The Hip Fracture Surgery in Elderly Patients (HIPELD) study: protocol for a randomized, multicenter controlled trial evaluating the effect of xenon on postoperative delirium in older patients undergoing hip fracture surgery

BackgroundStrategies to protect the brain from postoperative delirium (POD) after hip fracture are urgently needed. The development of delirium often is associated with the loss of independence, poor functional recovery, and increased morbidity, as well as increases in length of hospital stay, discharges to nursing facilities, and healthcare costs. We hypothesize that xenon may reduce the burden of POD, (i) by avoiding the need to provide anesthesia with a drug that targets the γ-amino-butyric acid (GABA)A receptor and (ii) through beneficial anesthetic and organ-protective effects.Methods and designAn international, multicenter, phase 2, prospective, randomized, blinded, parallel group and controlled trial to evaluate the incidence of POD, diagnosed with the Confusion Assessment Method (CAM), in older patients undergoing hip fracture surgery under general anesthesia with xenon or sevoflurane, for a period of 4 days post surgery (primary outcome) is planned. Secondary objectives are to compare the incidence of POD between xenon and sevoflurane, to evaluate the incidence of POD from day 5 post surgery until discharge from hospital, to determine the time to first POD diagnosis, to evaluate the duration of POD, to evaluate the evolution of the physiological status of the patients in the postoperative period, to evaluate the recovery parameters, to collect preliminary data to evaluate the economical impact of POD in the postoperative period and to collect safety data. Patients are eligible if they are older aged (≥ 75 years) and assigned to a planned hip fracture surgery within 48 h after the hip fracture. Furthermore, patients need to be willing and able to complete the requirements of this study including the signature of the written informed consent. A total of 256 randomized patients in the 10 participating centers will be recruited, that is, 128 randomized patients in each of the 2 study groups (receiving either xenon or sevoflurane).Trial registrationEudraCT Identifier: 2009-017153-35; ClinicalTrials.gov Identifier: NCT0119927

Sigma-1 receptor agonist fluvoxamine for postoperative delirium in older adults: report of three cases

<p>Abstract</p> <p>Background</p> <p>Postoperative delirium is a topic of great importance in the geriatric surgical specialty. Although antipsychotic drugs are the medications most frequently used to treat this syndrome, these drugs are associated with a variety of adverse events, including sedation, extrapyramidal side effects, and cardiac arrhythmias. Drug treatment for postoperative delirium requires careful consideration of the balance between the effective management of symptoms and potential adverse effects.</p> <p>Methods</p> <p>We report on a Japanese woman (an 86-year-old (open reduction and internal fixation of the right femoral neck fracture), and two Japanese men (an 86-year-old (abdominal aortic aneurysm stent grafting), and a 77-year-old (right upper lobectomy due to lung tumour)) in which the selective serotonin reuptake inhibitor and sigma-1 receptor agonist fluvoxamine was effective in ameliorating the postoperative delirium of these patients.</p> <p>Results</p> <p>Delirium Rating Scale scores in these patients dramatically decreased after treatment with fluvoxamine.</p> <p>Conclusions</p> <p>Doctors should consider fluvoxamine as an alternative approach to treating postoperative delirium in older patients in order to avoid the risk of side effects and increased mortality by antipsychotic drugs.</p

