Dr. S. K.

Jindal
www.jindalchest.com
 Changing Trends in Sepsis

1. Definitions & Prevalence

2. Risk factors

3. Pathophysiology

4. Organ system dysfunction

5. Establishing diagnosis

6. Treatment strategies

7. Future directions
 Definitions
Infection Invasion of sterile tissue by microorganism

Bacteremia Viable bacteria in blood

Sepsis Systemic inflammatory response

Severe sepsis Sepsis and organ dysfunction

Septic shock Sepsis with hypotension

Multiple organ Altered organ function in severely sick

dysfunction patients
syndrome
 Systemic Inflammatory Response
Syndrome
• Inflammatory response to a variety of severe clinical insults (vs. sepsis)

• Two or more of the following:

Temp >38°C or <36°C

HR >90 beats/min

RR >20 breath/min or PaCO2 <32 mm Hg

WBC > 12000/mm3 or < 4000/mm3 or

10% immature band form

 Clinical Frequency & Mortality (%)
(Mortality included in parentheses)
Study SIRS Sepsis Severe Septic
sepsis shock

Rangel Frausto (1995) 68 (7) 26 (16) 18 (20) 4 (46)

Pittet (1995) 93 (6) 49 (0) 16 (35) 7 (58)
Salvo (1995) 52 (27) 5 (36) 2 (52) 3 (82)
Saez-Llorem (1995) - 21 (16) 61 (40) 18 (62)
Proulx (1996) 82 23 4 2
Jones & Lowes (1996) 55 (23) 16 5 (38) 3 (56)
Muckart (1997) 88 (8) 14 (10) 14 (18) 20 (53)
Bossink (1998) 95 (6) 44 (13) - -
 Risk of Death in First 30 Days

• Overall ICU 20%

• Severe sepsis 30-50%
• Stroke 12-19%
• Ac. Myocardial infarction 8%
 ARDS in Tropics
Infective cause No. of patients
(Mortality)
1. Severe Pneumonia 27 (51.8%)
2. Sepsis 25 (52.0%)
Immunosuppresive drugs 9
Post operative 6
Chronic respiatory disease 3
Neurological 3
Enteric fever 2
Diabetes 2
3. Malaria 7 (42.9%)
4. Enteric fever 1 (0%)
5. ‘Viral’ synd. 4 (25.0%)
Jindal et al CCM 2002
 Risk Factors

• Diabetes mellitus • Extremes of age

• Burns, wounds, multiple trauma • Malignancy
• Immunosuppressives • Organ transplant
• Hepatic failure • Radiation therapy
• Invasive catheters, devices • Renal failure
• Hyposplenism • Indwelling urine catheter
• A.I.D.S.
 Pathophysiology
Infecting organism

Exotoxins Endotoxins

Stimulation & activation of macrophages, vascular endothelial and humoral

protein cascade system (both pro & anti inflammatory)

Mediators (AAM, Complement, cytokines, ACTH,

histamine, NO, OFR, PAF, Kinins, etc.)

Activation of neutrophils & endothelial cells

OFRs, NO, Proteases, VAS (etc.) Cellular adhesion molecules (Selectins,

integrins, ICAM, etc.)

Tissue and organ injury

 Organ Dysfunction

1. Cardiovascular

2. Pulmonary – ARDS

3. Neurological

4. Hepatic failure

5. Renal failure

6. Haematological: Coagulopathy

7. Others: Gastrointestinal, Metabolic

 ARDS

ALI

Septicemia

SIRS MODS
 Pathophysiology of Pulmonary Damage
Acute microvascular damage

• In situ thrombosis
Hypoxic pulmonary
• Platelet & neutrophil Increased permeability
vasoconstriction
aggregation

Fluid exudation
Increased Ppa

Alveolar flooding
Increased RV load

Hypoxaemia
Decreased RV function

Hypoxic organ
damage
 Cardiovascular Dysfunction
Sepsis

Mediators (NO)

Arteriolar and venous dilatation – damaged endothelium

Extravascular exudation

• Cardiac output Normal to low filling Decreased SVR

• Depressed myocardium pressures
• Cardiac failure

Hypotension

Septic shock
 Diagnosis Issues in Sepsis

1. Diagnosis of Infection: Bacteraemia

• Central venous catheter infection
• Ventilator associated pneumonia
• Surgical site and intra abd. sepsis
• Acute cholecystitis; sinusitis
• Invasive candidiasis

