This document provides information on methemoglobinemia, including: - Definition as an abnormal increase in methemoglobin levels in red blood cells above 1% - Symptoms vary based on methemoglobin levels and include cyanosis, headaches, and loss of consciousness - Causes include ingestion of drugs/toxins like local anesthetics, nitrates, sulfonamides, and certain antibiotics - Workup involves blood tests to check for anemia and enzyme levels to identify potential hereditary causes

1. DR.Al Hussein Ragab Zaky
Pediatrician And Neonatologist
Luxor International Hosp.
Methemoglobinemia
em : alhussein.neoped@yahoo.com
Mob : 01113033672-01012727282
Facebook : Al Hussein Ragab

3. DefinitionDefinition
MethemoglobinemiaMethemoglobinemia::
))congenital or acquiredcongenital or acquired)) occurs when red blood cellsoccurs when red blood cells
((RBCsRBCs)) contain methemoglobin at levels higher thancontain methemoglobin at levels higher than
1%1%..
Acquired methemoglobinemia isAcquired methemoglobinemia is
considerably more common thanconsiderably more common than
congenital formscongenital forms..

4. Symptoms are proportional to the methemoglobinSymptoms are proportional to the methemoglobin
level and include skin color changes and bloodlevel and include skin color changes and blood
color changes at levels up to 15%color changes at levels up to 15%
As levels rise above 15%, neurologic and cardiacAs levels rise above 15%, neurologic and cardiac
symptoms arise as a consequence of hypoxiasymptoms arise as a consequence of hypoxia..
Levels higher than 70% are usually fatalLevels higher than 70% are usually fatal..
Note chocolate brown color of methemoglobinemia.
In tubes 1 and 2, methemoglobin fraction is 70%; in tube 3, 20%; and in tube 4, normal.

5. Methemoglobin contains iron in the ferric state Fe+3Methemoglobin contains iron in the ferric state Fe+3
++22rather than the reduced ferrous form Ferather than the reduced ferrous form Fe found infound in
hemoglobinhemoglobin..
This structural change causes an alteration in the blood’s abilityThis structural change causes an alteration in the blood’s ability
to bind oxygento bind oxygen..
Methemoglobin is a naturally occurring oxidized metabolite ofMethemoglobin is a naturally occurring oxidized metabolite of
hemoglobin, and physiologic levelshemoglobin, and physiologic levels ((< 1%< 1%)) are normalare normal..
Problems arise as methemoglobin levels increaseProblems arise as methemoglobin levels increase..
Methemoglobin does not bind oxygen, thus effectively leadingMethemoglobin does not bind oxygen, thus effectively leading
to a functional anaemiato a functional anaemia..
Pathophysiology

6. The low level of methemoglobin is maintained through 2
important mechanisms. The first is the hexose-
monophosphate shunt pathway within the erythrocyte.
Through this pathway, oxidizing agents are reduced
by glutathione.
The second and more important mechanism involves
two enzyme systems, diaphorase I and diaphorase II,
and requires nicotinamide adenine dinucleotide
(NADH) and nicotinamide adenine dinucleotide
phosphate (NADPH), respectively, to reduce
methemoglobin to its original ferrous state.

7. NADH-dependent methemoglobin reduction
(diaphorase I pathway) is the major
enzymatic system involved.
Cytochrome b5 reductase plays a major role
in this process by transferring electrons
from NADH to methemoglobin, an action
that results in the reduction of
methemoglobin to hemoglobin. This
enzyme system is responsible for the
removal of 95-99% of the methemoglobin
that is produced under normal
circumstances.

8. NADPH-dependent methemoglobin reduction
(diaphorase II pathway) usually plays only a
minor role in the removal of methemoglobin.
This enzyme system utilizes glutathione
production and glucose-6-phosphate
dehydrogenase (G6PD) to reduce
methemoglobin to hemoglobin.
It assumes a larger and more important role in
methemoglobin regulation in patients with
cytochrome b5 reductase deficiencies.

