`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
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
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 time-
dependent risk of irreversible and
irreplaceable organ failure)
6
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
7
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
8
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
10
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
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
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
Time to Antimicrobial: Severe Sepsis
Ferrer et al, Crit Care Med 2014;42:1749-1755
Hospital M
ort
alit
y
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
Meta-
analysis:
IAA in
severe
infection
16OR Death
Paul AAC
2010;54:
4851–4863
17
CAP Septic Shock: Finnsepsis
Varpula et al, Acta Anesthesiol Scand 2007
18
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
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
-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
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
22
Time to Antimicrobial in Sepsis/Septic
Shock: Sterling Meta-analysis
Sterling et al, Crit Care Med, 2015:43:1907-1915
23
the “purgamentum init, exit
purgamentum” problem
Sterling et al, Crit Care Med, 2015:43:1907-1915
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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25
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
Early Antimicrobials in Sepsis
and Septic Shock: The Gold
Standard
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