ATS Clinical Year in Review Sepsis Charles L. Sprung, M.D.
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Transcript of ATS Clinical Year in Review Sepsis Charles L. Sprung, M.D.
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Department of Anesthesiology and Critical Care Medicine
Hadassah Medical Center
ATS Clinical Year in Review
Sepsis
Charles L. Sprung, M.D.
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Presenter DisclosuresPart 1: Personal financial relationships with commercial
interests relevant to this presentation during the past 12 months:
1. Eli Lilly & Co – Consultancies2. Novartis Corp- Other- Data Monitoring Committee 3. Takeda- Industry-sponsored grants4. Eisai, Corp- Other- Steering Committee + Industry-
sponsored grants5. Artisan Pharma, Inc- Other- Data Monitoring Committee 6. Hutchinson Technology Incorporated- Other- Data
Monitoring Committee
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Presenter Disclosures
Part 2: Personal financial relationships with non-commercial interests (e.g., government or other nonprofit funding) relevant to this presentation, within past 12 months:
No relationships to disclose
Part 3: Relevant institutional financial interests: No relationships to disclose
Part 4: Personal financial relationships with tobacco industry entities within the past 3 years:
No relationships to disclose
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• Russell JA, et al and the VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-87.
• Ferrer R, et al and Edusepsis Study Group. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. 2008;299:2294-2303.
• Moreno RP, et al and SAPS 3 Investigators. Sepsis mortality prediction based on predisposition, infection and response. Intensive Care Med 2008; 34:496–504.
• Dulhunty JM, et al and for the ANZICS Clinical Trials Group. Does severe non-infectious SIRS differ from severe sepsis? Results from a multi-centre Australian and New Zealand intensive care unit study. Intensive Care Med. 2008;34:1654-61.
Clinical Year in Review- Sepsis
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Surviving Sepsis Campaign Guidelines Vasopressors
• Either norepinephrine or dopamine as the first choice vasopressor agent to correct hypotension in septic shock.
Grade 1C
• Epinephrine, phenylephrine, or vasopressin should not be administered as the initial vasopressor in septic shock.
Grade 2C
• Vasopressin 0.03 units/min may be subsequently added to norepinephrine with anticipation of an effect equivalent to norepinephrine alone.
• Epinephrine be the first chosen alternative agent in septic shock that is poorly responsive to norepinephrine or dopamine. Grade 2B
Dellinger P. Crit Care Med 2008;36:296-327
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• In this multicenter, randomized, double-blind placebo-controlled study, patients in septic shock receiving a minimum of 5 μg of norepinephrine per minute were randomized to receive either low-dose vasopressin (0.01-0.03 U per minute) or norepinephrine (5 to 15 μg per minute) in addition to open-label vasopressors.
Clinical Year in Review- Sepsis
Russell JA. N Engl J Med 2008;358:877
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VASST PRIMARY HYPOTHESIS
• Low dose vasopressin (0.03 U/min) infusion compared to norepinephrine infusion decreases 28 day mortality from 60% to 50% in severe septic shock.
• N= 776 (power = 80%, α= 0.05)
Russell JA. N Engl J Med 2008;358:877
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VASST SECONDARY HYPOTHESES• The beneficial effects of vasopressin are more
pronounced in the subgroup of patients with more severe septic shock.
