Uterine Atony, Uterine Atony With Hemorrhage, Postpartum Hemorrhage, Cesarean Section Complications
Conditions
Keywords
calcium chloride, uterine atony, postpartum hemorrhage, cesarean delivery, intrapartum cesarean
Brief summary
Postpartum hemorrhage (PPH) is the leading cause of maternal morbidity and mortality worldwide. Up to 80% of PPH is caused by uterine atony, the failure of the uterine smooth muscle to contract and compress the uterine vasculature after delivery. Laboratory and epidemiological studies show that low extracellular and serum calcium levels, respectively, decrease uterine contractility. A pilot study performed by the investigators supports the hypothesis that intravenous calcium chloride is well tolerated and may have utility in preventing uterine atony. The proposed research will establish the relationship between uterine tone and calcium through a clinical trial with an incorporated pharmacokinetic and pharmacodynamic (PK/PD) study. In a randomized, placebo-controlled, double-blind trial, investigators will establish the effect of 1 gram of intravenous calcium chloride upon quantitative blood loss and uterine tone during cesarean delivery in parturients with high risk of uterine atony. Investigators will concurrently collect serial venous blood samples to measure calcium for PK/PD modeling in this pregnant study cohort. High-quality clinical research and development of novel therapeutics to manage uterine atony are critical to reduce the high maternal morbidity and mortality from PPH.
Interventions
DRUGCalcium chloride
See arm description above
DRUGSaline placebo
see arm description above
Sponsors
Foundation for Anesthesia Education and Research
Society for Obstetric Anesthesia and Perinatology
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The patient, obstetrician, anesthesiologist, and clinical research staff will be blinded to the intervention. Drugs will be labeled only as study drug
Intervention model description
Double blind, placebo controlled randomized clinical trial with 1:1 allocation
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Patient had a trial of labor for vaginal delivery prior to cesarean * Patient received an oxytocin infusion for labor augmentation or induction prior to cesarean
Exclusion criteria
* renal dysfunction with serum Cr \>1.0 mg/dL * known underlying cardiac condition * treatment with digoxin within the last 2 weeks for a maternal or fetal indication * treatment with a calcium channel blocker medication within 24 hours * hypertension necessitating intravenous antihypertensive medication within 24 hours * emergent case in which study participation could in any way impede patient care by the judgement of the obstetrician, anesthesiologist, or bedside nurse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Quantitative Blood Loss | measurement occurs at conclusion of operating room case | Standardized volumetric and gravimetric assessment of blood loss during cesarean. Note: will analyze all participants, but planned subgroup analysis will also occur excluding patients with non-atonic reasons for blood loss including hysterotomy extension, placental abruption, cervical or vaginal laceration, etc |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Postpartum Hemorrhage | operative course (within 4-6 hours of fetal delivery) | Postpartum hemorrhage was defined as quantitative blood loss \> 1000 milliliters during operative course |
| Number of Participants With Second Line Uterotonic Requirement | within 4 hours of delivery | Yes/no: did the patient require treatment with methylergonovine, carboprost, and/or misoprostol for uterine atony |
| Number of Patients With a Transfusion Requirement | 96 hours of delivery | Yes/no, if patient required transfusion of packed red blood cells prior to hospital discharge |
| Change in Hematocrit From Baseline | 1 day | Measured pre-delivery hematocrit minus measured post-operative day 1 hematocrit. Correction factor of 3 hematocrit points per unit packed red blood cells transfused |
| Total Oxytocin Bolus Requirement | Cesarean duration, within 4-6 hours of fetal delivery | Total dose oxytocin bolus during cesarean |
