Acquired Methemoglobinemia A Retrospective Series.1

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Acquired Methemoglobinemia
A Retrospective Series of 138 Cases at 2 Teaching Hospitals
Rachel Ash-Bernal, MD, Robert Wise, MD, and Scott M. Wright, MD
Abstract: Methemoglobin is a form of hemoglobin that does not
bind oxygen. When its concentration is elevated in red blood cells,
functional anemia and tissue hypoxia may occur. We performed a
retrospective case series to describe the cases of acquired met-
hemoglobinemia (methemoglobin level >2%) detected and the
clinical circumstances under which they occurred at 2 tertiary care
hospitals and affiliated outpatient clinics over 28 months. We sur-
veyed co-oximetry laboratory data to identify patients with met-
hemoglobinemia. We reviewed these patients’ medical records to
extract the clinical information and context.
One hundred thirty-eight cases of acquired methemoglobinemia
were detected over the 28 months. There was no gender pre-
disposition, and the condition occurred over a wide range of ages
(patients aged 4 days to 86 years). Cases occurred in many areas of
the hospital, including outpatient clinics. One fatality and 3 near-
fatalities were directly attributable to methemoglobinemia. Dapsone
was the most common etiology of acquired methemoglobinemia,
accounting for 42% of all cases. The mean peak methemoglobin
level among these individuals was 7.6%. In 5 of the patients with
the most severely elevated levels, 20% benzocaine spray (Hurri-
caine Topical Anesthetic spray, Beutlich Pharmaceuticals, Wauke-
gan, IL) was the etiology, associated with a mean peak
methemoglobin level of 43.8%. Eleven pediatric patients developed
methemoglobinemia either from exogenous exposure, such as
drugs, or due to serious illness, such as gastrointestinal infections
with dehydration. Almost all (94%) patients with methemoglobin-
emia were anemic.
Drugs that cause acquired methemoglobinemia are ubiquitous in
both the hospital and the outpatient setting. Acquired methemoglo-
binemia is a treatable condition that causes significant morbidity
and even mortality. We hope that a heightened awareness of met-
hemoglobinemia will result in improved recognition and treatment.
Primary prevention efforts have the potential to reduce the mor-
bidity and mortality associated with this condition.
(Medicine 2004;83:265–273)
INTRODUCTION
E rythrocytes are constantly exposed to oxidative stressfrom normal metabolism. If the mechanisms that defend
against oxidative stress are overwhelmed, the oxygen-
carrying ferrous ion (Fe2+) of the heme group is oxidized
to the ferric state (Fe3+). This converts hemoglobin to met-
hemoglobin, a non-oxygen-binding form of hemoglobin that
binds a water molecule instead of oxygen. Spontaneous
formation of methemoglobin is counteracted by the pro-
tective enzyme systems cytochrome-b5 reductase (major
pathway) and NADPH methemoglobin reductase (minor
pathway). These pathways normally maintain methemoglo-
bin levels at <1% of the total hemoglobin in healthy
people18,47,48,71. Exposure to exogenous oxidizing drugs and
their metabolites (such as benzocaine and dapsone) may
accelerate the rate of formation of methemoglobin up to
1000-fold47, overwhelming the protective enzyme systems
and acutely increasing methemoglobin levels36,65.
The presence of a ferric ion or ions on 1 or more heme
groups causes the entire hemoglobin molecule to change
conformation, shifting the oxygen-dissociation curve to the
left36,71. The combined effect of less oxygen being carried
and released at the tissues may cause acute severe func-
tional anemia. Therefore, a patient with a hemoglobin level
of 10 g/dL who has 50% in the methemoglobin form
has only 5 g/dL of functional hemoglobin32,121. Cyanosis
is observed in patients with methemoglobin concentrations
�1.5 g/dL27,32,71. The characteristic chocolate-brown blood is
diagnostic at the bedside (Figure 1)41,44. Increasing levels of
methemoglobin interfere with pulse oximetry readings, re-
porting lower measured oxygen saturation than the calculated
oxygen saturation yielded from the arterial blood gas5,112.
