Clinical trial NCT02492269
Conditions: Congenital Heart Disease
Sponsor: Aymen N Naguib
Start date: 2014-05-01; Completion date: 2024-12-01
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The overall goal of this project is to determine the role of anesthetic management in children undergoing cardiac surgery utilizing CPB in the setting of fast tracking and early extubation. An ideal anesthetic technique would ensure abolishing or diminishing stress response as would be evident by the stress markers levels and the level of two cerebral injury biomarkers (S 100 B and NSE). This should translate to better immediate postoperative outcome and hopefully improve both the short and the long term neurodevelopmental outcome in these children. The project is prospective, randomized and blinded study. The first and second aim of the study should be conducted over 2 year period. Our long term aim will be concluded when these children reach the school age.

Detailed description:

Arms: arm 1: Dexmedetomidine in addition to 15 µg/kg of fentanyl arm 2: Normal saline as a placebo in addition to 15 µg/kg of fentanyl
Interventions: intervention 1: Dexmedetomidine intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
Neurodevelopmental Outcome after Cardiac Surgery Utilizing CPB in 
Children: A Prospective, Double Blinded and Randomized Study  
 
 
NCT02492269 
 
 
January 5, 2022 


PROTOCOL TITLE: Neurodevelopmental Outcome after Cardiac Surgery 
 
Page 1 of 16 
HRP-503  v.12.10.18 
PROTOCOL TITLE: 
Neurodevelopmental Outcome after Cardiac Surgery Utilizing CPB in Children: A 
Prospective, Double Blinded and Randomized Study. 
PRINCIPAL INVESTIGATOR: 
Name:  Aymen Naguib, MD 
Department/Center: Anesthesiology/Heart Center 
Telephone Number:  614-722-5625 
Email Address:  Aymen.Naguib@nationwidechildrens.org 
VERSION NUMBER/DATE: 
Ver 4 / 05Jan2022 
 
REVISION HISTORY 
 
Revision 
# 
Version Date 
Summary of Changes 
Consent 
Change? 
1 
11/12/2019 
Long Term Approach: replacing Stanford-
Binet Intelligence Scales (5th ed.) at year 5 
with Differential Ability Scales-II (DAS-II) 
Yes 
2 
4/27/2020 
Adding the ABAS-II and that it will be mailed 
out during COVID-19 pandemic to 6.3 Aim 1 
Data Collection and Variables.  Adding ABAS-
II and the Child Behavior Checklist (CBL) to 
6.6 Long Term Approach. 
No 
3 
1/5/2022 
Adding Sample Size to 1.0 Study Summary 
No 
 
 
 
 
 
 
 
 
 
 
 


PROTOCOL TITLE: Neurodevelopmental Outcome after Cardiac Surgery 
 
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HRP-503  v.12.10.18 
1.0 
Study Summary 
 
Study Title 
Neurodevelopmental Outcome after Cardiac Surgery 
Utilizing CPB in Children 
Study Design 
Prospective, Double Blinded and Randomized Study 
Primary Objective 
The overall goal of this project is to determine the role of 
anesthetic management in infants and children undergoing 
cardiac surgery utilizing CPB and deep hypothermic cardiac 
arrest. 
Secondary 
Objective(s) 
 
Research 
Intervention(s)/ 
Investigational 
Agent(s)  
Fentanyl 
Dexmedetomidine 
IND/IDE #  
101911 
Study Population 
Children < 1 yr. of age undergoing CPB 
Sample Size 
50 
Study Duration for 
individual 
participants 
5 years 
Study Specific 
Abbreviations/ 
Definitions  
CPB = cardiopulmonary bypass 
ASD = atrial septal defect 
VSD = ventricular septal defect 
AVSD = atrioventricular septal defect 
TOF = tetralogy of fallot 
 
2.0 
Objectives 
2.1 The overall goal of this project is to determine the role of anesthetic 
management in infants and children undergoing cardiac surgery utilizing 
CPB and deep hypothermic cardiac arrest. An ideal anesthetic technique 
would ensure abolishing or diminishing stress response as would be 
evident by the stress markers levels and the level of two cerebral injury 
biomarkers (S 100 B and NSE) and may offer neuroprotection. This 
should translate to better immediate postoperative outcome and 
hopefully improve both the short and the long term neurodevelopmental 
outcome in these children.  
2.2 Specific Aim 1: Evaluate the immediate neurodevelopmental outcomes 
prior to discharge from hospital, day of post-op Cardiology Clinic visit 
(usually 1-3 months), 6 months and one year postoperatively. 
2.3 Hypothesis: The use of dexmedetomidine will lead to improved 
neuroprotection against the GABAA receptors agonists and possibly 
other insults such as brain ischemia. This will lead to improved 
neurodevelopmental outcome in the dexmedetomidine group. 


