Transcript Kein Folientitel - Yeudim

Department of Anesthesiology
and Critical Care Medicine
Hadassah Medical Center
ATS Clinical Year in Review
Sepsis
Charles L. Sprung, M.D.
Presenter Disclosures
Part 1: Personal financial relationships with commercial
interests relevant to this presentation during the past 12
months:
1. Eli Lilly & Co – Consultancies
2. Novartis Corp- Other- Data Monitoring Committee
3. Takeda- Industry-sponsored grants
4. Eisai, Corp- Other- Steering Committee + Industrysponsored grants
5. Artisan Pharma, Inc- Other- Data Monitoring Committee
6. Hutchinson Technology Incorporated- Other- Data Monitoring
Committee
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
Clinical Year in Review- Sepsis
•
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.
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
Clinical Year in Review- Sepsis
• In this multicenter, randomized, doubleblind 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.
Russell JA. N Engl J Med 2008;358:877
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
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
CENTRES
• 27 centres in Canada, Australia and US
Plasma Vasopressin
Norepinephrine vs. Vasopressin
140
Plasma vasopressin level (pmol/L, median +IQR)
120
100
NE
80
AVP
Off
AVP
60
40
20
0
Baseline
6 hours
24 hours
72hours
Timepoint
Russell JA. N Engl J Med 2008;358:877
7days
Mean Arterial Pressure
Vasopressin vs Norepinephrine
120
MAP (mmHg, mean +/-SD)
100
80
NE
60
AVP
40
20
0
0
5
10
15
20
Time from study drug infusion (days)
Russell JA. N Engl J Med 2008;358:877
25
30
Heart rate
Vasopressin vs Norepinephrine (p < 0.001)
130
Herat rate (beats / min, mean +/-SD)
120
110
100
NE
90
AVP
80
70
60
50
0
5
10
15
20
Time from study drug infusion (days)
Russell JA. N Engl J Med 2008;358:877
25
30
Heart rate
AVP vs. NE (Days 1 - 4, p < 0.001)
130
Herat rate (beats / min, mean +/-SD)
120
110
100
NE
90
AVP
80
70
60
50
0
5
10
15
20
Time from study drug infusion (days)
Russell JA. N Engl J Med 2008;358:877
25
30
Probability of survival
0.2
0.4
0.6
0.8
1
Survival - All Patients
Log-rank statistic
p = 0.27 day 28
p = 0.10 day 90
0
Vasopressin
Norepinephrine
0
10
30
50
70
90
Days since initiation of study drug
Russell JA. N Engl J Med 2008;358:877
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
Probability of survival
0.2
0.4
0.6
0.8
1
Survival - Less Severe Shock
Log-rank statistic
p = 0.05 day 28
p = 0.03 day 90
0
Vasopressin
Norepinephrine
0
10
30
50
70
90
Days since initiation of study drug
Russell JA. N Engl J Med 2008;358:877
Probability of survival
0.2
0.4
0.6
0.8
1
Survival - More Severe Shock
Log-rank statistic
p = 0.77 day 28
p = 0.92 day 90
0
Vasopressin
Norepinephrine
0
10
30
50
70
90
Days since initiation of study drug
Russell JA. N Engl J Med 2008;358:877
Clinical Year in Review- Comments
•
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
• 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).
Probability of survival
0.2
0.4
0.6
0.8
1
Survival - All Patients
Log-rank statistic
p = 0.27 day 28
p = 0.10 day 90
0
Vasopressin
Norepinephrine
0
10
30
50
70
90
Days since initiation of study drug
Russell JA. N Engl J Med 2008;358:877
Outcomes: Mortality NICE SUGAR Study
Intensive Glucose
Control
Conventional
Glucose Control
Odds ratio
(95% CI)
Dead at 28 days
670/3010
22.3%
627/3012
20.8%
1.09
(0.96 - 1.23)
P = 0.17
Dead at 90 days
829/3010
27.5%
751/3012
24.9%
1.14
(1.02 - 1.28)
P = 0.02
1.14
(1.01 - 1.29)
P = 0.04
Adjusted for operative admission,
Adjusted mortality geographic region, age, admission
at 90 days
source, APACHE II score, mechanical
ventilation
Finfer S. N Engl J Med 2009;360:1283
Interaction of Vasopressin Infusion,
Corticosteroid Treatment and Mortality of
Septic Shock
Russell et al. Crit Care Med 2009;37:811 - 818
Vasopressin /Corticosteroid Mortality
Interaction
Steroids
Steroids
NE
AVP
131 (44.7)
106 (35.9)
P
0.03
No
Steroids
No Steroids
NE
AVP
19 (21.3)
34 (33.7)
P
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
Clinical Year in Review- Sepsis
•
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
• 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.