Central Role of Pyrophosphate in Acellular Cementum Formation

Background: Inorganic pyrophosphate (PPi) is a physiologic inhibitor of hydroxyapatite mineral precipitation involved in regulating mineralized tissue development and pathologic calcification. Local levels of PPi are controlled by antagonistic functions of factors that decrease PPi and promote mineralization (tissue-nonspecific alkaline phosphatase, Alpl/TNAP), and those that increase local PPi and restrict mineralization (progressive ankylosis protein, ANK; ectonucleotide pyrophosphatase phosphodiesterase-1, NPP1). The cementum enveloping the tooth root is essential for tooth function by providing attachment to the surrounding bone via the nonmineralized periodontal ligament. At present, the developmental regulation of cementum remains poorly understood, hampering efforts for regeneration. To elucidate the role of PPi in cementum formation, we analyzed root development in knock-out ((-/-)) mice featuring PPi dysregulation. Results: Excess PPi in the Alpl(-/-) mouse inhibited cementum formation, causing root detachment consistent with premature tooth loss in the human condition hypophosphatasia, though cementoblast phenotype was unperturbed. Deficient PPi in both Ank and Enpp1(-/-) mice significantly increased cementum apposition and overall thickness more than 12-fold vs. controls, while dentin and cellular cementum were unaltered. Though PPi regulators are widely expressed, cementoblasts selectively expressed greater ANK and NPP1 along the root surface, and dramatically increased ANK or NPP1 in models of reduced PPi output, in compensatory fashion. In vitro mechanistic studies confirmed that under low PPi mineralizing conditions, cementoblasts increased Ank (5-fold) and Enpp1 (20-fold), while increasing PPi inhibited mineralization and associated increases in Ank and Enpp1 mRNA. Conclusions: Results from these studies demonstrate a novel developmental regulation of acellular cementum, wherein cementoblasts tune cementogenesis by modulating local levels of PPi, directing and regulating mineral apposition. These findings underscore developmental differences in acellular versus cellular cementum, and suggest new approaches for cementum regeneration

A retrospective analysis of clinical outcome of patients with chemo-refractory metastatic breast cancer treated in a single institution phase I unit

BACKGROUND AND METHODS: Novel approaches to treat chemo-refractory metastatic breast cancer (MBC) are currently under investigation. This retrospective series reviews the outcome of 70 MBC patients who have participated in 30 phase I trials at the Royal Marsden Hospital from 2002 to 2009. RESULTS: The median treatment lines before phase I trial entry for MBC was 5 (range: 1-12 lines). The overall response rate was 11.4% (95% CI: 4.0-18.9%) and the clinical benefit rate at 4 months was 20% (95% CI: 10.6-29.3). The median time to progression was 7.0 weeks (95% CI: 6.4-7.5) and median overall survival was 8.7 months (95% CI: 7.6-9.8) from start of first phase I treatment. No patients discontinued trial because of treatment-related toxicities. Abnormal lactate dehydrogenase, serum albumin <35 mg per 100 ml, >or=5 previous treatment lines, liver metastases and Eastern Cooperative Group performance status >or=2 at study entry were significantly associated with poor overall survival in multivariate analysis. CONCLUSION: This retrospective analysis provides evidence that patients with MBC tolerate phase I clinical trials and a significant proportion of patients with chemo-refractory disease, particularly those with triple-negative or Her2-positive breast cancer, may benefit from treatment

Epidemiology and outcomes of people with dementia, delirium and unspecified cognitive impairment in the general hospital: prospective cohort study of 10,014 admissions

Background&nbsp; Cognitive impairment of various kinds is common in older people admitted to hospital, but previous research has usually focused on single conditions in highly-selected groups and has rarely examined associations with outcomes. This study examined prevalence and outcomes of cognitive impairment in a large unselected cohort of people aged 65+ with an emergency medical admission.&nbsp; Methods&nbsp; Between January 1, 2012, and June 30, 2013, admissions to a single general hospital acute medical unit aged 65+ underwent a structured specialist nurse assessment (n = 10,014). We defined &lsquo;cognitive spectrum disorder&rsquo; (CSD) as any combination of delirium, known dementia, or Abbreviated Mental Test (AMT) score &lt; 8/10. Routine data for length of stay (LOS), mortality, and readmission were linked to examine associations with outcomes.&nbsp; Results&nbsp; A CSD was present in 38.5% of all patients admitted aged over 65, and in more than half of those aged over 85. Overall, 16.7% of older people admitted had delirium alone, 7.9% delirium superimposed on known dementia, 9.4% known dementia alone, and 4.5% unspecified cognitive impairment (AMT score &lt; 8/10, no delirium, no known dementia). Of those with known dementia, 45.8% had delirium superimposed. Outcomes were worse in those with CSD compared to those without &ndash; LOS 25.0 vs. 11.8 days, 30-day mortality 13.6% vs. 9.0%, 1-year mortality 40.0% vs. 26.0%, 1-year death or readmission 62.4% vs. 51.5% (allP &lt; 0.01). There was relatively little difference by CSD type, although people with delirium superimposed on dementia had the longest LOS, and people with dementia the worst mortality at 1 year.&nbsp; Conclusions&nbsp; CSD is common in older inpatients and associated with considerably worse outcomes, with little variation between different types of CSD. Healthcare systems should systematically identify and develop care pathways for older people with CSD admitted as medical emergencies, and avoid only focusing on condition-specific pathways such as those for dementia or delirium alone

