Effect of exogenous melatonin and its analogues on preventing delirium in critically ill patients: a meta-analysis_West China Medical Journal

Authors：

LI Wenrui ¹ , LI Na ¹ , ZHANG Zhigang ^1,2 , HAN Lulu ¹ , KONG Jiajia ¹ , WANG Zhenzhen ¹ , JI Kexin ¹ , ZENG Yinru ¹ ,  ZHANG Caiyun ^1,3

1. School of Nursing, Lanzhou University, Lanzhou, Gansu 730000, P. R. China;
2. Department of Critical Care Medicine, the First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;
3. Outpatient Department, the First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;

Corresponding author：

ZHANG Caiyun, Email: 13893601236@163.com

Keywords：

Melatonin; Delirium; Critically ill; Meta-analysis

DOI：

10.7507/1002-0179.202103083

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Objective To evaluate the effect of exogenous melatonin and its analogues on the prevention of delirium in critically ill patients by meta-analysis. Methods Randomized controlled trials of exogenous melatonin and its analogues in the prevention of delirium in critically ill patients were searched by computer from the Cochrane Library, PubMed, Web of Science, Embase, China National Knowledge Infrastructure, Chongqing VIP, Wanfang, and SinoMed databases. The trial group was treated with melatonin or its analogues, while the control group was treated with placebo. The retrieval period was from the establishment of database to January 14th, 2021. Two researchers independently evaluated the literature quality, and meta-analysis was performed using RevMan 5.4 software. Results A total of 11 randomized controlled trials containing 1177 patients were enrolled, including 588 patients in the trial group and 589 patients in the control group. The results showed that exogenous melatonin and its analogues could reduce the occurrence of delirium in critically ill patients [odds ratio (OR)=0.45, 95% confidence interval (CI) (0.22, 0.91), P=0.03] and shorten the time of mechanical ventilation [standard mean difference (SMD)=−0.49, 95%CI (−0.94, −0.03), P=0.04], while might not affect the mortality rate [OR=0.73, 95%CI (0.46, 1.17), P=0.19] or length of intensive care unit stay [SMD=−0.05, 95%CI (−0.26, 0.15), P=0.61]. Conclusions The current evidence shows that exogenous melatonin and its analogues have some effect on reducing the occurrence of delirium and shortening the duration of mechanical ventilation in critically ill patients, and have no significant effect on reducing the mortality or length of intensive care unit stay. The above conclusions need to be confirmed by more high-quality studies.

Citation： LI Wenrui, LI Na, ZHANG Zhigang, HAN Lulu, KONG Jiajia, WANG Zhenzhen, JI Kexin, ZENG Yinru, ZHANG Caiyun. Effect of exogenous melatonin and its analogues on preventing delirium in critically ill patients: a meta-analysis. West China Medical Journal, 2021, 36(11): 1570-1577. doi: 10.7507/1002-0179.202103083 Copy

