3.2.09. ezzeddine. methemoglobinemia (2)

8/3/2019 3.2.09. Ezzeddine. Methemoglobinemia (2)

1/22


2/22

MethemoglobinMethemoglobin

Altered state of hemoglobin in which the ferrousAltered state of hemoglobin in which the ferrous(Fe2+) irons of heme are oxidized to the Ferric(Fe2+) irons of heme are oxidized to the Ferric(Fe3+) state.(Fe3+) state.

Ferric hemes of methemoglobin are unable toFerric hemes of methemoglobin are unable to

bind oxygen, furthermore the oxygen affinity ofbind oxygen, furthermore the oxygen affinity ofany accompanying ferrous hemes in theany accompanying ferrous hemes in thehemoglobin tetramer is increased thushemoglobin tetramer is increased thusdecreasing O2 delivery to tissues-(left-shiftingdecreasing O2 delivery to tissues-(left-shifting

the O2 dissociation curve)the O2 dissociation curve)

Result- FUNCTIONAL ANEMIA-methemoglobinResult- FUNCTIONAL ANEMIA-methemoglobinmolecules unable to carry and deliver O2 to themolecules unable to carry and deliver O2 to thetissues.tissues.


3/22

O2 dissociation curveO2 dissociation curve


4/22

PathophysiologyPathophysiology

Autooxidation of Hgb to MetHgb occurs spontaneously atAutooxidation of Hgb to MetHgb occurs spontaneously ata slow rate in normal individuals , converting 0.5 to 3% ofa slow rate in normal individuals , converting 0.5 to 3% ofavailable hgb to methgb per day.available hgb to methgb per day.

The only physiologically important pathway for reducingThe only physiologically important pathway for reducingmetHgb back to Hgb is NADH-dependent reactionmetHgb back to Hgb is NADH-dependent reactioncatalyzed bycatalyzed by cytochrome b5 reductasecytochrome b5 reductase, and an alternate, and an alternatepathway is an enzyme utilizing NADPH generated bypathway is an enzyme utilizing NADPH generated byG6PD, however there is normally no electron carrierG6PD, however there is normally no electron carrierpresent in RBCs to interact withpresent in RBCs to interact with NADPH methemoglobinNADPH methemoglobinreductasereductase, as a result, electron acceptors, such as, as a result, electron acceptors, such as

methylene bluemethylene blue and flavin are required for this pathway toand flavin are required for this pathway toworkwork Formation and reduction of methgb maintains a steadyFormation and reduction of methgb maintains a steady

state level of methgb of aboutstate level of methgb of about 1% of total Hgb1% of total Hgb


5/22


6/22


7/22

Methemoglobinemia CausesMethemoglobinemia Causes CongentialCongential most common Cytochrome b5most common Cytochrome b5

reductase deficiencyreductase deficiency

AcquiredAcquired- in our case- in our case DAPSONEDAPSONE, but also, but also:: Acetonitri lecetonitri le (nail remover)(nail remover) Anestheticsnesthetics ie localie local (benzocaine, lidocaine, prilocaine)(benzocaine, lidocaine, prilocaine) Aniline Dyesnil ine Dyes Chlorateshlorates (matches, explosives, weed killers)(matches, explosives, weed killers) Dapsoneapsone Napthaleneapthalene (mothballs)(mothballs) Volatile Nitritesolati le Nitrites (Amyl, Butyl, Isobutyl)(Amyl, Butyl, Isobutyl) Nitroprussideitroprusside Sodium Nitrite/Silver nitrateodium Nitrite/Silver nitrate Phenacetinhenacetin Phenazopyridinehenazopyridine (Pyridium)(Pyridium) Quinonesuinones (chloroquine, primaquine)(chloroquine, primaquine) Sulfonamidesulfonamides Metaclopramideetaclopramide Riluzolei luzole Methylene Blueethylene Blue


