Toxicology — Therapeutic Drug Toxicity

113. Medication Adverse Effects

narrow-therapeutic-index drug toxicity · digoxin / lithium / anticoagulant complications · each has a specific antidote & a level that guides care · Super Compact

Sx: DIGOXIN: N/V, anorexia, confusion, visual changes (yellow-green halos), any arrhythmia esp brady/AV block + ↑automaticity (classic: PAT with block, bidirectional VT); hyperkalemia in acute toxicity = severity marker · LITHIUM: tremor, ataxia, confusion, dysarthria, myoclonus, hyperreflexia, seizures, nephrogenic DI, in severe → coma; chronic toxicity worse at lower levels · ANTICOAGULANTS: bleeding (GI, intracranial, soft tissue), ↑INR (warfarin), bruising · (narrow therapeutic index + a precipitant — usually a renal/volume change or interaction — tips a stable patient into toxicity)

Neg: denies missed renal decline/dehydration/drug interaction as the precipitant (the usual trigger for all three) · digoxin: denies giving IV calcium reflexively for hyperK without weighing Fab (caution); lithium: denies NSAID/ACEi/thiazide/dehydration interaction missed; anticoag: denies missed occult bleed (intracranial) or that reversal agent was withheld in major bleed

SHx: the specific drug + indication + chronic dose + last dose, recent dose/renal/volume/interaction changes (NSAIDs, diuretics, amiodarone/verapamil for dig, ACEi for lithium), adherence/accidental double-dose, acute vs chronic ingestion (intentional?), other anticoagulants/antiplatelets, falls/trauma (bleed risk)

Etiology: all three are narrow-therapeutic-index drugs where small pharmacokinetic shifts cause toxicity · digoxin inhibits Na/K-ATPase → ↑intracellular Ca (inotropy) but in excess → arrhythmias + hyperkalemia; renally cleared (AKI → accumulation) · lithium renally cleared, reabsorbed with Na → dehydration/↓GFR/Na-avid states (diuretics, NSAIDs, ACEi) raise levels · anticoagulants impair hemostasis → bleeding when supratherapeutic, traumatic, or with interactions

RF: renal impairment/AKI · dehydration/volume shifts · drug-drug interactions · elderly/low body weight · recent dose changes · intentional overdose · (anticoag) fall/trauma, age, prior bleed, dual antithrombotics

Data: DIGOXIN: digoxin level (timing matters — ≥6h post-dose), potassium (key — hyperK = severity), ECG/telemetry, renal function, Mg/Ca · LITHIUM: serum lithium level (serial), renal function, electrolytes/Na, TSH, ECG; correlate level with chronicity (chronic toxic at lower levels) · ANTICOAG: INR/PT (warfarin), CBC/H&H, type & screen, identify the agent (DOAC vs warfarin vs heparin), renal function, imaging for suspected bleed (CT head/abd) · glucose, co-ingestant screen if intentional

DDx: digoxin toxicity (level, hyperK, arrhythmia) · lithium toxicity (neuro + level) · anticoagulant bleeding (↑INR/bleed) · vs other arrhythmia/electrolyte causes, other encephalopathies, other bleeding diatheses/coagulopathies · sepsis/metabolic

Home Meds: HOLD the offending agent · correct the precipitant (renal/volume/interaction) · for anticoag, hold + reverse per bleed severity · review interacting drugs · adjust dosing to renal function on restart

Plan

CONSULT: Toxicology/Poison Control 1-800-222-1222 · Cardiology (digoxin arrhythmia) · Nephrology (lithium — dialysis; severe digoxin in renal failure) · Hematology (anticoag reversal) · ICU (instability) · GI/Neurosurgery (bleeding source)

– DIGOXIN TOXICITY:
  • Digoxin-immune Fab (DigiFab) is the antidote — give for life-threatening arrhythmias, hemodynamic instability, hyperkalemia >5–5.5 mEq/L (acute toxicity), or large known ingestion; dose by known amount ingested or serum level (empiric ~10–20 vials for acute severe/arrest, lower for chronic) per toxicology/package insert
  • Hyperkalemia: treat the toxicity with Fab (corrects K); traditionally AVOID IV calcium in digoxin toxicity (theoretical "stone heart" — controversial, but Fab is preferred); use insulin/glucose, etc. to shift K while giving Fab
  • Bradyarrhythmia: atropine, temporary pacing as bridge; treat ventricular arrhythmias with Fab (± lidocaine/magnesium); correct Mg/K; hold the drug; manage renal function
– LITHIUM TOXICITY:
  • IV isotonic saline to restore volume and enhance renal clearance (lithium is renally cleared); hold lithium, stop interacting drugs (NSAIDs, ACEi, thiazides), correct dehydration
  • HEMODIALYSIS for severe toxicity: significant neurotoxicity (seizures, ↓consciousness), renal failure, or very high levels (e.g. >4 mEq/L, or >2.5 with severe symptoms/renal impairment) — definitive removal; may need repeat (rebound from intracellular redistribution)
  • Supportive: seizure management (benzodiazepines), monitor neuro status, manage nephrogenic DI
– ANTICOAGULANT COMPLICATIONS (bleeding):
  • Warfarin: hold; major/life-threatening bleed → 4-factor PCC (e.g. 25–50 units/kg) + IV vitamin K 5–10 mg; non-major elevated INR → hold ± oral vitamin K per INR/bleeding
  • DOACs: dabigatran → idarucizumab (5 g IV); apixaban/rivaroxaban (factor Xa inhibitors) → andexanet alfa (or 4-factor PCC if andexanet unavailable); consider activated charcoal if very recent ingestion; dabigatran is dialyzable
  • Heparin → protamine; LMWH → partial protamine reversal
  • All: resuscitate (transfuse as needed), find + control the bleeding source (endoscopy, IR, surgery, neurosurgery for ICH), serial labs/imaging
– The unifying theme: these are narrow-index drugs, and the toxicity is almost always precipitated by a renal or volume change or a drug interaction — fix that precipitant alongside the specific antidote. Three things worth memorizing: in digoxin toxicity the potassium is your severity marker and Fab (not calcium) is the move; lithium that's neurotoxic or very high gets dialysis; and a major bleed on warfarin gets PCC plus vitamin K, while DOACs have their own specific reversal agents.
– PT/OT: per status (esp after lithium neurotoxicity or ICH)
– Trend: the relevant level (dig/lithium) serially, potassium + ECG (dig), neuro status (lithium), Hgb/INR + bleeding (anticoag), renal function (all), hemodynamics
– Escalation triggers: dig arrhythmia/instability/hyperK → Fab + ICU/cardiology; severe lithium neurotoxicity/high level → dialysis/nephrology; major/ICH bleed → reversal + ICU + source control (neurosurgery/GI/IR)
– Discharge checklist: toxicity resolved + level normalized/drug held appropriately; precipitant corrected + interacting drugs addressed; clear plan for resuming (or not) the agent with renal-adjusted dosing + monitoring schedule; anticoagulation strategy decided (resume/bridge/alternative) with hematology if needed; psychiatry if intentional; medication education; return precautions (palpitations/syncope, tremor/confusion, bleeding/black stools/headache)

113. Medication Adverse Effects

complete reference · digoxin toxicity + lithium toxicity + anticoagulant complications · drug-specific antidotes, correct the precipitant · Full Card

Symptoms / Associated Sx

• Digoxin: nausea, vomiting, anorexia, confusion, and visual changes (yellow-green halos); essentially any arrhythmia, especially bradycardia and AV block combined with increased automaticity (classically paroxysmal atrial tachycardia with block, or bidirectional VT); hyperkalemia in acute toxicity marks severity

• Lithium: tremor, ataxia, confusion, dysarthria, myoclonus, hyperreflexia, seizures, and nephrogenic diabetes insipidus, progressing to coma in severe cases; chronic toxicity is worse at lower levels

• Anticoagulants: bleeding (GI, intracranial, soft tissue), an elevated INR (warfarin), and bruising

• The common thread: a narrow therapeutic index plus a precipitant — usually a renal or volume change or a drug interaction — tips a stable patient into toxicity

Neg

• Pt denies a missed renal decline, dehydration, or drug interaction as the precipitant (the usual trigger for all three)

• For digoxin, pt denies that IV calcium was given reflexively for hyperkalemia without weighing Fab; for lithium, pt denies a missed NSAID, ACEi, thiazide, or dehydration interaction

• For anticoagulants, pt denies a missed occult bleed (intracranial) or that the reversal agent was withheld in a major bleed

Social History (SHx)

• The specific drug, its indication, the chronic dose, and the last dose

• Recent dose, renal, volume, or interaction changes (NSAIDs and diuretics; amiodarone or verapamil for digoxin; ACEi for lithium)

• Adherence and accidental double-dosing, and acute versus chronic ingestion (consider intent)

• Other anticoagulants or antiplatelets, and falls or trauma (bleed risk)

Main Etiology

• All three are narrow-therapeutic-index drugs in which small pharmacokinetic shifts cause toxicity

• Digoxin inhibits Na/K-ATPase, raising intracellular calcium for inotropy, but in excess causes arrhythmias and hyperkalemia; it is renally cleared, so AKI causes accumulation

• Lithium is renally cleared and reabsorbed with sodium, so dehydration, a reduced GFR, and sodium-avid states (diuretics, NSAIDs, ACEi) raise levels

• Anticoagulants impair hemostasis, causing bleeding when supratherapeutic, with trauma, or with interactions

RF

• Modifiable: dehydration and volume shifts, drug-drug interactions, recent dose changes, and (for anticoagulants) fall and trauma exposure and dual antithrombotic therapy

• Non-modifiable: renal impairment, advanced age and low body weight, and a prior bleed

Data

• Digoxin: a digoxin level (timing matters — at least 6 hours post-dose), potassium (the key marker, since hyperkalemia signals severity), ECG and telemetry, renal function, and magnesium and calcium

• Lithium: a serum lithium level (serial), renal function, electrolytes and sodium, TSH, and an ECG, with the level interpreted against chronicity (chronic toxicity occurs at lower levels)

• Anticoagulants: INR/PT (warfarin), CBC with hemoglobin and hematocrit, a type and screen, identification of the agent (DOAC versus warfarin versus heparin), renal function, and imaging for a suspected bleed (CT of the head or abdomen)

• Glucose and a co-ingestant screen if intentional

DDx

Digoxin toxicity (the level, hyperkalemia, arrhythmia) · lithium toxicity (neurologic features with the level) · anticoagulant bleeding (an elevated INR or bleeding) · versus other causes of arrhythmia or electrolyte derangement, other encephalopathies, and other bleeding diatheses or coagulopathies · sepsis or a metabolic cause

Home Meds

• Hold the offending agent and correct the precipitant (renal, volume, interaction)

• For anticoagulants, hold and reverse per the bleed severity

• Review interacting drugs and adjust dosing to renal function on restart

Plan

CONSULT: Toxicology/Poison Control (1-800-222-1222) · Cardiology (digoxin arrhythmia) · Nephrology (lithium dialysis; severe digoxin in renal failure) · Hematology (anticoagulant reversal) · ICU (instability) · GI/Neurosurgery (bleeding source)

• Digoxin toxicity:

• • Digoxin-immune Fab (DigiFab) is the antidote — given for life-threatening arrhythmias, hemodynamic instability, hyperkalemia above 5–5.5 mEq/L (acute toxicity), or a large known ingestion; dosed by the known amount ingested or the serum level (empirically ~10–20 vials for acute severe toxicity or arrest, fewer for chronic toxicity) per toxicology and the package insert

• • Hyperkalemia: treat the toxicity with Fab, which corrects the potassium; traditionally avoid IV calcium in digoxin toxicity (the theoretical "stone heart," controversial but with Fab preferred); use insulin and glucose to shift potassium while giving Fab

• • Bradyarrhythmia: atropine and temporary pacing as a bridge; treat ventricular arrhythmias with Fab (with lidocaine or magnesium as adjuncts); correct magnesium and potassium; hold the drug; and manage renal function

• Lithium toxicity:

• • IV isotonic saline to restore volume and enhance renal clearance (lithium is renally cleared); hold lithium, stop interacting drugs (NSAIDs, ACEi, thiazides), and correct dehydration

• • Hemodialysis for severe toxicity — significant neurotoxicity (seizures, reduced consciousness), renal failure, or very high levels (e.g. above 4 mEq/L, or above 2.5 with severe symptoms or renal impairment) — for definitive removal, which may need repeating because of rebound from intracellular redistribution

• • Supportive care: seizure management (benzodiazepines), monitoring of neurologic status, and management of nephrogenic diabetes insipidus

• Anticoagulant complications (bleeding):

• • Warfarin: hold it; for a major or life-threatening bleed, give 4-factor PCC (e.g. 25–50 units/kg) with IV vitamin K 5–10 mg; for a non-major elevated INR, hold with or without oral vitamin K per the INR and bleeding

• • DOACs: dabigatran is reversed with idarucizumab (5 g IV); apixaban and rivaroxaban (factor Xa inhibitors) with andexanet alfa (or 4-factor PCC if andexanet is unavailable); consider activated charcoal if ingestion was very recent; and dabigatran is dialyzable

• • Heparin is reversed with protamine, and LMWH with partial protamine reversal

• • All: resuscitate (transfuse as needed), find and control the bleeding source (endoscopy, IR, surgery, or neurosurgery for ICH), and follow serial labs and imaging

• PT/OT: per status, especially after lithium neurotoxicity or an intracranial hemorrhage

• Trend: the relevant level (digoxin or lithium) serially, potassium and the ECG (digoxin), neurologic status (lithium), hemoglobin, INR, and bleeding (anticoagulant), renal function (all), and hemodynamics

• Escalation triggers: a digoxin arrhythmia, instability, or hyperkalemia → Fab with ICU/cardiology; severe lithium neurotoxicity or a high level → dialysis and nephrology; a major or intracranial bleed → reversal, ICU, and source control (neurosurgery, GI, IR)

• Discharge checklist: toxicity resolved with the level normalized or the drug appropriately held; the precipitant corrected and interacting drugs addressed; a clear plan for resuming (or not) the agent with renal-adjusted dosing and a monitoring schedule; an anticoagulation strategy decided (resume, bridge, or alternative) with hematology if needed; psychiatry if intentional; medication education; return precautions for palpitations or syncope, tremor or confusion, and bleeding, black stools, or headache

Red Flags

• Digoxin toxicity with hyperkalemia, a life-threatening arrhythmia, or instability → digoxin-immune Fab (not calcium first) and ICU/cardiology

• Lithium with seizures, depressed consciousness, renal failure, or a very high level → hemodialysis

• A major or intracranial bleed on any anticoagulant → immediate agent-specific reversal and source control

• An unrecognized precipitant (AKI, dehydration, interaction) → the toxicity will recur if it isn't corrected

• Lithium rebound after dialysis → repeat levels, since intracellular stores redistribute

Senior IM Resident Pearls

• Toxicity of a narrow-index drug almost always has a precipitant. A renal or volume change or a new interaction tipped a previously stable patient — fix that, not just the level.

• In digoxin toxicity, the potassium is the severity marker. Hyperkalemia in acute toxicity signals danger, and Fab — not reflexive calcium — is the treatment that corrects it.

• Chronic lithium toxicity is dangerous at "lower" levels. Don't be reassured by a modestly elevated level in a chronically toxic, neurologically impaired patient — they may still need dialysis.

• Match the reversal agent to the anticoagulant. PCC plus vitamin K for warfarin, idarucizumab for dabigatran, andexanet (or PCC) for Xa inhibitors, protamine for heparin — know them cold.

• Lithium rebounds after dialysis. Recheck the level, because redistribution from cells can push it back up and require another run.

• Don't reflexively reverse a mildly elevated INR. Reversal is driven by bleeding severity, not the number alone — but a major or intracranial bleed gets immediate, aggressive reversal.

• Common mistake: giving IV calcium for the hyperkalemia of digoxin toxicity out of reflex — give Fab, which treats both the rhythm and the potassium.

Substance Use — Cannabis

114. Cannabinoid Hyperemesis Syndrome

cyclic vomiting in a heavy chronic cannabis user · recurrent nausea/vomiting · pathognomonic hot-water bathing relief · topical capsaicin + haloperidol, cessation is the cure · Super Compact

Sx: recurrent, cyclic, severe nausea + intractable vomiting + diffuse abdominal pain in a long-term heavy cannabis user · compulsive hot-water bathing/showering relieves symptoms (pathognomonic) · episodes last hours–days, recur over months–years with well intervals · often dehydration, weight loss, multiple prior ED visits with negative workups · (the hot-shower history is the single most useful clue — patients often don't volunteer the cannabis link and may take many years/visits to be diagnosed)

Neg: denies that life-threatening causes weren't excluded first (bowel obstruction, pancreatitis, DKA, pregnancy, ↑ICP, GI bleed, ACS, surgical abdomen) — CHS is partly a diagnosis of exclusion · denies missed dehydration/electrolyte/AKI complications · denies that opioids were given (worsen the cyclic-vomiting picture, don't help)

SHx: cannabis use — duration, frequency, amount, route (key: typically years of daily/near-daily use) · the hot-bathing behavior (ask directly) · prior similar episodes + prior workups · other substance use · ability/willingness to stop (cessation is curative)

Etiology: not fully understood — chronic high-dose cannabis paradoxically causes hyperemesis (opposite of its antiemetic effect), proposed mechanisms involving cannabinoid receptor dysregulation, effects on the gut and thermoregulation (TRPV1 — possibly why heat/capsaicin help), and accumulation of cannabinoids in fat · three phases: prodromal (morning nausea, fear of vomiting) → hyperemetic (intractable vomiting, hot bathing) → recovery (with abstinence)

RF: long-term (often years) heavy/daily cannabis use · younger adults · high-potency products · (the only true cure is cessation)

Data: largely to EXCLUDE other causes: BMP (electrolytes, AKI from vomiting), lipase, LFTs, glucose/ketones (DKA), pregnancy test, urinalysis, CBC · imaging (abd US/CT) as indicated to rule out obstruction/surgical abdomen · ECG (electrolytes/QT before antiemetics) · urine tox (confirms cannabis; corroborative) · lactate if concern · (no confirmatory test — diagnosis is clinical: chronic use + cyclic vomiting + hot-bathing relief + exclusion)

DDx: CHS (chronic cannabis, cyclic vomiting, hot-bath relief) · cyclic vomiting syndrome (no cannabis link) · gastroparesis · bowel obstruction/surgical abdomen · pancreatitis · DKA · pregnancy/hyperemesis · ↑ICP · gastroenteritis · psychogenic

Home Meds: hold non-helpful antiemetics if ineffective · avoid opioids (unhelpful, risk) · review for QT-prolonging combos before haloperidol · address the cannabis itself

Plan

CONSULT: GI (if diagnosis unclear, refractory, or to exclude other pathology) · Addiction Medicine/Psychiatry (cannabis cessation — the cure) · Toxicology/Poison Control (if needed)

– Exclude dangerous mimics first (obstruction, pancreatitis, DKA, pregnancy, surgical abdomen, ↑ICP) — CHS is a clinical diagnosis supported by exclusion + the classic history
– Acute symptom control (the CHS-specific toolkit):
  • Topical capsaicin cream (0.025–0.075%) to the abdomen — leverages the heat/TRPV1 mechanism that explains hot-water relief; cheap, useful first-line adjunct (warn re burning sensation, avoid mucous membranes)
  • Haloperidol (e.g. 0.05–0.1 mg/kg or ~2.5–5 mg IV/IM) or droperidol — dopamine antagonists, more effective than conventional antiemetics in CHS (watch QT/EPS — check ECG)
  • Benzodiazepines (lorazepam) as an adjunct for the anticipatory/anxiety component
  • Conventional antiemetics (ondansetron, metoclopramide, promethazine) often only partially effective but reasonable to try
  • Hot showers — patients will self-treat; allow it for comfort (caution re burns/dehydration)
– Supportive: IV fluid resuscitation + electrolyte repletion (correct K/Mg from vomiting), antiemetics, treat AKI from dehydration
– AVOID opioids — they don't help the cyclic vomiting, carry dependence risk, and can confuse the picture
– The definitive treatment is cannabis CESSATION: clear, non-judgmental education that cannabis is the cause and complete cessation is curative (symptoms resolve over days–weeks, may recur with resumption); link to addiction/cessation support; set expectations that cutting down isn't enough
– Ask about the hot showers — it's the most specific clue and patients rarely volunteer it. Once dangerous mimics are excluded, the CHS-specific tools (topical capsaicin and haloperidol) beat ordinary antiemetics, and the only actual cure is stopping cannabis entirely. Don't reach for opioids; they make this worse, not better.
– PT/OT: usually not needed unless deconditioned from recurrent illness
– Trend: hydration/electrolytes/renal function, vomiting frequency, response to capsaicin/haloperidol, QT on ECG, ability to tolerate PO
– Escalation triggers: severe dehydration/electrolyte derangement/AKI → aggressive resuscitation; refractory vomiting or diagnostic uncertainty → GI + broaden workup; QT prolongation → adjust antiemetic strategy
– Discharge checklist: tolerating PO + hydrated + electrolytes corrected; dangerous causes excluded; clear counseling that cannabis is causal and cessation is the cure; addiction/cessation referral; capsaicin/antiemetic plan for recurrences; PCP/GI follow-up; return precautions (inability to keep fluids down, severe pain, signs of dehydration)

