Anesthesia and the Developing Brain: a Comparison of Two Anesthetic Techniques
Phase: NA
Conditions: Anesthesia; Adverse Effect, Congenital Heart Disease, Neurodevelopmental Disorders
Sponsor: Stanford University

 
 
 
 
Anesthesia and the Developing Brain: a Comparison of Two Anesthetic 
Techniques 
Study Protocol and Statistical Analysis Plan 
NCT03882788 
March 14, 2012 

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Project Title: The effect of anesthetic agents on neurodevelopmental outcome in neonatal 
congenital heart disease patients 
COMIRB #06-0483 
Principal Investigator: Lisa Faberowski MD 
 
Co-Investigators: Chandra Ramamoorthy MD, Gary Pelz PhD, Don Olson, MD and Frank 
Hanley MD, Claudia Benkwitz MD. PhD 
  
Primary Contact: 
 
 
Study Objectives: 
 
Primary objective:  
To evaluate whether the type of anesthesia, narcotic-based versus inhalation-based (volatile) 
anesthesia, administered during cardiopulmonary bypass (CPB) surgery contributes to the wide 
variance in neurologic recovery and developmental outcomes after surgery in infants with 
congenital heart disease.  
 
Secondary objectives: 
1. To evaluate whether levels of metabolites in blood and urine using magnetic resonance 
spectroscopy preoperatively, intraoperatively and 2-5 days postoperatively can predict 
postoperative neurologic recovery and outcome. 
2. To examine whether postoperative neurodevelopmental status changes can be predicted by 
EEG (seizure activity) within the first two days after surgery. 
 
Background and Significance: 
Thirty thousand infants are born each year in the United States with congenital heart disease.  
Half of these infants require surgical intervention within the first year of life.  More importantly 
8-25% of these children develop neurologic sequelae, which can have a long-term detrimental 
effect on IQ and behavior (Bellinger 1991; duPlessis 1997; Hovels-Gurich 2001; Karl 2004).  
The question is whether there were predisposing neurologic factors preoperatively or were there 
intraoperative factors that led to the postoperative neurologic outcomes. 
 
Limperopoulos and colleagues have provided the strongest evidence of preoperative neurologic 
problems with both a formal neurobehavioral assessment and neurologic exam (Limperopoulos 
et al. 1997).  Using the Einstein Neonatal Neurobehavioral Assessment Scale (ENNAS), they 
were able to identify neurobehavioral and neurologic deficits in more than half of full term 
infants with cardiac defects, cyanotic and non-cyanotic, prior to surgical intervention. Most 
studies conclude that preoperative neurobehavioral evaluations and long-term developmental 
follow-up of infants undergoing cardiac surgery are very important. However, many institutions 
do not offer routine neurologic and developmental follow-up of these at risk infants.   
 
When drawing conclusions about the utility of differing strategies of CPB management and 
effects on neurologic outcome, one must consider the preoperative neurologic state.  Some 
studies find no difference in outcome and others report significant deficits occurring more often 

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with total circulatory arrest than low flow CPB (Limperopoulos 1999; Miller 1996; Brunberg 
1974; Bellinger 1991; Hesz 1988).  These studies were isolated to a single condition, 
transposition of the great arteries, and none of these studies examined the preoperative baseline 
neurologic or developmental status of the infants in order to be able to assess changes 
postoperatively. Furthermore, the question remains does the type of anesthetic predict later 
neurologic outcome? 
 
Recent evidence from animal research in rodents supports that anesthetics may cause 
neurodegeneration in the developing brain (Jevtovic-Tedorovic 2003).  This has been further 
supported by research in our own laboratory.  Neurodegeneration was most evident in rat pups, 7 
days in age and exposed to anesthesia for 5 hours.  Clearly, age and duration of anesthesia had an 
impact on anesthesia induced neurodegeneration (Faberowski 2004).  The pathognomic 
anesthetic for a prolonged anesthetic exposure in infants is that used for CPB.  The studies from 
Bellinger and others were during a period where high dose fentanyl was the primary anesthetic. 
Currently, volatile anesthetics seem to be the more commonly used anesthetic because of the 
work of Kurth and others.  Kurth et al (2001, 2002) demonstrated improved histiologic outcome 
in piglets who received a volatile anesthetic as opposed to a fentanyl anesthetic. 
 
