Severe sepsis and septic shock Zsolt Molnár University of Szeged AITI

Definition – 2000 years ago Hippocrates: Celsus: Breakdown of living tissues: „pepsis” and „sepsis” Celsus: Rubor Dolor Calor Tumor

Bőrtünetek: diffúz erythema

Definition – 2000 years ago Hippocrates: Celsus: Breakdown of living tissues: „pepsis” and „sepsis” Celsus: Rubor - Peripheral vasodilatation Dolor - Altered mental status Calor - Fever, hypothermia Tumor - Oedema

Tumor: generalizált ödéma

Definition – 2000 years ago Hippocrates: Celsus: Galen: Breakdown of living tissues: „pepsis” and „sepsis” Celsus: Rubor - Peripheral vasodilatation Dolor - Altered mental status Calor - Fever, hypothermia Tumor - Oedema Galen: Functio laesa

Definition – 2000 years ago Hippocrates: Celsus: Galen: Breakdown of living tissues: „pepsis” and „sepsis” Celsus: Rubor - Peripheral vasodilatation Dolor - Altered mental status Calor - Fever, hypothermia Tumor - Oedema Galen: Functio laesa - Organ dysfunction …organ dysfunction.

From blood poisoning to sepsis „Sepsis-syndrome” and Las Vegas: Fever or hypothermia (> 38 oC or < 36 oC) Tachycardia (>90/min) Leukocytosis or leukopenia (> 12 000cells/mm3, < 4000cells/mm3, or > 10% immature forms) Hypotension (<90mmHg) Bone RC, et al. N Engl J Med 1987; 317: 654 Consensus conference ACCP/SCCM: Infection Bacteraemia Systemic inflammatory response syndrome (SIRS) Sepsis = SIRS + Infection Severe sepsis (Sepsis + one organ dysfunction) Septic shock (hypoperfusion despite adequate fluid load) Multiple System Organ Failure (MSOF) ACCP/SCCM. Crit Care Med 1992; 20: 864

Definitive diagnoses

Pathomechanism I n s u l t Humoral activity M a c r o p h a g e s Endotoxin, Trauma, Sterile inflammation, Operation, etc. Humoral activity Interferon, Complement M a c r o p h a g e s TNF; IL-1,6,10; PAF P M N FR, PAF, Chemotaxis Fisiol. reactions Fever, Metabolic changes E n d o t h e l NO, E-selectin, NFkB Sepsis, SIRS MSOF Molnár and Shearer Br J Int Care Med 1998; 8: 12 8

Why do septic patients get into trouble?

The debt… DO2= (SV•P) • (Hb•1.39•SaO2+0.003•PaO2) ~ 1000ml/m (SaO2=100%) VO2 = CO • (CaO2 - CvO2) ~ 250 ml/min (ScvO2~70-75%) CO CaO2

The debt… DO2= (SV•P) • (Hb•1.39•SaO2+0.003•PaO2) ~ 1000ml/m (SaO2=100%) VO2 = CO • (CaO2 - CvO2) ~ 250 ml/min (ScvO2~70-75%) In critical illness: Shock = VO2>DO2 CO CaO2 VO2 DO2

Supportive therapy

Early supportive treatment „Early Goal-Directed Therapy” (EGDT) Rivers E et al. N Engl J Med 2001; 345: 1368 Septic patients treated for 6 hours in A&E: Control group (n=133): O2 CVP: 8-12 mmHg MAP >65 mmHg EGDT group (n=130): Same goals ScvO2 > 70% More fluid and blood More dobutamine Mortality: 46 vs. 30% (p=0.009)

Hemodynamic support in sepsis Ohm’s law:

Hemodynamic support in sepsis Ohm’s law: Severe sepsis, septic shock: Vasodilatation: SVR (MAP) low, CO high DO2/VO2 high Invasive haemodynamic monitoring: Arterial + central venous line Pulmonary artery catheter (Swan-Ganz) Arterial thermodylution (PiCCO)

How can we recognise it?