PROTOCOL TITLE: Neurodevelopmental Outcome after Cardiac Surgery 
 
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HRP-503  v.12.10.18 
2.4 Specific Aim 2: Identify the impact of dexmedetomidine on the stress 
response in children undergoing cardiac surgery utilizing 
cardiopulmonary bypass (CPB).   
2.5 Hypothesis: The use of dexmedetomidine will significantly reduce the 
stress response. Also, blunting the stress response and the possible 
associated intraoperative hemodynamic stability will be associated with 
lowering the levels of different metabolic, hormonal and cytokine stress 
markers.   
2.6 Long term Aim: Identify the impact of the use of dexmedetomidine on 
surgical stress and the neurodevelopmental outcome in children 
undergoing congenital cardiac surgery utilizing CPB less than one year 
of age. 
2.7 Hypothesis: The use of dexmedetomidine will provide neuroprotection 
to children undergoing cardiac surgery utilizing CPB less than one year 
of age. This neuroprotection could be related to the mere use of 
dexmedetomidine as it was demonstrated by the in-vitro and in-vivo 
animal studies (10, 11) or due to better blunting of the stress response in 
these patients. This alteration in the stress response will lead to an 
improvement in the immediate perioperative outcome and ultimately to 
an improved long term neurodevelopmental outcome. 
3.0 
Background 
3.1 Congenital heart defects are among the most common birth defects. It is 
estimated that more than 32,000 infants are born with congenital heart 
defects every year. This represents one of every 125 to 150 children born 
in the United States. Advances in the care of children undergoing 
congenital cardiac surgery allowed the improvement of the survival after 
these surgeries. In turn, the focus of outcome in children undergoing 
congenital heart surgery has shifted from cardiac survival to 
improvement in the neurodevelopmental outcome (1, 4, 14-16) and its 
substantial societal impact. Hence, improving these neurodevelopmental 
outcomes is of paramount importance and the goal of this investigation. 
Evaluation of children after undergoing surgical correction of CHD 
demonstrates a wide variety of neurodevelopmental delays including 
speech delay, cognitive impairment, visual-spatial and visual-motor 
skills, attention deficit disorder, motor delays and learning disabilities 
(17, 18). 
3.2 Most of these children will require surgical palliation using CPB during 
the first year of life. Some of these children will have some form of 
brain insult even prior to surgery. This could be due to cyanosis, severe 
acidosis or abnormal pattern of cerebral blood flow as in patients with 
hypoplastic left heart syndrome (HLHS) where some studies have shown 
the presence of brain ischemia on magnetic resonance imaging, even 
prior to surgery(19, 20). While these are preoperative factors that will 
ultimately affect the neurodevelopmental outcome, there are 


PROTOCOL TITLE: Neurodevelopmental Outcome after Cardiac Surgery 
 
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HRP-503  v.12.10.18 
perioperative insults that can be modulated, abolished or avoided 
completely.  For instance, surgical factors that increase stress response 
and the risk on end-organ perfusion, exposure to CPB and deep 
hypothermic cardiac arrest, are only few that are known to be directly 
responsible for these events. Exposure to anesthetic agents may add 
another component to the outcomes after pediatric cardiac surgery. The 
use of GABAA agonists such as propofol, barbiturates, and isoflurane, 
as well as medications that decrease excitatory transmission through 
NMDA glutamate receptors such as nitrous oxide and ketamine may 
trigger widespread neuronal apoptosis and eventually neurodegeneration 
during the vulnerable periods of brain development. 
3.3 In addition, an increased plasma level of biomarkers such as, S100B and 
neuron specific enolase (NSE), have been linked to neurological injury 
and neurological outcomes after ischemic brain injury (21). Other 
studies have shown that increased S100B and NSE levels during and 
after cardiac surgery in adults was correlated with worsening of 
neurological outcome (22). The S-100ß is a calcium binding protein that 
is normally found in the intra- and extracellular brain tissue. Its presence 
in the plasma indicates disruption of the blood brain barrier and brain 
injury. The S-100ß is eliminated by the kidney and has a half life of 1-2 
hours. On the other hand, NSE is an intracytoplasmic glycolytic enzyme 
that is found in the neurons and neuroendocrine cells. The detection of 
NSE in the plasma indicates high death rate of neurons and 
neuroendocrine cells.   
3.4 Recent in-vitro and in-vivo animal studies have shown the possible 
neuroprotective effect of dexmedetomidine, a selective α2-agonist. A recent 
study by Degos et al (11) has shown that the use of dexmedetomidine in mouse 
models provided modulation of brain derived neurotrophic factor expression. 
This modulation resulted in significant neuroprotective effect in vivo and in 
vitro. 
3.5 The stress response and associated inflammation have been shown to 
result in increased morbidity and mortality during the post-operative 
recovery period. However, due to their delicate metabolic balance, 
neonates and infants undergoing cardiac surgery are at even greater risk 
of experiencing complications and poor outcomes due to surgical stress 
and inflammation.  
3.6 While the stress response plays a major role in initiating the catabolic 
state that follow surgery, the cytokine release contributes to the end-
organ dysfunction (23, 24). The cytokines are produced mainly in the 
lungs and the myocardium and then spilled over into the circulation. 
There are proinflammatory cytokines, such as tumor necrosis factor-α 
(TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-
8). Also, there are compensatory anti-inflammatory cytokines such as 
interleukin-10 (IL-10) and interleukin-1 receptor antagonist (IL-1ra). 
The proinflammatory cytokine response in children undergoing cardiac 


