A42: Antidotes in Depth

Methylene blue is an extremely effective antidote for acquired methemoglobinemia. Methylene blue has other actions, including the inhibition of nitric oxide synthase and guanylyl cyclase, and the inhibition of the generation of oxygen free radicals. These actions may explain the beneficial effects of methylene blue in the treatment of refractory hypotension, hepatopulmonary syndrome, treatment of priapism, modulation of streptozocin-induced insulin deficiency, prevention and treatment of ifosfamide-induced encephalopathy, in the treatment of sepsis, and the reduction of the development of postsurgical peritoneal adhesions.^{15,16,21,25,34,44,52,59}

Methylene blue was initially recommended as an intestinal and urinary antiseptic and subsequently recognized as a weak antimalarial.²⁰ In 1933, Williams and Challis successfully used methylene blue for treatment of aniline-induced methemoglobinemia.⁶⁴

Chemistry

Methylene blue is tetramethylthionine chloride,²⁰ a basic thiazine dye with a molecular weight of 319 Da. It is deep blue in the oxidized state and colorless when reduced to leukomethylene blue.

Mechanisms of Action

Methylene blue is an oxidizing agent, which, in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and NADPH ­methemoglobin reductase, is reduced to leukomethylene blue (Fig. 127–4). Leukomethylene blue then becomes available to reduce methemoglobin to hemoglobin.^9,20,60 Reduction of methemoglobin via this NADPH pathway is limited under normal circumstances. However, in the presence of methylene blue, the role of the NADPH pathway is dramatically increased and becomes the most efficient means of methemoglobin reduction.

Recently, attention has focused on the ability of methylene blue to reverse refractory hypotension due to many causes including drug overdose, vasoplegia, and sepsis. Methylene blue inhibits nitric oxide synthase and guanylyl cyclase in vascular smooth muscle. This reduces the amount and effect of nitric oxide. Systemic vascular resistance and cardiac output increase, and the sensitivity of adrenergic receptors to sympathomimetics is enhanced.^{12,14,36,27,38,63}

Pharmacokinetics

The pharmacokinetics of methylene blue were studied in animals and human volunteers following intravenous (IV) and oral administration of 100 mg.^{9, 10, and 11,45} Methylene blue exhibits complex pharmacokinetics consistent with extensive distribution into deep compartments, followed by a slower terminal elimination, with a half-life of 5.25 hours. Peak concentrations after oral administration were reached in 1 to 2 hours, but were only approximately 80 to 90 nmol/L, as opposed to 8000 to 9000 nmol/L following IV administration. The substantial differences in whole blood concentrations achieved by these routes of administration can be attributed to extensive first-pass organ distribution into the intestinal wall and liver, following oral administration.³⁵ Total urinary excretion at 24 hours accounts for 28.6% of the drug following IV administration, compared with 18.5% after oral administration. In both instances, one third was in the leukomethylene blue form.

Pharmacodynamics

The onset of action of methylene blue for the reversal of methemoglobin is often within minutes. Maximum effects usually occur by 30 minutes.²³

Methylene blue is indicated in patients with symptomatic methemoglobinemia. This usually occurs at methemoglobin levels greater than 20%, but may occur at lower levels in anemic patients or those with cardiovascular, pulmonary, or central nervous system compromise.

Historically, sulfanilamide induced methemoglobinemia was reversed by methylene blue in IV doses of 1 to 2 mg/kg or oral doses of 65 to 130 mg, given every 4 hours.^22,61 With these regimens, a very rapid fall in methemoglobin was accompanied by disappearance of cyanosis. ­Subsequent investigations confirmed the effectiveness and safety of IV doses of 1 to 2 mg/kg in reversing the methemoglobinemia produced by sulfanilamide,⁶¹ aniline dye,¹³ silver nitrate, benzocaine, nitrites, phenazopyridine, and other xenobiotics.^55,58

The risk-to-benefit ratio of using methylene blue in a patient for methemoglobinemia must always be weighed as with any other drug. In this case, the benefit of using methylene blue for a patient with significant methemoglobinemia will almost always outweigh the risk of possibly precipitating serotonin toxicity in a patient taking an SSRI (refer to Adverse Events).

Methylene blue is ineffective in the treatment of sulfhemoglobinemia (Chap. 127).

Hypotension refractory to vasopressors occurs in the setting of sepsis, vasoplegia, and drug ingestion. Methylene blue has successfully reversed the low systemic vascular resistance in a few case studies and case reports.^{12,14,27,28,32,35,36,38,47,63}

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).

Methylene blue is a category X drug in pregnancy. IV methylene blue has led to fetal abnormalities, including atresia of the ileum and jejunum, ileal occlusions, hemolytic anemia, hyperbilirubinemia, and methemoglobinemia when used via intraamniotic injection. Human data suggest developmental toxicity when used in the second and third trimesters.⁶

There are no data available on lactation, but it is not likely to present a danger to the nursing infant.⁶

In most cases, a dose of 1 to 2 mg/kg given IV over 5 minutes, followed immediately by a fluid flush of 15 to 30 mL to minimize local pain, is both effective and relatively safe. In neonates, 0.3 to 1 mg/kg doses often are effective.^17,26 The onset of action is rapid, and maximal effects usually occur within 30 minutes.

Repetitive dosing of methylene blue may be required in conjunction with efforts to decontaminate the gastrointestinal tract when there is continued absorption or slow elimination of the xenobiotic producing the methemoglobinemia, such as with dapsone.

Intraosseous administration of 0.3 mL of 1% solution (1 mg/kg) of methylene blue over 3 to 5 minutes into the anterior tibia of a 6 week-old infant was well tolerated.^24,43 The dose of methylene blue for refractory hypotension is not established. Doses of 1 to 3 mg/kg increase systemic vascular resistance and mean arterial pressure and improve tissue oxygenation.²⁴ Although doses of 7 mg/kg may produce further increases in mean arterial pressure, this result is at the expense of decreasing splanchnic blood flow.²⁸

Methylene blue is available in 10 mL vials of a 1% solution for injection, ­containing 10 mg/mL.

• Methylene blue is an effective reducing agent for patients with acquired methemoglobinemia.

• When used in the proper dose, the onset of action for methylene blue is rapid and its adverse reactions are limited.

• Repeat doses often are required when methemoglobin-producing drugs with a long duration of effect, such as dapsone, are ingested.

References