Circadian rhythm refers to synchronization of the body's physiology with external day-night cycles. It’s an evolutionarily ancient adaptive mechanism seen in species ranging from plants to fruit flies to humans.
The circadian rhythm is generated by the hypothalamus and pineal gland. Light is the primary input to this system, entraining the circadian rhythm. The output from this system is melatonin secreted by the pineal gland. Melatonin levels peak at night, signaling the presence of night to organs throughout the body.
Circadian rhythms and melatonin are best known for their relationship to sleep. However, they have a much broader range of functions. Circadian rhythms cause many organs to enter a resting state at night (e.g. heart rate decreases, cortisol levels increase).
Pathophysiology: Circadian derangement & delirium in the ICU
ICU patients are often exposed to light, noise, and pain at night. It comes as no surprise that patients frequently have circadian rhythm derangement (e.g. insomnia, daytime somnolence).1 Physiologically, this is reflected in loss of a normal pattern of melatonin secretion, especially loss of nocturnal peaks.2 3 4 5 Melatonin depletion may be particularly associated with mechanical ventilation and sepsis.6 7 8
Circadian rhythm disruption may be dangerous. In the absence of circadian rhythms, some patients may remain stuck in a physiologically aroused state. This may cause deprivation of sleep, excessive inflammation, and persistent cardiovascular stress. Other patients may develop an inverted circadian rhythm with daytime somnolence, preventing them from obtaining high-quality sleep or participating in physical therapy.
The most obvious complication of circadian derangement is delirium. The brain requires restorative, high-quality sleep to function. Sleep deprivation and fragmentation will inevitably lead to delirium, even in otherwise healthy people. Many physicians trained before the era of work-hour restrictions have experienced this personally (including yours truly).9
Several studies have correlated the development of delirium with loss of cyclical melatonin secretion.10 For example, a prospective observational study among hospitalized patients showed that loss of melatonin secretion precedes the development of delirium by three days – suggesting a potential causative role.11
Evidence regarding melatonin agonists to prevent delirium
RCTs evaluating delirium prevention12
Melatonin agonists might restore normal circadian rhythmicity. This makes them attractive targets for the prevention and treatment of delirium. Four placebo-controlled RCTs shown below evaluated the ability of melatonin agonists to prevent delirium among mixed patient cohorts.13 14 15 16 Studies solely involving post-operative delirium aren’t included here, because the physiology of post-operative delirium may be unique.17 18 Furthermore, studies on surgical populations may suffer from problems sorting out true delirium versus normal emergence from anesthesia.
A rudimentary Forrest plot above shows results from these studies along with the combined data (which simply reflects pooling together all of the patients).19 Most studies found benefit from melatonin agonists. Jaiswal was discordant with the other studies, possibly for the following reasons:16
- Patients in Jaiswal et al were healthier, with a lower rate of delirium overall. The reduced incidence of delirium in this study decreased its power (note that power depends on both the sample size and the frequency of events).
- The median length of stay was only three days, which is shorter than the other studies. This may be too soon to see the effects of circadian derangement or benefit from melatonin agonists.
Mistraletti 2015: Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial.
This was a double-blind RCT involving 82 patients who had been intubated for >48 hours in a medical-surgical ICU.20 Patients were randomized to receive placebo versus 6 mg of melatonin nightly (3 mg at 8 PM plus 3 mg at midnight).
The primary endpoint was the amount of hydroxyzine administered (hydroxyzine is an antihistamine they used insomnia). Melatonin did indeed cause a significant reduction in hydroxyzine administration (p<0.01), as well as propofol administration. In parallel with weaning off sedatives, melatonin also hastened weaning from mechanical ventilation:
This data can be interpreted in various different ways. Perhaps melatonin directly reduced delirium, and thereby hastened recovery. Alternatively, melatonin may have merely reduced the use of deleriogenic medications (e.g. hydroxyzine). Regardless, melatonin improved clinical outcomes.
Five RCTs evaluated the ability of melatonin agonists to prevent delirium or optimize sleep. Four detected benefit, whereas one was neutral. None of the studies detected significant harm. These trials are small, with larger RCTs underway. However, they strongly suggest that the benefits of treatment outweigh risks.
