Trauma is a major cause of morbidity and mortality in people under the age of 50 years in the western world . Death can occur as a direct result of the trauma induced injury, or as result of a dysfunctional immune response . This excessive immune reaction is caused by the response to tissue injury, such as seen after trauma, surgery or burns. An overwhelming innate immune response is considered to be a major risk factor in the development of post-traumatic organ failure and sepsis. Additional injury, induced by surgical intervention, can increase the overall immune inflammatory reaction .
The lung is most often the first organ to be affected by an exaggerated systemic immune response, which can result in an acute respiratory distress syndrome (ARDS). This functional impairment can be followed by other organs, such as the liver, gastrointestinal tract and kidneys, leading to the so-called multiple organ dysfunction syndrome (MODS). Presence of ARDS and MODS is a major risk factor for mortality, long time morbidity, a prolonged hospital stay and high health care costs .
One of the early and systemically released cytokines in the early inflammatory response, is the pro-inflammatory cytokine interleukin-6 (IL-6). Therefore, this cytokine is widely used as an indicator for severity of the systemic inflammatory response in clinical studies . Serum IL-6 levels have been demonstrated to be closely related to the magnitude of the injury (burden of trauma/first hit) and to the operative procedure (second hit) [6, 7]. There is a correlation between the IL-6 concentration and the underlying injury severity. Patients with a Injury Severity Score (ISS) > 18 showed a more pronounced rise of IL-6 concentration compared to patients with a lower injury severity .
Femur fractures, have been found associated with a profound systemic inflammatory response [9–11]. Ideally, fractures should be managed without a clinically important delay to prevent excess blood loss, and preserve function. However, in case of femur fractures, internal fixation increases systemic inflammation . In trauma patients with an already activated inflammatory response, this increase greatly enhances the risk of an excessive immune response [13, 14]. To address this problem, the concept of damage control orthopedics (DCO) was developed [15, 16]. This concept aims at minimizing the surgically induced inflammatory response through limiting surgical procedures [16, 17]. However, DCO is a controversial approach, because limiting surgical procedures, can lead to a reduced quality of fracture healing, multiple interventions and a prolonged hospital stay. This places the treating surgeon with a difficult dilemma: early total care versus damage control [18–20].
Therefore, there is an unmet need for limiting/preventing the surgical induced inflammation, other than limiting or delaying surgery. Until now, there is a lack of pharmacological interventions that can reduce this surgery induced inflammation.
A promising intervention to attenuate the systemic innate immune response is the treatment with a high concentration of C1-esterase inhibitor (C1-INH) . C1-INH is an acute phase protein, produced by the liver in response to inflammatory conditions. C1-INH is a major inhibitor for both the complement and the contact system, and is, therefore, an important regulator of inflammatory reactions [22, 23]. Apart from the modulation of the these systems, C1-INH has also been shown to attenuate systemic inflammation independently of the activation of complement . In fact, Dorresteijn et al showed that administration of C1-INH, in a 'human endotoxemia model', attenuates the release of pro-inflammatory cytokines, including IL-6, in healthy male volunteers . This model evokes a systemic inflammatory response in the absence of complement activation [21, 25].
Aim of the study
The aim of this study is to ascertain whether administration of C1-INH in trauma patients with a femur fracture can reduce the release of pro-inflammatory cytokines and, therefore, will contribute to attenuation of the inflammatory response, in response to a surgical intervention (second hit). This study can provide proof of principle for C1-INH as a potential drug for the prevention of late inflammatory complications in trauma patients.