Annemarieke de Jonghe

Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial

Background: Disturbance of the sleep–wake cycle is a characteristic of delirium. In addition, changes in melatonin rhythm influence the circadian rhythm and are associated with delirium. We compared the effect of melatonin and placebo on the incidence and duration of delirium. Methods: We performed this multicentre, double-blind, randomized controlled trial between November 2008 and May 2012 in 1 academic and 2 nonacademic hospitals. Patients aged 65 years or older who were scheduled for acute hip surgery were eligible for inclusion. Patients received melatonin 3 mg or placebo in the evening for 5 consecutive days, starting within 24 hours after admission. The primary outcome was incidence of delirium within 8 days of admission. We also monitored the duration of delirium. Results: A total of 452 patients were randomly assigned to the 2 study groups. We subsequently excluded 74 patients for whom the primary end point could not be measured or who had delirium before the second day of the study. After these postrandomization exclusions, data for 378 patients were included in the main analysis. The overall mean age was 84 years, 238 (63.0%) of the patients lived at home before admission, and 210 (55.6%) had cognitive impairment. We observed no effect of melatonin on the incidence of delirium: 55/186 (29.6%) in the melatonin group v. 49/192 (25.5%) in the placebo group; difference 4.1 (95% confidence interval −0.05 to 13.1) percentage points. There were no between-group differences in mortality or in cognitive or functional outcomes at 3-month follow-up. Interpretation: In this older population with hip fracture, treatment with melatonin did not reduce the incidence of delirium. Trial registration: Netherlands Trial Registry, NTR1576: MAPLE (Melatonin Against PLacebo in Elderly patients) study; www.trialregister.nl/trialreg/admin/rctview.asp?TC=1576

The effects of melatonin versus placebo on delirium in hip fracture patients: study protocol of a randomised, placebo-controlled, double blind trial

BackgroundWith an ageing population, older persons become a larger part of the hospital population. The incidence of delirium is high in this group, and experiencing delirium has major short- and long-term sequelae, which makes prevention crucial. During delirium, a disruption of the sleep-wake cycle is frequently observed. Melatonin plays an important role in the regulation of the sleep-wake cycle, so this raised the hypothesis that alterations in the metabolism of melatonin might play an important role in the development of delirium. The aim of this article is to describe the design of a randomised, placebo controlled double-blind trial that is currently in progress and that investigates the effects of melatonin versus placebo on delirium in older, postoperative hip fracture patients.Methods/DesignAcutely hospitalised patients aged 65 years or older admitted for surgical repair of hip fracture are randomised (n = 452) into a treatment or placebo group. Prophylactic treatment consists of orally administered melatonin (3 mg) at 21:00 h on five consecutive days. The primary outcome is the occurrence of delirium, to be diagnosed according to the Confusion Assessment Method, within eight days after start of the study medication. Secondary outcomes are delirium severity, measured by the Delirium Rating Scale; duration of delirium; differences in subtypes of delirium; differences in total length of hospital stay; total dose of antipsychotics and/or benzodiazepine use during delirium; and in-hospital complications. In the twelve-month follow up visit, cognitive function is measured by a Mini-Mental state examination and the Informant Questionnaire on Cognitive Decline in the Elderly. Functional status is assessed with the Katz ADL index score (patient and family version) and grip strength measurement. The outcomes of these assessments are compared to the outcomes that were obtained during admission.DiscussionThe proposed study will contribute to our knowledge because studies on the prophylactic treatment of delirium with long term follow up remain scarce. The results may lead to a prophylactic treatment for frail older persons at high risk for delirium that is safe, effective, and easily implementable in daily practice.Trial registrationDutch Clinical Trial Registry: NTR1576

Rest-Activity Patterns in Patients with Delirium

OBJECTIVE Delirium is a frequent syndrome in elderly hospital patients. Symptoms typically show a fluctuating course during the day, with patients exhibiting disturbances of their sleep-wake rhythm. Delirium is frequently underdiagnosed, especially the so-called hypoactive subtype. Devices measuring 24-hr motor patterns could contribute to the recognition of delirium. The purpose of this paper is two-fold. First, the results of a pilot study are presented, in which 24-hr motor patterns of delirious patients are measured with a wrist-actigraph. Second, studies reporting 24-hr motor patterns in delirious patients are systematically reviewed. METHODS The pilot study included 9 patients, 65 years or older, with a hip fracture in need of surgical repair. For the review, MEDLINE and Embase were searched for studies on motor activity assessment in delirious patients. RESULTS In the pilot study, the 24-hr activity rhythm was severely disturbed during delirium, and most actigraphic sleep parameter estimates indicated significantly worse sleep during delirious nights. The systematic search resulted in 10 papers. In 3 papers, the sleep-wake rhythm of delirious patients was significantly different from that of nondelirious patients. In 5 papers, delirious patients could be classified into delirium subtypes. In the 2 remaining papers, 24-hr motor patterns of delirium subtypes were not significantly different. CONCLUSION Activity patterns revealed differences between delirious and nondelirious patients and between the different subtypes, even in small samples of patients. Future studies, with preferably larger sample sizes, should confirm the potential of activity pattern measuring devices in the early detection of delirium.

