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The Injury Severity Score (ISS) is the most commonly used injury scoring system in trauma research and benchmarking. An ISS greater than 15 conventionally defines severe injury; however, no studies evaluate whether ISS performs similarly between adults and children. Our objective was to evaluate ISS and Abbreviated Injury Scale (AIS) to predict mortality and define optimal thresholds of severe injury in pediatric trauma.Patients from the Pennsylvania trauma registry 2000–2013 were included. Children were defined as younger than 16 years. Logistic regression predicted mortality from ISS for children and adults. The optimal ISS cutoff for mortality that maximized diagnostic characteristics was determined in children. Regression also evaluated the association between mortality and maximum AIS in each body region, controlling for age, mechanism, and nonaccidental trauma. Analysis was performed in single and multisystem injuries. Sensitivity analyses with alternative outcomes were performed.Included were 352,127 adults and 50,579 children. Children had similar predicted mortality at ISS of 25 as adults at ISS of 15 (5%). The optimal ISS cutoff in children was ISS greater than 25 and had a positive predictive value of 19% and negative predictive value of 99% compared to a positive predictive value of 7% and negative predictive value of 99% for ISS greater than 15 to predict mortality. In single-system–injured children, mortality was associated with head (odds ratio, 4.80; 95% confidence interval, 2.61–8.84; p < 0.01) and chest AIS (odds ratio, 3.55; 95% confidence interval, 1.81–6.97; p < 0.01), but not abdomen, face, neck, spine, or extremity AIS (p > 0.05). For multisystem injury, all body region AIS scores were associated with mortality except extremities. Sensitivity analysis demonstrated ISS greater than 23 to predict need for full trauma activation, and ISS greater than 26 to predict impaired functional independence were optimal thresholds.An ISS greater than 25 may be a more appropriate definition of severe injury in children. Pattern of injury is important, as only head and chest injury drive mortality in single-system–injured children. These findings should be considered in benchmarking and performance improvement efforts.Epidemiologic study, level III.