114. Cannabinoid Hyperemesis Syndrome

complete reference · recurrent nausea/vomiting + heavy chronic marijuana use · capsaicin, haloperidol, cessation is curative · Full Card

Symptoms / Associated Sx

• Recurrent, cyclic, severe nausea with intractable vomiting and diffuse abdominal pain in a long-term heavy cannabis user

• Compulsive hot-water bathing or showering that relieves symptoms — a pathognomonic feature

• Episodes lasting hours to days, recurring over months to years with symptom-free intervals

• Often dehydration, weight loss, and multiple prior ED visits with negative workups

• The hot-shower history is the single most useful clue — patients often don't volunteer the cannabis link and may take years and many visits to be diagnosed

Neg

• Pt denies that life-threatening causes were not excluded first (bowel obstruction, pancreatitis, DKA, pregnancy, raised intracranial pressure, GI bleed, ACS, a surgical abdomen) — CHS is partly a diagnosis of exclusion

• Pt denies missed dehydration, electrolyte, or AKI complications

• Pt denies that opioids were given (they worsen the cyclic-vomiting picture and don't help)

Social History (SHx)

• Cannabis use — duration, frequency, amount, and route (typically years of daily or near-daily use)

• The hot-bathing behavior (ask directly)

• Prior similar episodes and prior workups

• Other substance use, and the willingness and ability to stop (cessation is curative)

Main Etiology

• The mechanism is not fully understood — chronic high-dose cannabis paradoxically causes hyperemesis, the opposite of its antiemetic effect

• Proposed mechanisms involve cannabinoid receptor dysregulation, effects on the gut and on thermoregulation (TRPV1, possibly explaining why heat and capsaicin help), and accumulation of cannabinoids in fat

• Three phases are described: a prodromal phase (morning nausea, fear of vomiting), a hyperemetic phase (intractable vomiting and hot bathing), and a recovery phase with abstinence

RF

• Modifiable: the cannabis use itself — cessation is the only true cure

• Non-modifiable contributors: long-term heavy or daily use (often over years), younger adult age, and high-potency products

Data

• Largely to exclude other causes: BMP (electrolytes, AKI from vomiting), lipase, LFTs, glucose and ketones (DKA), a pregnancy test, urinalysis, and CBC

• Imaging (abdominal ultrasound or CT) as indicated to rule out obstruction or a surgical abdomen

• An ECG (electrolytes and QT before antiemetics) and urine toxicology (confirms cannabis, corroborative); lactate if there is concern

• There is no confirmatory test — the diagnosis is clinical, resting on chronic use, cyclic vomiting, hot-bathing relief, and exclusion of other causes

DDx

Cannabinoid hyperemesis syndrome (chronic cannabis use, cyclic vomiting, hot-bath relief) · cyclic vomiting syndrome (without the cannabis link) · gastroparesis · bowel obstruction or a surgical abdomen · pancreatitis · DKA · pregnancy or hyperemesis gravidarum · raised intracranial pressure · gastroenteritis · a psychogenic cause

Home Meds

• Hold: non-helpful antiemetics if ineffective

• Avoid: opioids (unhelpful, with risk)

• Review: QT-prolonging combinations before haloperidol; address the cannabis itself

Plan

CONSULT: GI (if the diagnosis is unclear or refractory, or to exclude other pathology) · Addiction Medicine/Psychiatry (cannabis cessation — the cure) · Toxicology/Poison Control (if needed)

• Exclude dangerous mimics first (obstruction, pancreatitis, DKA, pregnancy, a surgical abdomen, raised ICP) — CHS is a clinical diagnosis supported by exclusion plus the classic history

• Acute symptom control (the CHS-specific toolkit):

• • Topical capsaicin cream (0.025–0.075%) to the abdomen — leveraging the heat/TRPV1 mechanism that explains hot-water relief; cheap and a useful first-line adjunct (warn about the burning sensation and avoid mucous membranes)

• • Haloperidol (e.g. 0.05–0.1 mg/kg, or ~2.5–5 mg IV/IM) or droperidol — dopamine antagonists more effective than conventional antiemetics in CHS (watch QT and extrapyramidal symptoms — check an ECG)

• • Benzodiazepines (lorazepam) as an adjunct for the anticipatory and anxiety component

• • Conventional antiemetics (ondansetron, metoclopramide, promethazine) — often only partially effective but reasonable to try

• • Hot showers — patients will self-treat; allow it for comfort (with caution about burns and dehydration)

• Supportive care: IV fluid resuscitation and electrolyte repletion (correcting potassium and magnesium from vomiting), antiemetics, and treatment of AKI from dehydration

• Avoid opioids — they don't help the cyclic vomiting, carry dependence risk, and can confuse the picture

• The definitive treatment is cannabis cessation: clear, non-judgmental education that cannabis is the cause and complete cessation is curative (symptoms resolve over days to weeks and may recur with resumption); link to addiction and cessation support; and set the expectation that cutting down is not enough

• PT/OT: usually not needed unless the patient is deconditioned from recurrent illness

• Trend: hydration, electrolytes, and renal function, vomiting frequency, the response to capsaicin and haloperidol, the QT on ECG, and the ability to tolerate oral intake

• Escalation triggers: severe dehydration, electrolyte derangement, or AKI → aggressive resuscitation; refractory vomiting or diagnostic uncertainty → GI and a broadened workup; QT prolongation → adjust the antiemetic strategy

• Discharge checklist: tolerating oral intake, hydrated, and electrolytes corrected; dangerous causes excluded; clear counseling that cannabis is causal and cessation is the cure; an addiction or cessation referral; a capsaicin and antiemetic plan for recurrences; primary care or GI follow-up; return precautions for inability to keep fluids down, severe pain, or signs of dehydration

Red Flags

• A dangerous mimic not yet excluded (obstruction, pancreatitis, DKA, pregnancy, surgical abdomen, raised ICP) → complete the workup before settling on CHS

• Severe dehydration, electrolyte derangement, or AKI from intractable vomiting → aggressive resuscitation

• QT prolongation before or after haloperidol/droperidol → reassess the antiemetic choice

• Refractory vomiting despite CHS-specific therapy → reconsider the diagnosis and involve GI

• Opioid use entrenching the cycle → discontinue and redirect to CHS-specific measures

Senior IM Resident Pearls

• Ask about the hot showers. It's the most specific clue and patients rarely volunteer it — the compulsive hot-water bathing essentially makes the diagnosis in a chronic user.

• CHS-specific drugs beat ordinary antiemetics. Topical capsaicin and haloperidol work where ondansetron often fails, because they engage the underlying mechanism.

• Cessation is the only cure. Cutting down isn't enough — counsel clearly and non-judgmentally that complete abstinence resolves it, and that resumption brings it back.

• Don't reach for opioids. They don't help cyclic vomiting, add dependence risk, and muddy the picture — a common reflex worth resisting.

• Still exclude the killers. The diagnosis is partly one of exclusion — a chronic cannabis user can also have pancreatitis, obstruction, or DKA, so don't anchor prematurely.

• Check a QT before the dopamine antagonist. Haloperidol and droperidol prolong the QT, especially with electrolyte losses from vomiting on board.

• Common mistake: repeated negative workups without ever connecting the cannabis and the hot showers — naming the syndrome and counseling cessation breaks the cycle of recurrent admissions.

Toxicology — Novel Psychoactive Substances

115. Synthetic Drug Intoxication

unpredictable, potent designer drugs · synthetic cannabinoids (K2/Spice) / designer stimulants (bath salts/cathinones) · benzodiazepines + supportive · tox screens often miss them · Super Compact

Sx: highly variable + often more severe/erratic than the natural drug · SYNTHETIC CANNABINOIDS (K2/Spice): agitation, psychosis, severe anxiety, seizures, tachycardia, hypertension, vomiting, AKI, can cause profound CNS depression OR agitation, occasionally severe (stroke, MI, death) — far more potent/unpredictable than cannabis · DESIGNER STIMULANTS / CATHINONES ("bath salts"): sympathomimetic storm — severe agitation, excited delirium, psychosis, paranoia, violent behavior, hyperthermia, tachycardia/HTN, rhabdomyolysis, seizures · (suspect when presentation is a severe stimulant/agitation syndrome but the standard tox screen is negative — these don't show on routine panels)

Neg: denies that a negative urine tox excluded intoxication (synthetics usually NOT detected on standard immunoassays) · denies missed hyperthermia/rhabdo/excited delirium · denies missed co-ingestant/adulterant · denies that severe agitation/psychosis was assumed purely primary psychiatric

SHx: reported substance + source (often sold as "legal"/"not for human consumption," herbal incense, "plant food"), route/amount/timing, prior use/reactions, co-ingestants, psychiatric history, context (where found, behavior) · constantly changing formulations

Etiology: lab-made compounds designed to mimic (and evade laws/testing) — synthetic cannabinoids are full agonists at CB1 (vs partial THC) → far more potent/toxic/unpredictable; synthetic cathinones are amphetamine-like, blocking/releasing monoamines → strong sympathomimetic + dopaminergic (psychosis, excited delirium) · potency, contaminants, and ever-changing chemistry make effects erratic and severe

RF: use of "legal high"/designer products · polysubstance use · younger users · psychiatric history · unknown potency/adulterants

Data: clinical (don't rely on tox screen — usually negative) · core temperature (hyperthermia), CK + renal function + K (rhabdo), BMP, glucose · ECG (QT, ischemia, arrhythmia) · head CT for neuro signs (stroke/ICH/seizure) · CBC, coags if severe; urinalysis (myoglobin) · acetaminophen/salicylate if intentional · specialized send-out confirmatory testing exists but not real-time useful · contact Poison Control (emerging-agent surveillance)

DDx: synthetic intoxication (severe sympathomimetic/agitation, negative standard screen) · cocaine/methamphetamine · serotonin syndrome/NMS (clonus/rigidity) · anticholinergic (dry skin) · primary psychosis · sepsis/CNS infection · thyroid storm

Home Meds: hold serotonergic/QT/sympathomimetic agents as relevant · reconcile psychiatric meds · no home "antidote" — supportive

Plan

CONSULT: Toxicology/Poison Control 1-800-222-1222 (emerging agents, guidance) · ICU (severe agitation/hyperthermia/instability) · Psychiatry (psychosis, agitation) · Nephrology (severe rhabdo/AKI)

– SUPPORTIVE CARE + BENZODIAZEPINES are the foundation (no specific antidote): benzodiazepines (diazepam 5–10 mg IV or lorazepam 2–4 mg IV, titrated/repeated, often large cumulative doses) for agitation, seizures, tachycardia, hypertension, and hyperthermia-driving agitation — the cornerstone for both classes
– Severe agitation / excited delirium (cathinones): escalate sedation aggressively (high-dose benzodiazepines ± antipsychotic adjunct e.g. haloperidol/droperidol with QT/seizure caution; ketamine for extreme agitation); prepare for intubation; ICU — same approach as severe methamphetamine excited delirium
– Hyperthermia (life-threatening): aggressive active cooling + deep sedation (± paralysis/intubation); a leading cause of death — treat immediately
– Hypertension: benzodiazepines first; if persistent → nitroglycerin/nitroprusside/phentolamine (avoid beta-blockers in the sympathomimetic-predominant picture)
– Seizures: benzodiazepines; status → standard protocol
– Rhabdomyolysis: aggressive IV fluids, monitor CK/renal function/K, treat hyperkalemia, watch for AKI
– Synthetic cannabinoid CNS depression: may instead present obtunded → supportive airway/ventilation, monitor (no naloxone benefit unless opioid co-ingestant/adulterant — some products are adulterated, e.g. with opioids → naloxone if opioid features)
– Psychosis/agitation: sedation + time; antipsychotics + psychiatry for persistent psychosis
– Supportive: fluids, electrolytes, glucose, quiet environment, chemical over physical restraint, continuous monitoring
– The defining trap is the negative tox screen: a patient with a severe stimulant or agitation syndrome and a "clean" panel should raise synthetics, because these designer drugs don't register on routine immunoassays. There's no antidote — benzodiazepines and aggressive supportive care carry the day, and the same excited-delirium triad (hyperthermia, rhabdomyolysis, acidosis) that threatens meth patients applies here. Call Poison Control; the chemistry changes constantly.
– PT/OT: once stable
– Trend: core temp, agitation/sedation, BP/HR, ECG, CK/renal function/K, mental status/psychosis, neuro exam, response to benzodiazepines
– Escalation triggers: excited delirium/uncontrolled agitation/hyperthermia → ICU + deep sedation/cooling/intubation; severe rhabdo/AKI → nephrology/dialysis; seizures/status → escalate; cardiac/neuro events → specialty
– Discharge checklist: toxicity + agitation resolved, psychosis cleared or psychiatry-managed, rhabdo/renal resolved; addiction referral + counseling on the unpredictability/danger of synthetics; psychiatry follow-up; harm-reduction education; return precautions (severe agitation, chest pain, neuro symptoms, dark urine)

115. Synthetic Drug Intoxication

complete reference · synthetic cannabinoids + designer stimulants · benzodiazepines, supportive care, often miss on tox screens · Full Card

Symptoms / Associated Sx

• Highly variable and often more severe and erratic than the natural drug being mimicked

• Synthetic cannabinoids (K2/Spice): agitation, psychosis, severe anxiety, seizures, tachycardia, hypertension, vomiting, and AKI; they can cause profound CNS depression or agitation and occasionally severe events (stroke, MI, death), being far more potent and unpredictable than cannabis

• Designer stimulants / cathinones ("bath salts"): a sympathomimetic storm with severe agitation, excited delirium, psychosis, paranoia, violent behavior, hyperthermia, tachycardia and hypertension, rhabdomyolysis, and seizures

• Suspect synthetics when the presentation is a severe stimulant or agitation syndrome but the standard tox screen is negative — these don't show on routine panels

Neg

• Pt denies that a negative urine toxicology excluded intoxication (synthetics are usually not detected on standard immunoassays)

• Pt denies a missed hyperthermia, rhabdomyolysis, or excited delirium, and denies a missed co-ingestant or adulterant

• Pt denies that severe agitation or psychosis was assumed to be purely a primary psychiatric disorder

Social History (SHx)

• The reported substance and its source (often sold as "legal" or "not for human consumption," as herbal incense, or as "plant food")

• Route, amount, and timing; prior use and reactions

• Co-ingestants and psychiatric history

• The context (where the patient was found, the behavior); formulations change constantly

Main Etiology

• Lab-made compounds designed to mimic established drugs while evading laws and testing

• Synthetic cannabinoids are full agonists at the CB1 receptor (versus partial-agonist THC), making them far more potent, toxic, and unpredictable

• Synthetic cathinones are amphetamine-like, blocking and releasing monoamines for a strong sympathomimetic and dopaminergic effect (psychosis, excited delirium)

• Variable potency, contaminants, and ever-changing chemistry make the effects erratic and severe

RF

• Modifiable: use of "legal high" or designer products, and polysubstance use

• Non-modifiable contributors: younger age, psychiatric history, and the inherently unknown potency and adulterants

Data

• Clinical assessment (don't rely on the tox screen — it's usually negative)

• Core temperature (hyperthermia), CK with renal function and potassium (rhabdomyolysis), BMP, and glucose

• ECG (QT, ischemia, arrhythmia)

• Head CT for neurologic signs (stroke, ICH, seizure); CBC and coagulation studies if severe; urinalysis (myoglobin); and acetaminophen/salicylate levels if intentional

• Specialized send-out confirmatory testing exists but is not useful in real time; contact Poison Control for emerging-agent surveillance

DDx

Synthetic drug intoxication (a severe sympathomimetic or agitation syndrome with a negative standard screen) · cocaine or methamphetamine · serotonin syndrome or NMS (clonus, rigidity) · anticholinergic toxicity (dry skin) · primary psychosis · sepsis or a CNS infection · thyroid storm

Home Meds

• Hold: serotonergic, QT-prolonging, and sympathomimetic agents as relevant

• Reconcile: psychiatric medications

• Note: there is no home "antidote" — management is supportive

Plan

CONSULT: Toxicology/Poison Control (1-800-222-1222 — emerging agents and guidance) · ICU (severe agitation, hyperthermia, instability) · Psychiatry (psychosis, agitation) · Nephrology (severe rhabdomyolysis or AKI)

• Supportive care and benzodiazepines are the foundation (there is no specific antidote): benzodiazepines (diazepam 5–10 mg IV or lorazepam 2–4 mg IV, titrated and repeated, often in large cumulative doses) for agitation, seizures, tachycardia, hypertension, and the agitation driving hyperthermia — the cornerstone for both classes

• Severe agitation or excited delirium (cathinones): escalate sedation aggressively (high-dose benzodiazepines with an antipsychotic adjunct such as haloperidol or droperidol, used with QT and seizure caution, and ketamine for extreme agitation); prepare for intubation; and admit to the ICU — the same approach as severe methamphetamine excited delirium

• Hyperthermia (life-threatening): aggressive active cooling with deep sedation (and paralysis/intubation if needed) — a leading cause of death that must be treated immediately

• Hypertension: benzodiazepines first, and if persistent, nitroglycerin, nitroprusside, or phentolamine (avoiding beta-blockers in the sympathomimetic-predominant picture)

• Seizures: benzodiazepines, with status epilepticus managed per the standard protocol

• Rhabdomyolysis: aggressive IV fluids with monitoring of CK, renal function, and potassium, treatment of hyperkalemia, and vigilance for AKI

• Synthetic cannabinoid CNS depression: the patient may instead present obtunded → supportive airway and ventilation with monitoring (naloxone is not beneficial unless there is an opioid co-ingestant or adulterant — some products are adulterated, even with opioids, so give naloxone if opioid features are present)

• Psychosis and agitation: sedation and time, with antipsychotics and psychiatry for persistent psychosis

• Supportive care: fluids, electrolytes, glucose, a quiet environment, chemical rather than physical restraint, and continuous monitoring

• PT/OT: once stable

• Trend: core temperature, agitation/sedation level, blood pressure and heart rate, the ECG, CK, renal function, and potassium, mental status and psychosis, the neurologic exam, and the response to benzodiazepines

• Escalation triggers: excited delirium, uncontrolled agitation, or hyperthermia → ICU with deep sedation, cooling, and intubation; severe rhabdomyolysis or AKI → nephrology and dialysis; seizures or status → escalate; cardiac or neurologic events → specialty care

• Discharge checklist: toxicity and agitation resolved, psychosis cleared or managed by psychiatry, and rhabdomyolysis and renal injury resolved; an addiction referral with counseling on the unpredictability and danger of synthetics; psychiatry follow-up; harm-reduction education; return precautions for severe agitation, chest pain, neurologic symptoms, or dark urine

Red Flags

• Excited delirium with hyperthermia → deep sedation, aggressive cooling, fluids, and a low threshold to intubate

• Hyperthermia, rhabdomyolysis, and acidosis together → the lethal triad, as in severe stimulant toxicity

• A negative tox screen falsely reassuring the team → synthetics evade routine testing; treat clinically

• Profound CNS depression from synthetic cannabinoids, possibly adulterated with opioids → support ventilation, consider naloxone if opioid features

• Seizures, stroke, or MI in a young user → these potent agents cause severe events

Senior IM Resident Pearls

• The negative tox screen is the trap. A severe stimulant or agitation syndrome with a "clean" panel should raise synthetics — they don't register on routine immunoassays.

• No antidote — benzodiazepines and supportive care win. Sedation controls the agitation, seizures, and downstream physiology for both synthetic cannabinoids and cathinones.

• The excited-delirium triad applies here too. Hyperthermia, rhabdomyolysis, and acidosis kill — cool aggressively, sedate deeply, hydrate, and intubate early.

• Synthetic cannabinoids are unpredictable. Unlike cannabis, the same product can cause profound depression in one patient and a seizing, psychotic crisis in another.

• Beware adulterants. Designer products are contaminated with anything — including opioids — so consider naloxone if there are opioid features despite a "cannabinoid" history.

