INTENSIVE CARE

Sepsis in 2018: a review Learning objectives

Catherine Wentowski After reading this article, you should be able to:
Nishith Mewada C define sepsis and septic shock (Sepsis-2 and Sepsis-3)
C describe clinical criteria required for the early diagnosis of
Nathan D Nielsen
sepsis
C formulate an initial treatment plan for the septic patient in a
critical care setting
Abstract
C describe secondary and adjunctive therapies presently avail-
Sepsis is responsible for tremendous morbidity, mortality and health-
able for refractory sepsis
care expenditure worldwide. Recently, the conceptualization of sepsis
has shifted away from one based upon the inflammatory response to
infection to one based upon a dysregulated immune response and
resulting organ dysfunction. Revised definitions of sepsis and septic
shock have been proposed in order to improve the specificity of the year. Hospital mortality rates for patients with sepsis are esti-
diagnostic criteria and to provide tools to facilitate accurate and timely mated to be as high as 35.3%.2 More timely and accurate
(i.e. early) diagnoses at the bedside. The crux of sepsis management recognition of at-risk patients is essential to improving patient
remains early identification and diagnostic testing, early antimicrobial care. To that end, this article will review recent changes in the
therapy, and early haemodynamic resuscitation. The most recent definitions and clinical guidelines for the treatment of sepsis.
guidelines recommend that first steps in this process should take
place within one hour from when sepsis is suspected. Additional Pathophysiology of sepsis
important new elements in the most recent sepsis management guide- At its onset, sepsis manifests as an overwhelming release of in-
lines include the use of dynamic parameters to assess fluid respon- flammatory mediators (sometimes referred to as ‘cytokine
siveness, a conservative fluid strategy following initial resuscitation storm’) in response to an infection. The immune responses to
(with ‘de-resuscitation’ when possible), serial re-assessments of hae- infection can be correlated with national defenses: components
modynamic status, and adaptable treatment plans. This article pro- of the innate immune system or ‘citizens’ (epithelial cells, mac-
vides a summary of the most recent clinical evidence and rophages, mast cells, innate lymphocytes) at the site of pathogen
professional guidelines for the diagnosis and treatment of the sepsis exposure activate and recruit circulating immune cells or
in the critical care setting. ‘troopers’ (neutrophils, NK cells, dendritic cells, platelets,
Keywords Critical care; intensive care; sepsis; septic shock monocytes, eosinophils). These cells have pathogen-recognition
receptors (PRRs) on their surface which bind to, and are acti-
Royal College of Anaesthetists CPD Matrix: 2C03
vated by, pathogen-associated molecular patterns (PAMPs) on
bacterial cell walls or damage-associated molecular patterns
(DAMPs) e host biomolecules released when danger is sensed
from a pathogen, burn, trauma, etc. This receptor binding initi-
ates an intracellular signaling cascade resulting in the activation
Introduction
of cytosolic transcription factors such as NF-kB and activator
Every year in the United Kingdom, an estimated 250,000 cases of protein 1 (AP-1), which in turn leads to the production of several
sepsis occur, claiming at least 46,000 lives. It constitutes a acute phase reactants, among them cytokines, coagulation fac-
staggering economic burden on the National Health Service tors and inducible nitric oxide synthetase, thus initiating the
(NHS) of £1.5e2.0 billion each year. Further, an aggregated immuno-inflammatory cascade. A subsequent chain reaction
annual cost to society from its long-term effects on survivors is involves the activation of even stronger ‘armed forces’, the
believed to be £15.6 billion.1 Robust epidemiological assessments adaptive immune response. This explosive activation and resul-
project that there are 31.5 million cases of sepsis annually tant immune ‘cytokine storm’ is believed to be the causative
worldwide, resulting in approximately 5.3 million deaths per pathway for septic shock.3
The end response to an infection is often a combination of
pro- and anti-inflammatory cascades. Once infection resolves, a
Catherine Wentowski MD MPH Division of Pulmonary and Critical balance is established between immune up-regulating and down-
Care Medicine, Ochsner Clinic Foundation, New Orleans, LA, USA. regulating processes, and immune memory is generated to pro-
Conflicts of interest: none declared. tect against future exposures. However, when the initial response
is excessive or dysregulated, this balancing process itself can
Nishith Mewada MD Division of Pulmonary Diseases, Critical Care
and Environmental Medicine, Department of Medicine, Tulane become dysfunctional. As sepsis persists, by about 24e48 hours
University School of Medicine, New Orleans, LA, USA. Conflicts of a shift towards an anti-inflammatory state is observed and pa-
interest: none declared. tients develop features consistent with immunosuppression. This
phase is known as sepsis-induced immunoparalysis.4 The ma-
Nathan D Nielsen MD MSc Division of Pulmonary Diseases, Critical
Care and Environmental Medicine, Department of Medicine, Tulane jority of septic shock-related deaths occur during this immuno-
University School of Medicine, New Orleans, LA, USA. Conflicts of paralysis phase. These patients are often not able to clear the
interest: none declared. initial infection and, in addition, are predisposed to new infection

