Clinical trial NCT03455218: Nitric Oxide Administration During Pediatric Cardiopulmonary Bypass Surgery to Prevent Platelet Activation
Official title: Nitric Oxide Administration During Pediatric Cardiopulmonary Bypass Surgery to Prevent Platelet activation-a Single Center Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Inflammation
Platelet Dysfunction
Keywords: Cardiopulmonary Bypass
Infant
Nitric Oxide
Thrombocytopenia
Blood Platelets
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
Collaborators: name: Mallinckrodt
name: Clinical & Translational Science Institute of Southeast Wisconsin
name: Versiti
First posted: 2018-03-06
Enrollment: 40
Sex: ALL
Maximum age (years): 1
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, Double Blinded, Placebo Controlled
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in Platelet Count
timeFrame: From baseline to end of cardiopulmonary bypass (2-6 hours)
measure: 30 Day Mortality
timeFrame: 30 days
measure: Hospital Length of Stay
timeFrame: 6 months
measure: Methemoglobin Level Pre-CPB
timeFrame: 24 hours
measure: Methemoglobin Level-End of CPB
timeFrame: 4 hours
measure: Methemoglobin Level-ICU Admit
timeFrame: 24 hours
Secondary outcomes:
measure: Change in Platelet Response to TRAP as Measured by P-selectin Expression
timeFrame: From baseline to end of cardiopulmonary bypass (2-6 hours)
measure: Change in Platelet Response to U46619 as Measured by P-selectin Expression
timeFrame: From baseline to end of cardiopulmonary bypass (2-6 hours)
measure: Change in Platelet Response to CRP as Measured by P-selectin Expression
timeFrame: From baseline to end of cardiopulmonary bypass (2-6 hours)
measure: Volume of Platelet Transfusion
timeFrame: 48 hours post-operatively
measure: Volume of Packed Red Blood Cell Transfusion
timeFrame: 48 hours post-operatively
measure: Transfusion Exposures
timeFrame: 48 hours post-operatively
measure: Length of Mechanical Ventilation
timeFrame: 30 days post-operatively
measure: Vasoactive Infusion Score
timeFrame: 24 hours post-operatively
measure: Number of Subjects Requiring Extracorporeal Membrane Oxygenation
timeFrame: 48 hours post-operatively
measure: Hospital Cost
timeFrame: 6 months post-operatively
Other outcomes:
Locations:
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
Study officials:
References:
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