Emergency & Toxicology

Cyanide poisoning: recognition and antidotes

Clinical Overview and When to Suspect Cyanide Poisoning

— Smoke inhalation from enclosed-space fires (burning wool, silk, polyurethane, nylon, plastics) — the single most common US exposure

— Industrial exposures: electroplating, metal refining, jewelry cleaning, photographic processing, fumigation

— Iatrogenic: prolonged or high-dose sodium nitroprusside infusion (>2 mcg/kg/min or >24–48 h), especially in renal failure

— Ingestion of cyanogenic plants/seeds (apricot, bitter almond, cassava, amygdalin/laetrile)

— Intentional poisoning/suicide, lab workers, gold mining, jeweler/chemist occupations

— Acetonitrile (artificial-nail remover) ingestion in children — delayed toxicity as it metabolizes to CN⁻

— Inhaled HCN gas or IV CN: seconds to minutes

— Ingested cyanide salts: minutes

— Acetonitrile/amygdalin: delayed hours (metabolic conversion)

Board pearl: Any fire victim with soot in the oropharynx, altered mental status, hypotension, and lactate ≥10 mmol/L has cyanide toxicity until proven otherwise — give hydroxocobalamin empirically; do not wait for confirmatory levels (turnaround is hours to days and clinically useless in real time).

Step 3 management: Recognition is the test — treatment is empirical. The exam rewards rapid pattern matching (fire + AMS + acidosis) and rejects "send cyanide level and wait."

Cyanide (CN⁻) is a rapidly lethal mitochondrial toxin that binds cytochrome c oxidase (complex IV) of the electron transport chain, halting aerobic ATP production and forcing anaerobic metabolism with profound lactic acidosis.

Key exposure scenarios that should trigger immediate suspicion on Step 3:

Onset:

Pathophysiologic hallmark: cells cannot extract oxygen despite normal arterial PaO₂ and SaO₂ → "arterialization" of venous blood, narrowed arteriovenous O₂ difference, and anion-gap metabolic acidosis with lactate often >10 mmol/L.

Presentation Patterns and Key History

— Headache, anxiety, dizziness, confusion

— Tachypnea and hyperpnea (driven by carotid body stimulation and acidosis)

— Tachycardia, hypertension (early sympathetic surge)

— Nausea, vomiting, abdominal pain

— Bitter almond odor on breath — classically taught but only ~40% of people can genetically detect it; do not rely on it

— Seizures, coma, trismus, opisthotonos

— Bradycardia, hypotension, cardiovascular collapse

— Apnea (paradoxical after initial hyperpnea)

— Pulmonary edema

— Death within minutes if untreated

— Source/duration of exposure, enclosed-space fire?

— Co-exposure to carbon monoxide (nearly universal in structural fires) — both must be treated

— Medications: nitroprusside drip duration and dose, renal function

— Suicide note, occupation (chemist, jeweler, electroplater, lab tech)

— Pediatric: access to acetonitrile nail remover, apricot pits, laetrile supplements

— Workplace exposure for mandatory OSHA reporting

Key distinction: Cyanide victims are not cyanotic despite the name — skin often appears cherry red or normal because venous blood remains oxygen-rich (cells can't use the O₂). True cyanosis is a late, agonal finding. Compare to methemoglobinemia (chocolate-brown blood, true cyanosis unresponsive to O₂) and CO poisoning (cherry-red, but with low SpO₂ on co-oximetry).

Board pearl: A fire victim "doing well" initially who then deteriorates en route or in the ED with lactic acidosis is the classic delayed-cyanide stem — give hydroxocobalamin empirically.

Time course is dose-dependent. High-dose inhalation produces collapse within seconds; lower-dose or ingestion evolves over minutes to hours.

Early/mild toxicity (think "air hunger without hypoxia"):

Severe toxicity:

Critical history to elicit on the CCS/USMLE stem:

Physical Exam Findings and Hemodynamic Assessment

— Early: tachycardia, hypertension, tachypnea/hyperpnea disproportionate to oxygenation

— Late: bradycardia, hypotension, apnea, cardiovascular collapse

— Anxiety, headache, confusion → obtundation → coma

— Generalized tonic-clonic seizures

— Mydriasis (fixed and dilated pupils in severe cases)

— Cherry-red or normal color — venous blood is arterialized

— In fire victims: facial burns, soot in nares/oropharynx, singed nasal hairs, carbonaceous sputum (also flag airway burn risk)

— Cyanosis is a terminal/agonal sign

— Pulmonary edema (non-cardiogenic)

— Arrhythmias, widened QRS, AV blocks in severe poisoning

— Funduscopy may show bright red retinal veins (arterialization)

— Normal SpO₂ and PaO₂ with profound metabolic acidosis

— Narrowed A–V O₂ gradient — central venous O₂ saturation often >90% (normal 65–75%) because tissues can't extract O₂

— Lactate ≥10 mmol/L in smoke-inhalation victims is ~94% sensitive/specific for clinically significant cyanide toxicity (Baud criteria)

Step 3 management: In the resuscitation bay, draw a simultaneous ABG and central or mixed venous gas. A venous PO₂ approaching arterial PO₂ with high SvO₂ and lactic acidosis in the right clinical context is essentially pathognomonic — start hydroxocobalamin immediately while continuing the rest of the toxidrome workup.