1.	Cascella M, Fiore M, Leone S, et al. Current controversies and future perspectives on treatment of intensive care unit delirium in adults. World J Crit Care Med, 2019, 8(3): 18-27.
2.	Gunther ML, Morandi A, Ely EW. Pathophysiology of delirium in the intensive care unit. Crit Care Clin, 2008, 24(1): 45-65.
3.	Pandharipande P, Cotton BA, Shintani A, et al. Prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients. J Trauma, 2008, 65(1): 34-41.
4.	Vasilevskis EE, Chandrasekhar R, Holtze CH, et al. The cost of ICU delirium and coma in the intensive care unit patient. Med Care, 2018, 56(10): 890-897.
5.	Brummel NE, Jackson JC, Pandharipande PP, et al. Delirium in the ICU and subsequent long-term disability among survivors of mechanical ventilation. Crit Care Med, 2014, 42(2): 369-377.
6.	Kiely DK, Marcantonio ER, Inouye SK, et al. Persistent delirium predicts greater mortality. J Am Geriatr Soc, 2009, 57(1): 55-61.
7.	Reiter RJ, Korkmaz A. Clinical aspects of melatonin. Saudi Med J, 2008, 29(11): 1537-1547.
8.	Sletten TL, Magee M, Murray JM, et al. Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: a double-blind, randomised clinical trial. PLoS Med, 2018, 15(6): e1002587.
9.	Bjorvatn B, Saxvig I, Wilhelmsen-Langeland A, et al. A randomized controlled trial of the effects of bright light and melatonin for delayed sleep phase disorder. Sleep Med, 2013, 14(Supp_S1): e74-e75.
10.	张燕平, 赵平. 褪黑素对老年女性患者术后早期认知功能障碍的影响. 中国医科大学学报, 2019, 48(5): 437-441.
11.	Nishikimi M, Numaguchi A, Takahashi K, et al. Effect of administration of ramelteon, a melatonin receptor agonist, on the duration of stay in the ICU: a single-center randomized placebo-controlled trial. Crit Care Med, 2018, 46(7): 1099-1105.
12.	Abbasi S, Farsaei S, Ghasemi D, et al. Potential role of exogenous melatonin supplement in delirium prevention in critically ill patients: a double-blind randomized pilot study. Iran J Pharm Res, 2018, 17(4): 1571-1580.
13.	Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 5.1. 0 [updated March 2011]. The Cochrane Collaboration, 2011. https://training.cochrane.org/handbook/archive/v5.1/.
14.	Bellapart J, Appadurai V, Lassig-Smith M, et al. Effect of exogenous melatonin administration in critically ill patients on delirium and sleep: a randomized controlled trial. Crit Care Res Pract, 2020(3): 3951828.
15.	Ford AH, Flicker L, Kelly R, et al. The healthy heart-mind trial: randomized controlled trial of melatonin for prevention of delirium. J Am Geriatr Soc, 2020, 68(1): 112-119.
16.	Gandolfi JV, Di Bernardo A, Chanes D, et al. The effects of melatonin supplementation on sleep quality and assessment of the serum melatonin in ICU patients: a randomized controlled trial. Crit Care Med, 2020, 48(12): e1286-e1293.
17.	Hatta K, Kishi Y, Wada K, et al. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry, 2014, 71(4): 397-403.
18.	Jaiswal SJ, Vyas AD, Heisel AJ, et al. Ramelteon for prevention of postoperative delirium: a randomized controlled trial in patients undergoing elective pulmonary thromboendarterectomy. Crit Care Med, 2019, 47(12): 1751-1758.
19.	Kasnavieh FH, Rezaeipandari H, Hadadzadeh M, et al. Effect of melatonin on incidence rate of delirium in elderly patients undergoing open-heart surgery without a pump: a clinical trial. Elderly Health J, 2019, 5(1): 32-39.
20.	Mistraletti G, Umbrello M, Sabbatini G, et al. Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial. Minerva Anestesiol, 2015, 81(12): 1298-1310.
21.	Soltani F, Salari A, Javaherforooshzadeh F, et al. The effect of melatonin on reduction in the need for sedative agents and duration of mechanical ventilation in traumatic intracranial hemorrhage patients: a randomized controlled trial. Eur J Trauma Emerg Surg, 2020, 22: 1-7.
22.	Vijayakumar HN, Ramya K, Duggappa DR, et al. Effect of melatonin on duration of delirium in organophosphorus compound poisoning patients: a double-blind randomised placebo controlled trial. Indian J Anaesth, 2016, 60(11): 814-820.
23.	Kotfis K, Marra A, Ely EW. ICU delirium - a diagnostic and therapeutic challenge in the intensive care unit. Anaesthesiol Intensive Ther, 2018, 50(2): 160-167.
24.	郭晋良, 王丹妮, 倪艳, 等. 基于褪黑素合成分泌探讨中医药改善睡眠的研究进展. 中华中医药学刊, 2021, 39(7): 99-102.
25.	刘丹, 安友仲. 褪黑素与谵妄. 中华危重病急救医学, 2013, 25(6): 382-384.
26.	郑清如, 卫婉蕊, 戈晓华. 成人谵妄相关生物标志物及其临床应用价值. 中国生物化学与分子生物学报, 2020, 36(11): 1288-1294.
27.	孙婷, 韩芳, 孙运良, 等. 重症监护病房谵妄患者 24 h 连续睡眠监测及褪黑素动态水平变化的研究. 中华危重病急救医学, 2014, 26(10): 726-729.
28.	熊照东, 潘学文, 朱卫东, 等. 术后血浆褪黑素水平与老年患者术后谵妄发生的相关性. 中国医师杂志, 2013, 15(7): 958-960.
29.	Han Y, Wu J, Qin Z, et al. Melatonin and its analogues for the prevention of postoperative delirium: a systematic review and meta-analysis. J Pineal Res, 2020, 68(4): e12644.
30.	黄定瑞. 渐进式早期康复训练对 ICU 机械通气病人谵妄、机械通气时间及 ICU 住院时间的影响. 全科护理, 2021, 19(4): 469-471.
31.	Dessap AM, Roche-Campo F, Launay JM, et al. Delirium and circadian rhythm of melatonin during weaning from mechanical ventilation: an ancillary study of a weaning trial. Chest, 2015, 148(5): 1231-1241.
32.	Khaing K, Nair BR. Melatonin for delirium prevention in hospitalized patients: a systematic review and meta-analysis. J Psychiatr Res, 2021, 133(4): 181-190.

