Nitric Oxide Administration During Pediatric Cardiopulmonary Bypass Surgery to Prevent Platelet activation-a Single Center Pilot Study
Phase: PHASE2
Conditions: Inflammation, Platelet Dysfunction
Sponsor: Medical College of Wisconsin

Title: Nitric Oxide Administration During Pediatric Cardiopulmonary 
Bypass Surgery to Prevent Platelet Activation 
 
NCT03455218 
Unique Protocol ID 1111115-1NO in CPB 001 
 
 
Study Protocol and Statistical Analysis Plan 
 
Document Date: 5/19/2020 
 
 
 

Protocol 
To complete the aims and objectives of this project we are planning a pilot randomized, double 
blinded, placebo controlled clinical trial of nitric oxide added to the sweep gas of the oxygenator 
during cardiac surgery requiring CPB in infants.   
Inclusion Criteria: Infants less than one year of age undergoing cardiac surgery with the use of 
cardiopulmonary bypass.   
Exclusion Criteria:  Prior surgery requiring CPB within the same hospitalization, pre-operative 
need for ECMO or mechanical circulatory support, known hypersensitivity to nitric oxide, 
known hemostatic or thrombotic disorder that results in an altered transfusion/anticoagulation 
protocol 
Equitable subject selection:  All patients will be considered for eligibility that meet the 
inclusion/exclusion criteria regardless of race, gender, or ethnic background.  Non-English 
speaking patients will be considered for inclusion if a suitable consent form can be approved 
prior to their surgical procedure.  A Spanish language short form will be submitted along with 
the initial study as we anticipate some eligible subjects will be Spanish speaking only.  Other 
languages encountered in eligible patients will be considered on an individual basis and if a 
suitable consent form can be drafted and approved prior to the patient’s surgical date, they will 
be considered for enrolment.    
Sample Size: 40 patients equally distributed amongst the treatment and placebo groups 
Power Calculation: using 0.05 as type 1 error tolerance and previous data from neonatal CPB 
studies, a minimum sample size of 12 patients is necessary to detect a difference of a change in 
platelet count (Specific Aim 1) of 50 with a power of 91%.  
Sample size justification:  In order to maximize the ability to estimate a sample size for a larger 
multi-institutional trial (Specific Aim 2) we need to maximize the number of patients enrolled 
within this local pilot trial.  Approximately 120 infants annually meet the inclusion/exclusion 
requirements annually at CHW.  Given experience with prior interventional studies in this 
population, we anticipate a consent rate of approximately 33%.  Therefore we anticipate being 
able to enroll 40 patients into this trial within one year. 
Randomization: Stratified to insure the number of patients with Society of Thoracic Surgery 
(STS) Mortality Class 1-3 and 4-5 surgeries are equally distributed.  
Justification for stratification of randomization:  The complexity of congenital cardiac surgery is 
known to significantly impact morbidity and mortality (16).  In order to insure an equal 
distribution of patients with this known confounder among groups we will stratify the 
randomization to insure an equal distribution to active and placebo groups.    
Recruitment: The PI and co-investigators have access to the cardiac surgical scheduling 
coordinators.  We will be in contact with them and browse the list of scheduled surgical patients 
at the weekly surgical conference.  The PI and co-investigators are also active clinicians within 
the cardiac intensive care unit and will be looking for eligible patients amongst the census of the 
intensive care unit within the normal course of their clinical duties.  No fliers or published 
materials will be used.  If the patient has an identified primary cardiologist at the time they are 
deemed to be eligible, we will contact them prior to approaching the patient/family to answer any 
questions they would have.   

Treatment:  A minimum sweep gas flow of 2.5 L/min will be used in all patients with CO2 added 
to maintain PaCO2 35-40 mmHg. All patients will have an INOmax DSIR device in line with the 
sweep gas.  Nitric oxide at a dose of 20 ppm will be added to the sweep gas of the treatment 
group from the initiation to the conclusion of CPB.  The placebo group will not receive nitric 
oxide but will be connected to the INOmax DSIR device.   
The INOmax DSIR  device and nitric oxide will be supplied by Mallinckrodt Pharmaceuticals. A 
letter indicating this support from Mallinckrodt is included in the package.         
Blinding:  All care providers involved in the clinical care of the patient will be blinded to 
treatment group (and methemoglobin levels) for 30 days post-operatively or hospital discharge 
(whichever is later).  A single study staff (perfusionist or respiratory care practitioner) will be 
responsible for nitric oxide delivery according to the randomization scheme outlined above. 
Study Measurements (Primary objectives in bold):   
Aim 1:  
Baseline and at conclusion of cardiac repair/prior to transfusion: Change in platelet count, 
platelet response to TRAP, U46619, and CRP (to be done at the Blood Research Institute) 
Aim 2: 
30 day (all cause) mortality, length of hospital stay post-operatively, transfusion volumes of 
platelets and pRBCs, total number of transfused products, length of mechanical ventilation post-
operatively, vasoactive infusion score (highest within the first 24 hours post-operatively), need 
for ECMO within 48 hours post-operatively, and total hospital cost.    
Aim 3: 
Baseline, at conclusion of CPB, and upon arrival to ICU: Methemoglobin levels 
 
 

Statistical Analysis Plan 
A redcap database will be created to collect all data fields and insure data integrity.  Statistical 
support will be through a qualified statistician from the Clinical and Translational Science 
Institute of Southeast Wisconsin, Dr. Chiang-Ching Huang.  We plan to compare continuous 
variables such as change in platelet count; platelet response to TRAP, U46619, and CRP; length 
of stay; length of mechanical ventilation; transfusion volumes; total hospital cost; and 
methemoglobin levels with either a Mann Whitney test or t-test.  A chi-square analysis will be 
used for dichotomous variables such as mortality and need for ECMO.  Multivariate or 
regression analysis will be done as needed to control for significant cofounders such as surgical 
complexity scoring, age, gender, race, ethnicity, weight, and presence of known genetic disorder.