Severe sepsis and septic shock

Zsolt MolnárUniversity of Szeged

AITI

Definition – 2000 years ago

• Hippocrates:– Breakdown of living tissues: „pepsis” and „sepsis”

• Celsus:– Rubor

– Dolor

– Calor

– Tumor

Bőrtünetek: diffúz erythema

• Hippocrates:– Breakdown of living tissues: „pepsis” and „sepsis”

• Celsus:– Rubor - Peripheral vasodilatation

– Dolor - Altered mental status

– Calor - Fever, hypothermia

– Tumor - Oedema

Definition – 2000 years ago

Tumor: generalizált ödéma

• Hippocrates:– 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:– 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

Definition – 2000 years ago

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

I n s u l tEndotoxin, Trauma, Sterile

inflammation, Operation, etc.

Humoral activityInterferon, Complement

M a c r o p h a g e sTNF; IL-1,6,10; PAF

P M NFR, PAF, Chemotaxis

E n d o t h e lNO, E-selectin, NFkB

Fisiol. reactionsFever, Metabolic changes

Sepsis, SIRS

MSOF

Pathomechanism

Molnár and Shearer Br J Int Care Med 1998; 8: 12

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

VO2DO2

CO CaO2

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)

• Ohm’s law:

Hemodynamic support in sepsis

I

UR

• Ohm’s law:

Hemodynamic support in sepsis

KCO

CVPMAP

I

USVR

• 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 4CNS (GCS) 15 13-14 10-12 7-9 ≤6CVS (P, inotr., lactate) ≤120 120-140 >140 Inotr. seLactate>5Resp (PaO2/FiO2) >300 226-300 151-225 76-150 ≤75Ren (seCreat) ≤100 101-200 201-350 351-500 >500Liver (seBi) ≤ 20 21-60 61-120 121-240 >240Hemat (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

Marshall JC et al. Crit Care Med 1995; 23: 1638

• 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

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: 141Luna 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

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

6 vs. 10 days

3 vs 5 days

Non-survivorsSurvivors

Proc

alci

toni

n (n

g m

l-1)

15

10

5

0

t 0

t 24

t 48

t 72

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: 1082-3Molnár Z, Bogár L. Crit Care Med 2006; 34: 2687-8

High postop PCT ≠ sepsis

Non-survivorsSurvivors

CRP (mg/L)

300

200

100

0

t 0

t 24

t 48

t 72

**p<0.05S = 130NS = 23

Surviving Sepsis Campaign – 2008Dellinger 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)

Resuscitation, infectionDellinger 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)

RecommendationsDellinger RP et al. Intensive Care Med 2008; 34: 17-60

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)

• 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!• Recognition

– Rationalised clinical and biochemical investigations

• Prevention:– Oxygen + fluid + monitoring (EGDT: ScvO2)

• Treatment:– EBM

• Sepsis– Less of a diagnosis…– …more like a concept

Summary

Motto

Diagnosis can wait, but cells can’t!

It doesn’t matter whether you’ve donethe right thing,

but whether you’ve doneeverything to do the right thing