28.3 Specific Poisonings: Sodium-Channel Blockers, Lithium, Valproate, Theophylline, Iron, Sulfonylureas & Methemoglobinemia

Sodium-Channel Blocking Agents

Tricyclic Antidepressants

Tricyclics combine sodium-channel blockade (wide QRS, negative inotropy), anticholinergic effects, alpha-1 blockade (hypotension), potassium-channel blockade (QT prolongation), and amine reuptake inhibition.

• ECG predictors: a QRS above 100 ms predicts seizures, a QRS above 160 ms predicts ventricular arrhythmia, and a terminal rightward 40 ms axis deviation (a prominent R in aVR, S in I and aVL) is characteristic.
• Management:
  1. Sodium bicarbonate: 1 to 2 mEq/kg boluses repeated for QRS narrowing and hypotension, then an infusion; target a serum pH of about 7.45 to 7.55. Both the sodium load and alkalinization reduce channel binding. Hypertonic saline is an alternative when alkalemia limits bicarbonate.
  2. Seizures: benzodiazepines. Avoid phenytoin, which is itself a sodium-channel blocker.
  3. Hypotension: fluids, then norepinephrine (direct-acting) rather than dopamine.
  4. Arrhythmias: bicarbonate and magnesium; lidocaine is the antiarrhythmic of choice if needed. Avoid class IA and IC agents, and avoid amiodarone (which prolongs QT and causes hypotension).
  5. Avoid physostigmine in tricyclic overdose: it has precipitated bradyasystolic arrest.
  6. Lipid emulsion and VA-ECMO for refractory cardiovascular collapse.
• Other sodium-channel blockers follow the same logic: diphenhydramine in massive overdose, carbamazepine, cocaine, propranolol (membrane-stabilizing), flecainide and other class I agents, hydroxychloroquine (also causing hypokalemia, treated with bicarbonate, potassium, and high-dose diazepam), and bupropion (seizures and wide complex).
• Local anesthetic systemic toxicity: neurologic excitation then cardiovascular collapse after regional anesthesia; treat with 20% lipid emulsion (1.5 mL/kg bolus then infusion), reduced-dose epinephrine, benzodiazepines, and prolonged resuscitation with ECMO standby. Avoid vasopressin, calcium-channel blockers, beta-blockers, and local anesthetic antiarrhythmics.

Lithium

• Acute toxicity: gastrointestinal symptoms predominate early, with neurologic features developing as lithium distributes into cells.
• Chronic toxicity: neurologic findings dominate at lower levels (tremor, ataxia, confusion, myoclonus, seizures), often precipitated by volume depletion, thiazides, NSAIDs, ACE inhibitors or ARBs, or kidney injury.
• Other effects: nephrogenic diabetes insipidus, hypothyroidism, hypercalcemia, and a low or negative anion gap from the unmeasured cation. Leukocytosis and ECG changes occur.
• Management:
  • Volume resuscitation with isotonic saline to restore kidney clearance; stop lithium and interacting drugs.
  • Whole-bowel irrigation with polyethylene glycol for sustained-release preparations; activated charcoal does not bind lithium.
  • Hemodialysis (EXTRIP 2015): recommended when the level is above 4 mEq/L with impaired kidney function, or above 5 mEq/L, or with severe neurologic features such as seizures or decreased consciousness; also suggested when the expected time to reach a level below 1 mEq/L exceeds 36 hours. Levels rebound after dialysis as lithium leaves cells, so recheck and repeat as needed.
  • SILENT syndrome (syndrome of irreversible lithium-effectuated neurotoxicity) can leave permanent cerebellar deficits.

Valproate

• Features of severe overdose: central nervous system depression and coma, hyperammonemia (with or without hepatic injury), metabolic acidosis, hypernatremia from sodium valproate load, hypocalcemia, cerebral edema, and pancreatitis or marrow suppression.
• Management:
  • Supportive care and airway protection; activated charcoal early.
  • L-carnitine 100 mg/kg IV (then 15 mg/kg every 4 to 6 hours) for hyperammonemia and hepatotoxicity.
  • Hemodialysis (EXTRIP 2015): recommended for a valproate concentration above about 1,300 micrograms/mL, or for coma, respiratory depression requiring mechanical ventilation, acute hyperammonemia, or a pH of 7.10 or less; suggested above about 900 micrograms/mL. Protein binding saturates at high concentrations, which makes the drug dialyzable.
  • Monitor ammonia and liver function; see also the hyperammonemia section.

