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Non-pharmacological approaches are preferred for promoting sleep in the ICU; however, limited but growing evidence supports the use of pharmacological agents.

In Part 1, we discussed the high incidence of significant sleep disturbances in the ICU, manifested by states of relative sleep deprivation. This often leads to disruption of the normal circadian rhythm and resultant adverse physical and mental consequences, such as increased likelihoods of delirium, neuro-hormonal and metabolic effects, cardiovascular complications, and diminished immune functioning. Since pharmacologic sleep aids are not routinely recommended or desired, non-pharmacologic approaches and interventions are considered most appropriate.

• Sleep-Wake Regulators: Some research into drugs affecting neurobiological pathways has suggested a lower risk of delirium with sleep-wake regulating substances such as melatonin-receptor and orexin-receptor antagonists, but data remain limited and of low certainty; routine administration awaits larger randomized trials.
• Hypnotic Agents: Although not usually recommended, sleep aids like hypnotics are frequently requested by ICU nurses and patients and routinely ordered by physicians. Despite this demand, efficacy and complication data are sparse, with melatonin and dexmedetomidine the best studied to date.
• Melatonin & Related Agents: Melatonin has been evaluated in roughly ten trials, about half showing sleep improvements and none reporting adverse events; it is likely the most prescribed ICU sleep aid. Ramelteon, a prescription melatonin-receptor agonist, appears safe but without significant ICU benefits. Suvorexant, a dual orexin-receptor antagonist, likewise shows neither clear benefit nor risk in this setting.
• Benzodiazepines & Antihistamines: Benzodiazepines, though common in ICU practice, reduce slow-wave and REM sleep and increase delirium risk. Antihistamines likely cause similar, though milder, disturbances and may be inappropriate, particularly in the elderly.
• Other Sedatives & Antidepressants: Gamma-aminobutyric acid modulators such as zolpidem and sedating antidepressants like trazodone lack formal ICU evaluation and may carry significant neuropsychiatric and physical risks in critically ill patients.
• Atypical Antipsychotics: Night-time doses of sedating atypical antipsychotics—notably quetiapine and olanzapine—are considered safe at hypnotic doses and are useful for sleep facilitation during ventilator weaning, with minimal QT-interval concerns.
• Opioids: Opioids, particularly fentanyl, do not improve sleep quality and distort normal architecture; they are not recommended for hypnotic purposes.
• Propofol: Propofol reliably prolongs total sleep time, especially post-surgery, but reduces slow-wave and REM sleep and elevates delirium risk, limiting its desirability as a routine sleep aid.
• Dexmedetomidine: Dexmedetomidine, an α-2 adrenergic agonist, has shown the most consistent benefits across at least ten of twelve studies, improving total sleep time, efficiency, deeper sleep stages, and reducing delirium. Nonetheless, bradycardia and hypotension may necessitate dose adjustments.

Future Directions

Ongoing clinical trials evaluating several of these agents in ICU populations will further clarify their roles and guide future recommendations.

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