CALL US...TM

The Official Newsletter of the California Poison Control System

 

 

Volume 7, Number 3
Summer 2009

 

 

Methemoglobin

 

INTRODUCTION

Methemoglobin is an altered form of hemoglobin in which the ferrous state, Fe2+, loses an electron and is oxidized to the ferric, Fe3+, state.  This change in the iron moiety renders hemoglobin incapable of carrying oxygen, leading to decreased oxygen delivery to tissues and a functional anemia.    This process naturally occurs in the body at low levels, and endogenous systems are in place to reduce the ferric state of iron back to the ferrous state. When an abnormal elevation in the methemoglobin level occurs and exceeds the body’s capacity of the methemoglobin reduction process, clinically significant methemoglobinemia results.  While typically not life-threatening, severe untreated methemoglobinemia can lead to grave hypoxic symptoms and death.  Methemoglobinemia should be suspected in a cyanotic patient without an apparent cardiovascular cause.

CASE PRESENTATION

A three year-old male presented to his pediatrician’s office with a two-day history of fever and oral lesions consistent with herpes gingivostomatitis.  His mother was advised to maximize his fluid intake and to treat his discomfort with acetaminophen.  Three days later, the child returned to the pediatrician with fevers to 103°F, worsening of his oral lesions, and minimal oral intake.  The pediatrician recommended a “Magic Mouthwash” prepared by the parents in a 1:1:1 solution consisting of diphenhydramine, aluminum hydroxide and benzocaine.  The benzocaine was erroneously dosed approximately ten times greater than indicated. The patient’s mother administered the solution which the child swallowed instead of expectorating.  Forty minutes following administration, the patient’s skin turned blue, and he was immediately transported to a pediatric emergency department. 

The child was born full-term and had no significant past medical history.  He was taking no other medications other than the “Magic Mouthwash” solution.   His family history was unremarkable. 

In the emergency department, the child’s vital signs were as follows:  temperature: 98.9°F, heart rate: 170 beats per minute, blood pressure was normal, respiratory rate: 30, and pulse oximeter reading: 87% on room air. He weighed 10 kilograms and was estimated to be 5 to 10 percent dehydrated.  The child was sitting on his mother’s lap without labored breathing. His oral mucosa, tongue and lips were dry with markedly swollen, erythematous and friable gums with diffuse vesicular lesions and ulcerated plaques.  Cardiac auscultation was normal. His lungs were clear.  His abdomen was soft and nontender.  He had no neurological deficits.  His skin was warm, dry and had a bluish discoloration.

The child was given high-flow supplemental oxygen by mask, but his pulse oximeter reading and skin color remained unchanged.  His hemoglobin was 12.1g/dL.  Blood gas co-oximetry results revealed a methemoglobin concentration of 57% and allowed for a definitive diagnosis of methemoglobinemia.

Ten milliliters of methylene blue 1% was given intravenously as treatment, and within one hour the bluish discoloration to the child’s skin had fully resolved. The patient’s pulse oximeter reading returned to 97% on room air, and his repeat methemoglobinemia concentration was 9%.

The child was admitted to the hospital for treatment of his dehydration with intravenous fluids. Acetaminophen was administered for oral pain relief.  The following day, the child was tolerating food and water, and he was discharged to home.

 Questions:

1.       What are common causes of methemoglobinemia?

2.       How is methemoglobinemia diagnosed?

3.       Is the severity of this child’s methemoglobinemia related to the dose of benzocaine that he ingested?

EPIDEMIOLOGY

 

Methemoglobinemia can be hereditary or acquired.  Hereditary cases are due to the presence of abnormal hemoglobin or an enzyme deficiency and are rare. Acquired methemoglobinemia occurs more frequently and is xenobiotic-induced (medications or other substances), with the topical anesthetic benzocaine generally cited as causing the most severely poisoned patients and the antimicrobial dapsone most commonly implicated in methemoglobin cases reported to poison centers.  The true incidence of acquired methemoglobinemia is unknown.  Estimated incidence based on methylene blue use (the treatment of methemoglobinemia) reported to the American Association of Poison Control Centers is reported to be approximately 100 cases per year.  This number is considered to be a gross underestimation due to underreporting of methemoglobinemia cases to poison control centers in the United States.

