ORIGINAL ARTICLE Is Interleukin 6 an Early Marker of Injury Severity Following Major Trauma in Humans? Florian Gebhard, MD; Helga Pfetsch, MSc; Gerald Steinbach, MD; Wolf Strecker, MD; Lothar Kinzl, MD; Uwe B. Bru¨ckner, MD Hypothesis: Interleukin 6 (IL-6), a multifunctional cy- of trauma and to relate these results to IL-6 release. tokine, is expressed by various cells after many stimuli and underlies complex regulatory control mechanisms. Results: As early as immediately after trauma, elevated IL-6 Following major trauma, IL-6 release correlates with in- plasma levels occurred. This phenomenon was pronounced jury severity, complications, and mortality. The IL-6 re- in patients with major trauma (ISS, .32). Patients with mi- sponse to injury is supposed to be uniquely consistent nor injury had elevated concentrations as well but to a far and related to injury severity. Therefore, we designed a lesser extent. In surviving patients, IL-6 release correlated prospective study starting as early as at the scene of the with the ISS values best during the first 6 hours after hos- unintentional injury to determine the trauma-related re- pital admission. All patients revealed increased C-reactive lease of plasma IL-6 in multiple injured patients. protein levels within 12 hours following trauma, reflecting the individual injury severity. This was most pronounced Patients and Methods: On approval of the local eth- in patients with the most severe (ISS, .32) trauma. ics committee, 94 patients were enrolled with different injuries following trauma (Injury Severity Score [ISS] me- Conclusions: To our knowledge, this is the first study that dian, 19; range, 3-75). The patients were rescued by a elucidates the changes in the IL-6 concentrations follow- medical helicopter. Subsets were performed according to ing major trauma in humans as early as at the scene of the the severity of trauma—4 groups (ISS, ,9, 9-17, 18-30, unintentional injury. The results reveal an early increase and .32)—and survival vs nonsurvival. The first blood of IL-6 immediately after trauma. Moreover, patients with sample was collected at the scene of the unintentional the most severe injuries had the highest IL-6 plasma lev- injury before cardiopulmonary resuscitation, when ap- els. There is strong evidence that systemic IL-6 plasma con- propriate. Then, blood samples were collected in hourly centrations correlate with ISS values at hospital admission. to daily intervals. Interleukin 6 plasma levels were de- Therefore, IL-6 release can be used to evaluate the impact termined using a commercial enzyme-linked immuno- of injury early regardless of the injury pattern. sorbent assay test. The short-term phase protein, C- reactive protein, was measured to characterize the extent Arch Surg. 2000;135:291-295 NTERLEUKIN 6 (IL-6) is obvi- reported excessively increased plasma lev- ously one of the earliest and most els for many days and demonstrated some important mediators of short- correlation with multiple organ dysfunc- term phase response. Based on tion. Even in patients with an isolated head a recent review of the literature, injury, an IL-6 response is reported.18 IBiffl et al1 summarized the properties of This study elucidates in patients (1) IL-6 and characterized its response to the early changes in IL-6 concentrations injury. There are also clinical studies1-13 in the systemic circulation following ma- that describe the IL-6 response to trauma, jor trauma, (2) whether the release and burns, and elective surgery. Although IL-6 time course of IL-6 reflect the severity of is considered to be a mediator of the physi- injury, and (3) whether this mediator pos- From the Department of ologic short-term phase reaction to in- sesses any predictive value for survival as Traumatology, Hand and jury, excessive and prolonged postinjury early as at hospital admission. Reconstructive Surgery elevations are associated with increased (Drs Gebhard, Strecker, and morbidity. RESULTS Kinzl and Ms Pfetsch), the In patients undergoing elective sur- Department of Clinical gery, increased IL-6 levels were detected The patients (67 men and 27 women) were Chemistry (Dr Steinbach), after skin incision12 within 90 minutes, aged 18 to 70 years (median, 28.5 years). and the Division of Surgical 3 Research, Department of lasting for several hours. This cytokine re- Seventy-six of these 94 patients survived General Surgery lease is related to the extent of the surgi- the trauma. Eighteen patients (14 men and (Dr Bru¨ckner), University cally induced trauma.4,10,14 Following ac- 4 women; median age, 39 years) died of of Ulm, Ulm, Germany. cidental trauma, some researchers15-17 severe head injury (n = 6) or major trauma ARCH SURG/ VOL 135, MAR 2000 WWW.ARCHSURG.COM 291 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 PATIENTS AND METHODS injury, immediately at hospital arrival, at 30 minutes