Sedation strategies in patients undergoing extracorporeal cardiopulmonary resuscitation

The optimal first-line sedative in critically ill patients is evolving, and sedation choice has the potential to influence clinical outcomes.1,2 The current data, however, on strategies in the critically ill cardiac patient requiring continuous infusion of sedative drugs remains limited. Prior randomized controlled trials (RCTs) including general medical and surgical critical care patients have demonstrated that the use of benzodiazepines in patients undergoing mechanical ventilation (MV) has been associated with higher rates of delirium, prolonged intensive care unit (ICU) length-of-stay, and longer MV duration.3,4 Similarly, in observational studies, the use of benzodiazepines for sedation has been associated with a higher risk mortality compared to propofol or dexmedetomidine-based sedation5,6 There is paucity of high-quality evidence on the optimal sedation practices in patients with cardiac arrest or in those undergoing extracorporeal cardiopulmonary resuscitation (ECPR). Defining the optimal analgosedation strategies, which refers to the combination of analgesia and sedation, in patients undergoing ECPR for out-of-hospital cardiac arrest (OHCA) remains an unmet clinical research need given ECPRs rapidly growing use worldwide and the potential for sedative choices to confound timing of neuroprognostication7,8 or influence post-arrest neurotoxicity.9–11 Studies focusing specifically in patients admitted to ICUs after OHCA have suggested that propofol-based sedation is associated with better outcomes. In a small open-label RCT that included 59 patients in Norway, the authors demonstrated that propofol plus remifentanil allowed faster neuroprognostication assessment and shorter MV duration when compared to midazolam plus fentanyl.12 Notably, in this small RCT, patients receiving propofol plus remifentanyl infusion required higher vasopressor doses administration, though it was underpowered for major clinical endopoints.12 Another study of 460 patients with OHCA from a prospective registry reported shorter awakening times and shorter MV duration with propofol-remifentanyl combination when compared to midazolam-fentanyl.13 These results remained consistent in a propensity-matched analysis including 80 matched-pairs from the original cohort. Such associations may be dependent on benzodiazepine dose, as recently demonstrated by a retrospective study of 2778 OHCA patients, where the use of more than 10 mg of midazolam/per day was associated with significant longer awakening times after OHCA.14 Little is known about the association between first-line sedative agents and outcomes in patients treated with ECPR. Shibahashi et al.15 performed a retrospective analysis of the support for ventricular fibrillation with extracorporeal circulation in Japan II registry that captured treatment and outcome on patients treated with ECPR from 36 participating institutions in Japan between 2013 and 2018. This present analysis included 109 propensity matched patients pairs to compare outcomes between patients who received propofol or midazolam sedation infusions. The authors performed a propensity matching analysis that included clinical and demographic information, baseline health status as well as cardiac arrest characteristics and ECPR features. The authors reported no difference in rates of MV (43% vs. 42%), 30-day survival (39.9% vs. 39.8%), or favourable neurological outcomes defined as a cerebral performance category of 1 or 2 at 30 days (17.6% vs. 18.5%). Similarly, there were no differences in vasopressor use at 24 h or death from cardiovascular aetiology. The authors also performed a sensitivity analysis in which 91 patients undergoing targeted temperature management during ECPR were included and demonstrated no differences in the outcomes of interest. The strengths of the study include data from a cohort derived from a large study with multiple centres, the rigorous propensity matched analysis that may help mitigate non-random treatment biases, and the detailed time-stamped cardiac arrest variables. The results are also externally consistent with other larger randomized clinical trials in the general critical care population that reported no difference in mortality between benzodiazepine-based sedation and propofol-based sedation regimens3,4 The study’s outcomes are also in line with international retrospective series of ECPR16 with rates of survival to hospital discharge of 30.8% and a rate of favourable neurological outcome of 15.3%. The weaknesses of the study include the lack of information regarding delirium rates and MV duration and its lack of data regarding neuroprognistication testing and protocols, haemodynamic and perfusion parameters, and lack of standardized criteria for withdrawal of life-sustaining therapies. Finally, the study was underpowered for hard clinical outcomes. The novelty of study is that it is the first multicentre analysis to explore sedation-related outcomes in this challenging clinical population. In addition, it complements the growing literature on ECPR where the evidence on the association between sedation choices and outcomes remains scant. The findings from this study suggest that either propofol or midazolam-based strategies are reasonable first-line options for sedation in ECPR patients; however, further research is necessary before drawing definitive conclusions. These results should encourage clinicians and researchers to further investigate analgosedation choice in ECPR population with RCTs (Figure 1). It remains unclear if sedative choices impact the incidence of delirium, MV time, or time to neuroprognostication with benzodiazepines in ECPR patients. Similarly, whether individual agents can modify post-arrest hypoxic-ischaemic brain injury has yet to be evaluated. Finally, with growing interest in personalized medicine, there is potential that analgosedation regiments could be tailored according to the degree of potential neurological injury, electroencephalographic, and imaging features, as well as haemodynamic status.17 There are currently ongoing RCTs that will allow us to better understand the synergistic effects of several interventions in survival after OHCA, such as sedation, temperature selection, and blood pressure targets,18 but until then, we should continue to practice by integrating the best available evidence into clinical practice. Research needs in analgosedation for patients undergoing ECPR. ECPR, extracorporeal cardiopulmonary resuscitation; ECMO, extracorporeal membrane oxygenation; EEG, electroencephalogram; MAP, mean arterial pressure; MV, mechanical ventilation; RCTs, randomized clinical trials, TTM, targeted temperature management. Shibahashi et al.15 should be congratulated for a novel and welcome contribution to the ECPR literature. Their findings raise new questions regarding the optimal analgosedation in this patient population and highlight the need to pursue further research to systematically assess different sedation agents in order to understand the ideal approach to minimize MV duration, decrease delirium rates, and improve neurological outcomes. None. The data underlying this article are available in the article and in its online supplementary material. Carlos L. Alviar (MD) and Sean van Diepen (MD, MSc)

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