This oxygen ‘‘saturation gap’’ may also be a diagnostic
clue5,32. Methylene blue, the treatment for methemoglobine-
mia, acts as a cofactor to NADPH methemoglobin reductase,
Medicine � Volume 83, Number 5, September 2004 265
From Divisions of General Internal Medicine (RAB, SMW) and Pulmonary
Medicine (RW), Johns Hopkins Bayview Medical Center, Johns Hopkins
University School of Medicine, Baltimore, Maryland.
Dr. Wright is an Arnold P. Gold Foundation Associate Professor of
Medicine.
Address reprint requests to: Scott M. Wright, MD, Division of General In-
ternal Medicine, Johns Hopkins Bayview Medical Center, 4940 Eastern
Avenue, Baltimore, MD 21224. Fax: 410-550-2715; e-mail: smwright@
jhmi.edu.
Copyright n 2004 by Lippincott Williams & Wilkins
ISSN: 0025-7974/04/8305-0265
DOI: 10.1097/01.md.0000141096.00377.3f
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accelerating its activity and increasing the rate of conversion
of methemoglobin to hemoglobin18.
Drugs that are ubiquitous in the hospital and outpatient
setting may cause acquired methemoglobinemia (Table 1).
Severe cases may lead to morbidity and mortality because
of attendant tissue hypoxia. Delayed diagnosis of methemo-
globinemia may lead to continued exposure of patients to
the etiologic agent. Only the co-oximetry test can accurately
detect the presence of abnormal and normal forms of he-
moglobin by measuring the methemoglobin, carboxyhe-
moglobin, and oxyhemoglobin and reporting them as a
percentage of the total hemoglobin concentration73. Healthy
patients who are not anemic usually have few symptoms
with methemoglobin levels <15%32,47. Levels of 20%–30%
may cause mental status changes, headache, fatigue, exer-
cise intolerance, dizziness, and syncope32,47. Levels greater
than 50% may result in dysrhythmias, seizures, coma, and
death32,47. Patients with comorbidities such as anemia,
cardiovascular disease, lung disease, sepsis, or the presence
of other abnormal hemoglobin species (eg, carboxyhemo-
globin, sulfehemoglobin, or sickle hemoglobin) may expe-
rience moderate to severe symptoms at much lower levels32.
Pediatric patients under 6 months old are at increased risk
of developing methemoglobinemia in the setting of gastro-
enteritis, dehydration, and sepsis32.
In this paper, we explore the extent of diagnosed met-
hemoglobinemia at 2 large teaching hospitals, attempt to
identify the etiologies, and describe the patient character-
istics of the affected individuals.
FIGURE 1. Normal arterial blood versus methemoglobin-
emia. Arterial whole blood with 1% methemoglobin (left)
versus arterial whole blood with 72% methemoglobin (right)
(methods described below). Note the characteristic chocolate-
brown color of the sample with an elevated methemoglobin
level. Both samples were briefly exposed to 100% oxygen and
shaken. This quick analysis is a good bedside test for
methemoglobinemia. The sample on the left turned bright
red, while the sample on the right remained chocolate-brown.
Methods: The whole blood samples were drawn at the same
time from the same person. Measured hemoglobin concen-
tration 11.7 g/dL. Calculated concentration of methemoglo-
bin: 11.7 g/dL � 0.01 = 0.117 g/dL (left) and 11.7 g/dL �
0.72 = 8.42 g/dL (right). Elevated methemoglobin level was
made in vitro by adding 0.1 mL of a 0.144 molar solution of
sodium nitrite (right), while 0.1 mL of normal saline was
added as a control (left). Co-oximetry measurements were
taken on both samples shortly after the blood was drawn and
20 minutes after the addition of sodiumnitrite solution. Both
blood samples were exposed to 100% oxygen before the
second measurement. (Protocol based on personal commu-
nication with Dr. Ali Mansouri, December 2002.)