• Call Poison Control. The chemistry changes constantly, and they track emerging agents and regional outbreaks that can guide management.

• Common mistake: ruling out drug toxicity because the urine screen is negative — these agents are specifically engineered to evade it, so trust the clinical picture.

Toxicology — Analgesics

116. Salicylate Toxicity

tinnitus + the classic mixed acid-base disorder · respiratory alkalosis + anion-gap metabolic acidosis together · urine alkalinization, dialysis · do NOT carelessly intubate · Super Compact

Sx: tinnitus + hearing changes (classic early), nausea/vomiting, hyperventilation/tachypnea, diaphoresis, fever · the hallmark: a MIXED acid-base disorder — primary respiratory alkalosis (direct respiratory center stimulation) PLUS a primary anion-gap metabolic acidosis · severe: altered mental status, agitation, seizures, hyperthermia, non-cardiogenic pulmonary edema, cerebral edema, coma, death; hypo- or hyperglycemia (neuroglycopenia possible with normal serum glucose) · (an acidemic, tachypneic, confused patient with tinnitus and a high anion gap → think salicylate; chronic toxicity in elderly is easily missed)

Neg: denies that a single level was trusted without serial trending (levels rise with ongoing absorption/enteric-coated/bezoar) · denies casual intubation (losing the compensatory hyperventilation → catastrophic acidemia) · denies missed combination/enteric-coated products · denies missed chronic toxicity (elderly, subtle) · denies under-recognized neurotoxicity

SHx: aspirin/salicylate dose + timing, acute vs chronic (chronic = elderly on therapeutic ASA + dehydration/renal decline, harder to spot), formulation (enteric-coated → delayed/prolonged), other salicylate sources (oil of wintergreen/methyl salicylate — highly concentrated, Pepto), co-ingestants, intent

Etiology: salicylate directly stimulates the medullary respiratory center → respiratory alkalosis; uncouples oxidative phosphorylation + impairs metabolism → lactate/ketoacid accumulation → anion-gap metabolic acidosis, heat generation (hyperthermia), ↑metabolic demand · acidemia increases the un-ionized fraction crossing into the CNS → worsening neurotoxicity (why pH management matters)

RF: intentional overdose · chronic therapeutic use + dehydration/renal impairment (elderly) · enteric-coated/concentrated products (oil of wintergreen) · delayed presentation · co-ingestants

Data: serum salicylate level — SERIAL (q1–2h until clearly falling; single level can mislead with ongoing absorption) · ABG/VBG + BMP (anion gap) — track the mixed disorder + pH · potassium (must correct for alkalinization to work), glucose (+ treat neuroglycopenia even if serum normal) · lactate, LFTs, coags (salicylate affects), CBC · core temp · acetaminophen + co-ingestant screen, pregnancy test · CXR (pulmonary edema) · ECG · renal function

DDx: salicylate toxicity (tinnitus, mixed alkalosis+AGMA, level) · DKA/other AGMA (toxic alcohols, lactic) · sepsis · other ASA-mimicking ingestions · primary hyperventilation/anxiety · serotonin syndrome/sympathomimetic (hyperthermia)

Home Meds: hold all salicylate sources (incl combination/topical) · review nephrotoxins · address co-ingestants · correct contributors (dehydration in chronic)

Plan

CONSULT: Toxicology/Poison Control 1-800-222-1222 · Nephrology (hemodialysis) · ICU (severe — neuro changes, instability, dialysis, airway) · Psychiatry (intentional)

– Fluid resuscitation + correct hypokalemia + glucose: IV fluids (volume-deplete, insensible/renal losses); replete potassium aggressively — urine alkalinization fails if hypokalemic (kidney exchanges K for H); give dextrose for any neuroglycopenia (AMS) even with a normal serum glucose
– URINE ALKALINIZATION with sodium bicarbonate (the mainstay): sodium bicarbonate IV bolus then infusion (e.g. ~150 mEq in 1 L D5W) titrated to urine pH 7.5–8 and to raise/maintain serum pH — this ion-traps salicylate in the urine (enhances renal elimination) AND keeps it out of the CNS (alkalemia favors the ionized form); monitor K closely (replace), watch for fluid overload/cerebral edema
– HEMODIALYSIS for severe toxicity — indications: very high level (e.g. >90–100 mg/dL acute, lower in chronic ~>60), altered mental status/seizures/cerebral edema, pulmonary edema, renal failure, severe acidemia refractory to bicarbonate, or clinical deterioration; definitive removal — involve nephrology early, don't delay
– Decontamination: activated charcoal if early/airway protected (esp enteric-coated/large ingestion; may repeat doses); consider for ongoing absorption
– AVOID/USE EXTREME CAUTION WITH INTUBATION (critical pitfall): these patients survive partly via a high minute ventilation compensating for the acidosis — sedation/paralysis/intubation can abolish that hyperventilation → abrupt severe acidemia, CNS salicylate shift, and arrest; if intubation is unavoidable, match the patient's high pre-intubation minute ventilation, pre-treat with bicarbonate, minimize apnea time, and consider dialysis instead/concurrently
– Supportive: cooling for hyperthermia, seizure control (benzodiazepines), manage pulmonary/cerebral edema, continuous monitoring
– Two things define management: alkalinize (serum and urine) to trap salicylate out of the brain and into the urine — and you cannot do that without correcting the potassium first. And the deadliest pitfall is intubating these patients carelessly: their frantic breathing is keeping them alive, and a ventilator that under-ventilates them relative to that drive will crash the pH and kill them. Trend serial levels — one number is not enough.
– PT/OT: per status
– Trend: serial salicylate levels (until clearly falling), ABG/pH + anion gap, potassium, glucose, mental status, urine pH/output, temp, respiratory status
– Escalation triggers: rising level, AMS/seizures, acidemia refractory to bicarbonate, pulmonary/cerebral edema, renal failure → urgent hemodialysis + ICU; need for airway → extreme caution + match minute ventilation + bicarbonate + dialysis
– Discharge checklist: levels clearly falling to non-toxic + clinically recovered + acid-base normalized; co-ingestants addressed; psychiatric evaluation + suicidality assessment if intentional; counsel on salicylate sources (incl topical/OTC); for chronic toxicity, review the contributing regimen/renal function; return precautions (tinnitus, confusion, fast breathing, vomiting)

116. Salicylate Toxicity

complete reference · tinnitus + mixed acid-base disorder · alkalinize, dialyze, avoid careless intubation · Full Card

Symptoms / Associated Sx

• Tinnitus and hearing changes (a classic early sign), nausea and vomiting, hyperventilation and tachypnea, diaphoresis, and fever

• The hallmark is a mixed acid-base disorder — a primary respiratory alkalosis (from direct respiratory center stimulation) together with a primary anion-gap metabolic acidosis

• Severe toxicity brings altered mental status, agitation, seizures, hyperthermia, non-cardiogenic pulmonary edema, cerebral edema, coma, and death

• Hypo- or hyperglycemia, with neuroglycopenia possible even when the serum glucose is normal

• An acidemic, tachypneic, confused patient with tinnitus and a high anion gap should prompt thought of salicylate; chronic toxicity in the elderly is easily missed

Neg

• Pt denies that a single level was trusted without serial trending (levels rise with ongoing absorption, enteric-coated products, or a bezoar)

• Pt denies a casual intubation (losing the compensatory hyperventilation can cause catastrophic acidemia)

• Pt denies missed combination or enteric-coated products, missed chronic toxicity (subtle in the elderly), and under-recognized neurotoxicity

Social History (SHx)

• Aspirin or salicylate dose and timing, and acute versus chronic toxicity (chronic toxicity occurs in the elderly on therapeutic aspirin with dehydration or renal decline and is harder to spot)

• Formulation (enteric-coated products cause delayed, prolonged absorption)

• Other salicylate sources (oil of wintergreen / methyl salicylate, which is highly concentrated, and Pepto-Bismol)

• Co-ingestants and intent

Main Etiology

• Salicylate directly stimulates the medullary respiratory center, producing a respiratory alkalosis

• It uncouples oxidative phosphorylation and impairs metabolism, causing lactate and ketoacid accumulation (an anion-gap metabolic acidosis), heat generation (hyperthermia), and increased metabolic demand

• Acidemia increases the un-ionized fraction that crosses into the CNS, worsening neurotoxicity — which is why pH management matters

RF

• Modifiable: intentional overdose, dehydration, and the use of enteric-coated or concentrated products (oil of wintergreen)

• Non-modifiable contributors: chronic therapeutic use with renal impairment (the elderly), delayed presentation, and co-ingestants

Data

• Serum salicylate level — serial (every 1–2 hours until clearly falling; a single level can mislead with ongoing absorption)

• An ABG or VBG with a BMP (anion gap) (to track the mixed disorder and pH)

• Potassium (must be corrected for alkalinization to work) and glucose (treat neuroglycopenia even if the serum level is normal)

• Lactate, LFTs, coagulation studies (salicylate affects them), and CBC; core temperature

• Acetaminophen and a co-ingestant screen, a pregnancy test, a CXR (pulmonary edema), an ECG, and renal function

DDx

Salicylate toxicity (tinnitus, a mixed alkalosis and anion-gap acidosis, and the level) · DKA or another anion-gap acidosis (toxic alcohols, lactic acidosis) · sepsis · other aspirin-mimicking ingestions · primary hyperventilation or anxiety · serotonin syndrome or a sympathomimetic (hyperthermia)

Home Meds

• Hold: all salicylate sources (including combination and topical products)

• Review: nephrotoxins; address co-ingestants

• Correct contributors (dehydration in chronic toxicity)

Plan

CONSULT: Toxicology/Poison Control (1-800-222-1222) · Nephrology (hemodialysis) · ICU (severe — neurologic changes, instability, dialysis, airway) · Psychiatry (intentional ingestion)

• Fluid resuscitation with correction of hypokalemia and glucose: IV fluids (patients are volume-depleted from insensible and renal losses); replete potassium aggressively, since urine alkalinization fails in the hypokalemic patient (the kidney exchanges potassium for hydrogen); and give dextrose for any neuroglycopenia (altered mental status) even with a normal serum glucose

• Urine alkalinization with sodium bicarbonate (the mainstay): a sodium bicarbonate IV bolus then infusion (e.g. ~150 mEq in 1 L of D5W) titrated to a urine pH of 7.5–8 and to raise and maintain the serum pH — this ion-traps salicylate in the urine (enhancing renal elimination) and keeps it out of the CNS (alkalemia favors the ionized form); monitor potassium closely and replace it, and watch for fluid overload and cerebral edema

• Hemodialysis for severe toxicity — indicated for a very high level (e.g. above 90–100 mg/dL acute, lower in chronic toxicity at around above 60), altered mental status, seizures, or cerebral edema, pulmonary edema, renal failure, severe acidemia refractory to bicarbonate, or clinical deterioration — for definitive removal; involve nephrology early and don't delay

• Decontamination: activated charcoal if early and the airway is protected (especially for enteric-coated or large ingestions, possibly in repeat doses), and consider it for ongoing absorption

• Avoid or use extreme caution with intubation (a critical pitfall): these patients survive partly through a high minute ventilation that compensates for the acidosis, so sedation, paralysis, and intubation can abolish that hyperventilation and cause abrupt severe acidemia, a CNS salicylate shift, and arrest; if intubation is unavoidable, match the patient's high pre-intubation minute ventilation, pre-treat with bicarbonate, minimize apnea time, and consider dialysis instead of or alongside it

• Supportive care: cooling for hyperthermia, seizure control (benzodiazepines), management of pulmonary and cerebral edema, and continuous monitoring

• PT/OT: per status

• Trend: serial salicylate levels (until clearly falling), the ABG/pH and anion gap, potassium, glucose, mental status, urine pH and output, temperature, and respiratory status

• Escalation triggers: a rising level, altered mental status or seizures, acidemia refractory to bicarbonate, pulmonary or cerebral edema, or renal failure → urgent hemodialysis and ICU; a need for an airway → extreme caution with matched minute ventilation, bicarbonate, and dialysis

• Discharge checklist: levels clearly falling to non-toxic with clinical recovery and a normalized acid-base status; co-ingestants addressed; a psychiatric evaluation and suicidality assessment if intentional; counseling on salicylate sources (including topical and OTC products); for chronic toxicity, review of the contributing regimen and renal function; return precautions for tinnitus, confusion, fast breathing, or vomiting

Red Flags

• Altered mental status, seizures, or cerebral edema → CNS salicylate accumulation → urgent dialysis

• A rising serial level or acidemia refractory to bicarbonate → hemodialysis

• Careless intubation abolishing the compensatory hyperventilation → catastrophic acidemia and arrest

• Hypokalemia preventing effective urine alkalinization → replete potassium aggressively

• Concentrated sources (oil of wintergreen) or enteric-coated products → delayed, severe, prolonged toxicity

Senior IM Resident Pearls

• The mixed acid-base picture is the fingerprint. A respiratory alkalosis and an anion-gap metabolic acidosis together, with tinnitus, should make you check a salicylate level.

• Alkalinize to trap it out of the brain and into the urine. Raising serum and urine pH both enhances elimination and keeps salicylate out of the CNS — the core of treatment.

• You can't alkalinize without fixing the potassium. A hypokalemic kidney reabsorbs hydrogen instead, defeating the bicarbonate — replete aggressively.

• Don't casually intubate. The frantic breathing is keeping the patient alive; a ventilator that under-ventilates relative to that drive crashes the pH — match the minute ventilation, pre-treat with bicarbonate, and consider dialysis instead.

• Trend serial levels. One number misleads — ongoing absorption from enteric-coated tablets or a bezoar can push the level up for hours.

• Treat neuroglycopenia even with a normal serum glucose. CNS glucose can be low despite a normal blood level, so give dextrose to the confused salicylate patient.

• Common mistake: waiting too long to involve nephrology — the indications for dialysis (high level, neurotoxicity, refractory acidosis) demand early consultation, not a last-minute call.

Toxicology — Gases

117. Carbon Monoxide Poisoning

the great mimic · headache / confusion / elevated carboxyhemoglobin · pulse ox lies — get co-oximetry · 100% O2, hyperbaric for severe · Super Compact

Sx: non-specific, dose-dependent — headache (most common), dizziness, nausea, malaise, confusion ("flu-like without fever") → syncope, chest pain/ischemia, seizures, coma, arrhythmia at high levels · multiple people/pets in same dwelling ill together (heater/generator/fire/smoke), worse indoors/better outdoors · classic "cherry-red" skin is rare/late · delayed neuropsychiatric sequelae (cognitive deficits, parkinsonism, personality change) days–weeks later · (easily missed — looks like viral illness, migraine, or intoxication; ask about exposure source and co-habitants)

Neg: denies that a normal pulse oximetry reassured (SpO2 falsely normal — standard pulse ox can't distinguish carboxyhemoglobin from oxyhemoglobin) · denies missed exposure source/co-victims · denies missed concurrent cyanide (smoke inhalation/fires) · denies missed cardiac ischemia · denies under-treated pregnant patient (fetus highly vulnerable)

SHx: exposure source + duration (faulty furnace/heater, generator indoors, car in garage, house fire/smoke, charcoal grill), enclosed space, others affected, timing/season (winter), occupational, suicidal intent · pregnancy (fetal Hgb binds CO avidly), cardiac/neuro comorbidity

Etiology: CO (colorless/odorless) binds hemoglobin with ~200–250× the affinity of O2 → carboxyhemoglobin → ↓O2-carrying capacity + leftward shift of the O2 dissociation curve (impaired tissue unloading) → tissue hypoxia; also binds myoglobin and cytochrome oxidase → impaired cellular respiration + direct cardiac/neuronal injury → ischemia, lipid peroxidation, and delayed CNS demyelination (the sequelae)

RF: faulty heating/generators/indoor combustion · house fires/smoke inhalation · winter/enclosed spaces · occupational exposure · suicidal intent · (worse outcomes) cardiac disease, pregnancy, extremes of age

Data: carboxyhemoglobin (COHb) level by CO-OXIMETRY (ABG/VBG co-oximetry — NOT standard pulse ox) · ABG (metabolic acidosis/lactate = tissue hypoxia) · ECG + troponin (ischemia/arrhythmia) · lactate (also consider cyanide in fires — high lactate) · BMP, CK (rhabdo), glucose · pregnancy test · CXR/CO + neuro exam; consider head CT/neuroimaging if severe; (COHb level guides but doesn't perfectly correlate with severity — treat the patient; smokers have a higher baseline)

DDx: CO poisoning (exposure, ↑COHb, co-victims) · viral illness/migraine · other toxic gas/cyanide (fire — co-exposure) · cardiac ischemia · other AMS/intoxication · DKA/other acidosis · meningitis

Home Meds: generally none specific to hold · supportive · address comorbid cardiac meds per ischemia · n/a antidote in meds

Plan

CONSULT: Toxicology/Poison Control 1-800-222-1222 · Hyperbaric medicine (HBO eligibility) · ICU (severe — coma, instability, cardiac) · Cardiology (ischemia/arrhythmia) · OB (pregnant)

– REMOVE from exposure + 100% OXYGEN immediately (the core treatment): high-flow 100% O2 via non-rebreather mask (or ETT if obtunded) — this dramatically shortens the CO half-life (from ~300 min on room air to ~60–90 min on 100% O2); continue until symptoms resolve and COHb is acceptably low (e.g. <5%, lower threshold if pregnant/cardiac)
– HYPERBARIC OXYGEN (HBO) — consider for severe poisoning to further speed elimination and reduce delayed neurologic sequelae; commonly considered indications: loss of consciousness/syncope, neurologic deficit or persistent neuro/cognitive symptoms, cardiac ischemia, severe metabolic acidosis, COHb roughly >25% (some use >15–20% in pregnancy), and pregnancy with significant exposure/fetal distress — discuss with hyperbaric/toxicology early (time-sensitive; transfer considerations)
– Pregnancy: fetal hemoglobin binds CO avidly and clears slowly → treat aggressively, longer O2 duration, lower threshold for HBO; monitor fetus; involve OB
– Support + workup: ECG/troponin and manage cardiac ischemia/arrhythmia; treat acidosis (improves with oxygenation — bicarbonate rarely needed); in fire/smoke victims consider concurrent cyanide toxicity (high lactate, persistent acidosis → hydroxocobalamin); IV fluids; treat rhabdo; seizure control (benzodiazepines)
– Monitor for + counsel on delayed neuropsychiatric sequelae (may emerge days–weeks later — arrange neuro/cognitive follow-up)
– The two traps are diagnosis and the pulse oximeter. CO poisoning masquerades as a viral illness, so ask about the heater, the generator, and whether others in the home are sick — and never be reassured by a normal SpO2, because a standard pulse ox reads carboxyhemoglobin as if it were oxygenated. Diagnosis requires co-oximetry. Treatment is 100% oxygen, with hyperbaric oxygen for the severe and the pregnant.
– PT/OT: cognitive/functional assessment if neuro involvement; rehab for sequelae
– Trend: COHb level (falling on O2), symptoms/neuro status, ABG/lactate/acidosis, ECG/troponin, fetal monitoring if pregnant
– Escalation triggers: LOC, neuro deficit, cardiac ischemia, severe acidosis, high COHb, pregnancy → HBO evaluation + ICU; suspected cyanide co-toxicity (fire) → hydroxocobalamin; instability → ICU
– Discharge checklist: symptoms resolved + COHb normalized on oxygen + cardiac complications addressed; exposure source identified + remediated (e.g. furnace inspection, CO detectors) — critical to prevent re-exposure of patient + others; psychiatric evaluation if intentional; neuro/cognitive follow-up for delayed sequelae; OB follow-up if pregnant; return precautions (recurrent/new neuro or cognitive symptoms, chest pain, headache)

117. Carbon Monoxide Poisoning

complete reference · headache + confusion + elevated carboxyhemoglobin · co-oximetry, 100% O2, hyperbaric oxygen · Full Card

Symptoms / Associated Sx

• Non-specific and dose-dependent: headache (the most common), dizziness, nausea, malaise, and confusion — a "flu-like illness without fever" — progressing to syncope, chest pain or ischemia, seizures, coma, and arrhythmia at high levels

• Multiple people or pets in the same dwelling becoming ill together (a heater, generator, fire, or smoke source), worse indoors and better outdoors

• The classic "cherry-red" skin is rare and late

• Delayed neuropsychiatric sequelae (cognitive deficits, parkinsonism, personality change) can appear days to weeks later

• Easily missed — it looks like a viral illness, migraine, or intoxication, so ask about the exposure source and co-habitants

Neg

• Pt denies that a normal pulse oximetry was reassuring (the SpO2 is falsely normal, since a standard pulse oximeter cannot distinguish carboxyhemoglobin from oxyhemoglobin)