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HRP-503  v.12.10.18 
surgery with CPB is characterized by large variation, compared to a 
generally well-defined response in adults. This is in contrast to the anti-
inflammatory response that shows a more clear release pattern in 
children. It is the balance between the pro and anti-inflammatory 
cytokines that may predict the outcome for children undergoing cardiac 
surgery with CPB, rather than the change in a specific cytokine value. 
3.7 Identifying a specific anesthetic regimen that will provide some 
neuroprotection while offering some blunting of the stress response may 
improve both immediate perioperative and long term 
neurodevelopmental outcome in children undergoing cardiac surgery 
with CPB under one year of age. 
3.8 Aim 1 Rationale: The possible neuroprotection of dexmedetomidine has 
been studied in-vitro and in-vivo animal models (10, 11). There are no 
prospective randomized studies that show the effect of utilizing such 
approach on the physiological stress response and the long-term 
neurodevelopmental outcome in children undergoing cardiac surgery. In 
addition, this neuroprotection will be associated with lowering the levels 
two of the cerebral injury biomarkers [serum S-100ß (S100ß) and 
neuron-specific enolase (NSE)]. This should correlate with a better 
postoperative neurodevelopmental scores at 1 month, 3 months, 6 
months and one year postoperatively. 
3.9 In our pilot study (12), we came to the conclusion that the use of a dose 
of fentanyl that is higher than 10 µg/kg in addition to dexmedetomidine 
should be associated with a better blunting of the stress response. In 
addition, in our preliminary, follow-up study, patients who had more 
blunting of the stress response showed better neurodevelopmental 
outcome, although it did not reach statistical significance in some cases 
likely due to the small sample size. 
3.10 Aim 2 Rationale: In our previous published study (12), we concluded 
that the use of a higher dose of fentanyl in addition to dexmedetomidine 
should provide better control of the stress response that will be superior 
to the use of fentanyl alone. In this study, we intend to prove the impact 
of dexmedetomidine on blunting these different stress markers even 
when compared to a higher dose of fentanyl alone. 
4.0 
Study Endpoints 
4.1 Change in cytokine levels, hormone levels, and neurodevelopmental 
testing scores. 
5.0 
Study Intervention/Investigational Agent 
5.1 Description:  Fentanyl (15 µg/kg) and Dexmedetomidine (1 µg/kg bolus 
followed by 0.5 µg/kg/hr until end of CPB) 
5.2 Drug/Device Handling: Research Pharmacy SOP for the Control of 
Investigational Drugs  


