Congenital Heart DiseasePhase 1/2NCT00585013
Inhaled NO as an Anti-inflammatory and Anti-reperfusion Agent in Infants and Children Undergoing Cardiopulmonary Bypass
A Phase 1/2 study testing Nitric Oxide in people with Congenital Heart Disease, run by Washington University School of Medicine at 1 site in United States.
Trial summary
Each year, there are over 400,000 cardiac surgical operations performed in the United States; of which 10,000 are performed on children. These operations are made possible by the use of the heart-lung bypass machine, also known as cardiopulmonary bypass. Read more about this study
- Who is it for?
- Ages Up to 16 years
- Conditions the study is for
- Congenital Heart Disease
- What is being tested?
- Nitric Oxide
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2008to Jun 2011
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 16 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Patients with the following congenital heart lesions who require cardiopulmonary bypass for surgical repair or palliation will be eligible:
- D-transposition of the great vessels (D-TGA)
- Tetralogy of Fallot (TOF)
- Children of age less than 16 years
Who cannot join
- Signs of persistently elevated pulmonary vascular resistance preoperatively
- Cardiac arrest one week prior to surgery
- Prior surgical procedure that required use of cardio-pulmonary bypass
- Acute or chronic infection such as sepsis or wound infections
- History of any pulmonary condition such as pneumonia or respiratory distress syndrome
- Patients that have received steroid treatment within the last month
Show all 11Show fewer
- DiGeorge syndrome
- Active bleeding disorder
- Any other condition associated with non-cardiac morbidity
- Use of another investigational drug
- Age over 16 years.
Trial locations and contacts
1 site in 1 country.
United States1 site
St. Louis Children's Hospital
St Louis, Missouri, 63110
About this study
Official title: A Trial of Inhaled Nitric Oxide (NO) as an Anti-Inflammatory and Anti-Reperfusion Agent in the Treatment of Infants and Children Undergoing Cardiopulmonary Bypass for Repair of Congenital Heart Disease
Each year, there are over 400,000 cardiac surgical operations performed in the United States; of which 10,000 are performed on children. These operations are made possible by the use of the heart-lung bypass machine, also known as cardiopulmonary bypass. This machine allows for the body to be supported while the heart is repaired. While this machine has been life saving, it has risks and can lead to a variety of complications.
One such complication results from the fact that the patient's blood is exposed to the foreign material of the machine, such as plastic tubing. In nearly all cases of cardiac surgery, this leads to a whole body response in the patient following the operation. This response, inflammation, is characterized by alterations in the function of the heart and lungs, fever, fluid retention, and bleeding disorders in the postoperative period. While this is usually temporary and self limiting, significant morbidity occurs in approximately 1-2% of cases where this inflammatory response is present. Additionally, children appear to be more susceptible to this response. This can lead to significant postoperative complications that are not associated with the actually surgical procedure performed on the heart.
Read more
The exact cause of this response is not fully understood. However, it is important to understand the triggers, timing, and pattern of this complex inflammatory response in order to modify or arrest it. Unlike other situations associated with this type of whole-body inflammatory reaction such as trauma or overwhelming infection, cardiac surgical teams have the advantage of knowing when the trigger will occur (i.e. during the cardiac operation) and hence have the opportunity for preemptive intervention in an effort to minimize the response. One such effort is the focus of this proposal.
Nitric oxide (NO) is a gas that has been used for years in the treatment of lung disease in infants. It has been life saving and safe. Recently, it has been investigated for its anti-inflammatory effects outside the lungs. We propose delivering NO to the source of the greatest inflammation in cardiac surgery, the cardiopulmonary bypass machine. It is our intention to show that in doing so; we can minimize the inflammation found in the first 24 hours following cardiac surgery in children. If we are correct, the reduction of this inflammation will result in less damage to other organs of the child's body and improved outcome following surgery.
Read the detailed description
- Hypothesis
Treatment of children during surgery employing cardiopulmonary bypass with inhaled, exogenous nitric oxide (iNO) delivered to the cardiopulmonary bypass circuit will:
- Modulate ischemia/reperfusion injury
- Influence endothelial dysfunction
- Ameliorate the bypass-triggered systemic inflammatory response
II. Specific Aims
Three specific aims will test this hypothesis:
Delivery of iNO to the cardiopulmonary bypass circuit will result in a decrease in:
- Measures of end-organ dysfunction often associated with CPB; pulmonary function, cardiac injury markers, serum creatinine, and neurologic injury markers.
