Dexmedetomidine- or Clonidine-Based Sedation Compared With Propofol in Critically Ill Patients The A2B Randomized Clinical Trial

Timothy S. Walsh, MD1; Richard A. Parker, MSc2; Leanne M. Aitken, PhD3; et al

2025년05월 19일

JAMA. Published online May 19, 2025.

DOI: 10.1001/jama.2025.7200

Abstract

Importance  Whether α2-adrenergic receptor agonist–based sedation, compared with propofol-based sedation, reduces time to extubation in patients receiving mechanical ventilation in the intensive care unit (ICU) is uncertain.

Objective  To evaluate whether dexmedetomidine- or clonidine-based sedation reduces duration of mechanical ventilation compared with propofol-based sedation (usual care).

Design, Setting, and Participants  Pragmatic, open-label randomized clinical trial conducted at 41 ICUs in the UK including adults who were within 48 hours of starting mechanical ventilation, were receiving propofol plus an opioid for sedation and analgesia, and were expected to require mechanical ventilation for 48 hours or longer. The median time from intubation to randomization was 21.0 (IQR, 13.2-31.3) hours. Recruitment occurred from December 2018 to October 2023; the last follow-up occurred on December 10, 2023.

Interventions  The bedside algorithms used targeted a Richmond Agitation-Sedation Scale score of −2 to 1 (unless clinicians requested deeper sedation). The algorithms supported uptitration in the dexmedetomidine- and clonidine-based sedation intervention groups and supported downtitration for propofol-based sedation followed by sedation primarily with the allocated sedation (dexmedetomidine or clonidine). If required, supplemental use of propofol was permitted.

Main Outcomes and Measures  The primary outcome was time from randomization to successful extubation. The secondary outcomes included mortality, sedation quality, rates of delirium, and cardiovascular adverse events.

Results  Among the 1404 patients in the analysis population (mean age, 59.2 [SD, 14.9] years; 901 [64%] were male; and the mean APACHE II score was 20.3 [SD, 8.2]), the subdistribution hazard ratio (HR) for time to successful extubation was 1.09 (95% CI, 0.96-1.25; P = .20) for dexmedetomidine (n = 457) vs propofol (n = 471) and was 1.05 (95% CI, 0.95-1.17; P = .34) for clonidine (n = 476) vs propofol (n = 471). The median time from randomization to successful extubation was 136 (95% CI, 117-150) hours for dexmedetomidine, 146 (95% CI, 124-168) hours for clonidine, and 162 (95% CI, 136-170) hours for propofol. In the predefined subgroup analyses, there were no interactions with age, sepsis status, median Sequential Organ Failure Assessment score, or median delirium risk score. Among the secondary outcomes, agitation occurred at a higher rate with dexmedetomidine vs propofol (risk ratio [RR], 1.54 [95% CI, 1.21-1.97]) and with clonidine vs propofol (RR, 1.55 [95% CI, 1.22-1.97]). Compared with propofol, the rates of severe bradycardia (heart rate <50/min) were higher with dexmedetomidine (RR, 1.62 [95% CI, 1.36-1.93]) and clonidine (RR, 1.58 [95% CI, 1.33-1.88]). Compared with propofol, mortality was similar over 180 days for dexmedetomidine (HR, 0.98 [95% CI, 0.77-1.24]) and clonidine (HR, 1.04 [95% CI, 0.82-1.31]).

Conclusions and Relevance  In critically ill patients, neither dexmedetomidine nor clonidine was superior to propofol in reducing time to successful extubation.

Trial Registration  ClinicalTrials.gov Identifier: NCT03653832

Visual Abstract. Dexmedetomidine- or clonidine-based sedation compared with propofol in critically ill patients

Key Points

Question   Does primary sedation with dexmedetomidine or clonidine (α2-adrenergic receptor agonists), compared with propofol-based sedation (usual care), decrease the time to successful extubation in critically ill patients receiving mechanical ventilation?

Findings  In this pragmatic, multicentered, randomized clinical trial including patients expected to require at least 48 hours of mechanical ventilation, neither dexmedetomidine- nor clonidine-based sedation decreased the time to successful extubation compared with propofol-based sedation.

Meaning  Among critically ill patients expected to require at least 48 hours of mechanical ventilation, neither dexmedetomidine- nor clonidine-based sedation was superior to propofol-based sedation.

요약

·         중요성 : 중환자실(ICU)에서 기계환기를 받고 있는 환자에게 α2-아드레날린 수용체 작용제(예: 덱스메데토미딘 또는 클로니딘) 기반 진정제가 프로포폴 기반 진정제보다 발관(기관 내관 제거)까지 걸리는 시간을 줄일 수 있는지 여부는 불확실하다.

·         목적 : 덱스메데토미딘 또는 클로니딘 기반 진정이 프로포폴 기반 진정보다 기계환기 기간을 단축시키는지 평가하는 것이 목적이다.

·         설계, 환경 및 참가자 :

-형태: 실용적인, 공개형 무작위 임상시험

-장소: 영국 내 41개 ICU

-대상: 기계환기 시작 후 48시간 이내 성인

프로포폴과 오피오이드로 진정 및 진통 치료 중

최소 48시간 이상의 기계환기가 예상되는 환자 

-무작위 배정 시점: 기관삽관 후 중앙값 21시간 (IQR 13.2–31.3시간)

-연구 기간: 2018년 12월 ~ 2023년 10월 (최종 추적: 2023년 12월 10일)

·         중재 :

-진정 목표: Richmond Agitation-Sedation Scale −2~+1

-덱스메데토미딘/클로니딘군: 용량 상향 조정 허용

-프로포폴군: 프로포폴 감량 후 진정 유지

-보조적으로 프로포폴 사용 가능

·         주요 결과 및 측정 : 

-1차 결과: 무작위 배정 후 성공적인 발관까지의 시간

-2차 결과: 사망률, 진정의 질, 섬망 발생률, 심혈관 이상 사건 등

·          결과 : 1404명을 분석, 평균 연령: 59.2세 (남성: 64%), 평균 APACHE II 점수: 20.3점

▣ 발관까지 걸린시간 

  ▪ 덱스메데토미딘 vs 프로포폴

  -중앙값 시간: 136시간 vs 162시간

-HR: 1.09 (95% CI: 0.96–1.25, P = 0.20)

▪ 클로니딘 vs 프로포폴

-중앙값 시간: 146시간 vs 162시간

-HR: 1.05 (95% CI: 0.95–1.17, P = 0.34)

▣ 부작용 및 2차 결과

  ▪ 초조/불안 증가:

-덱스메데토미딘 (RR 1.54), 클로니딘 (RR 1.55)

  ▪ 서맥(심박수 <50/min) 증가:

-덱스메데토미딘 (RR 1.62), 클로니딘 (RR 1.58)

  ▪ 180일 사망률:

-덱스메데토미딘 HR 0.98 (95% CI: 0.77–1.24)

-클로니딘 HR 1.04 (95% CI: 0.82–1.31)

·         결론 및 의의 : 중환자에서 덱스메데토미딘이나 클로니딘은 프로포폴보다 발관까지의 시간 단축에 우월하지 않았다. 또한, 더 많은 초조와 서맥 같은 부작용이 보고되었다.