Calcium Chloride for Prevention of Uterine Atony During Cesarean

Calcium Chloride in the Prevention of Uterine Atony During Cesarean in Women at Increased Risk of Hemorrhage: a Pilot Randomized Controlled Trial and Pharmacokinetic Study

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.

Study Overview

• Status: Completed
• Conditions: Cesarean Section Complications; Uterine Atony; Uterine Atony With Hemorrhage
• Intervention / Treatment: Drug: Calcium Chloride; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Lucile Packard Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Calcium Chloride; All included in intervention description. 1 gram of calcium chloride in total 60 milliliters normal saline; Other Names: calcium chloride intravenous; IV calcium
Placebo Comparator: 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.	Drug: Placebo; 60 milliliters normal saline; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Grading of Uterine Tone	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.	A one-time value collected 10 minutes after Cesarean fetal delivery
Estimated Blood Loss	In milliliters. By blinded obstetrician, taking into account drape, sponge, and suction canister contents	Immediately upon surgery completion, as patient exits operating theater
Change in Hematocrit	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.	Drawn on postoperative day 1 as standard care
Total Crystalloid During Cesarean	Amount of saline administered during cesarean	During entire Cesarean delivery record (generally about 2 hours)
Maximum Increase in Heart Rate From Baseline (Beats Per Minute)	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	first 45 minutes after study drug completion
Maximal Decrease in Heartrate From Baseline	Heart rate monitored for 45 minutes after study drug infusion (well past peak)	45 minutes after study drug infusion is complete
Maximal Increase in Mean Arterial Blood Pressure From Baseline	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.	While in the operating room, generally about 2 hours
Maximal Decrease in Mean Arterial Blood Pressure From Baseline	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.	While in the operating room, generally about 2 hours
Baseline Ionized Calcium Concentration	Ionized calcium levels measured by phlebotomy. Analyzed prior to any study drug administration.	Prior to study drug (up to 5 minutes for blood draw)
Clearance of Calcium Chloride	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).	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)
Volume of Distribution of Calcium Chloride	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	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)

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Study Chair: Brendan Carvalho, MBBCh FRCA, Stanford University

Publications and helpful links

General Publications

• Ansari JR, Kalariya N, Carvalho B, Flood P, Guo N, Riley E. Calcium chloride for the prevention of uterine atony during cesarean delivery: A pilot randomized controlled trial and pharmacokinetic study. J Clin Anesth. 2022 Sep;80:110796. doi: 10.1016/j.jclinane.2022.110796. Epub 2022 Apr 18.

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2019
• Primary Completion (Actual): July 30, 2021
• Study Completion (Actual): August 15, 2021

Study Registration Dates

• First Submitted: April 20, 2018
• First Submitted That Met QC Criteria: March 5, 2019
• First Posted (Actual): March 8, 2019

Study Record Updates

• Last Update Posted (Actual): April 28, 2022
• Last Update Submitted That Met QC Criteria: April 1, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Pregnancy Complications; Obstetric Labor Complications; Dystocia; Hemorrhage; Uterine Inertia; Physiological Effects of Drugs; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Calcium; Calcium, Dietary
• Other Study ID Numbers: 43076

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Investigators will consider sharing de-identified individual participant data including data analysis code with interested investigators on a case-by-case basis. Please email Dr. Ansari or Dr. Carvalho

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No