Transcript GLYCEMIC CONTROL IN THE CRITICALLY ILL

Traitements non Antibiotiques du
Choc Septique
Djillali ANNANE,
Hôpital Raymond Poincaré 92380
Garches,
[email protected]
TIME IS IMPORTANT
Patients with global tissue hypoxia and
early stage of disease
Fluid Therapy - Liters
14
*
12
10
8
6
Control
Treatment
*
4
2
0
0-6 hours
6-72 hours
* = P<0.01
0-72 hours
TYPE OF FLUID DOES NOT
REALLY MATTER
SAFE Flow Chart
n=7000
Albumin, n=3499
Alb, n=3100 (88.6%)
Other fluids, n=309 (8.8%)
No Alb, n=90 (2.6%)
Saline, n=3501
Saline, n=3019 (86,2%)
Other fluids, n=375 (10.7%)
No saline, n=107 (3%)
Lost to follow-up
n=26 (0.7%)
Lost to follow-up
n=41 ((1.2%)
Analyzed
n=3473 (99.3%)
Analyzed
n=3460 (98.8%)
Finfer et al, NEJM 2004
SAFE - Outcome Data
Finfer et al, NEJM 2004
CRISTAL
MULTI-NATIONAL RCT
publicly funded
(French Ministry for Health)
OBJECTIVE
TO COMPARE THE EFFICACY AND
SAFETY OF CRYSTALLOIDS AND
SYNTHETIC COLLOIDS WHEN GIVEN
FOR FLUID RESUSCITATION IN
CRITICALLY ILL PATIENTS
TYPE OF
CATECHOLAMINES DOES
NOT REALLY MATTER
Vasopressors for shock.
Müllner M et al, Cochrane Database Syst Rev. 2004;(3):CD003709.
Vasopressors for shock.
Müllner M et al, Cochrane Database Syst Rev. 2004;(3):CD003709.
ADJUVANT THERAPIES
Insulin Signaling Pathways That Regulate Glucose
Metabolism in Muscle Cells and Adipocytes
Role of Muscles Expression of Cytokines
in Insulin Resistance Syndrome
Saghizadeh, JCI 1996
(triangles) Insulin sensitive
(circles) Insulin resistant
(squares) Diabetic
Tumor Necrosis Factor-–Induced Insulin
Resistance in Adipocytes
Qi, Exp Biol Med 2000
Marked Reduction of GLUT4 in Muscle or Adipose
Tissue Causes Insulin Resistance
Minokoshi, JBC, 2003
Hyperglycemia and Outcome in the Acutely Ill
Umpierrez, JCEM 2002
Effects of Intensive Insulin Therapy on Survival in
Surgical ICU patients.
Van den Berghe, NEJM 2002
Intensive insulin therapy in the medical
ICU
Intensive insulin therapy in the medical ICU
Efficacy of Volume Substitution and
Insulin Therapy in Severe Sepsis
(VISEP Trial)
This study has been suspended.
Verified by German Competence Network Sepsis
August 2005
GLUCOCORTICOIDS
Keh et al, AJRCCM 2003
COCHRANE INFECTIOUS GROUP SYSTEMATIC REVIEW
CORTISOL RESPONSE TO ACTH
CORTISOL INCREMENT
nmol/l
BASAL CORTISOL nmol/l
0
500
1000
1500
1000
800
600
400
200
0
-200
-400
2000
250
NON SURVIVORS
SURVIVORS
Rothwell, Lancet 1991
Effect of Treatment With Low Doses of Hydrocortisone and
Fludrocortisone on Mortality in Patients With Septic Shock
Annane et al, JAMA. 2002
PROBABILITY TO BE ON
VASOPRESSOR
NON RESPONDERS
RR=1.889
100%
P=0.002
80%
60%
40%
20%
0%
0
4
8
12
16
20
24
TIME (days)
PLACEBO
STEROIDS
28
Effect of Treatment With Low Doses of Hydrocortisone and
Fludrocortisone on Mortality in Patients With Septic Shock
Annane et al, JAMA. 2002
PROBABILITY TO BE ON
VASOPRESSOR
RESPONDERS
100%
RR=0.853
80%
P=0.637
60%
40%
20%
0%
0
4
8
12
16
20
24
TIME (days)
PLACEBO
STEROIDS
28
AI AND SYSTEMIC INFLAMMATION
*
100000
10000
1000
*
*
Non responders
Responders
100
10
1
TNF
IL-6
IL-8
Probability of survival
AI AND SURVIVAL
1.00
D max > 9 µg/dl
0.75
0.50
0.25
0.00
0
D max  9 µg/dl
7
14
Time (days)
21
28
Annane, JAMA 2000
PROBABILITY OF
SURVIVAL
28-DAY SURVIVAL
IN NON RESPONDERS
100%
90%
80%
70%
60%
50%
40%
30%
HR = 0.670
p=0.023
0
4
8
12
16
20
24
28
TIME (days)
PLACEBO
STEROIDS
Annane, JAMA 2002
PROBABILITY OF
SURVIVAL
28-DAY SURVIVAL
IN RESPONDERS
100%
90%
80%
70%
60%
50%
40%
30%
0
4
8
12
16
20
24
28
TIME (days)
PLACEBO
STEROIDS
Annane, JAMA 2002
Coagulation Is Activated in Sepsis
16
6.0
*
5.0
12
4.0
TAT
complex
(ng/L)
D- 3.0
dimer
(mg/L) 2.0
8
*
*
*
*P <.05 vs controls
4
1.0
Controls
0.0
0
60
120
180
240
300
Time After Administration (min)
Healthy volunteers + TNF (n=6)
Healthy volunteers + LPS (n=6)
Levi et al. JAMA. 1993;270:975.