9. The NADPH-dependent methemoglobin
reduction pathway can be accelerated by
exogenous cofactors such as methylene
blue to as much as five times its normal
level of activity.
In the absence of further accumulation of
methemoglobin, these methemoglobin
reduction pathways can clear
methemoglobin at a rate of approximately
15% per hour.

11. EtiologyEtiology
Congenital (hereditary) methemoglobinemiaCongenital (hereditary) methemoglobinemia
Hereditary methemoglobinemias may be divided into two
categories as follows
Methemoglobinemia due to an altered form of
hemoglobin (ie, Hb M(
Methemoglobinemia due to an enzyme deficiency
(NADH reductase deficiency) that decreases the rate
of reduction of iron in the hemoglobin molecule

12. The four types are as followsThe four types are as follows
Type IType I – This is the most common variant, and the enzyme– This is the most common variant, and the enzyme
deficiency isdeficiency is limited to the erythrocyteslimited to the erythrocytes causing cyanosis;causing cyanosis;
cyanosis usually, but not always, developscyanosis usually, but not always, develops during infancyduring infancy
Type IIType II – Widespread deficiency of the enzyme occurs in– Widespread deficiency of the enzyme occurs in
various tissues, includingvarious tissues, including erythrocytes, liver, fibroblasts, anderythrocytes, liver, fibroblasts, and
brainbrain; it is associated with severe CNS symptoms, including; it is associated with severe CNS symptoms, including
encephalopathy, microcephaly, hypertonia, athetosis,encephalopathy, microcephaly, hypertonia, athetosis,
opisthotonos, strabismus, mental retardation, and growthopisthotonos, strabismus, mental retardation, and growth
retardationretardation; cyanosis is evident at an early age; cyanosis is evident at an early age
Type IIIType III – Although the– Although the hematopoietic systemhematopoietic system ((platelets, RBCs,platelets, RBCs,
and white blood cellsand white blood cells [[WBCsWBCs]])) is involved, the only clinicalis involved, the only clinical
consequence is cyanosisconsequence is cyanosis
Type IVType IV –– Like type ILike type I, this type has isolated involvement of the, this type has isolated involvement of the
erythrocytes but results inerythrocytes but results in chronic cyanosischronic cyanosis

13. Acquired methemoglobinemiaAcquired methemoglobinemia
Acquired methemoglobinemia is usually due to theAcquired methemoglobinemia is usually due to the
ingestion of drugs or toxic substancesingestion of drugs or toxic substances.. ExposureExposure
to such substances in amounts thatto such substances in amounts that exceed theexceed the
enzymatic reduction capacity of RBCsenzymatic reduction capacity of RBCs
precipitates symptomsprecipitates symptoms

14. Acquired methemoglobinemia is more frequent inAcquired methemoglobinemia is more frequent in
premature infants and infants younger than 4 monthspremature infants and infants younger than 4 months..
 Fetal hemoglobinFetal hemoglobin may oxidize more easily thanmay oxidize more easily than
adult hemoglobinadult hemoglobin
 The level of NADH reductase is lowThe level of NADH reductase is low at birth andat birth and
increases with age; it reaches adult levels by age 4increases with age; it reaches adult levels by age 4
monthsmonths
 Higher gastric pH inHigher gastric pH in infants may facilitate bacterialinfants may facilitate bacterial
proliferation, resulting in increased conversion ofproliferation, resulting in increased conversion of
dietary nitrates to nitritesdietary nitrates to nitrites
 An association between methemoglobinemia andAn association between methemoglobinemia and
acute gastroenteritisacute gastroenteritis in infants has been noted inin infants has been noted in
several studiesseveral studies.. This may be due to acidosis fromThis may be due to acidosis from
loss of stool bicarbonate, which impairs the alreadyloss of stool bicarbonate, which impairs the already
immature function of the methemoglobin reductaseimmature function of the methemoglobin reductase
system in these young patientssystem in these young patients

