Methaemoglobinaemia and arsenic poisoning

• Methaemoglobinaemia is an excess of haemoglobin in the ferric (Fe3+) form, which cannot carry oxygen. It produces cyanosis and chocolate-brown blood that does not improve with oxygen.
• Acquired cases come from oxidant drugs and chemicals: dapsone, nitrates and nitrites, nitroglycerin, and local anaesthetics such as benzocaine and prilocaine.
• Two clues are a pulse oximeter reading that sits near 85% and a gap between the oximeter saturation (SpO2) and the calculated arterial saturation (SaO2). Co-oximetry gives the true methaemoglobin percentage. ^[1]
• Intravenous methylene blue 1 to 2 mg per kg is first-line in symptomatic patients; it is ineffective and potentially harmful in G6PD deficiency, where exchange transfusion or high-dose ascorbic acid is used instead. ^[1][2]
• Arsenic poisoning is usually from contaminated water, soil, pesticides, or intentional ingestion. Acute illness is a bloody, rice-water gastroenteritis with hypovolaemic shock, QT prolongation and arrhythmias.
• Chronic arsenic causes skin pigmentation and keratosis, Mees lines in the nails, sensorimotor neuropathy, bone marrow suppression and cancer. Diagnosis rests on a 24-hour urine arsenic; chelation is dimercaprol 3 to 5 mg per kg intramuscularly every 4 to 6 hours until urine arsenic falls below 50 micrograms per litre. ^{[3][4] [1]}

By the end of this page you should be able to:

1. Explain why methaemoglobin cannot carry oxygen and why the oxygen dissociation curve shifts left.
2. List the common acquired causes and distinguish them from congenital causes.
3. Recognise the clinical clues (cyanosis, chocolate-brown blood, saturation gap, pulse oximeter near 85%) and choose the right test.
4. State the methylene blue dose, its limits, and the safety issue in G6PD deficiency.
5. Describe acute and chronic arsenic poisoning, including cancers, and interpret urine arsenic results. ^[4]
6. Plan chelation for arsenic and compare lead, mercury and iron poisoning.

In health about 1% of total haemoglobin is methaemoglobin, kept in check by the NADH-dependent cytochrome b5 reductase system. ^[1] A smaller, G6PD-dependent NADPH pathway exists but normally contributes little; it is the target that methylene blue activates. ^[1]

There are two broad types. Congenital forms are the result of deficient cytochrome b5 reductase (types I and II) or structurally abnormal haemoglobin (haemoglobin M disease). Acquired forms are by far the more common, and follow exposure to oxidising agents. ^[1]

The acquired causes are the ones you will meet clinically. Drugs and chemicals turn haemoglobin to its ferric form faster than the reducing systems can cope. ^[1]

• Antibiotics: dapsone (the classic culprit), sulfonamides, trimethoprim. Dapsone is lipophilic and can cause delayed or rebound methaemoglobinaemia.
• Analgesics and urinary antiseptics: phenazopyridine, phenacetin.
• Local anaesthetics: benzocaine, lidocaine, prilocaine, articaine, tetracaine, cetacaine. Topical benzocaine sprays and lozenges are a frequent cause, including in children.
• Nitrates and nitrites: nitroglycerin, sodium nitroprusside, amyl nitrite (poppers), nitrate-contaminated well water, contaminated (over-refrigerated or cured) food.
• Other oxidants: rasburicase, chloroquine and primaquine, metoclopramide, cyclophosphamide and flutamide, aniline dyes, naphthalene, chlorates and bromates, herbicides and pesticides. ^[1]

Congenital causes ^[1][2]:

• Cytochrome b5 reductase deficiency: type I affects red cells only and is relatively mild; type II affects all tissues and includes neurological impairment because the enzyme is deficient everywhere.
• Haemoglobin M disease: an autosomal dominant mutation of the alpha, beta or gamma chain that permanently raises methaemoglobin to 15 to 30%. These patients are often well with cyanosis as the only sign and do not respond to methylene blue or ascorbic acid; exchange transfusion may be needed. ^[1]
• G6PD deficiency is often wrongly thought to cause methaemoglobinaemia. It does not itself do so; it is a risk factor for haemolysis once oxidants are given. ^[1]

Presentation depends on how much of the haemoglobin has been oxidised and on the patient's cardiorespiratory reserve.