| Uterine Tone Numerical Rating Score, 7 Minutes After Fetal Delivery | 7 minutes after fetal delivery, 5 minutes after initiating study drug infusion | Uterine tone assessment: Obstetricians at the study institution use the following validated scale to grade uterine tone for all cesarean deliveries. The obstetrician places their hand directly on the uterine fundus and scores the adequacy of contraction. The interrater characteristics of this scale have been published (Cole et al, 2021). The scale ranges from 0-10. A score of 0 is the worst possible score and represents a flaccid, atonic uterus. A score of 10 is the best possible score and represents a firmly-contracted uterus. |
| Uterine Tone Numerical Rating Score, 12 Minutes After Fetal Delivery | 12 minutes after fetal delivery, 10 minutes after initiating study drug infusion | Uterine tone assessment: Obstetricians at the study institution use the following validated scale to grade uterine tone for all cesarean deliveries. The obstetrician places their hand directly on the uterine fundus and scores the adequacy of contraction. The interrater characteristics of this scale have been published (Cole et al, PMID 33652161). The scale ranges from 0-10. A score of 0 is the worst possible score and represents a flaccid, atonic uterus. A score of 10 is the best possible score and represents a firmly-contracted uterus. |
| Percent Change in Mean Arterial Pressure | every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline | Baseline mean arterial blood pressure recorded as average of first 6 mean arterial blood pressures recorded in operating room. Percent change calculated as measured mean arterial blood pressure minus baseline, divided by baseline. Reported here as the maximal decrease in mean arterial pressure. Repeated measures ANOVA reported in Statistical Analysis. |
| Percent Change in Heart Rate From Baseline | every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline | Baseline heart rate recorded as average of first 6 heart rates recorded in operating room. Percent change calculated as measured heart rate minus baseline, divided by baseline. Maximal % increase in heart rate reported here. Repeated measures ANOVA used to analyze overall trend in Statistical Analysis below. |
| Total Phenylephrine Requirement | Duration of operating room time, up to 240 minutes | Total phenylephrine in milligrams administered while in the operating room |
| Pharmacokinetics of Calcium Chloride - Baseline Ionized Calcium | In the operating room prior to study drug administration (generally <30 minutes prior to fetal delivery and study drug administration) | Measured using an Abbott istat machine and CG8+ cartridge to determine venous blood gas ionized calcium levels |
| Pharmacokinetics of Calcium Chloride - Peak Change in Ionized Calcium From 1 Gram of Calcium Chloride | At Tmax (conclusion of the 10-minute intravenous calcium chloride infusion | Generated from a 2-compartment population pharmacokinetic model in NONMEM using serial venous blood gas ionized calcium concentrations. |
| Pharmacodynamic Effect of Calcium Upon Uterine Tone NRS | Within 20 minutes of study drug administration | Data were not collected. This measure required blood specimens to be obtained at the time of tone scores and this was not done. |
| Fluid Requirement | Operating room duration, usually 2 hours | Total crystalloid required during cesarean delivery in mL |
Other
| Measure | Time frame | Description |
|---|---|---|
| Quantitative Blood Loss, Subgroup Quantitative Blood Loss (QBL, mL), Excluding Cases of Documented Non-atonic Bleeding | Calculated at conclusion of operating room case | Pre-specified subgroup analysis of primary outcome: Because the proposed mechanism of calcium action-improving uterine contractility-was not expected to improve bleeding from causes such as hysterotomy extension or arterial bleeding, the trial was powered for a prespecified subgroup analysis excluding patients with nonatonic blood loss documented in the surgeon's operative report. Documented nonatonic bleeding was defined as presence in the surgeon's operative report narrative of any of the following: hysterotomy extension, hysterotomy types other than low transverse (eg classical, T- or J-shaped), invasive or abnormally adherent placenta, placental abruption, uterine rupture, bleeding from leiomyomas, grade 3 or 4 vaginal lacerations, or cervical lacerations. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Calcium Chloride 1 gram of calcium chloride in total volume 60mL with sterile saline, delivered over 10 minute controlled infusion at a constant rate (360mL/hour) beginning 2 minutes after fetal delivery and 1 minute after delayed cord clamp. | 60 |
