have elevated intracranial pressure maintenance of cerebral perfusion, pressure is necessary and it has been suggested that fluid management be optimized; however, no guidelines have been developed. Adults with severe malaria may develop pulmonary edema and severe renal impairment, in these instances fluid may need to be restricted. Albumin has been studied, as it is suggested to improve microcirculatory flow and treat hypovolemia. Initial data from Phase II Clinical trials in children with malaria suggest that 4% albumin improves mortality compared with saline, particularly in those children with coma. Albumin is currently under investigation in a large study of children with sepsis and malaria. Other colloidal agents, including hetastarch and dextran 70, are also currently under investigation. Acetaminophen (paracetamol) may be used to reduce fever. It remains unclear if reduction in core temperature benefits cerebral consequences. Phenobarbital sodium, phenytoin, or benzodiazepines are utilized for seizure management. Benzodiazepines may have reduced efficacy as malarial infection appears to downregulate g-aminobutyric acid (GABA) receptors. Both phenytoin and phenobarbital have been used successfully to terminate prolonged seizures. Prophylactic anticonvulsant use has also been studied. Prophylactic administration of a single dose of phenobarbital reduced seizure frequency in studies of both Indian and Thai adults and Kenyan children with cerebral malaria; however, it was associated with an increased rate of death, probably due to depression of hyperpnea that compensated for metabolic acidosis in these unventilated patients. Standard treatment regimens have been used to manage hypoglycemia. Both the administration of glucose solutions and the administration of longer acting somatostatin analogs have been utilized successfully to manage hypoglycemia, the later in patients receiving quinine therapy. Theoretical concern has been raised whether the correction of hypoglycemia in the presence of tissue hypoxia may worsen brain tissue acidosis. A number of other adjunctive treatments have been studied. None have shown clear-cut improvement in clinical trials. Most were studied in conjunction with Cerebral Malaria quinine treatment; as such their efficacy in combination with artemisinin derivatives remains undetermined. None are recommended as standard management at this time. Corticosteroids were the initial agents studied in randomized controlled trials, as they were felt to have promise in reducing intracranial pressure and inflammatory response. Two randomized trials in Southeast Asian adults and a smaller study in Indonesian children did not demonstrate any benefit. In fact, in one trial dexamethasone demonstrated an increased rate of significant complications, including sepsis, gastrointestinal bleeding and prolonged recovery time from coma. Anti-inflammatory drugs, mannitol, urea, iron chelators (deferoxamine), low-molecular-weight dextran, heparin, pentoxyfylline (reduces cytokine secretion, prevents rosetting and reduce cytoadherence), hyperimmune globulin, dichloroacetate, and hyperbaric oxygen have shown either mixed results or no value. Monoclonal antibodies against TNF-a have been found to shorten fever duration but have shown no impact on mortality, and may actually increase morbidity from neurologic sequellae. N-acetylcysteine, another antioxidant which improves erythrocyte deformability and reduces TNF release is currently under trial. Erythropoietin is also currently being investigated, based on human and animal studies that suggest a neuroprotective effect with reduction in inflammatory response and apoptosis in the brain [3, 4]. Blood transfusions are indicated for severe anemia, with the amount and rapidity of transfusion different for children and adults. In children, fresh whole blood (10–20 ml/kg) is often transfused. In adults, small quantities of blood are administered over a more prolonged period due to concerns about fluid overload. The role of exchange transfusion in severe malaria is controversial. Exchange transfusion has been utilized when the level of parasitemia exceeds 10–20% of circulating erythrocytes. The WHO currently recommends that individuals with severe malaria receive exchange transfusion with a parasitemia >20%. Exchange transfusion also allows correction of severe anemia without the risk of fluid overload. Exchange transfusion is expensive. No data from well-conducted clinical trials demonstrate improved outcomes with exchange transfusion. Epidemiology Malaria is felt to be the most deadly vector-borne disease globally. An estimated 2.4 billion individuals live in malaria-endemic areas worldwide, with 300–500 million clinical episodes and approximately two million deaths C reported annually. 10% of admissions and 80% of deaths are due to central nervous system involvement. Plasmodium falciparum causes most cases of severe malaria and approximately 35–43% of all cases of malaria globally. More than 70% of falciparum malaria infections occur in children living in sub-Saharan Africa, although individuals of any age may become infected. Males and females are equally affected, but malaria, especially falciparum, can be devastating in pregnancy to both the mother and fetus. Malaria is seen increasingly in nonendemic countries due to individuals traveling to endemic areas for business and pleasure and infected individuals emigrating or traveling from endemic areas. Occasionally, malaria is seen in individuals who have traveled to an endemic area more than one year previously, during relapse in those previously infected, or in individuals in non-endemic areas who have been bitten by local mosquito populations which have become infected after biting a parasitemic individual, or in individuals who live near airports. Malaria is infrequently transmitted congenitally, in those who needle share, or in those who have received blood transfusions or organ transplant. More than 1,500 cases are diagnosed in the USA each year, most of which were acquired internationally. Malaria is transmitted via the bite of an infected female Anopheles spp mosquito obtaining a human blood meal. Anopheles mosquitoes predominantly bite between dusk and dawn. Malaria usually occurs below elevations of 1,000 m (3,282 ft). At risk areas include more than 100 countries, including portions of Central America, South America, the Caribbean, the Middle East, sub-Saharan Africa, Southeast Asia, the Indian Subcontinent and Oceania. Malaria, due to intense vector control efforts, ceased to be endemic in the USA in 1947. After malarial sporozoites are injected into the bloodstream by an infected mosquito, parasites develop in an asymptomatic hepatic stage. Infected hepatocytes burst, releasing merozoites which enter erythrocytes. P. falciparum is able to infect a red cell during any stage of its development. As such, P. falciparum cause asynchronous cycles of schizont lysis. This asynchronous release of trophozoites and hemazoin and other toxic metabolites does not necessarily produce the classically described cyclical paroxysms of fever, chills, and rigors. In late stages of infection, infected erythrocytes adhere to the capillary and venule endothelial cells, becoming sequestered in many areas of the body. The brain appears to be preferentially targeted. Parasites are metabolically active, consuming glucose and producing increased amounts of lactate via anaerobic glycolysis. 537 C 538 C Cerebral Malaria Current estimates suggest that nearly half of all children admitted to the hospital with falciparum malaria exhibit neurological signs and symptoms. In endemic areas, adults and children develop cerebral disease in similar proportions. The incidence of cerebral malaria in adults is higher in low and moderate transmission areas and areas of varying endemicity than in hyper- and holoendemic areas. In travelers, cerebral malaria occurs in approximately 2.4% of those documented with falciparum malaria infection. The pathophysiology of cerebral malaria is not completely understood, but appears to be multifactorial. First, sequestration of parasitized red blood cells produces mechanical clogging of the cerebral microvasculature. Infected red blood cells develop parasite-mediated changes in cytoadherent properties due to specific interaction between P. falciparum erythrocyte membrane protein (PfEMP-1) and ligands on endothelial cells, such as ICAM-1 or E-selectin. Parasitized cells and nonparasitized red blood cells selectively adhere to each other and to venule and capillary endothelium, termed rosetting. Decreased deformability of infected cells increases obstruction. Platelet microparticles also mediate clumping. Obstruction of the microcirculation leads to a critical reduction in oxygen supply and increase in lactic acidosis locally. Hemazoin is found in cerebral blood vessels on autopsy, suggesting that rupture of sequestered infected erythrocytes may produce local inflammation. Parasite and host immune response also contribute significantly to the pathophysiology of cerebral malaria. P.falciparum infection and RBC lysis releases both parasite toxins and host intracellular molecules. These are recognized by pattern recognition receptors on immune surveillance cells that promote the activation and release of both pro-inflammatory and anti-inflammatory cytokines from monocytes and neutrophils and upregulation of the expression of adhesion molecules and metabolic changes in endothelial cells. It is thought that this inflammatory response is initially beneficial to the host by reducing parasite growth and activating pathways to eliminate parasites and parasite and host toxins. At later stages, uncontrolled, this inflammatory response causes host damage directly and elimination pathways are inadequate to remove generated toxins. Increased amounts of macrophage-released TNF-a, IL-1, IL-6, IL-10, and other proinflammatory cytokines have been documented in murine models and patients with cerebral malaria. Several pediatric studies suggest an association between elevated levels of IL-1 receptor antagonist and severe malaria, while high levels of vascular endothelial growth factor have been found to be protective against death in patients with cerebral malaria. Nitric oxide (NO) has been suggested as a key effector for TNF in malaria pathogenesis. Cytokines upregulate nitric oxide synthase in leukocytes, vascular smooth muscle, microglia, and brain endothelial cells. One theory suggests that uncontrolled amounts of nitric oxide diffuse easily through the injured blood brain barrier. NO may change blood flow and decrease glutamate uptake, producing neuro-excitation. As a potent inhibitor of synaptic neurotransmission, NO also reduces the level of consciousness rapidly and reversibly, similar to that caused by general anesthetics and alcohol. This would explain reversible coma without residual neurological deficits. Apoptosis has been documented in the brainstems of adults who died from cerebral malaria; however, the level of caspase staining was not significantly higher than that in control individuals without malaria. The blood brain barrier is impaired in patients with cerebral malaria and vascular permeability is increased. T cells have been shown in murine models of cerebral malaria to impair endothelial cell function by perforinmediated mechanisms leading to blood brain barrier leakage. Postmortem analysis of individuals with cerebral malaria show widespread disruption of vascular cell junctional proteins (occludin and viculin). Diffuse brain swelling is demonstrated on imaging studies and autopsy materials. This swelling is not associated with vasogenic edema. Brain swelling is probably attributable to increased blood volume that occurs secondary to sequestration and increased cerebral blood flow. Greater than 80% of children with cerebral malaria develop elevated ICP and some develop severe intracranial hypertension, and herniation is more common in children. Intracranial hypertension is not seen as frequently in adults. Risk Factors A number of factors are associated with poor outcome in cerebral malaria. Historical factors include pretreatment at home with antimalarials and chronic malnutrition. Clinical factors include an abnormal respiratory pattern, hyperpyrexia, hypoperfusion with cool extremities, tachycardia, jaundice, prolonged seizures, and the absence of corneal reflexes or a coma score of 0 or 1. Laboratory factors include hyperparasitemia (>500,000/mL), leukocytosis (>10,000/mL), hypoglycemia, abnormal AST, and elevated lactate and urea levels. Mortality risk is very high in children less than 5 years of age. Young women during their first pregnancy are at increased risk. Malaria complications in pregnancy are thought to be mediated by placental sequestration of plasmodia and pregnancy-associated anemia and Cerebral Malaria decreases in immune function. Fetal complications include premature birth and low birth weight, severe anemia and death. Nonimmune individuals are also at increased risk. Individuals who live in malaria-endemic areas develop partial immunity to infection after repeated exposure; as such they experience less severe infections. Individuals with HIV coinfection are at increased risk for worsened clinical outcomes in both infections. Malaria and intestinal helminths often coexist in the same poor populations globally; as such increasing attention is being paid to the interaction between these organisms in coinfected individuals. Data from some recent field studies suggest that helminth coinfection may play a protective role in cerebral malaria, via Th2 response and the interaction between nitric oxide and the low affinity immunoglobulin E binding receptor CD23 [5]. Individuals with sickle cell trait (Hemoglobin S), and less so with Hemoglobin C, thalassemias, glucose-6phosphate-dehydrogenase deficiency (G6PD) are protected against infection and death from falciparum malaria. Individuals with Hemoglobin E may be protected against vivax malaria. Individuals of West African ancestry lacking RBC Duffy antigen are completely protected against P. vivax infection. Several TNF gene-promoter polymorphisms have been shown to be associated with an increased risk of cerebral malaria, neurological sequelae and death. Plasma levels of inducible TNF receptor proteins have been suggested as potential biomarkers of cerebral malaria severity and mortality risk. Evaluation and Assessment Almost all patients will have fever, rigors, and chills. Altered sensorium may be present initially or may develop over the course of 24–72 h. Coma usually develops rapidly in children, often after seizure activity. If seizure activity has occurred, the patient should remain unresponsive for more than 30 min to 1 h after active seizure activity to suggest the diagnosis of cerebral malaria rather than postictal state. Approximately 15–20% of adults demonstrate seizure activity. Most seizures appear generalized, but on EEG many are documented to have a focal origin. In adults, coma tends to develop more slowly and may not be associated with seizure activity. Mild neck stiffness may be present, but true meningismus is usually absent. Photophobia is rare. Malarial retinopathy has been demonstrated to be more specific than any other clinical or laboratory feature in distinguishing coma due to malaria from other etiologies. Malarial retinopathy consists of vessel changes, retinal pallor, hemorrhages, and less commonly papilledema. Retinal hemorrhages occur in C approximately 15% of cases and may have a white center. Pupils are normally reactive. Transient dysconjugate gaze may be seen. Motor examination usually demonstrates symmetrical upper motor neuron dysfunction, although muscle tone may be decreased. Bilateral extensor plantar reflexes may be seen in comatose patients. Pout reflex, bruxism, jaw spasm, opisthotonos, and decorticate and decerebrate posturing may be present, more commonly in children. Corneal reflexes are preserved except in deep coma. Patients often exhibit a change in diurnal rhythm, with excessive sleepiness during the day and difficulty sleeping at night. Patients may exhibit somnambulism. The criterion standard diagnostic test for malaria is the microscopic examination of Giemsa-stained blood smears by an appropriately trained individual, including a thin smear to determine the level of parasitemia and a thin smear to speciate the organism(s) present. Three negative sets of smears at 8–12 h intervals are required to rule out malaria. More than one species of malarial organism may be present. Microhematocrit centrifugation and Fluorescent dye Quantitative Buffy Coat staining may also be utilized; however, these do not allow speciation. Rapid testing (RDT) for P. falciparum and P. vivax has assumed a more prominent role in the last several years. RDTs are based on antibody recognition of histidine-rich protein 2 (HRP-2) parasite antigens. In most cases, they have been found to be as specific as microscopy, although they are not as reliable when parasite levels are <100 parasites/ml blood. A false positive may occur up 2 weeks post treatment due to the persistence of circulating antigen after parasite death. A list of currently available RDTs, and technical information, can be found at the WHO/WRPO site Malaria Rapid Diagnostic Tests (http://www.wpro.who.int/sites/rdt). PCR for parasite mRNA or DNA is specific, and more sensitive than microscopy; as such it will detect organisms at very low levels of parasitemia. It is more expensive, requires specific equipment, and does not provide an estimate of the parasite load. A number of factors globally, including a lack of diagnostic materials and of trained technicians to perform blood smears and rapid testing, low sensitivity of rapid tests in patients with low-level parasitemia, the inability of some treatment centers and hospitals to exclude other diagnoses, lack of severe symptoms in some individuals in endemic areas, a low specificity of the clinical features of the disease, and the concomitant occurrence of other organ dysfunctions and metabolic changes present in severe malaria contribute to both misdiagnosis and overdiagnosis of cerebral malaria. Overdiagnosis leads to unnecessary treatment with potentially dangerous drugs, 539 C 540 C Cerebral Malaria insufficient investigation of other potentially deadly causes, high mortality rates, and the development of resistance. Patients will have variable degrees of anemia, thrombocytopenia, and may have jaundice, hepatosplenomegaly, and renal dysfunction. It is important to determine if the patient is pregnant. A number of factors may contribute to neurological symptoms and signs in malaria. Coinfection may be present, and other causes of fever, such as bacterial meningitis/meningoencephalitis and viral encephalitis, must be considered and ruled out with lumbar puncture and CSF analysis. In malaria, CSF opening pressure is normal to elevated, fluid is clear, protein and lactate levels are elevated to varying degrees, and a mild pleocytosis is present with a white blood cell count less than 10/mL. Fever alone may cause impairment of consciousness, delerium and febrile seizures. Hypoglycemia due to cerebral infection or the use of antimalarials such as quinine may also produce altered mental status, neurological deficits or seizure activity. Hypoglycemia is most common in very young children and pregnant patients. Antimalarial drugs, including chloroquine, quinine, mefloquine and halofantrine may cause neuropsychiatric symptoms, including altered behavior, hallucinations, psychosis, and delerium and seizures. Hyponatremia in elderly patients, due to repeated vomiting, or secondary to injudicious fluid administration may lead to altered mental status and seizures. Severe anemia and hypoxemia may lead to altered mental status. Focal neurological deficits are rare in falciparum malaria and should suggest another cause. An EEG may be helpful in delineating ongoing seizure activity in the comatose individual. EEG may show a number of nonspecific abnormalities. Neuroimaging may demonstrate edema, cortical infarcts, hemorrhage, and white matter changes; however, these changes are non-diagnostic for cerebral malaria. MRI may show hemorrhagic lesions and infarction. After-care Thin and thick smears should be obtained weekly for at least one month after the patient is discharged to ensure resolution of parasitemia. Individuals with residual neurological issues should be followed to determine resolution or possibly provide additional rehabilitation in those with permanent disability. Prognosis Cerebral malaria carries a mortality of approximately 15% in children and 20% in adults. A common cause of death is acute respiratory arrest, which may be due to brain stem herniation. Prolonged duration and deeper level of coma, recurrent episodes of hypoglycemia, severe anemia, renal dysfunction, repeated seizures, and higher cerebral fluid lactate levels are predictors of a worsened prognosis. Cerebellar ataxia may occur without impaired consciousness and may occur up to 3–4 weeks after an attack of malaria. This usually recovers completely after 1–2 weeks. Other late neurological complications include the post-malaria neurological syndrome (PMNS), acute inflammatory demyelinating polyneuropathy (AIDP) and acute disseminated encephalomyelitis (ADEM). Malaria, and certain antimalarials such as mefloquine, can exacerbate preexisting psychiatric illness. Depression, paranoia, delusions, and personality changes also may develop during convalescence from cases of otherwise uncomplicated malaria. The prevalence of neuropsychiatric deficits ranges between 6% and 29% at the time of discharge from the hospital. Residual deficits are unusual in adults (<3%). Neurologic defects may improve rapidly over weeks to months or may occasionally persist following cerebral malaria, especially in children (10%). Individuals may experience long-term cognitive impairments in speech, language, memory and attention, ataxias, palsies, speech disturbances, deafness, and blindness. In one prospective study of Ugandan children aged 5–12 years, cognitive impairment, most prominently in attention, was present in 26.3% of children with cerebral malaria at 2-year follow-up [6]. Economics Cerebral malaria is one of the most life-threatening complications of malaria, with an annual incidence of 1.12 cases per 1,000 children, and a 7–18.6% mortality rate, often in the initial 24 h, despite rapid treatment. It accounts for 10% of pediatric admissions in some subSaharan hospitals. In 2004, the Disease Control Priorities in Developing Countries project estimated the global burden of malaria, expressed in disability adjusted life years (DALYs), as 42,280,000. References 1. 2. 3. Hanson J, Lee SJ, Mohanty S et al (2010) A simple score to predict the outcome of severe malaria in adults. Clin Infect Dis 50 (1):679–685 Dondorp A, Nosten F, Stepniewska K et al (2005) Artesunate versus quinine for treatment of severe falciparum malaria: a randomized trial. Lancet 366:717–725 Enwere GA (2005) A review of the quality of randomized clinical trials of adjunctive therapy for the treatment of cerebral malaria. Trop Med Int Health 10:1171–1175 Cerebral Perfusion Pressure 4. 5. 6. Mishra SJ, Newton CRJC (2009) Diagnosis and management of the neurological complications of falciparum malaria. Nature Rev Neurol 5:189–198 Basavaraju SV, Schantz P (2006) Soil-transmitted Helminths and Plasmodium falciparum Malaria: Epidemiology, clinical manifestations, and the role of nitric oxide in Malaria and geo-helminth coinfection. Do worms have a protective role in P.falciparum infection? Mt Sinai J Med 73(8):1098–1105 John CC, Bangirana P, Byarugaba J et al (2008) Cerebral malaria in children is associated with long-term cognitive impairment. J Pediatr 122(1):e92–e99 C 20–80 mmHg, there is a linear increase in CBF for an increase in PaCO2. Similarly, there is a linear relationship between CVR and CPP in the ranges of CPP 50–150 mmHg CPP. These variances together are called cerebral autoregulation and exist in order to maintain a nearconstant cerebral blood flow. Normal CPP is >50 mmHg. The critical threshold below which CBF diminishes and ischemia is produced varies per individual but normally is in the range of 50–60 mmHg; hence, it is a typical goal to maintain CPP >60 mmHg [2]. Clinical Relevance Cerebral Perfusion Pressure SAMUEL WALLER1, KATHRYN M. BEAUCHAMP2 1 Department of Neurological Surgery, University of Colorado School of Medicine, Denver, CO, USA 2 Department of Neurosurgery, Denver Health Medical Center, University of Colorado School of Medicine, Denver, CO, USA Synonyms CPP Definition Cerebral perfusion pressure (CPP) is the pressure at which the brain receives blood flow. Conceptually speaking, CPP is pressure at which the blood can force its way into the closed box that is the cranial vault and overcome the cranial vault’s intrinsic pressure. Clinically, CPP can be derived by taking the difference between the mean arterial pressure and the intracranial pressure (CPP = MAP – ICP). One cannot consider CPP without thinking about cerebral blood flow (CBF) as it is only intuitive that the pressure allows for the tissue to receive its required blood flow. Tissue requires adequate blood flow in order to maintain normal physiologic functioning. CBF is a difficult to measure and derive clinically without specialized equipment. Therefore, CPP is often utilized. Clinically, CBF is the CPP divided by the cerebral vascular resistance (CVR): CBF = CPP/CVR. It is well known that CBF rates of less than 20 mL per 100 g tissue/min lead to ischemia and, if prolonged, will lead to cell death [1]. In order to conceptualize cerebral blood flow, we then must think about cerebral vascular resistance. Cerebral vascular resistance is affected by the patient’s PaCO2 and CPP. That is to say that in the ranges of PaCO2 Typically, parameters such as cerebral blood flow and cerebral perfusion pressure matter in settings where an injury such as a stroke, hematoma, intracranial mass lesion, hydrocephalus or similar has occurred. In these settings, neurologic deterioration may be impending and interventions must be implemented in order to preserve brain tissue through preservation of cerebral blood flow. In these settings, again CBF is a difficult clinical number to assess at the bedside in order to help guide therapies but CPP can be derived relatively easily through monitoring of the patient’s intracranial pressure. Intracranial pressure monitoring is generally indicated in any patient whose Glascow Coma Score (GCS) is <9 and who has an abnormal brain imaging study or who has risk factors for intracranial hypertension (age >40, SBP<90, or decerebrate/decorticate posturing on motor examination). Other indications for intracranial pressure monitoring include patients with multiple system injuries requiring therapies that may be deleterious to cerebral blood flow and intracranial pressure such as high levels of positive end-expiratory pressure ventilator settings, high volumes of fluid required for resuscitation, or the need for heavy sedation. Relative contraindications to intracranial pressure monitoring include: (1) the awake patient, as they have a neurologic exam to follow, (2) coagulopathic patients in whom the risk of placing a monitor and causing an acute intracranial mass lesion (hemorrhage) is high, and (3) patients with an exam consistent with brain death who do not respond quickly to empiric therapies to lower intracranial pressure. Types of intracranial pressure monitoring include: intraventricular catheters, intraparenchymal monitors, subarachnoid screws, subdural monitors, epidural monitors, or in infants fontanometry. Of these, intraventricular catheters and intraparenchymal monitors are the most common. 541 C 542 C Cerebral Perfusion Pressure (CPP) without risking further ischemic injury; one must be cautious of the myocardial depressant effect of barbiturates c. Decompressive craniectomy, which opens the intracranial vault and physically creates more volume for the brain to expand into d. Hypothermia, again reduces cerebral metabolism but has multiple side effects including increased risk for infections, decline in cardiac index, pancreatitis, elevated creatinine clearance, and shivering, which can cause elevations in intracranial pressure [3] Means of treating intracranial pressure elevations in order to preserve cerebral perfusion pressure include the following [2]: 1. Elevate the head of the bed to 30 –45 in order to increase venous drainage of the brain 2. Keep the neck inline in order to prevent restriction of jugular venous outflow 3. Avoid tight trach or endotracheal tube taping in order to prevent restriction of jugular venous outflow 4. Avoid hypotension (SBP <90) by ensuring intravascular volume is normalized, use pressors if needed; this ensures cerebral perfusion is not compromised 5. Control hypertension in order to prevent cerebrovascular constriction 6. Avoid hypoxemia (pO2 <60 mmHg) in order to prevent further ischemic injury and cerebrovascular vasodilation, which increases intracranial pressure 7. Ventilate the patient to normocarbia; hyperventilation is useful as an adjunct for short-term control of intracranial hypertension but long term can worsen ischemic injuries 8. Light sedation More aggressive measures to control elevations in intracranial pressure include [2]: 1. Heavy sedation and/or paralysis, which reduces sympathetic tone and hypertension caused by movement and tensing abdominal vasculature 2. Drain 3–5 mL of cerebrospinal fluid (if an intraventricular catheter is present), which reduces intracranial volume and therefore the related pressure 3. Mannitol or similar osmotic therapy in order to draw fluid out of the brain parenchyma and possibly improve blood rheology 4. Hypertonic saline, bolus with 10–20 mL of 23.4% saline; when the serum osmolarity is less than 320, some patients refractory to osmotic diuretics will respond to hypertonic saline 5. Hyperventilate to a pCO2 near 30, which decreases cerebral blood flow and the related intracranial pressure 6. Continued refractory intracranial pressure may require more aggressive therapy and should prompt one to: a. Check a noncontrasted head CT in order to ensure there is not a new surgical intracranial lesion b. Barbiturate coma (thiopental or pentobarbital), which sedates, treats seizures, and reduces cerebral metabolism and thereby cerebral blood flow Goals of treatment of intracranial pressure include the following: 1. Intracranial pressure<20mmHg [4] 2. Cerebral perfusion pressure >60 mmHg Cerebral perfusion pressure critical threshold varies by the individual but is in the range of 50–60 mmHg before ischemic injury is encountered. Therefore, goals of treatment should be to maintain a CPP of 60 or greater, thereby ensuring that dips in CPP to levels where ischemia occurs are avoided. In summary, CPP is the clinical measure whereby physicians can ensure the brain receives the blood flow needed in order to prevent ischemic injury. This is accomplished by measures and treatments of intracranial pressure and monitoring of hemodynamics. References 1. 2. 3. 4. Astrup J, Siesjo BK, Symon L (1981) Thresholds in cerebral ischemia – the ischemic -penumbra. Stroke 12:723–725 Greenburg M (2006) Handbook of neurosurgery, 6th edn. Thieme Medical Publishers, New York Bratton SL, Chestnut RM, Ghajar J et al (2007a) Guidelines for the Management of Severe Traumatic Brain Injury. Journal of Neurotrauma. 24, supplement 1, 31–36 Bratton SL, Chestnut RM, Ghajar J et al (2007b) Guidelines for the Management of Severe Traumatic Brain Injury. Journal of Neurotrauma. 24, supplement 1, 65–68 Cerebral Perfusion Pressure (CPP) Defined as the difference between the mean arterial pressure (MAP) and the intracranial pressure (ICP); CPP = MAP – ICP. The target CPP in the setting of severe TBI is greater than or equal to 60 mmHg. Change Cerebral Trauma ▶ Traumatic Brain Injury, Initial Management C the vascular access device. However, a short extension tube might be connected to the catheter and might be considered a portion of the catheter to facilitate aseptic technique when changing administration sets [1]. Rationale Cerebrospinal Fluid Pressure Monitoring ▶ ICP Monitoring Cervical Rib Syndrome ▶ Thoracic Outlet Bloodstream infections associated with the insertion and maintenance of vascular access devices are among the most dangerous complications associated with health care. They have been shown to be associated with increases in patient morbidity and mortality and with a prolonged intensive care unit and hospital stay. Moreover, catheterrelated bloodstream infection is associated with high costs of care [2]. The method and frequency of changing catheters and catheter lines can influence the risk of infection. Methods of Central Venous Catheter Replacement Central venous catheters can be replaced by percutaneously inserting a new catheter at another body site or by placing a new catheter over a guide wire at the existing site. Percutaneous Insertion Cervicobrachial Syndrome ▶ Thoracic Outlet Change SONIA LABEAU1, DOMINIQUE VANDIJCK1, STIJN BLOT2 1 Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium 2 Department of General Internal Medicine & Infectious Diseases, Ghent University Hospital, Ghent, Belgium Synonyms Catheter and line/tubing/administration sets change; Replacement of vascular access devices and line/tubing/ administration sets A catheter’s insertion site directly influences the subsequent risk for infection. The density of skin flora at the insertion site is a major risk factor. After insertion, certain sites are easier to maintain clean and dry. Catheters inserted into an internal jugular vein are associated with a higher risk for infection than those inserted into a subclavian vein. For infection control purposes, the subclavian site is generally recommended. However, this recommendation must be balanced against individual patient-related and noninfectious issues such as patient comfort and mobility and the risk of mechanical complications. In adults, it is strongly recommended to avoid use of the femoral vein for central venous access due to a greater risk of infection and deep venous thrombosis. In children, the increased infection risk has not been demonstrated [3]. Other aspects of catheter insertion, such as the use of maximal sterile barriers, skin antisepsis, use of a checklist and insertion cart, selection of catheter type, and technical insertion issues, are beyond the scope of the current procedure. Definition Catheter change is defined as the replacement of a catheter in situ and its administration set(s) by a new catheter and administration set(s). Administration sets are defined as the area from the spike of tubing entering the fluid container to the hub of 543 Guide Wire Insertion Guide wire insertion has become an established method to replace a malfunctioning catheter or to exchange a pulmonary artery catheter for a central venous device when invasive monitoring had become superfluous. C 544 C Change The technique offers a better patient comfort and causes a significantly lower rate of mechanical complications as compared to percutaneous insertion at a new body site [2]. Guide wire-assisted catheter exchange to replace a malfunctioning catheter or to exchange an existing catheter is only recommended in the absence of evidence of infection at the catheter site or proven catheter-related bloodstream infection. Suspicion of catheter infection without evidence of infection at the catheter site should lead to removal of the catheter in situ and insertion of a new catheter over a guide wire; if subsequent tests demonstrate catheter-related infection, the newly inserted catheter should be removed and, if still required, another new catheter inserted at a different body site. In patients with catheter-related infection, replacement of catheters over a guide wire is not recommended. If continued vascular access is required in these patients, the concerned catheter is to be removed and to be replaced with another catheter at a different insertion site [2]. The above recommendations also pertain to the administration sets of pulmonary artery catheters [1]. In peripheral arterial catheters transducers are to be replaced at 96 h intervals. Continuous flush devices and intravenous tubing are to be replaced at the time the transducer is replaced [1]. Pre-existing Condition This procedure applies to adult patients with a central venous, pulmonary arterial or peripheral arterial intravascular device in place. Application The application described below only pertains to the change in administration sets of central venous catheters. Change in tubing of other vascular access devices can be extrapolated from this description. The procedure pertaining to the insertion of a catheter percutaneously or by guide wire assistance is beyond the scope of this procedure. Frequency of Catheter Replacement In central venous catheters, including peripherally inserted central catheters and hemodialysis catheters, routine catheter replacement without clinical indication has been shown not to reduce the rate of catheter colonization, nor the rate of catheter-related bloodstream infection [2]. The most recent SHEA/IDSA evidence-based recommendations to prevent central line-associated bloodstream infections in acute care hospitals strongly recommend catheter replacement on an as-needed basis only. Routine catheter replacement is not recommended, neither percutaneously nor over a guide wire [3]. In adults, peripheral artery catheters should not be replaced routinely to prevent catheter-related infection [1, 3], while in pediatric patients no recommendation for the frequency of catheter replacement is currently available [1]. Similarly, it is recommended not to replace pulmonary artery catheters to prevent catheter-related infection [1]. Frequency of Replacing Intravenous Tubing and Add-On Devices In central venous catheters intravenous sets not used for the administration of blood, blood products, or lipids should be replaced at intervals not longer than 96 h [3]. All tubing used to administer blood products or lipid emulsions should be replaced within 24 h of initiating the infusion [1, 4]. Moreover, all fluid administration tubing and connectors should be replaced when the central venous access device is replaced [2]. Data Collection Collect patient and catheter data. Inform about the need to continue catheterization. Preparation of Work Area Restrict activities around bed. Assure patient privacy and safety. Make room at the bedside area. Ensure good visibility. Adjust the bed height. Preparation of Material Clean catheter cart surface. Ensure all needed material is present. Apply appropriate hand hygiene. Open sterile field and dressing packs and prepare using aseptic technique. Hang new intravenous solution as ordered by physician in reach. Spike new solution bag with new administration set, protecting distal end from contamination. Prime intravenous line with appropriate solution to remove all air and clamp administration set with roller clamp. Preparation of Patient If possible, explain procedure to patient. Chemical and Physical Forces Assist/place patient into backrest position that is both comfortable and convenient for the procedure. Clear space around the insertion site of clothes and blankets. Procedure Take cart to bedside. Apply appropriate hand hygiene and put on nonsterile gloves. Place bed protection. Loosen and remove dressing. Observe dressing. Remove gloves and discard gloves and dressing. Apply appropriate hand hygiene. Observe and inspect catheter site. Take culture, if appropriate. Assess which type of dressing to use. Peel open dressing packet and open sterile field. Apply aseptic technique by no-touch technique. In case of dried blood or drainage at the insertion site, cleanse with sterile NaCl 0.9%. Disinfect the insertion site with a 2% chlorhexidine-based solution. Allow the insertion site to air dry. On the catheter tubing being changed, stop the infusion pump if applicable, and clamp the intravenous line with the roller clamp. Put on sterile gloves. Thoroughly swab catheter pigtail and line being changed 5 cm on both sides of port connection with 2% chlorhexidine-based solution and allow to air dry. According to the type of catheter in situ, clamp off the line of the catheter pigtail being changed with the blue slide clamp or close the catheter lock. Disconnect cleaned IV line from cleaned catheter pigtail. Connect new line to catheter pigtail. Remove blue slide clamp from pigtail or open catheter lock. Observe for adequate infusion flow. Observe for leakage or blood back up from catheter pigtail connection site. Apply appropriate dressing using aseptic technique and fix, avoiding traction and pressure, and bearing patient comfort and mobility in mind. Place new administration set and solution into infusion pump. Apply appropriate hand hygiene. Post-Procedure Care Install the patient comfortably. C Label IV administration set with time and date of change. Adjust the bed height. Remove trolley from bedside area. Dispose of waste according to the institutional instructions. Clean the cart surfaces and dry well. Documentation Document the lines that have been changed and site assessment in medical record and/or flow sheet. Record date and time of next line change on flow chart. Inform physician of signs of infection. References 1. 2. 3. 4. O’Grady NP, Alexander M, Dellinger EP, Gerberding JL, Heard SO, Maki DG, Masur H, McCormick RD, Mermel LA, Pearson ML, Raad II, Randolph A, Weinstein RA (2002) Guidelines for the prevention of intravascular catheter-related infections. MMWR 51:1–29 Pratt RJ, Petlowe CM, Wilson JA, Loveday HP, Harper PJ, Jones S, McDougall C, Wilcox MH (2007) EPIC2: national evidence-based guidelines for preventing healthcare-associated infections in NHS hospitals in England. J Hosp Infect 65:S1–S64 Marschall J, Mermel LA, Classen D, Arias KM, Podgorny K, Anderson DJ, Burstin H, Calfee DP, Coffin SE, Dubberke ER, Fraser V, Gerding DN, Griffin FA, Gross P, Kaye KS, Klompas M, Lo E, Nicolle L, Pegues DA, Perl TM, Saint S, Salgado CD, Weinstein RA, Wise R, Yokoe DS (2008) Strategies to prevent central line-associated bloodstream infections in acute care hospitals. Infect Control Hosp Epidemiol 29:S22–30 Labeau S, Vandijck D, Lizy C, Piette A, Verschraegen G, Vogelaers D, Blot S (2009) Replacement of administration sets used to administer blood, blood products, or lipid emulsions for the prevention of central line-associated bloodstream infection. Infect Control Hosp Epidemiol 30:494 Chelator A chelator is a chemical compound capable of sequestering a substrate atom, often a metal, via two or more chemical bonds. Chemical and Physical Forces They are involved in adsorption including Van der Waals forces generated by atomic and molecular interactions, ionic bonds generated by electrostatic forces and finally hydrophobic bonds. 