Methemoglobin as a marker of acute anemic stress in cardiac surgery

Nikhil Mistry^{1

2}, Gregory M T Hare^{2

3

4

5}, Nadine Shehata⁶, Robert S Kramer⁷, Hosam F Fawzy⁸, Robert A Baker⁹, Paula Carmona¹⁰, Richard Saczkowski¹¹, Daniela Filipescu¹², Christella S Alphonsus¹³, Antoine Rochon¹⁴, Alexander J Gregory¹⁵, Boris Khanykin¹⁶, Jonathan D Leff¹⁷, Eva Mateo¹⁸, Dimos Karangelis¹⁹, Juan C Tellez²⁰, Tarit Saha²¹, Dennis T Ko^{22

23

24}, Duminda N Wijeysundera^{2

3

5

23

24}, Subodh Verma^{5

25

26}, C David Mazer^{1

2

3

4

5

26}

Affiliations

¹ Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
² Department of Anesthesia, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
³ Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada.
⁴ Department of Physiology, University of Toronto, Toronto, ON, Canada.
⁵ Li Ka Shing Knowledge Institute of St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
⁶ Division of Hematology, Sinai Health System, Department of Medicine, University of Toronto, Toronto, ON, Canada.
⁷ Maine Medical Center Cardiovascular Institute, Portland, ME, USA.
⁸ Department of Cardiothoracic Surgery, Faculty of Medicine, University of Tanta, Tanta, Egypt.
⁹ Cardiac Surgery Research and Perfusion, Flinders University and Flinders Medical Centre, Adelaide, SA, Australia.
¹⁰ Cardiovascular-Anesthesia and Intensive Care. University Hospital La Fe, Valencia, Spain.
¹¹ Department of Cardiac Sciences, Perfusion Services, Kelowna General Hospital, Kelowna, BC, Canada.
¹² University of Medicine and Pharmacy Carol Davila, Emergency Institute for Cardiovascular Diseases "Prof. Dr. C.C. Iliescu", Bucharest, Romania.
¹³ Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa.
¹⁴ Montreal Heart Institute, Montreal, QC, Canada.
¹⁵ Department of Anesthesiology, Perioperative and Pain Medicine and Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
¹⁶ Cardiothoracic Anesthesiology Department, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁷ Montefiore-Einstein Center for Heart and Vascular Care, New York City, NY, USA.
¹⁸ Hospital General Universitario de València, València, Spain.
¹⁹ Department of Cardiothoracic Surgery, Democritus University of Thrace, Alexandroupolis, Greece.
²⁰ Marly Clinic, Bogotá, Cundinamarca, Colombia.
²¹ Department of Anesthesiology and Perioperative Medicine, Kingston General Hospital, Kingston, ON, Canada.
²² Schulich Heart Program, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
²³ Institute of Health Policy Management, and Evaluation, University of Toronto, Toronto, ON, Canada.
²⁴ ICES, Toronto, ON, Canada.
²⁵ Division of Cardiac Surgery, St. Michael's Hospital, Department of Surgery, University of Toronto, Toronto, ON, Canada.
²⁶ Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.

PMID: 37575193
PMCID: PMC10415918
DOI: 10.1016/j.isci.2023.107429

Methemoglobin as a marker of acute anemic stress in cardiac surgery

Nikhil Mistry et al. iScience. 2023.

. 2023 Jul 20;26(8):107429.

doi: 10.1016/j.isci.2023.107429. eCollection 2023 Aug 18.

Authors

Affiliations

¹ Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada.
² Department of Anesthesia, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
³ Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada.
⁴ Department of Physiology, University of Toronto, Toronto, ON, Canada.
⁵ Li Ka Shing Knowledge Institute of St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
⁶ Division of Hematology, Sinai Health System, Department of Medicine, University of Toronto, Toronto, ON, Canada.
⁷ Maine Medical Center Cardiovascular Institute, Portland, ME, USA.
⁸ Department of Cardiothoracic Surgery, Faculty of Medicine, University of Tanta, Tanta, Egypt.
⁹ Cardiac Surgery Research and Perfusion, Flinders University and Flinders Medical Centre, Adelaide, SA, Australia.
¹⁰ Cardiovascular-Anesthesia and Intensive Care. University Hospital La Fe, Valencia, Spain.
¹¹ Department of Cardiac Sciences, Perfusion Services, Kelowna General Hospital, Kelowna, BC, Canada.
¹² University of Medicine and Pharmacy Carol Davila, Emergency Institute for Cardiovascular Diseases "Prof. Dr. C.C. Iliescu", Bucharest, Romania.
¹³ Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa.
¹⁴ Montreal Heart Institute, Montreal, QC, Canada.
¹⁵ Department of Anesthesiology, Perioperative and Pain Medicine and Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
¹⁶ Cardiothoracic Anesthesiology Department, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁷ Montefiore-Einstein Center for Heart and Vascular Care, New York City, NY, USA.
¹⁸ Hospital General Universitario de València, València, Spain.
¹⁹ Department of Cardiothoracic Surgery, Democritus University of Thrace, Alexandroupolis, Greece.
²⁰ Marly Clinic, Bogotá, Cundinamarca, Colombia.
²¹ Department of Anesthesiology and Perioperative Medicine, Kingston General Hospital, Kingston, ON, Canada.
²² Schulich Heart Program, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
²³ Institute of Health Policy Management, and Evaluation, University of Toronto, Toronto, ON, Canada.
²⁴ ICES, Toronto, ON, Canada.
²⁵ Division of Cardiac Surgery, St. Michael's Hospital, Department of Surgery, University of Toronto, Toronto, ON, Canada.
²⁶ Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.