TABLE 1. Known Etiologies of Acquired Methemoglobinemia
Medications
Benzocaine100,104 used as a spray: endotracheal
intubation39,72,82,114, transesophageal echocardiography
(TEE)76,109, esophagogastroduodenoscopy (EGD)1,17,34,35,
bronchoscopy57,62; used as a topical cream for hemorrhoids
or teething preparation25,30,113
Cetacaine19,24,97,99,116
Chloroquine13,102
Dapsone70,77,87,95,118,119
EMLA (Eutectic Mixture of Local Anesthetics) topical
anesthetic (lidocaine 2.5% and prilocaine 2.5%)21,29,110,111
Flutamide46,56,58,98
Lidocaine111
Metoclopramide55,74
Nitrates15,51,68,86
Nitric oxide43
Nitroglycerin8,92
Nitroprusside6,9,106
Nitrous oxide66,69
Phenazopyridine (Pyridium)12,31,81
Prilocaine4,20–22,29,110,111,120
Primaquine13,51,53,90,96,102,103
Riluzole117
Silver nitrate45
Sodium nitrate26,33
Sulfonamides (sulfasalazine, sulfanilamide, sulfathiazide,
sulfapyridine, sulfamethoxazole)64,77,89,115
Medical conditions
Pediatric gastrointestinal infection, sepsis52,67,88,105
Sepsis59,75,84,104,114
Recreational drug overdose with amyl nitrate (a.k.a.
‘‘poppers’’)79,86
Sickle cell crisis40
Miscellaneous
Aniline dyes23,38
Fume inhalation (automobile exhaust, burning of wood
and plastics)54,60,63
Herbicides10,83,108
Industrial chemicals: nitrobenzene37,61, nitroethane
(found in nail polish, resins, rubber adhesives)42,85,101
Pesticides80
Petrol octane booster16
266 n 2004 Lippincott Williams & Wilkins
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METHODS
The Johns Hopkins Bayview Medical Center (JHBMC)
and the Johns Hopkins Hospital (JHH) have a total of 1300
inpatient beds. All co-oximetry data from July 1, 1999, to
October 25, 2002, were screened for methemoglobin levels
>1.5%. Methemoglobinemia is defined as a methemoglobin
level >1.5% in hospitalized patients2,3,78,107. In healthy
subjects, methemoglobin levels do not exceed 1%. Methe-
moglobin levels between 1% and 2% were considered
clinically insignificant and therefore were not investigated
extensively. Some patients had serial co-oximetry tests per-
formed over the course of hours or days. Only the peak
methemoglobin percentage for each patient is described
since the peak level was considered the most clinically
relevant. We reviewed electronic medical records and paper
charts for 138 cases of methemoglobinemia >2% and ex-
tracted all relevant clinical information (Table 2). Suspect
medications (see Table 1) and the dates and times of ad-
ministration were noted from the nursing and pharmacy
records. Correct identification of the inciting drug was
surmised from decreased serial methemoglobin levels,
clinical improvement after withdrawal of the drug, and/or
treatment with methylene blue. In 5 severe cases where
documentation of events was inadequate, we communicated
personally with the treating medical team. In some cases
we could not determine the etiology of methemoglobinemia
because the condition was unrecognized and therefore
untreated. In these cases, the etiology was classified as
‘‘unknown’’ (Table 3).
Chiron Ciba-Corning Model 855 and Instrumentation
Laboratories Model 682 blood gas analyzers measured met-
hemoglobin percentage. To ensure accuracy of measure-
ments, blood gas analyzers are calibrated weekly using a
low- and high-level hemoglobin dye mix. One patient spec-
imen is analyzed across each of 4 blood gas analyzers in
each hospital to verify concordance on a weekly basis. In
addition, 3 levels of control material are assayed every
8 hours. Every 4 months the American College of Pa-
thologists surveys the blood gas analyzers with 5 challenge
specimens.
The institutional review board approved this study.
