Two-center experience of cannabidiol use in adults with Dravet syndrome

We describe real-world experience with cannabidiol (CBD) in adults with Dravet Syndrome (DS) via GW Pharma early access programme at two UK neurology centres. Adults with genetically-confirmed DS had CBD added to existing therapy, titrated up to 20 mg/kg, as tolerated. The primary outcome measure was percentage reduction in convulsive seizures. Secondary outcome measures included changes in myoclonic seizures, and in cognition and quality of life as assessed by the Caregiver Global Impression of Change (CGIC), and incidence of adverse events (AEs). 18 adults (7 female; median age 27.5 years; range 20–51) were included. Median follow-up was 176 days. In one, another antiseizure drug, clobazam, was introduced during the programme. 3/17 (17.6%) had >30% reduction in convulsive seizures (range: 87.5–100%). AEs occurred in all, the most common being transaminitis (52.9%). Behavioural AEs led to discontinuation in 3/18 (16.7%), including a seizure-free responder. In 7/18, CBD was stopped due to lack of effect. 8/18 continue on treatment. Improvements in CGIC were reported in 41.2% and 47.1% by physicians and families, respectively. 17.6% achieved sufficient reduction in convulsive seizure frequency to qualify for NHS funding. AEs led to withdrawal in only 16.7%. Close monitoring and dose adjustments of other antiseizure drugs were necessary

Effect of individual patient risk, centre, surgeon and anaesthetist on length of stay in hospital after cardiac surgery: Association of Cardiothoracic Anaesthesia and Critical Care (ACTACC) consecutive cases series study of 10 UK specialist centres.

OBJECTIVES: To determine the relative contributions of patient risk profile, local and individual clinical practice on length of hospital stay after cardiac surgery. DESIGN: Ten-year audit of prospectively collected consecutive cardiac surgical cases. Case-mix adjusted outcomes were analysed in models that included random effects for centre, surgeon and anaesthetist. SETTING: UK centres providing adult cardiac surgery. PARTICIPANTS: 10 of 36 UK specialist centres agreed to provide outcomes for all major cardiac operations over 10 years. After exclusions (duplicates, cases operated by more than one consultant, deaths and procedures for which the EuroSCORE risk score for cardiac surgery is not appropriate), there were 107 038 cardiac surgical procedures between April 2002 and March 2012, conducted by 127 consultant surgeons and 190 consultant anaesthetists. MAIN OUTCOME MEASURE: Length of stay (LOS) up to 3 months postoperatively. RESULTS: The principal component of variation in outcomes was patient risk (represented by the EuroSCORE and remaining patient heterogeneity), accounting for 95.43% of the variation for postoperative LOS. The impact of the surgeon and centre was moderate (intra-class correlation coefficients ICC=2.79% and 1.59%, respectively), whereas the impact of the anaesthetist was negligible (ICC=0.19%). Similarly, 96.05% of the variation for prolonged LOS (>11 days) was attributable to the patient, with surgeon and centre less but still influential components (ICC=2.12% and 1.66%, respectively, 0.17% only for anaesthetists). Adjustment for year of operation resulted in minor reductions in variation attributable to surgeons (ICC=2.52% for LOS and 2.23% for prolonged LOS). CONCLUSIONS: Patient risk profile is the primary determinant of variation in LOS, and as a result, current initiatives to reduce hospital stay by modifying consultant performance are unlikely to have a substantial impact. Therefore, substantially reducing hospital stay requires shifting away from a one-size-fits-all approach to cardiac surgery, and seeking alternative treatment options personalised to high-risk patients

Creatinine clearance versus serum creatinine as a risk factor in cardiac surgery

BACKGROUND: Renal impairment is one of the predictors of mortality in cardiac surgery. Usually a binarized value of serum creatinine is used to assess the renal function in risk models. Creatinine clearance can be easily estimated by the Cockcroft and Gault equation from serum creatinine, gender, age and body weight. In this work we examine whether this estimation of the glomerular filtration rate can advantageously replace the serum creatinine in the EuroSCORE preoperative risk assessment. METHODS: In a group of 8138 patients out of a total of 11878 patients, who underwent cardiac surgery in our hospital between January 1996 and July 2002, the 18 standard EuroSCORE parameters could retrospectively be determined and logistic regression analysis performed. In all patients scored, creatinine clearance was calculated according to Cockcroft and Gault. The relationship between the predicted and observed 30-days mortality was evaluated in systematically selected intervals of creatinine clearance and significance values computed by employing Monte Carlo methods. Afterwards, risk scoring was performed using a continuous or a categorical value of creatinine clearance instead of serum creatinine. The predictive ability of several risk score models and the individual contribution of their predictor variables were studied using ROC curve analysis. RESULTS: The comparison between the expected and observed 30-days mortalities, which were determined in different intervals of creatinine clearance, revealed the best threshold value of 55 ml/min. A significantly higher 30-days mortality was observed below this threshold and vice versa (both with p < 0.001). The local adaptation of the EuroSCORE is better than the standard EuroSCORE and was further improved by replacing serum creatinine (SC) by creatinine clearance (CC). Differential ROC analysis revealed that CC is superior to SC in providing predictive power within the logistic regression. Variable rank comparison identified CC as the best single variable predictor, even better than the variable age, former number 1, and SC, previously number 9 in the standard set of EuroSCORE variables. CONCLUSION: The renal function is an important determinant of mortality in heart surgery. This risk factor is not well captured in the standard EuroSCORE risk evaluation system. Our study shows that creatinine clearance, calculated according to the Cockcroft and Gault equation, should be applied to estimate the preoperative renal function instead of serum creatinine. This predictor variable replacement gains a significant improvement in the predictive accuracy of the scoring model

