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

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2013 by University of Pittsburgh
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Mark Gladwin, University of Pittsburgh
ClinicalTrials.gov Identifier:
NCT01137656
First received: June 3, 2010
Last updated: January 8, 2013
Last verified: January 2013
  Purpose

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.


Condition Intervention Phase
Healthy
Drug: Acetylcholine and Blood
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Storage Lesion in Banked Blood Due to Disruption of Nitric Oxide (NO) Homeostasis

Resource links provided by NLM:


Further study details as provided by University of Pittsburgh:

Primary Outcome Measures:
  • Blood flow response to Acetylcholine. [ Time Frame: 5-10 days vs 35-42 days ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Change in blood flow response to fresh blood (5-10 days) in comparison to aged blood. [ Time Frame: 5-10 days vs 35-42 days ] [ Designated as safety issue: No ]
    A comparison of the change in blood flow responses at baseline and after infusion of 5-10 day old blood compared with the responses during infusion of 35-42 day old blood, each controlled for the opposite arm.

  • 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. [ Time Frame: 5-10 days versus 35-42 days ] [ Designated as safety issue: No ]

Estimated Enrollment: 36
Study Start Date: April 2010
Estimated Study Completion Date: April 2013
Estimated Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Acetylcholine and Blood
This is single arm study. Acetylcholine and blood is infused in brachial artery of non-dominant arm. Blood flow
Drug: Acetylcholine and Blood
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.
Other Names:
  • Miochol-e
  • Miochol

Detailed Description:

The increased storage time of transfused blood is associated with an increased risk of cardiovascular events and organ failure. The underlying biological mechanism as to why this happens is not understood. A major abnormality in aged blood is the reduced life span of red blood cells after they are infused. This is associated with rupture of the red blood cells and release of their contents. However, the degree of red blood cell rupture and release of the cell's contents in humans after transfusion has not been well studied. It has been seen that even low levels of red blood cell rupture severely decrease the amount of nitric oxide and other factors that effect how blood vessels function. The purpose of this study is to perform human forearm blood flow studies to evaluate wether there are a sufficient amount these factors released during red blood transfusion to significantly affect how blood vessel function in humans.

This study will enroll normal healthy volunteers between 18 to 50 years of age. 500 ml (1.0 unit) of blood will be collected from subjects who will then return in 5-10 days and be re-infused with the blood 5-10 days after storage.The subjects will return after 25-37 days and be infused with blood 35-42 days after storage. The study will use a tool called strain gauge plethysmography and the drug acetylcholine to measure the effect of fresh (i.e., 5-10 days) versus aged (35-42 days) autologous blood transfusions on forearm blood flow in healthy volunteers.

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

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

Exclusion Criteria:

  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01137656

Contacts
Contact: Suchitra Barge, MPH, MBBS 412-864-3290 barges@upmc.edu
Contact: Michael G Risbano, MD, MA risbanomg@upmc.edu

Locations
United States, Pennsylvania
University of Pittsburgh Medical Center Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Barge    412-864-3290    barges@upmc.edu   
Sponsors and Collaborators
Mark Gladwin
Investigators
Principal Investigator: Mark T Gladwin, M.D University of Pittsburgh and University of Pittsburgh medical center
  More Information

Publications:
Responsible Party: Mark Gladwin, Division Chief, Pulmonary, Allergy and Critical Care Medicine University of Pittsburgh Medical Center / Director, Vascular Medicine Institute of the University of Pittsburgh, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01137656     History of Changes
Other Study ID Numbers: 686, R01HL098032-01, RO1 HL098032-01
Study First Received: June 3, 2010
Last Updated: January 8, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Pittsburgh:
Blood storage
Blood transfusion
Aged blood
Blood Forearm
Storage lesion in blood

Additional relevant MeSH terms:
Acetylcholine
Nitric Oxide
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Cholinergic Agonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Anti-Asthmatic Agents
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Endothelium-Dependent Relaxing Factors
Gasotransmitters
Protective Agents

ClinicalTrials.gov processed this record on August 19, 2014