Nitric Oxide During Bypass for Arterial Switch Operation (NASO)
Primary Purpose
Low Cardiac Output Syndrome, Transposition of Great Vessels
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Nitric Oxide
Sponsored by
About this trial
This is an interventional prevention trial for Low Cardiac Output Syndrome focused on measuring Cardiopulmonary bypass, Congenital heart disease, Low cardiac output syndrome, Nitric oxide, Transposition of Great Arteries, Arterial switch operation
Eligibility Criteria
Inclusion criteria;
Each participant must meet all of the following criteria to be enrolled in this study:
- Infant aged greater than or equal to 36 weeks gestation
- Infants less than 2 years
- Diagnosed with TGA and requiring Arterial Switch Operation
- Consent of parents/guardian.
Exclusion criteria
Potential participants will be excluded if they meet any of the following criteria:
- They have multiple major congenital anomalies (anomalies which affect the infant's life expectancy or health status)
- They have multiple other cardiac abnormalities (with the exception of ASD, VSD or PDA)
- They weigh less than 2.2kgs.
- Prior surgical exposure to cardio-pulmonary bypass
Sites / Locations
- Texas Children's Hospital
- Royal Children's Hospital
- Stollery Cildren's Hospital
- Harapan Kita Children and Women's Hospital
- Institut Jantung Negara
- Alder Hey Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
No Intervention
Arm Label
Intervention arm
Control arm
Arm Description
• Intervention arm will receive nitric oxide 20 parts per million (ppm) into the oxygenator of a cardio-pulmonary bypass circuit
Control arm will not receive nitric oxide, they will receive standard bypass as per local policy
Outcomes
Primary Outcome Measures
Major adverse events
The primary outcome is the number of participants with major adverse events (MAEs) within 28 days post-operatively. MAEs include cardiac arrest, emergency chest opening, use of ECMO, and death.
Secondary Outcome Measures
Length of stay in ICU (hours)
Length of stay in ICU (hours) will be calculated from date and time of admission to ICU date and time of discharge to ICU.
Length of stay in hospital (days)
Length of stay in hospital (days) will be calculated from date and time of admission to hospital to date and time of discharge to hospital.
Ventilator-free days
Ventilator-free days will be calculated from date and time of intubation to date and time of extubation. Each day (or part of a day) will be counted as a day.
Inotrope hours
Inotrope hours will be calculated from data input into REDCAP.
Dialysis-free days
Dialysis-free days will be calculated from date and time of start of dialysis to date and time of stopping dialysis. Each day (or part of a day) will be counted as a day.
Inhaled NO hours
Inhaled NO hours will be calculated from data input into REDCAP.
ECMO-free days
ECMO-free days will be calculated from date and time of start of ECMO to date and time of stopping ECMO. Each day (or part of a day) will be counted as a day.
Closed sternum days
Closed sternum days will be calculated from date and time of start of chest opening (or return to ICU time if delayed chest closure) to date and time of chest closure. Each day (or part of a day) will be counted as a day.
Composite free-day score
This score is a combination of scores 1-8 to create a composite free-day score. Composite free-day score is a score highlighting the number of days free from post-operative complications including free of hospitalization within the first 28 days post operatively. For each score, the days free of complication will be calculated to create an individual free from score these will be then added together to create an overall free-from score. Higher scores suggest a better outcome (free from hospital and complications).
Full Information
NCT ID
NCT03661385
First Posted
September 4, 2018
Last Updated
May 10, 2023
Sponsor
Murdoch Childrens Research Institute
1. Study Identification
Unique Protocol Identification Number
NCT03661385
Brief Title
Nitric Oxide During Bypass for Arterial Switch Operation
Acronym
NASO
Official Title
A Randomised Controlled Trial of Nitric Oxide Administration During Cardiopulmonary Bypass in Infants Undergoing Arterial Switch Operation for Repair of Transposition of the Great Arteries
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
July 11, 2018 (Actual)
Primary Completion Date
March 23, 2022 (Actual)
Study Completion Date
April 23, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Murdoch Childrens Research Institute
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This trial will test if adding nitric oxide (NO) gas to the cardiopulmonary bypass (CPB) circuit in infants undergoing an arterial switch operation (ASO) for Transposition of the Great Arteries (TGA) changes the incidence of major postoperative adverse events (AEs).
Major postoperative AEs include cardiac arrest, emergency chest opening, use of ECMO (machine that acts as an artificial heart and lung during surgery), and death.
Participants will be randomised to receive oxygen plus nitric oxide (intervention arm) or oxygen without nitric oxide (control arm) during CPB.
Detailed Description
The incidence of congenital heart disease (CHD) is approximately 1/100 live born children, of which up to 50% require cardiac surgery to correct the underlying abnormality at some stage during their life. (Centre for Disease Control and Prevention, USA). Despite major improvements in CPB devices, the exposure of host blood to large artificial organ surfaces, combined with myocardial injury during planned myocardial ischemia, results in a significant systemic inflammatory response. CPB-triggered systemic inflammatory syndrome is responsible for the most serious and potentially life-threatening side effects associated with cardiac surgery. It is characterized by endotoxin release, leukocyte and complement activation, and widespread activation of inflammatory mediators, resulting in endothelial leak, increased oxygen consumption, and organ dysfunction.