CASE REPORTS
Two clinical cases are described below to illustrate the range
of presentations and diagnostic challenges of acquired methemo-
globinemia when concomitant cardiopulmonary conditions are
present or suspected.
Case 1
A 52-year-old man was admitted to the hospital because of
increasing dyspnea on exertion. As part of the evaluation, a
transesophageal echocardiogram was performed to rule out a patent
foramen ovale or other intracardiac shunt. Before the test, 20%
benzocaine spray (Hurricaine Topical Anesthetic spray, Beutlich
Pharmaceuticals, Waukegan, IL) was administered to anesthetize
the posterior pharynx. Shortly after the procedure the patient
became even more dyspneic, was intubated, and remained cyanotic
despite pH of 7.37, PaO2 of 248 mm Hg, PaCO2 of 60 mm Hg, and
calculated oxygen saturation (SaO2) of 99% on 100% oxygen. The
oxygen saturation measured by pulse oximetry (SpO2) was 75%.
The calculated oxygen saturation gap (arterial blood gas-calculated
SaO2 � pulse oximetry-measured SpO2) was 24%. Co-oximetry
showed a methemoglobin level of 51% and hemoglobin of
11.6 g/dL. Only 49% (5.7 g/dL) was functioning to carry and un-
load oxygen because 51% of hemoglobin (5.9 g/dL) was in the
methemoglobin form. This acute drop in the patient’s functional
hemoglobin from 11.7 g/dL to 5.7 g/dL coupled with his known
lung disease severely compromised his ability to oxygenate tissues.
Methylene blue was administered intravenously and quickly re-
versed the methemoglobinemia. Despite therapy, respiratory fail-
ure, renal failure, liver dysfunction, and deteriorating mental status
ensued, and the patient died after a cardiac arrest.
Case 2
A 34-year-old man with acquired immunodeficiency syn-
drome (AIDS) and a CD4 count of 178/mm3 presented to his
physician with several weeks of progressively worsening dyspnea
on exertion such that climbing a flight of stairs had become
difficult. He reported no cough, fever, or chills. One of his med-
ications was dapsone (100 mg by mouth daily) for Pneumocystis
carinii pneumonia prophylaxis that had been initiated 3 months
earlier. Physical exam was notable only for cyanotic extremities.
His resting pulse oximetry (SpO2) was 89%, arterial blood gas
PaO2 was 59 mm Hg, PaCO2 was 37 mm Hg, and arterial blood gas-
calculated SaO2 was 91% on room air. The calculated oxygen
saturation gap was 2%. He was admitted to the hospital for
evaluation of hypoxemia and for treatment of presumed Pneumo-
cystis carinii pneumonia. The work-up, including chest X-ray, chest
computed tomography (CT) scan, ventilation-perfusion scan, trans-
thoracic echocardiogram, bronchoalveolar lavage, and culture, was
negative for pathology. On the second hospital day, a co-oximetry
test was performed and revealed a methemoglobin level of 12.1%,
and the patient was diagnosed with acquired methemoglobinemia.
He had a modest decrease in his functional hemoglobin from
13 g/dL to 11.4 g/dL since 12.1% was methemoglobin (1.6 g/dL).
Dapsone was discontinued and pentamidine was started for Pneu-
mocystis carinii pneumonia prophylaxis. Within 24 hours his oxy-
gen saturation returned to normal, and dyspnea and cyanosis
resolved. He had no recurrence of cyanosis or dyspnea on follow-
up exams.