• Pt denies a missed exposure source or co-victims, and denies a missed concurrent cyanide toxicity (smoke inhalation, fires)

• Pt denies a missed cardiac ischemia and denies an under-treated pregnant patient (the fetus is highly vulnerable)

Social History (SHx)

• The exposure source and duration (a faulty furnace or heater, a generator used indoors, a car running in a garage, a house fire or smoke, a charcoal grill), an enclosed space, and others affected

• Timing and season (winter), and occupational exposure

• Suicidal intent

• Pregnancy (fetal hemoglobin binds CO avidly) and cardiac or neurologic comorbidity

Main Etiology

• CO (colorless and odorless) binds hemoglobin with roughly 200–250 times the affinity of oxygen, forming carboxyhemoglobin

• This reduces oxygen-carrying capacity and shifts the oxygen dissociation curve leftward (impairing tissue unloading), producing tissue hypoxia

• CO also binds myoglobin and cytochrome oxidase, impairing cellular respiration and causing direct cardiac and neuronal injury — ischemia, lipid peroxidation, and the delayed CNS demyelination responsible for the sequelae

RF

• Modifiable: faulty heating, indoor generator or combustion use, and enclosed-space exposure

• Non-modifiable contributors to worse outcomes: cardiac disease, pregnancy, and extremes of age; suicidal intent is also a factor

Data

• Carboxyhemoglobin (COHb) level by co-oximetry (ABG/VBG co-oximetry — not a standard pulse oximeter)

• ABG (a metabolic acidosis or lactate reflects tissue hypoxia)

• ECG with troponin (ischemia, arrhythmia)

• Lactate (also consider cyanide in fires, which causes a high lactate); BMP, CK (rhabdomyolysis), and glucose; a pregnancy test; and a neurologic exam, with a head CT or neuroimaging if severe

• The COHb level guides but does not perfectly correlate with severity — treat the patient, and remember smokers have a higher baseline

DDx

CO poisoning (an exposure, an elevated COHb, co-victims) · a viral illness or migraine · another toxic gas or cyanide (co-exposure in fires) · cardiac ischemia · another cause of altered mental status or intoxication · DKA or another acidosis · meningitis

Home Meds

• Generally no specific home medication to hold; management is supportive

• Address comorbid cardiac medications per the ischemia picture

• There is no medication-based antidote — oxygen is the treatment

Plan

CONSULT: Toxicology/Poison Control (1-800-222-1222) · Hyperbaric medicine (HBO eligibility) · ICU (severe — coma, instability, cardiac) · Cardiology (ischemia, arrhythmia) · Obstetrics (pregnant patients)

• Remove from exposure and give 100% oxygen immediately (the core treatment): high-flow 100% oxygen via non-rebreather mask (or an endotracheal tube if obtunded) — this dramatically shortens the CO half-life (from roughly 300 minutes on room air to about 60–90 minutes on 100% oxygen); continue until symptoms resolve and the COHb is acceptably low (e.g. below 5%, with a lower threshold in pregnancy or cardiac disease)

• Hyperbaric oxygen (HBO) — consider for severe poisoning to further speed elimination and reduce delayed neurologic sequelae; commonly considered indications include loss of consciousness or syncope, a neurologic deficit or persistent neurologic/cognitive symptoms, cardiac ischemia, severe metabolic acidosis, a COHb roughly above 25% (some use above 15–20% in pregnancy), and pregnancy with significant exposure or fetal distress — discuss with hyperbaric medicine and toxicology early, as it is time-sensitive and may involve transfer

• Pregnancy: fetal hemoglobin binds CO avidly and clears slowly, so treat aggressively with a longer oxygen duration and a lower threshold for HBO, monitor the fetus, and involve obstetrics

• Support and workup: obtain an ECG and troponin and manage cardiac ischemia or arrhythmia; treat acidosis (which improves with oxygenation, so bicarbonate is rarely needed); in fire or smoke victims consider concurrent cyanide toxicity (a high lactate and persistent acidosis suggest it — treat with hydroxocobalamin); give IV fluids; treat rhabdomyolysis; and control seizures (benzodiazepines)

• Monitor for and counsel on delayed neuropsychiatric sequelae (which may emerge days to weeks later — arrange neurologic and cognitive follow-up)

• PT/OT: cognitive and functional assessment if there is neurologic involvement, with rehabilitation for sequelae

• Trend: the COHb level (falling on oxygen), symptoms and neurologic status, the ABG, lactate, and acidosis, the ECG and troponin, and fetal monitoring if pregnant

• Escalation triggers: loss of consciousness, a neurologic deficit, cardiac ischemia, severe acidosis, a high COHb, or pregnancy → HBO evaluation and ICU; suspected cyanide co-toxicity (fire) → hydroxocobalamin; instability → ICU

• Discharge checklist: symptoms resolved, the COHb normalized on oxygen, and cardiac complications addressed; the exposure source identified and remediated (a furnace inspection, CO detectors) — critical to prevent re-exposure of the patient and others; a psychiatric evaluation if intentional; neurologic and cognitive follow-up for delayed sequelae; obstetric follow-up if pregnant; return precautions for recurrent or new neurologic or cognitive symptoms, chest pain, or headache

Red Flags

• A normal pulse oximetry giving false reassurance → use co-oximetry to measure carboxyhemoglobin

• Loss of consciousness, a neurologic deficit, cardiac ischemia, or severe acidosis → severe poisoning → HBO evaluation and ICU

• Pregnancy → the fetus is highly vulnerable; treat aggressively with a low HBO threshold

• A fire or smoke victim with a high lactate and persistent acidosis → concurrent cyanide toxicity → hydroxocobalamin

• An unremediated exposure source → re-exposure of the patient and other occupants

Senior IM Resident Pearls

• CO is the great mimic. It looks like a viral illness or migraine — ask about the heater, the generator, the season, and whether others at home are sick.

• Never trust the pulse oximeter here. A standard SpO2 reads carboxyhemoglobin as if it were oxygenated, so it can be reassuringly normal in a poisoned patient — diagnosis requires co-oximetry.

• 100% oxygen is the workhorse. It cuts the CO half-life roughly fourfold; start it immediately and continue until symptoms clear and the COHb falls.

• Know the HBO indications. Syncope, neurologic deficits, cardiac ischemia, severe acidosis, a very high COHb, and pregnancy push toward hyperbaric oxygen — and the decision is time-sensitive.

• Pregnancy demands aggression. Fetal hemoglobin holds CO longer than maternal, so treat the mother longer and at a lower HBO threshold than the maternal level alone would suggest.

• Think cyanide in fire victims. A persistent lactic acidosis after smoke inhalation suggests concurrent cyanide toxicity — hydroxocobalamin is the antidote.

• Common mistake: discharging back into the same poisoned environment — remediating the source and ensuring CO detectors are as important as treating the patient, and protects the whole household.

Toxicology — Toxic Alcohols

118. Ethylene Glycol Toxicity

antifreeze · high anion-gap acidosis + osmolar gap + AKI · calcium oxalate crystals · fomepizole blocks the toxic pathway, dialysis removes · Super Compact

Sx: three classic stages — (1) neurologic (0.5–12h): looks "drunk" (slurred speech, ataxia, euphoria) but no ethanol smell; nausea/vomiting → confusion, seizures, coma · (2) cardiopulmonary (12–24h): tachycardia, hypertension, tachypnea (Kussmaul from acidosis), heart failure/ARDS · (3) renal (24–72h): flank pain, oliguric AKI from calcium oxalate crystal deposition, hypocalcemia (tetany, ↑QT) · (an intoxicated-appearing patient with a severe anion-gap metabolic acidosis + osmolar gap + AKI/crystalluria, without ethanol on board → toxic alcohol)

Neg: denies waiting for confirmatory level before empiric treatment (levels are send-out/slow — treat on suspicion) · denies missed osmolar gap early/anion gap late (gaps shift as metabolism proceeds) · denies missed hypocalcemia/QT · denies missed co-ingested methanol/ethanol · denies delayed fomepizole/dialysis

SHx: ingestion of antifreeze/radiator fluid/de-icer (sweet taste — accidental peds/pets, intentional, or substitute-for-ethanol), amount/timing, intent, ethanol co-ingestion (delays toxicity), access to products · prior similar

Etiology: ethylene glycol itself causes inebriation + an early osmolar gap; alcohol dehydrogenase (ADH) metabolizes it to toxic acids — glycolic acid (→ anion-gap acidosis) and oxalic acid (→ calcium oxalate crystals → AKI + hypocalcemia) · as the parent alcohol is metabolized, the osmolar gap falls and the anion gap rises · fomepizole/ethanol block ADH, stopping toxic-metabolite formation

RF: intentional ingestion · ethanol substitute/access · accidental (children, pets, sweet taste) · delayed presentation/treatment · occupational

Data: ABG/VBG + BMP → anion gap (later), bicarbonate, AKI · osmolar gap (measured − calculated osmolality; elevated early) · ethylene glycol level (confirmatory, often send-out — don't wait to treat) · serum calcium (hypocalcemia), ECG (QT) · urinalysis: calcium oxalate crystals, ± fluorescence under Wood lamp (fluorescein in antifreeze — unreliable) · lactate (glycolate can falsely elevate some lactate assays), co-ingestant: methanol level, ethanol level, acetaminophen/salicylate · renal function trend

DDx: ethylene glycol (osmolar gap → AGMA, oxalate crystals, AKI, hypocalcemia) · methanol (visual sx, no crystals/AKI early) · DKA/alcoholic ketoacidosis · lactic acidosis · uremia · salicylate · isopropanol (osmolar gap, ketosis, no acidosis)

Home Meds: hold nephrotoxins · no causal home meds · correct contributors · address co-ingestants

Plan

CONSULT: Toxicology/Poison Control 1-800-222-1222 (early — diagnosis + dosing) · Nephrology (hemodialysis) · ICU (severe acidosis/instability/AKI)

– FOMEPIZOLE is the antidote — give EARLY/empirically on suspicion (don't wait for the confirmatory level): blocks alcohol dehydrogenase → halts formation of the toxic acids; loading dose 15 mg/kg IV, then 10 mg/kg q12h × 4 doses, then 15 mg/kg q12h thereafter (dose adjusted during/after dialysis — increased frequency); continue until level low/non-detectable + acidosis resolved
– Ethanol is an alternative ADH blocker if fomepizole unavailable (IV/PO titrated to a serum ethanol ~100–150 mg/dL) — harder to manage (monitoring, CNS depression); fomepizole strongly preferred
– HEMODIALYSIS for severe toxicity — indications: significant metabolic acidosis (e.g. pH <7.25–7.3), AKI/renal failure, very high ethylene glycol level, or clinical deterioration despite fomepizole; removes both parent alcohol and toxic metabolites + corrects acidosis — involve nephrology early (adjust fomepizole dosing around dialysis)
– Sodium bicarbonate for severe acidemia (adjunct/temporizing)
– Cofactor therapy (shunt metabolism to non-toxic pathways): thiamine + pyridoxine (vitamin B6) supplementation
– Correct hypocalcemia if symptomatic (tetany, seizures, QT) — but give calcium cautiously (may increase calcium oxalate precipitation); treat symptomatic/severe hypocalcemia
– Supportive: airway, IV fluids (maintain urine output), seizure control (benzodiazepines), monitor renal function (AKI may need temporary RRT), ECG/QT, manage co-ingestants
– The whole game is to block alcohol dehydrogenase before it turns ethylene glycol into the acids that destroy the kidneys — so give fomepizole on clinical suspicion, not after a send-out level returns. Dialysis clears what's already there and fixes the acidosis. The diagnostic clue is the toxic-alcohol fingerprint: an osmolar gap early that converts to an anion-gap acidosis, plus oxalate crystals, AKI, and hypocalcemia, in a "drunk" patient with no alcohol smell.
– PT/OT: per status (esp neuro involvement)
– Trend: anion gap/pH/bicarbonate, ethylene glycol level, renal function/urine output, calcium/QT, mental status, response to fomepizole/dialysis
– Escalation triggers: severe acidosis, AKI/renal failure, high level, or deterioration on fomepizole → hemodialysis + ICU + nephrology; symptomatic hypocalcemia → cautious calcium; airway/seizures → ICU
– Discharge checklist: acidosis resolved + level non-toxic + renal function recovering/plan for residual AKI; co-ingestants addressed; psychiatric evaluation + suicidality assessment if intentional; counsel on product storage/safety (accidental); nephrology follow-up if persistent renal injury; return precautions (decreased urination, confusion, palpitations, vision changes — re-evaluate)

118. Ethylene Glycol Toxicity

complete reference · high anion-gap acidosis + AKI · fomepizole early, dialysis, cofactors · Full Card

Symptoms / Associated Sx

• Three classic stages

• Stage 1 (neurologic, 0.5–12 hours): the patient looks "drunk" (slurred speech, ataxia, euphoria) but without an ethanol smell; nausea and vomiting progress to confusion, seizures, and coma

• Stage 2 (cardiopulmonary, 12–24 hours): tachycardia, hypertension, tachypnea (Kussmaul breathing from acidosis), and heart failure or ARDS

• Stage 3 (renal, 24–72 hours): flank pain, oliguric AKI from calcium oxalate crystal deposition, and hypocalcemia (tetany, QT prolongation)

• An intoxicated-appearing patient with a severe anion-gap metabolic acidosis, an osmolar gap, and AKI or crystalluria, without ethanol on board, suggests a toxic alcohol

Neg

• Pt denies waiting for the confirmatory level before empiric treatment (levels are send-out and slow — treat on suspicion)

• Pt denies a missed osmolar gap early or anion gap late (the gaps shift as metabolism proceeds)

• Pt denies a missed hypocalcemia or QT change, a missed co-ingested methanol or ethanol, and delayed fomepizole or dialysis

Social History (SHx)

• Ingestion of antifreeze, radiator fluid, or de-icer (sweet-tasting — accidental in children and pets, intentional, or as an ethanol substitute)

• Amount, timing, and intent

• Ethanol co-ingestion (which delays toxicity) and access to products

• Prior similar episodes

Main Etiology

• Ethylene glycol itself causes inebriation and an early osmolar gap

• Alcohol dehydrogenase (ADH) metabolizes it to toxic acids — glycolic acid (causing the anion-gap acidosis) and oxalic acid (forming calcium oxalate crystals that cause AKI and hypocalcemia)

• As the parent alcohol is metabolized, the osmolar gap falls and the anion gap rises

• Fomepizole and ethanol block ADH, stopping toxic-metabolite formation

RF

• Modifiable: access to and storage of antifreeze products, and the timeliness of treatment

• Non-modifiable contributors: intentional ingestion, accidental ingestion (children, pets, the sweet taste), and occupational exposure

Data

• An ABG/VBG with a BMP → the anion gap (later), bicarbonate, and AKI

• The osmolar gap (measured minus calculated osmolality; elevated early)

• An ethylene glycol level (confirmatory, often send-out — don't wait to treat)

• Serum calcium (hypocalcemia) and an ECG (QT)

• Urinalysis for calcium oxalate crystals, with or without fluorescence under a Wood lamp (fluorescein in antifreeze — unreliable)

• Lactate (glycolate can falsely elevate some lactate assays); co-ingestant testing with methanol, ethanol, and acetaminophen/salicylate levels; and a renal function trend

DDx

Ethylene glycol toxicity (an osmolar gap converting to an anion-gap acidosis, oxalate crystals, AKI, hypocalcemia) · methanol (visual symptoms, without early crystals or AKI) · DKA or alcoholic ketoacidosis · lactic acidosis · uremia · salicylate · isopropanol (an osmolar gap with ketosis but no acidosis)

Home Meds

• Hold: nephrotoxins

• No causal home medication; correct contributors

• Address co-ingestants

Plan

CONSULT: Toxicology/Poison Control (1-800-222-1222 — early, for diagnosis and dosing) · Nephrology (hemodialysis) · ICU (severe acidosis, instability, AKI)

• Fomepizole is the antidote — give it early and empirically on suspicion (don't wait for the confirmatory level): it blocks alcohol dehydrogenase, halting formation of the toxic acids; the loading dose is 15 mg/kg IV, then 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter (with dosing adjusted to a higher frequency during and after dialysis); continue until the level is low or undetectable and the acidosis has resolved

• Ethanol is an alternative ADH blocker if fomepizole is unavailable (IV or PO titrated to a serum ethanol of ~100–150 mg/dL), but it is harder to manage (monitoring, CNS depression) and fomepizole is strongly preferred

• Hemodialysis for severe toxicity — indicated for significant metabolic acidosis (e.g. pH below 7.25–7.3), AKI or renal failure, a very high ethylene glycol level, or clinical deterioration despite fomepizole — removes both the parent alcohol and the toxic metabolites and corrects the acidosis; involve nephrology early and adjust fomepizole dosing around dialysis

• Sodium bicarbonate for severe acidemia (an adjunct and temporizing measure)

• Cofactor therapy to shunt metabolism toward non-toxic pathways: thiamine and pyridoxine (vitamin B6) supplementation

• Correct hypocalcemia if symptomatic (tetany, seizures, QT prolongation) — but give calcium cautiously, since it may increase calcium oxalate precipitation; treat symptomatic or severe hypocalcemia

• Supportive care: airway management, IV fluids (maintaining urine output), seizure control (benzodiazepines), monitoring of renal function (AKI may need temporary renal replacement therapy), ECG/QT monitoring, and management of co-ingestants

• PT/OT: per status, especially with neurologic involvement

• Trend: the anion gap, pH, and bicarbonate, the ethylene glycol level, renal function and urine output, calcium and the QT, mental status, and the response to fomepizole and dialysis

• Escalation triggers: severe acidosis, AKI or renal failure, a high level, or deterioration on fomepizole → hemodialysis, ICU, and nephrology; symptomatic hypocalcemia → cautious calcium; airway compromise or seizures → ICU

• Discharge checklist: the acidosis resolved, the level non-toxic, and renal function recovering with a plan for residual AKI; co-ingestants addressed; a psychiatric evaluation and suicidality assessment if intentional; counseling on product storage and safety (accidental); nephrology follow-up if there is persistent renal injury; return precautions for decreased urination, confusion, palpitations, or vision changes

Red Flags

• A severe anion-gap acidosis with an osmolar gap in an intoxicated patient without ethanol → empiric fomepizole now, not after the level returns

• Severe acidosis, AKI, or a very high level → hemodialysis

• Oliguric AKI from calcium oxalate deposition → the renal stage; may need renal replacement therapy

• Symptomatic hypocalcemia (tetany, seizures, QT) → cautious calcium repletion

• Deterioration despite fomepizole → escalate to dialysis

Senior IM Resident Pearls

• Treat on suspicion, not on the level. Ethylene glycol levels are send-out and slow — give fomepizole when the clinical and lab picture fits, because every hour of unblocked ADH makes more kidney-destroying acid.

• Watch the gaps shift. Early there's an osmolar gap from the parent alcohol; as it's metabolized the osmolar gap closes and the anion gap opens — so a "normal" osmolar gap late doesn't exclude it.

• Fomepizole blocks, dialysis removes. The antidote stops new toxin formation; dialysis clears what's already there and corrects the acidosis — severe cases need both.

• Give calcium cautiously. It can worsen oxalate precipitation, so reserve repletion for symptomatic or severe hypocalcemia rather than chasing the number.

• Don't forget the cofactors. Thiamine and pyridoxine shunt metabolism toward non-toxic products and are cheap, safe adjuncts.

• Re-dose fomepizole around dialysis. Dialysis removes it, so the frequency increases during and after a run — coordinate with nephrology.

• Common mistake: waiting for the confirmatory level before starting the antidote — by the time it returns, the toxic metabolites have already done renal damage.

