Results from a double blinded, randomised, placebo-controlled, feasibility trial of melatonin for the treatment of delirium in older medical inpatients.

BACKGROUND: Delirium is common in elderly inpatients, causing distress, cognitive decline and death. No known intervention improves the course of delirium; current treatments are symptomatic, and limited by lack of efficacy and adverse effects. There is an urgent need to find an effective treatment for delirium. AIMS: To determine the feasibility of a trial of oral melatonin 5 mg nightly for five nights for the treatment of delirium in older medical inpatients, and determine the participants required to demonstrate a clinically and statistically significant decrease in severity of delirium in older medical inpatients treated with melatonin. METHODS: This was a double blinded, randomised controlled trial in general internal medicine units of a tertiary teaching hospital. Older (≥70 years) inpatients with confusion assessment method positive hyperactive or mixed delirium were suitable for inclusion. Subjects received melatonin 5 mg oral nightly for five nights or matching placebo. The primary outcome was the Memorial Delirium Assessment Scale (MDAS) administered daily. RESULTS: No adverse effects occurred due to melatonin. In the treatment group, the mean change in MDAS from baseline during treatment period was 2.5 ± 5.0 points, in the placebo group, 2.1 ± 4.1 points, a non-significant difference. A power calculation accounting for drop-out (31.0%), suggests 120 participants would be required to demonstrate with 90% power that melatonin 5 mg reduces the severity of delirium by 3 points or more on MDAS. CONCLUSIONS: A trial of the hypothesis that 5 mg melatonin nightly for five nights reduces delirium severity in older medical inpatients would require 120 patients, and is feasible.

Where are our patients? Retrospective cohort study of acute medical unit admissions during and prior to the COVID-19 pandemic.

Admissions to hospital have declined markedly during the COVID-19 pandemic in Australia. This may be due to patients not presenting with acute illness or managing their chronic illness at home. We reviewed a cohort admitted to the Acute Medical Unit of the Royal Melbourne Hospital during and before the pandemic and found admissions were more acutely unwell and more comorbid. This may lead to worse outcomes for those not presenting, as well as those presenting late. We recommend a public health campaign to encourage Australians to present to hospital if unwell.

Undiagnosed delirium is frequent and difficult to predict: Results from a prevalence survey of a tertiary hospital.

AIMS AND OBJECTIVES: To study the prevalence and determinants of undiagnosed delirium in a tertiary hospital. BACKGROUND: Delirium is a common inpatient condition. It is frequently undiagnosed in a variety of settings, but determinants of undiagnosed delirium are largely unknown, and the frequency of undiagnosed delirium across all inpatient units is uncertain. The utility of hospital-wide screening then is also uncertain. METHODS: Hospital-wide prevalence study conducted over 4 months, using a chart-based method. Gender, age, admitting unit, history of dementia and comorbidity were used in univariate and multivariate analyses to search for differences in patients with no delirium, with undiagnosed delirium and with diagnosed delirium. Sensitivity, specificity and number needed to screen were calculated from proportions in each group. Study was conducted in concordance with STROBE guidelines. RESULTS: Delirium was prevalent in 12.5% of all patients and undiagnosed in 24.1% of patients. Only age ≥65 years and a history of dementia predicted delirium, and undiagnosed delirium in both univariate and multivariate analyses. Age ≥65 years accounts for 92.3% sensitivity and 50.8% specificity for undiagnosed delirium in this group. History of dementia had a 23.0% sensitivity and 97.0% specificity. Twenty-eight patients would need to be screened to detect a case of undiagnosed delirium. DISCUSSION: There was a high rate of delirium and undiagnosed delirium in this cohort. Known risk factors for delirium also independently predict undiagnosed delirium; other factors were not found. CONCLUSION: Undiagnosed delirium is common and difficult to predict from patient baseline characteristics other than age. RELEVANCE TO CLINICAL PRACTICE: Assessment of all inpatients for delirium is recommended.