545 C 546 C Chest Bleeding Chest Bleeding ▶ Hemothorax Chest Compression (CC) ▶ Cardiopulmonary Resuscitation Chest Discomfort ▶ Chest Pain: Differential Diagnosis Chest Infection The “pain” may represent little more than a vague discomfort or sensation of heaviness all the way to the more classic description of “elephant sitting on my chest.” Furthermore, while the chest as an anatomic entity is clearly defined, many of the diseases that cause “chest pain” can present with pain outside the chest as well. An example would be the shoulder or epigastric pain presentation of ▶ acute coronary syndrome. Moreover, many of these diseases can present with non-pain symptoms. Unexplained shortness of breath is a common presentation of acute coronary syndrome in the elderly or of ▶ pulmonary embolism in patients of all ages. As a practical issue, providers learn the differential diagnosis of all of the diseases that can present with chest pain and then learn the alternate presentations of these diseases. Pathophysiology Afferent visceral nerve fibers from the intrathoracic organs traverse sympathetic ganglia en route to thoracic dorsal nerve roots and dorsal ganglia. Somatic afferent nerve fibers synapse in the same dorsal ganglia. This complex neurologic configuration leads to visceral pain that is often poorly localized, vague, and capable of radiation to other anatomic areas. ▶ Mediastinitis, Postoperative Differential Diagnosis Chest Pain: Differential Diagnosis JOHN TOBIAS NAGURNEY Department of Emergency Medicine, Massachussets General Hospital, Harvard Medical School, Boston, MA, USA Synonyms Ache; Chest discomfort; Heaviness Definition As the name implies, the term “chest pain” refers to “pain,” an uncomfortable or unpleasant body sensation that a patient experiences in the “chest” area. The chest is the area of the body located between the neck and the abdomen, and more formally as the area below the clavicles but above the inferior borders of the rib cage. It contains the lungs, the heart, and part of the aorta. The walls of the chest are supported by the dorsal vertebrae, the ribs, and the sternum. This definition represents a good starting point to think about the diseases that cause pain in this area, but is somewhat misleading for two reasons. The ability for the clinician to distinguish among the many diseases presenting with chest pain is truly important. Chest pain is the second most common presenting complaint among emergency department (ED) patients in the USA. The diagnoses of ▶ acute myocardial infarction or unstable angina pectoris are missed in EDs in 2–8% of patients. The missed diagnosis of myocardial infarction represents an estimated 20% of total dollars spent for medical malpractice claims. Because of these among other reasons, most ED providers are relatively conservative in their evaluation and admission practices for patients who present with chest pain. As a result, it is estimated that only a small percent of patients admitted to an observation or in-patient service to rule-out acute coronary syndromes turn out to have that disease. Chest pain represents a series of syndromes that are both common and difficult to diagnose. The difficulty in diagnosis occurs for a number of reasons. The first is that over 30 diseases or syndromes are scattered among the six different organ systems (lungs and pleura, heart and great vessels, gastroesophageal, nervous system, musculoskeletal system, and others, e.g., psychiatric) that are represented in the chest (Table 1) [1]. A second reason is that many of the diseases which present with chest pain are not easily identified by a single highly sensitive and specific diagnostic study or Chest Pain: Differential Diagnosis C 547 Chest Pain: Differential Diagnosis. Table 1 Diseases presenting with chest pain (Adapted from [1]) Organ system Emergent diagnoses Urgent but not critical diagnoses Nonemergent Cardiovascular Acute MI Unstable angina Aortic dissection Aortic aneurysm Cardiac tamponade Pericarditis Myocarditis Severe aortic stenosis Cardiomyopathy Mitral valve prolapse Noncritical valvular disease Pulmonary Pulmonary embolus Tension pneumothorax Pneumothorax Mediastinitis Pneumonia Pleuritis Cancer Pneumomediastinum Bronchitis Gastrointestinal Esophageal rupture Cholecystitis Acute pancreatitis Esophageal spasm Esophageal reflux Peptic ulcer disease Biliary colic Hiatal hernia Musculoskeletal Muscle strain Rib fracture Arthritis Tumor Costochondritis Neurological Spinal root compression Thoracic outlet syndrome Other Herpes zoster Post herpetic neuralgia Hyperventilation Panic attack procedure. For example, while an ▶ aortic dissection can usually be identified or excluded by an aortic dissection computerized axial tomography, magnetic resonance imaging, a trans-esophageal echocardiogram or an angiogram, pain from musculoskeletal origin is usually a diagnosis of exclusion. There is no single diagnostic test that definitively diagnoses an acute coronary syndrome. This diagnosis is made by a combination of the clinical presentation, electrocardiograms, cardiac biomarkers, and usually an anatomic or physiologic risk stratification test. When the data elements conflict, the definitive final diagnosis often remains in doubt and the term “non-cardiac chest pain” becomes the final diagnosis [2]. Given the fact that diagnosing the cause of chest pain in individual patients can be extremely challenging, the question becomes: what is the most reasonable approach when caring for such a patient? The establishment of the differential diagnosis is largely achieved through a consideration of the patient’s demographic data (age and sex), their past medical history, a consideration of risk factors for specific diseases, and the nuances of their chest pain story. The context of the chest pain is important. Chest pain that occurs after trauma has a different differential diagnosis than nontraumatic chest pain. Typically, the provider begins by addressing diseases in the differential diagnosis that, if undiagnosed and untreated, can potentially lead to death within minutes. Classically, these diseases include aortic dissection, massive pulmonary embolism, and acute coronary syndrome. Some authors include tension pneumothorax or pericardial tamponade as well [3]. A second set of diseases can cause potential mortality and significant morbidity, although usually less acutely than this highly lethal group. Examples of diseases in this second category include ▶ pneumonia and multiple rib fractures. The third set of diseases, far more common than the others, include diseases that cause pain, anxiety, and morbidity to patients but usually do not result in loss of life or limb. Examples of diseases in this category include gastroesophageal reflux disease, musculoskeletal chest pain, viral C 548 C Chest Pain: Differential Diagnosis pleurodynia, and herpes zoster. Typically, the patient remains under relatively intensive observation and monitoring until potentially life-threatening diseases are excluded. Once this has been accomplished, potential other diagnoses can be pursued during that hospitalization or as an outpatient. In summary, the primary goal in caring for a patient presenting with chest pain is to perform a brief but accurate risk stratification so that lifethreatening diseases can be intervened upon [4]. Most diseases which present with chest pain occur within relatively characteristic age and sex strata. For example, acute coronary syndrome becomes more common with advancing age and is rarely seen in premenopausal women. Conversely, pulmonary embolism is commonly seen in patients of all ages. Young women are at risk because many have risk factors such as pregnancy. After consideration of age and sex, most providers consider the patient’s risk factors for particular diseases. For acute coronary syndrome, aortic dissection, and pulmonary embolism these risk factors are relatively well defined. Unfortunately, none are hard-and-fast. For example, approximately 10–20% of patients presenting with acute myocardial infarction lack all five of the classic risk factors for that disease. For many diseases, a history of having had that disease previously represents an important risk factor. In the context of a presentation with acute chest pain, patients with a history of myocardial infarction or pulmonary embolism are more likely to have these respective diseases when compared to patients without such a history. Finally, establishing the differential diagnosis often requires that providers obtain an accurate and complete history of the patient’s chest pain story. Unfortunately, many elements of the chest pain story lack sensitivity, specificity, or both [5, 6]. Restated, the chest pain story allows the clinician to establish prior probabilities to be refined by diagnostic testing but these probabilities are at best approximate (Table 2). Pain Location The chest pain story begins with pain location. For practical purposes, pain that is substernal or left-sided is equivalent. Pain in these locations is consistent with fatal diseases such as acute coronary syndrome as well as non life-threatening diseases such as gastroesophageal reflux disease and ▶ pericarditis. Pain in the periphery of the chest is more consistent with a disease of pleural, pulmonary, or musculoskeletal origin. Associated with location is the concept of radiation, or extension of the pain into other areas of the body. Again, certain diseases have classic radiations. Examples include the pain of aortic dissection which typically radiates to the back or Chest Pain: Differential Diagnosis. Table 2 Elements of the chest pain story Element Specific details Comment Timing Average duration Seconds, minutes, or hours? Frequency Only once or multiple occurrences? Time of onset First time ever that the pain occurred? Time of most Within the past 6 h, 24 h, or recent episode longer? Location Right or left chest, upper or lower, central or peripheral? Radiation Where? Quality Best descriptive adjective for the pain? Precipitating factors Eating, breathing, exertion? Relieving factors Resting, nitroglycerin, antacids? Associated symptoms Diaphoresis, nausea, shortness of breath? that of acute myocardial infarction which often radiates to the left shoulder. Quality and Intensity The quality and intensity of the pain are the next characteristics that are usually considered. Both of them are, in general, nondiscriminating. The pain of acute myocardial infarction may be described as “pressure,” “heaviness,” “burning,” “aching,” or “discomfort.” The intensity of the pain is usually also nondiscriminating as well. For example, the intensity of pain in patients presenting with acute myocardial infarction or of acute aortic dissection is usually severe but can be mild or even nonexistent. Conversely, the pain from gastroesophageal reflux or musculoskeletal origin is usually mild but may be extremely severe. Timing of Pain The timing of the chest pain is probably the most difficult element of the chest pain story to capture. The concept of timing includes when the pain originally began, its typical duration, the frequency with which it occurs, and the onset of the most recent episode. While no hard-and-fast rules apply, some general principles are useful. One such Chest Wall Stabilization principle is that pain that has been going on for weeks or months does not usually cause major morbidity or mortality. Conversely, for a patient presenting with an acute myocardial infarction, the average interval between the onset of pain and presentation to an emergency department is between 3 and 9 h. The duration of chest pain from pulmonary, pleural, musculoskeletal, and gastrointestinal sources can be hours without interruption. The number of times per day or week that the pain occurs can be helpful as well. In general, pain that occurs frequently is usually less worrisome than pain that occurs occasionally. Finally, the time of the most recent occurrence can be used to determine the value of certain diagnostic tests such as cardiac biomarkers. Relieving and Precipitating Factors Cardiac pain is typically precipitated by exertion and relieved by rest. It is often relieved by stopping a strenuous activity. Chest pain from pleural, pulmonary, or musculoskeletal sources is often worsened by coughing or deep breathing. Examples include the pains of viral pleuritis, pulmonary embolism, pneumonia, or intercostal muscle strain. Associated Symptoms Symptoms that typically accompany the chest pain can increase the probability of certain diseases. For example, nausea and diaphoresis are common accompaniments to chest pain in patients presenting with acute coronary syndrome. A sour taste in a patient’s mouth during episodes of chest pain increases the possibility of gastroesophageal reflux disease. And acute neurologic symptoms accompanying chest pain increase the probability that the chest pain is caused by an aortic dissection. Cross-Reference to Disease ▶ Acute Coronary Syndrome ▶ Acute Myocardial Infarction ▶ Aortic Dissection ▶ Aortic Stenosis ▶ Pericarditis ▶ Pneumonia ▶ Pneumothorax, Tension Pneumothorax ▶ Pulmonary Embolism References 1. 2. Brown JE, Hamilton GC (2010) “Chest pain.” Rosen’s emergency medicine: concepts and clinical practice, 7th edn. Mosby Elsevier, Philadelphia, pp 132–141 Lenfant C (2010) Chest pain of cardiac and noncardiac origin. Metabolism 59(Suppl 1):S41–S46 3. 4. 5. 6. C Jones ID, Slovis CM (2001) Emergency department evaluation of the chest pain patient. Emerg Med Clin North Am 19:269–282 Jesse RL, Kontos MC (1997) Evaluation of chest pain in the emergency department. Curr Probl Cardiol 22:149–236 Goodacre S, Locker T, Morris F, Campbell S (2002) How useful are clinical features in the diagnosis of acute, undifferentiated chest pain? Acad Emerg Med 9:203–208 Swap CJ, Nagurney JT (2005) Value and limitations of chest pain history in the evaluation of patients with suspected acute coronary syndromes. JAMA 294(20):2623–2629 Chest Tube: Chest Drain or Thoracostomy Tube ▶ Thoracocentesis and Chest Tubes Chest Wall Stabilization DONALD D. TRUNKEY1, JOHN C. MAYBERRY2 1 Department of Surgery, Oregon Health & Science University, Portland, OR, USA 2 Trauma/Critical Care, Oregon Health & Science University, Portland, OR, USA Synonyms Fixation or repair; Flail chest stabilization; Rib and/or sternal fracture operative reduction and internal fixation (ORIF) Definition Chest wall stabilization is a surgical procedure in which rib and/or sternal fractures are reduced (i.e., the fracture ends are realigned and brought into proximity) and the fractures are fixated with a plating system. Pre-existing Condition Chest wall injury syndromes for which operative intervention may be indicated are listed in Table 1. Category recommendations are based upon review of literature and upon the authors’ experience. Flail chest is defined by three or more ribs fractured in two or more places. Paradoxical motion of the chest wall (i.e., flail motion) may or may not be visible. If the patient has already been endotracheally intubated and mechanically ventilated, the flail segment will not be externally 549 C 550 C Chest Wall Stabilization Chest Wall Stabilization. Table 1 Recommendations for chest wall stabilization for each indication Chest wall injury Category recommendation Flail chest II Chest wall implosion syndrome II Chest wall defect/pulmonary herniation I Intractable acute pain with displaced fractures III Thoracotomy for other (“on the way out”) III Displaced or comminuted acute sternal fracture III Rib or sternal fracture nonunion (pseudoarthrosis) III apparent. The diagnosis is established by CT scan. Two small, single center randomized trials and cohort comparison studies have demonstrated several benefits of early flail chest ORIF including decreased intensive care length of stay, less pneumonia, early return to work, and improved forced vital capacity (FVC) [1, 2]. Chest wall implosion syndrome is characterized by multiple, displaced rib fractures along the medial edge of the scapula, a clavicle fracture/dislocation, and often a scapular fracture. Although this injury does not meet the anatomic definition of flail chest, these patients are physiologically similar to patients with anterolateral flail chest, i.e., nearly all will require mechanical ventilation for respiratory failure [3]. Chest wall defect or acute pulmonary herniation is a rare injury where a portion of the chest wall is traumatically missing or the lung herniates through the chest wall, e.g., through an intercostal muscle tear with associated rib fractures. Operative repair is indicated to debride severely damaged tissue and to restore pulmonary mechanical integrity. A bioprosthesis such as acellular human or porcine dermis may be necessary to cover the tissue defect. Serial operations with staged repair are recommended for more severe tissue defects. Operative intervention is the standard of care based on the lack of an acceptable alternative to surgical repair [4]. An occasional patient with significant displacement including overriding of the fractured ribs will complain of intractable pain with attempts at mobilization which defies the usual attempts at pain control including epidural catheter infusion. This indication has not been studied, but in the authors’ experience ORIF of the displaced rib fractures can result in a dramatic improvement in pain and allow the patient to recuperate and return to normal function more rapidly. Thoracotomy for other indications or “on the way out” indicates a patient with rib fractures who requires a thoracotomy for a traumatic indication such as retained hemothorax, pulmonary laceration, ruptured diaphragm, or even aortic injury. As the surgeon is closing the thoracotomy it may be reasonable, depending on the nature of the rib fractures and the condition of the patient, to take extra time to include rib fracture ORIF with the intent of preventing future disability. This indication also applies to non-traumatic situations where ribs are fractured or purposely cut during thoracotomy exposure for elective surgery. Rib fracture ORIF for this indication can be considered safe in select patients but has not been studied for efficacy. Sternal fractures are occasionally acutely repaired when they are completely displaced or comminuted. The literature describing the operative techniques and results are case series only and include no comparison groups [5]. Acute sternal fracture ORIF is therefore an acceptable option in select patients and can be considered safe, but warrants a Category III recommendation only. Rib or sternal fracture nonunions (pseudoarthroses) occur in 1–5% of patients and can be a source of persistent pain and disability. Resection of the pseudocapsule and margins of the bony defect to reinitiate osteosynthesis in conjunction with internal fixation has been reported as successful and efficacious in case series [5]. The successful use of bone grafting techniques in situations of bone loss for both rib and sternal fracture nonunions has also been described. Neither indication has been studied in a controlled fashion and, therefore, warrants a Category III recommendation only. Four different levels of recommendations exist: ● Category I. Operative intervention is standard of care. ● Category II. Operative intervention is acceptable in selected patients based on the results of single-center randomized trials and case-control series. ● Category III. Operative intervention is not clearly indicated based on insufficient evidence. ● Category IV. Operative intervention has been demonstrated to have a lack of efficacy. Application Several plating systems have been used but none has proven superior to another. Both metal and absorbable plates have been used successfully [3]. Ribs are classified as membranous bone because of their relatively thin cortex Cholecystitis compared to their inner marrow and are not expected to hold a plate and/or screws as reliably as cortical or cancellous bone. Efficacious plating systems must also take into account the curvature of ribs and the constant stress of respiratory effort of the patient during the several weeks of healing process. References 1. 2. 3. 4. 5. Tanaka H, Yukioka T, Yamaguti Y, et al (2002) Surgical stabilization of internal pneumatic stabilization? A prospective randomized study of management of severe flail chest patients. J Trauma 52 (4):727–732; discussion 32 Marasco S, Cooper J, Pick A, Kossmann T (2009) Pilot study of operative fixation of fractured ribs in patients with flail chest. ANZ J Surg 79(11):804–808 Solberg BD, Moon CN, Nissim AA, Wilson MT, Margulies DR (2009) Treatment of chest wall implosion injuries without thoracotomy: technique and clinical outcomes. J Trauma 67(1):8–13; discussion Mayberry JC, Ham LB, Schipper PH, Ellis TJ, Mullins RJ (2009) Surveyed opinion of American trauma, orthopedic, and thoracic surgeons on rib and sternal fracture repair. J Trauma 66:875–879 Richardson JD, Franklin GA, Heffley S, Seligson D (2007) Operative fixation of chest wall fractures: an underused procedure? Am Surg 73(6):591–596; discussion 6–7 Chicago Disease ▶ Blastomycosis Childbed Fever C Chirodropid Jellyfish ▶ Jellyfish Envenomation C Chironex fleckerfi ▶ Jellyfish Envenomation Choice of Catheter Lumen ▶ Port Designation Cholangiopathy ▶ HIV-Related Cholecystitis Cholecystitis CHRISTOPHER M. WATSON1, ROBERT G. SAWYER2 1 Division of Trauma and Acute Care Surgery, Palmetto Health, Columbia, SC, USA 2 Department of Surgery, University of Virginia Health System, Charlottesville, VA, USA ▶ Puerperal Sepsis Synonyms Acute acalculous cholecystitis; Acute calculous cholecystitis; Acute cholecystitis Child-Pugh Also known as Child-Turcotte-Pugh is a prognostic scoring system used in patients with cirrhosis which consists of five components, namely, bilirubin, albumin, INR, ascites, and hepatic encephalopathy. Based on the levels of each of these parameters, a score of 1–3 is awarded for each component with a composite score of 6 or less equating to Child-Pugh A, 7–9 to Child-Pugh B, and 10 or more to Child-Pugh C disease. Prognosis worsens as an individual moves from Child-Pugh A through to Child-Pugh C cirrhosis. 551 Definition Cholecystitis is defined as inflammation of the gallbladder. The disease can present acutely without prior symptoms but more commonly after episodes of biliary colic, associated with or without gallstones, in which case the descriptor calculous or acalculous is added, respectively. In either case, it is believed that stasis of bile and gallbladder ischemia occur leading to inflammation of the gallbladder wall and eventually to surrounding structures as well resulting in a localized peritonitis. It was originally thought that the disease was solely attributable to infection. Later, in the 552 C Cholecystitis early 1940s, studies on animals demonstrated that stasis was a primary pathologic condition that was necessary but not sufficient for cholecystitis to develop. With further work, it became clearer that ischemia was also an important part of the pathogenesis. Since acute calculous cholecystitis develops as a result of impaction of a gallstone in the cystic duct, two conditions are met: bile stasis and localized ischemia from distension of the gallbladder wall. In acute acalculous cholecystitis (AAC), ischemia and stasis are also present although with distinct mechanisms. A generalized ischemic insult, whether from trauma, surgery, or a condition such as septic shock or vasopressor use, is thought to precede inflammation. Stasis is due to decreased gallbladder contraction secondary to starvation or the severe disease state itself. Traditionally, postoperative states or trauma were most commonly associated with the development of AAC, but a review of patients undergoing cholecystectomy for AAC found that infection was the most common admission diagnosis, with postoperative state and trauma in only 33% [1]. In the general medical and surgical population, patients with AAC tend to be sicker with higher Sequential Organ Failure Assessment (SOFA) scores [1], whereas in the trauma population other markers of severity, such as Injury Severity Score, number of units of packed red blood cells transfused, and tachycardia, are associated with AAC [2]. Although prolonged nil per os (NPO) status has been associated with this disease, the same study found 56% had received mainly enteral nutrition, while the remainder received mainly parenteral nutrition [1]. More indirect evidence seems to contradict this observation. A randomized controlled trial of postoperative patients receiving either enteral nutrition or intravenous saline infusion showed that gallbladder volume was lower with the former treatment thus indicating less stasis of bile [3]. There was no discussion of the proportion of patients developing AAC in either group. The role of bacteria in cholecystitis is still being defined. Matsushiro et al. evaluated 52 patients presenting with acute cholecystitis for the presence of bacteria in the gallbladder at the time of cholecystectomy [4]. They found bacteria present in 52% of those gallbladders with stones and 33% of those without stones, although the generally agreed upon culture positivity rate in acute cholecystitis is in the 60–80% range. Of those with stones, those gallbladders with impacted stones more likely had bacteria present. Time to surgery did not show significantly different bacteria in this study, although in other studies, patients undergoing cholecystectomy earlier than 72 h after symptoms began were less likely to have bacteria in their gallbladder. Also, infected bile seems to be more common with age. Further complicating the picture is the finding that the region of gallbladder cultured may also determine whether bacteria are recovered [5]. Specific organisms differ somewhat regionally, but enteric gram-negative aerobes, especially Escherichia coli and Klebsiella species, and Streptococcus (Enterococcus) faecalis predominated in the Matsushiro review. Other reviews demonstrated more anaerobes, accounting for as much as 25% of bacterial isolates [6]. Diagnosis Traditionally, clinical indicators of infection or inflammation and right upper quadrant abdominal pain, coupled with data from specific imaging modalities, have been used to diagnose both acute cholecystitis and AAC. Although fever and an abnormal white blood cell count (WBC) may be present, they are not invariably so. The Tokyo Guidelines require both local and systemic signs of inflammation to suspect cholecystitis, and typical imaging findings to confirm cholecystitis (Table 1) [7]. In AAC, Cholecystitis. Table 1 Tokyo guideline grading system for acute cholecystitis Mild (grade I) ● Does not meet the criteria for acute cholecystitis moderate (grade II) or severe (grade III) cholecystitis ● Also defined as a healthy patient with no organ dysfunction and mild local inflammation making cholecystectomy a low-risk procedure Moderate (grade II) cholecystitis – any one of the following ● WBC > 18,000/mm3 ● Palpable, tender, RUQ mass ● Duration of complaints >72 h ● Marked local inflammation (biliary peritonitis, pericholecystic abscess, hepatic abscess, gangrenous cholecystitis, emphysematous cholecystitis) Severe (grade III) cholecystitis – organ system dysfunction ● Cardiovascular dysfunction (requiring vasopressors or inotropes) ● Neurologic (depressed level of consciousness) ● Respiratory (P:F < 300) ● Renal dysfunction (oliguria, creatinine > 2.0 mg/dl) ● Hepatic (PT-INR > 1.5) ● Hematologic (platelet count <100,000/mm3) Source: Adapted from [21]. Cholecystitis fever may be present in only 13% and leukocytosis in only 54% [1]. Unlike acute appendicitis, where right lower quadrant pain and a correlative history may lead directly to the operating room without further study, imaging should always be included in the work-up of presumed acute cholecystitis. This is because no examination finding alone has been found sufficiently accurate to justify cholecystectomy, and associated findings, such as the presence of stones or dilated common bile duct, may change the procedure to include an intraoperative cholangiogram or common bile duct exploration. Also, signs of gangrenous, emphysematous, or perforated cholecystitis will affect prognosis and the likelihood of conversion to an open procedure. The most important imaging studies are focused ultrasonography (US) or scintigraphy (HIDA, Hepatobiliary iminodiacetic Acid), and computed tomography (CT) with intravenous contrast. More recently, modifications of these modalities have been introduced and may increase accuracy but have not penetrated the mainstream. Magnetic resonance imaging (MRI) may also have a role in the diagnosis of cholecystitis in difficult cases, but especially for possible malignancy or evaluation for CBD stones. Ultrasound US findings consistent with cholecystitis include gallstones, especially incarcerated, or debris echo; a positive sonographic Murphy’s sign; wall thickening (>4 mm); gallbladder distention (long axis >8 cm, short axis >4 cm); and pericholecystic fluid. Of these findings, the first three are considered the most specific [8], especially when considered together. For example, the findings of gallstones with a sonographic Murphy’s sign or wall thickening has a positive predictive value for cholecystitis of 92% and 95%, respectively [9]. But, sensitivity for the diagnosis of cholecystitis is, as with all US studies, operator dependent. In a later study, sensitivity of US diagnosis of cholecystitis compared with histology was only 48% [10], but a metaanalysis by Shea et al. reported a sensitivity of 94% for the diagnosis of acute cholecystitis [11]. Recently studies have evaluated surgeon-performed US as a modality for diagnosis of cholecystitis. These studies show that resident surgeons with minimal training could detect gallstones and cholecystitis as well as consultant radiologists [12]. Ultrasound also has a poor sensitivity when used alone for the detection of AAC. In a study of critically ill patients undergoing open cholecystectomy for presumed AAC, only 80% had an abnormal US prior to surgery [1]. Similarly, in a trauma ICU population, US had a sensitivity of 30% and specificity of 93% [13]. However, in another study of trauma patients, all patients with thickening and layering C of the gallbladder wall or necrotic degeneration, edema of the surrounding tissue, and/or impending rupture coupled with major clinical symptoms (pain and/or abdominal distention, hemodynamic instability requiring increasing amounts of vasopressors and/or fluid resuscitation and organ failure) were found to have AAC. Scintigraphy Hepatobiliary scintigraphy evaluates the biliary uptake of Tc-99 m-labeled iminodiacetic acid agents (Tc-99 m IDA) and has a high sensitivity and specificity for the diagnosis of acute cholecystitis. A study that does not show filling of the gallbladder with contrast within 60 min is considered positive for cholecystitis. Another sign that is suspicious for cholecystitis is a “rim sign,” defined as augmentation of radioactivity around the gallbladder fossa. After its introduction, scintigraphy was suggested as a first-line test in patients with presumed cholecystitis. Sensitivity and accuracy were 91% and 93% in an early study [14]. Specificity, however, was lacking. This led early investigators to suggest that a positive result indicated cholecystitis only when serum bilirubin was less than 5 mg/dl while in patients with bilirubin higher than 5 mg/dl the test was considered indeterminate. A negative test was considered reliable. However, an evaluation done a decade later found a similar sensitivity (94%), but a specificity of only 36% [15]. This low specificity led these later investigators to suggest HIDA be eliminated as a first-line study. Confounding the issue even more was a study comparing US, HIDA, and combined US/HIDA. HIDA was found to be more sensitive than US and again the recommendation was made to use HIDA as a first-line study, only using US when stones are suspected in order to evaluate for common bile duct dilation or obstructing stones [10, 16]. With better contrast agents and patient selection, specificity has improved. Also, morphine can be given to increase the tone of the sphincter of Oddi. Filling of the GB within 30 min is considered a negative test with a false-negative rate of only 0.5%. Filling between 30 min and 4 h increases the false-negative rate to 15–20% [17]. However, in a corroborating study, morphine cholescintigraphy had a sensitivity of 99%, a specificity of 91%, a positive predictive value of 0.9, a negative predictive value of 0.99, and an overall accuracy of 94%. This study detected both calculous and acalculous cholecystitis [18]. Computed Tomography Although not required in all cases of presumed cholecystitis, CT is often used when HIDA scintigraphy and US are indeterminate or to evaluate for associated pathology such as gangrenous or emphysematous cholecystitis. Both of 553 C 554 C Cholecystitis these latter findings carry a higher mortality than uncomplicated acute cholecystitis and require conversion to open procedure more often. The presence of these signs may lead to more urgent surgery and a more prolonged antibiotic course postoperatively. Findings consistent with acute cholecystitis are much the same as US, absent the sonographic Murphy’s sign of course. The detection of stones is also limited, such that only 75% of stones are seen on CT. As such, the most specific sign of cholecystitis is pericholecystic inflammatory changes. Overall sensitivity, specificity, and accuracy of CT for the diagnosis of cholecystitis in one study was 92%, 99%, and 94%, respectively [19], and in another directly comparing US with CT, was 100% accurate, sensitive, and specific for the diagnosis of acute cholecystitis [20]. For AAC, CT has a variable sensitivity. In a study by Laurila et al., only 58% of patients had CT signs of AAC prior to operation but in another study, CT was used to correctly diagnose AAC in six of seven patients with one false positive finding. CT may have an adjunctive role in patients with indeterminate US studies though [2]. Magnetic Resonance Imaging (MRI) and Other Imaging Modalities In a comparison of MRI with US, there was no difference in the diagnosis of acute cholecystitis with a sensitivity of 50% for both and specificities of 89% and 86% for US and MRI, respectively [21]. The authors suggested that limited MRI may be indicated for “sonographically challenging” patients. This likely means patients with large amounts of bowel gas or other anatomically hidden gallbladders and/or ductal structures. Cost-effectiveness was not evaluated, however. Another modality currently being investigated for both diagnosis and treatment of cholecystitis in the critically ill patient is bedside laparoscopy. Conclusion In conclusion, US should be performed as a first-line study for presumed cholecystitis because of its broad availability and ability to be performed at bedside. If in a patient with a clinical picture of acute cholecystitis and an US that shows stones and either a thickened GB wall or a sonographic Murphy’s sign, then the patient should be treated for cholecystitis. If the US is indeterminate, and clinical suspicion is low, morphine-HIDA scintigraphy should be used to rule-out the diagnosis. If, however, the clinical suspicion is high, CT scanning should be performed to try to rule-in the diagnosis. CT is also indicated for patients with known cholecystitis that may have emphysematous or gangrenous cholecystitis who would otherwise have been treated conservatively, since these signs indicate the need for urgent surgery. If on any of the imaging studies the patient has distal CBD dilation, an MRCP may be useful to evaluate for obstructing CBD stones unless the surgeon is experienced with CBD exploration. Treatment Controversy exists over the optimal treatment of acute cholecystitis. In an attempt to better define the categories of severity of cholecystitis and thus guide treatment, The Tokyo Guidelines were developed [7]. Experts in the fields of cholecystitis and cholangitis convened to develop standardized diagnostic criteria, a severity grading system, and a treatment guideline based on this grading system (Table 1). The categories were based on factors increasing the likelihood of conversion to an open procedure and the possibility of complications during surgery. Certain highrisk situations may increase the likelihood of conversion to an open procedure, such as a white-cell count of more than 18,000 cells/mm3 at the time of presentation, duration of symptoms of greater than 72–96 h, and an age over 60 years, all of which are indicators of a more advanced disease and increased likelihood of perforation or emphysematous changes [22]. These guidelines have not gained widespread acceptance yet and need to be validated in well-constructed trials. Patients with mild cholecystitis should be treated with antibiotics with or without early laparoscopic cholecystectomy, depending on the patient’s operative risk. Those with moderate cholecystitis are the most difficult to draw firm conclusions regarding treatment. These patients can also be treated with early laparoscopic cholecystectomy, especially if symptoms have been present for less than 96 h. In a prospective cohort study of laparoscopic versus open cholecystectomy for gangrenous cholecystitis, patients having a cholecystectomy completed laparoscopically had significantly shorter ICU stays, less ileus, but more abscess formation [23]. Bile leaks were more common in the laparoscopic group (12% versus 6% in the open group) but this did not reach statistical significance. Since conversion to open cholecystectomy is higher in this group, attempts at laparoscopic surgery should only be made in those that could tolerate an open surgical procedure and by an experienced laparoscopic surgeon. A Cochrane Review was performed evaluating studies of timing of cholecystectomy for acute cholecystitis. The authors noted that early laparoscopic cholecystectomy was feasible and preferred in some select patients as long as an experienced laparoscopic surgeon performed the procedure. This recommendation was Cholecystitis based on the observation that 17.5% of patients undergoing delayed treatment had recurrent cholecystitis requiring operation and of those undergoing laparoscopic surgery, 45% required conversion to an open procedure [24]. Because of the small size of the included studies, conclusions could not be made regarding the more rare complications, such as bile duct injury. Large population studies seem to imply a higher rate of bile duct injury in the early group. If these patients are poor operative risks, percutaneous cholecystostomy drainage is an alternative. In the most severe patients with organ failure, percutaneous drainage is preferred, but in the rare situation in which this cannot be accomplished, laparoscopic cholecystectomy should be performed if possible, with early conversion to open surgery if needed. Whether cholecystostomy should be followed by interval surgery or endoscopic sphincterotomy is also debated. In a study of patients in the ICU that had interval surgery during the same admission, the conversion rate was 14% compared to the hospital-wide conversion rate of 1.4% [25]. In another study of patients with Grade II or III cholecystitis in the ICU treated with percutaneous cholecystostomy tube placement only two of 21 patients at a mean of 17.5 months follow-up presented with recurrent cholecystitis, and both of these were successfully treated by conservative means [26]. The use of antibiotics in patients with acute cholecystitis is not controversial but the length of treatment continues to be a source of debate. In patients undergoing early cholecystectomy (<72 h from the onset of symptoms), standard perioperative (<24 h) antibiotics should be administered. In patients that are very ill from cholecystitis, had a delay in treatment >72 h, are immunosuppressed, are > 60 years old, or have concomitant cholangitis, a prolonged course of treatment, usually no longer than 7 days, is indicated. Although the Tokyo Guidelines do not comment on antibiotic length of treatment it can be extrapolated that patients with Grade I or II cholecystitis can have perioperative dosing lasting less than 24 h, while those with Grade III should likely receive a 7–14 day course. If infected with a resistant pathogen or associated bacteremia is noted, antibiotics may need to be continued for 14 days. The choice of antibiotic should include coverage for gram-negative enteric pathogens, as well as anaerobic bacteria. Enterococcal species need not be covered. In community acquired infections that are mild, ampicillin/sulbactam, ticarcillin/clavulinate, or ertapenem may be selected. In high-risk patients, and those with recent hospitalization or antibiotic use of more broadspectrum agents, such as pipericillin/tazobactam or meropenem. C 555 After-care Most patients that have cholecystitis treated adequately require no special aftercare. Patients can expect to spend between 1 and 7 days in the hospital depending on the severity of the cholecystitis, whether the surgery was laparoscopic or open, and whether prolonged antibiotics are administered. Patients are allowed to resume a regular diet as soon as ileus resolves which again is dependent on the type of surgery. Some patients may experience early fatty meal intolerance but this is expected to resolve within a few weeks as the patient alters their diet to compensate. Patients treated with percutaneous drain placement do require special care. The patient will be discharged with the tube in place. Most will have had the tube clamped prior to discharge and are educated about tube care and what symptoms should prompt resumption of drainage. If the tube was placed for calculous disease, a contrast study is performed to evaluate for remaining stones. If stones remain, a decision to remove these is made in conjunction with a surgeon, endoscopist, and interventional radiologist. If the patient is an operative candidate, cholecystectomy can be performed. In older more debilitated patients an endoscopic sphincterotomy can be performed with the expectation of good results. An alternative is exchange of the percutaneous cholecystostomy tube using a guidewire to a larger bore tube followed by stone extraction. When it has been verified that all stones are cleared and the common bile duct is patent, the tube can be removed. Prognosis Prognosis after cholecystectomy is excellent. If performed by an experienced laparoscopic surgeon the rate of complications is very low. Most studies comparing early to late cholecystectomy show that delayed surgery results in a relatively large number of patients presenting with recurrent cholecystitis requiring urgent operation prior to the planned cholecystectomy. A large number of these patients will need open surgery. From other studies that evaluate interval cholecystectomy, it appears that conversion rates are lower in those that actually make it to planned operation. References 1. Laurila J, Syrja LA, Laurila PA, Ala-Kokko TI (2004) Acute acalculous cholecystitis in critically ill patients. Acta Anaesthesiol Scand 48:986–991 2. Pelinka LE, Schmidhammer R, Hamid L et al (2003) Acute acalculous cholecystitis after trauma: a prospective study. J Trauma 55:323–329 3. Sustic A, Krznaric Z, Naravic M et al (2000) Infuence on gallbladder volume of early postoperative gastric supply of nutrients. Clin Nutr 19(6):413–416 C 556 C Chronic Bronchial Sepsis 4. Matsushiro T, Sato T, Umezawa A et al (1997) Pathogenesis and the role of bacteria in acute cholecystitis. J Hepatobiliary Pancreat Surg 4:91–94 5. Manolis EN, Filippou DK, Papadopoulos VP, Kaklamanos I, Katostaras T, Christianakis E, Bonatsos G, Tsakris A (2008) The culture site of the gallbladder affects recovery of bacteria in symptomatic cholelithiasis. J Gastrointest Liver Dis 17(2):179–182 6. Claesson B, Holmlund D, Mätzsch T (1984) Biliary microflora in acute cholecystitis and the clinical implications. Acta Chir Scand 150:229–237 7. Mayumi T, Takada T, Kawarada Y, Nimura Y, Yoshida M et al (2007) Results of the Tokyo consensus meeting Tokyo guidelines. J Hepatobiliary Pancreat Surg 14:114–121 8. Bennett GL, Balthazar EJ (2003) Ultrasound and CT evaluation of emergent gallbladder pathology. Radiol Clin North Am 41 (6):1203–1216 9. Ralls PW, Colletti PM, Lapin SA et al (1985) Real-time sonography in suspected acute cholecystitis: prospective evaluation of primary and secondary signs. Radiology 155:767–771 10. Kalimi R, Gecelter GR, Caplin D, Brickman M, Tronco GT, Love C, Yao J, Simms HH, Marini CP (2001) Diagnosis of acute cholecystitis: sensitivity of sonography, cholescintigraphy, and combined sonography-cholescintigraphy. J Am Coll Surg 193 (6):609–613 11. Shea JA, Berlin JA, Escarce JJ, Clarke JR, Kinosian BP, Cabana MD, Tsai WW, Horangic N, Malet PF, Schwartz JS et al (1994) Revised estimates of diagnostic test sensitivity and specificity in suspected biliary tract disease. Arch Intern Med 154(22): 2573–2581 12. Eiberg JP, Grantcharov TP, Eriksen JR, Boel T, Buhl C, Jensen D, Pedersen JF, Schulze S (2008) Ultrasound of the acute abdomen performed by surgeons in training. Minerva Chir 63(1):17–22 13. Puc MM, Tran HS, Wry PW, Ross SE (2002) Ultrasound is not a useful screening tool for acute acalculous cholecystitis in critically ill trauma patients. Am Surg 68(1):65–69 14. Bennett MT, Sheldon MI, dos Remedios LV, Weber PM (1981) Diagnosis of acute cholecystitis using hepatobiliary scan with technetium-99 m PIPIDA. Am J Surg 142(3):338–343 15. Johnson H Jr, Cooper B (1995) The value of HIDA scans in the initial evaluation of patients for cholecystitis. J Natl Med Assoc 87 (1):27–32 16. Alobaidi M, Gupta R, Jafri SZ, Fink-Bennet DM (2004) Current trends in imaging evaluation of acute cholecystitis. Emerg Radiol 10(5):256–258, Epub 2004 Mar 17 17. Hicks RJ, Kelly MJ, Kalff V (1990) Association between false negative hepatobiliary scans and initial gallbladder visualization after 30 min. Eur J Nucl Med 16:747–753 18. Flancbaum L, Choban PS, Sinha R, Jonasson O (1994) Morphine cholescintigraphy in the evaluation of hospitalized patients with suspected acute cholecystitis. Ann Surg 220(1):25–31 19. Bennett GL, Rusinek H, Lisi V, Israel GM, Krinsky GA, Slywotzky CM et al (2002) CT findings in acute gangrenous cholecystitis. AJR Am J Roentgenol 178:275–281 20. De Vargas Macclucca M, Lanciotti S, De Cicco ML, Bertini L, Colalacomo MC, Gualdi G (2006) Imaging of simple and complicated acute cholecystitis. Clin Ter 157(5):435–442 21. Oh KY, Gilfeather M, Kennedy A, Glastonbury C, Green D, Brant W, Yoon HC (2003) Limited abdominal MRI in the evaluation of acute right upper quadrant pain. Abdom Imaging 28(5):643–651 22. Strasberg SM (2008) Acute calculous cholecystitis. N Engl J Med 358 (26):2804–2811 23. Stefanidis D, Bingener J, Richards M et al (2005) Gangrenous cholecystitis in the decade before and after the introduction of laparoscopic cholecystectomy. JSLS 9:169–173 24. Gurusamy KS, Samraj K, Fusai G, Davidson BR (2008) Early versus delayed laparoscopic cholecystectomy for biliary colic. Cochrane Database Syst Rev 8(4):CD007196 25. Spira RM, Nissan A, Zamir O, Cohen T, Fields SI, Freund HR (2002) Percutaneous transhepatic cholecystectomy and delayed laparoscopic cholecystectomy in critically ill patients with acute calculous cholecystitis. Am J Surg 183:62–66 26. Griniatsos J, Petrou A, Pappas P et al (2008) Percutaneous cholecystostomy without interval cholecystectomy as definitive treatment of acute cholecystitis in elderly and critically ill patients. South Med J 101(6):586–590 Chronic Bronchial Sepsis ▶ Bronchitis and Bronchiectasis Chronic Bronchitis ▶ Decompensated Disease Chronic Obstructive Pulmonary Chronic Kidney Disease (CKD) ▶ Decreased Estimated Glomerular Filtration Rate (eGFR): Interpretation in Acute and Chronic Kidney Disease Chronic Lung Disease ▶ Decompensated Disease Chronic Obstructive Pulmonary Chronic Obstructive Airway Disease ▶ Decompensated Disease Chronic Obstructive Pulmonary Chylothorax C Chylous pleural effusion into the venous blood near the junction of the left jugular and left subclavian veins. Therefore, in the event that a patient has not had any recent oral intake, the appearance of the chyle may actually be clear. The diagnosis of a chylothorax is confirmed by the presence of chylomicrons in the pleural fluid. The thoracic duct is the final common channel through which all lymphatic fluid in the body reenters the blood stream. The thoracic duct originates at the cysterna chyli, typically between the third lumbar vertebrae and the tenth thoracic vertebrae. It then ascends along the anterior surface of the vertebral bodies, lying between the aorta and the azygos vein. At the level of the fifth thoracic vertebrae (T5), the thoracic duct crosses over from right to left and continues its ascent posterior to the aortic arch. Finally, it courses through the thoracic inlet where it ultimately empties into the venous system somewhere near the junction of the left internal jugular vein and left subclavian vein. While anatomic variations of the thoracic duct do exist, this is the most common course. Therefore, a thoracic duct injury below T5 will produce a right sided chylothorax but an injury above T5 will produce a left sided chylothorax. Definition Evaluation Chylothorax is defined as the presence of chyle in the thoracic cavity. This typically occurs when chyle leaks from the thoracic duct or one of its major branches into the pleural space. This leakage of chyle can be due to congenital abnormalities, traumatic injury of the thoracic duct, invasion of the thoracic duct by a tumor or malignancy, infection, or thrombosis of the venous system. Chyle is lymphatic fluid that is typically laden with free fatty acids, cholesterol and phospholipids resulting in a milky color to the fluid. The predominant cell type within chyle is lymphocytes. The concentration of free fatty acids, cholesterol