The early identification of mildly injured trauma patients and therefore overtriaged patients, if admitted to the TRR, is important to make TRR treatment more efficient and economical for a trauma centre. Although studies showed a correlation of IL-6 serum levels and injury severity in polytraumatised patients [21, 26,27,28,29,30,31,32], explicit data about correlation of IL-6 levels and injury severity in only mildly to moderately injured patients are missing. In addition, it was reported in multiple studies that IL-6 has a high predictive value for development of complications like sepsis, MODS or MOF and mortality, but we found no study, which evaluated the use of IL-6 to distinguish between mildly (ISS 0–8) and moderately injured trauma patients (ISS 9–15) as other studies focussed on patients with ISS of ≥ 9 or ≥ 16 [21,22,23,24,25].

Thus, to our knowledge this study is the first study, which evaluated whether IL-6 serum levels correlate with ISS in mildly (ISS 0–8) and moderately (ISS 9–15) injured patients, and whether IL-6 analysis is suitable for ruling out moderate anatomical injuries (ISS > 8) to support clinical decision making about overtriage and TRR treatment abortion. Especially in patients, who were admitted to the TRR solely based on trauma mechanism criteria, early IL-6 evaluation can be a promising additive tool to improve early differentiation of mildly and moderately injured trauma patients, as percentage of mild injuries in this cohort is high. An early and precise differentiation between mild and moderate injuries is of high clinical relevance as mortality rates in moderately injured patients are more than two times higher than in mildly injured patients and moderate injured patients can suffer from more severe injuries [16]. Point-of-care-testing (POCT) of IL-6 can measure results within 15 min and can therefore be easily integrated into the initial diagnostic assessment to improve the quality and efficiency of TRR treatment [33, 34].

Analysis of TTAs in our study between 2018 and 2021 showed that 37.7% of all TTAs based solely on trauma mechanism criteria. 80.9% of these patients were mildly injured, and another 13.9% were moderately injured resulting in only 5.3% severely injured patients. As ACS-COT seek for undertriage rates lower than 5% and overtriage rates lower than 50%, it is necessary to implement new strategies for early identification of overtriaged patients to have the option of an early abort of the TRR treatment to free resources, like POCT of biomarkers [8, 9].

This study reports that ISS correlates not only in severe and critical trauma or trauma in general as reported in other studies [21, 26,27,28,29,30,31,32], but also in anatomically mild and moderate trauma, with best correlation during early assessment at time of admission. In comparison to other biomarkers for early assessment of injury severity, which were analysed in other publications, IL-6 in our study showed a stronger correlation than copeptin, interleukin-10 (IL-10), creatinine, alkaline phosphatase, aspartate transaminase (AST) and alanine transaminase (ALT) [28, 35, 36]. Furthermore, IL-6 correlation with ISS in our study was comparable to IL-6 correlation in severe trauma patients what reflects the high potential for assessment of injury severity also in non-severe trauma patients [26].

Build on the strong correlation, ROC-analysis of IL-6 concentration at time of admission to predict an ISS of ≥ 9 in our study identified an IL-6 concentration of 11.6 pg/ml as the statistical best cut-off value (sensitivity: 0.667; specificity: 0.815). AUC and Youden index of this IL-6 concentration were comparable to studies, which utilized IL-6 to predict MODS after traumatic haemorrhagic shock [21] and sepsis in critical trauma patients (ISS ≥ 25) [25]. Although in our study IL-6 was not used to predict complications and mortality in severe and critical trauma patients, our results showed comparable predictive values of IL-6 in mildly to moderately injured patients. Therefore, we showed in this feasibility study that IL-6 is also a suitable tool for early differentiation between mild and moderate injuries and that IL-6 can serve, after adequate prospective pivotal validation, as a supportive diagnostic method in the multifactorial decision making of TRR treatment abortion. However, despite these promising results the clinical applicability should be validated on a representative cohort in a prospective study before it can be implemented with confidence in clinical routine.

Given that the objective of IL-6 concentration assessment in this study was to safely rule out moderate trauma severity (ISS > 8), a sensitivity of ≥ 0.9 for IL-6 levels at admission is justified. An IL-6 concentration of 2.9 pg/ml was the cut-off value with highest predictive power and a sensitivity ≥ 0.9 (sensitivity: 0.933; specificity: 0.370) in our study. As we found no study which evaluated the predictive power of a biomarker to predict moderate injuries, we compared our findings with other studies about biomarkers to predict severe injuries in trauma patients. In comparison to a study by Salvo et al. evaluating the serum biomarkers lactate and copeptin to predict severe injury with a high sensitivity of ≥ 95% and a specificity of 0.14 for lactate and 0.20 for copeptin, the predictive power of IL-6 in our study was higher, due to a higher specificity and an only slightly lower sensitivity [35]. A similar study by Hagebusch et al., who evaluated lactate to predict severe injury (ISS ≥ 16) in patients admitted to the TRR solely based on trauma mechanism criteria, reported a comparable AUC for lactate as we detected for IL-6 to predict moderate injuries [37].

