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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
120
See arm description above
see arm description above
Jessica Ansari
Pacifica, California, United States
Quantitative Blood Loss
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
Time frame: measurement occurs at conclusion of operating room case
Number of Participants With Postpartum Hemorrhage
Postpartum hemorrhage was defined as quantitative blood loss \> 1000 milliliters during operative course
Time frame: operative course (within 4-6 hours of fetal delivery)
Number of Participants With Second Line Uterotonic Requirement
Yes/no: did the patient require treatment with methylergonovine, carboprost, and/or misoprostol for uterine atony
Time frame: within 4 hours of delivery
Number of Patients With a Transfusion Requirement
Yes/no, if patient required transfusion of packed red blood cells prior to hospital discharge
Time frame: 96 hours of delivery
Change in Hematocrit From Baseline
Measured pre-delivery hematocrit minus measured post-operative day 1 hematocrit. Correction factor of 3 hematocrit points per unit packed red blood cells transfused
Time frame: 1 day
Total Oxytocin Bolus Requirement
Total dose oxytocin bolus during cesarean
Time frame: Cesarean duration, within 4-6 hours of fetal delivery
Uterine Tone Numerical Rating Score, 7 Minutes After Fetal Delivery
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.
Time frame: 7 minutes after fetal delivery, 5 minutes after initiating study drug infusion
Uterine Tone Numerical Rating Score, 12 Minutes After Fetal Delivery
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.
Time frame: 12 minutes after fetal delivery, 10 minutes after initiating study drug infusion
Fluid Requirement
Total crystalloid required during cesarean delivery in mL
Time frame: Operating room duration, usually 2 hours
Percent Change in Mean Arterial Pressure
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.
Time frame: every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline
Percent Change in Heart Rate From 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.
Time frame: every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline
Total Phenylephrine Requirement
Total phenylephrine in milligrams administered while in the operating room
Time frame: Duration of operating room time, up to 240 minutes
Pharmacokinetics of Calcium Chloride - Baseline Ionized Calcium
Measured using an Abbott istat machine and CG8+ cartridge to determine venous blood gas ionized calcium levels
Time frame: In the operating room prior to study drug administration (generally <30 minutes prior to fetal delivery and study drug administration)
Pharmacokinetics of Calcium Chloride - Peak Change in Ionized Calcium From 1 Gram of Calcium Chloride
Generated from a 2-compartment population pharmacokinetic model in NONMEM using serial venous blood gas ionized calcium concentrations.
Time frame: At Tmax (conclusion of the 10-minute intravenous calcium chloride infusion
Pharmacodynamic Effect of Calcium Upon Uterine Tone NRS
Data were not collected. This measure required blood specimens to be obtained at the time of tone scores and this was not done.
Time frame: Within 20 minutes of study drug administration
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