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This Nutlin-3a is similar to Routsi et al., who only could determine the MRC score in one-third of their patients although their patients were less ill than those in the present study [26]. Thus, as a clinical endpoint was not feasible, we regarded the CIPNM severity sum score, based on serial EPS and two muscle biopsies, as the most appropriate method of assessing the course of CIPNM in critically ill patients who are not fully awake. A total of 106 patients fulfilling the screening criteria (SIRS/Sepsis and MOF) were evaluated by a neurologist in order to only randomize patients with clinical signs of CIPNM. This evaluation was challenging as the majority of the patients was not fully awake. However, unlike the MRC scale assessment, its aim was not to measure CIPNM using a metric scale but to select patients with an advanced stage of CIPNM.

One-third (38 of 106) of patients met these criteria. CIPNM was confirmed in 97% (37 of 38) of patients at baseline based on EPS and muscle histology findings with relatively high CIPNM sum scores. Therefore, we regard the initial clinical evaluation as a valid tool to specifically select patients with an advanced stage of CIPNM, whereas the sensitivity of this evaluation may have been rather low [1].The differentiation between CIP and CIM is often not possible in critically ill patients by EPS alone. This shortcoming also could be compensated for by using the CIPNM severity sum score. Routsi et al., who suggested that electrical muscle stimulation may prevent CIPNM, used only a clinical score for muscle strength to assess CIPNM and, therefore, could not differentiate between CIP and CIM [26].

Another method to make a distinction between CIP and CIM is direct muscle stimulation [27]. However, as muscle biopsy is regarded as the gold standard, we did not use direct muscle stimulation in our study [4].Van den Berghe et al. found a reduced incidence of CIPNM in a pre-planned subgroup analysis of critically ill patients treated with IIT compared to conventional insulin therapy. Similarly, no differentiation between CIP and CIM was feasible in their study, as no histological assessment was done [13].It has been controversially discussed if discrimination between CIP and CIM is reasonable. However, exact differential diagnosis between these two entities leads to better prognostic information regarding long term disability [1,28]. CIM in combination with CIP is associated with a Batimastat more severe weakness and longer ICU length of stay than CIM alone [29]. Moreover, CIM has a better long-term prognosis than CIP [30].The main limitation of the present trial is the relatively small number of critically ill patients included in our trial prone to type II errors.

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