1. Cascella M, Fiore M, Leone S, et al. Current controversies and future perspectives on treatment of intensive care unit delirium in adults. World J Crit Care Med, 2019, 8(3): 18-27.
2. Gunther ML, Morandi A, Ely EW. Pathophysiology of delirium in the intensive care unit. Crit Care Clin, 2008, 24(1): 45-65.
3. Pandharipande P, Cotton BA, Shintani A, et al. Prevalence and risk factors for development of delirium in surgical and trauma intensive care unit patients. J Trauma, 2008, 65(1): 34-41.
4. Vasilevskis EE, Chandrasekhar R, Holtze CH, et al. The cost of ICU delirium and coma in the intensive care unit patient. Med Care, 2018, 56(10): 890-897.
5. Brummel NE, Jackson JC, Pandharipande PP, et al. Delirium in the ICU and subsequent long-term disability among survivors of mechanical ventilation. Crit Care Med, 2014, 42(2): 369-377.
6. Kiely DK, Marcantonio ER, Inouye SK, et al. Persistent delirium predicts greater mortality. J Am Geriatr Soc, 2009, 57(1): 55-61.
7. Reiter RJ, Korkmaz A. Clinical aspects of melatonin. Saudi Med J, 2008, 29(11): 1537-1547.
8. Sletten TL, Magee M, Murray JM, et al. Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: a double-blind, randomised clinical trial. PLoS Med, 2018, 15(6): e1002587.
9. Bjorvatn B, Saxvig I, Wilhelmsen-Langeland A, et al. A randomized controlled trial of the effects of bright light and melatonin for delayed sleep phase disorder. Sleep Med, 2013, 14(Supp_S1): e74-e75.
10. 张燕平, 赵平. 褪黑素对老年女性患者术后早期认知功能障碍的影响. 中国医科大学学报, 2019, 48(5): 437-441.
11. Nishikimi M, Numaguchi A, Takahashi K, et al. Effect of administration of ramelteon, a melatonin receptor agonist, on the duration of stay in the ICU: a single-center randomized placebo-controlled trial. Crit Care Med, 2018, 46(7): 1099-1105.
12. Abbasi S, Farsaei S, Ghasemi D, et al. Potential role of exogenous melatonin supplement in delirium prevention in critically ill patients: a double-blind randomized pilot study. Iran J Pharm Res, 2018, 17(4): 1571-1580.
13. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 5.1. 0 [updated March 2011]. The Cochrane Collaboration, 2011. https://training.cochrane.org/handbook/archive/v5.1/.
14. Bellapart J, Appadurai V, Lassig-Smith M, et al. Effect of exogenous melatonin administration in critically ill patients on delirium and sleep: a randomized controlled trial. Crit Care Res Pract, 2020(3): 3951828.
15. Ford AH, Flicker L, Kelly R, et al. The healthy heart-mind trial: randomized controlled trial of melatonin for prevention of delirium. J Am Geriatr Soc, 2020, 68(1): 112-119.
16. Gandolfi JV, Di Bernardo A, Chanes D, et al. The effects of melatonin supplementation on sleep quality and assessment of the serum melatonin in ICU patients: a randomized controlled trial. Crit Care Med, 2020, 48(12): e1286-e1293.