15. MethemoglobinaemiaMethemoglobinaemia Substances That CanSubstances That Can
CauseCause Organic and inorganic nitrites and nitratesOrganic and inorganic nitrites and nitrates (Many of these substances can(Many of these substances can
also be absorbed through the skin , Treatment of preterm infants withalso be absorbed through the skin , Treatment of preterm infants with
inhaled nitric oxide may lead to methemoglobinemiainhaled nitric oxide may lead to methemoglobinemia ((
 ChloratesChlorates are another group of oxidizing agentsare another group of oxidizing agents )) matches, explosives,matches, explosives,
and fungicidesand fungicides ((
 Topical and injected local anesthetics eg, benzocaine,lidocaine,Topical and injected local anesthetics eg, benzocaine,lidocaine,
prilocaine & phenazopyridineprilocaine & phenazopyridine (mucosal injury with resultant increased(mucosal injury with resultant increased
absorption or a previously undiagnosed methemoglobin reductaseabsorption or a previously undiagnosed methemoglobin reductase
enzyme deficiencyenzyme deficiency..((
 Idiopathic methemoglobinemia can occur in association with systemicIdiopathic methemoglobinemia can occur in association with systemic
acidosisacidosis.. This typically occurs in infants younger than 6 months and isThis typically occurs in infants younger than 6 months and is
usually caused by dehydration and diarrheausually caused by dehydration and diarrhea.. IdiopathicIdiopathic
methemoglobinemia is exacerbated by the lower levels of methemoglobinmethemoglobinemia is exacerbated by the lower levels of methemoglobin
reductase enzyme found in infantsreductase enzyme found in infants ((50% of adult levels50% of adult levels).).
 Analgesics and antipyreticsAnalgesics and antipyretics – Acetaminophen, acetanilide, phenacetin,– Acetaminophen, acetanilide, phenacetin,
and celecoxiband celecoxib
 Methylene blueMethylene blue ((high dose or in G6PDhigh dose or in G6PD--deficient patients)deficient patients)
 MetoclopramideMetoclopramide
 AntibioticsAntibiotics – Sulfonamides, nitrofurans, and para– Sulfonamides, nitrofurans, and para--aminosalicylic acidaminosalicylic acid
 IndustrialIndustrial//household agentshousehold agents – Aniline dyes, nitrobenzene, naphthalene– Aniline dyes, nitrobenzene, naphthalene
((moth ballsmoth balls)), aminophenol, and nitroethane, aminophenol, and nitroethane ((nail polish removernail polish remover))

16. Clinical PresentationClinical Presentation
The characteristic history in the congenital (hereditary)The characteristic history in the congenital (hereditary)
form of the condition is the presence ofform of the condition is the presence of diffuse,diffuse,
persistent, slate-gray cyanosis, often present frompersistent, slate-gray cyanosis, often present from
birth. There is no evidence of cardiopulmonarybirth. There is no evidence of cardiopulmonary
disease.disease. Patients with hereditary methemoglobinemiaPatients with hereditary methemoglobinemia
are asymptomatic despite the presence of cyanosis.are asymptomatic despite the presence of cyanosis.
The failure of 100% oxygen to correct cyanosis is veryThe failure of 100% oxygen to correct cyanosis is very
suggestive of methemoglobinemia.suggestive of methemoglobinemia.