Perioperative brain imaging studies have also been useful in documenting CNS injury such as 
hypoxic-ischemic encephalopathy and focal cortical infarctions (Gaynor 2003; Tavani 2004; 
Mahle 2003). Recently, serial proton magnetic resonance spectroscopy of the brain was used to 
evaluate children under two different intraoperative strategies: low flow versus normal flow CPB 
and low versus high hematocrit during CPB (Ashwal 2004).  In this series of eleven infants, long 
and short echo time single voxel magnetic resonance spectroscopy in occipital gray matter and 
neurologic assessment were obtained preoperatively and at two and five days postoperatively.  
Changes in brain N-acetyl-aspartate, and increases in myoinositol and glutamate/glutamine after 
surgery were sensitive in detecting postoperative neurologic changes; however, these changes 
could not be correlated to a difference in bypass strategy because of the limited number of 
children studied. Additionally, according to Newburger et al. (1993) and Rappaport (1998), 
postoperative seizure activity within 48 hours after CPB was most predictive of poor neurologic 
outcome at one year of age. 
The blood brain barrier in children less than one year of age is disrupted by CPB. We wish to 
study these changes in N-acetyl-aspartate, and increases in myoinositol and glutamate/glutamine 
via the use of blood and urine samples rather than cerebral spinal fluid (Cavaglia M 2004).  We 
wish to avoid lumbar puncture in a heparinized child and also avoid the transport of an unstable 
child to the MRI scanner, thus limiting our study to blood and urine specimens only.  We would 
like to confirm our findings via blood and urine with perioperative EEG monitoring for 48 hrs 
seizure activity and Bayley III testing at 18-24 months of age in the two anesthesia (narcotic-
based vs. volatile) groups.   

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Patient Accrual/Selection of Study Population: 
Neonates (children 30 days in age or less) diagnosed with congenital heart disease will be 
evaluated and potentially recruited from the NICU or CICU.  It is anticipated that 1 to 2 patients 
per week, approximately 50-100 patients will be eligible for the study in one year. Assuming at 
least 90% survival to discharge and 30% refusal, there will be 35-60 infants who could be 
recruited per year.   We wish to recruit 200 patients over 5 years. Assuming a 70-75% return 
rate, approximately 30-50 infants are expected to return for their 18 month follow-up.  
 
Inclusion/Exclusion Criteria: 
 
Inclusion Criteria: 
• All neonates less than 44 weeks post conceptional age age and greater than 32 weeks post 
conceptional age admitted to The Children’s Hospital for treatment of cyanotic heart disease 
requiring surgical intervention.   
• Admitting diagnosis of cyanotic heart disease.  
 
Exclusion Criteria: 
• Infants >44 weeks post conceptional age or <32 weeks post conceptional age on admission. 
• Infants with the diagnosis of acyanotic heart disease 
• Infants with documented central nervous system malformations. 
• Infants requiring unexpected postoperative ECMO support will be excluded. 
 
Consent and HIPAA authorization: 
All subjects will be consented prior to participation in this study and prior to randomization.  
Parents/guardians will be approached by one of the study anesthesiologists after the 
determination for surgical intervention has been made, usually the day prior to surgery.  The 
study anesthesiologists are all COMIRB certified and experienced in obtaining consent for 
research studies.  The study will be explained to the parents/guardians in a quiet area away from 
other patients to allow time for questions.  Parents will be asked to explain the study in their own 
words to assess understanding of the study.  A HIPAA authorization will be obtained at the same 
time as consent.  Parents/guardians will be given copies of both the consent and HIPAA 
authorization for their records. 
 
Subject Randomization/Determination of anesthetic maintenance: 
All infants enrolled in the study will receive a preoperative assessment by one of the cardiac 
anesthesiologists.  Since all of these infants will have a peripheral intravenous line 
preoperatively, the induction will be standardized to sevoflurane up to 8%, 2 mcg/kg of fentanyl 
and 1 mg/kg of rocuronium.  Induction is the period in which the airway is secured.  This usually 
takes 5-10 minutes in an otherwise normal infant.  
 