Toxicology — Toxic Alcohols

119. Methanol Toxicity

wood alcohol · visual disturbances + severe metabolic acidosis + osmolar gap · "snowfield" vision → blindness · fomepizole, folinic acid, dialysis · Super Compact

Sx: latent period (often 12–24h, longer if ethanol co-ingested) then — early inebriation/CNS depression (looks "drunk," no ethanol smell), nausea/vomiting/abdominal pain · hallmark VISUAL disturbances: blurred vision, "looking at a snowfield," photophobia, decreased acuity, central scotomata, dilated/sluggish pupils → permanent BLINDNESS (optic nerve injury) · severe high anion-gap metabolic acidosis, Kussmaul breathing; severe: seizures, coma, basal ganglia (putaminal) hemorrhage/necrosis → parkinsonism, death · (visual symptoms + a severe AGMA + osmolar gap in a "drunk" patient with no alcohol smell → methanol)

Neg: denies waiting for the confirmatory level before empiric treatment (send-out/slow — treat on suspicion) · denies missed osmolar gap early / anion gap late (shift with metabolism) · denies that the latent period falsely reassured · denies missed co-ingested ethylene glycol/ethanol · denies delayed fomepizole/dialysis (vision/life at stake)

SHx: ingestion of methanol-containing products — windshield washer fluid, antifreeze, solvents, moonshine/illicit or adulterated alcohol, fuel, some cleaners, amount/timing, intent, ethanol co-ingestion (delays/blunts toxicity), outbreak context (tainted bootleg alcohol affecting several people)

Etiology: methanol causes early inebriation + osmolar gap; alcohol dehydrogenase metabolizes it to formaldehyde then FORMIC ACID → severe anion-gap metabolic acidosis + direct optic nerve and basal ganglia toxicity (formate inhibits cytochrome oxidase, retinal/optic injury) · fomepizole/ethanol block ADH (stop formate formation); folinic acid/folate accelerates formate metabolism to non-toxic CO2

RF: intentional ingestion · illicit/adulterated alcohol (outbreaks) · ethanol substitute/access to solvents · delayed presentation/treatment · occupational

Data: ABG/VBG + BMP → severe anion gap, low bicarbonate · osmolar gap (elevated early) · methanol level (confirmatory, send-out — don't wait) · formate level if available (correlates with toxicity) · lactate, co-ingestant: ethylene glycol, ethanol, acetaminophen/salicylate · visual acuity/funduscopy (optic disc hyperemia/edema), neuro exam · consider head CT (basal ganglia changes in severe) · glucose, renal function

DDx: methanol (visual sx, severe AGMA, osmolar gap, latency) · ethylene glycol (AKI, oxalate crystals, no visual sx) · DKA/alcoholic ketoacidosis · lactic acidosis · salicylate · uremia · isopropanol (osmolar gap, no acidosis) · other optic neuropathy

Home Meds: no causal home meds · hold contributors · address co-ingestants

Plan

CONSULT: Toxicology/Poison Control 1-800-222-1222 (early — diagnosis, dosing, dialysis decisions) · Nephrology (hemodialysis) · ICU (severe acidosis/visual loss/instability) · Ophthalmology (visual assessment)

– FOMEPIZOLE is the antidote — give EARLY/empirically on suspicion (don't wait for the level; vision and life are at stake): blocks alcohol dehydrogenase → stops formic acid formation; loading 15 mg/kg IV, then 10 mg/kg q12h × 4 doses, then 15 mg/kg q12h (increased frequency during/after dialysis); continue until level low + acidosis resolved + asymptomatic
– Ethanol is the alternative ADH blocker if fomepizole unavailable (titrated to ~100–150 mg/dL serum) — harder to manage; fomepizole preferred
– FOLINIC ACID (leucovorin) or folic acid — enhances conversion of formate to non-toxic CO2/water (e.g. folinic acid 1 mg/kg, up to ~50 mg IV q4–6h); give as adjunct (methanol-specific — distinguishes from ethylene glycol's thiamine/pyridoxine)
– HEMODIALYSIS for severe toxicity — indications: severe metabolic acidosis (e.g. pH <7.25–7.3), visual symptoms/signs, high methanol level, renal failure, or deterioration despite therapy; removes methanol + formate + corrects acidosis — involve nephrology early (re-dose fomepizole around dialysis)
– Sodium bicarbonate for severe acidemia (adjunct; alkalinization also reduces formate's tissue penetration)
– Supportive: airway, IV fluids, seizure control (benzodiazepines), serial visual + neuro assessment, manage co-ingestants, ICU monitoring
– Methanol and ethylene glycol share a playbook — block alcohol dehydrogenase with fomepizole on suspicion, then dialyze the severe — but methanol has two signatures: it blinds (formic acid attacks the optic nerve) and its specific cofactor is folinic acid (not the thiamine/pyridoxine you'd give for ethylene glycol). Treat early; vision lost to formate doesn't come back, and outbreaks from tainted bootleg alcohol can present several patients at once.
– PT/OT: visual rehab + neuro/functional assessment if deficits (parkinsonism, visual loss)
– Trend: anion gap/pH/bicarbonate, methanol (± formate) level, visual symptoms/acuity, neuro status, response to fomepizole/dialysis
– Escalation triggers: severe acidosis, visual symptoms, high level, renal failure, or deterioration → urgent hemodialysis + ICU + nephrology; visual changes → ophthalmology; airway/seizures → ICU
– Discharge checklist: acidosis resolved + level non-toxic + visual/neuro status documented (residual deficits → rehab); co-ingestants addressed; psychiatric evaluation + suicidality assessment if intentional; public-health consideration if outbreak/tainted alcohol source; ophthalmology + neuro follow-up for sequelae; counsel on product/illicit-alcohol risks; return precautions (vision changes, confusion, fast breathing)

119. Methanol Toxicity

complete reference · visual disturbances + severe metabolic acidosis · fomepizole early, folinic acid, dialysis · Full Card

Symptoms / Associated Sx

• A latent period (often 12–24 hours, longer if ethanol is co-ingested), then early inebriation and CNS depression (looking "drunk" without an ethanol smell) with nausea, vomiting, and abdominal pain

• The hallmark visual disturbances: blurred vision, the sensation of "looking at a snowfield," photophobia, decreased acuity, central scotomata, and dilated, sluggish pupils — progressing to permanent blindness from optic nerve injury

• A severe high anion-gap metabolic acidosis with Kussmaul breathing; in severe cases, seizures, coma, and basal ganglia (putaminal) hemorrhage or necrosis causing parkinsonism, and death

• Visual symptoms with a severe anion-gap acidosis and an osmolar gap in a "drunk" patient without an alcohol smell suggest methanol

Neg

• Pt denies waiting for the confirmatory level before empiric treatment (send-out and slow — treat on suspicion)

• Pt denies a missed osmolar gap early or anion gap late (they shift with metabolism), and denies that the latent period was falsely reassuring

• Pt denies a missed co-ingested ethylene glycol or ethanol, and denies delayed fomepizole or dialysis (vision and life are at stake)

Social History (SHx)

• Ingestion of methanol-containing products — windshield washer fluid, antifreeze, solvents, moonshine or illicit/adulterated alcohol, fuel, and some cleaners

• Amount, timing, and intent

• Ethanol co-ingestion (which delays and blunts toxicity)

• An outbreak context (tainted bootleg alcohol affecting several people at once)

Main Etiology

• Methanol causes early inebriation and an osmolar gap

• Alcohol dehydrogenase metabolizes it to formaldehyde and then formic acid, producing a severe anion-gap metabolic acidosis and direct optic nerve and basal ganglia toxicity (formate inhibits cytochrome oxidase and injures the retina and optic nerve)

• Fomepizole and ethanol block ADH to stop formate formation, while folinic acid and folate accelerate the metabolism of formate to non-toxic CO2

RF

• Modifiable: access to solvents and illicit alcohol, and the timeliness of treatment

• Non-modifiable contributors: intentional ingestion, consumption of adulterated alcohol (outbreaks), and occupational exposure

Data

• An ABG/VBG with a BMP → a severe anion gap and low bicarbonate

• The osmolar gap (elevated early)

• A methanol level (confirmatory, send-out — don't wait)

• A formate level if available (correlates with toxicity)

• Lactate; co-ingestant testing with ethylene glycol, ethanol, and acetaminophen/salicylate levels; visual acuity and funduscopy (optic disc hyperemia or edema) and a neurologic exam; consideration of a head CT (basal ganglia changes in severe cases); and glucose and renal function

DDx

Methanol toxicity (visual symptoms, a severe anion-gap acidosis, an osmolar gap, and a latent period) · ethylene glycol (AKI and oxalate crystals, without visual symptoms) · DKA or alcoholic ketoacidosis · lactic acidosis · salicylate · uremia · isopropanol (an osmolar gap without acidosis) · another optic neuropathy

Home Meds

• No causal home medication

• Hold: contributors

• Address co-ingestants

Plan

CONSULT: Toxicology/Poison Control (1-800-222-1222 — early, for diagnosis, dosing, and dialysis decisions) · Nephrology (hemodialysis) · ICU (severe acidosis, visual loss, instability) · Ophthalmology (visual assessment)

• Fomepizole is the antidote — give it early and empirically on suspicion (don't wait for the level, as vision and life are at stake): it blocks alcohol dehydrogenase to stop formic acid formation; the loading dose is 15 mg/kg IV, then 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours (with increased frequency during and after dialysis); continue until the level is low, the acidosis has resolved, and the patient is asymptomatic

• Ethanol is the alternative ADH blocker if fomepizole is unavailable (titrated to ~100–150 mg/dL serum), but it is harder to manage and fomepizole is preferred

• Folinic acid (leucovorin) or folic acid — enhances conversion of formate to non-toxic CO2 and water (e.g. folinic acid 1 mg/kg, up to ~50 mg IV every 4–6 hours); give it as an adjunct (this is methanol-specific, distinguishing it from the thiamine and pyridoxine used for ethylene glycol)

• Hemodialysis for severe toxicity — indicated for severe metabolic acidosis (e.g. pH below 7.25–7.3), visual symptoms or signs, a high methanol level, renal failure, or deterioration despite therapy — removes methanol and formate and corrects the acidosis; involve nephrology early and re-dose fomepizole around dialysis

• Sodium bicarbonate for severe acidemia (an adjunct; alkalinization also reduces formate's tissue penetration)

• Supportive care: airway management, IV fluids, seizure control (benzodiazepines), serial visual and neurologic assessment, management of co-ingestants, and ICU monitoring

• PT/OT: visual rehabilitation and neurologic/functional assessment if there are deficits (parkinsonism, visual loss)

• Trend: the anion gap, pH, and bicarbonate, the methanol (and formate) level, visual symptoms and acuity, neurologic status, and the response to fomepizole and dialysis

• Escalation triggers: severe acidosis, visual symptoms, a high level, renal failure, or deterioration → urgent hemodialysis, ICU, and nephrology; visual changes → ophthalmology; airway compromise or seizures → ICU

• Discharge checklist: the acidosis resolved, the level non-toxic, and the visual and neurologic status documented (residual deficits → rehabilitation); co-ingestants addressed; a psychiatric evaluation and suicidality assessment if intentional; a public-health consideration if there is an outbreak or tainted-alcohol source; ophthalmology and neurology follow-up for sequelae; counseling on product and illicit-alcohol risks; return precautions for vision changes, confusion, or fast breathing

Red Flags

• Visual disturbances (the "snowfield," scotomata, decreased acuity) → impending permanent blindness → urgent fomepizole and dialysis

• A severe anion-gap acidosis with an osmolar gap in a "drunk" patient without ethanol → empiric fomepizole now

• A high methanol level or deterioration despite therapy → hemodialysis

• Basal ganglia injury → parkinsonism and a poor neurologic outcome

• An outbreak from tainted alcohol → several patients at once and a public-health issue

Senior IM Resident Pearls

• Methanol blinds. Formic acid attacks the optic nerve, and vision lost is often permanent — visual symptoms are a true emergency demanding immediate antidote and dialysis.

• Treat on suspicion, like ethylene glycol. The level is send-out and slow; give fomepizole when the acidosis, osmolar gap, and history fit, because formate is accumulating while you wait.

• The cofactor is folinic acid, not thiamine/pyridoxine. That's the key distinction from ethylene glycol — folinic acid speeds formate breakdown to harmless CO2.

• Beware the latent period. A patient can look deceptively well for 12–24 hours (longer with co-ingested ethanol) before crashing — don't be lulled by an early normal exam.

• Think outbreak. Tainted bootleg alcohol can poison many people at once — one methanol case should prompt thought about others and a public-health response.

• Re-dose fomepizole around dialysis. Dialysis removes it, so frequency increases during and after a run — coordinate with nephrology.

• Common mistake: attributing the visual complaints and acidosis to "just being drunk" — the absence of an ethanol smell with a severe gap acidosis should redirect you to a toxic alcohol immediately.

Toxicology — Hyperthermic Syndromes

120. Serotonin Syndrome

excess serotonergic activity · SSRI/SNRI/MAOI interactions · hyperthermia + CLONUS + hyperreflexia, rapid onset · stop the drug, benzodiazepines, cyproheptadine · Super Compact

Sx: triad — (1) neuromuscular: CLONUS (inducible/spontaneous/ocular — the key sign), hyperreflexia, tremor, myoclonus, rigidity (more LOWER-extremity predominant) · (2) autonomic: hyperthermia, tachycardia, hypertension, diaphoresis, mydriasis, flushing, diarrhea · (3) mental status: agitation, anxiety, confusion · RAPID onset (usually <24h, often within hours of a dose change/new agent) · severe → severe hyperthermia, rhabdomyolysis, DIC, seizures, death · (clonus + hyperreflexia + recent serotonergic change = serotonin syndrome; this distinguishes it from NMS, which has lead-pipe rigidity + bradyreflexia + slow onset)

Neg: denies missed serotonergic culprit/interaction (often a combination or a recently added drug — incl non-psychiatric: tramadol, linezolid, methylene blue, triptans, dextromethorphan, fentanyl, ondansetron, MDMA) · denies that it was mistaken for NMS (treatment/clues differ) · denies missed hyperthermia/rhabdo · denies missed other cause (sepsis, anticholinergic, sympathomimetic)

SHx: full med/substance review for serotonergic agents + recent changes (new start, dose increase, drug added to an SSRI, MAOI combinations — most dangerous), OTC/supplements (St John's wort, dextromethorphan), illicit (MDMA, cocaine), timing relative to onset, overdose vs therapeutic interaction

Etiology: excess CNS serotonergic activity — from a serotonergic overdose, or (classically) a drug interaction combining agents that increase serotonin (e.g. SSRI/SNRI + MAOI, + tramadol/linezolid/triptan/methylene blue) → overstimulation of serotonin receptors → the neuromuscular/autonomic/mental-status triad · onset is rapid (the temporal link to the medication change is a defining feature)

RF: multiple serotonergic agents / recent addition or dose increase · MAOI combinations (highest risk) · overdose · drug interactions via non-psychiatric meds · CYP interactions raising drug levels

Data: clinical diagnosis (Hunter Criteria — serotonergic agent + e.g. spontaneous clonus, or inducible clonus + agitation/diaphoresis, or ocular clonus + agitation, or tremor + hyperreflexia, or hypertonia + temp >38 + clonus) · core temperature, CK (rhabdo), renal function, BMP, CBC, coags (DIC if severe), LFTs · glucose · consider infection workup/CT/LP to exclude mimics · ECG · drug levels/co-ingestant + acetaminophen/salicylate if intentional

DDx: serotonin syndrome (clonus, hyperreflexia, rapid onset, serotonergic drug) · NMS (lead-pipe rigidity, bradyreflexia, slow onset, antipsychotic) · anticholinergic (dry skin, normal reflexes) · sympathomimetic · malignant hyperthermia (anesthesia) · meningitis/sepsis · thyroid storm

Home Meds: STOP all serotonergic agents immediately (SSRIs/SNRIs, MAOIs, tramadol, linezolid, triptans, etc.) · review for the interacting combination · don't restart until resolved + reconciled

Plan

CONSULT: Toxicology/Poison Control 1-800-222-1222 · ICU (severe hyperthermia/rigidity/instability) · Psychiatry (med reconciliation, restart planning)

– STOP all serotonergic agents immediately — the essential first step; most mild cases resolve within ~24h of removing the offending drug(s)
– BENZODIAZEPINES are first-line for agitation, tremor, and to blunt autonomic hyperactivity/hyperthermia-driving muscle activity: diazepam 5–10 mg IV or lorazepam 2–4 mg IV, titrated/repeated — cornerstone of moderate disease
– CYPROHEPTADINE (serotonin antagonist) — the specific antidote for moderate–severe cases not responding to benzodiazepines/supportive care: 12 mg PO/NG load, then 2 mg q2h while symptomatic (or 4–8 mg q6h), up to ~32 mg/day (PO/enteral only)
– Aggressive cooling for hyperthermia (external cooling); for SEVERE hyperthermia (e.g. >41°C) → immediate sedation, paralysis (non-depolarizing, e.g. rocuronium/vecuronium — AVOID succinylcholine if hyperkalemia/rhabdo) + intubation to stop muscular heat production (antipyretics don't work — heat is from muscle activity); this is the lifesaving move in extreme cases
– Severe autonomic instability: short-acting titratable agents (esmolol/nitroprusside for hypertension/tachycardia); avoid long-acting
– Supportive: IV fluids, treat rhabdomyolysis (fluids, monitor CK/K/renal function), seizure control (benzodiazepines), continuous monitoring, manage DIC if present
– The board-and-bedside discriminator is the exam: serotonin syndrome gives you clonus and hyperreflexia (especially in the legs) with a rapid onset after a serotonergic change, while NMS gives lead-pipe rigidity with bradyreflexia over days on an antipsychotic. Stop the drug, give benzodiazepines, add cyproheptadine if needed — and for the truly hyperthermic patient, the answer is paralysis and intubation, because the heat is coming from muscle activity that antipyretics can't touch.
– PT/OT: usually minimal unless prolonged/severe
– Trend: core temp, clonus/reflexes/rigidity, mental status, CK/renal function/K, autonomic vitals, coags (severe), response to benzodiazepines/cyproheptadine
– Escalation triggers: severe hyperthermia (>41°C), refractory rigidity/instability, rhabdo/DIC/renal failure → ICU + paralysis/intubation/cooling; not responding to benzos → cyproheptadine; diagnostic uncertainty vs NMS/sepsis → broaden
– Discharge checklist: resolved (usually rapid) + culprit identified/documented + rhabdo/renal resolved; medication reconciliation to prevent the dangerous combination from recurring (educate patient + future prescribers about the interaction); psychiatry for restart strategy + intentional-ingestion evaluation; return precautions (tremor, agitation, fever, muscle stiffness, confusion)

120. Serotonin Syndrome

complete reference · SSRI/SNRI interactions + hyperthermia + clonus · stop the drug, benzodiazepines, cyproheptadine · Full Card

Symptoms / Associated Sx

• A triad — neuromuscular: clonus (inducible, spontaneous, or ocular — the key sign), hyperreflexia, tremor, myoclonus, and rigidity (more lower-extremity predominant)

• Autonomic: hyperthermia, tachycardia, hypertension, diaphoresis, mydriasis, flushing, and diarrhea

• Mental status: agitation, anxiety, and confusion

• Rapid onset (usually within 24 hours, often within hours of a dose change or new agent)

• Severe cases bring severe hyperthermia, rhabdomyolysis, DIC, seizures, and death

• Clonus and hyperreflexia with a recent serotonergic change distinguish it from NMS, which has lead-pipe rigidity, bradyreflexia, and a slow onset

Neg

• Pt denies a missed serotonergic culprit or interaction (often a combination or a recently added drug, including non-psychiatric agents: tramadol, linezolid, methylene blue, triptans, dextromethorphan, fentanyl, ondansetron, MDMA)

• Pt denies that it was mistaken for NMS (the treatment and clues differ)

• Pt denies a missed hyperthermia or rhabdomyolysis, and denies a missed alternative cause (sepsis, anticholinergic, sympathomimetic)

Social History (SHx)

• A full medication and substance review for serotonergic agents and recent changes (a new start, a dose increase, a drug added to an SSRI, MAOI combinations — the most dangerous)

• OTC products and supplements (St John's wort, dextromethorphan)

• Illicit drugs (MDMA, cocaine)

• The timing relative to onset, and whether this is an overdose or a therapeutic interaction

Main Etiology

• Excess CNS serotonergic activity — from a serotonergic overdose or, classically, a drug interaction combining agents that increase serotonin (e.g. an SSRI/SNRI with an MAOI, tramadol, linezolid, a triptan, or methylene blue)

• Overstimulation of serotonin receptors produces the neuromuscular, autonomic, and mental-status triad

• The onset is rapid, and the temporal link to the medication change is a defining feature

RF

• Modifiable: the number of serotonergic agents, recent additions or dose increases, and MAOI combinations (the highest risk)

• Non-modifiable contributors: overdose, interactions via non-psychiatric medications, and CYP interactions raising drug levels

Data

• A clinical diagnosis (Hunter Criteria — a serotonergic agent plus, for example, spontaneous clonus, or inducible clonus with agitation or diaphoresis, or ocular clonus with agitation, or tremor with hyperreflexia, or hypertonia with a temperature above 38°C and clonus)

• Core temperature; CK (rhabdomyolysis), renal function, BMP, CBC, and coagulation studies (DIC if severe), and LFTs

