Serena Ezzeddine Morning Report March 2, 2009

Methemoglobin

Altered state of hemoglobin in which the ferrous (Fe2+) irons of heme are oxidized to the Ferric (Fe3+) state. Ferric hemes of methemoglobin are unable to bind oxygen, furthermore the oxygen affinity of any accompanying ferrous hemes in the hemoglobin tetramer is increased thus decreasing O2 delivery to tissues-(left-shifting the O2 dissociation curve) Result- FUNCTIONAL ANEMIA-methemoglobin molecules unable to carry and deliver O2 to the tissues.

O2 dissociation curve

Pathophysiology

Autooxidation of Hgb to MetHgb occurs spontaneously at a slow rate in normal individuals , converting 0.5 to 3% of available hgb to methgb per day. The only physiologically important pathway for reducing metHgb back to Hgb is NADH-dependent reaction catalyzed by cytochrome b5 reductase, and an alternate pathway is an enzyme utilizing NADPH generated by G6PD, however there is normally no electron carrier present in RBCs to interact with NADPH methemoglobin reductase, as a result, electron acceptors, such as methylene blue and flavin are required for this pathway to work Formation and reduction of methgb maintains a steady state level of methgb of about 1% of total Hgb

Methemoglobinemia Causes

Congential most common Cytochrome b5 reductase deficiency Acquired- in our case DAPSONE, but also:
Acetonitrile (nail remover) Anesthetics ie local (benzocaine, lidocaine, prilocaine) Aniline Dyes Chlorates (matches, explosives, weed killers) Dapsone Napthalene (mothballs) Volatile Nitrites (Amyl, Butyl, Isobutyl) Nitroprusside Sodium Nitrite/Silver nitrate Phenacetin Phenazopyridine (Pyridium) Quinones (chloroquine, primaquine) Sulfonamides Metaclopramide Riluzole Methylene Blue

Clinical Features

Cyanosis (mucous membranes and lips, also fingers)in the face of normal arterial PaO2detected when abs concentration of methemoglobin exceeds 1.5g/dl, equivalent to 812 % methgb. Cyanosis usually around 15% or greater methgb 20-45% can cause HA, lethargy, weakness, dizziness, tachycardia. >45% dyspnea, acidosis, cardiac arrythmias, heart failure, seizures, and coma >70% high mortality.

Clinical Clues to Diagnosis

Chocolate brown blood arterial

Pulse Oximetry Inaccurate The Saturation Gap

Pulse oximetry is based on light absorption of oxyhemoglobin and reduced hemoglobin at wavelengths of red light at 660nm and infrared at 940nm.O2 sat is calculated from the ratio of absorbance at these two wavelengths, and the ratio is compared to universal table of arterial O2 sats and absorbance ratios that have been produced from exposing volunteers to varying degrees of hypoxia. Methgb has 2 absorption peaks 630 and 960 nm. The absorbance of metHgb at 660 and 940 nm is similar resulting in 1:1 ratio-which corresponds to 85% o2 sat. As levels rise, O2 sat will fall on pulse ox and plateau at 85%. Definitive dx is made with co-oximetry which involves use of multiple wavelength spectrophotometers that measure levels of several hemoglobin species, including metHgb abd CarboxyHgb

The Saturation Gap Continued. . .

The limitation of co-oximetry is that it interprets all readings in the 630nm range as Methemoglobin, so false positives can occur in presence of other pigments including sulfhemoglobin and methylene blue. So confirm methemoglobin detected by cooximeter by the specific Evelyn-Malloy method, which involves addition of cyanide which binds methgb and changes peak to 635nm. Methgb is then expressed as percentage of total hemoglobin

DAPSONE and Methemoglobinemia

Many Case Reports are available In one of the largest retrospective studies out of Hopkins and one of its affliates, they described 138 cases of acquired methemoglobinemia at 2 tertialry care hospitals over 28 months, and Dapsone was the most common, accounting for 58 cases (42%), but those cases were generally mild, the most severe cases were due to the use of 20% benzocaine spray.

Dapsone

Dapsone well absorbed through GI tract, and hepatic oxidation is thought to be mediated through cytochrome P450 3A4. Dapsone N-hydroxylation is how its eliminated and becomes dapsone hydroxylamine which is a potent oxidant and thought to be responsible for methemoglonemia. One study in the British Journal of clinical pharmacology in 1992 observed that in patients who were on daily high dose dapsone for dermatitis herpetiformis, the levels of hydroxylamine dapsone was decreased with coadministration of Cimetidine, which inhibits the P450 system. There was a decrease in methemoglobin levels, cyanosis, and symptoms.

Dapsone
In

a pediatric study, 20% (3/15) of children with ALL on Dapsone developed metHgb, and the average duration of prophylaxis to diagnosis was 6.6 weeks, with mean metHgb levels in symptomatic patients 11.67%.

Dapsone and Methemoglobinemia

Important

to remember and think of especially in our patient populationTransplant patients, HIV patients, and Chemo/Radiation patients Discrepancy of pulse ox and arterial blood gas, mild cyanosis, or even hemodynamic instability as acts as a functional anemia.

Treatment of Acquired Methgb

First,

STOP OFFENDING AGENT! Methylene Blue given intravenously in a dose of 1-2 mg/kg over 5 minutes.
Response usually rapid Can be repeated in 1 hr, if needed

Treatment Continued
Doses

of Methylene Blue >15mg/kg can cause methemoglobinemia or worsen existing Methgb Rebound metHgb can also occur up to 12hrs post treatment due to continued absorption of drug or persistence of intermediate metabolites

Treatment

Cimetidine has been shown to reduce chronicly elevated levels of methemoglobinemia, but works over several weeks, so no use in acute situation Ascorbic acid can be used 300-1000mg/day in divided doses in chronic conditions not acute acquired cases Activated Charcoal can be used in acute poisoning, with multiple doses Hyperbaric Oxygen Exchange transfusion in resistant cases to methylene blue or severe cases with cardiovascular collapse

Treatment Caveat
Do

NOT give methylene blue to G6PD deficient patients since the reduction of methgb by MB is dependent upon NADPH generated by G6PD, and can cause hemolysis-can use moderate doses of Ascorbic acid.

References

Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia :a retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore) 2004;83:265-273. Zosel et al. Dapsone-Induced Methemoglobinemia:Case report and literature review. American Journal of Therapeutics 14, 585-587 (2007) Coleman et al. The use of Cimetidine to reduce dapsone-dependent methemoglobinemia in dermatitis herpetiformis patients. British Journal of Clinical Pharmacology (1992), 34, 244-249 ODwyer et al. A case of dapsone induced methemoglobinemia. Irish Journal of Medical Science (2008) 177:273-275. Turner et al. The Recognition, Physiology, and Treament of Medication induced Methemoglobinemia: A case Report. Anesthesia Prognosis 54:115117. 2007 Walker et al. Dapsone induced methemoglobinemia in a patient with glioblastoma. Journal of Neuro-oncology. February 2009 Hurford et al. Case 23-2004 : A 50 y/o Woman with low oxygen saturation.NEJM 2004; 351:380-87. Uptodate. Diagnosis and treatment of methemoglobinemia