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Prophylactic melatonin for delirium in intensive care (Pro-MEDIC): a randomized controlled trial

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Abstract

Purpose

Delirium is common in the critically ill, highly distressing to patients and families and associated with increased morbidity and mortality. Results of studies on preventative use of melatonin in various patient groups have produced mixed results. The aim of this study was to determine whether administration of melatonin decreases the prevalence of delirium in critically ill patients.

Methods

Multicentre, randomized, placebo-controlled, double-blind trial across 12 Australian ICUs recruiting patients from July 2016 to September 2019. Patients of at least 18 years requiring ICU admission with an expected length of stay (LOS) greater than 72 h; enrolled within 48 h of ICU admission. Indistinguishable liquid melatonin (4 mg; n = 419) or placebo (n = 422) was administered enterally at 21:00 h for 14 consecutive nights or until ICU discharge. The primary outcome was the proportion of delirium-free assessments, as a marker of delirium prevalence, within 14 days or before ICU discharge. Delirium was assessed twice daily using the Confusion Assessment Method for ICU (CAM-ICU) score. Secondary outcomes included sleep quality and quantity, hospital and ICU LOS, and hospital and 90-day mortality.

Results

A total of 847 patients were randomized into the study with 841 included in data analysis. Baseline characteristics of the participants were similar. There was no significant difference in the average proportion of delirium-free assessments per patient between the melatonin and placebo groups (79.2 vs 80% respectively, p = 0.547). There was no significant difference in any secondary outcomes including ICU LOS (median: 5 vs 5 days, p = 0.135), hospital LOS (median: 14 vs 12 days, p = 0816), mortality at any time point including at 90 days (15.5 vs 15.6% p = 0.948), nor in the quantity or quality of sleep. There were no serious adverse events reported in either group.

Conclusion

Enteral melatonin initiated within 48 h of ICU admission did not reduce the prevalence of delirium compared to placebo. These findings do not support the routine early use of melatonin in the critically ill.

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Funding

The Western Australia department of health and the John Hunter Charitable Trust Fund provided funding for this study. This was unrestricted with the funders taking no role in the design and conduct of the study, the analysis or the preparation of the manuscript or publications.

Author information

Authors and Affiliations

  1. Intensive Care Unit, Sir Charles Gairdner Hospital, Nedlands, WA, Australia

    Bradley Wibrow, Erina Myers & Matthew Anstey

  2. Medical School, University of Western Australia, Perth, WA, Australia

    Bradley Wibrow, Edward Litton, Kwok. M. Ho, Adrian Regli, Andrew Ford & Matthew Anstey

  3. Intensive Care Unit, John Hunter Hospital, Newcastle, NSW, Australia

    F. Eduardo Martinez

  4. School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Newcastle, NSW, Australia

    F. Eduardo Martinez

  5. School of Nursing, Midwifery, Health Sciences and Physiotherapy, Notre Dame University, Perth, WA, Australia

    Erina Myers

  6. Intensive Care Unit, Royal Perth Hospital, Perth, WA, Australia

    Andrew Chapman & Kwok. M. Ho

  7. Intensive Care Unit, St John of God Hospital, Subiaco, WA, Australia

    Edward Litton

  8. Intensive Care Unit, St John of God Murdoch Hospital, Murdoch, WA, Australia

    Adrian Regli

  9. Intensive Care Unit, Joondalup Health Campus, Joondalup, WA, Australia

    David Hawkins

  10. Royal Perth Hospital, Perth, WA, Australia

    Andrew Ford

  11. Intensive Care Unit, St George Hospital, Sydney, Australia

    Frank M. P. van Haren

  12. College of Health and Medicine, Australian National University, Canberra, Australia

    Frank M. P. van Haren

  13. University of New South Wales Medicine and Health, Sydney, Australia

    Frank M. P. van Haren

  14. Intensive Care Unit, Gosford and Wyong Hospitals, Gosford, Australia

    Simon Wyer

  15. Intensive Care Unit, Barwon Health, Geelong, Australia

    Joe McCaffrey

  16. Intensive Care Unit, Mater Hospital, Newcastle, Australia

    Alan Rashid

  17. School of Population and Global Health, University of Western Australia, Perth, Australia

    Erin Kelty & Kevin Murray

  18. School of Public Health, Curtin University, Perth, Australia

    Matthew Anstey

  19. School of Veterinary and Life Sciences, Murdoch University, Perth, WA, Australia

    Kwok. M. Ho

  20. Medical School, The University of Notre Dame Australia, 19 Mouat Street, Fremantle, 6959, Australia

    Adrian Regli

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  1. Bradley Wibrow
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Contributions

All authors have contributed to the study conception and design. Material preparation, data collection, and analysis were performed by BW, FEM, MA, EM, EK, and KM. The first draft of the manuscript was written by BW and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. RP—Pharmacist, Sir Charles Gairdner Hospital. RR, Research Coordinator, Sir Charles Gairdner Hospital. BR, Research Coordinator, Sir Charles Gairdner Hospital. GB—Research Coordinator, John Hunter Hospital. SW—Research Coordinator, Royal Perth Hospital. JF—Research Coordinator, St John of God Hospital, Subiaco. AP—Research Coordinator, St John of God Murdoch Hospital, Murdoch. SP—Research Coordinator, St John of God Murdoch Hospital, Murdoch. MN—Research Coordinator, Canberra Hospital. SS—Research Coordinator, Canberra Hospital. MD—Research Coordinator, Bunbury. VC—Intensivist and site investigator, Bunbury. AB—Research Coordinator, Barwon Health. TS—Research Coordinator, Barwon Health. KE—Research Coordinator Gosford Hospital. MK—Research Coordinator, Gosford Hospital. RG—Research Coordinator, Wyong Hospital. TM—Research Coordinator, Mater Hospital, Newcastle. JO—Sleep Scientist, Sir Charles Gairdner Hospital. GS—Sleep Scientist, Sir Charles Gairdner Hospital. BS—Sleep Physician, Sir Charles Gairdner Hospital. DH—Sleep Physician, Sir Charles Gairdner Hospital. GP—Sleep Scientist, John Hunter Hospital. MC, Senior Research Fellow and Group Leader, University of Western Australia. RN, Health Economist, Curtin University.

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Correspondence to Bradley Wibrow.

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Wibrow, B., Martinez, F.E., Myers, E. et al. Prophylactic melatonin for delirium in intensive care (Pro-MEDIC): a randomized controlled trial. Intensive Care Med 48, 414–425 (2022). https://doi.org/10.1007/s00134-022-06638-9

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