early antibiotics for sepsis and septic shock: a gold standard · surviving sepsis bundle 2012...
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`Anand Kumar MD, FRCPC, FCCP, FCCMProfessor of Medicine
University of Manitoba
Health Sciences Centre
St. Boniface Hospital
Winnipeg, Manitoba
For available slides: search “anand kumar” “medicine” “manitoba”
Email: [email protected]
Early Antibiotics for Sepsis and Septic Shock: A Gold Standard
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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
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The Gold Standard for Evidence
in Medical Science
• RCT?
– Generalizability
– Reproducibility!
• Glycemic control
• Physiologic corticosteroid therapy
• Activated protein C (drotrecogin-alfa)
• Goal-directed resuscitation
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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
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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 time-
dependent risk of irreversible and
irreplaceable organ failure)
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Time
Antiinflammatory
(endogenous)
CARS
SIRS RECOVERY
OrganInjury
van der Poll T, van Deventer SJH. Infect Dis Clin N Am
Infection
Antimicrobials
Sepsis and Septic Shock: An
Intensivist’s Immunologic View
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Microbial load
Inflammatory response
Toxic burden
Cellular dysfunction/tissue injury
TIME
Shock
Threshold
DEATH
An Injury Paradigm of Septic
Shock: The Golden HoursA Kumar, Virulence 2014;5:80–97
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An Injury Paradigm of Sepsis
and Septic Shock
Microbial load
Inflammatory response
Toxic burden
Cellular dysfunction/tissue injury
TIME
earlier
antimicrobial
therapy
Shock
Threshold
A Kumar, Virulence 2014;5:80–97
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0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
hrs post-implant
% s
urv
ival
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
1500 cfu
E. coli murine peritonitis/septic shock
mortality vs time of antibiotic initiation
Kumar et al, JID 2006
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Mean Arterial Pressure in Murine
Septic Shock
*
††
†††
†P < 0.0001
Time (hr)
0 12 24 36 48 60 72 84 96
MA
P (
mm
Hg
)
20
40
60
80
100
120
Kumar et al, JID 2006
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11Kumar et al. CCM. 2006:34:1589-96.
Cumulative Initiation of Effective
Antimicrobial Therapy and Survival in
Septic Shock
time from hypotension onset (hrs)
fraction o
f to
tal patients
0.0
0.2
0.4
0.6
0.8
1.0 survival fraction
cumulative antibioticinitiation
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12Kumar et al, CCM. 2006:34:1589-96.
Mortality Risk with Increasing Delays in
Initiation of Effective Antimicrobial Therapy
Time (hrs)
Odds R
atio o
f D
eath
(95%
Confidence I
nte
rval)
1
10
100
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Time to Antimicrobial: Severe Sepsis
Ferrer et al, Crit Care Med 2014;42:1749-1755
Hospital M
ort
alit
y
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Benefit of Early versus Late Antibiotics
Odds Ratio of Survival (95% CI)
0.01 0.1 1 10 100
BenefitHarm
* courtesy, C Natanson
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
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Impact of Appropriateness of Initial Antimicrobial
Therapy on Survival from Septic Shock
percent (%)
0 20 40 60 80 100
lcbi
cri
uti
sst
IAI
pneu
nosocomial
community
bacteremia -
bacteremia +
culture -
culture +
all
%survival
% appropriate
survival (%)
0 10 20 30 40 50 60 70 80
lcbi
cri
uti
sst
IAI
pneu
nosocomial
community
bacteremia -
bacteremia +
culture -
culture +
all
inappropriate
appropriate
Kumar et al, Chest 2009; 136:1237–1248
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Meta-
analysis:
IAA in
severe
infection
16OR Death
Paul AAC
2010;54:
4851–4863
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CAP Septic Shock: Finnsepsis
Varpula et al, Acta Anesthesiol Scand 2007
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Impact of Bundle Elements on
Mortality of Septic Shock
Hazard Ratio
1
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
4.25
Ferrer et al, AJRCCM 2009;180:861-6
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Barochia, et al. Crit Care Med. 2010 Vol. 38, No. 2
0.01 0.1 1 10 100
Favors Control Favors Bundle
p < 0.0001
Heterogeneity
I2 = 0%, p = 0.97
Overall Odds Ratio
of Survival (95% CI)
Trzeciak '06
Kortgen '06
Shapiro '06
Micek '06
Nguyen '07
Jones '07
Author/Yr
Studies of Severe Sepsis
Bundles Survival
El Solh ‘08
Rivers ‘01
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-3-2-10123
p < 0.0001
Favors Control Favors Bundle
Weighted Mean Difference (± 95% CI)
Heterogeneity
I2 = 0%, p = 0.89
Studies of Severe Sepsis Bundles
(what changes?): Hours to Antibiotics
Barochia, et al. Crit Care Med. 2010 Vol. 38, No. 2
Trzeciak '06
Kortgen '06
Shapiro '06
Micek '06
Nguyen '07
Jones '07
Author/Yr
El Solh ‘08
Rivers ‘01
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p = 0.0005
Studies of Severe Sepsis Bundles Resuscitation
Components (what changes?)
I2 = 89%
p < 0.0001
Author / Year
Trzeciak '06Kortgen '06Shapiro '06Micek '06Nguyen '07Jones '07
Overall not reportable
Crystalloid Usage (L)
-4 -2 0 2 4
El Solh ‘08
Rivers ‘01
Vasopressor Usage
0.0
001
0.0
01
0.0
1
0.1 1 10
10
0
10
00
10
000
I2 = 84%
p < 0.0001
Overall not reportable
I2 = 0%
p = 0.57
Barochia, et al. Crit Care Med.
2010 Vol. 38, No. 2
Inotropes
Favors Control Favors Bundle0.001 0.01 0.1 1 10 100 1000
Trzeciak '06Kortgen '06Shapiro '06Micek '06Nguyen '07Jones '07El Solh ‘08
Rivers ‘01
RBC
Favors Control Favors Bundle0.001 0.01 0.1 1 10 100 1000
I2 = 89%
p < .0001
Overall not reportable
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Time to Antimicrobial in Sepsis/Septic
Shock: Sterling Meta-analysis
Sterling et al, Crit Care Med, 2015:43:1907-1915
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the “purgamentum init, exit
purgamentum” problem
Sterling et al, Crit Care Med, 2015:43:1907-1915
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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)
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Time to Antimicrobial: Severe
Sepsis
0%
25%
50%
75%
100%
0-1 1.1-2 2.1-6 6.1-12
12.1-24
24.1-48
48.1-72
25%
19%
70%
81%86%
100% 100%
Timing with respect to dose of 1st appropriate antibiotic (hours)
Mortality and Timing of Appropriate Antibiotic Therapy
Kumar et al. July 2003 Septic Shock data set
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Early Antimicrobials in Sepsis
and Septic Shock: The Gold
Standard
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