Hematologic Syndromes: Hemolysis,

Methemoglobinemia,
and Sulfhemoglobinemia

Steven C. Curry and A. Min Kang

Contents Key Points in Hematologic Syndromes

Hemolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1. Oxidant hemolysis, methemoglobinemia,
Pathophysiology and Etiology . . . . . . . . . . . . . . . . . . . . . . . . 3 and sulfhemoglobinemia share common
Clinical Presentation and Diagnosis . . . . . . . . . . . . . . . . . . 4 etiologies and frequently coexist in the
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
same patient.
Methemoglobinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2. Methemoglobinemia or sulfhemo-
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 globinemia should be suspected when a
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 cyanotic patient does not have a signifi-
Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 cantly depressed arterial PaO2 or when the
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 history suggests toxic exposure to a known
Sulfhemoglobin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 etiologic agent.
Background and Characteristics . . . . . . . . . . . . . . . . . . . . . . 12 3. Methemoglobin impairs oxygen delivery
Formation and Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 by producing a functional anemia and by
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
shifting the oxygen-hemoglobin dissocia-
Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 tion curve to the left.
4. Oxygen carrying capacity can worsen,
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
while methemoglobin fractions decrease
or cyanosis improves if accompanying
hemolysis produces significant decreases
in hemoglobin concentrations.
5. Methylene blue enhances enzymatic reduc-
tion of methemoglobin but is
contraindicated in patients with glucose-6-
phosphate dehydrogenase deficiency.
6. Dual-wavelength pulse oximetry is
unreliable in the presence of methemoglo-
binemia or sulfhemoglobinemia.
7. Co-oximeters vary widely in their ability to
detect, measure, and report sulfhemo-
S.C. Curry (*) • A.M. Kang globinemia; some report sulfhemoglobin
Department of Medical Toxicology, Banner – University
as methemoglobin.
Medical Center Phoenix, Phoenix, AZ, USA
e-mail: Steven.Curry@bannerhealth.com; aaron.
kang@bannerhealth.com (continued)

# Springer International Publishing AG 2016 1

J. Brent et al. (eds.), Critical Care Toxicology,
DOI 10.1007/978-3-319-20790-2_9-2
2 S.C. Curry and A.M. Kang
8. Sulfhemoglobin cannot transport oxygen
but shifts the oxygen-hemoglobin dissocia-
tion curve to the right; impaired oxygen
delivery usually is not a problem unless
accompanying hemolysis or methemoglo-
binemia is significant.
9. Methylene blue does not lower
sulfhemoglobin fractions. Sulfhemoglobin
persists for the life of the erythrocyte.
Common Errors in Management of Hematologic
Syndromes
Failure to realize that arterial PaO2 is usually
normal or at baseline values in patients with
methemoglobinemia
Not recognizing that percent saturations
reported by many blood gas machines are cal-
culated, rather than measured, and can be
reported as normal despite hemoglobinopa-
thies such as methemoglobinemia
Forgetting to consider the total hemoglobin
concentration when assessing impairment of
oxygen carrying capacity from
methemoglobinemia
Failure to seek evidence of hemolysis in
patients with methemoglobinemia and vice
versa
Failure to understand whether a specific
co-oximeter being used in patient management
detects or reports sulfhemoglobinemia
Not realizing that dual-wavelength pulse
oximetry does not provide reliable
Fig. 1 Consequences of
erythrocytic oxidant stress
measurements of saturation in the presence of
methemoglobinemia or sulfhemoglobinemia
Forgetting that known glucose-6-phosphate
dehydrogenase deficiency is a contraindication
to therapy with methylene blue
Failure to recognize that Heinz bodies can-
not be seen on routine Wright’s stain of blood
Three main syndromes result from erythrocytic
oxidant stress. Removal of electrons from the
protein portion of hemoglobin and other erythro-
cytic macromolecules leads to oxidant hemolytic
anemia, characterized by Heinz bodies and bite
cells. Removal of electrons from the ferrous iron
in hemoglobin produces methemoglobinemia.
Lastly, oxidation of hemoglobin’s porphyrin ring
by sulfur results in sulfhemoglobinemia. The eti-
ology, pathophysiology, occurrence, diagnosis,
and treatment of oxidant-induced hemolytic ane-
mia, methemoglobinemia, and sulfhemo-
globinemia are entangled (Fig. 1) [1–3].
Some chemical agents responsible for oxidant
hemolysis, methemoglobinemia, or sulfhemo-
globinemia frequently lack oxidizing potential
in vitro. Their ability to produce oxidant stress is
explained most commonly, however, by electro-
philes produced from metabolism by cytochrome
P-450 enzymes. For example, dapsone, benzo-
caine, and some sulfonamides are metabolized to
hydroxylamines that are responsible for produc-
ing oxidant stress.
The circulating red blood cell lacks mitochon-
dria and depends on glycolysis and the hexose
monophosphate shunt for energy production
(Fig. 2). Adenosine triphosphate produced in
Hematologic Syndromes: Hemolysis, Methemoglobinemia, and Sulfhemoglobinemia
Fig. 2 Erythrocytic energy production. ADP adenosine
diphosphate, ATP adenosine triphosphate, G6PD glu-
cose-6-phosphate dehydrogenase, GSH reduced glutathi-
one, GSSG oxidized glutathione, NAD nicotinamide
glycolysis meets energy requirements, whereas
glycolytic production of reduced nicotine adenine
dinucleotide (NADH) is essential in maintaining
methemoglobin fractions within the normal range.
The hexose monophosphate shunt produces
reduced nicotine adenine dinucleotide phosphate
(NADPH), which is used to protect against
oxidant-induced hemolysis [4].
Hemolysis
Pathophysiology and Etiology
Erythrocytes constantly encounter oxidant stress
from multiple sources, including food, infection,
oxygen, drugs, and chemicals. Oxidation of the
protein portion of hemoglobin results in denatur-
ation and attachment of damaged protein to the
internal cell membrane, which is visible as Heinz
bodies with special staining of blood smears.