Other potential benefits of melatonin?
Circadian rhythm has a diverse range of physiologic effects. Therefore, re-establishment of a normal circadian rhythm could theoretically offer numerous benefits (e.g. anti-inflammatory, anti-arrhythmic, and anti-oxidant effects).21 Some evidence even suggests that melatonin improves peptic ulcer disease, which could theoretically reduce stress ulcer formation in the ICU.22
Melatonin and ramelteon are very similar agents. There is no clear data on which drug is superior. Currently, melatonin may be preferable for the following reasons:
(1) Impressive track record for safety
Melatonin is available over-the-counter in the United States, being used by about 3.5 million Americans.23 Despite broad exposure of the populace, severe side-effects don’t seem to be an issue. Allergy to melatonin cannot exist. The only well-documented side effect is drowsiness (which might be beneficial among patients on mechanical ventilation who require sedation).20 Clinical trials using huge doses of melatonin (e.g. 1,000 mg/day) haven’t detected additional side-effects. Although some articles list minor side-effects from melatonin (e.g. headache), placebo-controlled trials don’t find a difference in side effects when rigorously comparing melatonin versus placebo.24
(2) Cost & availability
Melatonin is widely available. It’s extremely cheap, with a dose costing well under a dollar. In contrast, the cost of an episode of delirium in the ICU can easily exceed thousands of dollars (e.g. by delaying extubation and prolonging ICU length of stay). Thus, even if melatonin is only marginally effective in reducing delirium, it will be cost-effective.
Ideal melatonin dose?
The ideal melatonin dose in the ICU is unknown. To make matters more confusing, the ideal therapeutic strategy is unclear. One could imagine various strategies:
- Physiologic replacement: Some patients simply lose melatonin production in the ICU. For these patients, it could make sense to give a low dose of melatonin which would generate physiogically normal levels.
- Overdrive suppression: Some patients will develop a phase-shifted circadian rhythm in the ICU (e.g. sundowning). In such patients, it could make sense to give a supraphysiologic dose of melatonin at night, to overpower the deranged endogenous circadian rhythm.
The dose of melatonin studied in clinical trials varies between 0.5 to 6 mg. Among critically ill patients, a 10 mg dose results in supra-physiologic morning levels.25 A systematic review focusing on elderly outpatients suggested an optimal dose of 0.3-2 mg.26 Until further research is available, roughly 1-3 mg QHS may be reasonable.
- ICU patients commonly suffer from disruption of circadian rhythms, with loss of nocturnal melatonin peaks. This correlates with delirium and poor clinical outcomes.
- Exogenous melatonin supplementation is cheap and safe (it’s available over-the-counter).
- Several small RCTs of melatonin agonists have been performed. Four of five studies detected benefit, with the fifth study being relatively underpowered. The most strongly supported benefit is delirium prevention.
- The use of melatonin in the ICU remains under investigation, with further RCTs pending. At this point in time, available evidence suggests that the benefits of melatonin outweigh potential harms (which seem to be minimal).
- Nishikimi 2018 RCT (The Bottom Line) – I would have written more about this study but The Bottom Line already covered it nicely, so please see their site for further discussion.
