title: Extracorporeal circulation increases nitric oxide-induced methemoglobinemia in vivo and in vitro.
abstract: OBJECTIVE
  Methemoglobinemia is a well-known side effect of nitric oxide inhalation. We tested the hypothesis whether cardiopulmonary bypass increases methemoglobin formation by nitric oxide.
  
  
  METHODS
  A two-phase study: a) a controlled, prospective in vivo study of inhaled nitric oxide treatment followed by b) a second, prospective and controlled in vitro study.
  
  
  METHODS
  Pediatric intensive care unit and research laboratory in a university hospital.
  
  
  METHODS
  The in vivo study consisted of 25 patients following open-heart surgery and 19 children with acute respiratory distress syndrome (ARDS) or persistent pulmonary hypertension of the newborn. The in vitro study consisted of 20 patients with and 20 patients without cardiopulmonary bypass.
  
  
  METHODS
  For the in vivo study, methemoglobin measurements were taken before and after application of 20 parts per million (ppm) of nitric oxide. For the in vitro study, red blood cells of patients were incubated with 32 ppm nitric oxide before and after surgery. Methemoglobin, glutathione, adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADHP) concentrations were compared.
  
  
  RESULTS
  For the in vivo study, nitric oxide inhalation increased methemoglobin from 0.2 +/- 0.1% to 1.2 +/- 0.7% in patients receiving nitric oxide after open-heart surgery and from 0.2 +/- 0.1% to 0.5 +/- 0.4% in ARDS/persistent pulmonary hypertension of the newborn patients (p < .01). For the in vitro study, nitric oxide incubation of red blood cells increased methemoglobin concentration from 3.7 +/- 1.9% preoperatively to 7.4 +/- 2.4% after open-heart surgery. This increase was not observed in patients who did not undergo cardiopulmonary bypass (3.6 +/- 1.6% vs. 3.6 +/- 1.9%; p < .001). In erythrocytes of patients undergoing extracorporeal circulation, there was no difference between pre- and postoperative glutathione, ATP, and NADH/NADPH concentrations.
  
  
  CONCLUSIONS
  Cardiopulmonary bypass is an important risk factor for methemoglobinemia when inhaled nitric oxide is applied. This risk is not secondary to diminished concentrations of energetic substrates.
authors.affiliation: Department of Pediatrics, Justus-Liebig-University of Giessen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Dötsch
authors.forename: S
authors.initials: S
authors.lastname: Demirakca
authors.forename: R
authors.initials: R
authors.lastname: Hamm
authors.forename: C
authors.initials: C
authors.lastname: Knothe
authors.forename: J
authors.initials: J
authors.lastname: Bauer
authors.forename: P G
authors.initials: PG
authors.lastname: Kühl
authors.forename: W
authors.initials: W
authors.lastname: Rascher
mesh_terms: D000280:Administration, Inhalation; D001774:Blood Chemical Analysis; D006348:Cardiac Surgical Procedures; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D004912:Erythrocytes / Q000378:metabolism*; D005112:Extracorporeal Circulation / Q000009:adverse effects; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008706:Methemoglobin / Q000032:analysis; D008708:Methemoglobinemia / Q000139:chemically induced / Q000209:etiology*; D009569:Nitric Oxide / Q000008:administration & dosage / Q000009:adverse effects*; D010547:Persistent Fetal Circulation Syndrome / Q000628:therapy; D011446:Prospective Studies; D012127:Respiratory Distress Syndrome, Newborn / Q000628:therapy
chemical_list: D009569:Nitric Oxide; D008706:Methemoglobin