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CompletedNCT03455218Updated Aug 13, 2020Results posted

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

A Phase 2/3 interventional study of Nitric Oxide and Placebo in Inflammation and Platelet Dysfunction, sponsored by Medical College of Wisconsin. Completed at 1 site in United States. Open to participants aged Up to 1 Year. Per ClinicalTrials.gov, last updated 2020-08-13.

Sponsored by Medical College of Wisconsin · Phase 2/3, Interventional, and Treatment

Phase
Phase 2/3
Study type
Interventional
Enrollment
40
Allocation
Randomized
Ages
Up to 1 Year
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Inflammation
  • Platelet Dysfunction

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Keywords

  • Cardiopulmonary Bypass
  • Infant
  • Nitric Oxide
  • Thrombocytopenia
  • Blood Platelets
03

Who can participate

Ages eligible
Up to 1 Year
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

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

Exclusion criteria

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
04

Study design

Phase
Phase 2 / Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
40 participants (actual)

Study arms

  • Experimental
    Nitric Oxide

    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 comparator
    Placebo

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

    Drug: Placebo · Device: INOmax

Interventions

  • DrugNitric Oxide

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

    Also known as: INOmax

  • DrugPlacebo

    INOmax device connected to oxygenator, but no gas is delivered

  • DeviceINOmax

    All patients will have the INOmax device connected to the oxygenator

    Also known as: inhaled nitric oxide delivery device

05

What researchers measure

Primary outcomes

  1. 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)

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

  2. 30 Day Mortality

    30 day all cause mortality

    Time frame: 30 days

  3. Hospital Length of Stay

    Length of stay in the hospital following the operation

    Time frame: 6 months

  4. Methemoglobin Level Pre-CPB

    Methemoglobin levels in the blood measured at baseline

    Time frame: 24 hours

  5. Methemoglobin Level-End of CPB

    Methemoglobin Level obtained at the end of cardiopulmonary bypass

    Time frame: 4 hours

  6. Methemoglobin Level-ICU Admit

    Methemoglobin level obtained at the time of ICU Admit

    Time frame: 24 hours

Secondary outcomes

  1. 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)

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

  2. 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)

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

  3. 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)

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

  4. Volume of Platelet Transfusion

    Volume per kg of platelet transfusion given to patient from the conclusion of cardiopulmonary bypass to 48 hours post-operatively

    Time frame: 48 hours post-operatively

  5. 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

    Time frame: 48 hours post-operatively

  6. Transfusion Exposures

    Total number of transfusion exposures for a patient from the conclusion of cardiopulmonary bypass to 48 hours post-operatively

    Time frame: 48 hours post-operatively

  7. Length of Mechanical Ventilation

    Time (days) spent on ventilator following the operation

    Time frame: 30 days post-operatively

  8. 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.

    Time frame: 24 hours post-operatively

  9. Number of Subjects Requiring Extracorporeal Membrane Oxygenation

    Dichotomous outcome-required extracorporeal membrane oxygenation within 48 hours post-operatively

    Time frame: 48 hours post-operatively

  10. Hospital Cost

    Total hospital cost at the time of discharge

    Time frame: 6 months post-operatively

06

Results

Posted Aug 13, 2020

Participant flow

Participant flow — Overall Study
MilestoneNitric OxidePlacebo
Started1822
Completed1822
Not completed00

Outcome measures

PrimaryChange 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)

Time frame:
From baseline to end of cardiopulmonary bypass (2-6 hours)
Reported as:
Mean · Count of platelets
Change in Platelet Count
Count of plateletsNitric OxidePlacebo
Change in Platelet Count-221 ± 107-242 ± 114
Statistical analysis
  • Nitric Oxide vs Placebo · t-test, 2 sided · p = 0.55
Primary30 Day Mortality

30 day all cause mortality

Time frame:
30 days
Reported as:
Count of participants · Participants
30 Day Mortality
ParticipantsNitric OxidePlacebo
30 Day Mortality00
PrimaryHospital Length of Stay

Length of stay in the hospital following the operation

Time frame:
6 months
Reported as:
Median · Days
Hospital Length of Stay
DaysNitric OxidePlacebo
Hospital Length of Stay8 (5 to 39.3)16.5 (8.3 to 28.8)
Statistical analysis
  • Nitric Oxide vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.30
PrimaryMethemoglobin Level Pre-CPB

Methemoglobin levels in the blood measured at baseline

Time frame:
24 hours
Reported as:
Mean · % methemoglobin
Methemoglobin Level Pre-CPB
% methemoglobinNitric OxidePlacebo
Methemoglobin Level Pre-CPB0.77 ± 0.420.99 ± 0.40
Statistical analysis
  • Nitric Oxide vs Placebo · t-test, 2 sided · p = 0.11
PrimaryMethemoglobin Level-End of CPB

