Calcium chloride for the prevention of uterine atony during cesarean delivery: A pilot randomized controlled trial and pharmacokinetic study

Study objective: To assess the feasibility, patient tolerance, pharmacokinetics, and potential effectiveness of a randomized controlled trial protocol investigating intravenous calcium chloride for the prevention of uterine atony during cesarean delivery. Design: Double-blind, randomized controlled pilot trial with nested population pharmacokinetic analysis. Setting: This study was performed at Lucile Packard Children's Hospital, from August 2018 to September 2019. Patients: Forty patients with at least two risk factors for uterine atony at the time of cesarean delivery. Interventions: One gram of intravenous calcium chloride (n = 20 patients) or a saline placebo control (n = 20 patients), in addition to standard care with oxytocin, upon umbilical cord clamping. Measurements: The primary efficacy-related outcome was the presence of uterine atony defined as the use of a second-line uterotonic medication, surgical interventions for atony, or hemorrhage with blood loss > 1000 mL. Blood loss, uterine tone numerical rating scores, serial venous blood calcium levels, hemodynamics, and potential side effects were also assessed. Main results: The study protocol proved feasible. The incidence of atony was 20% in parturients who received calcium compared to 50% in the placebo group (relative risk 0.38, P = 0.07, 95% CI 0.15-1.07, NNT 3.3). Calcium recipients tolerated the drug infusion well, with no adverse events and an equal incidence of potential side effects in the calcium and placebo groups. Ionized calcium concentration rose significantly in all patients who received calcium infusion, from baseline 1.18 mmol/L to peak levels 1.50-1.60 mmol/L. One-compartment population pharmacokinetics established clearance of 0.93 (95% CI 0.63-1.52) L/min and volume of distribution 76 (95% CI 49-94) L. Conclusions: In this pilot study, investigators found that intravenous calcium chloride was well-tolerated by the 20 patients assigned to receive the study drug and may be effective in prevention of uterine atony. A 1-g dose was sufficient to substantially increase calcium levels without any critically elevated lab values or concern for adverse side effects. These encouraging findings warrant further investigation of calcium as a novel agent to prevent uterine atony with an adequately powered clinical trial. Clinical trial registry NCT03867383 https://clinicaltrials.gov/ct2/show/NCT03867383