5.5 Toxidromes, Antidotes, Carbon Monoxide & Toxic Alcohols

Clinical Toxidromes and Emergency Antidotes

A toxidrome is a constellation of physical signs and physiological parameters characteristic of a specific class of toxin:

[!TIP] Exam Distinction: Anticholinergic vs Sympathomimetic: Both toxidromes present with tachycardia, hypertension, hyperthermia, and dilated pupils (mydriasis). The decisive differentiating clinical sign is the skin: anticholinergic toxicity produces bone-dry skin and dry axillae ("dry as a bone"), whereas sympathomimetic toxicity produces profuse diaphoresis (drenching sweat).

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Carbon Monoxide and Cyanide Toxicity

1. Carbon Monoxide (CO)

• Pathophysiology: Carbon monoxide binds to haemoglobin with 200 to 250 times greater affinity than oxygen, forming carboxyhaemoglobin (COHb). COHb cannot bind oxygen, halving oxygen-carrying capacity. Furthermore, CO binding shifts the oxyhaemoglobin dissociation curve sharply to the left (Haldane effect), locking remaining oxygen onto haemoglobin and preventing its release into ischaemic tissues. CO also inhibits mitochondrial cytochrome oxidase.
• Diagnostic Pitfall: Standard bedside pulse oximetry (SpO2) is falsely normal (e.g., 99–100%) because standard dual-wavelength pulse oximeters cannot distinguish between oxyhaemoglobin and carboxyhaemoglobin. Arterial or venous blood gas with dedicated co-oximetry is mandatory to quantify COHb percentage.
• Clinical Presentation: Headache (earliest symptom), nausea, malaise, dizziness, confusion, ataxia, angina, cardiac arrest. The textbook "cherry-red skin" is an exceptionally rare, post-mortem sign.
• Management:
  • Remove from source; immediately administer 100% normobaric oxygen via non-rebreather reservoir mask (reduces COHb half-life from 320 minutes on room air down to 80 minutes).
  • Hyperbaric Oxygen (HBO): Delivers 100% O2 at 2.5 to 3.0 atmospheres (reducing t1/2 to 20 minutes). Indications include: COHb > 25% (or > 15–20% in pregnancy), loss of consciousness, neurological deficits, myocardial ischaemia, or severe refractory acidosis.

2. Cyanide Toxicity

• Pathophysiology: Hydrogen cyanide gas is released during the combustion of synthetic plastics, wool, and polyurethane foams in domestic house fires (often co-existing with CO poisoning). Cyanide binds with high affinity to ferric (Fe3+) iron in cytochrome c oxidase (Complex IV) of the mitochondrial electron transport chain, arresting aerobic cellular respiration. Cells switch entirely to anaerobic metabolism, producing massive lactic acidosis.
• Signature Laboratory Clue: A patient pulled from a house fire with profound metabolic acidosis and an extraordinarily elevated serum lactate (> 8–10 mmol/L) despite adequate oxygenation. Venous blood remains bright red with a high mixed venous oxygen saturation (SvO2 > 90%) because peripheral tissues are incapable of extracting oxygen.
• Specific Antidote: Intravenous Hydroxocobalamin (Cyanokit). Hydroxocobalamin actively chelates cyanide, forming non-toxic cyanocobalamin (Vitamin B12), which is safely excreted in urine (turning urine dark red/purple). Avoid sodium nitrite in smoke inhalation because inducing methaemoglobinaemia will further impair oxygen-carrying capacity in the presence of co-existing carboxyhaemoglobin.

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Toxic Alcohols: Ethylene Glycol vs Methanol

Ethylene glycol (automobile antifreeze) and methanol (windscreen washer fluid, methylated spirits, bootleg alcohol) are parent alcohols that are relatively non-toxic themselves; however, they are metabolised by hepatic alcohol dehydrogenase (ADH) into devastatingly toxic organic acids.

+-----------------------------------------------------------------------------------------+
|                        Toxic Alcohol Metabolic Cascades                                 |
+-----------------------------------------------------------------------------------------+
|  ETHYLENE GLYCOL ---> | Alcohol Dehydrogenase | ---> Glycolic Acid ---> Oxalic Acid     |
|                                                                               |         |
|                                          Calcium Oxalate Crystal Precipitation        |
|                                          (Renal Tubular Necrosis & Hypocalcaemia)       |
|                                                                                         |
|  METHANOL ----------> | Alcohol Dehydrogenase | ---> Formaldehyde ---> Formic Acid      |
|                                                                               |         |
|                                          Optic Nerve Necrosis ("Snowstorm" Vision)      |
|                                          & Basal Ganglia / Putaminal Necrosis           |
+-----------------------------------------------------------------------------------------+

Laboratory Trajectory: The Shifting Gap Phenomenon

1. Early Phase (0–6 hours): Parent alcohol circulates unmetabolised. High concentration of low-molecular-weight molecules produces an elevated Serum Osmolar Gap (> 10 mOsm/kg), while the anion gap remains normal:

Calculated Osmolarity = 2 x [Na+] + [Glucose] + [Urea]  (all in mmol/L)

Osmolar Gap = Measured Osmolality (by freezing-point depression) - Calculated Osmolarity

1. Late Phase (> 12 hours): As alcohol dehydrogenase oxidises the parent alcohols, the osmolar gap steadily closes, and an enormous High Anion Gap Metabolic Acidosis (HAGMA) opens up due to circulating glycolate/oxalate or formate.

Key Clinical Distinctions

• Ethylene Glycol: Metabolised to oxalic acid, which precipitates with calcium to form needle- or envelope-shaped calcium oxalate crystals in the renal tubules, producing acute tubular necrosis, flank pain, microscopic haematuria, and marked hypocalcaemia (tetany, prolonged QT interval). Urine exhibits bright apple-green fluorescence under a Wood's UV lamp (due to fluorescein added to commercial antifreeze).
• Methanol: Metabolised to formic acid, which specifically poisons mitochondrial cytochrome oxidase in the retina and optic nerve. Patients describe visual blurring, visual loss, or visual hallucinations classically described as "standing in a snowstorm", with dilated unreactive pupils and optic disc hyperaemia on fundoscopy. Bilateral necrosis of the putamen (basal ganglia) is seen on neuroimaging.

Management of Toxic Alcohols

1. Block Alcohol Dehydrogenase (ADH):
   • Fomepizole (4-methylpyrazole): Competitive inhibitor of alcohol dehydrogenase with an affinity 8,000-fold higher than ethanol. First-line agent; administered as an IV bolus (15 mg/kg) followed by scheduled dosing.
   • Intravenous Ethanol Infusion: Second-line if fomepizole is unavailable. Competing substrate for ADH; titrated to achieve a target blood ethanol concentration of 100–150 mg/dL (22–33 mmol/L).
2. Emergency Haemodialysis: Rapidly eliminates parent alcohols and toxic acid metabolites while correcting severe acidosis. Absolute indications include: severe metabolic acidosis (pH < 7.25), visual symptoms (methanol), acute renal failure (ethylene glycol), or serum concentration > 50 mg/dL (> 8 mmol/L).