17. Symptoms are proportional to the fractionSymptoms are proportional to the fraction
of methemoglobinof methemoglobin ..
A normal methemoglobin fraction is about 1%A normal methemoglobin fraction is about 1% ((range, 0-3%range, 0-3%((
At methemoglobin levels of 3-15At methemoglobin levels of 3-15
a slight discolorationa slight discoloration ((eg, pale, gray, blueeg, pale, gray, blue)) of the skin may be presentof the skin may be present..
Patients with methemoglobin levels of 15-20%Patients with methemoglobin levels of 15-20%
may be relatively asymptomatic , apart from mild cyanosismay be relatively asymptomatic , apart from mild cyanosis..
Signs and symptoms at levels of 25-50% include the followingSigns and symptoms at levels of 25-50% include the following ::
HeadacheHeadache
DyspneaDyspnea
Lightheadedness, even syncopeLightheadedness, even syncope
WeaknessWeakness
ConfusionConfusion
Palpitations, chest painPalpitations, chest pain

18. Methemoglobin levels of 50-70% can cause theMethemoglobin levels of 50-70% can cause the
followingfollowing ::
CardiovascularCardiovascular -- Abnormal cardiac rhythmsAbnormal cardiac rhythms
CNSCNS -- Altered mental status; delirium, seizures, comaAltered mental status; delirium, seizures, coma
MetabolicMetabolic -- Profound acidosisProfound acidosis
At methemoglobin fractions exceeding 70%, deathAt methemoglobin fractions exceeding 70%, death
usually results.usually results.
N.BN.B
Any known family history of methemoglobinemia or glucose-6
phosphate dehydrogenase (G6PD) deficiency is important to
clarify.
The clinical effects of methemoglobinemia are exacerbated in the
presence of anemia.

19. Differential DiagnosesDifferential Diagnoses
 AcrodermatitisAcrodermatitis EnteropathicaEnteropathica
 AnemiaAnemia
 AsthmaAsthma
 Heart FailureHeart Failure
 Herb PoisoningHerb Poisoning
 Hydrocarbon ToxicityHydrocarbon Toxicity
 Metabolic AcidosisMetabolic Acidosis
 Pediatric AnaphylaxisPediatric Anaphylaxis
 Pulmonary EmbolismPulmonary Embolism
 RotavirusRotavirus

20. WorkupWorkup

Investigations to rule out hemolysisInvestigations to rule out hemolysis ((complete bloodcomplete blood
countcount [[CBCCBC]], reticulocyte count, peripheral smear review, lactate, reticulocyte count, peripheral smear review, lactate
dehydrogenasedehydrogenase [[LDHLDH]], bilirubin, haptoglobin & Heinz body preparation, bilirubin, haptoglobin & Heinz body preparation))

EndEnd--organ dysfunction or failureorgan dysfunction or failure ((liver function tests,liver function tests,
electrolytes, renal function testselectrolytes, renal function tests))
 Investigations to evaluate a hereditary causeInvestigations to evaluate a hereditary cause forfor
methemoglobinemia should be ordered when appropriatemethemoglobinemia should be ordered when appropriate..
Hemoglobin electrophoresis and DNA sequencing of theHemoglobin electrophoresis and DNA sequencing of the
globin chain gene can be used to identify hemoglobin Mglobin chain gene can be used to identify hemoglobin M..
 Specific enzyme assaysSpecific enzyme assays ((nicotinamide adeninenicotinamide adenine
dinucleotidedinucleotide [[NADHNADH]]–dependent reductase, cytochrome b5 reductase–dependent reductase, cytochrome b5 reductase))
may be determined, often in multiple cell linesmay be determined, often in multiple cell lines ((ie, platelets,ie, platelets,
granulocytes, and fibroblastsgranulocytes, and fibroblasts)), to diagnose inherited cases, to diagnose inherited cases..

21. ABGABG
The presence of methemoglobin canThe presence of methemoglobin can falsely elevate the calculatedfalsely elevate the calculated
oxygen saturationoxygen saturation when arterial blood gaseswhen arterial blood gases ((ABGsABGs)) are obtainedare obtained..
One possible clue to the diagnosis of methemoglobinemia is theOne possible clue to the diagnosis of methemoglobinemia is the
presence of apresence of a “ saturation gap ”“ saturation gap ” This occurs when there is aThis occurs when there is a
difference between the oxygen saturation measured on pulsedifference between the oxygen saturation measured on pulse
oximetry and the oxygen saturation calculated on the basis of ABGoximetry and the oxygen saturation calculated on the basis of ABG
resultsresults..
The partial pressure of oxygen PO2The partial pressure of oxygen PO2 value of the ABG measurementvalue of the ABG measurement
reflects plasma oxygen content and does not correspond to thereflects plasma oxygen content and does not correspond to the
oxygenoxygen--carrying capacity of hemoglobincarrying capacity of hemoglobin.. It should be within theIt should be within the
reference range in patients with methemoglobinemiareference range in patients with methemoglobinemia..
CO oximetryCO oximetry
Pulse oximetryPulse oximetry

