Appropriate Dosage of Vasopressor in Neonates and Infants

NCT ID: NCT06257316

Last Updated: 2024-02-15

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 132 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-02-15
• Study Completion Date: 2028-02-28

Brief Summary

In this study, the investigators will evaluate cerebral blood flow before and after drug infusion using ultrasound to suggest blood pressure criteria and dosage of ephedrine, a vasopressor, to maintain adequate cerebral blood flow in neonates and infants undergoing surgery and anesthesia.

Detailed Description

Improvements in surgical techniques and perioperative care in the neonate have resulted in a significant improvement in survival rates, with the mortality rate for neonatal noncardiac surgery being less than 5% in 2013, compared to 72% in 1947. As survival rates have improved, the question of long-term prognosis, especially concerning delayed cranial nerve development and subsequent quality of life, has emerged. In 48% of full-term infants undergoing non-cardiac surgery in the neonatal period for major congenital conditions (diaphragmatic hernia, esophageal atresia, abdominal wall defects, congenital megacolon, etc.) and 75% of preterm infants, brain damage is identified on post-operative brain MRI, and developmental testing reveals cognitive impairment in 3-56% and motor impairment in 0-77%.

motor disorders in 3-56% and 0-77%. Cognitive and motor deficits are known to occur in 45% of patients undergoing non-cardiac surgery for congenital conditions, excluding neurodevelopmental disorders caused by the concomitant congenital genetic disease itself.

Cerebral perfusion is regulated by arterial baroreflex, cerebral blood flow autoregulation, and flow metabolism, which are immature in the neonate and are lost under general anesthesia. This can lead to intraoperative changes in blood pressure, carbon dioxide concentration, intraventricular hemorrhage, and lateral ventricular hemorrhagic infarction, which can cause brain damage.

According to the Anaesthesia Practice in Children Observational Trial study, 32% of children undergoing general anesthesia and surgery develop hypotension that requires inotropes. The goal of maintaining arterial blood pressure at a constant level in infants during surgery is to maintain blood flow to vital organs, including the brain. However, there is a lack of evidence on what blood pressure should be maintained to maintain adequate cerebral perfusion in infants and how much hypotension is acceptable. The current definition of normal blood pressure in infants is based on birth weight and gestational age. For example, if the gestational age is 36 weeks, the recommendation is to maintain a mean arterial pressure of 36 mm Hg or higher. However, studies have shown that mean arterial pressure below this level does not affect prognosis as long as adequate perfusion is maintained. Furthermore, raising blood pressure to maintain normotension based on gestational age may lead to intraventricular hemorrhage. A recent study was published to determine the appropriate dose of ephedrine in infants with intraoperative hypotension and found that a higher dose (1.2 mg/kg) than the adult dose (0.1 mg/kg) was required to raise blood pressure, but the study was limited by the lack of confirmation of how raising blood pressure changes cerebral blood flow. Therefore, in this study, the investigators aimed to determine the changes in cerebral blood flow according to the dose of ephedrine infusion in neonates and infants as measured by the changes in blood flow in the internal carotid artery using transcranial ultrasound and to suggest blood pressure standards and ephedrine dosage for maintaining adequate cerebral blood flow in neonates and infants.

Conditions

Hypotension; Neonatal Hypotension; Intraoperative Complications

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

0.1mg/kg of ephedrine

If the mean arterial pressure decreases by more than 20% from baseline after induction of anesthesia and infusion of fluids until the start of surgery, a randomized dose of ephedrine will be administered.

Six single doses were evaluated using six cohorts (N=20 per cohort). Subjects received single doses of ephedrine intravenously: 0.1, 0.2, 0.3, 0.5, 1.0, 1.2 mg/kg.

Initially, 3 cohorts received the study drug at a given dose, after assessing the safety of ephedrine by the Korean Ministry of Food and Drug Safety, the additional 60 subjects in 3 cohorts received the study drug.

Group Type: ACTIVE_COMPARATOR

EPHEDrine Hydrochloride 5 mg/ml

Intervention Type: DRUG

In the present study, the expected rate of recovery of the internal carotid artery according to the dose of the inotropic agent was similar to that in a previous study in which the fraction maintaining mean arterial pressure within 80% of baseline by dose of inotropic agent was 0.9% for the ephedrine 0.1, 0.6, 0.8, 1. 0, 1.2, and 1.4 doses (mg/kg) were 9.9%, 21%, 41%, 47%, 65.5%, and 40%, respectively (Br J Anaesth. 2023 May;130(5):603-610), and it was assumed that the rate of internal carotid artery recovery by inotrope dose would be 90% of that result.

The study will randomize to dose in six cohorts and will include dose group and cohort variables in a logistic regression model to assess the trend between inotropic dose and rate of carotid revascularization after correcting for cohort effects on the outcome variable.

0.2mg/kg of ephedrine

If the mean arterial pressure decreases by more than 20% from baseline after induction of anesthesia and infusion of fluids until the start of surgery, a randomized dose of ephedrine will be administered.