More Severe septic shock: ≥ 15 μg/min norepinephrine Less Severe septic shock: 5 - 14 μg/min norepinephrine
• 90-day mortality, days alive & free of organ dysfunction, length of stay (ICU & hospital)
Russell JA. N Engl J Med 2008;358:877
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CENTRES
• 27 centres in Canada, Australia and US
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Plasma Vasopressin Norepinephrine vs. Vasopressin
Off AVP
NE
AVP
Russell JA. N Engl J Med 2008;358:877
0
20
40
60
80
100
120
140
Baseline 6 hours 24 hours 72hours 7days
Timepoint
Pla
sma
vaso
pre
ssin
leve
l (
pmol
/L, m
edia
n +
IQR
)
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Mean Arterial PressureVasopressin vs Norepinephrine
NE
AVP
Russell JA. N Engl J Med 2008;358:877
0
20
40
60
80
100
120
0 5 10 15 20 25 30
Time from study drug infusion (days)
MA
P (
mm
Hg
, m
ea
n +
/-S
D)
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Heart rate Vasopressin vs Norepinephrine (p < 0.001)
NE
AVP
Russell JA. N Engl J Med 2008;358:877
50
60
70
80
90
100
110
120
130
0 5 10 15 20 25 30
Time from study drug infusion (days)
He
rat
rate
(b
ea
ts /
min
, m
ea
n +
/-S
D)
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Heart rate AVP vs. NE (Days 1 - 4, p < 0.001)
NE
AVP
Russell JA. N Engl J Med 2008;358:877
50
60
70
80
90
100
110
120
130
0 5 10 15 20 25 30
Time from study drug infusion (days)
He
rat
rate
(b
ea
ts /
min
, m
ea
n +
/-S
D)
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Survival - All Patients
Log-rank statistic
p = 0.27 day 28
p = 0.10 day 90
VasopressinNorepinephrine
0 10 30 50 70 90
00.2
0.4
0.6
0.8
1
Days since initiation of study drug
Pro
babili
ty o
f surv
ival
Russell JA. N Engl J Med 2008;358:877
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Serious Adverse Events
Norepinephrine
(N=382)
Vasopressin
(N=397)
p
Myocardial infarction / ischemia 7 (1.8) 8 (2.0) 1.0
Cardiac arrest 8 (2.1) 3 (0.8) 0.14
Tachyarrythmia 3 (0.8) 4 (1.0) 1.0
Bradyarrythmia 3 (0.8) 4 (1.0) 1.0
Mesenteric ischemia 13 (3.4) 9 (2.3) 0.39
Hyponatremia 1 (0.3) 1 (0.3) 1.0
Digital ischemia 2 (0.5) 8 (2.0) 0.11
Cerebrovascular accident 1 (0.3) 1 (0.3) 1.0
Other 2 (0.5) 5 (1.3) 0.45
Total 40 (10.5) 41 (10.3) 1.0
Russell JA. N Engl J Med 2008;358:877
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Survival - Less Severe Shock
Log-rank statistic
p = 0.05 day 28
p = 0.03 day 90
VasopressinNorepinephrine
0 10 30 50 70 90
00.2
0.4
0.6
0.8
1
Days since initiation of study drug
Pro
babili
ty o
f surv
ival
Russell JA. N Engl J Med 2008;358:877
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Survival - More Severe Shock
Log-rank statistic
p = 0.77 day 28
p = 0.92 day 90
VasopressinNorepinephrine
0 10 30 50 70 90
00.2
0.4
0.6
0.8
1
Days since initiation of study drug
Pro
babili
ty o
f surv
ival
Russell JA. N Engl J Med 2008;358:877
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• This study demonstrates the comparable effectiveness of vasopressin to norepinephrine therapy for vasopressor treatment of septic shock.
• Vasopressin was used as an addition to norepinephrine and/or other vasopressor therapy for patients with relatively stable blood pressures on vasopressors, not rescue therapy for shock unresponsive to vasopressors.
• Similar adverse events in the two groups may have been due to the exclusion of patients with acute heart disease in the study.
• Vasopressin plus norepinephrine may decrease mortality compared to norepinephrine alone in less severe septic shock.
• Treatment started 12 hours after septic shock may be too late for a vasopressor or any other therapeutic agent to affect mortality.
Clinical Year in Review- Comments
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• Recent septic shock studies demonstrate lower mortalities- this study - 37%, Sprung (N Engl J Med. 2008;358:111-124 )- 33% and Annane (Lancet 2007; 360: 767−84)- 37% than those previously reported- Annane (JAMA 2002;288:862-870 )- 58% and Annane (Am J Respir Crit Care Med 2003;168:165-72)- 60%.