• Glucose; consideration of an infection workup, CT, or LP to exclude mimics; an ECG; and drug levels, a co-ingestant screen, and acetaminophen/salicylate levels if intentional

DDx

Serotonin syndrome (clonus, hyperreflexia, rapid onset, a serotonergic drug) · NMS (lead-pipe rigidity, bradyreflexia, slow onset, an antipsychotic) · anticholinergic toxicity (dry skin, normal reflexes) · sympathomimetic toxicity · malignant hyperthermia (in the anesthesia setting) · meningitis or sepsis · thyroid storm

Home Meds

• Stop all serotonergic agents immediately (SSRIs/SNRIs, MAOIs, tramadol, linezolid, triptans)

• Review for the interacting combination

• Don't restart until the syndrome has resolved and the medications are reconciled

Plan

CONSULT: Toxicology/Poison Control (1-800-222-1222) · ICU (severe hyperthermia, rigidity, instability) · Psychiatry (medication reconciliation, restart planning)

• Stop all serotonergic agents immediately — the essential first step; most mild cases resolve within about 24 hours of removing the offending drug(s)

• Benzodiazepines are first-line for agitation and tremor and to blunt the autonomic hyperactivity and the muscle activity driving hyperthermia: diazepam 5–10 mg IV or lorazepam 2–4 mg IV, titrated and repeated — the cornerstone of moderate disease

• Cyproheptadine (a serotonin antagonist) — the specific antidote for moderate-to-severe cases not responding to benzodiazepines and supportive care: a 12 mg PO/NG load, then 2 mg every 2 hours while symptomatic (or 4–8 mg every 6 hours), up to about 32 mg/day (PO/enteral only)

• Aggressive cooling for hyperthermia (external cooling); for severe hyperthermia (e.g. above 41°C), immediate sedation, paralysis (a non-depolarizing agent such as rocuronium or vecuronium — avoid succinylcholine if there is hyperkalemia or rhabdomyolysis), and intubation to stop muscular heat production (antipyretics don't work, since the heat comes from muscle activity) — the lifesaving move in extreme cases

• Severe autonomic instability: short-acting titratable agents (esmolol or nitroprusside for hypertension and tachycardia), avoiding long-acting agents

• Supportive care: IV fluids, treatment of rhabdomyolysis (fluids, monitoring CK, potassium, and renal function), seizure control (benzodiazepines), continuous monitoring, and management of DIC if present

• PT/OT: usually minimal unless the course is prolonged or severe

• Trend: core temperature, clonus, reflexes, and rigidity, mental status, CK, renal function, and potassium, autonomic vitals, coagulation studies (in severe cases), and the response to benzodiazepines and cyproheptadine

• Escalation triggers: severe hyperthermia (above 41°C), refractory rigidity or instability, or rhabdomyolysis, DIC, or renal failure → ICU with paralysis, intubation, and cooling; failure to respond to benzodiazepines → cyproheptadine; diagnostic uncertainty versus NMS or sepsis → broaden the workup

• Discharge checklist: the syndrome resolved (usually rapidly) with the culprit identified and documented and rhabdomyolysis and renal injury resolved; a medication reconciliation to prevent the dangerous combination from recurring (educating the patient and future prescribers about the interaction); psychiatry for a restart strategy and an intentional-ingestion evaluation; return precautions for tremor, agitation, fever, muscle stiffness, or confusion

Red Flags

• Severe hyperthermia (above 41°C) → sedation, paralysis, and intubation to stop muscular heat production; antipyretics don't work

• Spontaneous clonus, severe rigidity, or autonomic instability → severe disease requiring ICU care

• Rhabdomyolysis, DIC, or renal failure → markers of life-threatening hyperthermia

• An MAOI combination → the highest-risk interaction, often the most severe

• Misdiagnosis as NMS → the exam (clonus and hyperreflexia versus lead-pipe rigidity and bradyreflexia) and the time course distinguish them

Senior IM Resident Pearls

• The exam discriminates it from NMS. Clonus and hyperreflexia, especially in the legs, with a rapid onset after a serotonergic change — versus lead-pipe rigidity, bradyreflexia, and a slow onset on an antipsychotic.

• Onset is fast. Serotonin syndrome typically appears within hours of a dose change or new agent, unlike the days-long evolution of NMS.

• Stop the drug and give benzodiazepines first. Removing the culprit resolves most mild cases, and benzodiazepines calm the agitation and autonomic drive — cyproheptadine is the next step if that's not enough.

• For the truly hyperthermic, paralyze and intubate. The heat is generated by muscle activity that antipyretics can't address — neuromuscular paralysis is the lifesaving intervention.

• Look beyond the psychiatric list. Tramadol, linezolid, methylene blue, triptans, dextromethorphan, and fentanyl are common, easily overlooked serotonergic culprits.

• Avoid long-acting cardiovascular agents. Autonomic instability swings quickly, so use short-acting titratable drugs you can pull back fast.

• Common mistake: giving an antipsychotic to the "agitated" patient — it doesn't treat serotonin syndrome, can worsen the picture, and muddies the distinction from NMS; reach for benzodiazepines instead.

Toxicology — Hyperthermic Syndromes

121. Neuroleptic Malignant Syndrome

idiosyncratic reaction to dopamine blockade · antipsychotic exposure + lead-pipe rigidity + hyperthermia + ↑CK · slow onset · stop the antipsychotic, dantrolene, bromocriptine · Super Compact

Sx: classic tetrad — (1) severe generalized "LEAD-PIPE" RIGIDITY (+ bradyreflexia/hyporeflexia), (2) HYPERTHERMIA (often >40°C), (3) autonomic instability (labile BP, tachycardia, diaphoresis, tachypnea), (4) altered mental status (stupor, mutism, coma) · markedly ELEVATED CK (from rigidity/rhabdo), leukocytosis · SLOW onset over days (1–3+ days after starting/increasing an antipsychotic or stopping a dopamine agonist) · complications: rhabdomyolysis, AKI, DIC, respiratory failure, death · (lead-pipe rigidity + bradyreflexia + slow onset on an antipsychotic = NMS; contrast serotonin syndrome's clonus + hyperreflexia + rapid onset)

Neg: denies missed antipsychotic exposure or recent dopamine-agonist withdrawal (Parkinson meds stopped) · denies that it was mistaken for serotonin syndrome/sepsis/malignant hyperthermia (clues differ) · denies missed severe rhabdo/AKI/hyperK · denies missed infection mimicking (must exclude)

SHx: antipsychotic exposure — recent start, dose increase, or switch (typical > atypical risk, but any incl antiemetics — metoclopramide, prochlorperazine, promethazine); abrupt withdrawal of dopaminergic agents (levodopa/Parkinson meds); dehydration, agitation, restraint, high potency/depot, prior NMS, timing of onset

Etiology: central DOPAMINE (D2) receptor blockade (or abrupt loss of dopaminergic tone) → dysregulated thermoregulation (hypothalamus) + extrapyramidal rigidity (heat-generating) + autonomic dysfunction → hyperthermia, rigidity, rhabdomyolysis · idiosyncratic, not dose-dependent in the classic sense; onset is gradual (days), reflecting the mechanism vs serotonin syndrome's rapid receptor overstimulation

RF: high-potency typical antipsychotics · rapid dose escalation / depot formulations · dopamine-agonist withdrawal · dehydration, agitation, physical restraint · prior NMS · young males (epidemiologic)

Data: clinical diagnosis (antipsychotic exposure + rigidity + hyperthermia + autonomic/mental-status change) · CK (markedly elevated — key), renal function, K, BMP, CBC (leukocytosis), coags (DIC), LFTs · core temperature · EXCLUDE infection: cultures, ± LP, ± CT (must rule out CNS infection/sepsis) · urinalysis (myoglobin) · iron/other; ECG · drug screen

DDx: NMS (lead-pipe rigidity, bradyreflexia, slow onset, antipsychotic, ↑↑CK) · serotonin syndrome (clonus, hyperreflexia, rapid, serotonergic) · malignant hyperthermia (anesthesia/succinylcholine) · meningitis/encephalitis/sepsis · anticholinergic/sympathomimetic · heat stroke · lethal catatonia · thyroid storm

Home Meds: STOP the offending antipsychotic/dopamine blocker immediately (incl antiemetics like metoclopramide) · RESTART dopaminergic agents if NMS was triggered by their withdrawal · hold other contributors

Plan

CONSULT: Toxicology/Poison Control 1-800-222-1222 · ICU (hyperthermia/rigidity/instability/rhabdo — most cases) · Neurology · Psychiatry (med management, restart strategy) · Nephrology (severe rhabdo/AKI)

– STOP the causative agent immediately (antipsychotic / dopamine blocker, including antiemetics) — or RESTART the dopaminergic agent if NMS was precipitated by its withdrawal; the essential first step
– Aggressive supportive care + cooling (the foundation): ICU, external/active cooling for hyperthermia, aggressive IV fluids (rhabdomyolysis/AKI prevention), correct electrolytes (hyperkalemia from rhabdo), airway/respiratory support, DVT prophylaxis, monitor continuously — supportive care + cooling drives most recovery
– BENZODIAZEPINES (lorazepam/diazepam) for agitation and as adjunct (also helps if lethal catatonia in the differential)
– DANTROLENE (a muscle relaxant) for severe rigidity/hyperthermia — reduces heat generation by acting on skeletal muscle: e.g. 1–2.5 mg/kg IV, repeat to ~10 mg/kg/day; used in severe cases
– BROMOCRIPTINE (dopamine agonist) — restores dopaminergic tone: e.g. 2.5–5 mg PO/NG q6–8h, titrate; used in moderate–severe cases (don't stop abruptly — rebound); amantadine is an alternative
– Rhabdomyolysis management: aggressive fluids, monitor CK/K/renal function, treat hyperkalemia, watch for AKI (may need RRT) and DIC
– EXCLUDE infection (cultures ± LP/CT) — sepsis/CNS infection can mimic and coexist; treat empirically if uncertain
– ECT is a consideration for refractory NMS or when lethal catatonia overlaps (specialist-guided)
– The mirror image of serotonin syndrome: NMS evolves slowly over days on an antipsychotic, with lead-pipe rigidity and depressed reflexes rather than clonus and brisk ones, and a markedly elevated CK. Stop the dopamine blocker (or restart the dopamine agonist if its withdrawal caused it), cool aggressively, flood with fluids, and add dantrolene and bromocriptine for severe cases — but always exclude infection, because sepsis can look identical and can coexist.
– PT/OT: mobilization as recovers; functional assessment (esp after prolonged rigidity/ICU)
– Trend: core temp, rigidity, CK/renal function/K, mental status, autonomic vitals, coags, response to dantrolene/bromocriptine, infection workup
– Escalation triggers: severe hyperthermia/rigidity/instability, rhabdo/AKI/DIC, respiratory failure → ICU + dantrolene/bromocriptine + RRT; refractory → ECT consideration; uncertain dx → treat infection empirically
– Discharge checklist: resolved (can take days–weeks) + CK normalized + rhabdo/renal resolved; clear documentation of NMS + the causative drug to prevent re-exposure; psychiatry plan for future antipsychotic need (lower-potency/atypical, slow titration, delayed rechallenge after full recovery, monitoring); restart of Parkinson meds addressed; return precautions (rigidity, fever, confusion, dark urine)

121. Neuroleptic Malignant Syndrome

complete reference · antipsychotic exposure + rigidity + hyperthermia · stop the drug, cool, dantrolene, bromocriptine · Full Card

Symptoms / Associated Sx

• A classic tetrad — severe generalized "lead-pipe" rigidity (with bradyreflexia/hyporeflexia), hyperthermia (often above 40°C), autonomic instability (labile blood pressure, tachycardia, diaphoresis, tachypnea), and altered mental status (stupor, mutism, coma)

• A markedly elevated CK (from rigidity and rhabdomyolysis) and leukocytosis

• Slow onset over days (1–3 or more days after starting or increasing an antipsychotic, or stopping a dopamine agonist)

• Complications: rhabdomyolysis, AKI, DIC, respiratory failure, and death

• Lead-pipe rigidity, bradyreflexia, and a slow onset on an antipsychotic define NMS, in contrast to serotonin syndrome's clonus, hyperreflexia, and rapid onset

Neg

• Pt denies a missed antipsychotic exposure or recent dopamine-agonist withdrawal (Parkinson medications stopped)

• Pt denies that it was mistaken for serotonin syndrome, sepsis, or malignant hyperthermia (the clues differ)

• Pt denies a missed severe rhabdomyolysis, AKI, or hyperkalemia, and denies a missed infection mimicking the picture (which must be excluded)

Social History (SHx)

• Antipsychotic exposure — a recent start, dose increase, or switch (typical agents carry more risk than atypical, but any can cause it, including antiemetics such as metoclopramide, prochlorperazine, and promethazine)

• Abrupt withdrawal of dopaminergic agents (levodopa and other Parkinson medications)

• Dehydration, agitation, restraint, and high-potency or depot formulations

• Prior NMS and the timing of onset

Main Etiology

• Central dopamine (D2) receptor blockade (or abrupt loss of dopaminergic tone) dysregulates hypothalamic thermoregulation, produces extrapyramidal (heat-generating) rigidity, and causes autonomic dysfunction

• The result is hyperthermia, rigidity, and rhabdomyolysis

• It is idiosyncratic rather than dose-dependent in the classic sense, and the onset is gradual (over days), reflecting the mechanism — in contrast to serotonin syndrome's rapid receptor overstimulation

RF

• Modifiable: rapid dose escalation, depot formulations, dehydration, agitation, and physical restraint

• Non-modifiable contributors: high-potency typical antipsychotics, dopamine-agonist withdrawal, prior NMS, and young male sex (epidemiologic)

Data

• A clinical diagnosis (antipsychotic exposure plus rigidity, hyperthermia, and autonomic/mental-status change)

• CK (markedly elevated — a key finding), renal function, potassium, BMP, CBC (leukocytosis), and coagulation studies (DIC), with LFTs

• Core temperature

• Exclude infection: cultures, with LP and/or CT as needed (must rule out a CNS infection or sepsis)

• Urinalysis (myoglobin), an ECG, and a drug screen

DDx

NMS (lead-pipe rigidity, bradyreflexia, slow onset, an antipsychotic, a markedly elevated CK) · serotonin syndrome (clonus, hyperreflexia, rapid onset, a serotonergic agent) · malignant hyperthermia (anesthesia, succinylcholine) · meningitis, encephalitis, or sepsis · anticholinergic or sympathomimetic toxicity · heat stroke · lethal catatonia · thyroid storm

Home Meds

• Stop the offending antipsychotic or dopamine blocker immediately (including antiemetics like metoclopramide)

• Restart dopaminergic agents if NMS was triggered by their withdrawal

• Hold other contributors

Plan

CONSULT: Toxicology/Poison Control (1-800-222-1222) · ICU (hyperthermia, rigidity, instability, rhabdomyolysis — most cases) · Neurology · Psychiatry (medication management, restart strategy) · Nephrology (severe rhabdomyolysis or AKI)

• Stop the causative agent immediately (the antipsychotic or dopamine blocker, including antiemetics) — or restart the dopaminergic agent if NMS was precipitated by its withdrawal; the essential first step

• Aggressive supportive care and cooling (the foundation): ICU admission, external and active cooling for hyperthermia, aggressive IV fluids (to prevent rhabdomyolysis and AKI), correction of electrolytes (hyperkalemia from rhabdomyolysis), airway and respiratory support, DVT prophylaxis, and continuous monitoring — supportive care and cooling drive most of the recovery

• Benzodiazepines (lorazepam, diazepam) for agitation and as an adjunct (also helpful if lethal catatonia is in the differential)

• Dantrolene (a muscle relaxant) for severe rigidity and hyperthermia — reducing heat generation by acting on skeletal muscle: e.g. 1–2.5 mg/kg IV, repeated to about 10 mg/kg/day; used in severe cases

• Bromocriptine (a dopamine agonist) — restores dopaminergic tone: e.g. 2.5–5 mg PO/NG every 6–8 hours, titrated; used in moderate-to-severe cases (don't stop abruptly, given rebound risk); amantadine is an alternative

• Rhabdomyolysis management: aggressive fluids, monitoring of CK, potassium, and renal function, treatment of hyperkalemia, and vigilance for AKI (which may need renal replacement therapy) and DIC

• Exclude infection (cultures, with LP or CT as needed) — sepsis or a CNS infection can mimic and coexist, so treat empirically if uncertain

• ECT is a consideration for refractory NMS or when lethal catatonia overlaps (specialist-guided)

• PT/OT: mobilization as the patient recovers, with functional assessment (especially after prolonged rigidity or ICU care)

• Trend: core temperature, rigidity, CK, renal function, and potassium, mental status, autonomic vitals, coagulation studies, the response to dantrolene and bromocriptine, and the infection workup

• Escalation triggers: severe hyperthermia, rigidity, or instability, or rhabdomyolysis, AKI, DIC, or respiratory failure → ICU with dantrolene, bromocriptine, and renal replacement therapy; refractory disease → consideration of ECT; diagnostic uncertainty → empiric treatment of infection

• Discharge checklist: the syndrome resolved (which can take days to weeks) with the CK normalized and rhabdomyolysis and renal injury resolved; clear documentation of NMS and the causative drug to prevent re-exposure; a psychiatry plan for any future antipsychotic need (a lower-potency or atypical agent, slow titration, delayed rechallenge after full recovery, and monitoring); the restart of Parkinson medications addressed; return precautions for rigidity, fever, confusion, or dark urine

Red Flags

• Severe hyperthermia with lead-pipe rigidity → ICU, aggressive cooling, dantrolene, and bromocriptine

• A markedly elevated CK with rhabdomyolysis → AKI, hyperkalemia, and DIC risk; aggressive fluids and monitoring

• NMS precipitated by dopamine-agonist withdrawal → restart the dopaminergic agent

• An unexcluded infection → sepsis or CNS infection can mimic and coexist; culture and treat empirically if uncertain

• Refractory disease → consider ECT, especially if lethal catatonia overlaps

Senior IM Resident Pearls

• It's the mirror image of serotonin syndrome. Slow evolution over days on an antipsychotic, lead-pipe rigidity, and depressed reflexes — versus clonus, hyperreflexia, and a rapid onset.

• Supportive care and cooling do the heavy lifting. ICU monitoring, aggressive fluids, and active cooling drive most recoveries; dantrolene and bromocriptine are added for severe cases.

• Don't forget the dopamine-agonist withdrawal trigger. A Parkinson patient whose levodopa was stopped can develop NMS — and the fix is restarting the dopaminergic agent.

• Antiemetics count. Metoclopramide, prochlorperazine, and promethazine are dopamine blockers too, and a common overlooked cause in a non-psychiatric patient.

• Always exclude infection. Sepsis and CNS infection can look identical and can coexist — culture, consider an LP, and treat empirically when uncertain.

• The CK is your severity and tracking marker. A markedly elevated CK signals the rhabdomyolysis that threatens the kidneys — follow it and hydrate aggressively.

• Common mistake: re-prescribing the same antipsychotic on discharge — document NMS prominently and let psychiatry design a cautious, delayed rechallenge with a safer agent.

