The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study: protocol for an international multicentre randomised controlled trial

Introduction: Postoperative delirium is one of the most common complications of major surgery, affecting 10–70% of surgical patients 60 years and older. Delirium is an acute change in cognition that manifests as poor attention and illogical thinking and is associated with longer intensive care unit (ICU) and hospital stay, long-lasting cognitive deterioration and increased mortality. Ketamine has been used as an anaesthetic drug for over 50 years and has an established safety record. Recent research suggests that, in addition to preventing acute postoperative pain, a subanaesthetic dose of intraoperative ketamine could decrease the incidence of postoperative delirium as well as other neurological and psychiatric outcomes. However, these proposed benefits of ketamine have not been tested in a large clinical trial. Methods: The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study is an international, multicentre, randomised controlled trial. 600 cardiac and major non-cardiac surgery patients will be randomised to receive ketamine (0.5 or 1 mg/kg) or placebo following anaesthetic induction and prior to surgical incision. For the primary outcome, blinded observers will assess delirium on the day of surgery (postoperative day 0) and twice daily from postoperative days 1–3 using the Confusion Assessment Method or the Confusion Assessment Method for the ICU. For the secondary outcomes, blinded observers will estimate pain using the Behavioral Pain Scale or the Behavioral Pain Scale for Non-Intubated Patients and patient self-report. Ethics and dissemination The PODCAST trial has been approved by the ethics boards of five participating institutions; approval is ongoing at other sites. Recruitment began in February 2014 and will continue until the end of 2016. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement and popular media. Registration details The study is registered at clinicaltrials.gov, NCT01690988 (last updated March 2014). The PODCAST trial is being conducted under the auspices of the Neurological Outcomes Network for Surgery (NEURONS). Trial registration number NCT01690988 (last updated December 2013)

Recovery of consciousness and cognition after general anesthesia in humans

Understanding how the brain recovers from unconsciousness can inform neurobiological theories of consciousness and guide clinical investigation. To address this question, we conducted a multicenter study of 60 healthy humans, half of whom received general anesthesia for 3 hr and half of whom served as awake controls. We administered a battery of neurocognitive tests and recorded electroencephalography to assess cortical dynamics. We hypothesized that recovery of consciousness and cognition is an extended process, with differential recovery of cognitive functions that would commence with return of responsiveness and end with return of executive function, mediated by prefrontal cortex. We found that, just prior to the recovery of consciousness, frontal-parietal dynamics returned to baseline. Consistent with our hypothesis, cognitive reconstitution after anesthesia evolved over time. Contrary to our hypothesis, executive function returned first. Early engagement of prefrontal cortex in recovery of consciousness and cognition is consistent with global neuronal workspace theory

Estimating malaria transmission intensity from Plasmodium falciparum serological data using antibody density models.

BACKGROUND: Serological data are increasingly being used to monitor malaria transmission intensity and have been demonstrated to be particularly useful in areas of low transmission where traditional measures such as EIR and parasite prevalence are limited. The seroconversion rate (SCR) is usually estimated using catalytic models in which the measured antibody levels are used to categorize individuals as seropositive or seronegative. One limitation of this approach is the requirement to impose a fixed cut-off to distinguish seropositive and negative individuals. Furthermore, the continuous variation in antibody levels is ignored thereby potentially reducing the precision of the estimate. METHODS: An age-specific density model which mimics antibody acquisition and loss was developed to make full use of the information provided by serological measures of antibody levels. This was fitted to blood-stage antibody density data from 12 villages at varying transmission intensity in Northern Tanzania to estimate the exposure rate as an alternative measure of transmission intensity. RESULTS: The results show a high correlation between the exposure rate estimates obtained and the estimated SCR obtained from a catalytic model (r = 0.95) and with two derived measures of EIR (r = 0.74 and r = 0.81). Estimates of exposure rate obtained with the density model were also more precise than those derived from catalytic models. CONCLUSION: This approach, if validated across different epidemiological settings, could be a useful alternative framework for quantifying transmission intensity, which makes more complete use of serological data

Arthroscopic rotator cuff repair with a fibrin scaffold containing growth factors and autologous progenitor cells derived from humeral cBMA improves clinical outcomes in high risk patients