Erythrocytes filled with denatured hemoglobin
are trapped in the microcirculation of the spleen,
3
adenine dinucleotide, NADH reduced nicotinamide ade-
nine dinucleotide, NADP nicotinamide adenine dinucleo-
tide phosphate, NADPH reduced nicotinamide adenine
dinucleotide phosphate
where pieces of plasma membrane are removed
(resulting in bite cells) or where entire red blood
cells undergo destruction, producing extravascular
hemolysis (nonspherocytic) [3, 5]. Oxidant stress
may produce hemolysis by several additional
mechanisms, including depletion of intracellular
glutathione stores with direct damage to the eryth-
rocytic membrane and oxidation of other proteins,
such as enzymes needed for erythrocyte integrity.
Tremendous oxidant stress (e.g., chlorates) can
produce intravascular hemolysis as well.
The erythrocyte protects itself from oxidant-
induced hemolysis by reducing oxidants before
protein denaturation occurs [4]. Reduced glutathi-
one, nonenzymatically and enzymatically with
glutathione peroxidase, is responsible for most
reducing capacity in this regard. Catalase also
reduces hydrogen peroxide; ascorbate is a mild
reducing agent (Fig. 3).
Adequate stores of reduced glutathione are
maintained within the erythrocyte through the
conversion of NADPH to NADP (see Fig. 2).
NADPH formation requires a properly
4 S.C. Curry and A.M. Kang
Fig. 3 Protection against
hemolysis by reduction of
oxidants. GPX glutathione
peroxidase, GSH reduced
glutathione, RBC red
blood cell
functioning hexose monophosphate shunt.
Patients who display congenital deficiency of glu-
cose-6-phosphate dehydrogenase (G6PD), the
first enzyme in the hexose monophosphate
shunt, can be predisposed to hemolysis from
sources of oxidant stress that would not affect
normal phenotypes. The most common sources
of oxidant stress producing hemolysis in these
patients are infection, drugs, and food. Oxidant-
induced hemolysis can be produced in anyone,
however, if oxidant stress is severe enough, such
as after overdose with numerous drugs (e.g.,
phenazopyridine, dapsone) (Table 1).
Logically, substances producing oxidant
hemolysis share the ability to produce methemo-
globinemia and sulfhemoglobinemia. Some
agents are known better for producing hemolysis
than accompanying dyshemoglobinemias, how-
ever. Naphthalene, an aromatic hydrocarbon, pro-
duces hemolysis [6] and less commonly is
associated with severe methemoglobinemia. On
the other hand, chlorates [7] produce hemolysis
but also can cause marked methemoglobinemia.
Clinical Presentation and Diagnosis
Other than the expected effects of acute anemia,
complications of hemolysis include hyperkalemia
and pigment nephropathy. Jaundice may appear
after a few days. Methemoglobinemia and occa-
sionally sulfhemoglobinemia commonly accom-
pany Heinz body hemolytic anemia, and evidence
for this should be sought.
Hemolysis is diagnosed by showing decreases
in blood hemoglobin and serum haptoglobin
concentrations and a rise in plasma-free hemoglo-
bin concentration. Hemoglobinuria results when
plasma concentrations of hemoglobin increase
sufficiently to saturate haptoglobin and turn
plasma pink or red. In oxidant-induced disease,
bite cells may be noted on routine Wright’s stain
of blood [3]. Heinz bodies can be detected with
special staining, but they are not detectable with
Wright’s stain of blood. Spherocytes are typically
absent or only mildly increased in number.
Reticulocytosis is delayed for several days after
onset of hemolysis.
Treatment
In general, treatment is supportive with blood
transfusion, ensuring appropriate hydration, and
monitoring for hyperkalemia. Specific therapies
may be indicated with specific toxins (e.g.,
exchange transfusions for arsine, D-penicillamine
for copper). Intravenous N-acetylcysteine
prevented severe decreases in whole-blood gluta-
thione concentration in cats with acetaminophen-
induced methemoglobinemia [8], and in vitro
studies in human erythrocytes revealed that incu-
bation in solutions containing N-acetylcysteine
can prevent oxidant hemolysis produced by vari-
ous agents [9, 10]. No reports have shown N-
acetylcysteine’s effectiveness, however, at
preventing or lessening oxidant hemolysis in
humans with acute poisoning.
Hematologic Syndromes: Hemolysis, Methemoglobinemia, and Sulfhemoglobinemia 5

Table 1 Examples of agents producing oxidant stressa Table 1 (continued)

Acetanilid Metaflumizone
Aminophenols Methylene blue
p-Aminosalicylic acid Metobromuron
Amyl nitrite Metoclopramide
Aniline Monolinuron
Anilinoethanol Mushrooms
Arsineb Naphthalene
Benzocainec Naphthylamine
Benzoylphenylurea Nitratesc
Bismuth subnitrate Nitric oxide
Bromoaniline Nitrites
Bupivacainec Nitroalkanes
Chloramine Nitroaniline
Chloratesb Nitrobenzene
Chlorites Nitroethane
Chloroanilines Nitrofurans
Chloroquine Nitroglycerin
Chromatesb Nitrophenol
Clofazimine Pamaquine
Dichromates Pendimethalin
Cobalt preparations Phenacetin
Commercial inks Phenazopyridine
Copper sulfateb Phenetidine
Dapsone Phenols
Diaminodiphenylsulfone p-Phenylenediamine
Dimethylamine Phenylhydrazine
Dimethylaminophenol Phenylhydroxylamine
Dimethylaniline Piperazine
Dimethyl sulfoxide Plasmoquine
Dimethyltoluidine Prilocainec
Dinitrobenzene Primaquine
Dinitrophenols Propanil
Dinitrotoluene Pyridine
Flutamide Pyrogallol
Hydrazines Quinones
Hydroquinone Rasburicase/pegloticase
40 -Hydroxyacetanilid Resorcinol
Hydroxylamine Riluzole
Ifosfamide Sodium nitritec
Indoxacarb Stibineb
Isobutyl nitrite Sulfonamides
Lidocainec Sulfones
Local anestheticsc Sulofenur
(continued) (continued)
6 S.C. Curry and A.M. Kang
Table 1 (continued)
Tetralin
Tetranitromethane tetronal
Thiocolchicoside
Toluenediamine
Toluidine
Trichlorocarbanilide
Trinitrotoluene
Trional
Zopiclone
a
Poisoning (and sometimes therapeutic doses) by these agents
variously produces combinations of Heinz body hemolytic
anemia, methemoglobinemia, or sulfhemoglobinemia in indi-
vidual patients. Why some patients develop methemoglobi-
nemia, whereas others mainly develop sulfhemoglobinemia
or hemolysis, is not well understood
b
Known for producing extraordinarily severe hemolysis
c
Hemolysis usually not significant after a single therapeutic
dose, even when methemoglobinemia is present
Methemoglobinemia
Pathophysiology
Reduced hemoglobin (deoxyhemoglobin) con-
tains four ferrous (Fe2+) heme groups capable of
binding and transporting oxygen. Oxidation to the
ferric (Fe3+) state produces methemoglobin. Oxi-
dant stress produces denaturation of hemoglobin
with hemolysis and methemoglobin, explaining
the coexistence of both disorders in the same
patient (see Fig. 1).
