Prevention of Transfusion Related Acute Gut Injury (TRAGI) in Extremely Low Gestational Age Neonates (ELGANs) Using iNO

Study Overview
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Brief Summary
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The investigators seek to determine whether providing inhaled nitric oxide (iNO; a vasodilator) will improve the delivery of oxygen to the brain, kidney and intestines of preterm neonates during and after the subject receives a packed red blood cell transfusion (PRBC) for anemia vs. baseline period. The investigators will observe the effect of inhaled nitric oxide vs. placebo at these body sites to determine whether iNO will alter the fractional tissue oxygen extraction. Treatment and control groups will be compared to each other at equivalent epochs as will individual patients before, during and after the PRBC transfusion.

Detailed Description
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Selection criteria: 1) Neonates 24 0/7 to 27 6/7 weeks gestational age (GA) 2) More than 2 weeks postnatal age. 3) Anemia with Hct less than 28 % 4) >50 % total daily fluids is enteral 5) History of at least 1 prior PRBC transfusion ELGANs admitted to the neonatal intensive care unit (NICU) will be screened for the study. If patients meet the selection criteria, parents will be approached to obtain informed consent. Then the patient will be randomized to either iNO or placebo group before treatment. The treating physician will make the decision regarding timing of the PRBC transfusion to treat anemia for the subject. During the period of observation, near infrared spectroscopy (NIRS) monitoring will be performed on all enrolled subjects during which a non-invasive probe will be attached to the skin at 3 sites simultaneously- on abdomen below umbilicus, flank/back, and forehead for calculation of fractional tissue oxygen extraction ( FTOE) in conjunction with concurrent pulse oximetry recordings. Conventional vital signs, blood gas, lactate, haptoglobin and cytokines will be measured before and after the PRBC transfusion

Official Title
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Prevention of Transfusion Related Acute Gut Injury (TRAGI) in Extremely Low Gestational Age Neonates (ELGAN) Neonates Using iNO

Conditions
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Anemia

Intervention / Treatment
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* Drug: Inhaled Nitric Oxide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Neonates 24 0/7 to 27 6/7 weeks gestational age More than 2 weeks postnatal age. Anemia with hematocrit (Hct) less than 28 % More than 50 % total daily fluids is enteral History of at least 1 prior PRBC transfusion (preferably same donor) Exclusion Criteria: Prior history of necrotizing enterocolitis (NEC) to avoid a confounder Clinically significant patent ductus arteriosus (PDA) requiring treatment (Rx) within 24h Hypotensive for age or active bleeding < 50% of total fluids are enteral (breast milk or formula) Major congenital or surgical malformations Known chromosomal anomalies detected by antepartum testing or direct physical examination with subsequent postnatal laboratory confirmation Absence of parental or treating physician consent A concurrent randomized clinical trial (RCT) with another randomized drug Death expected < 48h Another major concern by the treating physician that either mandates or prohibits study treatment such as known adverse reaction to prior transfusion (Tx)

Ages Eligible for Study
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Minimum Age: 2 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: subjects are randomize into either of two groups: intervention or placebo
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inhaled Nitric Oxide<br>iNO will be given at 20 ppm, continuous, via inhalation before (1 hour), during (3 hours) and after (2 hours) elective blood transfusion and NIRS monitoring | Drug: Inhaled Nitric Oxide<br>* Nitric oxide gas will be added to the inhaled gas mixture that the patient was already receiving at baseline, using standard of care gas delivery systems adapted specifically for this study.<br>* Other names: iNO;|
| Active Comparator: Placebo<br>Placebo gas (nitrogen) will be given continuous, via inhalation at the same ppm, before (1 hour), during (3 hours) and after (2 hours) elective blood transfusion and NIRS monitoring | Drug: Placebo<br>* Placebo gas (nitrogen) will be added to the inhaled gas mixture that the patient was already receiving at baseline, using standard of care gas delivery systems specifically adapted for this study.<br>* Other names: Control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Increased NIRS oxygenation after a PRBC transfusion in iNO treated neonates vs Placebo | The investigators hypothesize that NIRS signal will be significantly higher in the iNO treated group during the 2nd hour after transfusion is concluded vs Placebo. NIRS will be measured continuously and averaged every 5 minutes to create a single hourly point for each subject before and after the transfusion for statistical analysis. | 19 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lower fractional tissue oxygen extraction (FTOE) in iNO treated neonates after PRBC transfusion vs Placebo | FTOE will be calculated from the 5 minute epochs of the recorded pulse oximeter and NIRS devices. The investigators hypothesize that FTOE will be significantly lower (i.e. improved) in the iNO treated group during the 2nd hour after transfusion is concluded vs Placebo. One entire hour before and another after the transfusion will be combined for each patient for statistical analysis. | 19 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TRAGI (transfusion related acute gut injury), inhaled nitric oxide (iNO), prematurity, PRBC transfusion, NEC (necrotizing enterocolitis), NIRS (near infrared spectroscopy), ELGAN (extremely low gestational age neonate)