2. Organ system dysfunction

 Suspecting Sepsis
A. Clinical signs:
• Fever / hypothermia
• Unexplained tachycardia, tachypnoea
• Signs of peripheral vasodilation
• Unexplained shock, Obtunded mentality
B. Haemodynamic or Laboratory parameters
• Low SVR / increased C.O.
• Increased O2 consumption
• Leukocytosis / neutropaenia
• Thrombocytopaenia / DIC
• Unexplained lactic acidosis or alterations in liver or renal function
• Increased procalcitonin, cytokines, CRP
 Bacteraemia

Symptoms & Signs

• Fever, chills, hypothermia
• Leucocytosis, left shift of neutrophils, neutropaenia
• Hypoalbuminaemia; Renal failure

What to do?
• Immediate blood cultures (2 to 3)
• Skin decontamination
• Adequate blood (10-30 ml per bottle)
CV Catheter Infection
• Blood and cath removal & culture

• Insertion site swab & culture

• Reinsertion – same or different site

Sinusitis
• Suspected with NT and NG tubes

• Maxillary sinus X-rays/CT

• Antral puncture
 Ventilator Associated Pneumonia

Risk Factors:
• Intubation, aspiration
• NG / enteral feeding tube
• Use of antacids, PPIs

What to do?
• Blood cultures
• Pl. aspiration (>10 mm)
• Endotracheal secretions
• Bronchoscopic specimens
 Management Issues

1. Use of antibiotics

2. Haemodynamic support

3. Source control

4. Airways and lung

5. Immunological therapy

6. Supportive & ancillary therapies

7. Future interventions
 Antibiotic use: Principles
1. Early use; appropriate drug
2. Avoid indiscriminate choices
3. Carefully analyse the costs
4. Avoid glycopeptides (vancomycin or teicoplanin) for presumed
Gram +ve infections (unless MRSA suspected)
5. No routine use of antifungals
6. Empiric therapy chosen on basis of clinical and prevalence data
 Antibiotic Use: Empiric choices

1. Severe sepsis – no neutropaenia

• Carbapenam monotherapy
• 3rd or 4th generation cephalosporin
• Beta lactam and aminoglycoside
2. Febrile, neutropaenia
• Extended spectrum carboxy- or ureido- penicillin with beta
lactamase inhibitor
3. Documented Gram –ve sepsis
• Aztreonam monotherapy or beta lactam and aminoglycoside
 Haemodynamics in Shock

Type PA occlusion Cardiac SVR

pressure output

Cardiogenic ↑ ↓ ↑

Hypovolaemic ↓ ↓ ↑

Distributive (sepsis) ↓or N ↑or N or↓ ↓

Obstructive ↑or N or↓ ↓ ↑

 Haemodynamic Support: Goals

MAP >60-65 mmHg

PCWP 15-18 mmHg

C.I. >4.0 L/min/m2 BSA for septic or Hmgic shock

 Haemodynamic Support

• Volume repletion – CVP monitoring

• Optimal Hb (9-10 gm/dl)

• Vasopressors:

Dopamine Increases CI and BP

Norepinephrine Improves BP, GFR

Dobutamine Increases CI (SV, HR)

 Fluid Management in Shock
Fluid challenge (5-20 ml/kg over 10 min)

Assess haemodynamic response

(BP, HR, urine output, mental state)

CVP monitoring

Increase by >7 mm Hg Increase by <3 mm Hg

over initial value over initial value

Discontinue Repeat fluid challenge

(Crystalloids are the mainstay of therapy)

 Airway and Lungs - ARDS

• Adequate supplemental O2

• Endotracheal intubation – mech vent

• Avoid NIPPV

• Use ‘permissive hypercapnia’ – low tidal volume (Pplat <30 cmH2O)

• Prone positioning ventilation if FiO2 requirement >0.60

• Restrict NO as salvage therapy

 Immunological Therapy: Do Not Use
• Corticosteroids in high doses (30 mg/kg) and for just 1-2 days
• Ibuprofen
• Prostaglandins (esp. PGE1)
• Pentoxifylline
• N-acetyl cysteine
• Selenium
• Antithrombin III
• Immunoglobulins
• Granulocyte Colony Stimulating Factor
• Growth hormones
• Haemofiltration (with renal indication)
 Ancillary Issues

1. DVT prophylaxis

2. Gastric mucosal cytoprotection

3. Nutritional support

4. Blood products

5. Intubation and mech. ventilation

6. Renal support - dialysis

 Supportive Therapies
1. DVT prophylaxis:

- Low dose unfractionated heparin (5000U BD or TDS) or

LMWH

- If contraindicated: mech. devices

2. Stress-ulcer prophylaxis

- Antacids, sucralfate

- H2 receptor antagonists

- Use of enteral nutrition

 Nutritional Support

• Hypercatabolic state

• Enteral nutrition preferred

• Daily: Calories 25-30 Kcal/kg usual body wt.