Methemoglobin Level obtained at the end of cardiopulmonary bypass

Time frame:
4 hours
Reported as:
Mean · % methemoglobin
Methemoglobin Level-End of CPB
% methemoglobinNitric OxidePlacebo
Methemoglobin Level-End of CPB1.56 ± 0.431.10 ± 0.43
Statistical analysis
  • Nitric Oxide vs Placebo · t-test, 2 sided · p = 0.002
PrimaryMethemoglobin Level-ICU Admit

Methemoglobin level obtained at the time of ICU Admit

Time frame:
24 hours
Reported as:
Mean · % methemoglobin
Methemoglobin Level-ICU Admit
% methemoglobinNitric OxidePlacebo
Methemoglobin Level-ICU Admit1.3 ± 0.491.08 ± 0.29
Statistical analysis
  • Nitric Oxide vs Placebo · t-test, 2 sided · p = 0.05
SecondaryChange 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)

Time frame:
From baseline to end of cardiopulmonary bypass (2-6 hours)
Reported as:
Median · Florescence arbitrary units
Change in Platelet Response to TRAP as Measured by P-selectin Expression
Florescence arbitrary unitsNitric OxidePlacebo
Change in Platelet Response to TRAP as Measured by P-selectin Expression24 (-6 to 39)30 (7 to 58)
Statistical analysis
  • Nitric Oxide vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.27
SecondaryChange 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)

Time frame:
From baseline to end of cardiopulmonary bypass (2-6 hours)
Reported as:
Median · Florescence arbitrary units
Change in Platelet Response to U46619 as Measured by P-selectin Expression
Florescence arbitrary unitsNitric OxidePlacebo
Change in Platelet Response to U46619 as Measured by P-selectin Expression51 (38 to 64)40 (19 to 70)
Statistical analysis
  • Nitric Oxide vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.57
SecondaryChange 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)

Time frame:
From baseline to end of cardiopulmonary bypass (2-6 hours)
Reported as:
Median · Florescence arbitrary units
Change in Platelet Response to CRP as Measured by P-selectin Expression
Florescence arbitrary unitsNitric OxidePlacebo
Change in Platelet Response to CRP as Measured by P-selectin Expression23 (-3 to 42)23 (-6 to 50)
SecondaryVolume of Platelet Transfusion

Volume per kg of platelet transfusion given to patient from the conclusion of cardiopulmonary bypass to 48 hours post-operatively

Time frame:
48 hours post-operatively
Reported as:
Median · mL/kg
Volume of Platelet Transfusion
mL/kgNitric OxidePlacebo
Volume of Platelet Transfusion4 (0 to 25)9.8 (0 to 32.6)
Statistical analysis
  • Nitric Oxide vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.48
SecondaryVolume 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

Time frame:
48 hours post-operatively
Reported as:
Median · mL/kg
Volume of Packed Red Blood Cell Transfusion
mL/kgNitric OxidePlacebo
Volume of Packed Red Blood Cell Transfusion3.1 (0 to 19.1)0 (0 to 26.1)
Statistical analysis
  • Nitric Oxide vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.96
SecondaryTransfusion Exposures

Total number of transfusion exposures for a patient from the conclusion of cardiopulmonary bypass to 48 hours post-operatively

Time frame:
48 hours post-operatively
Reported as:
Median · Transfusions
Transfusion Exposures
TransfusionsNitric OxidePlacebo
Transfusion Exposures2 (1 to 4)3 (1 to 4)
Statistical analysis
  • Nitric Oxide vs Placebo · t-test, 2 sided · p = 0.71
SecondaryLength of Mechanical Ventilation

Time (days) spent on ventilator following the operation

Time frame:
30 days post-operatively
Reported as:
Median · Hours
Length of Mechanical Ventilation
HoursNitric OxidePlacebo
Length of Mechanical Ventilation35.7 (0 to 111.5)28.2 (0 to 115.4)
Statistical analysis
  • Nitric Oxide vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.97
SecondaryVasoactive 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.

Time frame:
24 hours post-operatively
Reported as:
Median · VIS Score
Vasoactive Infusion Score
VIS ScoreNitric OxidePlacebo
Vasoactive Infusion Score9 (6.3 to 16.1)9.5 (5.5 to 15)
Statistical analysis
  • Nitric Oxide vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.53
SecondaryNumber of Subjects Requiring Extracorporeal Membrane Oxygenation

Dichotomous outcome-required extracorporeal membrane oxygenation within 48 hours post-operatively

Time frame:
48 hours post-operatively
Reported as:
Count of participants · Participants
Number of Subjects Requiring Extracorporeal Membrane Oxygenation
ParticipantsNitric OxidePlacebo
Number of Subjects Requiring Extracorporeal Membrane Oxygenation11
Statistical analysis
  • Nitric Oxide vs Placebo · Chi-squared · p = 1.0
SecondaryHospital Cost

Total hospital cost at the time of discharge

Time frame:
6 months post-operatively
Reported as:
Median · 1000's of dollars
Hospital Cost
1000's of dollarsNitric OxidePlacebo
Hospital Cost137.7 (99.5 to 490.7)224.3 (145.0 to 283.4)
Statistical analysis
  • Nitric Oxide vs Placebo · Wilcoxon (Mann-Whitney) · p = 0.46