• Chronic or inherited methaemoglobinaemia can be tolerated up to around 40%, with cyanosis as the only sign. ^[1]
• Healthy adults are usually asymptomatic below 10%.
• 10 to 20%: cyanotic, slate-grey skin and chocolate-brown blood, but no hypoxic symptoms.
• 20 to 30%: anxiety, light-headedness, headache, tachycardia, breathlessness and syncopal attacks. ^[1]
• 30 to 50%: fatigue, confusion, dizziness, tachypnoea, marked tachycardia, weakness. Dyspnoea, nausea and tachycardia generally occur above 30%; lethargy, stupor and deteriorating consciousness occur as levels reach 50%. ^[1]
• 50 to 70%: coma, seizures, arrhythmias, lactic acidosis, central nervous system depression. ^[1]
• Above 70%: profound hypoxia and death. ^[1]

The blood is chocolate-brown and does not turn red on shaking with air. A striking clue is a pulse oximeter saturation that hovers around 85% and will not rise with oxygen, because methaemoglobin absorbs equally at the two wavelengths the oximeter uses (660 nm and 940 nm). ^[1] At the same time the calculated arterial saturation (SaO2) on the arterial blood gas and the PaO2 may look normal, producing a saturation gap between SaO2 and SpO2 that is refractory to oxygen. ^[1]

Patients with coronary, pulmonary or cerebrovascular disease, sepsis, acidosis or anaemia tolerate much less methaemoglobin and should be treated when levels reach 10%; everyone with a level of 30% or more needs treatment. ^[1][2]

• Co-oximetry is the most effective test. It directly measures methaemoglobin by adding wavelengths of light (600 nm and 631 nm) to the standard pulse-oximeter pair. ^[1]
• The Evelyn-Malloy (cyanide) modification of co-oximetry removes methylene blue and sulfhaemoglobin as false positives; a sulfhaemoglobin band can mimic methaemoglobinaemia after dapsone, phenacetin or sulfonamides. ^[1]
• Full blood count and blood film to exclude haemolysis and anaemia; G6PD testing in anyone without a known history of methaemoglobinaemia before methylene blue is considered. ^[2]
• Enzyme assay (cytochrome b5 reductase activity) is the gold-standard test to distinguish hereditary deficiency from acquired disease; molecular testing confirms it. ^[2]
• Look for the culprit: recent benzocaine spray, dapsone, nitrate water, and check nitrite with a dipstick where available.

Methaemoglobin (% of haemoglobin) and typical picture:

• Under 10 (under 1.5 g/dL): none; normal. ^[1]
• 10 to 20 (1.5 to 3.0 g/dL): cyanosis, chocolate-brown blood, no hypoxic symptoms. ^[1]
• 20 to 30 (3.0 to 4.5 g/dL): anxiety, light-headedness, headache, tachycardia, breathlessness, syncope.
• 30 to 50 (4.5 to 7.5 g/dL): fatigue, confusion, dizziness, tachypnoea, marked tachycardia, weakness.
• 50 to 70 (7.5 to 10.5 g/dL): coma, seizures, arrhythmias, lactic acidosis.
• Over 70 (over 10.5 g/dL): profound hypoxia, death. ^[1]

1. Stop the oxidant and remove the patient from the source (including skin decontamination for aniline or pesticide exposure).
2. High-flow oxygen through a non-rebreather mask; it will not correct the co-oximetry reading but improves the remaining haemoglobin.
3. Methylene blue 1 to 2 mg per kg intravenously over 5 minutes (as a 1% solution) for symptomatic patients or for levels above 30% without symptoms, and above 20% when symptomatic. ^[1][2]
   • Repeat after 30 to 60 minutes if symptoms persist or the level stays above threshold, up to 5.5 mg per kg total. ^[2]
   • Do not exceed 7 mg per kg total; doses of 15 mg per kg or more can lyse red cells directly. ^[1]
   • Response is usually rapid. Rebound methaemoglobinaemia can occur up to 18 hours later with lipophilic agents such as benzocaine, so recheck levels. ^[1]
   • Give dextrose, which supplies NADPH through the hexose monophosphate shunt, and correct acid-base and volume disturbances.
   • It is usually ineffective or actually worsens haemolysis in G6PD deficiency, and it is contraindicated with serotonergic drugs because of serotonin syndrome and with monoamine oxidase inhibitors. ^[1]
4. Ascorbic acid acts slowly by non-enzymatic reduction and is useful as an adjunct, or when methylene blue is unavailable or contraindicated. Doses in the literature range from 1 g once to 10 g every 6 hours; there is no consistent recommendation. ^[1]
5. Alternatives when methylene blue fails or is contraindicated: high-dose ascorbic acid, exchange transfusion, hyperbaric oxygen, RBC transfusion. Exchange transfusion is the treatment for haemoglobin M disease, and RBC transfusion has been used at methaemoglobin levels above 70%. ^[1]
6. For dapsone specifically, cimetidine inhibits the cytochrome P450 conversion to dapsone hydroxylamine and limits further methaemoglobinaemia; use expert advice for ongoing therapy. ^[1]

