s-nitrosylation (sno) therapy during autologous blood transfusion

Conditions: Transfusion Related Complication

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).

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.

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 1. hemoglobin \> 12 g/dl 2. 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). 1. individuals who are pregnant, breastfeeding, or are unwilling to avoid pregnancy during the study. 2. individuals with an anatomic anomaly that would increase the risks associated with placement of the vascular catheters. 3. 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. 4. individuals with a recent history of antibiotic therapy (check for underlying cause). 5. individuals unwilling to refrain from taking any phosphodiesterase 5 (pde-5) inhibitor for at least 24 h prior to donation and/or autologous transfusion. 6. individuals taking a vitamin k antagonist (warfarin) or other anticoagulant (e.g. heparin, clopidogrel, enoxaparin or dalteparin). 7. individuals taking allopurinol, beta-adrenergic blockers, tricyclic antidepressants, meperidine (or related central nervous system (cns) agents), or nitrates. 8. 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. 9. individuals with blood pressure parameters outside the normal range, i.e., higher than 130 mm hg systolic and/or higher than 90 mm hg diastolic; mild hypertension is acceptable by the red cross for blood donation. 10. 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 2-3 hours.

Keywords: s-nitrosylation tissue oxygenation anemia-induced tissue hypoxia red blood cell transfusion