Benzocaine-induced methemoglobinemia during transesophageal echocardiography

              Birchem • Case Report JAOA • Vol 105 • No 8 • August 2005 • 381
Acquired or toxic methemoglobinemia is an uncommon
complication of topically administered anesthetic agents
in patients of all ages—but particularly in pediatric and
elderly patients. This report describes a case of acquired
methemoglobinemia that occurred after benzocaine spray
was applied orally to a 69-year-old white woman weighing
175 lb who was undergoing transesophageal echocardio-graphy.
Patient care was successfully managed. Funda-mental
concepts regarding methemoglobinemia are also
reviewed to heighten physician awareness of this poten-tially
life-threatening complication associated with the
application of common topical anesthetic agents.
Benzocaine spray is commonly used for local, topical anes-thesia
of mucous membranes before a variety of proce-dures
performed at physicians’ and dentists’ offices or in
hospitals on an outpatient basis. This medication is also
widely available to the public in several over-the-counter
formulations.
This article describes a case in which benzocaine was
applied to a patient’s throat using Hurricaine topical anes-thetic
aerosol spray (20% benzocaine) (Beutlich LP Pharma-ceuticals,
Waukegan, Ill) in preparation for transesophageal
echocardiography.
Benzocaine-induced methemoglobinemia is an
uncommon occurrence in clinical practice, and though few
reports of benzocaine-induced methemoglobinemia are avail-able
in the English-language cardiology literature, knowledge
of this potentially life-threatening condition is essential for
clinicians performing routine procedures in which topically
administered anesthetic agents are used.
When untreated, methemoglobinemia can lead to major
cardiopulmonary compromise, neurologic sequela, and even
death. Physicians who perform procedures involving the
application of topical anesthesia must be aware of these poten-tial
adverse effects.
Report of Case
On July 1, 2003, a 69-year-old white female patient weighing
175 lb presented at Mercy Medical Center in Mason City,
Iowa, for a transesophageal echocardiogram to assist in the
evaluation of intracardiac thrombus in preparation for syn-chronized
cardioversion.
The patient had a history of ischemic heart disease, post-coronary
artery bypass surgery, hypertension, postmenopausal
hyperlipidemia, type 2 diabetes mellitus, obesity, and symp-tomatic
atrial fibrillation that was believed to be recent though
the specific time of onset was unclear. She was a nonsmoker
and reported an unconfirmed allergy to diazepam. The patient
was currently taking the following medications: amiodarone,
aspirin, enoxaparin, glyburide, levothyroxine sodium, meto-prolol
succinate, niacin as a dietary supplement, rabeprazole
sodium, simvastatin, and warfarin sodium. Her physical exam-ination
preprocedure was notable only for atrial fibrillation, and
her oxygen saturation level was 99% by room-air pulse
oximetry. Previous laboratory studies were within normal
ranges, and an electrocardiogram performed the previous day
demonstrated atrial fibrillation with a controlled heart rate
and nonspecific changes.
During transesophageal echocardiogram, the patient’s
oxygen saturation level was measured at 90% by room-air
pulse oximetry, so the oxygen level (as delivered by nasal
cannula) was adjusted to a saturation level of 92%. Results
from the procedure were within normal limits; therefore, syn-chronized
cardioversion was completed and was successful.
At 15 minutes postprocedure, however, the patient devel-oped
central cyanosis, and her oxygen saturation level sud-denly
decreased to 70%. Her lung fields were clear and she did
not exhibit chest pain or arrhythmia. Vital signs were stable.
An arterial blood sample was taken and appeared chocolate
in color (Figure 1).
Methemoglobinemia was suspected and then confirmed
by arterial blood gases that were obtained using co-oximetry.
Oxygen was administered at 100% by mask. Arterial blood
gases were taken with pH, 7.47; PCO2, 33.1; PO2, 293; oxygen sat-uration,
56.7%; and methemoglobin at 41.1% of total
hemoglobin. Methylene blue, 2 mg, was delivered intra-venously,
and, as a result, one hour later, methemoglobin
levels had decreased to 18.4% with an improvement in the
symptoms of cyanosis. Two hours later, methemoglobin levels
were at 4% of total hemoglobin.