17. Hatta K, Kishi Y, Wada K, et al. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry, 2014, 71(4): 397-403.
18. Jaiswal SJ, Vyas AD, Heisel AJ, et al. Ramelteon for prevention of postoperative delirium: a randomized controlled trial in patients undergoing elective pulmonary thromboendarterectomy. Crit Care Med, 2019, 47(12): 1751-1758.
19. Kasnavieh FH, Rezaeipandari H, Hadadzadeh M, et al. Effect of melatonin on incidence rate of delirium in elderly patients undergoing open-heart surgery without a pump: a clinical trial. Elderly Health J, 2019, 5(1): 32-39.
20. Mistraletti G, Umbrello M, Sabbatini G, et al. Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial. Minerva Anestesiol, 2015, 81(12): 1298-1310.
21. Soltani F, Salari A, Javaherforooshzadeh F, et al. The effect of melatonin on reduction in the need for sedative agents and duration of mechanical ventilation in traumatic intracranial hemorrhage patients: a randomized controlled trial. Eur J Trauma Emerg Surg, 2020, 22: 1-7.
22. Vijayakumar HN, Ramya K, Duggappa DR, et al. Effect of melatonin on duration of delirium in organophosphorus compound poisoning patients: a double-blind randomised placebo controlled trial. Indian J Anaesth, 2016, 60(11): 814-820.
23. Kotfis K, Marra A, Ely EW. ICU delirium - a diagnostic and therapeutic challenge in the intensive care unit. Anaesthesiol Intensive Ther, 2018, 50(2): 160-167.
24. 郭晋良, 王丹妮, 倪艳, 等. 基于褪黑素合成分泌探讨中医药改善睡眠的研究进展. 中华中医药学刊, 2021, 39(7): 99-102.
25. 刘丹, 安友仲. 褪黑素与谵妄. 中华危重病急救医学, 2013, 25(6): 382-384.
26. 郑清如, 卫婉蕊, 戈晓华. 成人谵妄相关生物标志物及其临床应用价值. 中国生物化学与分子生物学报, 2020, 36(11): 1288-1294.
27. 孙婷, 韩芳, 孙运良, 等. 重症监护病房谵妄患者 24 h 连续睡眠监测及褪黑素动态水平变化的研究. 中华危重病急救医学, 2014, 26(10): 726-729.
28. 熊照东, 潘学文, 朱卫东, 等. 术后血浆褪黑素水平与老年患者术后谵妄发生的相关性. 中国医师杂志, 2013, 15(7): 958-960.
29. Han Y, Wu J, Qin Z, et al. Melatonin and its analogues for the prevention of postoperative delirium: a systematic review and meta-analysis. J Pineal Res, 2020, 68(4): e12644.
30. 黄定瑞. 渐进式早期康复训练对 ICU 机械通气病人谵妄、机械通气时间及 ICU 住院时间的影响. 全科护理, 2021, 19(4): 469-471.
31. Dessap AM, Roche-Campo F, Launay JM, et al. Delirium and circadian rhythm of melatonin during weaning from mechanical ventilation: an ancillary study of a weaning trial. Chest, 2015, 148(5): 1231-1241.
32. Khaing K, Nair BR. Melatonin for delirium prevention in hospitalized patients: a systematic review and meta-analysis. J Psychiatr Res, 2021, 133(4): 181-190.

West China Medical Journal

Effect of exogenous melatonin and its analogues on preventing delirium in critically ill patients: a meta-analysis

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