pneumonia, abdominal infections, surgical site infections) and concomitant therapies are mostly left to the discretion of the attending physician. benefit [2]; notably, despite encouraging results from experimental and phase-II clinical studies. The difficulty in translating our theoretical knowledge into successful multicenter RCTs and subsequent treatment recommendations may represent one reason, why the mortality of septic shock still averages between 40-60% [3], although the understanding of the underlying pathophysiology has considerably increased and international guidelines have widely been implemented. Just two examples for this dilemma: In 1995, Hebertson et al. described an attenuation of the decrease in left-ventricular contractility by tumor necrosis factor-alpha-(TNF) antibodies in endotoxemic pigs [4]. In the same year, Givner and colleagues reported a reduction in mortality of newborn rats with group B streptococcal disease due to the use of TNF-antibodies [5]. The subsequent pilot study on nine patients with septic shock revealed no side effects concerning the use of TNF-antibodies as an adjunct therapy regardless of the administered dose [6]. Only a few months later, the RCT with 141 patients receiving either placebo or TNF-receptor:Fc fusion protein in three different dosing regimens not only failed to show any survival benefit, but even suggested an increase in mortality associated with higher doses [7]. The “VAsopressin and Septic Shock Trial” (VASST) represents another, more recent example. Whereas there was consistent and extensive evidence from numerous experimental [8,9] as well as small clinical trials [10-12] about the efficacy and benefit of a supplementary low-dose infusion of arginine vasopressin (AVP) on catecholamine requirements and several other outcome measures in septic Rabbit Polyclonal to p19 INK4d shock, the large, multicenter VASST study revealed MK-0359 no significant difference in mortality between sole norepinephrine and combined AVP and norepinephrine in the overall population [13]. But even if the initial RCT has been successful, like for the use of stress-dose corticosteroids in septic shock [14], confirmation studies may turn out negative [15]. This may lead to a so-called “pendulum effect” [16], thereby leaving clinicians in frustration and uncertainty about how to treat their patients. The present article elucidates some of the difficulties in translating our knowledge from bench to bedside. == Basal differences between experimental and clinical research == First of all, we should keep in mind the elementary differences between experimental and clinical trials: preclinical studies are usually performed in young and healthy animals, whereas the majority of patients in the intensive care unit (ICU) suffer from multiple and severe co-morbidities such as MK-0359 chronic heart failure, diabetes, chronic kidney failure. Furthermore, preclinical research allows a well-defined injury (e.g. endotoxemia, cecal ligation and puncture, pneumonia) and perfectly standardized therapeutic interventions. Contrary, study populations of large RCTs are characterized by different sources of sepsis (e.g. pneumonia, abdominal infections, surgical site infections) and concomitant therapies are mostly left to the discretion of the attending physician. To increase the clinical relevance of experimental research, it has been suggested to use “higher fidelity animal models” in the future [17]. Among others, these are characterized by inclusion of older animals and different genetic lines. The fidelity is further increased by the use of “two-hit models” (e.g. pneumonia after following a trauma or burn injury) that mimic nosocomial sepsis secondary to an initial insult more realistically than “one-hit models”. An elementary difference between research in cardiology and critical care is that the pathophysiology and clinical symptoms between different patients with myocardial infarction, for example, are almost identical and quite specific, whereas critical care syndromes like the “systemic inflammatory response syndrome” (SIRS) or “acute respiratory distress syndrome” (ARDS) can be caused by numerous pathophysiological pathways MK-0359 and their diagnosis is based on rather unspecific definitions. As a consequence, the development of definite treatment strategies is more difficult. This hypothesis is supported by the fact that the current guidelines of the Surviving Sepsis Campaign contain 53 class I recommendations with only 8 being classified as grade A, whereas the guidelines for the treatment of ST-segment elevation myocardial infarction, for example, include 93 class I recommendations. Against this background, the first step in improving translational research in critical care is to increase the knowledge of the underlying pathophysiology by experimental research. == Patient characteristics in RCTs == A major problem of clinical RCTs is represented by their heterogeneity in several aspects: the severity of illness, the source of infection, the timing of intervention, and concomitant therapies. Severe sepsis and septic shock are associated with a different baseline risk of death. Inclusion of.