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HRP-503  v.12.10.18 
5.3 Aymen Naguib, MD is the holder of the IND and will follow all FDA 
regulations.   
6.0 
Procedures Involved* 
6.1 Describe and explain the study design. 
6.2 Aim 1 Approach: Baseline neurodevelopmental status will be evaluated 
preoperatively using the standardized cognitive score from the Bayley 
Scales of Infant Development-III. The language and motor scores from 
the Bayley-III will be treated as secondary outcomes. Children will be 
retested prior to discharge from the hospital, at their post-op cardiology 
visit (usually 1-3 months post-op), six month and one year 
postoperatively to evaluate their neurodevelopment and its possible 
correlation to the S100ß and NSE values. We will, also, prospectively 
collect the postoperative clinical data as a measure of perioperative 
clinical outcome. 
6.3 Aim 1 Data Collection and Variables: For the neurodevelopmental 
portion of the aim, children will have a baseline neurodevelopmental 
Bayley score during the preoperative period by our child Biobehavioral 
outcomes core team. These children will be retested at prior to discharge 
from the hospital, at their post-op cardiology visit (usually 1-3 months 
post-op), six month and one year postoperatively to evaluate 
neurodevelopment progress. Also, at each visit parents will complete the 
ABAS-II, a behavior rating scale.  This assessment will be mailed home 
for completion during the COVID-19 pandemic restrictions.  The 
neurodevelopmental scores will be correlated to the levels of the 
biomarkers S100ß and NSE. 
Postoperative cardiothoracic intensive care unit (CTICU) data collection 
will include: length of positive pressure ventilation support, total chest 
tube output during the first 24 hours post-operatively, postoperative 
platelets count, postoperative absolute neutrophil count and 
postoperative coagulation profile including; prothrombin time (PT), 
partial thromboplastin time (PTT), international normalized ratio (INR) 
and fibrinogen level. Data also included inotropic score upon arrival and 
at 24 hours post-operatively.  
The inotropic score will be calculated as follow: dopamine (µg/kg/min) 
times 1 + milrinone (µg/kg/min) times 10 + epinephrine (µg/kg/min) 
times 100 (25).  
Other data that will be collected include; total urine output during the 
first 24 hours post-op, blood urea nitrogen and creatinine upon arrival 
and at 24 hours post-op and the use of nurse-controlled analgesia (NCA) 
including starting opioid, the need to change the medication used and the 
total dose of opioids for the first 24 hours.  Other variables include: 
cardiac arrest requiring resuscitation, ventricular or atrial arrhythmia 
causing hemodynamic disturbances which require treatment, nosocomial 


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HRP-503  v.12.10.18 
infection during the hospitalization, disseminated intravascular 
coagulation (DIC), clinical evidence of seizures, the need for re-
intubation, length of ICU stay, the need for transfusing blood or blood 
products and total volume given, length of hospital stay and post-
operative mortality.   
6.4 Aim 2 Approach: We will perform a prospective, randomized and 
blinded study comparing fentanyl plus dexmedetomidine to fentanyl 
alone. Stress markers’ levels will be checked at five different points; at 
baseline, after sternotomy, after start of CPB, at the end of surgery and 
at 24 hours post operatively. These markers include; epinephrine, 
norepinephrine, ACTH, cortisol, glucose, lactate, TNF-α, IL-6, Il-8 and 
IL-10. The S100ß and NSE levels will be tested at baseline, end of 
surgery and 24 hours after surgery. 
6.5 Aim 2 Study Protocol and Data Collection: Patients will be randomly 
assigned to one of two groups: Group 1 (25 patients) will receive 
dexmedetomidine in addition to 15 µg/kg of fentanyl whereas Group 2 
(25 patients) will receive normal saline as a placebo in addition to 15 
µg/kg of fentanyl. 
Half of the fentanyl dose will be administered at the time of induction 
and after obtaining an intravenous access and the second half will be 
administered prior to skin incision. 
For the dexmedetomidine group, a bolus of the drug will be 
administered at 1 µg/kg over 10 min followed by an infusion at 0.5 
µg/kg/hr until the conclusion of cardiopulmonary bypass. 
For placebo, normal saline will be administered at 1 µg/kg over 10 min 
and then given as an infusion at 0.5 µg/kg/hr until the conclusion of 
cardiopulmonary bypass 
Per Standard of Care in our institution, mean arterial pressure and heart 
rate will be continuously monitored and recorded throughout the study 
period 
Blood samples will be drawn from an existing arterial line post-
induction, post-sternotomy, after beginning cardiopulmonary bypass, at 
the conclusion of surgery, and 24 hours postoperatively. 
Blood samples will be analyzed for relative amounts of cortisol, 
epinephrine, norepinephrine, ACTH, nitrated albumin, and cytokines 
such as Tumor Necrosis Factor-α, Interleukin 8, Interleukin 6, and 
Interleukin 10. 
Zero balance Ultrafiltrate (ZBUF) and Modified Ultrafiltrate fluid 
(MUF) will be collected at the conclusion of surgery and analyzed for 
cytokines such as Tumor Necrosis Factor-α, Interleukin 8, Interleukin 6, 
and Interleukin 10. 


