Evidence
Alert

Melatonin shows potential for reducing delirium among older people after surgery

Taking melatonin around the time of surgery is linked with lower odds of delirium onset in older people, compared with placebo or no treatment. In a systematic review and meta-analysis, around 15% of the melatonin group developed delirium after surgery compared with around 20% of the comparison group.

Delirium is an acute state of mental confusion associated with longer hospital stays and increased mortality. UK clinical guidelines do not recommend specific medications to prevent this condition due to a lack of consistent evidence.

Melatonin is a hormone produced naturally in the brain to regulate sleep. This systematic review combined data for around one thousand participants from six small-scale studies to assess its effectiveness, though melatonin is unlicensed for the prevention of delirium.

This is the most promising evidence yet for melatonin as an option to prevent post-operative delirium in older people. It is not conclusive because we cannot generalise the results beyond these six studies, which included observational data.

 

Why was this study needed?

Delirium involves confusion, impairment of communication, and withdrawal or agitation. This rapid onset condition is distressing for patients and their relatives. Up to half of people on surgical wards develop it, with the highest rates among older adults and those with dementia or other cognitive impairment.

Preventing delirium would give substantial cost savings due to impacts on hospital stays and complications.

Melatonin, the sleep hormone, is used in the treatment of insomnia and jet lag, and is associated with high NHS spend. Small-scale trials of melatonin for delirium prevention have had mixed findings for different patient populations.

This meta-analysis aimed to assess whether melatonin is effective for preventing delirium among older people after surgery.

 

What did this study do?

The researchers combined results from four double-blinded randomised controlled trials and two longitudinal observational studies in which the average age of participants was at least 50 years. The 1,155 participants were in hospital for heart, lung, orthopaedic or liver surgery.

Around half of them received either melatonin or an equivalent called ramelteon, with a daily 3 to 8mg dose for one to seven days, starting before or on the day of surgery. The other half received either a placebo or no treatment.

The included studies took place in Europe, Japan and Egypt, and were published in peer-reviewed journals up to 2017. The two largest studies had a substantial risk of bias due to either participant drop-out or observational study design.

 

What did it find?

  • Patients taking melatonin or ramelteon had a lower risk of developing delirium compared with placebo or no treatment (odds ratio [OR] 0.63, 95% confidence interval [CI] 0.46 to 0.87; six studies, 1,155 participants).
  • This reduction of delirium risk was substantially greater when the randomised trial showing a negative impact of melatonin was taken out of the analysis (OR 0.31, 95% CI 0.19 to 0.50; five studies, 777 participants). Factors contributing to this trial’s atypical result may include a lower melatonin dose, an older average age of participants, and a greater proportion having previously had delirium or cognitive impairment.
  • There was no difference between the results of randomised controlled trials and observational studies.

 

What does current guidance say on this issue?

NICE’s 2010 delirium guideline and a 2019 Scottish Intercollegiate Guidelines Network guideline do not include recommendations relating to melatonin.

For preventing delirium, the NICE guideline recommends non-pharmacological actions such as avoiding infection and dehydration, promoting mobility and sleep, creating as stable a physical environment as possible, and helping patients stay orientated in hospital.

 

What are the implications?

A 2018 NICE surveillance report concluded that new evidence is needed before a guideline recommendation can be given for melatonin in the prevention of delirium.

Melatonin appears to be safe for most people when used in the short term. It is not currently licensed in the UK for preventing delirium.

Melatonin’s effectiveness may vary according to patient characteristics such as age and clinical history, as well as the dose and formulation. We await the results of the Pro-MEDIC RCT on melatonin’s use for preventing delirium in the ICU setting.

 

Citation and Funding

Campbell AM, Axon DR, Martin JR et al. Melatonin for the prevention of postoperative delirium in older adults: a systematic review and meta-analysis. BMC Geriatrics. 2019;19:272.

This project received no specific funding.

 

Bibliography

BNF. British National Formulary: Melatonin. London: BMJ Group and Pharmaceutical Press; 2019.

Healthcare Improvement Scotland. Improving the care for older people: delirium toolkit. Edinburgh: Healthcare Improvement Scotland; 2019.

NHS website. Sudden confusion (delirium). London: Department of Health and Social Care; 2018.

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

NICE. 2018 surveillance of delirium: prevention, diagnosis and management (NICE guideline CG 103). London: National Institute for Health and Care Excellence; 2018.

Scottish Intercollegiate Guidelines Network. Risk reduction and management of delirium: a national clinical guideline. SIGN 157. Edinburgh: Healthcare Improvement Scotland; 2019.

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

 

Definitions

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Commentaries

Expert commentary

In surgical patients, delirium generally arises post-operatively, whereas in general medical patients, it is often present at hospital admission. Delirium prevention is thus potentially more feasible in the surgical setting but there are no recommended pharmacological treatments.

This recent systematic review shows that melatonin appears to reduce post-operative delirium. However, the evidence is limited, comprising only six studies from diverse populations and no benefit was seen in the largest study with the oldest patients.

Melatonin cannot, therefore, be recommended at present for prevention/treatment of post-operative delirium but larger trials, including older and cognitively impaired patients in whom the risk of delirium is greatest, are warranted.

Sarah Pendlebury, Associate Professor, Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford

The commentator declares no conflicting interests