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=1576Delirium in older inpatients is associated with a high risk of dementia and other complications that translate into increased mortality and health care costs.^1,2 The antipsychotic haloperidol has historically been the agent of choice for treating delirium, and it has increasingly been administered as a prophylactic for delirium or to reduce symptoms such as hallucinations and aggressive behaviour.^3,4 However, all antipsychotic treatments may induce serious cerebrovascular adverse effects and greater mortality, particularly among patients with dementia.^5,6 These effects led the US Food and Drug Administration to issue a serious warning against their use.⁷ In addition, benzodiazepines are still frequently used to treat delirium, despite their being known to elicit or aggravate delirium.^8,9Disturbances of the circadian sleep–wake cycle represent one of the core features of delirium,¹⁰ leading to the hypothesis that the neurotransmitter melatonin and changes in its metabolism may be involved in the pathogenesis of delirium.^11,12 Objective measurements have shown that melatonin metabolism is disturbed after abdominal and other types of surgery, insomnia, sleep deprivation and stays in the intensive care unit (ICU), all of which are also known to be factors that contribute to delirium.^13–16 These characteristics suggest an association between melatonin abnormalities and delirium.^17–22 Although proof of a causal relation is still lacking, inpatients might nevertheless benefit from melatonin supplementation therapy through postoperative maintenance or restoration of their sleep–wake cycle.^23–25 Although melatonin depletion is thought to be one of the mechanisms of delirium, few studies have investigated the effects of altering perioperative plasma concentrations of melatonin, in particular, the possible effects on postoperative delirium.The primary objective of this study was to assess the effects of melatonin on the incidence of delirium among elderly patients admitted to hospital as an emergency following hip fracture. Secondary outcomes were duration and severity of delirium, length of hospital stay, total doses of haloperidol and benzodiazepines administered to patients with delirium, mortality during the hospital stay, and functional status, cognitive function and mortality at 3-month follow-up.     

Home based care and standard hospital care for patients with severe mental illness: a randomised controlled trial.

OBJECTIVE--To compare the efficacy of home based care with standard hospital care in treating serious mental illness. DESIGN--Randomised controlled trial. SETTING--South Southwark, London. PATIENTS--189 patients aged 18-64 living in catchment area. 92 were randomised to home based care (daily living programme) and 97 to standard hospital care. At three months'' follow up 68 home care and 60 hospital patients were evaluated. MAIN OUTCOME MEASURES--Use of hospital beds, psychiatric diagnosis, social functioning, patients'' and relatives'' satisfaction, and activity of daily living programme staff. RESULTS--Home care reduced hospital stay by 80% (median stay six days in home care group, 53 days in hospital group) and did not increase the number of admissions compared with hospital care. On clinical and social outcome there was a non-significant trend in favour of home care, but both groups showed big improvements. On the global adjustment scale home care patients improved by 26.8 points and the hospital group by 21.6 points (difference 5.2; 95% confidence interval -1.5 to 12). Other rating scales showed similar trends. Home care patients required a wide range of support in areas such as housing, finance, and work. Only three patients dropped out from the programme. CONCLUSIONS--Home based care may offer some slight advantages over hospital based care for patients with serious mental illness and their relatives. The care is intensive, but the low drop out rate suggests appreciation. Changes to traditional training for mental health workers are required.     

Screening for psychosocial problems among primary care patients: a pilot study.

The symptoms that a patient presents to the doctor are often not the underlying concern that prompted the consultation. The success of consultations involving a hidden diagnosis depends on how well the patient can express his or her concerns to the doctor and on how skilfully the doctor can encourage this. This study tested the feasibility and acceptability of having patients complete a brief health index questionnaire designed to help them describe their underlying concerns to the doctor. In two family medicine centres 996 patients were asked to complete a questionnaire while waiting to see the doctor; 724 (73%) did so. An evaluation of their responses showed the method to be acceptable to most. The doctors judged that it added valuable information in 41% of all consultations and in 73% of consultations in which the patient presented with psychologic complaints. There was, nevertheless, considerable variation among the physicians in their acceptance of the approach. This variability is discussed in the light of alternative models of how, in practical terms, to treat the psychosocial dimensions of a patient''s complaint.     