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Please cite this article in press as: Wentowski C, et al., Sepsis in 2018: a review, Anaesthesia and intensive care medicine (2018), https://doi.org/
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 INTENSIVE CARE

from nosocomial pathogens. T-cell exhaustion, apoptosis and understanding of sepsis pathophysiology. The Third Interna-
anergy are now recongnized immunosuppressive mechanisms tional Consensus Definitions for Sepsis and Septic Shock (‘Sepsis-
observed in patients with fatal sepsis.5,6 3’), released in 2016, recongnized sepsis as more than an in-
flammatory response and acknowledged that both pro- and anti-
Definitions inflammatory processes, as well as major alterations in non-
immunologic systems play a role in the disease process.4 After
Over the course of the last three decades, considerable effort has
eliminating the term ‘severe sepsis’, sepsis was re-defined as
been expended in improving the recognition, categorization, and
‘life-threatening organ dysfunction caused by a dysregulated host
the algorithmic treatment of sepsis. From the early 1990s until
response to infection’. The statement further defined septic shock
recently, sepsis was diagnostically defined as a suspected infec-
as a ‘subset of sepsis in which profound circulatory failure,
tion accompanied by a pronounced systemic inflammatory
cellular, and metabolic abnormalities are associated with a
response syndrome (SIRS) (See Table 1). Patients were then
greater risk of mortality than with sepsis alone’. For a compari-
further categorized as having sepsis, severe sepsis or septic shock
son of differences between the Sepsis-2 and Sepsis-3 definitions,
based on organ dysfunction and fluid responsiveness. Though
please refer to Table 2.
this approach became critical care dogma, it failed to detect many
In addition to these conceptual definitions, the consensus
cases of sepsis – as many as one in eight for severe sepsis.7
committee also established a set of practical clinical guides to
The Society of Critical Care Medicine (SCCM) and the Euro-
facilitate diagnosis at the bedside. The authors selected the
pean Society of Intensive Care Medicine (ESICM) sought to revise
Sequential Organ Failure Analysis (SOFA) assessment to identify
the definition of sepsis by employing recent advancements in the
organ dysfunction (see Table 3). The clinical criteria for the
diagnosis of sepsis were modified to a SOFA score of 2 or more
Systemic inflammatory response syndromea (or a change of
2 in SOFA score), plus persistent hypotension
requiring the use of vasopressors to maintain a MAP >65 mmHg
Two or more of the following: and a serum lactate >2 mmol/L that persists despite adequate
fluid resuscitation (Table 4).
Temperature <36 C or >38 C
The SOFA score requires the knowledge of multiple laboratory
Heart rate >90/min
values (i.e. platelets, bilirubin, creatinine) that are not readily
Respiratory rate >20/min OR PaCO2<32 mmHg
available at the bedside outside of an acute care setting. Thus, the
WBC <4,000/mm3 OR >12,0000/mm3, or 10%
more cumbersome SOFA score was adapted to a quick SOFA
bands
(‘qSOFA’) to allow for simple, rapid assessments in the prehospital,
a
one RC, Balk RA, Cerra FB et al. American College of Chest Physicians/Soci- clinic, or emergency department environment (see Box 1). Based
ety of Critical Care Medicine Consensus Conference: definitions for sepsis and upon a cohort study of nearly 150,000 patients with suspected
organ failure and guidelines for the use of innovative therapies in sepsis. Crit
Care Med. 1992; 20 (6):864e874.
infection, the Sepsis-3 authors determined that the qSOFA assess-
ment was more predictive of the development of sepsis in at risk
Table 1 patients outside the ICU setting than the traditional SIRS criteria.8

