NIHR Signal A newer sedative agent may shorten length of stay in intensive care units

Published on 28 June 2016

Adults needing mechanical ventilation who were sedated with dexmedetomidine had reduced length of stay in intensive care and reduced duration of ventilation.

Various sedative drugs are available for use in England although it is unclear if one is better than the others. This review compared two alpha-2 agonist drugs (clonidine and dexmedetomidine) to other commonly used sedative drugs: propofol and the benzodiazepines midazolam and lorazepam for adults on mechanical ventilation.

A 2014 survey reported that, while clonidine is used in about a third of units, dexmedetomidine is not frequently used. The latter drug is expensive, and this review did not consider cost-effectiveness which will be an important factor if the drug is to be used more widely.

This review’s findings on dexmedetomidine support best practice guidelines which suggest modest benefits for non-benzodiazepines compared to benzodiazepines.

Share your views on the research.

Why was this study needed?

Care in intensive care units is costly. Most critically ill adults who require mechanical ventilation need sedation and various drugs and regimens are in use although none has been shown to be clearly better than the others.

Sedative drugs vary in the onset and duration of the sedation and in their adverse effects. Alpha-2 agonist drugs may allow patients to be awakened more easily, to be better able to communicate and have fewer breathing problems than with other sedative drugs. In 2014 about 10% of UK intensive care units used dexmedetomidine.

This study examined the effects of alpha-2 agonists compared to other available sedative drugs on rates of death, duration of mechanical ventilation, length of stay in intensive care and adverse events for adults who require mechanical ventilation.

What did this study do?

This was a systematic review of 18 randomised controlled trials (2,489 adults) carried out in patients receiving breathing support in intensive care units in the UK between 1999 and 2014.

Trials were included if they compared sedation using alpha-2 agonists with each other (dexmedetomidine versus clonidine) or if they compared either of these with propofol or a benzodiazepine.

The included trials were diverse in terms of clinical setting, dose of medication, patient characteristics and length of follow-up which reduces the reliability of the combined results. Six individual studies were at high risk of bias mainly because of a lack of blinding of participants, but this is unlikely to have influenced the main conclusion.

What did it find?

  • One trial comparing dexmedetomidine with clonidine found that target sedation level, with less need for additional sedation, was achieved in more patients who received dexmedetomidine than in those who received clonidine. Haemodynamic parameters appeared to be more stable among patients treated with dexmedetomidine.
  • Compared to propofol or benzodiazepines, adults treated with dexmedetomidine:
    • had significantly shorter lengths of stay in intensive care (mean difference ‑1.26 days, 95% confidence interval [CI] ‑1.96 to ‑0.55),
    • had significantly shorter duration of ventilation (mean difference ‑1.85 days, 95% CI ‑2.61 to ‑1.09),
    • had no greater risk of death (risk ratio [RR] 1.03, 95% CI 0.85 to 1.24) or delirium (RR 0.83, 95% CI 0.65 to 1.06).
  • There was no difference in adverse events such as high or low blood pressure or increased heart rate between dexmedetomidine and other types of sedative drugs or in the time spent in adequate sedation (not further defined).
  • Adults treated with dexmedetomidine had a higher rate of bradycardia (abnormally slow heart rate) than with other sedative drugs (RR 1.88, 95% CI 1.28 to 2.77).

What does current guidance say on this issue?

The Intensive Care Society’s 2014 review of best practice on Sedation for Patients in ICU states there is insufficient evidence to recommend a particular sedation regimen and says the type of sedation should be individualised to the patient’s requirements and situation. It does however state that evidence shows modest benefits in outcomes with non-benzodiazepine-based sedation (e.g. propofol, clonidine, dexmedetomidine) compared to benzodiazepines such as midazolam or lorazepam.

The 2014 Intensive Care National Audit and Research Centre national survey of 235 adult ICUs in the UK showed that propofol was the most widely used sedative. Of the units, 33% reported frequent use of clonidine, 32% of midazolam, 10% of dexmedetomidine, and less than 1% reported use of lorazepam.

What are the implications?

Adults requiring mechanical ventilation who were sedated with dexmedetomidine or clonidine had shorter length of stay in intensive care and duration of ventilation. There is an indication that dexmedetomidine may have a better cardiovascular safety profile than clonidine, but evidence is limited. The overall quality of evidence was low with uncertain or high risk of bias in the trials reviewed.

Dexmedetomidine is expensive. This review did not include trials that compared the costs of treatment so cost-effectiveness is unknown. However, stays in ICU are costly and this drug did reduce length of ICU stay so may well reduce overall costs.

It would be beneficial to know from future trials if particular sub groups of patients were more likely to benefit from treatment with dexmedetomidine as this review did not identify any subgroups.

Citation and Funding

Cruickshank M, Henderson L, MacLennan G, et al. Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review. Health Technol Assess. 2016;20(25).

This project was funded by the National Institute for Health Research Health Technology programme (project number 13/73/01).

Bibliography

ICNARC. Online reports. London: Intensive Care National Audit and Research Centre; 2016.

The Intensive Care Society (UK). Sedation for patients in ICU. London: The Intensive Care Society; 2014.

Why was this study needed?

Care in intensive care units is costly. Most critically ill adults who require mechanical ventilation need sedation and various drugs and regimens are in use although none has been shown to be clearly better than the others.

