Storage Lesion in Banked Blood Due to Disruption of Nitric Oxide (NO) Homeostasis

NCT01137656 | Completed Phase 1 DMC

• 2 other identifiers: 686R01HL098032-01
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to explore the impact of aged blood on endothelial function by measuring forearm blood flow during intra-arterial acetylcholine infusion in normal healthy human volunteers after infusion of autologous blood stored for 5-10 days or 35-42 days. Our hypothesis is that 1) the vasodilatory response to the infusion of acetylcholine will be reduced in the 35-42 day group compared with the 5-10 day group, because of scavenging of the NO released from the endothelium by the hemolytic process in the aged blood, 2) that the infusion of aged stored blood will produce vasoconstriction, measured by reduced forearm blood flow during infusion of the 35-42 day compared with the 5-10 day old blood, and that 3) there will be increases in venous levels of cell free plasma hemoglobin, red cell microparticles, red cell membrane damage, arginase levels and activity, decreased arginine levels, markers of oxidative stress (carbamylated proteins and nitrated tyrosine residues), and increases in plasma in vitro NO consumption during the infusion of 35-42 day old compared to 5-10 day old blood.

Conditions

Healthy

Keywords

Blood storage; Blood transfusion; Aged blood; Blood Forearm; Storage lesion in blood

Outcome Measures

Primary Outcomes (1)

• Blood flow response to Acetylcholine.

  The primary endpoint will be a comparison of the blood flow responses to the acetylcholine after infusion of 5-10 day old blood compared with the responses after infusion of 35-42 day old blood, each controlled for the opposite arm.

  5-10 days vs 35-42 days

Secondary Outcomes (2)

• Change in blood flow response to fresh blood (5-10 days) in comparison to aged blood.

  5-10 days vs 35-42 days

• Comparison in the levels of various biomarkers of aged blood will be examined in venous blood collected from the antecubital vein during the infusion of 5-10 days versus35-42 days old autologous blood.

  5-10 days versus 35-42 days

Study Arms (1)

Acetylcholine and Blood

OTHER

This is single arm study. Acetylcholine and blood is infused in brachial artery of non-dominant arm. Blood flow

Drug: Acetylcholine and Blood

Interventions

Acetylcholine and Blood DRUG

The Acetylcholine solution will be infused intra-arterially at the dosage of 7.5 ug/min for 3 minutes, then 15ug/min for 3 minutes, then 30 ug/min for 3 minutes, after the infusion of normal saline. It will then be infused at 7.5ug/min for 3 minutes, followed by 15ug/min for 3 minutes, followed by 30 ug/min for 3 minutes after the infusion of autologous blood. This will be performed at 5-10 days and 35-42 days of blood storage time.

Also known as: Miochol-e, Miochol

Acetylcholine and Blood

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female and 18 to 50 years of age.
• Able to read and comprehend the English language

You may not qualify if:

• Less than 18 or greater than 50 years of age.
• Female \< 110 lbs or 50 kg
• Male \< 110 lbs or 50 kg
• Hemoglobin \<12.5g/dl
• Past medical history or symptoms of blood dyscrasia, diabetes mellitus, hyperlipidemia, obstructive sleep apnea, hypertension, significant cardiac disease and / or known peripheral arterial disease.
• History of cigarette smoking within the last month
• Serum creatinine \>1.0 mg/dL
• Cognitively impaired subjects, or institutionalized persons and subjects unable or unwilling to complete written informed consent (no proxy consent will be obtained)
• Subjects with a history of blood donation within the last 60 days.
• Subjects who have performed other medical studies involving drug delivery in the last 30 days.
• Subjects with an oxygen saturation value \< 92%.
• Any STATIN drug (Fluvastatin, Lovastatin, Pravastatin, Simvastatin, Rosuvastatin) currently or in the 4 weeks prior to the screening day
• Any medication for the treatment of diabetes including oral hypoglycemics or insulin
• lab tests indicating blood dyscrasia, diabetes, hypertension or hypercholesterolemia.Females of childbearing potential who are pregnant or unwilling to undergo pregnancy testing; females with positive pregnancy testing on screening day will be excluded

Sponsors & Collaborators

• Mark Gladwin: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

Location

Related Publications (5)

• Greenwalt TJ, Bryan DJ, Dumaswala UJ. Erythrocyte membrane vesiculation and changes in membrane composition during storage in citrate-phosphate-dextrose-adenine-1. Vox Sang. 1984;47(4):261-70. doi: 10.1111/j.1423-0410.1984.tb01596.x.

  PMID: 6485302 BACKGROUND

• Rumsby MG, Trotter J, Allan D, Michell RH. Recovery of membrane micro-vesicles from human erythrocytes stored for transfusion: a mechanism for the erythrocyte discocyte-to-spherocyte shape transformation. Biochem Soc Trans. 1977;5(1):126-8. doi: 10.1042/bst0050126. No abstract available.

  PMID: 892138 BACKGROUND

• Dern RJ, Brewer GJ, Wiorkowski JJ. Studies on the preservation of human blood. II. The relationship of erythrocyte adenosine triphosphate levels and other in vitro measures to red cell storageability. J Lab Clin Med. 1967 Jun;69(6):968-78. No abstract available.

  PMID: 6025497 BACKGROUND

• Berezina TL, Zaets SB, Morgan C, Spillert CR, Kamiyama M, Spolarics Z, Deitch EA, Machiedo GW. Influence of storage on red blood cell rheological properties. J Surg Res. 2002 Jan;102(1):6-12. doi: 10.1006/jsre.2001.6306.

  PMID: 11792145 BACKGROUND

• Risbano MG, Kanias T, Triulzi D, Donadee C, Barge S, Badlam J, Jain S, Belanger AM, Kim-Shapiro DB, Gladwin MT. Effects of Aged Stored Autologous Red Blood Cells on Human Endothelial Function. Am J Respir Crit Care Med. 2015 Nov 15;192(10):1223-33. doi: 10.1164/rccm.201501-0145OC.

  PMID: 26222884 DERIVED

MeSH Terms

Interventions

Acetylcholine; Blood Specimen Collection

Intervention Hierarchy (Ancestors)

Biogenic Amines; Amines; Organic Chemicals; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Mark T Gladwin, M.D

  University of Pittsburgh and University of Pittsburgh medical center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Division Chief, Pulmonary, Allergy and Critical Care Medicine University of Pittsburgh Medical Center / Director, Vascular Medicine Institute of the University of Pittsburgh

Study Record Dates

• First Submitted: June 3, 2010
• First Posted: June 4, 2010
• Study Start: April 1, 2010
• Primary Completion: August 1, 2013
• Study Completion: September 1, 2013
• Last Updated: April 14, 2015

Record last verified: 2015-04

Locations

US (1)