Ketamine Sedation in the ICU (KANINE) RCT

Research question for the KANINE Pilot RCT Is it feasible to perform a larger RCT in mechanically ventilated adult critically ill patients requiring sedation to investigate whether an adjunctive ketamine infusion versus placebo improves patient important outcomes?

Pilot Study Design \& Study Centers This is a multi-centre, stratified, allocation-concealed, blinded parallel-group pilot RCT. The primary outcome for this pilot trial will be feasibility as assessed by three outcomes of consent rate, recruitment rate, and protocol adherence. The investigators plan to enroll patients at 4 study centers which are all academic teaching hospitals in Ontario (St Joseph's Hospital, Mount Sinai Hospital, Juravinski Hospital, and the Hamilton General Hospital).

Informed Consent When an eligible patient is identified, research coordinators will approach the patient's SDM a priori to explain the objectives of the trial along with its potential risks and benefits. The informed consent will also include the study protocol description, potential benefits, expected length of the study, and the option to withdraw from the study at any time. The investigators have submitted our REB application to Clinical Trials Ontario and are the final stages of ethics approval.

Allocation \& Randomization Once the research coordinators have identified a potentially eligible patient, they will log into our centralized data center. Once connected, computerized prompts will be given for preliminary identifying data. If eligibility criteria are met, a priori consent will be obtained and the patient will be randomly allocated in a 1:1 ratio to either adjunctive ketamine or placebo. Randomization will be stratified by site.

Experimental \& Control Interventions All eligible patients assigned to the treatment group will receive an adjunctive ketamine infusion at a fixed dose of 0.50 mg/kg/hour. This will be added to the existing sedative and/or analgesic regime that was selected by the bedside clinician (e.g., propofol and/or midazolam and/or dexmedetomidine and/or fentanyl). The dosing of the first-line sedative and/or analgesic infusion will be titrated to achieve the desired Richmond Agitation Sedation Scale (RASS) at the discretion of the healthcare team rather than titrating the fixed dose ketamine.

If the patient's RASS is lower than the goal, the first-line sedative drug will be titrated down. If the goal RASS has still not been achieved after the first-line sedative agent has been titrated all the way down and stopped, it is suggested that any other additional sedative infusion also be titrated down and stopped. If the goal RASS has still not been achieved, the study drug may be discontinued or held at the discretion of the healthcare team. If the RASS remains lower than the goal, the healthcare team will re-assess the patient to rule out other causes for their decreased level of consciousness. The healthcare team can subsequently resume the study drug infusion if they wish to keep the patient sedated. If the patient's RASS is higher than the goal, the first-line sedative drug will be titrated up as needed at the direction of the healthcare team. If the goal RASS has still not been achieved after the first-line sedative agent has been optimized (based on the discretion of the healthcare team), the study drug dose will not be adjusted and instead, the healthcare team may consider boluses of the primary sedative agent or a third non-ketamine sedative or analgesic infusion.

Unless meeting pre-specified stopping criteria, the study drug will continue for a maximum of 14 days or until the patient is extubated, has undergone a tracheostomy, or has died, whichever occurs first. If patients are re-intubated during the same ICU admission, they will resume the trial and study drug. The maximum duration of the study drug of 14 days will begin on the first day of enrolment (i.e. if a study drug is held for 2 days, the total duration of the patient being exposed to the study drug will still be 14 days from the initiation of the study drug meaning that the patient will not receive the study drug for an additional 2 days to account for the days they were not exposed to it). Conversely, if patients are or re-admitted to the ICU, they will not be eligible to resume the trial nor study drug. However, if a patient remains intubated after their first-line sedation and the study drug have been weaned off, and they need to resume sedatives, the study drug can be restarted. Study drug will continue for 14 days maximum as most intubated patients at that point in time have either been extubated or transitioned to a tracheostomy. If a patient undergoes a tracheostomy during their index ICU stay, the study drug will stop. Furthermore, all enrolled patients will have their liver enzymes tested weekly, or more frequently at the clinician's discretion.

Open-label continuous infusion ketamine will be disallowed while the patient is receiving the study drug. If open-label continuous infusion ketamine is used in this circumstance, it will be considered and recorded as a protocol violation. Open-label bolus ketamine will be allowed in the study.

Control Interventions Patients randomized to placebo will receive normal saline in a 150 mL bag that will look identical to the ketamine infusion. Healthcare providers will follow the same sedation titration chart outlined in Figure 3 and in the Experimental Interventions section. The investigators will disallow open-label continuous infusion ketamine use in both treatment groups.

If the healthcare team chooses to use an open-label continuous ketamine infusion as part of their treatment plan, the study drug would be held in that circumstance until the open-label continuous ketamine had been stopped. If the healthcare team chooses to use open-label bolus dosing of ketamine, the study drug would continue.

Blinding Patient allocation will be blinded to treating physicians, nurses, patients, the biostatisticians associated with the study, site investigators, and the research coordinators collecting the data.

Outcomes

Pilot Study Primary Feasibility Outcomes The primary outcome for the KANINE Pilot Trial is feasibility, which will be judged by 3 outcomes of recruitment rate, consent rate, and protocol adherence.

Recruitment rate:

The investigators define a successful recruitment rate of 0.5 patients per centre per month over the duration of the trial (or 2 patients per month overall across the 4 centres).

Consent rate:

The investigators will define >75% consent rate as successful.

Protocol adherence:

The investigators will define ≥75% protocol adherence as successful

Pilot Study Secondary Clinical Outcomes Ventilator-free days at 28 days, 28-day mortality, ICU mortality, ICU length of stay, tracheostomy, hospital mortality, hospital length of stay, delirium (using the validated Confusion Assessment Method for the ICU (CAM-ICU) score or Intensive Care Delirium Screening Checklist), delirium-free/coma-free days at 14 days, use of antipsychotics (total dosage), use of benzodiazepines (total dosage), post-traumatic stress disorder symptoms at 3 months post-ICU discharge using the validated Impact of Event Scale-Revised, continuous sedative and analgesic requirements over ICU stay, adverse events (arrhythmias, vomiting).

Pilot Study Data Collection Trained research coordinators at each site will screen and log patients admitted to the ICU daily. They will record the following on pre-established data abstraction forms that will be transcribed into a web-based case report form on REDCap Coud that will be encrypted and password protected. The online database the investigators plan to use fully complies with FDA and Health Canada rules for electronic data management.

Statistical Analysis

Sample Size The sample size for the pilot was calculated using a 95% confidence interval approach for protocol adherence. Protocol adherence is defined as: (i) not receiving open-label ketamine for patients in the control arm; and (ii) receiving ketamine for patients in the intervention arm. The lower bound for the confidence interval was set at the threshold for feasibility (75%) and an expected adherence rate (90%) was selected based on a previously published RCT24. Using a power of 80%, the require sample size is at least 48 patients. To be conservative, the investgiators will plan for 54 patients (approximately 27 per study arm). The investigators performed similar calculations for the consent rate outcome using a feasibility threshold of 75% and an expected consent rate of 90% leading to an identical sample size number.

KANINE Pilot Study Analysis Calculation of the 3 feasibility outcomes for the KANINE trial are noted in the outcomes section above. The analysis and reporting of results will follow the CONSORT guidelines for reporting of randomized pilot and feasibility trials25. The process of participant enrolment and flow throughout the study will be summarized using a flow-diagram. Participant demographics, medical history, and secondary outcomes will be summarized by treatment group using descriptive summary measures: expressed as mean and standard deviation or median and interquartile range for continuous variables, depending on the distribution, and number and percent for binary/categorical variables.