Calcium Chloride for Prevention of Uterine Atony During Cesarean

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Uterine Atony, Uterine Atony With Hemorrhage, Cesarean Section Complications

Intervention / Treatment
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* Drug: Calcium Chloride
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients are randomized via stratified, permuted block randomization to receive a single dose of either calcium chloride 1 gram administered intravenously or placebo at the time of fetal delivery.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Calcium Chloride<br>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<br>* All included in intervention description. 1 gram of calcium chloride in total 60 milliliters normal saline<br>* Other names: IV calcium;|
| Placebo Comparator: Placebo<br>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<br>* 60 milliliters normal saline<br>* Other names: Saline;|

What is the study measuring?
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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) |