Clinical trial NCT01529502: Pilot Study About the Harmful Effects of Blood Storage on Overweight People and the Role of iNO in This Setting
Official title: Effects of Stored Red Blood Cell Transfusion in Overweight Subjects With Endothelial Dysfunction: Influence of Inhaled Nitric Oxide (iNO)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Blood Transfusion
Endothelial Physiopathology
Nitric Oxide
Pulmonary Hypertension
Keywords: Blood Transfusion, Autologous
Blood Preservation/adverse effects
Blood Transfusion/adverse effects
Endothelium, Vascular/physiopathology
Hemoglobins
Nitric Oxide
Pulmonary Hypertension
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
First posted: 2012-02-08
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to determine whether storage time affects how human body responds to autologous blood transfusion. An autologous blood transfusion is when a person donates blood and then receives that same blood back in the transfusion. We also want to find out if in this situation inhaled nitric oxide can help to prevent the potential reduction of vasodilation capacity. Vasodilation capacity is the ability of the blood vessel to widen when needed.

Detailed description: The objective of this study is to assess effects of the storage of PRBC on pulmonary vasoconstriction measured as increase in pulmonary artery pressure and endothelial function measured as a change in reactive hyperemia index in overweight people with existing endothelial dysfunction at baseline.

The present study consists of three different parts, which will be scheduled in a randomized order on the same subject (crossover study).

During one phase of the study, 14 healthy human volunteers will donate a unit of Packed Red Blood Cells (PRBC), which will be leukoreduced and stored in Additive Solutions-1 (AS-1), and then transfused back to the subjects after 3 days of storage at 4º C in the MGH Blood Bank (Fresh Blood arm). The second part of the study consists in the collection of another unit of PRBC from the same volunteers which will be transfused back to them after 40 days of storage (Old Blood arm). Finally in the third part, like in the second one, one unit of PRBC will be withdraw and stored for 40 days, but 80 ppm (parts per million by volume) Nitric Oxide in air will be administered together with the transfusion. There will be a 2 weeks interval after each PRBC transfusion.

We hypothesize that old red blood cells stored under conventional conditions may trigger a complex, pro-inflammatory, pro-thrombotic and vasoconstriction response. We will compare the response to PRBC stored for 3 days with the response to PRBC stored for 40 days in the same healthy volunteers. We also want to test the hypothesis that inhaled nitric oxide may reverse these adverse effects.

We will monitor/measure the following parameters:

1. Pulmonary vasoconstriction by trans-thoracic echocardiography
2. Endothelium-mediated changes in vascular (arterial) tone, measured as reactive hyperemia index.

Eligibility criteria: Inclusion Criteria:

1. Have a photo ID
2. Age\>18 years old (required to provide informed consent)
3. Age \<60 years old
4. Mild impairment of endothelial function, assessed by post ischemic vasodilation (L_RHI,\<0.7) (38)
5. Body mass index (BMI) \>27 kg/m\^2 and \<40 kg/m\^2
6. Fasting during the days of transfusion.
7. Avoiding intake of high nitrate food (i.e. green leafy vegetables: lettuce, spinach) on the day prior to the study
8. Feel well on the day of blood donation
9. KG within normal limits
10. Normotensive (systolic blood pressure \<140 mmHg and diastolic \<90 mmHg)
11. Normal physical exam and blood test results as indicated by:

    1. WBC 4.5-11.0 n x103/μL
    2. HGB 12.0-17.5 gm/dl
    3. PLT 150-400 n x103/μL
    4. Plasma Sodium 135-145 mmol/L
    5. Plasma Potassium 3.4-4.8 mmol/L
    6. Plasma Chloride 98-108 mmol/L
    7. Plasma Carbon Dioxide 23.0-31.9 mmol/L
    8. Plasma Urea Nitrogen 8-25 mg/dl
    9. Plasma Creatinine 0.60-1.50 mg/dl
    10. Plasma Glucose 70-110 mg/dl
    11. Transaminase-SGPT 10-55 U/L
    12. Transaminase-SGOT 10-40 U/L
    13. Total Bilirubin \< 2 mg/dl
    14. Fasting plasma glucose \< 110 mg/dl
    15. Methemoglobin \< 3%

