May 1, 2019

Melatonin to Prevent ICU Delirium

Yet another therapeutic application
Delirium is a common complication among patients in the intensive care unit, but treatment options are limited and pose additional risks. Could melatonin, a simple and nontoxic intervention, be an effective therapy for this condition?


Baumgartner L, Lam K, Lai J, et al. Effectiveness of melatonin for the prevention of intensive care unit delirium. Pharmocotherapy. 2019;39(3):280-287.


To determine if melatonin is an effective therapy for prevention of intensive care unit (ICU) delirium


Retrospective, observational cohort study


The study included 232 adults (≥18 years of age): 117 patients in melatonin group and 115 patients in control group. Patients were admitted to medical or cardiac ICU between 2013-2017, and those given melatonin were compared to those who did not receive it. Exclusion criteria included use of antipsychotic or sleep medications prior to admission, primary neurologic condition or injury, hepatic encephalopathy, end-stage liver disease, active withdrawal from alcohol use, and any conditions preventing delirium screening.

Study Parameters Assessed

Development of delirium was determined by 2 consecutive positive scores on the Confusion Assessment Method for the ICU (CAM-ICU), within a 14-day period after inclusion. The CAM-ICU assessment was administered to participants every 12 hours.

Primary Outcome Measures

The occurrence of ICU delirium development in patients treated with melatonin; the dose of melatonin used. One secondary outcome was delirium-free days in a 28-day period.

Key Findings

The development of ICU delirium was much lower in the group of participants who received melatonin therapy.

Participants in the melatonin group experienced a significantly lower rate of delirium development compared to the control group (9 [7.7%] vs 28 [24.3%]; P=0.001).

The findings remained consistently significant when assessed in numerous other models that controlled for multiple variables. Controls included age, sex, history of hypertension, need for emergent surgery, Acute Physiology and Chronic Health Evaluation II score, mechanical ventilation, ICU length of stay, dexmedetomidine use, and benzodiazepine use.

As most patients who develop the condition are critically ill, an ideal intervention would be one with a high rate of risk reduction, additional health-supportive actions, and little to no side effects.

For those who did develop delirium, there was no statistical significance between groups. Participants in the melatonin group experienced 19.9 delirium-free days without coma, compared to 20.9 days in the control group (P=0.72).

Typical starting doses for melatonin were 3-6 mg nightly and doses were titrated up to 9-10 mg as needed for sleep. In the patients who developed delirium, the average dose was 3 mg, with a range of 1-5 mg.

Practice Implications

There are currently no US Food and Drug Administration (FDA)-approved pharmacological therapies to treat or prevent ICU delirium. Management often relies on antipsychotic medications, which carry their own significant risk profile; risks of antipsychotics include further neurological impairment and risk of death in older adults with dementia—a population that could crossover with those most likely to be affected by ICU delirium. As most patients who develop the condition are critically ill, an ideal intervention would be one with a high rate of risk reduction, additional health-supportive actions, and few to no side effects. Melatonin fits this ideal.

While not tracked in the current study under review, this simple and nontoxic intervention may impact overall outcomes. The authors note that “Intensive care unit (ICU) delirium is an acute brain dysfunction that has been associated with increased mortality, prolonged ICU and hospital lengths of stay, and development of post-ICU cognitive impairment.” This implies that further studies using melatonin in this patient population may show even more profound benefits.

Melatonin is a natural therapy with many other well-supported uses and generally mild side effects. It’s not entirely clear if melatonin’s usefulness in ICU delirium is grounded in its notable effects on circadian rhythm regulation (though this is likely one mechanism of action), or some other unknown mechanism. However, as sleep disparity is a concern and a plausible contributing factor in the development of delirium in critically ill patients, this, along with its proposed antioxidant, cardioprotective,1 neuroprotective,2 hepatoprotective,3 and esophagoprotective4 properties (all potentially important actions in the population of chronically ill patients), makes melatonin a viable and encouraging therapy option.

While the study does not provide evidence regarding optimal dose, the data suggests that nightly doses of 3.5 mg or greater may be of more benefit.

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  1. Jiki Z, Lecour S, Nduhirabandi F. Cardiovascular benefits of dietary melatonin: a myth or a reality? Front Physiol. 2018;9:528.
  2. Shu T, Fan L, Wu T, et al. Melatonin promotes neuroprotection of induced pluripotent stem cells-derived neural stem cells subjected to H 2 O 2 -induced injury in vitro. Eur J Pharmacol. 2018;825:143-150.
  3. Bonomini F, Borsani E, Favero G, Rodella L, Rezzani R. Dietary melatonin supplementation could be a promising preventing/therapeutic approach for a variety of liver diseases. Nutrients. 2018;10(9):1135.
  4. Majka J, Wierdak M, Brzozowska I, et al. Melatonin in prevention of the sequence from reflux esophagitis to Barrett’s esophagus and esophageal adenocarcinoma: experimental and clinical perspectives. Int J Mol Sci. 2018;19(7):2033.