Moderate dose melatonin for the abatement and treatment of delirium in elderly general medical inpatients: study protocol of a placebo controlled, randomised, double blind trial.

BACKGROUND: Delirium is a frequent, costly and morbid problem. No agent has been shown to modify the natural history of the condition, and current treatments have significant side effects. Prophylactic melatonin in low doses has been shown to prevent delirium developing. This trial then aims to determine the feasibility of a trial to assess if melatonin at a moderate dose effectively treats the symptoms of delirium and modifies the natural history, including abating symptoms after treatment cessation. METHODS/DESIGN: Elderly (≥70 years of age) patients admitted to the Royal Melbourne Hospital with delirium, and not requiring surgery, will be identified from the current practice of the investigators and through referral by other general medical unit staff. To facilitate this, other staff will be briefed on the project by investigators. Patients will be recruited with suitable informed and documented consent (person responsible) by the study investigators. They will receive orally either 5 mg melatonin (18 patients) or placebo (18 patients) nightly for 5 nights (or until discharged). During treatment, participants will be assessed by study staff using a validated scale of delirium severity (the Memorial Delirium Assessment Scale), and a validated measure of delirium state (Confusion Assessment Method) to determine if melatonin decreases the severity or the duration of delirium. Assessment will continue for a further two days after treatment has ceased, to determine if the treatment causes persisting abatement of symptoms, and to assess for adverse events. DISCUSSION: The on-going study described herein will contribute to our knowledge of available treatment options for elderly inpatients with delirium, where current pharmacological interventions show weak or no effect on hastening the resolution of delirium. As melatonin is safe, cheap, and potentially effective, it would be easily implementable in routine practice and could lead to significant outcome benefits for delirious inpatients. TRIAL REGISTRATION: The trial is registered with the Australia New Zealand Clinical Trials Registry (trial ID: ACTRN12614000101684 ) (registered 28/01/2014).

Melatonin does not reduce delirium severity in hospitalized older adults: Results of a randomized placebo-controlled trial.

BACKGROUND: Delirium is common in older inpatients, causing distress, cognitive decline, and death. Current therapies are unsatisfactory, limited by lack of efficacy and adverse effects. There is an urgent need for effective delirium treatment. Sleep wake cycle is disturbed in delirium; endogenous Melatonin is perturbed, and exogenous Melatonin is a safe and effective medication for sleep disorders. This study aims to determine the effect of oral Melatonin 5 mg immediate release (IR) nightly for five nights on the severity of delirium in older (≥65 years) medical inpatients. METHODS: This was a double-blinded, randomized controlled trial in general internal medicine units of a tertiary teaching hospital. Older inpatients with Confusion Assessment Method positive, hyperactive or mixed delirium within 48 h of admission or onset of in-hospital delirium were included. The primary outcome was change in delirium severity measured with the Memorial Delirium Assessment Scale (MDAS). A previous pilot trial showed 120 participants randomized 1:1 to Melatonin or Placebo would provide 90% power to demonstrate a 3-point reduction in the MDAS. RESULTS: One hundred and twenty participants were randomized, 61 to Melatonin 5 mg and 59 to Placebo. The medication was well tolerated. The mean MDAS improvement was 4.9 (SD 7.6) in the Melatonin group and 5.4 (SD 7.2) in the Placebo group, p-value 0.42, a non-significant difference. A post-hoc analysis showed length of stay (LOS) was shorter in the intervention group (median 9 days [Interquartile Range (IQR) 4, 12] vs. Placebo group 10 [IQR 6, 16] p-value = 0.033, Wilcoxon Rank Sum test). CONCLUSIONS: This trial does not support the hypothesis that Melatonin reduces the severity of delirium. This may be due to no effect of Melatonin, a smaller effect than anticipated, an effect not captured on a multidimensional delirium assessment scale, or a type II statistical error. Melatonin may improve LOS; this hypothesis should be studied.