Six single doses were evaluated using six cohorts (N=20 per cohort). Subjects received single doses of ephedrine intravenously: 0.1, 0.2, 0.3, 0.5, 1.0, 1.2 mg/kg.

Initially, 3 cohorts received the study drug at a given dose, after assessing the safety of ephedrine by the Korean Ministry of Food and Drug Safety, the additional 60 subjects in 3 cohorts received the study drug.

Group Type: ACTIVE_COMPARATOR

EPHEDrine Hydrochloride 5 mg/ml

Intervention Type: DRUG

In the present study, the expected rate of recovery of the internal carotid artery according to the dose of the inotropic agent was similar to that in a previous study in which the fraction maintaining mean arterial pressure within 80% of baseline by dose of inotropic agent was 0.9% for the ephedrine 0.1, 0.6, 0.8, 1. 0, 1.2, and 1.4 doses (mg/kg) were 9.9%, 21%, 41%, 47%, 65.5%, and 40%, respectively (Br J Anaesth. 2023 May;130(5):603-610), and it was assumed that the rate of internal carotid artery recovery by inotrope dose would be 90% of that result.

The study will randomize to dose in six cohorts and will include dose group and cohort variables in a logistic regression model to assess the trend between inotropic dose and rate of carotid revascularization after correcting for cohort effects on the outcome variable.

0.3mg/kg of ephedrine

If the mean arterial pressure decreases by more than 20% from baseline after induction of anesthesia and infusion of fluids until the start of surgery, a randomized dose of ephedrine will be administered.

Six single doses were evaluated using six cohorts (N=20 per cohort). Subjects received single doses of ephedrine intravenously: 0.1, 0.2, 0.3, 0.5, 1.0, and 1.2 mg/kg.

Initially, 3 cohorts received the study drug at a given dose, after assessing the safety of ephedrine by the Korean Ministry of Food and Drug Safety, the additional 60 subjects in 3 cohorts received the study drug.

Group Type: ACTIVE_COMPARATOR

EPHEDrine Hydrochloride 5 mg/ml

Intervention Type: DRUG

In the present study, the expected rate of recovery of the internal carotid artery according to the dose of the inotropic agent was similar to that in a previous study in which the fraction maintaining mean arterial pressure within 80% of baseline by dose of inotropic agent was 0.9% for the ephedrine 0.1, 0.6, 0.8, 1. 0, 1.2, and 1.4 doses (mg/kg) were 9.9%, 21%, 41%, 47%, 65.5%, and 40%, respectively (Br J Anaesth. 2023 May;130(5):603-610), and it was assumed that the rate of internal carotid artery recovery by inotrope dose would be 90% of that result.

The study will randomize to dose in six cohorts and will include dose group and cohort variables in a logistic regression model to assess the trend between inotropic dose and rate of carotid revascularization after correcting for cohort effects on the outcome variable.

0.5mg/kg of ephedrine

If the mean arterial pressure decreases by more than 20% from baseline after induction of anesthesia and infusion of fluids until the start of surgery, a randomized dose of ephedrine will be administered.

Six single doses were evaluated using six cohorts (N=20 per cohort). Subjects received single doses of ephedrine intravenously: 0.1, 0.2, 0.3, 0.5, 1.0, and 1.2 mg/kg.

Initially, 3 cohorts received the study drug at a given dose, after assessing the safety of ephedrine by the Korean Ministry of Food and Drug Safety, the additional 60 subjects in 3 cohorts received the study drug.

Group Type: ACTIVE_COMPARATOR

EPHEDrine Hydrochloride 5 mg/ml

Intervention Type: DRUG

In the present study, the expected rate of recovery of the internal carotid artery according to the dose of the inotropic agent was similar to that in a previous study in which the fraction maintaining mean arterial pressure within 80% of baseline by dose of inotropic agent was 0.9% for the ephedrine 0.1, 0.6, 0.8, 1. 0, 1.2, and 1.4 doses (mg/kg) were 9.9%, 21%, 41%, 47%, 65.5%, and 40%, respectively (Br J Anaesth. 2023 May;130(5):603-610), and it was assumed that the rate of internal carotid artery recovery by inotrope dose would be 90% of that result.

The study will randomize to dose in six cohorts and will include dose group and cohort variables in a logistic regression model to assess the trend between inotropic dose and rate of carotid revascularization after correcting for cohort effects on the outcome variable.

1.0mg/kg of ephedrine

If the mean arterial pressure decreases by more than 20% from baseline after induction of anesthesia and infusion of fluids until the start of surgery, a randomized dose of ephedrine will be administered.

Six single doses were evaluated using six cohorts (N=20 per cohort). Subjects received single doses of ephedrine intravenously: 0.1, 0.2, 0.3, 0.5, 1.0, and 1.2 mg/kg.

Initially, 3 cohorts received the study drug at a given dose, after assessing the safety of ephedrine by the Korean Ministry of Food and Drug Safety, the additional 60 subjects in 3 cohorts received the study drug.