1
4
7
Time After Hosp. Admission (day)
Survivors (n=23)
Nonsurvivors (n=25)
Lorente et al. Chest. 1993;103:1536.
Fibrinolysis Is Suppressed in Sepsis
tPA
Activity
(%)
500
50
400
40
300
PAI-1 30
(ng/mL)
200
20
100
10
0
0
60
120
180
240
300
Time after Administration (min)
60
120
180
240
300
Time after Administration (min)
Healthy volunteers + TNF (n=6)
Healthy volunteers + LPS (n=6)
Levi et al. JAMA. 1993;270:975.
AT in Severe Sepsis : Kybersept
• Primary end-point :
28-day all cause
mortality
• N = 2314 total
• AT levels achieved :
180% nl (120-230)
• Concomitant heparin :
1616 pts.
50
40
30
38.7 38.9
Placebo
AT
20
10
28-day mortality
Warren et al. JAMA 2001;286:1869-78
TFP007 Primary Cohort - 28-Day
Mortality
INR  1.2
(N=)
% Mortality
Overall
Placebo
TFPI
P value
(unadjusted)
(874)
33.9%
(880)
34.2%
.75 (.88)
P value from logistic regression adjusted for baseline APACHE II score and baseline log10 IL-6, per protocol.
Summary of 28-Day All Cause Mortality
Primary Analysis Results
2-sided p-value
0.005
Relative Risk Reduction
19.4%
Increase in Odds of Survival
38.1%
35
30.8%
30
24.7%
25
20
15
10
Placebo
(N=840)
Drotrecogin
Alfa
(activated)
(N=850)
5
0
G. Bernard, et al. N Engl J Med 2001;344:699-709
Subgroups – Disease Severity Measures
Primary
APACHE II
1st Quartile
2nd Quartile
3rd Quartile
4th Quartile
Cardiovascular Organ Failure
Yes
No
Cardiovascular SOFA
0 or 1
2 to 4
Shock Within 6 Hours
Yes
No
Any Shock
Yes
No
Respiratory Organ Failure
Yes
No
Respiratory SOFA
0 or 1
2 to 4
Mechanical Ventilation
Yes
No
N
Trt Plc
1690 24.7 30.8
433
440
366
451
15.1
22.5
23.5
38.1
12.1
25.7
35.8
49.0
1214 25.1 32.0
476 23.8 27.6
494 19.1 26.6
1196 27.3 32.4
1200 26.3 34.2
490 21.0 22.3
1362 26.0 32.5
328 19.7 23.3
1272 25.6 31.6
418 22.0 28.5
184 12.9 26.4
1479 26.4 31.7
1275 27.3 33.1
415 17.6 22.9
0.5 0.6 0.7 0.8 0.9 1
1.25
1.67
2
Relative Risk of Death (Point Estimate and 95% CI)
BLEEDING RISKS
a
ICH During
Infusion Period
Fatal ICH During
Infusion
Ongoing studies
Drotrecogin Alfa
(Activated)
9/1221 = 0.7%
PROWESS
Drotrecogin Alfa
(Activated)
2/850 = 0.2%
0/840 = 0.0%
4/1221 = 0.3%
2/850 = 0.2%
0/840 = 0.0%
a Studies are ongoing; rates are provisional.
PROWESS
Placebo
Drotrecogin Alfa (Activated) for Adults with Severe Sepsis and a Low Risk of Death
Edward Abraham, NEJM 2005