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

I. 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.

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.