Multi-centre randomised controlled trial of a smart phone-based event recorder alongside standard care versus standard care for patients presenting to the Emergency Department with palpitations and pre-syncope - the IPED (Investigation of Palpitations in the ED) study: study protocol for a randomised controlled trial

Background

Palpitations and pre-syncope are together responsible for 300,000 annual Emergency Department (ED) attendances in the United Kingdom (UK). Diagnosis of the underlying rhythm is difficult as many patients are fully recovered on ED arrival; and examination and presenting electrocardiogram (ECG) are commonly normal. The only way to establish the underlying heart rhythm is to capture an ECG during symptoms. Recent technology advances have led to several novel ECG monitoring devices appearing on the market. This trial aims to compare the symptomatic rhythm detection rate at 90?days of one such smart phone-based event recorder (AliveCor Heart Monitor and AliveECG) with standard care for participants presenting to the ED with palpitations and pre-syncope and no obvious cause in the ED.

Methods/Design

This is a multi-centre hospital ED / Acute Medical Unit (AMU) open label, randomised controlled trial. Participants will be recruited in 10 tertiary and district general hospitals in the UK. Participants aged ≥?16?years presenting with an episode of palpitations or pre-syncope with no obvious cause and whose underlying ECG rhythm during these episodes remains undiagnosed after clinical assessment will be included. Participants will be randomised to either: (1) the intervention arm, standard care plus the use of a smart phone-based event recorder; or (2) the control arm, standard care. Primary endpoint will be symptomatic rhythm detection rate at 90?days. A number of secondary clinical, process and cost-effectiveness endpoints will be collected and analysed. Analysis will be on an intention-to-treat basis.

Discussion

The Investigation of Palpitations in the ED (IPED) study aims to recruit 242 participants across 10 hospital sites. It will be the first study to investigate the ability of a smart phone-based event recorder to detect symptomatic cardiac rhythms compared to standard care for ED patients with palpitations and pre-syncope with no obvious cause in the ED. This smart phone event recorder will allow ED patients who have presented with palpitations or pre-syncope to record their ECG tracing if they have a further episode and may increase the rate of underlying rhythm diagnosis.

Trial registration

ClinicalTrials.gov, NCT02783898. Registered on 26 May 2016.

     

Hospital at home versus hospital care in patients with exacerbations of chronic obstructive pulmonary disease: prospective randomised controlled trial

ObjectivesTo compare “hospital at home” and hospital care as an inpatient in acute exacerbations of chronic obstructive pulmonary disease.DesignProspective randomised controlled trial with three months'' follow up.SettingUniversity teaching hospital offering secondary care service to 350 000 patients.PatientsSelected patients with an exacerbation of chronic obstructive pulmonary disease where hospital admission had been recommended after medical assessment.InterventionsNurse administered home care was provided as an alternative to inpatient admission.Results583 patients with chronic obstructive pulmonary disease referred for admission were assessed. 192 met the criteria for home care, and 42 refused to enter the trial. 100 were randomised to home care and 50 to hospital care. On admission, FEV₁ after use of a bronchodilator was 36.1% (95% confidence interval 2.4% to 69.8%) predicted in home care and 35.1% (6.3% to 63.9%) predicted in hospital care. No significant difference was found in FEV₁ after use of a bronchodilator at two weeks (42.6%, 3.4% to 81.8% versus 42.1%, 5.1% to 79.1%) or three months (41.5%, 8.2% to 74.8% versus 41.9%, 6.2% to 77.6%) between the groups. 37% of patients receiving home care and 34% receiving hospital care were readmitted at three months. No significant difference was found in mortality between the groups at three months (9% versus 8%).ConclusionsHospital at home care is a practical alternative to emergency admission in selected patients with exacerbations of chronic obstructive pulmonary disease.     

Promoting physical activity in patients with colon adenomas: a randomized pilot intervention trial

Background

Physical activity decreases risk of colon polyps and colon cancer and might reduce risk of colon cancer recurrence. Focusing on recent calls for translation of epidemiologic evidence into clinical care, our pilot study delivered an evidence-based physical activity intervention in adults with polyps, who are thus at elevated risk of developing colon cancer. The objective was to evaluate change in physical activity, measured by steps per day and minutes of moderate/vigorous physical activity.

Methods

Sixteen adults with adenomas detected and removed at screening colonoscopy were recruited to a 12-week physical activity intervention. Participants were randomized to receive a standard (30 minutes/day) or high (60 minutes/day) walking program. Physical activity was measured via blinded pedometer and accelerometer at baseline and follow-up. Intervention messages focused on self-monitoring using pedometers and overcoming barriers to engaging in physical activity.