PMID: 37575193
PMCID: PMC10415918
DOI: 10.1016/j.isci.2023.107429

Abstract

Biological evidence supports plasma methemoglobin as a biomarker for anemia-induced tissue hypoxia. In this translational planned substudy of the multinational randomized controlled transfusion thresholds in cardiac surgery (TRICS-III) trial, which included adults undergoing cardiac surgery requiring cardiopulmonary bypass with a moderate-to-high risk of death, we investigated the relationship between perioperative hemoglobin concentration (Hb) and methemoglobin; and evaluated its association with postoperative outcomes. The primary endpoint was a composite of death, myocardial infarction, stroke, and severe acute kidney injury at 28 days. We observe weak non-linear associations between decreasing Hb and increasing methemoglobin, which were strongest in magnitude at the post-surgical time point. Increased levels of post-surgical methemoglobin were associated with a trend toward an elevated risk for stroke and exploratory neurological outcomes. Our generalizable study demonstrates post-surgical methemoglobin may be a marker of anemia-induced organ injury/dysfunction, and may have utility for guiding personalized approaches to anemia management. Clinicaltrials.gov registration NCT02042898.

Keywords: Cardiovascular medicine; Health sciences; Public health; Surgery.

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Conflict of interest statement

RSK reports receiving grants from the NIH, speaker honorarium from the Cardiothoracic Research and Education Forum, and reports membership on an advisory board for Bio Products Laboratory. DF reports receiving grants financed by the Erasmus+ program, lecture; honoraria from Werfen Instrumentation Laboratory Comp., the American Society of Anesthesiology, University of Continuing Education Krems, Department for Health Sciences, Medicine and Research, Austria; leadership roles World Federation of Societies of Anesthesiologists, the Romanian Society of Anesthesia and Intensive Care, and European Sepsis Alliance; and has received equipment from Vifor Pharma Romania. AJG reports receiving consulting fees and honoraria from Edwards Lifesciences, and is a non-remunerated member of the executive board for the Society for Enhanced Recovery after Cardiac Surgery. JDL reports receiving grants or contracts from Edwards Lifesciences and the CTSA Seed Grant. SV holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. CDM reports advisory board honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, BioAge and PhaseBio; and DSMB honoraria from Cerus and Takeda. All other authors declare no competing interests.

Figures

**Figure 1**
Correlations between hemoglobin versus methemoglobin before and after surgery (A–C) The correlation between: pre-surgical hemoglobin versus pre-surgical methemoglobin (Panel A); post-surgical hemoglobin versus post-surgical methemoglobin (Panel B); and Delta (difference between pre-surgical and post-surgical) hemoglobin versus post-surgical methemoglobin (Panel C) in the whole cohort. The plotted lines of best fit and 95% confidence intervals were estimated using restricted cubic splines. p value for non-linearity: p < 0.001 at pre-surgical time point, p < 0.001 at post-surgical time point. p = 0.67 for delta.

**Figure 2**
Association between post-surgical methemoglobin and clinical outcomes CI; Confidence interval; MetHb, methemoglobin. There was statistical evidence of a non-linear association only between post-surgical methemoglobin and the additional neurological outcome of delirium; therefore, post-surgical methemoglobin was modeled as a non-linear term for this outcome. Models adjusted for age, sex, diabetes status, preoperative renal function, preoperative left ventricular function, baseline chronic pulmonary disease, planned surgery, red blood cell transfusion, and hemoglobin concentration. The x axis is presented on a log-transformed scale.

See this image and copyright information in PMC

References

1. Hare G.M.T., Mazer C.D. Anemia: Perioperative Risk and Treatment Opportunity. Anesthesiology. 2021;135:520–530. doi: 10.1097/aln.0000000000003870. - DOI - PubMed
1. Warner M.A., Shore-Lesserson L., Shander A., Patel S.Y., Perelman S.I., Guinn N.R. Perioperative Anemia: Prevention, Diagnosis, and Management Throughout the Spectrum of Perioperative Care. Anesth. Analg. 2020;130:1364–1380. doi: 10.1213/ane.0000000000004727. - DOI - PubMed
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1. World Health Organization . World Health Organization; 2011. Haemoglobin Concentrations for the Diagnosis of Anaemia and Assessment of Severity.
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Methemoglobin as a marker of acute anemic stress in cardiac surgery

Affiliations

Methemoglobin as a marker of acute anemic stress in cardiac surgery

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Associated data

LinkOut - more resources

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