Calcium Chloride for Prevention of Blood Loss During Intrapartum Cesarean Delivery

Phase 3

Completed

Conditions: Uterine Atony
Uterine Atony With Hemorrhage
Postpartum Hemorrhage
Cesarean Section Complications

Interventions: Drug: Saline placebo
Drug: Calcium chloride

Registration Number: NCT05027048

Lead Sponsor: Stanford University

Brief Summary: Postpartum hemorrhage (PPH) is the leading cause of maternal morbidity and mortality worldwide. Up to 80% of PPH is caused by uterine atony, the failure of the uterine smooth muscle to contract and compress the uterine vasculature after delivery. Laboratory and epidemiological studies show that low extracellular and serum calcium levels, respectively, decrease uterine contractility. A pilot study performed by the investigators supports the hypothesis that intravenous calcium chloride is well tolerated and may have utility in preventing uterine atony. The proposed research will establish the relationship between uterine tone and calcium through a clinical trial with an incorporated pharmacokinetic and pharmacodynamic (PK/PD) study. In a randomized, placebo-controlled, double-blind trial, investigators will establish the effect of 1 gram of intravenous calcium chloride upon quantitative blood loss and uterine tone during cesarean delivery in parturients with high risk of uterine atony. Investigators will concurrently collect serial venous blood samples to measure calcium for PK/PD modeling in this pregnant study cohort. High-quality clinical research and development of novel therapeutics to manage uterine atony are critical to reduce the high maternal morbidity and mortality from PPH.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 120

Inclusion Criteria

Patient had a trial of labor for vaginal delivery prior to cesarean
Patient received an oxytocin infusion for labor augmentation or induction prior to cesarean

Exclusion Criteria

renal dysfunction with serum Cr >1.0 mg/dL
known underlying cardiac condition
treatment with digoxin within the last 2 weeks for a maternal or fetal indication
treatment with a calcium channel blocker medication within 24 hours
hypertension necessitating intravenous antihypertensive medication within 24 hours
emergent case in which study participation could in any way impede patient care by the judgement of the obstetrician, anesthesiologist, or bedside nurse

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Saline placebo	Saline placebo	60mL sterile saline, delivered over 10 minute controlled infusion at a constant rate (360mL/hour) beginning 2 minutes after fetal delivery and 1 minute after delayed cord clamp. This intervention occurs IN ADDITION TO standard care with oxytocin 2 unit bolus and infusion at 7.5 units per hour which begins immediately after fetal delivery.
Calcium chloride	Calcium chloride	1 gram of calcium chloride in total volume 60mL with sterile saline, delivered over 10 minute controlled infusion at a constant rate (360mL/hour) beginning 2 minutes after fetal delivery and 1 minute after delayed cord clamp. This intervention occurs IN ADDITION TO standard care with oxytocin 2 unit bolus and infusion at 7.5 units per hour which begins immediately after fetal delivery.

Primary Outcome Measures

Name	Time	Method
Quantitative Blood Loss	measurement occurs at conclusion of operating room case	Standardized volumetric and gravimetric assessment of blood loss during cesarean. Note: will analyze all participants, but planned subgroup analysis will also occur excluding patients with non-atonic reasons for blood loss including hysterotomy extension, placental abruption, cervical or vaginal laceration, etc

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Postpartum Hemorrhage	operative course (within 4-6 hours of fetal delivery)	Postpartum hemorrhage was defined as quantitative blood loss \> 1000 milliliters during operative course
Number of Participants With Second Line Uterotonic Requirement	within 4 hours of delivery	Yes/no: did the patient require treatment with methylergonovine, carboprost, and/or misoprostol for uterine atony
Fluid Requirement	Operating room duration, usually 2 hours	Total crystalloid required during cesarean delivery in mL
Pharmacokinetics of Calcium Chloride - Baseline Ionized Calcium	In the operating room prior to study drug administration (generally <30 minutes prior to fetal delivery and study drug administration)	Measured using an Abbott istat machine and CG8+ cartridge to determine venous blood gas ionized calcium levels
Number of Patients With a Transfusion Requirement	96 hours of delivery	Yes/no, if patient required transfusion of packed red blood cells prior to hospital discharge
Change in Hematocrit From Baseline	1 day	Measured pre-delivery hematocrit minus measured post-operative day 1 hematocrit. Correction factor of 3 hematocrit points per unit packed red blood cells transfused
Total Oxytocin Bolus Requirement	Cesarean duration, within 4-6 hours of fetal delivery	Total dose oxytocin bolus during cesarean
Uterine Tone Numerical Rating Score, 7 Minutes After Fetal Delivery	7 minutes after fetal delivery, 5 minutes after initiating study drug infusion	Uterine tone assessment: Obstetricians at the study institution use the following validated scale to grade uterine tone for all cesarean deliveries. The obstetrician places their hand directly on the uterine fundus and scores the adequacy of contraction. The interrater characteristics of this scale have been published (Cole et al, 2021). The scale ranges from 0-10. A score of 0 is the worst possible score and represents a flaccid, atonic uterus. A score of 10 is the best possible score and represents a firmly-contracted uterus.
Uterine Tone Numerical Rating Score, 12 Minutes After Fetal Delivery	12 minutes after fetal delivery, 10 minutes after initiating study drug infusion	Uterine tone assessment: Obstetricians at the study institution use the following validated scale to grade uterine tone for all cesarean deliveries. The obstetrician places their hand directly on the uterine fundus and scores the adequacy of contraction. The interrater characteristics of this scale have been published (Cole et al, PMID 33652161). The scale ranges from 0-10. A score of 0 is the worst possible score and represents a flaccid, atonic uterus. A score of 10 is the best possible score and represents a firmly-contracted uterus.
Percent Change in Mean Arterial Pressure	every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline	Baseline mean arterial blood pressure recorded as average of first 6 mean arterial blood pressures recorded in operating room. Percent change calculated as measured mean arterial blood pressure minus baseline, divided by baseline. Reported here as the maximal decrease in mean arterial pressure. Repeated measures ANOVA reported in Statistical Analysis.
Percent Change in Heart Rate From Baseline	every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline	Baseline heart rate recorded as average of first 6 heart rates recorded in operating room. Percent change calculated as measured heart rate minus baseline, divided by baseline. Maximal % increase in heart rate reported here. Repeated measures ANOVA used to analyze overall trend in Statistical Analysis below.
Total Phenylephrine Requirement	Duration of operating room time, up to 240 minutes	Total phenylephrine in milligrams administered while in the operating room
Pharmacokinetics of Calcium Chloride - Peak Change in Ionized Calcium From 1 Gram of Calcium Chloride	At Tmax (conclusion of the 10-minute intravenous calcium chloride infusion	Generated from a 2-compartment population pharmacokinetic model in NONMEM using serial venous blood gas ionized calcium concentrations.
Pharmacodynamic Effect of Calcium Upon Uterine Tone NRS	Within 20 minutes of study drug administration	Data were not collected. This measure required blood specimens to be obtained at the time of tone scores and this was not done.