01.08.2010 | Research | Ausgabe 4/2010 Open Access

A systematic review of randomized controlled trials exploring the effect of immunomodulative interventions on infection, organ failure, and mortality in trauma patients
- Zeitschrift:
- Critical Care > Ausgabe 4/2010
Electronic supplementary material
Competing interests
Authors' contributions
Introduction
Materials and methods
Search
Selection
Quality assessment
Data abstraction
Results
Search and selection
Quality assessment
Study
|
Patients randomized
|
Groups similar at baseline
|
Groups treated equally
|
All patients accounted for
|
Assessor blinded or objective
|
Intention to treat analysis
|
TOTAL (max 6)
|
Level of Evidence
|
---|---|---|---|---|---|---|---|---|
Browder et al, 1990 [
29]
|
1
|
1
|
1
|
1
|
1
|
1
|
6
|
1b
|
Bulger et al, 2008 [
19]
|
1
|
1
|
1
|
1
|
1
|
1
|
6
|
1b
|
Croce et al, 1998 [
24]
|
1
|
0°
|
1
|
1
|
1
|
1
|
5
|
2b
|
de Felippe et al, 1993 [
30]
|
1
|
1
|
1
|
1
|
1
|
0
|
5
|
2b
|
Douzinas et al, 2000 [
32]
|
1
|
0*
|
1
|
1
|
1
|
0
|
4
|
2b
|
Dries et al, 1998 [
18]
|
1
|
1
|
1
|
1
|
1
|
0
|
5
|
2b
|
Glinz et al, 1985 [
20]
|
1
|
1
|
1
|
1
|
1
|
1
|
6
|
1b
|
Livingston et al, 1994 [
31]
|
1
|
1
|
1
|
1
|
1
|
1
|
6
|
1b
|
Marzi et al, 1993 [
25]
|
1
|
1
|
1
|
1
|
1
|
1
|
6
|
1b
|
Miller & Lim, 1985 [
14]
|
1
|
n.r.
|
1
|
1
|
1
|
0
|
4
|
2b
|
Nakos et al, 2002 [
26]
|
1
|
1
|
1
|
1
|
1
|
1
|
6
|
1b
|
Nathens et al, 2006 [
21]
|
1
|
1
|
1
|
1
|
1
|
1
|
6
|
1b
|
Polk et al, 1992 [
22]
|
1
|
0°
|
1
|
1
|
1
|
1
|
5
|
2b
|
Rhee et al, 2000 [
23]
|
1
|
0
|
1
|
1
|
1
|
1
|
5
|
2b
|
Rizoli et al, 2006 [
27]
|
1
|
0
|
1
|
1
|
1
|
0
|
4
|
2b
|
Seekamp et al, 2004 [
16]
|
1
|
1
|
1
|
1
|
1
|
1
|
6
|
1b
|
Vassar et al, 1991 [
15]
|
1
|
1
|
1
|
1
|
1
|
1
|
6
|
1b
|
Waydhas et al, 1998 [
28]
|
1
|
1
|
1
|
1
|
1
|
0
|
5
|
2b
|
Study characteristics
Study
|
Patients
|
Intervention
|
|||||||
---|---|---|---|---|---|---|---|---|---|
n
|
Age (range)
|
ISS (range, ± SD)
|
Test
|
Control
|
Delivery
|
Initiation
|
Duration
|
Length of follow-up
|
|
Browder et al, 1990 [
29]
|
38
|
34 (18-65)
|
24 (8-41)
|
Glucan
|
placebo (saline)
|
i.v.
|
after exploratory laparotomy or thoracotomy
|
7 days
|
10 days
|
Bulger et al, 2008 [
19]
|
209
|
38 (13-90)
|
28 (0-75)
|
Hypertonic saline + Dextran
|
Lactated Ringer solution
|
i.v.
|
initial reperfusion fluid
|
single dose
|
28 days
|
Croce et al, 1998 [
24]
|
16
|
32 (15-75)
|
29
|
Partial liquid ventilation with perflubron
|
Conventional mechanical ventilation
|
Inhaled
|
day of admission
|
4 days
|
hospital discharge
|
de Felippe et al, 1993 [
30]
|
41
|
35 (16-76)
|
n.r.*
|
Glucan
|
placebo
|
i.v.
|
12-145 hr (mean 46.2 hr) after admission
|
3-17 days
|
hospital discharge
|
Douzinas et al, 2000 [
32]
|
39
|
32
|
24 (16-50)
|
Immunoglobulin
|
placebo (albumin)
|
i.v.
|
12 hr after admission
|
6 days
|
hospital discharge
|
Dries et al, 1998 [
18]
|
73
|
31
|
34 (21-59)
|
rhIFN-γ
|
placebo
|
s.c.