22. A quick and easy bedside testA quick and easy bedside test for determining whetherfor determining whether
dark blood is due to methemoglobinemia is to bubble 100% oxygendark blood is due to methemoglobinemia is to bubble 100% oxygen
in a tube that contains the dark bloodin a tube that contains the dark blood.. Blood that remains dark likelyBlood that remains dark likely
does so because of the presence of methemoglobindoes so because of the presence of methemoglobin ..
Another simple testAnother simple test is to place 1-2 drops of blood on whiteis to place 1-2 drops of blood on white
filter paper, then evaluate for color change upon exposure to oxygenfilter paper, then evaluate for color change upon exposure to oxygen
. (. (This test can be accelerated by gently blowing supplementalThis test can be accelerated by gently blowing supplemental
oxygen onto the filter paperoxygen onto the filter paper.).) Deoxygenated hemoglobin changesDeoxygenated hemoglobin changes
from dark red or violet to bright red, whereas methemoglobinfrom dark red or violet to bright red, whereas methemoglobin
remains brownremains brown ..
Serum levels of nitrites or other offending drugsSerum levels of nitrites or other offending drugs
may be determinedmay be determined.. Often, these results are not immediatelyOften, these results are not immediately
available, and treatment may have to be started empirically if theavailable, and treatment may have to be started empirically if the
index of suspicion is highindex of suspicion is high..

23. ManagementManagement
Early clinical recognition of methemoglobinemia is
paramount. Treatment is determined by the
symptoms:
 Severe methemoglobinemia can be lifeSevere methemoglobinemia can be life--threatening and necessitatethreatening and necessitate
emergency therapyemergency therapy
 Chronic mild methemoglobinemia may be completely asymptomaticChronic mild methemoglobinemia may be completely asymptomatic
and necessitate no specific therapyand necessitate no specific therapy
 No pharmacologic treatment exists for hereditary forms ofNo pharmacologic treatment exists for hereditary forms of
methemoglobinemiamethemoglobinemia
Initial care includes the followingInitial care includes the following::
 Administration of supplemental oxygenAdministration of supplemental oxygen
 Determination of the underlying etiology (eg, toxin orDetermination of the underlying etiology (eg, toxin or
drug)drug)
 Removal of the offending oxidizing substanceRemoval of the offending oxidizing substance

24. After acute exposure to an oxidizing agent, it is advisable to treat
patients with methemoglobin levels of 20% or higher (or lower
levels, such as 10%, if there are significant comorbidities
especially in the presence of end-organ dysfunction .
Treatment modalities include the following :
Methylene blue – This is the primary emergency treatment for
documented symptomatic methemoglobinemia (1-2mg/kg up to a total
Of 50 mg in adults & older childern) as a 1% solution in IV saline over 3-5
min . NB MB is it self an oxidant in greater than 7mglkg
(contraindicated in G6PD deficiency and ineffective with hemoglobin
M(
Exchange transfusion - This can be considered for patients who do
not respond to methylene blue or G6PD-deficient individuals who are
severely symptomatic
Hyperbaric oxygen treatment – This is another option when
methylene blue therapy is ineffective or contraindicated
IV hydration and bicarbonate (for metabolic acidosis)
Other medications – These include ascorbic acid, riboflavin, cimetidine,
and N -acetylcysteine
Dietary measures – Avoidance of precipitants in food or drink