Uterine AtonyPhase 1/2NCT03867383
Calcium Chloride for Prevention of Uterine Atony During Cesarean
A Phase 1/2 study testing Calcium Chloride in people with Uterine Atony and Uterine Atony With Hemorrhage, run by Stanford University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 50 years, women only
- Conditions the study is for
- Uterine Atony, Uterine Atony With Hemorrhage, Cesarean Section Complications
- What is being tested?
- Calcium Chloride
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Mar 2019to 15 Aug 2021
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- 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
Show all 12Show fewer
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Lucile Packard Children's Hospital
Stanford, California, 94305
About this study
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
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.
Read the 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.
- Being tested
- Calcium Chloride, Placebo
- Medical subject headings
- Uterine Inertia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Calcium ChlorideDrug
Also called calcium chloride intravenous, IV calcium
All included in intervention description.
1 gram of calcium chloride in total 60 milliliters normal saline
PlaceboDrug
Also called Saline
60 milliliters normal saline
| Study group | Role | What they receive |
|---|---|---|
| Calcium Chloride | Experimental | 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. Receives: Drug: Calcium Chloride |
| Placebo | Placebo comparator | 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. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: From time of fetal delivery until 4 hours after fetal delivery
Secondary outcomes (11)
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.
Measured: 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
Measured: 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.
Measured: Drawn on postoperative day 1 as standard care
Total Crystalloid During Cesarean
Amount of saline administered during cesarean
Measured: 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
Measured: 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)
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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
Measured: 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)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Mar 2019
- Study start15 Mar 2019
- Primary completion30 Jul 2021
- Study completion15 Aug 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Uterine AtonyStudies of the same condition, open and under way.
- More trials run by Stanford UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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 blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- Stanford University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Brendan Carvalho, Stanford University
- Investigators
- Brendan Carvalho, MBBCh FRCA, Study chair, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03867383
- Sponsor's protocol ID
- 43076
- Status last verified
- Apr 2022
- First submitted
- 20 Apr 2018
- Last updated
- 28 Apr 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: 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
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.
PubMed 35447502
Study at a glance
From the registry record, last updated by the sponsor on 28 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03867383
- Acronym / sponsor ID
- 43076
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- Stanford UniversityUniversity, hospital or other
- Study start
- 15 Mar 2019 (actual)
- Primary completion
- 30 Jul 2021 (actual)
- Study completion
- 15 Aug 2021 (actual)
- First posted
- 8 Mar 2019 (actual)
- Results
- Posted 28 Apr 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| Calcium Chloride | Experimental | Drug: Calcium ChlorideNon-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. |
| Placebo | Placebo comparator | Drug: PlaceboNon-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. |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (12 listed)
- 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
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Calcium ChlorideAlso: calcium chloride intravenous, IV calciumAll included in intervention description. 1 gram of calcium chloride in total 60 milliliters normal saline | Drug | Calcium Chloride |
| PlaceboAlso: Saline60 milliliters normal saline | Drug | Placebo |
Primary outcome
Uterine Atony
Time frame: 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
11 secondary outcomes
Grading of Uterine Tone
Time frame: A one-time value collected 10 minutes after Cesarean fetal delivery
Estimated Blood Loss
Time frame: Immediately upon surgery completion, as patient exits operating theater
Change in Hematocrit
Time frame: Drawn on postoperative day 1 as standard care
Total Crystalloid During Cesarean
Time frame: During entire Cesarean delivery record (generally about 2 hours)
Maximum Increase in Heart Rate From Baseline (Beats Per Minute)
Time frame: first 45 minutes after study drug completion
Maximal Decrease in Heartrate From Baseline
Time frame: 45 minutes after study drug infusion is complete
Maximal Increase in Mean Arterial Blood Pressure From Baseline
Time frame: While in the operating room, generally about 2 hours
Maximal Decrease in Mean Arterial Blood Pressure From Baseline
Time frame: While in the operating room, generally about 2 hours
Baseline Ionized Calcium Concentration
Time frame: Prior to study drug (up to 5 minutes for blood draw)
Clearance of Calcium Chloride
Time frame: 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
Time frame: 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)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Apr 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 35447502Ansari 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.
- Individual participant dataSharing planned: No. 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
Related trials for Uterine Atony
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Oxytocin Bolus Versus Infusion in High-Risk Patients Undergoing Elective Cesarean Section (INBOX-HR)
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Brendan Carvalho, MBBCh FRCA study chair
Stanford University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Calcium Chloride in people with Uterine Atony and Uterine Atony With Hemorrhage, run by Stanford University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 28 Apr 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Uterine Atony (time frame: From time of fetal delivery until 4 hours after fetal delivery). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03867383, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Apr 2022.