Board pearl: Pulse oximetry is falsely reassuring in cyanide poisoning. SpO₂ measures hemoglobin saturation, not tissue O₂ utilization. A "normal sat" does not exclude lethal toxicity.

Vital signs evolve in two phases:

Neurologic (most sensitive early):

Skin/mucosa:

Cardiopulmonary:

Eye:

Hemodynamic signature:

Diagnostic Workup — Initial Labs, ABG, and Bedside Studies

— ABG with co-oximetry: normal PaO₂, normal SaO₂, high anion-gap metabolic acidosis; co-oximetry quantifies carboxyhemoglobin (CO) and methemoglobin simultaneously

— Venous blood gas for SvO₂ — elevated SvO₂ (>90%) with arterialized venous appearance is highly suggestive

— Lactate — the single most useful real-time marker

· Smoke inhalation + lactate ≥10 mmol/L → presumptive cyanide toxicity

· Pure CN ingestion + lactate ≥8 mmol/L correlates with toxic blood levels

— Anion gap, bicarbonate, electrolytes, BUN/Cr, glucose

— CBC, coags, LFTs

— CK (rhabdo from seizures/hypoperfusion)

— Troponin, ECG — ischemic changes from impaired mitochondrial function; watch for QRS widening, AV block, ST changes

— Pregnancy test in any reproductive-age female (affects nitrite use — see chunk 10)

— Acetaminophen/salicylate, ethanol, urine tox if suicidal ingestion is plausible

Key distinction: Lactic acidosis + normal oxygenation + smoke exposure = cyanide until proven otherwise. Lactic acidosis + normal oxygenation + nitroprusside drip = cyanide until proven otherwise. Both bypass the wait for a level.

CCS pearl: Order ABG with co-oximetry, lactate, BMP, troponin, ECG, CXR, urine pregnancy, and a comprehensive tox screen simultaneously — and administer hydroxocobalamin before results return if clinical suspicion is high.

Cyanide levels are NOT useful acutely — turnaround is hours to days. Treatment is empirical based on clinical syndrome.

Immediate bedside/lab panel:

Chest X-ray: pulmonary edema, smoke-inhalation injury patterns

CO-oximetry is mandatory in any fire victim — concomitant CO poisoning is the rule, not the exception

Diagnostic Workup — Advanced and Confirmatory Studies

— <0.5 mg/L: usually asymptomatic (background; smokers may run 0.1–0.4)

— 0.5–1.0 mg/L: flushing, tachycardia

— 1.0–2.5 mg/L: obtundation

— >2.5–3.0 mg/L: coma, seizures, often lethal without antidote

— Confirms diagnosis post hoc; useful for forensic, occupational, and quality-review purposes

— Useful in chronic nitroprusside exposure monitoring, especially with renal failure

— Toxicity at thiocyanate >10 mg/dL

— Head CT if persistent AMS or focal deficits — late survivors of severe poisoning can develop basal ganglia (especially putamen and globus pallidus) and substantia nigra lesions, similar to CO poisoning, leading to delayed parkinsonism and dystonia

— Bronchoscopy if significant airway burn suspected

Board pearl: Hydroxocobalamin colors plasma, urine, and skin deep red/magenta for 2–7 days, which falsely elevates or interferes with numerous colorimetric lab assays (creatinine, AST, bilirubin, magnesium, iron, urinalysis, hemoglobin co-oximetry — can artifactually raise carboxyhemoglobin readings). Alert the lab and interpret post-treatment values cautiously.

Whole-blood cyanide levels (send-out, retrospective only):

Plasma thiocyanate (CN⁻ metabolite):

Serum lactate trend: best real-time surrogate; should fall within hours of effective antidote

Mixed/central venous O₂ saturation: persistently elevated supports diagnosis and tracks response

Methemoglobin level: essential before and during nitrite-based antidote therapy (see chunk 7); target induced MetHb ~20–30%, avoid >30%

Imaging:

EEG if subclinical status epilepticus suspected in comatose patient

Forensic considerations: in suspected homicide or workplace death, preserve blood in gray-top (sodium fluoride) tubes, document chain of custody, notify medical examiner

Risk Stratification and First-Line Management Logic

— Smoke-inhalation victim with AMS + hypotension or lactate ≥10

— Known/suspected cyanide ingestion with coma, seizure, hemodynamic instability, or severe acidosis

— Nitroprusside-associated unexplained lactic acidosis, tachyphylaxis, or AMS — stop the drip first

— Airway: intubate for AMS, airway burn, apnea; avoid mouth-to-mouth resuscitation of victims (rescuer exposure risk)

— Breathing: 100% FiO₂ via non-rebreather or ventilator — improves cellular oxygen availability and is mandatory regardless of SpO₂; also treats co-existing CO

— Circulation: IV crystalloid, vasopressors (norepinephrine first line) for refractory hypotension

— Decontamination:

· Remove contaminated clothing, irrigate skin with copious water

· Activated charcoal within 1 hour of oral ingestion (binds CN poorly but binds co-ingestants; reasonable in suicidal poly-ingestion)

· Do not induce emesis

— Rescuer safety: PPE, ventilated space, avoid contaminated vomit/gastric contents

Step 3 management: The correct order set is "100% O₂ + hydroxocobalamin IV + supportive ABCs + decontamination + treat CO" — all started in parallel within minutes of ED arrival.