Objective signs of organ dysfunction 0 1 2 3 4 CNS (GCS) 15 13-14 10-12 7-9 ≤6 CVS (P, inotr., lactate) ≤120 120-140 >140 Inotr. seLactate>5 Resp (PaO2/FiO2) >300 226-300 151-225 76-150 ≤75 Ren (seCreat) ≤100 101-200 201-350 351-500 >500 Liver (seBi) ≤ 20 21-60 61-120 121-240 >240 Hemat (TCT) >120 81-120 51-80 21-50 ≤20 Cook R et al. Crit Care Med 2001; 29: 2046 Most frequent early signs: Arterial hypoxemia: 60% Arterial hypotension: 57% Metabolic acidosis: 47% Atrial fibrillation: >10% Altered level of consciousness: >10% Bogár L. Infektológia 2007; 14: 1-6 Low DE, et al. J Gastrointest Surg 2007; 11: 1395

Organ dysfunction and outcome SOFA score dinamics and outcome: 0-1. day CVS (p=0.0010) Creat (p=0.0001) PaO2/FiO2 (p=0.0469) Se creat increase and mortality ~100µmol/24h p<0.05 Levy MM et al. Crit Care Med 2005; 33: 2194 It is not just the actual value of a certain marker that predicts outcome, but the kinetics within a 24 h period. Marshall JC et al. Crit Care Med 1995; 23: 1638

Labortory signs of sepsis Fever (>38oC), WBC (>12 000): Low sensitivity (~50%) Galicier L and Richet H. Infect Control Hosp Epidemol 1985; 6: 487 Blood culture: Early results after 24 h only Low sens/spec, especially in pneumonia caused sepsis (~30%) Meakins JL. In: Crit Care: State of the Art 1991; 12: 141 Luna CM et al. Chest 1999; 116: 1075 TNF-, IL-6,1,8: Short half life Expensive tests Serum procalcitonin (PCT), C-reaktive protein (CRP) Senzitivity (%): 88(80-93) vs 75(62-84), p<0.05 Specificity (%): 81(67-90) vs 67(56-67), p<0.05 Simon L et al. Clin Infect Dis 2004; 39: 206

≥1ng/ml or increasing (alert) <1ng/ml or decreasing (non-alert) Procalcitonin increase in early identification of critically ill patients at high risk of mortality Jensen JU et al. Crit Care Med 2006; 34: 2596-2602 PCT change/24h ≥1ng/ml or increasing (alert) <1ng/ml or decreasing (non-alert)

Procalcitonin increase in early identification of critically ill patients at high risk of mortality Jensen JU et al. Crit Care Med 2006; 34: 2596-2602

Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial Nobre V, et al. Am J Respir Crit Care Med. 2008;177:498-505 PCT vs control PCT-group (after day 3): 90% reduction <0.25 ng/ml 3 vs 5 days 6 vs. 10 days

High postop PCT ≠ sepsis NS = 23 *p<0.05 * Data are presented as minimum, maximum, 25-75% percentile and median. For statistical analysis Mann-Whitney U test was used. Szakmány T, Molnár Z. Can J Anaesth 2003; 50: 1082-3 Molnár Z, Bogár L. Crit Care Med 2006; 34: 2687-8 6 7 7

Surviving Sepsis Campaign – 2008 Dellinger RP et al. Intensive Care Med 2008; 34: 17-60

Resuscitation, infection Dellinger RP et al. Intensive Care Med 2008; 34: 17-60 EGDT Chrystalloid or colloid (1B) Diagnosis 2/more immediate blood cultures (1C) Immediate radiology (1C) Antibiotics Within 1 h in severe sepsis (1D), septic shock (1B) Broad spectrum ABs (1B) De-escalation strategy (2D) Stop ABs in case of infection is not proven (1D)

Recommendations Vasopressors, inotropes Bloos products Dellinger RP et al. Intensive Care Med 2008; 34: 17-60 Vasopressors, inotropes Bloos products Activated protein C (rhAPC) „Xigris” Glucose control Steroid Stb…(85 recommendations)

Therapeutic evidence and outcome

Economic implications of an evidence-based sepsis protocol: Can we improve outcome and lower cost? Shorr AF et al. Crit Care Med 2007; 35: 1257 Módszerek Retrospective post-hoc analysis Pre-protocol: 2004-2005 (n=60) Protocol: 2005-2006 (n=60) Surviving Sepsis Campaign: Early AB EGDT Vasopressor/inotrope Transfusion rhAPC Corticosteroids

Economic implications of an evidence-based sepsis protocol: Can we improve outcome and lower cost? Shorr AF et al. Crit Care Med 2007; 35: 1257 Mortality: 48 vs. 30% (p=0.04)

Summary Severe sepsis – mortality can be reduced! Recognition Rationalised clinical and biochemical investigations Prevention: Oxygen + fluid + monitoring (EGDT: ScvO2) Treatment: EBM

Summary Severe sepsis – mortality can be reduced! Sepsis Recognition Rationalised clinical and biochemical investigations Prevention: Oxygen + fluid + monitoring (EGDT: ScvO2) Treatment: EBM Sepsis Less of a diagnosis… …more like a concept

Motto Diagnosis can wait, but cells can’t! It doesn’t matter whether you’ve done the right thing, but whether you’ve done everything to do the right thing