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HRP-503  v.12.10.18 
S100ß and NSE levels will be tested at baseline, end of surgery and 24 
hours after surgery. 
Arterial blood gases, glucose and lactate levels will be recorded at each 
of the blood draw time points 
Per Standard of Care at our institution, cross clamp time and bypass time 
will be recorded. 
At the start of the case, the attending anesthesiologist will receive two 
syringes for the study drugs. The first syringe will be labeled “study 
drug - fentanyl”. Half of the drug volume will be administered at 
induction of anesthesia and the second half of the volume will be 
administered prior to skin incision. The second syringe will be labeled 
“study drug - dexmedetomidine/placebo at a concentration of 4µg/ml”.  
The dexmedetomidine/placebo will be administered after obtaining the 
intravenous access as a loading dose of 1 mcg/kg over 10 minutes 
followed by an infusion at a rate of 0.5µg/kg/hr. The 
dexmedetomidine/placebo infusion will be discontinued after separation 
from CPB. 
Blood collection and storage: 3 ml of blood will be collected at five time 
points including: after induction of anesthesia (baseline), after 
sternotomy, after initiation of CPB, at the conclusion of surgery 
(separation from CPB and administration of protamine and prior to skin 
closure) and at 24 hours post-operatively. The S100ß and NSE levels 
will be tested at baseline, end of surgery and 24 hours after surgery. In 
addition, a sample of zero balance Ultrafiltrate (ZBUF) and modified 
ultrafiltrate (MUF) fluid will be collected after separation from CPB and 
the conclusion of MUF. Blood samples will be collected in tubes with 
EDTA preservative and centrifuged at 1,500 x g, at 4oC degrees, for 10 
minutes.  The plasma will be aliquoted and stored at -80oC degrees until 
analysis.  Plasma will be thawed on ice and centrifuged at 14,000 x g for 
1 min prior to analysis.  Arterial blood gases, glucose and lactate levels 
will be recorded at each of the blood drawing time points. 
Hormone assays:  ACTH and cortisol will be assayed by ELISA (Cal 
Biotech, Spring Valley, CA).  Epinephrine and norepinephrine will be 
also assayed by ELISA (2-CAT; Rocky Mountain Scientific, Centennial, 
CO).  All assays will be performed according to the manufacturer's 
instructions. 
Cytokine assays: Cytokine levels in plasma and MUF samples will be 
measured at The Research Institute at Nationwide Children's Hospital 
using the MesoScale cytokine multiplex ELISA format (MesoScale 
Discovery, Rockville, MD).  Measured cytokines include IFN-γ, IL-1β, 
IL-10, IL-12 p70, IL-6, IL-8 and TNF-α.  Manufacturer-provided 
standards and controls will be included in each run to generate 
calibration curves.   


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HRP-503  v.12.10.18 
S100B:  Plasma S100ß levels will be measured by colorimetric ELISA 
analysis using a commercially available kit (BioVendor R&D, Inc., 
Candler, NC) with included calibration controls.   
Neuron-specific enolase (NSE):  Plasma enolase-2 (neuron-specific 
enolase) will be measured using a Quantikine ELISA kit (R&D Systems, 
Inc., Minneapolis, MN) with included calibration controls. 
Tracheal Extubation Criteria: Assuming there are no preoperative 
contraindications for early tracheal extubation, the trachea will be 
extubated at the conclusion of the surgical procedure according to set 
criteria in our institution. After separation from CPB, hemodynamic 
stability without the need for vasopressor administration and absence of 
arrhythmias must be observed to ensure tracheal extubation.  After 
reversal of heparin with protamine and achievement of hemostasis, the 
chest will be closed. If the patient continues to maintain stable 
hemodynamics after chest closure, a trial of spontaneous ventilation will 
be allowed after reversal of the neuromuscular relaxants. If the patient 
continues to maintain stable hemodynamics with acceptable respiratory 
rate, tidal volume and expected arterial oxygen saturation at the 
conclusion of the procedure, the trachea will be extubated.   
Intraoperative data collection included: Age, weight, gender, diagnosis, 
induction time (from the start of the induction of anesthesia to first blood 
gas), bispectral index (BIS) value, cerebral saturation data, baseline 
hemoglobin, baseline platelets count, acute normovolemic hemodilution 
(ANH) volume prior to CPB, CPB circuit prime constituents, red blood 
cell (RBC) administration, additional blood products (platelet, 
cryoprecipitate and plasma) and total volume of each product given, UF 
and MUF volume, cardiopulmonary bypass time, aortic cross clamp 
time, and the time of tracheal extubation if applicable. 
6.6 Long Term Approach: Baseline neurodevelopmental status will be 
evaluated preoperatively using the Bayley-III. Enrolled subjects will be 
re-evaluated at 5 years of age by administering the Differential Ability 
Scales-II (DAS-II).  Parents will also complete the ABAS-II and the 
Child Behavior Checklist (CBL). 
7.0 
Data and Specimen Banking* 
7.1 Data and specimens will not be banked for future use. 
8.0 
Sharing of Results with Subjects* 
8.1 Subjects will receive results of the neurodevelopmental testing in the 
form of a post-visit letter from the Biobehavioral Outcomes Core.  
9.0 
Study Timelines* 
9.1 An individual study subject’s participation in the study should last 
approximately 5 years.  