Comparison of Sepsis-2 and Sepsis-3a

Sepsis-2 Sepsis-3

Publication year 2001 2016

Mechanism (pathophysiology) Physiological inflammatory response (SIRS) to Dysregulated immune response to infection
infection
Spectrum SIRS / sepsis / severe sepsis / septic Sepsis / septic shock
shock / MODS
Predictive validity for in-hospital mortality 0.64 (95% CI, 0.62e0.66) 0.74 (95% CI, 0.73e0.76)
(Area under the curve, p<0.001)3
Sensitivity/specificity [ Sensitivity Y Sensitivity
Y Specificity [ Specificity
Definition of septic shock Acute circulatory failure characterized by Subset of sepsis in which underlying
persistent arterial hypotension unexplained by circulatory and cellular metabolism
other causes abnormalities are profound enough to
substantially increase mortality
Practical considerations Three of four SIRS criteria obtainable at Multiple laboratory test results required to
bedside without need for laboratory testing calculate SOFA score; qSOFA can be used as
substitute prior to test availability
a
Singer M, Deutschman CS, Seymour CW et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315 (8):801e810.

Table 2

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Sequential [sepsis-related] organ failure assessment score (SOFA)a

Score
System 0 1 2 3 4

Respiratory
PaO2/FiO2, mmHg
400 <400 <300 <200 with respiratory <100 with respiratory
support support
Coagulation
Platelets, x 103/mL
150 <150 <100 <50 <20
Liver
Bilirubin, mg/dL <1.2 1.2e1.9 2.0e5.9 6.0e11.9 >12.0
Cardiovascular
MAP
70 mmHg MAP<70 mmHg Dopamine<5 or Dopamine 5e15 or Dopamine>15 or
dobutamine norepinephrine 0.1 or norepinephrine>0.1 or
(any dose)b epinephrine0.1b epinephrine>0.1b
Central nervous system
Glasgow Coma Scale scorec 15 13e14 10e12 6e9 <6
Renal
Creatinine, mg/dL <1.2 1.2e1.9 2.0e3.4 3.5e4.9 >5.0
Urine output, mL/day <500 <200

Abbreviations: FiO2, fraction of inspired oxygen; MAP, mean arterial pressure.

a
Vincent JL, Moreno R, Takala J et al. Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. The SOFA (Sepsis-related Organ
Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med. 1996; 22 (7): 707e710.
b
Catecholamine doses are given as mg/kg/min for at least 1 hour.
c
Glasgow Coma Scale scores range from 3 to 15; higher score indicates better neurologic function. Teasdale G, Jennett B. Assessment of coma and impaired conscious-
ness. A practical scale. Lancet. 1974; 2: 81e84.

Table 3

Sepsis-3 criteria for sepsis/septic shocka It should be noted that the new definitions proposed by
Sepsis-3 have not been universally accepted. Almost immedi-
Sepsis qSOFA
2 plus evidence of infection ately, investigators attempted to compare SIRS and qSOFA as
Septic shock Sepsis plus persistent hypotension requiring sepsis screening modalities. In a recently published study, Fer-
administration of vasopressors to maintain a nando et al. performed a retrospective meta-analysis comparing
MAP>65 mmHg and a lactate >2mmol/L the prognostic accuracy of SIRS to qSOFA and found qSOFA to
despite adequate fluid resuscitation have poor sensitivity and moderate specificity to predict short-
a
Adapted from: Singer M, Deutschman CS, Seymour CW et al. The Third In- term mortality; SIRS criteria displayed superior sensitivity.9
ternational Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Though Sepsis-3 incorporated the qSOFA methodology, some
JAMA. 2016; 315 (8):801e810. clinicians still prefer SIRS and this remains an active area of
discussion in the critical care community.
Table 4