The anesthetic maintenance will be determined using a computer-generated randomization table 
and assigning each patient to one of the two anesthetic regimens (see Table 1).  For instance, 
subject #1 is enrolled in the study and consent obtained.  The randomization table says that 
subject #1 is assigned to receive a volatile anesthetic, isoflurane. That subject’s maintenance will 

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be with a volatile anesthetic, isoflurane.    Isoflurane was chosen as the maintenance anesthetic 
because it is the only anesthetic vaporizer currently available for our CPB machines.   
 
Table1. Anesthetic maintenance assignment 
 
Random # assignment 
Narcotic-based 
Volatile 
Subject 1 
 
X 
Subject 2 
 
X 
Subject 3 
X 
 
Subject 4 
 
 
Subject 5 
 
X 
Subject 6 
X 
 
Subject 7 
X 
 
 
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 MAC indicates that at this concentration 50% 
of the patients will not move when surgically stimulated. We 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.  These concentrations of 
isoflurane represent 1.0 to 1.2 MAC of anesthesia.  Rocuronium or pancuronium will be used for 
muscle relaxation.  Narcotic, fentanyl will be administered at no greater than 2 mcg/kg/hr.  
However, the primary anesthetic during CPB will be isoflurane with no narcotic administered 
during CPB. 
 
Narcotic-based anesthetic:  
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.  The 
anesthetic may be supplemented with midazolam 0.05 mg/kg/hr but not to exceed 1.0 mg/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.  Total narcotic based anesthetic is also a standard technique in managing neonates 
undergoing CPB.  However, the primary anesthetic during CPB will be fentanyl with no 
isoflurane administered during CPB 
 
Postoperative Sedative and Analgesic Care: 
As per our institutional standard of care, postoperative sedation will consist of fentanyl infusions 
of 2-10 mcg/kg/hr for the first 48 hours postoperatively.   
 
Data collection: 
Detailed chart review and data collection will be performed to obtain data for multivariate 
analyses including 1) socio-demographic data, 2) presence of metabolic acidosis*, 3) intubation,  
4) history of palliative intervention procedure-prostaglandins, atrial septostomy, 5) age at 
surgery, 6) length of circulatory arrest and duration of CPB, 7) complications of surgery, and 8) 
head ultrasound or MRI studies if obtained for clinical indications. 

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* Presence of a metabolic acidosis and increased lactate as result of poor systemic oxygenation 
can occur in this population secondary to a restrictive ASD and inadequate mixing.  The 
oxygenation provided to the lower body may be initially insufficient in patients with cyanotic 
heart disease and thus produce metabolic acidosis. 
 
Determination of CNS injury, recovery, and neurodevelopmental outcome.  
 
Table 2:  Summary and Timeline of Procedures Performed  
 Times of testing 
NMRS-
blood* 
NMRS-
urine* 
EEG 
Bayley III 
Exam 
Prior to surgery 
X 
X 
X 
 
During anesthesia  
and prior to CPB 
X 
X 
X 
 
During CPB 
X 
X 
X 
 
Immediately after CPB X 
X 
X 
 
6 h 
X 
X 
X 
 
12 h 
X 
X 
X 
 
24 h 
X 
X 
X 
 
48 h 
X 
X 
X 
 
72 h 
X 
X 
 
 
18 – 24 m 
 
 
 
X 
CPB= CPB, h= hours after CPB, m= months after surgery/CPB, NMRS= Nuclear magnetic 
resonance spin spectroscopy 
 
* Blood and urine samples will not be required after 120 hours postoperatively. If the arterial line \is 
removed before 72 hours, this is the endpoint of the study; all samples will be from an arterial line 
which is a standard of care for anesthesia and critical care monitoring. 
 