Cyanide poisoning is a clinical diagnosis — antidote administration must not wait for confirmatory levels.

Empiric antidote indications (treat now):

ABC priorities parallel antidote delivery (do simultaneously, not sequentially):

Seizures: benzodiazepines (lorazepam, midazolam)

Acidosis: sodium bicarbonate for severe acidemia (pH <7.1) while antidote works; definitive correction follows mitochondrial reactivation

Hyperbaric oxygen: indicated for concomitant CO toxicity with classic criteria (LOC, neuro deficit, CO-Hb >25%, pregnancy with CO-Hb >15%, ischemic ECG)

Pharmacotherapy — First-Line Antidote: Hydroxocobalamin

— Mechanism: vitamin B12a precursor; its cobalt(III) center directly chelates CN⁻ to form cyanocobalamin (vitamin B12), which is renally excreted

— Dose:

· Adults: 5 g IV over 15 minutes; repeat 5 g for severe/persistent toxicity (max 10 g)

· Pediatrics: 70 mg/kg IV (max 5 g per dose)

— Safe in smoke inhalation because it does not induce methemoglobinemia (critical when CO is co-present — inducing MetHb on top of CO-Hb would be catastrophic)

— Safe in pregnancy (Category C, but preferred over nitrites)

— Chromaturia (red urine) for up to 5 weeks

— Red/magenta skin discoloration for 1–2 weeks

— Transient hypertension (mild, usually self-limited)

— Allergic/anaphylactoid reactions (rare)

— Acute kidney injury and oxalate nephropathy/crystalluria

— Lab interference: falsely alters colorimetric assays (Cr, AST, bili, Mg, glucose, co-oximetry) — communicate with lab

— May interfere with hemodialysis machines (color-based blood-leak detectors trigger false alarms)

— Provides sulfur donor to rhodanese enzyme, converting CN⁻ to renally excreted thiocyanate

— Adult dose: 12.5 g IV (50 mL of 25% solution) over 10–30 min

— Slow onset; useful as adjunct to hydroxocobalamin or as prophylaxis during nitroprusside infusions

— Safe in pregnancy, CO co-exposure, and pediatrics

Board pearl: Hydroxocobalamin is the preferred US antidote for fire victims because it treats CN without compromising oxygen-carrying capacity. The old "cyanide antidote kit" (amyl nitrite/sodium nitrite/thiosulfate) is contraindicated when CO is present — inducing MetHb plus carboxyhemoglobinemia can be lethal.

Hydroxocobalamin (Cyanokit) — first-line antidote in the US and clearly preferred on Step 3 for all scenarios, especially smoke inhalation.

Adverse effects:

Sodium thiosulfate — adjunctive/synergistic:

Pharmacotherapy — Nitrite-Based Antidote Kit and Adjuncts

— Amyl nitrite (inhaled pearls): used in pre-hospital/no-IV settings, 30 seconds on / 30 seconds off

— Sodium nitrite 300 mg IV (10 mL of 3%) over 5 minutes in adults; pediatric: 0.15–0.33 mL/kg of 3% solution based on hemoglobin (dose-by-Hgb table) to avoid lethal MetHb

— Sodium thiosulfate 12.5 g IV follows

— Induce methemoglobinemia (target ~20–25%); MetHb's ferric iron binds CN⁻ to form cyanmethemoglobin, freeing cytochrome oxidase

— Also cause vasodilation (NO release) — contributes to hypotension

— Smoke inhalation / suspected CO co-exposure — inducing MetHb on top of CO-Hb dangerously reduces oxygen-carrying capacity (avoid!)

— Hypotension (nitrites vasodilate)

— G6PD deficiency (hemolysis risk)

— Pregnancy (fetal MetHb)

— Neonates/infants (high baseline fetal Hgb susceptibility)

— Dicobalt edetate (available in Europe/UK) — direct chelator; significant toxicity (anaphylactoid, hypotension); not preferred

— Hydroxocobalamin + thiosulfate: synergistic; give through separate IV lines (precipitate when mixed)

— ECMO/VA-ECMO: rescue in refractory cardiovascular collapse — case-report level but reasonable in tertiary centers

— Hemodialysis: removes thiocyanate (the metabolite), especially useful in nitroprusside toxicity with renal failure

Step 3 management: If the stem says "structure fire" or "smoke inhalation," pick hydroxocobalamin. If it says "isolated cyanide ingestion at a jewelry plating facility, no CO concern, hypertensive, normal G6PD," nitrite + thiosulfate is acceptable but hydroxocobalamin is still safer and preferred.

