Alpha 2 Agonists for Sedation to Produce Better Outcomes From Critical Illness (A2B Trial): A Randomised, Parallel-group, Allocation Concealed, Controlled, Open, Phase 3 Pragmatic Clinical and Cost- Effectiveness Trial With Internal Pilot
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,437
- 试验地点
- 38
- 主要终点
- Time to first successful extubation post-randomisation (hours).
研究概览
简要总结
Many patients in intensive care (ICU) need help to breathe on a breathing machine and need pain killers and sedatives to keep them comfortable and pain free. However, keeping patients too deeply sedated can make their ICU stay longer, can cause ICU confusion (delirium) and afterwards may cause distressing memories. Ideally patients should be kept less sedated, but it is difficult to get the balance of sedation and comfort right.
The investigators want to know whether starting an alpha2-agonist drug early in ICU can help keep patients more lightly sedated but still comfortable, and whether patients spend less time on the ventilator. The investigators also want to know how safe they are and if they can improve important outcomes during ICU stay and during recovery. The investigators also want to know if they are value for money.
详细描述
Many patients in intensive care (ICU) need help to breathe on a breathing machine and need pain killers and sedatives to keep them comfortable and pain free. However, keeping patients too deeply sedated can make their ICU stay longer, can cause ICU confusion (delirium), and afterwards may cause distressing memories. Ideally, the investigators want to keep patients less sedated, but it is difficult to get the balance of sedation and comfort right.
For sedation, most ICUs use a drug called 'propofol' that is good at reducing anxiety and making people sleepy, but is not a pain killer, so additional pain killers are needed. There are two other drugs used less often called 'alpha-2 agonists' that have both sedative and pain-killing actions, which may make it easier for patients to be more awake and comfortable on the ventilator. The two drugs are called clonidine and dexmedetomidine.
The investigators want to know whether starting an alpha2-agonist drug early in ICU, and using this instead of propofol as much as possible, can help keep patients more lightly sedated but still comfortable, and whether patients spend less time on the ventilator with these drugs. The investigators also want to know how safe these drugs are and if improve important outcomes during ICU stay can be improved (like delirium, comfort, and safety) and during recovery (like bad memories, anxiety, and depression). The investigators also want to know if they are value for money.
The trial will include 1437 participants needing to be on a ventilator for at least 2 days. Participants will be allocated to one of three groups by chance. One group will continue to receive propofol; one group will receive dexmedetomidine; and one group will receive clonidine. All participants will receive extra pain relief if needed, and participants in the dexmedetomidine and clonidine groups will continue to receive propofol if they need this in addition. Nurses and doctors will alter the doses of sedation drugs to try and reduce or stop them, but always aiming to have participants lightly sedated and comfortable. The trial will compare if participants on dexmedetomidine or clonidine come off the ventilator quicker than those just on propofol. The trial will examine whether there was a difference between the groups in the number of participants who experienced delirium in ICU, compare how comfortable participants were, and measure if participants memories of being in the ICU differed.
Patients who were in the trial will be followed up for up to 180 days afterwards because the investigators want to compare if there were differences in the after-effects of being ill in ICU between the groups. Participants will be asked to complete questionnaires that will assess their memories of the ICU experience at 90 days after entering the trial. At 180 days, participants will be asked to complete questionnaires so that the investigators can detect how patients feel about their quality of life or if they suffer from anxiety, depression or stress. Note that for patients recruited during the final months of recruitment, the 90 and 180 days follow will be truncated and not collected. This was agreed with the TSC and funder to reduce trial costs and enable trial completion.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient requiring mechanical ventilation (MV) in an ICU
- •Aged 18 or over
- •Within 48 hours of first episode of mechanical ventilation in ICU
- •Requiring sedation with propofol
- •Expected to require a total of 48 hours of MV or more in ICU
- •Expected to require a further 24 hours of MV or more at the time of randomisation in the opinion of the responsible clinician
排除标准
- •Acute brain injury (traumatic brain injury; intracranial haemorrhage; ischaemic brain injury from stroke or hypoperfusion)
- •Post-cardiac arrest (where there is clinical concern about hypoxic brain injury)
- •Status epilepticus
- •Continuous therapeutic neuromuscular paralysis at the time of screening or randomisation
- •Guillain-Barre Syndrome
- •Myasthenia gravis
- •Home ventilation
- •Fulminant hepatic failure
- •Patient not expected to survive 24 hours by responsible clinician
- •Decision to provide only palliative or end-of-life care
- •Known allergy to one of the study drugs
- •Untreated second or third degree heart block
- •Transferred from another Intensive Care Unit in which MV occurred for >6 hours
- •Enrolled on another CTIMP
- •Previously enrolled on the A2B Trial
- •Patient known to have experienced a period with heart rate <50 beats per minute for 60 minutes or longer since commencing mechanical ventilation in the ICU
研究组 & 干预措施
Dexmedetomidine Group
For dexmedetomidine, the regimen will follow the manufacturer's guidance and regimens used in previous trials. Dexmedetomidine will be up and down titrated against sedation targets set by clinical staff and reviewed at regular intervals, and documented at least daily. No loading dose will be administered. The starting dose will be 0.7 µg.kg-1.hour-1 titrated to a maximum dose 1.4 µg.kg-1 hour-1. Lower starting doses will be used at clinical discretion for patients with cardiovascular instability.
