CONGENITAL methemoglobinemia is a rare disease caused by the oxidation of iron from the ferrous to the ferric state in the protoporphyrin ring, which forms the prosthetic group (heme) of hemoglobin. 1The current report presents a patient with congenital methemoglobinemia who developed severe oxyhemoglobin desaturation during induction of anesthesia.

The patient was a 22-yr-old man who was scheduled for turbinectomy 1 month ago in another institution, but the operation was cancelled after induction of anesthesia with thiopental because the patient developed severe cyanosis and multiple ventricular extrasystoles. The patient was ventilated with 100% oxygen, which was followed by improvement of cyanosis and restoration of normal sinus rhythm.

The patient was rescheduled in our institution for the same surgery. Preoperative medical clearance did not reveal any cardiopulmonary disease and he was not on any medication. He was premedicated with meperidine (60 mg), promethazine (25 mg), and atropine (0.5 mg) intramuscularly. In the operating room, it was noticed that the patient’s fingers and lips were blue.

Pulse oximetry on room air revealed an oxygen saturation measured by pulse oximetry (Spo2) of 91%. The pulse oximeter was checked on the anesthetist’s finger and showed an Spo2of 98%. Congenital methemoglobinemia was suspected. An arterial canula was inserted before induction of anesthesia, and an arterial blood gas analysis, measured by ABL700 series radiometer (Copenhagen, Denmark), revealed the following results: arterial oxygen concentration (Sao2), 96.8% (functional saturation); partial pressure of alveolar oxygen (PAo2), 90 mmHg; oxyhemoglobin, 79.2% (fractional saturation); reduced hemoglobin, 2.2%; carboxyhemoglobin, 0.2%; methemoglobin, 18.4%; hematocrit, 54.7%; hemoglobin, 17.9 g/dl. Lidocaine, 1 mg/kg, was injected intravenously before induction of anesthesia in order to minimize pain during the subsequent intravenous propofol administration, and to blunt the hemodynamic response to tracheal intubation. The patient was not preoxygenated before the injection of lidocaine. The patient immediately developed unconsciousness and apnea, associated with severe cyanosis and a decrease in Spo2to 79%. An arterial blood sample for gas analysis was taken, and intermittent positive pressure ventilation with 100% face mask oxygen was started; the Spo2increased from 79% to 91%. Arterial blood gas analysis during the apneic episode showed a Pao2of 60 mmHg, associated by a decrease of the oxyhemoglobin saturation to 72%, although there was no significant change of the methemoglobin concentration. Repeating arterial blood gas analysis after ventilation with 100% oxygen revealed the following: Sao2, 99.5%; Pao2, 481 mmHg; oxyhemoglobin, 80%; methemoglobin, 19.4%. Methylene blue, 1 mg/kg, was injected intravenously over 3 min. The patient regained consciousness 10 min later, and the Spo2increased from 79% to 96%. An arterial blood gas analysis showed the following: Sao2, 99.6%; Pao2, 324 mmHg; oxyhemoglobin, 93.9%; methemoglobin, 4.7%. The operation was cancelled.

A summary of the changes in the pulse oximetry, the arterial blood gases, as well as the methemoglobin concentrations on room air during apnea, after ventilation with 100% oxygen, and after methylene blue administration, are shown in table 1.

The current patient had congenital methemoglobinemia, as evidenced by the high methemoglobin concentration (18.4%), and the low fractional oxyhemoglobin saturation (79.2%), in the presence of a normal Pao2and the absence of exposure to any oxidant stress. The intravenous administration of lidocaine was complicated by severe oxyhemoglobin desaturation that was managed by ventilation with 100% oxygen and administration of methylene blue.

The normal hemoglobin molecule contains a reduced (ferrous) iron molecule [Fe++]. Hemoglobin-containing iron in the ferric state [Fe+++] is termed methemoglobin. In normal individuals, a small amount of the hemoglobin in erythrocytes is oxidized to methemoglobin. Methemoglobin is reduced to deoxyhemoglobin enzymatically, hence methemoglobin concentration remains less than 2%. Cytochrome b5 reductase (nicotinamide-adenine dinucleotide reduced form [NADH] reductase) is the enzyme responsible for methemoglobin reduction. Patients homozygous for this enzymatic deficiency have congenital methemoglobinemia. 2The acquired form of methemoglobinemia results from exposure to an appropriate oxidant stress in sufficient quantities to overwhelm the metabolic process that reconverts methemoglobin to hemoglobin. 3In patients with acquired or congenital methemoglobinemia, cyanosis is detectable when methemoglobin concentration exceeds 1.5 g/dl. Our patient presented with cyanosis without exposure to any oxidant stress because he had a methemoglobin concentration of 3.29 g/dl (18.4%). The absorbance characteristics of methemoglobin are such that the pulse oximeter shows an Spo2around 85%, regardless of the Pao2. 4 

When the iron in a hemoglobin molecule is oxidized to the ferric state, not only the heme group is incapable of combining with oxygen, but the affinity of the remaining heme groups for oxygen is increased because of allosteric effects. This is the molecular basis of the left-shifted oxyhemoglobin dissociation curve in patients with methemoglobinemia. Thus, methemoglobinemia can severely limit oxygen delivery not only because the oxygen carrying capacity of the hemoglobin molecule is reduced, but also because the oxygen carried by the remaining normal heme groups is less readily released to the tissues. 5 

Our patient developed severe cyanosis on a previous occasion and ventricular extrasystoles after an induction dose of thiopental. The severe oxyhemoglobin desaturation is not attributed to an increased methemoglobin concentration, because thiopental is not known to be an oxidant stress. In the second occasion, he developed unconsciousness, apnea, and a decrease of Spo2to 79% after intravenous lidocaine. Local anesthetics such as prilocaine and benzocaine have been associated with methemoglobin formation. 3,6However, it is controversial whether lidocaine can induce methemoglobinemia. 7–9In our patient, lidocaine administration did not worsen methemoglobinemia. In fact, what presumably occurred is that even a “normal” degree of respiratory depression or decreasing Pao2after any respiratory depressant, and not lidocaine per se  (which would be unnoticed in normal patients), resulted in marked desaturation in a patient with congenital methemoglobinemia who had only a modest amount of normal hemoglobin available.

In our patient, the severe oxyhemoglobin desaturation after lidocaine administration was managed by ventilation with 100% oxygen. Also, the intravenous administration of methylene blue 1 mg/kg reduced the methemoglobin concentration from 18.4% to 4.7%. Methylene blue is the cofactor for nicotinamide-adenine dinucleotide phosphate reduced form [NADPH] methemoglobin reductase. This enzyme remains inactive physiologically, but will be activated by methylene blue. 1It is recommended that patients with congenital methemoglobinemia should be adequately oxygenated before, during and after recovery from anesthesia, in order to avoid hypoxemia and prevent further detrimental decrease in the oxyhemoglobin saturation. Also, methylene blue may be administered prophylactically before induction of anesthesia.

The current report presents a patient with congenital methemoglobinemia with methemoglobin concentration of 18.4% and Spo2of 91%. The oxygen delivery in the patient may be compromised by the decreased oxyhemoglobin concentration and by the shift of the oxyhemoglobin dissociation curve to the left. The patient developed severe oxyhemoglobin desaturation after intravenous administration of lidocaine. Worsening of methemoglobinemia did not cause the patient’s cyanosis. In fact, what presumably occurred is that even a “normal” degree of respiratory depression after any respiratory depressant (which would be unnoticed in normal patients) may have resulted in marked desaturation in a patient with congenital methemoglobinemia.

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