Reduced (ferrous) hemoglobin continuously
undergoes conversion to methemoglobin within
erythrocytes, to a large extent from the oxidizing
power of oxygen. Values for methemoglobin are
reported most commonly in percentages (frac-
tions). These fractions represent the percentage
of all hemoglobin pigments present as methemo-
globin. Methemoglobin fractions in whole blood
are normally less than 1–2 %. When fractions
exceed this value, methemoglobinemia is said to
be present. Hemoglobinemia refers to the pres-
ence of excess hemoglobin in plasma, whereas
methemoglobinemia refers to elevated circulating
fractions of methemoglobin within erythrocytes.
Methemoglobin does not transport oxygen.
Ferric heme groups impair unloading of oxygen
by ferrous heme on the same hemoglobin tetra-
mer, shifting the oxygen-hemoglobin dissociation
curve to the left [4]. Serious signs and symptoms
from methemoglobinemia result from impaired
oxygen delivery to tissues and from cyanosis,
which can be seen before significant impairment
of oxygenation.
Visible cyanosis is produced by 5 g of normal
deoxyhemoglobin per 1 dL of capillary blood
[11]. Because methemoglobin is dark brown,
however, only 1.5 g of methemoglobin per dL of
blood is required to produce noticeable discolor-
ation [12]. In nonanemic patients, about 10–15 %
methemoglobinemia produces cyanosis without
significant impairment of oxygen delivery. Pro-
gressive increases in methemoglobin fractions to
20–40 % in nonanemic patients are accompanied
by headache, dyspnea, tachypnea, tachycardia,
and mild hypertension. Further increases in met-
hemoglobin fractions into the 40–55 % range
(without anemia) may begin to produce confu-
sion, lethargy, and metabolic acidosis. Additional
increases result in coma, seizures, bradycardia,
ventricular dysrhythmias, and hypotension; near
70 % methemoglobinemia results in death. We
have seen one nonanemic patient who was
awake with 73 % methemoglobinemia after ben-
zocaine exposure during a transesophageal echo-
cardiogram who complained only of weakness
and voices and noises sounding distant.
Anemic patients experience more severe
impairment of oxygen delivery and more severe
signs and symptoms at given methemoglobin
fractions than nonanemic patients. Anemic
patients also exhibit less profound cyanosis at
given methemoglobin fractions.
Although inactivation of oxidants is the main
mechanism by which oxidant hemolysis is
prevented, oxidant inactivation remains relatively
unimportant in maintaining methemoglobin frac-
tions within the normal range. Patients with con-
genital glutathione deficiency, G6PD deficiency,
Hematologic Syndromes: Hemolysis, Methemoglobinemia, and Sulfhemoglobinemia
catalase deficiency, and scurvy do not have ele-
vated methemoglobin fractions. Rather, methe-
moglobin fractions are maintained at low levels
by allowing methemoglobin to form and then
immediately enzymatically reducing it back to
ferrous hemoglobin.
Erythrocytic cytochrome-b5 reductase
accounts for virtually all normal methemoglobin
reduction (Fig. 4) [13]. In this process, electrons
from NADH (produced in glycolysis) are used to
reduce cytochrome b5, which reduces methemo-
globin to form ferrous hemoglobin. Normal enzy-
matic methemoglobin reduction requires an intact
glycolytic pathway for NADH production, the
presence of cytochrome b5, and adequate activity
of cytochrome-b5 reductase. The normal rate of
enzymatic methemoglobin reduction exceeds
spontaneous background methemoglobin forma-
tion rate by several 100-fold. Heterozygous eryth-
rocytic cytochrome-b5 reductase-deficient
patients ordinarily exhibit normal methemoglobin
fractions but are predisposed to developing met-
hemoglobinemia in response to oxidant stress.
Compound heterozygous and homozygous
patients display congenital methemoglobinemia
[13, 14].
A second erythrocytic reducing enzyme,
NADPH methemoglobin reductase, normally
remains minimally active or completely inactive
because of the absence of an electron transfer
intermediate (e.g., cytochrome b5) to serve as a
cofactor for enzymatic methemoglobin reduction.
Methylene blue (methylthioninium chloride) is an
acceptable electron acceptor/donor intermediate,
however, and markedly accelerates NADPH met-
hemoglobin reductase activity [4]. In this pathway
(see Fig. 4), electrons are transferred from NADPH
(produced in the hexose monophosphate shunt) to
methylene blue to form leukomethylene blue.
Leukomethylene blue donates an electron to met-
hemoglobin to produce ferrous hemoglobin.
Reduction of methemoglobin by this pathway
requires an intact hexose monophosphate shunt, a
cofactor such as methylene blue, and normal activ-
ity of erythrocytic NADPH methemoglobin reduc-
tase. In vitro, some methemoglobin reduction can
7
be shown by glutathione and ascorbate, but these
are thought to be relatively minor in vivo.
The predisposition of infants to methemoglo-
binemia is explained by normally low erythro-
cytic cytochrome-b5 reductase activity and
cytochrome b5 concentrations. Oxidant stress
resulting from gastroenteritis and other infections
is the most common cause of acquired methemo-
globinemia in this age group [15, 16].
