Is interleukin 6 an early marker of injury severity following major trauma in humans?

HYPOTHESIS: Interleukin 6 (IL-6), a multifunctional cytokine, is expressed by various cells after many stimuli and underlies complex regulatory control mechanisms. Following major trauma, IL-6 release correlates with injury severity, complications, and mortality. The IL-6 response to injury is supposed to be uniquely consistent and related to injury severity. Therefore, we designed a prospective study starting as early as at the scene of the unintentional injury, to determine the trauma-related release of plasma IL-6 in multiple injured patients. PATIENTS AND METHODS: On approval of the local ethics committee, 94 patients were enrolled with different injuries following trauma (Injury Severity Score [ISS] median, 19; range, 3-75). The patients were rescued by a medical helicopter. Subsets were performed according to the severity of trauma--4 groups (ISS, <9, 9-17, 18-30, and >32)-and survival vs nonsurvival. The first blood sample was collected at the scene of the unintentional injury before cardiopulmonary resuscitation, when appropriate. Then, blood samples were collected in hourly to daily intervals. Interleukin 6 plasma levels were determined using a commercial enzyme-linked immunosorbent assay test. The short-term phase protein, C-reactive protein, was measured to characterize the extent of trauma and to relate these results to IL-6 release. RESULTS: As early as immediately after trauma, elevated IL-6 plasma levels occurred. This phenomenon was pronounced in patients with major trauma (ISS, >32). Patients with minor injury had elevated concentrations as well but to a far lesser extent. In surviving patients, IL-6 release correlated with the ISS values best during the first 6 hours after hospital admission. All patients revealed increased C-reactive protein levels within 12 hours following trauma, reflecting the individual injury severity. This was most pronounced in patients with the most severe (ISS, >32) trauma. CONCLUSIONS: To our knowledge, this is the first study that elucidates the changes in the IL-6 concentrations following major trauma in humans as early as at the scene of the unintentional injury. The results reveal an early increase of IL-6 immediately after trauma. Moreover, patients with the most severe injuries had the highest IL-6 plasma levels. There is strong evidence that systemic IL-6 plasma concentrations correlate with ISS values at hospital admission. Therefore, IL-6 release can be used to evaluate the impact of injury early regardless of the injury pattern.

[Prognostic importance of preclinically evaluated biochemical mediators in polytrauma]. / Prognostische Bedeutung präklinisch erfasster biochemischer Mediatoren beim Polytrauma.

UNLABELLED: There is compelling data from several clinical studies on the impact of various anti- and proinflammatory mediators on traumatized patients. Immediate trauma-related results, however, are only available from animal experiments so far. Therefore, in this prospective clinical study the following questions were addressed: (I) Is there any marker in the preclinical phase that give information independent of and better than conventional studies conducted so far, (II) does this possible factor prove to be a (significant) predictor of late complications and/or poor overall outcome, and (III) does this mediator provide information that can alter treatment decisions? METHODS: Upon approval of the local IRB/IEC, 85 patients (pts) were enrolled who suffered from multiple injuries. The pts were rescued by the helicopter-based service of the German Army Hospital in Ulm. The first blood samples were drawn at the site of accident and at admission, then in hourly to daily intervals. The plasma concentrations of following mediators were analyzed: Prostanoids, products of O2-radicals, soluble adhesion molecules, various cytokines, C-reactive protein, creatinine kinase, and neopterin. All values were calculated in relation to the actual plasma protein content to eliminate fluid-induced dilution effects. Subsets of patients were performed according to the severity of trauma (ISS < 9; 9-17; 18-31; > 32), based on the different injury pattern, and survivors versus nonsurvivors as well. RESULTS: As early as at the scene of accident, all patients revealed a severity-dependent increase in most mediators' plasma levels. There was, however, also a pattern-related inflammatory response that was most pronounced in pts who had suffered from thoracic trauma irrespective of whether it was associated with multiple trauma. In a total, 15 pts died within 72 h after the accident. In those casualties, the plasma concentrations of prostaglandin E2 (P < 0.03), glutathione (P < 0.01) as well as creatinine kinase (P < 0.05) were more markedly elevated when compared with survivors. CONCLUSION: Although there were severity-dependent as well as pattern-related releases of various mediators, which in part were more apparent in nonsurviving patients, we failed in proving any predictive marker to specifically discriminate outcome.

Early posttraumatic increase in production of nitric oxide in humans.

Since nitric oxide (NO) contributes to both circulatory disorders and host defense, we analyzed the NO production in (poly)trauma patients (pts) in a prospective (pre)clinical study starting as early as at the scene of accident. Upon approval of the local IRB/EC, 85 multiple injured pts were enrolled. Subsets were performed according to trauma severity (ISS) and injury pattern, and between survivors versus nonsurvivors. The first blood sample was collected at the scene of accident, then in hourly to daily intervals. NO production was assessed by measuring nitrate+nitrite plasma levels. To estimate dilution effects, all values were calculated according to the actual plasma protein content. The extent of trauma was appraised by C-reactive protein (CRP) levels. Immediately after trauma, NO2-+NO3- plasma levels were always elevated. This was most pronounced in thoracic injury, irrespective of whether it was combined with multiple trauma. Nitrate+nitrite levels returned to normal within 24 h. CRP generation increased during 12 h following trauma and was most marked in severest trauma (ISS >50). For the first time, we show very early data following major trauma that demonstrate that NO overproduction starts immediately after trauma. However, systemic NO2-+NO3- levels actually reflect the severity of injury only during the first 2 h. Thereafter, NO generation is rather related to the individual trauma pattern, e.g., chest trauma. Nonetheless, the role of NO after severe trauma and especially in thoracic injury remains unclear and should further be elucidated in a specific study.

[Detection of NO liberation in the early phase of trauma]. / Nachweis einer NO-Freisetzung in der Frühphase nach Trauma.

Both, burn trauma and sepsis induce the generation of reactive oxygen intermediates which often coincides with increased nitric oxide (NO) levels. NO takes part in both circulatory disorders and cell protection. Therefore, in a prospective (pre-)clinical study we focused on the detection of NO in polytrauma patients (pts) starting as early as at the scene of accident. Upon approval of the local ethics committee, pts with an injury severity score (ISS) ranging from 9 to 75 (mean 22) were enrolled. Subsets were performed according to the different injury pattern (long bone fractures, head injury, polytrauma with and without damage to the thorax, isolated chest trauma). The first blood sample was obtained at the scene of accident. Then, blood was collected in hourly to daily intervals. NO production was assessed by the nitrate + nitrite plasma levels. To eliminate dilution effects following volume substitution, all values were recalculated on the plasma protein content. Immediately after trauma, NO plasma levels were elevated. This was most pronounced in pts that have experienced thoracic injuries irrespective of with or without additional polytrauma. There is evidence that NO production always starts immediately after major trauma but depends on the individual trauma pattern. In addition, the results reveal that lethal outcome is associated with an increased NO generation in the early post-injury period. We conclude that NO overproduction does not necessarily prime an overall protection in patients that have suffered from mechanical trauma. The role of NO after severe trauma and especially in thoracic injury should further be elucidated in a specific study on that topic.