Diagnosis: Serotonin syndrome caused by serotonergic polypharmacy

Common causative combinations

• SSRI or SNRI plus an MAOI
• SSRI or SNRI plus tramadol
• Multiple antidepressants
• Linezolid plus a serotonergic medication
• Dextromethorphan combined with serotonergic drugs
• Serotonergic recreational substances
• Certain combinations involving migraine medications

Characteristic features

• Rapid onset after initiation, dose increase, interaction, or overdose
• Agitation or confusion
• Diaphoresis

• Tachycardia and hypertension
• Diarrhea
• Tremor
• Hyperreflexia
• Clonus
• Hyperthermia

Treatment principles

1. Stop serotonergic agents.
2. Stabilize airway, breathing, and circulation.
3. Control agitation and muscle activity with benzodiazepines.
4. Administer intravenous fluids.
5. Use active external cooling.
6. Treat severe hyperthermia aggressively.
7. Consider cyproheptadine in selected cases.
8. Monitor CK, renal function, electrolytes, ECG, and acid-base status.

Clinical Pearl: Clonus is one of the most useful clues separating serotonin toxicity from many competing diagnoses.

NPLEX Trap: Do not diagnose anxiety or panic disorder in a patient with objective clonus, hyperreflexia, hyperthermia, and serotonergic medication exposure.

Reference basis: Contemporary reviews emphasize clinical diagnosis, neuromuscular excitation, withdrawal of serotonergic agents, sedation, cooling, and supportive care.

Diagnosis: Neuroleptic malignant syndrome following increased haloperidol exposure

Potential triggers

• High-potency antipsychotics
• Rapid dose escalation
• Parenteral or long-acting antipsychotic administration
• Dehydration
• Agitation and physical restraint
• Abrupt withdrawal of dopamine-enhancing therapy in Parkinson disease
• Dopamine-blocking antiemetics such as metoclopramide

Typical findings

• Hyperthermia
• Severe generalized rigidity
• Altered mental status
• Autonomic instability

• Elevated CK
• Leukocytosis
• Myoglobinuria
• Acute kidney injury

Treatment principles

• Stop the causative medication
• Intensive supportive care
• Cooling
• Intravenous fluids
• Electrolyte and renal monitoring
• Prevention of thromboembolism and aspiration
• Consider dantrolene, bromocriptine, or amantadine in severe cases
• Delay and carefully supervise any future reintroduction of antipsychotic therapy

Clinical Pearl: NMS generally develops over one to several days, whereas serotonin toxicity often develops within hours.

NPLEX Trap: Do not mistake the severe rigidity for an uncomplicated extrapyramidal adverse effect.

Reference basis: Reviews describe NMS as a potentially fatal dopamine-related drug reaction requiring immediate medication withdrawal and aggressive supportive management.

Diagnosis: Chronic digoxin toxicity with bradyarrhythmia and ventricular ectopy

Risk factors

• Older age
• Reduced kidney function
• Dehydration
• Low body mass
• Drug interactions
• Hypokalemia, hypomagnesemia, or hypercalcemia
• Medication errors

Potential interacting medications

• Amiodarone
• Verapamil
• Certain macrolides
• Some antiarrhythmics
• P-glycoprotein inhibitors

Clinical manifestations

• Nausea, vomiting, or anorexia
• Confusion or weakness
• Visual disturbances
• Bradycardia or AV block
• Atrial or ventricular arrhythmias
• Hyperkalemia in severe acute toxicity

Treatment principles

• Stop digoxin
• Continuous ECG monitoring
• Assess potassium, magnesium, calcium, and renal function
• Correct contributing electrolyte abnormalities carefully
• Treat unstable arrhythmias
• Administer digoxin immune Fab for life-threatening toxicity

Clinical Pearl: Almost any arrhythmia may occur, although rapidly conducted atrial tachyarrhythmias are less typical.

NPLEX Trap: Do not determine severity from the serum digoxin concentration alone.

Reference basis: Recent consensus recommendations emphasize clinical assessment, ECG monitoring, renal and electrolyte evaluation, and early digoxin immune Fab for life-threatening toxicity.

