The tryptophan depletion theory in delirium: not confirmed in elderly hip fracture patients.

BACKGROUND: The tryptophan depletion theory assumes that low tryptophan levels are present in delirium. These lower levels may be regarded as a biochemical marker for cellular immune activation, which may lead to increased catabolism of tryptophan into kynurenine via stimulation of the enzyme indoleamine 2,3-dioxygenase (IDO) by interferon-γ. OBJECTIVE: To compare plasma tryptophan and kynurenine levels, and IDO activity in hospitalized patients with and without delirium. METHODS: Repeated plasma samples were prospectively collected in hip fracture patients, aged 65 years and older. The presence of delirium was assessed daily. The associations of a delirious state and tryptophan, kynurenine, and the kynurenine/tryptophan ratio measured in samples taken 'before', 'during delirium', and 'after delirium' were analyzed with linear mixed models. RESULTS: A total of 469 samples from 140 patients were collected. Adjusted for the days on which they were drawn, there was no difference for all three measured factors in patients with and without delirium, except for an association between a higher kynurenine/tryptophan ratio and delirium in a subgroup analysis in preoperative samples. CONCLUSIONS: The results do not confirm the previously found lower tryptophan levels in delirium on which the tryptophan depletion theory is based. However, a preoperative higher kynurenine/tryptophan ratio could be indicative of delirium.

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

BACKGROUND: With 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/DESIGN: Acutely 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. DISCUSSION: The 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 REGISTRATION: Dutch Clinical Trial Registry: NTR1576.

Cortisol, interleukins and S100B in delirium in the elderly.

In independent studies delirium was associated with higher levels of cortisol, interleukin(IL)s, and S100B. The aim of this study was to simultaneously compare cortisol, IL-6, IL-8, and S100B levels in patients aged 65years and older admitted for hip fracture surgery with and without delirium. Cortisol, IL-6, IL-8, and S100B were assayed in repeated blood samples. 120 patients (mean age 84years, 62 patients with delirium) were included. Highest levels of IL-8 (27.1, 95% Confidence Interval (CI): 13.6-53.1pg/ml) and cortisol (666, 95% CI: 475-859nmol/L) were before delirium, but of IL-6 (84.3, 95% CI: 46.5-151.4pg/mL) and S100B (0.18, 95% CI: 0.12-0.24 microg/L) during delirium. In multivariable analysis cortisol, LogIL-6, and LogS100B were significantly associated with delirium, but adjusted for pre-existing cognitive impairment, only LogS100B remained significantly associated. Cortisol, IL-6 and S100B may have a role in the pathogenesis of delirium, but S100B is the strongest independent marker.

Cortisol, insulin, and glucose and the risk of delirium in older adults with hip fracture.

OBJECTIVES: To determine the relationship between perioperative delirium and cortisol, glucose, and insulin in older adults acutely admitted for hip fracture. DESIGN: Prospective cohort study. SETTING: Tertiary university center. PARTICIPANTS: Consecutive individuals aged 65 and older acutely admitted for hip fracture were invited to participate. MEASUREMENTS: All participants were repeatedly examined to determine presence and severity of delirium. Blood samples for cortisol, glucose, and insulin were drawn at 11:00 a.m. Differences in characteristics of participants with and without delirium were evaluated using t-tests and Mann-Whitney tests. A logistic regression analysis was performed to correct for other important risk factors for delirium. RESULTS: One hundred forty-three participants, 70 (49%) with delirium and 73 (51%) without, were included. In univariate analyses, there was a trend toward higher cortisol levels (odds ratio = 1.003 (95% confidence interval = 1.001-1.004, P = .004), but this association was not statistically significant after multivariable analysis and may reflect an association between high cortisol and preexisting cognitive and functional impairment, and there was no association with insulin or glucose levels. Adjusting for sex and prefracture cognitive and functional impairment made the trend with cortisol and delirium statistically nonsignificant. CONCLUSION: Delirium in older adults acutely admitted for hip fracture may be linked with higher cortisol concentrations, but it may be that this association reflects an association between higher cortisol and preexisting cognitive and functional impairment.