Evidence
Alert

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

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.

 

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.

Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre

 

Definitions

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.

Commentaries

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