Benzocaine-Induced Methemoglobinemia
During Transesophageal Echocardiography
Sandra Kaye Birchem, DO
From the Mercy Medical Center–North Iowa in Mason City.
Please address correspondence to Sandra Kaye Birchem, DO, 3701
Brookridge Ct, Unit 701, Des Moines, IA 50317-4956.
E-mail: sandikayeb@hotmail.com
CASE REPORT
382 • JAOA • Vol 105 • No 8 • August 2005
The patient was admitted to inpatient care and was
observed overnight. The next morning, her methemoglobin
level had decreased to 0.9%. The rest of her hospitalization
(2 days total) was uneventful, and she was discharged that
day with no further complications.
Review of Literature
Methods
A search of published literature was performed using the
National Library of Medicine’s MEDLINE database. The fol-lowing
search terms were used: methemoglobinemia, benzocaine,
oxygen delivery, and methylene blue.
Discussion
Acquired methemoglobinemia is thought to be a complication
of benzocaine, a topical anesthetic commonly used for a variety
of procedures, including dental procedures, endoscopy, and
endotracheal intubation. Since the condition was first docu-mented
in a 1950 case report by Bernstein,1 fewer than 100
cases were reported as of 1994.
In addition to benzocaine products, various other chem-icals
and medications can accelerate the formation of methe-moglobin,
such as acetanilide, aniline dyes, antimalarial agents,
flutamide, metoclopramide hydrochloride, nitrate and nitrite
compounds, nitric oxide (inhaled), phenacetin, phenazopyri-dine
hydrochloride, phenytoin, probenecid, sodium nitro-prusside,
and sulfonamides. It is thought that some of these
agents may cause methemoglobinemia indirectly, by the for-mation
of oxygen-free radicals during their breakdown, rather
than directly from the chemical or medication itself.2
None of the other medications the patient was then
taking—except the benzocaine—has been associated with
methemoglobinemia. The underlying mechanism of benzo-caine-
induced methemoglobinemia is not clear, but it appears
to involve direct oxidation of the heme iron.
  Etiologic Process and Pathophysiology
Methemoglobinemia refers to the presence of an elevated, cir-culating
fraction of methemoglobin within the erythrocytes.
Normal hemoglobin contains an iron molecule that exists in
the divalent ferrous state (Fe2+). Methemoglobin results from
the conversion of the iron ferrous ion (Fe2+) into a trivalent
ferric (Fe3+) state, making it unable to bind oxygen (ie, unable
to carry oxygen and carbon dioxide).3 Methemoglobinemia
increases the affinity of normal hemoglobin for oxygen,
thereby hindering oxygen release in the tissue. This condition
results in severe cyanosis out of proportion to the degree of
respiratory distress and a dark pigment that causes blood
to appear chocolate in color. Methemoglobin is continuously
formed in red blood cells and is reduced to deoxyhemoglobin
by nicotinamide adenine dinucleotide phosphate (NADPH)-
dependent methemoglobinemia. In a normal physiologic
state, the methemoglobin level is less than 2% of normal
hemoglobin.4
Methemoglobinemia can be either hereditary or acquired
(toxic). Hereditary methemoglobinemia is caused by a defi-ciency
of NADPH methemoglobin reductase, an erythrocyte
enzyme that usually maintains methemoglobin levels within
the normal range. This autosomal recessive disease is most
common in the Inuit population and in Alaskan Native Amer-icans.
Hemoglobin M is another form of congenital methe-
Birchem • Case Report
CASE REPORT
Amyl nitrite
Benzocaine
Dapsone (diaminodiphenylsulfone)
Fentanyl citrate
Lidocaine
Nitroglycerin
Phenazopyridine hydrochloride
Prilocaine hydrochloride
Procaine
Sulfamethoxazole
Sulfisoxazole (sulfafurazole)
Figure 2. Methemoglobinemic agents: A partial
list of medications associated with methe-moglobinemia.
