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

NCT ID: NCT03455218

Last Updated: 2020-08-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-04-25
• Study Completion Date: 2019-05-05

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.

Conditions

Inflammation; Platelet Dysfunction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Nitric Oxide

20 ppm of Nitric Oxide delivered to the oxygenator via the INOmax device for the duration of the cardiopulmonary bypass time

Group Type: EXPERIMENTAL

Nitric Oxide

Intervention Type: DRUG

20 ppm of Nitric Oxide gas delivered to the oxygenator for the duration of cardiopulmonary bypass

INOmax

Intervention Type: DEVICE

All patients will have the INOmax device connected to the oxygenator

Placebo

INOmax device attached to the oxygenator, but no gas is delivered through the device

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

INOmax device connected to oxygenator, but no gas is delivered

INOmax

Intervention Type: DEVICE

All patients will have the INOmax device connected to the oxygenator

Interventions

Nitric Oxide

20 ppm of Nitric Oxide gas delivered to the oxygenator for the duration of cardiopulmonary bypass

Intervention Type: DRUG

Placebo

INOmax device connected to oxygenator, but no gas is delivered

Intervention Type: DRUG

INOmax

All patients will have the INOmax device connected to the oxygenator

Intervention Type: DEVICE

Other Intervention Names

INOmax; inhaled nitric oxide delivery device

Eligibility Criteria

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

• Maximum Eligible Age: 1 Year
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mallinckrodt

INDUSTRY

Sponsor Role: collaborator

Clinical & Translational Science Institute of Southeast Wisconsin

OTHER

Sponsor Role: collaborator

Versiti

OTHER

Sponsor Role: collaborator

Medical College of Wisconsin

OTHER

Sponsor Role: lead

Responsible Party

Robert Niebler, MD

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

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Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

1111115-1NO in CPB 001

Identifier Type: -

Identifier Source: org_study_id