Inhaled NO as an Anti-inflammatory and Anti-reperfusion Agent in Infants and Children Undergoing Cardiopulmonary Bypass

Congenital Heart Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00585013
• Other study ID #: CHECP1
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: December 20, 2007
• Last updated: November 3, 2015
• Start date: January 2008
• Est. completion date: June 2011

Study information

• Verified date: November 2015
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical 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. 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.

Description:

I. Hypothesis

Treatment of children during surgery employing cardiopulmonary bypass with inhaled, exogenous nitric oxide (iNO) delivered to the cardiopulmonary bypass circuit will:

1. Modulate ischemia/reperfusion injury

2. Influence endothelial dysfunction

3. 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:

1. Measures of end-organ dysfunction often associated with CPB; pulmonary function, cardiac injury markers, serum creatinine, and neurologic injury markers.

2. Measures of inflammatory response, specifically IL-6 and TNFa via its antioxidant properties.

3. 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: June 2011
• Est. primary completion date: June 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 16 Years

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

• DiGeorge syndrome

• Active bleeding disorder

• Any other condition associated with non-cardiac morbidity

• Use of another investigational drug

• Age over 16 years.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Congenital Heart Disease
• Heart Defects, Congenital
• Heart Diseases

Intervention

Drug:
• Nitric Oxide
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.

Locations

Country	Name	City	State
United States	St. Louis Children's Hospital	St. Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Washington University School of Medicine	INO Therapeutics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	48 hours	No
Primary	Myocardial Injury	Troponin levels correlate with myocardial injury. Greater troponin levels represent greater myocardial injury	48 hours	No
Primary	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.	48 hours	No
Primary	Ischemic Injury as Measured by Lactate Levels	Lactate levels correlate to ischemic injury. Higher values represent more injury.	48 hours	No
Secondary	Incidence of Methhemoglobin >5%, Gene Expression Profiles, and S100B.		48 hours	No