S-Nitrosylation (SNO) Therapy During Autologous Blood Transfusion

Study Overview
=================
Brief Summary
-----------------
The Purpose of the study is to test the hypothesis that administration of an S-nitrosylating (SNO) agent can improve tissue oxygenation during transfusion of packed red blood cells (RBCs).

Detailed Description
-----------------
Transfusion is the most common therapeutic intervention employed to maintain and/or improve tissue and end-organ oxygen delivery. Despite the conceptual simplicity of this treatment recent studies indicate that RBC infusion often produces little clinical benefit and may actually harm the recipient by exacerbating rather than correcting anemia-induced tissue hypoxia. The main driver/regulator of tissue oxygenation is blood flow not blood oxygen content. In turn flow into the microvasculature is controlled by small molecules called S-nitrosothiols (SNOs), the most important of which is S-nitrosylated hemoglobin (SNO-Hb). The investigators determined that storage of human blood leads to rapid losses in SNO-Hb that are precisely paralleled by losses in the ability of stored RBCs to dilate blood vessels and thereby deliver oxygen. The investigators have now recently completed an autologous human blood transfusion that confirms the pre-clinical findings in that administration of 1 unit of packed RBCs to young healthy subjects did not improve tissue oxygenation and reduced circulating SNO-Hb levels. This novel mechanism for the loss of physiological activity in banked blood and, more importantly, a putative intervention for its correction, raise the possibility that restoration of NO bioactivity could correct the deficit in oxygen delivery. As such, The Investigators plan to repeat our transfusion study with the addition of administering an S-nitrosylating agent during RBC infusion.

Official Title
-----------------
Phase 1 Study of S-Nitrosylation Therapy to Improve Tissue Oxygenation During Autologous Blood Transfusion in Healthy Volunteer

Conditions
-----------------
Transfusion Related Complication

Intervention / Treatment
-----------------
* Drug: SNO
* Drug: Normal Saline
* Drug: Red Blood Cell


