Abstract:

Background
Mortality from sepsis and septic shock remains high. Results of trials on intravenous immunoglobulins (IVIG) as adjunctive therapy for sepsis have been conflicting. This is an update of a Cochrane review (2002).

Objectives
To estimate the effects of IVIG on mortality and duration of hospitalization in patients with sepsis or septic shock.

Search strategy
We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue 4), MEDLINE (1966 to October 2008), and EMBASE (1988 to October 2008). We contacted investigators in the field for unpublished data.

Selection criteria
We included randomized controlled trials comparing IVIG (monoclonal or polyclonal) with placebo or no intervention in patients with bacterial sepsis or septic shock.

Data collection and analysis
Two reviewers independently assessed the studies for inclusion, methodologic quality and data abstraction. We conducted pre-specified subgroup analyses by type of immunoglobulin preparation.

Main results
Forty-two of 84 potentially eligible studies met our inclusion criteria. Pooled analysis of polyclonal and monoclonal IVIG was not done due to clinical heterogeneity. Subgroup analysis of 10 polyclonal IVIG trials in adults (n = 1430) and seven trials on IgM-enriched polyclonal IVIG (n = 528) showed significant reductions in mortality compared to placebo or no intervention (RR 0.81; 95% CI 0.70 to 0.93 and RR 0.66; 95% CI 0.51 to 0.85, respectively). Subgroup analysis of polyclonal IVIG in neonates showed no significant reduction in mortality for standard (RR 0.90; 95% CI 0.46 to 1.76; 4 trials, n = 174) and IgM-enriched polyclonal IVIG (RR 0.57; 95% CI 0.31 to 1.04; 3 trials, n = 164). Sensitivity analysis of trials with low risk of bias showed no reduction in mortality with polyclonal IVIG in adults (RR 0.97; 95% CI 0.81 to 1.15; 5 trials, n = 945) and neonates (RR 0.41; 95% CI 0.16 to 1.08; 3 trials, n = 128). Mortality was not reduced among patients (8 trials, n = 4671) who received anti-endotoxin antibodies (RR 0.99; 95% CI 0.91 to1.06) while anti-cytokines (9 trials, n = 7893) demonstrated a marginal reduction in mortality (RR 0.92; 95% CI 0.86 to 0.97).

Authors' conclusions
Polyclonal IVIG reduced mortality among adults with sepsis but this benefit was not seen in trials with low risk of bias. Among neonates, no reduction in mortality was seen with polyclonal IVIG. Most of the trials were small and the totality of the evidence is insufficient to support a robust conclusion of benefit. Adjunctive therapy with monoclonal IVIGs remains experimental.