JAMA 2008;299(19):2294-2303
PERCEPTION
Study Timeline
a before-and-after intervention study
BASELINE
DATA COLLECTION
NOV-DEC
854 patients
2005
EDUCATIONAL
PROGRAMME
POST-EDUCATION
DATA COLLECTION
LONG-TERM
FOLLOW-UP
MAR-JUN
1465 patients
MAR-JUN
247 patients
JAN-FEB
2006
2007
THE SPANISH NETWORK
59 ICUs (21% of all Spanish ICUs)
3
1
2
2
1
General Coordination:
Antonio Artigas
Ricard Ferrer
(Sabadell, Barcelona)
13
8
4
9
3
SSC Coordination
9
M. Levy
6
24
3
Area Coordinators:
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)
Educational Program
General
Coordination
Design EP
Educational Material
Sepsis Definitions
Sepsis early recognition
Sepsis treatments
Area
Coordinators
Area Coordinators + PI
Homogenize the EP
Educational Program: Homogeneity
Interview
Hospital
Manager
ICU
Physicians
PI
Clinical training
ED
Medical Ward
Nurses
Surgical Ward
Graphic material:
distribution and display
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.
Process-of-care variables
SEPSIS RESUSCITATION BUNDLE
6H
SEPSIS MANAGEMENT BUNDLE
24H
Resuscitation Bundle (6H)
* p<0.05
90
80
68.9
62.4
70
% Compliance
60
50.1
66.5
54.4 *
46.7
50
40.9
39.0 *
*
40
26.7
30
21.4 *
20
11.4
6.3
10
*
10.0
5.3
*
0
Lactate
Blood Cultures
Antibiotics
Fluids +
Vasopresors
Preintervention
CVP>8
Intervention
SvcO2>70
All
Management Bundle (24h)
* p<0.05
85.7
90
82.7
80
70
54.7
% Compliance
60
50
45.4
*
51.9
44.3
*
49.6
44.6
*
40
30
15.7
20
10.9
*
10
0
Steroids
APC
Glucose
Preintervention
Intervention
IPP
All
Educational Program and Mortality
28d Mortality: Kaplan-Meier curve
p= .036
50
p= .01
44
39.7
40
36.4
31.1
30
%
20
10
0
Hospital Mortality
Preintervention
ICU Mortality
Intervention
Absolute reduction: 4.3%
Relative reduction 10%
SSC objective was 25%!
Impact of Baseline Compliance
30
Resuscitation Bundle
25
25
20
20
% 15
% 15
10
5
0
Management Bundle
30
*
10
*
*
*
5
0
Pre-Intervention
Cat 1
Post-Intervention
Cat 2
Cat 3
Cat 1
Post-Intervention
Cat 2
Cat 3
Mortality
50
45
Pre-Intervention
*
40
% 35
30
* p<0.05
25
20
Pre-Intervention
Cat 1
Post-Intervention
Cat 2
Cat 3
Cat 1: < 4 tasks (n= 20)
Cat 2: 4-5 tasks (n= 19)
Cat 3: > 5 tasks (n= 20)
Resuscitation Bundle (6H)
Long-term follow up (23 centers)
* p<0.05
90
80
71.0
*
70
61.1
% Compliance
60.5
65.4
59.1
*
56.7
53.5
60
50
*
69.6
65.2
53.0
44.7
42.8
40
*
39.3
30.0
25.2
30
14.6
10.0 13.7
20
12.9*
7.3
6.3
10
0
Lactate
Blood Cultures
Antibiotics
Preintervention
Fluids + Vasopresors
Intervention
CVP>8
Long-term
SvcO2>70
All
Management Bundle (24h)
Long-term follow up (23 centers)
100
87.8
* p<0.05
89.6 94.8
90
80
*
69.7
70
*
% Compliance
59.1
59.1
*
60
51.0
49.0
50
44.3
56.3
44.7
38.4
40
*
30
19.6
20
9.4
10
0
Steroids
APC
Preintervention
Glucose
Intervention
IPP
Long-term
All
26.7
Educational Program and Mortality
Long-term follow up (23 centers)
50
42.5
38.7
38,5
40
30
%
20
10
0
Hospital Mortality
Preintervention
Intervention
Long-term
Clinical Year in Review- Sepsis
• 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- Comments
• 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
• 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- Sepsis
•
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.
