Methemoglobinemia, Isoniazid, Sulfonylurea & Local Anesthetic Toxicity
Four poisonings, four specific rescues
Methemoglobinemia
Mechanism. Methemoglobin forms when heme iron is oxidized from the ferrous (Fe²⁺) to the ferric (Fe³⁺) state. Ferric heme cannot carry oxygen, and the remaining ferrous hemes hold their oxygen more tightly (a left-shifted curve), so tissues are starved despite a normal PaO₂. NADH-dependent cytochrome b5 reductase normally keeps methemoglobin around 1%.
Causes. Oxidant drugs and chemicals: benzocaine and other topical anesthetics (a spray before endoscopy or TEE is classic), prilocaine, dapsone, nitrites and nitrates, primaquine, rasburicase, and sulfonamides. Infants are vulnerable because of low cytochrome b5 reductase activity, especially with nitrate-contaminated well water or diarrheal illness. Rare congenital forms include cytochrome b5 reductase deficiency and hemoglobin M.
| Level | Typical features |
|---|---|
| 10–20% | Cyanosis, often little else |
| 20–30% | Headache, anxiety, dyspnea, tachycardia |
| 30–50% | Fatigue, confusion, lightheadedness, tachypnea |
| 50–70% | Seizures, arrhythmias, metabolic acidosis, coma |
| >70% | Often fatal |
Diagnosis. Cyanosis fails to improve with 100% oxygen, and the blood is chocolate-brown and stays brown when exposed to air. Standard pulse oximetry drifts toward about 85% as the level rises, whatever the true saturation, while the blood gas shows a normal PaO₂ and a falsely normal calculated saturation, a saturation gap. Co-oximetry, which reads multiple wavelengths, confirms the diagnosis and measures the level.
Treatment. Stop the oxidant and give oxygen. Give IV methylene blue, 1–2 mg/kg over 5 minutes, to symptomatic patients (usually levels above 20%) or to anyone above 30%. NADPH-dependent methemoglobin reductase converts it to leukomethylene blue, which reduces ferric iron back to ferrous, usually within an hour. The dye turns urine blue-green and briefly lowers the oximeter reading. Dapsone's long half-life can cause recurrence and repeat dosing.
Methylene blue needs NADPH from the G6PD-driven pentose phosphate pathway, so in G6PD deficiency it fails and can trigger hemolysis; use exchange transfusion, ascorbic acid, or hyperbaric oxygen instead. It also inhibits MAO-A and can precipitate serotonin syndrome with SSRIs, SNRIs, or MAO inhibitors.
Isoniazid overdose
Mechanism. Isoniazid and its hydrazine metabolites inhibit pyridoxine kinase and bind pyridoxine, depleting pyridoxal 5′-phosphate. That cofactor is required by glutamic acid decarboxylase, which converts glutamate to GABA, so GABA falls and seizures become refractory to benzodiazepines alone.
Presentation. Ingestions from about 20 mg/kg are toxic. The classic triad is refractory seizures, anion-gap metabolic (lactic) acidosis driven by the seizures, and coma, typically within a few hours. Suspect it in anyone with access to tuberculosis medication.
Treatment. Give IV pyridoxine gram for gram with the isoniazid ingested; if the amount is unknown, give 5 g (70 mg/kg in children). Benzodiazepines act synergistically at GABA-A receptors and should be given together. Phenytoin is ineffective because the problem is GABA deficiency, not a sodium-channel focus.
At therapeutic doses, isoniazid-induced B6 depletion causes peripheral neuropathy, prevented with pyridoxine 25–50 mg daily; isoniazid also causes hepatitis.
Sulfonylurea overdose
Mechanism. Sulfonylureas bind the SUR1 subunit and close β-cell ATP-sensitive K⁺ channels, depolarizing the cell and forcing insulin release regardless of glucose. Overdose causes hypoglycemia that can be delayed many hours and recurs after dextrose, because each dextrose load stimulates more insulin. A single tablet can cause dangerous hypoglycemia in a toddler, and renal failure prolongs the effect (glyburide has active metabolites).
Treatment. Correct hypoglycemia with IV dextrose, then add octreotide (typically 50 μg SC every 6 hours in adults), a somatostatin analog that blocks further insulin secretion and prevents rebound hypoglycemia. Feed patients who are awake. Admit and check glucose frequently for at least 24 hours, including children who swallowed a single pill and are euglycemic on arrival.
Hypoglycemia with high insulin and high C-peptide points to a sulfonylurea or an insulinoma, and a sulfonylurea screen separates them; high insulin with low C-peptide means exogenous insulin.
Local anesthetic systemic toxicity
| Agent | Class | Key point |
|---|---|---|
| Lidocaine | Amide | Maximum 4.5 mg/kg plain, 7 mg/kg with epinephrine |
| Bupivacaine | Amide | Maximum about 2.5 mg/kg; most cardiotoxic |
| Chloroprocaine | Ester | Rapidly hydrolyzed by plasma esterases; least systemic toxicity |
| Benzocaine, prilocaine | Ester, amide | Cause methemoglobinemia |
Why bupivacaine is worst. It binds cardiac sodium channels avidly and releases slowly, so conduction block and ventricular arrhythmias persist, and cardiac arrest can occur with little warning. Prevention: respect maximum doses, aspirate before injecting, inject incrementally, and use ultrasound guidance.
Progression. Early CNS signs are perioral numbness, metallic taste, tinnitus, lightheadedness, and agitation, followed by seizures and then CNS depression with coma or respiratory arrest. Cardiovascular toxicity follows: bradycardia, conduction block, ventricular arrhythmias, and collapse.
- Stop and call for helpStop injecting and get the lipid emulsion.
- Airway and oxygenVentilate with 100% oxygen; hypoxia and acidosis worsen toxicity.
- SeizuresBenzodiazepines; avoid large propofol doses in unstable patients.
- 20% lipid emulsion1.5 mL/kg over 2–3 minutes, then 0.25 mL/kg/min; repeat the bolus for persistent instability.
- Modified ACLSEpinephrine in small boluses (≤1 μg/kg); no vasopressin, calcium channel blockers, β-blockers, or more local anesthetic (lidocaine, procainamide); amiodarone for ventricular arrhythmias.
- Refractory arrestProlonged CPR, with cardiopulmonary bypass or ECMO as a bridge while the drug redistributes.
Propofol is not a substitute for lipid emulsion; its lipid content is small and it depresses the myocardium.