Nitric Oxide Administration During Pediatric Cardiopulmonary Bypass Surgery to Prevent Platelet Activation

Phase 2

Completed

Conditions: Inflammation
Platelet Dysfunction

Interventions: Drug: Placebo
Drug: Nitric Oxide
Device: INOmax

Registration Number: NCT03455218

Lead Sponsor: Medical College of Wisconsin

Brief Summary: Open heart surgery requires the use of a cardiopulmonary bypass (CPB) circuit. As blood flows across the artificial surfaces of the CPB circuit, platelets are activated and consumed. This activation results in a profound inflammatory reaction and need for transfusion. This reaction is intensified in younger, smaller patients undergoing longer, more complex open heart surgery. Nitric oxide is naturally released by vascular endothelial surfaces and acts as a signaling molecule which prevents platelet activation. The investigators hypothesize that the addition of the nitric oxide to the sweep gas of the oxygenator during cardiopulmonary bypass surgery will replace this natural endothelial function and thus prevent platelet activation and consumption. The investigators plan to test this hypothesis with a pilot double blinded, randomized trial of 40 patients less than a year of age undergoing cardiac surgery requiring CPB.

Detailed Description: Open heart surgery requires the use of a CPB circuit. As blood flows across the artificial surfaces of the CPB circuit, platelets are consumed (1). The investigators recently completed a prospective observational trial of neonates undergoing cardiac surgery requiring CPB. In this trial the investigators demonstrated a dramatic decrease in platelet count from baseline to intraoperatively. The platelet count rebounded with transfusion and normalized by the time of admission to the cardiac intensive care unit (CICU). Despite prophylactic transfusion of blood products to all patients, 41% experienced excessive postoperative bleeding (defined in terms of chest tube output and need for reoperation).

Further investigation by Dr. Debra Newman in her lab at the Blood Research Institute delineated the platelet defect associated with CPB in the neonates more clearly. Dr. Newman found a significant decrease in the platelet responsiveness to thrombin receptor activating protein (TRAP), thromboxane A2 analog (U46619), and collagen-related peptide (CRP). Further analysis revealed that the effect of CPB on platelet responsiveness to TRAP and U46619 is likely dependent on its effect on platelet count, whereas CPB affects platelet responsiveness to CRP independently of platelet count.

In children, postoperative blood loss and transfusion of blood products has been shown to contribute significantly to the morbidity and mortality of surgeries that require CPB (2, 3). In addition to the need for blood product replacement, the activation of platelets contributes to the intense inflammatory reaction seen in surgeries requiring CPB (4). Patients with a less intense inflammatory response post-operatively generally do better with less morbidity (5).

The oxygenator membrane surface of the CPB pump is a large contributor to the surface area of CPB circuit. As a major contributor to the surface area of the circuit and the location of the gas interface, the oxygenator is a significant contributor to the hemostatic and inflammatory stimulus of CPB. Advances in oxygenator technology have modified the surface to prevent interaction with the blood, but no artificial surface has been found to be as inert as the natural endothelium of the vasculature (5).

A major mechanism by which endothelial surfaces inhibit activation of platelets is by producing nitric oxide (6). Nitric oxide is lipophilic and traverses cellular membranes where it acts on intracellular signaling pathways in platelets to prevent platelet activation and aggregation (7). The artificial surface of the CPB pump does not produce nitric oxide and hence is devoid of this potent inhibitor of platelet activation.

In multiple experimental ex-vivo models of CPB, the addition of nitric oxide to the sweep gas of the oxygenator resulted in preserved platelet counts, preserved platelet function, and decreased markers of platelet activation (8-11).

Multiple clinical trials of nitric oxide administration during CPB have shown positive results. Chung et al. showed in a group of 41 adults undergoing coronary artery surgery requiring CPB that the addition of nitric oxide to the oxygenator resulted in a preservation of platelet numbers, a decrease in markers of platelet activation, and less post-operative blood loss (12). Checchia et al. investigated the effect of nitric oxide in a group of sixteen infants undergoing repair of tetralogy of Fallot and found the patients treated with nitric oxide had an improvement in clinical outcomes of length of stay in the intensive care unit and number of hours requiring mechanical ventilation (13). James et al. showed a 50% decrease in the incidence of low cardiac output syndrome in a randomized trial of 198 children. The effect was most profound in the younger children and those undergoing the most complex repairs (14). These patients are also the ones demonstrated to have the most intense inflammatory reaction postoperatively (15).