Figure 1. An arterial blood sample was taken and appeared choco-late
in color.
JAOA • Vol 105 • No 8 • August 2005 • 383
studies that calculate oxygen saturation from the dissolved
oxygen values have been known to report normal oxygen sat-uration
even in the presence of a markedly impaired oxygen-carrying
capacity.7,8 Therefore, co-oximetry is the diagnostic test
of choice for methemoglobinemia, because this testing method
measures both the concentration of methemoglobin and oxy-hemoglobin.
  Treatment
When a patient is diagnosed with methemoglobinemia, initial
attention should be directed to improving oxygen delivery.
Treatment for symptomatic methemoglobinemia (typically
with methemoglobin levels of  30%) includes administra-tion
of methylene blue, delivered intravenously, 1 mg to 2mg
per kg of body weight, over five minutes. This treatment may
be repeated if the methemoglobinemia does not resolve within
30 minutes.
Methylene blue (methylthionine chloride) itself is an oxi-dant.
The metabolic product of methylene blue, called
leukomethylene blue, is the reducing agent and provides an
artificial electron acceptor via the NADPH-dependent
pathway.9,10
Patients with methemoglobinemia who are asymptomatic
should be admitted to inpatient care and observed to ensure
moglobinemia characterized by an abnormal hemoglobin
molecule.
Acquired methemoglobinemia results from exposure to
noxious substances that cause the rate of methemoglobin for-mation
to exceed its rate of reduction. This cause is particularly
relevant when clinicians are treating pediatric and elderly
patients.5 In clinical practice, the most common medications
associated with methemoglobinemia are linked to an alanine
ring that is found in many over-the-counter medications and
in all anesthetics (Figure 2).6
Although nearly all topical anesthetic preparations have
been associated with methemoglobinemia, benzocaine is the
most common and is the largest component of Cetacaine top-ical
anesthetic (benzocaine/butamben/tetracaine hydrochlo-ride)
(Cetylite Industries, Pennsauken, NJ) formulations.6
  Diagnosis
Methemoglobinemia should be immediately suspected in any
patient who has central cyanosis and a decrease in oxygen
saturation level that develops after the administration of ben-zocaine
for topical anesthesia.
Administration of high concentrations of oxygen via nasal
cannula in these patients typically does not correct the decrease
in oxygen saturation levels. In patients to whom topical ben-zocaine
has been administered, if a decrease in oxygen satu-ration
cannot be attributed to cardiac or pulmonary prob-lems—
as determined by physical examination—arterial blood
gases should be checked, including the methemoglobin level.
A blood sample taken from a patient with methemoglobinemia
has a distinct chocolate color (Figure 3).
Other signs and symptoms associated with methe-moglobinemia
are described in Table. Even in severe cases of
methemoglobinemia, the directly measured PO2 level is usu-ally
normal, because it is the arterial PO2 measures that will
show dissolved oxygen in the blood. As a result, laboratory
Birchem • Case Report
CASE REPORT
Table
Methemoglobinemia
Common Signs and Symptoms by Methemoglobin Level*
Signs and Symptoms† Methemoglobin Level (%)‡
Coma  55
Cyanosis, acquired methemoglobinemic 10 to 20
Death  70
Dizziness  55
Heart failure  55
Lethargy  55
Muscle weakness  30
Nausea  30
None  10
Respiratory arrest  55
Seizure  55
Stupor  55
Tachycardia  30
Vomiting  55
* Source: Pasternack AS. A puzzling case of methemoglobinemia in the
intensive care unit. Hosp Physician. 2004:30–32,38.
† Other signs and symptoms include: ataxia, drowsiness, dyspnea, fatigue,
and headache. Patients with methemoglobinemia may have signs and
symptoms that appear sooner or grow more intense with lower
methemoglobin levels if the condition is concomitant with anemia or if
myocardial damage or abnormal hemoglobins are present.