and phospholipids varies depending upon absorption of these products from the small intestine. The ingestion of triglycerides and phospholipids results in their absorption by the intestinal epithelium. Upon absorption, those triglycerides that contain fatty acids of 12 carbons or less are absorbed directly into the blood stream. These are termed medium-chain triglycerides. Triglycerides composed of fatty acids that are longer than 12 carbons (long-chain triglycerides) are not directly absorbed into the bloodstream. Instead, longchain triglycerides are complexed with cholesterol, phospholipids, and binding proteins to form lipoproteins. Once assembled, the lipoproteins are transported through the lymphatic system, eventually arriving in the thoracic duct. Once in the thoracic duct, lipoproteins are emptied Patients with a chylothorax may have symptoms that are commonly associated with any type of pleural effusion including shortness of breath, fatigue, chest discomfort, and cough. The presence of chyle in the pleural space does not cause any irritation of the pleura. Therefore, patients will not typically complain of pleuritic chest pain if their effusion is secondary to a chylothorax. Patients with chylothorax will have evidence of a pleural effusion on plain radiographs and/or computed tomography (CT) of the chest. However, radiographic imaging alone cannot distinguish chylothorax from other causes of pleural effusions. Definitive diagnosis of a chylothorax requires sampling of the pleural fluid. While the classic description of a chylothorax is the return of milky white fluid, this is not always present and the return of clear fluid from the pleural space does not exclude chylothorax. The presence of chylomicrons in the pleural fluid is the gold standard for diagnosing a chylothorax. Once the diagnosis of chylothorax has been made, the etiology of the chyle leak must be further investigated. The etiology of a chylothorax typically falls into one of three categories: congenital, traumatic, or neoplastic. By far the two most common causes of chylothorax are trauma and neoplasms [1]. Obtaining a thorough history will often elucidate the cause. Common surgical procedures associated with the development of a chylothorax include Chronic Salicylate Toxicity ▶ Salicylate Overdose Churg–Strauss Syndrome ▶ Pulmonary-Renal Syndrome Chylothorax LAURA J. MOORE Department of Surgery, The Methodist Hospital Research Institute, Houston, TX, USA Synonyms 557 C 558 C Chylothorax esophagectomy, pneumonectomy, repair of aortic aneurysm, radical lymph node dissections of the neck, chest, or abdomen, and surgery for the removal of mediastinal tumors. In addition, blunt or penetrating trauma can result in injury to the thoracic duct with subsequent development of a chylothorax. Obstruction of the thoracic duct by tumor is the most common cause for non-traumatic chylothorax. Lymphoma is the by far the most common malignancy seen in non-traumatic cases of chylothorax, accounting for 70% of the cases. Other potential but uncommon causes include congenital atresia of the thoracic duct, mediastinal radiation, and transdiaphragmatic passage of chylous ascitic fluid in patients with cirrhosis [1]. In the event that the etiology of the chylothorax remains unclear, diagnostic imaging may be helpful. CT scan of the chest may reveal underlying tumor or mediastinal lymphadenopathy that had been previously undiagnosed. If available, lymphangiography or lymphoscintigraphy can be utilized to define lymphatic anatomy and identify the source of the leak [2]. This can be potentially useful for operative planning purposes. Treatment Having a basic understanding of lipid metabolism and thoracic duct anatomy is helpful in understanding the role of various therapies in the management of chylothorax (see above). The treatment plan should be individualized for each patient and should take into account the underlying etiology, duration, symptoms, nutritional status, and other co morbid conditions. Treatment options can be broadly categorized into nonoperative and operative therapies. Most clinicians would favor an initial trial of nonoperative therapy for a period of 1–2 weeks. However, in those patients this may be associated with longer hospital stays and an increased risk of complications. Therefore, the risk versus benefit of nonoperative therapy must be critically evaluated on a patient by patient basis. Nonoperative Management The initial step in the nonoperative management of chylothorax is placement of a tube thoracostomy to drain the pleural space and allow for re-expansion of the lung. Tube thoracostomy is preferred over repeated thoracentesis because it allows for apposition of the pleural surface which may promote sealing of the site of the leak and because thoracentesis alone rarely results in complete drainage of the effusion. In addition, repeated thoracentesis unnecessarily exposes the patient to the risk of pneumothorax or hemothorax. A key component of the nonoperative management of chylothorax is an assessment of the patient’s nutritional status. Because chyle is rich with triglycerides, proteins, and electrolytes the ongoing loss of these substances can result is significant malnutrition and electrolyte abnormalities. Hyponatremia and hypocalcemia are the most commonly encountered electrolyte disturbances. The severity of these derangements is dependent upon the volume and duration of the chyle leak. Monitoring the patient’s nutritional status through weekly weights, serum prealbumin and transferrin levels, and nitrogen balance is critical. Manipulation of a patient’s enteral intake can decrease the volume of chyle generated and therefore increase the chances of the leak sealing with nonoperative management. As mentioned above, long-chain triglycerides are unable to be absorbed directly into the blood stream by the enterocytes. Therefore, they must be packaged as lipoproteins and travel through the thoracic duct before re-entering the blood stream. By removing longchain triglycerides from the diet, the volume of chyle transported through the thoracic duct can be significantly decreased. Instituting a low fat, medium-chain triglyceride diet will result in closure of the leak in 50% of cases [3]. Total parenteral nutrition may be utilized in the event that dietary modification is unsuccessful and surgical management is not an option. In those patients with chylothorax due to malignancy, therapies targeted the primary malignancy may be of benefit but the results are inconsistent [1]. Chemical pleurodesis may be useful in patients that are not surgical candidates that have failed chemotherapy and radiation therapy. Talc, tetracycline, and bleomycin have all been used successfully for chemical pleurodesis. In addition, somatostatin has been shown to reduce the production of intestinal chyle with results decrease in chyle leak [6]. Operative Management The surgical treatment of chylothorax involves ligation of the thoracic duct. Surgical treatment should be considered first line therapy in those patients with post surgical chylothorax. This is because conservative management of post surgical chylothorax has been associated with increased mortality when compared with surgical treatment [4, 5]. Patients that have failed a trial of nonoperative therapy should also be managed surgically. As a general rule of thumb, two groups of patients will likely fail conservative management; (1) those patients with a chyle leak of greater than 1.5 L/day and (2) those patients with a sustained chyle leak of 1 L/day for 5 consecutive days. In these patients, surgical intervention should be considered, as it will likely result in better outcomes. Circulatory Assist Devices Once the decision to pursue operative intervention has been made, there are several techniques that can be utilized to ligate the thoracic duct. Operative approaches include open and thoracoscopic. In general, operating on the same side as the effusion is preferred. Selective ligation of the thoracic duct at the site of the leak may be performed if the leak can be identified. Methylene blue may be mixed with a fat source such as olive oil or cream and administered enterally to help visualize the site of the leak. Once the leak is identified, the thoracic duct is ligated above and below the site of the leak. In the event that the leak cannot be easily identified, further dissection around the thoracic duct to identify the leak is discouraged, as this may lead to further injury to the thoracic duct and its tributaries. Instead, mass ligation of the soft tissues lying between the aorta, spine, esophagus, and pericardium should be performed just above the diaphragmatic hiatus in the right chest. After-care The main focus following resolution of a chylothorax is to ensure correction of any nutritional, immunologic, or electrolyte abnormalities that may have occurred. This can include weekly assessments of nutritional status, monitoring for evidence of immunosuppression, and electrolyte replacement. Prognosis The prognosis for patients with chylothorax is highly variable and dependent upon the underlying etiology. With more aggressive management, there has been a decrease in the morbidity and mortality associated with this condition. Patients with iatrogenic or traumatic chylothorax have the best prognosis for recovery. Those patients with malignant chylothorax tend to have a worse prognosis. Cross Reference ▶ Pleural Disease and Pneumothorax References 1. 2. 3. 4. 5. Nair SK, Petko M, Hayward MP (2007) Aetiology and management of chylothorax in adults. Eur J Cardiothorac Surg 32(2):362–369 Ngan H, Fok M, Wong J (1988) The role of lymphography in chylothorax following thoracic surgery. Br J Radiol 61(731):1032–1036 Fernández Alvarez JR, Kalache KD, Graŭel EL (1999) Management of spontaneous congenital chylothorax: oral medium-chain triglycerides versus total parenteral nutrition. Am J Perinatol 16(8):415–420 Al-Zubairy SA, Al-Jazairi AS (2003) Octreotide as a therapeutic option for management of chylothorax. Ann Pharmacother 37(5):679–682 Orringer MB, Bluett M, Deeb GM (1988) Aggressive treatment of chylothorax complicating transhiatal esophagectomy without thoracotomy. Surgery 104(4):720–726 C 559 Chylous Pleural Effusion ▶ Chylothorax C Circulation ▶ Capillary Refill Circulatory Assist Devices ARES KRISHNA MENON1, RÜDIGER AUTSCHBACH2 1 Klinik f. Thorax-, Herz-, Gefäßchirurgie, Klinikum der RWTH, Aachen, Germany 2 Clinic for THG Surgery, University of Aachen, Aachen, Germany Synonyms Biventricular Assist Device (BVAD); Left Ventricular Assist Device (LVAD); Left Ventricular Assist System (LVAS); Mechanical Circulatory Assist; Mechanical Circulatory Support (MCS); Right Ventricular Assist Device (RVAD); Ventricular Assist Device (VAD) Definition and History After the first use of cardio pulmonary bypass (CPB) in the 1950s and the increasing number of cardiac procedures, the need for extended circulatory assistance in patients who could not be weaned from CBP was obvious. After the first experimental use of ventricular assist devices (VAD) in 1963 De Bakey introduced the first clinical use of a VAD in a patient after aortic valve replacement. Only a few months later the group of Denton Cooley presented their first successful use of an assisted circulation as a bridge to transplantation (BTT). During these pioneering works two different systems were surveyed: Pneumatically driven rubber-tube or sac pumps which offer a pulsatile flow and continuous flow devices like, for example, centrifugal pumps. As recorded in the recommendations of the National Heart Advisory Group the importance of mechanical support was recognized by the National Institute of Health in the USA in 1964. The former initial goal was to develop a total artificial heart (TAH). While the first TAH program was abandoned in 1991due to the enormous rate of severe complications, the National Heart and Lung Institute 560 C Circulatory Assist Devices meanwhile put its effort in the development and evaluation of left ventricular assist devices (LVADs). This led to the Food and Drug Administration (FDA) approval of LVAD for BTT use in 1994. Thus, under high volume sponsored research during the last 20 years, two different types of devices became available: Pulsatile VADs as well as the newer and smaller continuous flow pumps. Both systems are usable for intracorporeal and paracorporeal implantation. According to the degree of individual disease, more or less all appliances can be used as a univentricular support for LVAD, as a right ventricular assist device (RVAD), or as a biventricular assist device (BVAD). Pre-existing Condition The treatment of heart failure is of tremendous growing interest even at the intensive and intermediate care units in our hospitals. In heart failure or even in cardiogenic shock patients the caring physician has to decide whether to treat the patient with medication only or to use circulatory support to stabilize hemodynamics and preserve organ function. The so-called Intention to Treat (ITT) in the rising use of VADs for mechanical cardiac support is the key issue and has essential influence on the choice of the individual device: Whether as for Bridge to Recovery (BTR), Bridge to Transplantation (BTT), or for long-term circulatory support as the so-called Destination Therapy (DT). Other patients fall in the category of Bridge to Candidacy (BTC). These are patients who at the time of an urgent device implantation are either critically ill and have not been completely evaluated for OHTor are bearing a major or relative contraindication to transplantation. Furthermore, the type of the support needed has to be considered: Is an univentricular assist device sufficient? or is the use of a biventricular device (BVAD) crucial?. Indications for Assisted Circulation Usually, the use of a VAD is indicated in case of severe heart failure which is refractory to the conservative treatment options. If the patient is not able to offer adequate systemic oxygen delivery to maintain normal end-organ function despite maximal medical therapy, mechanical support is indicated. The common hemodynamic criteria for device implantation include a systolic blood pressure less than 80 mmHg, mean arterial pressure less than 65 mmHg, cardiac index less than 2.0 L/min/m2, pulmonary capillary wedge pressure greater than 20 mmHg, and a systemic vascular resistance greater than 2100 dyn-s/cm [1]. The large variety of diseases treated with assisted circulation devices includes both acute and chronic forms of heart failure. The acute cardiogenic shock is one of the main reasons for treating the patient in an emergency ward or chest pain unit. There are several reasons for cardiogenic shock. Acute myocardial infarction, for example, complicated by cardiogenic shock has a very high mortality rate. A trend towards early intervention reached a better outcome by early and more aggressive coronary reperfusion strategies such as percutaneous intervention, coronary bypass surgery, or aortic counterpulsation. Moreover, up to 6% of patients after heart operation are still suffering from low output syndrome, the post-cardiotomy shock, especially after complex surgical procedures like heart transplantation, multivalve replacement, or treatment of severely impaired left ventricular function. Depending on the age of patients who require assisted circulation, there are some other typical indications. Myocarditis or dilated cardiomyopathy (DCM) affects the younger patient group with an often unpredictable outcome. The global dilatation of both, the left and right ventricle, often leads to a biventricular heart failure and therefore requires an adequate biventricular support. Moreover, a rare indication for VAD therapy is a complex ventricular arrhythmia, if refractory to medical treatment. The second and also large cohort of patients which is considered for AC is the chronic heart failure group. An estimated 2–5 million patients are suffering from heart failure worldwide [2]. The continued aging of mankind leads to a growing number of patients. The incidence and prevalence of this disease is obviously age dependant: On an average 2–5% of the population aged 65–70 years and about 10% in the group of persons aged more than 70 years are affected, and around 500,000 new cases per year are registered. In spite of all advances in medical treatment of severe heart failure the prognosis of the patients is poor. In patients with severe heart failure more than 50% die within 1 year. These patients have to be divided in two groups: Those who are eligible for orthotopic heart transplantation (OHT), and those, who are not. OHT is the only treatment that provides substantial individual benefit, but with fewer than 4,000 donors available per year worldwide its impact is epidemiologically trivial. Additionally, we find a growing number of patients who are ineligible for cardiac transplantation because of advanced age, presence of diabetes mellitus with end-organ damage, chronic renal failure, or pulmonary hypertension. Therefore, the limitations of cardiac transplantation procedures have stimulated the development of alternative approaches to the treatment of severe heart failure. For these reasons within the chronic heart failure group of patients assisted circulation is exercisable as a BTT or as destination therapy. Circulatory Assist Devices Device Selection Due to the above-mentioned circumstances the treating physician has to decide, which specific blood pump would be the appropriate tool for the individual patient. The operative risk of the implantation procedure has to be weighed against the potential lifestyle and survival benefit with mechanical support, the already stated intention to treat. C assisted circulation, the ECMO is widespread and leads to a remarkable improvement in survival rates of these high-risk cases. The very new Tandem Heart paracorporeal centrifugal pump (CardiacAssist, Inc., Pittsburgh, Penn., USA) can easily be implanted via percutaneous insertion of the groin vessels without a surgical procedure. In doing so, the inflow cannula is brought up the femoral vein and through the atrial septum into the left atrium percutaneously. Application Axial Flow Pumps Short-Term Circulatory Support A large variety of technical devices do exist to support the failing heart for a short time period. These devices have the advantage of an easy implantation technique based on the hope of an early cardiac recovery or bridging the patient to use a more permanent ventricular device. Intra-Aortic Balloon Pump (IAPB) Kantrowicz and coworkers presented the first clinical use of an Intra Aortic Balloon Pump (IABP) for the treatment of cardiogenic shock after myocardial infarction in 1968. Once percutaneously placed in the descending aorta, its diastolic pulsation and systolic deflation is triggered by ECG or arterial pressure, resulting in reduction of afterload and improvement of coronary perfusion. The application of IABP is widespread because of its uncomplicated use and improved outcome in the treatment of myocardial infarction, postcardiotomy shock, postinfarction VSD, or acute mitral valve regurgitation caused by posterior wall infarction [3]. Critical limp perfusion is a rare, but severe complication, and therefore IABP use has to be considered deliberatively in case of peripheral vascular disease. Centrifugal Pumps Originally used for CPB, centrifugal pumps were thereafter in many cases also applied for assisted circulation because of the low costs, uncomplicated implantation techniques, and easy handling. The Biomedicus BioPump (Medtronic Inc., Minneapolis MN, USA), the Sarns centrifugal pump (3-M Health Care, Ann Arbor, Michigan, USA), and the newer Centrimag (Levitronix Inc.) are the most common pumps in this field. Placed paracorporeally, the implantation could either be achieved via cannulation of the groin vessels or – in case of postcardiotomy shock – via connection to the cannulas of the CBP intraoperatively. In case of a collateral respiratory failure, the connection to an oxygenator is possible, resulting in an extra corporeal membrane oxygenation system (ECMO). Especially in the pediatric field of The microaxial blood pump Impella Recover Device (Impella CardioSystems AG, Aachen, Germany) is a newer short-term support system for up to 7 days. Brought through the aortic valve inside the left ventricle percutaneously, this pump generates flow up to 5 L/min. Therefore, it can be used as an ideal tool for postcardiotomy support or myocardial infarction with cardiac shock to establish a rapid unloading of the failing left ventricle. Since last year a paracardiac right-ventricular device (RVMBP) of the Impella family was available until the product was withdrawn from the European market. Pulsatile Short-Term Pumps A dual chamber polyurethane blood sac pump, the Abiomed BVS 5000i (Abiomed Cardiovascular, Inc., Danvers, Mass. USA) is a passively filled, pulsatile shortterm assist device for the use after postcardiotomy shock. This device can be used for univentricular as well as for biventricular support generating flows up to 6 L/min. Its cost-effectiveness and the ease of implantation have lead to a widespread use, especially for the BTR short term, or a bridging to another, more permanent system, the bridge to bridge (BTB). The same company introduced another, more complex pulsatile, paracorporeal, fully automated device with pneumatically driven full-to-empty mode: the AB 5000. Similar to the older paracorporeal long-term devices, such as Berlin Heart Excor (Berlin Heart Inc. Berlin, Germany) or the Thoratec PVAD (Thoratec Inc., California, USA), the AB 5000 is able to reach a complete unloading of the failing left or right ventricle and, got FDA approval for 30 days in the USA, so far. All of these short-term devices have the advantage of a more or less easy implantation and application. The main disadvantage of almost every short-term pump is the impossible mobilization of the patient. Only the newer, more costly devices such as the Centrimag or the AB 5000 do allow for a better mobilization of the individual patient. However, they touch the boarder of the permanent VADs not only clinically, but financially in particular. 561 C 562 C Circulatory Assist Devices Long-Term Circulatory Support Pulsatile Devices The first generation of LVADs are electromechanically or pneumatically controlled mechanical assist systems. They are used for BTT or DT and generate pulsatile blood flow up to 10 L/min. Some examples for the permanent use of VADs are the paracorporeal systems Excor (Berlin Heart, Germany) (Fig. 1), Thoratec PVAD (Thoratec, California, USA), and the Medos HIA (Medos Inc., Aachen Germany). The pump chambers of the Excor and HIA are offered in different sizes so that pediatric use is possible. Patients treated with these large, bulky devices are difficult to mobilize, also because of the risk of kinking the grafts and the large control units. The following, implantable pulsatile devices are brought into a huge preperitoneal pocket connected to a percutaneous driveline. The HeartMate XVE (Thoratec Inc.) is the most used implantable VAD with more than 4,000 implantations worldwide. The peculiarity of the HeartMate XVE is its structured inner surface, leading to a neointima formation to reduce the risk of thrombus formation. Because this device has biological valves, anticoagulation is not necessary. A large amount of clinical experience has been gained with the Heartmate LVAD. The pioneering REMATCH trial [4] was established by using this device for DT. Historically, it is necessary to mention two other systems which were withdrawn from the market in 2005 and 2008 respectively: The LionHeart 2000 LVAD (Arrow International, PA, USA) and the Novacor LVAS(Baxter Healthcare/Worldheart Inc.) devices. The Novacor is implanted in the same approach as the Heartmate VXE, including the typical connection to a console by a percutaneous driveline. The fully implantable Lion Heart was powered by transcutaneous energy transfer, thereby obviating the need for external lines, which is a common course of infection in LVAD recipients. A pump controller was implanted as well regulating the external power supply. The external power pack with rechargeable and replaceable batteries could be removed from the transcutaneous site maximal 30 min. The inside of this system achieves unidirectional blood flow by mechanical heart valves and therefore necessitates Warfarin or Heparin treatment. The system was licensed for trials in Europe and the USA for long-term support in patients with end-stage-heart failure. Because of some major technical failures, for example, fatal fracture of the blood sac, the device was displaced from the market in 2005. The Novacor device was developed in the 1970s. Its regulatory approval in Europe and the USA for BTT came in the 1994 and 1998, respectively, followed by a regulatory approval for long-term support in Europe. More than 1,800 implantations could be accomplished worldwide. It carries biological valves for achievement of unidirectional flow, although because of the inner structure of this device systemic anticoagulation is mandatory as well in the LionHeart. Here, similar to the technical failures of the LionHeart, the durability was obviously very limited and consequently the Novacor LVAD was withdrawn from the market in 2008. Continuous Flow Devices Circulatory Assist Devices. Figure 1 Excor One of the most promising advances in the field of circulatory assist devices is the development of axial flow pumps, like the HeartMate II (Thoratec) (Fig. 2), the Micromed DeBakey (MicroMedTechnology Inc., Houston , TX, USA), the Incor (Berlin Heart), and the Jarvik 2000 (Jarvik Heart Inc., NY, USA) (Table 1). These devices, the so-called second generation of VADs, generate continuous flow via a very small electromagnetically actuated impeller that rotates at high speeds and are able to provide up to 10 L/min flow. Moreover, in the implantable pulsatile devices the particular inflow cannula is connected to the LV apex, the outflow graft to the ascending aorta. The remarkably small size of these devices allows Circulatory Assist Devices Circulatory Assist Devices. Figure 2 HeartMate II for enormous reduction in surgical trauma caused by a diminishment of the preperitoneal or even intrapericardial pump pocket. This is why the use for patients with a small body surface area is now possible, resulting in FDA approval for pediatric use for the MicoMed device. The other systems are now under trial for this indication. Moreover, these axial pumps are generating no relevant noise. Permanent anticoagulation therapy is necessary, but after early experiences are initiated and not until a minimum 12–24 h after implantation. The unique design of the Jarvik consists of an impeller, which is placed in the LV apex directly as a sort of inflow cannula housing the pump. Therefore, less invasive implantation is possible via a lateral thoracotomie leading the outflow graft to the descending aorta, in case a sternotomy should be avoided. This device operates at fixed rate motor speeds that are set by the controller at between 8,000 and 12,000 rpm with an average capacity of 5–7 L/min. Another implantation feature of this small pump is a titanium pedestal screwed into the very well-vascularized skull with a transcutaneous connector that attaches to the power cord. The MicroMed DeBakey AD is a titanium electromagnetically actuated axial flow pump with a maximum flow capacity C of 10 L/min at 10,000 rpm, but usually is initiated at 8,000 rpm, resulting in a 5–6 L flow per minute. It carries a special ultrasonic flow probe at the outflow graft site, which allows for exact flow measurements. The HeartMate II (Fig. 3) is a newer device and obtained its approval in Europe a few years ago and FDA approval for BTT was obtained in 2009. Fabricated with titanium, it operates at speeds between 6,000 and 12,000 rpm resulting in a flow up to 10 L/min in a fixed or automatic operating mode (http://www.thoratec.com/about-us/media-room/ videos.aspx). An overview is shown in Table 1. The recently developed implantable centrifugal circulatory assist devices represent the so-called third generation of implantable LVADs. Examples are the VentrAssist (Ventracor Inc., Australia), the HVAD (Hardware Inc., USA), and the DuraHeart (Terumo Inc., Japan).These devices use the magnetic technology in which rotating blades or an impeller is magnetically suspended within a column of blood, obviating the need for contact-bearing moving parts. The DuraHeart is a magnetically suspended centrifugal pump with impeller blades, magnetic bearing, and a direct motor. Its relatively large volume (200 mL) requires an implantation pocket, which is clearly bigger than the ones needed for axial pumps. The DuraHeart works with speeds of 2,000–3,000 rpm and creates a flow between 5–6 L/min. The VentrAssist device is a smaller titanium centrifugal pump with a carbon coating at its inner surface. It was implanted worldwide in more than 200 patients as a LVAD in CE marked use-and-pilot trials, but the company became bankrupt in spring 2009. The HVAD system was introduced recently and has just gained CE approval. It has a volume of only 50 mL and is directly implanted at the surface of the LV apex, allowing an intrapericardial pocket. The speed range of 2,000–3,000 rpm creates a flow up to 8–10 L/min. All centrifugal VADs require systemic anticoagulation. The Total Artificial Heart Severe failure of both the left and right ventricle of the human heart necessitates sometimes even more than the implantation of a paracorporeal BVAD. In selected cases like structural heart diseases, for example, hypertrophic cardiomyopathy or complex congenital cardiac diseases after a large number of operations with mechanical valve prosthesis inside, the orthotopic positioning of a totally implantable artificial heart (TAH) is required. The CradioWest (Syn Cardia Inc., Tucson, AZ, USA) is a pneumatically driven orthotopic, implantable biventricular assist system and at present the only available TAH. Its rigid pump housing contains dual spherical 563 C 564 C Circulatory Assist Devices Circulatory Assist Devices. Table 1 Characteristics of the most common continuous flow left ventricular assist devices (LVAD). Status: June 30, 2009 Terumo DuraHeart Heartware HVAD Jarvik Heart Jarvik 2000 MicroMed De Bakey HeartAssist Thoratec BerlinHeart HeartMate II Incor Ventracor VentrAssista System Axial Axial Centrifugal Centrifugal Centrifugal Axial centrifugal Weight gr. 280 200 298a 590 145 90 92 Size mm 81  43 120  43 40  60 5–10 5–10 5–10 Volume 30 mL 71  31 Max. flow 73  46  85 Volume 50 mL 5–7 5–10 Yes No 5–10 5–10 100 100 Yes Yes No Under investigation Under investigation under investigation Yes No No No No Yes Implantations 2900 CE Yes 500 Yes Yesa FDA-adult Yes Under investigation FDA-pediatric No Under investigation 200 300 a Company went bankrupt 2009 polyurethane chambers. The inflow and outflow conduits are made of Dacron and carry mechanical valve prosthesis (Medtronic Inc. USA). The stroke volume is about 70 mL and the CardioWest is able to generate a maximum flow of 10 L/min. The condition of insufficient space inside the patients’ thorax is a major problem. It requires a minimum BSA of 1.7 m2 or ventricular volumes of the native heart from more than 1.5 L. In Europe the pneumatic drivelines are connected to a smaller console, which allows for a better mobilization of the patient. The CW got the CE and FDA approval for BTT use. Implantation Technique A very large variety of surgical implantation techniques are necessary to accommodate an appropriate function of the specific device. In most cases cardiac support systems are implanted for left heart failure, since isolated insufficiency of the right ventricle is rare. Whereas in the short-term devices mostly an access to the groin vessels is sufficient; the devices for permanent support require a median sternotomy or another adequate access to the left ventricle and the aorta. The fully heparinized patient is put on CPB and the apex of the left ventricle is exposed for the insertion of the inflow cannula of the VAD, which is usually done by beating the heart on pump without cardioplegic arrest. After having prepared the device pocket in the preperitoneal or intrapericardial position, the driveline is tunneled and brought out of the skin in the right upper quadrant. The correct position of the LV apex is cut with a special core knife, the myocardium is removed, and the Circulatory Assist Devices. Figure 3 External equipment LV is accurately inspected. The thrombi have to be removed carefully and trabecular structures have to be excised in case they might hinder the free flow to the inflow cannula. The apex cannula is then fixed to the left Circulatory Assist Devices ventricle by 2-0 polypropylene sutures reinforced by felt pledges. The device once brought in correct position is then connected and the outflow graft, a Dacron vascular prosthesis, is sutured into an end-to-side anastomosis to the aorta followed by the careful de-airing of the device. Subsequently, the patient is weaned from CPB while the VAD is initiated. In this context, the correct position of the inflow cannula has to be monitored carefully by transesophageal echocardiography (TEE) to ensure an unrestricted blood flow to the assist device. In LVAD implantation particular interest is then given to the right ventricle and the right atrium to safeguard the adequate systolic function and to obviate a persistent PFO, which might have been hidden by an assumed high left atrium pressure before a LVAD implantation due to low cardiac output. Protamine is admitted and meticulous hemostasis is established before chest drains are placed and the sternum is closed with permanent wires. To minimize trauma of the device or the outflow graft, a Gore-Tex surgical membrane can be used to cover these delicate structures before the sternum is closed. The use of phosphodiesterase inhibitors, inhaled nitric oxide and aggressive inotropic support of the right ventricle in case of any impaired systolic right ventricular function should be applied very liberally. Again, the TEE is an ideal and essential tool for the effective treatment of a patient after LVAD implantation beside the information from the measurements of the pulmonary artery catheter. After having reached stable conditions in the operating theatre a seamless constant treatment of these patients should always be the main goal. Such is the postoperative care at the ICU. Decent monitoring of a stable right heart hemodynamic, excellent oxygenation, and proper function of the device to guarantee a sufficient perfusion of all organs is the main target of the intensive care doctor, who then should always be very alert to the drain blood loss and the urine output. Well-dosed substitution of blood products like plasma or platelets should be applied whenever it is needed. Antibiotics should be given minimum 48 h postoperatively for prophylactic use. Outcome of Circulatory Assist Device Treatment Randomized Evaluation of Mechanical assistance for the Treatment of Congestive Heart Failure (REMATCH) trail is a landmark in the history of clinical trials in heart failure [4]. The study included end-stage heart failure patients who were ineligible for cardiac transplantation and randomized them to either surgical therapy (implantation of a HeartMate XVE LVAD) or optimal medical treatment. All patients were classified in NYHA class IV, LV EF <25%, and C either peak oxygen consumption < 12–14 mL/KG/min or dependence on inotropes. Within the cohort of these critically ill the 1- and 2-year survival rates of 52% and 23% in LVAD recipients were significantly better than the 25% and 8% survival observed in patients treated with maximum medical therapy [4]. Despite more adverse events in the LVAD group the survival rate and quality of life were better in these patients. Later on, this tendency continued resulting in an improvement of the 2-year survival of 37% in the LVAD group versus 12% in the medical group (Late REMATCH). Bleeding, infection, and multiorgan failure were the major cause of early mortality after LVAD implantation. Long-term mortality was mostly related to device dysfunction and infectious complications. Sepsis and local infections were the most common cause of morbidity and mortality in LVAD recipients and account for 25% of deaths. In the post-Rematch area, the 1-year survival increased to 56% with an in-hospital mortality of 27% after LVAD surgery [5]. Again the main causes for death were sepsis, right heart failure, and multiorgan failure. The Interagency Registry for Mechanically assisted Circulatory support (INTERMACS) database, funded by the US National Heart, Lung and Blood Institute (NHLBI), is a new registry for patients who receive durable FDA-approved mechanical circulatory support devices for the treatment of advanced heart failure [6]. The patients’ clinical status before VAD implantation was classified into seven different INTERMACS levels, grated from 1, representing the sickest patients in severe cardiogenic shock, to 7, representing an advanced NYHA level III. The first report presented in 2008 gives a further positive tendency in the development of VAD treatment in more than 400 patients. Included were BTT, as well as DT, or BTR patients. The overall survival rate was 56% after 1 year, but with a close look at the extent of support, LVAD recipients had a much better survival rate (67%), than the BVAD cohort (<40%). The main causes of death were central neurologic events (18% of all deaths), multiorgan failure (16%), right ventricular failure and arrhythmias (15%), and infections (8%). By multivariable analysis the risk factors for early death were INTERMACS level 1, older age, ascites at the time of implant, higher bilirubin level, and placement of a BVAD or Total Artificial Heart. The results of an early European study on the axial flow HeatMate II device for LVAD proved far better than the early experiences with pulsatile devices [7]. After 1 year a comparable survival was observed in both, the DT (69%), and the BTT (63%) group of patients. Main causes of death in this multicentre trial were multiorgan failure and cerebrovascular accidents. The survival remained stable in this cohort of LVAD recipients even after 6 months. 565 C 566 C Circulatory Collapse This correlates to the findings of the first studies with axial flow devices in the USA. Adverse Events (AE) In the Rematch trial, non-neurologic bleedings, neurologic events, and perioperative bleeding were the most common complications [4]. Recently, the INTERMACS data analysis showed comparable results, with bleeding and infection as the most common adverse events in the early and late postoperative period [6]. Neurologic events were most likely in the first 1–2 months after implant. Device malfunction, formerly the second most frequent cause of death (Rematch), was relatively uncommon during the duration of follow-up, with 84% freedom at 6 months. Moreover, malfunction of the newer axial flow devices was totally absent in the European HeartMate II study. The most common adverse events in this trial were bleeding requiring surgery (21% of all AE), cardiac arrhythmias (19%), and sepsis (11%) which occurred mainly without exception in the early postoperative period (<90 days), whereas the driveline and local infections were the most common AE of the late period [7]. A remarkable reduction of neurologic events was also notable in the newer data analysis. Right heart failure, one of the most common AE after LVAD implantation in the earlier studies, seems to play a cumulatively minor role in last examinations. Coming out of an incidence of 20%, the right heart failure after LVAD implantation is clearly reduced to less than 10% as well in the INTERMACS data base, as well in the European HeartMate II study. Conclusions Circulatory assist devices have become a major therapeutic option in treatment of either acute or chronic heart failure patients. In the last years, long-term circulatory support has made a great deal of progress, and the trends towards better device durability and reduced complication rates will most likely continue to improve through the development of more innovative ventricular assist devices. References 1. 2. 3. 4. Pagani FD, Aaronson KD (2003) Mechanical devices for temporary support. In: Franco KL, Verrier ED (eds) Advanced therapy in cardiac surgery, 2nd vol. BC Decker, Hamilton, Ontario Hunt SA, Abraham WT, Chin MH et al (2005) ACC/AHA 2005 Guideline update for the diagnosis and management of chronic heart failure in the adult—summary article. Circulation 112:1825 Aggarwal S, Cheema F, Oz M, Naka Y (2008) Long-term mechanical circulatory support. In: Cohn LH (ed) Cardiac Surgery in the Adult. McGraw-Hill, New York, pp 1609–1628 Rose EA, Gelijns AC, Moskowitz AJ, Moskowitz AJ, Heijan DF, Stevenson LW, Dembitsky W, Long JW, Ascheim DD, Tierney AR, 5. 6. 7. Levitan RG, Watson JT, Meier P (2001) Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 345:1435–1443 Lietz K, Long JW, Kfoury AG, Slaughter MS et al (2007) Outcomes of left ventricular Assist Device Implantation as Destination Therapy in the post-REMATCH Era-Implications for Patient Selection. Circulation 116:497–505 Kirklin JK, Naftel DC, Stevenson LW, Kormos RL, Pagani FD, Miller MA, Ulisney K, Young JB (2008) INTERMACS Database for Durable Devices for Circulatory Support: First Annual Report. J Heart Lung Transplant 27:1065–1072 Stüber M, Sander K, Lahpor J, Ahn H, Litzler PY, Drakos SG, Musumeci F, Schlensak Ch, Friedrich I, Gustaffson R, Oertel F, Leprince P (2008) HeartMate II Left Ventricular Assist Device, early European experience. Eur J Cardiothorac Surg 34:289–294 Circulatory Collapse ▶ Shock, Ultrasound Assessment Cl H2O ▶ Free-Water Clearance Classification of Pulmonary Hypertension Functional classification of pulmonary hypertension modified after the New York heart association functional classification according to the World Health Organization 1998. Class I: No limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope. Class II: Slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class III: Marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class IV: Inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/ or fatigue may even be present at rest. Discomfort is increased by any physical activity. Clostridium difficile-Associated Diarrhea Clearance The volume of blood that is cleared from a given solute in the time unit. C Clostridium difficile Infection ▶ Clostridium difficile-Associated Diarrhea C ▶ eGFR, Concept of Clostridium difficile-Associated Diarrhea Clenched-Fist Injury ▶ Bite Injuries Clinical Pulmonary Infection Score (CPIS) Clinical score suggested for the diagnosis of VAP composed of the severity of infiltrate, body temperature, tracheal secretions, oxygenation derangement, positivity of endotracheal aspirate cultures, and white blood cell response. Closed Forequarter Amputation ▶ Scapulothoracic Dissociation ANDREW M. MORRIS Mount Sinai Hospital and University Health Network, University of Toronto, Toronto, ON, Canada Synonyms Antibiotic-associated diarrhea; Clostridium difficileassociated disease; Clostridium difficile infection; Clostridium difficile diarrhea; Pseudomembranous colitis Definition Clostridium difficile-associated diarrhea (CDAD) is a colonic infection caused by the overgrowth of the anaerobic Gram-positive bacillus, C. difficile. Patients may be asymptomatically colonized, but CDAD severity ranges from mild watery diarrhea to severe diarrhea with pseudomembranous colitis. Although C. difficile has various virulent factors, two pro-inflammatory exotoxins (Toxins A and B) appear to contribute most to the watery diarrhea [1]. Epidemiology Closed Head Injury (CHI) ▶ Traumatic Brain Injury-Fluid Management Clostridium botulinum ▶ Biological Terrorism, Botulinum Toxin Clostridium difficile Diarrhea ▶ Clostridium difficile-Associated Diarrhea 567 CDAD is an emerging infectious disease in most healthcare institutions worldwide. Recently, a more virulent fluoroquinolone-resistant strain, known as the ribotype 027 (BI/NAP1) strain, has emerged. The prevalence of C. difficile colonization ranges from 7–11% in acutely ill hospitalized patients to 1–2% in the general population. An estimated 178,000 cases of nosocomial CDAD occur in the USA annually, reflecting an incidence of roughly 50 per 1,000 patient-days or 5 per 1,000 admissions, although there is wide variability in reported rates, which are rising worldwide. Data on incidence in critical care units outside an outbreak setting are unclear, although one study reported a rate of 3.2 per 1,000 patient-days. Transmission is via C. difficile spores, which can remain on surfaces for prolonged periods and can also be transmitted directly person-to-person. However, CDAD usually requires altered fecal flora, which is most commonly caused by antibiotic use but can also be altered 568 C Clostridium difficile-Associated Disease by chemotherapy, radiation, proton-pump inhibitors, anti-peristaltic agents, stool softeners, enemas, and nasogastric feeds or drainage. Prevention The only effective method of prevention is avoiding (or minimizing) antimicrobial use. Most antimicrobials reduce the concentration of healthy fecal flora, allowing overgrowth of C. difficile. Infection control measures such as hand washing and barrier precautions clearly reduce transmission from index cases and can avert or halt outbreaks. site of care. Mortality in the ICU setting has recently been reported to be 37%. Population-based mortality of CDAD appears to be rising, with associated mortality in the USA of 5.7 per million population in 1999 and 23.7 per million in 2004. Whether this is due to a higher case fatality, an increasing incidence of disease, or both is uncertain. Economics The attributable patient cost of CDAD in the USA ranges from $6.408 to $9.124, costing US hospitals $1.14 to $1.62 billion annually [2]. Treatment References The most important first step in managing CDAD is to remove predisposing factors such as antimicrobials, proton-pump inhibitors, etc. Many cases of mild disease can be effectively managed with metronidazole 500mg po (preferred over iv) tid for 10–14 days. More severe or refractory cases often require vancomycin 125mg qid enterally (oral, nasogastric, or via enema). General surgeons should be consulted rather early in the course of illness in moderate to severe cases: undoubtedly, deaths may occur because of delayed surgery. Relapses occur in 5–10% of cases; management of relapses is beyond the scope of this text. 1. 