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Calcium Chloride for Prevention of Uterine Atony During Cesarean

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03867383
Recruitment Status : Recruiting
First Posted : March 8, 2019
Last Update Posted : April 4, 2019
Sponsor:
Information provided by (Responsible Party):
Brendan Carvalho, 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.

Condition or disease Intervention/treatment Phase
Uterine Atony Uterine Atony With Hemorrhage Cesarean Section Complications Drug: Calcium Chloride Drug: Placebo Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Randomization has been performed and study ID designation to drug or placebo arm allocated to opaque envelopes prior to subject enrollment. An anesthesiologist not involved in clinical care of the patient or data entry or analysis opens the envelope at the time of subject enrollment and prepares the study drug versus placebo in a 60mL syringe, labeled only with subject ID#. Drug and placebo appear identical as clear solutions and are administered by the same protocol.

The key designating whether each study ID patient received calcium or placebo has been uploaded to the redCAP data entry database and cannot be retrieved without entering a passcode.

Primary Purpose: Prevention
Official Title: 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
Actual Study Start Date : March 15, 2019
Estimated Primary Completion Date : April 30, 2021
Estimated Study Completion Date : March 30, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bleeding Calcium

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 Name: Saline




Primary Outcome Measures :
  1. Uterine atony [ Time Frame: From time of fetal delivery until 4 hours after fetal delivery ]

    The primary outcome of interest is the presence or absence of clinical uterine atony, as defined the by the presence of 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 :
  1. Pharmacokinetics of calcium chloride in pregnant women [ Time Frame: minutes after drug delivery (0-90) ]
    Change in ionized calcium concentration over time. Blood calcium concentration will be 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 will be evaluated with NONMEM (Non Linear Mixed Effects Modeling) to determine whether a 1, 2 or 3 compartment model is optimal to describe the data. Results will be expressed as the appropriate coefficients and exponents depending on the optimal model. Participants undergo up to 3 phlebotomy specimens to allow measurement of the serum ionized calcium. Samples are drawn at baseline, at random time points after study drug administration while in the operating room, and upon arrival to the recovery room

  2. Grading of uterine tone [ Time Frame: A one-time value collected 10 minutes after Cesarean fetal delivery ]
    Subjective assessment of uterine tone by the obstetrician, from 0-100%

  3. Quantitative blood loss [ Time Frame: Immediately upon surgery completion, as patient exits operating theater ]
    In milliliters. This one-time value is calculated by Labor and Delivery nurses as a standard of care, calculated by weighing surgical laps and sponges and accounting for suction canister and surgical drape contents as soon as skin incision is closed

  4. Average heart rate (beats per minute) [ Time Frame: 15 minutes after study drug infusion is complete ]
    Heart rate is recorded every minute throughout delivery. Heart rate values over the first 15 minutes after study drug completion will be averaged to compare calcium chloride to placebo group

  5. Average blood pressure (millimeters mercury) [ Time Frame: 15 minutes after study drug infusion is complete ]
    Blood pressure is recorded every minute throughout delivery. Blood pressure values over the first 15 minutes after study drug completion will be averaged to compare calcium chloride to placebo group

  6. Cumulative Phenylephrine dose (micrograms per kilogram) [ Time Frame: During entire Cesarean delivery record (generally about 2 hours) ]
    Total phenylephrine administered during Cesarean divided by patient weight in kilograms

  7. Side effect: pain at IV site [ Time Frame: During or in the 30 minutes after study drug infusion ]
    Yes/no

  8. Side effect: arrhythmia including tachycardia or bradycardia [ Time Frame: During or in the 30 minutes after study drug infusion ]
    Yes/no

  9. Change in hematocrit [ Time Frame: Drawn on postoperative day 1 as standard care ]
    Changes from preoperative to standard postoperative day 1 hematocrit in patients



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Study being conducted in pregnant women undergoing Cesarean delivery
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03867383


Contacts
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Contact: Jessica R Ansari, MD 760-845-0328 jansari@stanford.edu
Contact: Edward Riley, MD (650) 498-7787 edriley@stanford.edu

Locations
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United States, California
Lucile Packard Children's Hospital Recruiting
Stanford, California, United States, 94305
Contact: Brendan Carvalho, MBBCh, FRCA    650-861-8607    carvalb@stanford.edu   
Contact: Jessica Ansari, MD    7608450328    jansari@stanford.edu   
Sponsors and Collaborators
Stanford University
Investigators
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Study Chair: Brendan Carvalho, MBBCh FRCA Stanford University

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Responsible Party: Brendan Carvalho, Professor, Stanford University
ClinicalTrials.gov Identifier: NCT03867383    
Other Study ID Numbers: 43076
First Posted: March 8, 2019    Key Record Dates
Last Update Posted: April 4, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Investigators will happily share de-identified individual participant data including consent documents and data analysis code with interested investigators on a case-by-case basis. Please email Dr. Ansari or Dr. Carvalho

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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
Additional relevant MeSH terms:
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Calcium, Dietary
Calcium
Calcium-Regulating Hormones and Agents
Uterine Inertia
Hemorrhage
Pathologic Processes
Dystocia
Obstetric Labor Complications
Pregnancy Complications
Physiological Effects of Drugs
Bone Density Conservation Agents