Sodium nitrite + sodium thiosulfate ("cyanide antidote kit") — legacy regimen, second-line in the US where hydroxocobalamin is available:

Mechanism of nitrites:

Contraindications/cautions for nitrites:

Monitor MetHb q30 min during nitrite therapy; if MetHb >30% or symptomatic → methylene blue is contraindicated here because it would liberate CN⁻ back — instead exchange transfusion or hyperbaric O₂

Other adjuncts:

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher mortality from baseline cardiopulmonary reserve loss

— Lower seizure threshold; more prone to cardiac dysrhythmias

— Hydroxocobalamin remains first-line; monitor for transient hypertension which can be more pronounced and may unmask coronary ischemia

— Lower threshold to admit to ICU even with apparently mild presentation

— Excretion of cyanocobalamin (the CN-bound complex) is renal — accumulates in AKI/ESRD but rarely clinically significant in single-dose acute use

— Thiocyanate accumulation is the bigger problem with sodium thiosulfate or chronic nitroprusside — thiocyanate is dialyzable; symptoms include tinnitus, hyperreflexia, AMS, psychosis at >10 mg/dL

— Hemodialysis indicated for thiocyanate toxicity in renal failure

— Hydroxocobalamin doses do not require renal adjustment in acute resuscitation

— Lab interference with the dialysis circuit's blood-leak detector — coordinate with nephrology and dialysis nursing

— Endogenous detoxification via rhodanese (hepatic, also muscle/kidney) is impaired → lower threshold for thiocyanate accumulation when sulfur donors are given chronically

— Antidote dosing largely unchanged in acute scenario

— Avoid in renal failure if alternatives exist (clevidipine, nicardipine)

— Limit dose to <2 mcg/kg/min and duration to <24–48 h

— Co-infuse sodium thiosulfate when high-dose or prolonged use is unavoidable

— Monitor mental status, acidosis, lactate, and thiocyanate level (in renal disease)

Board pearl: A postoperative cardiac patient on a nitroprusside drip for 72 hours who develops AMS, lactic acidosis, and tachyphylaxis has cyanide toxicity — stop the drip, give hydroxocobalamin, and switch to nicardipine or clevidipine. Hemodialysis if AKI and rising thiocyanate.

Elderly:

Renal impairment / dialysis-dependent patients:

Hepatic impairment:

Nitroprusside-specific considerations (a common Step 3 ICU scenario):

Special Populations — Pregnancy, Pediatrics, and Other Subgroups

— Cyanide and its antidotes cross the placenta; fetal mortality is high in maternal poisoning

— Hydroxocobalamin is the antidote of choice — minimal fetal harm, no MetHb induction

— Avoid sodium nitrite — induces fetal methemoglobinemia (fetal Hgb is especially susceptible); risks fetal hypoxia and demise

— Sodium thiosulfate is considered safe and a reasonable adjunct

— Maternal resuscitation is fetal resuscitation — left lateral tilt, 100% O₂, full antidote dosing; do not under-dose for fetal concerns

— Continuous fetal monitoring if ≥24 weeks viable; consider perimortem cesarean per ACOG criteria if maternal arrest

— Acetonitrile (artificial-nail glue remover) — classic delayed pediatric ingestion; metabolized over 3–12 hours to CN⁻ → child appears well, then crashes

— Apricot pits, bitter almonds, cassava, laetrile/amygdalin supplements

— Hydroxocobalamin 70 mg/kg IV (max 5 g); first-line

— Sodium nitrite must be dose-adjusted by hemoglobin concentration to avoid lethal MetHb — use weight-based tables; preferred to avoid entirely if hydroxocobalamin is available

— Sodium thiosulfate 400 mg/kg (max 12.5 g)

— Electroplaters, jewelers, miners (gold/silver leaching), chemists, fumigators, firefighters

— OSHA reporting for workplace exposure

— Workplace exposure limits (PEL): HCN 10 ppm 8-hour TWA

— Often involves potassium or sodium cyanide salts; very rapid onset

— Psychiatry consultation, suicide precautions, safety hold once stabilized

Key distinction: A toddler who "ate something from mom's nail kit" and is asymptomatic at 2 hours but altered at 6 hours — think acetonitrile delayed conversion. Admit and observe even apparently well children with suspected ingestion.