8/22

Clinical FeaturesClinical Features

Cyanosis (mucous membranes and lips, alsoCyanosis (mucous membranes and lips, alsofingers)in the face of normal arterial PaO2-fingers)in the face of normal arterial PaO2-detected when abs concentration ofdetected when abs concentration ofmethemoglobin exceeds 1.5g/dl, equivalent to 8-methemoglobin exceeds 1.5g/dl, equivalent to 8-

12 % methgb. Cyanosis usually around 15% or12 % methgb. Cyanosis usually around 15% orgreater methgbgreater methgb 20-45% can cause HA, lethargy, weakness,20-45% can cause HA, lethargy, weakness,

dizziness, tachycardia.dizziness, tachycardia.

>45% dyspnea, acidosis, cardiac arrythmias,>45% dyspnea, acidosis, cardiac arrythmias,heart failure, seizures, and comaheart failure, seizures, and coma >70% high mortality.>70% high mortality.


9/22

Clinical Clues to DiagnosisClinical Clues to Diagnosis


10/22

Chocolate brown blood arterialChocolate brown blood arterial


11/22

Pulse Oximetry InaccuratePulse Oximetry InaccurateThe Saturation GapThe Saturation Gap Pulse oximetry is based on light absorption ofPulse oximetry is based on light absorption of

oxyhemoglobin and reduced hemoglobin at wavelengthsoxyhemoglobin and reduced hemoglobin at wavelengthsof red light at 660nm and infrared at 940nm.O2 sat isof red light at 660nm and infrared at 940nm.O2 sat iscalculated from the ratio of absorbance at these twocalculated from the ratio of absorbance at these twowavelengths, and the ratio is compared to universal tablewavelengths, and the ratio is compared to universal table

of arterial O2 sats and absorbance ratios that have beenof arterial O2 sats and absorbance ratios that have beenproduced from exposing volunteers to varying degrees ofproduced from exposing volunteers to varying degrees ofhypoxia.hypoxia.

Methgb has 2 absorption peaksMethgb has 2 absorption peaks 630 and 960 nm630 and 960 nm. The. Theabsorbance of metHgb at 660 and 940 nm is similarabsorbance of metHgb at 660 and 940 nm is similar

resulting in 1:1 ratio-which corresponds toresulting in 1:1 ratio-which corresponds to 85% o2 sat85% o2 sat. As. Aslevels rise, O2 sat will fall on pulse ox and plateau atlevels rise, O2 sat will fall on pulse ox and plateau at85%.85%.

Definitive dx is made withDefinitive dx is made with co-oximetryco-oximetry which involves usewhich involves useof multiple wavelength spectrophotometers that measureof multiple wavelength spectrophotometers that measure

levels of several hemoglobin species, including metHgblevels of several hemoglobin species, including metHgbabd CarboxyHgbabd CarboxyHgb


12/22

The Saturation Gap Continued. . .The Saturation Gap Continued. . .

The limitation of co-oximetry is that it interpretsThe limitation of co-oximetry is that it interpretsall readings in the 630nm range asall readings in the 630nm range asMethemoglobin, so false positives can occur inMethemoglobin, so false positives can occur inpresence of other pigments includingpresence of other pigments including

sulfhemoglobin and methylene blue.sulfhemoglobin and methylene blue.

So confirm methemoglobin detected by co-So confirm methemoglobin detected by co-oximeter by the specificoximeter by the specific Evelyn-Malloy method,Evelyn-Malloy method,

which involves addition of cyanide which bindswhich involves addition of cyanide which bindsmethgb and changes peak to 635nm. Methgb ismethgb and changes peak to 635nm. Methgb isthen expressed asthen expressed as percentage of totalpercentage of totalhemoglobinhemoglobin


13/22

DAPSONE and MethemoglobinemiaDAPSONE and Methemoglobinemia

Many Case Reports are availableMany Case Reports are available

In one of the largest retrospective studies out ofIn one of the largest retrospective studies out of

Hopkins and one of its affliates, they describedHopkins and one of its affliates, they described

138 cases of acquired methemoglobinemia at 2138 cases of acquired methemoglobinemia at 2tertialry care hospitals over 28 months, andtertialry care hospitals over 28 months, and

Dapsone was the most common, accounting forDapsone was the most common, accounting for

58 cases (42%), but those cases were generally58 cases (42%), but those cases were generally

mild, the most severe cases were due to the usemild, the most severe cases were due to the useof 20% benzocaine spray.of 20% benzocaine spray.