NO is an endogenous anti-inflammatory mediator that helps to protect endothelial beds and immunologically active cells. NO has a myocardial protective effect by reducing reperfusion injury. NO generation is essential for regulation of endothelial function and microvascular inflammation. However, dysregulation of endogenous NO during CPB may aggravate the subsequent inflammatory response.
A randomized controlled study adding NO into the bypass circuit was conducted by the Royal Children's Hospital in Melbourne on 198 children. This pilot study confirmed the positive effects of gaseous NO reported in the U.S. trial, as well as a reduction in the incidence of low cardiac output syndrome (LCOS). Other improved patient outcomes included a reduced need for extracorporeal life support (ECLS), trends towards a reduced length of stay, and shorter duration of ventilation. In light of these promising preliminary results from these two separate studies, a large multicentre trial to test these findings in children requiring cardiac surgery is needed.
The NASO study is running concurrently with the Nitric Oxide during Cardio Pulmonary Bypass during surgery for congenital heart defects: A Randomised Controlled Trial study (ANZCTR Trial Registry ID: ACTRN12617000821392) within Australia (run by Lady Cilento, Brisbane). This study is aiming to look at the effects of Nitric Oxide on all children under the age of 2 years undergoing bypass surgery for CHD.
TGA presents in 5-7% of all patients with congenital heart disease and isolated TGA is managed in a similar manner all over the world. The surgical treatment for this is the ASO. Hence this single operation and diagnosis provides an appropriate setting to evaluate the efficacy of NO in the CPB circuit. By allowing each centre to have their own protocols of care (pre, intra and postoperatively) and only collecting 'routine clinical data", the investigators anticipate each centre having high rates of screening and consent.
Patients will be stratified by centre and by age at time of surgery. Participants will be randomized into one of two arms:
Intervention arm will receive NO 20 parts per million (ppm) into the oxygenator of a cardio-pulmonary bypass circuit
Control arm will not receive NO
At the end of CPB, the participants will return to the Intensive Care Unit where normal care will continue.
A total of 800 participants will be enrolled in the study and will be stratified by centre and age at time of surgery.
Study aims to investigate whether exposure to gaseous NO reduces the incidence of postoperative major adverse events in infants on cardiopulmonary bypass.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Low Cardiac Output Syndrome, Transposition of Great Vessels
Keywords
Cardiopulmonary bypass, Congenital heart disease, Low cardiac output syndrome, Nitric oxide, Transposition of Great Arteries, Arterial switch operation
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Double blinded, randomised controlled, parallel study comparing an intervention with a control.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Perfusionist (operating bypass) is unblinded to randomisation. They will randomize patient in a computer base (REDcap).Randomization is blinded to all other staff and the nitric oxide container is draped. Nitric oxide container will be attached in all cases.
Allocation
Randomized
Enrollment
300 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Intervention arm
Arm Type
Active Comparator
Arm Description
• Intervention arm will receive nitric oxide 20 parts per million (ppm) into the oxygenator of a cardio-pulmonary bypass circuit
Arm Title
Control arm
Arm Type
No Intervention
Arm Description
Control arm will not receive nitric oxide, they will receive standard bypass as per local policy
Intervention Type
Drug
Intervention Name(s)
Nitric Oxide
Intervention Description
Addition of nitric oxide 20ppm into bypass circuit
Primary Outcome Measure Information:
Title
Major adverse events
Description
The primary outcome is the number of participants with major adverse events (MAEs) within 28 days post-operatively. MAEs include cardiac arrest, emergency chest opening, use of ECMO, and death.
Time Frame
28 days post intervention
Secondary Outcome Measure Information:
Title
Length of stay in ICU (hours)
Description
Length of stay in ICU (hours) will be calculated from date and time of admission to ICU date and time of discharge to ICU.
Time Frame
This will be calculated from date and time of admission to ICU to date and time of discharge from ICU in hours up to 28 days
Title
Length of stay in hospital (days)
Description
Length of stay in hospital (days) will be calculated from date and time of admission to hospital to date and time of discharge to hospital.
Time Frame
28 days (or until hospital discharge)
Title
Ventilator-free days
Description
Ventilator-free days will be calculated from date and time of intubation to date and time of extubation. Each day (or part of a day) will be counted as a day.
Time Frame
28 days (or until ICU discharge)
Title
Inotrope hours
Description
Inotrope hours will be calculated from data input into REDCAP.
Time Frame
Number of hours inotropes have been administered during first 28 days post operatively
Title
Dialysis-free days
Description
Dialysis-free days will be calculated from date and time of start of dialysis to date and time of stopping dialysis. Each day (or part of a day) will be counted as a day.
