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

NCT03455218 | Completed Phase 2 Results FDA Drug FDA Device

• 1 other identifier: 1111115-1NO in CPB 001
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Inflammation; Platelet Dysfunction

Keywords

Cardiopulmonary Bypass; Infant; Nitric Oxide; Thrombocytopenia; Blood Platelets

Outcome Measures

Primary Outcomes (6)

• Change in Platelet Count

  Change in platelet count from baseline to conclusion of cardiopulmonary bypass = (Platelet count at end of CPB) - (Platelet count prior to start of CPB)

  From baseline to end of cardiopulmonary bypass (2-6 hours)

• 30 Day Mortality

  30 day all cause mortality

  30 days

• Hospital Length of Stay

  Length of stay in the hospital following the operation

  6 months

• Methemoglobin Level Pre-CPB

  Methemoglobin levels in the blood measured at baseline

  24 hours

• Methemoglobin Level-End of CPB

  Methemoglobin Level obtained at the end of cardiopulmonary bypass

  4 hours

• Methemoglobin Level-ICU Admit

  Methemoglobin level obtained at the time of ICU Admit

  24 hours

Secondary Outcomes (10)

• Change in Platelet Response to TRAP as Measured by P-selectin Expression

  From baseline to end of cardiopulmonary bypass (2-6 hours)

• Change in Platelet Response to U46619 as Measured by P-selectin Expression

  From baseline to end of cardiopulmonary bypass (2-6 hours)

• Change in Platelet Response to CRP as Measured by P-selectin Expression

  From baseline to end of cardiopulmonary bypass (2-6 hours)

• Volume of Platelet Transfusion

  48 hours post-operatively

• Volume of Packed Red Blood Cell Transfusion

  48 hours post-operatively

Study Arms (2)

Nitric Oxide

EXPERIMENTAL

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

Drug: Nitric Oxide; Device: INOmax

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo; Device: INOmax

Interventions

Nitric Oxide DRUG

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

Also known as: INOmax

Nitric Oxide

Placebo DRUG

INOmax device connected to oxygenator, but no gas is delivered

Placebo

INOmax DEVICE

All patients will have the INOmax device connected to the oxygenator

Also known as: inhaled nitric oxide delivery device

Nitric Oxide; Placebo

Eligibility Criteria

• Age: Up to 1 Year
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Medical College of Wisconsin: lead
• Mallinckrodt: collaborator
• Clinical & Translational Science Institute of Southeast Wisconsin: collaborator
• Versiti Blood Health: collaborator

Study Sites (1)

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (18)

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  PMID: 11722116 BACKGROUND

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  PMID: 8614966 BACKGROUND

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  PMID: 7877314 BACKGROUND

• Rinder CS, Bonan JL, Rinder HM, Mathew J, Hines R, Smith BR. Cardiopulmonary bypass induces leukocyte-platelet adhesion. Blood. 1992 Mar 1;79(5):1201-5.

  PMID: 1371416 BACKGROUND

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  PMID: 9315800 BACKGROUND

• Radomski MW, Vallance P, Whitley G, Foxwell N, Moncada S. Platelet adhesion to human vascular endothelium is modulated by constitutive and cytokine induced nitric oxide. Cardiovasc Res. 1993 Jul;27(7):1380-2. doi: 10.1093/cvr/27.7.1380.

  PMID: 7504587 BACKGROUND

• Naseem KM, Roberts W. Nitric oxide at a glance. Platelets. 2011;22(2):148-52. doi: 10.3109/09537104.2010.522629. Epub 2010 Nov 4.

  PMID: 21050056 BACKGROUND

• Annich GM, Meinhardt JP, Mowery KA, Ashton BA, Merz SI, Hirschl RB, Meyerhoff ME, Bartlett RH. Reduced platelet activation and thrombosis in extracorporeal circuits coated with nitric oxide release polymers. Crit Care Med. 2000 Apr;28(4):915-20. doi: 10.1097/00003246-200004000-00001.

