Alpha2 agonists for sedation to produce better outcomes for adults with critical illness: a synopsis of the A2B RCT with cost-effectiveness and process evaluation.

Abstract / Summary

Most mechanically ventilated intensive care unit patients require sedation and analgesia for comfort. Current usual care is propofol-based sedation plus an opioid analgesic. The alpha2 agonists dexmedetomidine and clonidine are potential alternative sedatives, but their clinical and cost-effectiveness are uncertain. To evaluate the clinical and cost-effectiveness and safety of alpha2 agonists (dexmedetomidine and clonidine) compared with propofol for sedating adult intensive care unit patients. Pragmatic open-label three-arm trial. Embedded process and economic evaluation. Forty-one intensive care units in the UK. Recruitment from December 2018 to October 2023. Participants were 1437 adults within 48 hours of starting mechanical ventilation expected to require ≥ 48 hours of mechanical ventilation [analysis population: propofol (N = 471), dexmedetomidine (N = 457), and clonidine-based (N = 476) sedation]. Median time from intubation to randomisation was 21.0 (first, third quartile: 13.2, 31.3) hours. In all groups, bedside algorithms targeted a Richmond Agitation Sedation Scale of -2 to + 1 unless clinicians requested deeper sedation. Intervention groups' algorithms supported alpha2-agonist up-titration and propofol down-titration followed by sedation primarily with allocated alpha2 agonist. Supplemental propofol was permitted if required. Primary outcome was time to successful extubation, analysed allowing for death as a competing risk. Secondary outcomes included mortality, sedation quality, rates of delirium and cardiovascular adverse events. Long-term outcomes included: experience of intensive care unit care; anxiety, depression and post-traumatic stress; cognitive function; health-related quality of life. Mean (standard deviation) patient age was 59.2 (14.9) years; 901 (65%) male. The sub-distribution hazard ratio for time to successful extubation for dexmedetomidine versus propofol was 1.09 (95% confidence interval 0.96 to 1.25; p = 0.20) and for clonidine versus propofol was 1.05 (0.95 to 1.17; p = 0.34), with hazard ratio > 1 favouring alpha2 agonist. Median (95% confidence interval) hours from randomisation to successful extubation was: propofol 162 (136 to 170); dexmedetomidine 136 (117 to 150); and clonidine 146 (124 to 168). There was no effect interaction with age, sepsis status, median Sequential Organ Failure Assessment Score, or median Prediction of Delirium in intensive care unit patients' delirium risk score. Delirium rates were similar, but agitation occurred at higher rate than propofol with both alpha2 agonists [dexmedetomidine vs. propofol risk ratio (95% confidence intervals) 1.54 (1.21 to 1.97); clonidine vs. propofol 1.55 (1.22 to 1.97)]. Rates of severe bradycardia (rate < 50/minute) were higher with both alpha2 agonists compared with propofol [dexmedetomidine vs. propofol rate ratio (95% confidence interval) 1.62 (1.36 to 1.93); clonidine vs. propofol 1.58 (1.33 to 1.88)]. Mortality was similar over 180 days follow-up [dexmedetomidine vs. propofol hazard ratio (95% confidence interval) 0.98 (0.77 to 1.24); clonidine vs. propofol 1.04 (0.82 to 1.31)]. Process evaluation indicated a range of contextual factors at intensive care unit and individual level that influenced intervention delivery, including: intensive care unit culture, prior clinician opinions/beliefs, staffing pressures (exacerbated by the COVID-19 pandemic), clinician experience and concerns about alpha2-agonist side effects. There was no difference in cost-effectiveness between the groups. This was a pragmatic unblinded trial, with associated risk of performance and ascertainment bias. Future trials should explore the effectiveness of alpha2 agonists as sedatives in other populations, for example paediatric critical care and acute brain injury. In mechanically ventilated critically ill patients, neither dexmedetomidine- nor clonidine-based sedation was superior for major clinical outcomes or more cost-effective compared with propofol-based sedation. This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/93/01. Intensive care unit patients needing support from breathing machines need medications (sedatives and painkillers) to keep them comfortable. There is evidence that keeping people as awake as possible during care helps them recover, but the best way to achieve this is uncertain. This programme of work compared the use of propofol (currently the most widely used sedative) with two drugs called ‘alpha2 agonists’ (dexmedetomidine and clonidine). Some evidence suggests alpha2 agonists have advantages over propofol, by enabling patients to be more awake and comfortable on the breathing machine. They may also decrease confusion (delirium), which is common and distressing during intensive care unit care. However, there are also concerns that these drugs, especially dexmedetomidine, may not be safe for some patients. In a large trial randomising patients to receive either propofol (usual care) or dexmedetomidine or clonidine as their main sedative (with additional propofol if required), we found no important differences in the time taken to come off the breathing machine. Most measures of patient comfort were similar, but more patients experienced agitation with both dexmedetomidine and clonidine. These sedatives caused higher rates of abnormally slow heart rate compared with propofol, which was a concern to medical and nursing staff caring for patients. We found no important differences in patient survival or well-being during 6 months’ follow-up, and no evidence that either drug offers better value for money if used as the main sedation agent compared with propofol. Our work suggests we should not use alpha2agonists as the main sedative for all intensive care unit patients. There is some uncertainty about our findings, because we found issues like clinician experience and pre-existing beliefs and concerns about alpha2 agonists influenced how they were used. We also cannot exclude that they may have advantages in specific patients based on individual clinicians’ judgement.

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