- Sleep-protective monitoring to reduce ICU delirium (PulmCrit).1.Bellapart J, Boots R. Potential use of melatonin in sleep and delirium in the critically ill. Br J Anaesth. 2012;108(4):572-580. [PubMed]2.Mistraletti G, Sabbatini G, Taverna M, et al. Pharmacokinetics of orally administered melatonin in critically ill patients. J Pineal Res. 2010;48(2):142-147. [PubMed]3.Olofsson K, Alling C, Lundberg D, Malmros C. Abolished circadian rhythm of melatonin secretion in sedated and artificially ventilated intensive care patients. Acta Anaesthesiol Scand. 2004;48(6):679-684. [PubMed]4.Verceles A, Silhan L, Terrin M, Netzer G, Shanholtz C, Scharf S. Circadian rhythm disruption in severe sepsis: the effect of ambient light on urinary 6-sulfatoxymelatonin secretion. Intensive Care Med. 2012;38(5):804-810. [PubMed]5.Shilo L, Dagan Y, Smorjik Y, et al. Patients in the intensive care unit suffer from severe lack of sleep associated with loss of normal melatonin secretion pattern. Am J Med Sci. 1999;317(5):278-281. [PubMed]6.Perras B, Kurowski V, Dodt C. Nocturnal melatonin concentration is correlated with illness severity in patients with septic disease. Intensive Care Med. 2006;32(4):624-625. [PubMed]7.Frisk U, Olsson J, Nylén P, Hahn R. Low melatonin excretion during mechanical ventilation in the intensive care unit. Clin Sci (Lond). 2004;107(1):47-53. [PubMed]8.Mundigler G, Delle-Karth G, Koreny M, et al. Impaired circadian rhythm of melatonin secretion in sedated critically ill patients with severe sepsis. Crit Care Med. 2002;30(3):536-540. [PubMed]9.Once during my training, I was awake for 50 hours consecutively (weekend call). At the end of that period I could function but lost the ability to maintain attention. When writing a patient note I would start a sentence, fall asleep for a second, wake up, and there would be a string of random words on the page. Despite numerous attempts I was unable to write coherently. .10.Miyazaki T, Kuwano H, Kato H, et al. Correlation between serum melatonin circadian rhythm and intensive care unit psychosis after thoracic esophagectomy. Surgery. 2003;133(6):662-668. [PubMed]11.Ángeles-Castellanos M, Ramírez-Gonzalez F, Ubaldo-Reyes L, Rodriguez-Mayoral O, Escobar C. Loss of melatonin daily rhythmicity is asociated with delirium development in hospitalized older adults. Sleep Sci. 2016;9(4):285-288. [PubMed]12.Not all of these studies listed delirium incidence as the primary outcome (e.g., Nishikimi used ICU length of stay as the primary endpoint). .13.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. [PubMed]14.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. [PubMed]15.Al-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin S, Esbaugh J, Dasgupta M. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry. 2011;26(7):687-694. [PubMed]16.Jaiswal S, McCarthy T, Wineinger N, et al. Melatonin and Sleep in Preventing Hospitalized Delirium: A Randomized Clinical Trial. Am J Med. May 2018. [PubMed]17.Chen S, Shi L, Liang F, et al. Exogenous Melatonin for Delirium Prevention: a Meta-analysis of Randomized Controlled Trials. Mol Neurobiol. 2016;53(6):4046-4053. [PubMed]18.Shigeta H, Yasui A, Nimura Y, et al. Postoperative delirium and melatonin levels in elderly patients. Am J Surg. 2001;182(5):449-454. [PubMed]19.Yep, I know this isn’t a formal meta-analysis, but you get the idea. .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. [PubMed]21.Fink T, Glas M, Wolf A, et al. Melatonin receptors mediate improvements of survival in a model of polymicrobial sepsis. Crit Care Med. 2014;42(1):e22-31. [PubMed]22.Brzozowska I, Strzalka M, Drozdowicz D, Konturek S, Brzozowski T. Mechanisms of esophageal protection, gastroprotection and ulcer healing by melatonin. implications for the therapeutic use of melatonin in gastroesophageal reflux disease (GERD) and peptic ulcer disease. Curr Pharm Des. 2014;20(30):4807-4815. [PubMed]23.Use of Complementary Health Approaches in the U.S. National Health Interview Survey (NHIS). https://nccih.nih.gov/research/statistics/NHIS/2012/natural-products/melatonin.24.Andersen L, Gögenur I, Rosenberg J, Reiter R. The Safety of Melatonin in Humans. Clin Drug Investig. 2016;36(3):169-175. [PubMed]25.Bourne R, Mills G, Minelli C. Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care. 2008;12(2):R52. [PubMed]26.Vural E, van M, de R. Optimal dosages for melatonin supplementation therapy in older adults: a systematic review of current literature. Drugs Aging. 2014;31(6):441-451. [PubMed]
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