Transcript Current issues in the management of adult sepsis

Current issues in the management
of adult sepsis
Jon Cohen
MRF
London Nov 2007
Current controversies
• Low dose steroids
• Intensive insulin therapy
– tight glycaemic control
• Activated protein C
• Goal directed therapy
Effect of steroids on 28 day mortality
RR 0.88 (0.78 to 0.99) p = 0.03
Favours treatment
Annane et al, BMJ 2004 329:480
Favours control
Effect of steroids on shock reversal
RR 1.6 (1.27 to 2.03) p < 0.0001
Favours control
Annane et al, BMJ 2004 329:480
Favours treatment
CORTICUS
• International, prospective double-blind RCT
of hydrocortisone in patients with moderate
– severe septic shock
• HC 50 mg q6h for 5 d then tapering to d 11.
No fludrocortisone.
• Primary EP 28 d mortality in nonresponders
• Approx 500 patients enrolled, study closed
Nov 2005
CORTICUS - Results
• No effect on 28 day mortality in
whole population or pre-identified
subgroups
• Did not reverse shock in whole
population or pre-identified subgroups
• Did reduce the time to shock reversal
• No significant problem with superinfection
Sprung et al., 2007
Intensive insulin therapy in critically ill patients
Tight glycaemic control=
80-110 mg/dl (4.4-6.1 mmol/l)
Van den Berghe et al, NEJM 2001 345:1359
Intensive insulin therapy in medical patients
on ICU
Van den Berghe et al, N Engl J Med 2006 354:449
Intensive insulin therapy in medical patients
on ICU for > 3 days
ARR (%)
OR (95% CI)
P value
ICU mortality
38.1--- 31.3
Δ 6.8%
0.69 (0.50-0.95)
0.02
In hospital
mortality
52.5 --- 43.0
Δ 9.5%
0.63 (0.46-0.89)
0.003
OR and p value corrected for type & severity of illness
Van den Berghe et al, N Engl J Med 2006 354:449
Growing concerns about tight glycaemic control
• Uncertainty about feeding regimen and
highly selected pt population in first NEJM
study. Single centre study.
• Failure of second NEJM study to confirm
clear survival benefit
• German VISEP study terminated because
of XS hypoglycaemia & no survival benefit
PROWESS – Drotrecogin alfa (activated)
[activated protein C] in sepsis
mortality (%)
Placebo
Absolute reduction
aPC
in risk (%)
P
value
All treated pts
30.8
24.7
6.1
0.005
All treated pts
stratified
32.1
25.7
6.4
0.009
All randomised
pts
31.3
24.8
6.5
0.003
Bernard et al, N Engl J Med 2001 344:699
Drotrecogin alfa – UK NICE guidelines
• Drotrecogin alfa (activated) is recommended for
use in adult patients who have severe sepsis
that has resulted in multiple organ failure (that is,
two or more major organs have failed) and who
are being provided with optimum intensive care
support.
• The use of Drotrecogin alfa (activated) should
only be initiated and supervised by a specialist
consultant with intensive care skills and
experience in the care of patients with sepsis
NICE Technology appraisal 84; September 2004
Drotrecogin alfa (activated) is not effective in
adults with severe sepsis and a low risk of death*,
and is associated with an increased rate of
serious bleeding
* APACHE II < 25 or
Single organ failure
Abraham et al, NEJM 2005 353: 1332. ADDRESS trial group
Meta-analysis of 28d mortality outcomes
in the two RCTs of drotrecogin alfa
Costa et al, BMC Anesthesiol 2007; 7:5
PROWESS – Continuing debate
• Is there confidence in the baseline
comparability of the populations –
especially the subpopulations?
• There are variable outcomes depending
on the severity marker used (IL6, APII,
SOFA)
• There is no confirmatory study
• ADDRESS severe subgroup did not show
benefit
Haemodynamic monitoring in sepsis – Background
• Long standing “discussions” about how to
measure/quantify shock
• Clinical and laboratory biomarkers poorly
defined
• Role of invasive monitoring uncertain
• Shoemaker develops “goal directed therapy”
based on CI, DO2 & VO2, but clinical studies fail
to support this approach
Recent recommendations on haemodynamic
monitoring in shock
• Shock now defined on the basis of tissue
dysoxia
• Hypotension not a requirement
• Lactate only useful biomarker
• Routine measurement of CO not required
• PAC not helpful
• Support for Early Goal Directed Therapy
Antonelli et al, International Consensus Conference, Intensive Care Med 2007 33:575 - 590
Early Goal Directed Therapy
• ER admissions with severe sepsis/shock
treated for 6 h before ICU transfer
• Protocol designed to achieve:
– CVP ≥ 8 – 12 mmHg
– MAP ≥ 65 mmHg
– ScvO2 ≥ 70%
– Urine output ≥ 0.5 ml/kg.hr
Rivers et al, N Engl J Med 2001 345:1368-77
Early goal-directed therapy in sepsis
Standard
therapy
n=133
Active
therapy
n=130
p
But….
•
Unexpectedly
high
placebo
mortality
In hospital mortality (%)
• Unusual (ER) population
30.5
0.009
All patients
• Single centre 46.5
study
Severe sepsis
30.0
14.9
0.06
Septic shock
56.8
42.3
0.04
Rivers et al, N Engl J Med 2001 345:1368
Current controversies
• Low dose steroids ? / Not confirmed
• Intensive insulin therapy ? / Not
confirmed
• Activated protein C ?/ Requires
confirmation
• Goal directed therapy ?/ Requires
confirmation
Updated version, 2008, in press
Experimental & Investigational Agents, 2007
• Statins
• Cytokines
– Polyclonal anti-TNF
– MIF
– HMG-B1
• Cholinergic pathway
– JCI 2007 111:289
• Coagulation pathway
– TFPI
– AT
• Anti-TLR strategies
– TAK 242
– Eritoran
TAK-242
• Novel small molecule signal transduction
inhibitor
• Effective when given up to 4 h after LPS
challenge in mice
• Phase I human studies confirm broad
inhibition of cytokines
• Excellent safety profile
TAK-242 exhibits a TLR4-specific mode of action
E5564 inhibits LPS-induced TLR4-mediated NF-kB reporter activity
HEK293 cells stably transfected with TLR4, MD-2, and a luciferase reporter gene
driven by an NF-kB-dependent promotor
Mullarkey et al, J Pharmacol Exp Ther 2003 304:1093
Mean change in heart rate from baseline among healthy
volunteers with experimental endotoxemia who received
E5564 or placebo
Lynn et al, J Infect Dis 2003 187:631
Phase II study of Eritoran (E5564) in sepsis
N = 293
28 d mortality (%)
Placebo
33.3
Low dose
32.0
High dose
26.9
Eisai, press release, Aug 2005
RRR (%)
p
6.4
0.34
Phase II study of Eritoran (E5564) in sepsis
High risk subgroup
N = 162
28 d mortality (%)
RRR (%)
p
Placebo
50.9
Low dose
37.9
13
0.17
High dose
33.3
17.6
0.07
Eisai, press release, Aug 2005
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