| Saline Placebo 60mL sterile saline, delivered over 10 minute controlled infusion at a constant rate (360mL/hour) beginning 2 minutes after fetal delivery and 1 minute after delayed cord clamp. | 60 |
| Total | 120 |
Baseline characteristics
| Characteristic | Total | Calcium Chloride | Saline Placebo |
|---|---|---|---|
| Advanced maternal age (n, %) | 46 Participants | 28 Participants | 18 Participants |
| Age, Continuous | 33.3 years STANDARD_DEVIATION 5.2 | 33.8 years STANDARD_DEVIATION 5.2 | 32.8 years STANDARD_DEVIATION 5.2 |
| Asthma (n, %) | 10 Participants | 3 Participants | 7 Participants |
| Body Mass index (kg/m^2) | 31.9 kg/m^2 STANDARD_DEVIATION 5.4 | 31.6 kg/m^2 STANDARD_DEVIATION 4.6 | 32.2 kg/m^2 STANDARD_DEVIATION 6.1 |
| Chorioamnionitis (n, %) | 17 Participants | 9 Participants | 8 Participants |
| Diabetes, all causes (n, %) | 18 Participants | 7 Participants | 11 Participants |
| Gestational age (completed weeks) | 39 completed weeks | 39 completed weeks | 39 completed weeks |
| Gravida (n) | 1 pregnancies | 1 pregnancies | 1 pregnancies |
| Hours of oxytocin exposure during labor | 17.4 hours STANDARD_DEVIATION 12.1 | 16.3 hours STANDARD_DEVIATION 12 | 18.5 hours STANDARD_DEVIATION 12.1 |
| Hypertension from all causes (n, %) | 24 Participants | 7 Participants | 17 Participants |
| Indication: failed operative vaginal delivery | 4 Participants | 1 Participants | 3 Participants |
| Indication: fetal intolerance of labor | 34 Participants | 16 Participants | 18 Participants |
| Indication: first stage arrest | 61 Participants | 31 Participants | 30 Participants |
| Indication: maternal request | 4 Participants | 1 Participants | 3 Participants |
| Indication: other | 5 Participants | 3 Participants | 2 Participants |
| Indication: second stage arrest | 38 Participants | 20 Participants | 18 Participants |
| Maximum oxytocin dose in labor | 12.1 milliunits per minute STANDARD_DEVIATION 8.8 | 11.7 milliunits per minute STANDARD_DEVIATION 8.5 | 12.4 milliunits per minute STANDARD_DEVIATION 9.1 |
| Multiple gestation (n, %) | 2 Participants | 1 Participants | 1 Participants |
| Para | 0 Prior pregnancies | 0 Prior pregnancies | 0 Prior pregnancies |
| Preeclampsia (n, %) | 11 Participants | 4 Participants | 7 Participants |
| Race/Ethnicity, Customized Asian | 43 Participants | 24 Participants | 19 Participants |
| Race/Ethnicity, Customized Hispanic or Latina | 40 Participants | 17 Participants | 23 Participants |
| Race/Ethnicity, Customized Non-hispanic black | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Non-hispanic white | 28 Participants | 16 Participants | 12 Participants |
| Race/Ethnicity, Customized Other or declines to state | 7 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Female | 120 Participants | 60 Participants | 60 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Trial of Labor after Cesarean (TOLAC) (n, %) | 8 Participants | 5 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 60 | 0 / 60 |
| other Total, other adverse events | 23 / 60 | 25 / 60 |
| serious Total, serious adverse events | 0 / 60 | 0 / 60 |
Outcome results
Primary
Quantitative Blood Loss
Standardized volumetric and gravimetric assessment of blood loss during cesarean. Note: will analyze all participants, but planned subgroup analysis will also occur excluding patients with non-atonic reasons for blood loss including hysterotomy extension, placental abruption, cervical or vaginal laceration, etc
Time frame: measurement occurs at conclusion of operating room case
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Calcium Chloride | Quantitative Blood Loss | 840 milliliters |
| Saline Placebo | Quantitative Blood Loss | 1051 milliliters |
p-value: <0.0595% CI: [-33, 410]inverse Gaussian distribution and log li
Secondary
Change in Hematocrit From Baseline
Measured pre-delivery hematocrit minus measured post-operative day 1 hematocrit. Correction factor of 3 hematocrit points per unit packed red blood cells transfused
Time frame: 1 day
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Calcium Chloride | Change in Hematocrit From Baseline | 7.8 Percentage of hematocrit |
| Saline Placebo | Change in Hematocrit From Baseline | 9.6 Percentage of hematocrit |
95% CI: [-3.6, 0.2]Regression, Linear
Secondary
Fluid Requirement
Total crystalloid required during cesarean delivery in mL
Time frame: Operating room duration, usually 2 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Calcium Chloride | Fluid Requirement | 1594 milliliters | Standard Deviation 762 |