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HRP-503  v.12.10.18 
9.2 All study subjects should be enrolled within 5 years of study start. 
9.3 The study should be completed within 10 years of study start.  
10.0 Inclusion and Exclusion Criteria* 
10.1 Inclusion: Patients less than one year of age and outside the neonatal 
period who are undergoing repair of atrial septal defect (ASD), 
ventricular septal defect (VSD), atrioventricular septal defect (AVSD), 
tetralogy of fallot (TOF) or biventricular repair with left to right 
shunting physiology will be recruited.  
10.2 Exclusion:  Patients with the diagnosis of AVSD and pulmonary 
hypertension.  Patients less than 1 year and requiring any of the 
following repairs: HLHS, Aortic arch reconstruction, Arterial switch, 
TOF with pulmonary atresia.  Patients diagnosed with developmental 
delays or any syndrome associated with developmental delays. 
10.3 We are including children, and will not include: 
• 
Adults unable to consent 
• 
Pregnant women 
• 
Prisoners 
11.0 Vulnerable Populations* 
11.1 The research involves greater than Minimal Risk to subjects, but 
presents the prospect of direct benefit to the individual subjects.   
11.2 Because of the prospect of direct benefit, permission of one parent is 
sufficient even if the other parent is alive, known, competent, reasonably 
available, and shares legal responsibility for the care and custody of the 
child.   
12.0 Local Number of Subjects 
12.1 50 
13.0 Recruitment Methods 
13.1 Potential subjects will be recruited from the cardiology clinic or from 
preadmission testing (PAT) clinic. 
13.2 Subjects will be patients undergoing cardiac surgery here at NCH. 
13.3 Potential subjects will be identified by looking at the surgery schedule or 
the PAT clinic schedule in EPIC. 
13.4 Subjects will receive $10 for the baseline visit and $25 for each 
subsequent study visit: prior to discharge from the hospital, 1-3 months, 
six months and one year postoperatively.  They’ll also receive $25 for 
the visit at 5 years of age.  All payments will be via ClinCard. 
14.0 Withdrawal of Subjects* 


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HRP-503  v.12.10.18 
N/A 
15.0 Risks to Subjects* 
15.1 The most common side effect of receiving Dexmedetomidine is 
temporary high blood pressure when the dose is started, but treatment of 
the high blood pressure is rarely needed. In studies with adults, common 
side effects were low blood pressure (28%), high blood pressure (16%), 
nausea (11%), slow heartbeat (7%), fever (5%), vomiting (4%), 
difficulty breathing (4%), fast heartbeat (3%), and anemia (3%). 
15.2 The most common side effects of Fentanyl are reduced air flow into the 
lungs, breathing that slows or stops, muscle tightness, and slow heartbeat 
that requires treatment. Fentanyl may also cause high blood pressure, 
low blood pressure, dizziness, blurred vision, nausea, vomiting, 
excessive sweating, uncontrolled tightening of the vocal cords that 
makes breathing difficult, excessive happiness, shrinking of the eye 
pupils, and tightening of the airways. Rarely, it can cause air flow into 
the lungs to be reduced again after surgery as the drug wears off. 
16.0 Potential Benefits to Subjects* 
16.1 The potential benefits are a reduction in stress response during cardiac 
surgery and early extubation leading to less post-operative morbidity and 
mortality and better outcomes. 
17.0 Data Management* and Confidentiality 
17.1 Aim 1 Statistics and Data Analysis: One-way repeated ANOVA will 
be used to test differences of neurodevelopmental Bayley scores at 
discharge, 1 month - 3 months, 6 months and one year of age. For 
repeated two group comparison, we can conduct a paired-t test or 
Wilcoxon signed rank sum test, where appropriate.  One-way ANOVA 
or Kruskal Wallis test will be used to detect group differences.  
Association between Neurodevelopmental scores and S100ß / NSE 
levels will be assessed using Pearson linear correlation or Spearman’s 
rank correlation, where appropriate. Multivariate stepwise regression 
models will be used to evaluate the predictive power of the different 
stress markers on the different clinical outcomes including postoperative 
mortality, cardiac arrest requiring resuscitation, arrhythmias, sepsis, 
DIC, clinical evidence of seizures, reintubation (if patient was extubated 
in the OR), length of ventilator use in the CTICU, inotropic scores, 
length of CTICU stay and length of hospital stay. Logistic stepwise 
models will be used for dichotomous outcomes including; postoperative 
mortality, cardiac arrest requiring resuscitation, arrhythmias, sepsis, 
DIC, clinical evidence of seizures, reintubation (if patient was extubated 
in the OR) and inotropic scores. Linear stepwise regression models will 
be used for the continuous outcomes of length of ventilator use, length 
of ICU stay and length of hospital stay. 


