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

Inflammation Clinical Trial

Official title:

Nitric Oxide Administration During Pediatric Cardiopulmonary Bypass Surgery to Prevent Platelet activation-a Single Center Pilot Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03455218
• Other study ID #: 1111115-1NO in CPB 001
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: April 25, 2018
• Est. completion date: May 5, 2019

Study information

• Verified date: July 2020
• Source: Medical College of Wisconsin
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: May 5, 2019
• Est. primary completion date: April 20, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 1 Year

Eligibility

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

Related Conditions & MeSH terms

• Inflammation
• Platelet Dysfunction

Intervention

Drug:
• Nitric Oxide
20 ppm of Nitric Oxide gas delivered to the oxygenator for the duration of cardiopulmonary bypass
• Placebo
INOmax device connected to oxygenator, but no gas is delivered

Device:
• INOmax
All patients will have the INOmax device connected to the oxygenator

Locations

Country	Name	City	State
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin

Sponsors (4)

Lead Sponsor	Collaborator
Medical College of Wisconsin	Clinical & Translational Science Institute of Southeast Wisconsin, Mallinckrodt, Versiti

Country where clinical trial is conducted

United States, 

References & Publications (18)

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. — View Citation

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. — View Citation

Chambers LA, Cohen DM, Davis JT. Transfusion patterns in pediatric open heart surgery. Transfusion. 1996 Feb;36(2):150-4. — View Citation

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. — View Citation

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. — View Citation

de Graaf JC, Banga JD, Moncada S, Palmer RM, de Groot PG, Sixma JJ. Nitric oxide functions as an inhibitor of platelet adhesion under flow conditions. Circulation. 1992 Jun;85(6):2284-90. — View Citation

Despotis GJ, Avidan MS, Hogue CW Jr. Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg. 2001 Nov;72(5):S1821-31. Review. — View Citation

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. — View Citation

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. Epub 2016 Sep 30. — View Citation

Konishi R, Shimizu R, Firestone L, Walters FR, Wagner WR, Federspiel WJ, Konishi H, Hattler BG. Nitric oxide prevents human platelet adhesion to fiber membranes in whole blood. ASAIO J. 1996 Sep-Oct;42(5):M850-3. — View Citation

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. — View Citation

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. — View Citation

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. Review. Erratum in: Platelets. 2011;22(2):152. — View Citation

Petäjä J, Lundström U, Leijala M, Peltola K, Siimes MA. Bleeding and use of blood products after heart operations in infants. J Thorac Cardiovasc Surg. 1995 Mar;109(3):524-9. — View Citation

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. — View Citation

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. — View Citation

Wan S, LeClerc JL, Vincent JL. Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies. Chest. 1997 Sep;112(3):676-92. Review. — View Citation

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. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	30 Day Mortality	30 day all cause mortality	30 days
Primary	Hospital Length of Stay	Length of stay in the hospital following the operation	6 months
Primary	Methemoglobin Level Pre-CPB	Methemoglobin levels in the blood measured at baseline	24 hours
Primary	Methemoglobin Level-End of CPB	Methemoglobin Level obtained at the end of cardiopulmonary bypass	4 hours
Primary	Methemoglobin Level-ICU Admit	Methemoglobin level obtained at the time of ICU Admit	24 hours
Secondary	Change in Platelet Response to TRAP as Measured by P-selectin Expression	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)	From baseline to end of cardiopulmonary bypass (2-6 hours)
Secondary	Change in Platelet Response to U46619 as Measured by P-selectin Expression	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)	From baseline to end of cardiopulmonary bypass (2-6 hours)
Secondary	Change in Platelet Response to CRP as Measured by P-selectin Expression	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)	From baseline to end of cardiopulmonary bypass (2-6 hours)
Secondary	Volume of Platelet Transfusion	Volume per kg of platelet transfusion given to patient from the conclusion of cardiopulmonary bypass to 48 hours post-operatively	48 hours post-operatively
Secondary	Volume of Packed Red Blood Cell Transfusion	Volume per kg of packed red blood cell transfusion given to patient from the conclusion of cardiopulmonary bypass to 48 hours post-operatively	48 hours post-operatively
Secondary	Transfusion Exposures	Total number of transfusion exposures for a patient from the conclusion of cardiopulmonary bypass to 48 hours post-operatively	48 hours post-operatively
Secondary	Length of Mechanical Ventilation	Time (days) spent on ventilator following the operation	30 days post-operatively
Secondary	Vasoactive Infusion Score	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.	24 hours post-operatively
Secondary	Number of Subjects Requiring Extracorporeal Membrane Oxygenation	Dichotomous outcome-required extracorporeal membrane oxygenation within 48 hours post-operatively	48 hours post-operatively
Secondary	Hospital Cost	Total hospital cost at the time of discharge	6 months post-operatively