|
within 30 hr of injury
|
21 days or hospital discharge
|
60 days
|
Glinz et al, 1985 [
20]
|
150
|
39 (15-78)
|
30 (9-66)
|
Immunoglobulin
|
placebo (albumin)
|
i.v.
|
within 24 hr of starting mechanical ventilation
|
12 days
|
42 days
|
Livingston et al, 1994 [
31]
|
98
|
30 (>16)
|
30 (±8)
|
rhIFN-γ
|
placebo
|
s.c.
|
day of admission
|
10 days
|
30 days
|
Marzi et al, 1993 [
25]
|
24
|
32 (18-57)
|
34 (27-57)
|
superoxide dismutase
|
placebo (sucrose)
|
i.v.
|
within 48 hr of injury
|
5 days
|
14 days
|
Miller & Lim, 1985 [
14]
|
28
|
n.r.
|
>10
|
Dextran + standard treatment
|
standard treatment
|
i.v.
|
within 12 hr of admission
|
5 days
|
4 weeks
|
Nakos et al, 2002 [
26]
|
21
|
49 (35-67)
|
41 (24-62)
|
rhIFN-γ
|
placebo
|
inhaled
|
2nd or 3rd day after admission
|
7 days
|
hospital discharge
|
Nathens et al, 2006 [
21]
|
268
|
42 (>17)
|
24 (±11)
|
Leukoreduced (<5 × 10^6 WBC) RBC transfusion
|
Nonleukoreduced (5 × 10^9WBC) RBC transfusion
|
i.v.
|
within 24 hr of injury
|
28 days
|
28 days
|
Polk et al, 1992 [
22]
|
193
|
32 (>15)
|
33 (>20)
|
rhIFN-γ
|
placebo
|
s.c.
|
day of admission
|
10 days
|
90 days
|
Rhee et al, 2000 [
23]
|
116
|
40 (>18)
|
20 (±11)
|
rhMAbCD18
|
placebo
|
i.v.
|
day of admission
|
single dose
|
hospital discharge
|
Rizoli et al, 2006 [
27]
|
24
|
48 (>16)
|
26 (±11)
|
Hypertonic saline + Dextran
|
placebo (saline)
|
i.v.
|
upon arrival in de emergency department
|
single dose
|
hospital discharge
|
Seekamp et al, 2004 [
16]
|
84
|
36 (17-72)
|
32 (17-59)
|
Anti-L-Selectin (Aselizumab)
|
placebo
|
i.v.
|
within 6 hr of injury
|
single dose
|
42 days
|
Vassar et al, 1991 [
15]
|
48
|
36
|
31 (±3)
|
Prostaglandin E1
|
placebo
|
i.v.
|
24-48 hr after hospital admission
|
7 days
|
hospital discharge
|
Waydhas et al, 1998 [
28]
|
40
|
33 (18-70)
|
41 (±13)
|
Antithrombin III
|
placebo (albumin)
|
i.v.
|
within 6 hr of injury
|
4 days
|
hospital discharge
|
Outcomes
Infection
|
MOF, Mortality
|
Inflammation
|
||||||
---|---|---|---|---|---|---|---|---|
Test intervention
|
Study
|
Test group (relative to control)
|
Effect
|
Test group (relative to control)
|
Effect
|
Test group (relative to control)
|
Effect
|
|
Reduce immune paralysis
|
Plasma expander
|
Miller & Lim, 1985 [
14]
|
Mortality 0 vs 0 n.s.
|
No effect
|
immune reactive capacity n.s.
|
No effect
|
||
Rizoli et al, 2006 [
27]
|
pneumonia 0.5% vs 0.5% n.s.
|
No effect
|
Mortality 0 vs 14.3% n.s., MOF score 1.68 vs 1.9 n.s.
|
No effect
|
WBC n.s.; decreased toward normal: CD11b, CD62L, CD16, and TNFα; increased toward normal: CD14, IL-1RA, and IL-10 all
P < 0.05
|
SIRS↓ and CARS↓↑
|
||
Bulger et al, 2008 [
19]
|
nosocomial infections 18.2% vs 15.2% n.s.
|
No effect
|
ARDS-free survival, MOF, mortality 29.1% vs 22.2% n.s.
|
No effect
|
||||
Immuno-globulin
|
Glinz et al, 1985 [
20]
|
any 47% vs 68%
P = 0.02, pneumonia 37% vs 58%
P = 0.01, sepsis 18% vs 26% n.s.
|
↓
|
Mortality from infection* 12% vs 11% n.s.
|
No effect
|
acute phase proteins n.s.
|
No effect
|
|
Douzinas et al, 2000 [
32]
|
pneumonia 10% vs 61%
P = 0.003
|
↓
|
Mortality rom infection* 0 vs 0
|
No effect
|
C3 and CH50 n.s., C4 increased p = 0.04, increased serum bactericidal activity
P < 0.000001
|
CARS↓
|
||
IFN- γ
|
Polk et al, 1992 [
22]
|
major 39% vs 35%, minor 20% vs 28%, pneumonia 27% vs 24% n.s.