2. Poutanen SM, Simor AE (2004 Jul 6) Clostridium difficile-associated diarrhea in adults. CMAJ 171(1):51–58 Scott II RD (2009) The direct medical costs of healthcare-associated infections in U.S. hospitals and the benefits of prevention. Department of Health and Human Services, Centers for Disease Control and Prevention Clostridium difficile-Associated Disease ▶ Clostridium difficile-Associated Diarrhea Evaluation CDAD should be considered in all patients with new, unexplained watery diarrhea. In the ICU, certain feeds (especially high-osmotic feeds) and bowel regimens may be the underlying cause of diarrhea, but they may also be contributing factors to CDAD. Diagnosis of CDAD is challenging because of the lack of a highly sensitive and specific test. CDAD is unlikely in patients with fewer than three bowel movements per day, and testing is therefore not advised. When testing is indicated, the best test (>90% sensitive, and >97% specific) is a quantitative PCR (qPCR) which gives results in hours. The C. difficile qPCR tests for a gene that codes for toxin B or its regulators, although most laboratories do not perform this test. The more common enzyme immunoassays test for either toxin A or toxins A and B; they are only about 70% sensitive although specificity and turnaround time are comparable to qPCR. Tissue culture cytotoxicity assay has similar diagnostic characteristics to qPCR, but results are only available after about 48 h and so it is falling out of favor. Prognosis CDAD carries overall 1–2% mortality, although there is a wide variability of reported mortality, depending on the Closure Time (PFA) The closure time, or platelet function analyzer, is an in vitro test of primary hemostasis. The assay measures the time necessary for whole blood to occlude a ring coated with collagen and adenosine diphosphate (ADP) or collagen and epinephrine while circulated through a cartridge at high shear flow. CMR ▶ Cardiac Magnetic Resonance Imaging Cnidaria ▶ Jellyfish Envenomation Coagulation, Monitoring at the Bedside CO (Cardiac Output) ▶ MostCare Monitor Coagulation, Monitoring at the Bedside WERNER BAULIG, DONAT R. SPAHN, MICHAEL T. GANTER Institute of Anesthesiology, University Hospital Zurich, Zurich, Switzerland Definition Bedside coagulation monitoring is useful and essential in assessing patients’ hemostatic status with minimal time delays. The primary goal of therapeutic interventions in the coagulation system is to keep the optimal and individual balance between sufficient hemostasis and prevention of thrombosis. In severely bleeding patients, early evidence suggests that treatment directed at aggressive and targeted hemostatic resuscitation can lead to dramatic reductions in mortality. For example, by specific and goal-directed treatment guided by transfusion algorithms, coagulopathic patients may be optimized readily, thereby minimizing exposure to blood products, reducing costs and improving patients’ outcome. Pre-existing Condition Point of care (POC) monitoring of blood coagulation at the patient’s bedside is becoming increasingly important in the perioperative period to guide both pro- and anticoagulant therapies. This monitoring, for example, allows diagnosing potential causes of hemorrhage, to guide hemostatic therapies, to predict the risk of bleeding during consecutive surgical procedures, and to identify patients at risk for thrombotic events [1]. Routine laboratory-based coagulation tests (e.g., PT/ INR, aPTT, Fibrinogen) measure clotting times and factors in recalcified plasma after activation with different coagulation activators. Platelet numbers are given to complete overall coagulation assessment. Although accurate, standardized, and used for a long time, the value obtained by routing coagulation testing has been questioned in the perioperative setting because values are measured in plasma, no information on platelet function (PF) is available, and there is a time delay of at least 45–60 min from sampling to obtaining the results. POC coagulation C monitoring may overcome several limitations of routine coagulation testing. Blood is analyzed bedside close to the patient and not necessarily in the central laboratory. The coagulation status is assessed in whole blood, better describing the physiological clot development by letting the plasmatic coagulation system interact with platelets and red cells. Furthermore, results are available earlier and clot development can be visually displayed real-time using certain devices. According to their main objective and function, POC coagulation analyzers can be categorized into (i) techniques analyzing combined plasmatic coagulation, platelet function, and fibrinolytic system, i.e., viscoelastic techniques, (ii) instruments assessing therapeutic anticoagulation like the activated clotting time (ACT) or heparin management devices, and (iii) specific ▶ platelet function analyzers. Viscoelastic Coagulation Monitoring Thrombelastography (TEG®), Rotational Thrombelastometry (ROTEM®) Thrombelastography is a method to assess the overall coagulation function and was first described by Hartert in 1948. Because the thrombelastograph measures the shear elasticity of the blood sample, thrombelastography is sensitive to all interacting cellular and plasmatic components such as coagulation and fibrinolysis. The thrombelastograph measures and graphically displays the time until initial fibrin formation, the kinetics of fibrin formation and clot development, and the ultimate strength and stability of the fibrin clot as well as fibrinolysis. In the earlier literature, the terms thrombelastography, thrombelastograph, and TEG have been used generically. However, in 1996, thrombelastograph and TEG® became a registered trademark of the Haemoscope Corporation (Niles, IL, USA) and from that time onwards these terms have been employed to describe the assay performed using hemoscope instrumentation only. Alternatively, Pentapharm GmbH (Munich, Germany) markets a modified instrumentation using the terminology rotational thrombelastometry, ROTEM®. The TEG® (Haemonetics Corp., formerly Haemoscope Corp, Niles, IL, USA) measures the clot’s physical property by the use of a stationary cylindrical cup that holds the blood sample and is oscillated through an angle of 4 45’. Each rotation cycle lasts 10 s. A pin is suspended in the blood by a torsion wire and is monitored for motion (Fig. 1, TEG®). The torque of the rotation cup is transmitted to the immersed pin only after fibrin–platelet bonding has linked the cup and pin together. The strength of these 569 C C Coagulation, Monitoring at the Bedside fibrin–platelet bonds affects the magnitude of the pin motion. Thus, the output is directly related to the strength of the formed clot. As the clot retracts or lyses, these bonds are broken and the transfer of cup motion is again diminished. The rotation movement of the pin is converted by a mechanical-electrical transducer to an electrical signal finally being displayed as the typical TEG® tracing (Fig. 2, TEG®). The ROTEM® (tem International GMBH, formerly Pentapharm GmbH, Munich, Germany) technology avoids some limitations of traditional instruments for thrombelastography, especially the susceptibility to mechanical shocks. Signal transmission of the pin suspended in the blood sample is carried out via an optical detector system, not by a torsion wire and the movement is initiated from the pin, not from the cup. Furthermore, 4 5 the instrument is equipped with an electronic pipette (Fig. 1, ROTEM®). ▶ TEG®/ROTEM® both measure and graphically display the changes in viscoelasticity at all stages of the developing and resolving clot (Fig. 2, TEG®/ROTEM®), i.e., the time until initial fibrin formation (TEG® reaction time [R]; ROTEM® clotting time [CT]), the kinetics of fibrin formation and clot development (TEG® kinetics [K], alpha angle [a]; ROTEM® clot formation time [CFT], alpha angle [a]), the ultimate strength and stability of the fibrin clot (TEG® maximum amplitude [MA]; ROTEM® maximum clot firmness [MCF]), and clot lysis (fibrinolysis). TEG®/ROTEM® are fibrinolysis-sensitive assays and allow for diagnosis of hyperfibrinolysis in bleeding patients. To determine the fibrinogen influence, 5 5 4 2 4 2 3 3 1 3 1 TEG ROTEM 1 2 SONOCLOT Coagulation, Monitoring at the Bedside. Figure 1 Working principles of viscoelastic point of care (POC) coagulation devices. TEG®. rotating cup with blood sample (1), coagulation activator (2), pin and torsion wire (3), electromechanical transducer (4), data processing (5). ROTEM®. Cuvette with blood (1), activator added by pipetting (2), pin and rotating axis (3), electromechanical signal detection via light source and mirror mounted on axis (4), data© processing (5). SONOCLOT®. Blood sample in cuvette (1), containing activator (2), disposable plastic probe (3), oscillating in blood sample mounted on electromechanical transducer head (4), data processing (5) 125 PF CFT K R MA CL 100 MCF CT 75 LY α α CR TEG Time ROTEM Clot Signal Clot firmness 50 Clot firmness 570 Time 25 ACT 0 0 5 SONOCLOT 10 15 20 25 30 Minutes Coagulation, Monitoring at the Bedside. Figure 2 Typical TEG®/ROTEM® tracing and Sonoclot Signature. TEG®. R = reaction time, K = kinetics, a = slope between R and K, MA = maximum amplitude, CL = clot lysis. ROTEM®. CT = clotting time, CFT = clot formation time, a = slope of tangent at 2 mm amplitude, MCF = maximal clot firmness, LY = Lysis. SONOCLOT®. ACT = activated clotting time, CR = clot rate, PF = platelet function Coagulation, Monitoring at the Bedside tests can be performed eliminating platelet function by a GPIIb/IIIa inhibitor (e.g., fib-TEM). This concept has been proven to work and a good correlation of this modified MA/MCF with fibrinogen levels determined by Clauss method has been shown. Most common tests for both technologies are listed in Table 1. The repeatability of measurements by both devices has shown to be acceptable, provided they are performed exactly as outlined in the user’s manuals. Sonoclot Coagulation and Platelet Function Analyzer (Sonoclot®) The Sonoclot Analyzer® (Sienco Inc., Arvada, CO) has been introduced in 1975 by von Kaulla et al. The Sonoclot® measurements are based on the detection of C viscoelastic changes of a whole blood or plasma sample. A hollow probe is immersed into the blood sample and oscillates vertically in the sample (Fig. 1, Sonoclot®). The changes in impedance to movement imposed by the developing clot are measured. Different cuvettes with different coagulation activators/inhibitors are commercially available (Table 1). Normal values for tests run by the ▶ Sonoclot® Analyzer depend largely on the type of sample (whole blood vs plasma, native vs citrated sample) and cuvette used. The Sonoclot® Analyzer provides information on the entire hemostasis process both in a qualitative graph, known as the Sonoclot® Signature (Fig. 2, Sonoclot®) and as quantitative results: the activated clotting time (ACT), the clot rate (CR), and the platelet function (PF). Coagulation, Monitoring at the Bedside. Table 1 Commercially available tests for viscoelastic point of care coagulation devices (Modified according to [1]) Assay Activator inhibitor Proposed indication ® Thrombelastograph hemostasis system (TEG ) Kaolin Kaolin Overall coagulation assessment including platelet function Heparinase Kaolin + heparinase Specific detection of heparin effect (modified kaolin test adding heparinase to inactivate present heparin) Platelet mapping ADP arachidonic acid Platelet function, monitoring anti-platelet therapy (aspirin, ADP-, GPIIb/ IIIa inhibitors) Native None Nonactivated assay Also used to run custom hemostasis tests ® Rotational thrombelastometry (ROTEM ) ex-TEM TF Extrinsic pathway; fast assessment of clot formation and fibrinolysis in-TEM Contact activator Intrinsic pathway; assessment of clot formation and fibrin polymerization fib-TEM TF + GPIIb/IIIa antagonist Qualitative assessment of fibrinogen function ap-TEM TF + Aprotinin Fibrinolytic pathway; fast detection of fibrinolysis when used together with ex-TEM hep-TEM Contact activator + heparinase Specific detection of heparin (modified in-TEM test adding heparinase to inactivate present heparin) na-TEM None Nonactivated assay Also used to run custom hemostasis tests Sonoclot® coagulation and platelet function analyzer SonACT Celite kACT Kaolin High-dose heparin management High-dose heparin management gbACT+ Glass beads Overall coagulation and platelet function assessment H-gbACT+ Glass beads + heparinase Overall coagulation and platelet function assessment in presence of heparin; detection of heparin Native None Nonactivated assay Also used to run custom hemostasis tests ACT = activated clotting time, TF = tissue factor, ADP = adenosine diposphate, GPIIb/IIIa = glycoprotein IIb/IIIa receptor 571 C 572 C Coagulation, Monitoring at the Bedside The ACT is the time in seconds from the activation of the sample until the beginning of a fibrin formation. This onset of clot formation is defined as a certain upward deflection of the Sonoclot® Signature and is detected automatically by the machine. Sonoclot®’s ACT corresponds to the conventional ACT measurement (see below), provided that cuvettes containing a high concentration of typical activators (celite, kaolin) are being used. The CR, expressed in units/min, is the maximum slope of the Sonoclot® Signature during initial fibrin polymerization and clot development. PF is reflected by the timing and quality of the clot retraction. PF is a calculated value, derived by using an automated numeric integration of changes in the Sonoclot® Signature after fibrin formation has completed (see manufacturer’s reference). In order to obtain reliable results for PF, cuvettes containing glass beads for specific platelet activation (gbACT+) should be used. The nominal range of values for the PF goes from 0, representing no PF (no clot retraction and flat Sonoclot® Signature after fibrin formation), to approximately 5, representing strong PF (clot retraction occurs sooner and is very strong, with clearly defined, sharp peaks in the Sonoclot® Signature after fibrin formation). patient hypothermia, inadequacy of specimen warming, hemodilution, quantitative and qualitative platelet abnormalities, or aprotinin infusion. Furthermore, low factor XII levels, which are found in patients with sepsis and patients undergoing renal replacement therapy may lead to falsely high ACT values. Heparin Concentration Measurement Bedside Monitoring of Anticoagulation Because of the limitations of ACTestimating plasma levels of heparin, POC devices have been developed to more accurately measure heparin concentration. The most studied device is the Hepcon HMS Plus Hemostasis Management System (Medtronic, Minneapolis, MN). It calculates heparin doses before initiation of CPB by performing a heparin dose response, measuring heparin concentrations, and calculating protamine doses based on residual heparin levels. A number of clinical studies report that Hepcon guided anticoagulation results in higher total heparin but lower protamine doses than conventional management and may thereby decrease activation of the coagulation and inflammatory cascade [2]. Results are provided readily, however, higher costs, more complex handling, greater dimensions compared to a conventional ACT device, and lack of large studies showing benefit on patient’s outcome limited its widespread use so far. Activated Clotting Time Monitoring Oral Anticoagulants The ACT is a functional test of the intrinsic clotting pathway and has been developed for guiding unfractioned heparin-induced anticoagulation at the bedside, particularly during cardiac surgery, extracorporeal membrane oxygenation (ECMO), and coronary interventions. Originally described by Hattersley in 1966, ACT reflects the amount of time to form a clot by contact activation of the coagulation cascade. Several ACT instruments are commercially available and ACT measurements can be performed using different coagulation activators, each with unique characteristics and various interactions. Results from different ACT tests cannot be used interchangeably. This variability highlights the importance of establishing appropriate instrument-specific reference values for monitoring anticoagulation. ACT monitoring of heparinization is not without limitations, and its use has been criticized because of significant variability and the poor correlation with plasma heparin concentrations during cardiopulmonary bypass (CPB). It has been suggested that many factors – patient, operator, and equipment – can alter ACT. Therefore, ACT prolongation during CPB is not necessarily caused by heparin administration alone and may be associated with Several POC coagulation devices have been developed to measure the effects of oral anticoagulants (warfarin therapy) and to provide modified prothrombin time (PT)/ INR values. The last-generation devices include the Harmony (Lifescan Inc./Johnson & Johnson, Milpitas, CA) and the INRatio (Hemosense, Inc., Milpitas, CA). Harmony uses thromboplastin as coagulation activator and detects clot formation by light transmission; INRatio uses electrochemical detection of changes in impedance in the blood sample. Results are available immediately in both devices and correlation with PT/INR performed by conventional laboratory coagulation analyzers was good (R > 0.9). No vein puncture is required and test results are readily available for clinical use, particularly during phases of rapid changes in the coagulation state [1]. Platelet Function Monitoring Currently, an increasing number of patients are on antiplatelet medication, such as cyclooxygenase-1 (COX-1) inhibitors, adenosine diphosphate (ADP) antagonists, and glycoprotein (GP) IIb/IIIa inhibitors. In these patients, knowledge of residual platelet function (PF) is highly warranted in order to maintain an optimal and individual balance between platelet function and C Coagulation, Monitoring at the Bedside Whole Blood Impedance Platelet Aggregometry The novel impedance aggregometer ▶ Multiplate® (Dynabyte, Munich, Germany) represents a significant progress in platelet aggregometry and avoids several methodological problems of the original turbidimetric platelet aggregometry, especially by using whole blood, disposable test cuvettes, standardized commercially available test reagents, an automated pipetting system, and rapidly available results. Furthermore, this assay has a high sensitivity in detecting effects of acetylsalicylic acid, thienopyridines, and GPIIb/IIIa inhibitors on platelets. The principle of Multiplate® impedance platelet aggregometry is based on two silver-coated conductive copper electrodes immersed into whole blood and the ability of activated platelets to adhere to the electrode surface. The instrument continuously measures the change of electrical resistance, which is proportional to the amount of platelets attached to the electrodes. The measured impedance values are transformed to arbitrary aggregation units (AU), which are plotted against the time (Fig. 3). Three parameters are provided: aggregation units (AU), velocity (AU/min), and area under the aggregation curve (AUC), where AUC has the highest diagnostic power. The device has five channels, therefore, parallel testing of five blood samples with different platelet activators at the same time is possible. Multiplate® has some limitations: it requires high sample volumes, test results are not independent of the actual platelet number, and running the tests is timeconsuming and expensive. Additionally, as with other platelet function tests, a resting time of 30 min after blood sampling is recommended before running the tests, which may impede immediate detection of platelet dysfunction intraoperatively. 150 135 120 Aggregation C 105 Aggregation inhibition, i.e., bleeding and thrombosis. Traditional assays, such as turbidimetric platelet aggregometry, are still considered clinical standards of PF testing. Turbidimetric platelet aggregometry is one of the most widely used tests to identify and diagnose PF defects. However, conventional platelet aggregometry is labor intensive, costly, time-consuming, and requires a high degree of experience and expertise to perform and interpret. Another important limitation of this technique is that platelets are tested under relatively low shear conditions and in free solution within platelet-rich plasma conditions that do not accurately simulate primary hemostasis. Because of these disadvantages of conventional platelet aggregometry, new automated technologies have been developed to measure PF and several techniques can be used at the bedside [3]. 573 90 S1 Velocity 75 60 S2 45 AUC 30 15 0 0 1 2 3 Min 4 5 6 Coagulation, Monitoring at the Bedside. Figure 3 Whole blood impedance platelet aggregometry: Mulitplate® tracing. The measured impedance values are transformed to arbitrary aggregation units (AU), which are plotted against the time. Measurements are performed in duplicates (S1, S2) and averaged against each other. Velocity (AU/min), aggregation (AU), and area under the aggregation curve (AUC) (Modified according to [5]) VerifyNowTM/Ultegra The ▶ VerifyNowTM Analyzer (Accumetrics, San Diego, CA) incorporates the technique of optical platelet aggregometry. Initially, this technique was distributed as Ultegra Rapid Platelet Function Analyzer (RPFA). The original RPFA assay measured agglutination of fibrinogen-coated beads in response to platelet stimulation. Activated platelets stick to the beads with a consecutive increase in light transmission (Fig. 4). Variation of light absorbance over time is displayed as platelet aggregation units. Early clinical investigations yielded conflicting results and the assay has been modified to the VerifyNowTM assay, now detecting effects of acetylsalicylic acid, ADP-, and GPIIb/IIIa antagonists. This assay has been used, for example, to determine clopidogrel response in clinical trials and its results correlated well with those of platelet aggregometry. VerifyNowTM tests are easy to perform, and only small sample volumes without necessity of pipetting are required. The absence of flow conditions and the scarce consistency over time in the identification of aspirinresistant individuals are the limitations of this assay. 574 C Coagulation, Monitoring at the Bedside 1 5 2 3 6 1 2 4 3 7 Coagulation, Monitoring at the Bedside. Figure 4 Working principle of the VerifyNowTM/Ultegra device. The VerifyNowTM assay uses platelet agonists (arachidonic acid [aspirin assay], adenosine diphoshate [P2Y12 assay], or thrombin receptor agonist peptide [IIb/IIIa assay]) to activate platelets. As the platelets are activated and start to aggregate with the fibrinogen-coated beads light transmission increases, which will be measured by the light detector. Light source (1), platelet (2), fibrinogen-coated beads (3), activated platelets attached to beads (4), whole blood (5), platelet agonist (6), light detector measuring light transmission (7) Platelet Function Analyzer (PFA-100®) The PFA-100® assay (Dade Behring, Schwalbach, Germany) has been clinically introduced in 1985 by Katzer and Born as a screening test for inherent and acquired platelet disorders, as well as von Willebrand’s disease. Citrated whole blood is aspirated at high shear rates through a capillary with a membrane-coated microaperture (collagen and either epinephrine [COLEPI] or ADP [COL-ADP]). Both shear stress and platelet agonists lead to attachment, activation, and aggregation of platelets forming a plug and occluding this microaperture (Fig. 5). The time taken to occlude the aperture is known as closure time (CT) and is a function of platelet number and reactivity, von Willebrand factor activity, and hematocrit. The main advantages of this assay are that it does not require fibrin formation, provides rapid results, and is particularly useful in the diagnosis of von Willebrand’s disease and overall platelet dysfunction. However, to get valid results a hematocrit 30% and platelet counts 100  103/L are required. Additionally, citrate concentration, blood type, and leukocyte count may interfere Coagulation, Monitoring at the Bedside. Figure 5 Platelet function analyzer PFA-100®. Citrated whole blood is aspirated at high shear rates through a capillary (1) with a membrane coated microaperture (2). The membrane may be coated with collagen and epinephrine (COL-EPI), or collagen and adenosine diphosphate (COL-ADP) to activate platelets (3). The closure time of PFA-100® is the time taken for activated platelets to occlude the membrane with its accuracy. While early reports suggested a high sensitivity for detection of acetylsalicylic acid by prolonged PFA-100® COL-EPI closure time in association with normal values for COL-ADP, more recent investigations cannot confirm these results. Modified Thrombelastography: Platelet Mapping Since conventional TEG®/ROTEM® are not sensitive to targeted pharmacological platelet inhibition, a more sophisticated test has been recently developed for the TEG® to specifically determine platelet function in presence of anti-platelet therapy (modified TEG®, Platelet Mapping). Briefly, the maximal hemostatic activity of the blood specimen is first measured by a kaolin-activated whole blood sample. Then, further measurements are performed in presence of heparin to eliminate thrombin activity: reptilase and Factor XIII (Activator F) generate a cross-linked fibrin clot to isolate the fibrin contribution to the clot strength. The contribution of the ADP or TxA2 receptors to the clot formation is provided by the addition of the appropriate agonists, ADP, or arachidonic acid. The results from these different tests are then compared to each other and the platelet function is calculated. Platelet mapping seems to be a suitable procedure for the assessment of all three classes of anti-platelet agents, Coagulation, Monitoring at the Bedside but at present the sensitivity and specificity compared to laboratory platelet aggregometry has not been determined in detail. Additionally, the reagents are expensive, multiple channels are required to run the tests, and well-trained personnel are required for optimal performance, limiting its use as POC procedure. Platelet-Activated Clotting Time Platelet-activated clotting time (PACT; HemoSTATUS, MedtronicHemoTec, Inc., Parker, CA) is a modified whole blood-activated clotting time test (ACT) adjoining platelet activation factor (PAF) to the reagent mixture for detection of platelet responsiveness by shortening the kaolin-activated clotting time in whole blood samples. Until now, only two studies investigating the correlation to clinical bleeding in patients undergoing cardiac surgery have been performed and their results were controversial. ICHOR/Plateletworks System This platelet count ratio assay from Helena Laboratories (Beaumont, TX) simply compares whole blood platelet count in a control EDTA blood sample with the platelet count in a similar sample that has been exposed to a platelet activator. In patients without platelet dysfunction or anti-platelet drug treatment, the presence of the agonist reduces platelet counts close to zero, due to aggregation of most of the platelets. The findings of recent studies indicate that adding the agonist ADP to the test sample appears useful for the assessment of both P2Y12 inhibitors (clopidrogrel) and GPIIb/IIIa antagonists. Minimal sample preparation and whole blood processing are advantages of this assay. The main disadvantage, however, is the lack of sufficient investigations. Impact Cone and Plate(Let) Analyzer The Impact Cone and Plate(let) Analyzer (CPA, DiaMed, Israel) tests whole blood platelet adhesion and aggregation under artificial flow conditions. A small amount of whole blood is exposed to a uniform shear in a spinning cone and platelet adhesion to the polystyrene wells is automatically analyzed by an inbuilt microscope. The quantity of moistening the surface of the plates (surface covering) depends on platelet function, fibrinogen, von Willebrand’s factor levels, and the bioavailability of GPIb and GPIIa/IIIa receptors. Test duration accounts less than 6 min. The addition of arachidonic acid and ADP to the test specimens may assess the effect of acetylsalicylic acid and ADP antagonists on platelets. The Impact Analyzer is a simple and rapid whole blood platelet analyzer requiring small sample volumes. Test results are however dependent C 575 on platelet count and hematocrit. Furthermore, only limited published data are available on its clinical performance so far. Applications In patients sustaining severe trauma or undergoing major surgery, such as cardiac, aortic, and hepatic surgery, maintaining an adequate coagulation status is essential besides preserving sufficient blood volume and oxygen carrying capacity. These patients require sophisticated and real-time coagulation monitoring to adequately assess and treat hemostasis based on the underlying cause of bleeding (e.g., metabolic disorders, hypothermia, lack of clotting factors, dilutional coagulopathy, platelet dysfunction, hypo-, or hyperfibrinolytic state). Monitoring Pro-coagulant Therapy Modern practice of coagulation management is based on the concept of specific component therapy and requires rapid diagnosis and monitoring of the pro-coagulant therapy (i.e., clotting times, clot kinetics, and clot strengthening). Fibrinogen is a key coagulation factor (substrate to form a clot). Fibrinogen levels can be assessed by measuring clot strength (MCF/MA) in the presence of platelet inhibition by a GPIIb/IIIa inhibitor (e.g., fib-TEM) or by assessing Sonoclot®’s CR. Fibrinogen substitution should be considered in a bleeding patient, if MCF levels are lower than 9 mm in a fib-TEM test. Factor XIII is needed for cross-linking fibrin, therefore stabilizing the clot, increasing clot strength and resistance to fibrinolysis. There are reports on patients with unexplained intraoperative bleeding due to decreased factor XIII and subsequent stabilization after substitution. In order to study thrombin generation, modified TEG®/ROTEM® parameters (based on the original tracing) have been introduced recently: maximum velocity of clot formation (maximum rate of thrombus generation, MaxVel), time to reach MaxVel (time to maximum thrombus generation, tMaxVel), and total thrombus generation (area under the curve, TTG). These parameters are supposed to be more sensitive to rVIIa than standard TEG®/ ROTEM® parameters and dilute tissue factor should be used as coagulation activator for best sensitivity. Antifibrinolytic drugs (e.g., tranexamic and epsilon aminocaproic acid) are used to treat hyperfibrinolysis and to reduce bleeding and transfusion requirements in complex surgical procedures. Antifibrinolytic therapy may be predicted in vitro in TEG®/ROTEM® with certain tests already containing an antifibrinolytic agent (e.g., ap-TEM). Ap-TEM predictive for a good patient response would then show a significantly improved C 576 C Coagulation, Monitoring at the Bedside initiation/propagation phase compared to ex-TEM and or disappearance of signs of hyperfibrinolysis. There are no conclusive studies on monitoring desmopressin (DDAVP) therapy so far. During hepatic surgery and particularly orthotopic liver transplantation (OLT) large derangement in the coagulation status makes POC coagulation monitoring highly desirable. Decreased synthesis and clearance of clotting factors and platelet defects lead to impaired hemostasis and hyperfibrinolysis [5]. Systemic inflammatory response syndrome (SIRS), sepsis, and disseminated intravascular coagulation (DIC) may further complicate a preexisting coagulopathy. Finally, dramatic hyperfibrinolysis may occur during the anhepatic phase of OLT and immediately following organ reperfusion, resulting from accumulation of tissue plasminogen activator due to inadequate hepatic clearance, a release of exogenous heparin, and endogenous heparin-like substances, as well as an overt activation of the complement system. In addition to the hemorrhagic risk associated with hepatic surgery and OLT, hypercoagulability and thrombotic complication have been described in the postoperative period and this can adequately be assessed with TEG®/ROTEM®. Monitoring Anticoagulant Therapy The complex process of anticoagulation with heparin for cardiopulmonary bypass (CPB), antagonism with protamine, and postoperative hemostasis therapy in patients undergoing cardiac surgery cannot be performed without careful and accurate bedside coagulation monitoring. ACT and Sonoclot® Analyzer have been used to guide heparin management for CPB measuring the activated clotting time (ACT) and its accuracy and performance have been shown to be comparable. Furthermore, the Sonoclot® Analyzer has been shown to reliably detect pharmacological GPIIb/IIIa inhibition and successfully used to assess the coagulation status and platelet function successfully in patients undergoing cardiac surgery [6]. Viscoelastic POC coagulation devices have been applied, with limited success, to predict excessive bleeding after CPB. However, large prospective and retrospective studies have demonstrated a significant decrease in perioperative and overall transfusion requirement if hemostasis management was guided by TEG®/ROTEM®-based algorithms. To detect non-heparin-related hemostatic problems even in presence of large amounts of heparin during CPB, tests with heparinase have been developed for each instrument (Table 1) and algorithms based on heparinasemodified TEG® resulted in a significant reduction of hemostatic products. Additionally, perioperative administration of drugs with specific anti-platelet activity theoretically requires specific platelet function monitoring at the bedside to guarantee optimal hemostatic management. However, the current commercially available platelet function POC devices are of limited use since these devices often require frequent quality controls and well-trained personnel to run the tests accurately, are time consuming, and expensive. Furthermore, large studies showing the reliability and clinical usability are lacking for most of these POC platelet analyzers. Monitoring Hypercoagulability and Thrombosis Recognized risk factors for thrombosis are generally related to one or more elements of Virchow’s triad (stasis, vessel injury, and hypercoagulability). Major surgery has been shown to induce a hypercoagulable state in the postoperative period and this hypercoagulability has been implicated in the pathogenesis of postoperative thrombotic complications, including deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), ischemic stroke, and vascular graft thrombosis. Identifying hypercoagulability with conventional nonviscoelastic laboratory tests is difficult unless the fibrinogen concentration or platelet count is markedly increased. However, hypercoagulability is readily being diagnosed by viscoelastic POC coagulation analyzers and TEG®/ ROTEM® have been increasingly used in the assessment of postoperative hypercoagulability for a variety of surgical procedures. Hypercoagulability is being diagnosed if the R/CT time is short and the MA/MCF is increased (exceeding 65–70 mm) [1]. References 1. 2. 3. 4. 5. 6. Ganter MT, Hofer CK (2008) Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg 106:1366–1375 Aziz KA, Masood O, Hoschtitzky JA, Ronald A (2006) Does use of the Hepcon point-of-care coagulation monitor to optimise heparin and protamine dosage for cardiopulmonary bypass decrease bleeding and blood and blood product requirements in adult patients undergoing cardiac surgery? Interact Cardiovasc Thorac Surg 5:469–482 Michelson AD (2009) Methods for the measurement of platelet function. Am J Cardiol 103:20A–26A Heindl B, Spannagl M (2008) Gerinnunsmanagement beim periopereativen Blutungsnotfall. Uni-Med Verlag Bremen, 1-Auflage, p 57 Dickinson KJ, Troxler M, Homer-Vanniasinkam S (2008) The surgical application of point-of-care haemostasis and platelet function testing. Br J Surg 95:1317–1330 Gibbs NM (2009) Point-of-care assessment of anti platelet agents in the perioperative period: a review. Anaesth Intensive Care 37:354–369 Coagulopathy Coagulopathy JEFFRY L. KASHUK Division of Trauma, Acute Care and Critical Care Surgery and Section of Acute Care Surgery, Penn State Hershey Medical Center, Hershey, PA, USA Synonyms Acute coagulopathy of trauma; posttraumatic DIC Definition Hemorrhagic shock leading to postinjury coagulopathy accounts for approximately half of deaths worldwide of patients arriving at the hospital with acute injury. This death rate has improved only marginally over the past 25 years despite the widespread adoption of damage control techniques. Accordingly, postinjury coagulopathy, defined as continued hemorrhage and ooze despite appropriate surgical control of the bleeding site, remains the main challenge for improved outcome in this critically injured cohort. Previous studies have shown that among patients presenting with massive acute blood loss, the majority succumb to refractory coagulopathy despite surgical control of their bleeding. Although the entity has been recognized for over 40 years, the pathogenesis of associated coagulation abnormalities and appropriate treatment has remained a matter of debate. Contributing factors to the “bloody vicious cycle,” proposed by our group over 25 years ago [1], focused on acidosis, hypothermia, and dilutional effects from excess crystalloid. Recent evidence, however, suggests that coagulopathy exists very early after injury and that the condition is initially independent of clotting factor deficiency, as over one third of multiply injured patients are coagulopathic by conventional laboratory assessment on arrival to the emergency department. The fact that this subset of patients also has an increased incidence of subsequent multiple organ failure (MOF) and death underscores the importance of understanding the pathogenesis of early postinjury coagulopathy. Brohi and Cohen [2] have suggested that the mechanism of acute endogenous coagulopathy is mediated by the thrombomodulin pathway via activated protein C, leading to increased fibrinolysis. Such a process may be teleologically protective by inducing an “autoanticoagulation” state that could potentially protect critical tissue beds in the circulation from thrombosis in the face of an activated coagulation system responding to systemic shock and tissue factor release. C 577 Treatment A uniform approach to management of postinjury coagulopathy remains a substantial challenge, due to the fact that hemostasis represents a fusion of multiple dynamic reactions with complex interactions of thrombin, fibrinogen, platelets, other protein clotting factors, Ca2+, and endothelium. Furthermore, the contributions of tissue factor release modified by hypothermia and acidosis in the development of early acute coagulopathy appear important, and this process may be initiated by either endothelial-based tissue factor or collagen pathways in the setting of systemic shock[3]. Our updated “bloody vicious cycle” [4] emphasizes the fact that early postinjury coagulopathy (“acute endogenous coagulopathy”) occurs very soon after injury and is unrelated to clotting factor deficiency and thus resistant to factor replacement. Rather, this injury complex is triggered by cellular ischemia and exposed tissue factor, activating endothelium well before clotting factor depletion occurs. However, with continued blood loss and clot formation in tissue, factor depletion ultimately occurs, leading to a “systemic coagulopathy,” which unquestionably requires factor repletion to restore coagulation homeostasis. Regardless of the mechanisms involved, current clinical massive transfusion protocols promoting “damage control resuscitation”; i.e., pre-emptive transfusion of plasma, platelets, and fibrinogen, appropriately represent an initial attempt to replete substrate for the coagulation system. But appropriate continued use of these expensive, limited resources with potential untoward effects mandates rapid assessment of the patient’s response to the administration of blood components via real-time assessment of coagulation function. Strategies for Blood Component Replacement Traditionally, fresh frozen plasma (FFP) is prepared by isolating the plasma from the cellular components, via centrifugation of whole blood within 6–8 h of collection. However, with the advent of apheresis methods little platelet-poor plasma is made and most FFP is platelet-rich plasma, which is then frozen. Some plasma (especially AB plasma) is collected by apheresis and many centers use thawed plasma, often referred to as FP24. Regardless of the plasma source, the hemostatic activity of the various coagulation factors can be maintained for long periods of time when frozen; however, upon thawing the concentrations of the various components decrease with the most significant factors being V and VIII. In the injured patient requiring factor replacement, the conversion of prothrombin to thrombin requires the coagulation factors XII, XI, IX, and VIII, along with activated factors X and V. C 578 C Coagulopathy Thus, the initial management of postinjury coagulopathy requires the administration of thawed fresh frozen plasma (FFP), which contains the above-mentioned coagulation factors and up to 400 mg of fibrinogen. Red blood cell concentrates contain minimal amounts of plasma and coagulation factors. Consequently, isolated administration of RBC transfusion in the absence of plasma will further potentiate postinjury coagulopathy because of its limited hemostatic potential. The exact dosing and timing of FFP administration is one of the most widely debated topics in trauma. The “evidence-based” European guidelines for the management of bleeding in major trauma recommends a dose of 10–15 mg/kg of FFP in patients with massive bleeding complicated with coagulopathy, defined as INR >1.5, although these guidelines readily recognize a lack of prospective data. A significant drawback of this approach is the time discrepancy related to the assessment of coagulation parameters and the coagulation status at the time when laboratory values become available. Based on this notion, current US protocols have recommended the pre-emptive substitution of plasma by a standardized ratio of FFP to RBC. We noted that >85% of transfusions were accomplished within 6 h postinjury [4]. Accordingly, we have focused on this narrower time frame for assessing the effects of resuscitation strategies. Furthermore, our results suggested that the survival threshold appeared to be in the range of 1:2–1:3 of FFP to RBC. Platelet concentrates have been traditionally prepared from pooling platelets obtained through centrifugation via individual units of whole blood. Currently, apheresis or “single-donor” collections result in fewer donor exposures for a given dose of platelets. Furthermore, apheresis platelets contain between 210 and 250 mL of donor plasma, although clotting factors that are present will diminish rapidly at typical storage temperatures (20–24 C). Clearly, the lack of an accurate assessment of platelet function, as opposed to platelet count, appears to be a significant limiting factor. Thus, the relationship of platelet count to hemostasis and the contribution of the platelet to formation of a stable clot in the injured patient remain largely unknown. The complex relationship of thrombin generation to platelet activation requires dynamic evaluation of clot function, as opposed to static measurements of platelet count, or older methods of clot assessment, such as the bleeding time, which is of no use in the trauma setting. Accordingly, there is no direct evidence to support an absolute trigger for platelet transfusions in trauma. While the “classic” threshold for platelet transfusion has been 50 K/mm3, a higher target level at 100 K/mm3 has been suggested for multiply injured patients and patients with massive hemorrhage. A pool of four to eight platelet concentrates, or one single-donor platelet apheresis unit, have been suggested to provide adequate hemostasis related to thrombocytopenia in bleeding patients, increasing the platelet count by 30–50 K/mm3. Similar to plasma and packed red cell administration, platelet transfusion is also associated with immunological complications, with a reported incidence of >200 per 100,000 transfused patients. Based on the fact that platelet counts >100  109/L are unlikely to contribute to coagulopathy, routine platelet administration in this patient cohort appears unjustified at this time. Cryoprecipitate is the cold insoluble fraction formed when FFP is thawed at 4 C. “Cryo” is rich in factors VIII, XIII, VWF, and fibrinogen. Generally, fibrinogen levels greater than 50 mg/dL have been considered sufficient to support physiologic hemostasis. Although recent reports have suggested that fibrinogen should be replaced early in coagulopathic trauma patients with hypofibrinogenemia, none have recommended pre-emptive administration. Many guidelines recommend a replacement threshold for plasma fibrinogen levels <100 mg/dL (1 g/L), using either fibrinogen concentrate (3–4 g) or cryoprecipitate (50 mg/kg or 15–20 units). It is often underappreciated, however, that FFP, pooled platelets, and even packed red blood cells contain fibrinogen. Accordingly, evaluation of plasma fibrinogen levels after administration of component therapy with FFP and platelets during massive resuscitation may avoid unnecessary use of cryoprecipitate. Four units of FFP contain approximately 1,500 mg of fibrinogen, equivalent to one pooled cryoprecipitate pack (1,400 mg). A pooled ten pack of platelets contains approximately 300 mg of fibrinogen. Currently there is no scientific evidence available to support pre-emptive fibrinogen replacement in patients at risk for postinjury coagulopathy. Thrombelastography The complexity of the coagulation process and the current evolving understanding of the fundamental mechanisms driving postinjury coagulopathy underscore the lack of available evidence-based studies linking coagulation with mortality. Rapid, real-time functional assessment of coagulation function appears imperative to guide goaldirected therapy of specifically identified coagulation abnormalities. Recent experience with thrombelastography in our institution [5] suggests that this technology may provide Coagulopathy a real-time viscoelastic analysis of the blood clotting process, and