Group Type: ACTIVE_COMPARATOR

EPHEDrine Hydrochloride 5 mg/ml

Intervention Type: DRUG

In the present study, the expected rate of recovery of the internal carotid artery according to the dose of the inotropic agent was similar to that in a previous study in which the fraction maintaining mean arterial pressure within 80% of baseline by dose of inotropic agent was 0.9% for the ephedrine 0.1, 0.6, 0.8, 1. 0, 1.2, and 1.4 doses (mg/kg) were 9.9%, 21%, 41%, 47%, 65.5%, and 40%, respectively (Br J Anaesth. 2023 May;130(5):603-610), and it was assumed that the rate of internal carotid artery recovery by inotrope dose would be 90% of that result.

The study will randomize to dose in six cohorts and will include dose group and cohort variables in a logistic regression model to assess the trend between inotropic dose and rate of carotid revascularization after correcting for cohort effects on the outcome variable.

1.2mg/kg of ephedrine

If the mean arterial pressure decreases by more than 20% from baseline after induction of anesthesia and infusion of fluids until the start of surgery, a randomized dose of ephedrine will be administered.

Six single doses were evaluated using six cohorts (N=20 per cohort). Subjects received single doses of ephedrine intravenously: 0.1, 0.2, 0.3, 0.5, 1.0, and 1.2 mg/kg.

Initially, 3 cohorts received the study drug at a given dose, after assessing the safety of ephedrine by the Korean Ministry of Food and Drug Safety, the additional 60 subjects in 3 cohorts received the study drug.

Group Type: ACTIVE_COMPARATOR

EPHEDrine Hydrochloride 5 mg/ml

Intervention Type: DRUG

In the present study, the expected rate of recovery of the internal carotid artery according to the dose of the inotropic agent was similar to that in a previous study in which the fraction maintaining mean arterial pressure within 80% of baseline by dose of inotropic agent was 0.9% for the ephedrine 0.1, 0.6, 0.8, 1. 0, 1.2, and 1.4 doses (mg/kg) were 9.9%, 21%, 41%, 47%, 65.5%, and 40%, respectively (Br J Anaesth. 2023 May;130(5):603-610), and it was assumed that the rate of internal carotid artery recovery by inotrope dose would be 90% of that result.

The study will randomize to dose in six cohorts and will include dose group and cohort variables in a logistic regression model to assess the trend between inotropic dose and rate of carotid revascularization after correcting for cohort effects on the outcome variable.

Interventions

EPHEDrine Hydrochloride 5 mg/ml

In the present study, the expected rate of recovery of the internal carotid artery according to the dose of the inotropic agent was similar to that in a previous study in which the fraction maintaining mean arterial pressure within 80% of baseline by dose of inotropic agent was 0.9% for the ephedrine 0.1, 0.6, 0.8, 1. 0, 1.2, and 1.4 doses (mg/kg) were 9.9%, 21%, 41%, 47%, 65.5%, and 40%, respectively (Br J Anaesth. 2023 May;130(5):603-610), and it was assumed that the rate of internal carotid artery recovery by inotrope dose would be 90% of that result.

The study will randomize to dose in six cohorts and will include dose group and cohort variables in a logistic regression model to assess the trend between inotropic dose and rate of carotid revascularization after correcting for cohort effects on the outcome variable.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Newborns and infants under 2 years of age undergoing surgery under general anesthesia at Seoul National University Hospital

Exclusion Criteria

• Premature infants with a gestational age of less than 37 weeks
• Children with a history of brain disease (hydrocephalus, brain tumor, etc.)
• Patients with a history of hypoxic/ischemic brain injury
• Children with fused fontanels
• Children with uncorrected congenital cardiac malformations such as patent ductus arteriosus
• Patients with hypersensitivity to ephedrine and its components
• Patients with hypertension
• Patients with thyrotoxicosis
• Patients with renal impairment and those taking thyroid medication
• Glaucoma patients
• Diabetic patients
• Patients with prostatic hyperplasia
• Patients with chromophobe cell tumors
• Patients taking or within 2 weeks of discontinuing monoamine oxidase inhibitors
• Patients with ischemic heart disease
• Patients receiving foxglove preparations
• Patients with cardiac disease
• Patients receiving inotropic agents and those with abnormal baseline blood pressure
• Those who are taking or need to take concomitant contraindicated medications
• Those who require halogenated anesthetics such as chloroform, cyclopropane, and halothane because concomitant administration may cause ventricular arrhythmias.
• Those who are expected to require these agents because they may cause arrhythmias or cardiac arrest when coadministered with catecholamines such as epinephrine and isoproterenol.

• Maximum Eligible Age: 2 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Seoul National University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Eun-hee Kim

Clinical associate professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Eun-Hee Kim, M.D., Ph.D.

Role: STUDY_CHAIR

Seoul National University Hospital

Central Contacts

Eun-Hee Kim, M.D., Ph.D.

Role: CONTACT

beloveun@snuh.org

+82-2-2072-3664

Other Identifiers

2312-009-1489

Identifier Type: -

Identifier Source: org_study_id