Etiology
Congenital Causes
Patients with compound heterozygous or homo-
zygous deficiency for erythrocytic cytochrome-b5
reductase have congenital methemoglobinemia
and can be treated with oral methylene blue to
lower methemoglobin fractions. In addition, sev-
eral mutant hemoglobin species (hemoglobin M)
in which the iron remains in the ferric form have
been described. Most of these patients have con-
genital methemoglobinemia unresponsive to
methylene blue. Rare mutant unstable hemoglo-
bins undergo denaturation to produce congenital
Heinz body hemolytic anemias; some of these
also oxidize to form methemoglobin. These
hemoglobins would be expected to produce dis-
ease before adulthood [5, 13].
Acquired Causes
Most cases of methemoglobinemia in adults and
non-neonates are acquired, resulting from expo-
sure to chemical agents (see Table 1). One of the
most common causes is benzocaine, which is
metabolized to a methemoglobin-producing
agent. Methemoglobinemia resulting from topical
benzocaine spray used to perform
transesophageal echocardiograms, endotracheal
intubations, bronchoscopies, or other endoscopic
procedures has been described repeatedly in the
literature [17, 18]. The use of benzocaine-
containing teething ointments and hemorrhoidal
creams also has produced methemoglobinemia in
some patients, even after therapeutic doses.
Prilocaine is the second local anesthetic most
8 S.C. Curry and A.M. Kang
Fig. 4 Mechanisms of maintaining low methemoglobin
(MetHbFe3+) fractions through MetHbFe3+ reduction. Sig-
nificant MetHbFe3+ reduction in vivo occurs only through
cytochrome-b5 reductase, which uses reduced nicotine
adenine dinucleotide (NADH) as a reducing agent. Methy-
lene blue markedly enhances MetHbFe3+ reduction by
acting as a cofactor for reduced nicotine adenine dinucle-
otide phosphate (NADPH) MetHbFe3+ reductase, an
closely associated with methemoglobinemia, but
methemoglobinemia has resulted from many
anesthetics, including lidocaine and bupivacaine
[19, 20]. Methemoglobinemia usually follows
overdose of phenazopyridine (Pyridium) or dap-
sone and occasionally results from therapeutic
use. A plethora of additional prescription drugs
have been associated with methemoglobinemia;
examples are valproate [21], clofazimine [22],
flutamide [23], and ifosfamide [24]. Oral over-
doses with nitroglycerin and organic nitrates
(which are esters of nitrite) and therapeutic doses
of intravenous nitroglycerin are well known to
produce methemoglobinemia [25].
The conversion of nitrates to nitrites by bacte-
ria in the upper gastrointestinal tract has produced
fatal methemoglobinemia in infants who ingest
well water high in nitrate concentrations –
so-called well-water methemoglobinemia
[26]. Nitrite contamination of public drinking
water also explained a large outbreak of methe-
moglobinemia [27]. Methemoglobinemia results
from ingestion of meat containing excessive
amounts of sodium nitrite as a preservative [28]
enzyme that normally plays no role in MetHbFe3+ reduc-
tion. Riboflavin can act like methylene blue and has been
used in cases of congenital methemoglobinemia. Ascor-
bate and glutathione are responsible for a minority of
MetHbFe3+ reduction in vitro but play an insignificant
role in normal MetHbFe3+ reduction and there is limited
evidence for their effectiveness in treating methemoglobi-
nemia. HbFe2+, normal ferrous hemoglobin
and from the recreational use of inhalational
nitrites (e.g., isobutyl nitrite). Illicit drugs can be
adulterated with local anesthetics as in the case of
cocaine [29]. Aniline has been sold as the hallu-
cinogen 2C-E, with resultant methemoglobinemia
[30]. Topical contact with aniline dyes found in
printing ink on diapers, leather dyes in new shoes,
and commercial marking crayons has produced
methemoglobinemia and death [4]. The ingestion
of nitroethane, found in some over-the-counter
fingernail products, produces methemoglobine-
mia [31]. In Asia, ingestions of the herbicide
propanil is a cause of methemoglobinemia [32].
As expected, most agents producing methemo-
globinemia also produce oxidant-induced hemo-
lysis, and both disorders commonly coexist in the
same patient. Hemolysis can be extraordinarily
severe after poisonings by chlorates, arsine,
stibine, and chromates. Methemoglobinemia
resulting from local anesthetics usually is not
accompanied by serious hemolysis. G6PD defi-
ciency has not been reported to predispose to
methemoglobinemia except for the suggestion
that hemolysis in these patients masks
Hematologic Syndromes: Hemolysis, Methemoglobinemia, and Sulfhemoglobinemia
methemoglobinemia because older erythrocytes
predisposed to increased methemoglobin forma-
tion are the very same ones more susceptible to
hemolysis [33].
Diagnosis
The use of multiwavelength co-oximetry allows
for the diagnosis of methemoglobinemia. It is
important that the sample is analyzed soon after
collection as methemoglobin concentrations can
increase ex vivo. Modern co-oximeters measure
the absorption of multiple wavelengths of ultravi-
olet light by blood and calculate concentrations of
oxyhemoglobin, reduced hemoglobin, methemo-
globin, and carboxyhemoglobin. Because
co-oximetry determines methemoglobin concen-
trations by measuring absorption of light, sub-
stances that interfere with light absorption can
produce false results on some co-oximeters,
depending on the model. Hyperlipemia, such as
that seen after the infusion of lipid emulsions or
in patients with diabetes mellitus, has resulted in
reporting of falsely elevated methemoglobin frac-
tions [34]. Co-oximetry may be unreliable for sev-
eral minutes immediately after a dose of methylene
blue [35]. As discussed later, sulfhemoglobin is
handled in various ways, depending on the specific
instrument, but some co-oximeters cannot differ-
entiate between sulfhemoglobin and methemoglo-
bin, reporting elevated methemoglobin fractions in
both instances.
