Clinical trial NCT01883713: 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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Other Functional Disturbances Following Cardiac Surgery
Keywords: anemia
CPB
methemoglobin
hypoxia
Lead sponsor: Unity Health Toronto
Sponsor class: OTHER
First posted: 2013-06-21
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: heart surgery with cardiopulmonary bypass

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

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).

Primary outcomes:
measure: Arterial methemoglobin levels
timeFrame: 18 months
Secondary outcomes:
measure: Cerebral tissue oxygen saturation
timeFrame: 18 months
measure: Plasma erythropoietin levels
timeFrame: 18 months
measure: Plasma nitrate/nitrite levels
timeFrame: 18 months
measure: Plasma hepcidin levels
timeFrame: 18 months
Other outcomes:
measure: Adverse outcomes including mortality, myocardial infarction, low output syndrome, stroke and renal dysfunction
timeFrame: 18 months
Locations:
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
Study officials:
affiliation: Unity Health Toronto
name: Gregory Hare, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.