Lessons learnt in the first year of an Australian pediatric cardio oncology clinic.

BACKGROUND: Modern oncological therapies together with chemotherapy and radiotherapy have broadened the agents that can cause cardiac sequelae, which can manifest for pediatric oncology patients while on active treatment. Recommendations for high-risk patients who should be monitored in a pediatric cardio-oncology clinic have previously been developed by expert Delphi consensus by our group. In 2022 we opened our first multidisciplinary pediatric cardio-oncology clinic adhering to these recommendations in surveillance and management. OBJECTIVES: Our pediatric cardio-oncology clinic aimed to: (i) Document cardiovascular toxicities observed within a pediatric cardio-oncology clinic and. (ii) Evaluate the applicability of the Australian and New Zealand Pediatric Cardio-Oncology recommendations. METHODS: Monthly multidisciplinary cardio-oncology clinics were conducted in an Australian tertiary pediatric hospital. Structured standardised approaches to assessment were built into the electronic medical record (EMR). All patients underwent baseline echocardiogram and electrocardiogram assessment together with vital signs in conjunction with standard history and examination. RESULTS: Nineteen (54%) individuals had a documented cardiovascular toxicity or pre-existing risk factor prior to referral. The two most common cardiovascular toxicities documented during clinic review included Left Ventricular Dysfunction (LVD) and hypertension. Of note 3 (8.1%) patients had CTCAE grade III LVD. An additional 10 (27%) patients reviewed in clinic had CTCAE grade I hypertension. None of these patients had hypertension noted within their referral. Cascade testing for cardiac history was warranted in 2 (5.4%) of patients. CONCLUSIONS: Pediatric cardio-oncology clinics are likely beneficial to documenting previously unrecognised cardiotoxicity and relevant cardiac family histories, whilst providing an opportunity to address lifestyle risk factors.

Orthostatic Hypotension and Orthostatic Intolerance Symptoms in Geriatric Rehabilitation Inpatients, RESORT.

OBJECTIVES: Orthostatic hypotension (OH) and orthostatic intolerance symptoms are common in older community-dwelling adults and are associated with reduced quality of life and detrimental health outcomes. This study aimed to determine the prevalence, co-occurrence and determinants of OH and orthostatic intolerance symptoms in geriatric rehabilitation inpatients. DESIGN: Observational, longitudinal cohort, "REStORing the health of acutely unwell adulTs" (RESORT). SETTING AND PARTICIPANTS: Geriatric rehabilitation inpatients (n = 1505) of a tertiary teaching hospital in Melbourne, Australia. METHODS: OH was defined as a drop in systolic blood pressure by ≥20 mm Hg and/or diastolic blood pressure by ≥10 mm Hg within three 3 of moving from supine to a standing or sitting position. Symptoms were recorded following the 3 minutes. Determinants included sociodemographics, reason for admission, cognitive health, nutritional status, physical performance, frailty, morbidity, medication use, length of stay (LOS), and number of geriatric conditions. Independent t-tests, Mann-Whitney U tests or χ2 tests were used to analyze differences between inpatients with and without OH and symptoms. Logistic regression analyses were used to ascertain the determinants. RESULTS: OH and orthostatic intolerance symptoms were prevalent in 19.8% (standing: 21.4%, sitting: 18.2%) and 22.6% (standing: 25.0%, sitting: 20.2%) of inpatients, respectively. Symptoms were reported by 32.8% of inpatients with OH and 20.1% without OH. Higher number of comorbidities and geriatric conditions, low functional independence, and longer LOS were determinants of OH. Female gender, higher number of morbidities and geriatric conditions, low functional independence, depression risk, poor physical performance, musculoskeletal and "other" reasons for admission, and long LOS during geriatric rehabilitation were determinants of symptoms. CONCLUSIONS AND IMPLICATIONS: OH and orthostatic intolerance symptoms occur in one-fifth of geriatric rehabilitation inpatients, however, the co-occurrence is low and determinants differ. Poorer health in patients with orthostatic intolerance symptoms highlights the need to assess symptoms in clinical practice, independent of an OH diagnosis.