Toxicology — Toxidromes

122. Sympathomimetic Toxicity

the catecholamine-excess toxidrome · cocaine / methamphetamine / MDMA · benzodiazepines + cooling, avoid beta-blockers · diaphoretic skin distinguishes it from anticholinergic · Super Compact

Sx: the sympathomimetic toxidrome — agitation/anxiety/psychosis, tachycardia, HYPERTENSION, HYPERTHERMIA, mydriasis, DIAPHORESIS (moist skin — key), tremor, hyperreflexia, seizures · end-organ: chest pain/ACS, arrhythmia, stroke, rhabdomyolysis, excited delirium · MDMA specifically: also hyponatremia (excess water intake + SIADH → seizures/cerebral edema), serotonergic features, hyperthermia at "rave" exertion · (MOIST/diaphoretic skin distinguishes sympathomimetic from anticholinergic, which is DRY; bowel sounds present, normal-to-loose vs anticholinergic ileus)

Neg: denies that a beta-blocker was given (unopposed alpha — avoid in cocaine-predominant) · denies missed hyperthermia (lethal — check core temp) · denies missed MDMA-related hyponatremia (check sodium — distinct, dangerous) · denies missed rhabdo/ACS/stroke · denies confusing it with anticholinergic (skin/bowel differ) or serotonin syndrome (clonus)

SHx: agent (cocaine, methamphetamine, amphetamines, MDMA/"ecstasy," cathinones, prescription stimulants, decongestants), route/amount/timing, binge, co-ingestants (alcohol, opioids), setting (rave/exertion/heat for MDMA), water intake (MDMA hyponatremia), psychiatric/cardiac history

Etiology: excess catecholamine activity — agents increase release and/or block reuptake of norepinephrine, dopamine, serotonin → alpha + beta adrenergic overstimulation → vasoconstriction, ↑HR/BP/contractility, CNS stimulation, hyperthermia (psychomotor agitation + impaired heat dissipation) · MDMA adds prominent serotonin release (→ hyponatremia via SIADH + behavior, hyperthermia, serotonergic toxicity); danger from sympathetic overdrive + hyperthermia/rhabdo

RF: high-dose/binge stimulant use · MDMA at raves (exertion, heat, water-loading) · co-stimulants · underlying cardiac disease · dehydration/exertion (hyperthermia, rhabdo)

Data: core temperature (hyperthermia) · ECG + troponin (ischemia/arrhythmia/QT) · CK + renal function + K (rhabdo), BMP · SODIUM (MDMA hyponatremia — can be severe), glucose · head CT for neuro signs/severe HTN (stroke/ICH) · urine tox (may miss MDMA/synthetics — clinical) · CXR; coags if severe; acetaminophen/salicylate if intentional

DDx: sympathomimetic (moist skin, mydriasis, present bowel sounds, agitation) · anticholinergic (DRY skin, ileus, urinary retention) · serotonin syndrome (clonus, hyperreflexia, serotonergic drug) · NMS (rigidity, antipsychotic) · thyroid storm · sepsis · alcohol/sedative withdrawal · pheochromocytoma

Home Meds: hold stimulants/sympathomimetics/decongestants · avoid beta-blockers acutely (esp cocaine) · hold serotonergic agents (MDMA overlap) · reconcile QT agents

Plan

CONSULT: Toxicology/Poison Control 1-800-222-1222 · ICU (severe agitation/hyperthermia/instability/hyponatremia) · Cardiology (ACS/arrhythmia) · Neurology/Neurosurgery (stroke/ICH) · Nephrology (severe rhabdo/AKI/Na)

– BENZODIAZEPINES are the cornerstone (agitation, tachycardia, hypertension, hyperthermia-driving agitation, seizures): diazepam 5–10 mg IV or lorazepam 2–4 mg IV, titrated/repeated — calming the patient controls most of the physiology; may need large cumulative doses
– Aggressive cooling for hyperthermia (life-threatening): active external cooling + deep sedation (± paralysis/intubation in extreme cases); antipyretics ineffective (heat is from muscle/agitation) — treat immediately
– AVOID beta-blockers acutely (especially cocaine-predominant) — unopposed alpha → worse vasoconstriction/hypertension; use benzodiazepines first, then if persistent HTN → nitroglycerin, nitroprusside, or phentolamine (titratable)
– Chest pain/ACS: benzodiazepines + aspirin/nitrates; cardiology for true MI · wide-complex arrhythmia → sodium bicarbonate 1–2 mEq/kg IV (Na-channel effect, e.g. cocaine)
– Rhabdomyolysis: aggressive IV fluids, monitor CK/renal function/K, treat hyperkalemia, watch AKI
– MDMA-specific HYPONATREMIA: check sodium; symptomatic/severe hyponatremia (seizures, cerebral edema) → hypertonic (3%) saline, careful correction; fluid restriction for milder SIADH-pattern — do NOT reflexively give hypotonic fluids to the agitated MDMA patient (can worsen hyponatremia)
– Seizures: benzodiazepines (correct sodium/glucose); status → protocol
– Stroke/ICH: emergent imaging + specialty
– Supportive: IV fluids (balance against MDMA hyponatremia), electrolytes, glucose, quiet environment, chemical over physical restraint, monitoring; psychosis usually resolves with sedation/time
– The toxidrome anchors are benzodiazepines and cooling, with beta-blockers avoided — the same playbook whether it's cocaine, meth, or MDMA. Two distinguishing pearls: the skin is MOIST (versus the dry skin of anticholinergic toxicity), and MDMA carries a unique trap — hyponatremia from water-loading and SIADH that can seize and herniate, so check a sodium and don't reflexively pour in hypotonic fluids.
– PT/OT: once stable
– Trend: core temp, agitation/sedation, BP/HR, ECG/troponin, CK/renal function/K, sodium (MDMA), mental status, neuro exam
– Escalation triggers: severe hyperthermia/excited delirium/instability → ICU + deep sedation/cooling/intubation; severe rhabdo/AKI → nephrology; symptomatic hyponatremia → hypertonic saline + ICU; MI/arrhythmia/stroke → specialty
– Discharge checklist: toxicity/agitation resolved, hyperthermia/rhabdo/sodium corrected, cardiac/neuro complications excluded; addiction referral + counseling; MDMA-specific harm-reduction (heat, hydration balance); psychiatry if intentional; return precautions (chest pain, neuro symptoms, severe agitation, dark urine, confusion/seizure)

122. Sympathomimetic Toxicity

complete reference · cocaine + methamphetamine + MDMA · benzodiazepines, cooling, avoid beta-blockers, watch MDMA hyponatremia · Full Card

Symptoms / Associated Sx

• The sympathomimetic toxidrome — agitation, anxiety, or psychosis, tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis (moist skin — a key sign), tremor, hyperreflexia, and seizures

• End-organ effects: chest pain or ACS, arrhythmia, stroke, rhabdomyolysis, and excited delirium

• MDMA specifically also causes hyponatremia (from excess water intake plus SIADH, leading to seizures and cerebral edema), serotonergic features, and hyperthermia at "rave" exertion

• Moist, diaphoretic skin distinguishes a sympathomimetic from anticholinergic toxicity (which is dry), and bowel sounds are present (versus the ileus of anticholinergic toxicity)

Neg

• Pt denies that a beta-blocker was given (unopposed alpha — avoid in cocaine-predominant toxicity)

• Pt denies a missed hyperthermia (lethal — check the core temperature) and a missed MDMA-related hyponatremia (check the sodium — distinct and dangerous)

• Pt denies a missed rhabdomyolysis, ACS, or stroke, and denies confusing it with anticholinergic toxicity (skin and bowel differ) or serotonin syndrome (clonus)

Social History (SHx)

• The agent (cocaine, methamphetamine, amphetamines, MDMA/"ecstasy," cathinones, prescription stimulants, decongestants), route, amount, and timing, and binge use

• Co-ingestants (alcohol, opioids)

• The setting (rave, exertion, heat for MDMA) and water intake (MDMA hyponatremia)

• Psychiatric and cardiac history

Main Etiology

• Excess catecholamine activity — these agents increase the release and/or block the reuptake of norepinephrine, dopamine, and serotonin, producing alpha- and beta-adrenergic overstimulation

• This causes vasoconstriction, increased heart rate, blood pressure, and contractility, CNS stimulation, and hyperthermia (from psychomotor agitation and impaired heat dissipation)

• MDMA adds prominent serotonin release (causing hyponatremia via SIADH and behavior, hyperthermia, and serotonergic toxicity); the danger comes from sympathetic overdrive plus hyperthermia and rhabdomyolysis

RF

• Modifiable: high-dose or binge stimulant use, MDMA use at raves (exertion, heat, water-loading), co-stimulant use, and dehydration or exertion

• Non-modifiable contributors: underlying cardiac disease

Data

• Core temperature (hyperthermia)

• ECG with troponin (ischemia, arrhythmia, QT)

• CK with renal function and potassium (rhabdomyolysis), and BMP

• Sodium (MDMA hyponatremia, which can be severe) and glucose

• A head CT for neurologic signs or severe hypertension (stroke, ICH); urine toxicology (may miss MDMA and synthetics — clinical diagnosis); a CXR; coagulation studies if severe; and acetaminophen/salicylate levels if intentional

DDx

Sympathomimetic toxicity (moist skin, mydriasis, present bowel sounds, agitation) · anticholinergic toxicity (dry skin, ileus, urinary retention) · serotonin syndrome (clonus, hyperreflexia, a serotonergic drug) · NMS (rigidity, an antipsychotic) · thyroid storm · sepsis · alcohol or sedative withdrawal · pheochromocytoma

Home Meds

• Hold: stimulants, sympathomimetics, and decongestants

• Avoid: beta-blockers acutely (especially with cocaine)

• Hold: serotonergic agents (MDMA overlap); reconcile QT-prolonging agents

Plan

CONSULT: Toxicology/Poison Control (1-800-222-1222) · ICU (severe agitation, hyperthermia, instability, hyponatremia) · Cardiology (ACS, arrhythmia) · Neurology/Neurosurgery (stroke, ICH) · Nephrology (severe rhabdomyolysis, AKI, sodium derangement)

• Benzodiazepines are the cornerstone (agitation, tachycardia, hypertension, the agitation driving hyperthermia, and seizures): diazepam 5–10 mg IV or lorazepam 2–4 mg IV, titrated and repeated — calming the patient controls most of the physiology, and large cumulative doses may be needed

• Aggressive cooling for hyperthermia (life-threatening): active external cooling with deep sedation (and paralysis/intubation in extreme cases); antipyretics are ineffective since the heat comes from muscle activity and agitation — treat immediately

• Avoid beta-blockers acutely (especially cocaine-predominant toxicity) — unopposed alpha worsens vasoconstriction and hypertension; use benzodiazepines first, and if hypertension persists, nitroglycerin, nitroprusside, or phentolamine (titratable)

• Chest pain/ACS: benzodiazepines with aspirin and nitrates, and cardiology for a true MI; a wide-complex arrhythmia (a sodium-channel effect, e.g. from cocaine) is treated with sodium bicarbonate 1–2 mEq/kg IV

• Rhabdomyolysis: aggressive IV fluids with monitoring of CK, renal function, and potassium, treatment of hyperkalemia, and vigilance for AKI

• MDMA-specific hyponatremia: check the sodium; for symptomatic or severe hyponatremia (seizures, cerebral edema), give hypertonic (3%) saline with careful correction, and use fluid restriction for milder SIADH-pattern hyponatremia — do not reflexively give hypotonic fluids to the agitated MDMA patient, as this can worsen the hyponatremia

• Seizures: benzodiazepines (correcting sodium and glucose), with status epilepticus managed per the protocol

• Stroke/ICH: emergent imaging and specialty care

• Supportive care: IV fluids (balanced against MDMA hyponatremia), electrolytes, glucose, a quiet environment, chemical rather than physical restraint, and monitoring; psychosis usually resolves with sedation and time

• PT/OT: once stable

• Trend: core temperature, agitation/sedation level, blood pressure and heart rate, the ECG and troponin, CK, renal function, and potassium, sodium (MDMA), mental status, and the neurologic exam

• Escalation triggers: severe hyperthermia, excited delirium, or instability → ICU with deep sedation, cooling, and intubation; severe rhabdomyolysis or AKI → nephrology; symptomatic hyponatremia → hypertonic saline and ICU; MI, arrhythmia, or stroke → specialty care

• Discharge checklist: toxicity and agitation resolved, hyperthermia, rhabdomyolysis, and sodium corrected, and cardiac/neurologic complications excluded; an addiction referral and counseling; MDMA-specific harm-reduction advice (heat, hydration balance); psychiatry if intentional; return precautions for chest pain, neurologic symptoms, severe agitation, dark urine, or confusion and seizure

Red Flags

• Hyperthermia or excited delirium → a true emergency; deep sedation, aggressive cooling, and a low threshold to intubate

• MDMA hyponatremia with seizures or cerebral edema → hypertonic saline; avoid hypotonic fluids

• Chest pain or a wide-complex arrhythmia → ACS and sodium-channel effects; avoid beta-blockers, use bicarbonate

• Severe rhabdomyolysis → AKI, hyperkalemia, and compartment syndrome

• A focal deficit or severe hypertension → stroke or intracranial hemorrhage → emergent imaging

Senior IM Resident Pearls

• Benzodiazepines and cooling, no beta-blockers. The same toxidrome playbook applies whether the drug is cocaine, methamphetamine, or MDMA — sedation controls the whole picture.

• The skin tells you the toxidrome. Moist, diaphoretic skin marks a sympathomimetic; dry skin points to anticholinergic toxicity — a quick bedside discriminator.

• MDMA has a hyponatremia trap. Water-loading plus SIADH can drop the sodium enough to seize and herniate — check it, and don't reflexively pour in hypotonic fluids.

• Hyperthermia is the killer. Measure the core temperature actively and cool aggressively — antipyretics won't help heat generated by muscle activity.

• Sodium bicarbonate for the wide QRS. Cocaine's sodium-channel blockade responds to bicarbonate, as in TCA toxicity.

• Chemical sedation over restraints. Fighting restraints worsens hyperthermia and rhabdomyolysis — sedate rather than simply tie down.

• Common mistake: giving an agitated MDMA patient liberal hypotonic IV fluids — it can precipitate or worsen the dangerous hyponatremia; check the sodium first.

Toxicology — Toxidromes

123. Anticholinergic Toxicity

muscarinic blockade · "mad, hot, dry, red, blind, full" — delirium / hyperthermia / urinary retention · DRY skin distinguishes it from sympathomimetic · benzos, cooling, physostigmine in select cases · Super Compact

Sx: the classic mnemonic — "mad as a hatter" (delirium, agitation, hallucinations), "hot as a hare" (hyperthermia), "dry as a bone" (DRY skin/axillae + dry mouth — key), "red as a beet" (flushing), "blind as a bat" (mydriasis, blurred vision), "full as a flask" (urinary retention) · also ↓/absent bowel sounds (ileus), tachycardia, tremor/myoclonus, seizures; severe: hyperthermia, rhabdo, wide QRS if Na-channel-blocking agent (TCA, diphenhydramine) · (DRY skin + urinary retention + ileus distinguish it from sympathomimetic, which is DIAPHORETIC with present bowel sounds)

Neg: denies missed anticholinergic source (often OTC/combination — antihistamines, sleep aids, antspasmodics, TCAs, antipsychotics, atropine, jimsonweed/plants) · denies missed urinary retention (check bladder) · denies missed Na-channel/wide-QRS agent (diphenhydramine/TCA → bicarbonate) · denies confusing DRY anticholinergic with DIAPHORETIC sympathomimetic · denies missed hyperthermia

SHx: ingestion of anticholinergic agents — diphenhydramine/antihistamines (very common), TCAs, antipsychotics, scopolamine, oxybutynin, atropine, dimenhydrinate, cyclobenzaprine, plants (jimsonweed/Datura, deadly nightshade), dose/timing, intent, combination/OTC products, prior · elderly on anticholinergic burden (delirium)

Etiology: blockade of muscarinic acetylcholine receptors (central + peripheral) → central (delirium, agitation, seizures) + peripheral antimuscarinic effects (mydriasis, ↓sweating → hyperthermia, ↓secretions, tachycardia, ileus, urinary retention, flushing) · some agents add other toxicity (TCA/diphenhydramine: Na-channel blockade → wide QRS/arrhythmia; antihistamine effects)

RF: intentional overdose · OTC antihistamine/sleep-aid access · elderly/polypharmacy anticholinergic burden · combination products · plant ingestion (recreational/accidental)

Data: clinical (the toxidrome) + bladder scan (retention) · ECG (wide QRS/QT — esp diphenhydramine/TCA → think Na-channel) · core temperature · BMP, CK (rhabdo), renal function, glucose · acetaminophen + salicylate (combination/intentional), consider TCA · urine tox (corroborative) · consider CT/LP to exclude other AMS causes if unclear

DDx: anticholinergic (DRY skin, retention, ileus, mydriasis) · sympathomimetic (DIAPHORETIC, bowel sounds present) · serotonin syndrome (clonus, hyperreflexia) · NMS (rigidity, antipsychotic) · sepsis/CNS infection · alcohol/sedative withdrawal · primary psychosis · thyroid storm

Home Meds: hold all anticholinergic agents (antihistamines, TCAs, antispasmodics, bladder antimuscarinics) · review the anticholinergic burden · don't add more deliriogenic/anticholinergic drugs

Plan

CONSULT: Toxicology/Poison Control 1-800-222-1222 (esp before physostigmine) · ICU (severe agitation/hyperthermia/wide-QRS/instability) · Psychiatry (intentional) · Cardiology (arrhythmia)

– SUPPORTIVE CARE + BENZODIAZEPINES are the foundation for agitation, delirium, seizures, and hyperthermia-driving agitation: diazepam 5–10 mg IV or lorazepam 2–4 mg IV, titrated/repeated — the safe first-line for the agitated anticholinergic patient
– Aggressive cooling for hyperthermia (active external cooling ± sedation/paralysis in severe) — these patients can't sweat, so hyperthermia is dangerous; antipyretics ineffective
– PHYSOSTIGMINE (acetylcholinesterase inhibitor) — the specific antidote, for select cases: reverses central + peripheral anticholinergic effects; consider for significant agitated delirium or severe anticholinergic toxicity WITHOUT contraindications — e.g. ~0.5–2 mg slow IV (over ≥5 min), with cardiac monitoring + atropine at bedside; CONTRAINDICATED / use extreme caution if wide QRS / Na-channel blockade (TCA or other), conduction delay, or reactive airway/bowel-bladder obstruction (risk of bradyasystole, seizures, cholinergic crisis); discuss with toxicology — never give empirically to an undifferentiated wide-QRS overdose
– Wide QRS (>100 ms) from a Na-channel-blocking agent (diphenhydramine in large OD, TCA): sodium bicarbonate 1–2 mEq/kg IV bolus, repeat/infusion to narrow QRS (treat as TCA-type — see also management of Na-channel toxicity); avoid physostigmine here
– Urinary retention: bladder scan + Foley catheter (comfort + prevents injury)
– Decontamination: activated charcoal if early + airway protected (anticholinergic ileus may extend the window, but weigh aspiration risk in delirium)
– Rhabdo/seizures: IV fluids + monitor CK/renal function (rhabdo); benzodiazepines for seizures
– Supportive: monitoring, fluids, electrolytes, glucose, manage co-ingestants (acetaminophen/salicylate/TCA)
– The bedside discriminator is the skin: anticholinergic toxicity is DRY (and brings urinary retention and a quiet ileus), while a sympathomimetic is drenched in sweat with active bowel sounds. Benzodiazepines and cooling handle most cases safely. Physostigmine is the elegant antidote but a dangerous one — never give it to a wide-QRS or TCA picture, and call toxicology first; the agitated diphenhydramine overdose in particular can hide sodium-channel blockade that needs bicarbonate, not an anticholinesterase.
– PT/OT: once stable (esp elderly delirium)
– Trend: mental status/agitation, core temp, ECG (QRS/QT), CK/renal function, bladder/urine output, response to benzodiazepines/physostigmine
– Escalation triggers: severe agitation/hyperthermia/instability → ICU + sedation/cooling; wide QRS/arrhythmia → sodium bicarbonate + ICU/cardiology (NOT physostigmine); seizures/rhabdo → escalate; physostigmine candidate → toxicology + monitored setting
– Discharge checklist: toxicity resolved + delirium cleared + ECG normal + retention resolved; co-ingestants addressed; psychiatric evaluation + suicidality assessment if intentional; for elderly, deprescribe anticholinergic burden + document; counsel on OTC antihistamine/sleep-aid risks; return precautions (confusion, fever, inability to urinate, palpitations)

123. Anticholinergic Toxicity

complete reference · delirium + urinary retention + hyperthermia · benzodiazepines, cooling, physostigmine in select cases · Full Card

Symptoms / Associated Sx

• The classic mnemonic — "mad as a hatter" (delirium, agitation, hallucinations), "hot as a hare" (hyperthermia), "dry as a bone" (dry skin and axillae with a dry mouth — a key sign), "red as a beet" (flushing), "blind as a bat" (mydriasis, blurred vision), and "full as a flask" (urinary retention)

• Also reduced or absent bowel sounds (ileus), tachycardia, tremor or myoclonus, and seizures

• Severe toxicity brings hyperthermia, rhabdomyolysis, and a wide QRS if the agent also blocks sodium channels (TCA, diphenhydramine)

• Dry skin, urinary retention, and ileus distinguish it from a sympathomimetic, which is diaphoretic with present bowel sounds

Neg

• Pt denies a missed anticholinergic source (often OTC or combination products — antihistamines, sleep aids, antispasmodics, TCAs, antipsychotics, atropine, jimsonweed and other plants)

• Pt denies a missed urinary retention (check the bladder) and a missed sodium-channel/wide-QRS agent (diphenhydramine, TCA → bicarbonate)

• Pt denies confusing the dry anticholinergic picture with a diaphoretic sympathomimetic, and denies a missed hyperthermia

Social History (SHx)

• Ingestion of anticholinergic agents — diphenhydramine and other antihistamines (very common), TCAs, antipsychotics, scopolamine, oxybutynin, atropine, dimenhydrinate, cyclobenzaprine, and plants (jimsonweed/Datura, deadly nightshade)

