Effects of the neurological wake-up test on clinical examination, intracranial pressure, brain metabolism and brain tissue oxygenation in severely brain-injured patients

Titrating sedatives and analgesics to achieve the right balance between deep sedation and wakefulness and to ameliorate patients' comfort in the intensive care unit (ICU) is an integral part of critical care [1]. Over-sedation can lead to prolonged duration of mechanical ventilation and ICU stay and increase the incidence of secondary complications, including nosocomial infections and delirium.

Daily interruption of sedation trials (IS-trials) have been implemented in many surgical and medical ICUs after randomized controlled trials demonstrated that IS decreased the duration of mechanical ventilation, shortened the hospital stay and may, in combination with spontaneous breathing trials, improve outcome in medical intensive care patients [2‐6]. Another important issue of IS-trials is that the amount of sedatives and analgesics could also be reduced [2, 3]; however, the result of a recent meta-analysis of five randomized controlled trials comparing IS with no interruption in 699 critically ill patients challenges previous findings as a reduction in duration of mechanical ventilation, length of ICU stay or mortality could not be confirmed [7].

IS-trials in patients with acute brain injury are not well studied and the only case series, including 12 patients with traumatic brain injury (TBI) and 9 subarachnoid hemorrhage (SAH) patients, showed that the risk of elevated intracranial pressure (ICP) and low cerebral perfusion pressure (CPP) is evident during these trials [8, 9]. Cerebral hypoperfusion and raised ICP may result in an imbalance of energy supply and demand especially for the injured brain and, therefore, aggravate the risk for metabolic distress and brain tissue hypoxia [10‐16]. These potential side-effects of IS-trials have not been investigated so far and may limit their clinical benefit in severely brain injured patients. We hypothesized that IS-trials may be harmful for these patients and examined the effects of IS-trials on brain hemodynamic changes, brain tissue oxygen tension and metabolism using multimodal neuromonitoring devices in patients with acute brain injury.

Baseline characteristics are shown in Table 1. Neuromonitoring was initiated at Day 2 after ictus (IQR, 1 to 4) and maintained for 9 days (IQR, 6 to 13). IS trials were performed in all patients, however, not on weekends (n = 40), at the day of neuromonitoring probes insertion (n = 20), due to technical problems (n = 14) and when patients were off sedation (n = 19) leaving 82 of 175 days eligible for awakening trials (47%). Interruption of sedation and analgesics was not attempted on 28 days (34%) due to hemodynamic instability (on 7 days), critical ICP values at baseline (on 12 days), and the need for sedatives (on 9 days), resulting in a total of 54 IS-trials being performed.

In the present study we evaluated the effect of interruption of sedatives and analgesics on neurologic assessment, hemodynamic changes, brain metabolism and brain tissue oxygen tension in acutely brain injured patients. Our main findings were that IS-trials were not attempted on one-third of eligible days due to safety concerns, and that one-third of performed trials had to be stopped due to a critical increase in ICP and impending brain tissue hypoxia. All IS-trials were associated with cardiopulmonary stress, and detection of a new neurological deficit that led to a change in management occurred in only one trial (2%).