RESULTS
A total of 5248 co-oximetry tests were performed on
2167 patients during the 28 months reviewed. Of these, 3221
co-oximetry tests were performed on 1496 patients at
JHBMC and 2027 co-oximetry tests on 671 patients at
JHH. There were 660 co-oximetry test results with met-
hemoglobin levels >1.5% in 414 patients. Thus, 12.5% of
all co-oximetry tests and 19.1% of all patients who had a co-oximetry test showed elevated methemoglobin levels. Of
n 2004 Lippincott Williams & Wilkins 267
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these, 149 co-oximetry tests in 87 patients were from
JHBMC and 511 co-oximetry tests in 327 patients were from
JHH. Therefore, at JHBMC 4.6% of co-oximetry tests and
5.8% of patients tested showed elevated methemoglobin
levels. At JHH, 25.2% of co-oximetry tests and 48.7% of
patients tested showed elevated methemoglobin levels. The
different distribution of positive tests between the 2 hospitals
may be a reflection of the greater number of negative co-
oximetry tests performed at the JHBMC in the cardiac
catheterization lab, and the greater number of positive tests
secondary to dapsone in the JHH patient population. For
comparison, 358,805 arterial blood gas tests were performed
TABLE 2. Characteristics of 138 Patients With Methemoglobinemia
No. of Patients (%)
Total patients 138
Gender (female/male) 62/76 (45/55)
Mean age ± SD (yr) 43.4 ± 20.7
Peak methemoglobin
Mean % ± standard deviation (range) 8.4% ± 10.9% (2.1%–60.1%)
Mild methemoglobinemia (methemoglobin <8%) 103 (75)
Moderate methemoglobinemia (8%–20%) 24 (17)
Severe methemoglobinemia (>20%) 11 (8)
Hemoglobin (g/dL) female mean ± standard deviation (range) 9.7 ± 1.8 (4.0–12.8)
Hemoglobin (g/dL) male mean ± standard deviation (range) 10.5 ± 2.0 (6.1–15.1)
Location in hospital system
Medicine 50 (36)
Operating room 21 (15)
Surgery 20 (14)
Outpatient clinic (rheumatology, HIV, dermatology, oncology) 17 (12)
Intensive care unit 13 (9)
Pediatrics 11 (8)
Emergency department 4 (3)
Cardiac catheterization lab 2 (1)
Underlying illness/condition
During or within 24 hours of surgery including: heart, renal, lung, pancreas transplant,
open heart surgery for valvuloplasty, CABG, orthopedic, plastic, vascular surgery
32 (23)
AIDS 32 (23)
Lymphoma and leukemia 8 (6)
Dermatologic condition (folliculitis, dermatitis, Sweet syndrome, pyoderma gangrenosum) 8 (6)
Dehydration, gastroenteritis (pediatric) 6 (4)
Systemic lupus erythematosis, scleroderma, linear IgA 5 (4)
Cardiac pathology (cardiomyopathy, coronary artery disease) 5 (4)
Sepsis 3 (2)
Cystic fibrosis and chronic obstructive pulmonary disease 2 (1)
Miscellaneous (gangrene, sickle cell crisis, burn, fume inhalation, GI pathology,
late postsurgical complication)
37 (25)
Documented signs and symptoms of patients with methemoglobin > 8% (n = 35)
Hypoxia measured by pulse oximetry 20 (57)
Dyspnea 16 (46)
Tachypnea 11 (31)
Cyanosis 10 (28)
Fatigue 6 (17)
Change in mental status 6 (17)
Headache 5 (14)
Chest pressure 2 (6)
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in this academic teaching hospital system during the same
time period.
One hundred thirty-eight patients with peak methemo-
globin levels >2% were identified. The mean peak met-
hemoglobin level was 8.4% (range, 2.1%–60.1%). The
average age of patients with methemoglobinemia was 43.4
years (see Table 2). The youngest affected patient was aged
4 days and the oldest, 86 years. Forty-five percent of patients
were female. Ninety-five percent of the women and 94%
of the men were anemic at the time of the elevated met-
hemoglobin, defined as hemoglobin <12 g/dL for women
and <14 g/dL for men.