干预措施: Dexmedetomidine (Drug)
Clonidine Group
For clonidine, the regimen is designed to be equipotent with dexmedetomidine based on known pharmacokinetics and pharmacodynamics. The chosen regimen is similar to that currently used in many UK ICUs as part of routine 'off label' practice. Clonidine will be up and down titrated against sedation targets set by clinical staff and reviewed at regular intervals, and at least daily. No loading dose will be administered. The starting dose will be 1.0µg.kg-1.hour-1 titrated to a maximum dose of 2 µg.kg-1.hour-1. Lower starting doses will be used at clinical discretion for patients with cardiovascular instability.
干预措施: Clonidine (Drug)
Usual Care (Propofol) Group
Usual Care Group : Patients will continue to receive intravenous propofol according to usual current care . The sedation targets, weaning, and sedation discontinuation procedures will follow the same clinical targets as for the clonidine and dexmedetomidine groups.
干预措施: Propofol (Drug)
结局指标
主要结局
Time to first successful extubation post-randomisation (hours).
时间窗: Ventilation status will be recorded twice daily from the date of randomisation until the date of documented successful extubation, or 180 days, whichever comes first.
How many hours are participants on the study ventilated for?
次要结局
- Analgesia quality as measured by Sedation Quality Assessment Tool (SQAT)(Analgesia quality will be assessed daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first.)
- Incidence of Drug-related adverse events - Bradycardia; hypotension; hypertension; cardiac arrhythmias; cardiac arrest(The incidence of drug-related adverse events as documented in the medical records will be recorded daily from the date of randomisation until the date of documented successful extubation, or 28 days, whichever comes first.)
- Health related Quality of Life (90 day) assessed by Euroqol tool (EQ-5D-5L)(90 days post ICU discharge)
- Duration of Delirium during ICU stay(Delirium will be assessed twice daily during ICU stay using the Confusion-Agitation method for ICU (CAM-ICU). Delirium will be assessed from the date of randomisation until the date of ICU discharge, or 28 days, whichever comes first.)
- Relative/Partner/Friend (PerLR) assessment of patient communication(Participant communication will be assessed by a Relative/Partner/Friend daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first.)
- Sedation quality as measured by Richmond Agitation and Sedation Scale (RASS)(Sedation quality will be assessed 4 hourly during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first.)
- Sedation quality as measured by Sedation Quality Assessment Tool (SQAT)(Sedation quality will be assessed daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first.)
- Analgesia quality as measured by Richmond Agitation and Sedation Scale (RASS)(Analgesia quality will be assessed 4 hourly during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first.)
- Ability to co-operate with care(Ability to co-operate with care will be assessed twice daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first.)
- Relative/Partner/Friend (PerLR) assessment of wakefulness(Participant wakefulness will be assessed by a Relative/Partner/Friend daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first.)
- Length of ICU stay(ICU status will be recorded daily from the date of randomisation until the date of ICU discharge, or 180 days, whichever comes first.)
- Delirium prior to successful extubation(Delirium will be assessed twice daily during ICU stay using the Confusion-Agitation method for ICU (CAM-ICU). Delirium will be assessed from the date of randomisation until the date of ICU discharge, or 28 days, whichever comes first.)
- Number of hours to first optimum sedation as measured by a RASS score of -2 or greater(Level of sedation will be assessed 4 hourly during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first.)
- Ability to communicate pain(Ability to communicate pain will be assessed twice daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first.)
- Relative/Partner/Friend (PerLR) assessment of patient comfort(Comfort of participant will be assessed by a Relative/Partner/Friend daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first.)
- Patient experience of ICU care measured at 90 days(90 days post ICU discharge)
- Cognitive function assessed at 180 days using the Montreal Cognitive Assessment Tool (Postal or Telephone)(180 days post ICU discharge)
- Health related Quality of Life (30 day) assessed by Euroqol tool (EQ-5D-5L)(30 days post ICU discharge)
- Number of days to first optimum sedation as assessed by the Sedation Quality Assessment Tool (SQAT)(Level of sedation will be assessed daily during the period of ventilation from the date of randomisation until the participant is successfully extubated, or 28 days, whichever comes first.)
- Occurrence of Anxiety and depression at 180 days(180 days post ICU discharge)
- Occurrence of Post-traumatic stress at 180 days(180 post ICU discharge)
- Health related Quality of Life (recalled) assessed by Euroqol tool (EQ-5D-5L)(30 days post ICU discharge - recalled prior to hospital admission)
- Incidence of Mortality(The incidence of death as documented in the medical records will be recorded from the date of randomisation until the date of the last follow-up visit at 180 days.)
- Health related Quality of Life (180 day) assessed by Euroqol tool (EQ-5D-5L)(180 days post ICU discharge)