Other diagnostic clues commonly lead to the
presumed diagnosis of methemoglobinemia
before co-oximetry is considered. Generalized
cyanosis in the presence of a normal arterial PO2
usually represents methemoglobinemia. As
expected, cyanosis from methemoglobinemia per-
sists despite oxygen therapy. Patients with signif-
icant methemoglobinemia may exhibit chocolate-
colored or abnormally dark blood. When methe-
moglobin fractions exceed 10–15 % in a
nonanemic patient, a drop of blood allowed to
dry on filter paper appears noticeably brown com-
pared with venous blood from a normal person
[36]. In fact, the degree of color change can be
used to estimate methemoglobin fraction
9
[37]. Many blood gas instruments do not measure
percent hemoglobin saturation but report a calcu-
lated value derived from the PaO2 and pH. This
calculated saturation represents what the satura-
tion should be in the absence of abnormal hemo-
globin pigments. In methemoglobinemia, the true
percent saturation as determined by co-oximetry
is lower than the calculated percent saturation as
reported by many blood gas instruments. The
difference between the calculated and measured
saturation is termed the saturation gap and nor-
mally is less than 3–5 % in arterial blood. Large
saturation gaps in arterial blood almost always
result from methemoglobin or carboxyhe-
moglobin and less commonly result from
sulfhemoglobin.
Dual-wavelength pulse oximeters, the most
commonly used devices, neither accurately nor
reliably measure percent saturation in the presence
of methemoglobinemia [38]. Depending on the true
oxygen saturation, dual-wavelength pulse oximetry
may read falsely low or falsely high. The most
common response to methemoglobinemia is that
pulse oximeters read falsely high saturations,
although reported saturations may decrease below
the normal range. When the diagnosis of methemo-
globinemia has been made, the pulse oximeter
should be removed from the patient so that medical
personnel are not misled by unreliable readings.
Over the last several years, pulse co-oximeters
have become available that measure methemoglo-
bin fractions (Masimo Corporation, Irvine, CA)
and appear to provide consistent results across a
wide range of hypoxia states [39]. As these devices
are incorporated into regular use, methemoglobine-
mia may become more commonly recognized.
Blood should be drawn to screen for hemolysis
(hemoglobin, blood smear, Heinz body stain,
plasma-free hemoglobin, serum haptoglobin), for
arterial blood gases and co-oximetry, and for rou-
tine laboratory studies. Methemoglobinemia does
not change measurement of total blood hemoglo-
bin concentration by the clinical laboratory. How-
ever, as noted earlier, it is important that a full
blood count is obtained as methemoglobin con-
centration should be interpreted in the context of
total hemoglobin. An electrocardiogram may help
exclude myocardial ischemia.
10
Methemoglobin fractions commonly increase
after death. Postmortem methemoglobin concen-
trations do not reliably reflect antemortem
methemoglobinemia [40].
Differential Diagnosis
Arterial PaO2, in the absence of other causes of
hypoxemia, is normal in methemoglobinemia,
distinguishing abnormal coloration from hypoxia.
The cyanosis from methemoglobinemia does not
respond to oxygen therapy.
Patients with sulfide poisoning have been
reported to exhibit an unusual, poorly character-
ized discoloration of the skin and other organs,
mainly as a postmortem finding. Rare cases of
tellurium exposures have produced blue discolor-
ation. Some patients with severe cyanide toxicity
exhibit cyanosis, and many other signs and symp-
toms of cyanide poisoning would be similar to
signs and symptoms of methemoglobinemia. Nor-
mal arterial PaO2 and increased saturation gaps
also characterize carbon monoxide poisoning
and sulfhemoglobinemia, and some co-oximeters
measure and report sulfhemoglobin as methemo-
globin. Skin discoloration from dermal contact
with new blue clothing or blue towels has been
confused with methemoglobinemia, but this dis-
coloration is removed with washing the skin.
Excessive administration of methylene blue can
produce skin discoloration that may be confused
with continuing methemoglobinemia or cyanosis
from other causes.
Treatment
Patients should receive oxygen to maximize oxy-
gen carrying capacity of remaining normal
hemoglobin.
Asymptomatic Patients
Some patients with methemoglobinemia exhibit
cyanosis but lack other signs and symptoms and
do not require specific treatment. After exposure
to the offending agent ends, methemoglobin
S.C. Curry and A.M. Kang
levels usually return to normal within 36 h with
some exceptions (e.g., dapsone, nitroethane).
Most of these patients require admission to the
hospital, however, to follow them clinically for
worsening signs and symptoms, to monitor for
onset of hemolysis, and to follow serial methemo-
globin fractions. Assuming normal hemoglobin
concentrations, asymptomatic patients usually
exhibit methemoglobin fractions between 10 %
and 15 %.
Symptomatic Patients
Patients who are symptomatic from methemoglo-
binemia (e.g., tachycardia, dyspnea, confusion,
and headache) should be considered for specific
antidotal therapy with methylene blue [41–43]
(level of evidence II-2), in the absence of a history
of G6PD deficiency (see later). Parenteral methy-
lene blue should be given intravenously over
3–5 min at an initial dose of 1–2 mg/kg
(0.1–0.2 mL/kg of a 1 % solution). Resolution of
cyanosis usually occurs within 5–25 min. If the
patient is seriously symptomatic and no response
occurs within 15 min or if the patient remains
moderately symptomatic without any improve-
ment for 30–60 min, repeat doses of 1 mg/kg
(0.1 mL/kg of a 1 % solution) should be given.
If methemoglobin levels are readily available,
repeat determinations of methemoglobin fractions
should be performed before repeat dosing of
methylene blue because large doses of methylene
blue produce discoloration of the skin. The total
amount of methylene blue given during the first
few hours generally should not exceed 5–7 mg/kg.
Intraosseous infusion of methylene blue has been
described when intravenous access cannot be
obtained [44].
Patients with methemoglobinemia always
should be closely followed for evidence of hemo-
lysis because the latter is common whether or not
patients receive methylene blue. Hemolysis may
be clinically apparent on presentation or, most
commonly, appears 2–3 days after admission and
after methemoglobin fractions have decreased.
Some toxins are known for producing methe-
moglobinemia that is refractory or only partially
responsive to methylene blue therapy. In most
Hematologic Syndromes: Hemolysis, Methemoglobinemia, and Sulfhemoglobinemia
instances, this situation results from the inability
of methemoglobin reduction, even in the presence
of methylene blue, to keep up with profound
oxidant stress. Examples of these toxins include
aniline, nitrobenzene, and chlorates [7, 45, 46].
