Reports of the paradoxical induction of methemoglobinemia by methylene blue suggest an equilibrium between the direct oxidization of hemoglobin to methemoglobin by methylene blue and its ability (through the NADPH and NADPH methemoglobin reductase pathway, and leukomethylene blue production) to reduce methemoglobin to hemoglobin.4,5 Methylene blue does not produce methemoglobin at doses of 1 to 2 mg/kg. The equilibrium seems to favor the reducing properties of methylene blue, unless excessively large doses of methylene blue are administered,3,19,62 or the NADPH methemoglobin reductase system is abnormal. This equilibrium constant may vary substantially, as 20 mg/kg IV in dogs and 65 mg/kg intraperitoneally in rats failed to produce methemoglobinemia.54 In early studies, 50 to 100 mL of a 1% concentration (500–1000 mg) of methylene blue was used intravenously in volunteers39 as well as in the treatment of patients with aniline dye induced methemoglobinemia.64 In these studies, methemoglobin levels, measured when symptoms were most pronounced, were approximately 1.0 g/dL (0.4%–8.3% of total hemoglobin), and unlikely to be solely responsible for the adverse effects demonstrated. Other consequential adverse effects included shortness of breath, tachypnea, chest discomfort, a burning sensation of the mouth and stomach, initial bluish tinged skin and mucous membranes, paresthesias, restlessness, apprehension, tremors, nausea and vomiting, dysuria, and excitation. Urine and vomitus may appear blue in color. These limited studies led to the recommendation to avoid doses higher than 7 mg/kg.
In high doses, methylene blue can induce acute hemolytic anemia independent of the presence of methemoglobinemia.19,33 In dose–response studies in glucose-6-phosphate dehydrogenase (G6PD) deficient homozygous African American men, daily doses of 390 to 780 mg (5.5–11 mg/kg) of methylene blue produced hemolysis,31 which was comparable with the results following exposure to 15 mg of primaquine base.31 Because of the sensitivity of neonates (hemoglobin F and diminished NADH reductase) to these risks, the smallest effective dose of methylene blue should be used.24,30 Because any oxidizing agent can independently induce a Heinz body hemolytic anemia, the specific contribution of methylene blue often is difficult to elucidate.30
Since methylene blue is a dye it will alter pulse oximeter readings.7 Large doses may interfere with the ability to detect a clinical decrease in cyanosis; therefore, repeat cooximeter measurements and arterial blood gas analysis should be used in conjunction with clinical findings to evaluate improvement.
Intraamniotic injection of methylene blue may result in a number of adverse effects, including infants born with blue skin (with resultant inaccurate pulse oximetry readings),43 methemoglobinemia, hemolysis, phototoxic skin reactions,46 or intestinal obstruction.7,8,29,33,37,42,49,57 One infant exposed in utero at 5.5 weeks was normal at birth.29 An excessive dose of enterally administered methylene blue that subsequently leaked into the peritoneum of a premature neonate most likely was responsible for a hemolytic anemia appearing 3 days later.1
Methylene blue leads to a bluish-green discoloration of the urine, and can potentially cause dysuria.48 IV methylene blue is irritating and exceedingly painful. It may cause local tissue damage even in the absence of extravasation.49 Subcutaneous and intrathecal administrations are contraindicated.49
Two recent reviews reveal an association between an encephalopathy and the use of methylene blue for localization of parathyroid tumors in women on serotonin reuptake inhibitors.41,56 Five out of 132 patients in the first review developed one or more of the following: confusion, expressive aphasia, lethargy, and vertigo, which lasted from 2 to 3 days. The second review detailed seven patients with signs and symptoms consistent with serotonin toxicity. It should be noted that these patients usually received 3 to 5 mg/kg of methylene blue as a continuous infusion over 1 hour. A subsequent in vitro study documented the ability of methylene blue to competitively bind to monoamine oxidase A, raising the possibility that methylene blue might interact with serotonergic xenobiotics by acting as a monamine oxidase inhibitor.50 Two recent reviews also conclude that methylene blue has the potential to interact with drugs that elevate serotonin to cause serotonin excess and toxicity.18,40
High doses of methylene blue (7 mg/kg) have the potential to decrease splanchnic blood flow in the setting of septic shock.28
One author suggests that methylene blue directly inactivates lactic acid giving a potentially false impression of improved perfusion.14 However, this finding needs to be confirmed.
Use in Patients with Glucose-6-Phosphate Dehydrogenase Deficiency
Methylene blue is frequently hypothesized to be ineffective in reversing methemoglobinemia in patients with G6PD deficiency41 because G6PD is essential for generation of NADPH (Chap. 23). Without NADPH, methylene blue cannot reduce methemoglobin. However, G6PD deficiency is an X-linked hereditary deficiency with more than 400 variants. The red cells containing the more common G6PD A– variant found in 11% of African Americans retain 10% residual activity, mostly in younger erythrocytes and reticulocytes. By contrast, the enzyme is barely detectable in those of Mediterranean descent who have inherited the defect. Therefore, it is impossible to predict before the use of methylene blue which persons will or will not respond, and to what extent. Currently, it appears that most individuals have adequate G6PD and express deficiency states in relative terms. This variable expression of their deficiency allows an effective response to most oxidant stresses. In addition, in theory, normal cells might convert methylene blue to leukomethylene blue, which might diffuse into G6PD deficient cells and effectively reduce methemoglobin to hemoglobin.2
Before assuming that G6PD deficiency is responsible for a continued elevation of methemoglobin levels despite administration of methylene blue, ongoing xenobiotic absorption and or continued methemoglobin production must be excluded. On the other hand, when therapeutic doses of methylene blue fail to have an impact on the methemoglobin concentration, the possibility of G6PD deficiency should be considered, and further doses of methylene blue should not be administered because of the risk of methylene blue induced hemolysis. In these cases, exchange transfusion and hyperbaric oxygen are potential alternatives for treating methemoglobinemia (Chap. 127).