Study of Methemoglobin as a Biomarker of Tissue Hypoxia During Acute Hemodilution in Heart Surgery Patients

A Prospective Analysis of Methemoglobin as a Biomarker of Tissue Hypoxia During Acute Hemodilutional Anemia in Patients Undergoing Heart Surgery

Acute and chronic anemia continue to be associated with increased mortality in a number of clinical settings, including cardiac and non-cardiac surgery. However, "We have no clinical measures that let us know of impending insufficient oxygenation as anemia progresses" (R.B. Weiskopf). The current proposal is based on experimental and clinical data which suggest that plasma methemoglobin (MetHb) may be a sensitive biomarker of tissue hypoxia and "anemic stress" in surgical patients.

Hypothesis: Increased methemoglobin is a biomarker of tissue hypoxia during acute anemia.

Primary Objective: To demonstrate a direct relationship between decreased Hb and increased MetHb in patients undergoing acute hemodilution on cardiopulmonary bypass (CPB).

Study Overview

• Status: Completed
• Conditions: Other Functional Disturbances Following Cardiac Surgery
• Intervention / Treatment: Device: Brain Oximetry

Detailed Description

Acute and chronic anemia continue to be associated with increased mortality in a number of clinical settings, including cardiac and non-cardiac surgery. 1-6 However, as recently stated by one of the pioneers of anemia research; Dr. R.B. Weiskopf: "We have no clinical measures that let us know of impending insufficient oxygenation as anemia progresses".7 Toward achieving this goal, we have developed experimental models to define the adaptive mechanisms which maintain oxygen homeostasis during acute anemia. Our research has identified that increased nitric oxide (NO) production by nitric oxide syntheses (NOSs) may be an important survival mechanism in acute anemia.3;8;9 Experimental data suggests that nNOS may promote survival by maintaining oxygen (O2) homeostasis during acute anemia.10 Resultant increases in nitric oxide (NO) contributes to adaptive cell signaling mechanisms and also increase oxidation of hemoglobin (Hb) to methemoglobin (MetHb).3 In addition, oxygen extraction results in increased levels of deoxyhemoglobin which has been proposed to act as a nitrite (NO2-) reductase to generate additional bioactive NO, thereby promoting vasodilation in hypoxic vascular beds.11-15 Thus, by more than one mechanism, increased MetHb may be indicative of hemoglobin desaturation, tissue hypoxia and activation of adaptive tissue responses to anemia. These responses may identify the threshold for local tissue hypoxia or "anemic stress". In attempt to determine if such mechanisms are active in humans we performed a retrospective study in patients undergoing cardiopulmonary bypass (CPB) during heart surgery to determine if plasma MetHb increased as Hb decreased during CPB. We observed an inverse relationship between Hb and MetHb that was independent of red blood cell transfusion and exogenous nitrate use

• Study Type: Observational
• Enrollment (Actual): 68

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

heart surgery with cardiopulmonary bypass

Description

Inclusion Criteria:

• patients undergoing heart surgery using cardiopulmonary bypass at St. Michael's Hospital who have a pre-operative Hb value greater than 90 g/L, no evidence of hypoxemia (SaO2 > 90%) and no history of congenital methemoglobinemia.

Exclusion Criteria:

• severe hypoxemia, acute or chronic renal failure requiring dialysis, emergency surgery or the lack of a PA catheter (current standard of care at St. Michael's Hospital is to insert a PA catheter in > 90% of patients).

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Heart surgery during CPB; All patients undergoing heart surgery using cardiopulmonary bypass who have a pre-operative Hb value greater than 90 g/L, no evidence of hypoxemia (SaO2 > 90%) and no history of congenital methemoglobinemia. Exclusion criteria will include severe hypoxemia, acute or chronic renal failure requiring dialysis, emergency surgery or the lack of a PA catheter. Non invasive brain oximetry will be used to assess the brain oxygen tension during surgical procedure.

Device: Brain Oximetry; Non invasive brain oximeter will be applied on the patient's forehead to monitor the brain oxygen saturation throughout the surgery.; Other Names: Nonin equinox oximeter

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arterial methemoglobin levels	To determine if there is an association between increased methemoglobin and tissue hypoxia following heart surgery	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebral tissue oxygen saturation		18 months
Plasma erythropoietin levels		18 months
Plasma nitrate/nitrite levels		18 months
Plasma hepcidin levels	Relationship between plasma hepcidin levels and hemoglobin levels	18 months

Other Outcome Measures

Outcome Measure	Time Frame
Adverse outcomes including mortality, myocardial infarction, low output syndrome, stroke and renal dysfunction	18 months

Collaborators and Investigators

• Sponsor: Unity Health Toronto
• Investigators: Principal Investigator: Gregory Hare, MD, PhD, Unity Health Toronto

Publications and helpful links

General Publications

• Hare GMT, Han K, Leshchyshyn Y, Mistry N, Kei T, Dai SY, Tsui AKY, Pirani RA, Honavar J, Patel RP, Yagnik S, Welker SL, Tam T, Romaschin A, Connelly PW, Beattie WS, Mazer CD. Potential biomarkers of tissue hypoxia during acute hemodilutional anemia in cardiac surgery: A prospective study to assess tissue hypoxia as a mechanism of organ injury. Can J Anaesth. 2018 Aug;65(8):901-913. doi: 10.1007/s12630-018-1140-0. Epub 2018 Apr 25.

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): August 1, 2016

Study Registration Dates

• First Submitted: March 11, 2013
• First Submitted That Met QC Criteria: June 19, 2013
• First Posted (Estimate): June 21, 2013

Study Record Updates

• Last Update Posted (Actual): April 17, 2018
• Last Update Submitted That Met QC Criteria: April 16, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: anemia; hypoxia; CPB; methemoglobin
• Additional Relevant MeSH Terms: Signs and Symptoms, Respiratory; Hypoxia
• Other Study ID Numbers: REB# 12-015