14/22

DapsoneDapsone

Dapsone well absorbed through GI tract, and hepaticDapsone well absorbed through GI tract, and hepaticoxidation is thought to be mediated through cytochromeoxidation is thought to be mediated through cytochromeP450 3A4. Dapsone N-hydroxylation is how its eliminatedP450 3A4. Dapsone N-hydroxylation is how its eliminatedand becomes dapsone hydroxylamine which is a potentand becomes dapsone hydroxylamine which is a potent

oxidant and thought to be responsible foroxidant and thought to be responsible formethemoglonemia.methemoglonemia. One study in the British Journal of clinical pharmacologyOne study in the British Journal of clinical pharmacology

in 1992 observed that in patients who were on daily highin 1992 observed that in patients who were on daily highdose dapsone for dermatitis herpetiformis, the levels ofdose dapsone for dermatitis herpetiformis, the levels of

hydroxylamine dapsone was decreased with co-hydroxylamine dapsone was decreased with co-administration of Cimetidine, which inhibits the P450administration of Cimetidine, which inhibits the P450system. There was a decrease in methemoglobin levels,system. There was a decrease in methemoglobin levels,cyanosis, and symptoms.cyanosis, and symptoms.


15/22

DapsoneDapsone

In a pediatric study, 20% (3/15) ofIn a pediatric study, 20% (3/15) of

children with ALL on Dapsone developedchildren with ALL on Dapsone developed

metHgb, and the average duration ofmetHgb, and the average duration of

prophylaxis to diagnosis was 6.6 weeks,prophylaxis to diagnosis was 6.6 weeks,with mean metHgb levels in symptomaticwith mean metHgb levels in symptomatic

patients 11.67%.patients 11.67%.


16/22

Dapsone and MethemoglobinemiaDapsone and Methemoglobinemia

Important to remember and think ofImportant to remember and think of

especially in our patient population-especially in our patient population-

Transplant patients, HIV patients, andTransplant patients, HIV patients, and

Chemo/Radiation patientsChemo/Radiation patients Discrepancy of pulse ox and arterial bloodDiscrepancy of pulse ox and arterial blood

gas, mild cyanosis, or even hemodynamicgas, mild cyanosis, or even hemodynamic

instability as acts as a functional anemia.instability as acts as a functional anemia.


17/22

Treatment of Acquired MethgbTreatment of Acquired Methgb

First,First, STOP OFFENDING AGENTSTOP OFFENDING AGENT!!

Methylene BlueMethylene Blue given intravenously in agiven intravenously in a

dose ofdose of1-2 mg/kg over 5 minutes1-2 mg/kg over 5 minutes..

Response usually rapidResponse usually rapid

Can be repeated in 1 hr, if neededCan be repeated in 1 hr, if needed


18/22

Treatment ContinuedTreatment Continued

Doses of Methylene Blue >15mg/kg canDoses of Methylene Blue >15mg/kg can

cause methemoglobinemia or worsencause methemoglobinemia or worsen

existing Methgbexisting Methgb

Rebound metHgb can also occur up toRebound metHgb can also occur up to

12hrs post treatment due to continued12hrs post treatment due to continued

absorption of drug or persistence ofabsorption of drug or persistence of

intermediate metabolitesintermediate metabolites


19/22

TreatmentTreatment

Cimetidine has been shown to reduce chronicly elevatedCimetidine has been shown to reduce chronicly elevatedlevels of methemoglobinemia, but works over severallevels of methemoglobinemia, but works over severalweeks, so no use in acute situationweeks, so no use in acute situation

