PCT-assisted antibiotic therapy

Transcription

1 PCT-assisted antibiotic therapy Prof. Zsolt Molnár Department of Anaesthesia and Intensive Care University of Szeged Hungary

2 Problems with the definition of sepsis

3 Definitive diagnoses with definitive treatment

4 Sepsis is not a definitive diagnosis Sepsis-syndrome and Las Vegas : Fever or hypothermia (> 38.3 o C or < 35.0 o C) Tachycardia (>90/min) Leukocytosis or leukopenia (> cells/mm 3, < 4000cells/mm 3, or > 10% immature forms) Hypotension (<90mmHg)

5 Sepsis is not a definitive diagnosis Sepsis-syndrome and Las Vegas : Fever or hypothermia (> 38.3 o C or < 35.0 o C) Tachycardia (>90/min) Leukocytosis or leukopenia (> cells/mm 3, < 4000cells/mm 3, or > 10% immature forms) Hypotension (<90mmHg)

6 Sepsis is not a definitive diagnosis 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

7 Sepsis definition SSC 2012 Sepsis is not a disease but a consensus

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

9 DAMP = Damage Assosiated Molecular Pattern PAMP = Pathogen Associated Molecular Pattern DAMP SIRS versus PAMP SIRS G+ Surgery, Trauma, Pancreatitis Isch-reperf. G- F (Courtesy of Janos Fazakas)

10 PCT kinetics after esophagectomy 15 S = 130 NS = 23 *p<0.05 * 2-5 ng/ml Procalcitonin (ng ml-1) 10 5 t 0 t 24 t 48 0 Survivors Non-survivors 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:

11 The expected course of PCT concentrations in a surgical patient without serious bacterial infection Lindberg et al., Scand J Clin Lab Invest 2002; 62:

12 Differential diagnostic value of procalcitonin in surgical and medical patients with septic shock Clec h et al. Crit Care Med 2006; 34: Medical patients: SIRS: PCT = 0.3 ( ) ng/ml Septic shock: PCT = 8.4 ( ) ng/ml PAMP Surgical patients: SIRS: PCT = 5.7 ( ) ng/ml Septic shock: PCT = 34 (7-76) ng/ml DAMP+PAMP Sepsis homogenious group of patients ie One size does not fit all 1 ng/ml, sens: 80% - spec: 94% 9.7 ng/ml, sens: 91% - spec: 74%

13 Nature Reviews Immunology Volume 13 December Proinlflammation Antiinlflammation

14 Nature Reviews Immunology Volume 13 December Overwhelming inflammation vs. prolonged immunosupression: Both can be deadly! Proinlflammation Antiinlflammation

15 Immunosupression over time less PCT response Priority of PCT kinetics over absolute values?

16

17 Is this patient septic or not?

18 I have never treated SEPSIS in my life! But

19 Does the patient have infection or not? Infection = ABs No infection = No ABs

20 Signs of infection Clinical signs: Most important Not good enough Fever (>38 o C), WBC (>12 000): Low sensitivity (~50%) Poooor! Galicier L and Richet H. Infect Control Hosp Epidemol 1985; 6: 487 Microbiology: Results: 24 hours or more Very late!

21 We need biomarkers! At least 173 of them!! My favourite is: procalcitonin (PCT)

22 The 3 fundamental questions to answer 1. Is there infection should I start empirical ABs? 2. Is it effective? 3. When should I stop?

23 Is there infection?

24 Christ-Crain M, et al. Lancet 2004; 363: Relative reduction in AB exposure : 50% No difference in outcome Proven infection: 21%

25 Layios N, et al. Crit Care Med 2012; 39: Limitations: 40% surgical patients (0.25, 0.5, 1.0 ng/ml cut off too low) In the whole sample ~90% of patients with PCT>1ng/ml received ABs

26 The EProK-study Trásy D et al.,(in review)

27 Increasing procalcitonin may be a good indicator of starting empirical antibiotic treatment in critically ill patients Patients with suspected infection = 209 PCT available at T -1 = 114 Infection = 85 No-infection = 29

28 Predicting infection (T -1 T 0 ) Trásy D et al.,(manuscript under submission) 77 % 85 % Kinetics over absolute values! Forget about CRP, WBC and T!

29 Tsangaris at al.: BMC Infectious Disease 2009;9: Infection Increasing PCT/24 h: May be a good indicator of infection The PCT value on the day of fever onset must be compared with previous day PCT values (chronic critically ill patient) No change in PCT/24 h: May be a good indicator of no infection Day before fever No infection

30 How does it work in clinical practice? Medical patients: SIRS: PCT = 0.3 ( ) ng/ml Septic shock: PCT = 8.4 ( ) ng/ml Clec h et al. Crit Care Med 2006; 34: Surgical patients: You admitted 2 hemodynamically stable critically ill patients from the ward SIRS: PCT = 5.7 ( ) ng/ml Septic shock: PCT = 34 (7-76) ng/ml AB yes? AB yes AB no 1 ng/ml, sens: 80% - spec: 94% 3 ng/ml 1-3 ng/ml 5-3 ng/ml AB no? AB yes AB no 9.7 ng/ml, sens: 91% - spec: 74%

31 Is the AB effective?

32 International guidelines

33 local protocols

34 BMC Infectious Diseases 2007, 7:21 28%

35 The EProK-study Trásy D et al.,(under review)

36 The EProK-study Patients with suspected infection= 209 Proven infection = 169 Effective AB = 127 (77%) Ineffective AB = 38 (23%) No infection = 44 Kinetics of PCT during T 0 -T 16 -T 24 : vs. Trásy D et al.,(under review) May indicate effective/ineffective AB treatment

37 PCT-kinetics to predict AB-effectiveness Trásy D et al.,(under review) PCT t 0 - t 16 PCT t 0 - t 24 55% 71% ( ) 75% ( ) 46% ( ) 89% ( ) < % 73% ( ) 82% ( ) 56% ( ) 91% ( ) <0.001 ICU mortality: Effective: 35%, Ineffective: 62%, p<0.001

38 Surgical and medical patients

39 The EProK-study Trásy D et al.,(under review) Medical: ~ 5ng/ml Surgical: ~20 ng/ml Absolute values are different, but kinetics are similar

40 Stopping AB-therapy

41 Lancet 2010; 375:

42 Mean difference without ABs: 2.7 days Relative reduction in AB exposure: 23% Lancet 2010; 375:

43 Inexperienced units Low (and fixed!) cut off values (<0.1 ng/ml or >90% decrease) Powered for 25% (3.75 day) reduction underpowered to show a significant 2 day reduction

44 Surviving Sepsis Guideline Dellinger RP et al Crit Care Med 2013; 41:

45 The 3 main answers with PCT 1. Is there infection? 2. Is the AB effective? 3. When to stop? Brave to withhold ABs Helps decision within h You may reduce AB exposure

46 Final thoughts

47 The most important lesson Auguste Rodin: The Thinker (1880)

48 Motto It doesn t matter whether you ve done the right thing, but whether you ve done everything to do the right thing (Rephrased by ZM from Bhagavad Gita)

49 Free for junior doctors (<29)!