Instituting Surveillance Guidelines and Adverse Outcomes in Preeclampsia

OBJECTIVE: To assess the incidence of combined adverse maternal and perinatal outcomes in women with preeclampsia before and after introducing standardized assessment and surveillance. METHODS: This study was a preintervention (retrospective) compared with a postintervention (prospective) cohort comparison in a single-tertiary, perinatal unit that included women admitted to hospital with preeclampsia. We interrogated an existing retrospective 24-month database and then introduced the guidelines, assessing the incidence of the combined adverse maternal and perinatal outcomes for 41 months (September 2003 through February 2007). Tests of organ (dys)function were performed at least as often as on the day of admission, admission day ؉1, every Monday and Thursday, day of delivery, and delivery day ؉1. All data were checked for errors. The combined maternal outcome was maternal death or one or more of hepatic failure, hematoma, or rupture, Glasgow coma score of less than 13, stroke, at least two seizures, cortical blindness, need for positive inotrope support, myocardial infarction, infusion of any third antihypertensive, renal dialysis, renal transplantation, at least 50% FIO 2 for greater than 1 hour, intubation, or transfusion of at least 10 units of blood products. The combined perinatal outcome was perinatal or infant mortality, bronchopulmonary dysplasia, necrotizing enterocolitis, grade III/IV intraventricular hemorrhage, cystic periventricular leukomalacia, or stage 3-5 retinopathy of prematurity. RESULTS: Two hundred ninety-five and 405 women were in the preintervention and postintervention cohorts, respectively. The incidence of adverse maternal outcome fell (5.1% to 0.7%; Fisher P<.001; odds ratio 0.14, 95% confidence interval 0.04 -0.49). Perinatal outcomes did not change. CONCLUSION: Standardized surveillance of women with preeclampsia was associated with reduced maternal risk. (Obstet Gynecol 2007;110:121-7

Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free): A Protocol for a Multi-centre Randomized Cluster Crossover Trial

Delirium is common after cardiac surgery and is associated with adverse outcomes. Administration of benzodiazepines before and after cardiac surgery is associated with delirium; guidelines recommend minimizing their use. Benzodiazepine administration during cardiac surgery remains common because of its recognized benefits. The Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free) trial is a randomized cluster crossover trial evaluating whether an institutional policy of restricting intraoperative benzodiazepine administration (ie, ≥ 90% of patients do not receive benzodiazepines during cardiac surgery), as compared with a policy of liberal intraoperative benzodiazepine administration (ie, ≥ 90% of patients receive ≥ 0.03 mg/kg midazolam equivalent), reduces delirium. Hospitals performing ≥ 250 cardiac surgeries a year are included if their cardiac anesthesia group agrees to apply both benzodiazepine policies per their randomization, and patients are assessed for postoperative delirium every 12 hours in routine clinical care. Hospitals apply the restricted or liberal benzodiazepine policy during 12 to 18 crossover periods of 4 weeks each. Randomization for all periods takes place in advance of site startup; sites are notified of their allocated policy during the last week of each crossover period. Policies are applied to all patients undergoing cardiac surgery during the trial period. The primary outcome is the incidence of delirium at up to 72 hours after surgery. The B-Free trial will enroll ≥ 18,000 patients undergoing cardiac surgery at 20 hospitals across North America. Delirium is common after cardiac surgery, and benzodiazepines are associated with the occurrence of delirium. The B-Free trial will determine whether an institutional policy restricting the administration of benzodiazepines during cardiac surgery reduces the incidence of delirium after cardiac surgery.Clinicaltrials.gov registration number: NCT03928236 (First registered April 26, 2019). Résumé: L’état confusionnel est fréquent après une chirurgie cardiaque et il est associé à des complications. L’administration de benzodiazépines avant et après une chirurgie cardiaque est associée à l’état confusionnel; dans les lignes directrices, on recommande de réduire leur utilisation au minimum. L’administration de benzodiazépines pendant une chirurgie cardiaque demeure fréquente, en raison des leurs bienfaits reconnus. L’essai B-Free (Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium ou l’anesthésie sans benzodiazépine en contexte de chirurgie cardiaque pour la réduction de l’état confusionnel postopératoire) est un essai à répartition aléatoire par grappes et avec permutation, visant à évaluer si une politique institutionnelle de restriction de l’administration peropératoire de benzodiazépines (c.-à-d. que ≥ 90 % des patients ne reçoivent pas de benzodiazépines durant une chirurgie cardiaque) réduit l’état confusionnel, comparativement à une politique d’administration peropératoire libérale de benzodiazépines (c.-à-d. que ≥ 90 % des patients reçoivent ≥ 0,03 mg/kg d’équivalent du midazolam). Des hôpitaux effectuant au moins 250 chirurgies cardiaques par année sont inclus dans l’essai si leurs équipes d’anesthésie cardiaque acceptent d’appliquer les deux politiques relatives aux benzodiazépines en vertu de la répartition aléatoire et si les patients sont évalués toutes les 12 heures, en ce qui a trait à l’état confusionnel postopératoire, dans le cadre des soins cliniques habituels. Les hôpitaux mettent en œuvre la politique d’administration restreinte ou libérale de benzodiazépines durant 12 à 18 périodes de permutation de 4 semaines chacune. La répartition aléatoire de l’ensemble des périodes a lieu avant le début de l’essai à l’hôpital; les établissements sont avisés de la politique qui leur est attribuée au cours de la dernière semaine de chaque période de permutation. Les politiques sont appliquées à tous les patients qui subissent une chirurgie cardiaque durant la période de l’essai. Le critère d’évaluation principal est l’incidence de l’état confusionnel dans les 72 heures suivant l’intervention chirurgicale. L’étude B-Free inclura au moins 18 000 patients qui subiront une chirurgie cardiaque dans 20 hôpitaux en l’Amérique du Nord. L’état confusionnel est fréquent après une chirurgie cardiaque, et les benzodiazépines sont associées à la survenue de l’état confusionnel. L’essai B-Free permettra de déterminer si une politique institutionnelle de restriction de l’administration de benzodiazépines durant une chirurgie cardiaque réduit l’incidence de l’état confusionnel après une telle chirurgie.Clinicaltrials.gov registration number: NCT03928236 (First registered April 26, 2019)

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics