Calcium Chloride for Prevention of Blood Loss During Intrapartum Cesarean Delivery

Study Overview
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Brief Summary
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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.

Official Title
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Calcium Chloride for Prevention of Blood Loss From Uterine Atony During Intrapartum Cesarean Delivery (CALBLOC): a Double Blind, Randomized, Placebo Controlled Trial and Nested Population Pharmacokinetic and Pharmacodynamic Analysis

Conditions
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Uterine Atony, Uterine Atony With Hemorrhage, Postpartum Hemorrhage, Cesarean Section Complications

Intervention / Treatment
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* Drug: Calcium chloride
* Drug: Saline placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double blind, placebo controlled randomized clinical trial with 1:1 allocation
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Calcium chloride<br>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. This intervention occurs IN ADDITION TO standard care with oxytocin 2 unit bolus and infusion at 7.5 units per hour which begins immediately after fetal delivery. | Drug: Calcium chloride<br>* See arm description above<br>|
| Placebo Comparator: Saline placebo<br>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. This intervention occurs IN ADDITION TO standard care with oxytocin 2 unit bolus and infusion at 7.5 units per hour which begins immediately after fetal delivery. | Drug: Saline placebo<br>* see arm description above<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | measurement occurs at conclusion of operating room case | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Uterine tone numerical rating score | Uterine tone assessment | 2, 7, and 12 minutes after fetal delivery. The absolute 12 minute score as well as delta from 12-2 and 12-7 minute scores will be analyzed | 
| Second line uterotonic requirement | Yes/no: did the patient require treatment with methylergonovine, carboprost, and/or misoprostol for uterine atony | within 4 hours of delivery | 
| Fluid requirement | Total crystalloid required during cesarean delivery in mL | Operating room duration, usually 2 hours | 
| Total oxytocin bolus requirement | Total dose oxytocin bolus during cesarean | Cesarean duration, usually about 2 hours | 
| Transfusion requirement | Yes/no and total units packed red blood cells | 96 hours of delivery | 
| Pharmacokinetics of calcium chloride | analyzed in NONMEM using serial venous blood gas ionized calcium levels from willing participants | Within 4 hours of study drug administration | 
| Pharmacodynamic effect of calcium upon uterine tone NRS | also analyzed in NONMEM | Within 20 minutes of study drug administration | 
| 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. | every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline | 
| Percent change in mean arterial blood pressure from 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. | every 5 minutes for 30 minutes after study drug infusion initiation, compared to baseline | 
| Total phenylephrine requirement | Total phenylephrine in milligrams administered while in the operating room | Duration of operating room time | 
| 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 | 1 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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calcium chloride, uterine atony, postpartum hemorrhage, cesarean delivery, intrapartum cesarean