Ascorbic acid can be used 300-1000mg/day in dividedAscorbic acid can be used 300-1000mg/day in divideddoses in chronic conditions not acute acquired casesdoses in chronic conditions not acute acquired cases

Activated Charcoal can be used in acute poisoning, withActivated Charcoal can be used in acute poisoning, withmultiple dosesmultiple doses

Hyperbaric OxygenHyperbaric Oxygen

Exchange transfusion in resistant cases to methylene blueExchange transfusion in resistant cases to methylene blueor severe cases with cardiovascular collapseor severe cases with cardiovascular collapse


20/22

Treatment CaveatTreatment Caveat

Do NOT give methylene blue to G6PDDo NOT give methylene blue to G6PD

deficient patients since the reduction ofdeficient patients since the reduction of

methgb by MB is dependent upon NADPHmethgb by MB is dependent upon NADPH

generated by G6PD, and can causegenerated by G6PD, and can causehemolysis-can use moderate doses ofhemolysis-can use moderate doses of

Ascorbic acid.Ascorbic acid.


21/22
http://photobucket.com/http://images.google.com/imgres?imgurl=http://www.wunderkabinett.co.uk/gallery/albums/userpics/10003/blue_man.jpg&imgrefurl=http://www.wunderkabinett.co.uk/damndata/index.php%3F/archives/1185-Why-so-blue.html&usg=__lw6Amd1gH-h965g4nRHz2YikMTY=&h=317&w=470&sz=30&hl=en&start=14&um=1&tbnid=yUdlK4Arlwq6TM:&tbnh=87&tbnw=129&prev=/images%3Fq%3Dmethemoglobinemia%2Band%2Bblue%2Bman%26um%3D1%26hl%3Den%26rlz%3D1T4SUNA_enUS311US286%26sa%3DN


22/22

ReferencesReferences

Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia :aAsh-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia :aretrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore)retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore)2004;83:265-273.2004;83:265-273.

Zosel et al. Dapsone-Induced Methemoglobinemia:Case report and literatureZosel et al. Dapsone-Induced Methemoglobinemia:Case report and literaturereview. American Journal of Therapeutics 14, 585-587 (2007)review. American Journal of Therapeutics 14, 585-587 (2007)

Coleman et al. The use of Cimetidine to reduce dapsone-dependentColeman et al. The use of Cimetidine to reduce dapsone-dependent

methemoglobinemia in dermatitis herpetiformis patients. British Journal ofmethemoglobinemia in dermatitis herpetiformis patients. British Journal ofClinical Pharmacology (1992), 34, 244-249Clinical Pharmacology (1992), 34, 244-249 ODwyer et al. A case of dapsone induced methemoglobinemia. Irish JournalODwyer et al. A case of dapsone induced methemoglobinemia. Irish Journal

of Medical Science (2008) 177:273-275.of Medical Science (2008) 177:273-275. Turner et al. The Recognition, Physiology, and Treament of MedicationTurner et al. The Recognition, Physiology, and Treament of Medication

induced Methemoglobinemia: A case Report. Anesthesia Prognosis 54:115-induced Methemoglobinemia: A case Report. Anesthesia Prognosis 54:115-117. 2007117. 2007

Walker et al. Dapsone induced methemoglobinemia in a patient withWalker et al. Dapsone induced methemoglobinemia in a patient withglioblastoma. Journal of Neuro-oncology. February 2009glioblastoma. Journal of Neuro-oncology. February 2009

Hurford et al. Case 23-2004 : A 50 y/o Woman with low oxygenHurford et al. Case 23-2004 : A 50 y/o Woman with low oxygensaturation.NEJM 2004; 351:380-87.saturation.NEJM 2004; 351:380-87.

Uptodate. Diagnosis and treatment of methemoglobinemiaUptodate. Diagnosis and treatment of methemoglobinemia

3.2.09. ezzeddine. methemoglobinemia (2)

Documents