could serve as the template for clinical applications of the cell-based model of coagulation. Subsequent treatment protocols could then be tailored based on specific evaluation of clot formation as a representative assay of the coagulation process. Whole blood (0.35 mL) is placed in a rotating metal cuvette heated to 37 C. A piston is suspended in the sample, and the rotational motion is transferred to the piston as fibrin strands form between the wall of the cuvette and the piston. An electronic amplification system allows for the characteristic tracing to be recorded (see Fig. 1). Thrombelastography (TEG) assesses clot strength from the time of initial fibrin formation, to clot retraction, ending in fibrinolysis. Of significance, TEG is the only single test that can provide information on the balance between two important and opposing components of coagulation, namely thrombosis and lysis, while the battery of traditional coagulation tests, which include bleeding time, prothrombin time (PT), partial thromboplastin time (PTT), thrombin time, fibrinogen levels, factor assays, platelet counts, and functional assays are based on isolated, static end points. Furthermore, TEG takes into account the interaction of the entire clotting cascade and C platelet function in whole blood. The PT is limited as a measure of only the extrinsic clotting system, which includes activation of factor VIIa, Xa, and IIa, while the PTT test is limited by enzymatic reactions in the intrinsic system, including the activation of factor XIIa, XIa, IXa, and IIa. Furthermore, it is well known that hypothermia affects various aspects of the coagulation process and leads to functional coagulation abnormalities. Platelet dysfunction is directly influenced by concentrations of thrombin and fibrinogen, and previous work in our laboratory and by others has demonstrated platelet dysfunction related to hypothermia, acidosis, and hypocalcemia. Rapid thromboelastography (r-TEG) differs from conventional TEG because tissue factor is added to the whole blood specimen, resulting in a rapid reaction and subsequent analysis. Given the importance of rapid, real-time assessment of coagulation function in trauma, r-TEG appears to be ideal for this purpose. Our recent studies with this technique suggest that a reduction of blood product use may be accomplished [5]. Furthermore, an important aspect of such monitoring is that the results are available point of care (POC), transmitted directly to the operating room computer screens within minutes, enabling prompt resuscitation strategies based on the r-TEG results. Coagulation Fibrinolysis Torsion wire Maximum Amplitude (mm) Plate lets (MA) Pin LY α Cup 0.36 mL whole blood (Clotted) TEG ACT Heating element, sensor and controller Enzymatic a 4°45 Time (s) Fibrinogen (K, α) Thrombolysins (Ly3O, EPL) b Coagulopathy. Figure 1 Technique of Thrombelastography (reprinted with permission from Hemoscope Corporation, Niles, IL). (a) A torsion wire suspending a pin is immersed in a cuvette filled with blood. A clot forms while the cuvette is rotated 45 degrees, causing the pin to rotate depending on the clot strength. A signal is then discharged to the transducer that reflects the continuity of the clotting process. The subsequent tracing (b) corresponds to the entire coagulation process from thrombin generation to fibrinolysis. The R value, which is recorded as TEG-ACT in the rapid TEG specimen, is a reflection of enzymatic clotting factor activation. The K value is the interval from the TEG-ACT to a fixed level of clot firmness, reflecting thrombin’s cleavage of soluble fibrinogen. The α is the angle between the tangent line drawn from the horizontal base line to the beginning of the cross-linking process. The MA, or maximum amplitude, measures the end result of maximal platelet-fibrin interaction, and the LY 30 is the percent lysis which occurs at 30 minutes from the initiation of the process, which is also calculated as the EPL, or estimated percent lysis 579 C 580 C Coagulopathy The various components of the r-TEG tracing are depicted in Fig. 1. The r value represents initial thrombin generation and is a reflection of enzymatic clotting factor activation. It is recorded as TEG-ACT for the r-TEG assay, which includes tissue factor. K is the interval measured from the TEG-ACT to a fixed level of clot firmness or the point that the amplitude of the tracing reaches 20 mm; this reflects thrombin’s ability to cleave soluble fibrinogen. The a is the angle between the tangent line drawn from the base horizontal line to the beginning of the cross-linking process, measured in degrees, and is affected primarily by the rate of thrombin generation, which directly influences the conversion of fibrinogen to fibrin; thus the higher the angle, the greater the rate of clot formation. The maximum amplitude (MA) measures the maximum amplitude, and is the end result of maximal platelet–fibrin interaction via the GPIIb-IIIa receptors, which simulates the end product of coagulation via the platelet plug. G is a computergenerated value reflecting the complete strength of the clot from the initial fibrin burst through fibrinolysis and is calculated from A (amplitude), which begins at the bifurcation of the tracing. This is based on a curvilinear relationship: G = (5000  A)/(100 A). Conceptually, G is the best measure of clot strength because it reflects the contributions of the enzymatic and platelet components of hemostasis. Normal coagulability is defined as G between 5.3 and 12.4 dynes/cm2 (Haemoscope Corporation, Niles, IL). The r-TEG tracing represents a global analysis of hemostatic function from initial thrombin generation to clot lysis. Component Blood Product Therapy Guided by Rapid(r) TEG Transfusion therapy guided by r-TEG has become an integral part of resuscitation in our institution. Using this technology, a variety of coagulation abnormalities have been noted, which in the past would have been overlooked. The various r-TEG values, being derived from a single measurement of whole blood coagulation, are not independent measurements, but a continuum of blood coagulation with interactions between all components. For instance, thrombin liberates fibrinopeptides from fibrinogen, allowing association with other fibrinogen molecules for “soluble fibrin” and subsequently thrombin-activated factor XIII converts “soluble” into “cross-linked” fibrin. Furthermore, thrombin affects platelet function due to combined effects with factor VIII and von-Willibrand factor. In contrast, routine laboratory coagulation tests represent variables that cannot always be compared to r-TEG by simple linear association. Our current protocol of component transfusion therapy emphasizes goal-directed treatment based on r-TEG findings, with the rapid availability of sufficient FFP to provide a final ratio in the range of 1:2–1:3 of FFP to packed red blood cells. Goal-directed therapy enables accurate, stepwise correction of coagulation dysfunction by comparative assessment of the r-TEG tracings generated. Primary fibrinolysis has a distinctive tracing, which should prompt treatment with epsilonaminocaproic acid (Amicar), a lysine analogue which binds reversibly to the kringle domain of the enzymogen plasminogen, preventing its activation to plasmin, which can therefore not split fibrin. Furthermore, we have observed post-fibrinolysis consumptive coagulopathy, which represents diffuse clotting factor deficiency secondary to massive consumption of factors after fibrinolysis. This severe deficit of thrombin may be an indication for r-VIIa, and we have noted rapid improvement with normalization of r-TEG patterns after such treatment. Platelet dysfunction is evident by narrowed maximum amplitude (MA), and decreased clot strength (G value), and the impact of fibrinogen are readily detected on r-TEG as expressed by the angle and K value. r-TEG may allow for improved resuscitation based on real-time coagulation monitoring. The potential benefits of such an approach include (1) reduction of transfusion volumes via specific, goal-directed treatment of identifiable coagulation abnormalities, (2) earlier correction of coagulation abnormalities with more efficient restoration of physiological homeostasis, (3) improved survival in the acute hemorrhagic phase due to improved hemostasis from correction of coagulopathy, and (4) improved outcomes in the later phase due to attenuation of immunoinflammatory complications, including adult respiratory distress syndrome (ARDS) and multiple organ dysfunction (MOF). References 1. 2. 3. 4. 5. Kashuk J, Moore EE, Milikan JS et al (1982) Major abdominal vascular trauma – a unified approach. J Trauma 22:672 Brohi K, Cohen MJ, Ganter MT et al (2008) Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma 64:1211–1121 Furie B, Furie BL (2008) Mechanisms of thrombus formation. N Engl J Med 359:938–949 Kashuk JL, Moore EE, Johnson JL et al (2008) Postinjury life threatening coagulopathy: is 1:1 fresh frozen plasma: packed red blood cells the answer? J Trauma 65:261–270 Kashuk JL, Moore EE, Wohlauer M et al (2009) Point of care rapid thrombelatography improves management of life threatening postinjury coagulopathy J Trauma (in press) Cocaine Cocaine JUDD E. HOLLANDER Department of Emergency Medicine, University of Pennsylvania, Philadelphia, PA, USA Synonyms Cocaine toxicity; Stimulant toxicity Definition Medical complications temporally associated with cocaine use may occur in many different organ systems. Most severe cocaine-related toxicity and deaths follow intense sympathetic stimulation (e.g., tachycardia, hypertension, dilated pupils, and increased psychomotor activity). Increased psychomotor activity generates heat production, which can lead to severe hyperthermia and rhabdomyolysis. Cocaine-associated cardiovascular effects are common. Myocardial infarction (MI) due to cocaine occurs in approximately 6% of patients presenting with cocaineassociated chest pain [1] and is increased 24-fold in the hour after cocaine use. In patients aged 18–45 years, 25% of MIs are attributed to cocaine use and is most common in patients without large cocaine exposures. Cardiac conduction disturbances (e.g., prolonged QRS and QTc) and cardiac dysrhythmias (e.g., sinus tachycardia, atrial fibrillation/flutter, supraventricular tachycardias, idioventricular rhythms, ventricular tachycardia, and ventricular fibrillation) may occur after cocaine use. The neurologic effects are varied. Altered mental status and seizures are typically short lived and without serious sequelae but serious conditions such as cerebral infarction, intracerebral bleeding, subarachnoid hemorrhage, transient ischemic attacks, and spinal infarction also occur. Cocaine is associated with a sevenfold increased risk of stroke in women. Pulmonary complications of cocaine include asthma exacerbation, pneumothorax, pneumomediastinum, noncardiogenic pulmonary edema, alveolar hemorrhage, pulmonary infarction, pulmonary artery hypertrophy, and acute respiratory failure. The inhalation of cocaine is typically associated with deep Valsalva maneuvers to maximize drug delivery and can cause pneumothorax, pneumomediastinum, and noncardiogenic pulmonary edema. The intestinal vascular system is particularly sensitive to cocaine effects because the intestinal walls have a wide C distribution of alpha-adrenergic receptors with resulting acute intestinal infarction. Patients who present after ingesting packets filled with cocaine are “body packers” or “body stuffers.” Body packers swallow carefully prepared condom or latex packets filled with large quantities of highly purified cocaine to smuggle it into the country. Body stuffers are typically smaller time drug dealers who swallow packets of cocaine while avoiding police. Toxicity occurs when cocaine leaks from the ingested packets. The most severe manifestations of cocaine toxicity are seen in body packers carrying large quantities of cocaine who have dehiscence of a package with a large amount of cocaine. Chronic cocaine use can predispose patients to other medical conditions. Chronic users develop left ventricular hypertrophy that can lead eventually to a dilated cardiomyopathy and heart failure. This is in contrast to the acute cardiomyopathy from cocaine that appears to have a reversible component after cessation of cocaine use. Chronic severe cocaine users can present with lethargy and a depressed mental status that is a diagnosis of exclusion (cocaine washout syndrome). This self-limited syndrome usually abates within 24 h but can last for several days and is thought to result from excessive cocaine usage that depletes essential neurotransmitters. Treatment The initial management of cocaine-toxic patients should focus on airway, breathing, and circulation. Treatments are directed at a specific sign, symptom, or organ system affected and are summarized in Table 1. Sympathomimetic Toxidrome/Agitation Patients with sympathetic excess and psychomotor agitation are at risk for hyperthermia and rhabdomyolysis. Management focuses on lowering body temperature, halting further muscle damage and heat production, and ensuring good urinary output. The primary agents used for muscle relaxation and control of agitation are benzodiazepines. Doses beyond those typically used for patients without cocaine intoxication may be required. Antipsychotic agents are useful in mild cases, but their safety in severe cocaine-induced agitation is not clear. Elevations in core body temperatures should be treated aggressively with iced water baths or cool water mist with fans. Some cases of severe muscle overactivity may require general anesthesia with nondepolarizing neuromuscular blockade. Nondepolarizing agents are preferred over succinylcholine, because succinylcholine may increase the risk of hyperkalemia in patients with cocaine-induced 581 C 582 C Cocaine Cocaine. Table 1 Treatment summary for cocaine-related medical conditions Medical condition Treatments Cardiovascular Dysrhythmias Sinus tachycardia Observation Oxygen Diazepam or lorazepam Supraventricular tachycardia Oxygen Diazepam or lorazepam Consider diltiazem, verapamil, or adenosine If hemodynamically unstable: cardioversion Ventricular dysrhythmias Oxygen Diazepam or lorazepam Consider Sodium bicarbonate and/or lidocaine or amiodarone If hemodynamically unstable: defibrillation Acute coronary syndrome Oxygen Aspirin Diazepam or lorazepam Nitroglycerin Heparin For ST-segment elevation (STEMI): Percutaneous intervention (angioplasty and stent placement) preferred. Consider fibrinolytic therapy. Consider morphine sulfate, phentolamine, verapamil, or glycoprotein IIb/IIIa inhibitors Hypertension Observation Diazepam or lorazepam Consider nitroglycerin, phentolamine, and nitroprusside Pulmonary edema Furosemide Nitroglycerin Consider morphine sulfate or phentolamine Hyperthermia Diazepam or lorazepam Cooling methods If agitated, consider paralysis and intubation Neuropsychiatric Anxiety and agitation Diazepam or lorazepam Seizures Diazepam or lorazepam Intracranial hemorrhage Surgical consultation Cocaine washout syndrome Supportive care Consider Phenobarbital Rhabdomyolysis IV hydration Consider sodium bicarbonate or mannitol If in acute renal failure: hemodialysis Body packers Activated charcoal Whole-bowel irrigation Laparotomy or endoscopic retrieval Cocaine C rhabdomyolysis. Plasma cholinesterase metabolizes both succinylcholine and cocaine; therefore, prolonged clinical effects of either or both agents might occur when both are used. use, since these dysrhythmias are presumably related to sodium channel-blocking effects of cocaine. Lidocaine can be used when dysrhythmias appear to be related to cocaine-induced ischemia. Hypertension Seizures Patients with severe hypertension can usually be safely treated with benzodiazepines. When benzodiazepines alone are not effective, nitroglycerin, nitroprusside, or phentolamine can be used. Beta-blockers are contraindicated because in the setting of cocaine intoxication, they cause unopposed alpha-adrenergic stimulation with subsequent exacerbation of hypertension. Benzodiazepines and phenobarbital are the first- and second-line drugs, respectively. Phenytoin is not recommended in cases associated with cocaine. Although no studies have compared barbiturates to phenytoin for control of cocaine-induced seizures, barbiturates are theoretically preferable because they also produce central nervous system (CNS) sedation and are generally more effective for toxin-induced convulsions. Newer agents have not been well studied in the setting of cocaine intoxication. Myocardial Ischemia or Infarction Patients with cocaine-associated myocardial ischemia or infarction should be treated with aspirin, benzodiazepines, and nitroglycerin as first-line agents. Benzodiazepines decrease the central stimulatory effects of cocaine, thereby indirectly reducing its cardiovascular toxicity. Benzodiazepines have a comparable and possibly an additive effect to nitroglycerin with respect to chest pain resolution and hemodynamic parameters for patients with chest pain. Weight-based unfractionated heparin or enoxaparin, as well as clopidogrel are reasonable to use in patients with documented ischemia. Patients who do not respond to these initial therapies can be treated with phentolamine or calcium channel-blocking agents. In the acute setting, beta-blockers are contraindicated, as they can exacerbate cocaine-induced coronary artery vasoconstriction [1, 2]. When patients have ST-segment elevation and require reperfusion, primary percutaneous coronary intervention (PCI) is preferred over fibrinolytic therapy due to a high rate of false-positive ST-segment elevations in patients with cocaine-associated chest pain, even in the absence of acute myocardial infarction (AMI), as well as the possibility of an increased rate of cerebral complications in patients with repetitive cocaine use [2]. Dysrhythmias Supraventricular dysrhythmias may be difficult to treat. Initially, benzodiazepines should be administered. Adenosine can be given, but its effects may be temporary. The use of calcium channel blockers in association with benzodiazepines appears to be most beneficial. Beta-blockers should be avoided. Ventricular dysrhythmias can be managed with benzodiazepines, lidocaine, or sodium bicarbonate. Bicarbonate is preferred in patients with QRS widening and ventricular dysrhythmias that occur soon after cocaine Cerebrovascular Infarction Cocaine can lead to both ischemic and hemorrhagic strokes. Most of these patients should be managed similarly to patients with non-cocaine-associated cerebrovascular infarctions with two exceptions: The utility of tPA in patients with recent cocaine-associated cerebrovascular events is unknown; blood pressure management should follow the recommendations that are mentioned above. Aortic Dissection Cocaine use can lead to aortic dissection. Various studies have found that 1–37% of aortic dissections may be due to cocaine. Treatment is similar to other patients with aortic dissection but medical management should be adjusted to try avoid beta-blockade. Body Stuffers and Packers Body stuffers who manifest clinical signs of toxicity should be treated similarly to other cocaine-intoxicated patients. Gastrointestinal decontamination with activated charcoal should be performed. Assessment for unruptured cocaine packages should be considered. In some cases, whole bowel may be necessary. Body packers are typically asymptomatic at the time of detention when passing immigration. In patients who present with symptoms or develop symptoms of cocaine toxicity or rapidly deteriorate because of exposure to huge doses of cocaine, immediate surgical removal of the ruptured packages may be necessary. Evaluation/Assessment Patients manifesting cocaine toxicity should have a complete evaluation focusing on the history of cocaine use, signs, and symptoms of sympathetic nervous system excess, and evaluation of specific organ system complaints. 583 C 584 C Cocaine Toxicity It is important to determine whether signs and symptoms are due to cocaine itself, underlying structural abnormalities, or cocaine-induced structural abnormalities. Laboratory Tests Since some patients may deny cocaine use, urine testing may be helpful. If the patient manifests moderate or severe toxicity, laboratory evaluation may include a complete blood cell count, serum electrolytes, glucose, blood urea nitrogen, creatinine, creatine kinase (CK), cardiac marker determinations, arterial blood gas analysis, and urinalysis. Hyperglycemia and hypokalemia may result from sympathetic excess. Rhabdomyolysis can be diagnosed by an elevation in CK. Cardiac troponin I or T should be used to identify acute MI in symptomatic patients with cocaine use. with or without clopidogrel for patients who received stent placement. The role of nitrates and calcium channel blockers remains speculative and should be used for symptomatic relief. The use of beta-adrenergic antagonists, although useful in patients with previous MI and cardiomyopathy needs special consideration in the setting of cocaine abuse. Since recidivism is high in patients with cocaine-associated chest pain (60% admit to cocaine use in the next year), beta-blocker therapy should probably be avoided in many of these patients. References 1. Imaging and Other Tests Chest radiography and electrocardiography should be obtained in patients with potential cardiopulmonary complaints. Computerized tomography (CT) of the head can be used to evaluate seizure or stroke. Patients with concurrent headache, suspected subarachnoid hemorrhage, or other neurologic manifestations may necessitate lumbar puncture after head CT to rule out other CNS pathology. After-care The appropriate diagnostic evaluation should follow general principles for the specific complication that occurred. For risk stratification in patients who presented with potential coronary artery disease, it is recommended that most patients receive imaging with some form of stress testing or CT coronary angiography. 2. 3. 4. McCord J, Jneid H, Hollander JE, de Lemos JA, Cercek B, Hsue P, Gibler WB, Ohman EM, Drew B, Philippides G, Newby LK (2008) Management of cocaine-associated chest pain and myocardial infarction a scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Circulation 117:1897–1907 Hollander JE (1995) Management of cocaine associated myocardial ischemia. N Engl J Med 333:1267–1272 Hollander JE, Hoffman RS, Burstein J, Shih RD, Thode HC, the Cocaine Associated Myocardial Infarction Study (CAMI) Group (1995) Cocaine associated myocardial infarction. Mortality and complications. Arch Intern Med 155:1081–1086 Weber JE, Shofer FS, Larkin GL, Kalaria AS, Hollander JE (2003) Validation of a brief observation period for patients with cocaine associated chest pain. N Engl J Med 348:510–517 Cocaine Toxicity ▶ Cocaine Prognosis Patient prognosis is dependent upon the type of complication the patient had from cocaine use. Continued cocaine usage, however, is associated with an increased likelihood of recurrent symptoms, and therefore, aggressive drug rehabilitation may be useful. Cessation of cocaine is the hallmark of secondary prevention. Recurrent chest pain is less common and MI and death are rare in patients who discontinue cocaine [2–4]. Aggressive risk factor modification is indicated in patients with MI or with evidence of premature atherosclerosis, coronary artery aneurysm, or ectasia. This includes smoking cessation, hypertension control, diabetes control, and aggressive lipid-lowering therapy. While these strategies have not been tested specifically for patients with cocaine, they are standard of care for patients with underlying coronary artery disease. Patients with evidence of atherosclerosis may be candidates for long-term antiplatelet therapy with aspirin Coccidioidomycosis JULIE P. CHOU1, TOM LIM1, ANDREW G. LEE2, CHRISTOPHER H. MODY3 1 Department of Internal Medicine, University of Calgary, Calgary, AB, Canada 2 Department of Radiology, University of Calgary, Calgary, AB, Canada 3 Departments of Internal Medicine and Microbiology, Immunology and Infectious Disease, University of Calgary, Calgary, AB, Canada Synonyms California valley fever; Desert fever; San Joaquin valley fever; Valley fever Coccidioidomycosis C 585 Definition Coccidioidomycosis is an infection caused by the dimorphic fungi of the genus Coccidioides. Coccidioides species are endemic to semiarid regions of the western hemisphere, including the San Joaquin Valley of California, the south-central region of Arizona, and northwestern Mexico. They can also be found in parts of Central and South America. Infection is generally acquired through inhalation, whereby infectious arthroconidia reach the lower respiratory tract. Only a small proportion of infected individuals will come to medical attention, as the majority of infections are subclinical. Although a wide spectrum of manifestations is possible, the majority of primary infections present with symptoms and signs comparable to community-acquired pneumonia or an upper respiratory tract infection. In addition to nonspecific symptoms such as chest pain, cough, and fever, other presenting complaints may include marked fatigue, arthralgias, erythema nodosum, and erythema multiforme. Peripheral eosinophilia and an elevated erythrocyte sedimentation rate can be observed. A pulmonary infiltrate with or without hilar adenopathy can be evident on chest x-ray or CT scan (Fig. 1). In immunocompetent hosts, primary pulmonary coccidiodomycosis is usually a self-limiting disease. However, patients with suppressed cellular immunity, such as those with HIV infection, solid organ transplant recipients, or individuals receiving chronic corticosteroid treatment, are predisposed to disseminated disease. African-American, Hispanic men, and pregnancy, place individuals at increased risk for disseminated disease. Extrapulmonary infection can be found in any organ system, but most commonly affects skin, bones, joints, and meninges. CSF analysis should be performed in patients with primary coccidioidomycosis presenting with CNS symptoms, and in patients who are severely ill warranting intensive care unit admission, or patients that may find it difficult to be followed by a physician. Others at risk include patients who are receiving TNF-alpha inhibitor therapy. They are more likely to develop symptoms when infected. Preexisting diabetes mellitus is associated with a higher likelihood of developing chronic pulmonary coccidioidomycosis, in particular cavitary disease. Because of the concern for hemoptysis from cavities, these patients require close monitoring. Treatment Immunocompetent Patients Immunocompetent patients are unlikely to present to the intensive care unit and treatment is usually not required in C Coccidioidomycosis. Figure 1 Coccidioidomycosis in two different patients. (a) A peripheral pulmonary infiltrate on computed tomography. (b) Thin-walled cavities as a late sequela of coccidioidomycosis primary pulmonary coccidioidomycosis. However, if the symptoms persist for greater than 6 weeks, therapy should be considered. Immunosuppressed Patients Patients with risk factors for disseminated disease are offered treatment when they present with primary pulmonary coccidioidomycosis. All forms of disseminated coccidioidomycosis require antifungal therapy. First-line therapy for treating chronic coccidioidomycosis is an oral azole. Ketoconazole, fluconazole, and itraconazole have all been well studied. Itraconazole may be superior in treating bone and join disease than fluconazole. Amphotericin B is reserved for the most severe cases of coccidioidomycosis or for those who fail to respond to azoles. Although the evidence is lacking for superiority in treatment using liposomal amphotericin B, it should be considered for therapy in individuals with underlying renal disease. 586 C Coelenterata The duration of therapy is generally prolonged for chronic coccidioidomycosis, with a minimum course of 12–18 months. A longer course might be considered in immunocompromised patients. Moreover, if the meninges are involved, lifelong azole antifungal therapy is required because of a high relapse rate. Although intravenous amphotericin B lacks efficacy in the treatment of Coccidioides meningitis, intrathecal amphotericin B can be used in cases refractory to azole therapy, or in situations when a more rapid response is desired. As for other classes of antifungal agents, the echinocandins have yet to be adequately assessed in coccidioidomycosis. By contrast, there are small series and case reports suggesting efficacy of voriconazole and posaconazole when used as salvage therapy. However, no definitive recommendation can be made at this time. Relapses are common in this population of patients. While the prognosis is good for most people with pulmonary coccidioidomycosis, many patients have protracted fatigue after resolution of pulmonary symptoms. References 1. Dewsnup DH, Galgiani JN, Graybill JR, Diaz M, Rendon A, Cloud GA, Stevens DA (1996) Is it ever safe to stop azole therapy for Coccidioides immitis meningitis? Ann Intern Med 124:305–310 Coelenterata ▶ Jellyfish Envenomation Evaluation/Assessment The diagnosis can be established by detecting the presence of anticoccidioidal antibody in the serum via a variety of techniques including ELISA, immunodiffusion, tube precipitin, and complement fixation assays. It should be remembered; however, that critically ill patients may not mount an effective antibody response and thus, may have false negative serology. Alternatively, the diagnosis can also be confirmed by identifying coccidioidal spherules in tissue or by culturing the organism from a clinical specimen. In the future, polymerase chain reaction (PCR) and real-time PCR may play a greater role in diagnostics. However, no commercial methods are currently available for direct detection of C. immitis from patient specimens. After-care For patients with severe infection, immunosuppression or other risk factors for dissemination, lifelong follow-up may be required. In milder cases, patients require close monitoring of their disease every 2–4 weeks following initial diagnosis. After noting improvement of their symptoms, clinic visits may be extended to intervals of every 3–6 months, for up to 2 years. Changes in complement fixation serologic titers can be useful, as a rise in titer is usually associated with disease progression. Radiographic abnormalities should be reexamined on a periodic basis. Coelenterate ▶ Jellyfish Envenomation Cold Sore ▶ Herpes Simplex Collapse ▶ Syncope Collapsed Lung ▶ Pneumothorax Prognosis For patients that have had a critical illness with disseminated disease, the outlook depends on the anatomic site of infection and the underlying immune status of the patient. Colloid Challenge ▶ Fluid Challenge Colloids Colloids LEWIS J. KAPLAN, ROSELLE CROMBIE, GINA LUCKIANOW Department of Surgery, Yale University School of Medicine, New Haven, CT, USA Synonyms Plasma volume expander (PVE); Synthetic colloid (as opposed to biologically active colloids such as fresh frozen plasma and human albumin) Trade Names As the number of colloid products is legion, a complete listing of all manufactured colloids available throughout the world is beyond the scope of this chapter. A partial listing of commonly utilized colloids is presented in Table 1. Class and Category All colloids belong to the class of drugs known as plasma volume expanders. The category of different colloids relates to the specific composition of each colloid. Nonetheless, unique differences within each category explain the differing efficacies and plasma half-lives, and often frequency of use. Following is a general categorization of commonly utilized colloids for plasma volume expansion. Of note, hypertonic saline preparations are not colloids even though they are used for plasma volume expansion and will not be further discussed within this chapter. General Principles of Colloids [1] Colloids are defined as a preparation of a homogenous noncrystalline substance that is dispersed throughout another substance that is usually a water-based solution (for medical use). The colloid may be large macromolecules or microparticles, which do not settle and are not separable from their suspending solution by filtration or centrifugation. Colloids are generally polydispersed, representing a span of molecular sizes that characterize a single preparation. Molecular weight (MW) which is generally constant may be described in two different fashions: 1. Weight-averaged MW: (# molecules at each weight X particle weight)/total weight of all molecules 2. Number-averaged MW: mean of all particle weights Furthermore, the weight distribution pattern may be assessed by the colloid oncotic pressure ratio, a ratio that C reflects the osmotic activity to a colloid solution across membranes with different pore sizes. In general practice, the size, persistence, efficacy at plasma volume expansion, side effect profile, and, of course, product approval by regulatory agencies, tend to govern clinician product selection. The clinician should remain acutely aware that the colloid preparations contribute very little free water to the patient’s system and therefore, should always be utilized with maintenance solutions to avoid inadvertently creating a hyperoncotic state (see Adverse Reactions below). Starches [1] Starches are synthetic colloid preparations derived from amylopectin extracted from either maize or sorghum. Amylopectin is a D-glucose polymer that is synthetically modified with hydroxyethyl substitutions at the second carbon (C2) as well as the sixth carbon (C6) with rather few substitutions occurring at the third carbon (C3); hydroxylation retards the rate of hydrolysis by plasma nonspecific a-amylases. Starches are characterized by their average molecular weight and average molecular size as they exist as a polydispersed preparation of different molecular weight and sizes. Thus, starches may be further classified by their average molecular weight into high MW (>450 kDa), medium MW ( 200 kDa), and low MW (70–130 kDa). Furthermore, they are characterized by the C2/C6 substitution ratio; the greater the ratio, the slower the degradation. The number of hydroxyethyl groups per 100 glucose groups is known as the degree of substitution (DS) or substitution ratio (MS); ratios are expressed as a number spanning 0–1. In a fashion similar to the C2/C6 substitution ratio, the greater the DS or MS, the longer the half-life (t½). By way of example, Hextend is a commercially available starch used in the USA. It may be characterized as a large MW starch (670 kDa) with a high degree of substitution (0.7). The last two characteristics are the concentration of the prepration and the diluent in which the colloid is prepared. Hextend is a 6% starch preparation is a balanced salt solution. Changing the diluent may change important consequences of administration rendering the product functionally different. For instance, Hextend’s predecessor, Hespan, is the identical starch in every way but was prepared in a saline base. Hespan contains a FDA black box warning with regard to volume of administration and induced bleeding risk; no such black box exists for Hextend. Table 1 presents commonly utilized colloid preparations and their characteristics. 587 C 588 C Colloids Colloids. Table 1 Common starch-based colloids used for resuscitation Colloid MW/DS Concentration Diluent C2/C6 HES 130/0.4 6% 10% NSS 9:1 Volulyte HES130/0.4 6% Balanced solution 6:1 Pentastarch HES 200/0.5 6% 10% NSS 5:1 Hextenda HES 670/0.7 6% Balanced solution 4.5:1 Hespana HES 670/0.7 6% NSS 4.5:1 Voluven a HES = hydroxyethyl starch NSS = 0.9% normal saline solution MW = molecular weight in kiloDaltons (kDa) DS = degree of substitution Note: not all colloids are available in the US Food and Drug Administration; approved colloids are indicated by (a) Gelatins [1] Gelatins are preparations created from the hydrolysis of bovine collagen and then further modified by either succinylation (polygeline; Gelofusine) of urea linkage (Hemaccel). Succinylation results in no change in MW but a significant increase in molecular size; no such changes occur with urea linkage. The diluents are different between the two products with only Hemaccel being prepared with calcium and potassium. It is important to note that the only cases of prion-related disease derived from cattle involve food-based disease transmission, not pharmaceutical preparations. Dextran 40 appears to have clinical use at present due to issues with allergic reaction and bleeding with Dextran 70. Combination Preparations Combinations of hypertonic saline and hyperoncotic starch are available as well. These preparations rely on starch plasma volume expansion and the concentrationdependent movement of water from the extravascular space to the intravascular domain on the basis of creating a hyperoncotic plasma space. Their efficacy or outcome advantage over other colloid solutions has yet to be demonstrated. Dextrans [1] Indications [2, 3] Dextrans are fairly homogenous preparations of D-glucose polymers principally joined by a-1,6 bonds creating linear macromolecules that are characterized by their concentration into two commercially available preparations, Dexran 40 (MW avg = 40 kDa) and Dextran 70 (MW avg = 70 kDa). The glucose moieties are derived from enzymatic cleavage of sucrose generated by Leuconostoc bacteria utilizing the enzyme dextran sucrase yielding high molecular weight detrains that are modified into the final product using acid hydrolysis and ethanol-based fractionation processes. Clearance is proportional to MW with 50–55 kDa molecules being readily renally filtered and excreted unchanged in the urine such that 70% of a Dextran 40 dose is excreted unchanged over a 24-h period. Molecules with a larger MW undergo GI clearance or cleavage within the reticuloendothelial system via extant dextranases. Only Colloids are indicated for the treatment of suspected or proven hypovolemia that requires plasma volume expansion. However, as there is increasing evidence that hyperchloremic metabolic acidosis (HCMA) deleteriously impacts outcomes, likely through activation of inflammatory pathways, colloid administration may have a selective advantage. In general, one needs to administer much less colloid than crystalloid to achieve equivalent plasma volume expansion, and therefore, one delivers much less chloride to the patient’s system. Thus, plasma volume expansion with colloids reduces the likelihood of creating a HCMA when large volume plasma volume expansion is required for the restoration of appropriate perfusion. Dosage Dosage of different preparations varies with local geography as a reflection of different regulatory bodies’ approval Colloids process. However, certain commonalities may be articulated. The general goal of a plasma volume expansion challenge is to provide 5% plasma volume expansion (PVE) for those with hypovolemia but no hypotension, and to provide 10% PVE for those with hypotension as an initial bolus. Thus, based on the properties of Hextend, 250 cc of the solution is appropriate for hypovolemia, but 500 cc is ideal for hypotension. Given the properties of the smaller MW starch Voluven, the same volumes would be used in identical scenarios. However, the dose of Voluven would need to be repeated more frequently based on its shorter t½ than Hextend. The reader should be aware that more frequent dosing is not a deleterious property, but rather reflects the biologic behavior of the colloid, and may be advantageous in certain circumstances (see Contraindications below). Preparation/Composition The preparation and composition of many of the commercially available colloid solutions are presented in Table 1. The reader should be aware that new products and preparations are in development and therefore, the listing in Table 1 should be viewed as only a partial presentation. Contraindications The main contraindications for synthetic colloid administration are allergy or intolerance to the colloid or its diluent. A further contraindication is hypervolemia in a patient with dialysis-dependent renal failure as if one induces heart failure or pulmonary edema, starch is not dialyzable and one must wait for enzymatic degradation. Along similar lines, chronic renal insufficiency (although not dialysis dependent) as well as evolving acute renal failure are relative contraindications for long half-life starches. The need for >20 cc/kg bw in 24 h is a contraindication for Hespan specifically, although not for Hextend according to the US Food and Drug Administration. Some authors have advanced the notion that sepsis is a contraindication for starch-based colloid administration but the authors of this chapter do not believe that such a claim is justified (see below). Adverse Reactions Allergic reaction is exceedingly rare with starch or gelatin products, but appears to be a limiting factor with large MW Dextrans. Perhaps the most notable adverse reaction is that of suspected renal dysfunction presenting as acute kidney injury or acute renal failure in patients who have undergone PVE using starch-based synthetic colloids in the setting of sepsis. The reader is encouraged to critically C review this literature as there are several key features that call the conclusions into serious question. A review of actual practice in 3,147 patients in 198 European Union ICUs during 2 weeks in May 2002 identified that colloid administration was often a combination of different colloids, and not limited to a single colloid [4]. Furthermore, in clinical practice, there was no difference in any measured or derived index of renal function, or the need for renal replacement therapy, with regard to colloid administration of any variety including hyper- or hypooncotic albumin, starches, gelatin, and dextran; approximately 15% of ICUs used more than one colloid at the same time on a given patient. The reader should recall that since there are a multitude of colloid preparations, comparing across multiple studies is exceptionally difficult as the preparations differ in MW, DS, diluent, volume, whether or not there was a fluid administration protocol, when in the clinical course did the patient receive colloid, and whether there was a pressure or flow-based monitoring system guiding therapy. Furthermore, delays prior to presentation, persistence of shock, timing of pressor use, specific pressors used, rapidity of resuscitation (before or after the vigorous volume expansion popularized by the Early Goal-Directed Therapy trial), the rapidity of source control, and the number of hypotensive episodes all influence renal perfusion. None of the trials are controlled for the presence of hyperchlormic metabolic acidosis, an entity known to reduce renal perfusion in an independent fashion. Furthermore, the definitions utilized for renal failure all differ, and many studies were performed prior to the recognition of acute kidney injury as a distinct entity. Additionally, the indications for renal replacement therapy are not uniform and some studies use the need for RRT as the definition of renal failure. Thus, drawing any conclusion from the case reports, case series, and few large but heterogenous trials that claim starch-based PVE indices renal injury and failure is problematic at best. Furthermore, trials such as the VISEP study comparing pentastarch to lactated Ringers solution either overresuscitate the pentastarch group or under-resuscitate the LR group depending on your perspective as both groups received identical volumes of fluid [5]. This ignores the basic concept underpinning colloid-based PVE – colloid are better retained in the plasma space and therefore, one administers a smaller volume. It is little surprising that the pentastarch group evidences a higher CVP and a lower hemoglobin than the LR group based on unequal fluid administration. Also, there was an unequal distribution of patients requiring emergency operative undertakings to the pentastarch group – the at-risk group for acute tubular necrosis, AKI, and ARF! 589 C 590 C Colonization Perhaps equally important is the unreported presence or absence of concomitant maintenance fluid in trials addressing colloid administration versus crystalloidbased plasma volume expansion regimens. An important trial evaluated several different fluids for PVE in the treatment of shock, but categorized the fluids based on whether the fluid was hyper- or hypo-oncotic and determined the occurrence of renally relevant events [6]. Crystalloids were compared to hypo-oncotic albumin and gelatin versus hyperoncotic starch versus hyperoncotic albumin. Importantly, all of the renally relevant events including the need for renal replacement therapy occurred in the hyperoncotic groups. Unfortunately, the definition of ARF used in this trial was a doubling of baseline creatinine, or the need for dialysis. This study underscores the need to avoid creating an inadvertent hyperoncotic state when using hyperoncotic PVEs at least in patients with shock. It is likely that this observation may be extended to those with hypovolemia without shock as well, but the decreased effective circulating volume that characterizes septic and hypovolemic shock places this patient population at particular risk for hyperoncoticity when the principle administerd fluid is a hyperoncotic colloid. Current bias has begun to focus on the use of low MW and lesser substituted starch-based colloids such as Voluven (6% HES, 130/0.4 prepared in saline) and its counterpart agent, Volu-Lyte that is prepared in a balanced salt solution in a fashion similar to that of Hespan and Hextend. Since the lower MW and less substituted compounds have a shorter half-life, it is expected that renal accumulation will occur less frequently and present a reduced risk of AKI and ARF as a consequence of starch administration in sepsis. However, the concerns articulated above may not support such notions, and there are other elements that remain unidentified. For instance, since starch has been identified in the renal tubular cells of those with ARF who have received starch-based PVE, we do not know if the starch presence is causative or simply coincident and of no functional consequence. Data are conflicting even in the renal transplantation patient population. Moreover, since one does not biopsy normal kidneys, one does not know if a patient who received a starch-based PVE regimen and who did not change their creatinine also had starch molecules accumulate in their renal tubular cells. While there is much bias and speculation, the medical community appears to be divided into those who have already lost their clinical equipoise with regard to starch and renal injury and those who are awaiting data. Drug Interactions There are no significant drug interactions noted for colloid preparations. There is some concern, although unfounded, that calcium containing colloids may not be administered through the same IV line as blood products for fear of clotting. In clinical practice, given the rapid rate of administration of each agent, clotting is not clinically identified. Mechanisms of Action Colloids serve to expand plasma volume by exerting osmotic activity and having synthetic modification to retard the rate of degradation or filtration, thus preserving their plasma half-life. Incidental modification of rheology is also noted with colloid administration that is mediated in part by altering RBC flexibility through small-diameter vessels, and in part through reductions in viscosity [7]. As a result, some observations identify colloid-based support of microcirculatory delivery of oxygen as judged by muscle tissue oximetry compared to non-colloid-based PVE regimens when fluids and blood products were administered on protocol and titrated to a CVP measurement. Cross-References ▶ Intravenous Fluids References 1. 