Clinical Pharmacokinetic Monitoring of Free Valproic Acid Levels: A Systematic Review.

BACKGROUND: Current guidelines recommend therapeutic drug monitoring as a critical component of valproic acid (VPA) therapy. Due to high protein binding, the active unbound (free) portion of VPA can be misrepresented by total VPA serum levels in certain clinical scenarios. Monitoring free VPA serum levels may be warranted when assessing the clinical response to VPA therapy. OBJECTIVES: The aims were to conduct a systematic review to identify a therapeutic range for free VPA serum levels; to explore the correlation of free VPA serum levels with clinical toxicity and therapeutic benefit; and to examine predictors of discordance between free and total VPA levels. METHODS: Medline, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, BIOSIS Previews, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from the time of database inception to June 20, 2021. Randomized controlled trials and observational studies that evaluated any patient receiving VPA with free VPA level monitoring were included. RESULTS: Of 189 citations, we identified 27 relevant studies, which included 14 observational studies, two case series, and 11 case reports. Three studies provided a therapeutic range for free VPA levels between 20 and 410 µmol/L. Two studies suggested the occurrence of hyperammonemia and thrombocytopenia at free VPA serum levels above 60 µmol/L and 103.3 µmol/L, respectively. Two studies suggested an upper limit for neurotoxicity at free VPA serum levels of 70 µmol/L and 207.9 µmol/L. Hypoalbuminemia was identified as a predictor of therapeutic discordance. CONCLUSIONS: This review demonstrates a paucity of data informing the clinical utility of free VPA serum levels. Further high-quality trials are needed to validate an optimal therapeutic range for free VPA levels.

Temporal and external validation of the fullPIERS model for the prediction of adverse maternal outcomes in women with pre-eclampsia.

The fullPIERS model is a risk prediction model developed to predict adverse maternal outcomes within 48 h for women admitted with pre-eclampsia. External validation of the model is required before implementation for clinical use. We assessed the temporal and external validity of the fullPIERS model in high income settings using five cohorts collected between 2003 and 2016, from tertiary hospitals in Canada, the United States of America, Finland and the United Kingdom. The cohorts were grouped into three datasets for assessing the primary external, and temporal validity, and broader transportability of the model. The predicted risks of developing an adverse maternal outcome were calculated using the model equation and model performance was evaluated based on discrimination, calibration, and stratification. Our study included a total of 2429 women, with an adverse maternal outcome rate of 6.7%, 6.6%, and 7.0% in the primary external, temporal, and combined (broader) validation cohorts, respectively. The model had good discrimination in all datasets: 0.81 (95%CI 0.75-0.86), 0.82 (95%CI 0.76-0.87), and 0.75 (95%CI 0.71-0.80) for the primary external, temporal, and broader validation datasets, respectively. Calibration was best for the temporal cohort but poor in the broader validation dataset. The likelihood ratios estimated to rule in adverse maternal outcomes were high at a cut-off of ≥30% in all datasets. The fullPIERS model is temporally and externally valid and will be useful in the management of women with pre-eclampsia in high income settings although model recalibration is required to improve performance, specifically in the broader healthcare settings.

Labetalol for hypertension in pregnancy.

INTRODUCTION: Labetalol is one of the most commonly used antihypertensive medications for the treatment of hypertension during pregnancy, an increasingly common and leading cause of maternal mortality and morbidity worldwide. AREAS COVERED: The literature reviewed included the 2014 Canadian national pregnancy hypertension guideline and its references. The additional published literature was retrieved through searches of Medline, CINAHL, and The Cochrane Library using appropriate controlled vocabulary (e.g., pregnancy, hypertension, pre-eclampsia, pregnancy toxemias) and key words (e.g., diagnosis, evaluation, classification, prediction, prevention, prognosis, treatment, and postpartum follow-up).Results were restricted to systematic reviews, randomized controlled trials, controlled clinical trials, and observational studies published in French or English, Jan-Mar/14. The unpublished literature was identified by searching websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. We evaluated the impact of interventions on substantive clinical outcomes for mothers and babies. EXPERT OPINION: Labetalol is a reasonable choice for treatment of severe or non-severe hypertension in pregnancy. However, we should continue our search for other therapeutic options.