Management
Irrespective of debates over the definition of sepsis, the corner-
Quick Sequential Organ Failure Analysis (qSOFA) scorea
stone of effective treatment is indisputably early identification
and aggressive, targeted management. Successful treatment re-
qSOFA criteria: ‡ 2 of the following quires fluid resuscitation with a focus on perfusion and early
administration of antibiotics. The most recent 2018 Surviving
Respiratory rate >22/min Sepsis Campaign (SSC) Bundle Update introduced the ‘1-hour
Change in mental status Bundle’.10 This new bundle combines elements of the prior 3-
Systolic blood pressure <100 mmHg and 6-hour Bundles into an algorithm that emphasizes the im-
a mediate treatment of septic patients. The first elements of the
Adapted from: Singer M, Deutschman CS, Seymour CW et al. The Third
International Consensus Definitions for Sepsis and Septic Shock (Sepsis- bundle are diagnostic: measuring a lactate level and obtaining
3).JAMA.2016; 315 (8):801e810. blood cultures prior to administration of antibiotics. The
remainder of the bundle addresses management: early antimi-
crobial administration, fluid resuscitation, and if required,
Box 1 vasopressor support (see Box 2).

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When the source of infection is unclear, empiric coverage

Surviving Sepsis Campaign 1-h Bundlea should be initiated. For the majority of patients, antimicrobial
coverage should include either an extended spectrum beta lac-
tam, a third or fourth generation cephalosporin, or a carbape-
C Measure lactate level (follow serial measurements if initial
nem. Additional consideration should be paid to meticillin-
level >2mmol/L)
resistant Staphylococcus aureus (MRSA) risk factors and if pre-
C Obtain blood cultures prior to administering antibiotics
sent, empiric vancomycin administration is advised. Wide-
C Administer broad spectrum antibiotics
spread use of combination therapy, the use of multiple
C Begin rapid administration of 30mL/kg of crystalloid for hy-
antibiotics with different pharmacodynamic profiles and
potension or lactate
4mmol/L
mechanisms of action to treat the same organism, is a topic of
C Start vasopressors if patient is hypotensive during or after
some debate, though early studies reported a synergistic effect
fluid resuscitation to maintain a MAP
65mmHg
with the addition of an aminoglycoside to a beta-lactam12 and
a
later studies assessed the addition of a fluoroquinolone. Com-
Levy MM, Evans LE, Rhodes A. The surviving sepsis campaign bundle:
2018 update. Intensive care medicine. 2018 Jun 1; 44 (6):925e8. bination therapy has been shown to improve survival in the
most critically ill patients (i.e.: in septic shock where the mor-
tality risk is greater than 25%).13 In the appropriate clinical
Box 2
context (e.g. suspected influenza), empiric anti-viral therapy is
often appropriate. Likewise, clinical scenarios that include
immunosuppression, total parenteral nutrition, or recent
Early antimicrobial therapy and source control abdominal surgery may justify the use of empiric anti-fungal
For patients with presumed sepsis, early empiric broad-spectrum therapy. Once microbial data are available, prompt de-
antibiotic therapy should be initiated within 1 hour of presenta- escalation of therapy is imperative.
tion. Ideally, microbiologic data should be obtained prior to Source control, a crucial element of proper sepsis treatment,
administering antibiotics. However, if obtaining cultures will may require more invasive interventions than antimicrobial
delay antibiotic administration, then antibiotic therapy should administration alone. The removal of potentially infected inva-
always take priority. In multiple studies, the prompt adminis- sive devices is highly recommended; this includes urinary and
tration of antibiotics was associated with improved survival.10,11 central venous catheters. Prompt consultation with surgical or
The selection of appropriate empiric antibiotic therapy is essen- interventional radiology services is advised to address scenarios
tial for decreasing mortality in septic patients and should be such as an empyema, joint infection, cholecystitis or intra-
guided by clinical presentation and local antimicrobial resistance abdominal catastrophe. Generally, the least invasive interven-
patterns, as well as the patient’s risk factors for particular or- tion capable of providing source control is the preferred option. A
ganisms (see Table 5).11 Comorbidities contributing to chronic multidisciplinary approach to early intervention (<6 h) can
illness (e.g. human immunodeficiency virus, combined variable improve patient mortality.14
immunodeficiency, diabetes mellitus) and the presence of inva-
sive medical devices (e.g. central venous catheters, urinary Fluid resuscitation
catheters) should also be weighed when selecting initial anti- Prompt fluid resuscitation should be initiated upon the diagnosis
biotic regimens. of sepsis. Current guidelines strongly recommend the initiation of

Risk factors from select organisms

Pseudomonas aeruginosa (and other MRSA VRE Invasive candidiasis
resistant Gram negative rods)