Qualitative insights into the feelings, knowledge, and impact of SUDEP: A narrative synthesis

People with epilepsy (PWE) have a two- to threefold increased chance of premature death due to the condition. Interested in exploring the first-person perspective on this topic, we conducted a narrative synthesis to present the qualitative insight of PWE, their family, friends, and healthcare providers (HCPs) in relation to epilepsy-related death. A comprehensive electronic search of all peer-reviewed qualitative studies was conducted through databases using relevant keywords and Medical Subject Headings (MeSH) terms. Handsearching and exploration of pertinent gray literature was conducted thereafter. After a comprehensive literature search, the decisions of inclusion of literature were discussed and confirmed between the two authors. A total of 20 peer-reviewed papers were included. Within this, 17 were qualitative or mixed methods studies, and three were gray literature and guidelines/recommendations in discussing sudden unexpected death in epilepsy (SUDEP) with PWE and their families. The resultant main categories were the following: a) understanding of SUDEP and b) discussion of SUDEP. Findings show that there is an overall lack of understanding of unexpected epilepsy-related death for PWE and their relations. The literature focused on the education of PWE and their family in relation to SUDEP, and therefore, there is a lack of discussion on the general topic of epilepsy-related death. Findings show the conflicting perceptions, feelings, and thought processes that occur in learning about and deciding to discuss SUDEP as a HCP, PWE, or family/friend of a PWE. The literature suggests that it would be appropriate and necessary to discuss the topic of SUDEP with patients and their family members upon diagnosis

Cognitive behavioural therapy for adults with dissociative seizures (CODES): a pragmatic, multicentre, randomised controlled trial.

