Pharmacokinetics of Acetaminophen in Pediatric Patients With Congenital Heart Disease
Conditions: Congenital Heart Disease
Sponsor: Peter Winch

 
Pharmacokinetics of Acetaminophen in Pediatric Patients With Congenital 
Heart Disease 
 
 
NCT04278625 
 
 
November 30, 2021 

PROTOCOL TITLE: Acetaminophen in congenital heart disease  
 
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HRP-503  v.12.10.18 
 
PROTOCOL TITLE: 
Pharmacokinetics of acetaminophen in pediatric patients with congenital heart 
disease  
PRINCIPAL INVESTIGATOR: 
Peter Winch, MD, MBA 
Anesthesiology and Pain Management 
(614) 722-3131 
Peter.winch@nationwidechildrens.org 
VERSION NUMBER/DATE: 
Version 4/November 23, 2021 
 
REVISION HISTORY 
 
Revision 
# 
Version Date 
Summary of Changes 
Consent 
Change? 
1 
2/24/2021 
Adding additional intraoperative and 
postoperative data to be collected.  Changing 
hospital laboratory to NMS labs. 
No 
2 
3/17/2021 
Increasing the amount of blood drawn 
Yes 
3 
11/23/2021 
Increasing the sample size to 32 to replace the 
2 subjects who had to be withdrawn 
Yes 
 
 
 
 
 
 
 
 
 
 
 

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1. Study Summary 
 
Study Title 
Pharmacokinetics of acetaminophen in pediatric patients 
with congenital heart disease  
Study Design 
Prospective cohort study  
Primary Objective 
To measure serum acetaminophen concentrations in two 
groups of patients with congenital heart disease (cyanotic 
and acyanotic) and to determine pharmacological parameters 
based on these levels.   
Secondary 
Objective(s) 
Not applicable 
Research 
Intervention(s)/ 
Investigational 
Agent(s)  
Not applicable 
IND/IDE #  
Not applicable 
Study Population 
Pediatric patients presenting for repair of congenital heart 
disease  
Sample Size 
32  
Study Duration for 
individual 
participants 
6 hours 
Study Specific 
Abbreviations/ 
Definitions  
Not applicable 
 
2. 
Objectives 
This is a prospective study of pediatric patients with congenital heart 
disease, in which acetaminophen serum concentrations will be 
measured following a single intraoperative intravenous dose of 
acetaminophen. These levels will be used to develop a 
pharmacokinetic model. Serum concentrations will be compared 
between two groups of patients: (1) cyanotic patients presenting for 
the Fontan completion operation and (2) patients with acyanotic 
congenital heart disease presenting for repair via median sternotomy.  
3. Background 
Pediatric patients presenting for cardiac surgery are at risk for a wide 
range of perioperative complications, including both acute pain and 
chronic pain, with associated decrements in postoperative quality of 
life. The immediate post-operative approach to analgesia for these 
patients continues to focus on opioid medications as the mainstay of 
therapy, although the benefits of a multimodal approach are being 
more clearly recognized. Acetaminophen is routinely used in many 
institutions for the perioperative management of pediatric patients 

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undergoing major surgical procedures, including patients presenting 
for cardiac surgery. The adjunctive use of acetaminophen improves 
analgesia and decreases opioid requirements thereby limiting opioid-
related adverse effects. The pharmacokinetics of acetaminophen 
have been studied in many surgical populations; however, there are 
limited data for patients who are undergoing repair of congenital 
heart defects especially those with cyanotic congenital heart disease. 
This knowledge deficit is especially important for subsets of this 
population, who may be at risk for alterations in acetaminophen 
metabolism and therefore more susceptible to adverse reactions. The 
predominant pathway of acetaminophen metabolism is via 
glucuronidation to inactive metabolites; a smaller fraction is 
oxidized to highly reactive metabolites. Patients with cyanotic 
congenital heart disease, such as those patients presenting for the 
Fontan completion operation, may have depleted endogenous 
antioxidants and higher levels of oxidative stress, which could 
predispose them to a higher risk of acetaminophen related toxicity in 
the perioperative period. The objective of this study is to determine 
acetaminophen concentrations and develop a pharmacokinetic model 
in pediatric patients undergoing palliation or repair of congenital 
heart disease, with a comparison between partially and fully palliated 
cyanotic lesions and acyanotic lesions.   
 
