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

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ClinicalTrials.gov Identifier: NCT01883713
Recruitment Status : Completed
First Posted : June 21, 2013
Last Update Posted : April 17, 2018
Sponsor:
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
Change History
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
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
Removed Location Countries  
 
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
Current Responsible Party Unity Health Toronto
Original Responsible Party Same as current
Current Study Sponsor Unity Health Toronto
Original Study Sponsor Same as current
Collaborators Not Provided
Investigators
Principal Investigator: Gregory Hare, MD, PhD Unity Health Toronto
PRS Account Unity Health Toronto
Verification Date April 2018