- Measures of inflammatory response, specifically IL-6 and TNFa via its antioxidant properties.
- Platelet activation and aggregation leading to reduced transfusion requirements.
III. Introduction and Background
- Cardiopulmonary bypass leads to ischemia/reperfusion injury. One of the mediators of this injury is oxygen radical production. NO is known to bind oxygen radical species.
- Cardiopulmonary bypass leads to endothelial dysfunction. This is mediated through cell-free hemoglobin binding endogenous NO, as seen in sickle cell disease.
- Both of these factors, separately and in combination, perpetuate the inflammatory response triggered by CPB. NO affects this response by interfering with this process. Additionally, NO is known to affect neutrophil chemotaxis as well as platelet activation and aggregation, both of which further amplify the inflammatory response.
IV. Basic Protocol Experimental Design In a prospective, randomized, controlled, blinded pilot trial we will compare 20 ppm of iNO delivered to the CPB circuit. Our study will target children undergoing cardiopulmonary bypass (CPB) for surgery for the correction of transposition of great arteries (TGA) and Tetralogy of Fallot (TOF).
Subjects Inclusion Undergoing repair of TGA and TOF < 16 years of age Exclusion Age > 16 years of age Pregnancy Known bleeding disorder
Treatment Protocol Following informed consent, blood will be drawn pre-operatively for baseline characteristics (methemoglobin, venous saturation, CBC, S100, gene expression profiles, BNP, cTnI, IL-6, IL-8, lactate, TNFalpha)[Table, Blood sample for Study]. Intra-operatively we will use a standardized anesthetic protocol unless contraindicated by specific patient clinical characteristics. Intraoperative measurements will include: aortic cross clamp time, and total cardiopulmonary bypass time. Intraoperative hemodynamic measurements will include: mean systemic blood pressure (MAP), central venous pressure, right atrial pressure pulmonary artery pressure, and pulmonary capillary wedge pressure (when available). Blood samples will be drawn following CPB upon arrival to the ICU and will be analyzed as above. Repeat blood samples for each will be drawn again after 12, 24, and 48 hours. Patients will be followed to the time of discharge. Ventilator settings, length of ICU and hospital stay will be recorded. All measurements in both groups will be the same. Time points will be referenced from the time of admission to the PICU for both groups.
- Conditions
- Congenital Heart Disease
- Being tested
- Nitric Oxide
- Keywords
- Inhaled Nitric Oxide (NO), Anti-inflammatory, Anti-reperfusion agent
- Medical subject headings
- Heart Defects, Congenital
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nitric OxideDrug
Also called NO gas
Patients will receive standard care with the addition of NO gas. During cardiopulmonary bypass, NO at 20 ppm will be added to the sweep gas of the extracorporeal circuit. Following termination of cardiopulmonary bypass, inhaled NO will be discontinued.
| Study group | Role | What they receive |
|---|---|---|
| Nitric Oxide Delivery Group | Experimental | Patients will receive standard care with the addition of NO gas. During cardiopulmonary bypass, NO at 20 ppm will be added to the sweep gas of the extracorporeal circuit. Following termination of cardiopulmonary bypass, inhaled NO will be discontinued. Receives: Drug: Nitric Oxide |
| Placebo | No intervention | Placebo delivery of oxygen at standard dose. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Serum Inflammatory Mediators Post CPB
Inflammation measured through the measurement inflammatory mediators, serum interleukin-6, serum interleukin-8, and tumor necrosis factor. Baseline (preoperative, 0h, 12h, 24h, and 48h.
Measured: 48 hours
Myocardial Injury
Troponin levels correlate with myocardial injury. Greater troponin levels represent greater myocardial injury
Measured: 48 hours
Myocardial Function as Measured by B-type Natiuretic Peptide (BNP) Levels
BNP levels correlate to ventricular and myocardial performance, function, and strain. Higher values represent greater strain and decreased function.
Measured: 48 hours
Ischemic Injury as Measured by Lactate Levels
Lactate levels correlate to ischemic injury. Higher values represent more injury.
Measured: 48 hours
Secondary outcomes (1)
Incidence of Methhemoglobin >5%, Gene Expression Profiles, and S100B.
Measured: 48 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jan 2008 (estimated)
- Study startJan 2008
- Primary completionJun 2011
- Study completionJun 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Congenital Heart DiseaseStudies of the same condition, open and under way.