• Predisposition: Premorbid
illnessConcept
with reduced probability of
The PIRO
short term survival. Cultural or religious beliefs, age, gender.
• Insult: Culture and sensitivity (infection) of infecting pathogens;
detection of disease amenable to source control.
• Response: SIRS, other signs of sepsis, shock, C-reactive
protein.
• Organ: Organ dysfunction as number dysfunction of failing
organs or composite score (e.g., MODS; SOFA; LOD).
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.
Clinical Year in Review- Sepsis
• 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.
SAPS 3 PIRO Score
Predisposition
•
•
•
•
•
Age
Intra-hospital location
Co-Morbidities
Length of stay in the hospital
Reasons for ICU admission
Response/Organ
dysfunction/failure
Injury
•
•
•
•
Acquisition of infection
Extension of infection
Site of infection
Agent
•
•
•
•
•
•
•
Renal dysfunction
Coagulation dysfunction
Cardiovascular failure
Respiratory failure
Renal failure
Coagulation failure
CNS failure
Moreno R. Intensive Care Med 2008;34:496-504
Clinical Year in Review- Sepsis
• Hospital mortality was 41%.
• The SAPS 3 PIRO score had excellent
predictive value for mortality and the PIRO
components independently contributed to
outcome prediction.
SAPS 3 INFECTION MODEL SCORE
SHEET
Moreno R. Intensive Care Med 2008;34:496-504
PROGNOSTIC PERFORMANCE:
Discrimination
ROC-Kurve
SAPS 3 model:
aROC: 0.735
(95% CI: 0.716-0.754)
1,0
Sensitivity
0,8
0,6
0,4
0,2
SAPS 3
model
PIRO
model
0,0
0,0
0,2
0,4
0,6
1 - Specificity
0,8
1,0
PIRO model:
aROC: 0.772
(95% CI: 0.754-0.790)
Diagonale Segmente ergeben sich aus Bindungen.
Clinical Year in Review- Comments
•
•
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.
Does severe non-infectious SIRS differ
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
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?
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
Clinical Year in Review- Sepsis
• 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.
Mortality was similar in patients with SS and
SNISIRS
Dulhunty JM. Intensive Care Med. 2008;34:1654-61
Organ dysfunction due to infectious & noninfectious insults is common & frequently present
on admission to the ICU
2500
ICU prevalence:
2119
SS – 20% (707/3543)
Number of patients
2000
SNISIRS – 28% (980/3543)
1570
1500
1152
1000
891
822
602
668
560
500
728
486
453
627
364
352
514
307
271
253
203
221
160
202
70
39
106 31
17
45 16
12
21
28
0
1
2
3
4
5
6
7
14
Day of admission
No organ dysfunction
SNISIRS
SS
Prevalence of organ failure differed
80
70
60
50
% 40
30
20
10
0
Resp.
Haem.
Liver
SS
Card.
SNISIRS
CNS
Renal
Causes of death differed
180
160
140
120
100
N
80
60
40
20
0
Multi-organ Neurofailure
logical
Cardiac
arrest
Isolated
resp.
failure
SS
Haem.
shock
Pulmonary
embolism
SNISIRS
Other
Unknown
Clinical Year in Review- Comments
• 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
• 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.