4. Study Endpoints 
The primary end point is plasma concentrations at various time 
points following a single intraoperative intravenous dose of 
acetaminophen.  
5. Study Intervention/Investigational Agent 
 
Not applicable 
 
6. Procedures Involved* 
6.1 Describe and explain the study design. 
This is a prospective study in which serum levels of acetaminophen 
will be measured following a single intravenous dose administered 
intraoperatively. We will enroll patients with cyanotic and acyanotic 
congenital heart disease who are presenting before surgical palliation 
(cyanotic patients), or for surgical repair requiring a median 
sternotomy (acyanotic patients). These patients already routinely 
receive acetaminophen intravenously in the operating room during 
sternal closure, as part of a comprehensive pain management 
strategy. Blood samples will be drawn post-procedure at pre-
specified time points and acetaminophen concentrations will be 

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measured. We have an existing relationship with an expert in 
pediatric pharmacokinetics, Dr. Brian Anderson, who will perform 
the pharmacokinetic calculations for this aspect of the study.  
6.2 Provide a description of all research procedures being performed 
and when they are performed, including procedures being performed 
to monitor subjects for safety or minimize risks. 
Intravenous acetaminophen is routinely administered 
intraoperatively for patients undergoing cardiac surgery at our 
institute. A single dose of 15 mg/kg will be administered at the 
conclusion of the surgical procedure following cardiopulmonary 
bypass, at the start of sternal closure (first sternal wire/suture). With 
informed consent obtained pre-operatively, a member of the research 
team will collect blood samples from each patient at the pre-
specified time points (total of 7) following the acetaminophen 
administration. Each sample will require 1-2 mL of blood. No 
additional acetaminophen will be administered until after the 6 hour 
concentration is obtained. These patients, based on the nature of their 
surgeries, will have existing invasive vascular access in place. The 
only deviation from the standard perioperative management of these 
patients will be the collection of blood samples at the following time 
points:  
  
15-20 minutes 
  
30-40 minutes 
  
50-70 minutes 
  
80-100 minutes 
  
2, 4 and 6 hours   
6.3 Describe: 
• 
Procedures performed to lessen the probability or magnitude 
of risks. 
There are minimal risks to subjects in this study, as they 
already receive intravenous acetaminophen as part of their pain 
control management plan, and will have existing vascular 
access that will allow for blood sampling. 
• 
All drugs and devices used in the research and the purpose of 
their use, and their regulatory approval status. 
Not applicable. 
• 
The source records that will be used to collect data about 
subjects. (Attach all surveys, scripts, and data collection 
forms.) 

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Not applicable 
6.4 What data will be collected during the study and how that data will 
be obtained. 
Demographic data will be collected for each patient from the electronic 
medical records. This will include age, gender, weight, diagnosis, actual 
procedure performed, pre-operative medications, and any documented 
allergies. We will record intraoperative fluid and blood product 
administration, intraoperative medications, and whether patient was 
extubated in the OR, as well as duration of cardiopulmonary bypass and 
cross clamp time (if applicable). The dose of acetaminophen administered 
in the operating room will be recorded from the intraoperative medical 
record. Results from the acetaminophen concentration assays, analyzed at 
NMS labs, will be recorded into the research records. We will also record 
blood product administration and medications in the ICU up to the 6-hour 
PK sample collection. 
6.5 If there are plans for long-term follow-up (once all research related 
procedures are complete), what data will be collected during this 
period.  
Not applicable 
6.6 For Humanitarian Use Device (HUD) uses provide a description of 
the device, a summary of how you propose to use the device, 
including a description of any screening procedures, the HUD 
procedure, and any patient follow-up visits, tests or procedures. 
Not applicable 
7. Data and Specimen Banking - Not applicable 
 
 
8. Sharing of Results with Subjects - Not applicable 
 
 
9. Study Timelines - Not applicable 
 
10. Inclusion and Exclusion Criteria* 
10.1 Describe how individuals will be screened for eligibility. 
Following identification of potential participants (see below; partial 
waiver of HIPAA authorization requested), they will be approached 
and informed about the study as part of an informed consent process. 
This will take place at the pre-admission testing visit or if no PAT 
visit is scheduled, the day of surgery. After consent, potential 
participants will be asked a series of questions (data collection form 
to be attached) in order to verify eligibility for inclusion in the study.  

