Journal Article Annotations
2018, 2nd Quarter

Delirium

Annotations by Maalobeeka Gangopadhyay, MD; and Lex Denysenko, MD, FACLP
July 2018

Melatonin and sleep in preventing hospitalized delirium: a randomized clinical trial
Low-dose nocturnal dexmedetomidine prevents ICU delirium. A randomized, placebo-controlled trial

PUBLICATION #1 — Delirium

Melatonin and sleep in preventing hospitalized delirium: a randomized clinical trial

Jaiswal SJ, McCarthy TJ, Wineinger NE, et al

Abstract: Am J Med 2018 May 3 (Epub ahead of print)

PURPOSE: Studies suggest that melatonin may prevent delirium, a condition of acute brain dysfunction occurring in 20%-30% of hospitalized older adults that is associated with increased morbidity and mortality. We examined the effect of melatonin on delirium prevention in hospitalized older adults while measuring sleep parameters as a possible underlying mechanism.

METHODS: This was a randomized clinical trial measuring the impact of 3mg of melatonin nightly on incident delirium and both objective and subjective sleep in inpatients age ≥65years, admitted to internal medicine wards (non-intensive care units). Delirium incidence was measured by bedside nurses using the confusion assessment method. Objective sleep measurements (night-time sleep duration, total sleep time per 24hours, and sleep fragmentation as determined by average sleep bout length) were obtained via actigraphy. Subjective sleep quality was measured using the Richards Campbell Sleep Questionnaire.

RESULTS: Delirium occurred in 22.2% (8/36) of subjects who received melatonin vs in 9.1% (3/33) who received placebo (P = .19). Melatonin did not significantly change objective or subjective sleep measurements. Nighttime sleep duration and total sleep time did not differ between subjects who became delirious vs those who did not, but delirious subjects had more sleep fragmentation (sleep bout length 7.0 ± 3.0vs 9.5 ± 5.3 min; P = .03).

CONCLUSIONS: Melatonin given as a nightly dose of 3mg did not prevent delirium in non-intensive care unit hospitalized patients or improve subjective or objective sleep.

On PubMed: Am J Med 2018 May 3 (Epub ahead of print)

Annotation

Type of study: Randomized controlled trial

The finding: Melatonin 3mg at 9pm did not significantly decrease delirium incidence in any of the four analyses used, although none of the analyses reached statistical significance. Melatonin also did it significantly improve sleep duration. Sleep fragmentation was associated with delirium.

Strength and weaknesses: This is a randomized controlled trial, but it did not achieve power to determine an effect for melatonin on delirium prevention. The study used a 3mg dose and at a 9pm interval with in-tent that it would improve sleep quality, and this may have influenced outcomes. Rather than using a gold-standard delirium assessment such as the Delirium Rating Scale, the study relied on CAM screening at bedside without inter-rater reliability assessed. Actigraphy but not gold-standard polysomnography was used.

Relevance: Delirium prevention should be in the purview of all inpatient consultation-liaison psychiatrists, and the use of melatonin for delirium prevention has gained much attention in recent years. This study suggests further studies are needed to determine the best dose nd timing of mela-tonin for delirium prevention.

Opinion: Melatonin agonists have been shown to have improvement in delirium prevention in three prior studies. The mechanism is likely not related to improving sleep, but may be related to improving circadian rhythm, modulating neurotransmitter function, attenuating inflammatory signaling molecules (cytokines, adiponectin), or antioxidant effects. Melatonin begins to increase in normal individuals after 6pm, but in elderly patients, nightly endogenous melatonin increases tend to occur later in the night. Thus, administration of melatonin at non-sedating doses (less than 3mg, and perhaps as low as 0.5) and at 6pm rather than bedtime, may be key to effectiveness of melatonin in delirium prevention, although further studies are needed.

PUBLICATION #2 — Delirium

Low-dose nocturnal dexmedetomidine prevents ICU delirium. A randomized, placebo-controlled trial

Skrobik Y, Duprey MS, Hill NS, Devlin JW

Abstract: Am J Respir Crit Care Med 2018; 197(9):1147-1156

RATIONALE: Dexmedetomidine is associated with less delirium than benzodiazepines and better sleep architecture than either benzodiazepines or propofol; its effect on delirium and sleep when administered at night to patients requiring sedation remains unclear.

OBJECTIVES: To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill adults.

METHODS: This two-center, double-blind, placebo-controlled trial randomized 100 delirium-free critically ill adults receiving sedatives to receive nocturnal (9:30 p.m. to 6:15 a.m.) intravenous dexmedetomidine (0.2 μg/kg/h, titrated by 0.1 μg /kg/h every 15 min until a goal Richmond Agitation and Sedation Scale score of -1 or maximum rate of 0.7 μg/kg/h was reached) or placebo until ICU discharge. During study infusions, all sedatives were halved; opioids were unchanged. Delirium was assessed using the Intensive Care Delirium Screening Checklist every 12 hours throughout the ICU admission. Sleep was evaluated each morning by the Leeds Sleep Evaluation Questionnaire.

MEASUREMENTS AND MAIN RESULTS: Nocturnal dexmedetomidine (vs. placebo) was associated with a greater proportion of patients who remained delirium-free during the ICU stay (dexmedetomidine [40 (80%) of 50 patients] vs. placebo [27 (54%) of 50 patients]; relative risk, 0.44; 95% confidence interval, 0.23-0.82; P = 0.006). The average Leeds Sleep Evaluation Questionnaire score was similar (mean difference, 0.02; 95% confidence interval, 0.42-1.92) between the 34 dexmedetomidine (average seven assessments per patient) and 30 placebo (six per patient) group patients able to provide one or more assessments. Incidence of hypotension, bradycardia, or both did not differ significantly between groups.

CONCLUSIONS: Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay; patient-reported sleep quality appears unchanged.

On PubMed: Am J Respir Crit Care Med 2018; 197(9):1147-1156

Annotation

Type of study: Randomized controlled trial

The finding: Subjects who received nocturnal low-dose dexmedetomidine were less likely to develop delirium. Dexmedetomidine subjects required less fentanyl for sedation, optimal sedation was more readily achieved in the dexmedetomidine group, and patients reported feeling less tired during the daytime (although sleep quality did not differ). Midazolam infusion rates did not differ between the two groups.

Strength and weaknesses: This is a well-designed multi-center randomized controlled trial. The trial was of 3-year duration, during which time other implemented delirium-prevention implantation strategies may have influenced results. 26% enrollment of eligible patients may have compromised external validity. A gold standard for assessment of delirium severity was not used (screening tool only). Polysomnography was not used to assess sleep quality. Patients were not followed after leaving ICU in terms of delirium incidence.

Relevance: This is the first RCT showing reduced incidence of delirium using dexmedetomidine. The acquisition cost of using low dose nocturnal dexmedetomidine compared to potentially higher dosing of dexmedetomidine round-the-clock may be of interest from a cost perspective. A possible opioid-sparing effect of dexmedetomidine due to improved analgesia rather than its effect on sedation warrants further study.