Melatonin to prevent delirium in the intensive care unit

Relation

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

Objective

To determine whether melatonin is an effective therapy for preventing delirium in the intensive care unit (ICU).

Draft

Retrospective observational cohort study

Participant

The study included 232 adults (≥18 years): 117 patients in the melatonin group and 115 patients in the control group. Patients were admitted to the medical or cardiac intensive care unit between 2013 and 2017, and those given melatonin were compared with those who did not receive it. Exclusion criteria included use of antipsychotics or hypnotics before admission, primary neurologic disease or injury, hepatic encephalopathy, end-stage liver disease, active withdrawal from alcohol consumption, and any medical condition precluding delirium screening.

Study parameters assessed

The development of delirium was determined by 2 consecutive positive Confusion Assessment Method for the ICU (CAM-ICU) results within 14 days of admission. The CAM-ICU assessment was administered to participants every 12 hours.

Primary outcome measures

The occurrence of delirium in the intensive care unit in patients treated with melatonin; the melatonin dose used. A secondary endpoint was delirium-free days in a 28-day period.

Key insights

The development of intensive care delirium was significantly 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%] versus 28 [24.3%];P=0.001).

The results remained consistently significant when evaluated in numerous other models that controlled for multiple variables. Controls included age, sex, history of hypertension, need for emergency surgery, Acute Physiology and Chronic Health Assessment II score, mechanical ventilation, intensive care unit length of stay, dexmedetomidine use, and benzodiazepine use.

Since most patients who develop this condition are critically ill, an ideal intervention would be one with a high rate of risk reduction, additional health support measures, and little to no side effects.

For those who developed 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 of melatonin were 3-6 mg per night and doses were titrated to 9-10 mg depending on sleep needs. In 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 pharmacologic therapies to treat or prevent delirium in the intensive care unit. Treatment often relies on antipsychotic medications, which carry their own significant risk profile; The risks of antipsychotics include further neurological impairment and the risk of death in older adults with dementia - a population that may overlap with those most likely to experience delirium in the intensive care unit. Since most patients who develop this condition are critically ill, an ideal intervention would be one with a high rate of risk reduction, additional health support measures, and few to no side effects. Melatonin corresponds to this ideal.

Although this simple and nontoxic intervention is not pursued in the current study, it may influence the overall results. The authors note that “intensive care unit (ICU) delirium is an acute brain dysfunction that has been associated with increased mortality, longer intensive care unit and hospital lengths of stay, and the development of post-ICU cognitive impairment.” This implies that further studies with melatonin may show even more profound benefits in this patient population.

Melatonin is a natural therapy with many other well-supported uses and generally mild side effects. It is not entirely clear whether melatonin's usefulness in ICU delirium is due to its remarkable effects on circadian rhythm regulation (although this is likely one mechanism of action) or to some other unknown mechanism. However, since sleep differences are a concern and a plausible factor in the development of delirium in critically ill patients, this, along with proposed antioxidant, cardioprotective,¹neuroprotective,²hepatoprotective,³and esophagoprotective⁴Properties (all potentially important effects in the population of chronically ill patients) make melatonin a viable and encouraging therapeutic option.

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