Exclusion Criteria:

1. Psychiatric disturbances such as anxiety, depression, schizophrenia requiring pharmacological treatment or hospitalization in the last year
2. Systemic disease with or without any functional limitation
3. Pregnancy determined by urine pregnancy test, detecting presence of human chorionic gonadotropin (hCG), or less than six weeks postpartum
4. Active smoking. Volunteers may be enrolled if they quit smoking for more than 1 year.
5. Excess alcohol use: more than ½ L/day of wine consumption or equivalent
6. Any current use of a medication other than: over-the-counter oral medications, herbal remedies, nutritional supplements, and oral contraceptives.
7. Antibiotic use within 48 hours of blood donation
8. Use of NSAIDS, corticosteroids, aspirin during the past 7 days
9. Dental work within 24 hours prior to the donation
10. Received or donated blood in the last 4 months
11. Have had any forms of cancer with the exceptions of basal cell skin cancer or treatment for in situ uterine cervical cancer
12. Currently enrolled in another research study

Primary outcomes:
measure: Systolic Pulmonary Artery Pressure
timeFrame: Post-transfusion
Secondary outcomes:
measure: Endothelial Function: Reactive Hyperemia Index
timeFrame: Post-transfusion
Other outcomes:
measure: Hemolysis
timeFrame: before and after blood transfusion
measure: Nitric Oxide Metabolites
timeFrame: Before and after blood transfusion
measure: Concentration of Cytokines
timeFrame: Before and after blood transfusion
measure: Activation of Platelets
timeFrame: Before and after blood transfusion
measure: Activation of Inflammatory Lipid Mediators
timeFrame: Before and after blood transfusion
measure: Changes in Gene Expression
timeFrame: Before and after blood transfusion
measure: Endothelial Function
timeFrame: Before and after blood transfusion
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Masachusetts General Hospital
name: Warren Zapol, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hendrickson JE, Hillyer CD. Noninfectious serious hazards of transfusion. Anesth Analg. 2009 Mar;108(3):759-69. doi: 10.1213/ane.0b013e3181930a6e.
citation: Koch CG, Li L, Sessler DI, Figueroa P, Hoeltge GA, Mihaljevic T, Blackstone EH. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med. 2008 Mar 20;358(12):1229-39. doi: 10.1056/NEJMoa070403.
citation: Bennett-Guerrero E, Veldman TH, Doctor A, Telen MJ, Ortel TL, Reid TS, Mulherin MA, Zhu H, Buck RD, Califf RM, McMahon TJ. Evolution of adverse changes in stored RBCs. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17063-8. doi: 10.1073/pnas.0708160104. Epub 2007 Oct 11.
citation: Cardillo C, Kilcoyne CM, Cannon RO 3rd, Panza JA. Interactions between nitric oxide and endothelin in the regulation of vascular tone of human resistance vessels in vivo. Hypertension. 2000 Jun;35(6):1237-41. doi: 10.1161/01.hyp.35.6.1237.
citation: Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation. 1993 May;87(5):1468-74. doi: 10.1161/01.cir.87.5.1468.
citation: Hod EA, Brittenham GM, Billote GB, Francis RO, Ginzburg YZ, Hendrickson JE, Jhang J, Schwartz J, Sharma S, Sheth S, Sireci AN, Stephens HL, Stotler BA, Wojczyk BS, Zimring JC, Spitalnik SL. Transfusion of human volunteers with older, stored red blood cells produces extravascular hemolysis and circulating non-transferrin-bound iron. Blood. 2011 Dec 15;118(25):6675-82. doi: 10.1182/blood-2011-08-371849. Epub 2011 Oct 20.
citation: Berra L, Pinciroli R, Stowell CP, Wang L, Yu B, Fernandez BO, Feelisch M, Mietto C, Hod EA, Chipman D, Scherrer-Crosbie M, Bloch KD, Zapol WM. Autologous transfusion of stored red blood cells increases pulmonary artery pressure. Am J Respir Crit Care Med. 2014 Oct 1;190(7):800-7. doi: 10.1164/rccm.201405-0850OC.