NIHR Signal Low-dose sedative reduces sudden confusion after major surgery in older adults

Published on 21 December 2016

Giving a low-dose sedative to older adults in intensive care after surgery reduces sudden confusion, also known as delirium, without increasing the risk of adverse effects.

In this Chinese trial, adults aged 65 or over were given an intravenous drip of the sedative dexmedetomidine on their first day in intensive care following non-heart surgery. Nine percent experienced delirium up to seven days later compared to 23% who received salt-solution placebo. They were less likely to have high blood pressure or fast heart rate, without any increase in the number with low blood pressure or heart rate.

Delirium is common after major surgery and in the intensive care setting, especially in older people. Delirium can increase risk of complications and need for longer-term care.

A safe treatment that reduces risk of delirium after surgery and the time spent in intensive care by older adults could be better for patients and cost saving for the NHS.

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Why was this study needed?

It is estimated that 11 to 51% of older people develop delirium after major surgery. Delirium, which is noticeable decline in brain function, can increase illness and risk of death, and can slow recovery. This can mean longer hospital stays and more time in intensive care.

The ideal aim would be to reduce the risk of delirium developing, for example by controlling temperature and infection. If it does occur there are a number of non-medical steps such as calming and reassurance. Sedatives such as benzodiazepines may make the condition worse.

Dexmedetomidine is a light sedative used in intensive care. Previous studies found it reduced rates of delirium among mechanically-ventilated patients compared to other sedatives. However, it can slow heart rate and lower blood pressure and needs to be used cautiously in people with heart disease.

Researchers wanted to see if low-dose dexmedetomidine could reduce the rates of delirium in older adults after surgery, whether they were ventilated or not.

What did this study do?

This randomised controlled trial included 700 adults aged 65 or over, recruited on admission to intensive care after non-heart surgery, in two hospitals in Beijing, China.

Patients were treated for one day with an intravenous infusion of either dexmedetomidine, dose 0.1 microgram/kg per hour, or salt-solution placebo. They were assessed for delirium from 24 hours after surgery, twice daily for seven days, using the Confusion Assessment Method for ICU (CAM-ICU). Other outcomes included length of stay in ICU and in hospital, adverse events and death from any cause by 30 days.

The trial has several strengths. Patients and assessors were unaware of treatment allocation, and all those randomised were included in the analysis. However, post-surgery intensive care practice may differ between China and the UK, which may limit applicability.

What did it find?

  • Dexmedetomidine reduced risk of delirium after surgery. Nine percent of patients (32 of 350) became delirious compared to 23% (79 of 350) given salt-solution placebo. This translates to an absolute difference of about 13% and a relative 65% reduced risk (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.22 to 0.54). Researchers calculated about eight people would need to be treated to prevent one case of delirium.
  • Fewer people in the dexmedetomidine group experienced high blood pressure (10%) compared with the placebo group (18%; OR 0.50, 95% CI 0.32 to 0.78). Fast heart rate was also less common (7% vs. 14% of the placebo group; OR 0.44, 95% CI 0.26 to 0.75).
  • Length of stay in intensive care was slightly shorter among patients given dexmedetomidine, an average 20.9 hours compared to 21.5 hours for those given placebo (hazard ratio 1.18, 95% CI 1.02 to 1.37). There were no statistically significant differences between the groups in length of hospital stay or 30-day death rates.
  • Dexmedetomidine reduced risk of delirium regardless of whether or not the person was receiving mechanical ventilation.
  • There were some differences in characteristics between groups. More patients in the placebo group had kidney problems or needed blood transfusion during surgery. More patients receiving dexmedetomidine also had their drug infusion modified or interrupted (32 versus 16), but the reasons for this are not explored.

What does current guidance say on this issue?

NICE guidelines cover prevention, diagnosis and management of delirium, but do not address post-operative delirium, specifically. People should be assessed for delirium risk factors on admission to hospital or long-term care. Age 65 or over is a known risk factor. Preventative measures include preventing infection and dehydration, reducing confusion and helping people stay orientated. Checking daily for signs of delirium, with specialist assessment as necessary, are also recommended.

Delirium should primarily be treated by removing the cause if known and with non-medical measures. Short term use of haloperidol or olanzapine is suggested if people are a risk to themselves or others, or non-medical measures are ineffective.

What are the implications?

Patients, clinicians and managers would welcome new initiatives that improve cognitive function and reduce time in intensive care and shorten hospital stays. This study shows promise as one intervention that could reduce delirium in this at-risk patient group, without apparently increasing risk of heart and vascular complications. Before practice changes based on this single study, it would be useful to repeat the findings in the UK and to rule out harms by studying the drug for longer. Using a sedative drug should not replace the need for good post-operative care to remove any treatable cause for delirium.

