Feasibility Study: Precision Sedation in Intensive Care Using Neurophysiologic and Respiratory Targets.

1. INTRODUCTION A significant proportion of the patients admitted to an intensive care unit (ICU) undergo mechanical ventilation.1,2 It is common practice to administer sedative and analgesic drugs to these patients, to improve their comfort and their interaction with the ventilator. Careful titration of analgesia and sedation is important to prevent pain and discomfort in this population of patients, but oversedation has been associated with increased mortality and morbidity. Optimizing sedation practice may reduce mortality, duration of mechanical ventilation and ICU length of stay, resulting in reduced costs and improved resource utilization. The recommended strategy is to titrate sedation using scales or scores based on clinical criteria.6 There is variability in the specific domains they assess (e.g. consciousness, cognition, and comprehension), and in their implementation (about 88% of units use a sedation scale, with variability in the sedation scale used). There is also an inherent subjectiveness to these scales, with important variability among healthcare providers resulting in significant over-sedation in the ICU.

The current Pain, Agitation/sedation, Delirium, Immobility and Sleep disruption (PADIS) guidelines focuses on early rehabilitation and quick ventilator liberation, but has become criticized for relying on clinical sedation scores to guide sedation alone. A panel of experts, mostly from the collaborative group who authored the PADIS guidelines, have recently provided an updated "state of the art" narrative review to support clinicians in their management of sedation/analgesia with a revised "ABCDEF-R" bundle (R = Respiratory-drive control). This review highlights giving priority to the management of mechanical-ventilator and respiratory-drive related factors to avoid the unnecessary use of medications. As arousal level poorly correlates with markers of patient respiratory effort, and some potentially injurious ventilator dyssynchrony may actually be exacerbated by deeper sedation15 there is a need for new sedation titration strategies less reliant on scales that only assess arousal.

New techniques and devices (such as Bispectral Index, State Entropy, Auditory evoked potentials, Narcotrend Index, Patient State Index monitoring) have been developed with the purpose of providing an objective measurement of patient's sedation. The Bispectral Index monitor is possibly the most studied and adapted. Bispectral Index monitoring is based on the processing of electroencephalographic signals from the brain. The device uses three or four electrodes applied to the patient's forehead. The electrodes record the raw frontal electroencephalogram (EEG) signal and process it through both standard and proprietary algorithms to provide processed EEG parameters of brain electrical activity. These parameters correlate to various states of wakefulness, and can also measure and quantify burst suppression, a specific pattern of brain activity that indicates deep coma with severely reduced brain activity. Although induction of burst suppression using sedatives can be warranted in special circumstances such as status epilepticus, it is normally considered a measurement of over-sedation.

Bispectral Index or EEG monitoring is quite well established for monitoring anaesthesia depth. Recent studies have shown that titrating anaesthesia depth towards a goal of a Bispectral Index between 50-60 and avoiding burst suppression yields less delirium, shorter stay in recovery and for certain vulnerable groups improved cognitive function when tested 1 year after anesthesia. The usefulness of Bispectral Index or EEG monitoring in the ICU setting has been considerably less studied. A recent Cochrane systematic review only identified four studies (256 participants) comparing processed EEG guided sedation to standard care. These studies had severe limitations; one study (50 adults) failed to demonstrate reduced length of ICU stay, two studies (155 adults) failed to demonstrate reduced duration of ventilation, and one study (105 adults) did not find any differences in adverse events. The overall assessment was that the level of evidence is very low, and that there is insufficient evidence to provide any guidance on the use of processed EEG to guide sedation in the ICU.

This feasibility study is the first step in a larger project to develop and evaluate a novel treatment strategy for sedation during intensive care. The feasibility study seeks to optimize feasibility and safety by identifying optimal inclusion criteria, methods of measuring neurophysiologic and respiratory targets and outcome measures. The results from the pilot study will help guide the final planning and implementation of a larger clinical randomized controlled trial comparing a novel approach to individualized sedation using neurophysiologic and respiratory targets to standard care in multiple intensive care units at Oslo University Hospital. 2. HYPOTHESIS, AIMS AND STUDY OBJECTIVES The planned study will focus on investigating the feasibility and safety of precision sedation in the ICU, using a combination of neurophysiologic and respiratory targets.