Description

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.

Hypothesis: Precision sedation titrated to neurophysiologic and respiratory targets is safe and feasible.

Aims and objectives Feasibility Study: Investigate the safety and feasibility of a novel precision sedation strategy.

1. Compare adverse events such as accidental removal of tubes and lines, use of sedatives, opioids or vasopressors above recommended ranges, or other unexpected adverse events between intervention and control groups.
2. Evaluate the actual use and perceived clinical usefulness of processed EEG parameters such as Bispectral index, suppression ratio, accumulated suppression time, spectral edge frequency and median frequency, to adjust and improve the sedation titration strategy prior to main trial.
3. Determine whether length of intensive care stay, time to spontaneous eye opening and time to following commands after daily interruption of sedation, and incidence and duration of delirium are feasible outcomes for a larger clinical trial.
4. PROJECT METHODOLOGY The initial pilot study will evaluate the safety and feasibility of our precision sedation strategy and allow us to refine the neurophysiologic and respiratory elements of the strategy before planning a larger randomized controlled trial. Patients will be randomized to receive either precision sedation or traditional sedation, with dosing guided by clinical assessment alone. The results of these studies have the potential to improve the management of sedation in the ICU, reduce the incidence of adverse outcomes associated with excessive sedation, and improve patient outcomes. The findings will also have important implications for healthcare providers and policymakers, as they may inform the development of guidelines and protocols for sedation management in the ICU.

3.1 Project arrangements, method selection and analyses The "precision sedation in intensive care" project group is well established and functioning. Infrastructure for continuous patient inclusion and data collection is already in place.

3.1.1 Study design and statistical power The study is designed as a 100 patient randomized, controlled feasibility trial where 50 patients will be randomized to precision sedation using neurophysiologic and respiratory targets and 50 patients will be randomized to standard care (control group) across three locations - Surgical Intensive Care Units at Oslo University Hospital Ullevål and Rikshospitalet, and Intensive Care Unit, Sorlandet Hospital, Arendal. No formal power analysis is performed for this feasibility study, but 100 patients across two locations should provide enough patients to assess the feasibility of intervention, data collection and analysis for the relevant patient groups.

3.1.2 Study population Inclusion Criteria 1) All adult (age≥18 years) 2) Admitted to ICU 3) Estimated need for sedation > 24 hours All criteria must be met for inclusion. Exclusion Criteria 1) Patients admitted for palliative care 2) Patients admitted with restrictions in care (no ventilator treatment) 3) Contraindication for daily interruption of sedation Any criteria present leads to exclusion.

3.1.3 Intervention EEG monitoring will be initiated and recorded for both intervention and control groups immediately after randomization and continue for up to 7 days or until extubation, but health care providers will be blinded for all EEG parameters in the control group.

3.2 Participants, organization and collaborations The Steering Committee will coordinate the study. Locally, the study will be managed and coordinated by Site Investigators (SI) at each location. The site investigators will be responsible for data collection and maintenance of study documentation.

3.3 Budget Division of Emergencies and Critical Care, Oslo University Hospital (OUH) is covering costs related to data collection including follow-up, office supplies and some training costs. Costs related to salary for PhD student has been secured from South-Eastern Heath Authority. Costs related to disposable equipment for EEG monitoring has been secured from Charlottefondet.

3.4 Plan for activities, visibility, and dissemination 2024: Complete data collection, data analysis and interpretation. 2025: Prepare manuscript while using the results from this feasibility study plan for a larger study to evaluate effectiveness of a novel precision sedation strategy.

3.4 Plan for implementation The results of this study will be highly anticipated within the participating intensive care units. The project will have widespread involvement from health care providers, and the investigators expect the trial results will lead to the planning of a larger randomized controlled trial on precision sedation. The investigators plan to present the feasibility study results at national and international conferences and publish our findings in a peer-reviewed journal.

4. STATISTICAL METHODS AND DATA ANALYSIS The study design is unblinded, but all data analyses will be performed blinded to the allocation to intervention or control to the extent possible. Data will be analysed by the intention-to-treat principle. Continuous data will be presented as mean ± standard deviation (SD) or median (quartiles) depending on data distribution. Categorical data will be presented as number of total (%). Continuous efficacy variables will be analysed using independent T-tests for comparisons between the treatment arms. Categorical data will be compared using Chi-square with continuity correction. If necessary, values will be log-transformed to meet the assumptions of the tests. Temporal trends between groups will be compared using a generalised mixed model with an unstructured covariance matrix.

5. USER INVOLVEMENT The investigators plan to recruit a user representative to the steering committee to ensure user involvement in the practical planning of the study. The study will be presented for and discussed with the research committee at the Division of Emergencies and Critical Care, Oslo University Hospital. The research committee is multidisciplinary with user representation, and their insights and suggestions will be sought throughout the planning, execution and dissemination phase of this study. Ethical aspects of conducting research on unconscious patients unable to consent prior to inclusion will be discussed specifically.

6. ETHICAL CONSIDERATIONS This study will be conducted according to the principles of the Declaration of Helsinki as stated in the current version of Fortaleza, Brazil, 2013. The protocol and any subsequent modifications will be reviewed and approved by the Regional Ethical Committee South-East, and Data Protection Officer, Oslo University Hospital.

Whenever possible, informed written consent will be obtained prior to study inclusion. For patients unable to provide informed consent at time of randomization the investigators will seek advice from the regional ethics committee and the Oslo University Hospital Data Protection Officer. In previous studies including patients unable to provide consent the regional ethics committee has advised including and randomizing without consent based on family consultation. Final written consent has then been obtained as soon as the patients was deemed able to provide informed consent. The investigators will adhere to the procedures mandated by the regional ethics committee and Data Protection Officer. Patient autonomy to withdraw from the study at any time will be respected.

All participating researchers are obliged to declare any conflicts of interest or financial interest related to the study.