Arsenic is a naturally occurring element. Inorganic arsenic (the more toxic form) is found in rock, soil and groundwater, and in occupational and historical uses such as wood preservatives, pesticides and metal smelting. ^[4] Organic arsenic from seafood is essentially non-toxic and can confound urine testing. ^[3][4]

Important sources:

• Contaminated well or groundwater (the commonest route worldwide; the US EPA drinking water standard is 10 micrograms per litre). ^[4]
• Rice and crops grown in contaminated soil or irrigated with contaminated water. ^[4]
• Occupational exposure in mining, smelting, pesticide application, and semiconductor manufacture. ^[4]
• Traditional or imported homeopathic and naturopathic remedies; contaminated soils; CCA-treated wood. ^[4]
• Acute ingestion, usually suicidal or homicidal. ^[3]

Acutely, arsenic is a cellular poison: it disrupts mitochondrial respiration, uncouples oxidative phosphorylation and damages small blood vessels. The fatal dose of arsenic trioxide may be as little as 1 to 2.5 mg per kg. ^[3]

Classically there is a severe, rapidly progressing haemorrhagic gastroenteritis within 30 minutes to several hours of ingestion: burning in the mouth and throat, a metallic or garlic taste, intense thirst, severe abdominal pain, violent vomiting, and bloody or rice-water diarrhoea with dehydration, electrolyte upset, shock and possible intestinal perforation. ^[3]

Other early features:

• Cardiac: sinus tachycardia, QT prolongation, ST depression, flattened T waves, ventricular tachycardia (including torsades), ventricular fibrillation and heart failure from capillary leak. ^[3]
• Neurological: encephalopathy, seizures, coma; a peripheral neuropathy resembling Guillain-Barre syndrome, with pins-and-needles and shock-like pain in the feet, progressing to numbness and motor weakness. ^[3]
• Renal: glomerular damage and tubular necrosis leading to oliguria and renal failure. ^[3]
• Hepatic, haematological and mucocutaneous: hepatitis; bone marrow suppression with anaemia, leucopenia or pancytopenia; periorbital oedema and flushing. ^[3]

Patients who survive the acute phase may still develop delayed neuropathy and marrow suppression; peripheral neuropathy is often only partly reversible over months to years. ^[3]

Chronic low-dose exposure, most often from drinking water over years, produces its own signature:

• Skin: the hallmark is pigmentation change (raindrop pigmentation, diffuse darkening with small hypopigmented spots on the trunk, neck and face) plus keratosis (diffuse thickening or nodules on the palms and soles). These take about 3 to 7 years to appear and can be precursors to non-melanoma skin cancer. ^[3][4]
• Nails: Mees lines, transverse white lines across the nails, which appear after acute or chronic exposure. ^[3]
• Nervous system: a symmetric stocking-glove sensory (more than motor) neuropathy that can be the only symptom of chronic exposure. ^[4]
• Haematological: anaemia, leucopenia, thrombocytopenia from bone marrow suppression. ^[4]
• Cardiovascular and metabolic: increased risk of vascular disease and type 2 diabetes. ^[4]
• Cancer: arsenic is a human carcinogen. Associations are strongest for lung cancer, non-melanoma skin cancer and bladder cancer, with limited evidence for kidney, liver and prostate cancer. ^[4]

Because symptoms are non-specific and often delayed, diagnosis depends on timing and the right specimen.

