Pilot Study About the Harmful Effects of Blood Storage on Overweight People and the Role of iNO in This Setting

Inflammation Clinical Trial

Official title:

Effects of Stored Red Blood Cell Transfusion in Overweight Subjects With Endothelial Dysfunction: Influence of Inhaled Nitric Oxide (iNO)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01529502
• Other study ID #: Blood Study Overweight
• Status: Completed
• Phase: Phase 2
• First received: February 6, 2012
• Last updated: January 29, 2014
• Start date: March 2012
• Est. completion date: December 2013

Study information

• Verified date: January 2014
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

Description:

The objective of this study is to assess effects of the storage of PRBC on endothelial function, inflammation and platelet activation 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 markers/parameters:

1. Endothelium-mediated changes in vascular (arterial) tone

2. Tissue oxygen saturation will be continuously assessed during and after blood transfusion

3. Hemolysis as quantified by changes in plasma haptoglobin level, plasma free hemoglobin, LDH level, bilirubin level, iron level, ferritin, and transferrin

4. Changes of plasma and red blood cell levels of circulating nitrate, nitrite, RXNO, RNNO, NO-heme

5. Concentration of cytokines, such as IL-6, IL-8, IL-10, IL-12, TNF, IFN-γ

6. Activation of platelets through circulating P-selectin expression on platelets

7. Activation of inflammatory lipid mediators

8. Changes in gene expression profiling analyzing RNA microarray of circulating leukocytes

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: December 2013
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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/m2 and <35 kg/m2

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Blood Transfusion
• Endothelial Physiopathology
• Hemoglobins
• Inflammation
• Nitric Oxide

Intervention

Procedure:
• Red blood Cells auto-transfusion
Withdrawal from 14 overweight volunteers of one unit of red blood cells and auto-transfusion after 3 days storage time. The same 14 subjects will be included in every arm of the study.
• Red blood Cells auto-transfusion
Withdrawal from the same 14 overweight volunteers of one unit of red blood cells and auto-transfusion after 40 days storage time.

Drug:
• Inhaled Nitric Oxide (iNO) administration
Subjects will breath iNO (80ppm) for 10 minutes before, during and for one hour after the autologous old-blood transfusion.

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Massachusetts General Hospital

Country where clinical trial is conducted

United States, 

References & Publications (6)

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. Epub 2007 Oct 11. — View 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. — View Citation

Hendrickson JE, Hillyer CD. Noninfectious serious hazards of transfusion. Anesth Analg. 2009 Mar;108(3):759-69. doi: 10.1213/ane.0b013e3181930a6e. Review. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Endothelial Function		Baseline	No
Primary	Endothelial Function		10 min after transfusion	No
Primary	Endothelial function		1h after transfusion	No
Primary	Endothelial Function		4h after transfusion	No
Secondary	Hemolysis		Baseline	No
Secondary	Nitric Oxide metabolites		Baseline	No
Secondary	Concentration of cytokines		Baseline	No
Secondary	Activation of platelets		Baseline	No
Secondary	Activation of inflammatory lipid mediators		Baseline	No
Secondary	Changes in gene expression		Baseline	No
Secondary	Hemolysis		10 min after transfusion	No
Secondary	Nitric Oxide Metabolites		10 min after transfusion	No
Secondary	Concentration of cytokines		10 min after transfusion	No
Secondary	Activation of platelets		10 min after transfusion	No
Secondary	Activation of inflammatory lipid mediators		10 min after transfusion	No
Secondary	Changes in gene expression		10 min after transfusion	No
Secondary	Hemolysis		1h after transfusion	No
Secondary	Nitric Oxide metabolites		1h after transfusion	No
Secondary	Concentration of cytokines		1h after transfusion	No
Secondary	Activation of platelets		1h after transfusion	No
Secondary	Activation of inflammatory lipid mediators		1h after transfusion	No
Secondary	Changes in gene expression		1h after transfusion	No
Secondary	Hemolysis		2h after transfusion	No
Secondary	Nitric Oxide metabolites		2h after transfusion	No
Secondary	Concentration of cytokines		2h after transfusion	No
Secondary	Activation of platelets		2h after transfusion	No
Secondary	Activation of inflammatory lipid mediators		2h after transfusion	No
Secondary	Changes in gene expression		2h after transfusion	No
Secondary	Hemolysis		4h after transfusion	No
Secondary	Nitric Oxide metabolites		4h after transfusion	No
Secondary	Concentration of cytokines		4h after transfusion	No
Secondary	Activation of platelets		4h after transfusion	No
Secondary	Activation of inflammatory lipid mediators		4h after transfusion	No
Secondary	Changes in gene expression		4h after transfusion	No