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CALL US...TM
The Official Newsletter of the
California
Volume 7, Number 3
Summer 2009
Methoglobin
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
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.
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.
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