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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Calcium Chloride | Drug | All included in intervention description. 1 gram of calcium chloride in total 60 milliliters normal saline |
|
| 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:
| From time of fetal delivery until 4 hours after fetal delivery |
| 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. |
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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:
Exclusion Criteria:
Study being conducted in pregnant women undergoing Cesarean delivery
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| Name | Affiliation | Role |
|---|---|---|
| Brendan Carvalho, MBBCh FRCA | Stanford University | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Lucile Packard Children's Hospital | Stanford | California | 94305 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35447502 | Derived | 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. |
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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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| ID | Title | Description |
|---|---|---|
| FG000 | 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. Calcium Chloride: All included in intervention description. 1 gram of calcium chloride in total 60 milliliters normal saline |
| FG001 | 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. Placebo: 60 milliliters normal saline |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. Calcium Chloride: All included in intervention description. 1 gram of calcium chloride in total 60 milliliters normal saline |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Uterine Atony | The primary outcome of interest is the presence of clinical uterine atony, as defined the by any of the following:
| Posted | Count of Participants | Participants | From time of fetal delivery until 4 hours after fetal delivery |
|
Any event within the 5 days of delivery
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. Calcium Chloride: All included in intervention description. 1 gram of calcium chloride in total 60 milliliters normal saline |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| IV line discomfort | Product Issues | Systematic Assessment | Mild changes in HR and blood pressure are defined as changes from the patient's baseline which are not associated with symptoms and did not require any treatment with medication or fluid. |
This was a pilot study not designed to definitively assess primary and secondary outcomes.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jessica Ansari | Stanford University | 760-845-0328 | jansari@stanford.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 10, 2018 | Nov 19, 2021 | Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Apr 9, 2018 | Sep 15, 2021 | ICF_002.pdf |
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| ID | Term |
|---|---|
| D014593 | Uterine Inertia |
| ID | Term |
|---|---|
| D004420 | Dystocia |
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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| ID | Term |
|---|---|
| D002122 | Calcium Chloride |
| D002118 | Calcium |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D017610 | Calcium Compounds |
| D007287 | Inorganic Chemicals |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
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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.
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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.
| Placebo | Drug | 60 milliliters normal saline |
|
|
| 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) |
| BG001 | 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. Placebo: 60 milliliters normal saline |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Gestational age | Median | Inter-Quartile Range | weeks of gestation |
|
| OG001 | 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. Placebo: 60 milliliters normal saline |
|
|
| Secondary | 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. | Posted | Median | Inter-Quartile Range | score on a scale | A one-time value collected 10 minutes after Cesarean fetal delivery |
|
|
|
| Secondary | Estimated Blood Loss | In milliliters. By blinded obstetrician, taking into account drape, sponge, and suction canister contents | Quantitative blood loss was not able to be performed, so estimated blood loss was used for all participants | Posted | Median | Inter-Quartile Range | milliters | Immediately upon surgery completion, as patient exits operating theater |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | hematocrit (%) | Drawn on postoperative day 1 as standard care |
|
|
|
| Secondary | Total Crystalloid During Cesarean | Amount of saline administered during cesarean | Posted | Median | Inter-Quartile Range | mL | During entire Cesarean delivery record (generally about 2 hours) |
|
|
|
| Secondary | 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 | Posted | Mean | Standard Deviation | beats per minute | first 45 minutes after study drug completion |
|
|
|
| Secondary | Maximal Decrease in Heartrate From Baseline | Heart rate monitored for 45 minutes after study drug infusion (well past peak) | Posted | Mean | Standard Deviation | beats per minute | 45 minutes after study drug infusion is complete |
|
|
|
| Secondary | 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. | All participants | Posted | Median | Inter-Quartile Range | mmHg | While in the operating room, generally about 2 hours |
|
|
|
| Secondary | 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. | All participants | Posted | Median | Inter-Quartile Range | mmHg | While in the operating room, generally about 2 hours |
|
|
|
| Secondary | Baseline Ionized Calcium Concentration | Ionized calcium levels measured by phlebotomy. Analyzed prior to any study drug administration. | Because this outcome was assessed at baseline prior to study drug administration, participants in the active and placebo groups who consented to phlebotomy were combined for this analysis. | Posted | Mean | 95% Confidence Interval | millimol per liter | Prior to study drug (up to 5 minutes for blood draw) |
|
|
|
| Secondary | 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). | Patients who received calcium chloride and consented to blood sampling for PK analysis. Patients who received placebo were not included since they did not receive calcium chloride and had no data collected for the outcome. | Posted | Mean | 95% Confidence Interval | L/min | 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) |
|
|
|
| Secondary | 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 | Patients who received calcium chloride and consented to blood sampling for PK analysis. Patients who received placebo were not included since they did not receive calcium chloride and had no data collected for the outcome. | Posted | Mean | 95% Confidence Interval | Liters | 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) |
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| 0 |
| 20 |
| 0 |
| 20 |
| 6 |
| 20 |
| EG001 | 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. Placebo: 60 milliliters normal saline | 0 | 20 | 0 | 20 | 6 | 20 |
|
| Nausea or vomiting | Gastrointestinal disorders | Systematic Assessment | Any patient who experienced nausea or vomiting counted toward this tally. |
|
| Hypertension | Cardiac disorders | Systematic Assessment | Any hypertension above the patient's baseline blood pressure noted in the 30 minutes after starting study drug |
|
| Arrhythmia | Cardiac disorders | Systematic Assessment | Any bradycardia with heart rate <60, tachycardia with heart rate >100, or other arrhythmia (anything other than normal sinus rhythm) noted within 30 minutes of the study drug administration |
|
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| D000091642 | Urogenital Diseases |
| D017606 |
| Chlorine Compounds |
| D008673 | Metals, Alkaline Earth |
| D004602 | Elements |
| D008670 | Metals |
| D001779 | Blood Coagulation Factors |
| D001685 | Biological Factors |
| D017670 | Sodium Compounds |