72yo female with recent diagnosis Bullous pemphigoid, HLD presenting complaining of a week of rapid HR in 90s, palpitations, higher than normal BP, and cold blue fingers, toes and blue tint to lips. In triage patient was found to be 89 on RA and placed on 2 L NC rises to 95% other vitals are stable. PIT cardiac w/u including CXR, trop, cbc, cmp, mg, EKG is completely normal. 

On exam she 91% on 2L, and drops to 87 requiring increased O2, with no respiratory distress or increased work of breathing. She is relaxed and able to talk in full sentences and at length, her lungs are clear, equal and non-diminished in all lung fields, heart is RRR. She has cyanotic lips fingers, and toes, but her hands, fingers, and feet are warm with strong equal distal pulses. 

She denies smoking hx, any lung disease including asthma/COPD, house fires, SOB, cp, drug use, fever, chills, n/v, lightheadedness, syncope. She says she has been on topical, PO steroids and some antibiotics for bullous pemphigoid recently, but has been using them without issue for >1 month. Pt says she had cold blue hands several months ago with neg w/u. Pharmacy rx review showed dapsone, confirmed with pt.

Methemoglobinemia:

There are 2 kinds; congenital and acquired methemoglobinemia. Congenital methemoglobinemia happens when individuals do not reduce methemoglobin (hemoglobin with iron in ferric/oxidized state that is unable to reversable bind oxygen) back to functional hemoglobin (ferrous/oxygen-binding hemoglobin) at a normal rate. Congenital causes are found in individuals from consanguineous unions; or in certain isolated populations and present with cyanosis and severe developmental abnormalities in infants. Acquired methemoglobinemia is an increase in the production of methemoglobin due to drugs/other agents at standard prescribed doses as well as overdoses and poisonings. In normal individuals there is a slow auto-oxidation of hemoglobin to methemoglobin, but normal enzymatic mechanisms, using NADH-dependent cytochrome b5 reductase and a G6PD facilitated pathway, keep the amount of methemoglobin at less than 1 %. Increased amounts of methemoglobin lead to a functional anemia as the oxygen carrying capacity is decreased.

            Acquire methemoglobinemia is commonly caused by dapsone and topical anesthetics like benzocaine and lidocaine. However, dapsone, topical anesthetics and other oxidizers are commonly added to heroin, cocaine and other illicit drugs and are likely the cause of acquired methemoglobinemia in drug abusers. Dapsone undergoes enterohepatic recirculation and levels of methb can remain high causing individuals to potentially need retreatment. Other agents are nitrates, nitrites, nitroglycerin, amino salicyclic acid, chloroquine, metoclopramide, sulfonamides, methylene blue, naphthalene, hydrogen peroxide, chlorates, chromates, benzene, antifreeze, aniline, aniline dyes and more. Aniline and derivatives are seen in industry(paints, varnishes, inks, dyes) and are resistant to treatment. 

Diagnosis:  

ABG with Co-oximetry, Evelyn-Malloy method, Rad-57 pulse oximeter 

Signs and symptoms:

• Cyanosis; pale, gray or blue colored skin/lips/nailbeds, lightheadedness, headaches, tachycardia, fatigue, dyspnea, lethargy. As levels increase individuals exhibit respiratory depression, altered mental status, coma, shock, seizures and death. 
• Sudden onset of cyanosis and hypoxia after oxidizing agent. 
• Hypoxia unrelieved with increasing amounts of oxygen
• Cyanosis with normal pO2
• Clinically cyanosis is detected at 8% -12% methemoglobin (methb)
• Methb >30%- 40% are associated with severe hypoxic symptoms and have high mortality rates 
• Blood color described as chocolate brown, dark red, chocolate, or brownish to blue in color

Differential Diagnosis

• Airway obstruction
• Asthma
• Interstitial Lung Disease
• COPD
• Atelectasis
• Pulmonary Embolism
• Hypoventilation 
• Pulmonary edema
• Pneumonia
• Pulmonic stenosis
• Congestive Heart Failure
• Non-Hemoglobin related causes
• Methemoglobinemia
• Polycythemia Vera
• Sulhemoglobin
• Central Cyanosis (Cyanosis of the trunk and head)

Treatment:

ABCs, 100% oxygen, if methb <20% stop offending agent. When >20% methb treatment with Methylene blue or ascorbic acid (vitamin C) is necessary. For reference methylene blue rapidly reduces toxic levels within 10-60 min, whereas ascorbic acid requires multiple doses and may take 24 + hours to work. For symptomatic and/or severe methb inotropes, ventilators, blood or exchange transfusion, or hyperbaric oxygen may be necessary.

Methylene blue 1-2mg/kg IV over 5-30min; 1 hour after treatment recheck level and if still over >20% or rapidly increasing levels, retreat with methylene blue 1-2mg/kg IV over 5-30min. Methylene blue can also cause serotonin syndrome. Methylene blue is contraindicated in G6PD deficient individuals. Toxic dose of methylene blue is >7mg/kg and may cause chest pain, dyspnea, and hemolysis. Methylene blue can also cause serotonin syndrome

Case resolution:

The patient had a methb > 9.1%; after discussing with the lab and RT, our machine top number of detection is apparently 9.1% I called poison control and was advised by the toxicologist to keep on 100% O2, and to give methylene blue at 1mg/kg IV over 5-30min and repeat for second dose 1 hour later if still elevated (>20% methb). After treatment patient’s lips and fingers/toes were drastically back to their normal pink color. Repeat was 5.8 after 1 hour, so repeat dose not recommended, but poison control/toxicologist did recommend an overnight stay. Toxicologist said that after stopping dapsone (which she had taken that morning) there is a risk of rebound methb and need for further treatment. Pt did rebound slightly in hospital, but did not elevate enough for re-treatment and was safely discharged home.

Take home points:

• Regular ABG/VBG will not have methb %, you need to order co-oximetry 
• Since arterial oxygen partial pressure is normal in patients with methemoglobinemia, blood gas analysis will give falsely high levels of oxygen saturation, while a significant portion of hemoglobin is in the non-oxygen carrying methemoglobin form.
• Routine pulse oximetry is inaccurate and will overestimate the fractional oxygen saturation in the presence of methemoglobin 
• Oxidants added to illicit drugs can cause methb
• Common scenarios: children with gastroenteritis and increased nitrates from gut bacteria, children drinking well/contaminated water with nitrates from fertilizer run-off, adult on dapsone or antimalarials

Authors:
Mary Skiffey, DO
Peer reviewed and edited by:
Marc Immerman, MD