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Our objective was to systematically review randomized, controlled trials of fluid resuscitation in animal models of uncontrolled hemorrhage and to explore potential sources of heterogeneity.We conducted an electronic bibliographic search of published research, reviewed reference lists of included trials, and contacted authors about unpublished studies. We included all unconfounded, randomized, controlled trials of fluid resuscitation (timing, volume, or resuscitation targets) in animal models of uncontrolled hemorrhage. The outcome measure was mortality at the end of the scheduled follow-up period of the trial. Two reviewers independently applied the selection criteria to the trial reports. A third reviewer resolved disagreements.Forty-four trials compared fluid versus no fluid resuscitation. There was marked heterogeneity in the effect of fluid resuscitation on the risk of death, much of which was explained by the hemorrhage model used. In aortic injury models, the adjusted relative risk of death with fluid resuscitation was 0.48 (95% confidence interval [CI], 0.33–0.71). In organ incision models, the adjusted relative risk of death was 0.76 (95% CI, 0.49–1.18). In tail resection models, the adjusted relative risk of death was 0.69 (95% CI, 0.38–1.25) if 50% or more was removed and 1.86 (95% CI, 1.13–3.07) if less than 50% was removed. In other vascular injury models, the adjusted relative risk of death with fluid resuscitation was 1.70 (95% CI, 1.01–2.85), respectively. Nine trials compared hypotensive versus normotensive resuscitation. The relative risk of death with hypotensive resuscitation was 0.37 (95% CI, 0.27–0.50).Fluid resuscitation appears to reduce the risk of death in animal models of severe hemorrhage but increases the risk of death in those with less severe hemorrhage. Excessive fluid resuscitation could therefore be harmful in some situations. Hypotensive resuscitation reduced the risk of death in all the trials investigating it. An evaluation of the potential impact of hypotensive resuscitation in humans could now be warranted.