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NIHR Signal Benzodiazepines may increase length of stay and chance of delirium in intensive care

Published on 18 December 2018

doi: 10.3310/signal-000700

Benzodiazepines given during mechanical ventilation in intensive care could increase the risk of a longer hospital stay and delirium compared to other sedatives.

A range of sedatives are used to reduce psychological distress in critically ill patients, but prior to this study, it was not clear which drugs are most effective. This systematic review looked at all the evidence from randomised controlled trials for the effectiveness of six different types of sedative used in people given mechanical ventilation. It then compared each drug type with each other, and placebo.

There was no difference between type of sedation in the number of patients who survived and were discharged from intensive care. Results suggest benzodiazepines prolong the length of stay in intensive care compared with propofol and increase the risk of delirium compared with dexmedetomidine.

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Why was this study needed?

Most mechanically ventilated patients receive sedatives to keep them comfortable and to facilitate treatment. Inappropriate sedation can prolong the patient’s reliance on mechanical ventilation, increase the risk of infections, such as pneumonia, and increase the costs of treatment.

Previous studies of the effects of different sedatives have been limited to head-to-head comparisons of two drugs in clinical trials, and so the overall optimal drugs for sedation in intensive care remain unclear. A previous systematic review comparing alpha-2 agonists (dexmedetomidine and clonidine) with each other or propofol or benzodiazepine concluded that patients treated with alpha-2 agonists had a shorter length of stay in hospital and shorter duration of ventilation.

This study set out to compare the effects of all sedative drugs and drug combinations that have been tested in randomized controlled trials. It aimed to compare their effects on a patient’s overall risk of death by time of discharge, duration of stay in intensive care, and side effects such as delirium.

What did this study do?

This systematic review included 31 randomized controlled trials involving 4,491 patients who received one of seven treatments during mechanical ventilation in intensive care: propofol, benzodiazepines, inhalation anaesthetics, dexmedetomidine, propofol with benzodiazepines, ketamine with benzodiazepines or placebo.

The analysis used an approach where evidence from trials is used to estimate the comparative effectiveness of other drugs that have not been directly compared against each other (indirect evidence). Although this is a potential limitation in this study, there were no statistical inconsistencies between the direct and indirect evidence.

As the trials were diverse in terms of types of patients, aim of sedation and detail on how the sedatives were used it is not possible to say for certain precisely who the results might apply to. Sample sizes for each comparison also varied from as few as 12 participants. These factors affect reliability of the conclusions.  The reviewers did not carry out a thorough assessment of the quality of the trials, so we have to be cautious with the results.

What did it find?

  • Analysis of 13 trials that reported deaths from any cause at the time of discharge showed no significant difference between the seven sedative interventions (including placebo) or combined drugs (total deaths 236/1,294).
  • Nineteen trials looked at duration of intensive care stay, and taken together, these showed that benzodiazepines might be associated with a three day longer hospital stay compared to propofol. However, there was considerable variation between the trials for these results.  
  • Six studies reported information on the effect of sedatives on delirium, and their combined results suggest that benzodiazepines pose a greater risk of delirium than dexmedetomidine (odds ratio 2.59, 95% confidence interval 1.08 to 7.4). Dexmedetomidine was most like to reduce delirium, and placebo was the worst for reducing it compared to propofol or benzodiazepines.
  • There were no significant differences in the number of patients with hypotension, or in the duration of mechanical ventilation, between sedatives.

What does current guidance say on this issue?

The Intensive Care Society’s 2014 review of best practice for analgesia and sedation states that there is insufficient evidence to recommend a particular sedation regimen and that the type of sedation should be individualised to the patient’s requirements and situation. However, it also notes that the current evidence supports modest benefits in outcomes with non-benzodiazepine based sedation versus benzodiazepines.

What are the implications?

Although this study included more trials than the previous review, there was insufficient data to perform a comprehensive network analysis for all six drug strategies for each outcome.  

There is weak evidence that benzodiazepines may have more adverse effects than other drugs. The major variation in reasons for ventilation on the ICU and level of sedation required also hampers direct comparisons between the drugs. Therefore there is still no clear evidence for use of a particular sedative or sedative combination in intensive care.