Diagnosis: Chronic lithium toxicity caused by dehydration, kidney dysfunction, and drug interactions

Common manifestations

• Coarse tremor
• Ataxia
• Dysarthria
• Confusion
• Myoclonus
• Hyperreflexia
• Seizure
• Nausea and diarrhea
• Bradycardia or other ECG abnormalities

Important interactions

• Thiazide diuretics
• NSAIDs
• ACE inhibitors
• ARBs
• Dehydration and sodium depletion

Treatment principles

• Stop lithium
• Stop contributing medications
• Administer isotonic fluids when appropriate
• Monitor renal function, sodium, calcium, thyroid function, ECG, and serial lithium levels
• Obtain toxicology and nephrology consultation
• Use hemodialysis in severe poisoning
• Monitor for rebound after dialysis

Clinical Pearl: Chronic toxicity can cause severe neurologic manifestations at concentrations that may be less dramatic than those seen after a large acute ingestion.

NPLEX Trap: Do not use activated charcoal as the primary gastrointestinal decontamination treatment because lithium is not effectively adsorbed.

Reference basis: EXTRIP recommends extracorporeal treatment for severe lithium poisoning and identifies neurologic deterioration, dangerous dysrhythmia, renal dysfunction, and concentration as major decision factors.

Diagnosis: Metformin-associated lactic acidosis precipitated by acute kidney injury and shock

Predisposing factors

• Acute kidney injury
• Advanced chronic kidney disease
• Severe dehydration
• Sepsis
• Shock
• Hypoxemia
• Hepatic failure
• Excessive ingestion
• Continued medication during a severe acute illness

Key investigations

• Blood gas
• Lactate

• Electrolytes and anion gap
• Glucose and ketones
• Renal and hepatic function
• CBC and cultures when infection is possible
• ECG
• Toxicology consultation

Treatment principles

• Stop metformin
• Stabilize airway, breathing, and circulation
• Treat shock and the precipitating condition
• Monitor glucose and electrolytes
• Consider bicarbonate as a bridge in selected critically ill patients
• Initiate hemodialysis or another appropriate extracorporeal treatment when severe criteria are present

Clinical Pearl: A normal glucose concentration does not exclude a life-threatening metformin-related metabolic emergency.

NPLEX Trap: Do not attribute severe lactate elevation automatically to metformin without also investigating sepsis, shock, ischemia, and other causes.

Reference basis: EXTRIP identifies severe acidemia, marked lactate elevation, failure of supportive measures, shock, and renal impairment as important indications for extracorporeal treatment.

Diagnosis: SGLT2-inhibitor–associated euglycemic DKA

Common triggers

• Fasting
• Surgery
• Acute infection
• Vomiting or dehydration
• Low-carbohydrate or ketogenic diet
• Insulin reduction or omission
• Pregnancy
• Excessive alcohol consumption

Diagnostic pattern

• DKA symptoms
• Elevated beta-hydroxybutyrate
• High-anion-gap metabolic acidosis
• Glucose that is normal or only moderately elevated

Treatment principles

• Stop the SGLT2 inhibitor
• Intravenous fluids
• Intravenous insulin

• Early dextrose
• Potassium and electrolyte management
• Treat the precipitating condition
• Continue treatment until ketoacidosis resolves rather than stopping when glucose normalizes

Clinical Pearl: The glucose concentration may appear reassuring while the acidemia is life-threatening.

NPLEX Trap: Do not withhold insulin because the patient is euglycemic; insulin is necessary to stop ketone production.

Reference basis: FDA information continues to warn of ketoacidosis with dapagliflozin, and clinical reviews emphasize ketone and anion-gap assessment plus insulin, fluids, and dextrose treatment.

Diagnosis: Factor-Xa-inhibitor–associated intracerebral hemorrhage

Immediate assessments

• Airway and consciousness
• Last anticoagulant dose
• Blood pressure
• CBC and renal function
• Medication interactions
• Noncontrast CT
• Repeat imaging for expansion
• Neurosurgical assessment

Treatment principles

• Stop anticoagulation
• Reverse anticoagulant activity promptly
• Control severe blood pressure using a monitored approach
• Manage intracranial pressure
• Treat seizures when present
• Assess need for surgery
• Prevent aspiration, thrombosis, and other complications
• Reassess the future indication and timing for anticoagulation only after stabilization

Clinical Pearl: A routine PT or INR may not accurately quantify the anticoagulant effect of apixaban.