Reducing intensive care stay by less than one hour may have limited resource implications in this setting. However, preventing delirium could have more far reaching implications in terms of managing complications and longer term care needs. This evidence may inform the next NICE delirium guideline update.

Citation and Funding

Su X, Meng Z-T, Wu X-H, et al. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet. 2016;388(10054):1893-1902.

No funding information was provided for this study, although the investigators list declarations of interest from pharmaceutical companies and support from grants and fellowships.

Bibliography

NICE. Delirium: prevention, diagnosis and management. CG103. London: National Institute for Health and Care Excellence; 2010.

Kronzer VL, Avidan MS. Preventing postoperative delirium: all that glisters is not gold. Lancet 2016. 2016;388(10054):1854-1856.

Why was this study needed?

It is estimated that 11 to 51% of older people develop delirium after major surgery. Delirium, which is noticeable decline in brain function, can increase illness and risk of death, and can slow recovery. This can mean longer hospital stays and more time in intensive care.

The ideal aim would be to reduce the risk of delirium developing, for example by controlling temperature and infection. If it does occur there are a number of non-medical steps such as calming and reassurance. Sedatives such as benzodiazepines may make the condition worse.

Dexmedetomidine is a light sedative used in intensive care. Previous studies found it reduced rates of delirium among mechanically-ventilated patients compared to other sedatives. However, it can slow heart rate and lower blood pressure and needs to be used cautiously in people with heart disease.

Researchers wanted to see if low-dose dexmedetomidine could reduce the rates of delirium in older adults after surgery, whether they were ventilated or not.

What did this study do?

This randomised controlled trial included 700 adults aged 65 or over, recruited on admission to intensive care after non-heart surgery, in two hospitals in Beijing, China.

Patients were treated for one day with an intravenous infusion of either dexmedetomidine, dose 0.1 microgram/kg per hour, or salt-solution placebo. They were assessed for delirium from 24 hours after surgery, twice daily for seven days, using the Confusion Assessment Method for ICU (CAM-ICU). Other outcomes included length of stay in ICU and in hospital, adverse events and death from any cause by 30 days.

The trial has several strengths. Patients and assessors were unaware of treatment allocation, and all those randomised were included in the analysis. However, post-surgery intensive care practice may differ between China and the UK, which may limit applicability.

What did it find?

  • Dexmedetomidine reduced risk of delirium after surgery. Nine percent of patients (32 of 350) became delirious compared to 23% (79 of 350) given salt-solution placebo. This translates to an absolute difference of about 13% and a relative 65% reduced risk (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.22 to 0.54). Researchers calculated about eight people would need to be treated to prevent one case of delirium.
  • Fewer people in the dexmedetomidine group experienced high blood pressure (10%) compared with the placebo group (18%; OR 0.50, 95% CI 0.32 to 0.78). Fast heart rate was also less common (7% vs. 14% of the placebo group; OR 0.44, 95% CI 0.26 to 0.75).
  • Length of stay in intensive care was slightly shorter among patients given dexmedetomidine, an average 20.9 hours compared to 21.5 hours for those given placebo (hazard ratio 1.18, 95% CI 1.02 to 1.37). There were no statistically significant differences between the groups in length of hospital stay or 30-day death rates.
  • Dexmedetomidine reduced risk of delirium regardless of whether or not the person was receiving mechanical ventilation.
  • There were some differences in characteristics between groups. More patients in the placebo group had kidney problems or needed blood transfusion during surgery. More patients receiving dexmedetomidine also had their drug infusion modified or interrupted (32 versus 16), but the reasons for this are not explored.

What does current guidance say on this issue?

NICE guidelines cover prevention, diagnosis and management of delirium, but do not address post-operative delirium, specifically. People should be assessed for delirium risk factors on admission to hospital or long-term care. Age 65 or over is a known risk factor. Preventative measures include preventing infection and dehydration, reducing confusion and helping people stay orientated. Checking daily for signs of delirium, with specialist assessment as necessary, are also recommended.

Delirium should primarily be treated by removing the cause if known and with non-medical measures. Short term use of haloperidol or olanzapine is suggested if people are a risk to themselves or others, or non-medical measures are ineffective.

What are the implications?