Adverse events

Collected over From the start of the operation till the time of hospital discharge. All patients were observed for adverse events from the start of the operation in which they were enrolled in the study till the time of hospital discharge following the operation. This ranged from 3 to 200 days.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Nitric Oxide0/18 (0%)3/18 (16.7%)8/18 (44.4%)
Placebo0/22 (0%)1/22 (4.5%)10/22 (45.5%)
Most frequent serious events
Most frequent serious events
EventNitric OxidePlacebo
Cardiac ArrestCardiac disorders1/181/22
Heart block requiring pacemakerCardiac disorders1/180/22
Unplanned reoperationCardiac disorders1/180/22
Most frequent other events
Most frequent other events
EventNitric OxidePlacebo
Arrhythmia requiring temporary pacemakerCardiac disorders7/188/22
SepsisInfections and infestations3/181/22
ChylothoraxRespiratory, thoracic and mediastinal disorders2/182/22
Pulmonary hypertensionCardiac disorders2/180/22
SeizureNervous system disorders1/181/22

Baseline characteristics

Age, Continuous
Age, Continuous(Days)Nitric OxidePlaceboTotal
Mean100.6 ± 77.7112.4 ± 92.5107.1 ± 85.3
Sex: Female, Male
Sex: Female, Male(Participants)Nitric OxidePlaceboTotal
Female9918
Male91322
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Nitric OxidePlaceboTotal
American Indian or Alaska Native101
Asian101
Native Hawaiian or Other Pacific Islander000
Black or African American101
White131932
More than one race000
Unknown or Not Reported235
Weight
Weight(Kilogram)Nitric OxidePlaceboTotal
Mean4.62 ± 1.504.80 ± 1.484.72 ± 1.47
Known Genetic Disorder
Known Genetic Disorder(Participants)Nitric OxidePlaceboTotal
Count of participants121527
STAT Category
STAT Category(Participants)Nitric OxidePlaceboTotal
STAT Category 1 & 2101020
STAT Category 3-581220
Total Cardiopulmonary Bypass Time
Total Cardiopulmonary Bypass Time(Minutes)Nitric OxidePlaceboTotal
Median123.5 (98.8 to 155.3)115.0 (96 to 160.3)115.0 (96.5 to 158.8)
Total Aortic Cross Clamp Time
Total Aortic Cross Clamp Time(Minutes)Nitric OxidePlaceboTotal
Mean77.4 ± 40.674.1 ± 45.475.6 ± 42.8
07

Study locations

1 site
  • Children's Hospital of Wisconsin
    Milwaukee, Wisconsin 53226, United States
08

References and documents

Publications

  • 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. doi: 10.1016/s0003-4975(01)03211-8. PubMed 11722116 ↗
  • Chambers LA, Cohen DM, Davis JT. Transfusion patterns in pediatric open heart surgery. Transfusion. 1996 Feb;36(2):150-4. doi: 10.1046/j.1537-2995.1996.36296181928.x. PubMed 8614966 ↗
  • Petaja J, Lundstrom 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. doi: 10.1016/S0022-5223(95)70284-9. PubMed 7877314 ↗
  • 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. PubMed 1371416 ↗
  • Wan S, LeClerc JL, Vincent JL. Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies. Chest. 1997 Sep;112(3):676-92. doi: 10.1378/chest.112.3.676. PubMed 9315800 ↗
  • 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. PubMed 7504587 ↗
  • 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. Erratum In: Platelets. 2011;22(2):152. PubMed 21050056 ↗
  • 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. PubMed 10809259 ↗
  • 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. doi: 10.1161/01.cir.85.6.2284. PubMed 1591842 ↗
  • 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. doi: 10.1097/00002480-199609000-00111. PubMed 8945004 ↗
  • 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. PubMed 8607682 ↗
  • 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. PubMed 15821644 ↗
  • 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. PubMed 23228403 ↗
  • 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. PubMed 27686343 ↗
  • 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. PubMed 18249331 ↗
  • 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. PubMed 9390579 ↗
  • 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. PubMed 10468251 ↗
  • 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. PubMed 28274558 ↗

Study documents

  • Protocol and statistical analysis plan · May 19, 2020

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Undecided — we are willing to share the IPD if requested by another investigator. Please contact the principle investigator if interested

09

Registry details

Key details

Study ID
NCT03455218
Lead sponsor
Medical College of Wisconsin
Collaborators
Mallinckrodt, Clinical & Translational Science Institute of Southeast Wisconsin, Versiti
Responsible party
Robert Niebler, MD (Associate Professor, Medical College of Wisconsin) — Principal investigator
First posted
Mar 6, 2018
Start date
Apr 25, 2018
Primary completion
Apr 20, 2019
Completion
May 5, 2019
Results posted
Aug 13, 2020
Last update
Aug 13, 2020

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
Yes
View the source record on ClinicalTrials.gov ↗

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Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

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Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

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