Methemoglobinemia occurred in virtually all locations
of the hospital (see Table 2). The reasons for ordering co-
oximetry tests varied based on the area of the hospital and
the clinical context. In the intensive care units and the in-
patient surgery, medicine, and pediatrics floors, co-oximetry
tests were ordered to evaluate cyanosis and dyspnea. Co-
oximetry tests were ordered in outpatient dermatology,
rheumatology, and human immunodeficiency virus (HIV)
clinics to detect methemoglobinemia in dyspneic patients
on long-term dapsone treatment. Methemoglobinemia was
sometimes found incidentally. For example, 32 cases were
identified intra- or post-operatively, where co-oximetry tests
were commonly ordered by anesthesiologists to obtain an
immediate hemoglobin level to monitor blood loss or to
evaluate cyanosis. Two patients with methemoglobinemia
were identified during cardiac catheterizations. The hemo-
globin concentration obtained from serial co-oximetry tests
during cardiac catheterization is used in the Fick equation to
calculate cardiac output. There were many cases in which
the rationale for ordering co-oximetry testing could not be
determined based on chart review.
Five of the most severe adult cases of acquired met-
hemoglobinemia were caused by topical 20% benzocaine
spray, with a mean peak methemoglobin level of 43.8%
(range, 19.1%–60.1%) (see Table 3). In this group there was
1 fatality (Case 1), and 3 near-fatalities. The most common
etiology of acquired methemoglobinemia was dapsone, with
a mean peak methemoglobin level of 7.6%, accounting
for 42% of all cases. Dapsone was primarily being used
for Pneumocystis carinii prophylaxis in patients who were
immunocompromised from AIDS, chemotherapy, or immu-
nosuppressive drugs. However, 8 patients were taking dap-
sone for treatment of dermatologic disorders. In 56 cases of
mild methemoglobinemia (mean peak, 3.6%), the etiology
could not be determined based on chart review; 22 of these
were detected incidentally in the operating room during long
surgical procedures, and 10 were observed during the post-
operative recovery period.
There were 11 pediatric patients (<12 yr) affected, with
a mean peak methemoglobin of 22% (median, 15.5%; range,
2.8%–59.5%). Six of these patients, infants with a mean age
of 30 days, were dehydrated. Dehydration occurred in the
setting of gastroenteritis, sepsis, or caretaker neglect. Three
pediatric patients with leukemia developed methemoglobin-
emia related to dapsone use for Pneumocystis carinii pro-
phylaxis. Two pediatric cases of methemoglobinemia were
detected during surgery. The 3 most severe cases were
treated with methylene blue and hydration. The remaining
8 patients were treated with intravenous hydration, or dis-
continuation of dapsone, or were untreated.
Glucose-6-phosphate dehydrogenase (G6PD) defi-
ciency is a known, albeit rare, risk factor for acquired
methemoglobinemia7,49,50. Of the 138 cases of methemo-
globinemia, only 5 patients were tested for G6PD deficien-
cy, 1 of the whom was found to be G6PD deficient.
Thirty-three (94%) of 35 patients with methemoglobin-
emia >8% had documented clinically significant signs and
symptoms that were thought to be related to acquired met-
hemoglobinemia. These symptoms included hypoxia, dys-
pnea, tachypnea, cyanosis, fatigue, change in mental status,
headache, and chest pressure. Twelve of these 35 cases were
treated with methylene blue and withdrawal of the offend-
ing drug, 9 cases were treated by withdrawal of the offending
drug alone, 8 patients received no treatment, and 6 pediatric
patients were treated with hydration.
Discontinuation of dapsone occurred in 18 (17.5%) of
the 42 mild cases of dapsone-associated methemoglobin-
emia, and 2 of these were treated with methylene blue. In the
mildest case of symptomatic methemoglobinemia treated
with methylene blue, the patient had a peak level of 4.7%.
