ObjectiveTo evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome.MethodsPatients aged 4–10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol). Safety assessments were clinical laboratory tests, physical examinations, vital signs, ECGs, adverse events (AEs), seizure frequency, and suicidality.ResultsThirty-four patients were randomized (10, 8, and 9 to the 5, 10, and 20 mg/kg/d CBD groups, and 7 to placebo); 32 (94%) completed treatment. Exposure to CBD and its metabolites was dose-proportional (AUC0–t). CBD did not affect concomitant AED levels, apart from an increase in N-CLB (except in patients taking stiripentol). The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury and all recovered. No other clinically relevant safety signals were observed.ConclusionsExposure to CBD and its metabolites increased proportionally with dose. An interaction with N-CLB was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. CBD resulted in more AEs than placebo but was generally well-tolerated.Classification of evidenceThis study provides Class I evidence that for children with Dravet syndrome, CBD resulted in more AEs than placebo but was generally well-tolerated.

We conducted a literature review of the intensive care unit-acquired weakness syndromes (critical illness polyneuropathy, critical illness myopathy and critical illness neuromyopathy) with the primary objective of determining their incidence as a combined group. Studies were identified through MEDLINE, Embase, Cochrane Database and article reference list searches and were included if they evaluated the incidence of one or more of these conditions in an adult intensive care unit population. The incidence of an intensive care unit-acquired weakness syndrome in the included studies was 40% (1080/2686 patients, 95% confidence interval 38-42%). The intensive care unit populations included were heterogeneous though largely included patients receiving mechanical ventilation for seven or more days. Additional prespecified outcomes identified that the incidence of intensive care unit-acquired weakness varied with the diagnostic technique used, being lower with clinical (413/1276, 32%, 95% CI 30-35%) compared to electrophysiological techniques (749/1591, 47%, 95% CI 45-50%). Approximately a quarter of patients were not able to comply with clinical evaluation and this may be responsible for potential underreporting of this condition.

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in Clinical Guideline 83: Rehabilitation after critical illness has set challenging recommendations regarding the routine evaluation for, and provision of, rehabilitation within critical care units. There is no published information regarding current practice in the UK. To establish current practice in Scotland we undertook a telephone survey of all 23 Scottish ICU lead clinicians and physiotherapists -96% of lead clinicians and 100% of lead physiotherapists completed the survey. Routine assessment for physical (median two (IQR 1-3 [range 0-4])) and non-physical sequelae (median zero (IQR 0-2 [range 0-5])) is low. Aproximately half of ICUs (52%) provide an individualised, structured rehabilitation programme, 32% include activities of daily living and all provide low intensity rehabilitation (eg limb stretching and positioning exercises). There are significant differences (all p<0.05) in the number of units routinely providing more intensive rehabilitation (eg mobilising) while patients have an endotracheal tube versus once extubated.

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Summary When developing a new medicine for children, the potential to extrapolate from adult efficacy data is well recognized. However, significant assumptions about the similarity of adults and children are needed for extrapolations to be biologically plausible. One such assumption is that of similar exposure–response (E–R‐) relationships. Motivated by applications to antiepileptic drug development, we consider how data that are available from existing trials of adults and adolescents can be used to quantify prior uncertainty about whether E–R‐relationships are similar in adults and younger children. A Bayesian multivariate meta‐analytic model is fitted to existing E–R‐data and adjusted for external biases that arise because these data are not perfectly relevant to the comparison of interest. We propose a strategy for eliciting expert prior opinion on external biases. From the bias‐adjusted meta‐analysis, we derive prior distributions quantifying our uncertainty about the degree of similarity between E–R‐relationships for adults and younger children. Using these we calculate the prior probability that average pharmacodynamic responses in adults and younger children, both on placebo and at an effective concentration, are sufficiently similar to justify a complete extrapolation of efficacy data. A simulation study is performed to evaluate the operating characteristics of the approach proposed.