Proteins 1.3 – 2 g/kg
Glucose 30-70% of nonprotein calories
Maintain s. glucose <225 mg/dl
Lipids 15-30% of nonprotein calories
 Risk Factors for Mortality in ARDS

RR (95% CI)

Sepsis 3.50 (1.57-7.8)

>3 organ failure prior to admn. 3.00 (1.43-6.3)

APACHE III >57 6.13 (1.65-22.6)

SAPS II >39 10.18 (1.49-69.7)

Gupta et al, Respirology 2001

 Reducing Sepsis Mortality:
New Directions

1. Low tidal volumes in ALI / ARDS

2. Early goal-directed therapy (EGDT)

3. Use of drotrecogin alpha (activated)

4. Moderate dose corticosteroids

5. Tight control of blood sugar

 Low Tidal Volumes in ALI

• TV of 6 ml/kg ideal body wt. significantly reduces mortality

• Reduces volutrauma

Questions: Acidosis
Distressing for patient (sedation & staff
education)
Intrinsic PEEP
 Early Goal Directed Therapy

An attempt to adjust cardiac preload, after load and contractility to

balance systemic O2 delivery with O2 demand

• CVP, arterial line & Foley cath.

CVP of 8-12 mmHg; MAP > 65 mmHg; Urine output at least 0.5
ml/kg/h

• Monitored for SVO2 > 70%

Given: More IV fluids & blood transfusion

More inotropic support (dobutamine)

 Drotrecogin Alfa (Activated)
• Severe depletion of protein C in sepsis – high mortality
• Activated protein C: Anticoagulation
Profibrinolysis
Anti inflammatory
• Significantly reduces mortality
• Window period: 48 hrs
• Risk of bleeding
• No biochemical markers
• Very high cost
 Moderate-dose Corticosteroids

• Relative adrenal deficiency common in septic shock

• Moderate dose (200-300 mg HC daily) for refractory septic shock

• Better to do ACTH test before starting steroids

 Corticosteroids in Sepsis
Severe sepsis / septic shock
(Prigent et al 2003)
Plasma cortisol levels

Cortisol 15 µg/dL Cortisol >15 µg/dL

ACTH stimulation test

Cortisol rise <9 µg/dL Cortisol rise >9 µg/dL

Cortisol >34 µg/dL Cortisol 34 µg/dL

Adrenal failure

Tissue resistance to No adrenal failure

Replacement therapy
glucocorticoids
No teatment
 Tight Blood-Sugar Control
• Hyperglycaemia – common

• Hyperglycaemia (>100 mg/dl, >6.1 mmol/L) predisposes to specific ICU

complications

• High levels of insulin like growth factor binding protein predicts mortality

• Strict protocol of low-dose insulin admn. and repeated blood sugar

assessments

• Especially for surgical patients

 Summary Recommendations

1. For mech. vent., use low TV

2. EGDT: Early aggressive therapy: Generous use of fluids & inotropes
3. Drotrecogin alpha for recent onset sepsis & septic shock
4. Moderate-dose CS for refractory shock
5. Tight control of blood sugar close to physiological levels
 Agents in Development
Segara (afelimomab) Anti TNF- Fab antibody fragment

Cyto TAB Anti TNF- polyclonal antibody

Tifacogin Anti tissue factor

Pafase ( PAF) Degrades PAF

Neurprex (Opebecan) Bactericidal permeability increasing

proteins

Lipid A analogs (antiendotoxins), Anti CD14 monoclonal antibody, dextran-

bound polymyxin, Phospholipase II inhibitors, NO scavengers and NOS
inhibitors (etc.)
 SUMMARY

• Sepsis continues to threaten hospital services involved in care of the

sick

• Major changes have taken place in most areas

• Intensive care offering an ‘ICU package’ has improved survival