• Physicians should be aware of the less recognized detrimental effects of catecholamines including stimulation of bacterial growth, increasing factors related to bacterial virulence and biofilm formation, affects on immune-cell populations and metabolic derangements which may not be present with alternatives such as vasopressin (Singer M. Lancet 2007;370:636-637).
Clinical Year in Review- Comments
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Survival - All Patients
Log-rank statistic
p = 0.27 day 28
p = 0.10 day 90
VasopressinNorepinephrine
0 10 30 50 70 90
00.2
0.4
0.6
0.8
1
Days since initiation of study drug
Pro
babili
ty o
f surv
ival
Russell JA. N Engl J Med 2008;358:877
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Outcomes: Mortality NICE SUGAR Study
Intensive Glucose Control
Conventional Glucose Control
Odds ratio
(95% CI)
Dead at 28 days670/3010
22.3%
627/3012
20.8%
1.09
(0.96 - 1.23)P = 0.17
Dead at 90 days829/3010
27.5%
751/3012
24.9%
1.14
(1.02 - 1.28)P = 0.02
Adjusted mortality at 90 days
Adjusted for operative admission, geographic region, age, admission
source, APACHE II score, mechanical ventilation
1.14
(1.01 - 1.29)P = 0.04
Finfer S. N Engl J Med 2009;360:1283
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Interaction of Vasopressin Infusion, Corticosteroid Treatment and Mortality of
Septic Shock
Russell et al. Crit Care Med 2009;37:811 - 818
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Vasopressin /Corticosteroid Mortality Interaction
Steroids Steroids P No
Steroids
No Steroids P
NE AVP NE AVP
131 (44.7) 106 (35.9) 0.03 19 (21.3) 34 (33.7) 0.06
0.008 (1)
0.001 (2)
1. Interaction statistic by logistic regression.2. Age-adjusted interaction statistic by logistic regression Russell et al. Crit Care Med 2009;37:811 - 818
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• Russell JA, et al and the VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-87.
• Ferrer R, et al and Edusepsis Study Group. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. 2008;299:2294-2303.
• Moreno RP, et al and SAPS 3 Investigators. Sepsis mortality prediction based on predisposition, infection and response. Intensive Care Med 2008; 34:496–504.
• Dulhunty JM, et al and for the ANZICS Clinical Trials Group. Does severe non-infectious SIRS differ from severe sepsis? Results from a multi-centre Australian and New Zealand intensive care unit study. Intensive Care Med. 2008;34:1654-61.
Clinical Year in Review- Sepsis
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• Most studies of new therapeutic agents to decrease the high mortality of patients with severe sepsis have been negative.
• Clinical study results and evidence-based guidelines are often not translated into clinical practice.
Clinical Year in Review- Sepsis
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EDUCATIONALPROGRAMME
POST-EDUCATIONDATA COLLECTION
NOV-DEC854 patients JAN-FEB MAR-JUN
1465 patients
2005 2006
BASELINE DATA COLLECTION
a before-and-after intervention study
2007
LONG-TERMFOLLOW-UP
MAR-JUN247 patients
JAMA 2008;299(19):2294-2303
Study Timeline
PE
RC
EP
TIO
N
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THE SPANISH NETWORK
59 ICUs (21% of all Spanish ICUs)3 1
2
2
1
13
8
9
9
24
6
3
4
3
J. Ibañez
(Palma de Mallorca)
R. Ferrer
(Sabadell)
G. González-Díaz
(Murcia)Manuel Quintana (Talavera)
J. Blanco
(Valladolid)Mª Victoria de la Torre (Málaga)
E. Palencia
(Madrid)
J. Garnacho
(Sevilla)
Area Coordinators:
General Coordination:Antonio ArtigasRicard Ferrer(Sabadell, Barcelona)
SSC CoordinationM. Levy
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Educational Program
Sepsis DefinitionsSepsis early recognitionSepsis treatments
Design EP
GeneralCoordination
AreaCoordinators
Area Coordinators + PI
Homogenize the EP
Educational Material
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Educational Program: Homogeneity
PI
HospitalManager
Interview
Physicians
Nurses
ICU
ED
Medical Ward
Surgical Ward
Graphic material: distribution and display
Clinical training
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Inclusion Criteria
• All ICU admissions from the emergency department or from wards because of severe sepsis or septic shock.
