Exhaled Carbon Monoxide and Red Blood Cell Turnover

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03288233
Recruitment Status : Recruiting
First Posted : September 20, 2017
Last Update Posted : September 20, 2017
VA Office of Research and Development
Information provided by (Responsible Party):
Robert Cohen, M.D., University of Cincinnati

Brief Summary:
Hemoglobin A1C (HbA1c) is the cornerstone of blood sugar monitoring. As HbA1c is formed by the covalent reaction of glucose with hemoglobin throughout the lifespan of the red blood cell (RBC), it is used as a surrogate marker for integrated mean blood glucose over time. The HbA1c value therefore is dependent on the average amount of time the RBC spends in the circulation (mean RBC age or MRBC). However, our previous studies measuring red cell lifespan using either an age cohort label (ex vivo labeling with biotin) or a population label (stable isotope) have demonstrated, contrary to established dogma, that the MRBC varies substantially among individuals and is sufficiently variable to affect HA1c interpretation in a significant percentage of individuals with diabetes. Although the stable isotope method is suitable for clinical studies, it has limited potential for application to large population of subjects. A potential alternative to the stable isotope approach that could be applied routinely to the average patient in the clinic is measurement of exhaled carbon monoxide (eCO) concentration, a reflection of RBC heme turnover. In general, the primary advantage of applying exhaled breath analyses to human clinical diagnostics and therapeutic monitoring is that this technique is noninvasive, safe, simple, and provides near-real time measurements. The purpose of this observational study is to optimize the collection of eCO in a normal control population followed by measurement in a cohort of subjects previously assessed by either the SI or biotin methods for comparison.

Condition or disease Intervention/treatment
Diabetes Mellitus Healthy Diagnostic Test: Breath carbon monoxide measurement

Detailed Description:

Recently Investigators have demonstrated that RBC lifespan has substantial inter-individual variation even in people without diabetes or obvious hematologic diseases affecting RBC lifespan (5,6). Investigators combined Endocrinology-Hematology research group has taken a leading role in applying state-of-the-art methods for RBC survival measurement.The published articles articles are now cited when investigators refer to the state of the art understanding of true RBC lifespan (7). Using a biotin labeling method that involves ex vivo labeling of cells with biotin and then re-infusion of those cells, Investigators were able to demonstrate that RBC lifespan is sufficiently heterogeneous even in the hematologically normal population with normal reticulocyte count to significantly affect HbA1c interpretation (5). Recognizing the limitations of the safe but relatively invasive biotin technique, Investigators more recently developed a stable isotope (SI) in which RBC heme is labeled with orally administered 15N-glycine (6). This is a benign and noninvasive technique and expands the scope of RBC lifespan studies to sizable epidemiologic and physiologic studies, a number of which investigators are initiating and planning.

However, the feasibility of making the findings translatable to widespread patient care has been perceived as a limitation to the merit of answering these scientific questions. The SI approach still requires multiple blood measurements over months (6). This proposed project is designed to test the feasibility of a method to satisfy the unmet clinical need for measuring RBC survival easily, noninvasively, and inexpensively. The goal is to access most individuals with or at risk for diagnosis of diabetes in or near most doctors' offices. Over the next year Investigators intend to determine whether exhaled alveolar carbon monoxide (eCO), a measure of heme breakdown and hence of RBC turnover, can be used in this manner to provide a single point measure of RBC lifespan. Interestingly, heme metabolism is the only known endogenous source of carbon monoxide in people (8) and there are recent studies by others suggesting its potential for measuring RBC lifespan (9,10) Now that technology has advanced to measure CO with sufficient sensitivity and cost, investigators will explore the use of instrumentation at the same time investigators expand their studies using the SI approach. The results from this method will be compared with a previous small population of subjects that had lifespan measured by biotin and/or SI technique.

