9.4 Additional Antidotes: Methemoglobinemia, Isoniazid, Sulfonylureas, Valproate, Sympathomimetics & LAST

9.4 Additional Antidotes: Methemoglobinemia, Isoniazid, Sulfonylureas, Valproate, Sympathomimetics & LAST

Methemoglobinemia and Methylene Blue

Mechanism and Causes

Methemoglobin forms when the iron in hemoglobin is oxidized from the ferrous (Fe2+) to the ferric (Fe3+) state. Ferric heme cannot carry oxygen, and the remaining heme groups hold oxygen more tightly, shifting the dissociation curve to the left. Normal red cells keep methemoglobin near 1% using NADH-dependent cytochrome b5 reductase.

Common oxidizing causes in emergency practice:

• Topical anesthetics, especially benzocaine sprays and gels; FDA warns against benzocaine teething products in children under 2 years.
• Dapsone, whose hydroxylamine metabolite causes prolonged, recurrent methemoglobinemia.
• Nitrites and nitrates: inhaled alkyl nitrites ("poppers") and nitrate-contaminated well water used for infant formula.
• Phenazopyridine, primaquine, rasburicase (in G6PD deficiency) and aniline dyes.

Recognition

Suspect methemoglobinemia when cyanosis does not improve with oxygen, blood looks chocolate-brown, and pulse oximetry stays near 85% regardless of the arterial oxygen tension. This difference between the pulse oximetry reading and the calculated saturation is the "saturation gap." Co-oximetry confirms the diagnosis.

Anemia, coronary disease or lung disease make patients symptomatic at lower levels.

Methylene Blue

• Indication: symptoms of hypoxia, or a methemoglobin level above about 20 to 30% even without symptoms.
• Dose: 1 to 2 mg/kg IV over 5 minutes; repeat 1 mg/kg after about 1 hour if the level or symptoms persist. Cumulative doses above about 7 mg/kg can themselves cause hemolysis and methemoglobinemia.
• Mechanism: NADPH-methemoglobin reductase converts methylene blue to leucomethylene blue, which reduces methemoglobin back to hemoglobin. The NADPH comes from the G6PD pathway.

With dapsone, the long half-life causes rebound, so monitor co-oximetry and consider multiple-dose activated charcoal.

Isoniazid: Pyridoxine Is the Antidote

Isoniazid (INH) depletes pyridoxal 5'-phosphate, the cofactor for glutamic acid decarboxylase. GABA synthesis falls, and the result is the classic triad of:

1. Seizures that do not respond to benzodiazepines alone
2. Anion-gap metabolic acidosis (lactate from seizures and impaired lactate metabolism)
3. Coma

Ingestions above about 20 mg/kg can be toxic, and seizures become likely above about 35 to 40 mg/kg. Gyromitra mushrooms and hydrazine cause the same picture.

Benzodiazepines act together with pyridoxine because both increase GABA activity. Phenytoin does not work for INH seizures. Pyridoxine injection is commonly supplied at 100 mg/mL, so a 5 g dose means 50 mL from many small vials. Stocking and a preparation plan are therefore pharmacy problems. If IV pyridoxine is unavailable, crushed tablets can be given by nasogastric tube.

Sulfonylureas: Octreotide

Glipizide, glyburide and glimepiride stimulate insulin release by closing pancreatic beta-cell potassium channels. A single tablet can cause serious hypoglycemia in a toddler. The onset may be delayed many hours with extended-release or long-acting products.

Why Dextrose Alone Fails

Dextrose corrects the glucose, but the rise in glucose triggers more sulfonylurea-driven insulin secretion. Patients then cycle through rebound hypoglycemia. Prophylactic dextrose in a well, normoglycemic child is not recommended because it can mask the onset of hypoglycemia.

Octreotide

Octreotide is a somatostatin analogue that blocks calcium entry into beta cells and stops insulin release.

• Adults: 50 to 100 mcg SC or IV every 6 to 8 hours.
• Children: about 1 to 1.5 mcg/kg SC or IV every 6 to 8 hours.
• Continue while hypoglycemia recurs, then monitor glucose for at least 12 to 24 hours after the last dose.

Glucagon gives only a short rise and also stimulates insulin, so it is a bridge, not a treatment. Octreotide does not help an insulin overdose, because the insulin is exogenous; that patient needs dextrose and feeding.