- More trials run by Washington University School of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- Washington University School of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- Mallinckrodt
- Responsible party
- Sponsor
- Investigators
- Paul Checchia, MD, Principal investigator, Washington University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00585013
- Sponsor's protocol ID
- CHECP1
- Status last verified
- Nov 2015
- First submitted
- 20 Dec 2007
- Last updated
- 4 Nov 2015
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 23228403
Study at a glance
From the registry record, last updated by the sponsor on 4 Nov 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Trial of Inhaled Nitric Oxide (NO) as an Anti-Inflammatory and Anti-Reperfusion Agent in the Treatment of Infants and Children Undergoing Cardiopulmonary Bypass for Repair of Congenital Heart Disease
- ClinicalTrials.gov ID
- NCT00585013
- Acronym / sponsor ID
- CHECP1
- Conditions
- Congenital Heart Disease
- Keywords
- Inhaled Nitric Oxide (NO), Anti-inflammatory, Anti-reperfusion agent
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- Washington University School of MedicineUniversity, hospital or other
- Collaborators
- Mallinckrodt
- Study start
- Jan 2008
- Primary completion
- Jun 2011 (actual)
- Study completion
- Jun 2011 (actual)
- First posted
- 2 Jan 2008 (estimated)
- Results
- Posted 4 Nov 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Each year, there are over 400,000 cardiac surgical operations performed in the United States; of which 10,000 are performed on children. These operations are made possible by the use of the heart-lung bypass machine, also known as cardiopulmonary bypass. This machine allows for the body to be supported while the heart is repaired. While this machine has been life saving, it has risks and can lead to a variety of complications.
One such complication results from the fact that the patient's blood is exposed to the foreign material of the machine, such as plastic tubing. In nearly all cases of cardiac surgery, this leads to a whole body response in the patient following the operation. This response, inflammation, is characterized by alterations in the function of the heart and lungs, fever, fluid retention, and bleeding disorders in the postoperative period. While this is usually temporary and self limiting, significant morbidity occurs in approximately 1-2% of cases where this inflammatory response is present. Additionally, children appear to be more susceptible to this response. This can lead to significant postoperative complications that are not associated with the actually surgical procedure performed on the heart.
The exact cause of this response is not fully understood. However, it is important to understand the triggers, timing, and pattern of this complex inflammatory response in order to modify or arrest it. Unlike other situations associated with this type of whole-body inflammatory reaction such as trauma or overwhelming infection, cardiac surgical teams have the advantage of knowing when the trigger will occur (i.e. during the cardiac operation) and hence have the opportunity for preemptive intervention in an effort to minimize the response. One such effort is the focus of this proposal.
Nitric oxide (NO) is a gas that has been used for years in the treatment of lung disease in infants. It has been life saving and safe. Recently, it has been investigated for its anti-inflammatory effects outside the lungs. We propose delivering NO to the source of the greatest inflammation in cardiac surgery, the cardiopulmonary bypass machine. It is our intention to show that in doing so; we can minimize the inflammation found in the first 24 hours following cardiac surgery in children. If we are correct, the reduction of this inflammation will result in less damage to other organs of the child's body and improved outcome following surgery.
Detailed description
- Hypothesis
Treatment of children during surgery employing cardiopulmonary bypass with inhaled, exogenous nitric oxide (iNO) delivered to the cardiopulmonary bypass circuit will:
- Modulate ischemia/reperfusion injury
- Influence endothelial dysfunction
- Ameliorate the bypass-triggered systemic inflammatory response
II. Specific Aims
Three specific aims will test this hypothesis:
Delivery of iNO to the cardiopulmonary bypass circuit will result in a decrease in:
- Measures of end-organ dysfunction often associated with CPB; pulmonary function, cardiac injury markers, serum creatinine, and neurologic injury markers.
- Measures of inflammatory response, specifically IL-6 and TNFa via its antioxidant properties.
- Platelet activation and aggregation leading to reduced transfusion requirements.
III. Introduction and Background
- Cardiopulmonary bypass leads to ischemia/reperfusion injury. One of the mediators of this injury is oxygen radical production. NO is known to bind oxygen radical species.
- Cardiopulmonary bypass leads to endothelial dysfunction. This is mediated through cell-free hemoglobin binding endogenous NO, as seen in sickle cell disease.
