Frailty measurement and outcomes in interventional studies: protocol for a systematic review of randomised control trials.

INTRODUCTION: Frailty is associated with reduced functional capacity, decreased resistance to stressors and is predictive of a range of adverse health outcomes, including dependency, hospitalisation and mortality. Early identification of frailty may prevent, reduce and postpone adverse health outcomes. However, there is a need for additional evidence to guide decision-making for the care of frail patients since frail persons are frequently excluded from studies, the differential impact of frailty is often not examined in clinical trials and few large-scale clinical trials examining frail cohorts have been conducted. Randomised control trials (RCTs) published to date have used a diverse range of definitions of frailty, as well as a variety of outcome measures. The objective of this systematic review is to comprehensively characterise the frail populations enrolled and the end points reported in frailty RCTs. METHODS AND ANALYSIS: We will identify all RCTs reporting on the outcome of interventions in adult (age ≥18 years) frail populations as defined by authors, in all settings of care. Databases will include MEDLINE, CINAHL, EMBASE, PsycInfo, Global Health, the Joanna Briggs database and Cochrane Library. Two reviewers will independently determine trial eligibility. For each included trial, we will conduct duplicate independent data extraction, inter-rater reliability, risk of bias assessment and evaluation of the quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach. ETHICS AND DISSEMINATION: This systematic review will comprehensively identify RCTs including frail patients to identify how frailty is measured and which outcomes are reported. The results of this systematic review may inform clinicians caring for persons with frailty, facilitate conduct of future RCTs and inform future efforts to develop common data elements and core outcomes for frailty studies. Our findings will be disseminated through conference presentation and publication in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42017065233.

Stepwise Rostrocaudal Brainstem Anesthesia as a Complication of Local Anesthesia: A Case Report.

Iatrogenic cranial nerve palsies can rarely complicate neurosurgical, oral maxillofacial, and otolaryngological procedures. Among the most serious complications of cranial nerve palsy is upper airway obstruction, which is life threatening. We present a case of multiple cranial nerve palsies evolving rapidly in a rostrocaudal stepwise fashion after infiltration of lidocaine to repair a cerebrospinal fluid leak in a patient postoccipital craniectomy. This led to hypoxic respiratory failure requiring mechanical ventilation before resolving spontaneously. This is the first known case of accidental brainstem anesthesia secondary to lidocaine infiltration at an occipital craniectomy site and serves to caution clinicians who manage similar patients.

The impact of frailty on intensive care unit outcomes: a systematic review and meta-analysis.

PURPOSE: Functional status and chronic health status are important baseline characteristics of critically ill patients. The assessment of frailty on admission to the intensive care unit (ICU) may provide objective, prognostic information on baseline health. To determine the impact of frailty on the outcome of critically ill patients, we performed a systematic review and meta-analysis comparing clinical outcomes in frail and non-frail patients admitted to ICU. METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PubMed, CINAHL, and Clinicaltrials.gov. All study designs with the exception of narrative reviews, case reports, and editorials were included. Included studies assessed frailty in patients greater than 18 years of age admitted to an ICU and compared outcomes between fit and frail patients. Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. The primary outcomes were hospital and long-term mortality. We also determined the prevalence of frailty, the impact on other patient-centered outcomes such as discharge disposition, and health service utilization such as length of stay. RESULTS: Ten observational studies enrolling a total of 3030 patients (927 frail and 2103 fit patients) were included. The overall quality of studies was moderate. Frailty was associated with higher hospital mortality [relative risk (RR) 1.71; 95% CI 1.43, 2.05; p < 0.00001; I 2 = 32%] and long-term mortality (RR 1.53; 95% CI 1.40, 1.68; p < 0.00001; I 2 = 0%). The pooled prevalence of frailty was 30% (95% CI 29-32%). Frail patients were less likely to be discharged home than fit patients (RR 0.59; 95% CI 0.49, 0.71; p < 0.00001; I 2 = 12%). CONCLUSIONS: Frailty is common in patients admitted to ICU and is associated with worsened outcomes. Identification of this previously unrecognized and vulnerable ICU population should act as the impetus for investigating and implementing appropriate care plans for critically ill frail patients. Registration: PROSPERO (ID: CRD42016053910).

