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 increasedP < 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.