Microscale Analysis for quantifying Nitric Oxide induced Hypoxemia in Methemoglobinemia

Methemoglobinemia is a disorder of the blood caused by abnormally high levels of methemoglobin (MetHb) in the red blood cell (RBC) resulting from simultaneous uptake of oxygen (O2) and nitric oxide (NO) by the human lungs. MetHb is produced in the RBC by irreversible oxidation of the oxygen carrying ferrous ion (Fe) of the heme group of the hemoglobin (Hb) molecule to its nonoxygen binding ferric state (Fe). The oxidation is induced by NO, which is directly inhaled by the patient or synthesized in excess by L-Arginine present in endothelial cells, or is produced from oxidizing nitrates ingested through drinking water or pharmaceutical agents. In this work, we study the role of NO in the pathophysiology of methemoglobinemia and perform quantitative analysis of the relation between levels of NO inhaled by the patient and the severity of the disease. Reactions of NO occurring in the RBC with both Hb and oxyhemoglobin are considered in conjunction with the reaction between oxygen and Hb to form oxyhemoglobin and that for the reduction of MetHb to Hb. Our dynamic simulations of NO and O2 uptake in the RBC under continuous exposure to both gases reveal that at the end of the pulmonary transit time of 1 s, the oxygen saturation in the RBC equilibrate at 98% while breathing NO-free room air but decreases monotonically to 93% as the concentration of NO increases to 5 ppm and further down to 50% when the NO level in the blood increases to 80ppm. We show that an NO level of 10 ppm or higher while breathing in room air may be considered to be the critical NO concentration for Methemoglobinemia since it causes severe hypoxemia in patients by decreasing the oxygen saturation level to below its critical value of 91%. We simulate the effects of oxygen therapy on MetHb and oxygen saturation levels in the blood and quantify the severity of hypoxemia by stratifying Methemoglobinemia patients who are oxygen responsive from those who fail to respond to pure oxygen. Our dynamic simulations reveal that ventilating patients with pure oxygen serves as an effective therapeutic strategy for NO levels of less than 10ppm in the RBC. Otherwise, Methemoglobinemia may be treated with methylene blue 1% solution (10mg/ml, 1-2 mg/kg) administered intravenously slowly over five minutes. This treatment is affected through the enzyme-inducing effect of methylene blue on levels of diaphorase II (NADPH methemoglobin reductase) which helps in the reduction of MetHb (Fe) back to hemoglobin (Fe) by providing an electron. Our kinetic modeling of this metabolic pathway reveals that methylene blue restores the iron in Hb to its oxygen-carrying state in less than a second of reaching the RBC.