• All ICU patients who develop severe sepsis or septic shock.
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Process-of-care variables
SEPSIS RESUSCITATION BUNDLE
SEPSIS MANAGEMENT BUNDLE
6H
24H
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Resuscitation Bundle (6H)
* p<0.05
*
*
*
*
* *0
10
20
30
40
50
60
70
80
90
% C
om
pli
an
ce
Lactate Blood Cultures Antibiotics Fluids +Vasopresors
CVP>8 SvcO2>70 All
Preintervention Intervention
39.0
50.1 54.4
62.4 66.5
68.9
40.9
46.7
21.4
26.7
6.3
11.4
5.3
10.0
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Management Bundle (24h)
* p<0.05
* * *
*
0
10
20
30
40
50
60
70
80
90
% C
om
pli
an
ce
Steroids APC Glucose IPP All
Preintervention Intervention
45.4
54.7
44.3
51.9
44.6
49.6
85.782.7
10.9
15.7
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Educational Program and Mortality
4439.7
36.4
31.1
0
10
20
30
40
50
%
Hospital Mortality ICU Mortality
Preintervention Intervention
p= .036 p= .01
Absolute reduction: 4.3%Relative reduction 10%
28d Mortality: Kaplan-Meier curve
Absolute reduction: 4.3%Relative reduction 10%SSC objective was 25%!
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Impact of Baseline Compliance
0
5
10
15
20
25
30
Pre-Intervention Post-Intervention
%
Cat 1 Cat 2 Cat 3
0
5
10
15
20
25
30
Pre-Intervention Post-Intervention
%
Cat 1 Cat 2 Cat 3
20
25
30
35
40
45
50
Pre-Intervention Post-Intervention
%
Cat 1 Cat 2 Cat 3
Resuscitation Bundle Management Bundle
Mortality
* p<0.05
***
*
*
Cat 1: < 4 tasks (n= 20)Cat 2: 4-5 tasks (n= 19)Cat 3: > 5 tasks (n= 20)
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Resuscitation Bundle (6H)
0
10
20
30
40
50
60
70
80
90
% C
om
pli
an
ce
Lactate Blood Cultures Antibiotics Fluids + Vasopresors CVP>8 SvcO2>70 All
Preintervention Intervention Long-term
Long-term follow up (23 centers) * p<0.05
* **
*
*
42.8
61.1
69.6
53.5
60.5 59.165.4
71.0
56.7
44.7
53.0
65.2
25.2
30.0
39.3
10.0 13.7 14.6
6.3
12.97.3
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Management Bundle (24h)
0
10
20
30
40
50
60
70
80
90
100
% C
om
pli
an
ce
Steroids APC Glucose IPP All
Preintervention Intervention Long-term
Long-term follow up (23 centers) * p<0.05
*
* *
*
44.3
59.1
69.7
38.4
49.0
59.1
44.7
51.056.3
87.889.6 94.8
9.4
19.6
26.7
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Educational Program and Mortality
42.538.7
0
10
20
30
40
50
%
Hospital Mortality
Preintervention Intervention Long-term
38,5
Long-term follow up (23 centers)
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• At baseline, process of care compliance rates were extremely low.
• After the intervention, compliance improved in the sepsis resuscitation and management bundles and hospital mortality decreased from 44% to 40%.
• Long-term follow-up revealed that compliance with sepsis resuscitation bundles returned to baseline but compliance with sepsis management and mortality remained stable in relation to the post-intervention period.
Clinical Year in Review- Sepsis
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• This study demonstrated that a national educational program decreased hospital mortality in patients with severe sepsis.
• The study suggests that quality improvement programs using bundles of care may be more effective in decreasing mortality in sepsis than new treatments.