It is important to weigh pros and cons of IS-trials in patients with acute brain injury. Spontaneous awakening trials have been considered safe in medical and surgical ICU patients, but have not been validated for NICU patients [2‐6]. In a recent meta-analysis, including 699 critically ill patients, daily sedation interruption was not associated with a reduction in duration of mechanical ventilation, length of ICU stay or mortality, and the authors call for more evidence before IS-trials should be recommended [7]. This may especially hold true for acutely brain injured patients, where an imbalance of energy supply and demand is common and additional stress may result in cerebral metabolic distress and brain tissue hypoxia [10‐16]. We observed a sympathetic stress response with increased heart rate, respiratory rate and MAP during all IS-trials, which is in line with a recent report showing an excess of endogenous catecholamines and corticoids during neurologic wake-up tests [24]. Of interest is the observed effect of IS-trials on cerebral oxygen balance. P_btO₂ increased in patients where the IS-trial could be completed with a positive correlation of P_btO₂ and CPP, which may be explained by increased oxygen delivery without excessive energy consumption [25]. In patients who failed the trial, we observed a decrease in P_btO₂ to critical values (< 20 mmHg) in 67% of IS-trials. In parallel, elevation in ICP was observed, which may increase the demand of oxygen and, therefore, decrease brain tissue oxygen tension. Normalization of P_btO₂ after ICP decreased to normal values supports this hypothesis. Increased systemic oxygen utilization may also result in low brain P_btO₂ 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 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 P_btO₂ 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 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 P_btO₂ 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. An increase in GCS and the FOUR score was observed in half of our patients. Evidence of a new focal neurologic deficit was found in only one SAH patient with known cerebral vasospasm who developed motor weakness of the lower limb. Repeated intra-arterial verapamil application resulted in increased perfusion and prevented cerebral infarction.

With limited clinical benefit of IS-trials in NICU patients, a sedation algorithm guided by commonly used sedation scales may be sufficient. However, the problem with this approach is that we still lack validated sedation scales to guide the neurointensivist in the management of acutely brain injured patients. At the end of each IS-trial, sedatives and analgesics were restarted at half the previous dose and titrated to the desired level of sedation. We believe that this strategy is important to prevent over-sedation of our NICU patients, which is a strong predictor for delirium and prolonged ICU stay. We used a fairly advanced sedation regimen, including dexmedetomidine, on our patients which may not be standard in other NICUs, which may have contributed to our findings and also explain differences to positive trials on medical patients [2‐6].

Several potential weaknesses of this study deserve mention. The sample size is small and the population heterogeneous; however, a subanalysis, including SAH patients only, did not change our findings. Still, a potential selection bias limits generalizability of our data to all patients with severe brain injury since only poor grade patients that fulfill the inclusion criteria outlined in the methods section underwent multimodal neuromonitoring (that is, GCS < 8). One may argue that hemodynamic deterioration during IS-trials should be expected in this selective patient population; however, these are the patients with highest risk for secondary brain damage (that is, delayed cerebral ischemia (DCI)) where a proper clinical exam may uncover deterioration early. In one-third of our trials, critical ICP elevation was observed even after a specialized clinician considered the patient's condition as safe. Another point why our results should not be generalized is that IS-trials were limited to the neuromonitoring time and we may have missed important trial days. Neuromonitoring was started at Day 2 after ictus and the initial 48 hours may even be more critical for sedation interruption, even resulting in a higher number of side effects and safety concerns than described in this study. By increasing the sample size we would have been able to better describe a hemodynamic and clinical profile of patients where IS-trials are at high risk for being aborted. Another potential bias in this study is the large number of days when IS-trials were not attempted due to weekend days, or where the intervention was not considered safe. We do not know how these patients would have performed; however, based on our results, it is very likely that patients who were excluded from the trial due to hemodynamic or cerebral hemodynamic abnormalities would have deteriorated further during the trial. Another limitation is that we did not measure cerebral blood flow (CBF) and the status of cerebral autoregulation in all patients, however, observed an increase in respiratory rate in all patients. Hyperventilation is associated with cerebral vasoconstriction and decreased CBF and limited energy supply to the brain (oxygen and glucose delivery).

Interruption of sedation revealed new relevant clinical information in only one trial. A large number of trials could not be performed or had to be stopped due to safety issues. Although serious brain metabolic changes were not observed, related side effects may overcome clinical benefit in severely brain injured patients and the information gained by multimodal neuromonitoring can be used to safely conduct IS-trials in certain patients and disease states. Contrarily, long-term benefits of IS-trials in selected patients with severe brain injury may still prove beneficial. Future studies should evaluate the ability of advanced neuromonitoring techniques to determine patients most suitable for daily sedation interruption.