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To investigate negative pressure wound therapy (NPWT) to prevent wound dehiscence and infection after high-risk lower extremity trauma.Prospective randomized multicenter clinical trial.Four Level I trauma centers.Blunt trauma patients with one of three high-risk fracture types (tibial plateau, pilon, calcaneus) requiring surgical stabilization.Incisional NPWT (Group B) was applied to the closed surgical incisions of patients randomized to the study arm of this trial, whereas standard postoperative dressings (Group A) were applied to the control patients.Acute and chronic wound dehiscence and infection.Two hundred forty-nine patients with 263 fractures have enrolled in this study with 122 randomized to Group A (controls) and 141 to Group B (NPWT). There was no difference between the groups in the distribution of calcaneus (39%), pilon (17%), or tibial plateau (44%) fractures. There were a total of 23 infections in Group A and 14 in Group B, which represented a significant difference in favor of NPWT (P = 0.049). The relative risk of developing an infection was 1.9 times higher in control patients than in patients treated with NPWT (95% confidence interval, 1.03–3.55).There have been no studies evaluating incisional NPWT as a prophylactic treatment to prevent infection and wound dehiscence of high-risk surgical incisions. Our data demonstrate that there is a decreased incidence of wound dehiscence and total infections after high-risk fractures when patients have NPWT applied to their surgical incisions after closure. There is also a strong trend for decreases in acute infections after NPWT. Based on our data in this multicenter prospective randomized clinical trial, NPWT should be considered for high-risk wounds after severe skeletal trauma.