Increased systemic oxygen utilization may also result in low brain PbtO2 levels, which is supported by the observation of systemic desaturation in 5 of 18 trials that had to be aborted and the notification of shivering during IS-trials, as noted by the BSAS-score [21]. The BSAS-score Dovitinib cancer increased by two points, reflecting shivering with involvement of the neck, thorax and gross movement of the upper extremities [21], which was common in patients who failed the IS-trial. Shivering can trigger massive increases in systemic resting energy expenditure, and oxygen consumption [21,22], and can potentially increase the risk of brain tissue hypoxia [16]. Therefore, shivering should be effectively treated by pharmacological and non-pharmacological means [26].

A marked increase in ICP and critical decrease in CPP has been previously described in TBI and SAH patients during neurologic wake up trials [8]. Similarly, we found that elevated ICP was the most often reported failure criteria in our trials. Restarting sedation resulted in an ICP decrease to normal values without the need for additional osmotherapy.Patients who failed the trial had a trend towards higher LPR and lower brain glucose at trial start and during the observation period. This reflects that these patients were already more prone to brain metabolic distress at trial start, which may be a valuable safety consideration of IS-trials in critically ill neurologic patients. Anaerobic metabolism and mitochondrial dysfunction is common after severe head injury and associated with the initial trauma, increased ICP, global cerebral edema after SAH, focal or generalized brain edema, fever, seizures and others [10-16].

Recently, derangement in neuronal signal processing and energy metabolism potentially leading to sustained neuronal depolarization and depression of brain electrical activity have been described after SAH and TBI [27,28]. In these conditions of deranged cerebral metabolism, the human brain may be more vulnerable to systemic and cerebral stress. It is important to mention that ICP increases and PbtO2 decreases did not result in brain metabolic changes in our patients, most likely due to the short duration of these episodes as all of these parameters were predefined as trial-failure criteria.

Without online cerebral hemodynamic Batimastat and brain oxygenation values IS-trials may result in prolonged episodes of elevated ICP or brain tissue hypoxia which are associated with anaerobic brain metabolism and poor outcome [11,12,29]. For further comparative studies, monitoring ICP and PbtO2 during IS-trials seems important, whereas microdialysis parameters seem to discriminate at baseline without adding further information during IS-trials.One of the major rationales in the benefit of daily awakening trials is the additional information gained from a reliable clinical assessment.