This patient, with chronic lymphocytic leukemia and auto-
immune hemolytic anemia, was taking dapsone for Pneumo-
cystis carinii pneumonia prophylaxis.Two dermatologic
patients with peak methemoglobin levels of 3.6% and 6.5%,
TABLE 3. Etiologies Related to Acquired Methemoglobinemia
in 138 Patients
Etiologic Agent
or Context
Total
Cases
Mean Peak
Methemoglobin %
± Standard
Deviation (Range)
Dapsone 58 7.6 ± 6.2 (2.1–34.1)
Surgery 32 3.3 ± 2.4 (2.1–16)
Unknown 24 4.1 ± 2.8 (2.1–12.0)
Dehydration
(pediatric)
6 28.0 ± 21.2 (8.3–59.5)
20% benzocaine 5 43.8 ± 15.1 (19.1–60.1)
Primaquine 5 6.2 ± 3.9 (2.3–12.6)
Dapsone and primaquine 4 16.5 ± 8.9 (4.9–24.0)
Other (sepsis, sickle
cell crisis, insecticide
and fume inhalation)
4 7.2 ± 6.3 (2.8–16.2)
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respectively, were treated with cimetidine and the dapsone
was continued at a reduced dosage.
DISCUSSION
Acquired methemoglobinemia is fairly common and
causes morbidity and mortality in both the inpatient and
outpatient settings. Drugs that may induce methemoglobin-
emia are widely used in clinical settings. Acquired met-
hemoglobinemia is often unrecognized and thus untreated.
The current study serves to identify the incidence of met-
hemoglobinemia among patients who had co-oximetry
performed over 28 months at an academic institution and
to characterize the clinically significant cases. To our knowl-
edge, this is the largest study of the problem.
In the current study, almost all patients with peak
methemoglobin of 8% or higher had documented symptoms
consistent with methemoglobinemia (see Table 2). Rapid
recognition of methemoglobinemia and treatment with meth-
ylene blue may decrease morbidity. There was often a
significant delay in the treatment of acquired methemoglo-
binemia. Arterial blood gas technicians who noticed the
chocolate-colored blood and performed a co-oximetry test
to confirm the diagnosis of methemoglobinemia detected 3
severe cases after benzocaine exposure. In other cases, ex-
tensive evaluation for other etiologies of cyanosis and
dyspnea were performed before methemoglobinemia was
considered, as in Case 2, described above.
The co-oximetry test is sensitive, inexpensive, and
relatively noninvasive. Co-oximetry testing should be ordered
for symptomatic patients with a recent history of exposure to
1 of the suspect drugs listed in Table 1. The decision-making
process of when to treat acquired methemoglobinemia is
somewhat analogous to that of transfusing an anemic patient.
The underlying etiology, severity of symptoms, comorbid-
ities, and potential for organ damage from tissue hypoxia
guide treatment more than the absolute methemoglobin level.
Previous treatment recommendations were based on healthy,
young people32. While healthy patients may not become
symptomatic until methemoglobin levels exceed 15%47,
patients with concurrent hematologic, cardiovascular, or
pulmonary disease have symptoms at much lower levels32,121.
Mild symptoms may be adequately treated with sup-
plemental oxygen to maximize the oxygen-carrying capacity
of remaining normal hemoglobin and with discontinuation
of the causative medication. Red blood cells’ cytochrome-b5
reductase pathway may reduce the methemoglobin to he-
moglobin at a rate of approximately 15% per hour in healthy
individuals, assuming no ongoing methemoglobin produc-
tion28. Chronic low-level methemoglobinemia such as that
often caused by dapsone has been reported to be partially
controlled with cimetidine, which inhibits cytochrome P-450
conversion to the oxidizing metabolite responsible for the
methemoglobinemia14. However, cimetidine works slowly,
and therefore has no place in the management of acute
symptomatic acquired methemoglobinemia32.
Moderate to severe symptoms may be further treated
with methylene blue 1% solution (10 mg/mL) 1–2 mg/kg
administered intravenously slowly over 5 minutes followed
by intravenous flush with normal saline32. The treatment
goals include resolution of symptoms and the reversion to a
normal methemoglobin level. Improvement of cyanosis is a
poor marker for adequate treatment. Serial methemoglobin
levels are more reliable to monitor adequate response to
treatment. Repeat methylene blue doses may be necessary44.