Community acquired: C Colonization with MDROs C Liver transplant C Central venous catheter
C IV antibiotic use within 90 days C Recent MRSA infection C Known colonization C Broad spectrum antibiotics
C Colonization with MDROs C Known MRSA colonization C Prolonged use of broad C Plus one of the following
Hospital acquired: C Purulence or abscess of the spectrum antibiosis C Parenteral nutrition
C IV antibiotics within 90 days skin or IV access site C Profound C Dialysis
C Five or more days of hospitalization C Severe rapidly progressive immunosuppression C Recent abdominal surgery
prior to onset necrotizing pneumonia C Necrotizing pancreatitis
C Requiring acute renal replacement C Immunosuppressive agents
therapy
C Septic shock
C Colonization with MDROs

Adapted from Derensinski, Stan. ‘Severe Sepsis and Septic Shock Antibiotic Guide.’ Stanford Antimicrobial Safety and Sustainability Program. Stanford Health. May 2017.
http://med.stanford.edu/bugsanddrugs/guidebook/_jcr_content/main/panel_builder_1454513702/panel_0/download_1586531681/file.res/Sepsis%20ABX%202017-05-
25.pdf

Table 5

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the infusion of 30 mL/kg of IV crystalloid fluid within 1 hour of lower than expected for a shock state.23 The use of low-dose
sepsis identification if hypotension is present.10 However, the vasopressin or terlipressin is an effective treatment for refractory
type of fluid to be used for resuscitation remains an active area of shock. Furthermore, the addition of vasopressin has been noted
debate. In 2004, the SAFE trial compared clinical outcomes in to have a ‘dose sparing’ effect on norepinephrine requirements,
critically ill patients receiving volume resuscitation with either potentially decreasing the risk of tachyarrhythmia24,25 and other
normal saline or albumin.15 No significant difference in all-cause catecholamine-associated side-effects.
mortality was noted between the two groups, though a sub-group In low doses, adrenaline/epinephrine is an inotrope, but at
analysis did show unfavourable outcomes when albumin was higher doses it demonstrates vasoconstrictive properties. A head-
administered to patients with traumatic brain injury. The com- to-head comparison of norepinephrine to epinephrine in septic
bination of the increased expense of albumin infusion and an shock showed no difference in mortality, but increase in adverse
absence of data to support a clear benefit led the Surviving Sepsis events in the epinephrine arm.26 It is important to note that
Campaign (SSC) to recommend crystalloids as the volume epinephrine infusions often cause hyperlactatemia, limiting the
resuscitation agents of choice. usefulness of lactate clearance as an indicator of response to
Which crystalloid to use is also a matter of active debate, but therapy.
as more data become available, balanced salt solutions such as The choice between adrenaline/epinephrine and vasopressin
lactated Ringer’s or PlasmaLyte are likely to emerge as the rec- as a second-line agent should be based upon the patient’s current
ommended options. For example, a recently completed trial of hemodynamic status and underlying physiology, particularly the
nearly 8000 patients found the use of balanced crystalloids in presence of (or risk for) tachyarrhythmias or elevated lactate
critically ill patients slightly decreased mortality, the use of renal levels.
replacement therapy, and persistent renal dysfunction when Previously considered the first-line vasopressor for septic
compared to 0.9% saline solution.16 shock, dopamine has fallen out of favour. A 2015 meta-analysis
While adequate resuscitation is essential, fluid overload is compared the use of norepinephrine to dopamine in patients
associated with increased mortality,17 making perfusion assess- with septic shock and found decreased all-cause mortality in the
ment an essential part of the treatment algorithm. Careful norepinephrine treated patients.27 The abundance of data on its
attention to fluid management with de-resuscitation 24e48 hours arrhythmogenic properties in conjunction with a less favourable
after successful resuscitation decreases the ICU length of stay and hemodynamic profile overall make dopamine a less desirable
increases ventilator-free days.18 choice in the treatment of septic shock. Consequently, it should
be reserved for a select patient population (e.g. septic patients
Perfusion assessment with bradycardia, low risk of tachycardia).22,28
Once initial fluid resuscitation has been completed, frequent There are little data about the use of phenylephrine in patients
reassessment of systemic perfusion using dynamic variables is with septic shock. Due to its potential to cause splanchnic
recommended. While prior iterations of the SSC recommended vasoconstriction, and an absence of robust clinical data sup-
the use of early goal-directed therapy-based resuscitation pro- porting its safety in septic shock, its use should be limited in
tocols, where perfusion was assessed by a combination of central patients with sepsis.22
venous pressure (CVP) and central venous oxygen saturation The ATHOS-3 trial presented a new option for management of
levels, the most recent SSC guidelines favour alternative dynamic vasodilatory shock e angiotensin II (ATII). In this recently
measures.19 Techniques such as passive leg raising maneuvers, published multicenter randomized controlled trial (RCT) of pa-
pulse pressure variation, and point-of-care ultrasound assess- tients with catecholamine refractory vasodilatory shock, the
ments are now recommended as means to gauge whether a pa- group treated with ATII demonstrated a significant increase in
tient requires further volume resuscitation. These dynamic blood pressure, and no significant difference in adverse events
assessments and reassessments of perfusion are now regarded as was noted between the groups.29 Though large scale clinical data
essential to improving patient outcomes. are not available at this time, ATII appear to be a promising
Serum lactate continues to play a role as an indirect marker of therapy for catecholamine refractory shock.
tissue perfusion. The SSC guidelines recommend a serum lactate A subset of patients with septic shock will develop septic
assay at baseline, and, if elevated, serial monitoring until cardiomyopathy. These patients typically have little cardiac
normalization. Several randomized controlled trials using lactate reserve at baseline and are unable to generate a compensatory
guided resuscitation have shown significant reductions in cardiac output during vasodilatory shock. If cardiac output re-
mortality.20,21 mains low despite use of vasopressors, initiation of inotropic
therapy is appropriate. The Surviving Sepsis Campaign Guide-
Vasopressors lines recommend dobutamine as the preferred inotrope, though
Mean arterial pressure (MAP) is the driving factor behind sys- data show similar improvements in cardiac output with the use
temic perfusion. When hypotension persists despite adequate IV of epinephrine as a single agent as with dobutamine paired with
fluid resuscitation, vasopressors should be administered. At norepinephrine.10
present, the SSC recommends noradrenaline/norepinephrine as
the first-line vasopressor.22 If a second agent is necessary to Diagnostic techniques
achieve MAP goals, vasopressin or adrenaline/epinephrine are
the recommended options. Microbiological cultures
Patients with septic shock are hypothesized to have a ‘relative Positive blood cultures are demonstrable evidence of systemic
vasopressin deficiency’, meaning that levels of vasopressin are infection. If sepsis is suspected, current guidelines recommend