BACKGROUND: Dissociative seizures are paroxysmal events resembling epilepsy or syncope with characteristic features that allow them to be distinguished from other medical conditions. We aimed to compare the effectiveness of cognitive behavioural therapy (CBT) plus standardised medical care with standardised medical care alone for the reduction of dissociative seizure frequency. METHODS: In this pragmatic, parallel-arm, multicentre randomised controlled trial, we initially recruited participants at 27 neurology or epilepsy services in England, Scotland, and Wales. Adults (≥18 years) who had dissociative seizures in the previous 8 weeks and no epileptic seizures in the previous 12 months were subsequently randomly assigned (1:1) from 17 liaison or neuropsychiatry services following psychiatric assessment, to receive standardised medical care or CBT plus standardised medical care, using a web-based system. Randomisation was stratified by neuropsychiatry or liaison psychiatry recruitment site. The trial manager, chief investigator, all treating clinicians, and patients were aware of treatment allocation, but outcome data collectors and trial statisticians were unaware of treatment allocation. Patients were followed up 6 months and 12 months after randomisation. The primary outcome was monthly dissociative seizure frequency (ie, frequency in the previous 4 weeks) assessed at 12 months. Secondary outcomes assessed at 12 months were: seizure severity (intensity) and bothersomeness; longest period of seizure freedom in the previous 6 months; complete seizure freedom in the previous 3 months; a greater than 50% reduction in seizure frequency relative to baseline; changes in dissociative seizures (rated by others); health-related quality of life; psychosocial functioning; psychiatric symptoms, psychological distress, and somatic symptom burden; and clinical impression of improvement and satisfaction. p values and statistical significance for outcomes were reported without correction for multiple comparisons as per our protocol. Primary and secondary outcomes were assessed in the intention-to-treat population with multiple imputation for missing observations. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN05681227, and ClinicalTrials.gov, NCT02325544. FINDINGS: Between Jan 16, 2015, and May 31, 2017, we randomly assigned 368 patients to receive CBT plus standardised medical care (n=186) or standardised medical care alone (n=182); of whom 313 had primary outcome data at 12 months (156 [84%] of 186 patients in the CBT plus standardised medical care group and 157 [86%] of 182 patients in the standardised medical care group). At 12 months, no significant difference in monthly dissociative seizure frequency was identified between the groups (median 4 seizures [IQR 0-20] in the CBT plus standardised medical care group vs 7 seizures [1-35] in the standardised medical care group; estimated incidence rate ratio [IRR] 0·78 [95% CI 0·56-1·09]; p=0·144). Dissociative seizures were rated as less bothersome in the CBT plus standardised medical care group than the standardised medical care group (estimated mean difference -0·53 [95% CI -0·97 to -0·08]; p=0·020). The CBT plus standardised medical care group had a longer period of dissociative seizure freedom in the previous 6 months (estimated IRR 1·64 [95% CI 1·22 to 2·20]; p=0·001), reported better health-related quality of life on the EuroQoL-5 Dimensions-5 Level Health Today visual analogue scale (estimated mean difference 6·16 [95% CI 1·48 to 10·84]; p=0·010), less impairment in psychosocial functioning on the Work and Social Adjustment Scale (estimated mean difference -4·12 [95% CI -6·35 to -1·89]; p<0·001), less overall psychological distress than the standardised medical care group on the Clinical Outcomes in Routine Evaluation-10 scale (estimated mean difference -1·65 [95% CI -2·96 to -0·35]; p=0·013), and fewer somatic symptoms on the modified Patient Health Questionnaire-15 scale (estimated mean difference -1·67 [95% CI -2·90 to -0·44]; p=0·008). Clinical improvement at 12 months was greater in the CBT plus standardised medical care group than the standardised medical care alone group as reported by patients (estimated mean difference 0·66 [95% CI 0·26 to 1·04]; p=0·001) and by clinicians (estimated mean difference 0·47 [95% CI 0·21 to 0·73]; p<0·001), and the CBT plus standardised medical care group had greater satisfaction with treatment than did the standardised medical care group (estimated mean difference 0·90 [95% CI 0·48 to 1·31]; p<0·001). No significant differences in patient-reported seizure severity (estimated mean difference -0·11 [95% CI -0·50 to 0·29]; p=0·593) or seizure freedom in the last 3 months of the study (estimated odds ratio [OR] 1·77 [95% CI 0·93 to 3·37]; p=0·083) were identified between the groups. Furthermore, no significant differences were identified in the proportion of patients who had a more than 50% reduction in dissociative seizure frequency compared with baseline (OR 1·27 [95% CI 0·80 to 2·02]; p=0·313). Additionally, the 12-item Short Form survey-version 2 scores (estimated mean difference for the Physical Component Summary score 1·78 [95% CI -0·37 to 3·92]; p=0·105; estimated mean difference for the Mental Component Summary score 2·22 [95% CI -0·30 to 4·75]; p=0·084), the Generalised Anxiety Disorder-7 scale score (estimated mean difference -1·09 [95% CI -2·27 to 0·09]; p=0·069), and the Patient Health Questionnaire-9 scale depression score (estimated mean difference -1·10 [95% CI -2·41 to 0·21]; p=0·099) did not differ significantly between groups. Changes in dissociative seizures (rated by others) could not be assessed due to insufficient data. During the 12-month period, the number of adverse events was similar between the groups: 57 (31%) of 186 participants in the CBT plus standardised medical care group reported 97 adverse events and 53 (29%) of 182 participants in the standardised medical care group reported 79 adverse events. INTERPRETATION: CBT plus standardised medical care had no statistically significant advantage compared with standardised medical care alone for the reduction of monthly seizures. However, improvements were observed in a number of clinically relevant secondary outcomes following CBT plus standardised medical care when compared with standardised medical care alone. Thus, adults with dissociative seizures might benefit from the addition of dissociative seizure-specific CBT to specialist care from neurologists and psychiatrists. Future work is needed to identify patients who would benefit most from a dissociative seizure-specific CBT approach. FUNDING: National Institute for Health Research, Health Technology Assessment programme