• 24-hour urine arsenic is the key test for recent exposure. Normal total urinary arsenic is under 50 micrograms per litre if no seafood has been eaten; over 100 micrograms is usually considered abnormal. ^[3]
• Speciation matters: total arsenic includes non-toxic organic arsenic (arsenobetaine, arsenocholine) from seafood within the previous 48 hours, which can push total urinary arsenic into the thousands. Ask about recent shellfish or seaweed intake, or request speciated arsenic, which separates toxic inorganic from organic forms. ^[3][4]
• Blood arsenic is usually under 7 micrograms per 100 mL in non-exposed people; arsenic leaves blood within 1 to 2 hours, so a normal level does not exclude poisoning. ^[3]
• Hair and nails reflect long-term exposure but are easily contaminated externally and have no accepted reference range; they are adjuncts, not proof. ^[3][4]
• Abdominal radiograph may show radiopaque ingested arsenic; a complete blood count looks for marrow suppression. ^[3]

Acute poisoning is an intensive-care problem.

• Supportive care first: aggressive intravenous fluid and electrolyte resuscitation (the shock is hypovolaemic from capillary leak and gut losses), airway protection, monitoring of cardiac rhythm, treatment of arrhythmias, and correction of acid-base disturbance. ^{[3] [2]}
• Gastrointestinal decontamination: do not induce emesis; gastric lavage within 1 hour of a large ingestion; activated charcoal and whole-bowel irrigation may be used. ^{[3] [6]}
• Chelation for symptomatic or significantly exposed patients should not wait for laboratory confirmation, but should be led by a medical toxicologist or poison centre. ^[3][4]
  • Dimercaprol (BAL) is the agent most often recommended acutely: 3 to 5 mg per kg intramuscularly every 4 to 6 hours, continued until the 24-hour urinary arsenic falls below 50 micrograms per litre. ^[3]
  • Contraindications to BAL: pre-existing renal disease, pregnancy (except life-threatening poisoning) and concurrent medicinal iron, with which it forms a highly toxic complex. An increased risk of haemolysis also exists in G6PD deficiency. ^[3]
  • Side effects of BAL tend to appear at 5 mg per kg: hypertension, tachycardia, nausea, vomiting, salivation, lacrimation, headache and sweating. ^[3]
  • Succimer (DMSA) is a less toxic, water-soluble oral alternative, often started once the patient improves or when renal impairment makes BAL unsafe; it is approved for paediatric lead poisoning and used off-label for arsenic. ^[3]
  • Asymptomatic patients should not be chelated without a 24-hour urinary arsenic level; a recent significant exposure with marked GI or cardiovascular symptoms justifies early chelation. ^[3]
• D-penicillamine has been used but is avoided in penicillin-allergic patients and remains controversial. ^[3]

Chronic poisoning is managed differently: the priority is to identify and eliminate the source (safe water, diet, occupation). Symptoms usually improve after exposure stops, though neuropathy may be slow or incomplete. Chelation has an uncertain benefit once neuropathy is established. ^[4]

Survival depends on the dose received and on how quickly treatment starts. Early BAL may not prevent delayed effects entirely. Peripheral neuropathy is often only partly reversible over months to years, and arsenic-related cancers carry the long latency of the exposure. ^[3][4]

• Methaemoglobinaemia: the diagnosis is clinical once you spot cyanosis with a normal or near-normal PaO2 and chocolate-brown blood. A co-oximeter may not be available, but arterial blood gas with co-oximetry is usually present in larger hospitals; where it is not, treat empirically on history and colour. Methylene blue is cheap and stable and should be stocked where oxidative drugs are used; remember G6PD, especially in malaria-endemic and Mediterranean regions.
• Arsenic: the priorities are recognising the exposure (contaminated well water, pesticides, remedies), supporting the circulation, and arranging chelation through a poison centre. Urine arsenic may need to be sent away. Source identification and community water testing matter more than chelation for chronic exposure.
• For mercury and iron, supportive care and early poison-centre contact are the realistic first steps; chelators and deferoxamine should be part of the antidote stock of any acute hospital. ^[5][6]

Acute gastroenteritis; anaemia (approach); glucose-6-phosphate dehydrogenase deficiency; lead poisoning; heavy metal toxicity; peripheral neuropathy; chronic kidney disease; drug-induced methemoglobinaemia; paediatric poisoning; dermatology of the hands (keratosis and pigmentation).