The Effect of Anesthesia on Neurodevelopmental Outcome (NDO)

• Sponsor: Stanford University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03882788
• Collaborator: The Gerber Foundation (Other)
• Enrollment: 153
• Location: 1
• Arms: 2
• Actual Duration (Months): 90.9
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Anesthesia; Adverse Effect; Congenital Heart Disease; Neurodevelopmental Disorders	Drug: Isoflurane; Drug: Fentanyl (high dose); Drug: Fentanyl (low dose)	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 153 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Masking Description: EEG, metabolic/NMRS analysis and neurodevelopment outcome is blinded.
• Primary Purpose: Prevention
• Official Title: Anesthesia and the Developing Brain: a Comparison of Two Anesthetic Techniques
• Actual Study Start Date: Apr 22, 2013
• Actual Primary Completion Date: Nov 19, 2020
• Actual Study Completion Date: Nov 19, 2020

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. Bayley III [Assessed once between age 18 to 48 months (approximately 2 hours to assess), up to 48 months from study start]

   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.

2. Electroencephalogram [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)]

   Brain electrical activity: observation is for brain region specific abnormal or seizure activity. Number of participants with abnormal EEG are reported.

Secondary Outcome Measures

1. Choline [0-72 hours]

   blood levels: time and patient dependent variation, observed patient related trends over time

2. Glutamate [0-72 hours]

   blood levels:time and patient dependent variation, observed patient related trends over time

3. N-acetylaspartate (Naa) [0-72 hours]

   blood levels:time and patient dependent variation, observed patient related trends over time

4. Lactate [0-72 hours]

   blood levels:time and patient dependent variation, observed patient related trends over time

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Day to 36 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford Childrens hospital	Palo Alto	California	United States	94305

Sponsors and Collaborators

• Stanford University
• The Gerber Foundation

Investigators

• Principal Investigator: Lisa W Faberowski, MD, MSc, Stanford University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 14, 2012

More Information

Publications

None provided.

• Responsible Party: Stanford University
• ClinicalTrials.gov Identifier: NCT03882788
• Other Study ID Numbers: NDO
• First Posted: Mar 20, 2019
• Last Update Posted: May 9, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Heart Diseases; Heart Defects, Congenital; Neurodevelopmental Disorders; Fentanyl; Isoflurane

Study Results

Participant Flow

Pre-assignment Detail	Randomization data are available for only 89 of the 153 participants enrolled.

Arm/Group Title	Narcotic Based Anesthesia	Volatile Anesthesia
Arm/Group Description	Participants receive fentanyl 5 mcg/kg/hr not to exceed 10 mcg/kg/hr (high dose).	Participants receive volatile anesthetic isoflurane (1.5-2.0%) as primary anesthetic; participants also receive rocuronium or pancuronium for muscle relaxation, and fentanyl at no greater than 2 mcg/kg/hr (low dose).
Period Title: Overall Study
STARTED	44	45
COMPLETED	44	45
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Narcotic Based Anesthesia	Volatile Anesthesia	Total
Arm/Group Description	Participants receive fentanyl 5 mcg/kg/hr not to exceed 10 mcg/kg/hr (high dose).	Participants receive volatile anesthetic isoflurane (1.5-2.0%) as primary anesthetic; participants also receive rocuronium or pancuronium for muscle relaxation, and fentanyl at no greater than 2 mcg/kg/hr (low dose).	Total of all reporting groups
Overall Participants	44	45	89
Age (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	8.1 (8.5)	6.2 (8.5)	7.1 (8.5)
Sex: Female, Male (Count of Participants)
Female	18 40.9%	20 44.4%	38 42.7%
Male	26 59.1%	25 55.6%	51 57.3%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	20 45.5%	18 40%	38 42.7%
Black or African American	1 2.3%	2 4.4%	3 3.4%
Asian	9 20.5%	8 17.8%	17 19.1%
Hispanic	14 31.8%	15 33.3%	29 32.6%
Native Hawaiian or Other Pacific Highlander	0 0%	2 4.4%	2 2.2%
Region of Enrollment (Count of Participants)
United States	44 100%	45 100%	89 100%

Outcome Measures

1. Primary Outcome

Title	Bayley III
Description	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.
Time Frame	Assessed once between age 18 to 48 months (approximately 2 hours to assess), up to 48 months from study start

Outcome Measure Data

Analysis Population Description

Participants with a completed Bayley III assessment are included in the analysis.