Some methemoglobin-producing toxins pos-
sess long half-lives and produce prolonged met-
hemoglobinemia. Dapsone produces
methemoglobinemia and hemolysis lasting for
days [47, 48]. In these cases, it may be necessary
to administer methylene blue as a continuous
infusion. Methylene blue is dissolved in the crys-
talloid of choice and, based only on case reports,
started at 0.1 mg/kg/h (0.01 mL/kg/h of a 1 %
methylene blue solution) [47], although personal
experience indicates that higher rates may be
required at times. It is important to follow serial
methemoglobin fractions and total hemoglobin
concentrations.
Most methylene blue is excreted unchanged by
the kidneys. Although patients with renal insuffi-
ciency do not require changes in initial methylene
blue doses, they should receive lower continuous
infusion doses of the drug based on creatinine
clearance. No specific guidelines for dosing in
renal failure patients have been developed.
Methylene blue should not be given to patients
with known G6PD deficiency. These patients have
low red blood cell NADPH concentrations,
impairing augmentation of NADPH methemoglo-
bin reductase by methylene blue [49]. Methylene
blue triggers hemolysis in patients with G6PD
deficiency, which would impair oxygen delivery
further [2, 50]. Methylene blue should never be
withheld from symptomatic patients, however,
simply because a history of G6PD deficiency can-
not be excluded.
Large doses of methylene blue in normal vol-
unteers have been associated with dysuria,
substernal chest pain, nausea, tachycardia, hyper-
tension, and anxiety [51]. In our experience, how-
ever, patients with methemoglobinemia do not
voice or experience these effects from methylene
blue. Urine initially turns blue and then green.
Although authors have cautioned that methylene
blue paradoxically may increase methemoglobin
fractions when given in large doses (e.g., 5 mg/kg
11
over 35–70 min) [52], this has not been thought to
be a significant problem in humans receiving
recommended doses. This phenomenon has been
attributed largely to results of in vitro studies
during hypoxic conditions [53, 54]. Worsening
hemolysis also has been alleged after methylene
blue therapy, even in patients with normal G6PD
activity, but these allegations mainly arise from
case reports in which hemolysis was expected
from the agent producing methemoglobinemia
[55], making causal relationships unclear.
Fetuses and newborns seem to be sensitive to
hemolytic actions of methylene blue. Intra-
amniotic injections of methylene blue, sometimes
using large doses, have been associated with
delivery of newborns with Heinz body hemolytic
anemia. Hemolysis also has been reported in new-
borns receiving methylene blue through feeding
tubes [56, 57]. Reports of newborns with methe-
moglobinemia after intra-amniotic injection of
methylene blue [58] could reflect a peculiar sus-
ceptibility of neonates, the effects of a large rela-
tive dose of methylene blue, or in utero hypoxic
conditions favoring methylene blue-induced oxi-
dant stress in the fetus. Regardless of these con-
cerns, the administration of methylene blue to a
symptomatic patient with methemoglobinemia
has never been proved to worsen
methemoglobinemia.
Cimetidine has been used to help control met-
hemoglobinemia from dapsone. Cimetidine
inhibits cytochrome P-450 conversion of dapsone
to the oxidizing metabolite responsible for methe-
moglobinemia, dapsone hydroxylamine. In
patients receiving 1,200 mg/day of cimetidine
orally while taking therapeutic doses of dapsone,
circulating methemoglobin fractions decreased by
an average of 25 % [59] (level I). However, evi-
dence for cimetidine’s effectiveness in treatment
for dapsone overdose should be considered level
III as there are no studies describing its effective-
ness in this setting. Ascorbic acid works slowly
and generally is considered ineffective for treat-
ment of acute acquired methemoglobinemia [4].
Riboflavin also can accept electrons from
NADPH methemoglobin reductase and enhance
methemoglobin reduction in a manner similar to
12
that of methylene blue. Although endogenous
riboflavin concentrations are not high enough to
account for significant methemoglobin reduction,
large oral doses (e.g., 60–100 mg/day) have been
used successfully in patients with congenital met-
hemoglobinemia [60, 61]. The safety and efficacy
of intravenous or oral riboflavin for the treatment
of acquired acute methemoglobinemia have not
been described.
Incubation of erythrocytes in high concentra-
tions of N-acetylcysteine seems to enhance met-
hemoglobin reduction [62]. These concentrations
of N-acetylcysteine cannot be achieved safely in
humans, however, and a randomized controlled
trial found that conventional doses of intravenous
N-acetylcysteine were ineffective in reducing
nitrite-induced methemoglobin fractions in
human volunteers [63].
It is important always to monitor total oxygen
carrying capacity by following total hemoglobin
concentrations, methemoglobin fractions, and
true percent saturation of oxyhemoglobin. A
decrease in methemoglobin fraction from 25 %
to 15 % would result in worsened oxygen delivery
if accompanying hemolysis has resulted in a
decrease of the hemoglobin concentration from
15 g/dL to 5 g/dL. In addition, the development
of anemia alone may result in resolution of cya-
nosis despite worsening of oxygen delivery, with-
out a decrease in methemoglobin fractions. In
most persons, 15 % methemoglobinemia with a
hemoglobin concentration of 15 g/dL would pro-
duce visible cyanosis, whereas 20 % methemo-
globinemia in patients with a hemoglobin
concentration of 5 g/dL produces no visible dis-
coloration and yet may be lethal. Interpreting dis-
appearance of cyanosis to mean that the patient
has improved must be done with caution.
After initial signs and symptoms of methemo-
globinemia have been addressed, routine gastro-
intestinal and skin decontamination should be
performed as indicated. If the clinician chooses
to use ascorbic acid in treating acquired methe-
moglobinemia, recommended doses historically
have been 0.5–1 g of ascorbic acid given every
6 h intravenously or orally [4], though a recent
anecdotal report describes using higher doses
(described below) [64]. Evidence supporting
S.C. Curry and A.M. Kang
ascorbic acid’s effectiveness in treating acquired
methemoglobinemia is level III.
