Adjunctive ketamine for sedation in critically ill mechanically ventilated patients: an active-controlled, pilot, feasibility clinical trial

Objective Ketamine has been shown to decrease sedative requirements in intensive care unit (ICU). Randomized trials are limited on patient-centered outcomes. We designed this pilot trial to evaluate the feasibility of a large randomized controlled trial (RCT) testing the effect of ketamine as an adjunct analgosedative compared with standard of care alone as a control group (CG) in critically ill patients with mechanical ventilation (MV). We also provided preliminary evidence on clinically relevant outcomes to plan a larger trial. Material and methods Pilot, active-controlled, open-label RCT was conducted at medical, surgical, and transplant ICUs at a large tertiary and quaternary care medical institution (King Faisal Specialist Hospital and Research Center, Saudi Arabia). The study included adult patients who were intubated within 24 h, expected to require MV for the next calendar day, and had institutional pain and sedation protocol initiated. Patients were randomized in a 1:1 ratio to adjunct ketamine infusion 1–2 μg/kg/min for 48 h or CG alone. Results Of 437 patients screened from September 2019 through November 2020, 83 (18.9%) patients were included (43 in CG and 40 in ketamine) and 352 (80.5%) were excluded. Average enrollment rate was 3–4 patients/month. Consent and protocol adherence rates were adequate (89.24% and 76%, respectively). Demographics were balanced between groups. Median MV duration was 7 (interquartile range [IQR] 3–9.25 days) in ketamine and 5 (IQR 2–8 days) in CG. Median VFDs was 19 (IQR 0–24.75 days) in ketamine and 19 (IQR 0–24 days) in the CG (p = 0.70). More patients attained goal Richmond Agitation–Sedation Scale at 24 and 48 h in ketamine (67.5% and 73.5%, respectively) compared with CG (52.4% and 66.7%, respectively). Sedatives and vasopressors cumulative use, and hemodynamic changes were similar. ICU length-of-stay was 12.5 (IQR 6–21.2 days) in ketamine, compared with 12 (IQR 5.5–23 days) in CG. No serious adverse events were observed in either group. Conclusions Ketamine as an adjunct analgosedative agent appeared to be feasible and safe with no negative impact on outcomes, including hemodynamics. This pilot RCT identified areas of improvement in study protocol before conducting a large, adequately powered, multicenter RCT which is likely justified to investigate ketamine association with patient-centered outcomes further. Trial registration ClinicalTrials.gov: NCT04075006. Registered on 30 August 2019. Current controlled trials: ISRCTN14730035. Registered on 3 February 2020 Supplementary Information The online version contains supplementary material available at 10.1186/s40560-021-00569-1.

2. Recently intubated and commenced on mechanical ventilation within the last 24-hours.
4. Expected to require MV longer than 24-hours. 5. Expected to be on the KFSH&RC sedation protocol.
6. There is no objection of the ICU attending for enrollment.
Patients with the above inclusion criteria and has one of the following exclusion criteria were screened then excluded: • Patients with a history of dementia or psychiatric disorders or those on any antipsychotic or antidepressant medications at home.
• Known hypersensitivity to ketamine.
• Patients with expected targeted RASS score of − 5, e.g., patients on continuous infusion neuromuscular blockade.
• Patients on dexmedetomidine as the primary sedative prior to randomization.
• Patients with cardiogenic shock, acute decompensated heart failure, or myocardial infarction.
• History of end-stage liver failure (Child-Pugh score C).
• Patients identified as Do Not Resuscitate (DNR) or those expected to die within 24-hours.
• Patients with refractory status epilepticus who are receiving ketamine infusion.
• Proven or suspected status asthmaticus (the dose of this indication differed from the recommended dose for analgosedation).
• Intellectual disability that precluded delirium assessment.
• Transfer from an external facility.
• History of substance abuse.
• Situations where high blood pressure could trigger dangerous complications, such as aortic dissection.
• Repeated ICU admissions within same hospital visit.
• Those who participated in another interventional trial.   (2) Consent rate was defined as (>70%), protocol adherence was defined as receipt of study fluid for >75% of all intravenous fluids administered in the ICU excluding blood products and medication infusions The protocol adherence was 73.1 in conservative O2 group and 75.2% in usual care group Coe S et al. A protocol for a randomised double-blind placebo-controlled feasibility study to determine whether the daily consumption of flavonoid-rich pure cocoa has the potential to reduce fatigue in people with relapsing and remitting multiple sclerosis (RRMS) (5) Successful adherence to the intervention was defined as at least 75% of the participants having completed cocoa consumption. Higher % than this is considered satisfactory. An adherence rate lower than this would require substantial changes to the intervention and require further piloting  The scoring system's intercept is expressed as −6.31; the other numbers represent the shrunken regression coefficients (weight) of each risk factor.