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HRP-503  v.12.10.18 
17.2 Aim 2 Statistics and Data Analysis: Descriptive statistics will be 
computed to summarize all variables of interest. For continuous 
variables, mean and standard deviation will be provided for normally 
distributed data or median and range for non-normally distributed data. 
Count with frequency and percentage will be estimated for categorical 
variables. 
Two sample t-test or Wilcoxon rank-sum test, where appropriate, will be 
used to test effect differences for stress response markers and other 
continuous clinical variables such as age, weight and induction time, 
etc…, between the two groups in each of the five point measurements. A 
Chi-square test or Fisher Exact Test with Bonferroni Correction (based 
on data observations) will evaluate the relationship for categorical 
clinical data. A mixed model will also be used to estimate overall 
difference and time trend for these stress biomarkers with repeated 
measurements. Type I error will be strongly controlled at α=0.05 for 
single comparisons and with adjustment for multiple comparisons. 
17.3 Research records will be stored in a locked cabinet and password 
protected computer.  Only certified research personnel will be given 
access to identifiable subject information. 
18.0 Provisions to Monitor the Data to Ensure the Safety of Subjects* 
18.1 The study will be monitored in compliance with the relevant parts of 21 
CFR and according to the ICH GCP Guidelines. The procedures outlined 
in the protocol and case report forms will be carefully reviewed by the 
PI and staff prior to study initiation to ensure appropriate interpretation 
and implementation. No deviations from the protocol shall be made 
except in emergency situations where alternative treatment is necessary 
for the protection, proper care and wellbeing of subjects. 
18.2 All subjects will be clinically monitored as it pertains to routine 
anesthetic care during the surgical procedure. This includes the use of 
standard ASA (American Society of Anesthesiology) monitors which 
measure ventilation (end tidal C02, inspired anesthetic gases), 
oxygenation (pulse oximetry), temperature and circulation (heart rate, 
blood pressure and EKG assessments). In addition, all subjects will have 
BIS (Bispectral Index) monitoring used to assess the depth anesthetic as 
well as guide titration of anesthetic agents.  
18.3 Amendments will be submitted to the Nationwide Children’s Hospital 
IRB for their review and approval prior to implementation. When an 
amendment to a protocol substantially alters the study design or 
increases potential risk to the study subject, the Informed Consent Form 
will be revised and if applicable, subject's consent to continue 
participation will again be obtained. 
19.0 Provisions to Protect the Privacy Interests of Subjects 


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19.1 Subject information will not be given to any other investigators. Subjects 
and their information will be closely monitored and guarded by study 
staff; there will be limited access to patients and their information by 
trained study staff; and subject information will only be shared and 
discussed between study staff specific to this study. 
19.2 Subject recruitment will be cleared through the cardiothoracic nurse 
practitioners prior to approaching the patient to ensure that the family is 
not being overwhelmed by multiple study teams. 
20.0 Compensation for Research-Related Injury 
20.1 None 
21.0 Economic Burden to Subjects 
21.1 None. 
22.0 Consent Process 
22.1 We will be following “SOP: Informed Consent Process for Research 
(HRP-090)”. 
22.2 The consent process will begin in the PAT clinic by PI, Sub-
Investigators, Study Coordinators, and/or trained research staff. 
22.3 The study will be thoroughly explained to the patient’s family. There 
will be ample time allotted for questions and answers. An explanation of 
voluntary participation will take place, and the family will be asked if 
they are interested in participating in the study. If the parent(s), or legal 
guardian agrees to participate they will be asked to sign consent forms. 
The patient will then be enrolled in the study with the understanding that 
they can elect to stop the study and be withdrawn from the study at any 
time.  
23.0 Process to Document Consent in Writing 
23.1 We will be following “SOP: Written Documentation of Consent (HRP-
091).”  
24.0 Setting 
24.1 Potential subjects will be identified and recruited from the cardiology or 
PAT clinic.  Research procedures will be performed in the main OR, 
CTICU, and biobehavioral core. 
25.0 Resources Available 
25.1 The department of Anesthesiology and Pain Medicine has 2 research 
coordinators and 2 research associates that will be enrolling subjects for 
this study.  All study staff will be trained on the study procedures.  
25.2 We will also be utilizing the psychologists and research associates from 
the biobehavioral core for the neurodevelopmental testing. 