NMR spectroscopy of blood and urine samples 
Blood samples: 
Blood samples will be obtained from a peripheral arterial catheter routinely placed as per 
protocol for procedures requiring CPB. Blood will be obtained at 9 time points:  Prior to surgery, 
during anesthesia and prior to bypass, during CPB, immediately after bypass, and 6,12, 24, 48 
and 72 hours after bypass. Heparin-preserved whole blood (0.5 mL) will be used for NMR 
analysis. All samples will be placed on ice, then frozen and stored at -78 degree until extraction. 
Prior to NMR analysis, 0.5 mL of blood will be extracted using a dual methanol/ chloroform 
extraction developed in our laboratory (Serkova et al., 2005). This allows for protein 
precipitation and separation of water-soluble and lipid metabolites. Blood will be carefully 
vortexed and processed with 1 mL of cold chloroform/methanol (1:1, vol/vol). After 
centrifugation, the supernatants will be collected and the pellets will be re-suspended with 0.5 
mL of chloroform/methanol, centrifuged, and the supernatants will be collected. The supernatant 
will be washed with 0.5 mL ice-cold water. The water phase will be removed and added to the 
pellet. One mL of water will be added and the pellet will be centrifuged and the supernatant will 
be lyophilized overnight (water-soluble extracts). Afterwards the water-soluble part will be 
dissolved in 0.5 mL D2O and analyzed by proton NMR. The lipids in the organic phase will be 

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evaporated to dryness under a stream of nitrogen at 50°C. The lipid extracts will be dissolved in 
0.6 mL of deuterated chloroform/ methanol (2:1, vol/vol) for 1H-NMR analysis. 
 
Urine collection:  
Urine (3 mL) will be collected from a foley catheter routinely placed for surgical procedures 
requiring CPB at 10 time points:  Prior to surgery, during anesthesia and prior to bypass, during 
CPB, immediately after bypass, and 6,12, 24, 48 and 120 hours after bypass. 
 
Urine and blood samples will be centrifuged to remove possible proteins if present. The samples 
will be placed on ice, then frozen and stored at -78 degree until extraction. Prior to NMR 
analysis, the pH will be adjusted to 5.7 using K2HPO4/ KH2PO4-buffer. The samples will be 
lyophilized overnight, and re-dissolved in 0.5 mL of D2O for NMR. 
 
Proton quantitative NMR on blood and urine extracts. All water-soluble and lipid extracts will 
be analyzed using a 500 MHz high-resolution Bruker DRX system. An inverse TXI 5-mm 
probehead will be used for all experiments. In order to suppress water residue in extracts, a 
standard Bruker water presaturation sequence will be used (“zgpr”)  (operating frequency for 
proton channel: 500.24 MHz; power level pl1=3 dB; power level for water suppression pl9=55 
dB; power angle p1=7.5 µsec (90° pulse); power angle for water suppression p12=60 µs; water 
suppression at O1=4.76 ppm; relaxation delay d1=12.85 sec (5*T1); delay for power switching 
d12=20 µs; short delay d13=3 µs; spectral width sw=12ppm; total number of scans ns=40). An 
external standard substance, trimethylsilyl propionic-2, 2, 3, 3,-d4 acid (TMSP, 20 and 50 mM in 
D2O) will be added into a thin glass capillary. The final TMSP concentration (0.5 mmol/L and 
1.2 mmol/L) in the capillary will be calculated prior to NMR experiments on study extracts using 
a standard amino acid solution. The TMSP capillary will be placed into the NMR tube during the 
experiment (0.5 mmol/L for water-soluble extracts and 1.2 mmol/L for lipid extracts) and served 
as an external standard which allowed for absolute metabolite quantification in each study 
extract. 1H chemical shifts will be referred to TMSP signal at 0 ppm. After performing Fourier 
transformation and making phase and baseline corrections, each 1H peak will be integrated using 
1D WINNMR program (Bruker Biospin Inc., Fremont, CA). The absolute concentrations of 
single metabolites will be then referred to the TMSP integral and calculated according to the 
equation (1): 
M
V :
9
:I
C
Nx
:
Ix
   
Cx  
×
×
=
 (1) 
where  Cx = metabolite concentration 
 
Ix = integral of metabolite 1H peak 
 
Nx = number of protons in metabolite 1H peak (from CH, CH2, CH3, etc.) 
 