PURPOSE: To report the clinical outcomes after biologically augmented rotator cuff repair (RCR) with a fibrin scaffold derived from autologous whole blood and supplemented with concentrated bone marrow aspirate (cBMA) harvested at the proximal humerus. METHODS: Patients who underwent arthroscopic RCR with biologic augmentation using a fibrin clot scaffold (“Mega- Clot”) containing progenitor cells and growth factors from proximal humerus BMA and autologous whole blood between April 2015 and January 2018 were prospectively followed. Only high-risk patients in primary and revision cases that possessed relevant comorbidities or physically demanding occupation were included. Minimum follow-up for inclusion was 1 year. The visual analog score for pain (VAS), American Shoulder and Elbow Surgeons (ASES), Simple Shoulder Test (SST), Single Assessment Numerical Evaluation (SANE), and Constant-Murley scores were collected preoperatively and at final follow-up. In vitro analyses of the cBMA and fibrin clot using nucleated cell count, colony forming units, and live/dead assays were used to quantify the substrates. RESULTS: Thirteen patients (56.9 ± 7.7 years) were included. The mean follow-up was 26.9 ± 17.7 months (n = 13). There were significant improvements in all outcome scores from the preoperative to the postoperative state: VAS (5.6 ± 2.5 to 3.1 ± 3.2; P < .001), ASES (42.0 ± 17.1 to 65.5 ± 30.6; P < .001), SST (3.2 ± 2.8 to 6.5 ± 4.7; P = .002), SANE (11.5 ± 15.6 to 50.3 ± 36.5; P < .001), and Constant-Murley (38.9 ± 17.5 to 58.1 ± 26.3; P < .001). Six patients (46%) had retears on postoperative MRI, despite all having improvements in pain and function except one. All failures were chronic rotator cuff tears, and all were revision cases except one (1.6 ± 0.5 previous RCRs). The representative sample of harvested cBMA showed an average of 28.5 ± 9.1 × 10(6) nucleated cells per mL. CONCLUSIONS: Arthroscopic rotator cuff repairs that are biologically augmented with a fibrin scaffold containing growth factors and autologous progenitor cells derived from autologous whole blood and humeral cBMA can improve clinical outcomes in primary, as well as revision cases in high-risk patients. However, the incidence of retears remains a concern in this population, demanding further improvements in biologic augmentation. LEVEL OF EVIDENCE: IV, therapeutic case series

Evaluation of the 3-Minute Diagnostic Confusion Assessment Method for identification of postoperative delirium in older patients

Importance: Delirium is a common postoperative complication in older patients that often goes undetected and might lead to worse outcomes. The 3-Minute Diagnostic Confusion Assessment Method (3D-CAM) might be a practical tool for routine clinical diagnosis of delirium. Objective: To assess the 3D-CAM for detecting postoperative delirium compared with the long-form CAM used for research purposes. Design, Setting, and Participants: This cohort study of older patients enrolled in ongoing clinical trials between 2015 and 2018 was conducted at a single tertiary US hospital. Included participants were aged 60 years or older undergoing major elective surgical procedures that required at least a 2-day hospital stay. Data were analyzed between February and April 2019. Exposures: Surgical procedures of at least 2 hours in length requiring general anesthesia with planned extubation. Main Outcomes and Measures: Patients were concurrently assessed for delirium using the 3D-CAM assessment and the long-form CAM, scored based on a standardized cognitive assessment. Agreement between these 2 methods was tested using Cohen κ with repeated measures, a generalized linear mixed-effects model, and Bland-Altman analysis. Results: Sixteen raters conducted 471 concurrent CAM and 3D-CAM interviews including 299 patients (mean [SD] age, 69 [6.5] years), the majority of whom were men (152 [50.8%]), were White (263 [88.0%]), and had noncardiac operations (211 [70.6%]). Both instruments had good intraclass correlation (0.84 for the CAM and 0.98 for the 3D-CAM). Cohen κ demonstrated good overall agreement between the CAM and 3D-CAM (κ = 0.71; 95% CI, 0.58 to 0.83). According to the mixed-effects model, there was statistically significant disagreement between the 3D-CAM and CAM (estimated difference in fixed effect, -0.68; 95% CI, -1.32 to -0.05; P = .04). Bland-Altman analysis showed the probability of a delirium diagnosis with the 3D-CAM was more than twice the probability of a delirium diagnosis with the CAM (probability ratio, 2.78; 95% CI, 2.44 to 3.23). Conclusions and Relevance: The 3D-CAM instrument demonstrated agreement with the long-form CAM and might provide a pragmatic and sensitive clinical tool for detecting postoperative delirium, with the caveat that the 3D-CAM might overdiagnose delirium

Ability of postoperative delirium to predict intermediate-term postoperative cognitive function in patients undergoing elective surgery at an academic medical centre: protocol for a prospective cohort study

IntroductionPostoperative delirium (POD) is a common complication in elderly patients, characterised by a fluctuating course of altered consciousness, disordered thinking and inattention. Preliminary research has linked POD with persistent cognitive impairment and decreased quality of life. However, these findings maybe confounded by patient comorbidities, postoperative complications and frailty. Our objective is to determine whether POD is an independent risk factor for persistent impairments in attention and executive function after elective surgery. Our central hypothesis is that patients with POD are more likely to have declines in cognition and quality of life 1 year after surgery compared with patients without POD. We aim to clarify whether these associations are independent of potentially confounding factors. We will also explore the association between POD and incident dementia.Methods and analysisThis study will recruit 200 patients from the ongoing Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) study. Patients who live ≤45 miles from the study centre or have a planned visit to the centre 10–16 months postoperatively will be eligible. Patients with POD, measured by the Confusion Assessment Method, will be compared with patients without delirium. The primary outcome of cognitive function and secondary outcomes of quality of life and incident dementia will be compared between cohorts. Cognition will be measured by Trails A and B and Stroop Color and Word Test, quality of life with Veteran’s RAND 12-item Health Survey and incident dementia with the Short Blessed Test. Multivariable regression analyses and a Cox proportional hazards analysis will be performed. All results will be reported with 95% CIs and α=0.05.Ethics and disseminationThe study has been approved by the Washington University in St. Louis Institutional Review Board (IRB no 201601099). Plans for dissemination include scientific publications and presentations at scientific conferences.Trial registration numberNCT02241655.</jats:sec