• Despite the fact that the interventions were rather simple, not institution specific and did not include more sophisticated, effective methods, mortality still decreased.
Clinical Year in Review- Comments
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• Baseline compliance was rather poor and although compliance improved, the improvement rates were not dramatic nor sustained, especially for some bundles which would seem important in decreasing mortality such as antibiotic administration.
• Recent studies of steroid therapy (Sprung CL. N Engl J Med. 2008;358:111-124) and glucose control (Brunkhorst FM. N Engl J Med 2008;358:125-39; Finfer S. N Engl J Med 2009;360:1283-97) showing a lack of benefit in decreasing mortality raise questions as to the benefit of these bundles used in this study in decreasing mortality.
• The design without a control group makes it difficult to establish a causal connection between the intervention, improvement in process of care variables and outcome.
Clinical Year in Review- Comments
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• Russell JA, et al and the VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877-87.
• Ferrer R, et al and Edusepsis Study Group. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. 2008;299:2294-2303.
• Moreno RP, et al and SAPS 3 Investigators. Sepsis mortality prediction based on predisposition, infection and response. Intensive Care Med 2008; 34:496–504.
• Dulhunty JM, et al and for the ANZICS Clinical Trials Group. Does severe non-infectious SIRS differ from severe sepsis? Results from a multi-centre Australian and New Zealand intensive care unit study. Intensive Care Med. 2008;34:1654-61.
Clinical Year in Review- Sepsis
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The PIRO ConceptThe PIRO Concept• Predisposition: Premorbid illness with reduced
probability of short term survival. Cultural or religious beliefs, age, gender.
• Insult: Culture and sensitivity (infection) of infecting pathogens; detection of disease amenable to source control.
Levy MM, Fink MP, Marshall JC, et al. (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.
Intensive Care Med 29:530-538.
• Organ: Organ dysfunction as number dysfunction of failing organs or composite score (e.g., MODS; SOFA; LOD).
• Response: SIRS, other signs of sepsis, shock, C-reactive protein.
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• PIRO (predisposition, infection, response, organ dysfunction/failure), a system for risk stratification, remains a concept that has not been tested clinically.
• Using the SAPS 3 database, 2628 patients in the ICU for > 48 hours were evaluated to determine the usefulness of PIRO for predicting mortality in patients with infection and sepsis.
Clinical Year in Review- Sepsis
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SAPS 3 PIRO ScoreSAPS 3 PIRO Score
Predisposition
• Age• Intra-hospital location• Co-Morbidities• Length of stay in the
hospital• Reasons for ICU
admission
Injury
• Acquisition of infection• Extension of infection• Site of infection• Agent
Response/Organdysfunction/failure
• Renal dysfunction• Coagulation dysfunction• Cardiovascular failure• Respiratory failure• Renal failure• Coagulation failure• CNS failure
Moreno R. Intensive Care Med 2008;34:496-504
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• Hospital mortality was 41%.
• The SAPS 3 PIRO score had excellent predictive value for mortality and the PIRO components independently contributed to outcome prediction.
Clinical Year in Review- Sepsis
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SAPS 3 INFECTION MODEL SCORE SHEETSAPS 3 INFECTION MODEL SCORE SHEET
Moreno R. Intensive Care Med 2008;34:496-504
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PROGNOSTIC PERFORMANCE: PROGNOSTIC PERFORMANCE: DiscriminationDiscrimination
SAPS 3 model:
aROC: 0.735
(95% CI: 0.716-0.754)
PIRO model:
aROC: 0.772
(95% CI: 0.754-0.790)1,00,80,60,40,20,0
1 - Specificity
1,0
0,8
0,6
0,4
0,2
0,0
Se
ns
itiv
ity
PIROmodel
SAPS 3model
Diagonale Segmente ergeben sich aus Bindungen.
ROC-Kurve
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• This is the first study addressing the question as to which factors affect the outcome of patients with sepsis in which the three levels of predisposition, injury and response were addressed together.
• This study demonstrates the clinical validity of the PIRO concept whose components independently contributed to mortality prediction.