Pregnancy:

Pediatrics:

Smoke inhalation in children: lower threshold for empiric hydroxocobalamin given small reserve and rapid deterioration

Occupational populations:

Suicidal ingestion:

Complications and Adverse Outcomes

— Cardiovascular collapse — refractory hypotension, bradyarrhythmias, asystole

— Refractory metabolic acidosis even after antidote (poor prognostic marker)

— Status epilepticus

— Non-cardiogenic pulmonary edema / ARDS — particularly with smoke inhalation

— Myocardial ischemia/infarction — mitochondrial dysfunction in coronary tissue; troponin elevations common

— Acute kidney injury — pre-renal from shock, hemoglobinuria, oxalate nephropathy from hydroxocobalamin

— Rhabdomyolysis from seizures or prolonged hypoperfusion

— Hepatic injury — centrilobular necrosis

— Delayed neurologic sequelae mimicking CO poisoning: parkinsonism, dystonia, cognitive impairment, personality change

— MRI: bilateral basal ganglia (putamen, globus pallidus) and substantia nigra lesions

— Peripheral neuropathy

— Persistent lactic acidosis if antidote insufficient

— Hydroxocobalamin: oxalate nephropathy/AKI, transient hypertension, chromaturia, allergic reactions, lab interference

— Sodium nitrite: profound hypotension, lethal MetHb, hemolysis in G6PD

— Thiosulfate: thiocyanate accumulation in renal failure → tinnitus, AMS, psychosis

— Lactate persistently >10 after 2 doses of antidote

— Cardiac arrest at presentation (mortality >80%)

— GCS 3 with fixed pupils on arrival

— Need for vasopressors >24 hours

Step 3 management: Survivors with severe poisoning warrant outpatient neurology follow-up at 2–4 weeks and a low threshold for MRI brain if delayed cognitive, motor, or movement symptoms emerge — counsel the patient/family about delayed sequelae at discharge.

Board pearl: Delayed parkinsonism after cyanide or CO is levodopa-responsive in some cases; refer early.

Acute complications:

Subacute/delayed complications (days to weeks):

Antidote-related adverse events:

Prognostic markers of poor outcome:

When to Escalate — ICU, Consults, and Inpatient Triage

— Any AMS, seizure, hemodynamic instability, or persistent acidosis

— Need for vasopressors, mechanical ventilation, or close neuro/hemodynamic monitoring

— Concomitant significant CO poisoning

— Post-cardiac arrest survivors

— Pediatric ingestions with delayed-conversion toxins (acetonitrile, amygdalin) — observe ≥24 h even if initially well

— Medical toxicology / regional Poison Control (1-800-222-1222 in US) — call early, ideally before the second dose of antidote, and document the consult

— Pulmonology / burn service for inhalation/burn co-injury

— Hyperbaric medicine for CO co-exposure meeting criteria

— Nephrology for AKI, dialysis-dependent patients, or thiocyanate toxicity

— Psychiatry for any suicidal ingestion — safety hold and inpatient evaluation

— Ophthalmology if alkali/chemical eye exposure

— Social work / occupational medicine for workplace exposures

— Forensic pathology / medical examiner for deaths and suspected homicide

— Decontaminate before transport into the resuscitation bay where possible

— Staff PPE; ventilate the area; double-bag contaminated clothing

— Notify hospital safety officer for HAZMAT events

CCS pearl: On a CCS case, the high-yield order set sequence is: "ABCs, 100% O₂, IV access ×2, hydroxocobalamin 5 g IV, sodium thiosulfate 12.5 g IV, labs including lactate and co-oximetry, Poison Control consult, ICU admission, Psychiatry consult if intentional." Toggle to ICU location, continue serial lactates and neuro exams every 1–2 hours initially.

All suspected cyanide poisoning patients require admission, almost always to an ICU.

ICU admission criteria:

Step-down/floor admission acceptable only for mild, isolated exposures with normal vitals, normal mental status, normal lactate, and reliable observation for at least 6–12 hours (longer for delayed-onset toxins).

Consultations:

Hospital safety:

Key Differentials — Other Toxicologic Causes of High-Lactate Coma

— Carbon monoxide poisoning

· Cherry-red skin, headache, AMS, low SpO₂ on co-oximetry only (pulse ox falsely normal)

· Treat with 100% O₂ ± hyperbaric O₂ for LOC, neuro deficits, CO-Hb >25% (or >15% in pregnancy), pregnancy, age >36, prolonged exposure

· Often co-exists with cyanide in fire victims — treat both

— Hydrogen sulfide (H₂S)

· "Rotten egg" odor (but olfactory fatigue), structural collapse in sewers/manure pits/oil fields

· Same mitochondrial mechanism (inhibits cytochrome oxidase)

· Treatment: removal, 100% O₂, sodium nitrite (induce MetHb to sequester sulfide); hydroxocobalamin not effective

— Sodium azide — chemistry lab/airbag manufacturing exposure; profound hypotension; no specific antidote, supportive

— Methemoglobinemia (nitrites, dapsone, benzocaine, aniline dyes)

· True cyanosis unresponsive to oxygen, chocolate-brown blood

· Treat with methylene blue 1–2 mg/kg IV (avoid in G6PD deficiency — use ascorbic acid)

— Salicylate poisoning — mixed respiratory alkalosis + anion gap acidosis, tinnitus, hyperthermia

— Toxic alcohols (methanol, ethylene glycol) — high osmolar gap + anion gap acidosis; fomepizole/dialysis

— Iron, INH, metformin, propofol infusion syndrome — also produce severe lactic acidosis

Key distinction: CO vs cyanide vs MetHb in a fire victim:

— CO: low SpO₂ on co-oximetry, elevated CO-Hb, cherry red, treat with HBO

— CN: normal SpO₂, lactate ≥10, narrow A–V O₂ gap, treat with hydroxocobalamin

— MetHb: low SpO₂ that doesn't improve with O₂, chocolate-brown blood, treat with methylene blue

Board pearl: A patient pulled from a closet fire often has all three — treat empirically with 100% O₂ + hydroxocobalamin, defer methylene blue unless documented severe MetHb.