  PMID: 10809259 BACKGROUND

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  PMID: 1591842 BACKGROUND

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  PMID: 8945004 BACKGROUND

• Mellgren K, Friberg LG, Mellgren G, Hedner T, Wennmalm A, Wadenvik H. Nitric oxide in the oxygenator sweep gas reduces platelet activation during experimental perfusion. Ann Thorac Surg. 1996 Apr;61(4):1194-8. doi: 10.1016/0003-4975(96)00017-3.

  PMID: 8607682 BACKGROUND

• Chung A, Wildhirt SM, Wang S, Koshal A, Radomski MW. Combined administration of nitric oxide gas and iloprost during cardiopulmonary bypass reduces platelet dysfunction: a pilot clinical study. J Thorac Cardiovasc Surg. 2005 Apr;129(4):782-90. doi: 10.1016/j.jtcvs.2004.06.049.

  PMID: 15821644 BACKGROUND

• Checchia PA, Bronicki RA, Muenzer JT, Dixon D, Raithel S, Gandhi SK, Huddleston CB. Nitric oxide delivery during cardiopulmonary bypass reduces postoperative morbidity in children--a randomized trial. J Thorac Cardiovasc Surg. 2013 Sep;146(3):530-6. doi: 10.1016/j.jtcvs.2012.09.100. Epub 2012 Dec 8.

  PMID: 23228403 BACKGROUND

• James C, Millar J, Horton S, Brizard C, Molesworth C, Butt W. Nitric oxide administration during paediatric cardiopulmonary bypass: a randomised controlled trial. Intensive Care Med. 2016 Nov;42(11):1744-1752. doi: 10.1007/s00134-016-4420-6. Epub 2016 Sep 30.

  PMID: 27686343 BACKGROUND

• Eisses MJ, Chandler WL. Cardiopulmonary bypass parameters and hemostatic response to cardiopulmonary bypass in infants versus children. J Cardiothorac Vasc Anesth. 2008 Feb;22(1):53-9. doi: 10.1053/j.jvca.2007.06.006. Epub 2007 Aug 22.

  PMID: 18249331 BACKGROUND

• Miller BE, Mochizuki T, Levy JH, Bailey JM, Tosone SR, Tam VK, Kanter KR. Predicting and treating coagulopathies after cardiopulmonary bypass in children. Anesth Analg. 1997 Dec;85(6):1196-202. doi: 10.1097/00000539-199712000-00003.

  PMID: 9390579 BACKGROUND

• Williams GD, Bratton SL, Riley EC, Ramamoorthy C. Coagulation tests during cardiopulmonary bypass correlate with blood loss in children undergoing cardiac surgery. J Cardiothorac Vasc Anesth. 1999 Aug;13(4):398-404. doi: 10.1016/s1053-0770(99)90210-0.

  PMID: 10468251 BACKGROUND

• Berger JT, Holubkov R, Reeder R, Wessel DL, Meert K, Berg RA, Bell MJ, Tamburro R, Dean JM, Pollack MM; Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Morbidity and mortality prediction in pediatric heart surgery: Physiological profiles and surgical complexity. J Thorac Cardiovasc Surg. 2017 Aug;154(2):620-628.e6. doi: 10.1016/j.jtcvs.2017.01.050. Epub 2017 Feb 10.

  PMID: 28274558 BACKGROUND

MeSH Terms

Conditions

Inflammation; Thrombocytopenia

Interventions

Nitric Oxide; Endothelium-Dependent Relaxing Factors

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Blood Platelet Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Cytopenia

Intervention Hierarchy (Ancestors)

Reactive Nitrogen Species; Free Radicals; Inorganic Chemicals; Nitrogen Oxides; Nitrogen Compounds; Oxides; Oxygen Compounds; Organic Chemicals; Vasodilator Agents; Cardiovascular Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Results Point of Contact

• Title: Robert Niebler, MD
• Organization: Medical College of Wisconsin

rniebler@mcw.edu

4142663360

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: Randomized, Double Blinded, Placebo Controlled

Study Record Dates

• First Submitted: February 6, 2018
• First Posted: March 6, 2018
• Study Start: April 25, 2018
• Primary Completion: April 20, 2019
• Study Completion: May 5, 2019
• Last Updated: August 13, 2020
• Results First Posted: August 13, 2020

Record last verified: 2020-07

Locations

US (1)