The Effect of Anesthesia on Neurodevelopmental Outcome (NDO) (NDO)

Anesthesia and the Developing Brain: a Comparison of Two Anesthetic Techniques

The purpose of this study is to assess whether the type of anesthesia, narcotic-based versus inhalational anesthesia administered during cardiopulmonary bypass (CPB) surgery contributes to the wide variation in neurologic recovery and developmental outcome after surgery in infants with congenital heart disease.

Study Overview

• Status: Completed
• Conditions: Neurodevelopmental Disorders; Congenital Heart Disease; Anesthesia; Adverse Effect
• Intervention / Treatment: Drug: Isoflurane; Drug: Fentanyl (low dose); Drug: Fentanyl (high dose)

Detailed Description

All subjects will be consented prior to participation in this study and prior to randomization.

All the subjects enrolled in the study will receive a preoperative assessment by one of the cardiac anesthesiologists and receive standardized induction with sevoflurane up to 2%, 2 mcg/kg of fentanyl and 1 mg/kg of rocuronium. The anesthetic maintenance will be determined using a computer- generated randomization table and assigning each patient to one of the two anesthetic regimens. Both of these anesthetic techniques are standard of care and are commonly used for these procedures.

Anesthetic Technique:

Volatile anesthetic:

In volatile anesthetic technique, maintenance of anesthesia will be standardized to the volatile anesthetic isoflurane. Isoflurane will be used for the study since this is what is presently available on the CPB machines. Anesthesia at 1.0 minimum anesthetic concentration (MAC) indicates that at this concentration 50% of the patients will not move when surgically stimulated. Anesthesiologists commonly use about 1.2-1.4 MAC in neonates, since the MAC value in infants is higher than that of children and adults. Isoflurane will be delivered at 1.5-2.0%% as required for anesthetic management.

Rocuronium or pancuronium will be used for muscle relaxation. Narcotic, fentanyl will be administered at no greater than 2 mcg/kg/hr.

Narcotic-based anesthetic:

In narcotic based anesthetic technique, no volatile anesthetics will be used except during induction.

Maintenance of anesthesia will be with fentanyl 5 mcg/kg/hr not to exceed 10 mcg/kg/hr.

The anesthetic may be supplemented with dexmedetomidine 0.05 mcg/kg/hr but not to exceed 1.0 mcg/kg/hr. Narcotic-based anesthetic will be used by the cardiac anesthesia team and the CPB technician throughout the operative case. 5 mcg/kg/hr of fentanyl is felt to represent 0.6 MAC of anesthesia.

Postoperative Sedative and Analgesic Care:

As per institutional standard of care, postoperative sedation will consist of fentanyl infusions of 2-4 mcg/kg/hr for the first 48 hours postoperatively.

A total of 9 Blood samples will be collected at different time points throughout the entire study for metabolomics determination (NAA/Cr and Chol/Cr)

EEG monitoring will be done for baseline in the pre-operative period for 15-20 minutes, during surgery and post-operatively up to 48 hours and prior to discharge for 15-20 minutes. Neurological and behavioral testing including Bayley Exam III will be done at 18-48 months.

• Study Type: Interventional
• Enrollment (Actual): 153
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94305
      • Stanford Childrens hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 3 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Neonates of at least 32 weeks of gestation, infants and children up to 2 years of age admitted to The Children's Hospital for treatment of cyanotic or non-cyanotic heart disease requiring surgical intervention.
• Admitting diagnosis of cyanotic or non-cyanotic heart disease

Exclusion Criteria:

• Neonates less than 32 weeks of gestational age, and children more than 2 years of age.
• Any documented central nervous system malformations.
• Any potential subject requiring unexpected postoperative Extracorporeal membrane oxygenation (ECMO) support

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Volatile Anesthesia; In volatile anesthetic technique, maintenance of anesthesia will be standardized to the anesthesia will be standardized to the volatile anesthetic isoflurane. Rocuronium or pancuronium will be used for muscle relaxation. Additionally, narcotic fentanyl will be administered at no greater than 2 mcg/kg/hr (low dose). However, the primary anesthetic during CPB will be isoflurane with no narcotic administered during CPB.	Drug: Isoflurane; Isoflurane (volatile anesthesia) will be delivered at 1.5-2.0%% as required for anesthetic management.; Drug: Fentanyl (low dose); Fentanyl (narcotic anesthesia) maintenance will be with fentanyl 2 mcg/kg/hr.
ACTIVE_COMPARATOR: Narcotic based anesthesia; In narcotic based anesthetic technique, no volatile anesthetics will be used past induction. Maintenance of anesthesia will be with fentanyl 5 mcg/kg/hr not to exceed 10 mcg/kg/hr (high dose).	Drug: Fentanyl (high dose); Fentanyl (narcotic anesthesia) maintenance will be with fentanyl 5 mcg/kg/hr not to exceed 10 mcg/kg/hr.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bayley III	Neurodevelopmental assessment scores are age dependent and based motor and behavioral abilities, often reported for normal or abnormal for age. Bayley Scales of Infant and Toddler Development, third edition, (Bayley III) is an instrument designed to measure the developmental functioning of infants and toddlers between the ages of 1 month and 42 months (age adjustments for prematurity are accommodated with the tool). It provides age specific composite scores for cognitive (91 items, score min 55 max 145), language (98 items, score min 47 max 153), and motor (138 items, score min 46 max 154) skills. For all scales, higher scores are better and lower scores indicate possible delay/deficit.	Assessed once between age 18 to 48 months (approximately 2 hours to assess), up to 48 months from study start
Electroencephalogram	Brain electrical activity: observation is for brain region specific abnormal or seizure activity. Number of participants with abnormal EEG are reported.	EEG taken immediately prior to surgery, during surgery, during cardiovascular intensive care unit (CVICU) stay (up to 48 hours after surgery), and immediately prior to discharge (between 5 to 20 minutes to assess EEG at each time point)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Choline	blood levels: time and patient dependent variation, observed patient related trends over time	0-72 hours
Glutamate	blood levels:time and patient dependent variation, observed patient related trends over time	0-72 hours
N-acetylaspartate (Naa)	blood levels:time and patient dependent variation, observed patient related trends over time	0-72 hours
Lactate	blood levels:time and patient dependent variation, observed patient related trends over time	0-72 hours

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: The Gerber Foundation
• Investigators: Principal Investigator: Lisa W Faberowski, MD, MSc, Stanford University

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 22, 2013
• Primary Completion (ACTUAL): November 19, 2020
• Study Completion (ACTUAL): November 19, 2020

Study Registration Dates

• First Submitted: May 5, 2016
• First Submitted That Met QC Criteria: March 17, 2019
• First Posted (ACTUAL): March 20, 2019

Study Record Updates

• Last Update Posted (ACTUAL): May 9, 2022
• Last Update Submitted That Met QC Criteria: May 6, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Diseases; Heart Defects, Congenital; Neurodevelopmental Disorders; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Anesthetics, Inhalation; Fentanyl; Isoflurane
• Other Study ID Numbers: NDO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No IPD will be shared with other researchers