C = TMSP concentration 
 
I = integral of TMSP 1H peak at 0 ppm (:9 since TMSP has 9 protons) 
 
V = volume of the extract  
 
M = volume of blood sample (0.5 mL) 
 
Data interpretation for NMR (“metabolomics”). Urine and blood 1H-NMR spectra will be 
statistically analyzed by two-phase principle component analysis in order to determine (i) the 
group clustering (PCA score) and (ii) the marker identification (PCA plot) for volatile anesthetic 

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group versus the intravenous anesthetic group. Once distinguished by PCA, the changes in 
absolute concentrations of metabolic markers will be analyzed by un-paired Student t-test. 
 
Neurologic exams and neurobehavioral testing: 
At 18-24 months after surgery, a clinical neurologic examination will again be performed by the 
study neonatologist to determine the presence of abnormal and/or asymmetric muscle tone and 
persistent or abnormal primitive reflexes. Head circumference and other growth parameters will 
also be measured. Neurocognitive and motor status will be assessed by a neonatologist using the 
Bayley Scales of Infant Development- Third Edition (Bayley III), which is the most frequently 
used standardized assessment of developmental milestone achievement in infants and young 
children.  The Bayley III measures cognitive and motor development resulting in both an index 
score, comparable to an IQ score, and an age equivalent.  The Behavior Rating Scale of the 
Bayley III combines observation and parent report and is divided into factors measuring 
attention/arousal, orientation/engagement, emotional regulation and motor quality.  
 
Risks: 
There are no additional risks to participating in the study.  Both narcotic-based and volatile 
anesthetics are standard practice at The Children's Hospital. 
 
Benefits: 
There is no direct benefit to the patient or the patient’s family. The results of this research may 
help physicians evaluate the efficacy of different anesthetics by better defining the biologic 
potential for long-term neurologic and neurobehavioral outcome. It may also lead to new 
approaches to the study and use of neuroprotective agents and better selection of infants who 
might benefit from early intervention services after discharge, as well as provide a means of 
more accurately predicting neuropathology, recovery and long term neurodevelopmental 
outcome in infants with congenital heart disease.  
 
Subject payment: 
Families will receive 
 to compensate for travel time at the 18-month follow up visit. 
 
Costs to the subject: 
There will be no costs incurred upon the subject or family.  MRI spectroscopy of blood and 
urine, EEG studies and Bayley III evaluations will be covered by the research protocol.  
 
Data analysis and monitoring: 
The dependent variable or primary outcome of concern is the child's neurodevelopmental status 
at 18-24 months post surgery for congenital heart disease (CHD).  The data used to index 
neurodevelopmental status include the socioeconomic status, preoperative status- intubation, 
prostaglandin infusion, atrial septostomy, preoperative diagnosis of cyanotic heart disease with 
or without a ventricular septal defect, presence of a non-restrictive versus restrictive atrial septal 
defect, neurological exam, tests of developmental achievement and MRI spectroscopy data.  
MRI spectroscopy data include: Peak area metabolite levels for N-acetylaspartate, creatinine, 
choline, and the lactate doublet.  Peak area metabolite levels will be calculated as a ratio of the 
above variables. 
 

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The independent variable of concern is the anesthetic, categorized specifically by narcotic-based 
or volatile anesthetic.  Our estimates of sample size requirements assume a conservative 20% 
(Bellinger 1991; duPlessis 1997; Hovels-Gurich 2001; Karl 2004) incidence in 
neurodevelopment disabilities, which indicates that we may assess 200 children before reaching 
the desired proportion of poor outcome cases. However, if the effect is strong, or if the incidence 
of developmental disability is higher than expected, we may demonstrate at least trends toward 
differences in outcome groups by the end of two years.  Subjects lost to follow up or withdrawn 
from the study for any reason will be reported and analyzed in a sub group analysis.   
 
A designated statistician will provide data analysis at the end of the study. 
 
Data Safety and Monitoring Plan: 
 
Hard copies of all data collection sheets will be kept in the study coordinator’s locked file 
cabinet in a locked office.  Data will be entered in an Excel spreadsheet for later analysis.  All 
investigators have password protected computers with Windows XP operating systems as 
required for TCH security systems standards.  The computers are backed up to the TCH network 
on a nightly basis so that data will be protected and recoverable in case of a catastrophic 
computer failure.  The subjects will only be identified on the sheet by a study number.  The key 
linking the study number to the subject will be held only by the investigators on password 
protected computers in a secure office. 
 
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