after hospital arrival, at every other hour during the first PATIENT SELECTION 12 hours, and at 24, 72, 120, and 240 hours thereafter. Blood was drawn into ammonium-heparinate–coated Following the approval of the All-University Ethics Review syringes (Sarstedt, Nu¨ mbrecht, Germany). The first Board, 94 patients were enrolled in this study. Exclusion sample from the scene of the unintentional injury was criteria were age younger than 18 or older than 70 years, immediately processed in the helicopter using an expe- urgent administration of major intravenous volume resusci- dition centrifuge (model EBA 6S; Hettich, Tuttlingen, tation before the first blood sample was obtained, preg- Germany) and stored on ice during the flight. The fol- nancy, any metabolic disorder, injuries secondary to acute lowing samples were spun at 2500g in a refrigerated 4°C heart attack or stroke, and the patient’s withdrawn consent. centrifuge (model 3K12; Sigma-Aldrich Corp, St Louis, No colloids were allowed before the first blood sampling. The Mo). The plasma was separated, fractionated, and imme- resuscitation regimen was the same in all patients, consist- diately frozen (−70°C) until the time of assay. ing of crystalloids (contained in Ringer lactate solution) and Circulating IL-6 levels were measured using a ran- hydroxyethyl starch solution (HAES 200/0.5), and did not dom access chemiluminescence-immunoassay system (IM- differ from the commonly used therapeutic approach. MULITE IL-6; DPC Biermann GmbH, Bad Nauheim, Germany). The duration of processing was approximately TRAUMA SCORE 70 minutes, and the sensitivity was 1 pg/mL (range, 2-2000 pg/mL; reference values, 1-11 pg/mL). The test was stan- The severity of injury was assessed by the Injury Severity dardized according to National Institute for Biological Stan- Score (ISS), based on the Abbreviated Injury Scale (AIS).19 dards and Control and World Health Organization proto- For these post hoc calculations, the ISS assessment was based col 89/548. on the final diagnosis of each patient. To elucidate whether The plasma concentration of the C-reactive protein increased IL-6 production is related to the severity of trauma (CRP) was measured to estimate the extent of trauma (regardless of the location of the injury itself), patients were impact on each individual.20 A turbidimetric method divided into 4 groups according to the ISS: was used (Hoffmann-LaRoche, Grenzach Whylen, 1. Values less than 9, which indicate minor injury Germany). Reference values in healthy individuals are (n = 11; 10 men and 1 woman) provided that no AIS value below 4 mg/mL. exceeded 2 points (ISS median, 3; range, 2-8). 2. Values from 9 to 17, which indicate medium in- STATISTICS jury (n = 29; 20 men and 9 women), covering a maximum of 2 AIS values of 3 points (ISS median, 11; range, 9-17). All results are presented as mean ± SD or SEM if not 3. Values from 18 to 30, which indicate severe injury indicated otherwise. A nonparametric Friedman 2-way (n = 38; 26 men and 12 women), consisting of a maximum analysis of variance was performed to evaluate differ- of 2 AIS values of 4 points (ISS median, 27; range, 18-30). ences between groups or in a variable over time. The 4. Values greater than 32, which indicate the most se- Wilcoxon signed rank test was used to analyze differ- vere injury (n = 16; 11 men and 5 women) (ISS median, ences between 2 periods of measurement, and the Mann- 45; range, 32-75). Whitney rank sum test indicated specific group differ- ences. An a adjustment according to Bonferroni-Holm PLASMA IL-6 ASSAYS was applied when appropriate. Significance was accepted at the 95% confidence level (P#.05). In addition, the For IL-6 measurements, 2 mL of peripheral venous results were analyzed using linear or exponential regres- blood was collected at the scene of the unintentional sion formulas. (n = 12; thoracic and abdominal injuries with irrevers- ter trauma (from immediately at the site of the uninten- ible hemorrhagic shock) within 36 hours of the unin- tional injury to 6 hours later), patients with severe and most tentional injury. The median ISS of the nonsurvivors was severe injury showed clearly increasing plasma levels of higher (37.5 points; range, 25-75 points) than the me- IL-6 (eg, for time points immediately at hospital arrival dian ISS of the survivors (17 points; range, 2-48 points). vs 2, 4, and 6 hours later, the ISS was 9-17 vs .32; P = .03). An analysis of the mean circulating IL-6 plasma lev- In contrast, patients with minor or medium injuries re- els according to the ISS classification revealed a clear dif- vealed lower IL-6 levels during the first day. Thereafter up ference between the groups (Figure 1). Immediately at to the third day after admission, there was a decrease of the site of the unintentional injury, there were elevated IL-6 concentrations in all groups (data not shown).