2. 3. 4. 5. 6. 7. Grocott M, Mythen M, Gan TJ (2005) Perioperative fluid management and outcomes in adults. Anesth Analg 100:1093–1106 Mike James review of colloids Boldt J (2002) Hydroxyethyl starch as a risk factor for acute renal failure: Is a change of practice indicated? Drug Saf 25(12):837–846 Sakr Y, Payen D, Reinhart K et al (2007) Effects of hydroxyethyl starch administration on renal function in critically ill patients. Br J Anaesth 98(2):216–224 Brunkhorst FM, Engel C, Bloos F et al (2008) Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 358:125–139 Schortgen F, Girou E, Deye N et al (2008) The risk associated with hyperoncotic colloids in patients with shock. Inten Care Med 34(12):2157–2168 Neff TA, Fischler L, Mark M et al (2005) The influence of two different hydroxyethyl starch solutions (6% HES 130/0.4 and 200/ 0.5) on blood viscosity. Anesth Analg 100:1773–1780 Colonization The process whereby microorganisms inhabit a specific body site (such as the skin, bowel, or chronic ulcers) without causing a detectable host immune response, cellular damage, or clinical signs and symptoms. It involves Coma adherence of organisms to epithelial cells, proliferation, and persistence at the site of attachment. The presence of the microorganism may be of varying duration and may become a potential source of transmission. Colonoscopy ▶ Gastrointestinal Endoscopy Coma DERRICK SUN, KATHRYN M. BEAUCHAMP Department of Neurosurgery, Denver Health Medical Center, University of Colorado School of Medicine, Denver, CO, USA Synonyms Blackout; Encephalopathy; Stupor; Unconsciousness; Vegetative state Definition Coma is defined as the state of profound unconsciousness, from which the patient cannot be aroused to respond appropriately to external stimuli. It originates from the Greek word meaning “deep sleep or trance.” It represents an acute and life-threatening emergency, requiring rapid diagnosis and intervention in order to preserve brain function and life. Coma lies on a spectrum of terms used to describe varying degrees of alteration of consciousness, including lethargy, stupor, and obtundation. The Glasgow Coma Scale (GCS) is a simple and objective scoring system used by health-care professionals to quickly assess the severity of brain dysfunction, composed of three tests: eye-opening response, verbal response, and motor response. Eye opening is graded from 1 to 4. Verbal response is graded from 1 to 5. In intubated patients, a score of “1” is given for verbal response with a modifier of “T.” Motor response is graded from 1 to 6. The GCS score, a sum of all three components, ranges from 3 (deep coma or death) to 15 (fully awake person). GCS score of 8 or less is generally accepted as operational definition for coma. Consciousness is defined as the state of awareness of oneself and one’s surrounding environment. Consciousness C has two major interconnected components: wakefulness (i.e., arousal) and awareness. Both components are necessary to maintain consciousness. Wakefulness is dependent on a network of neurons called the ascending reticular activating system (ARAS), originating in the midbrain and rostral pontine tegmentum and projecting to the diencephalon (hypothalamus and midline and intralaminar nuclei of the thalamus). From there, widespread projections are sent to bilateral cerebral cortex. Damage to the ARAS would result in impairment of wakefulness. Awareness, sometimes referred to as the “content” of consciousness, represents the sum of all functions mediated by cerebral cortical neurons and their reciprocal projections to and from subcortical structures [1]. These functions include sensation and perception, attention, memory, executive function, and motivation. Awareness requires wakefulness, but wakefulness may be observed in the absence of awareness, as in the case of vegetative state. The vegetative state describes a state of wakefulness without awareness. The vegetative patient exhibits sleep– wake cycles, evident by “eyes-open” periods, without evidence of awareness of self or environment. The term persistent vegetative state is reserved for patients who remain in the vegetative state for at least 30 days. The minimally conscious state (MCS) is a condition defined by severely impaired consciousness with minimal but definite behavioral evidence of self or environmental awareness [2]. Like the vegetative state, MCS may be a transitional state during recovery from coma, or progression of worsening neurologic disease. Another condition worth recognizing is the locked-in syndrome, in which the patient has complete paralysis of all four limbs and the lower cranial nerves. The locked-in syndrome is not a disorder of consciousness, as the patient retains awareness. The most common cause is a lesion in the base and tegmentum of the midpons, interrupting the descending cortical motor fibers responsible for limb movement, while preserving vertical eye movement and eye opening. A high level of suspicion on the part of the clinician is required to make this diagnosis. Psychogenic unresponsiveness may mimic coma, and is characterized by normal neurologic exam, including normal oculocephalic and oculovestibular reflexes. Patient may sometimes forcibly close the eyelids. If psychogenic etiology is suspected, an electroencephalogram (EEG) may be helpful to aid in diagnosis. In more challenging cases, Amytal interview can be used, wherein the patient is slowly injected with an anxiolytic drug while repeated neurologic exam is performed. Patients with psychogenic unresponsiveness should exhibit improvement in function. 591 C 592 C Coma Brain death is defined as the irreversible cessation of all functions of the entire brain, such that the brain is no longer capable of maintaining respiratory or cardiovascular function. Etiology and Pathophysiology Coma could be caused by focal or “structural” conditions that lead to disruption of the ARAS anywhere in the brain stem, bilateral diencephalon, or diffuse bilateral cerebral cortex. On the other hand, systemic or “metabolic” disorders that interfere with the normal metabolism of the brain and disturb normal neuronal activity could also lead to coma. Structural Etiology Structural causes of coma can be categorized into “compressive” or “destructive” lesions. Compressive lesions (e.g., intracranial hemorrhage or tumor) may cause impairment of consciousness by several mechanisms: (1) by directly distorting the ARAS or its projection, (2) by increasing ICP and thus impairing cerebral blood flow, (3) by distorting and displacing normal brain tissue, (4) by causing edema and further distortion of brain, or (5) by causing herniation [2]. Compressive lesion such as epidural hematoma classically results from traumatic fracture of the skull that lacerates a meningeal vessel branch. Blood accumulates between the skull and the dura, causing brain compression and shift. Some patients exhibit a period of lucid interval after trauma, until the expanding hematoma grows large enough to cause displacement of the diencephalon and brain stem, leading to impaired consciousness. Subdural hematoma usually results from tearing of bridging cerebral veins. They are more commonly seen in elderly or alcoholic patients with cerebral atrophy, or patients who are anticoagulated with warfarin, clopidogrel, or aspirin. Acute subdural hematoma has a high mortality rate due to high association with other injuries, such as brain contusions. Subarachnoid hemorrhage, when due to rupture of aneurysm, has high rates of mortality and morbidity. As the blood in the subarachnoid space breaks down, inflammatory reaction is incited, resulting in cerebral vasospasm. Delayed brain ischemia and infarction can occur. Hydrocephalus can also complicate subarachnoid hemorrhage due to impairment of cerebrospinal fluid absorption, leading to elevated intracranial pressure (ICP) and impairment of consciousness. Brain tumors often present with headaches, focal neurologic deficits, or seizures. They may present with impaired consciousness due to compression or infiltration of the diencephalon or due to herniation. Destructive lesions (e.g., cerebral infarct) cause coma by directly damaging the ARAS or its projections. Bilateral cortical or subcortical infarcts, due to cardioembolism or severe bilateral carotid stenosis, could result in coma. Although impairment of consciousness rarely occurs due to unilateral cerebral hemispheric infarct, it may occur in delayed fashion secondary to edema of infarcted tissue causing compression of the other hemisphere and diencephalon. Occlusion of the thalamo-perforators branches of the basilar artery can lead to infarcts of bilateral thalami, causing coma or hypersomnolence [2]. Pontine hemorrhage, usually due to uncontrolled hypertension, is characterized by sudden onset of coma, pinpoint pupils, breathing irregularity, and ophthalmoplegia. Cerebellar hemorrhage, another possible consequence of uncontrolled hypertension, presents with occipital headache, nausea and vomiting, unsteadiness, and ataxia. Early diagnosis and treatment is crucial, as once the patient is comatose, surgical intervention is often futile. Traumatic brain injury (TBI) is another common cause of coma. Mechanism of loss of consciousness in TBI may be due to shearing forces applied to the ARAS. Diffuse axonal injury (DAI) is associated with severe TBI, and portends a poor prognosis. Herniation Syndromes The Monro–Kellie doctrine hypothesizes that the central nervous system and its accompanying fluids are enclosed in a rigid container, and the sum of the volume of the brain, cerebrospinal fluid (CSF), and intracranial blood remains constant. An increase in volume of one component (e.g., a growing mass lesion) can be compensated to a degree by the displacement of an equal volume of another component (e.g., CSF). When this compensatory mechanism is overwhelmed, even a small increase in volume will lead to a large increase in pressure. The differential pressure gradient between adjacent intracranial compartments leads to herniation. Several herniation syndromes are commonly described. Uncal herniation occurs when a mass lesion in a lateral cerebral hemisphere pushes the uncus, or medial temporal lobe, medially and inferiorly over the tentorial edge. Uncal herniation causes stretching of ipsilateral oculomotor nerve, which leads to fixed and dilated pupil. Hemiparesis, either contralateral or ipsilateral, could result from compression of the cerebral peduncles. The posterior cerebral artery runs along the tentorial notch, and its compression could lead to ischemia of ipsilateral occipital lobe, leading to visual field deficit. In central herniation, or transtentorial herniation, pressure from expanding supratentorial mass lesion displaces the Coma diencephalon caudally. In addition to distorting the ARAS, branches of the basilar artery are also stretched, leading to brainstem hemorrhage. Tonsillar herniation results when the cerebellar tonsils are pushed caudally down the foramen magnum, causing direct compression of the medulla; fourth ventricular CSF outflow is closed off, leading to further increase in intracranial pressure. Subfalcine herniation, or cingulate herniation, occurs when one cerebral hemisphere pushes medially under the rigid falx cerebri, causing displacement of the cingulate gyrus. Branches of the anterior cerebral artery are sometimes pushed against the falx, leading to ischemia of medial cerebral hemispheres. Metabolic Etiology Diffuse, multifocal, and metabolic diseases cause stupor and coma due to interruption in delivery of oxygen or substrates (e.g., hypoxia, ischemia, hypoglycemia), alterations in neuronal excitability and signaling (e.g., drug toxicity, acid–base imbalance), or changes in brain volume (e.g., hypernatremia, hyponatremia) [3]. Hypoxia and ischemia can lead to impairment of consciousness. The brain has one of the highest metabolic rates of any organ and requires a constant supply of oxygen, glucose, and cofactors to generate energy, synthesize proteins, and carry out electrical and chemical reactions. The brain lacks reserves of its essential substrates, and therefore it is vulnerable to even temporary cessation of substrates or blood flow [2]. Cerebral autoregulation maintains cerebral blood flow at a relatively constant rate over a range of systemic blood pressure. When autoregulation fails in the extremes of systemic blood pressure, cerebral blood flow decreases and lactic acid builds up, leading to a decrease in pH and impairment in ATP generation. Neuronal cell death could occur due to calcium influx and free radical formation [2]. Glucose is a major substrate for brain metabolism. Profound hypoglycemia causes damage to the cerebral hemispheres, producing laminar or pseudolaminar necrosis in severe cases [2]. Hypoglycemia could present as delirium, stroke, or coma; therefore, finger-stick glucose should be checked on all patients presenting with impaired consciousness. Wernicke’s encephalopathy is a syndrome caused by thiamine deficiency, with classic symptoms of confusion, ataxia, and ophthalmoplegia. If left untreated, Wernicke’s encephalopathy could progress to Korsakoff ’s syndrome, an irreversible syndrome characterized by amnesia and confabulation. Acute liver failure causes increased permeability of blood-brain barrier, leading to cerebral edema and C elevated ICP. Elevated ICP is a major cause of death in patients with acute liver failure [2]. Elevated ammonia level is implicated in hepatic encephalopathy, although direct correlation between ammonia level and degree of clinical impairment is lacking. Clinical presentation varies from delirium to obtundation. Hyperventilation with respiratory alkalosis is common. Nystagmus, dysconjugate eye movement, and muscle spasticity have been described. Decorticate or decerebrate posturing is possible with deep coma. Renal failure may lead to uremic encephalopathy. The precise pathophysiology of uremic encephalopathy is not clear. Furthermore, treatment of uremia by hemodialysis may cause rapid change in osmolarity, leading to rapid water shifts and cerebral edema, which could result in coma. Endocrinopathies such as panhypopituitarism, adrenal insufficiency, hypothyroidism, and hyperthyroidism have all been implicated as causes of coma. Patients with diabetes may present with nonketotic hyperglycemic hyperosmolar coma or coma from diabetic ketoacidosis. Many drugs can cause coma. Sedative drugs such as benzodiazepines and barbiturates, opioids, and ethanol can cause impairment of consciousness, as can psychotropic drugs such as tricyclic antidepressants, lithium, and selective serotonin reuptake inhibitors; anticholinergic drugs, amphetamines, and illicit drugs all can cause delirium and coma. Acid–base imbalance, especially respiratory acidosis, and electrolyte derangements such as hyper- and hyponatremia, hyperand hypocalcemia, and hypophophatemia can result in delirium, stupor, and coma. Infectious and inflammatory diseases of the central nervous system, including meningitis, encephalitis, and cerebral vasculitis could present with impaired consciousness. Seizures and postictal states can also present as coma. In one series of comatose patients without overt clinical seizure activity, EEG demonstrated nonconvulsive status epilepticus in 8% of patients [2]. Seizure produces an increase in cerebral metabolic demand, and sustained seizures can lead to hypoxic-ischemic brain damage if untreated. Treatment When presented with the unconscious patient, basic principles of life support apply. Check airway, ensure breathing and oxygenation, and maintain circulation. Intubate the patient if GCS  8. The PaO2 should be maintained above 100 mmHg and the pCO2 kept ideally between 35 and 40 mmHg. The mean arterial pressure (MAP) should be 593 C 594 C Coma maintained above 70 mmHg to ensure adequate brain perfusion. Intravascular volume depletion should be corrected, and vasopressors may need to be used to maintain systemic pressure. Hypertension should be treated cautiously, keeping in mind that for patients with chronic hypertension, a sudden drop in blood pressure may lead to relative hypoperfusion of the brain. Finger-stick glucose should be checked, and both hyperglycemia and hypoglycemia should be treated. Glucose should be administered along with thiamine to avoid precipitating Wernicke’s encephalopathy. If narcotic overdose is suspected, naloxone can be given intravenously and repeated as necessary. Keep in mind that, while naloxone has duration of action of 2–3 h, some narcotics have a much longer half-life. Thus, close observation is needed for patients who recover after naloxone administration. If benzodiazepine overdose is suspected, flumazenil, a benzodiazepine antagonist, is sometimes used. Gastric lavage with activated charcoal is sometimes utilized for suspected drug ingestion. If the stuporous or comatose patient is relatively stable, an emergency CTscan should be obtained. However, if elevated ICP is suspected, or if impending or active herniation is suspected, intracranial hypertension needs to be treated first. Hyperventilation to PaCO2 between 25 and 30 mmHg will transiently lower ICP while other therapeutic measures take effect. Mannitol, a hyperosmolar agent, may be given as a bolus to draw water from the brain, thus lowering ICP. Mannitol is also reported to lower blood viscosity and thus improve cerebral perfusion. Alternatively, hypertonic saline can be given either as a bolus of 23.4% solution or as a continuous drip of 3% solution to lower ICP. Seizures must be quickly diagnosed and treated, as repeated or continuous seizures (i.e., status epilepticus) could cause secondary brain injury. Lorazepam should be administered to stop generalized seizures, followed by a loading dose of phenytoin or valproic acid. When these measures fail, general anesthesia with propofol or pentobarbital may be necessary. If meningitis or encephalitis is suspected, broad spectrum antimicrobials should be instituted after blood cultures are obtained. A CT scan should be obtained to rule out a mass lesion prior to lumbar puncture, although treatment should not be delayed while waiting for culture results. Steroid is used as an adjunct to antibiotics in bacterial meningitis to decrease inflammatory response. Additional therapy should be tailored toward specific etiology. Evaluation and Assessment The prompt diagnosis and treatment of patient in coma is crucial to outcome. Coma caused by some metabolic derangements, such as hypoglycemia, is reversible if appropriate and timely therapy is instituted. Coma due to compression from subdural hematoma or epidural hematoma could be reversible if promptly diagnosed and surgically evacuated. Therefore, the evaluation and assessment of the unconscious patient ought to proceed in a rapid, systematic, and focused manner, sometimes simultaneously with treatment. When possible, history should be obtained from patient’s relatives, friends, paramedics, or police. The onset and progression of coma sometimes could give clues to the etiology. General physical exam looking for signs of trauma or systemic medical illness should be performed. Periorbital ecchymosis (raccoon eyes), drainage of clear or bloody fluid from the ears or nose, and skull base ecchymosis (Battle’s sign) are all signs of trauma. A quick neurologic exam should be performed, assessing verbal response, eye opening, and motor response. Brainstem reflexes such as pupillary light reflex, oculocephalic reflex, oculovestibular reflex, and corneal reflex should be tested. Deep tendon reflexes and skeletal muscle tone should also be assessed. Respiratory pattern should be noted as regular, periodic, or ataxic, or combination of these. Cheyne–Stokes respiration is a pattern of periodic breathing with phases of hyperpnea alternating with apnea. The depth of respiration waxes and wanes in a crescendo–decrescendo manner. It is generally seen in patients with diffuse forebrain lesions, uremia, hepatic failure, or heart failure. Sustained hyperventilation is sometimes seen in patients with hepatic coma, sepsis, diabetic ketoacidosis, meningitis, or pulmonary edema. True central neurogenic hyperventilation is rare, and may be due to midbrain or pons lesions. Apneustic breathing is characterized by prolonged pause at full inspiration, and it usually reflects lesion in the pons, as seen in patients with brainstem strokes from basilar artery occlusion. Ataxic breathing, or irregular, gasping respiration, implies damage to the medullary respiratory center. Cluster breathing is characterized by periods of rapid irregular respiration, followed by apneic spells, and is indicative of lesion in the medulla. Emergency laboratory tests for evaluation of coma should include complete blood count, electrolyte panel, coagulation studies, ammonia, arterial blood gas, cerebrospinal fluid studies, and electrocardiogram. Additional studies, such as liver function test, thyroid and adrenal Coma depasse function tests, blood culture, urine culture, and toxicology screen should be considered. After-care The cost of caring for a patient in the comatose state carries beyond the acute intensive care setting. Coma is often a transient stage; few patients remain in eyes-closed coma for more than 10–14 days [4]. Patients ultimately will die, recover, or transition to vegetative state. The comatose and vegetative patients have shortened life expectancy due to several factors, often succumbing to respiratory or urinary tract infections, multisystem organ failure, and respiratory failure [5]. Survival of these patients depends, to some degree, on the quality and intensity of medical treatment and nursing care. Proper skin care, such as frequent turning and repositioning, helps reduce incidence of decubitus ulcers. Daily passive range of motion exercise helps reduce limb contractures. Tracheostomy and percutaneous gastric feeding tube are often necessary for maintaining airway and providing nutrition and hydration [5]. Prognosis The prognosis for coma is variable and largely dependent on the etiology, location, and severity of brain damage. The Glasgow Outcome Scale (GOS) is often used to grade the level of functional recovery from coma: Grade 5 indicates recovery to previous level of function; Grade 4 describes patients who recover with moderate disability but remains independent; Grade 3 indicates recovery with severe disability with dependence on others for daily support; Grade 2 indicates recovery to vegetative state, and Grade 1 indicates no recovery. In one series of 500 patients with nontraumatic coma, 16% led an independent life at some point within the first year (GOS grade 4 or 5), while 11% regained consciousness but was dependent on others for activities of daily living, 12% never improved beyond the vegetative state, and 61% died without recovery from coma [4]. Patients who survived nontraumatic coma made most of their recovery within the first month. Longer duration of coma was associated with worse chance of functional recovery. Among different disease processes, subarachnoid hemorrhage had the worst outcome, while hepatic encephalopathy and other metabolic causes had the best. Lack of verbal response, eye opening, motor response, pupillary light reflex, corneal reflex, oculocephalic response, oculovestibular response, or spontaneous eye movements were all independently C associated with lack of recovery to independent function. Coma arising from TBI portends better prognosis than nontraumatic coma [2]. A comprehensive review by the Brain Trauma Foundation listed several factors with class I prognostic evidence. Advanced age was predictive of poor outcome, with 56% of patients younger than 20 and only 5% of patients older than 60 able to achieve GOS of 4 or 5. Each lower GCS score was associated in a stepwise fashion with progressively worse outcome. Absent pupillary light reflex or oculocephalic response at any point in the illness predicts an outcome of less than 4 on the GOS. Hypotension and hypoxia were also independent predictors of poor outcome. Abnormal neuroimaging findings such as compression of basal cisterns or midline shift of brain structures, indicative of elevated ICP, were predictive of poor outcome. While EEG is useful in identifying nonconvulsive status epilepticus in the comatose patient, it has not been shown to be predictive of outcome. Somatosensory-evoked potentials (SSEPs), on the other hand, are a better predictor. In several studies, bilateral absence of cortical SSEPs predicted death or vegetative state in almost all patients [2]. Cross-References ▶ Encephalopathy and Delirium References 1. 2. 3. 4. 5. Young GB, Pigott SE (1999) Neurobiological basis of consciousness. Arch Neurol 56:153–157 Posner JB, Saper CB et al (2007) Plum and Posner’s diagnosis of stupor and coma. Contemporary Neurology Series 71, 4th edn. Oxford University Press, New York Stevens RD, Bhardwaj A (2006) Approach to the comatose patient. Crit Care Med 34(1):31–41 Levy DE, Bates D, Caronna JJ et al (1981) Prognosis of nontraumatic coma. Ann Intern Med 94:293–301 The Multi-Society task Force on PVS (1994) Medical aspects of the persistent vegetative state – second of two parts. N Engl J Med 330:1572–1579 Coma depasse ▶ Brain Death ▶ Death by Neurologic Criteria 595 C 596 C Community-Acquired Pneumonia (CAP) Community-Acquired Pneumonia (CAP) Confusion ▶ Septic Encephalopathy ▶ Burns, Pneumonia ▶ Pneumonia, Empiric Management Congenital Heart Disease in Children Compliance Ratio between the change in volume determined by a change in pressure (Crs = DV/DP), depending on the elastic properties of the respiratory system. JONATHAN R. EGAN, MARINO S. FESTA The Children’s Hospital at Westmead, Westmead, Australia Synonyms Cardiac disease; Heart disease Definition Complicated Intra-abdominal Infections ▶ Abdominal Cavity Infections Complicated Parapneumonic Effusion Fluid in the pleural space that does not resolve spontaneously with treatment of the underlying infection, and requires drainage with therapeutic thoracentesis or placement of a chest tube. ▶ Empyema Computed Tomography ▶ Imaging for Acute Abdominal Pain Confirmed STSS Clinical case definition+isolation of GAS from a normally sterile site. Malformation of the heart present at birth. Characteristics It is estimated that 4–10 liveborn infants per 1,000 are diagnosed with congenital heart disease (CHD), with approximately 40% diagnosed in the first year of life and the remainder some time in childhood or adulthood [1]. The majority of lesions are amenable to surgical repair or palliation and it has been estimated that the prevalence of adults with CHD in the USA is increasing by approximately 5% per annum [2]. CHD may present in the newborn period or later in childhood, usually with heart failure, central cyanosis, episodic collapse, or as an incidental finding of a heart murmur: Heart Failure Tachypnea, worse with exertion or feeding in an infant, is a common sign of heart failure in CHD. This is most common in conditions that allow blood to shunt from left to right (i.e., from the systemic to pulmonary circulation), or in conditions that obstruction to flow through the heart at the level of the valves, pulmonary veins, or either ventricular outflow tract causing pulmonary venous congestion. In the infant, sweating with feeds and hepatomegaly are commonly seen, and though dependent edema may occur, pitting edema of the peripheries is much less common than in adults. Severe heart failure may manifest at the time of spontaneous closure of the patent ductus arteriosus at or around 1 week of age in a previously asymptomatic neonate with an obstructive lesion of the left heart such as critical aortic stenosis, hypoplastic left Congenital Heart Disease in Children heart syndrome (HLHS), interrupted aortic arch, or severe coarctation of the aorta. In later infancy and early childhood, undiagnosed CHD leading to increased pulmonary blood flow or obstruction to pulmonary venous drainage (e.g., ventricular septal defect, atrioventricular septal defect, patent ductus arteriosus, anomalous pulmonary venous drainage) may cause chronic heart failure leading to impaired growth and failure to thrive. A chest X-ray will usually show cardiomegaly and increased pulmonary vascular markings, with the notable exception of obstructed total anomalous pulmonary venous drainage of the infradiaphragmatic type where marked pulmonary congestion is present in the absence of cardiomegaly. The normal fall in pulmonary vascular resistance in the postnatal period may lead to increasing left-to-right shunt and pulmonary blood flow in the first week of life. Similarly, increased inspired oxygen or respiratory alkalosis may both decrease pulmonary vascular resistance and lead to worsening heart failure. Central Cyanosis Cyanosis of the lips and tongue in the newborn infant is indicative of desaturation of arterial hemoglobin and may be readily identified by direct comparison with the mother. Typically the baby with cyanotic congenital heart disease looks otherwise well with little or no respiratory difficulty. An arterial blood sample pO2 taken in maximal inspired oxygen will not exceed 100 mmHg. The most common cause of cyanotic heart disease in the newborn period is transposition of the great arteries where separation of the pulmonary and systemic circulation requires mixing either at the level of the atrium via the patent foramen ovale, or via a patent ductus arteriosus or sometimes via a ventricular septal defect, to allow oxygenated blood to cross the systemic circulation. Other CHD resulting in decreased pulmonary blood flow (e.g., pulmonary atresia with an intact ventricular septum, tetralogy of Fallot, tricuspid atresia, Ebstein’s anomaly) or anomolous to pulmonary venous return to the right atrium (e.g., total anomalous pulmonary venous drainage with or without obstruction to the pulmonary venous blood flow) may present with central cyanosis commonly in the newborn period, or later in infancy or childhood. Incidental Murmur It remains common for less severe forms of CHD to be diagnosed in childhood by detection of a significant murmur on routine or coincidental examination. C Significant murmurs may be caused by turbulent flow across abnormal structures (e.g., patent ductus arteriosus, pulmonary stenosis) or connections (e.g., ventricular septal defect) or due to increased flow across normal structures (e.g., atrial septal defect causing left-to-right shunt and a pulmonary flow murmur). Episodic Collapse Infants and children may have episodes of extreme tachycardia or bradycardia associated with alteration of consciousness, pallor, and sometimes collapse. Signs of heart failure may initially be absent, especially in infants, and develop over several hours if the abnormal rhythm persists. Supraventricular tachycardia is a rapid tachyarrhythmia with a rate usually over 220 bpm that may present de novo in infants and older children. The electrocardiograph (ECG) is characterized by the absence of P waves and absolutely regular R–R interval. Up to a third of cases have an underlying structural heart abnormality and a proportion of the remainder have a short PR interval with a delta wave on electrocardiograph (ECG) during normal sinus rhythm implying early excitation via an accessory pathway (Wolf–Parkinson–White syndrome). Recurrent ventricular tachycardia is a recognized cause of sudden death in childhood and may be associated with a family history of sudden death. Prolonged QT syndromes (e.g., Romano-Ward syndrome or if associated with sensorineural deafness Jervell and Lange-Nielsen syndrome) due to inherited defects in myocardial potassium channel function that allow early repolarization typically present with episodes of torsades de point causing sudden collapse or death. Inherited defects of myocardial sodium channels (e.g., Brugada syndrome) may present with sudden onset of ventricular arrhythmia in older children and young adults [3]. Congenital complete heart block may present with heart failure in the prenatal (hydrops fetalis) or postnatal period and may be associated with maternal anticardiolipin syndrome. Management Fetal Screening An effective antenatal screening program may help improve prenatal detection of life-threatening CHD. This allows parents the choice of termination of pregnancy and the chance of improved outcomes by avoiding unanticipated postnatal collapse and the careful planning of perinatal care [4]. 597 C 598 C Congenital Heart Disease in Children Postnatal Stabilization Stabilization of the newborn with CHD depends on detailed knowledge of the cardiac anatomy and assessment of the changing physiology in the postnatal period. This can only be achieved by a multidisciplinary approach to care. Transthoracic echocardiography with Doppler measurement and color flow mapping is essential to confirm diagnosis based on prenatal ultrasound or clinical examination and to rule out additional lesions. Cardiac catheterization is usually reserved for complex cases or if an interventional procedure is indicated. Full history and examination for associated abnormalities or syndromes should be undertaken. A systematic approach to stabilization of the airway and breathing is required in the initial postnatal period prior to cardiac assessment. This may include intubation and ventilation to normalize lung volumes and reduce left ventricular wall stress in some cases. In cases of suspected or known duct-dependent CHD (e.g., transposition of the great arteries with intact ventricular septal defect (VSD), hypoplastic left heart syndrome, interrupted aortic arch), the neonate should be commenced on an intravenous infusion of epoprostenol (Prostacyclin) in order to maintain the duct open (usual dose 5–25 ng/kg/min). Care should be taken to ensure that the baby maintains an adequate preload after starting the infusion as systemic vascular resistance and cardiac filling pressures are likely to fall. The self-ventilating neonate should also be closely observed for apnea at this time as this is known to be associated with commencement of epoprostenol infusion. Babies with single ventricle anatomy and physiology, in which a single ventricle effectively supplies pulmonary and systemic blood flow (e.g., hypoplastic left heart syndrome, pulmonary atresia) are sensitive to changes to systemic and pulmonary vascular resistance, which will influence the relative flow to the two circuits. Hence, in addition to maintaining good cardiac output by attention to adequate preload and myocardial contractility, manipulation of factors to influence the vascular resistance in the systemic and pulmonary circulations should be used to allow adequate systemic blood flow. Avoidance of noxious stimuli, maintenance of normothermia and appropriate analgesia are important, in addition to pharmacological manipulation by systemic vasodilators, in order to avoid a situation of increased systemic vascular resistance leading to excess pulmonary flow and decreased systemic oxygen delivery. This situation may be exacerbated by the normal fall in pulmonary vascular resistance in the postnatal period, or by use of high inspired oxygen or hyperventilation, both of which should be avoided. Babies born with separated pulmonary and systemic circulations (e.g., transposition of the great arteries) are dependent on communications between the atria, ventricles, or at the level of the patent ductus arteriosus to allow adequate mixing of oxygenated and desaturated blood. This may need to be augmented at the level of the atrial connection by a balloon atrial septostomy following femoral or umbilical vein catheterization soon after birth in babies where low systemic arterial oxygen saturation of hemoglobin (usually below 70–75%) is significantly contributing to decreased systemic oxygen delivery. Preductal pulseoximetry saturations should be monitored, usually in the right hand, in order to monitor saturation of blood reaching the brain and myocardium. Cardiac Surgery and Cardiopulmonary Bypass Surgery, if required, may be in the neonatal period, or early or late childhood. The aim of surgery may be corrective or palliative, and surgery may need to be conducted on more than one occasion in a staged approach. In a significant proportion of cases, cardiopulmonary bypass (CPB) and some degree of cooling is required to allow adequate oxygenation of vital organs during surgery, which requires an empty heart and usually a period of cardiac standstill. Occasionally, a short period of low-flow CPB or of complete hypothermic circulatory arrest may be required to allow a relatively bloodless field during complex surgery on the aorta. Clearly, this is a time of high risk with potential for embolic or ischemic damage and the prospect of disturbed physiology in the postoperative period following myocardial and end-organ reperfusion. Advances in the care of newborns with CHD have meant that neonatal reparative surgery is increasingly possible. Though complex and challenging, early repair offers significant advantages. These include early elimination of cyanosis and of congestive heart failure, optimal circulation for growth and development, and reduced anatomic distortion from palliative procedures. Palliative cardiac surgery remains the only option in infants with an anatomical single ventricle (e.g., hypoplastic left heart syndrome). This usually requires a threestaged approach. Firstly, pulmonary blood flow is secured via a systemic to pulmonary arterial shunt. Later, in infants without elevated pulmonary vascular resistance and with adequate atrioventricular valve and diastolic ventricular function, a cavopulmonary anastamosis is created so that systemic venous return is directed directly into the pulmonary arteries. This is done in two stages, firstly by directing return from the superior vena cava to the pulmonary arteries via a bidirectional cavopulmonary Congestive Heart Failure (Glenn) anastamosis and later by the additional redirection of the inferior vena cava flow, either via a lateral tunnel through the atrium or via an extra-cardiac conduit, to create a complete cavopulmonary (Fontan) circulation. Rearrangement of the systemic and pulmonary circulation to operate “in series” in this way leads to correction of cyanosis. However, given the paucity of long-term outcome data, total cavopulmonary circulation remains viewed as a palliative rather than a curative procedure. Care of the postoperative cardiac surgical patient is complex and requires knowledge of the underlying anatomy and physiology and details of the surgery and intraoperative course. A progressive low cardiac output state, not attributable to any residual or undiagnosed cardiac lesion, which reaches its nadir usually by 12-h postoperatively, occurs in a significant proportion of patients [5]. This complexity is managed by mechanical ventilation and pharmacological support to optimize myocardial function, pulmonary and systemic afterload, and supportive intensive care therapy. Lesions with increased pulmonary blood flow or increased pulmonary venous pressure may predispose to increased postoperative pulmonary artery pressures and increased reactivity of the pulmonary vasculature in the postoperative period, necessitating the use of inhaled nitric oxide as a selective pulmonary vasodilator in some cases. A small number of patients require extracorporeal mechanical oxygenation (ECMO) support to allow myocardial rest and adequate time for recovery following cardiac surgery. Early postoperative extubation may be of benefit in some patients, particularly in those with cavopulmonary anastamosis, and should be considered in any patient known to have had a smooth intraoperative course and without signs of excessive bleeding, hypoxemia, or low cardiac output state in the early postoperative period. After-care Medical management usually involves diuretic therapy with or without ACE inhibitors in the weeks and months following surgery. Regular assessment for late surgical complications including wound infection, chylothorax, postcardiotomy immune pericarditis (Dressler’s syndrome), and for residual lesions is undertaken before gradual tapering of medical follow-up. In the case of more complex lesions where further operative interventions or transplant may be required, ongoing follow-up through to adulthood is mandatory and these patients should be transitioned to adult congenital heart disease programs. In addition to echocardiographic and cardiac catheter assessments, cardiac magnetic resonance imaging C may also be useful in the assessment of cardiac function in some patients. In infants following Stage 1 palliation of HLHS, significant interstage mortality may be reduced by careful monitoring of saturations and weight gain either in hospital or at home. Orthotopic heart transplantation should be considered in infants and children with severe intractable forms of CHD. Prognosis CHD is responsible for the most deaths in the first year of life of any other birth defect. While most CHD occurs as an isolated congenital malformation, CHD is more common in several genetic conditions, including Trisomy 21 (Down syndrome), Noonan syndrome, Marfan syndrome, Trisomy 13 (Patau syndrome), and DiGeorge syndrome, and prognosis depends on the type of CHD, as well as any underlying condition. Advances in perfusion practice, surgical techniques, and postoperative care have all led to overall decreased perioperative mortality. Long-term morbidity, including abnormal neurodevelopmental outcomes, particularly in patients with single ventricle physiology or following prolonged postoperative recovery has been noted and is the topic of ongoing research. References 1. 2. 3. 4. 5. 