• Arash Afshari, Jørn Wetterslev, Jesper Brok, and Ann Merete Møller.
• Department of Paediatric and Obstetric Anaesthesiology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen Ø, Denmark, 2100. arriba_a@yahoo.dk
• Cochrane Db Syst Rev. 2008 Jan 1(3):CD005370.

BackgroundCritical illness is associated with uncontrolled inflammation and vascular damage which can result in multiple organ failure and death. Antithrombin III (AT III) is an anticoagulant with anti-inflammatory properties but the efficacy and any harmful effects of AT III supplementation in critically ill patients are unknown.ObjectivesTo assess the benefits and harms of AT III in critically ill patients.Search StrategyWe searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); MEDLINE; EMBASE; Science Citation Index Expanded; International Web of Science; CINAHL; LILACS; and the Chinese Biomedical Literature Database (up to November 2006). We contacted authors and manufacturers in the field.Selection CriteriaWe included all randomized clinical trials, irrespective of blinding or language, that compared AT III with no intervention or placebo in critically ill patients.Data Collection And AnalysisOur primary outcome measure was mortality. We each independently abstracted data and resolved any disagreements by discussion. We presented pooled estimates of the intervention effects on dichotomous outcomes as relative risks (RR) with 95% confidence intervals (CI). We performed subgroup analyses to assess risk of bias, the effect of AT III in different populations (sepsis, trauma, obstetric, and paediatric patients), and the effect of AT III in patients with or without the use of concomitant heparin. We assessed the adequacy of the available number of participants and performed a trial sequential analysis to establish the implications for further research.Main ResultsWe included 20 randomized trials with a total of 3458 participants; 13 of these trials had high risk of bias. When we combined all trials, AT III did not statistically significantly reduce overall mortality compared with the control group (RR 0.96, 95% CI 0.89 to 1.03; no heterogeneity between trials). A total of 32 subgroup and sensitivity analyses were carried out. Analyses based on risk of bias, different populations, and the role of adjuvant heparin gave insignificant differences. AT III reduced the multiorgan failure score among survivors in an analysis involving very few patients. AT III increased bleeding events (RR 1.52, 95% CI 1.30 to 1.78).Authors' ConclusionsAT III cannot be recommended for critically ill patients based on the available evidence. A randomized controlled trial of AT III, without adjuvant heparin, with prespecified inclusion criteria and good bias protection is needed.

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