Time Frame
28 days (or until ICU discharge)
Title
Inhaled NO hours
Description
Inhaled NO hours will be calculated from data input into REDCAP.
Time Frame
Number of hours inhaled NO have been administered during first 28 days post operatively
Title
ECMO-free days
Description
ECMO-free days will be calculated from date and time of start of ECMO to date and time of stopping ECMO. Each day (or part of a day) will be counted as a day.
Time Frame
28 days (or until ICU discharge)
Title
Closed sternum days
Description
Closed sternum days will be calculated from date and time of start of chest opening (or return to ICU time if delayed chest closure) to date and time of chest closure. Each day (or part of a day) will be counted as a day.
Time Frame
28 days (or until ICU discharge)
Title
Composite free-day score
Description
This score is a combination of scores 1-8 to create a composite free-day score. Composite free-day score is a score highlighting the number of days free from post-operative complications including free of hospitalization within the first 28 days post operatively. For each score, the days free of complication will be calculated to create an individual free from score these will be then added together to create an overall free-from score. Higher scores suggest a better outcome (free from hospital and complications).
Time Frame
28 days (or until hospital discharge)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
0 Days
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria;
Each participant must meet all of the following criteria to be enrolled in this study:
Infant aged greater than or equal to 36 weeks gestation
Infants less than 2 years
Diagnosed with TGA and requiring Arterial Switch Operation
Consent of parents/guardian.
Exclusion criteria
Potential participants will be excluded if they meet any of the following criteria:
They have multiple major congenital anomalies (anomalies which affect the infant's life expectancy or health status)
They have multiple other cardiac abnormalities (with the exception of ASD, VSD or PDA)
They weigh less than 2.2kgs.
Prior surgical exposure to cardio-pulmonary bypass
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Warwick Butt
Organizational Affiliation
MRCI
Official's Role
Principal Investigator
Facility Information:
Facility Name
Texas Children's Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Royal Children's Hospital
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3050
Country
Australia
Facility Name
Stollery Cildren's Hospital
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
AB T6G 2B7
Country
Canada
Facility Name
Harapan Kita Children and Women's Hospital
City
Jakarta
Country
Indonesia
Facility Name
Institut Jantung Negara
City
Kuala Lumpur
ZIP/Postal Code
50400
Country
Malaysia
Facility Name
Alder Hey Hospital
City
Liverpool
ZIP/Postal Code
L12 21ap
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
9525554
Citation
Chello M, Mastroroberto P, Perticone F, Celi V, Colonna A. Nitric oxide modulation of neutrophil-endothelium interaction: difference between arterial and venous coronary bypass grafts. J Am Coll Cardiol. 1998 Mar 15;31(4):823-6. doi: 10.1016/s0735-1097(97)00560-3.
Results Reference
background
PubMed Identifier
16443673
Citation
Hataishi R, Rodrigues AC, Neilan TG, Morgan JG, Buys E, Shiva S, Tambouret R, Jassal DS, Raher MJ, Furutani E, Ichinose F, Gladwin MT, Rosenzweig A, Zapol WM, Picard MH, Bloch KD, Scherrer-Crosbie M. Inhaled nitric oxide decreases infarction size and improves left ventricular function in a murine model of myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2006 Jul;291(1):H379-84. doi: 10.1152/ajpheart.01172.2005. Epub 2006 Jan 27.
Results Reference
background
PubMed Identifier
12607717
Citation
Levy JH, Tanaka KA. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg. 2003 Feb;75(2):S715-20. doi: 10.1016/s0003-4975(02)04701-x.
Results Reference
background
PubMed Identifier
10435044
Citation
Zahler S, Massoudy P, Hartl H, Hahnel C, Meisner H, Becker BF. Acute cardiac inflammatory responses to postischemic reperfusion during cardiopulmonary bypass. Cardiovasc Res. 1999 Mar;41(3):722-30. doi: 10.1016/s0008-6363(98)00229-6.
Results Reference
background
PubMed Identifier
23228403
Citation
Checchia PA, Bronicki RA, Muenzer JT, Dixon D, Raithel S, Gandhi SK, Huddleston CB. Nitric oxide delivery during cardiopulmonary bypass reduces postoperative morbidity in children--a randomized trial. J Thorac Cardiovasc Surg. 2013 Sep;146(3):530-6. doi: 10.1016/j.jtcvs.2012.09.100. Epub 2012 Dec 8.
Results Reference
result
PubMed Identifier
27686343
Citation
James C, Millar J, Horton S, Brizard C, Molesworth C, Butt W. Nitric oxide administration during paediatric cardiopulmonary bypass: a randomised controlled trial. Intensive Care Med. 2016 Nov;42(11):1744-1752. doi: 10.1007/s00134-016-4420-6. Epub 2016 Sep 30.
Results Reference
result
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Nitric Oxide During Bypass for Arterial Switch Operation
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