Variability of Delirium Motor Subtype Scale-Defined Delirium Motor Subtypes in Elderly Adults with Hip Fracture: A Longitudinal Study

To examine changes in motor subtype profile in individuals with delirium.

Underrepresentation of patients with pre-existing cognitive impairment in pharmaceutical trials on prophylactic or therapeutic treatments for delirium: A systematic review

OBJECTIVE Representation of hospitalized patients with pre-existing cognitive impairment in pharmaceutical delirium trials is important because these patients are at high risk for developing delirium. The aim of this systematic review is to investigate whether patients with cognitive impairment were included in studies on pharmacological prophylaxis or treatment of delirium and to explore the motivations for their exclusion (if they were excluded). STUDY DESIGN This study was a systematic review. A MEDLINE search was performed for publications dated from 1 January 1985 to 15 November 2012. Randomized and non-randomized controlled trials that investigated medication to prevent or treat delirium were included. The number of patients with cognitive impairment was counted, and if they were excluded, motivations were noted. RESULTS The search yielded 4293 hits, ultimately resulting in 31 studies that met the inclusion criteria. Of these, five studies explicitly mentioned the percentage of patients with cognitive impairment that were included. These patients comprised a total of 8% (n = 279 patients) of the 3476 patients included in all 31 studies. Ten studies might have included cognitively impaired patients but did not mention the exact percentage, and sixteen studies excluded all patients with cognitive impairment. The motivations for exclusion varied, but most were related to the influence of dementia on delirium. CONCLUSION The exclusion of patients with pre-existing cognitive impairment hampers the generalizability of the results of these trials and leaves clinicians with limited evidence about the pharmacological treatment of this group of vulnerable patients who have an increased risk of side effects.

Distinct Cognitive Trajectories in the First Year After Hip Fracture

Change in cognitive functioning is often observed after hip fracture. Different patterns, with both improvement and decline, are expected, depending on premorbid cognitive functioning and events that occur during hospitalization. These patterns are unknown and important for older hip fracture patients with different levels of premorbid cognitive functioning.

Effectiveness of melatonin for sundown syndrome and delirium.

To the Editor: We read with interest the recent article by Lammers and Ahmed in which they address the role of melatonin for sundown syndrome in dementia and delirium. We agree that the medical treatment of sundowning in individuals with dementia and sleep–wake rhythm disturbances in individuals with delirium with traditional medications of choice (e.g., antipsychotics, benzodiazepines, cholinesterase inhibitors) often fail. Treatment with melatonin could be an interesting alternative. The authors cite three previous randomized controlled trials and case series on the effect of melatonin in individuals with dementia that found improvement of sundown syndrome and a study that found no effect on sleep, circadian rhythms, or agitation. There are five additional studies available on the effectiveness of melatonin on sundown syndrome in dementia (reviewed in). Four of these studies found a positive effect, and one study did not found a significant effect on sleep quality. They state that two articles were found on the efficacy of melatonin as treatment for delirium, both with a positive effect. Also, with respect to delirium, another study found that melatonin once a day preoperatively reduced the incidence of postoperative delirium. Furthermore, the results of a large multicenter randomized clinical trial in individuals with hip fracture will soon be available, and other trials will follow according to the trial registers. Circadian rhythm, which melatonin regulates, may be an important factor contributing to sundown syndrome, but in delirium, in addition to this mechanism of maintaining or restoring the sleep–wake cycle, other properties of melatonin could be responsible because melatonin has chronobiotic and nonchronobiotic properties and may therefore play a direct role in the pathogenesis of delirium. Central nervous system inflammation and dopaminergic imbalance are thought to primarily cause delirium. Melatonin is one of the many anti-inflammatory molecules that are produced at the sites of lesions during the recovery phase of an inflammatory response, and it is involved in the modulation of central dopaminergic functions. In conclusion, we think of melatonin as a high-potential drug without serious side effects for the treatment of delirium that will hopefully in future research also show to have an effect on the long-term prognosis of individuals after delirium.