Duration of MV
• Was recorded as either the number of calendar days from intubation to extubation or until ICU discharge or death, whichever occurred first.
• This outcome was chosen as a patient-centered outcome and based on the mechanistic plausibility data that showed ketamine possibly has a bronchodilatory effect and maintains respiratory drive and airway reflexes • Any clinically significant worsening in a study participant's condition based on clinical judgment compared to the baseline status at the time of randomization was recorded as an AE. This is applied whether or not the AE is considered to be related to the study treatment.
• Tachycardia was defined as a heart rate > 150 beats per minute • Hyper or hypotension was classified as systolic blood pressure ≥ 180 mmHg and ≤ 90 mmHg, respectively • Tracheostomy, and unplanned extubation (self-extubation) were reported as proportion of patients within 28 days post-randomization • Hypersalivation: defined as frequent suctioning the first 48 h after randomization (interval between suctioning episodes 2 h or less). We calculated the modified Clinical Pulmonary Infection Score (CPIS) to differentiate secretions caused by patients' underlying lung pathology (ventilator-associated pneumonia [VAP]) vs ketamine-associated hypersalivation • Physical restraint was reported as proportion of patients within 48 h after randomization • The incidence of delirium was reported as proportion of patients starting on antipsychotics and positive CAM-ICU score to assess the incidence of delirium 48 h after randomization. The presence of delirium was also confirmed through a psychiatrist consultation • We believe the administration of sedative agents is standard of practice in the ICU to minimize a patient's discomfort while on MV. Hence, the expected adverse effects will not exceed what is encountered during daily practice

Serious adverse events
• Included death or potentially life-threatening adverse effects that requires inpatient hospitalization or prolongation of hospitalization, or results in permanent or significant disability/incapacity, congenital anomaly/birth defect, or the investigator considers significant.
• An independent Research Advisory Council at our institution served as a Data Safety Monitoring Committee (DSMC) and reviewed all adverse events (including all deaths). This committee included faculty with expertise in various disciplines engaged in human subjects' research from the hospital and research centre, and also community members. ICU consultants might be invited to assist from time to time with complex issues. The committee conducted periodic reviews at the discretion of the Chair, and an expedited review is done for all serious unexpected adverse events (SUAEs). The committee has the authority to suspend or halt recruitment if necessary.
• No formal interim analysis of efficacy was undertaken due to possible small numbers that might preclude determination of a statistically significant difference in outcomes between the arms. No stopping rules is specified.
Recruitment rate An average recruitment rate was calculated as the total number of recruited patients, divided by the number of study months.

Consent rate
Was defined as the proportion of patients who consented to enrolment out of those approached Adherence rate We defined adherence rate as receiving > 75% of protocolized intervention and assessment of protocol deviation and violation. The adherence to the protocol was assessed daily by the research team and developed as a checklist in REDCAP. Research coordinators documented all reasons for protocol non-adherence. We employed strategies to improve adherence and intervention fidelity if needed.
Calculation of consent and recruitment rate were not analysed by group but the adherence rate was assessed for each group ( refer to   Data presented as n (%), mean ± sd, or median (interquartile range).
a CPIS score was used to differentiate secretions caused by patients' underlying lung pathology      Data presented as n (%), mean ± sd, or median (interquartile range).
a This sensitivity analysis was conducted to address whether the discrepancy in numbers of patients who did not complete 48h of trial (due to extubation and sedation weaned off) would contaminate the interpretation of the results of this pilot study. This analysis included per-protocol population, defined as mITT population after exclusion of subjects who did not complete 48-hours post-randomization. The results were consistent with primary analysis.
b VFDs were calculated by subtracting number of ventilation days from 28 after assigning VFD=0 for patients who died during 28 days. Studies that showed Opioid-sparing effect and reduction of sedatives