6. Hoffman JI (1990) Congenital heart disease: incidence and inheritance. Pediatr Clin North Am 37:25–43 Brickner ME, Hillis LD, Lange RA (2000) Congenital heart disease in adults: first of two parts. N Engl J Med 342:256–263 Towbin JA (2004) Molecular genetic basis of sudden cardiac death. Pediatr Clin North Am 51(5):1229–1255 Khoshnood B, De Vigan C, Vodovar V, Goujard J, Lhomme A, Bonnet D, Goffinet F (2005) Trends in prenatal diagnosis, pregnancy termination, and perinatal mortality of newborns with congenital heart disease in France, 1983–2000: a population based evaluation. Pediatrics 115(1):95–101 Wernovsky G, Wypij D, Jonas RA, Mayer JE Jr, Hanley FL, Hickey PR, Walsh AZ, Cahng AC, Castaneda AR, Newburger JW, Wessel DL (1995) Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants. Circulation 92(8):2226–2235 Nugent AW, Daubeney PE, Chondros P, Carlin JB, Cheung M, Wilkinson LC, Davis AM, Kahler SG, Chow CW, Wilkinson JL, Weintraub RG (2003) The epidemiology of childhood cardiomyopathy in Australia. N Engl J Med 348(17):1639–1646 Congestive Heart Failure ▶ Heart Failure, Biomarkers ▶ Heart Failure Syndromes, Treatment 599 C 600 C Conscious Sedation Conscious Sedation JOHN H. BURTON Department of Emergency Medicine, Carilion Clinic Virginia Tech Carilion School of Medicine, Roanoke, VA, USA Synonyms Deep sedation; Procedural sedation; Sedation Definition The phrase “conscious sedation” has historically been applied to the administration of sedative or analgesic medications for suppression of a patient’s level of consciousness in preparation for, and during, a painful or anxiety-provoking medical procedure. Conscious sedation as applied to many modern procedures is a misnomer, particularly in the intensive care unit (ICU) or emergency department (ED) setting. In these practice environments, a depth of patient relaxation and sedation well below “conscious” is frequently intended. Many providers attempt to be more descriptive in the depth of intended sedation by adding the descriptors “mild,” “moderate,” or “deep” for any encounter. Others have been proponents for the terms “procedural sedation” or “procedural sedation and analgesia” in an attempt to emphasize a depth of sedation and analgesia that will be consistent with the one best suited for the intended procedure. Regardless of the terminology used, the practice of conscious sedation is an essential component of sedation and/or analgesia for many procedural interventions. The proper use of conscious sedation will confer significant benefits to both the patient and the medical provider. For patients, relief of pain, anxiety, and amnesia to the procedure event are obvious desirable outcomes. Similarly, more relaxed and comfortable patients will translate to an improved experience for medical providers with enhanced patient safety, improved procedure success, and less angst for the pain and suffering inflicted on the patient on behalf of the medical procedure [1]. Depth of Conscious Sedation The depth of intended patient sedation and relaxation can be broadly characterized as mild, moderate, and deep levels of suppressed consciousness. These categorizations exist along a broad spectrum for the depth of patient sedation intended for the procedure. A state of general anesthesia completes the spectrum and describes a depth of sedation characterized by unresponsiveness to all stimuli and the absence of airway protective reflexes. Minimal sedation typically describes a patient with a near-baseline level of alertness. This level of sedation does not impair the ability to follow commands or respond to verbal stimuli. Under a state of minimal sedation, cardiovascular and ventilatory functions are not threatened or impaired. Moderate sedation describes a depth of consciousness characterized by many or all of the following: eyelid ptosis, slurred speech, and delayed or altered responses to verbal stimuli. Event amnesia will frequently occur under moderate sedation levels. The patient airway should be minimally threatened by apnea or ventilatory suppression under moderate sedation depths. Similarly, while the likelihood of cardiovascular embarrassment is small, monitoring of cardiovascular status is appropriate for changes in patient oxygenation, blood pressure, and heart rate. Deep sedation renders the patient level of consciousness unresponsive to most verbal commands with preservation of airway protective reflexes and noxious, painful stimuli. Event amnesia is typical of deep levels of sedation. Monitoring for deep sedation encounters should emphasize the significant potential for reduction in ventilation and cardiovascular complications including changes to heart rate, heart rhythm, and blood pressure. The potential for apnea should also prompt the consideration for more sensitive ventilation monitoring techniques, including exhaled, end-tidal carbon dioxide levels. Pre-existing Condition Minimal, moderate, and deep sedation have all been described in the medical literature for conditions that invoke pain, anxiety, and complex medical procedures that may require minimal patient movement and optimized muscle relaxation. In the ICU setting, conscious sedation should be distinguished conceptually from continuous sedation. The former would be employed toward procedures or events requiring sedation or relaxation, while the latter would imply the use of sedative agents for continuous sedation for patient comfort during periods of mechanical ventilation or to supplement ongoing medical treatment and stabilization. For example, an intubated ICU patient may be treated with a propofol infusion for continuous sedation. This patient may require a procedure, such as tube thoracostomy, that may provoke consideration of a plan for increased sedation and/or analgesia to address the pain associated with this procedure. In most other settings, including emergency or gastroenterology procedures, for example, the likelihood that the patient will be under any Conscious Sedation form of continuous sedation is much smaller and therefore, a treatment plan for conscious sedation will be initiated from a normal level of patient consciousness. Conscious Sedation Procedures Common procedures in which conscious sedation will be utilized in the ICU or emergency setting are listed in Table 1. Procedures such as electrical cardioversion or sedation for radiological imaging may be viewed as events where the addition of an analgesic agent is of limited benefit given the limited amount or complete absence of pain prior to or following the procedure. In these events, the conscious sedation plan may be simplified to emphasize a sedation strategy with minimal or no analgesic considerations. Procedures such as orthopedic fracture or dislocation reduction are typical of encounters where both patient relaxation and analgesia should be considered in the sedation plan. These patients will have analgesic requirements prior to, during, and following the treatment procedure. These patients should have a conscious sedation plan that incorporates a baseline analgesic treatment plan in addition to the planned sedation. Pre-sedation Considerations Preexisting medical illnesses should be considered in the formulation of any conscious sedation treatment plan. Acute or chronic illnesses may render a patient to be at elevated risk for adverse events during conscious sedation, Conscious Sedation. Table 1 Common procedures in the ICU or emergency setting where conscious sedation should be considered ICU Chest tube thoracostomy C specifically cardiovascular or ventilatory embarrassment. The contemplation of the use of sedation or analgesic agents should then incorporate these risks into both the decision to use conscious sedation or the selection of specific treatment agents. Conditions such as hemorrhagic shock or sepsis may render a significant degree of cardiovascular instability or risk with conscious sedation. Similarly, traumatic facial injuries, or morbid obesity may render challenges to assisted ventilation in the case of respiratory suppression. At a minimum, preparatory considerations prior to conscious sedation should include a history of present illness, past medical history, and focused physical examination directed toward airway and cardiovascular assessment. The oral intake of fluids or solids prior to sedation, NPO status, remains a subject of debate among physicians caring for conscious sedation patients [2]. More brief periods of suppressed consciousness as well as lighter depths of sedation during conscious sedation render limited analogies to the operating room patient experience and NPO requirements in that setting. There have been exceptionally few reports in the medical literature of adverse outcomes related to NPO status for conscious sedation patients. Additionally, there are many large series of patients undergoing deep sedation levels with no aspiration or ingested solids/fluids complications. These observations further support the position that the application of operative patient anesthesia principles is of limited utility to the typical conscious sedation patient. Finally, the emergent or critical nature of many procedures in the emergency or ICU setting prompts consideration of a risk/benefit paradigm for any patient requiring a medical procedure and conscious sedation. Taken in summary, the risks of aspiration or obstruction from recent solid or fluid intake must be balanced with the benefits derived from an immediate or timelier sedation intervention [3]. Abscess incision and debridement Ventriculostomy placement Central venous or arterial line placement Complex wound management, e.g., burn wound care Emergency Orthopedic fracture or dislocation reduction Complex laceration repair Abscess incision and debridement Foreign body removal Central venous line placement Electrical cardioversion Lumbar puncture Radiological imaging Application Planned Depth of Sedation and Procedure Minimal or light conscious sedation is usually performed for procedures that are less painful, particularly with the use of local anesthesia, and require light levels of patient relaxation. Typical light sedation encounters include procedures such as lumbar puncture, radiological studies, simple fracture reductions in combination with local anesthesia, and abscess incision and drainage. Agents and combinations typically utilized for light sedation include fentanyl, midazolam, and low-dose ketamine (Tables 2 and 3). Moderate and deep conscious sedation is usually performed for procedures that require greater degrees of 601 C 602 C Conscious Sedation Conscious Sedation. Table 2 Agents commonly utilized for conscious sedation Analgesia agents Conscious Sedation. Table 3 Common agents, dosing, and depth of sedation associated with each agent for patient conscious sedation Fentanyl Morphine sulfate Hydromorphone Sedation agents Repeat dosea (mg/ kg) Agent Initial dose (mg/kg) Midazolam 0.03 0.03 Titrate to desired depth Etomidate 0.15–0.20 0.1 Deep sedation only Propofol 0.5–1.0 0.5 Deep sedation only Methohexital 1.0 0.5 Deep sedation only Ketamine 0.5 Moderate and deep sedation Benzodiazepines, e.g., midazolam Barbiturates, e.g., methohexital Propofol Etomidate Ketaminea a Ketamine has both analgesic and sedation properties patient relaxation. These procedures often have greater associated levels of pain and anxiety. Common moderate or deep sedation encounters include procedures such as complex orthopedic fracture or dislocation reductions, tube thoracostomy, and more complex wound and debridement procedures including burn dressing changes or large abscess incision and drainage. Agents utilized for moderate or deep sedation include higher dose ketamine, etomidate, methohexital, and propofol as single agents or in combination with an analgesic agent (Table 3). Monitoring the depth of conscious sedation is best performed with the use and documentation of a standardized sedation assessment scale. Examples of this include the Ramsay Scale (Table 4) or the modified Aldrete-Parr Scale. Each of these scales, and other similar patient assessment tools, utilize a standard set of predicted impairment assessment in a number of body systems or categories. Given that the most clinically relevant complications associated with conscious sedation encounters are adverse respiratory events, patient depth of sedation monitoring should emphasize respiratory assessment in addition to depth of awareness. Selection of Conscious Sedation Agents With the exception of ketamine, the most substantial pharmacologic effects of sedation medications impact patient levels of consciousness with minimal to no analgesic effects [4]. Given that the majority of sedation procedures will involve pain, most conscious sedation encounters should incorporate an analgesic approach to augment the planned sedation depth. The dosing of analgesic and sedative agents should be standardized in a weight-based fashion. Selection of a specific analgesic, sedative, or combination should take 1.0 Depth of sedation a Some providers may prefer a continuous drip infusion to a repeatbolus dosing strategy Conscious Sedation. Table 4 Ramsey sedation scale Score Responsiveness 1 Patient is anxious and agitated or restless, or both 2 Patient is cooperative, oriented, and tranquil 3 Patient responds to commands only 4 Patient exhibits brisk response to light glabellar tap or loud auditory stimulus 5 Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus 6 Patient exhibits no response into consideration the patient’s prior experience with sedation as well as the desired duration of clinical affects. The use of short-acting agents such as propofol and etomidate has gained wide-spread acceptance. Briefacting sedative agents confer shorter periods of impaired levels of consciousness and subsequently less risk for adverse respiratory events. An additional benefit to shorter periods of impaired consciousness is reduced monitoring times that allow for reduced allocations of intense patient monitoring by medical staff. Conscious sedation agents are typically dosed in weight-based bolus increments in the emergency setting (Table 3). In the ICU setting, the use of continuous infusions following an initial bolus is more commonplace Continuous Renal Replacement Therapy (CRRT) given the frequent use of continuous drip infusions from these providers. Patients who require longer periods of analgesia, such as those with fractures, will benefit from strategies emphasizing longer-acting analgesic agents, such as morphine or hydromorphone, coordinated with sedative dosing. A combination of agents is a common practice for conscious sedation agent selection. The combination of midazolam and fentanyl has historically been a strategy used in many settings. Recently, the combination of ketamine and propofol (“ketofol”) has gained a degree of interest. This combination, typically with bolus dosages less than those employed with the use of propofol or ketamine alone, 0.5–0.75 mg/kg for each agent, has been argued to ameliorate the adverse risks associated with ketamine or propofol alone while also capitalizing on the benefits of each drug: a risk/benefit balance for each agent in combination. There remains a great deal of variation in the selection of sedation and dosing regimens for conscious sedation between medical providers and medical settings. Provider experience as well as institution or medical consultant preferences may substantially influence individual approaches. A great deal of research has been performed addressing comparative considerations for agent selection, dosing, and patient procedures for conscious sedation principles. Any institutional or medical provider approach toward conscious sedation should be built upon a foundation derived from the extensive findings in the medical literature. References 1. 2. 3. 4. Miner JR, Burton JH (2007) Clinical practice advisory: emergency department procedural sedation with propofol. Ann Emerg Med 50:182–187 Green SM, Roback MG, Miner JR, Burton JH, Krauss B (2007) Fasting and emergency department procedural sedation and analgesia: a consensus-based clinical practice advisory. Ann Emerg Med 49:454–461 Miner JR, Martel ML, Meyer M, Reardon R, Biros MH (2005) Procedural sedation of critically ill patients in the emergency department. Acad Emerg Med 12(2):124–128 American Society of Anesthesiologists (2002) Task force on sedation and analgesia by non-anesthesiologists: practice guidelines for sedation and analgesia by non-anesthesiologists. Anesthesiology 96:1004–1017 Consumption Coagulopathy ▶ Disseminated Intravascular Coagulation C 603 Contact Precautions A set of practices used to prevent patient-to-patient transmission of infectious agents that are spread by direct or indirect contact with the patient. Health-care workers caring for patients on contact precautions wear a gown and gloves for interactions that may involve contact with the patient or patient’s environment. In addition, patients are placed in a single room or shared room with other patients on contact precautions for the same indication. Continuous Arterio-venous Hemofiltration (CAVHF) ▶ Hemofiltration in the ICU Continuous Cardiac Output (CCO) ▶ Cardiac Output, Measurements Continuous Hemodialysis (CVVHD) ▶ Hemofiltration in the ICU Continuous Positive Airway Pressure (CPAP) ▶ Noninvasive Ventilation Continuous Renal Replacement Therapy (CRRT) ▶ Hemofiltration in the ICU C 604 C Continuous Veno-venous Hemodiafiltration (CVVHDF) Continuous Veno-venous Hemodiafiltration (CVVHDF) ▶ Hemofiltration in the ICU Recently the Acute Kidney Injury Network (AKIN) proposed a consensus definition where AKI is defined as an increase of 0.3 mg/dL or 50% or greater occurring within a 48 h time period [4]. Treatment Continuous Veno-venous Hemofiltration (CVVHF) ▶ Hemofiltration in the ICU The treatment of established CI-AKI is not different from other types of AKI and consists of prevention of hypotension and hypovolemia and stop administration of potential nephrotoxic agents. For a more detailed discussion on the treatment of AKI we refer to the specific chapters on this in this textbook. Prevention Contrast Medium-Induced Nephropathy ▶ Contrast Nephropathy Contrast Nephropathy ERIC A. J. HOSTE Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium Established risk factors for development of CI-AKI include an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, diabetes mellitus, volume depletion, nephrotoxic drugs, anemia, and hemodynamic instability [5]. ICU patients have often one or more of these risk factors, and are therefore at greater risk for development of CI-AKI. Also intra-arterial administration of radio contrast medium, high volume of contrast medium, and contrast medium with high osmolality are associated with higher risk for CI-AKI. Preventive measures for CI-AKI can be categorized into four groups: withdrawal of nephrotoxic drugs, volume expansion, pharmacologic therapies, and hemofiltration or hemodialysis. We will discuss these in detail. Withdrawal of Nephrotoxic Drugs Synonyms Contrast medium-induced nephropathy; Contrastassociated acute kidney injury; Contrast-induced nephropathy All nephrotoxic drugs should be withdrawn >24 h before contrast administration in patients at risk for CI-AKI (GFR<60 mL/min) [5]. Volume Expansion Definition Several definitions for contrast-induced acute kidney injury (CI-AKI) have been used in medical literature. CIAKI is typically defined as an increase of serum creatinine of 0.5 mg/dL or 25% or more within 2 days following contrast medium administration [3]. Multiple variations on this definition are used: some use only the absolute increase and others only the relative increase of serum creatinine, the observation period may be increased up to 5 days, and some use the more specific cut off of an absolute increase of 1 mg/dL. The European Society of Urogenital Radiology defines CI-AKI by an increase of serum creatinine of 0.5 mg/dL or 25% or greater within 3 days following intravascular administration of radio contrast medium, without an alternative etiology. Volume expansion with crystalloids at a rate of 1–1.5 mL/kg for 1–12 h before the procedure, and continued for 6 to 12 h afterwards, has an established role in reducing the risk for CI-AKI. Isotonic saline 0.9% was in one trial superior to half isotonic saline 0.45% in prevention of CI-AKI. Isotonic sodium bicarbonate (3 mL/kg/h for 1 h before the procedure and at 1 mL/kg/h for 6 h after the procedure) was superior to isotonic saline in prevention of CI-AKI, in a number of smaller studies and in meta-analyses [1]. Although, the number of patients studied, and heterogeneity of the studies, preclude a firm conclusion. Pharmacological Therapy No adjunct pharmacological therapy to date has been proven efficacious for reducing the risk for CI-AKI [5]. Contrast Nephropathy The CIN Consensus Working Panel has divided the drugs that have been evaluated into three categories based on their results [5]. Positive Results These drugs are potentially beneficial, but need further evaluation. ● Theophylline/aminophyllin These adenosine antagonists block the potent intrarenal vasoconstrictor adenosine, which also is a mediator of tubulo-glomerular feedback. A metaanalysis including seven trials and 480 patients demonstrated a significant decline in serum creatinine after contrast administration. ● Statins Retrospective data from large databases demonstrated that patients who were treated with statins had a lower incidence of CI-AKI. This can be explained because statins have beneficial effects on endothelial function, maintain nitric oxide production, and reduce oxidative stress. A prospective randomized study published after the recommendations, in 304 patients undergoing coronary angiography, could not demonstrate a beneficial effect when 80 mg atorvastatin was administered daily, 48 h before and after the contrast procedure. ● Ascorbic acid A small prospective randomized study in 231 patients undergoing cardiac catheterization demonstrated a lower incidence for patients treated with oral ascorbic acid (3 g before and two times 2 g after the procedure). ● Prostaglandin E1 Two small studies including 130 and 125 patients found that the vasodilator prostaglandin E1 and its synthetic analogue misoprostol were effective in reducing the risk for CI-AKI. Neutral ● N-acetylcysteine (NAC) Although NAC is often administered for prevention of CI-AKI, the evidence supporting its use is weak. Over 27 prospective randomized studies and meta-analyses found conflicting results regarding the potential beneficial effects of NAC on CI-AKI. The majority of studies were in patients undergoing non-coronary or coronary angiography with intra-arterial administration of contrast medium. Studies were heterogeneous as several dosing regimes were evaluated, in different cohorts, and different outcomes were assessed. C A study in volunteers suggested that the beneficial effects of NAC could be attributed to an effect on serum creatinine concentration, and not on glomerular filtration rate. However, recent data could not confirm this. ● Fenoldopam/dopamine Three small studies and one uncontrolled study suggested that renal dose dopamine could prevent CI-AKI. This could not be confirmed in a prospective randomized study. Fenoldopam, a selective dopamine-A1 receptor agonist, was beneficial in several uncontrolled studies, but not in two prospective randomized studies. ● Calcium channel blockers Several small studies evaluated the effects of amlodipine, nifedipine, nitrendipine, and felodipine on risk for CI-AKI, but found no consistent effect. ● Atrial natriuretic peptide (ANP) Two small studies could not demonstrate a beneficial effect of ANP on the occurrence of CI-AKI. Negative Effects ● Furosemide, mannitol, and dual endothelin receptor antagonist These drugs were evaluated in small studies with conflicting and negative results on prevention of CI-AKI. Hemofiltration or Hemodialysis Hemodialysis can effectively remove contrast media. However, even when administered within 1 h after contrast administration, hemodialysis was not effective in reducing the incidence of CI-AKI. The CIN Consensus Working Panel agreed that in patients with severe renal impairment (GFR <20 mL/kg/ min), hemodialysis should be planned in case CI-AKI occurs [5]. Hemofiltration was beneficial in preventing CI-AKI in two studies, when administered 4–6 h before the procedure, and continued for 18–24 h afterwards. These studies were flawed as the primary endpoint CI-AKI, defined by a 25% increase of serum creatinine, is affected by hemofiltration. Secondary endpoints, such as in-hospital and 1-year mortality, were also positively affected by the intervention. Further data are therefore needed. Evaluation/Assessment It is important to identify risk factors for CI-AKI in patients who will undergo a contrast procedure. After the procedure it is recommended to monitor serum creatinine concentration for 3–5 days in order to diagnose occurrence of CI-AKI. 605 C 606 C Contrast-Associated Acute Kidney Injury After-care The therapy for CI-AKI is similar to other forms of AKI in ICU patients, and consists of optimization of volume status, and withdrawal of nephrotoxic drugs. Further, one needs to monitor and tread for consequences of CIAKI such as hyperkalemia and other electrolyte abnormalities, volume overload, and acidosis. Contrast-Induced Nephropathy ▶ Contrast Nephropathy Conus Medullaris Syndrome Prognosis Patients who develop CI-AKI are at greater risk for inhospital mortality and 1-year mortality [3]. Levy et al. found a 5.5-fold increased risk of hospital death, even after correction for other comorbidities [2]. Risk of death is greater in patients with need for treatment with renal replacement therapy, and in patients with chronic kidney disease before the procedure. The risk for developing need for dialysis is currently estimated as <1% in patients with CI-AKI in low risk patients. Data in ICU patients are scarce; one study found that 3.5% of 486 ICU patients needed treatment with dialysis after contrast administration. Another study in 139 ICU patients found a nonsignificant higher incidence of dialysis in patients with CI-AKI (19% versus 6%, p = 0.091). CI-AKI is also associated with other adverse cardiovascular outcomes such as myocardial infarction, bypass surgery, pulmonary edema, cardiogenic shock, bleeding requiring transfusion, and vascular complications. Also, length of hospital stay is longer in patients who have CI-AKI. References 1. 2. 3. 4. 5. Hoste EA, De Waele JJ, Gevaert SA, Uchino S, Kellum JA (2010) Sodium bicarbonate for prevention of contrast-induced acute kidney injury: a systematic review and meta-analysis. Nephrol Dial Transplant 25:747–758 Levy EM, Viscoli CM, Horwitz RI (1996) The effect of acute renal failure on mortality. A cohort analysis. JAMA 275:1489–1494 McCullough PA, Adam A, Becker CR et al (2006) Epidemiology and prognostic implications of contrast-induced nephropathy. Am J Cardiol 98:5–13 Mehta RL, Kellum JA, Shah SV et al (2007) Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11:R31 Stacul F, Adam A, Becker CR et al (2006) Strategies to reduce the risk of contrast-induced nephropathy. Am J Cardiol 98:59–77 Contrast-Associated Acute Kidney Injury ▶ Contrast Nephropathy SCOTT E. BELL1, KATHRYN M. BEAUCHAMP2 1 Department of Neurosurgery, School of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA 2 Department of Neurosurgery, Denver Health Medical Center, University of Colorado School of Medicine, Denver, CO, USA Definition Conus medullaris syndrome (CMS) arises from a spectrum of clinicopathologic entities representing dysfunction of the lowest level of the spinal cord, termed the conus medullaris, which consists of the sacral segments. There is a subset of spinal cord injuries referred to as spinal cord injury syndromes, to which conus medullaris syndrome belongs, that are grouped by their respective symptomatology, including central cord syndrome, Brown-Sequard syndrome, anterior cord syndrome, posterior cord syndrome, and cauda equina syndrome. While CMS is classically associated with pathophysiologic disruption isolated to the conus medullaris, it may also be associated with a widespread spinal cord process that includes the conus medullaris, which leads to the generalized syndromic symptoms. By nature of its anatomy, this is an illness characterized by both upper motor and lower motor neuron signs and symptoms that manifest in the perineal region and lower extremities. The spinal cord ends at the level of the last thoracic to second lumbar vertebrae in a normal adult, with the remainder of the spinal canal being occupied by the cauda equina. This corresponds to the level of the thoracolumbar junction. It is an important concept to recall that the vertebral column level deviates from the spinal cord level starting in the cervical spine. A depiction of this relationship is seen in Fig. 1. In general, the spinal cord level is considered to reside roughly one to two levels above its corresponding vertebral level (at which the nerve root exits) for most of the cervical and upper thoracic spinal cord, three to four levels above for the lower thoracic and lumbar spinal cord, and five or more levels above for the sacral spinal cord. With this relationship in mind, it is to Conus Medullaris Syndrome C1 CI C2 Subarachnoid space CII C3 CIII Cervical Enlargement C4 CIV C5 CV C6 CVI C7 CVII C8 TI T1 TII T2 TIII T3 TIV C nontraumatic causes of spinal cord disease is more difficult due to its rarity and the lack of consensus and consistency in reporting. Conus medullaris syndrome as a whole is quite a rare process, with a diverse array of etiologies (Table 1). Definitive epidemiologic information about CMS is sparse. In a series of 839 patients reviewed retrospectively of spinal cord injury (SCI) rehabilitation admissions from 1992 to 2004 at an urban tertiary care center, 1.7% had CMS [1]. A European study reported an average annual incidence of conus medullaris syndrome at 1.5 per million population, and prevalence of 4.5 per 100,000 population, over the study period 1996–2004 from etiologies of all types [2]. T4 TV Etiology TVI The most common causes of CMS are reported as compression from herniated intervertebral disc, and vertebral fracture at the thoracolumbar junction [2]. The mechanisms at the root of CMS specifically, underlying these etiologies, are multimodal. The acute or primary mechanism involves ischemia and direct injury to neuropil and neuronal cells at that location by compression, traction, contusion, and/or laceration. The secondary mechanism involves a complex cascade of chemical signals and inflammatory mediators, ion conduction and matrix derangements, cellular respiratory insults, and cytotoxic neurotransmitters that results in the propagation of irreversible injury. Other etiologies of conus medullaris syndrome includes any lesion that disrupts the grey and/or white matter of the spinal cord at that level. Such lesions may include infiltrative, compressive, demyelinating, ischemic, or inflammatory processes produced by tumors, trauma, infections, or autoimmune and metabolic diseases. Varying combinations of primary and secondary mechanisms of spinal cord injury are responsible for the spectrum of conus medullaris syndrome seen in all etiologies of this disease. Tumors of the spine cause damage to the conus medullaris by compressive and infiltrative mechanisms. The most common intramedullary tumor of the conus medullaris is ependymoma [3]. They develop from the ependymal cells lining the filum terminale, and less often the ependymal cells of the ventriculus terminalis. This structure is an ependymal-lined termination of the central canal, residing at the transition from conus medullaris to filum terminale. Less frequently encountered intramedullary tumors at the conus include lowgrade astrocytomas and rarely glioblastoma multiforme. This later form has been shown to occur at the conus as either primary occurrence or as identified in holocord disease. The most common extramedullary tumors at the conus medullaris are peripheral nerve sheath tumors, T5 T6 TVII T7 TVIII T8 TIX T9 TX T10 TXI T11 Lumbar Enlargement TXII T12 LI Sacral Cord L1 LII L2 Cauda Equina LIII L3 LIV Filum Terminale (pial part) L4 LV L5 End of dural/ subarachnoid space SI SII S1 SIII S2 SIV S3 SV S4 S5 Cu Filum Terminale (dural part) Conus Medullaris Syndrome. Figure 1 Relationship of spinal cord and nerve roots to vertebral level (Adapted from Drake et al. 2008) say that a conus medullaris lesion occurs at the vertebral level approximately L1, but affects the lower sacral segments of the spinal cord. Spinal cord injury occurs at a reported annual incidence of 40 per million population, with 11,000 new cases each year in the United States. Epidemiology of 607 C 608 C Conus Medullaris Syndrome Conus Medullaris Syndrome. Table 1 Reported etiologies of conus medullaris syndrome Inflammatory Tumor Infection Non-tumor Trauma Transverse myelitis Ependymoma Staphylococcus Sarcoidosis HNP Longitudinal myelitis Astrocytoma Tuberculosis Cavernoma Burst Neuromyelitis optica GBM Schistosomiasis AVF/AVM Fracture Lupus erythematosus Ganglioglioma Cysticercosis Amyloid angiopathy Fracture dislocation Ventriculus terminus cyst Spinal stenosis Parainfectious myelitis Meningioma PNET Teratoma Hemangioblastoma Tethered cord Metastases Infarct Chordoma Dermoid cyst Peripheral nerve sheath tumor Epidermoid cyst GBM glioblastoma multiforme, PNET primitive neuroectodermal tumor, AVF arteriovenous fistula, AVM arteriovenous malformation, HNP herniated nucleus pulposus meningioma, and metastases. In contrast to the brain, intramedullary metastases occur much less commonly, likely owing to the difference in blood flow between the brain and spine [3]. Epidermoid and dermoid cysts may be congenital or acquired, and can occur at the conus medullaris. They arise from retained integument within the spinal canal, with or without a sinus tract to the surface. These lesions are due to one of two mechanisms [3]. They may be associated with developmental malformative rests, as well as being acquired by lumbar puncture or after surgery to close myelomeningocele early in life. They can be the source of recurrent infections, and may expand to compress the conus, or cause local vascular derangement producing CMS. Teratomas are congenital, and likewise arise from rests of misplaced tissue. There is debate whether these arise from a migratory problem during development, or from a dysembryogenic-type mechanism. At the conus, they are frequently associated with dysembryogenic defects such as split cord and myelomeningocele. Inflammatory diseases are rarely associated with conus medullaris syndrome, precluding analysis as a series. However, reports of inflammatory demyelinating diseases that are either isolated to the conus or involving the conus in holocord-type fashion are reported as case reports in the literature. The most common entities showing CMS symptoms include transverse myelitis, NMO, and longitudinal myelitis. Their occurrences have been described in cases where the mechanism is likely autoimmune response after systemic infection or vaccine [4]. Likewise, other systemic inflammatory diseases, such as lupus erythematosus, have been identified in cases where initial presentation of the disease was by way of CMS [5]. Thus far, due to the rarity of these entities, no known specific pathophysiologic process has been described for these causes of CMS. While tethered cord syndrome is considered as a distinct entity, it may be considered within the spectrum of CMS. This process exerts its deleterious effect on the medullary conus by placing tension on the spinal vessels, and cord itself. This ultimately leads to ischemia by a variety of pathophysiologic mechanisms. One such mechanism of dysfunction as a result of tethered cord includes metabolic derangements leading to increased reduction states of certain oxidase systems in the mitochondria of nerve cells, which appears to be related to ischemia in this area. Mild-to-moderate redox derangements have been reversed with surgical untethering; however, severe cases are more refractory. Indeed, there have been reports of conus medullaris syndrome after spinal meningitis. Other infectious processes that have been reported affecting the conus medullaris include epidural or intramedullary abscesses from staphylococcus, tuberculosis, as well as schistosomiasis and neurocystercircosis. It is generally accepted that these infections seed via hematogenous route through the valveless system of vascular plexuses around the thoracolumbar junction, or by local phlegmon formation. Holocord processes may present with conus medullaris syndrome signs and symptoms, in conjunction with other neurologic deficits related to its associated spinal cord pathophysiology. The term “holocord” is used to define diffuse Conus Medullaris Syndrome C 609 Conus Medullaris Syndrome. Table 2 Conus medullaris syndrome vs cauda equina syndrome Conus medullaris syndrome Cauda Equina syndrome Presentation Sudden (inflammatory lesions), insidious (tumors), bilateral Acute (trauma), gradual (stenosis), may be unilateral Reflexes Hyperreflexia; knee jerk preserved, ankle jerk affected Hyporeflexia; knee jerk and ankle jerk both affected Radicular pain Less severe More severe Low back pain Local low back pain only; rarely radiation to perineum Low back pain with dermatomal radiation Sensory Perianal localization to sensory disturbance; Stereotypic “saddle anesthesia;” asymmetric and symptoms/signs symmetric and bilateral; sensory dissociation present unilateral disturbance possible; no sensory dissociation; possible dermatomal sensory disturbances possible with parasthesias Motor strength Usually symmetric; spastic paraparesis, less pronounced; fasciculations possible Asymmetric and unilateral motor weakness possible; areflexic paraparesis; atrophy common Impotence Frequent Less frequent; erectile dysfunction including inability to maintain erection, inability to ejaculate Sphincter dysfunction Urinary retention and atonic anal sphincter causes overflow incontinence; presents early Urinary retention; presents late Source: Adapted from Dawodu et al. (2009) involvement of multiple, or all, regions of the spinal cord in a disease process. This has been seen in as diverse an array of pathologies as there are focal disruptions of the conus itself. Some of the more common holocord processes include infiltrative tumors with widespread dissemination; syringomyelia from compressive pathologies; and neuromyelitis optica, which shows “longitudinal myelitis” type imaging and clinical findings. Another etiology worth mention is that of ischemic injury or infarction of the conus medullaris. This occurs through a variety of mechanisms, and is thought to represent approximately 1% of stroke cases. Embolism has been described from sickle cell anemia, epidural steroid injection, antiphospholipid antibodies, and abdominal surgical procedures. Other mechanisms include vascular malformations producing a blood flow “steal” phenomenon whereby blood flow bypasses the arteriole and capillary level by arteriovenous shunting. Clinical Presentation The symptoms of conus medullaris syndrome may present acutely or insidiously, depending upon the etiology. These symptoms will show mixed upper motor and lower motor neuron signs of the perineum and distal lower extremities, with an emphasis on UMN. Lower motor neuron deficits are due to the presence of lumbar nerve roots present within the thecal sac prior to exit at their respective vertebral level. Due to the anatomic relationship between the conus medullaris and the cauda equina, CMS may be easily confused with cauda equina syndrome to the complacent observer. One must take careful measure to distinguish these disease processes during the evaluation of bowel and bladder, and lower extremity dysfunction. Both syndromes produce weakness and sensory dysfunction of the saddle region as well as variable parts of the lower extremities. Some distinguishing characteristics are outlined in Table 2 . Local back pain, if present, is typically an early symptom, followed by bowel and bladder retention. The pain will be more aching in nature, rather than the sharp, sudden pain associated with cauda equina syndrome. Motor dysfunction is typically a late sign in conus medullaris syndrome. A common sign of severe spinal cord dysfunction includes diminished or absent bulbocavernosus and anal sphincter reflexes. This is likewise represented in conus medullaris syndrome. Once distinguished from the differentials, attention can be turned to narrowing the list of possible etiologies of the problem. The acuity of onset and history lends to the distinction between surgical lesions and medical lesions. Tumors, vascular malformations, and other surgically remediable lesions tend to present with a more insidious onset. Exceptions to this are those acute processes, such as injury, visibly expansile lesions, hemorrhages, etc., which may require immediate decompression to save neural tissue. Otherwise, acute onset symptomatology tends to occur in those nonsurgical processes, such as autoimmune and inflammatory etiologies, which are more amenable to medical treatments. C 610 C Conus Medullaris Syndrome Imaging studies are an important adjunct for any diagnostic workup. Of particular importance will be an MRI with and without gadolinium of the entire spine to examine the neural axis for findings. Cystic lesions will be isointense with CSF on both T1Wand T2W images. Tumors may show rim-enhancement or varying degrees of homogeneous or heterogeneous lesion enhancement, depending upon the type of tumor. Inflammatory or demyelinating processes may show rim-enhancement as well. The distinguishing characteristic is that tumors typically have an expansile quality identifiable at the conus, while inflammatory processes usually do not. However, this must be taken in the context of the clinical picture. In the absence of acute symptoms and an expansile lesion, tumor is more likely; whereas acute symptoms and an expansile mass may be a harbinger for hemorrhage, for example. Computed tomography of the spine for bony involvement is important for surgical planning and prognosticating, but would not supplant the use of MRI. The diagnostic value of a contrastenhancing MRI outweighs that of CT scan, and would preclude its usefulness in the later. Electrophysiologic studies, such as electromyography and nerve conduction velocities, can be useful in distinguishing central from peripheral nervous system processes of duration longer than 2–4 weeks. They are useless in providing information on the nature of symptoms of shorter duration due to the pathophysiology underlying acute denervation, demyelination, and neuromuscular conduction defects. Treatment Treatment for conus medullaris syndrome varies based on etiology. As previously mentioned, discrete lesions within the conus identifiable on imaging should be approached with microsurgical technique for biopsy, debulking, and rarely radical resection if curable etiology is known. If traumatic injuries are present with conus medullaris compression, decompression and stabilization at the earliest possible juncture in the patient’s acute stages of illness has been argued to be important for optimal convalescence. When to operate under these circumstances depends upon many factors, including hemodynamic instability and associated injuries of a more critical nature. The debate of when spinal cord injuries should be operated has led to much discord in the surgical literature of the traumatized spine. Whether due to a trauma or nontraumatic causes, the rationale for treading lightly in this region of the spinal cord lies in the functional forgiveness of the location. Once definitively injured, those neuronal elements responsible for bowel, bladder, and sexual function rarely recover. This is directly opposed to those elements at other locations in the spinal cord responsible for somatic sensory and motor function, which carry a good prognosis with rehabilitation, after incomplete injury. However, there are circumstances, as in the case of ependymoma, where gross total resection will likely lead to cure. In these cases, it is imperative to use meticulous surgical technique in order to minimize the potential for permanent disability. If it is determined that a nonsurgical lesion is present, the medical treatment depends upon the nature of the lesion. If infection is suspected, antibiotic therapy is initiated only after an organism is identified, either through blood cultures or image-guided aspiration. Then dual agent, IV antibiotics must be initiated for long-term therapy. This treatment for intramedullary and epidural infections can be very successful. In those refractory cases, or cases of acute worsening, surgical debridement may be necessary in addition. If an inflammatory process is suspected, high-dose steroid therapy is the gold standard. Multiple cases of inflammatory conus medullaris syndrome have been shown to be quickly responsive to these treatments, sometimes leading to complete remission of symptoms. More frequently, partial recovery occurs, with gradual improvement to only some disability in weeks to months. In some cases, it is useful or necessary to synergize with other immune modulators, such as IV-IG, cyclophosphamide, and azathioprine. Prognosis Often the prognosis for conus medullaris syndrome is more related to the etiology than to the syndrome itself. If the underlying cause is a malignant process, this is far and away the more decisive factor in prognostication than the presence of CMS. However, if CMS is due to a lesion affecting the conus in isolation, then prognosis is related to the degree of neuronal tissue damage. Frequently, with today’s techniques of intensive rehabilitation and targeted medical therapy, lesions isolated to the conus medullaris causing CMS will improve to acceptable functional levels, if not full recovery. In rare cases, isolated CMS leads to permanent paraplegia and pelvic sphincter dysfunction. References 1. 2. 3. McKinley W, Santos K, Meade M, Brooke K (2007) Incidence and outcomes of spinal cord injury clinical syndromes. J Spinal Cord Med 30:215–224 Podnar S (2007) Epidemiology of cauda equina and conus medullaris lesions. Muscle Nerve 35:529–531 Ebner FH, Roser F, Acioly MA, Schoeber W, Tatagiba M (2009) Intramedullary lesions of the conus medullaris: differential diagnosis and surgical management. Neurosurg Rev 32:287–301 Convective Clearance 4. 5. Pradhan S, Gupta RK, Kapoor R, Shashank S, Kathuria MK (1998) Parainfectious conus myelitis. J Neurol Sci 161:156–162 Katramados AM, Rabah R, Adams MD, Huq AH, Mitsias PD (2008) Longitudinal myelitis, aseptic meningitis, and conus medullaris infarction as presenting manifestations of pediatric systemic lupus erythematosus. Lupus 17:332–336 Convection The physical mechanism by which a solute is dragged across a semipermeable membrane in association with ultrafiltered plasma water. This water and solute shift is secondary to a pressure gradient across the membrane. Convective Clearance ZHONGPING HUANG1, WILLIAM R. CLARK2,3, CLAUDIO RONCO4 1 Department of Mechanical Engineering, Widener University, Chester, PA, USA 2 Gambro Renal Products, Lakewood, CO, USA 3 Nephrology Division, Indiana University School of Medicine, Indianapolis, IN, USA 4 Department of Nephrology, St. Bortolo Hospital, Vicenza, Italy C with HD. However, ▶ clearance of larger molecules is limited due to HD’s primarily diffusive nature. In clinical practice, HD therapy prescription is driven largely by factors influencing urea clearance. On the other hand, convective modalities, namely, ▶ hemofiltration and hemodiafiltration, are capable of removing solutes over a wider MW array than can HD. In AKI, these therapies typically are provided on an extended basis as continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF), being part of the CRRT spectrum. In a study employing CVVH, Ronco and colleagues [1] reported a direct relationship between daily ultrafiltrate volume and survival in critically ill AKI patients. A normalized ultrafiltration rate of 35 mL/kg/h or more (on average) was associated with a mortality of approximately 45% while a more standard ultrafiltrate rate (mean, 20 mL/kg/h) was associated with a mortality of approximately 65%. Although subsequent studies in which convection has contributed relatively less to total solute clearance have produced mixed results [2], the Ronco study remains the “gold standard” with respect to convective solute removal in AKI. This chapter provides a review of the determinants of convective solute removal. This is followed by an overview of the manner in which CVVH and CVVHDF are applied clinically. Application Convective Clearance Synonyms Solvent drag; Ultrafiltration Definition The mechanism of ▶ convection may be described as solvent drag: if a pressure gradient exists between the two sides of a semipermeable (porous) membrane, when the molecular dimensions of a solute are such that passage through the membrane is possible, the solute is swept (“dragged”) across the membrane in association with ultrafiltered plasma water. Pre-existing Condition Although conventional hemodialysis (HD) remains the most commonly used treatment modality for the management of patients with acute kidney injury (AKI), continuous renal replacement therapy (CRRT) is used increasingly in this setting. The removal of low-molecular weight (MW) nitrogenous waste products is very effective The determinants of convective clearance differ significantly from those of diffusion, which is primarily a concentration gradient-driven process. On the other hand, convective solute removal is determined primarily by the sieving properties of the filter membrane used and the ultrafiltration rate. The mechanism by which convection occurs is termed solvent drag. If the molecular dimensions of a solute are such that transmembrane passage to some extent occurs, the solute is swept (“dragged”) across the membrane in association with ultrafiltered plasma water. Thus, the rate of convective solute removal can be modified either by changes in the rate of solvent (plasma water) flow or by changes in the mean effective pore size of the membrane. As discussed below, the blood concentration of a particular solute is an important determinant of its convective removal rate. Both the water and solute permeability of an ultrafiltration membrane are influenced by the phenomena of secondary membrane formation and concentration 611 C 612 C Convective Clearance polarization. The exposure of an artificial surface to plasma results in the nonspecific, instantaneous adsorption of a layer of proteins, the composition of which generally reflects that of the plasma itself. This layer of proteins, by serving as an additional resistance to mass transfer, effectively reduces both the water and solute permeability of an extracorporeal membrane. Evidence of this is found in comparisons of solute sieving coefficients determined before and after exposure of a membrane to plasma or other protein-containing solution. Although concentration polarization primarily pertains to plasma proteins, it is distinct from secondary membrane formation. Concentration polarization specifically relates to ultrafiltration-based processes and applies to the kinetic behavior of an individual solute. Accumulation of a solute that is predominantly or completely rejected by a membrane used for ultrafiltration of plasma occurs at the blood compartment membrane surface. This surface accumulation causes the solute concentration just adjacent to the membrane surface (i.e., the submembranous concentration) to be higher than the bulk (plasma) concentration. By definition, concentration polarization is applicable in clinical situations in which relatively high ultrafiltration rates are used. Conditions that promote the process are high ultrafiltration rate (high rate of convective transport), low blood flow rate (low shear rate or membrane “sweeping” effect), and the use of ▶ post-dilution (rather than ▶ pre-dilution) replacement fluids (increased local solute concentrations). Post-dilution CRRT The location of replacement fluid delivery in the extracorporeal circuit during CRRT has a significant impact on solute removal and therapy requirements. (For the purpose of the rest of this chapter, CRRT refers either to CVVH or CVVHDF.) Replacement fluid can be delivered to the arterial blood line prior to the hemofilter (predilution mode) or to the venous line after the hemofilter (post-dilution mode). In post-dilution CRRT, the relationship between solute clearance and ultrafiltration rate is relatively straightforward. In this situation, solute clearance is determined primarily by and related directly to the solute’s sieving coefficient and the ultrafiltration rate. (Sieving coefficient is defined as the ratio of the solute concentration in the filtrate to the simultaneous plasma concentration.) For a given solute, the extent to which it partitions from the plasma water into the red blood cell mass and the rate at which it is transported across red blood cell membranes also influences clearance. For example, the volume of distribution of both urea and creatinine includes the red blood cell water. However, while urea movement across red blood cell membranes is very fast, the movement of creatinine is significantly less rapid. Furthermore, red blood cell membranes are completely impermeable to many uremic toxins. A prominent example of this is the low MW protein toxin class, for which the volume of distribution is the extracellular fluid. These observations lead to the obvious conclusion that hematocrit also influences solute clearance in CRRT. Finally, through its effect on secondary membrane formation and concentration polarization (see above), plasma total protein concentration is also a determinant of solute clearance in CRRT. For a given volume of replacement fluid over the entire MW spectrum of uremic toxins, post-dilution CRRT provides higher solute clearance than does pre-dilution CRRT. As discussed below, the relative inefficiency of the latter mode is related to the dilution-related reduction in solute concentrations, which decreases the driving force for convective mass transfer. Despite its superior efficiency with respect to replacement fluid utilization, post-dilution CRRT is limited inherently by the attainable blood flow rate. More specifically, the ratio of the ultrafiltration rate to the plasma flow rate delivered to the filter, termed the filtration fraction, is the limiting factor. In general, a maximal filtration fraction of approximately 25% usually guides prescription in post-dilution CRRT. At filtration fractions beyond these values, concentration polarization and secondary membrane effects become prominent and may impair hemofilter performance. The blood flow limitations imposed by the use of temporary catheters for CRRT accentuate the filtration fraction-related constraints on maximally attainable ultrafiltration rate in the post-dilution mode. Therefore, the ultrafiltrate volumes shown by Ronco and colleagues to improve survival can usually be achieved only in the predilution mode. As discussed below, efficient utilization of replacement fluid in acute pre-dilution CRRT is an important consideration. Pre-dilution HF From a mass transfer perspective, the use of pre-dilution has several potential advantages over post-dilution. First, both hematocrit and blood total protein concentration are reduced significantly prior to the entry of blood into the hemofilter. This effective reduction in the red cell and protein content of the blood attenuates the secondary membrane and concentration polarization phenomena described above, resulting in improved mass transfer. Pre-dilution also favorably impacts mass transfer due to augmented flow in the blood compartment, because Convective Clearance pre-filter mixing of blood and replacement fluid occurs. This achieves a relatively high membrane shear rate, which also reduces solute-membrane interactions. Finally, pre-dilution may also enhance mass transfer for some compounds by creating concentration gradients that induce solute movement out of red blood cells. The above mass transfer benefits must be weighed against the predictable dilution-induced reduction in plasma solute concentrations, one of the driving forces for convective solute removal. The extent to which this reduction occurs is determined mainly by the ratio of the replacement fluid rate to the blood flow rate. Indeed, a frequently overlooked consideration is the important influence of blood flow rate on solute clearance. For small solutes, which are distributed in the blood water (BW) component within the blood passing through the hemofilter, the operative clearance equation in predilution CRRT is: K ¼ QF