Results

Participants in both arms significantly increased objectively measured minutes of moderate/vigorous physical activity over the course of the intervention. Both arms exceeded the intervention goal, but there was not a significant difference between arms at follow-up. Results were similar for pedometer measured physical activity, with a significant overall increase in steps/day from baseline to follow-up, but no between arm difference in change.

Conclusion

Simple interventions of minimal contact time focusing on walking can significantly increase physical activity in individuals at increased risk of developing colon cancer.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01476631","term_id":"NCT01476631"}}NCT01476631     

Markers of cerebral damage during delirium in elderly patients with hip fracture

Background  

S100B protein and Neuron Specific Enolase (NSE) can increase due to brain cell damage and/or increased permeability of the blood-brain-barrier. Elevation of these proteins has been shown after various neurological diseases with cognitive dysfunction. Delirium is characterized by temporal cognitive deficits and is an important risk factor for dementia. The aim of this study was to compare the level of S100B and NSE of patients before, during and after delirium with patients without delirium and investigate the possible associations with different subtypes of delirium.     

Serum resistin in older patients with hip fracture: Relationship with comorbidity and biochemical determinants of bone metabolism

Objectives

To determine the relationship of serum resistin concentrations to biochemical determinants of bone metabolism, comorbidity and outcomes in patients with hip fracture (HF).

Methods

In 256 consecutive patients (mean age 81.9 ± 7.8 years; 71.1% women) serum levels of resistin (determined by ELISA), biochemical parameters of bone turnover and mineral metabolism as well as routine haematological and biochemical parameters were measured. Clinical data were recorded prospectively.

Results

In multivariate analysis cervical HF (OR = 1.81; 95% CI 1.05–3.11), diabetes (OR = 2.60; 95% CI 1.23–5.51) and history of stroke (OR = 2.67; 95% CI 1.17–6.13) were significant independent predictors of higher resistin levels (?16.26 ng/ml, median value). The independent correlates of serum resistin levels in patients with cervical HF were serum osteocalcin and magnesium (both negatively associated) and in patients with trochanteric HF, serum PTH, calcium and age (all positively associated). Resistin and glomerular filtration rate were the only independent (inverse) predictors of serum osteocalcin. Resistin levels on admission did not predict short-term outcomes.

Conclusions

In older patients with HF there is a significant association of higher resistin levels with cervical fracture, type 2 diabetes and history of stroke, which is partly influenced by the reciprocal interaction between resistin and osteocalcin. However, the design of the study does not prove causality and further prospective studies are needed to clarify these relationships.     

Palliative care among elderly cancer patients: Own experience

Background

Annually, more than 27,000 persons die of cancer in the Czech Republic. It is known that in addition to the demographic aging of the Czech population, the cancer burden is increased.

Aim

These data clearly demonstrate the need for affordable and good follow-up care for patients, especially for older patients and/or patients with no other cancer treatment due to irreversible progression of tumor.

Materials and methods

We are talking about so-called palliative cancer care, which can be provided at different levels. One of the most common forms of palliative cancer care is hospice care.

Results

Our clinic in the years 2008–2010 received a total of 446 patients. 288 of them were women and 158 men. The average age of women was 61 years (age range 20–81 years). The average age of men was 56 years (age range 18–96 years). The performance status was in the fitness category PS-0 (8%), PS-1 (54%), PS-2 (33%) and PS-3 (5%).

Conclusion

Currently the outpatient palliative cancer care are coming more into the forefront. This type of care allows patients to stay as long as possible at home among their close relatives. Prerequisite for a well working outpatient palliative care is cooperation with general practitioners and home health care agencies.     

Routine care of peripheral intravenous catheters versus clinically indicated replacement: randomised controlled trial

Objective To compare routine replacement of intravenous peripheral catheters with replacement only when clinically indicated.Design Randomised controlled trial.Setting Tertiary hospital in Australia.Participants 755 medical and surgical patients: 379 allocated to catheter replacement only when clinically indicated and 376 allocated to routine care of catheter (control group).Main outcome measure A composite measure of catheter failure resulting from phlebitis or infiltration.Results Catheters were removed because of phlebitis or infiltration from 123 of 376 (33%) patients in the control group compared with 143 of 379 (38%) patients in the intervention group; the difference was not significant (relative risk 1.15, 95% confidence interval 0.95 to 1.40). When the analysis was based on failure per 1000 device days (number of failures divided by number of days catheterised, divided by 1000), no difference could be detected between the groups (relative risk 0.98, 0.78 to 1.24). Infusion related costs were higher in the control group (mean $A41.02; £19.71; €24.80; $38.55) than intervention group ($A36.40). The rate of phlebitis in both groups was low (4% in intervention group, 3% in control group).Conclusion Replacing peripheral intravenous catheters when clinically indicated has no effect on the incidence of failure, based on a composite measure of phlebitis or infiltration. Larger trials are needed to test this finding using phlebitis alone as a more clinically meaningful outcome.Registration number Australian New Zealand Clinical Trials Registry ACTRN12605000147684.     

