Calcium Chloride for Prevention of Uterine Atony During Cesarean

Phase 1

Completed

Conditions: Uterine Atony
Uterine Atony With Hemorrhage
Cesarean Section Complications

Interventions: Drug: Placebo
Drug: Calcium Chloride

Registration Number: NCT03867383

Lead Sponsor: Stanford University

Brief Summary: In this pilot study, investigators will administer calcium chloride or placebo to pregnant women undergoing Cesarean delivery who have been identified as high risk for hemorrhage due to poor uterine muscle contraction, or atony. They will assess whether a single dose of calcium given immediately after the delivery of the fetus decreases the incidence of uterine atony and bleeding for the mother. The pharmacokinetics of calcium chloride in pregnant women will also be established. Data from this pilot study of 40 patients will be used to determine sample size and appropriateness of a larger randomized clinical trial.

Detailed Description: Poor contraction of the uterus, also known as uterine atony, is the leading cause of severe blood loss during Cesarean section, both in the US and worldwide. Exogenous calcium has been shown to increase uterine muscle contraction in in vitro and in animal studies. Calcium is also an essential factor in normal blood clotting. Anesthesiologists commonly administer intravenous calcium chloride during Cesarean as well as other types of surgery, but formal randomized studies to determine efficacy in improving uterine tone have not been performed.

In this pilot, randomized controlled study, the anesthesiologist will administer a one-time dose of intravenous calcium chloride 1gram versus placebo at the time of fetal delivery to women identified as having high risk of hemorrhage during Cesarean delivery. Primary outcome assessed will be a composite measure of uterine atony. Data from the pilot study will be used to perform power and sample size calculations for a larger study. Secondary outcomes assessed will include total blood loss, subjective assessment of uterine tone by the blinded obstetrician performing surgery, safety, side effects, and pharmacokinetic profile of calcium chloride in pregnant women.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 40

Inclusion Criteria

Pregnant female subjects at Lucile Packard Children's hospital / Stanford hospital undergoing Cesarean will be screened for inclusion in the study based upon presence of at least 2 risk factors for uterine atony/ postpartum hemorrhage. The risk factors include the following:

intrapartum Cesarean delivery
failed operative vaginal delivery with forceps or vacuum
magnesium infusion
chorioamnionitis
multiple gestation
polyhydramnios
preterm delivery <37 weeks
prior history of postpartum hemorrhage
labor induction or augmentation with oxytocin
advanced maternal age
obesity with body mass index >40

Exclusion Criteria

a degree of case urgency to which taking time to consent for the study could compromise patient care, determined by anesthesiologist or obstetrician
patient age <18 years or >50 years
renal dysfunction with serum Creatinine > 1.0
abnormal cardiac function or history of arrhythmia
patient taking digoxin
patient currently taking a calcium channel blocker for a cardiovascular indication

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Non-participating anesthesiologist prepares the placebo solution, which is 60 milliliters normal saline, labeled only with the study ID number. The solution is administered intravenously utilizing an Alaris syringe pump and microbore tubing, with infusion starting immediately at the time of fetal delivery at a rate of 360 milliliters per hour. This is a one-time administration. Patients continue to receive all standard care during the Cesarean including 1 unit oxytocin bolus at the time of fetal delivery + continuous oxytocin infusion at 7.5 units per hour per our institution's protocol.
Calcium Chloride	Calcium Chloride	Non-participating anesthesiologist prepares the drug solution, which is 1 gram of calcium chloride diluted into a total volume of 60 milliliters normal saline, labeled only with the study ID number. The solution is administered intravenously utilizing an Alaris syringe pump and microbore tubing, with infusion starting immediately at the time of fetal delivery at a rate of 360 milliliters per hour (for a calcium infusion rate of 100 milligrams /minute until the full 1 gram dose is administered). This is a one-time administration. Patients continue to receive all standard care during the Cesarean including 1 unit oxytocin bolus at the time of fetal delivery + continuous oxytocin infusion at 7.5 units per hour per our institution's protocol.

