Early Antibiotics for Sepsis and Septic Shock: A Gold Standard Anand Kumar MD, FRCPC, FCCP, FCCM Professor of Medicine University of Manitoba Health Sciences Centre St. Boniface Hospital Winnipeg, Manitoba For available slides: search anand kumar medicine manitoba Email: akumar61@yahoo.com `
Surviving Sepsis Bundle 2012 Severe Sepsis 3-Hour Resuscitation Bundle administer broad spectrum antimicrobials (1 hr) lactate level blood cultures prior to administration of antimicrobials 30 ml/kg crystalloid for hypotension or lactate 4 mmol/l
The Gold Standard for Evidence in Medical Science RCT? Generalizability Reproducibility! Glycemic control Physiologic corticosteroid therapy Activated protein C (drotrecogin-alfa) Goal-directed resuscitation 3
The Gold Standard for Evidence in Biological Science Biologic rationale a reasonable hypothesis Reproducibility across a wide range of study designs including observational studies; in the case of early antimicrobials Experimental animal studies Direct observational human data Indirect but related observational data Bundle analysis 4
Speed is Life The speed of clearance of the microbial pathogen is the critical determinant of outcome in septic shock (and other conditions where there is a timedependent risk of irreversible and irreplaceable organ failure) 5
Sepsis and Septic Shock: An Intensivist s Immunologic View Antimicrobials Infection CARS SIRS Organ Injury Antiinflammatory (endogenous) Time RECOVERY van der Poll T, van Deventer SJH. Infect Dis Clin N Am 6
An Injury Paradigm of Septic Shock: The Golden Hours A Kumar, Virulence 2014;5:80 97 Cellular dysfunction/tissue injury DEATH Inflammatory response Toxic burden Shock Threshold Microbial load TIME 7
An Injury Paradigm of Sepsis and Septic Shock earlier antimicrobial therapy Cellular dysfunction/tissue injury Shock Threshold Microbial load Inflammatory response Toxic burden A Kumar, Virulence 2014;5:80 97 TIME 8
% survival E. coli murine peritonitis/septic shock mortality vs time of antibiotic initiation 100 1500 cfu 80 60 40 20 0 sham (n=20) no Rx (n=20) saline (n=10) Ab Rx 0h (n=10) Ab Rx 6h (n=10) Ab Rx 12h (n=10) Ab Rx 15h (n=10) Ab Rx 18h (n=10) time response p<.0001 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Kumar et al, JID 2006 hrs post-implant 9
MAP (mm Hg) Mean Arterial Pressure in Murine 120 Septic Shock 100 80 * 60 40 P < 0.0001 20 0 12 24 36 48 60 72 84 96 Time (hr) Kumar et al, JID 2006 10
Cumulative Initiation of Effective Antimicrobial Therapy and Survival in Septic Shock fraction of total patients 1.0 survival fraction cumulative antibiotic initiation 0.8 0.6 0.4 0.2 0.0 Kumar et al. CCM. 2006:34:1589-96. time from hypotension onset (hrs) 11
Odds Ratio of Death (95% Confidence Interval) Mortality Risk with Increasing Delays in Initiation of Effective Antimicrobial Therapy 100 10 1 Kumar et al, CCM. 2006:34:1589-96. Time (hrs) 12
Hospital Mortality Time to Antimicrobial: Severe Sepsis Ferrer et al, Crit Care Med 2014;42:1749-1755
Benefit of Early versus Late Antibiotics Author Year N Diagnosis Miner 2001 171 Meningitis Larche 2002 88 Bact/pneumonia* Houck 2004 13,771 Pneumonia Proulx 2005 118 Meningitis Meehan 1997 14,069 Pneumonia Gacouin 2002 213 Legionella Iregui 2006 107 VAP Lodise 2003 167 S. aureus Kang 2003 123 P. aeruginosa * courtesy, C Natanson 0.01 0.1 1 10 100 Harm Benefit Odds Ratio of Survival (95% CI)