| Saline Placebo | Fluid Requirement | 1502 milliliters | Standard Deviation 892 |
Secondary
Number of Participants With Postpartum Hemorrhage
Postpartum hemorrhage was defined as quantitative blood loss \> 1000 milliliters during operative course
Time frame: operative course (within 4-6 hours of fetal delivery)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Calcium Chloride | Number of Participants With Postpartum Hemorrhage | 24 Participants |
| Saline Placebo | Number of Participants With Postpartum Hemorrhage | 34 Participants |
95% CI: [0.48, 1.03]Regression (poisson with robust SE)
Secondary
Number of Participants With Second Line Uterotonic Requirement
Yes/no: did the patient require treatment with methylergonovine, carboprost, and/or misoprostol for uterine atony
Time frame: within 4 hours of delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Calcium Chloride | Number of Participants With Second Line Uterotonic Requirement | 18 Participants |
| Saline Placebo | Number of Participants With Second Line Uterotonic Requirement | 24 Participants |
95% CI: [0.46, 1.23]Poisson regression with robust SE
Secondary
Number of Patients With a Transfusion Requirement
Yes/no, if patient required transfusion of packed red blood cells prior to hospital discharge
Time frame: 96 hours of delivery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Calcium Chloride | Number of Patients With a Transfusion Requirement | 5 Participants |
| Saline Placebo | Number of Patients With a Transfusion Requirement | 9 Participants |
95% CI: [0.2, 1.56]
Secondary
Percent Change in Heart Rate From Baseline
Baseline heart rate recorded as average of first 6 heart rates recorded in operating room. Percent change calculated as measured heart rate minus baseline, divided by baseline. Maximal % increase in heart rate reported here. Repeated measures ANOVA used to analyze overall trend in Statistical Analysis below.
Time frame: every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Calcium Chloride | Percent Change in Heart Rate From Baseline | 0 percent change |
| Saline Placebo | Percent Change in Heart Rate From Baseline | 10 percent change |
Comparison: Repeated measures ANOVA used to assess for difference between groups in the % change from baseline heart rate.p-value: 0.011ANOVA
Secondary
Percent Change in Mean Arterial Pressure
Baseline mean arterial blood pressure recorded as average of first 6 mean arterial blood pressures recorded in operating room. Percent change calculated as measured mean arterial blood pressure minus baseline, divided by baseline. Reported here as the maximal decrease in mean arterial pressure. Repeated measures ANOVA reported in Statistical Analysis.
Time frame: every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Calcium Chloride | Percent Change in Mean Arterial Pressure | 16 percent change |
| Saline Placebo | Percent Change in Mean Arterial Pressure | 12 percent change |
Comparison: Repeated measures ANOVA used to analyze differences between groups.p-value: 0.348ANOVA
Secondary
Pharmacodynamic Effect of Calcium Upon Uterine Tone NRS
Data were not collected. This measure required blood specimens to be obtained at the time of tone scores and this was not done.
Time frame: Within 20 minutes of study drug administration
Population: Data not collected (unable to obtain blood specimens at the time of tone scores)
Secondary
Pharmacokinetics of Calcium Chloride - Baseline Ionized Calcium
Measured using an Abbott istat machine and CG8+ cartridge to determine venous blood gas ionized calcium levels
Time frame: In the operating room prior to study drug administration (generally <30 minutes prior to fetal delivery and study drug administration)
Population: A total of 35 trial participants consented to provide serial blood specimens for ionized calcium measurement and pharmacokinetic analysis, per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Calcium Chloride | Pharmacokinetics of Calcium Chloride - Baseline Ionized Calcium | 1.15 mmoL / liter | Standard Deviation 0.02 |
| Saline Placebo | Pharmacokinetics of Calcium Chloride - Baseline Ionized Calcium | 1.16 mmoL / liter | Standard Deviation 0.03 |
p-value: 0.25t-test, 2 sided
Secondary
Pharmacokinetics of Calcium Chloride - Peak Change in Ionized Calcium From 1 Gram of Calcium Chloride
Generated from a 2-compartment population pharmacokinetic model in NONMEM using serial venous blood gas ionized calcium concentrations.