Same-category mitochondrial / cellular-asphyxiant differentials:

Key Differentials — Non-Toxicologic Causes

— High lactate, hypotension, AMS; distinguished by infectious source, fever, leukocytosis; SvO₂ may be high in distributive shock but slower onset and clinical context differ

— Pulmonary edema, low CO, low SvO₂ (opposite of cyanide's high SvO₂); ECG/echo guide

— Hypoxia, hypotension, RV strain; D-dimer, CTPA, bedside echo

— Organophosphates (SLUDGE/DUMBELS, miosis, fasciculations) — atropine + pralidoxime

— Opioids (miosis, hypoventilation) — naloxone

— Beta-blocker/CCB (bradycardia, hypotension) — glucagon, calcium, high-dose insulin

— TCA (wide QRS, seizure) — sodium bicarbonate

— Digoxin — digoxin-specific Fab

Step 3 management: In any undifferentiated comatose patient, the universal "coma cocktail" assessment is: D5–10 (or D50 if low glucose), naloxone, thiamine, O₂, and consider toxidrome-specific antidotes. Cyanide makes the list when the lactate is disproportionately high and oxygenation is preserved.

Board pearl: Normal A–a gradient + lactic acidosis + cardiovascular collapse = think cellular asphyxiants (CN, H₂S, CO, MetHb) rather than primary respiratory or cardiac causes.

Septic shock

Cardiogenic shock / massive MI

Pulmonary embolism (massive)

Status epilepticus of any cause — transient lactate elevation, resolves with seizure control; cyanide-induced seizures persist beyond benzodiazepines without antidote

Severe DKA / HHS — anion-gap acidosis with glucose and ketones present; clear history

Hypoglycemia — easy to miss; check fingerstick glucose immediately in every altered patient

Hypothyroid coma / adrenal crisis / hepatic encephalopathy — slower course

Anaphylaxis — hypotension and bronchospasm but with urticaria, angioedema, exposure history

Trauma / occult hemorrhage — pulled-from-fire victim may also have blunt trauma; FAST exam, hemoglobin

Intracranial catastrophe (SAH, stroke) — focal exam, head CT

Other antidote-requiring toxidromes:

Secondary Prevention, Discharge Planning, and Long-Term Strategy

— Document the exposure source, mechanism, duration, and any co-exposures (CO especially)

— Counsel on delayed neurologic sequelae (parkinsonism, cognitive change) — return precautions

— Provide written discharge instructions including hospital and Poison Control contact

— Notify OSHA and the employer occupational health program

— Workplace evaluation for engineering controls (ventilation, scrubbers), PPE upgrades, and worker training

— Limit reassignment until medical clearance

— Periodic biological monitoring (urine thiocyanate, blood CN) in high-risk industries

— Smoke detector and CO detector verification at home — prescribe/refer patients without working detectors

— Fire-prevention counseling, escape planning

— Pulmonary rehab if airway/parenchymal injury

— Inpatient psychiatry admission, suicide-risk assessment, lethal-means restriction counseling

— Outpatient psychiatry follow-up within 1 week of discharge, with safety plan and crisis line documented

— Remove access to cyanide compounds at home/work

— Institutional protocols limiting nitroprusside duration and dose

— Use alternatives (nicardipine, clevidipine, esmolol, nitroglycerin) when feasible

— Prophylactic thiosulfate co-infusion when prolonged nitroprusside is unavoidable

— Bundled order sets in EHR; pharmacy alerts at 24 and 48 hours

Step 3 management: Schedule PCP follow-up within 1–2 weeks, neurology at 2–4 weeks for severe cases, psychiatry within 1 week for intentional poisoning, and occupational medicine for workplace exposures. Document the longitudinal plan and who owns each follow-up.

For survivors of acute cyanide poisoning:

Occupational exposures:

Smoke-inhalation survivors:

Suicidal ingestion:

Iatrogenic (nitroprusside) prevention:

Medication reconciliation at discharge — review for any drugs (dapsone, benzocaine) that could precipitate methemoglobinemia in those who received nitrites

Follow-Up, Monitoring Parameters, and Counseling

— Serial lactate every 1–2 h initially, then every 4–6 h until normalized

— ABG/VBG, anion gap, electrolytes, renal function q6–12 h

— Continuous telemetry for at least 24 h after antidote

— Neurologic checks q1–2 h while in ICU

— Methemoglobin q30 min during/after nitrite therapy

— Thiocyanate level in renal failure or prolonged thiosulfate/nitroprusside exposure

— Watch for transient hypertension (usually self-resolving)

— Trend creatinine for oxalate nephropathy/AKI; obtain urinalysis (oxalate crystals)