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Describe the criteria that define who will be included or excluded in 
your final study sample. 
Inclusion criteria:  
Pediatric patients between age 2 and 6 years of age, presenting for 
Fontan palliation or for surgical repair requiring median 
sternotomy, will be included in the study. Only patients who receive 
intravenous acetaminophen in the operating room will have serum 
levels drawn.  
Exclusion criteria:  
Patients will be excluded if they have documentation of an allergy 
to acetaminophen, severe hepatic disease or other contraindications 
to acetaminophen use, or if they have received acetaminophen 
within 24 hours of their procedure.  
 
Indicate specifically whether you will include or exclude each of 
the following special populations: (You may not include members 
of the above populations as subjects in your research unless you 
indicate this in your inclusion criteria.) 
 
Children will be included in this study. 
 
11. Vulnerable Populations* 
We have reviewed the checklist HRP-416, and have provided sufficient 
information in this application for completion of the checklist.  
 
12. Local Number of Subjects 
12.1 Indicate the total number of subjects to be accrued locally. 
We will enroll 32 patients for this study, with 15 patients in each 
group (2 subjects in the acyanotic group had to be withdrawn, so we 
will replace those subjects). 
12.2 If applicable, distinguish between the number of subjects who are 
expected to be enrolled and screened, and the number of subjects 
needed to complete the research procedures (i.e., numbers of 
subjects excluding screen failures.) 
We would anticipate screening 20 patients for each group (for a total 
of 40 patients screened). 
 
13. Recruitment Methods 

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We are requesting a partial waiver of HIPAA research authorization in order to identify 
potential participants, using clinic and operating room schedule. On a weekly basis, the 
cardiac operating room schedule will be reviewed to identify patients presenting for 
eligible procedures (Fontan palliation or surgical correction of congenital heart disease 
with median sternotomy). Patient name, name and date of scheduled procedure, and date 
of pre-admission testing visit will be noted (data collection form to be attached). If no 
pre-admission testing visit is scheduled, but a cardiac catheterization is scheduled, the 
date of the catheterization will be noted. In cases of ambiguity in the operating room or 
cardiac catheterization schedule or uncertainty as to nature of procedure, the chart will be 
reviewed to clarify the planned procedure.  Only the minimum data necessary will be 
used to identify participants, who will then be approached and informed about the study 
as part of the informed consent process. No additional data will be recorded until the 
informed consent process is complete.  
 
14. Withdrawal of Subjects - Not applicable 
 
 
 
15. Risks to Subjects* 
15.1 List the reasonably foreseeable risks, discomforts, hazards, or 
inconveniences to the subjects related the subjects’ participation in 
the research. Include as may be useful for the IRB’s consideration, a 
description of the probability, magnitude, duration, and reversibility 
of the risks. Consider physical, psychological, social, legal, and 
economic risks. 
There are minimal risks to the participants in this study. Intravenous 
acetaminophen is approved by the US FDA for use in this 
population. The subjects will receive no medications beyond those 
routinely incorporated into the post-operative care of this patient 
population, and the blood samples will be taken from pre-existing 
vascular access sites. No changes in clinical management will be 
made for the subjects, who are already receiving numerous 
medications as well as undergoing repeated blood sampling. 
16. Potential Benefits to Subjects 
 
There are no direct benefits to the patients in this study.  
 
17. Data Management* and Confidentiality 
Serum acetaminophen concentrations will be obtained and used to 
calculate pharmacologic parameters; these will include volume of 
distribution and elimination half-life. Concentrations and 
pharmacologic parameters will be compared between the two patient 
groups. 

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17.1 Describe the steps that will be taken to secure the data (e.g., 
training, authorization of access, password protection, encryption, 
physical controls, certificates of confidentiality, and separation of 
identifiers and data) during storage, use, and transmission. 
Research records will be stored in password protected computer files, to which 
only trained members of the research team will have access.  
17.2 Describe any procedures that will be used for quality control of 
collected data.  
NA 
17.3 Describe how data or specimens will be handled study-wide: 
• 
What information will be included in that data or associated 
with the specimens? Patient identification will be associated 
with the specimens.  
• 
Where and how data or specimens will be stored? 
• 
How long the data or specimens will be stored? 
The specimens will be stored until the completion of the study.  
• 
Who will have access to the data or specimens? 
A member of the research team will be responsible for collecting and 
transporting the specimens. Only members of the research team who 
have completed necessary training will have access to the study data, 
which will be stored in password protected files.  
18. Provisions to Monitor the Data to Ensure the Safety of Subjects* 
NA 
 
19. Provisions to Protect the Privacy Interests of Subjects 
Potential subjects and their families will be identified through review of operating room 
schedules. To avoid unnecessary or unapproved intrusion into the subjects’ medical 
histories, only the absolute minimum necessary information will be noted from a 
patient’s chart (with requested partial HIPAA waiver) prior to obtaining the consent to 
participate. No information will be recorded for the patients whose guardians refuse entry 
into the study. Additionally, all consent procedures will take place in private rooms. 
Access to the patients’ charts for the sake of the study will be strictly limited to study 
personnel who have completed all necessary training regarding research with human 
subjects.  
 