Failure to Respond to Methylene Blue
When patients with methemoglobinemia do not
improve with methylene blue therapy, several
possibilities should be considered (Table 2).
First, exposure to large amounts of drugs or
chemicals can produce methemoglobin at rates
greater than reducing capacity, even with methy-
lene blue therapy. When methemoglobin fractions
do not return to normal because of continued
methemoglobin formation, methylene blue ther-
apy almost always results in at least a transient
decrease in methemoglobin fractions. As noted
earlier, recurrent methemoglobinemia is common
after exposure to etiologic agents with prolonged
absorption or long half-lives. Second, patients
who do not respond to methylene blue also may
be suffering from unrecognized G6PD deficiency.
Third, patients with congenital NADPH methe-
moglobin reductase deficiency also fail to respond
to methylene blue [4]. Fourth, sulfhemo-
globinemia can be mistaken for methemoglobine-
mia (see later). Fifth, repeated doses or large doses
of methylene blue produce blue skin coloration
that may be mistaken for
methemoglobinemia [65].
For patients who cannot receive or fail to
respond to methylene blue, treatment options are
limited. Blood transfusions and exchange trans-
fusions [46] have been used and suggested when-
ever refractory methemoglobin fractions
approach 70 % in nonanemic patients. Hyperbaric
oxygen can be a temporizing measure that pro-
vides adequate oxygen delivery during prepara-
tion of blood transfusions. Oxygen toxicity limits
the amount of time a patient can stay in a hyper-
baric chamber, however. Oral riboflavin could be
given (60–100 mg/day divided into three doses),
but its efficacy is unknown in this setting, and it
would not be expected to be effective in patients
with G6PD deficiency. Intravenous ascorbic acid
(500 mg) also can be given [4], although it is
stated that it works too slowly to be helpful for
acquired methemoglobinemia. High-dose
ascorbic acid (10 g IV q 6 h) has been described
in dapsone poisoning [64].
Hematologic Syndromes: Hemolysis, Methemoglobinemia, and Sulfhemoglobinemia
Table 2 Possible explanations when methemoglobinemia
fails to respond to methylene blue
Overwhelming oxidant stress from ingestant or toxin
G6PD deficiency
NADPH methemoglobin reductase deficiency
Sulfhemoglobinemia
Blue skin discoloration from other sources
Hypoxemia (recheck arterial PO2)
G6PD glucose-6-phosphate dehydrogenase, NADPH
reduced nicotinamide adenine dinucleotide phosphate
Sulfhemoglobin
Background and Characteristics
Sulfhemoglobin is a green molecule in which a
sulfur atom has been incorporated into the por-
phyrin ring of hemoglobin [66]. Sulfhemoglobin
cannot transport oxygen. No significant circulat-
ing sulfhemoglobin normally exists, but
sulfhemoglobin fractions increase in some per-
sons in response to oxidant stress. In contrast to
methemoglobin, sulfhemoglobin persists for the
life of the erythrocyte and does not undergo con-
version back to hemoglobin. Only 0.5 g/dL of
sulfhemoglobin produces slate-gray cyanosis
(e.g., approximately 3 % sulfhemoglobin in a
patient with a total hemoglobin concentration of
16 g/L).
Although sulfhemoglobin cannot transport
oxygen, additional factors usually prevent serious
impairment of oxygen delivery in nonanemic
patients. During sulfhemoglobinemia, hemoglo-
bin tetramers usually contain only one or two
sulfurated heme isomers, preventing extremely
elevated sulfhemoglobin fractions. Sulfurated
heme moieties in hemoglobin shift unaffected
heme moieties toward the unliganded confirma-
tion, reducing oxygen affinity of normal heme
subunits and shifting the oxygen-hemoglobin dis-
sociation curve to the right, which enhances oxy-
gen delivery to tissues and partially ameliorates
the effects of reduced oxygen binding capacity
[67]. In contrast, methemoglobin and carboxyhe-
moglobin shift the dissociation curve to the left,
compounding impaired oxygen delivery to
tissues.
13
Sulfhemoglobin, methemoglobin, and hemo-
globin M possess similar light absorption spectra.
This fact prevented many early authors from
distinguishing among these three pigments.
Some multiwavelength co-oximeters today report
sulfhemoglobin as methemoglobin. In addition,
early studies of “sulfhemoglobinemia” from
hydrogen sulfide mixed with blood in vitro may
have represented nothing more than a mixture of
oxidized, denatured hemoglobin pigments that
were unrelated to what is termed sulfhemoglobin
today [68]. Readers must interpret cautiously con-
fusing older medical literature on reports of
sulfhemoglobinemia, which has been suggested
to be better termed pseudosulfhemoglobin
[69]. These articles might represent true reports
of sulfhemoglobinemia, methemoglobinemia,
hemoglobin M disease, various species of dena-
tured hemoglobin from hydrogen sulfide mixed
with blood in vitro, combinations of the afore-
mentioned, or perhaps other chemical
compounds.
Formation and Etiology
Agents that produce sulfhemoglobinemia (see
Table 1) usually are known better for their ability
to produce methemoglobinemia and hemolysis.
Methemoglobinemia and sulfhemoglobinemia
have followed exposures to metoclopramide [70,
71], flutamide [23, 72], dapsone [73], and
phenazopyridine [74]. Methemoglobinemia,
sulfhemoglobinemia, and especially hemolysis
may coexist in the same patient [73]. Why expo-
sure to the same substance produces sulfhemo-
globinemia in one person, methemoglobinemia
in another, and both in another person remains
unknown.
Sulfhemoglobin forms when elemental sulfur
binds to the β-pyrrole ring of the heme moiety,
where it persists for the life of the erythrocyte
[66]. Although early authors suggested that the
sulfur responsible for oxidizing hemoglobin was
found in the etiologic chemical, many drugs that
produce sulfhemoglobinemia do not contain sul-
fur. It also was an older belief that vague gastro-
intestinal dysfunction alone produced hemolytic
14
anemia, sulfhemoglobinemia, and methemoglobi-
nemia from the presumed absorption of endoge-
nously produced nitrites and sulfides – so-called
enterogenous cyanosis. Evidence indicates, how-
ever, that patients with enterogenous cyanosis
were ingesting surreptitiously analgesics known
to cause such disorders [75].