- Both of these factors, separately and in combination, perpetuate the inflammatory response triggered by CPB. NO affects this response by interfering with this process. Additionally, NO is known to affect neutrophil chemotaxis as well as platelet activation and aggregation, both of which further amplify the inflammatory response.
IV. Basic Protocol Experimental Design In a prospective, randomized, controlled, blinded pilot trial we will compare 20 ppm of iNO delivered to the CPB circuit. Our study will target children undergoing cardiopulmonary bypass (CPB) for surgery for the correction of transposition of great arteries (TGA) and Tetralogy of Fallot (TOF).
Subjects Inclusion Undergoing repair of TGA and TOF < 16 years of age Exclusion Age > 16 years of age Pregnancy Known bleeding disorder
Treatment Protocol Following informed consent, blood will be drawn pre-operatively for baseline characteristics (methemoglobin, venous saturation, CBC, S100, gene expression profiles, BNP, cTnI, IL-6, IL-8, lactate, TNFalpha)[Table, Blood sample for Study]. Intra-operatively we will use a standardized anesthetic protocol unless contraindicated by specific patient clinical characteristics. Intraoperative measurements will include: aortic cross clamp time, and total cardiopulmonary bypass time. Intraoperative hemodynamic measurements will include: mean systemic blood pressure (MAP), central venous pressure, right atrial pressure pulmonary artery pressure, and pulmonary capillary wedge pressure (when available). Blood samples will be drawn following CPB upon arrival to the ICU and will be analyzed as above. Repeat blood samples for each will be drawn again after 12, 24, and 48 hours. Patients will be followed to the time of discharge. Ventilator settings, length of ICU and hospital stay will be recorded. All measurements in both groups will be the same. Time points will be referenced from the time of admission to the PICU for both groups.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Nitric Oxide Delivery Group | Experimental | Drug: Nitric OxidePatients will receive standard care with the addition of NO gas. During cardiopulmonary bypass, NO at 20 ppm will be added to the sweep gas of the extracorporeal circuit. Following termination of cardiopulmonary bypass, inhaled NO will be discontinued. |
| Placebo | No intervention | –Placebo delivery of oxygen at standard dose. |
Who may qualify
- Ages
- Up to 16 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (4 listed)
- Patients with the following congenital heart lesions who require cardiopulmonary bypass for surgical repair or palliation will be eligible:
- D-transposition of the great vessels (D-TGA)
- Tetralogy of Fallot (TOF)
- Children of age less than 16 years
Key exclusion criteria (11 listed)
- Signs of persistently elevated pulmonary vascular resistance preoperatively
- Cardiac arrest one week prior to surgery
- Prior surgical procedure that required use of cardio-pulmonary bypass
- Acute or chronic infection such as sepsis or wound infections
- History of any pulmonary condition such as pneumonia or respiratory distress syndrome
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nitric OxideAlso: NO gasPatients will receive standard care with the addition of NO gas. During cardiopulmonary bypass, NO at 20 ppm will be added to the sweep gas of the extracorporeal circuit. Following termination of cardiopulmonary bypass, inhaled NO will be discontinued. | Drug | Nitric Oxide Delivery Group |
Primary outcome
Serum Inflammatory Mediators Post CPB
Time frame: 48 hours
Inflammation measured through the measurement inflammatory mediators, serum interleukin-6, serum interleukin-8, and tumor necrosis factor. Baseline (preoperative, 0h, 12h, 24h, and 48h.
Myocardial Injury
Time frame: 48 hours
Troponin levels correlate with myocardial injury. Greater troponin levels represent greater myocardial injury
Myocardial Function as Measured by B-type Natiuretic Peptide (BNP) Levels
Time frame: 48 hours
BNP levels correlate to ventricular and myocardial performance, function, and strain. Higher values represent greater strain and decreased function.
Ischemic Injury as Measured by Lactate Levels
Time frame: 48 hours
Lactate levels correlate to ischemic injury. Higher values represent more injury.
1 secondary outcome
Incidence of Methhemoglobin >5%, Gene Expression Profiles, and S100B.
Time frame: 48 hours
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Nov 2015.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 23228403Checchia 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paul Checchia, MD principal investigator
Washington University School of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Nitric Oxide in people with Congenital Heart Disease, run by Washington University School of Medicine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Nov 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Nov 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Serum Inflammatory Mediators Post CPB (time frame: 48 hours). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00585013, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Nov 2015.