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26.0 Multi-Site Research* 
26.1 N/A 
 
27.0  Protected Health Information Recording 
 
1.0 
Indicate which subject identifiers will be recorded for this research. 
☒  Name 
☐  Complete Address 
☒  Telephone or Fax Number 
☐  Social Security Number (do not check if only used for ClinCard) 
☒  Dates (treatment dates, birth date, date of death) 
☒  Email address , IP address or url 
☒  Medical Record Number or other account number 
☐  Health Plan Beneficiary Identification Number 
☐  Full face photographic images and/or any comparable images (x-rays) 
☐  Account Numbers 
☐  Certificate/License Numbers 
☐  Vehicle Identifiers and Serial Numbers (e.g. VINs, License Plate Numbers) 
☐  Device Identifiers and Serial Numbers 
☐  Biometric identifiers, including finger and voice prints 
☐  Other number, characteristic or code that could be used to identify an individual 
☐  None (Complete De-identification Certification Form) 
 
2.0   
Check the appropriate category and attach the required form* on the Local Site 
Documents, #3. Other Documents, page of the application.  (Choose one.) 
☒  Patient Authorization will be obtained. (Include the appropriate HIPAA language 
(see Section 14 of consent template) in the consent form OR attach the HRP-900, 
HIPAA AUTHORIZATION form.) 
☐  Protocol meets the criteria for waiver of authorization. (Attach the HRP-901, 
WAIVER OF HIPAA AUTHORIZATION REQUEST form.) 
☐  Protocol is using de-identified information. (Attach the HRP-902, DE-
IDENTIFICATION CERTIFICATION form.) (Checked "None" in 1.0 above) 
☐  Protocol involves research on decedents. (Attach the HRP-903, RESEARCH ON 
DECEDENTS REQUEST form.) 
☐  Protocol is using a limited data set and data use agreement. (Contact the Office of 
Technology Commercialization to initiate a Limited Data Use Agreement. 
 
*Find the HIPAA forms in the IRB Website Library, Templates. 
 
Attach the appropriate HIPAA form on the “Local Site Documents, #3. Other 
Documents”, page of the application. 
 
3.0    How long will identifying information on each participant be maintained? 


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Following publication of study results, research records will be stored for a period of 
3-5 years and then will be destroyed by placing in a secure shredding bin. 
 
4.0 
Describe any plans to code identifiable information collected about each 
participant.  None 
 
5.0 
Check each box that describes steps that will be taken to safeguard the 
confidentiality of information collected for this research: 
☒ Research records will be stored in a locked cabinet in a secure location 
☒ Research records will be stored in a password-protected computer file 
☐ The list linking the assigned code number to the individual subject will be 
maintained separately from the other research data 
☒ Only certified research personnel will be given access to identifiable subject 
information 
 
6.0 
Describe the provisions included in the protocol to protect the privacy interests 
of subjects, where "privacy interests" refer to the interest of individuals in being 
left alone, limiting access to them, and limiting access to their information. (This 
is not the same provision to maintain the confidentiality of data.) 
 
Subject information will not be given to any other investigators. Subjects and their 
information will be closely monitored and guarded by study staff; there will be 
limited access to patients and their information by trained study staff; and subject 
information will only be shared and discussed between study staff specific to this 
study. 
 
Confidential Health Information 
 
1.0 
Please mark all categories that reflect the nature of health information to be 
accessed and used as part of this research. 
 
☒  Demographics (age, gender, educational level) 
☒  Diagnosis 
☒  Laboratory reports 
☐  Radiology reports 
☒  Discharge summaries 
☒  Procedures/Treatments received 
☒  Dates related to course of treatment (admission, surgery, discharge) 
☐  Billing information 
☒  Names of drugs and/or devices used as part of treatment 
☐  Location of treatment 
☐  Name of treatment provider 
☐  Surgical reports 
☒  Other information related to course of treatment 


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☐  None 
 
2.0 
Please discuss why it is necessary to access and review the health information 
noted in your response above. 
It is necessary to meet the objectives of the study and to analyze the data. 
 
3.0 
Is the health information to be accessed and reviewed the minimal necessary to 
achieve the goals of this research?  ☒ Yes    ☐ No 
 
4.0 
Will it be necessary to record information of a sensitive nature?  ☐ Yes   ☒ No 
 
5.0 
Do you plan to obtain a federally-issued Certificate of Confidentiality as a means 
of protecting the confidentiality of the information collected?  ☐ Yes   ☒ No