Background:

Care of critically ill patients in intensive care units (ICUs) often requires potentially invasive or uncomfortable procedures, such as mechanical ventilation (MV). Sedation can alleviate pain and discomfort, provide protection from stressful or harmful events, prevent anxiety and promote sleep. Various sedative agents are available for use in ICUs. In the UK, the most commonly used sedatives are propofol (Diprivan^®, AstraZeneca), benzodiazepines [e.g. midazolam (Hypnovel^®, Roche) and lorazepam (Ativan^®, Pfizer)] and alpha-2 adrenergic receptor agonists [e.g. dexmedetomidine (Dexdor^®, Orion Corporation) and clonidine (Catapres^®, Boehringer Ingelheim)]. Sedative agents vary in onset/duration of effects and in their side effects. The pattern of sedation of alpha-2 agonists is quite different from that of other sedatives in that patients can be aroused readily and their cognitive performance on psychometric tests is usually preserved. Moreover, respiratory depression is less frequent after alpha-2 agonists than after other sedative agents.

Objectives:

To conduct a systematic review to evaluate the comparative effects of alpha-2 agonists (dexmedetomidine and clonidine) and propofol or benzodiazepines (midazolam and lorazepam) in mechanically ventilated adults admitted to ICUs.

Data sources:

We searched major electronic databases (e.g. MEDLINE without revisions, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and Cochrane Central Register of Controlled Trials) from 1999 to 2014.

Methods:

Evidence was considered from randomised controlled trials (RCTs) comparing dexmedetomidine with clonidine or dexmedetomidine or clonidine with propofol or benzodiazepines such as midazolam, lorazepam and diazepam (Diazemuls^®, Actavis UK Limited). Primary outcomes included mortality, duration of MV, length of ICU stay and adverse events. One reviewer extracted data and assessed the risk of bias of included trials. A second reviewer cross-checked all the data extracted. Random-effects meta-analyses were used for data synthesis.

Results:

Eighteen RCTs (2489 adult patients) were included. One trial at unclear risk of bias compared dexmedetomidine with clonidine and found that target sedation was achieved in a higher number of patients treated with dexmedetomidine with lesser need for additional sedation. The remaining 17 trials compared dexmedetomidine with propofol or benzodiazepines (midazolam or lorazepam). Trials varied considerably with regard to clinical population, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded outcome assessors. Compared with propofol or benzodiazepines (midazolam or lorazepam), dexmedetomidine had no significant effects on mortality [risk ratio (RR) 1.03, 95% confidence interval (CI) 0.85 to 1.24, I² = 0%; p = 0.78]. Length of ICU stay (mean difference –1.26 days, 95% CI –1.96 to –0.55 days, I² = 31%; p = 0.0004) and time to extubation (mean difference –1.85 days, 95% CI –2.61 to –1.09 days, I² = 0%; p < 0.00001) were significantly shorter among patients who received dexmedetomidine. No difference in time to target sedation range was observed between sedative interventions (I² = 0%; p = 0.14). Dexmedetomidine was associated with a higher risk of bradycardia (RR 1.88, 95% CI 1.28 to 2.77, I² = 46%; p = 0.001).

Limitations:

Trials varied considerably with regard to participants, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded assessors.

Conclusions:

Evidence on the use of clonidine in ICUs is very limited. Dexmedetomidine may be effective in reducing ICU length of stay and time to extubation in critically ill ICU patients. Risk of bradycardia but not of overall mortality is higher among patients treated with dexmedetomidine. Well-designed RCTs are needed to assess the use of clonidine in ICUs and identify subgroups of patients that are more likely to benefit from the use of dexmedetomidine.

Study registration:

This study is registered as PROSPERO CRD42014014101.

Funding:

The National Institute for Health Research Health Technology Assessment programme. The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates.

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 13/73/01. The contractual start date was in October 2014. The draft report began editorial review in May 2015 and was accepted for publication in November 2015. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Moira Cruickshank, Lorna Henderson, Graeme MacLennan, Cynthia Fraser, Marion Campbell and Miriam Brazzelli’s institution received funding from the UK Department of Health to undertake this work. Anthony Gordon has received research support and speaker fees from Orion Pharmaceuticals [a manufacturer of dexmedetomidine (Dexdor^®, Orion Corporation)] outside the submitted work. He also declares research support and/or personal/speaker fees from Tenax Therapeutics Inc., from HCA International and from Ferring Pharmaceuticals Inc., and former membership of the Baxter Healthcare Advisory Board (1-day meeting, 10 September 2012) in relation to previous research projects. Marion Campbell declares former membership of the National Institute for Health Research Health Services and Delivery Research Researcher-led Board (2009–15).