Materials and Methods s32

Materials and Methods

This prospective, non-blinded, randomized-controlled trial was conducted in the 24-bed medical ICU at NewYork-Presbyterian Hospital, Columbia University Medical Center, an academic medical center located in New York where an ECMO program has been established since the 1980s. The Columbia University Medical Center Institutional Review Board approved the study, written informed consent was obtained from each subject’s health care surrogate prior to randomization, and was registered on www.clinicaltrials.gov (NCT01938079).

The medical ICU is a closed unit with an established analgesia and sedation protocol for patients receiving ECMO. Analgesia is provided with a fentanyl infusion and changed to hydromorphone if the dose of fentanyl reaches 400 mcg/hr. The choice of sedative is limited to midazolam infusion for the concern of propylene glycol toxicity with high doses of lorazepam and propofol-related infusion syndrome with high doses and extended infusions of propofol [1, 2]. At the commencement of ECMO all patients are deeply sedated to a Richmond Agitation Sedation Scale (RASS) of -5 [3]. Specific bolus dosing and increases of continuous infusions are left up to the discretion of the medical team. When it is appropriate to achieve wakefulness, down-titration of both the opioid and benzodiazepine infusions occurs at the discretion of the medical team. The ECMO circuit consists of either the combination of a Rotaflow centrifugal pump (Maquet Cardiovascular, Rastatt, Germany), Quadrox i oxygenator (Maquet), Cobe E Pack tubing (Sorin, Milan, Italy) and heat exchanger, or the CARDIOHELP support system (Maquet Cardiovascular).

Consecutive patients from November 2013 through December 2014 were considered for inclusion in the study if they were at least 18 years of age, admitted to the medical ICU requiring mechanical ventilation and receiving venovenous ECMO for severe ARDS, defined by the Berlin criteria, and requiring deep sedation (RASS of -5) [4]. Patients were excluded if they had a documented allergy to ketamine, were deemed to have an increased requirement for opioids or sedatives because of substance abuse or trauma, or presence of a condition preventing delirium assessment including an acute neurologic event or baseline congnitive impairment.

At the time of enrollment the following baseline demographics were collected: age, sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score [5], sequential organ failure assessment (SOFA) score [6], cause of hypoxemic respiratory failure, days of hospital stay prior to ECMO cannulation, and number of days requiring mechanical ventilation. Data during the ICU stay was collected daily until the patient was discharged from the ICU or died. These data included cumulative opioid and benzodiazepine requirements, the time at which the medical team decided to achieve wakefulness (goal RASS -3 or lower), and need for renal replacement therapy. The level of sedation was documented at the commencement of ECMO and every 12 hours thereafter until ICU discharge or death. Delirium was monitored in all patients using the Confusion Assessment Method for the ICU (CAM-ICU) [7] every 12 hours only when wakefulness was achieved (RASS of -3 or higher) until ICU discharge or death. All opioids were converted to fentanyl equivalents (0.1 mg of fentanyl = 1.5 mg hydromorphone) and all sedatives were converted to midazolam equivalents (0.5 mg lorazepam = 1 mg midazolam) [8-10].

Subjects were randomized to receive ketamine (protocol group) plus standard sedation practices or standard sedation practices alone (control group) at the start of ECMO. Ketamine was dosed as a 40 mg IV bolus followed by a continuous infusion at 5 micrograms/kg/min in addition to standard sedation practices. Ketamine was continued until the medical team chose to achieve wakefulness or for 7 days, whichever came first. We estimated that with a sample of 20 patients, the study would have 90% power to detect an absolute reduction of 30% in daily requirements of fentanyl or hydromorphone with the use of ketamine, at a one-sided type I error rate of 5%. All drug and patient data are summarized as median [interquartile rage (IQR)] or frequencies and percentages for continuous and categorical variables, respectively. Median (IQR) was used, as it is less influenced by skewed distributions, which are highly likely to occur given the sample size of the present study. Statistical differences between the two groups were measured using the Mann-Whitney U test and Fisher’s exact test for continuous and categorical variables, respectively.

To examine, the trend of (and differences between) the RASS scores in the protocol and control group from the 24-hours before DTAW to the subsequent 72 hours after were examined using repeated measures ANOVA. In addition, we also examined the associations between the variables in the univariate analysis and the separate RASS scores (at 24-hours before the DTAW and at 72-hours after DTAW) using multivariate linear regressions. Unless otherwise stated a p-value ≤ 0.05 signified statistical significance. All analyses were preformed using SPSS 23.0 (IBM corp., Armonk, NY).

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