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The 'second hit' phenomenon is based on the fundamental concept that sequential insults, which are individually innocuous, can lead to overwhelming physiologic reactions. This response can be expressed in several organic systems and can be examined by measurement of several parameters.The purpose of this study was to evaluate the incidence of systemic effects of intramedullary nailing and the role of concurrent head and thoracic injuries as they have been recorded in vivo. We also wanted to determine what would be the optimal animal model for future research and what variables should be investigated.We reviewed the available literature of animal studies that used surgery, and particularly nailing, as a second hit. The reviewed studies were retrieved through an electronic search of the MEDLINE database. We analyzed the methods of creating the first and second hits (nailing), the characteristics of the animal models, the variables examined, and the pathophysiologic responses, which appeared after the second hit.Second hit reamed intramedullary nailing was found to provoke consumption of coagulation factors, whereas the effect of unreamed nailing on coagulation factors appears inconsistent. Hemodynamic factors were affected only transiently by the second hit, whereas the pulmonary function was affected only when the first hit included lung injury.Thoracic and head injuries predispose to an aggravated second hit. Primate animal models are considered to be closer to clinical reality and should be preferred for future studies. Future studies should include measurements of proinflammatory and antiinflammatory markers.