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drawing two sets of blood cultures, both aerobic and anaerobic. 33 trials and concluded that corticosteroids generally reduce
However, blood culture yield is variable and is dependent upon mortality among patients with sepsis (though the evidence was
sampling technique. Care must be taken to adequately prepare rated as low quality).34 Based on this, the 2016 Surviving Sepsis
the skin with antiseptic agent and to inoculate each bottle with a Campaign Guidelines recommended 200 mg per day of IV hy-
minimum of 10 mL of blood. Ideally, cultures should be obtained drocortisone for patients who have persistent circulatory failure
prior to the administration of antibiotics. Cultures of other bodily despite adequate fluid resuscitation and vasopressor therapy.
fluids should also be obtained as clinically indicated (e.g. However, the role of steroids in septic shock does remain an
sputum, urine, cerebrospinal fluid, etc.). active area of research. The recently published ADRENAL trial
(ADjunctive corticosteroid tREatment iN criticAlly ilL) random-
Lactate ized critically ill patients to receive hydrocortisone 200mg/day
Elevated serum lactate is a marker of disease severity in sepsis. versus placebo. No difference in mortality was noted but there
The etiology of the rise in lactate is multifactorial, including was a significant improvement in reversal of shock, length of stay
anaerobic metabolism resulting from inadequate oxygen delivery in ICU, ventilator-free days and fewer blood transfusions.35
and accelerated aerobic glycolysis. Several randomized Conversely, a multicentre, randomized controlled trial adminis-
controlled trials reported that a lactate-guided resuscitation tering hydrocortisone plus fludrocortisone (versus placebo) to
strategy in patients with septic shock reduced mortality.22 As patients in septic shock did find a reduction in all-cause mortality
such, measurement of lactate is a mainstay of sepsis treatment in the treatment group.36 Much like the evidence, the critical care
protocols and is included in the current clinical criteria for the community remains divided on the use of steroids in septic
diagnosis of septic shock. shock.