Arm/Group Title	Narcotic Based Anesthesia	Volatile Anesthesia
Arm/Group Description	Participants receive fentanyl 5 mcg/kg/hr not to exceed 10 mcg/kg/hr (high dose).	Participants receive volatile anesthetic isoflurane (1.5-2.0%) as primary anesthetic; participants also receive rocuronium or pancuronium for muscle relaxation, and fentanyl at no greater than 2 mcg/kg/hr (low dose).
Measure Participants	10	18
Cognitive Standard Score	91 (10)	93 (15)
Language Standard Score	88 (11)	90 (18)
Motor Standard Score	97 (13)	90 (15)

2. Primary Outcome

Title	Electroencephalogram
Description	Brain electrical activity: observation is for brain region specific abnormal or seizure activity. Number of participants with abnormal EEG are reported.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Narcotic Based Anesthesia	Volatile Anesthesia
Arm/Group Description	Participants receive fentanyl 5 mcg/kg/hr not to exceed 10 mcg/kg/hr (high dose).	Participants receive volatile anesthetic isoflurane (1.5-2.0%) as primary anesthetic; participants also receive rocuronium or pancuronium for muscle relaxation, and fentanyl at no greater than 2 mcg/kg/hr (low dose).
Measure Participants	44	45
Abnormal preoperative EEG	0 0%	0 0%
Abnormal intraoperative EEG	1 2.3%	1 2.2%
Abnormal EEG in CVICU	0 0%	1 2.2%
Abnormal EEG predischarge	0 0%	0 0%

3. Secondary Outcome

Title	Choline
Description	blood levels: time and patient dependent variation, observed patient related trends over time
Time Frame	0-72 hours

Outcome Measure Data

Analysis Population Description

Data were not collected for this outcome measure.

Arm/Group Title	Narcotic Based Anesthesia	Volatile Anesthesia
Arm/Group Description	Participants receive fentanyl 5 mcg/kg/hr not to exceed 10 mcg/kg/hr (high dose).	Participants receive volatile anesthetic isoflurane (1.5-2.0%) as primary anesthetic; participants also receive rocuronium or pancuronium for muscle relaxation, and fentanyl at no greater than 2 mcg/kg/hr (low dose).
Measure Participants	0	0

4. Secondary Outcome

Title	Glutamate
Description	blood levels:time and patient dependent variation, observed patient related trends over time
Time Frame	0-72 hours

Outcome Measure Data

Analysis Population Description

Data were not collected for this outcome measure.

Arm/Group Title	Narcotic Based Anesthesia	Volatile Anesthesia
Arm/Group Description	Participants receive fentanyl 5 mcg/kg/hr not to exceed 10 mcg/kg/hr (high dose).	Participants receive volatile anesthetic isoflurane (1.5-2.0%) as primary anesthetic; participants also receive rocuronium or pancuronium for muscle relaxation, and fentanyl at no greater than 2 mcg/kg/hr (low dose).
Measure Participants	0	0

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data were not collected for this outcome measure.

Arm/Group Title	Narcotic Based Anesthesia	Volatile Anesthesia
Arm/Group Description	Participants receive fentanyl 5 mcg/kg/hr not to exceed 10 mcg/kg/hr (high dose).	Participants receive volatile anesthetic isoflurane (1.5-2.0%) as primary anesthetic; participants also receive rocuronium or pancuronium for muscle relaxation, and fentanyl at no greater than 2 mcg/kg/hr (low dose).
Measure Participants	0	0

6. Secondary Outcome

Title	Lactate
Description	blood levels:time and patient dependent variation, observed patient related trends over time
Time Frame	0-72 hours

Outcome Measure Data

Analysis Population Description

Data were not collected for this outcome measure.

Arm/Group Title	Narcotic Based Anesthesia	Volatile Anesthesia
Arm/Group Description	Participants receive fentanyl 5 mcg/kg/hr not to exceed 10 mcg/kg/hr (high dose).	Participants receive volatile anesthetic isoflurane (1.5-2.0%) as primary anesthetic; participants also receive rocuronium or pancuronium for muscle relaxation, and fentanyl at no greater than 2 mcg/kg/hr (low dose).
Measure Participants	0	0

Adverse Events

Time Frame	48 months
Adverse Event Reporting Description	Participants with randomization data are included in the analysis.
Arm/Group Title	Narcotic Based Anesthesia		Volatile Anesthesia
Arm/Group Description	Participants receive fentanyl 5 mcg/kg/hr not to exceed 10 mcg/kg/hr (high dose).		Participants receive volatile anesthetic isoflurane (1.5-2.0%) as primary anesthetic; participants also receive rocuronium or pancuronium for muscle relaxation, and fentanyl at no greater than 2 mcg/kg/hr (low dose).
All Cause Mortality
	Narcotic Based Anesthesia		Volatile Anesthesia
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/44 (6.8%)		1/45 (2.2%)
Serious Adverse Events
	Narcotic Based Anesthesia		Volatile Anesthesia
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/44 (15.9%)		10/45 (22.2%)
Blood and lymphatic system disorders
Sepsis	0/44 (0%)		1/45 (2.2%)
Cardiac disorders
Cardiopulmonary arrest	0/44 (0%)		2/45 (4.4%)
Hypotension	1/44 (2.3%)		2/45 (4.4%)
Arrythmia	4/44 (9.1%)		3/45 (6.7%)
Metabolism and nutrition disorders
Metabolic acidosis	0/44 (0%)		1/45 (2.2%)
Vascular disorders
Bleeding	2/44 (4.5%)		1/45 (2.2%)
Other (Not Including Serious) Adverse Events
	Narcotic Based Anesthesia		Volatile Anesthesia
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/45 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.