Impact of Appropriateness of Initial Antimicrobial Therapy on Survival from Septic Shock all culture + culture - bacteremia + bacteremia - community nosocomial pneu IAI sst uti cri all culture + culture - bacteremia + bacteremia - community nosocomial pneu IAI sst uti cri inappropriate appropriate lcbi %survival % appropriate 0 20 40 60 80 100 0 10 20 30 40 50 60 70 80 percent (%) survival (%) Kumar et al, Chest 2009; 136:1237 1248 lcbi 15
Metaanalysis: IAA in severe infection Paul AAC 2010;54: 4851 4863 OR Death 16
CAP Septic Shock: Finnsepsis Varpula et al, Acta Anesthesiol Scand 2007 17
Impact of Bundle Elements on Mortality of Septic Shock p value 0-1 hr.008 1-3 hr.127 3-6 hr.419 prev AbRx.383 fluid challenge.966 low dose steroid.688 apc.004.25 1 Hazard Ratio 4 Ferrer et al, AJRCCM 2009;180:861-6 18
Author/Yr Rivers 01 Trzeciak '06 Kortgen '06 Shapiro '06 Micek '06 Nguyen '07 Jones '07 El Solh 08 Studies of Severe Sepsis Bundles Survival Overall Odds Ratio of Survival (95% CI) p < 0.0001 Heterogeneity I 2 = 0%, p = 0.97 0.01 0.1 1 10 100 Favors Control Favors Bundle Barochia, et al. Crit Care Med. 2010 Vol. 38, No. 2
Studies of Severe Sepsis Bundles (what changes?): Hours to Antibiotics Author/Yr Rivers 01 Trzeciak '06 Kortgen '06 Shapiro '06 Micek '06 Nguyen '07 Jones '07 El Solh 08 3 2 1 0-1 -2 p < 0.0001 Favors Control Favors Bundle Weighted Mean Difference (± 95% CI) -3 Heterogeneity I 2 = 0%, p = 0.89 Barochia, et al. Crit Care Med. 2010 Vol. 38, No. 2
0.0001 0.001 0.01 0.1 10 100 1000 10000 Studies of Severe Sepsis Bundles Resuscitation Components (what changes?) Author / Year Rivers 01 Trzeciak '06 Kortgen '06 Shapiro '06 Micek '06 Nguyen '07 Jones '07 El Solh 08 Rivers 01 Trzeciak '06 Kortgen '06 Shapiro '06 Micek '06 Nguyen '07 Jones '07 El Solh 08 Barochia, et al. Crit Care Med. 2010 Vol. 38, No. 2 Crystalloid Usage (L) Overall not reportable -4-2 0 2 4 Inotropes I 2 = 89% p < 0.0001 I 2 = 0% p = 0.57 p = 0.0005 0.001 0.01 0.1 1 10 100 1000 Favors Control Favors Bundle Vasopressor Usage Overall not reportable 1 RBC Overall not reportable I 2 = 84% p < 0.0001 I 2 = 89% p <.0001 0.001 0.01 0.1 1 10 100 1000 Favors Control Favors Bundle
Time to Antimicrobial in Sepsis/Septic Shock: Sterling Meta-analysis Sterling et al, Crit Care Med, 2015:43:1907-1915 22
the purgamentum init, exit purgamentum problem Sterling et al, Crit Care Med, 2015:43:1907-1915 23
Requirements for an appropriate time to antimicrobial study 1. Plausible biologic rationale 2. Index to appropriate antimicrobial Systematic bias to null 3. Index to an appropriate clinical start-point Physiologic parameter vs administrative Inclusion of patients with unclear start-point (systematic bias to null) 24
Time to Antimicrobial: Severe Sepsis 100% 75% Mortality and Timing of Appropriate Antibiotic Therapy 100% 100% 86% 81% 70% 50% 25% 25% 19% 0% 0-1 1.1-2 2.1-6 6.1-12 12.1-24 24.1-48 48.1-72 Timing with respect to dose of 1st appropriate antibiotic (hours) Kumar et al. July 2003 Septic Shock data set 25
Early Antimicrobials in Sepsis and Septic Shock: The Gold Standard 26