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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods/Design</p> <p>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.</p> <p>Discussion</p> <p>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.</p> <p>Trial registration</p> <p>Dutch Clinical Trial Registry: <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1576">NTR1576</a></p

Genetic instability in lung cancer: concurrent analysis of chromosomal, mini- and microsatellite instability and loss of heterozygosity

To investigate what kind of genetic instability plays important roles in lung carcinogenesis, we analyzed micro- and minisatellite instability, loss of heterozygosity (LOH) and chromosome instability in 55 cases of lung cancer, including, 10 squamous cell, 5 large cell, and 3 small cell carcinomas, and 37 adenocarcinomas. Analysis of minisatellite instability, the mechanism of which is different from microsatellite instability, has not been reported previously. Minisatellite instability was detected in only one case (1/55, 1.8%), and the frequency of microsatellite instability was low, being found only in three cases (3/55, 5.5%). In contrast, LOH, for at least in one locus, was observed in 27 cases (49.1%). In adenocarcinomas, the frequency of LOH was higher in poorly differentiated compared to more differentiated carcinomas. For chromosome instability, a similar correlation between differentiation grade and instability was observed in adenocarcinomas. And instability was more common in large cell and small cell carcinomas than in adenocarcinomas. Our analysis showed that chromosome instability and LOH, rather than mini- and microsatellite instability, play significant roles in the development of lung cancer

Diagnoses, problems and healthcare interventions amongst older people with an unscheduled hospital admission who have concurrent mental health problems: a prevalence study

Background Frail older people with mental health problems including delirium, dementia and depression are often admitted to general hospitals. However, hospital admission may cause distress, and can be associated with complications. Some commentators suggest that their healthcare needs could be better met elsewhere. Methods We studied consecutive patients aged 70 or older admitted for emergency medical or trauma care to an 1800 bed general hospital which provided sole emergency medical and trauma services for its local population. Patients were screened for mental health problems, and those screening positive were invited to take part. 250 participants were recruited and a sub-sample of 53 patients was assessed by a geriatrician for diagnoses, impairments and disabilities, healthcare interventions and outstanding needs. Results Median age was 86 years, median Mini-Mental State Examination score at admission was 16/30, and 45% had delirium. 19% lived in a care home prior to admission. All the patients were complex. A wide range of main admission diagnoses was recorded, and these were usually complicated by falls, immobility, pain, delirium, dehydration or incontinence. There was a median of six active diagnoses, and eight active problems. One quarter of problems was unexplained. A median of 13 interventions was recorded, and a median of a further four interventions suggested by the geriatrician. Those with more severe cognitive impairment had no less medical need. Conclusions This patient group, admitted to hospital in the United Kingdom, had numerous healthcare problems, and by implication, extensive healthcare needs. Patients with simpler conditions were not identified, but may have already been rapidly discharged or redirected to non-hospital services by the time assessments were made. To meet the needs of this group outside the hospital would need considerable investment in medical, nursing, therapy and diagnostic facilities. In the meantime, acute hospitals should adapt to deliver comprehensive geriatric assessment, and provide for their mental health needs