Theophylline and Other Xanthines

• Toxicity: adenosine antagonism and catecholamine release produce vomiting, tachycardia, tachyarrhythmias, agitation, tremor, and seizures that are often refractory.
• Metabolic signature: hypokalemia, hypophosphatemia, hypomagnesemia, hyperglycemia, and a lactic and metabolic acidosis.
• Acute versus chronic: acute overdose causes toxicity at higher levels (above about 90 to 100 micrograms/mL), while chronic accumulation causes seizures at much lower levels (as low as 40 to 60 micrograms/mL) in older patients.
• Management:
  • Multiple-dose activated charcoal (theophylline has enterohepatic and enteroenteric recirculation).
  • Benzodiazepines, then barbiturates, for seizures; avoid phenytoin, which is ineffective.
  • Beta-blockade (esmolol, with caution in asthma) for tachyarrhythmia with hypotension.
  • Potassium replacement, recognizing that hypokalemia is a shift and will rebound.
  • Hemodialysis for seizures, life-threatening arrhythmia, shock, or a very high level (EXTRIP recommends it above 100 micrograms/mL in acute poisoning and above 60 micrograms/mL in chronic toxicity, or at lower levels with severe features). Caffeine overdose follows the same approach.

Iron

• Five phases: gastrointestinal (0 to 6 hours, with vomiting and hematemesis), apparent improvement (6 to 24 hours), shock with metabolic acidosis and hepatotoxicity (12 to 48 hours), hepatic failure (2 to 3 days), and late gastric outlet obstruction from scarring (weeks).
• Diagnosis: a serum iron level 4 to 6 hours after ingestion (toxic above about 350 micrograms/dL, severe above 500), an anion gap acidosis, radiopaque tablets on abdominal radiograph, and leukocytosis with hyperglycemia.
• Management:
  • Whole-bowel irrigation for large ingestions; charcoal does not bind iron.
  • Aggressive fluid resuscitation.
  • Deferoxamine 15 mg/kg/h IV for shock, acidosis, persistent vomiting, lethargy, or a serum iron above about 500 micrograms/dL. It turns urine "vin rose." Watch for hypotension (infusion rate-related), ARDS with prolonged infusion beyond 24 hours, and Yersinia infection risk.
  • Endoscopy or surgery for gastric bezoars.

Sulfonylureas and Other Antihyperglycemics

• Sulfonylureas and meglitinides: prolonged hypoglycemia; treat with dextrose plus octreotide 50 to 100 micrograms subcutaneously every 6 to 12 hours to suppress insulin secretion, and observe for at least 24 hours after the last octreotide dose (see the hypoglycemia section).
• Metformin: overdose or accumulation in kidney failure causes metformin-associated lactic acidosis with a very high lactate and severe acidemia. Treat with supportive care, bicarbonate for severe acidemia, and hemodialysis (EXTRIP recommends it for a lactate above 20 mmol/L, pH of 7.0 or less, or failure of standard measures), which corrects acidosis and removes the drug.
• Insulin overdose: dextrose infusion with potassium replacement and prolonged observation.
• GLP-1 receptor agonists and DPP-4 inhibitors: rarely cause hypoglycemia alone, but cause vomiting, pancreatitis, and delayed gastric emptying that matters for aspiration risk.
• SGLT2 inhibitors: euglycemic ketoacidosis (see the endocrine section).

Methemoglobinemia

• Mechanism: oxidation of heme iron to the ferric state, which cannot bind oxygen and shifts the remaining hemoglobin's dissociation curve leftward.
• Causes: dapsone, local anesthetics (benzocaine, prilocaine), nitrates and nitrites (including "poppers"), phenazopyridine, sulfonamides, rasburicase, nitric oxide, aniline dyes, and well water nitrates.
• Clues:
  • Cyanosis that does not improve with oxygen.
  • A saturation gap: pulse oximetry reads around 85% (often fixed) while the arterial PaO2 and calculated saturation are normal or high.
  • Chocolate-brown blood that does not turn red on exposure to air.
  • Co-oximetry confirms the methemoglobin fraction.
• Severity: symptoms begin around 15% to 20% (headache, fatigue), with dyspnea and confusion by 30% to 50%, and seizures, acidosis, arrhythmia, and death above about 50% to 70%. Anemia makes any fraction more dangerous, since the absolute functional hemoglobin is lower.
• Treatment:
  • Remove the agent; give oxygen.
  • Methylene blue 1 to 2 mg/kg IV over 5 minutes for symptomatic patients or a level above about 20% to 30%, repeated once if needed. It acts through NADPH methemoglobin reductase.
  • Contraindicated or ineffective in G6PD deficiency (it causes hemolysis and depends on NADPH); use exchange transfusion or hyperbaric oxygen instead.
  • Avoid methylene blue with serotonergic drugs when possible (serotonin syndrome risk), and note that it transiently makes pulse oximetry read falsely low.
  • Dapsone-induced methemoglobinemia recurs because of the long half-life and active metabolites: use cimetidine and repeat methylene blue dosing, with activated charcoal for recirculation.
  • Sulfhemoglobinemia looks similar but does not respond to methylene blue.