Also, as the current study does not state which countries the trials took place in, it’s not clear whether the findings would apply to the UK.

Citation and Funding

Wang H, Wang C, Wang Y et al. Sedative drugs used for mechanically ventilated patients in intensive care units: a systematic review and network meta-analysis. Curr Med Res Opin. 2018; 25 Sep. Doi: 10.1080/03007995.2018.1509573.

This study was funded by the National Natural Science Foundation of China (No.81402462, 81571871 and 81770276), Nn10 program, Distinguished Young Scholars Fund of Harbin Medical University Cancer Hospital, the Yuweihan Fund for Distinguished Young Scholars of Harbin Medical University, Harbin Science and Technology Innovation Scholar Fund(2017RAXXJ087) and Heilongjiang Province Postdoctoral Research Fund. 

Bibliography

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).

Pandharipande P, Shintani A, Peterson J et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology. 2006;104(1):21-6.

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

Why was this study needed?

Most mechanically ventilated patients receive sedatives to keep them comfortable and to facilitate treatment. Inappropriate sedation can prolong the patient’s reliance on mechanical ventilation, increase the risk of infections, such as pneumonia, and increase the costs of treatment.

Previous studies of the effects of different sedatives have been limited to head-to-head comparisons of two drugs in clinical trials, and so the overall optimal drugs for sedation in intensive care remain unclear. A previous systematic review comparing alpha-2 agonists (dexmedetomidine and clonidine) with each other or propofol or benzodiazepine concluded that patients treated with alpha-2 agonists had a shorter length of stay in hospital and shorter duration of ventilation.

This study set out to compare the effects of all sedative drugs and drug combinations that have been tested in randomized controlled trials. It aimed to compare their effects on a patient’s overall risk of death by time of discharge, duration of stay in intensive care, and side effects such as delirium.

What did this study do?

This systematic review included 31 randomized controlled trials involving 4,491 patients who received one of seven treatments during mechanical ventilation in intensive care: propofol, benzodiazepines, inhalation anaesthetics, dexmedetomidine, propofol with benzodiazepines, ketamine with benzodiazepines or placebo.

The analysis used an approach where evidence from trials is used to estimate the comparative effectiveness of other drugs that have not been directly compared against each other (indirect evidence). Although this is a potential limitation in this study, there were no statistical inconsistencies between the direct and indirect evidence.

As the trials were diverse in terms of types of patients, aim of sedation and detail on how the sedatives were used it is not possible to say for certain precisely who the results might apply to. Sample sizes for each comparison also varied from as few as 12 participants. These factors affect reliability of the conclusions.  The reviewers did not carry out a thorough assessment of the quality of the trials, so we have to be cautious with the results.

What did it find?

  • Analysis of 13 trials that reported deaths from any cause at the time of discharge showed no significant difference between the seven sedative interventions (including placebo) or combined drugs (total deaths 236/1,294).
  • Nineteen trials looked at duration of intensive care stay, and taken together, these showed that benzodiazepines might be associated with a three day longer hospital stay compared to propofol. However, there was considerable variation between the trials for these results.  
  • Six studies reported information on the effect of sedatives on delirium, and their combined results suggest that benzodiazepines pose a greater risk of delirium than dexmedetomidine (odds ratio 2.59, 95% confidence interval 1.08 to 7.4). Dexmedetomidine was most like to reduce delirium, and placebo was the worst for reducing it compared to propofol or benzodiazepines.
  • There were no significant differences in the number of patients with hypotension, or in the duration of mechanical ventilation, between sedatives.

What does current guidance say on this issue?

The Intensive Care Society’s 2014 review of best practice for analgesia and sedation states that there is insufficient evidence to recommend a particular sedation regimen and that the type of sedation should be individualised to the patient’s requirements and situation. However, it also notes that the current evidence supports modest benefits in outcomes with non-benzodiazepine based sedation versus benzodiazepines.

What are the implications?

Although this study included more trials than the previous review, there was insufficient data to perform a comprehensive network analysis for all six drug strategies for each outcome.  

There is weak evidence that benzodiazepines may have more adverse effects than other drugs. The major variation in reasons for ventilation on the ICU and level of sedation required also hampers direct comparisons between the drugs. Therefore there is still no clear evidence for use of a particular sedative or sedative combination in intensive care.