Influence of surgery onto the appearance of the hip joint periarticular calcification in patients with the acetabular fracture

The intention of this study was to investigate the influence of surgery onto the appearance of the hip joint periarticular calcification in different groups of patients who suffered the acetabular fracture. A series of 103 patients with the acetabular fracture was analysed in a retrospective case-control study during a seven-year period. The patients were divided into two groups. The case group was comprised of 21 patients who were operated on due to the posterior acetabular wall fracture, while the control group was formed from 82 patients who underwent conservative treatment and who suffered complex acetabular fracture. To obtain the results, the rate and grade of the hip joint post-injury periarticular calcification formation were observed and analysed. They were considerably lower in patients from the case group who were operated on, compared to patients from the control group where the hip joint arthrosis was more common. In conclusion, considering the results of this paper, the rate and grade of the hip joint osteodegenerative changes may be highly decreased by surgery in patients who sustained the acetabular fracture.     

Integration of autologous dendritic cell-based immunotherapy in the standard of care treatment for patients with newly diagnosed glioblastoma: results of the HGG-2006 phase I/II trial

Purpose

Dendritic cell (DC)-based tumor vaccination has rendered promising results in relapsed high-grade glioma patients. In the HGG-2006 trial (EudraCT 2006-002881-20), feasibility, toxicity, and clinical efficacy of the full integration of DC-based tumor vaccination into standard postoperative radiochemotherapy are studied in 77 patients with newly diagnosed glioblastoma.

Patients and methods

Autologous DC are generated after leukapheresis, which is performed before the start of radiochemotherapy. Four weekly induction vaccines are administered after the 6-week course of concomitant radiochemotherapy. During maintenance chemotherapy, 4 boost vaccines are given. Feasibility and progression-free survival (PFS) at 6?months (6mo-PFS) are the primary end points. Overall survival (OS) and immune profiling, rather than monitoring, as assessed in patients’ blood samples, are the secondary end points. Analysis has been done on intent-to-treat basis.

Results

The treatment was feasible without major toxicity. The 6mo-PFS was 70.1?% from inclusion. Median OS was 18.3?months. Outcome improved significantly with lower EORTC RPA classification. Median OS was 39.7, 18.3, and 10.7?months for RPA classes III, IV, and V, respectively. Patients with a methylated MGMT promoter had significantly better PFS (p?=?0.0027) and OS (p?=?0.0082) as compared to patients with an unmethylated status. Exploratory “immunological profiles” were built to compare to clinical outcome, but no statistical significant evidence was found for these profiles to predict clinical outcome.

Conclusion

Full integration of autologous DC-based tumor vaccination into standard postoperative radiochemotherapy for newly diagnosed glioblastoma seems safe and possibly beneficial. These results were used to power the currently running phase IIb randomized clinical trial.     

Preclinical cost analysis of orthopaedic implants: a custom versus standard cementless femoral component for revision total hip arthroplasty

A preclinical cost analysis method was introduced to assess the cost effectiveness of using a custom implant instead of standard “off-the-shelf” implants for revision total hip arthroplasty. Finite element models of proximal femur–implant systems were constructed and an array of environmental factors, including loads and bone properties, was incorporated into a computer experiment to evaluate relative motion between implant and bone. Implant performance related cost was then determined from relative motion measures using a quality loss function. Unit manufacturing cost was added to implant performance cost to determine the cost difference between the two implants. The reduction in relative motion achieved by the custom implant with respect to an equivalent-lengthed standard implant justified its additional unit manufacturing costs. In response to these results and suggestions by surgeons, we increased the length of the standard implant by 50 mm and performed an identical series of analyses. We found that increasing the stem length to 120 mm substantially decreased the relative motion of the standard implant to values less than for the custom implant. This case study provides preliminary evidence that a surgical inventory consisting of longer-stemmed standard implants or modular distal stems is more cost effective than designing custom devices on a case-by-case basis. Additional design studies are warranted before generalizing such a claim.