Animal studies suggest that sulfur from intes-
tinal bacterial metabolism in combination with
oxidant stress from various agents might be
responsible for sulfhemoglobin formation. Rats
with jejunal pouches that received phenacetin
were more likely to develop sulfhemoglobinemia
than controls; neomycin prevented phenacetin-
induced sulfhemoglobin formation [76]. Neomy-
cin use for treatment of sulfhemoglobinemia in
humans has been described in case reports [77].
Diagnosis
In early attempts to clarify what was being mea-
sured when “sulfhemoglobin” was reported to be
present, Michel and Harris [78] reported that the
addition of cyanide or dithionite (hydrosulfite) to
blood eliminated the spectral absorption of met-
hemoglobin immediately, whereas the spectral
absorption of sulfhemoglobin remained. This sim-
ple test did not exclude hemoglobin M (or perhaps
other oxidation products of hemoglobin), how-
ever, which also remains after addition of these
compounds. Carrico and colleagues [79] reported
that carbon monoxide would bind to
sulfhemoglobin to produce carbonmonoxysulfhe-
moglobin, a compound with a downfield shift,
whereas neither methemoglobin nor hemoglobin
M bound carbon monoxide. Light absorption in
the presence of cyanide (or dithionite) and carbon
monoxide, then, served for several years as labo-
ratory tools to measure “sulfhemoglobin” frac-
tions and concentrations, although it is not
known confidently exactly what species always
was being measured. Park and Nagel [67]
reported that electrophoresis with isoelectric
focusing reliably delineates the three pigments,
and isoelectric focusing generally serves as the
gold standard today, although various methods
of analysis (e.g., gas chromatography, manual
S.C. Curry and A.M. Kang
spectrophotometry) are used at reference
laboratories.
Results from isoelectric focusing, manual
spectrophotometric analysis, or other reference
methods do not return for hours to days, whereas
multiwavelength co-oximetry results are available
within minutes in most intensive care units. Dif-
ferent brands of co-oximeters and various models
from the same manufacturer vary in how they
handle sulfhemoglobin [80]. The older IL
282 and IL 482 (Instrumentation Laboratory,
Inc., Lexington, MA) do not distinguish between
methemoglobin and sulfhemoglobin and report
sulfhemoglobin as methemoglobin [71, 72,
81]. Zwart and colleagues [82] showed that a
reported methemoglobin fraction greater than
10 % in combination with a negative carboxyhe-
moglobin fraction on these instruments suggests
that at least some sulfhemoglobin is present. Con-
versely the IL 682 is said to indicate
sulfhemoglobin fractions greater than 1.5 %
[81]. Some multiwavelenth co-oximeters will
alert that sulfhemoglobin is present, but not pro-
vide quantification [83]. Wu and Kenny [84]
noted that Radiometer OSM3 co-oximeter
reported falsely elevated oxygen saturations in
the presence of sulfhemoglobinemia, unless the
blood specimen was analyzed with a service pro-
gram configuration that could be activated only by
a company representative. The intensivist must be
familiar with how his or her particular
co-oximeter handles and reports sulfhemoglobin
(if at all) and sometimes must remain skeptical of
claims made by a manufacturer regarding the abil-
ity to detect and quantify sulfhemoglobin
accurately.
Few data exist on accuracy of dual-wavelength
pulse oximetry in the presence of sulfhemo-
globinemia. We have seen one woman with
slate-gray cyanosis and 18.6 % sulfhemoglobin
(total hemoglobin 9 g/dL) whose pulse oximeter
read in the 60 % range despite an elevated arterial
PaO2 and absent methemoglobin (true saturation
about 81 %). Aravindhan and Chisholm [67]
described a 48-year-old woman with an arterial
PaO2 of 99 mmHg, 28 % sulfhemoglobinemia,
and a pulse oximeter reading of 85 % (true satu-
ration about 72 %). Langford and Sheikh [85]
Hematologic Syndromes: Hemolysis, Methemoglobinemia, and Sulfhemoglobinemia
noted a pulse oximeter reading of 92–94 % satu-
ration with a sulfhemoglobin fraction of 16 %
(true saturation about 84 %).
Clinical Presentation
The diagnosis of sulfhemoglobinemia usually is
considered when confronted with a cyanotic or
slate-gray patient who has a normal PaO2.
Depending on the co-oximeter being used, met-
hemoglobin fractions may be reported as normal,
or methemoglobin fractions may be reported as
elevated and remain so after methylene blue ther-
apy (other causes of this scenario were described
previously). Except for discoloration, most
patients with sulfhemoglobinemia remain asymp-
tomatic, unless other abnormal hemoglobins are
present (e.g., methemoglobin), or the typical
accompanying oxidant hemolytic anemia is
severe. Discoloration most often appears slate
gray and lasts for weeks or months due to the
irreversible nature of sulfhemoglobin [12]. The
coexistence of methemoglobinemia and anemia
may alter the color of cyanosis and clinical
symptoms.
Historically the most common drugs causing
sulfhemoglobinemia were acetanilid, phenacetin,
and sulfonamides. Bromo-Seltzer was the most
common cause, but acetanilid, the offending
ingredient, since has been removed as an ingredi-
ent. More recent reports describe sulfhemo-
globinemia resulting from dapsone [73],
dimethyl sulfoxide [86], flutamide [72],
metoclopramide [71], and phenazopyridine [74].
Treatment
There is no specific antidote for sulfhemo-
globinemia. No beneficial effect results from ther-
apy with methylene blue. Treatment centers on
ensuring adequate oxygen delivery to tissues by
correcting coexistent methemoglobinemia and
anemia (from hemolysis) and ensuring maximal
oxygen carrying capacity with administration of
oxygen when the patient is symptomatic. Trans-
fusions usually are required only in patients
15
whose coexisting hemolytic anemia is severe,
which increases the total hemoglobin concentra-
tion and decreases the sulfhemoglobin fraction.
Patients need follow-up on an outpatient basis
for several weeks because sulfhemoglobin con-
centrations decrease only as the red blood cell
population is replaced in the absence of the
offending agent.
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