Primary Outcome Measures

Name	Time	Method
Uterine Atony	From time of fetal delivery until 4 hours after fetal delivery	The primary outcome of interest is the presence of clinical uterine atony, as defined the by any of the following: 1. Administration of \> 1 bolus of oxytocin 2. Increase in the oxytocin infusion rate above the standard 7.5units/hour 3. Administration of a second line uterotonic including methylergonovine, carboprost, or misoprostol 4. Mechanical surgical interventions for uterine atony including placement of an intrauterine balloon, B-lynch sutures, or O'Leary sutures 5. Requirement for embolization of the uterine arteries by interventional radiology 6. Estimated blood loss\> 1000 milliliters 7. Transfusion of blood products during or within 4 hours of Cesarean

Secondary Outcome Measures

Name	Time	Method
Grading of Uterine Tone	A one-time value collected 10 minutes after Cesarean fetal delivery	Subjective assessment of uterine tone by the obstetrician, from 0-100%. Obstetricians were blinded to study assignment arm, and were instructed that 0% indicates a completely atonic (un-contracted) uterus, and 100% indicates a perfectly, firmly contracted uterus. They were asked to provide this score by palpating the fundus (top) of the uterus as soon as the study drug infusion was complete.
Estimated Blood Loss	Immediately upon surgery completion, as patient exits operating theater	In milliliters. By blinded obstetrician, taking into account drape, sponge, and suction canister contents
Change in Hematocrit	Drawn on postoperative day 1 as standard care	Changes from preoperative to standard postoperative day 1 hematocrit in patients. The hematocrit represents the percentage by volume of red blood cells in a blood sample and decreases after losing blood. The change in hematocrit was calculated by subtracting the number obtained the morning after surgery from the number obtained prior to surgery.
Total Crystalloid During Cesarean	During entire Cesarean delivery record (generally about 2 hours)	Amount of saline administered during cesarean
Maximum Increase in Heart Rate From Baseline (Beats Per Minute)	first 45 minutes after study drug completion	Heart rate is recorded every minute throughout delivery. Heart rate values over the first 45 minutes after study drug completion will be compared to baseline calcium chloride to placebo group
Maximal Decrease in Heartrate From Baseline	45 minutes after study drug infusion is complete	Heart rate monitored for 45 minutes after study drug infusion (well past peak)
Maximal Increase in Mean Arterial Blood Pressure From Baseline	While in the operating room, generally about 2 hours	Baseline mean arterial pressure was established upon entry into the operating room after at least 3 minutes had passed since positioning onto the operating room bed and prior to commencement of the cesarean delivery or to block placement. Mean arterial blood pressure was recorded every 5 minutes from this baseline timepoint until completion of the cesarean. Maximal increase was calculated as the difference between the baseline and the highest recorded mean arterial blood pressure.
Maximal Decrease in Mean Arterial Blood Pressure From Baseline	While in the operating room, generally about 2 hours	Baseline mean arterial pressure was established upon entry into the operating room after at least 3 minutes had passed since positioning onto the operating room bed and prior to commencement of the cesarean delivery or to block placement. Mean arterial blood pressure was recorded every 5 minutes from this baseline timepoint until completion of the cesarean. Maximal decrease was calculated as the difference between the baseline and the lowest recorded mean arterial blood pressure.
Volume of Distribution of Calcium Chloride	Samples drawn at baseline, at random time points after study drug administration while in the operating room, and upon arrival to the recovery room (up to 90 minutes)	Pharmacokinetic parameters were analyzed based upon ionized calcium concentrations over time. Blood calcium concentration was measured at the following time points: baseline (pre-drug delivery), 0-20 minutes after drug administration, and 20-90 minutes after delivery. The resulting values for concentration over time were evaluated with NONMEM
Baseline Ionized Calcium Concentration	Prior to study drug (up to 5 minutes for blood draw)	Ionized calcium levels measured by phlebotomy. Analyzed prior to any study drug administration.
Clearance of Calcium Chloride	Samples drawn at baseline, at random time points after study drug administration while in the operating room, and upon arrival to the recovery room (up to 90 minutes)	Pharmacokinetic parameters were analyzed based upon ionized calcium concentrations over time. Blood calcium concentration was measured at the following time points: baseline (pre-drug delivery), 0-20 minutes after drug administration, and 20-90 minutes after delivery. The reported values for concentration over time were obtained using NONMEM (Non Linear Mixed Effects Modeling).