Sedative drugs vary in the onset and duration of the sedation and in their adverse effects. Alpha-2 agonist drugs may allow patients to be awakened more easily, to be better able to communicate and have fewer breathing problems than with other sedative drugs. In 2014 about 10% of UK intensive care units used dexmedetomidine.

This study examined the effects of alpha-2 agonists compared to other available sedative drugs on rates of death, duration of mechanical ventilation, length of stay in intensive care and adverse events for adults who require mechanical ventilation.

What did this study do?

This was a systematic review of 18 randomised controlled trials (2,489 adults) carried out in patients receiving breathing support in intensive care units in the UK between 1999 and 2014.

Trials were included if they compared sedation using alpha-2 agonists with each other (dexmedetomidine versus clonidine) or if they compared either of these with propofol or a benzodiazepine.

The included trials were diverse in terms of clinical setting, dose of medication, patient characteristics and length of follow-up which reduces the reliability of the combined results. Six individual studies were at high risk of bias mainly because of a lack of blinding of participants, but this is unlikely to have influenced the main conclusion.

What did it find?

  • One trial comparing dexmedetomidine with clonidine found that target sedation level, with less need for additional sedation, was achieved in more patients who received dexmedetomidine than in those who received clonidine. Haemodynamic parameters appeared to be more stable among patients treated with dexmedetomidine.
  • Compared to propofol or benzodiazepines, adults treated with dexmedetomidine:
    • had significantly shorter lengths of stay in intensive care (mean difference ‑1.26 days, 95% confidence interval [CI] ‑1.96 to ‑0.55),
    • had significantly shorter duration of ventilation (mean difference ‑1.85 days, 95% CI ‑2.61 to ‑1.09),
    • had no greater risk of death (risk ratio [RR] 1.03, 95% CI 0.85 to 1.24) or delirium (RR 0.83, 95% CI 0.65 to 1.06).
  • There was no difference in adverse events such as high or low blood pressure or increased heart rate between dexmedetomidine and other types of sedative drugs or in the time spent in adequate sedation (not further defined).
  • Adults treated with dexmedetomidine had a higher rate of bradycardia (abnormally slow heart rate) than with other sedative drugs (RR 1.88, 95% CI 1.28 to 2.77).

What does current guidance say on this issue?

The Intensive Care Society’s 2014 review of best practice on Sedation for Patients in ICU states there is insufficient evidence to recommend a particular sedation regimen and says the type of sedation should be individualised to the patient’s requirements and situation. It does however state that evidence shows modest benefits in outcomes with non-benzodiazepine-based sedation (e.g. propofol, clonidine, dexmedetomidine) compared to benzodiazepines such as midazolam or lorazepam.

The 2014 Intensive Care National Audit and Research Centre national survey of 235 adult ICUs in the UK showed that propofol was the most widely used sedative. Of the units, 33% reported frequent use of clonidine, 32% of midazolam, 10% of dexmedetomidine, and less than 1% reported use of lorazepam.

What are the implications?

Adults requiring mechanical ventilation who were sedated with dexmedetomidine or clonidine had shorter length of stay in intensive care and duration of ventilation. There is an indication that dexmedetomidine may have a better cardiovascular safety profile than clonidine, but evidence is limited. The overall quality of evidence was low with uncertain or high risk of bias in the trials reviewed.

Dexmedetomidine is expensive. This review did not include trials that compared the costs of treatment so cost-effectiveness is unknown. However, stays in ICU are costly and this drug did reduce length of ICU stay so may well reduce overall costs.

It would be beneficial to know from future trials if particular sub groups of patients were more likely to benefit from treatment with dexmedetomidine as this review did not identify any subgroups.

Citation and Funding

Cruickshank M, Henderson L, MacLennan G, et al. Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review. Health Technol Assess. 2016;20(25).

This project was funded by the National Institute for Health Research Health Technology programme (project number 13/73/01).

Bibliography

ICNARC. Online reports. London: Intensive Care National Audit and Research Centre; 2016.

The Intensive Care Society (UK). Sedation for patients in ICU. London: The Intensive Care Society; 2014.

Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review

Published on 1 April 2016

Cruickshank M, Henderson L, MacLennan G, Fraser C, Campbell M, Blackwood B, Gordon A, Brazzelli M.

Health Technology Assessment Volume 20 Issue 25 , 2016

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. 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.

A variety of sedative agents are available for the management of critically ill patients in ICUs. In the UK, the most commonly used drugs are:

  • propofol
  • benzodiazepines, midazolam and lorazepam
  • alpha-2 adrenergic receptor agonists, dexmedetomidine and clonidine.
  • opioids such as morphine or fentanyl

Dexmedetomidine is a newer, selective alpha-2 receptor agonist which has sedative, analgesic, anxiolytic and sympatholytic effects and differs from others in that patients can be aroused readily. Dexmedetomidine does not depress the respiratory system as much as other sedative agents.

Expert commentary

These studies show that we still do not have an ideal sedative agent for critically ill patients. They are an illustration of how difficult it is to complete good comparative studies in this population without risk of serious bias. Do the alpha-2 agonists have a role? Probably; key benefits were observed in terms of ICU length of stay and time to extubation. Dexmedetomidine was associated with bradycardia but with no associated increase in mortality. However, questions remain about how useful the alpha-2 agonists will be in terms of achieving optimal sedation.

Dr Barbara Philips, Reader and Honorary Consultant Intensive Care Medicine, St George's, University of London