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Recently, there has been a move away from early total care in patients with severe, multiple injuries to damage control orthopedics (DCO) in an attempt to limit the physiologic insult resulting from operative treatment after trauma. For femoral shaft fracture, this entails initial external fixation and subsequent conversion to an intramedullary nail (IMN). We sought to quantify the inflammatory response to initial surgery and conversion and link this to subsequent organ dysfunction and complications.Patients with femoral shaft fracture and a New Injury Severity Score of 20 or more were included. Data were retrospectively collected for 4 days at admission and at exchange procedure (external fixation to intramedullary nail), and the Systemic Inflammatory Response Syndrome (SIRS) score and the Marshall multiorgan dysfunction score were calculated.One hundred seventy-four patients met the inclusion criteria. The DCO group had significantly more severe injuries (New Injury Severity Score of 25.4 vs. 36.2, p < 0.0001) and significantly more head and thoracic injuries (both p < 0.0001). The mean SIRS score was significantly higher in the IMN group, from 12 hours until 72 hours postoperatively (p < 0.05). The mean peak postoperative SIRS score was significantly higher in the IMN group than in the DCO group, at the primary procedure and at conversion, as was the time with an SIRS score greater than 1. At conversion in the DCO group, the preoperative SIRS score correlated with magnitude and duration of elevation in the SIRS and multiorgan dysfunction scores (p < 0.0001).It would appear that despite more severe injuries in the DCO group, patients had a smaller, shorter postoperative SIRS and did not suffer significantly more pronounced organ failure than the IMN group. DCO patients undergoing conversion while their SIRS score was raised suffered the most pronounced subsequent inflammatory response and organ failure. According to these data, DCO treatment was associated with a lesser systemic inflammatory response than early total care for femur fractures. The inflammatory status of the patient may be a useful adjunct in clinical decision making regarding the timing of conversion to an intramedullary device.