‡ Proportion of methemoglobin to total hemoglobin.
Figure 3. A blood sample taken from a patient with methemo-globinemia
has a distinct chocolate color.
384 • JAOA • Vol 105 • No 8 • August 2005
that levels of methemoglobin have decreased. Most cases of
methemoglobinemia resolve within 24 to 72 hours. If levels of
methemoglobin persistently increase—as may be the case if
continued absorption of the responsible agent occurs—repeated
dosing of methylene blue may be necessary. Dosing should not
exceed 7 mg per kg, however, because higher doses of methy-lene
blue may result in dyspnea, tremors, or hemolytic anemia.
If patients respond poorly to methylene blue, as seen in
patients with glucose-6-phosphate dehydrogenase [G6PD]
deficiency, or in severe cases of methemoglobinemia (methe-moglobin
levels of  70%), exchange transfusions or hemodial-ysis
may be necessary.3 Patients with a G6PD deficiency who
show a decreased production of NADPH will not respond to
treatment with methylene blue.3,7 In these cases, exchange
transfusions or hemodialysis should be begun immediately.
Comment
This report of case and literature review highlight the poten-tially
life-threatening adverse effects of commonly used top-ical
anesthetics, which may result in benzocaine-induced
methemoglobinemia in some patients. Cyanosis in the absence
of cardiopulmonary symptoms should alert the physician to
the possibility of an intraerythrocytic hemoglobin abnormality,
in particular methemoglobinemia.
The diagnosis is mainly clinical—based the presence of
chocolate-colored blood and cyanosis that remains unre-sponsive
to oxygen therapy—with high index of suspicion.
Diagnosis should be confirmed by co-oximetry. The treat-ment
of choice is low-dose, intravenous methylene blue, which
should be made readily available at medical and dental facil-ities
where topical anesthetics are frequently used.
References
1. Bernstein BM. Cyanosis following use of anesthesin; case report. Rev Gas-troenterol.
1950;17:123.
2. Ferraro-Borgida MJ, Mulhern SA, DeMeo MO, Bayer MJ. Methe-moglobinemia
from perineal application of an anesthetic cream. Ann Emerg
Med. 1996;27:785–788.
3. Novaro GM, Aronow HD, Militello MA, Garcia MJ, Sabik EM. Benzocaine-induced
methemoglobinemia: experience from a high-volume transesophageal
echocardiography laboratory. J Am Soc Echocardiogr. 2003;16:170–175.
4. Ellenhorn MJ. Respiratory toxicology. Ellenhorn’s Medical Toxicology:
Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, Md: Lip-pincott
Williams & Wilkins; 1996:1496–1499.
5. Bunn HF. Disorders of hemoglobin. In: Wilson JD, Braunwald E, Issel-bacher
KJ, Petersdorf RG, Martin JB, Fauci AS, et al, eds. Harrison’s Principles
of Internal Medicine. 12th ed. New York, NY: McGraw-Hill Health Profes-sion
Division; 1991:1543–1552.
6. Khan NA, Kruse JA. Methemoglobinemia induced by topical anesthesia:
a case report and review. Am J Med Sci. 1999;318:415–418.
7. Rodriguez LF, Smolik LM, Zbehlik AJ. Benzocaine-induced methe-moglobinemia:
report of a severe reaction and review of the literature. Ann
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8. Barker SJ, Tremper KK, Hyatt J. Effects of methemoglobinemia on pulse
oximetry and mixed venous oximetry. Anesthesiology. 1989;70:112–117.
9. Sass MD, Caruso CJ, Axelrod DR. Mechanism of the TPNH-linked reduction
of methemoglobin by methylene blue. Clin Chim Acta. 1969;24:77–85.
10. DiSanto AR, Wagner JG. Pharmacokinetics of highly ionized drugs. II.
Methylene blue—absorption, metabolism, and excretion in man and dog
after oral administration. J Pharm Sci. 1972;61:1086–1090.
Birchem • Case Report
CASE REPORT