• This PIRO system modeling the risk of mortality from sepsis attributes different weights to specific organ failures which is different than other scores which give all organ failures the same weight.
• Although provocative, the proposed system should be prospectively validated in an independent cohort to demonstrate its specific usefulness and clinical utility.
Clinical Year in Review- Comments
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Does severe non-infectious SIRS differ Does severe non-infectious SIRS differ from severe sepsis?from severe sepsis?
Results from a multi-centre Australian and New Zealand intensive care unit study
Dulhunty JM1,2, Lipman J1,2, Finfer S3-5, and the Sepsis Study Investigators for the ANZICS Clinical Trials Group
Intensive Care Med. 2008;34:1654-1661
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Background• Systemic inflammatory response syndrome (SIRS) -
physiological & laboratory abnormalities that accompany
inflammation
• Severe sepsis (SS) – well-described (high mortality & treatment
costs)
• Severe non-infectious SIRS (SNISIRS) – poorly described
SS = infection + SIRS + organ dysfunction
SNISIRS = non-infectious insult + SIRS + organ dysfunction
What is the mortality rate and cause of death in SNISIRS?
Is there a difference in the time-course of organ failure between SS and SNISIRS?
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Methods• Prospective inception cohort study involving 23 ICUs
• Inclusion criteria: all elective & unscheduled ICU admissions ≥ 48 hours or < 48 hours with SIRS/organ dysfunction
• Patients screened daily for SIRS, an infectious focus & organ dysfunction from day 1 to ICU discharge or day 28
• SOFA scores used to monitor organ dysfunction
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• The ICU prevalence of SS and SNISIRS was 20% and 28%, respectively.
• ICU (27% vs. 25%) and 28-day (33% vs. 32%) mortalities were similar in both groups.
• Multi-organ failure was the most common cause of death in SS and neurological failure in SNISIRS.
• The time to peak organ dysfunction, overall duration of organ dysfunction and ICU stay were shorter in SNISIRS patients.
Clinical Year in Review- Sepsis
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Mortality was similar in patients with SS and SNISIRS
Days post ICU admission
2824201612840
Su
rviv
al %
100
80
60
40
20
0
SNISIRSSS
P = 0.50
Dulhunty JM. Intensive Care Med. 2008;34:1654-61
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Organ dysfunction due to infectious & non-infectious insults is common & frequently present
on admission to the ICU
ICU prevalence:
SS – 20% (707/3543)
SNISIRS – 28% (980/3543)
2119
1570
1152
891
728627
514
202106
271203
17 124539
160
486
822
668
352
70221
16
364307 253
31
602 560453
0
500
1000
1500
2000
2500
1 2 3 4 5 6 7 14 21 28
Day of admission
Nu
mb
er
of
pa
tie
nts
No organ dysfunction SNISIRS SS
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Prevalence of organ failure differed
Resp.Haem. Liver
Card.CNS
Renal
0
10
20
30
40
50
60
70
80
%
SS SNISIRS
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Causes of death differed
Multi-organfailure
Neuro-logical
Cardiacarrest
Isolatedresp.
failure
Haem.shock
Pulmonaryembolism
Other Unknown
0
20
40
60
80
100
120
140
160
180
N
SS SNISIRS
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• This study demonstrates that organ dysfunction from both SS and SNISIRS are common in ICU patients.
• The fact that SNISIRS is common in ICU patients should alert intensivists to the fact that many of these patients do not require antibiotics. Continued antibiotic use in these patients could lead to unnecessary increased antibiotic resistance.
• This is the first study to evaluate the type and time course of organ dysfunction comparing SS to SNISIRS.
Clinical Year in Review- Comments
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• The similar mortalities of SNISIRS compared to SS require further investigation.
• Although the study prospectively evaluated a large number of patients, the findings in SNISIRS patients may relate to the specific case mix and geographic location of the patients.
• The study is limited by the lack of data on the time course of organ dysfunction prior to ICU admission.
Clinical Year in Review- Comments