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

• ClinicalTrials.gov Identifier: NCT01883713
• Recruitment Status: Completed
• First Posted: June 21, 2013
• Last Update Posted: April 17, 2018
• Sponsor: Unity Health Toronto
• Information provided by (Responsible Party): Unity Health Toronto

Tracking Information

• First Submitted Date: March 11, 2013
• First Posted Date: June 21, 2013
• Last Update Posted Date: April 17, 2018
• Study Start Date: January 2013
• Actual Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 7, 2014)

Arterial methemoglobin levels [ Time Frame: 18 months ]

To determine if there is an association between increased methemoglobin and tissue hypoxia following heart surgery

Original Primary Outcome Measures (submitted: June 19, 2013)

Arterial and mixed venous methemoglobin levels [ Time Frame: 18 months ]

To determine if there is an association between increased methemoglobin and tissue hypoxia following heart surgery

Current Secondary Outcome Measures (submitted: February 7, 2014)

• Cerebral tissue oxygen saturation [ Time Frame: 18 months ]
• Plasma erythropoietin levels [ Time Frame: 18 months ]
• Plasma nitrate/nitrite levels [ Time Frame: 18 months ]
• Plasma hepcidin levels [ Time Frame: 18 months ]
  Relationship between plasma hepcidin levels and hemoglobin levels

Original Secondary Outcome Measures (submitted: June 19, 2013)

• Cerebral tissue oxygen saturation [ Time Frame: 18 months ]
• Plasma erythropoietin levels [ Time Frame: 18 months ]
• Plasma nitrate/nitrite levels [ Time Frame: 18 months ]

• Current Other Pre-specified Outcome Measures (submitted: June 19, 2013): Adverse outcomes including mortality, myocardial infarction, low output syndrome, stroke and renal dysfunction [ Time Frame: 18 months ]
• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Study of Methemoglobin as a Biomarker of Tissue Hypoxia During Acute Hemodilution in Heart Surgery Patients
• Official Title: A Prospective Analysis of Methemoglobin as a Biomarker of Tissue Hypoxia During Acute Hemodilutional Anemia in Patients Undergoing Heart Surgery

Brief Summary

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).

• 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
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Plasma will be retained for analysis of plasma erythropietin, hepcidin and and nitrate/nitrite levels

• Sampling Method: Non-Probability Sample
• Study Population: heart surgery with cardiopulmonary bypass
• Condition: Other Functional Disturbances Following Cardiac Surgery

Intervention

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 Name: Nonin equinox oximeter

Study Groups/Cohorts

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.

Intervention: Device: Brain Oximetry

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 16, 2018): 68
• Original Estimated Enrollment (submitted: June 19, 2013): 50
• Actual Study Completion Date: August 2016
• Actual Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT01883713
• Other Study ID Numbers: REB# 12-015
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Unity Health Toronto
• Study Sponsor: Unity Health Toronto
• Collaborators: Not Provided

Investigators

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

• PRS Account: Unity Health Toronto
• Verification Date: April 2018