Amnioinfusion for Intrauterine Neuroprotection

Study Overview
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Brief Summary
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Hypoxic ischemic encephalopathy (HIE), a serious brain injury in infants, occurs in 2-9 per 1,000 infants after delivery. Up to 60% of infants diagnosed with HIE die and 25% of the survivors have long-term neurologic deficits. Risk factors for HIE include abnormal fetal heart tracings and intrauterine infection. Therapeutic whole-body cooling of infants with HIE is standard of care after delivery, with only 7-9 at-risk infants needing to be treated to prevent one infant from suffering long-term neurologic deficits. However, animal studies show that therapeutic cooling may be more beneficial when given in utero at the time of an insult, rather than after delivery. Though therapeutic cooling in utero has yet to be explored in humans, an established in utero fluid delivery system during labor-amnioinfusion-provides a unique opportunity for in utero intervention. We propose a pilot randomized controlled trial to test the feasibility and preliminary effects of room temperature amnioinfusion on tissue injury including HIE.

Detailed Description
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Hypoxic ischemic encephalopathy (HIE), a serious brain injury in infants, occurs in 2-9 per 1,000 infants after delivery. Up to 60% of infants diagnosed with HIE die and 25% of the survivors have long-term neurologic deficits. Risk factors for HIE include abnormal fetal heart tracings and intrauterine infection. In addition, maternal fever is associated with a four to five-fold increased risk of HIE. Two phases leading to HIE are recognized: neuronal death from cellular hypoxia and further injury from exhaustion of energy stores. Therapeutic cooling of infants with HIE provides neuroprotection by reducing metabolic demands and suppressing toxic processes. Studies show that whole-body cooling of infants reduces the risk of neurologic motor and cognitive deficits with brain imaging suggesting that human infants who are cooled earlier have a greater benefit. Moreover, animal studies show that brain cooling may be more beneficial when given in utero at the time of an insult during the first phase of cellular hypoxia, rather than after delivery. Though therapeutic cooling in utero has yet to be explored in humans, an established in utero fluid delivery system-amnioinfusion- provides a unique opportunity for in utero intervention. Amnioinfusion (AI), the administration of fluid via an intrauterine catheter inserted through the cervix, is a common intervention during labor to improve fetal heart tracings and reduce cesarean delivery. Introduced in 1983, it used warm saline due to a theoretical concern for fetal shock from cold fluids. Subsequent studies showed no advantage of warm fluids, and fluids at room temperature ( 25oC) have become standard. AI can lower in utero temperature by 1.0°C (36.4°C versus 37.4°C, P<0.01). This 1.0°C degree of cooling has been associated a 6% reduction in brain energy utilization which could be protective against neurological injury. This suggests that AI can be leveraged to lower in utero and fetal temperatures to protect against neurologic injury. Expanding the indication for AI is a novel approach to reduce neurologic injury in utero. However, there is a gap in the acceptability and efficacy of amnioinfusion for this indication. To fill this gap, we propose a pilot randomized controlled trial to test the feasibility and effects of amnioinfusion with fluids at room temperature on infants at high risk for neurologic injury including HIE.

Official Title
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Amnioinfusion for Intrauterine Neuroprotection: A Pilot Randomized Controlled Trial

Conditions
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Lactic Acidemia

Intervention / Treatment
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* Procedure: Amnioinfusion at room temperature (intervention arm)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Maternal age >18 years old Singleton Term gestational age at time of admission (>37 weeks 0 days); Exclusion Criteria: Major fetal anomaly Active substance or alcohol use Contraindications to intrauterine pressure catheter placement (e.g. placental previa, human immunodeficiency virus, Hepatitis C) Fetal growth restriction Inability to consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Amnioinfusion for intrapartum risk factors for neurologic morbidity versus no amnioinfusion.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amnioinfusion at room temperature (intervention arm)<br>Routine amnioinfusion will be administered via an intrauterine catheter inserted through the cervix. Normal saline at room temperature will be infused per hospital protocol at a rate of 600 milliliters/hour for the first hour followed by 180 milliliters/hour. A plastic applicator will be used to introduce a flexible disposable general-purpose temperature probe into the uterus. The probe will be guided to the contralateral side of the uterus from the intrauterine pressure catheter. Intrauterine temperature will then be measured by DataThermII continuous temperature monitor. This monitor has accuracy of 0.1 °C and will store temperature measurements every 10 minutes until delivery. The temperature data will be downloaded into a computer software. The DataThermII has been previously used in prior research to measure intrauterine temperature. | Procedure: Amnioinfusion at room temperature (intervention arm)<br>* Routine amnioinfusion and intrauterine temperature probe sensor<br>|
| No Intervention: Standard of care (control arm)<br>Women in this group will have the temperature probe placed and temperate measured as described in experimental arm. They will otherwise receive current standard of care (i.e. no amnioinfusion). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Umbilical artery lactate | Cord blood lactate at the time of delivery | Within 15 minutes of delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of eligible patients who consent to study | Number of patients approached and consented | Throughout study completion, an average of 1 year | 
| Ottawa Decisional self-efficacy scale | The Decisional Self-Efficacy Scale measures self-confidence or belief in one's ability to make decisions, including participate in shared decision making will be compared between arms. The scale consists of 11 questions on a five-point Likert scale from 0 to 5. Scores range from 0 (not at all confident) to 100 (very confident). A score of 0 means extremely low self efficacy and a score of 100 means extremely high self efficacy. | Scale collected once from date of delivery following randomization until hospital discharge but within the first week | 
| Labour Agentry Scale | Labour Agentry Scale, an instrument measuring expectancies and experiences of personal control during childbirth will be compared between arms. The Labour Agentry Scale consists of 29 short affirmative statements (e.g. 'I felt confident' and 'I felt tense'). Respondents were asked to rate each statement on a seven-point Likert scale from 1 (representing rarely) to 7 (representing almost always). Possible total scores for the Labour Agentry Scale range from 29 (indicating feelings of control rarely) to 203 (reflecting feelings of control almost always). | Scale collected once from date of delivery following randomization until hospital discharge but within the first week | 
| Intrauterine temperature | Temperature of uterus | 10-minute intervals from date/time of randomization until date/time of delivery, assessed only until fetus is delivered or end of second stage of labor. | 
| Neonatal core temperature | Core temperature | Within 10 minutes of birth | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Umbilical cord gases, Neonatal neurologic morbidity, Amnioinfusion