Study Type : Observational
Estimated Enrollment : 30 participants
Observational Model: Other
Time Perspective: Cross-Sectional
Official Title: Measurement of Exhaled Lower Respiratory Carbon Monoxide and Correlation With Previous Measures of Red Cell Lifespan
Actual Study Start Date : April 2015
Estimated Primary Completion Date : May 2018
Estimated Study Completion Date : August 2018

Group/Cohort Intervention/treatment
Primary Group Diagnostic Test: Breath carbon monoxide measurement
Participants will be asked to breath in designed breathing circuits or hold their breath for short period of time and then their breath samples will be collected in special bags and the carbon monoxide and carbon dioxide will be measured with electrochemical techniques.

Primary Outcome Measures :
  1. Average end expiratory alveolar concentration of Carbon monoxide (ppm) in morning before breakfast [ Time Frame: four consecutive weeks ]
    In this preliminary phase of the study we use a device that has not been used in the United States before (Carbolyzer II, Taiyo, Japan) as a surrogate marker for red blood cell (RBC) removal or turnover in human subjects. Published studies and the company literature for the Carbolyzer mBA-2000 would suggest sufficient capability for the purposes of such measurements. This project will test more rigorously the validity of these specifications for this application. First, the detector will be standardized in more detail with measurement of the CO content of defined mixtures in the range needed for sufficient sensitivity. The device will calibrated prior with known concentrations of a mixture of carbon monoxide in air at three points (0-3-12 ppm). In addition, investigators will evaluate alternative CO detection devices for suitability which do not alter the experience of the participating subject or the accompanying risks and benefits.

  2. Average end expiratory alveolar concentration of CO (ppm) in morning 30 min after breakfast [ Time Frame: four consecutive weeks ]
    similar to outcome 1

  3. Average end expiratory alveolar concentration of CO (ppm) 30 min after lunch [ Time Frame: one day sampling ]
    similar to outcome 1

  4. Average end expiratory alveolar concentration of CO (ppm) 5 hours after lunch [ Time Frame: one day sampling ]
    similar to outcome 1

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Healthy adults with Diabetes aged 18 to 75 years previously measured for red blood cell lifespan

Inclusion Criteria:

  • Subjects will be between age 18 and 75 years, non-pregnant, with a goal of equal gender and race (Caucasian vs. African-American) distribution

Exclusion Criteria:

  • known hemoglobinopathy or RBC disorder
  • positive pregnancy test (in women of child-bearing potential or are breast feeding or planning pregnancy during the course of the study;
  • baseline serum creatinine >1.5 mg/dl
  • CBC outside the normal range
  • history of GI blood loss or coagulopathy
  • urine microalbumin >100 mcg/mg creatinine (spot collection);
  • transaminases >3 X the upper limit of normal
  • presence of serum antibodies to biotinylated proteins (which could interfere with the biotin RBC labeling protocol)
  • greater than or equal to NYHA stage 3 heart failure;
  • active infection;
  • known rheumatologic disease
  • uncontrolled hypo-or hyperthyroidism or an underlying illness known to be associated with either body wasting or changes in serum proteins
  • lung transplantation, irradiation, recent surgery, recent intensive care admission, asthma, COPD, cystic fibrosis, smoking, recent hematoma, uncontrolled hypo- or hyperthyroidism or an underlying illness known to be associated with either body wasting or changes in serum proteins (e.g. certain malignancies including multiple myeloma or tuberculosis).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03288233

Contact: Shahriar Arbabi, MD 513-558-3088

United States, Ohio
University of Cincinnati Recruiting
Cincinnati, Ohio, United States, 45220
Contact: Colleen Rogge, BSN    513-475-6478   
Contact: Stephanie Donnelly, MBA    513-558-2639   
Principal Investigator: Robert Cohen, MD         
Sponsors and Collaborators
University of Cincinnati
VA Office of Research and Development
Principal Investigator: Robert Cohen, MD University of Cincinnati

Responsible Party: Robert Cohen, M.D., Professor of Medicine, University of Cincinnati Identifier: NCT03288233     History of Changes
Other Study ID Numbers: CR2_2015-1070
First Posted: September 20, 2017    Key Record Dates
Last Update Posted: September 20, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No plan to share the IPD

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Robert Cohen, M.D., University of Cincinnati:
Hemoglobin A1c
End tidal carbon monoxide

Additional relevant MeSH terms:
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Carbon Monoxide
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Physiological Effects of Drugs