S
½Q BW =ðQ BW þ QS ފ ð1Þ where K is solute clearance, QBW is blood water flow rate, QF is ultrafiltration rate, S is sieving coefficient, and QS is the substitution (replacement) fluid rate. At a given QF value, pre-dilution CVVH is always less efficient than post-dilution CVVH with respect to fluid utilization, as discussed above. A sieving coefficient of 1.0 implies equivalence of blood water and ultrafiltrate concentrations, resulting in small solute clearances that are effectively C equal to QF in post-dilution CVVH. As Eq. 1 indicates, the larger QS is relative to QBW, the smaller is the entire fraction represented by the third term on the right-hand side. In turn, the smaller is this term, the greater is the loss of efficiency (relative to post-dilution) due to dilution. Since employing a relatively low QS is not an option in high-dose CVVH due to the direct relationship that exists between QF and QS, attention needs to be focused on achieving blood flow rates that are significantly higher than what have been used traditionally in CRRT (i.e., 150 mL/min or less). In fact, widespread attainment of doses consistent with the intermediate and high-dose arms in the study performed by Ronco and colleagues (35–45 mL/h/kg) cannot occur unless blood flow rates of approximately 250 mL/min or more become routine in pre-dilution CVVH. Evidence supporting the critical importance of QB in pre-dilution CVVH appears in Fig. 1 [3]. For this singlepool modeling analysis, a dose equivalent to 35 mL/h/kg in post-dilution is targeted. In addition, a filter operation of 20 h per day is assumed to account for differences in prescribed versus delivered therapy time. For patients of varying body weight, the substitution fluid requirements to attain the above dose are shown as a function of QB. For low blood flow rates (= 150 mL/min), these data suggest that substitution fluid rates required to achieve this dose are impractically high in the majority of patients (>70 kg) due to a “chasing the tail” phenomenon. To achieve the 200 Replacement fluid flow (ml/min) 180 160 140 120 Patient Size 100 100 kg 80 85 kg 70 kg 60 55 kg 40 40 kg 20 0 100 150 200 250 300 Blood flow (ml/min) 350 400 Convective Clearance. Figure 1 Substitution fluid requirements as a function of blood flow rate in pre-dilution CVVH (Reprinted from [3]. With permission from Elsevier) 613 C C Corlopam® dose target, a high ultrafiltration rate is required. However, the concomitant requirement of a similarly high substitution fluid rate has a relatively substantial dilutive effect on solute concentrations at low QB. On the other hand, for QB values greater than 250 mL/min, the dilutive effect of the substitution fluid is attenuated significantly and with the resultant improvement in fluid efficiency, the target dose can be delivered practically to a broad range of patients. The operating principle of CVVHDF is that total clearance can be augmented by combining diffusion and convection. Due to the relatively low flow rates used for these therapies, changes in solute concentrations within the filter are also relatively small. This allows total solute clearance to be estimated by simply adding the diffusive and convective components. In other words, no interaction between the two mass transfer processes occurs. 50 Clearance (mL/min) 614 Urea Creatinine Vancomycin Inulin 40 30 20 10 20 40 Ultrafiltration rate (mL/min) 60 Convective Clearance. Figure 2 Solute clearance (mL/min) as a function of ultrafiltration rate (mL/min) in pre-dilution CVVH (Reprinted from [4]. With permission from Elsevier) Practical Considerations At least until recently, the ultrafiltration rate (QF) in CVVH has typically been in the 1–2 L/h range. However, in response to outcome data published by Ronco and colleagues, prescription of significantly higher QF values is occurring. In post-dilution CVVH, the mode employed in the Ronco study, the relationship between solute clearance and QF is quite straightforward, as mentioned previously. For reasons also described above, the relationship between clearance and QF may not be as predictable in pre-dilution, relative to the case of post-dilution. Consequently, the claim that QF is a dose surrogate in predilution CVVH needs to be demonstrated. To this end, Huang and colleagues have investigated the effect of QF on solute removal parameters in pre-dilution CVVH [4]. For a blood flow rate of 200 mL/min, removal parameters were measured at QF values of 20, 40, and 60 mL/min, corresponding to 17, 34, and 51 mL/h/kg for a 70 kg patient. These parameters are measured for solutes of varying MW. The relationship between solute clearance and QF for urea, creatinine, vancomycin, and inulin appears in Fig. 2. Overall, these data are consistent with a convective therapy for two reasons. First, for each solute, the clearance-QF relationship is linear, confirming a direct relationship between these two parameters. Second, for a given QF over the solute MW range investigated, clearance is not strongly dependent on molecular weight, at least in comparison to hemodialysis. Specifically, very little difference in clearance is observed between the two small solutes and between the two middle molecule surrogates as a function of QF. On the other hand, reflecting its diffusive basis, HD is associated with much larger differences in clearance over the same MW range. The authors concluded that, because an orderly relationship exists between QF and solute clearance, QF is a reasonable dose surrogate in pre-dilution CVVH, as has been suggested for post-dilution CVVH and for CVVHDF. Overall, these data seem to validate the use of effluent-based dosing, which has been employed in two recent international trials evaluating the relationship between CRRT dose and outcome [5]. References 1. 2. 3. 4. 5. Ronco C, Bellomo R, Hommel P, Brendolan A, Dan M, Piccinni P, LaGreca G (2000) Effects of different doses in continuous veno-venous hemofiltration on outcomes in acute renal failure: a prospective, randomized trial. Lancet 355:26–30 Saudan P, Niederberger M, De Seigneux S et al (2006) Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure. Kidney Int 70:1312–1317 Clark WR, Turk JE, Kraus MA, Gao D (2003) Dose determinants in continuous renal replacement therapy. Artif Organs 27:815–820 Huang ZP, Letteri JJ, Clark WR, Zhang W, Gao D, Ronco C (2007) Ultrafiltration rate as a dose surrogate in pre-dilution hemofiltration. Int J Artif Organs 30:124–132 Huang Z, Letteri JJ, Clark WR, Ronco C (2008) Operational characteristics of continuous renal replacement therapy modalities used for critically ill patients with acute kidney injury. Int J Artif Organs 31:525–534 Corlopam® ▶ Fenoldopam Coronary Computerized Tomographic Angiography Coronary Computerized Tomographic Angiography JUDD E. HOLLANDER1, HAROLD LITT2 1 Department of Emergency Medicine, University of Pennsylvania, Philadelphia, PA, USA 2 Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA Synonyms Coronary CTA; CT coronary angiography Definition A computed tomography examination of the heart acquired with ECG-synchronization during the arterial phase of intravenous contrast enhancement designed to visualize native coronary arteries and/or bypass grafts. Pre-existing Condition Coronary Artery Disease Coronary CTA is primarily used to evaluate the presence or absence of coronary artery disease. It has a high degree of diagnostic accuracy when compared to cardiac catheterization as the criterion standard. In a meta-analysis of 2,515 patients from 41 studies, the subset imaged on a 64slice scanner had a per patient sensitivity of 98% with a specificity of 92% for detection of significant coronary artery disease [1]. Newer generation scanners have even greater diagnostic performance. Potential Acute Coronary Syndrome Of the nearly eight million patients presenting annually to US emergency departments for evaluation of chest pain, 80–85% are not ultimately found to have a cardiac cause for their symptoms. However, given the prevalence and clinical significance of coronary artery disease, excluding a cardiac cause of chest pain remains a challenging clinical problem and often mandates extensive testing. Although clinical algorithms can successfully risk stratify patients, they have not typically been considered useful in identifying the group of patients who can be discharged safely from the emergency department without requiring an inpatient evaluation. It is well established that patients without coronary artery disease are at very low risk for adverse cardiovascular events, even when they have symptoms that would otherwise be consistent with a potential acute coronary C syndrome. Recent cardiac catheterization with normal or minimally diseased vessels is known to be useful to “rule out” an acute coronary syndrome in such patients. Coronary CTA, as a noninvasive surrogate for catheterization, can be used to risk stratify patients with respect to coronary artery disease and subsequently ACS immediately after onset of symptoms, thus avoiding hospitalization. Application Coronary CTA has several promising clinical applications at the present time, including: (1) identifying patients who present with a potential acute coronary syndrome (often in the ED) who may safely be discharged; (2) to evaluate patients for coronary artery disease, either as a first test or after indeterminate or suspected false positive stress test, avoiding unnecessary invasive cardiac catheterization; and (3) to evaluate stent or bypass graft patency and location in patients with symptoms after percutaneous coronary intervention (PCI) or bypass graft surgery (CABG). Coronary CTA to “Rule Out” Acute Coronary Syndrome Coronary CTA has high diagnostic accuracy (Fig. 1). Janne d’Othee et al. [1] found a sensitivity of 98% and specificity of 92% relative to cardiac catheterization using 64 slice scanners. Based upon this high diagnostic accuracy, centers with experience in coronary CTA have developed clinical pathways that allow for rapid disposition of patients who present with potential acute coronary syndromes found not to have coronary artery disease. This strategy is based upon the observation noted above that patients without coronary disease at cardiac catheterization are considered to be at low risk for adverse cardiovascular events. Coronary CTA performs at least as well as myocardial perfusion imaging in identifying patients at low risk for cardiovascular events. Observational studies of symptomatic patients presenting to the ED have found that patients with normal coronary CTA results are at low risk for adverse events over varying time periods of up to one year. Many small studies (35–103 subjects) have followed patients up to 15 months and have uniformly found that low- to intermediate-risk patients without coronary disease do well during this time period. One study of 568 patients in which coronary CTA was used for clinical decision making demonstrated that patients discharged from the ED following a negative study were at very low risk of 30-day cardiovascular events [2]. In a group of 481 patients with a TIMI score of less than or equal to two without a stenosis of 50% or more who were followed for 615 C 616 C Coronary Computerized Tomographic Angiography a b Coronary Computerized Tomographic Angiography. Figure 1 Forty-three-year-old male who presented to the ED with chest pain who was found to have an 80% stenosis in the proximal LAD. (a) CCTA demonstrates that the lesion is caused by noncalcified plaque and (b) corresponding catheter angiography performed prior to stenting lesion up to 1 year, there were no patients who had definite cardiovascular events [3]. A coronary CTA based strategy to evaluate low- to intermediate-risk patients in the ED is cost effective. Chang et al. [4] found that immediate coronary CTA was more cost effective in the short term and was associated with a shorter length of stay than observation unit management with coronary CTA, observation unit management with stress test and admission with hospitalist directed care in a cohort of patients similar to this study. Short term benefits occur due to the reduced length of stay and lower cost of coronary CTA relative to single photon emission computed tomography (SPECT) imaging. Coronary CTA has also been associated with reduced utilization of coronary angiography, reduced revisit and readmission rate in other studies. Clinical Utility to Diagnose or “Rule Out” Coronary Artery Disease Given the high diagnostic accuracy of coronary CTA compared to cardiac catheterization, several groups have evaluated whether coronary CTA can reduce equivocal test results from stress nuclear imaging as well as the likelihood of receiving an invasive diagnostic procedure like cardiac catheterization. Weustink et al. [5] compared the accuracy and clinical utility of stress testing and coronary CTA for identifying patients who require invasive coronary angiography (cardiac catheterization). They found that stress testing was not as accurate as coronary CTA. In low-risk patients (<20% pretest probability of disease), a negative stress test or a negative coronary CTA confirmed no need for invasive angiography. On the other hand, a positive stress test only yielded a positive predictive value of 50%, meaning half the tests were false positive. In patients with an intermediate (20–80%) pretest probability of disease, a positive coronary CTA predicted need for invasive angiography (93% post-test probability of disease) and a negative result confirmed lack of need for further testing (<1% post test probability). Population-based data from Canada has found that the rate of normal invasive coronary angiograms was relatively reduced by 15% (absolute reduction of 5%) in an institution that implemented coronary CTA. Thus, it appears that use of coronary CTA can reduce confusion from false positive and false negative stress tests and lead to more appropriate use of invasive coronary angiography. Evaluation of Symptomatic Patients after PCI or CABG Surgery In patients who have previously undergone revascularization, recurrent chest pain may be caused by a variety of factors including progression of native vessel disease, stent or bypass graft stenosis or occlusion, and sternotomy or pericardiotomy complications (Fig. 2). For those patients in whom the chest pain is not clearly anginal, coronary CT may allow discrimination among these conditions. If repeat sternotomy is contemplated, whether for repeat CABG, valve replacement, or other reason, CT can Coronary Computerized Tomographic Angiography C 617 C a b Coronary Computerized Tomographic Angiography. Figure 2 Seventy-two-year-old male with recurrent chest pain one year after PCI. (a) CCTA shows patent stent in the circumflex artery, but progression of disease in the LAD (b), with up to 70% stenosis caused by calcified and non-calcified plaque demonstrate the course and position of bypass grafts relative to the sternum, decreasing operative complications. Coronary CT can also identify the course of the internal mammary arteries and location of target vessels for minimally invasive “keyhole” CABG surgery. Additional Uses Selection for CT coronary arteriography may also include patients with unexplained or atypical chest pain when an aberrant origin of the coronary artery is considered possible; concerns such as pulmonary embolism or aortic dissection; evaluation of an ischemic etiology for a newly diagnosed cardiomyopathy and/or heart failure; preoperative or preprocedural evaluation of the coronary arteries, cardiac structures, and thoracic anatomy; and evaluation of cardiac and/or coronary artery anomalies. Indications in patients who have previously undergone CABG and/or percutaneous coronary intervention (PCI) include patients with new or recurrent symptoms of chest pain to confirm graft/stent patency or detect graft/ stent stenoses or other complications; and for patients who are scheduled for additional cardiac surgery (e.g., aortic valve replacement or bypass graft revision) when preoperative definition of anatomic detail, including the bypass grafts, is critical. Difficulties with Interpretation provides information regarding anatomy. Anatomical abnormalities will not always be the explanation for clinical complaints. In some patients, a “noncritical” stenosis of 60% might be impeding flow to explain the symptoms while in another patient, a typically “critical” stenosis of 90% may not be causing the symptoms. In some situations, a functional test will be required to determine whether the anatomical abnormality explains the symptoms. A wall motion abnormality in the distribution of the stenosis may confirm that the stenosis is clinically relevant. Decreased myocardial perfusion, as evidenced by nuclear imaging, magnetic resonance imaging or contrast perfusion study will similar demonstrate clinical relevance of the stenosis. Myocardial Bridging Myocardial bridging is a congenital abnormality where a portion of a major coronary artery has an intramyocardial segment. Although usually not clinically significant, myocardial bridging has also been linked to clinical complications such as ischemia, spasm, dysrhythmias and sudden death. In some series, coronary CTA has identified myocardial bridging in as many as 50% of patients, although dynamic compression occurs in only about a quarter of these patients. Whether or not myocardial bridging detected on coronary CTA is associated with adverse events in patients who are otherwise at low risk is not known. Anatomy Versus Function Although coronary CTA is usually performed to evaluate the coronary arteries, sometimes the interpretation of the results or the findings can be difficult. Coronary CTA Incidental Findings Coronary CTA will often include images of the thorax and the upper abdomen. As a result, abnormalities of other 618 C Coronary CTA structures within these spaces can be observed. The rate of incidental findings reported in the literature is near 40%. Some incidental findings are clinically relevant and might explain the symptoms leading to the test (e.g., pulmonary embolism, aortic dissection, and malignancies). Others are incidental findings that can lead to further diagnostic evaluation, which may or may not have been otherwise necessary, potentially increasing costs. The most costeffective approach to incidental findings remains to be determined. References 1. 2. 3. Artifacts and Study Quality Janne d’Othee B, Siebert W, Cury R, Jadvar H, Dunn EJ, Hoffman U (2008) A systematic review on diagnostic accuracy of CT based detection of significant coronary artery disease. Eur J Radiol 65:449–461 Hollander JE, Chang AM, Shofer FS, McCusker CM, Baxt WG, Litt HI (2009) Coronary computerized tomographic angiography for rapid discharge of low risk chest patients with potential acute coronary syndromes. Ann Emerg Med 53:295–304 Hollander JE, Chang AM, Shofer FS, Collin MJ, Walsh KM, McCusker CM, Baxt WG, Litt HI (2009) One year outcomes following coronary computerized tomographic angiography for evaluation of emergency department patients with potential acute coronary syndrome. Acad Emerg Med 16:693–698 Chang AM, Shofer FS, Weiner MG, Synnestvedt MB, Litt HI, Baxt WG, Hollander JE (2008) Actual financial comparison of four strategies to evaluate patients with potential acute coronary syndromes. Acad Emerg Med 15:649–655 Weustink AC, Mollet NR, Neefjes LA et al (2010) Diagnostic accuracy and clinical utility of noninvasive testing for coronary artery disease. Ann Intern Med 152:630–639 Factors that result in decreased study quality include patient obesity, elevated heart rate, dysrhythmia, and coronary artery calcification. A heart rate of less than 70 is generally desirable for coronary CTA, although newer technologies are loosening this restriction. Oral or intravenous beta blockers are most commonly used for heart rate control when necessary. Sublingual nitroglycerin, administered at the time of the scan, may improve coronary visualization through vasodilation. Coronary CTA study quality may be compromised in patients with atrial fibrillation, as well as those with frequent premature ectopic beats. The presence of a large amount of coronary calcium may obscure the adjacent coronary lumen, and result in overestimation of the degree of stenosis, though this issue is ameliorated by recent technological advances in image acquisition, reconstruction, and post-processing. 4. Radiation Risk JEREMY CORDINGLEY Adult Intensive Care Unit, Royal Brompton Hospital, London, UK As with all x-ray imaging studies, there is radiation exposure. For coronary CTA the radiation exposure varies widely between institutions and patients. It is dependent upon patient-related factors such as the weight of the patient (larger patients have more exposure) and the rhythm (sinus rhythm has less exposure). With respect to institutional and scanner-related factors, shorter scan lengths, electrocardiographic, controlled tube modulation, 100-kV tube voltage, sequential ECG-triggered scanning techniques, and experience in cardiac CTA are all associated with lower radiation doses without associated decreases in image quality. The long-term consequences of radiation exposure from medical imaging are not well known. They are based upon modeling rather than actual data, but it seems prudent to limit the radiation exposure when possible. Although dependent upon institutional protocol, myocardial perfusion imaging often has more radiation exposure than coronary CTA, and newer CT techniques result in doses similar to or lower than cardiac catheterization. CTmay also decrease dose by reducing the need for additional testing. 5. Coronary CTA ▶ Coronary Computerized Tomographic Angiography Coronary Syndromes, Acute Synonyms Acute myocardial infarction (MI); Non-ST elevation myocardial infarction (NSTEMI); STelevation myocardial infarction (STEMI); Unstable angina (UA) Definition Acute coronary syndromes (ACS) are a spectrum of illness caused by reduction in blood flow to the myocardium because of atherosclerotic disease of one or more coronary arteries and defined by clinical presentation, ECG findings, and biochemical markers of myocardial cell damage. An ACS occurs when blood supply to an area of myocardium is acutely reduced by sudden narrowing or obstruction of the vascular lumen by acute intravascular thrombosis on an atherosclerotic plaque through damaged endothelium. Blood supply becomes insufficient to meet metabolic demands resulting in myocardial ischemia. Coronary Syndromes, Acute The main clinical ACS syndromes that occur are unstable angina, non-ST elevation myocardial infarction (NSTEMI), and ST elevation myocardial infarction (STEMI) [1]. Unstable angina – Clinical presentation is of ischemic chest pain that does not resolve rapidly with sublingual glyceryl trinitrate and is not associated with ECG changes of ST elevation or increased serum concentration of biochemical markers of myocardial necrosis. NSTEMI – Clinical presentation of myocardial ischemia associated with increased serum concentration of biochemical markers of myocardial necrosis but no ECG ST elevation. STEMI – Clinical presentation of myocardial ischemia with ECG changes that should include the presence of one of: greater than 2 mm ST elevation in two adjacent chest leads, greater than 1 mm ST elevation in two limb leads (adjacent) or new bundle branch block and is associated with an increased serum concentration of biochemical markers of myocardial necrosis. Since the widespread availability of highly sensitive biochemical markers of myocardial cell necrosis (troponin I and T), many patients previously classified as having unstable angina now fall into the category of NSTEMI. In practice, decision making about the need for emergency myocardial reperfusion therapy (thrombolytic drugs or percutaneous coronary intervention (PCI)) is based on the presence or absence of new ST elevation. The 2007 ESC (European Society of Cardiology) guidelines therefore classify patients into two categories based on the implications for patient management: ● ST elevation ACS (STE-ACS): Chest pain and ST elevation (STE) for greater than 20 min – immediate goal is to rapidly reestablish coronary flow by primary coronary intervention (PCI) or pharmacological thrombolysis. ● Non-ST elevation ACS (NSTE-ACS): Chest pain without ST elevation for greater than 20 min – immediate management is to treat myocardial ischemia. Serial ECG monitoring and measurements of biochemical markers of myocardial necrosis will guide further management. Evaluation/Assessment History Most patients have chest pain that typically feels like pressure on the chest and may radiate to the left arm, neck, or jaw. The pain may be intermittent or continuous, and there may be associated symptoms including nausea C and abdominal pain. Chest pain may be atypical or may be absent (more common in patients with diabetes mellitus). Some patients may have had increasing frequency and severity of chest pain over days or weeks (crescendo angina). Symptoms are not helpful in differentiating STE- and NSTE-ACS. There may be a history or family history of coronary artery disease or conditions known to be associated with increased incidence such as diabetes mellitus, hyperlipidemia, peripheral or cerebrovascular disease, hypertension, and smoking. Physical Examination Full physical examination should be carried out but is often normal. There may be evidence of previous cardiovascular interventions, or signs of heart failure. Specific complications of myocardial infarction with physical signs include pericarditis, mitral regurgitation, and ventricular septal rupture. Physical signs of other potential diagnoses, for example, pneumothorax, should be sought. Investigations ECG – 12-lead ECG should be carried out as soon as possible after presentation and repeated after 6 and 24 h and compared, if possible, to previous recordings. Presence of new ST elevation as defined in STEMI (above) leads to a diagnosis of STE-ACS and immediate revascularization therapy. ST depression of at least 0.5 mm in two adjacent leads is seen in patients with NSTE-ACS, with a poorer prognosis associated with deeper ST segment depression. T wave inversion may also occur, but in a small proportion of patients with NSTE-ACS the ECG is normal. Use of right and extended left chest electrode positions may be helpful in identifying right and posterior ischemia. Stress ECG testing is indicated for risk assessment in asymptomatic patients, without diagnostic resting ECG changes or elevated troponin concentrations, prior to hospital discharge. Biochemical markers of myocardial cell necrosis – Elevated serum troponin T or I concentrations are the most sensitive and specific markers of myocardial cell death and useful as prognostic markers and therefore used to determine management of patients with NSTEACS. However, troponin concentrations may not start to rise above reference concentration for at least 3 h after the ACS has started, and in NSTE-ACS this time may be considerably longer. Further troponin measurements should be carried out 6–12 h after episodes of chest pain. Elevated troponin concentrations are found in conditions unrelated to ACS including sepsis, renal failure, cardiac failure, and acute aortic dissection, and therefore troponin 619 C 620 C Coronary Syndromes, Acute concentrations need to be interpreted in the clinical context and in conjunction with other investigations. Chest X-ray – There may be evidence of an enlarged heart or pulmonary edema. May be required to exclude differential diagnoses. Echocardiography – Transthoracic echocardiography (TTE) should ideally be carried out in assessment of ACS and may be useful in assessing ischemia-induced regional myocardial motion abnormalities, assessing potential complications of myocardial infarction such as ischemic mitral regurgitation and excluding differential diagnoses. Rapid, focused TTE assessment of severely ill patients by non-cardiologists is being promoted by courses such as FEER-Germany and FEEL-UK in order to increase patient access to emergency echocardiography and allow faster recognition of life-threatening complications. Coronary angiography – The current gold standard for imaging of coronary arteries and carries rare but serious risks of CVA, arrhythmia, pericardial hemorrhage, arterial dissection and/or obstruction, renal failure, and anaphylaxis. This technique also facilitates reperfusion therapy using angioplasty with or without coronary artery stenting. Differential Diagnosis of Chest Pain/ACS Aortic dissection – May present with chest pain and can cause ACS if dissection involves coronary arteries. Other vascular diagnoses that can mimic ACS include aortic aneurysm and aortic coarctation. Esophageal spasm Gastric ulceration or perforation, cholecystitis, pancreatitis Chest wall pain Pleural pain, pneumonia, pulmonary embolism, and infarction Pericardial disease Other types of heart disease, e.g., myocarditis, valvular (e.g., aortic stenosis) Treatment The treatment of ACS is an area in which evidence relating to new physical and drug treatments becomes available frequently and there are often changes to best practice. Readers should consult the latest guidelines from the ESC and ACC/AHA (American College of Cardiology/American Heart Association) [2, 3, 4, 5]. Patients with an oxygen saturation <90% should receive supplemental oxygen and an intravenous cannula placed, with blood simultaneously sampled for measurement of troponin, creatinine, glucose, and full blood count. Pain not responding to sublingual nitrate should be managed with intravenous nitrate infusion and morphine with an antiemetic. Basic observations should be recorded, continuous ECG monitoring attached, and 12-lead ECG recorded. Cardiac arrest should be managed with standards ALS protocols. Management will be determined by classification into NSTE-ACS, STE-ACS, or low likelihood of ACS. NSTE-ACS Management is based on risk assessment of the likelihood of further coronary events and death with high-risk patients being managed with earlier coronary angiography and revascularization and lower risk patients managed with medical treatment alone. Risk Stratification Factors associated with an increased risk of death in patients with ACS include previous coronary artery disease, main stem or three vessel disease, persistent chest pain, diabetes mellitus, increasing age, heart rate, creatinine, Kilip class [6] (Table 1), concentration of biomarkers of myocardial necrosis, ST segment changes, decreasing systolic blood pressure, and occurrence of cardiac arrest. A number of risk scoring systems have been developed to calculate both risks of in-hospital death and mortality over longer time periods. Examples of risk scoring systems include GRACE [7] (Global Registry of Acute Coronary Events) TIMI, FRISC, and PURSUIT. Medical Therapy Antiplatelet drugs ● Aspirin All patients, without contraindications, should receive standard uncoated oral aspirin 160–325 mg (chewed) on presentation with an ACS and continued at 75–100 mg daily. ● Clopidogrel Coronary Syndromes, Acute. Table 1 Kilip classification General Presentation All patients presenting with suspected ACS should be assessed rapidly using a standard ABCDE approach. 1. No evidence of heart failure 2. Elevated JVP/crackles on lung auscultation 3. Acute pulmonary edema 4. Cardiogenic shock Coronary Syndromes, Acute All patients, without contraindications, should receive oral clopidogrel 300 mg, followed by 75 mg daily, and continued for 12 months. A dose of 600 mg should be considered in patients about to undergo PCI. Patients receiving clopidogrel and requiring urgent CABG should stop it 5 days prior to surgery if this is clinically possible. ● Glycoprotein IIb/IIIa inhibitors Tirofiban or eptifibatide treatment, in addition to aspirin and clopidogrel, is indicated for patients who are at high risk of continued coronary events, and should be used in combination with an anticoagulant. For patients that have not received either and undergo PCI, abciximab should be used. ● Careful assessment of the relative risks of hemorrhagic complications versus further coronary thrombosis should be made prior to administering these drugs. Anticoagulants All patients presenting with NSTE-ACS should receive anticoagulants in addition to antiplatelet drugs. Choice of agent will depend on the clinical scenario, risk assessment of further coronary events, and potential hemorrhagic complications. ● Heparin Low molecular weight heparins (LMWH) have advantages over unfractionated heparin (UH) in being easier to administer, require less monitoring, and are associated with a lower incidence of heparin induced thrombocytopenia (HIT). ● Fondaparinux (Factor Xa inhibitor) Alternative to heparin for patients not undergoing urgent angiography and PCI and associated with a lower incidence of hemorrhagic complications. ● Bivalarudin and other direct thrombin inhibitors Alternative to heparin with fewer hemorrhagic complications. Antianginal Agents ● Nitrates – If sublingual GTN is ineffective in relieving ischemic chest pain, intravenous infusion should be used, but may cause hypotension and is contraindicated in patients taking PDE-5 inhibitors (e.g., sildenafil). ● Beta-blockers – If there are no contraindications, betablocking drugs should be administered with a target heart rate of 50–60 bpm. Care should be taken in patients with evidence of AV conduction block or significant left ventricular dysfunction. C ● Calcium channel blockers – Indicated for the treatment of angina secondary to coronary vasospasm, particularly dihydropiridines (e.g., nifedipine). In other situations, calcium channel antagonists may be used as alternatives in patients who are unable to take or in addition to beta-blockers. Dihydropyridines should not be used without combination with a betablocker in patients with non-vasospastic angina. Revascularization High-risk patients should have urgent coronary angiography followed by revascularization particularly when there is continuing or unresolving chest pain with dynamic ST segment changes, hemodynamic instability, heart failure, or life-threatening arrhythmias. Patients in a medium- to high-risk group, without lifethreatening complications, should have coronary angiography performed within 72 h and revascularization (PCI or CABG) if indicated. Low-risk patients should undergo a noninvasive test of inducible ischemia while in hospital and undergo coronary angiography if positive. STE-ACS Following initial assessment and management (as above), patients with STE-ACS presenting within 12 h of symptom require urgent coronary reperfusion therapy using either PCI or thrombolytic drugs. Risk assessment can be carried out using one of the established systems (e.g., TIMI risk score for STEMI). Aspirin should be given to all patients without contraindications (as for NSTE-ACS). Patients undergoing PCI should have clopridogrel loading dose (300 or 600 mg). During PCI, heparin (UH) is given to reduce thrombotic complications; bivaluridin may be used as an alternative. The GP IIb/IIIa inhibitor abciximab has been shown to improve outcome post PCI and may be commenced during the procedure and infused intravenously for 12 h afterward. ACEI should be started in the first 24 h in high-risk patients and continued. Beta-blockers are useful in decreasing further ischemia but should be avoided in patients with unstable hemodynamics, AV conduction block, or asthma. Reperfusion Therapy ● PCI – Is indicated urgently for patients with STE-ACS within 12 h of onset of symptoms. Patients presenting after 12 h from the onset of symptoms with continuing evidence of ischemia should also be managed with urgent angiography and PCI. 621 C 622 C Coronary Syndromes, Acute Longer time to coronary reperfusion is associated with increased mortality. ESC guidelines recommend that the time from first medical contact to intracoronary balloon inflation should be less than 2 h in all patients and less than 90 min in those with a large area of myocardial infarction and low risk of hemorrhage. Primary PCI should be used, where available in preference to pharmacological thrombolysis in all patients but particularly in patients with cardiogenic shock or heart failure and in patients with contraindications to fibrinolytic drugs. ● Fibrinolytic therapy – Is indicated in circumstances when PCI cannot be performed within recommended times or is contraindicated. Pre-hospital administration is associated with improved outcomes compared to in-hospital. Fibrinolysis is associated with 1% risk of intracranial hemorrhage which is more common in women, hypertensives, increasing age, and patients with known cerebrovascular disease. In addition, there is approximately 10% risk of other serious hemorrhage. Because of these risks, fibrinolytic therapy is contraindicated in patients with a previous history of hemorrhagic stroke (or unknown etiology) and within 6 months of an ischemic stroke. Other absolute contraindications are: known bleeding disorder, central nervous system tumors or trauma, head injury, major trauma or surgery within the last 3 weeks, gastrointestinal hemorrhage within the previous month, aortic dissection, and puncture sites that are not compressible. Relative contraindications to thrombolytic therapy are: oral anticoagulants, TIA in the last 6 months, severe hypertension, pregnancy including up to 1 week postpartum, active peptic ulceration, advanced liver disease, infective endocarditis, and failure to respond to cardiopulmonary resuscitation. Complications of ACS Streptokinase should not be readministered because antibody generation reduces its activity and can increase the risk of allergic reactions. In the event of evidence of failure of pharmacological thrombolysis (approximately 20% patients) or reinfarction (approximately 10% patients), urgent coronary angiography and PCI are indicated. If this is not possible, a second dose of antifibrinolytic agent may be given (not streptokinase if already administered). Patients presenting after 12 h from initial symptoms should be treated with aspirin, clopidogrel, and an antithrombin drug. Acute right ventricular failure may present with the findings of low cardiac output, ST elevation in inferior and right sided chest leads associated with elevated JVP but no evidence of pulmonary edema. Right ventricular failure is difficult to manage, and it is important to ensure adequate left ventricular preload and maintain coronary perfusion pressure. Early coronary reperfusion should be undertaken. Arrhythmia These are common following STE-ACS and are managed using standard algorithms. Cardiogenic Shock Patients have a low cardiac output state usually associated with hypotension and elevated left atrial pressure. Early revascularization is indicated with appropriate supportive therapy which may include mechanical circulatory support with an intra-aortic balloon pump or ventricular assist device. Mitral Regurgitation May occur because of annular dilatation or papillary muscle dysfunction or rupture. Clinical features are of mitral regurgitation which may be severe and require support with an intra-aortic balloon pump and afterload reduction. Treatment is early surgical valve repair or replacement. Ventricular Rupture ● Ventricular septal rupture – Diagnosis suspected because of deteriorating clinical condition with new systolic murmur, increase in oxygen saturation of a catheter moved from the right atrium to ventricle, and appearances on echocardiography. Management is stabilization followed by surgical repair, though small lesions have been closed with percutaneous devices. ● Free wall rupture – Diagnosis suspected because of rapidly