PATHOPHYSIOLOGY

 

Methemoglobin is an altered state of hemoglobin created in the presence of an oxidizing stress when the deoxygenated iron moiety is oxidized from the divalent state (Fe 2+) to form the trivalent form of hemoglobin (Fe 3+).  This abnormal state of hemoglobin alters its ability to bind and release oxygen.  These effects lead to tissue hypoxia and functional anemia.  Untreated, severe methemoglobinemia can lead to death. 

Due to the loading and unloading of oxygen from hemoglobin and interactions of oxidizing agents, the body chronically has a low level of methemoglobin that it spontaneously reduces to ferrous hemoglobin (Fe 2+) through predominantly the action of NADH methemoglobin reductase and the electron donor NADH.   A secondary system utilizing the enzyme NADPH methemoglobin reductace is reliant on the enzyme glucose-6-phosphate dehydrogenase (G6PD) to be active and is responsible for reducing a small percentage of the body’s methemoglobin.  When exposed to a large amount of an oxidizing agent, these endogenous systems are overwhelmed and an elevated methemoglobin concentration is the result (acquired methemoglobinemia).

Multiple precipitants of acquired methemoglobinemia exist in the form of medications or other xenobiotics.  Some of the most common medications known to induce methemoglobinemia are topical anesthetics, including benzocaine, dapsone, and phenazopyridine, a bladder anesthetic.  Among the xenobiotics, nitrates and nitrites are powerful oxidizing agents.  These molecules are found in food (hot dogs and sausage), well water, vegetables, pharmaceuticals, and industrial compounds.  Infants are particularly prone to methemoglobin through gastrointestinal bacterial action converting less toxic nitrate preservatives to more oxidative nitrites.  Meanwhile, nitrites are often abused for their ability to enhance perceived euphoria through vasodilation.

CLINICAL PRESENTATION

 

One of the earliest signs of methemoglobinemia is central and peripheral cyanosis which develops as the methemoglobin concentrations exceed 1.5g/dL [(percentage methemoglobinemia) x (hemoglobin value)].  Thus, the presence of cyanosis is a function of the body’s total hemoglobin concentration.  In healthy individuals, cyanosis occurs with methemoglobin levels greater than 8-12%, although these lower levels are usually asymptomatic in most people.  Increasing levels may lead to headache, dizziness, dyspnea, and tachypnea.  Also with increasing levels, arterial blood drawn may appear chocolate brown in color, failing to brighten up to a clear red color in air.  With higher levels above 40%, CNS depression or seizures may result. Severe hypoxic symptoms and death can occur with levels greater than 70%.  Importantly, susceptibility to an oxidant’s effects and its metabolites may be idiosyncratic, explaining why some individuals develop methemoglobinemia and others do not after exposure to the same oxidizing stressors.

Suggested risk factors for the development of methemoglobinemia include:  patients with hereditary deficiencies of methemoglobin reductase; concomitant use of oxidizing agents; excessive dosing of the offending oxidative agent; compromised or abraded skin; and neonates less than six months of age (due to underactive NADH methemoglobin reductase). 

DIAGNOSIS

While clinical symptoms are critical to making the diagnosis, the use of a pulse oximeter is not reliable for diagnosing methemoglobinemia.  Pulse oximeters are designed to estimate oxygen saturation by measuring differences in absorption of light (i.e. the wavelength) at varying oxyhemoglobin and deoxyhemoglobin concentrations.  Pulse oximeters are not calibrated to specifically detect methemoglobin and can result in false reassurance.  In the setting of methemoglobinemia, pulse oximeter readings are typically mildly abnormal and do not correct with supplemental oxygen.   While the pulse oximeter reading may be slightly abnormal, the PaO2 measured on arterial blood gas is normal in methemoglobinemia.  PaO2 measurement reflects the amount of dissolved oxygen, not hemoglobin-bound oxygen. 