Despite these promising studies, several questions remain. The mechanism of platelet preservation has not been delineated. The collaboration between clinicians at Children's Hospital of Wisconsin and Dr. Newman at the Blood Center of Wisconsin has been established and has experience in investigating the effects of CPB on platelets in infants. This collaboration is poised to help define the mechanism of nitric oxide in preserving platelet function during CPB in infants. All studies to date have been single center and underpowered to investigate clinical outcomes of interest such as mortality and length of hospital stay. Dr. Niebler has begun to assemble a multi-center study team. Local data is necessary to help guide the power calculation in determining the sample size for this larger study and to demonstrate the capabilities of the local institution in leading a trial of this magnitude.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

Inclusion Criteria

Infants less than one year of age
Undergoing cardiac surgery with the use of cardiopulmonary bypass

Exclusion Criteria

Prior surgery requiring CPB within the same hospitalization
Pre-operative need for extracorporeal membrane oxygenation or mechanical circulatory support
Known hypersensitivity to nitric oxide
Known hemostatic or thrombotic disorder that results in an altered transfusion/anticoagulation protocol

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	INOmax device attached to the oxygenator, but no gas is delivered through the device
Placebo	INOmax	INOmax device attached to the oxygenator, but no gas is delivered through the device
Nitric Oxide	INOmax	20 ppm of Nitric Oxide delivered to the oxygenator via the INOmax device for the duration of the cardiopulmonary bypass time
Nitric Oxide	Nitric Oxide	20 ppm of Nitric Oxide delivered to the oxygenator via the INOmax device for the duration of the cardiopulmonary bypass time

Primary Outcome Measures

Name	Time	Method
Change in Platelet Count	From baseline to end of cardiopulmonary bypass (2-6 hours)	Change in platelet count from baseline to conclusion of cardiopulmonary bypass = (Platelet count at end of CPB) - (Platelet count prior to start of CPB)
30 Day Mortality	30 days	30 day all cause mortality
Hospital Length of Stay	6 months	Length of stay in the hospital following the operation
Methemoglobin Level Pre-CPB	24 hours	Methemoglobin levels in the blood measured at baseline
Methemoglobin Level-End of CPB	4 hours	Methemoglobin Level obtained at the end of cardiopulmonary bypass
Methemoglobin Level-ICU Admit	24 hours	Methemoglobin level obtained at the time of ICU Admit

Secondary Outcome Measures

Name	Time	Method
Change in Platelet Response to TRAP as Measured by P-selectin Expression	From baseline to end of cardiopulmonary bypass (2-6 hours)	The P-selectin expression measured as a mean florescence was measured in platelets stimulated with thrombin receptor activating protein (TRAP) was measured at baseline and at conclusion of cardiopulmonary bypass. Mean of each assessment measured multiple times at each time point. Median change values were reported. The change in these values is the outcome measure = (Platelet response to TRAP at end of CPB) - (Platelet response to TRAP prior to CPB)
Change in Platelet Response to U46619 as Measured by P-selectin Expression	From baseline to end of cardiopulmonary bypass (2-6 hours)	The P-selectin expression measured as a mean florescence was measured in platelets stimulated with U46619 was measured at baseline and at conclusion of cardiopulmonary bypass. Mean of each assessment measured multiple times at each time point. Median change values were reported. The change in these values is the outcome measure = (Platelet response to U46619 at end of CPB) - (Platelet response to U46619 prior to CPB)
Change in Platelet Response to CRP as Measured by P-selectin Expression	From baseline to end of cardiopulmonary bypass (2-6 hours)	The P-selectin expression measured as a mean florescence was measured in platelets stimulated with CRP was measured at baseline and at conclusion of cardiopulmonary bypass. Mean of each assessment measured multiple times at each time point. Median change values were reported. The change in these values is the outcome measure = (Platelet response to CRP at end of CPB) - (Platelet response to CRP prior to CPB)
Volume of Platelet Transfusion	48 hours post-operatively	Volume per kg of platelet transfusion given to patient from the conclusion of cardiopulmonary bypass to 48 hours post-operatively
Volume of Packed Red Blood Cell Transfusion	48 hours post-operatively	Volume per kg of packed red blood cell transfusion given to patient from the conclusion of cardiopulmonary bypass to 48 hours post-operatively
Transfusion Exposures	48 hours post-operatively	Total number of transfusion exposures for a patient from the conclusion of cardiopulmonary bypass to 48 hours post-operatively
Length of Mechanical Ventilation	30 days post-operatively	Time (days) spent on ventilator following the operation
Vasoactive Infusion Score	24 hours post-operatively	Highest vasoactive infusion score (VIS) within 24 hours post-operatively. Vasoactive infusion score is based on the dose of the vasoactive infusions the patient is given VIS = Dopamine dose (μg/kg/min) + Dobutamine dose (μg/kg/min) +100 × epinephrine dose (μg/kg/min) + 10 X Milrinone dose (μg/kg/min) +10,000 × Vasopressin dose (U/kg/min) + 100 × Norepinephrine dose (μg/kg/min). The minimum value is 0 if the patient is not on any vasoactive medications. There is no "maximum" score as there is no "maximum" dose of vasoactive medications. Higher scores indicate that the patient is on more vasoactive medications which is generally considered worse.
Number of Subjects Requiring Extracorporeal Membrane Oxygenation	48 hours post-operatively	Dichotomous outcome-required extracorporeal membrane oxygenation within 48 hours post-operatively
Hospital Cost	6 months post-operatively	Total hospital cost at the time of discharge