Patients, clinicians and managers would welcome new initiatives that improve cognitive function and reduce time in intensive care and shorten hospital stays. This study shows promise as one intervention that could reduce delirium in this at-risk patient group, without apparently increasing risk of heart and vascular complications. Before practice changes based on this single study, it would be useful to repeat the findings in the UK and to rule out harms by studying the drug for longer. Using a sedative drug should not replace the need for good post-operative care to remove any treatable cause for delirium.

Reducing intensive care stay by less than one hour may have limited resource implications in this setting. However, preventing delirium could have more far reaching implications in terms of managing complications and longer term care needs. This evidence may inform the next NICE delirium guideline update.

Citation and Funding

Su X, Meng Z-T, Wu X-H, et al. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet. 2016;388(10054):1893-1902.

No funding information was provided for this study, although the investigators list declarations of interest from pharmaceutical companies and support from grants and fellowships.

Bibliography

NICE. Delirium: prevention, diagnosis and management. CG103. London: National Institute for Health and Care Excellence; 2010.

Kronzer VL, Avidan MS. Preventing postoperative delirium: all that glisters is not gold. Lancet 2016. 2016;388(10054):1854-1856.

Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial

Published on 21 August 2016

Su, X.,Meng, Z. T.,Wu, X. H.,Cui, F.,Li, H. L.,Wang, D. X.,Zhu, X.,Zhu, S. N.,Maze, M.,Ma, D.

Lancet , 2016

BACKGROUND: Delirium is a postoperative complication that occurs frequently in patients older than 65 years, and presages adverse outcomes. We investigated whether prophylactic low-dose dexmedetomidine, a highly selective alpha2 adrenoceptor agonist, could safely decrease the incidence of delirium in elderly patients after non-cardiac surgery. METHODS: We did this randomised, double-blind, placebo-controlled trial in two tertiary-care hospitals in Beijing, China. We enrolled patients aged 65 years or older, who were admitted to intensive care units after non-cardiac surgery, with informed consent. We used a computer-generated randomisation sequence (in a 1:1 ratio) to randomly assign patients to receive either intravenous dexmedetomidine (0.1 mug/kg per h, from intensive care unit admission on the day of surgery until 0800 h on postoperative day 1), or placebo (intravenous normal saline). Participants, care providers, and investigators were all masked to group assignment. The primary endpoint was the incidence of delirium, assessed twice daily with the Confusion Assessment Method for intensive care units during the first 7 postoperative days. Analyses were done by intention-to-treat and safety populations. This study is registered with Chinese Clinical Trial Registry, www.chictr.org.cn, number ChiCTR-TRC-10000802. FINDINGS: Between Aug 17, 2011, and Nov 20, 2013, of 2016 patients assessed, 700 were randomly assigned to receive either placebo (n=350) or dexmedetomidine (n=350). The incidence of postoperative delirium was significantly lower in the dexmedetomidine group (32 [9%] of 350 patients) than in the placebo group (79 [23%] of 350 patients; odds ratio [OR] 0.35, 95% CI 0.22-0.54; p<0.0001). Regarding safety, the incidence of hypertension was higher with placebo (62 [18%] of 350 patients) than with dexmedetomidine (34 [10%] of 350 patients; 0.50, 0.32-0.78; p=0.002). Tachycardia was also higher in patients given placebo (48 [14%] of 350 patients) than in patients given dexmedetomidine (23 [7%] of 350 patients; 0.44, 0.26-0.75; p=0.002). Occurrence of hypotension and bradycardia did not differ between groups. INTERPRETATION: For patients aged over 65 years who are admitted to the intensive care unit after non-cardiac surgery, prophylactic low-dose dexmedetomidine significantly decreases the occurrence of delirium during the first 7 days after surgery. The therapy is safe. FUNDING: Braun Anaesthesia Scientific Research Fund and Wu Jieping Medical Foundation, Beijing, China. Study drugs were manufactured and supplied by Jiangsu Hengrui Medicine Co, Ltd, Jiangsu, China.

Expert commentary

Postoperative delirium can lead to prolonged hospital stay, the development of further comorbidities and reduced patient and family satisfaction. It often has more than one cause and the way it presents can vary.

Multicomponent interventions can successfully reduce the incidence of delirium in the older surgical patient. It is therefore essential that patients deemed high-risk for developing postoperative delirium are identified early with management incorporating a multidisciplinary approach.

Although various agents have been trialed, no single pharmacological intervention has been shown to prevent delirium. Dexmedetomidine could potentially prove to be a powerful ally, in conjunction with patient optimisation, in preventing postoperative delirium.

Dr Mevan Gooneratne, Consultant Anaesthetist, The Royal London Hospital, Age Anaesthesia Association Council Member