1. Severe sepsis and septic shock Zsolt Molnár University of Szeged AITI

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

3. Bőrtünetek: diffúz erythema

4. 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

5. Tumor: generalizált ödéma

6. 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

7. 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.

8. From blood poisoning to sepsis
„Sepsis-syndrome” and Las Vegas:
Fever or hypothermia (> 38 oC or < 36 oC)
Tachycardia (>90/min)
Leukocytosis or leukopenia (> cells/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

9. Definitive diagnoses

10. 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

11. Why do septic patients get into trouble?

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

13. The debt…
DO2= (SV•P) • (Hb•1.39•SaO •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

14. Supportive therapy

15. 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)

16. Hemodynamic support in sepsis
Ohm’s law:

17. 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)

18. How can we recognise it?

19. Objective signs of organ dysfunction
CNS (GCS) ≤6
CVS (P, inotr., lactate) ≤ >140 Inotr. seLactate>5
Resp (PaO2/FiO2) > ≤75
Ren (seCreat) ≤ >500
Liver (seBi) ≤ >240
Hemat (TCT) > ≤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

20. 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

21. 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

22. ≥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:
PCT change/24h
≥1ng/ml or increasing (alert)
<1ng/ml or decreasing (non-alert)

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

24. 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:
PCT vs control
PCT-group (after day 3):
90% reduction
<0.25 ng/ml
3 vs 5 days
6 vs. 10 days

25. 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:
Molnár Z, Bogár L. Crit Care Med 2006; 34: 6 7 7

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

27. 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)

28. 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)

29. Therapeutic evidence and outcome

30. 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: (n=60)
Protocol: (n=60)
Surviving Sepsis Campaign:
Early AB
EGDT
Vasopressor/inotrope
Transfusion
rhAPC
Corticosteroids

31. 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)

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

33. 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

34. 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