Also, as the current study does not state which countries the trials took place in, it’s not clear whether the findings would apply to the UK.

Citation and Funding

Wang H, Wang C, Wang Y et al. Sedative drugs used for mechanically ventilated patients in intensive care units: a systematic review and network meta-analysis. Curr Med Res Opin. 2018; 25 Sep. Doi: 10.1080/03007995.2018.1509573.

This study was funded by the National Natural Science Foundation of China (No.81402462, 81571871 and 81770276), Nn10 program, Distinguished Young Scholars Fund of Harbin Medical University Cancer Hospital, the Yuweihan Fund for Distinguished Young Scholars of Harbin Medical University, Harbin Science and Technology Innovation Scholar Fund(2017RAXXJ087) and Heilongjiang Province Postdoctoral Research Fund. 

Bibliography

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).

Pandharipande P, Shintani A, Peterson J et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology. 2006;104(1):21-6.

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

Sedative drugs used for mechanically ventilated patients in Intensive Care Units: a systematic review and network meta-analysis

Published on 9 August 2018

Wang, H.,Wang, C.,Wang, Y.,Tong, H.,Feng, Y.,Li, M.,Jia, L.,Yu, K.

Curr Med Res Opin , 2018

BACKGROUND: The effects of different sedative drugs on all-cause mortality rate, duration of ICU stay, and risk of delirium in mechanically ventilated ICU patients are unclear. This meta-analysis aimed to compare the effectiveness and safety of individual sedative drugs and combined drugs in mechanically ventilated ICU patients. MATERIALS AND METHODS: MEDLINE, EMBASE, Cochrane, EBSCohost, and ISIWeb of Science databases were searched for studies that assessed sedation in ICU mechanically ventilated patients. A Bayesian random-effects model was used to combine the direct comparisons and indirect evidence. RESULTS: Thirty-one randomized, controlled trials were included, which consisted of 4491 patients who received one of seven sedative drugs or a combination of drugs. There were no significantly different regarding the all-cause mortality rate. Compared to propofol, inhalation anesthetics (hazard ratio (HR) 0.121; 95% confidence interval (CI) -7.58 to 7.62), alpha agonists (HR 2.2; 95% CI 0.776 to 5.22), propofol with benzodiazepines (HR 0.306; 95% CI -6.97 to 7.65), ketamine with benzodiazepines (HR 6.57; 95% CI -6.05 to 19.1) and placebo (HR 2.4; 95% CI -5.37 to 10.3), benzodiazepines (HR 3.62; 95% CI 0.834 to 6.2) may increase the duration of ICU stay. Compared to alpha agonists, propofol (HR 2.4; 95% CI 0.304 to 21.1) and placebo (HR 6.12; 95% CI 0.745 to 54.6), benzodiazepines (HR 2.59; 95% CI 1.08 to 7.4) were associated with incremental risks of delirium. CONCLUSION: Compared to propofol, benzodiazepines may increase the duration of ICU stay. Compared to alpha agonists, benzodiazepines were associated with an increased risk of delirium.

Expert commentary

An association between commonly prescribed sedatives and delirium was first demonstrated in 2006. Choice of delirium-minimum sedatives is clearly of importance to our patients’ clinical outcomes and costs.

Applying a network meta-analysis to evaluate the comparative effectiveness of multiple sedatives on delirium occurrence, Wang and colleagues concluded dexmedetomidine is the best choice for both delirium incidence and length of ICU stay.

Nevertheless, currently in almost the entire UK ICUs don’t use dexmedetomidine as first-line choice of sedation in spite of its potential benefits. Wang and colleagues findings, however, will probably unlikely guide to change the current practice and this report lacked explicit detail related to variation between the comparison groups.

Fang Gao Smith, NIHR Senior Investigator; Professor in Anaesthesia, Critical Care Medicine, University of Birmingham; Consultant in Critical Care Medicine, University Hospitals Birmingham NHS Foundation Trust

Rajnikant Laxmishanker Mehta, Senior Medical Statistician/Epidemiologist, Institute of Applied Health Research/Birmingham Clinical Trials Unit, University of Birmingham

The commentators declare no conflicting interests