— Inform patient: red urine and skin discoloration for days to weeks — benign, expected

— Alert lab to all colorimetric assay interference

— Normal mental status, normal vitals off vasopressors ≥24 h

— Normalized lactate and acid-base

— Resolution of seizures, arrhythmias

— Psychiatric clearance if intentional

— Reliable disposition and follow-up

— PCP at 1–2 weeks — reassess neuro and renal recovery, medication reconciliation, mental health screening

— Neurology at 2–4 weeks if any severe poisoning — repeat exam, consider MRI if delayed symptoms

— Psychiatry weekly initially if suicidal ingestion

— Occupational medicine within 2 weeks for workplace exposures and return-to-work clearance

— Pulmonary follow-up at 4–6 weeks if inhalation/airway injury

— Avoidance of repeat exposure, home safety (detectors, ventilation)

— Warning signs of delayed sequelae: tremor, slowness, mood/cognitive change

— Vitamin B12 status — generally unaffected clinically, but levels may be elevated for weeks after hydroxocobalamin

Board pearl: Tell patients to expect red-tinged urine for up to 5 weeks after hydroxocobalamin — failing to warn them is a classic cause of unnecessary ED revisits.

In-hospital monitoring:

Hydroxocobalamin-specific monitoring:

Discharge readiness criteria:

Outpatient follow-up cadence:

Counseling topics:

Ethical, Legal, and Patient Safety Considerations

— Occupational/workplace exposure → OSHA and state occupational health authority; employer notification

— Mass-casualty / HAZMAT events → local health department, hospital emergency operations, FBI if intentional release (potential terrorism / weapon of mass destruction)

— Death → medical examiner / coroner with preservation of biological specimens in proper tubes for forensic analysis

— Suspected homicide / poisoning → law enforcement; preserve chain of custody

— Comatose patient with imminent death → emergency exception (implied consent); document the indication and lack of decisional capacity

— Pediatric patient → consent from parent/guardian; do not delay life-saving antidote for legal formalities

— Pregnant patient → maternal antidote indicated even if some theoretical fetal risk; emphasize that maternal resuscitation is the best fetal therapy; document shared decision-making with surrogate if patient is incapacitated

— Suicidal patient refusing treatment → typically lacks decisional capacity due to active mental illness and acute toxidrome; treat under emergency exception and psychiatric hold (state-specific, e.g., 5150 / EPO)

— Lab interference from hydroxocobalamin persisting for days — ensure receiving floor/ICU and outpatient lab know; falsely elevated/depressed creatinine, bilirubin, magnesium, glucose can prompt incorrect dose changes

— Communication of CO co-exposure — both diagnoses must be on the problem list; missing CO means missing HBO referral

— Suicide means restriction — remove access to industrial cyanide and ensure home/work safety plan before discharge

— Hospital cyanide antidote kits expire — verify stocking schedules

— Pre-hospital responders need PPE training to avoid secondary exposure (mouth-to-mouth resuscitation of cyanide victims has caused rescuer toxicity)

— Cyanide is a DHS-designated chemical weapon agent — facility decontamination protocols apply

Step 3 management: Document capacity assessment for any suicidal poisoning patient before initiating involuntary psychiatric hold, and clearly communicate both the medical and psychiatric problem lists at handoff to inpatient teams.

Mandatory reporting:

Informed consent edge cases:

Transition-of-care safety risks:

Patient safety / systems:

High-Yield Associations and Rapid-Fire Clinical Facts

— 5 g IV (adults), 70 mg/kg (peds)

— Red urine for up to 5 weeks, red skin 1–2 weeks

— Transient hypertension, oxalate nephropathy/AKI

— Massive lab interference (Cr, AST, bili, Mg, co-oximetry)

— Safe in pregnancy and smoke inhalation

Board pearl: If a stem mentions "firefighter," "house fire," "industrial accident at a plating plant," or "patient on nitroprusside drip in CT-ICU," plus AMS and lactic acidosis with normal SpO₂, the answer is hydroxocobalamin — almost without exception on Step 3.

Mechanism: binds Fe³⁺ in cytochrome a₃ (complex IV) → halts oxidative phosphorylation → forced anaerobic metabolism → lactic acidosis

Classic odor: bitter almonds — only ~40% of population can detect (genetic)

Cherry-red skin: shared with carbon monoxide; both arterialize venous blood

Narrowed A–V O₂ difference with SvO₂ >90% — pathognomonic

Smoke inhalation = CO + CN until proven otherwise

Lactate ≥10 mmol/L in fire victim → presumptive CN toxicity (Baud)

Nitroprusside toxicity: dose >2 mcg/kg/min or duration >24–48 h, especially in renal failure → tachyphylaxis, lactic acidosis, AMS

Acetonitrile (nail glue remover) in children → delayed CN toxicity (3–12 h)

Amygdalin/laetrile (apricot pits, "alternative cancer therapy") → CN release via beta-glucosidase

Cassava root (improperly processed) → endemic CN exposure in parts of Africa, causes konzo (spastic paraparesis) and tropical ataxic neuropathy