Rebound methemoglobinemia up to 12 hours post-methylene
blue treatment has been reported due to continued absorption
of the inciting drug, toxic intermediate metabolites, and
prolonged half-life in the setting of renal and/or liver
dysfunction32,91,94. If symptoms persist despite adequate
treatment, further work-up for additional etiologies of the
patient’s symptoms is indicated. Critical cases of methemo-
globinemia may require hemodialysis or exchange transfu-
sion therapy11,37,108.
Anemia may be a risk factor for acquired methemo-
globinemia. Ninety-four percent of the patients with met-
hemoglobinemia in the current study were anemic. Anemic
patients may be more sensitive to symptoms of methemo-
globinemia because of their lower functional hemoglobin
reserve. Severe methemoglobinemia itself is associated with
Heinz body hemolysis secondary to oxidative stress on the
erythrocyte32,44. Also, dapsone is known to cause hemolytic
anemia in some patients32.
Benzocaine spray was implicated in 5 cases of severe
methemoglobinemia during the study period (see Table 3).
Benzocaine spray gains rapid direct access to the blood
stream through the highly vascular pharyngeal mucosa5. The
amount of drug administered varies with the length of time
the valve of the spray can is depressed. The manufacturer
recommends 1 spray of the drug in a less-than-1-second
burst. Three 1-second sprays administer a dose of up to 600
mg93. The current spray can does not allow consistent
administration of the proper amount of the drug, which may
have been a contributing factor in the 5 severe cases of
methemoglobinemia caused by benzocaine spray. Benzo-
caine spray has been removed from the formulary of the
pharmacies at JHBMC as a result of several cases of se-
vere benzocaine-induced methemoglobinemia.
Several limitations of this study should be considered.
First, the 414 patients with methemoglobin levels >1.5%
are almost certainly an underrepresentation of the true num-
ber of cases of methemoglobinemia that occurred during
the study period. One-quarter of the methemoglobinemia
cases with methemoglobin >2% in this study were dis-
covered incidentally. This occurred primarily perioperatively
or in the cardiac catheterization lab when the co-oximetry
270 n 2004 Lippincott Williams & Wilkins
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test was used to evaluate other data provided by the test,
such as the hemoglobin and/or oxyhemoglobin concentra-
tion. With large numbers of patients with HIV taking dap-
sone for Pneumocystis carinii pneumonia prophylaxis, the
incidence may increase further. Second, the etiology of the
methemoglobinemia could not be established in a number of
patients based on chart review due to documentation that was
inadequate. Third, co-oximetry testing is only performed
with physicians’ orders. Although performing co-oximetry
testing on all patients being tested for arterial blood gases
would provide better data about the incidence of methemo-
globinemia (both acquired and congenital), the cost is pro-
hibitive. If co-oximetry tests had been performed on every
blood aliquot sent for arterialblood gas analysis during the
28-month study, the incurred cost at $25.00 per test would
have been approximately $9 million. Finally, the technical
limitation of the blood gas analyzers to measure methemo-
globin is a source of potential bias.
Primary prevention efforts have the potential to reduce
the morbidity and mortality associated with this condition.
Strategies that may be effective include the following: 1)
educating physicians about the incidence of methemoglobin-
emia, the culprit etiologies, the signs and symptoms, and
the implications of ‘‘saturation gap’’ in patients monitored
with SpO2; 2) instituting an automatic alert on co-oximetry
reports for methemoglobin levels >2%; 3) training physi-
cians and arterial blood gas technicians to look for the
characteristic chocolate-brown color of blood containing
methemoglobin and to order a co-oximetry test for such pa-
tients; and 4) discontinuing the use of 20% benzocaine spray.
ACKNOWLEDGMENTS
The authors thank blood-gas technicians Lisa Glorioso,
Gary Paxton, and Dan Sennett for their exemplary service
to the patients of JHBMC. We gratefully acknowledge the
assistance of Dr. John Boitnott with data collection for this
study and Dr. Ali Mansouri for his insights.
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