A 2015 Update on Ventilator-Associated Pneumonia: New Insights on Its Prevention, Diagnosis, and Treatment.

Ventilator-associated pneumonia (VAP), an infection of the lower respiratory tract which occurs in association with mechanical ventilation, is one of the most common causes of nosocomial infection in the intensive care unit (ICU). VAP causes significant morbidity and mortality in critically ill patients including increased duration of mechanical ventilation, ICU stay and hospitalization. Current knowledge for its prevention, diagnosis and management is therefore important clinically and is the basis for this review. We discuss recent changes in VAP surveillance nomenclature incorporating ventilator-associated conditions and ventilator-associated events, terms recently proposed by the Centers for Disease Control. To the extent possible, we rely predominantly on data from randomized control trials (RCTs) and meta-analyses.

Recombinant and plasma-derived factor VIII products induce distinct splenic cytokine microenvironments in hemophilia A mice.

The use of plasma-derived factor VIII (pdFVIII) concentrates in hemophilia A has been reported to result in reduced anti-FVIII antibody formation. In this study, we have investigated whether the cytokine microenvironment induced by pdFVIII has an influence on reducing anti-FVIII antibody titers in hemophilic mice. Microarray and confirmatory quantitative reverse transcription polymerase chain reaction (RT-PCR) experiments show that pdFVIII infusion causes a different transcriptional profile in dendritic cells than recombinant FVIII (rFVIII). Both treatments caused up-regulation of proinflammatory gene expression, but rFVIII and pdFVIII treatments promote expression of genes that induce Th1 and Th2 responses, respectively. Moreover, administration of rFVIII or pdFVIII concentrates resulted in distinct T-cell splenic cytokine microenvironments. rFVIII induced the release of Th1 cytokines and IL-10, whereas pdFVIII induced the release of Th2 cytokines and transforming growth factor-beta. We have also observed high titers of anti-human von Willebrand factor (VWF) antibodies in the pdFVIII-treated mice and propose that this results from antigenic competition. We further investigated the role of this phenomenon using infusions of FVIII and increasing concentrations of recombinant human factor IX (FIX). These studies show an inverse relationship between increasing concentrations of FIX and the production of anti-FVIII antibodies. In summary, these studies report new mechanisms that contribute to reduced anti-FVIII antibody development in hemophilia A after pdFVIII infusions.

Anti-CD3 prevents factor VIII inhibitor development in hemophilia A mice by a regulatory CD4+CD25+-dependent mechanism and by shifting cytokine production to favor a Th1 response.

Non-Fc-receptor binding anti-CD3 Ab therapy, in the setting of several different autoimmune disorders, can induce antigen-specific and long-lasting immunologic tolerance. Because factor VIII (FVIII) inhibitor formation is the most serious treatment-related complication for hemophilia A patients, we tested the efficacy of anti-CD3 to prevent FVIII inhibitor formation in hemophilia A BALB/c and C57BL/6 mice. A short course of low-dose anti-CD3 significantly increased expression of CD25 and the proportion of CD4+CD25+ regulatory T cells in the spleen and potently prevented the production of inhibitory and non-neutralizing anti-FVIII antibodies in both strains of mouse. Depleting the CD4+CD25+ cells during anti-CD3 therapy completely ablated tolerance to FVIII. Further phenotypic characterization of regulatory cells in tolerant mice showed a consistently higher number of CD4+GITR+ and CD4+FoxP3+ cells in both strains of mice. In addition, in tolerant C57BL/6 mice we observed an increase in CD4+CD25+ CTLA-4+ and CD4+CD25+mTGF-beta1+ cells. Finally, in vitro cytokine profiling demonstrated that splenocytes from tolerant BALB/c and C57BL/6 were polarized toward a Th1-immune response. Taken together, these findings indicate that anti-CD3 induces tolerance to FVIII and that the mechanism(s) regulating this response almost certainly occurs through the generation of several distinct regulatory T-cell lineages and by influencing cytokine production and profile.