Educational Workshop

Transcription

1 Educational Workshop EW02: Management of severe sepsis and septic shock anno 2015 Arranged with ESGBIS & International Sepsis Forum (ISF) Convenors: W. Joost Wiersinga, Amsterdam, NL Tom van der Poll, Amsterdam, NL Faculty: Jean Marc Cavaillon, Paris, FR Evangelos Giamarellos-Bourboulis, Athens, GR Mervyn Singer, London, UK Marked in red = no handouts available

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3 SEVERE SEPSIS MANAGEMENT ISSUES IN SPECIAL HOSTS Ε. J. Giamarellos-Bourboulis, MD, PhD Associate Professor of Medicine 4 th Department of Internal Medicine University of Athens, Medical School, Greece Guest Professor, Center for Sepsis Control and Care, Jena University Hospital, Germany DISCLOSURE OF INTEREST Un-restricted educational grants from: AlfaWassermann SpA, Italy AbbVie SA, USA BRAHMS GmbH, Germany Merck Hellas SA Sanofi-Aventis Hellas SA Polyphor SA, CH Funded research by FP7 project HemoSpec Scientific advise/speaker for: AbbVie SA Biotest GmbH, Germany BRAHMS GmbH, Germany Clinigen SA Novartis SA, CH UNCOMPLICATED SEPSIS Any clinically or microbiologically documented Temperature >38 0 infection C or <36 0 C+ 2: Pulse rate >90 beats/min Breath rate >20/min or PaCO 2 <32 mmhg White blood cells >12000/mm 3 or <4000 mm 3 or >10% immature bands Levy M, et al. Crit Care Med 2003; 31: 1250

4 SEVERE SEPSIS Sepsis hypoperfusion + 1 organ failure ARDS PaO 2 /FiO 2 <200 + diffuse shadows in chest X-ray Central nervous system Abrupt change of mental status Acute renal failure Urine output <0.5 ml/h/kg weight last 2 h + normal balance Metabolic acidosis ph <7.30 or base deficit > 5 mmol/l + lactate > 2 x upper normal Acute coagulopathy PLTs < /mm 3 or INR >1.5 SEPTIC SHOCK Severe sepsis + systolic blood pressure < 90 mmhg despite adequate fluid resuscitation NEED FOR VASOPRESSORS Levy M, et al. Crit Care Med 2003; 31: 1250 WHAT IS A SPECIAL HOST? Immunocompromised (e.g. neutropenic) Under a situation heavily imposing on the microbiology Type of infection Type of failing organ NEED FOR AN INDIVIDUALIZED APPROACH

5 EARLY ANTIMICROBIALS!!! (Kumar A, et al. Crit Care Med 2006; 34: 1589) Outcome Cumulative effective antimicrobial therapy 100 Survival (%) Time (h) after hypotension HELLENIC SEPSIS STUDY GROUP ΕΛΛΗΝΙΚΟ ΙΝΣΤΙΤΟΥΤΟ ΜΕΛΕΤΗΣ ΤΗΣ ΣΗΨΗΣ HELLENIC INSTITUTE FOR THE STUDY OF SEPSIS : 32 CENTERS : 3 CENTERS 29% OF TOTAL ICU BEDS : 2 CENTERS : 1 CENTER POLYMICROBIAL INFECTIONS: ER ADMISSION (Koupetori M, et al. BMC Infect Dis 2014; 14: 272) * *p< 0.05 between the two periods

6 RESISTANCE PATTERNS: ER ADMISSION (Koupetori M, et al. BMC Infect Dis 2014; 14: 272) *p< 0.05 between the two periods DRIVERS OF RESISTANCE OUTSIDE THE ICU (Koupetori M, et al. BMC Infect Dis 2014; 14: 272) OR 95%CI p APACHE II> History of COPD Pigtail ureter catheterization Chronic hemodialysis Intake of antibiotics 3 months Residence in long-term care facility < DE-ESCALATION POLICY (Koupetori M, et al. BMC Infect Dis 2014; 14: 272) log-rank: p: HR 95%CI p S.sepsis/shock Age Gender disease De-escalation log-rank: p: HR 95%CI p S.sepsis/shock < Age Gender disease De-escalation

7 POLYMICROBIAL INFECTIONS: PRESENTATION AFTER ICU ADMISSION (Koupetori M, et al. BMC Infect Dis 2014; 14: 272) RESISTANCE PATTERNS: PRESENTATION AFTER ICU ADMISSION (Koupetori M, et al. BMC Infect Dis 2014; 14: 272) TAKE CARE IN NEUTROPENIA! (Dellinger RP, et al. Crit Care Med 2013; 41: 580) Cover empirically Pseudomonas aeruginosa + Acinetobacter baumannii + MRSA Recent exposure to hospital environment and/or antimicrobials? Resistance surveillance of the hospital (for hospitalacquired sepsis) The length of treatment should be 14 days.