Biomarkers Vitamin C (thiamine)

A myriad of novel biomarkers (e.g. supar, presepsin, cell-free Vitamin C as an adjunctive therapy for sepsis has received
plasma DNA) are under study with the aim of improving diag- considerable media attention. At present, while the results from a
nostic precision, more accurate prognostication, and ultimately, single centre retrospective trial using vitamin C with thiamine
monitoring treatment response. However, most have not been and glucocorticoids are intriguing,37 there are no multicentre,
shown to have the sensitivity, specificity, or cost-efficacy randomized controlled trials to support the routine use of
necessary to justify use in clinical practice.30 vitamin C or thiamine in patients with sepsis.38
Procalcitonin (PCT) is the most studied sepsis biomarker.31 A
precursor to the hormone calcitonin, levels are routinely elevated Blood purification techniques
in the setting of systemic bacterial infection. Thus far, studies Endotoxin is circulating in 50% of patients in septic shock and is
show procalcitonin to be useful in decreasing the duration of associated with poor outcomes.39 The EUPHRATES trial
antibiotic treatment.32 Elevations of PCT can be seen in unin- attempted to neutralize endotoxin via a polymyxin fibre in a
fected patients, however, particularly in patients with renal dis- hemoperfusion device.40 EUPHRATES was the largest RCT to
ease. Based upon available data, the SSC suggests using study this technology, but was terminated early due to failure to
procalcitonin to limit or discontinue antibiotic therapy only. An achieve the primary endpoint. Other techniques, such as extra-
elevated procalcitonin in itself is insufficient to determine the corporeal plasma filtration to remove pro- and anti-inflammatory
initiation (or not) of antibiotics.22 mediators from the bloodstream, are under evaluation.41 While
the concept remains appealing, at this time data are lacking to
Molecular techniques
support its efficacy.
Identifying and treating the offending organism in a timely
manner is often a challenge. Conventional blood cultures can
Glycaemic control
take up to 72 hours to provide a definitive result. Recently
Glycaemic control in sepsis is a much-debated topic. On one
developed molecular techniques can detect pathogens far more
hand, hyperglycaemia can exert an immunosuppressive effect
quickly. Ongoing evaluations of pathogen identification tech-
diminishing the body’s ability to mount a competent immune
niques using multiplex polymerase chain reaction (PCR), PCR/
response. On the other, the anti-inflammatory effects of insulin
electrospray ionized mass spectroscopy (ESI MS), and function-
may inhibit cellular autophagy and negatively impact a patient’s
alized nanoparticles coupled with magnetic resonance have
capacity to clear infection.42
shown promise with the capability of identifying organisms in
Evidence shows that severe hyperglycaemia in patients with
under 6 hours with reasonable sensitivity and specificity. Further
sepsis is associated with increased 30-day mortality.43 On the
studies and cost analyses will determine whether these tech-
other hand, the NICE-SUGAR trial, a large, multicentre, ran-
niques are incorporated into general clinical practice, but in the
domized controlled trial compared intensive insulin control (81
near future these techniques may very well obviate the need for
e108 mg/dL) to conventional insulin control (<180 mg/dL), and
conventional blood cultures.33
reported increased mortality due to hypoglycaemia with inten-
sive insulin therapy.44 With both hyper- and hypoglycaemia
Adjunctive therapies associated with adverse outcomes, current recommendations are
Steroids to start insulin after blood glucose levels exceed 180mg/dL
Despite the physiological plausibility for the effectiveness of (10mmol/L) with the goal of maintaining levels less than 180mg/
steroids in septic shock, the data are conflicting on their efficacy dL. There is no specific lower threshold target, but avoidance of
in clinical practice. In 2015, a review by Annane et al. analysed hypoglycaemia and wide swings in glucose levels is advised.

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Anticoagulants (including thrombomodulin and 5 Hotchkiss RS, Tinsley KW, Swanson PE, et al. Sepsis-induced
heparin) apoptosis causes progressive profound depletion of B and CD4þ
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18 Silversides JA, Major E, Ferguson AJ, et al. Conservative fluid
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Please cite this article in press as: Wentowski C, et al., Sepsis in 2018: a review, Anaesthesia and intensive care medicine (2018), https://doi.org/
10.1016/j.mpaic.2018.11.009