|
No effect
|
Mortality 9.2% vs 12.5% n.s.
|
No effect
|
HLA-DR increased
P = 0.0001
|
CARS↓
|
|
Livingston et al, 1994 [
31]
|
major infection 48% vs 31% n.s.
|
No effect
|
WBC decreased
P < 0.05, HLA-DR increased
P < 0.05
|
SIRS↓ and CARS↓
|
||||
Dries et al, 1998 [
18]
|
major infection 49% vs 58% n.s.
|
No effect
|
Mortality 13% vs 42%
P = 0.017
|
↓
|
TNFα, IL-1β, IL-2, IL-4, IL-6 n.s.
|
No effect
|
||
Nakos et al, 2002 [
26]
|
ventilator-associated pneumonia 9% vs 50% p < 0.05
|
↓
|
Mortality 27% vs 40% n.s.
|
No effect
|
HLA-DR expression, IL-1β, phospholipase A2 all increased
P < 0.05; total cells in BAL and IL-10 decreased
P < 0.01
|
SIRS↓ and CARS↓
|
||
Glucan
|
Browder et al, 1990 [
29]
|
sepsis 9.5% vs 49%
P < 0.05
|
↓
|
Mortality from sepsis* 0 vs 18% n.s.
|
No effect
|
IL-1β decreased
P < 0.05, TNFα n.s.
|
SIRS↓
|
|
de Felippe et al, 1993 [
30]
|
pneumonia 9.5% vs 55%
P < 0.01, sepsis 9.9% vs 35%
P < 0.05, either or both 14.3% vs 65%
P < 0.001
|
↓
|
Mortality: general 23.5% vs 42.1%, related to infection 4.8% vs 30%
P < 0.05
|
↓
|
||||
Reduce hyper inflammation
|
Superoxide dismutase
|
Marzi et al, 1993 [
25]
|
Mortality 17% vs 8.3% n.s. MOF score n.s.
|
No effect
|
WBC count, CRP, PMN-elastase and IL-6 n.s.; phospholipase A2 and conjugated dienes decreased
P < 0.05
|
SIRS↓
|
||
Antithrombin III
|
Waydhas et al, 1998 [
28]
|
Mortality 15% vs 5%, MOF 20% vs 30% n.s
|
No effect
|
soluble TNF receptor II, neutrophil elastase, IL-RA, IL-6, and IL-8 n.s.
|
No effect
|
|||
Anti-CD18
|
Rhee et al, 2000 [
23]
|
major and minor 38% vs 40% n.s.
|
No effect
|
Mortality 5.8% vs 6.7%, MOF score n.s.
|
No effect
|
WBC increased
P-value not reported
|
SIRS↑
|
|
Anti-L-Selectin
|
Seekamp et al, 2004 [
16]
|
67% vs 55% n.s.
|
No effect
|
MOF n.s., mortality 11% vs 25% n.s.
|
No effect
|
WBC, IL-6, IL-10, neutrophil elastase, C3a, procalcitonin n.s.
|
No effect
|
|
Leukoreduced blood
|
Nathens et al, 2006 [
21]
|
30% vs 36% n.s.
|
No effect
|
Mortality 19% vs 15% n.s. MOF score 6.6 vs 5.9 n.s.
|
No effect
|
|||
Perflubron
|
Croce et al, 1998 [
24]
|
pneumonia 50% vs 3 75% n.s.
|
No effect
|
Mortality 8.3% vs 25% n.s.
|
No effect
|
WBC, neutrophils, IL-6, and IL-10 all decreased p < 0.01; capillary leak (BAL protein), TNFα, IL-1β, and IL-8 n.s.
|
SIRS↓
|
|
Prostaglandin E1
|
Vassar et al, 1991 [
15]
|
sepsis 28% vs 30%, major wound inf. 65% vs 72%, n.s.
|
No effect
|
Mortality 26% vs 28%, ARDS 13% vs 32%, MOF 30% vs 32% n.s.
|
No effect
|
PMN superoxide production increased toward normal
P < 0.02
|
CARS↓
|
Discussion
Conclusions
Key messages
-
Inflammatory complications, such as MOF and severe infection, are the most common cause of late death in trauma patients.
-
An array of potentially immunomodulative interventions have been tested in a heterogeneous group of trauma patients in RCTs.
-
Extensive disparity in study populations impairs inter-trial evaluation of efficacy of different (immunomodulative) interventions. Therefore, more standardized inclusion criteria are recommended.
-
In most studies, the inflammatory parameters differed significantly between the test and control groups. However, significant changes in infection, MOF, and mortality rates were only measured in studies testing immunoglobulin, IFN-γ, and glucan.
-
A recommendation can be made to administer immunoglobulin, IFN-γ or glucan to improve the outcome of trauma patients.