The European System for Cardiac Operative Risk Evaluation (EuroSCORE) is not appropriate for withholding surgery in high-risk patients with aortic stenosis: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>The European System for Cardiac Operative Risk Evaluation (EuroSCORE) is a widely used risk assessment tool in patients with severe aortic stenosis to determine operability and to select patients for alternative therapies such as transcatheter aortic valve implantation. The objective of this study was to determine the accuracy of the EuroSCORE in predicting mortality following aortic valve replacement (AVR).</p> <p>Methods</p> <p>The logistic EuroSCORE was determined for all consecutive patients that underwent conventional AVR between 1995 and 2005 at our institution. Provincial Vital Statistics were used to determine all-cause mortality. The accuracy of the prognostic risk prediction provided by logistic EuroSCORE was assessed by comparing observed and expected operative mortality.</p> <p>Results</p> <p>During the study period, a total of 1,421 patients underwent AVR including 237 patients (16.7%) that had a logistic EuroSCORE > 20. Among these patients, the mean predicted operative mortality was 38.7% (SD = 18.1). The actual mortality of these patients was significantly lower than that predicted by EuroSCORE (11.4% vs. 38.7%, observed/expected ratio 0.29, 95% CI 0.15–0.52, P < 0.05). The EuroSCORE overestimated mortality within all strata of predicted risk. Although medium-term mortality is significantly higher among patients with EuroSCORE > 20 (log rank P = 0.0001), approximately 60% are alive at five years.</p> <p>Conclusion</p> <p>Actual operative mortality in patients undergoing AVR is significantly lower than that predicted by the logistic EuroSCORE. Additionally, medium-term survival following AVR is acceptable in high-risk patients with EuroSCORE > 20. More accurate risk prediction models are needed for risk-stratifying patients with severe aortic stenosis.</p

Amaze: a double-blind, multicentre randomised controlled trial to investigate the clinical effectiveness and cost-effectiveness of adding an ablation device-based maze procedure as an adjunct to routine cardiac surgery for patients with pre-existing atrial fibrillation

Background: Atrial fibrillation (AF) can be treated using a maze procedure during planned cardiac surgery, but the effect on clinical patient outcomes, and the cost-effectiveness compared with surgery alone, are uncertain. Objectives: To determine whether or not the maze procedure is safe, improves clinical and patient outcomes and is cost-effective for the NHS in patients with AF. Design: Multicentre, Phase III, pragmatic, double-blind, parallel-arm randomised controlled trial. Patients were randomised on a 1 : 1 basis using random permuted blocks, stratified for surgeon and planned procedure. Setting: Eleven acute NHS specialist cardiac surgical centres. Participants: Patients aged ≥ 18 years, scheduled for elective or in-house urgent cardiac surgery, with a documented history (> 3 months) of AF. Interventions: Routine cardiac surgery with or without an adjunct maze procedure administered by an AF ablation device. Main outcome measures: The primary outcomes were return to sinus rhythm (SR) at 12 months and quality-adjusted life-years (QALYs) over 2 years after randomisation. Secondary outcomes included return to SR at 2 years, overall and stroke-free survival, drug use, quality of life (QoL), cost-effectiveness and safety. Results: Between 25 February 2009 and 6 March 2014, 352 patients were randomised to the control (n = 176) or experimental (n = 176) arms. The odds ratio (OR) for return to SR at 12 months was 2.06 [95% confidence interval (CI) 1.20 to 3.54; p = 0.0091]. The mean difference (95% CI) in QALYs at 2 years between the two trial arms (maze/control) was –0.025 (95% CI 0.129 to 0.078; p = 0.6319). The OR for SR at 2 years was 3.24 (95% CI 1.76 to 5.96). The number of patients requiring anticoagulant drug use was significantly lower in the maze arm from 6 months after the procedure. There were no significant differences between the two arms in operative or overall survival, stroke-free survival, need for cardioversion or permanent pacemaker implants, New York Heart Association Functional Classification (for heart failure), EuroQol-5 Dimensions, three-level version score and Short Form questionnaire-36 items score at any time point. Sixty per cent of patients in each trial arm had a serious adverse event (p = 1.000); most events were mild, but 71 patients (42.5%) in the maze arm and 84 patients (45.5%) in the control arm had moderately severe events; 31 patients (18.6%) in the maze arm and 38 patients (20.5%) in the control arm had severe events. The mean additional cost of the maze procedure was £3533 (95% CI £1321 to £5746); the mean difference in QALYs was –0.022 (95% CI –0.1231 to 0.0791). The maze procedure was not cost-effective at £30,000 per QALY over 2 years in any analysis. In a small substudy, the active left atrial ejection fraction was smaller than that of the control patients (mean difference of –8.03, 95% CI –12.43 to –3.62), but within the predefined clinically equivalent range. Limitations: Low recruitment, early release of trial summaries and intermittent resource-use collection may have introduced bias and imprecise estimates. Conclusions: Ablation can be practised safely in routine NHS cardiac surgical settings and increases return to SR rates, but not survival or QoL up to 2 years after surgery. Lower anticoagulant drug use and recovery of left atrial function support anticoagulant drug withdrawal provided that good atrial function is confirmed. Further work: Continued follow-up and long-term clinical effectiveness and cost-effectiveness analysis. Comparison of ablation methods. Trial registration: Current Controlled Trials ISRCTN82731440.NIHR Health Technology Assessment programm