Initial orthostatic hypotension and orthostatic intolerance symptom prevalence in older adults: A systematic review.

BACKGROUND: Initial orthostatic hypotension is a clinically relevant syndrome in older adults which has been associated with symptoms of orthostatic intolerance. The aim of this systematic review was to determine the prevalence of orthostatic intolerance symptoms in older adults with initial orthostatic hypotension. METHODS: MEDLINE (from 1946), EMBASE (from 1974) and Cochrane were searched to December 6th, 2019 using the terms "initial orthostatic hypotension", "postural hypotension" and "older adults". Study selection involved the following criteria: published in English; mean or median age ≥ 65 years and diagnosis of initial orthostatic hypotension encompassed a decrease in systolic blood pressure by ≥ 40  mmHg and/or diastolic blood pressure by ≥ 20  mmHg within a maximum of 1 min following a postural change. RESULTS: Of 8311 articles, 12 articles reporting initial orthostatic hypotension prevalence in 3446 participants with a mean age of 75 (6 SD) years (56.5% female) were included. Five initial orthostatic hypotension definition variations were utilised and symptoms were reported in six articles (968 participants, mean age 73.4 (6.1 SD) years, 56% female). The prevalence of symptoms in older adults with initial orthostatic hypotension ranged from 24 to 100% and was dependent on variations in timing or the inclusion of symptoms in the initial orthostatic hypotension definition. CONCLUSIONS: Where orthostatic intolerance symptoms were reported, a large proportion of older adults with a diagnosis of initial orthostatic hypotension were symptomatic. However, the literature on initial orthostatic hypotension and orthostatic intolerance symptoms is scarce and a variety of definitions of initial orthostatic hypotension are utilised.

Timing and methods of frailty assessments in geriatric trauma patients: A systematic review.

INTRODUCTION: The trauma population is aging and better prognostic measures for geriatric trauma patients are required. Frailty rather than age appears to be associated with poor outcomes. This systematic review aimed to identify the optimum frailty assessment instrument and timing of assessment in patients aged over 65 years admitted to hospital after traumatic injury. The secondary aim was to evaluate outcomes associated with frailty in elderly trauma populations. METHODS: This systematic review was registered with the PROSPERO International Prospective Register of Systematic Reviews (CRD42018090620). A MEDLINE and EMBASE literature search was conducted from inception to June 2019 combining the concepts of injury, geriatric, frailty, assessment and prognosis. Included studies were in patients 65 years or older hospitalised after injury and exposed to an instrument meeting consensus definition for frailty assessment. Study quality was assessed using criteria for review of prognostic studies combined with a GRADE approach. RESULTS: Twenty-eight papers met inclusion criteria. Twenty-eight frailty or component instruments were reported, and assessments of pre-injury frailty were made up to 1-year post injury. Pre-injury frailty prevalence varied from 13% (13/100) to 94% (17/18), with in-hospital mortality rates from 2% (5/250) to 33% (6/18). Eleven studies found an association between frailty and mortality. Eleven studies reported an association between frailty and a composite outcome of mortality and adverse discharge destination. Generalisability and assessment of strength of associations was limited by single centre studies with inconsistent findings and overlapping cohorts. CONCLUSIONS: Associations between frailty and adverse outcomes including mortality in geriatric trauma patients were demonstrated despite a range of frailty instruments, administering clinicians, time of assessment and data sources. Although evidence gaps remain, incorporating frailty assessment into trauma systems is likely to identify geriatric patients at risk of adverse outcomes. Consistency in frailty instruments and long-term geriatric specific outcome measures will improve research relevance. LEVEL OF EVIDENCE: Level III prognostic.