In order to establish a definitive diagnosis of methemoglobinemia, either venous or arterial blood co-oximetry analysis is necessary.  Most modern blood co-oximeters can spectrophotometrically identify four subspecies of hemoglobin (oxyhemoglobin, deoxyhemoglobin, carboxyhemoglobin, and methemoglobin) based on the unique light absorption spectrum of each.   The blood co-oximetry results will reveal the percentage of the blood that is comprised of methemoglobin.  Some newer commercial bedside pulse oximeters have the capability to measure methemoglobinemia as well.

TREATMENT

The majority of patients with methemoglobinemia will not need treatment beyond discontinuing the precipitating agent.  In these patients, the body’s endogenous mechanisms for reducing methemoglobin will occur.

Treatment with methylene blue is recommended for symptomatic patients with methemoglobin blood levels greater than 20% or asymptomatic patients with levels of 25-30%.  Patients with anemia or cardiovascular disease may require treatment at lower percentages due to their greater risk of clinically significant hypoxia.  Methylene blue facilitates the reduction of the ferric state of hemoglobin back to the ferrous state through the contribution of NADPH from the hexose monophosphate shunt, an enzyme system present in the red cell.  NADPH from the hexose monophosphate shunt is one of the body’s endogenous mechanisms to reduce methemoglobin.  Methylene blue serves as an exogenous electron carrier for the electrons donated from NADPH and forms leukomethylene blue.  The latter directly reduces the ferric state of hemoglobin back to the ferrous state.  

Methylene blue may be ineffective for patients with limited reducing capabilities such as patients with G6PD deficiencies, patients who are depleted of NADPH (chronically ill) and infants less than four months old with immature NADH methemoglobin reductase.  In these patients, administration of methylene blue can result in hemolysis.  The typical starting dose of methylene blue is 1-2 mg/kg (0.1-0.2 mL/kg of 1% solution) intravenously slowly over 5 minutes.  This dose may be repeated in 30-60 minutes.  Body fluids such as tears, saliva and urine may turn greenish blue following methylene blue administration.

Discussion of case questions

 

1.         What are common causes of methemoglobinemia?

Medications such as topical anesthetics, dapsone, and phenazopyridine are the most commonly implicated drugs in causing methemoglobinemia.  Other xenobiotics that are frequently implicated include nitrites and nitrates.  Multiple precipitants of methemoglobinemia exist.  Less common are hereditary causes of methemoglobinemia.

2.          How is methemoglobinemia diagnosed?

A venous or arterial blood co-oximeter analysis will give a percentage of the methemoglobin in the blood.  This is the way to definitively diagnose methemoglobinemia.  The arterial blood may have a chocolate brown appearance.  The pulse oximeter reading will typically be mildly abnormal and the PaO2 will be normal.

3.         Is the severity of this child’s methemoglobinemia related to the dose of benzocaine that he ingested?

One of the suggested risk factors for the development of methemoglobinemia is excessive dosing of the precipitating agent.  In this case, development of methemoglobinemia after administration of benzocaine appears to be dose-dependent since the dosing was in excess of that indicated and the child swallowed the solution instead of expectorating it.

CONSULTATION ASSISTANCE

 

Consultation with a specialist in poison information or with a medical toxicologist can be obtained free of charge by calling the California Poison Control System at 1-800-222-1222.

This issue of CALL US... was written by Allyson Kreshak, MD


CALL US... is published by the California Poison Control System. Editorial Board: Executive Director, Stuart E. Heard, PharmD; CPCS Medical Directors: Timothy E. Albertson, MD, Richard F. Clark, MD, Richard Geller, MD, Kent R. Olson, MD; CPCS Managing Directors: Judith Alsop, PharmD, Thomas E. Kearney, PharmD, Lee Cantrell, PharmD.  Assistant Editors: Binh Ly, MD, Cyrus Rangan, MD, and Aaron Schneir, MD. Editor: Richard F. Clark, MD.

The California Poison Control System is operated by the School of Pharmacy, University of California, San Francisco.  (callus@calpoison.org)