Time frame: At Tmax (conclusion of the 10-minute intravenous calcium chloride infusion
Population: Participants who participated in the nested pharmacokinetic study and were randomly assigned to the calcium chloride group.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Calcium Chloride | Pharmacokinetics of Calcium Chloride - Peak Change in Ionized Calcium From 1 Gram of Calcium Chloride | 0.39 mmoL / liter |
Secondary
Total Oxytocin Bolus Requirement
Total dose oxytocin bolus during cesarean
Time frame: Cesarean duration, within 4-6 hours of fetal delivery
Population: Note: institutional standard policy is a 2 unit oxytocin bolus at the time of fetal delivery, with additional boluses prn
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Calcium Chloride | Total Oxytocin Bolus Requirement | 3 units |
| Saline Placebo | Total Oxytocin Bolus Requirement | 3 units |
Secondary
Total Phenylephrine Requirement
Total phenylephrine in milligrams administered while in the operating room
Time frame: Duration of operating room time, up to 240 minutes
Population: Total of documented phenylephrine bolus and infusion administration during operative course
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Calcium Chloride | Total Phenylephrine Requirement | 1.02 milligrams |
| Saline Placebo | Total Phenylephrine Requirement | 1.09 milligrams |
Secondary
Uterine Tone Numerical Rating Score, 12 Minutes After Fetal Delivery
Uterine tone assessment: Obstetricians at the study institution use the following validated scale to grade uterine tone for all cesarean deliveries. The obstetrician places their hand directly on the uterine fundus and scores the adequacy of contraction. The interrater characteristics of this scale have been published (Cole et al, PMID 33652161). The scale ranges from 0-10. A score of 0 is the worst possible score and represents a flaccid, atonic uterus. A score of 10 is the best possible score and represents a firmly-contracted uterus.
Time frame: 12 minutes after fetal delivery, 10 minutes after initiating study drug infusion
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Calcium Chloride | Uterine Tone Numerical Rating Score, 12 Minutes After Fetal Delivery | 7 units on a scale |
| Saline Placebo | Uterine Tone Numerical Rating Score, 12 Minutes After Fetal Delivery | 7 units on a scale |
p-value: 0.566Wilcoxon (Mann-Whitney)
Secondary
Uterine Tone Numerical Rating Score, 7 Minutes After Fetal Delivery
Uterine tone assessment: Obstetricians at the study institution use the following validated scale to grade uterine tone for all cesarean deliveries. The obstetrician places their hand directly on the uterine fundus and scores the adequacy of contraction. The interrater characteristics of this scale have been published (Cole et al, 2021). The scale ranges from 0-10. A score of 0 is the worst possible score and represents a flaccid, atonic uterus. A score of 10 is the best possible score and represents a firmly-contracted uterus.
Time frame: 7 minutes after fetal delivery, 5 minutes after initiating study drug infusion
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Calcium Chloride | Uterine Tone Numerical Rating Score, 7 Minutes After Fetal Delivery | 7 units on a scale |
| Saline Placebo | Uterine Tone Numerical Rating Score, 7 Minutes After Fetal Delivery | 6.5 units on a scale |
p-value: 0.415Wilcoxon (Mann-Whitney)
Other Pre-specified
Quantitative Blood Loss, Subgroup Quantitative Blood Loss (QBL, mL), Excluding Cases of Documented Non-atonic Bleeding
Pre-specified subgroup analysis of primary outcome: Because the proposed mechanism of calcium action-improving uterine contractility-was not expected to improve bleeding from causes such as hysterotomy extension or arterial bleeding, the trial was powered for a prespecified subgroup analysis excluding patients with nonatonic blood loss documented in the surgeon's operative report. Documented nonatonic bleeding was defined as presence in the surgeon's operative report narrative of any of the following: hysterotomy extension, hysterotomy types other than low transverse (eg classical, T- or J-shaped), invasive or abnormally adherent placenta, placental abruption, uterine rupture, bleeding from leiomyomas, grade 3 or 4 vaginal lacerations, or cervical lacerations.
Time frame: Calculated at conclusion of operating room case
Population: Pre=specified subgroup analysis, excluded cases of documented nonatonic bleeding (mostly due to hysterotomy extension, present in 21 participants allocated to calcium and 20 participants allocated to placebo).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Calcium Chloride | Quantitative Blood Loss, Subgroup Quantitative Blood Loss (QBL, mL), Excluding Cases of Documented Non-atonic Bleeding | 759 milliliters |
| Saline Placebo | Quantitative Blood Loss, Subgroup Quantitative Blood Loss (QBL, mL), Excluding Cases of Documented Non-atonic Bleeding | 922 milliliters |
p-value: <0.0595% CI: [159, 515]Inverse Gaussian regression, log link