Participation Criteria
=================
Eligibility Criteria
-----------------
Eligibility Criteria Recruiting and studying of healthy human subjects with no pre-existing pathologic conditions from the local population. As a result the inclusion criteria is deliberately broad. Inclusion Criteria Hemoglobin > 12 g/dl Healthy, non-pregnant adults with no pre-existing blood disorders or disease states that impact oxygen delivery. 2a. Active blood and platelet donors will be sought as study participants since these individuals are familiar with the routines for blood withdrawal and re-infusion. Exclusion Criteria The exclusion criteria is derived from the American Red Cross(ARC) Standard Operating Procedure (SOP) for autologous donation AND the parameters set out in the investigational new drug application (IND). Individuals who are pregnant, breastfeeding, or are unwilling to avoid pregnancy during the study. Individuals with an anatomic anomaly that would increase the risks associated with placement of the vascular catheters. Individuals who report chronic diseases requiring medication of the heart, lungs, kidney, liver, etc or afflicted with any acute or chronic pathology that in the opinion of the screening physician makes them unsuitable for study. Individuals with a recent history of antibiotic therapy (check for underlying cause). Individuals unwilling to refrain from taking any phosphodiesterase 5 (PDE-5) inhibitor for at least 24 h prior to donation and/or autologous transfusion. Individuals taking a vitamin K antagonist (warfarin) or other anticoagulant (e.g. heparin, clopidogrel, enoxaparin or dalteparin). Individuals taking allopurinol, beta-adrenergic blockers, tricyclic antidepressants, meperidine (or related central nervous system (CNS) agents), or nitrates. Individuals on long-term antihistamine therapy 8a. The study physician will determine on a case by case basis the suitability for inclusion of individuals who control seasonal or acute allergies with occasional antihistamine use. Individuals with blood pressure parameters outside the normal range of 90-180 mm Hg systolic and 50-100 mm Hg diastolic. Individuals with heart rates outside the range of 50 to 100 beats per minutes or with a pathologic irregularity. 10a. Pulses lower than 50 may be acceptable if the study participant participates in endurance training. The study physician will be consulted for evaluation. 11. Individuals with an inherited or acquired blood coagulation disorder, congenital methemoglobinemia, or a familial hemoglobinopathy that impacts oxygen delivery (e.g. sickle cell). 12. Individuals with any illness that may increase the risks associated with the study. 13. Individuals who previously received blood products to treat an acute condition will be evaluated on a case by case basis. 14. Individuals who report an acute or chronic disease state that may impact oxygen delivery. 15. Individuals with evidence of diminished lung capacity. 16. Individuals who might have difficulty with the placement of a face mask (e.g. claustrophobia, uncontrolled asthma, severe allergies, sensitive skin) and/or the inhalation of a product for approximately 1-2 hr.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is an open-label phase I trial. Healthy young adult volunteers that would considered eligible by American Red Cross standards to donate blood will be screened by qualified practitioners for eligibility to participate in the above mentioned study. We anticipate an accrual number of 20, with subjects randomized to receive their blood (n=15) or saline (n=5) while breathing an SNO agent.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Blood transfusion with SNO agent<br>Autologous blood transfusion packed red blood cells (RBCs) while inhaling S-nitrosylating agent (SNO) A single intra venous blood transfusion of one unit of packed Red Blood Cells (RBCs) will be given over the standard transfusion flow rate of 5 ml/min under the direction of a physician or a licensed medical professional. Inhalation of SNO agent, 20-40 parts per million will occur during the transfusion. | Drug: SNO<br>* S-nitrosylating agent (SNO) Inhalation<br>Drug: Red Blood Cell<br>* Blood transfusion (RBCs)<br>|
| Placebo Comparator: Normal Saline with SNO agent<br>Normal Saline Transfusion while inhaling S-nitrosylating agent (SNO) A single intra venous infusion of one unit of normal saline, will be given over the standard transfusion flow rate of 5 ml/min under the direction of a physician or a licensed medical professional. Inhalation of the SNO agent at 20-40 parts per million, will occur during the transfusion. | Drug: SNO<br>* S-nitrosylating agent (SNO) Inhalation<br>Drug: Normal Saline<br>* Normal Saline transfusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygenation Defined as change in arterial blood oxygenation | tested by arterial blood oxygen content difference - arterial blood gas (ABG) An ABG is a blood test that measures the acidity, or potential of hydrogen (pH), and the levels of oxygen (O2) and carbon dioxide (CO2) from an artery. The test is used to check the function of the patient's lungs and how well they are able to move oxygen and remove carbon dioxide. The aforementioned five components all have different normal values and represent different aspects of the blood gas. According to the National Institute of Health, typical normal values are: pH: 7.35-7.45 Partial pressure of oxygen (PaO2): 75 to 100 mmHg Partial pressure of carbon dioxide (PaCO2): 35-45 mmHg Bicarbonate (HCO3): 22-26 milliequivalent/Liter (mEqL) Oxygen saturation (O2 Sat): 94-100% | pre infusion and post infusion (every 3 to 6 hours, for 24 hours) | 
| Oxygenation Defined as change in venous blood oxygenation CO2 ABG vs. VBG: VBG CO2 6mm Hg higher | tested by venous blood oxygen content difference - venous blood gas (VBG). An ABG is a blood test that measures the acidity, or pH, and the levels of oxygen (O2) and carbon dioxide (CO2) from an a vein. The test is used to check the function of the patient's lungs and how well they are able to move oxygen and remove carbon dioxide. pH ABG vs. VBG: VBG pH 0.03-0.05 lower HCO3 ABG vs. VBG: VBG HCO3 1.5-2.0 mEq/L lower CO2 ABG vs. VBG: VBG CO2 6mm Hg higher | pre infusion and post infusion (every 3 to 6 hours, for 24 h) | 
| Increase in peripheral tissue oxygenation | tested with near infrared spectroscopy. An Infrared spectroscopy (IR spectroscopy or vibrational spectroscopy) involves the interaction of infrared radiation with matter. It covers a range of techniques, mostly based on absorption spectroscopy. As with all spectroscopic techniques, it can be used to identify and study chemicals. | continuous monitoring from start of transfusion until next morning. Approximately 24 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
S-Nitrosylation, Tissue Oxygenation, Anemia-induced tissue hypoxia, Red blood cell Transfusion