Early Antibiotics for Sepsis and Septic Shock: A Gold Standard

Transcription

1 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 akumar61@yahoo.com `

2 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

3 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

4 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

5 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

6 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

7 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

8 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

9 % survival E. coli murine peritonitis/septic shock mortality vs time of antibiotic initiation cfu 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< Kumar et al, JID 2006 hrs post-implant 9

10 MAP (mm Hg) Mean Arterial Pressure in Murine 120 Septic Shock * P < Time (hr) Kumar et al, JID

11 Cumulative Initiation of Effective Antimicrobial Therapy and Survival in Septic Shock fraction of total patients 1.0 survival fraction cumulative antibiotic initiation Kumar et al. CCM. 2006:34: time from hypotension onset (hrs) 11

12 Odds Ratio of Death (95% Confidence Interval) Mortality Risk with Increasing Delays in Initiation of Effective Antimicrobial Therapy Kumar et al, CCM. 2006:34: Time (hrs) 12

13 Hospital Mortality Time to Antimicrobial: Severe Sepsis Ferrer et al, Crit Care Med 2014;42:

14 Benefit of Early versus Late Antibiotics Author Year N Diagnosis Miner Meningitis Larche Bact/pneumonia* Houck ,771 Pneumonia Proulx Meningitis Meehan ,069 Pneumonia Gacouin Legionella Iregui VAP Lodise S. aureus Kang P. aeruginosa * courtesy, C Natanson Harm Benefit Odds Ratio of Survival (95% CI)

15 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 percent (%) survival (%) Kumar et al, Chest 2009; 136: lcbi 15

16 Metaanalysis: IAA in severe infection Paul AAC 2010;54: OR Death 16

17 CAP Septic Shock: Finnsepsis Varpula et al, Acta Anesthesiol Scand

18 Impact of Bundle Elements on Mortality of Septic Shock p value 0-1 hr hr hr.419 prev AbRx.383 fluid challenge.966 low dose steroid.688 apc Hazard Ratio 4 Ferrer et al, AJRCCM 2009;180:

19 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 < Heterogeneity I 2 = 0%, p = Favors Control Favors Bundle Barochia, et al. Crit Care Med Vol. 38, No. 2

20 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 p < Favors Control Favors Bundle Weighted Mean Difference (± 95% CI) -3 Heterogeneity I 2 = 0%, p = 0.89 Barochia, et al. Crit Care Med Vol. 38, No. 2

21 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 Vol. 38, No. 2 Crystalloid Usage (L) Overall not reportable Inotropes I 2 = 89% p < I 2 = 0% p = 0.57 p = Favors Control Favors Bundle Vasopressor Usage Overall not reportable 1 RBC Overall not reportable I 2 = 84% p < I 2 = 89% p < Favors Control Favors Bundle

22 Time to Antimicrobial in Sepsis/Septic Shock: Sterling Meta-analysis Sterling et al, Crit Care Med, 2015:43:

23 the purgamentum init, exit purgamentum problem Sterling et al, Crit Care Med, 2015:43:

24 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

25 Time to Antimicrobial: Severe Sepsis 100% 75% Mortality and Timing of Appropriate Antibiotic Therapy 100% 100% 86% 81% 70% 50% 25% 25% 19% 0% Timing with respect to dose of 1st appropriate antibiotic (hours) Kumar et al. July 2003 Septic Shock data set 25

26 Early Antimicrobials in Sepsis and Septic Shock: The Gold Standard 26