Zolpidem for Severe Insomnia Associated With Delirium in Critical Illness

Delirium is a neuropsychiatric syndrome characterized by fluctuating disturbances in attention, arousal, and cognition and is frequently accompanied by sleep-wake cycle disruption.¹ Management emphasizes nonpharmacologic sleep promotion, with pharmacologic treatment reserved for selected cases and generally favoring agents with favorable cognitive safety profiles.^2,3 Nonbenzodiazepine hypnotics (“Z-drugs”), including zolpidem, are typically avoided in older adults because of concerns regarding delirium and other adverse events.^4,5

We describe a critically ill patient with sepsis and persistent delirium whose severe, refractory insomnia failed to respond to nonpharmacologic strategies and multiple pharmacologic interventions. After careful risk-benefit assessment, zolpidem was introduced with rapid improvement in sleep continuity accompanied by improvement in delirium severity and bedside cognitive performance.

Case Report

Mr A was a 71-year-old man admitted to the intensive care unit with community-acquired pneumonia complicated by sepsis, hypotension, metabolic derangements, and severe hypoactive delirium with sleep-wake dysregulation. Psychiatry was consulted for refractory insomnia thought to be perpetuating delirium and impairing rehabilitation.

Throughout his intensive care unit course, sleep occurred only in brief, fragmented intervals with prolonged nocturnal wakefulness. Despite minimal agitation, insomnia contributed to daytime confusion and limited participation in physical and occupational therapy.

Sequential nighttime pharmacologic interventions were trialed, including agents with favorable cognitive safety profiles (ramelteon, daridorexant) and other sedating medications (doxepin, trazodone, quetiapine, pregabalin, guanfacine), without sustained improvement in sleep continuity or cognition. After resolution of sepsis-related hypotension and metabolic derangements, persistent severe insomnia was identified as a potentially modifiable contributor to ongoing delirium.

Zolpidem 5 mg nightly was initiated after careful risk-benefit consideration. Within 1 night, nursing documentation noted improved nocturnal sleep continuity, restoration of daytime alertness, and reduced cognitive fluctuation. The Delirium Rating Scale-R-98 score improved from 27 to 19. Bedside cognitive testing also improved: Months of the Year Backwards was completed with 1 self-corrected error (previously unable), and Craft Story 21 immediate recall improved from 1/25 to 18/25 units. Zolpidem was briefly increased to 10 mg nightly to maintain sleep continuity as other sedatives were tapered and then discontinued prior to discharge without recurrence of insomnia or delirium.

Discussion

Sleep-wake cycle disruption is increasingly recognized as a core feature of delirium pathophysiology rather than a secondary consequence.¹ In hospitalized and critically ill patients, delirium is associated with fragmented nocturnal sleep, reduced rapid eye movement sleep, and increased daytime sleep, contributing to impaired attention, cognitive processing, and engagement in rehabilitation.³

Pharmacologic approaches to sleep disturbance in delirium are constrained by safety concerns and limited high-quality evidence. Guidelines emphasize nonpharmacologic sleep promotion as first-line management, reserving medications for selected cases.^2,3,5 Within this framework, nonbenzodiazepine hypnotics (“Z-drugs”) are generally not recommended for routine use in older adults.

Concerns regarding Z-drugs derive primarily from literature describing delirium and other neuropsychiatric adverse effects as potential complications of zolpidem exposure. Case reports and observational studies document episodes of zolpidem-associated delirium, parasomnias, and complex behaviors, often in patients with advanced age, polypharmacy, psychiatric comorbidity, or prolonged exposure.⁴ However, this literature is heterogeneous and largely reflects outpatient or chronic use rather than monitored, short-term use during acute medical illness. Importantly, these reports do not demonstrate clear dose-dependent deliriogenic effects analogous to benzodiazepines or address scenarios in which profound sleep deprivation itself contributes to persistent delirium.⁴

In the present case, zolpidem was introduced only after extensive trials of standing nighttime pharmacologic interventions failed to restore sleep or improve cognition. Zolpidem’s short elimination half-life and preferential α1-subunit γ-aminobutyric acid type A receptor binding confer predominantly hypnotic effects with limited next-day accumulation, permitting cautious titration, close monitoring, and prompt discontinuation once sleep normalized. Although this response should not be generalized, the case illustrates that in rare instances of severe, refractory insomnia perpetuating delirium, time-limited use of zolpidem may confer clinical benefit when alternative strategies have failed.

Article Information

Published Online: June 11, 2026. https://doi.org/10.4088/PCC.26cr04204
© 2026 Physicians Postgraduate Press, Inc.
Prim Care Companion CNS Disord 2026;28(3):26cr04204
Submitted: February 3, 2026; accepted March 16, 2026.
To Cite: Gunther M, Maldonado JR, Jiang S. Zolpidem for severe insomnia associated with delirium in critical illness. Prim Care Companion CNS Disord 2026;28(3):26cr04204.
Author Affiliations: Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University (Gunther, Maldonado); Department of Psychiatry, College of Medicine, University of Florida, Gainesville, Florida (Jiang).
Corresponding Author: Matthew Gunther, MD, Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, 401 Quarry Road, Palo Alto, CA 94304 ([email protected]).
Financial Disclosure: None.
Funding/Support: None.
Additional Information: Information has been de-identified to protect patient anonymity.