20. Compensation for Research-Related Injury 
NA 

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21. Economic Burden to Subjects 
There will be no costs for subjects in this study.  
22. Consent Process 
22.1 Indicate whether you will you be obtaining consent, and if so 
describe: 
A member of the research team will obtain consent from the 
parents/guardians of the subjects in the study. These patients are seen 
the preoperative testing clinic in preparation for surgery, and they 
will be approached at this pre-operative visit regarding this study. 
Research staff will follow the Informed Consent Process for 
Research studies. If patients are presenting for cardiac 
catheterization immediately preceding their operative intervention, 
without a preoperative testing visit, they will be approached at the 
time of the cardiac catheterization.  
• 
Any waiting period available between informing the 
prospective subject and obtaining the consent. 
There is usually at least one day between the evaluation at the pre-
operative clinic or the cardiac catheterization and the actual day of 
the operation. Potential participants will have this time to consider 
their desire to participate in the study.  
• 
Subjects who are not yet adults (infants, children, teenagers) 
The expected patient population for this project will be children 
between 2 and 6 years of age, who would not be expected to provide 
assent for inclusion in the study. Their parents/legal guardians will 
be approached to obtain consent for inclusion in this research.  
Parental permission will be obtained from one parent even if the other 
parent is alive, known, competent, reasonably available, and shares 
legal responsibility for the care and custody of the child.  
If the patient is in the custody of a person other than their parent, 
consent will be obtained from the person legally able to provide 
surgical and anesthesia consent for the operation.  
Based on the expected age of the participants, assent will not be 
obtained.  
23. Process to Document Consent in Writing 
23.1 We will be following “SOP: Written Documentation of Consent 
(HRP-091).”  

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23.2 We will attach the appropriate consent form.  
24. Setting 
24.1 Describe the sites or locations where your research team will 
conduct the research. 
The sample collection will take place in the operating room and in 
the cardiothoracic intensive care unit at the prespecified time points.  
25. Resources Available 
Our department has successfully completed a similar study in a 
population of pediatric patients undergoing bariatric surgery, 
confirming the availability of the necessary resources for the 
completion of the current investigation. Based on the surgical case 
volume at our institute in this patient population, we would not 
anticipate difficulty in achieving the desired recruitment numbers for 
the study.  
26. Multi-Site Research* 
NA 
 
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.) 

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☒  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? 
Identifying information will be kept until study completion.  
 
4.0 
Describe any plans to code identifiable information collected about each 
participant. 
NA 
 
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 
☒  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.) 
Please see above in section 18. 
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) 

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☒  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 
☐  None 
 
2.0 
Please discuss why it is necessary to access and review the health information 
noted in your response above. 
The above information is necessary for us to describe our patient population, 
ensure that they meet the enrollment specifications, and evaluate the outcomes of 
the study.  
 
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 
 
 
 
References 
 
1. 
Lauridsen, M.H., et al., Chronic pain in children after cardiac surgery via 
sternotomy. Cardiology in the Young, 2014. 24(5): p. 893-899. 
2. 
Matsuda, M., et al., Post‐surgical chronic pain and quality of life in children 
operated for congenital heart disease. Acta Anaesthesiologica Scandinavica, 
2019. 63(6): p. 745-750. 
3. 
Bigeleisen, P.E. and N. Goehner, Novel approaches in pain management in 
cardiac surgery. Current Opinion in Anesthesiology, 2015. 28(1): p. 89-94. 
4. 
Zeilmaker-Roest, G.A., et al., An international survey of management of pain and 
sedation after paediatric cardiac surgery. BMJ paediatrics open, 2017. 1(1). 

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5. 
Morita, K., Surgical reoxygenation injury of the myocardium in cyanotic patients: 
clinical relevance and therapeutic strategies by normoxic management during 
cardiopulmonary bypass. General thoracic and cardiovascular surgery, 2012. 
60(9): p. 549-556.