A Phase 1/2 interventional study of Calcium Chloride and Placebo in Uterine Atony, Uterine Atony With Hemorrhage and Cesarean Section Complications, sponsored by Stanford University. Completed at 1 site in United States. Open to female participants aged 18 Years to 50 Years. Per ClinicalTrials.gov, last updated 2022-04-28.
Sponsored by Stanford University · Phase 1/2, Interventional, and Prevention
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.
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.
34 studies on the registry are indexed under Uterine Inertia; 6 are open to participants now.
This study's enrollment of 40 is below the median of 100 across 21 interventional studies indexed under Uterine Inertia.
Browse Uterine Inertia studies →Stanford University is the lead sponsor of 2,117 studies on the registry; 425 are open to participants now.
Of its 259 completed or terminated interventional studies of FDA-regulated products, 197 (76%) have results posted.
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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:
Exclusion Criteria:
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
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
All included in intervention description. 1 gram of calcium chloride in total 60 milliliters normal saline
Also known as: calcium chloride intravenous, IV calcium
60 milliliters normal saline
Also known as: Saline
Uterine Atony
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
Time frame: From time of fetal delivery until 4 hours after fetal delivery
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.
Time frame: 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
Time frame: 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.
Time frame: Drawn on postoperative day 1 as standard care
Total Crystalloid During Cesarean
Amount of saline administered during cesarean
Time frame: 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
Time frame: 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)
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
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
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
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)
| Milestone | Calcium Chloride | Placebo |
|---|---|---|
| Started | 20 | 20 |
| Completed | 20 | 20 |
| Not completed | 0 | 0 |
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
| Participants | Calcium Chloride | Placebo |
|---|---|---|
| Uterine Atony | 4 | 10 |
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.
| score on a scale | Calcium Chloride | Placebo |
|---|---|---|
| Grading of Uterine Tone | 89 (80 to 90) | 80 (75 to 89) |
In milliliters. By blinded obstetrician, taking into account drape, sponge, and suction canister contents
| milliters | Calcium Chloride | Placebo |
|---|---|---|
| Estimated Blood Loss | 750 (600 to 800) | 850 (650 to 1000) |
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.
| hematocrit (%) | Calcium Chloride | Placebo |
|---|---|---|
| Change in Hematocrit | 7.7 ± 4.4 | 6.7 ± 2.6 |
Amount of saline administered during cesarean
| mL | Calcium Chloride | Placebo |
|---|---|---|
| Total Crystalloid During Cesarean | 1200 (1000 to 2000) | 1750 (1500 to 2000) |
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
| beats per minute | Calcium Chloride | Placebo |
|---|---|---|
| Maximum Increase in Heart Rate From Baseline (Beats Per Minute) | 15.4 ± 8.8 | 14.2 ± 7.7 |
Heart rate monitored for 45 minutes after study drug infusion (well past peak)
| beats per minute | Calcium Chloride | Placebo |
|---|---|---|
| Maximal Decrease in Heartrate From Baseline | 19.1 ± 13.1 | 16.7 ± 14.4 |
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.
| mmHg | Calcium Chloride | Placebo |
|---|---|---|
| Maximal Increase in Mean Arterial Blood Pressure From Baseline | 15.4 (11.0 to 19.8) | 14.2 (10.3 to 17.8) |
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.
| mmHg | Calcium Chloride | Placebo |
|---|---|---|
| Maximal Decrease in Mean Arterial Blood Pressure From Baseline | 33.8 (25.2 to 40.9) | 32.0 (21.1 to 43.7) |
Ionized calcium levels measured by phlebotomy. Analyzed prior to any study drug administration.
| millimol per liter | All Participants |
|---|---|
| Baseline Ionized Calcium Concentration | 1.18 (1.16 to 1.19) |
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).
| L/min | Calcium Chloride |
|---|---|
| Clearance of Calcium Chloride | 0.93 (0.63 to 1.52) |
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
| Liters | Calcium Chloride |
|---|---|
| Volume of Distribution of Calcium Chloride | 76 (49 to 91) |
Collected over Any event within the 5 days of delivery. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Calcium Chloride | 0/20 (0%) | 0/20 (0%) | 6/20 (30%) |
| Placebo | 0/20 (0%) | 0/20 (0%) | 6/20 (30%) |
| Event | Calcium Chloride | Placebo |
|---|---|---|
| Nausea or vomitingGastrointestinal disorders | 4/20 | 2/20 |
| ArrhythmiaCardiac disorders | 2/20 | 3/20 |
| HypertensionCardiac disorders | 0/20 | 2/20 |
| IV line discomfortProduct Issues | 1/20 | 0/20 |
| Age, Categorical(Participants) | Calcium Chloride | Placebo | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 20 | 20 | 40 |
| >=65 years | 0 | 0 | 0 |
| Sex: Female, Male(Participants) | Calcium Chloride | Placebo | Total |
|---|---|---|---|
| Female | 20 | 20 | 40 |
| Male | 0 | 0 | 0 |
| Race/Ethnicity, Customized(Participants) | Calcium Chloride | Placebo | Total |
|---|---|---|---|
| Race/Ethnicity — Asian | 4 | 6 | 10 |
| Race/Ethnicity — Black | 0 | 1 | 1 |
| Race/Ethnicity — Hispanic/Latina | 4 | 4 | 8 |
| Race/Ethnicity — White | 10 | 8 | 18 |
| Race/Ethnicity — Mixed | 1 | 1 | 2 |
| Race/Ethnicity — Other/Decline to disclose | 1 | 0 | 1 |
| Region of Enrollment(participants) | Calcium Chloride | Placebo | Total |
|---|---|---|---|
| United States | 20 | 20 | 40 |
| Gestational age(weeks of gestation) | Calcium Chloride | Placebo | Total |
|---|---|---|---|
| Median | 38.4 (36.8 to 39.6) | 39.0 (35.7 to 39.7) | 38.6 (36.2 to 39.6) |
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Plan to share: 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
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