Valproic Acid

Valproate overdose causes CNS depression, hyperammonemia (with or without liver injury), delayed cerebral edema, metabolic acidosis, hypernatremia, hypocalcemia and pancytopenia. Protein binding saturates at high concentrations, so the free fraction rises sharply.

• L-carnitine: valproate depletes carnitine and impairs urea-cycle function. For hyperammonemia, hepatotoxicity or a large ingestion with CNS depression, give 100 mg/kg IV over 30 minutes (maximum 6 g), then about 15 mg/kg IV every 4 hours until improvement.
• Extracorporeal treatment (EXTRIP 2015): recommended for a valproate concentration above 1,300 mg/L, cerebral edema or shock. Suggested above 900 mg/L, with coma or respiratory depression requiring ventilation, acute hyperammonemia, or pH of 7.10 or lower. Intermittent hemodialysis is the preferred modality.
• Carbapenems lower valproate concentrations by 60 to 100% within a day, so seizures can follow when the two are combined (Section 18.1).

Sympathomimetic Toxicity

Cocaine, amphetamines and synthetic cathinones cause agitation, tachycardia, hypertension, hyperthermia, seizures, rhabdomyolysis and acute coronary syndrome.

• Benzodiazepines first: titrate diazepam, lorazepam or midazolam to control agitation, heart rate and blood pressure.
• Temperature drives mortality: use ice-water immersion or aggressive evaporative cooling. Antipyretics do not work because the hypothalamic set point is normal. Severe hyperthermia may need intubation with a non-depolarizing paralytic.
• Avoid succinylcholine in severe cases: rhabdomyolysis raises potassium, and plasma cholinesterase also metabolizes cocaine, so the two compete.
• Persistent hypertension after sedation: phentolamine 1 to 5 mg IV, nitroglycerin or a calcium channel blocker. Beta-blockers are generally avoided during acute intoxication because of the theoretical risk of unopposed alpha stimulation; observational data are mixed.
• Cocaine-associated chest pain: aspirin, benzodiazepines and nitroglycerin. A wide QRS from cocaine's sodium-channel blockade responds to sodium bicarbonate 1 to 2 mEq/kg, as in tricyclic toxicity (Section 9.1).

Local Anesthetic Systemic Toxicity (LAST)

Presentation

Early CNS signs are perioral numbness, metallic taste, tinnitus and agitation. These progress to seizures and coma. Cardiovascular toxicity starts with hypertension and tachycardia and then turns to bradycardia, QRS widening, ventricular dysrhythmias and asystole. Bupivacaine is the most cardiotoxic. Most cases begin within minutes, but toxicity can be delayed with continuous infusions or large-volume blocks.

Maximum Recommended Doses

The values below are commonly cited ceilings. Confirm them against product labeling and institutional policy, add up doses given at all sites, and use lower doses for older adults and for patients with heart or liver disease.

Worked example: a 70-kg patient needs a laceration repair with plain 1% lidocaine (10 mg/mL). 4.5 mg/kg × 70 kg = 315 mg, which is capped at 300 mg. 300 mg ÷ 10 mg/mL = 30 mL maximum. With 1% lidocaine with epinephrine, 7 mg/kg × 70 kg = 490 mg, or 49 mL. For 0.25% bupivacaine (2.5 mg/mL), 175 mg is 70 mL.

Treatment (ASRA 2020 Checklist)

1. Stop the local anesthetic, call for help and ask for the LAST kit.
2. Give 100% oxygen and manage the airway; hypoxia and acidosis worsen toxicity.
3. Treat seizures with a benzodiazepine; avoid propofol if the patient is hemodynamically unstable.
4. Give 20% lipid emulsion:
   • Above 70 kg: 100 mL over 2 to 3 minutes, then 200 to 250 mL over 15 to 20 minutes.
   • 70 kg or less: 1.5 mL/kg (lean body weight) over 2 to 3 minutes, then about 0.25 mL/kg/min.
   • If instability persists, repeat the bolus once or twice and double the infusion rate. The upper limit is about 12 mL/kg.
5. Modify ACLS: use small epinephrine doses (1 mcg/kg or less). Avoid vasopressin, calcium channel blockers, beta-blockers and other local anesthetics such as lidocaine or procainamide.
6. Arrange extracorporeal support early if the patient does not respond.
7. Monitor for at least 4 to 6 hours after a cardiovascular event and at least 2 hours after a limited CNS event.

Lipid emulsion interferes with many laboratory tests and can cause pancreatitis, so draw needed labs before large doses when possible.