• Dose, timing, and intent

• Combination and OTC products, and prior episodes

• An elderly patient carrying an anticholinergic burden (delirium)

Main Etiology

• Blockade of muscarinic acetylcholine receptors, both central and peripheral

• Central effects (delirium, agitation, seizures) combine with peripheral antimuscarinic effects (mydriasis, reduced sweating causing hyperthermia, reduced secretions, tachycardia, ileus, urinary retention, flushing)

• Some agents add other toxicity — TCAs and diphenhydramine block sodium channels (a wide QRS and arrhythmia), and antihistamines have their own effects

RF

• Modifiable: access to OTC antihistamines and sleep aids, anticholinergic burden in the elderly, and combination products

• Non-modifiable contributors: intentional overdose and plant ingestion (recreational or accidental)

Data

• Clinical diagnosis (the toxidrome) with a bladder scan (retention)

• ECG (a wide QRS or QT — especially with diphenhydramine or TCA, prompting thought of sodium-channel blockade)

• Core temperature

• BMP, CK (rhabdomyolysis), renal function, and glucose

• Acetaminophen and salicylate levels (combination or intentional ingestion), with consideration of a TCA; urine toxicology (corroborative); and consideration of CT or LP to exclude other causes of altered mental status if unclear

DDx

Anticholinergic toxicity (dry skin, retention, ileus, mydriasis) · sympathomimetic toxicity (diaphoretic, with present bowel sounds) · serotonin syndrome (clonus, hyperreflexia) · NMS (rigidity, an antipsychotic) · sepsis or a CNS infection · alcohol or sedative withdrawal · primary psychosis · thyroid storm

Home Meds

• Hold all anticholinergic agents (antihistamines, TCAs, antispasmodics, bladder antimuscarinics)

• Review the anticholinergic burden

• Don't add more deliriogenic or anticholinergic drugs

Plan

CONSULT: Toxicology/Poison Control (1-800-222-1222 — especially before physostigmine) · ICU (severe agitation, hyperthermia, wide QRS, instability) · Psychiatry (intentional ingestion) · Cardiology (arrhythmia)

• Supportive care and benzodiazepines are the foundation for agitation, delirium, seizures, and the agitation driving hyperthermia: diazepam 5–10 mg IV or lorazepam 2–4 mg IV, titrated and repeated — the safe first-line for the agitated anticholinergic patient

• Aggressive cooling for hyperthermia (active external cooling, with sedation/paralysis in severe cases) — these patients cannot sweat, so hyperthermia is dangerous and antipyretics are ineffective

• Physostigmine (an acetylcholinesterase inhibitor) — the specific antidote, for select cases: it reverses central and peripheral anticholinergic effects and may be considered for significant agitated delirium or severe anticholinergic toxicity without contraindications (e.g. ~0.5–2 mg by slow IV over at least 5 minutes, with cardiac monitoring and atropine at the bedside); it is contraindicated, or used with extreme caution, if there is a wide QRS or sodium-channel blockade (TCA or other), a conduction delay, reactive airway disease, or bowel/bladder obstruction (risk of bradyasystole, seizures, and cholinergic crisis) — discuss with toxicology and never give it empirically to an undifferentiated wide-QRS overdose

• Wide QRS (>100 ms) from a sodium-channel-blocking agent (diphenhydramine in large overdose, TCA): sodium bicarbonate 1–2 mEq/kg IV bolus, repeated or as an infusion to narrow the QRS (treat as a TCA-type picture); avoid physostigmine here

• Urinary retention: a bladder scan and a Foley catheter (for comfort and to prevent bladder injury)

• Decontamination: activated charcoal if early and the airway is protected (the anticholinergic ileus may extend the window, but weigh the aspiration risk in a delirious patient)

• Rhabdomyolysis and seizures: IV fluids with monitoring of CK and renal function (rhabdomyolysis), and benzodiazepines for seizures

• Supportive care: monitoring, fluids, electrolytes, glucose, and management of co-ingestants (acetaminophen, salicylate, TCA)

• PT/OT: once stable, especially in elderly delirium

• Trend: mental status and agitation, core temperature, the ECG (QRS, QT), CK and renal function, bladder and urine output, and the response to benzodiazepines and physostigmine

• Escalation triggers: severe agitation, hyperthermia, or instability → ICU with sedation and cooling; a wide QRS or arrhythmia → sodium bicarbonate and ICU/cardiology (not physostigmine); seizures or rhabdomyolysis → escalate; a physostigmine candidate → toxicology and a monitored setting

• Discharge checklist: toxicity resolved with the delirium cleared, the ECG normal, and retention resolved; co-ingestants addressed; a psychiatric evaluation and suicidality assessment if intentional; for the elderly, deprescribing of the anticholinergic burden with documentation; counseling on OTC antihistamine and sleep-aid risks; return precautions for confusion, fever, inability to urinate, or palpitations

Red Flags

• A wide QRS from a sodium-channel-blocking agent (diphenhydramine, TCA) → sodium bicarbonate, not physostigmine

• Hyperthermia in a patient who cannot sweat → aggressive cooling; antipyretics don't work

• Severe agitated delirium → benzodiazepines first, with physostigmine only in select cases after toxicology input

• Physostigmine given to a wide-QRS or TCA picture → risk of bradyasystole, seizures, and cholinergic crisis

• Unrecognized urinary retention → bladder injury; scan and catheterize

Senior IM Resident Pearls

• The skin is the discriminator. Anticholinergic toxicity is dry, with urinary retention and a quiet ileus, while a sympathomimetic is drenched in sweat with active bowel sounds.

• Benzodiazepines and cooling handle most cases safely. They calm the agitation and control the hyperthermia without the risks of the antidote.

• Physostigmine is elegant but dangerous. Never give it to a wide-QRS or TCA picture, keep atropine at the bedside, and call toxicology first — it can precipitate bradyasystole and seizures.

• The diphenhydramine overdose hides a second mechanism. In large ingestions it blocks sodium channels like a TCA, so a wide QRS needs bicarbonate, not an anticholinesterase.

• Check the bladder. Urinary retention is part of the toxidrome and easily missed — a bladder scan and a Foley prevent injury and add diagnostic confirmation.

• Hyperthermia is dangerous because they can't sweat. Impaired heat dissipation makes active cooling essential in the hot anticholinergic patient.

• Common mistake: giving physostigmine empirically to an undifferentiated agitated overdose — if there's a sodium-channel agent on board, you can cause asystole; differentiate first and treat the wide QRS with bicarbonate.

Toxicology — Cardiotoxic Overdose

124. Tricyclic Antidepressant (TCA) Overdose

a true toxicological emergency · wide QRS + arrhythmias + seizures · multi-mechanism (Na-channel + anticholinergic + alpha + GABA) · sodium bicarbonate is the antidote · Super Compact

Sx: can deteriorate FAST — cardiac (the killer): wide QRS (>100 ms), sinus tachycardia, terminal R wave in aVR, ventricular arrhythmias (VT/VF), hypotension, conduction block · neuro: altered mental status, agitation → coma, SEIZURES · anticholinergic toxidrome (dry/flushed/mydriasis/retention/ileus/hyperthermia) · classically a patient who looks okay then crashes within hours · (an overdose with a widening QRS, hypotension, seizures, and anticholinergic signs → TCA; QRS width predicts seizures and arrhythmia — watch it closely)

Neg: denies that an initially-well patient was under-monitored (rapid deterioration) · denies that bicarbonate was delayed for a widening QRS/hypotension/arrhythmia · denies giving class IA/IC/III antiarrhythmics (worsen Na-channel block) · denies missed co-ingestants (acetaminophen/salicylate) · denies flumazenil given (seizure risk with TCA)

SHx: TCA agent + dose + timing (amitriptyline, nortriptyline, imipramine, clomipramine, doxepin), intent (usually intentional — high lethality, narrow margin), access (often prescribed for depression/pain/migraine), co-ingestants, prior overdoses, psychiatric history

Etiology: FOUR mechanisms: (1) fast Na-channel blockade (myocardial — wide QRS, arrhythmia, the lethal effect), (2) anticholinergic (toxidrome, tachycardia), (3) peripheral alpha-1 blockade (vasodilation, hypotension), (4) GABA-A antagonism / CNS effects (seizures) · also K-channel effects (QT) · acidosis + the Na-channel block worsen cardiotoxicity (why alkalinization helps)

RF: intentional overdose (most) · access to TCAs (depression, chronic pain, migraine, neuropathy) · large ingestion · co-ingestion of proconvulsants/cardiotoxins · delayed presentation

Data: ECG IMMEDIATELY + continuous telemetry — QRS width is the key prognostic marker (>100 ms → seizure risk; >160 ms → ventricular arrhythmia risk); terminal R wave in aVR (≥3 mm) suggests TCA · ABG/VBG (pH — guides bicarbonate), BMP, potassium · fingerstick glucose · acetaminophen + salicylate levels (intentional) · core temp · CK · TCA levels exist but DON'T guide acute management (treat clinically/ECG) · CXR, pregnancy test

DDx: TCA overdose (wide QRS, aVR R wave, anticholinergic, seizures, hypotension) · other Na-channel-blocking OD (diphenhydramine, cocaine, class I antiarrhythmics, carbamazepine) · other anticholinergic · hyperkalemia (wide QRS) · other AMS/seizure causes · cardiac conduction disease

Home Meds: hold all TCAs + other Na-channel/QT/proconvulsant agents · psychiatric med review · reconcile co-ingestants · do not restart TCA without psychiatric reassessment

Plan

CONSULT: Toxicology/Poison Control 1-800-222-1222 (urgent) · ICU (essentially all significant ingestions — airway, telemetry, instability) · Cardiology (refractory arrhythmia) · Psychiatry (intentional — after stabilization)

– Early aggressive airway + monitoring: low threshold to intubate (rapid deterioration, seizures, coma); continuous cardiac monitoring + serial ECGs; ICU
– SODIUM BICARBONATE is the antidote (for QRS widening, ventricular arrhythmia, or hypotension): 1–2 mEq/kg IV bolus, repeat to narrow the QRS, then an infusion (e.g. 150 mEq NaHCO3 in 1 L D5W) titrated to a target serum pH ~7.45–7.55 and a narrowing QRS — works by increasing extracellular sodium (overcomes the Na-channel block) AND alkalinizing (reduces drug binding to the channel); the central, life-saving intervention — give early for QRS >100 ms, hypotension, or arrhythmia
– Seizures: benzodiazepines (lorazepam/diazepam) first-line; treat aggressively (seizures worsen acidosis → worse cardiotoxicity); AVOID flumazenil (seizure risk); barbiturate/propofol if refractory; phenytoin NOT recommended
– Arrhythmias: sodium bicarbonate first; for refractory ventricular arrhythmias → lidocaine (class IB, acceptable); AVOID class IA (procainamide), IC, and III (amiodarone/sotalol) antiarrhythmics (worsen Na-channel blockade/conduction); magnesium for torsades; correct hypokalemia/acidosis
– Hypotension: IV fluids + sodium bicarbonate first; then vasopressors (norepinephrine — direct alpha agonist preferred to counter alpha-1 blockade); consider IV lipid emulsion therapy for refractory cardiovascular collapse (per toxicology); ECMO/mechanical support as a last resort in refractory arrest
– Decontamination: activated charcoal if early + airway protected (large ingestion; weigh aspiration risk)
– Supportive: treat hyperthermia (cooling), manage co-ingestants, correct electrolytes, glucose
– Treat the ECG, not the level: the QRS width is your roadmap — over 100 ms warns of seizures, over 160 ms of ventricular arrhythmia — and sodium bicarbonate is the answer to all of it (widening QRS, arrhythmia, hypotension), because it both floods the sodium channel and alkalinizes away the drug's binding. The patient who looks fine can crash within hours, so monitor early and intubate with a low threshold. And know the "do-nots": no class IA/IC/III antiarrhythmics, no flumazenil, no phenytoin.
– PT/OT: per status after recovery
– Trend: QRS width + rhythm (serial ECG/telemetry), pH (bicarbonate titration), potassium, mental status/seizures, BP, core temp, response to bicarbonate
– Escalation triggers: widening QRS, ventricular arrhythmia, hypotension, seizures, or coma → bicarbonate + ICU + intubation; refractory arrhythmia/shock → lidocaine, norepinephrine, lipid emulsion, mechanical support; deterioration → toxicology-guided escalation
– Discharge checklist: cardiac monitoring until ECG normalized + asymptomatic for an appropriate observation window (QRS normal, no arrhythmia/seizure off treatment); co-ingestants addressed; psychiatric evaluation + suicidality risk assessment (intentional, high-lethality means) before discharge; medication safety counseling + limit future TCA access; psychiatry follow-up; return precautions (palpitations/syncope, seizures, confusion)

124. Tricyclic Antidepressant (TCA) Overdose

complete reference · wide QRS + arrhythmias + seizures · sodium bicarbonate, benzodiazepines, avoid class IA/IC/III · Full Card

Symptoms / Associated Sx

• Can deteriorate fast — the cardiac effects are the killer: a wide QRS (>100 ms), sinus tachycardia, a terminal R wave in aVR, ventricular arrhythmias (VT/VF), hypotension, and conduction block

• Neurologic: altered mental status and agitation progressing to coma, and seizures

• An anticholinergic toxidrome (dry, flushed, mydriasis, retention, ileus, hyperthermia)

• Classically a patient who looks okay and then crashes within hours

• An overdose with a widening QRS, hypotension, seizures, and anticholinergic signs suggests a TCA — and the QRS width predicts seizures and arrhythmia, so watch it closely

Neg

• Pt denies that an initially-well patient was under-monitored (rapid deterioration is characteristic)

• Pt denies that bicarbonate was delayed for a widening QRS, hypotension, or arrhythmia, and denies that class IA, IC, or III antiarrhythmics were given (they worsen the sodium-channel block)

• Pt denies missed co-ingestants (acetaminophen, salicylate) and denies that flumazenil was given (seizure risk with a TCA)

Social History (SHx)

• The TCA agent, dose, and timing (amitriptyline, nortriptyline, imipramine, clomipramine, doxepin)

• Intent (usually intentional — high lethality with a narrow margin)

• Access (often prescribed for depression, pain, or migraine)

• Co-ingestants, prior overdoses, and psychiatric history

Main Etiology

• Four mechanisms: fast sodium-channel blockade (myocardial — the wide QRS, arrhythmia, and lethal effect), anticholinergic effects (the toxidrome and tachycardia), peripheral alpha-1 blockade (vasodilation and hypotension), and GABA-A antagonism with CNS effects (seizures)

• Potassium-channel effects also prolong the QT

• Acidosis and the sodium-channel block worsen cardiotoxicity — which is why alkalinization helps

RF

• Modifiable: access to TCAs (depression, chronic pain, migraine, neuropathy) and co-ingestion of proconvulsants or cardiotoxins

• Non-modifiable contributors: intentional overdose (most cases), a large ingestion, and delayed presentation

Data

• An ECG immediately with continuous telemetry — the QRS width is the key prognostic marker (>100 ms → seizure risk; >160 ms → ventricular arrhythmia risk); a terminal R wave in aVR (≥3 mm) suggests a TCA

• An ABG/VBG (pH — guides bicarbonate), BMP, and potassium

• Fingerstick glucose

• Acetaminophen and salicylate levels (intentional ingestion)

• Core temperature and CK; TCA levels exist but don't guide acute management (treat clinically and by ECG); and a CXR and pregnancy test

DDx

TCA overdose (a wide QRS, an aVR R wave, anticholinergic features, seizures, hypotension) · another sodium-channel-blocking overdose (diphenhydramine, cocaine, class I antiarrhythmics, carbamazepine) · another anticholinergic toxicity · hyperkalemia (a wide QRS) · other causes of altered mental status or seizure · cardiac conduction disease

Home Meds

• Hold all TCAs and other sodium-channel, QT-prolonging, or proconvulsant agents

• Review psychiatric medications and reconcile co-ingestants

• Don't restart the TCA without psychiatric reassessment

Plan

CONSULT: Toxicology/Poison Control (1-800-222-1222 — urgent) · ICU (essentially all significant ingestions — airway, telemetry, instability) · Cardiology (refractory arrhythmia) · Psychiatry (intentional ingestion — after stabilization)

• Early aggressive airway and monitoring: a low threshold to intubate (rapid deterioration, seizures, coma), continuous cardiac monitoring with serial ECGs, and ICU admission

• Sodium bicarbonate is the antidote (for QRS widening, ventricular arrhythmia, or hypotension): 1–2 mEq/kg IV bolus, repeated to narrow the QRS, then an infusion (e.g. 150 mEq of sodium bicarbonate in 1 L of D5W) titrated to a target serum pH of ~7.45–7.55 and a narrowing QRS — it works by increasing extracellular sodium (overcoming the channel block) and alkalinizing (reducing drug binding to the channel); the central, life-saving intervention, given early for a QRS above 100 ms, hypotension, or arrhythmia

• Seizures: benzodiazepines (lorazepam, diazepam) first-line, treated aggressively (seizures worsen acidosis and therefore cardiotoxicity); avoid flumazenil (seizure risk); use a barbiturate or propofol if refractory; and phenytoin is not recommended

• Arrhythmias: sodium bicarbonate first; for refractory ventricular arrhythmias, lidocaine (class IB, acceptable); avoid class IA (procainamide), IC, and III (amiodarone, sotalol) antiarrhythmics (they worsen the sodium-channel block and conduction); magnesium for torsades; and correct hypokalemia and acidosis

• Hypotension: IV fluids and sodium bicarbonate first, then vasopressors (norepinephrine — a direct alpha agonist preferred to counter the alpha-1 blockade); consider IV lipid emulsion therapy for refractory cardiovascular collapse (per toxicology); and ECMO or mechanical support as a last resort in refractory arrest

• Decontamination: activated charcoal if early and the airway is protected (a large ingestion, weighing the aspiration risk)

• Supportive care: treat hyperthermia (cooling), manage co-ingestants, and correct electrolytes and glucose

• PT/OT: per status after recovery

• Trend: the QRS width and rhythm (serial ECG and telemetry), pH (bicarbonate titration), potassium, mental status and seizures, blood pressure, core temperature, and the response to bicarbonate

• Escalation triggers: a widening QRS, ventricular arrhythmia, hypotension, seizures, or coma → bicarbonate, ICU, and intubation; refractory arrhythmia or shock → lidocaine, norepinephrine, lipid emulsion, and mechanical support; deterioration → toxicology-guided escalation

• Discharge checklist: cardiac monitoring until the ECG has normalized and the patient is asymptomatic for an appropriate observation window (a normal QRS with no arrhythmia or seizure off treatment); co-ingestants addressed; a psychiatric evaluation and suicidality risk assessment (an intentional, high-lethality means) before discharge; medication safety counseling and limiting future TCA access; psychiatry follow-up; return precautions for palpitations or syncope, seizures, or confusion

Red Flags

• A widening QRS (>100 ms) → seizure and arrhythmia risk → sodium bicarbonate now

• A QRS above 160 ms or ventricular arrhythmia → high risk; bicarbonate, lidocaine if refractory, and ICU

• An initially-well patient → can crash within hours; monitor early and intubate with a low threshold

• Hypotension refractory to fluids and bicarbonate → norepinephrine and consider lipid emulsion and mechanical support

• The "do-nots": class IA/IC/III antiarrhythmics, flumazenil, and phenytoin all worsen the picture

Senior IM Resident Pearls

• Treat the ECG, not the level. The QRS width is the roadmap — over 100 ms warns of seizures, over 160 ms of ventricular arrhythmia — and TCA levels don't guide acute care.

• Sodium bicarbonate is the answer to almost everything. Widening QRS, ventricular arrhythmia, and hypotension all respond, because it both floods the sodium channel and alkalinizes away the drug's binding.

• The well-looking patient can crash within hours. Monitor early, get serial ECGs, and keep a low threshold to intubate — TCA overdose is notorious for rapid deterioration.

• Know the "do-nots." No class IA, IC, or III antiarrhythmics (they worsen the sodium-channel block), no flumazenil (seizures), and no phenytoin — these are classic wrong moves.

• Norepinephrine for the hypotension. A direct alpha agonist counters the alpha-1 blockade better than agents relying on endogenous catecholamine release.

• The terminal R wave in aVR is a clue. A prominent R wave in aVR supports the diagnosis and flags sodium-channel toxicity on the ECG.

• Common mistake: discharging or under-monitoring an intentional ingestion that "looks fine" — observe on telemetry until the ECG normalizes, and always complete the psychiatric and suicidality assessment given the high lethality of the means.