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Temporary abdominal closure (TAC) after damage control surgery (DCS) for injured patients has been generalized to septic patients. However, direct comparisons between these populations are lacking. We hypothesized that patients with intra-abdominal sepsis would have different resuscitation requirements and lower primary fascial closure rates than trauma patients.We performed a 3-year retrospective cohort analysis of patients managed with TAC for trauma (n = 77) or intra-abdominal sepsis (n = 147). All patients received negative pressure wound therapy (NPWT) TAC with intention for planned relaparotomy and sequential abdominal closure attempts at 24- to 48-hour intervals.At presentation, trauma patients had higher rates of hypothermia (31% vs. 18%), severe acidosis (27% vs. 14%), and coagulopathy (68% vs. 48%), and septic patients had higher vasopressor infusion rates (46% vs. 27%). Forty-eight hours after presentation, septic patients had persistently higher vasopressor infusion rates (37% vs. 17%), and trauma patients had received more red blood cell transfusions (6.0 U vs. 0.0 U), fresh frozen plasma (5.0 U vs. 0.0 U), and crystalloid (8,290 vs. 7,159 ml). Among patients surviving to discharge, trauma patients had higher primary fascial closure (PFC) rates (90% vs. 76%). For trauma patients, independent predictors of failure to achieve PCF were ≥2.5 L NPWT output at 48 hours, ≥10 L crystalloid administration at 48 hours, and ≥10 U PRBC + FFP at 48 hours. For septic patients, relaparotomy within 48 hours predicted successful PFC; requirement for ≥3 diagnostic/therapeutic laparotomies predicted failure to achieve PFC.Traumatic injury and intra-abdominal sepsis are associated with distinct pathophysiologic insults, resuscitation requirements, and outcomes. Failure to achieve primary fascial closure in trauma patients was attributable to the triad of hypothermia, acidosis, and coagulopathy; failure to achieve fascial closure in septic patients was dependent upon operative course. Indications and optimal techniques for TAC may differ between these populations.Therapeutic study, level IV; prognostic study, level III.