8 THE NEED FOR BROAD TREATMENT (Bucaneve G, et al. J Clin Oncol 2014; 32: 1463) High-risk neutropenic fever Prospective, multicenter, randomized, unblinded Pip/tazo (n= 203, analysed= 190) Pip/tazo + tigecycline (n= 187, analyzed= 174) Primary endpoint: Successful response Failure= death; persistence of bacteremia >24 hours; development of MODS; infection relapse 7 days after discontinuation; toxicity Factors related with failure of empiric treatment: Monotherapy (OR: 2.86,; p< ) Acute leukemia (OR: 2.54; p: 0.002) THE FRENCH STUDY (JAMA 2002; 288: 862) (START hydrocortisone replacement 3-8 h from onset of hypotension) CORTICUS TRIAL (N Engl J Med 2008; 358: 111 (START hydrocortisone replacement <72 h from onset of hypotension)

9 THE APPROACH OF THE HELLENIC SEPSIS STUDY GROUP (1) (Katsenos C, et al. Crit Care Med 2014; 42: 1651) Late: >9hrs from vasopressors (n= 124) Early: <9hrs from vasopressors (n= 46) log-rank: p: THE APPROACH OF THE HELLENIC SEPSIS STUDY GROUP (2) (Katsenos C, et al. Crit Care Med 2014; 42: 1651) Late: >9hrs from vasopressors (n= 124) Early: <9hrs from vasopressors (n= 46) log-rank: p: AN EFFECT ON TNFα- PRODUCTION BY CIRCULATING MONOCYTES (Katsenos C, et al. Crit Care Med 2014; 42: 1651) p: 0.019

10 A CRITICAL CARE CONDITION Male, 60 yrs Θ: 39 0 C Hypoxemia SAP: 85mmHg Unanswered dilemmas: Are early antimicrobials the only solution? Is there some evident adjunctive therapy ( ignored # not fancy )? SEVERE COMMUNITY-ACQUIRED PNEUMONIA (Restrepo MI, et al. Eur Resp J 2009; 33: 153) (-) Macrolide (n= 133) (+) Macrolide (n= 104) 56.9% Mortality on day % p< % p: % Severe sepsis Macrolide-resistant pathogens META-ANALYSIS OF 16 OBSERVATIONAL STUDIES (Nie W, et al. J Antimicrob Chemother 2014; 69: 1441)

11 SUBGROUP ANALYSIS OF MORTALITY RISK (Nie W, et al. J Antimicrob Chemother 2014; 69: 1441) Characteristic No of studies OR (95%CIs) p All studies ( ) < Severe ( ) < Pneumococcal ( ) 0.03 PROSPECTIVE, RANDOMIZED APPROACH (Garin N, et al. JAMA Intern Med 2014; 174: 1894) Community-acquired pneumonia Cefuroxime or amoxycillin/clavulanate Clarithromycin 500mg bid iv or po Monotherapy β-lactam / β-lactam + clarithromycin combination Primary endpoint: patients not reaching clinical stability on day 7 Powered for non-inferiority BENEFITS OF ADDING CLARITHROMYCIN (Garin N, et al. JAMA Intern Med 2014; 174: 1894) Monotherapy (n= 291) Combination (n= 289) p: % of patients 41.2% 33.6% 7.9% p: % Instability Day 7 30-day readmission

12 SURVIVING SEPSIS CAMPAIGN 2012 (Dellinger RP, et al. Crit Care Med 2013, 41: ) Addition of a macrolide for patients with septic shock after Streptococcus pneumoniae bacteremia Grade of evidence 2Β 200 patients with VAP + Sepsis/ Severe Sepsis/Septic Shock (ACCP/SCCM 1992) 100 iv PLACEBO + ANTIBIOTICS** 100 iv CLARITHROMYCIN* + ANTIBIOTICS** *1000mg iv daily within one hour x 3 days **Standard of Care (NCT ) Giamarellos-Bourboulis EJ, et al. Clin Infect Dis 2008; 46; 1157 MORTALITY BY SEPTIC SHOCK + MODS PLACEBO CLARITHROMYCIN p: p: Mortality (%) % 38.9% Odds ratio for death

13 EFFECT ON RESOLUTION OF VAP % resolved cases 80% 60% 40% 20% Placebo Clarithromycin p: %: 10 days 50%: 15.5 days 0% Days STUDY FLOW CHART (Giamarellos-Bourboulis EJ, et al. J Antimicrob Chemother 2014; 69: 1111) COMMUNITY-ACQUIRED OR HOSPITAL-ACQUIRED SEPSIS (n= 654) Gram-negative bacteremia/acute pyelonephritis/acute intrabdominal infection EXCLUDED (n= 54) Macrolide intake (n= 53) Denial to consent (n=1) PLACEBO (N= 298) Premature discontinuation= 20 Analyzed= (NCT ) EudraCT number IV CLARITHROMYCIN (n= 302) 1000 mg daily one hour infusion x 4 days Premature discontinuation= 49 Analyzed= 302 STUDY ENDPOINTS Primary endpoint Mortality by severe sepsis/shock and MODS Secondary endpoint Time to resolution of underlying infection Exploratory endpoint Hospitalization cost

14 MORTALITY BY SEPTIC SHOCK + MODS PLACEBO CLARITHROMYCIN Mortality (%) % p: % Odds ratio for death p: % patients EFFECT ON INFECTION RESOLUTION IN SEVERE SEPSIS/SHOCK p: Placebo Clarithromycin 50%: 6 days 50%: 10 days Days FINANCIAL BENEFIT p:

15 GOLDEN HOUR IV fluids until CVP in normal Blood culture Broad-spectrum antimicrobials (potential for bolus injection first) The septic patient is a VIP V: Ventilate I: Infuse P: Pump