Based on the underlying prevalence of 14.6% for moderately injured patients in our study population and a NPV of 0.970 for IL-6 of ≥ 2.9 pg/ml only one patient (2.4%) was falsely rule out and so falsely identified as mildly injured. This reflects the high predictive value and high level of patients’ safety of IL-6 determination at time of admission for moderate injuries. By ruling out moderate anatomical injuries in TRR patients with an IL-6 level below 2.9 pg/ml at time of admission IL-6 determination can support clinical decision about early abortion of TRR treatment of clinically unsuspicious patients at an early timepoint prior to extended diagnostics like whole body CT scan. Anatomically mildly injured patients suffer at the maximum from MAIS 2 in one anatomical location with MAIS 1 in two other anatomical locations, or MAIS 2 in two anatomical locations without any further injury in another anatomical location. Depending on the individual status, clinical appearance and comorbidities of the mildly injured patients, it can be considered to abort the TRR treatment and follow up on these patients in the regular emergency department with a reduced medical team. Therefore, identifying mildly injured patients by IL-6 determination at admission can reduce numbers of complete TRR treatments of patients with solely trauma mechanism criteria by 24.8% and overall complete TRR treatments by 9.4% as the TRR treatment could be potentially aborted at an early stage. Although overall number of TTA cannot be reduced, the potential to diminish completed TRR treatment including extended diagnostics with following ICU admissions for monitoring due to common institutional practices, can result in a significant reduction of human resources and financial burden, as TRR/ICU treatment costs are high and IL-6 POCT is a rapid and cheap diagnostic tool [33, 34, 38].

Although an IL-6 cut-off at 2.9 pg/ml at time of admission ruled out moderate injuries in 23.8% of all patients correctly, 54.8% of patients with IL-6 ≥ 2.9 pg/ml were only mildly injured. To further identify overtriage patients, which could be subject to early TRR treatment abort, we evaluated whether a two-step testing procedure with IL-6 determination 1 h after admission can improve predictive values for moderate injuries and can increase numbers of negative tested patients. The test combination rose the percentage of negative tested patients from 26.2% after the first test to 50% after the second test. This higher rate of negative tested patients resulted in a better false-positive rate of 25% and therefore reduced overtriage rates to 50%, but increased undertriage rates from 6.6% to 21.4% and so clearly above the recommended ACS-COT undertriage rate recommendation. Therefore, we do not recommend the two-step rule out protocol without other clinical assessment tools.

In general, a pre-test selection of the right patient is important, as the NPV depends on prevalence and any biomarker determination can delay resuscitation in seriously injured patients. Therefore, biomarkers to predict injury severity should be used exclusively in patients admitted to TRR based on trauma mechanism criteria, as risk of severe injury is lower in this group than in patients with TTA due to injury criteria. Like all biomarkers, IL-6 determination should always be used as an additive tool to support clinical decision making and not as a stand-alone criterion, as downgrading is a multifactorial process, which is based on several different parameters and assessments. It is important that patients eligible for IL-6 determination to rule out moderate injuries should show normal vital signs and should be able to be treated in the emergency department, as the patient should be transferred there if IL-6 is < 2.9 pg/ml. An unclear patient status, unstable or fluctuate vital signs, relevant comorbidities, a geriatric patient status and other risk factors for posttraumatic complications should be carefully evaluated, and in any situation where clinical stability is uncertain, IL-6–based decision-making should be avoided. Hence, the use of IL-6 determination at time of admission to support decision making for safe TRR treatment abortion of clinical stable patients based on other parameters can be beneficial. This is underlined by the fact that the only patient, in which IL-6 determination falsely ruled-out a moderate anatomical injury severity, presented with a moderate respiratory insufficiency, which was under the level of ACS-COT TTA criteria. Consequently, the combination of clinical assessment and IL-6 determination identified all anatomically moderately injured patients correctly.

Even though IL-6 concentration at time of admission correlates with elapsed time between trauma and admission, we still detected a good sensitivity and NPV for IL-6 at time of admission to predict moderate injuries in our study group (time between accident and arrival at TRR: 56.7 min (IQR 42.0–73.5 min)). As mean time between accident and admission at the hospital in Germany ranges between 60 and 66 min, this indicates that IL-6 measurements at time of admission are robust against time differences in most cases [39].

According to data of large trauma registers around the world male patients sustain trauma and undergo TRR treatment more often than females [39,40,41]. The sex distribution in our study was also not equal (62% male in our study), but representative for overall sex distribution in German TRRs, as the German TraumaRegister DGU® reported a male sex in 69.9% of all cases over the last 10 years [39].

Due to high numbers of mildly injured patients, among patients treated in the TRR based on trauma mechanism criteria only, distribution between mildly and moderately injured patients was not balanced. In addition, the presented feasibility study is limited by the comparatively small case series of fifty patients, as it was designed retrospectively as a pilot study to evaluate, whether defining cut-off values of IL-6 to differentiate between mildly and moderately injured patients is possible.

Nevertheless, as this pilot study proofed that IL-6 at time of admission can retrospectively differentiate between mild and moderate injuries, it is a solid fundament for a subsequent prospective pivotal study with a far larger sample size to generate robust confirmatory data before this test can be implemented as a supportive marker into the clinical routine of downgrading algorithms. Therefore, a large multi-centre, prospective study for further evaluation of IL-6 to early identify overtriaged and only mildly injured patients admitted to TRR based on trauma mechanism criteria should be performed before this method can be recommended to be part of the TRR standard-of-care.