Chronic low-level CN: smokers run higher baseline thiocyanate

Tobacco amblyopia — historically linked to chronic CN exposure plus B12 deficiency

Hydroxocobalamin:

Sodium nitrite: induces MetHb; avoid in fire victims, pregnancy, infants, G6PD

Sodium thiosulfate: substrate for rhodanese → thiocyanate (renally excreted); slow onset; safe adjunct

Methylene blue is contraindicated for nitrite-induced MetHb in CN poisoning (would release CN back)

Delayed neuro sequelae: parkinsonism, dystonia, basal ganglia lesions on MRI — same pattern as CO

H₂S: same mechanism as CN; nitrites work, hydroxocobalamin doesn't

Poison Control US hotline: 1-800-222-1222

Board Question Stem Patterns

— Answer: Hydroxocobalamin 5 g IV (plus 100% O₂; treat presumed CO concomitantly; consider HBO).

— Answer: Stop nitroprusside, give hydroxocobalamin + thiosulfate, switch to nicardipine, consider HD for thiocyanate.

— Answer: Acetonitrile, metabolized to cyanide. Treat with hydroxocobalamin 70 mg/kg.

— Answer: Hydroxocobalamin; psychiatry hold once stabilized.

— Answer: Sodium nitrite — induces MetHb on top of CO-Hb, worsening O₂ delivery.

— Answer: Cobalt directly chelates CN to form cyanocobalamin (vitamin B12), renally excreted.

— Answer: Hydroxocobalamin colorimetric interference; recheck via enzymatic assay.

— Answer: Delayed cyanide (or CO) basal ganglia injury; refer to neurology, trial levodopa.

Step 3 management: Distractors usually include "send cyanide level and observe" — wrong; "methylene blue" — wrong (would liberate CN); "wait for confirmatory testing" — wrong. Empiric hydroxocobalamin is almost always the correct action.

Stem 1 — Structural fire: "A 45-year-old firefighter is brought in from an apartment fire. He has soot in his nares, GCS 9, BP 80/40, HR 130. SpO₂ 100% on NRB. Lactate 14, pH 7.05, anion gap 28. Next best step?"

Stem 2 — Nitroprusside-induced: "Postop CABG patient on nitroprusside 4 mcg/kg/min for 36 hours develops confusion and lactic acidosis. Creatinine 2.4. Next step?"

Stem 3 — Pediatric delayed: "A 3-year-old drank from his mother's artificial-nail remover 4 hours ago. Initially well, now lethargic with tachypnea. Most likely toxin?"

Stem 4 — Suicide in chemist: "Lab worker found unresponsive with empty potassium cyanide vial. Skin cherry red, normal SpO₂."

Stem 5 — Why not nitrite?: "Fire victim with elevated CO-Hb. Which antidote is contraindicated?"

Stem 6 — Mechanism question: "Mechanism of hydroxocobalamin in CN poisoning?"

Stem 7 — Lab interference: "Why did the patient's creatinine appear 4.5 mg/dL when GFR appears normal?"

Stem 8 — Long-term sequela: "Three weeks after smoke-inhalation cyanide poisoning, patient develops tremor and bradykinesia. MRI shows bilateral putaminal lesions."

One-Line Recap

Cyanide poisoning is a clinical diagnosis — any patient with smoke inhalation, intentional ingestion, or prolonged nitroprusside exposure who presents with altered mental status, hemodynamic collapse, and a profound anion-gap lactic acidosis despite normal SpO₂ should receive empiric IV hydroxocobalamin (5 g adult / 70 mg/kg pediatric) plus 100% oxygen immediately, without waiting for confirmatory cyanide levels.

High-yield recap bullets:

Board pearl: When in doubt on a Step 3 stem about a fire victim with shock and lactic acidosis — give hydroxocobalamin. It is the safest, broadest, and most exam-correct answer in modern US emergency toxicology.

Recognize: smoke inhalation + AMS + lactate ≥10 + normal SpO₂ + narrow A–V O₂ gap = cyanide until proven otherwise; cherry-red skin, not cyanosis.

Treat empirically: hydroxocobalamin 5 g IV first-line (safe with CO co-exposure, in pregnancy, and pediatrics); add sodium thiosulfate 12.5 g as synergistic adjunct; avoid sodium nitrite in fire victims, pregnancy, infants, and G6PD because it induces methemoglobinemia on top of carboxyhemoglobinemia.

Manage in parallel: 100% O₂ for everyone, treat coexisting CO with HBO when criteria met, vasopressors for shock, benzodiazepines for seizures, bicarbonate for severe acidemia, decontamination with rescuer PPE, and call Poison Control (1-800-222-1222) early.

Plan ahead: ICU admission, serial lactates, watch for hydroxocobalamin-induced AKI, hypertension, red urine for 5 weeks, and lab interference; counsel about delayed parkinsonism/basal ganglia injury; psychiatry for intentional ingestion, occupational medicine and OSHA reporting for workplace exposure, and switch from nitroprusside to nicardipine/clevidipine with hospital-level protocols to prevent iatrogenic recurrence.