NPLEX Trap: Do not give aspirin to a patient with focal neurologic deficits until intracranial hemorrhage has been excluded.

Reference basis: AHA/ASA guidance emphasizes immediate anticoagulant reversal in intracerebral hemorrhage, with andexanet alfa for factor Xa inhibitors and specific antidotes for other anticoagulants.

Diagnosis: Suspected fentanyl-related opioid overdose

Classic findings

• Reduced consciousness
• Respiratory depression
• Pinpoint pupils
• Hypoxemia
• Bradycardia or hypotension in severe cases

Emergency treatment

1. Activate emergency medical services.
2. Open and protect the airway.
3. Provide rescue breathing or bag-mask ventilation.
4. Administer oxygen.
5. Give naloxone.
6. Repeat naloxone when necessary.
7. Begin CPR if there is no pulse.
8. Observe for recurrent toxicity.

After stabilization

• Screen for co-ingestants
• Evaluate aspiration and pulmonary edema
• Provide take-home naloxone education
• Discuss evidence-based treatment for opioid-use disorder
• Use a nonjudgmental harm-reduction approach

Clinical Pearl: A response to naloxone supports opioid toxicity, but failure to respond immediately does not exclude it; ventilation must continue while other causes are evaluated.

NPLEX Trap: Do not focus on obtaining a drug history while the patient is apneic or severely hypoventilating.

Reference basis: CDC guidance identifies naloxone as a lifesaving opioid-overdose reversal medication and emphasizes emergency response and restoration of breathing.

Diagnosis: Acute potentially toxic acetaminophen ingestion

Assessment

• Exact product and dose
• Time of ingestion
• Single versus repeated ingestion
• Extended-release or combination product
• Co-ingestants
• Acetaminophen concentration
• AST, ALT, INR, bilirubin
• Creatinine, electrolytes, glucose
• Acid-base status in severe poisoning

Treatment principles

• Contact a poison centre or toxicologist
• Consider activated charcoal after a substantial recent ingestion when the airway is protected
• Use the treatment nomogram only for an acute single ingestion with a reliable time
• Start N-acetylcysteine when indicated

• Do not stop treatment solely because a standard infusion duration has ended; reassess the concentration, liver tests, INR, and clinical condition
• Arrange liver-transplant assessment when acute liver failure develops

Clinical Pearl: Patients can appear well during the initial phase of a potentially fatal overdose.

NPLEX Trap: Do not apply the standard nomogram to repeated supratherapeutic ingestion or an unknown ingestion time.

Reference basis: The 2023 US–Canadian consensus statement provides evidence-based recommendations for assessment, nomogram use, early N-acetylcysteine, and management of delayed or complex presentations.

Diagnosis: Glyburide-induced recurrent hypoglycemia

Risk factors for severe or prolonged episodes

• Older age
• Chronic kidney disease
• Poor oral intake

• Medication error
• Long-acting sulfonylurea
• Drug interactions
• Liver dysfunction

Clinical manifestations

• Sweating
• Tremor
• Palpitations
• Hunger
• Confusion
• Abnormal behaviour
• Focal neurologic deficits
• Seizure
• Coma

Treatment principles

1. Confirm glucose immediately.
2. Correct symptomatic hypoglycemia with dextrose.
3. Provide oral carbohydrate when safe.
4. Administer octreotide for clinically important sulfonylurea toxicity.
5. Monitor glucose frequently.
6. Correct potassium and other electrolyte disturbances.
7. Observe for recurrence after therapy is stopped.
8. Reassess the future diabetes regimen.

Clinical Pearl: Hypoglycemia may mimic stroke, intoxication, seizure, or psychiatric illness.

NPLEX Trap: Do not discharge a patient with sulfonylurea-associated hypoglycemia after a single response to dextrose.

Reference basis: Toxicology reviews support dextrose plus octreotide for sulfonylurea-related hypoglycemia and continued observation because delayed or recurrent episodes may occur.

Diagnosis: Severe verapamil poisoning with cardiogenic and vasodilatory shock

Major manifestations

• Bradycardia
• AV block
• Hypotension
• Reduced contractility
• Hyperglycemia
• Lactic acidosis
• Altered consciousness
• Pulmonary edema

Treatment principles

1. Stabilize airway, breathing, and circulation.
2. Contact a poison centre or medical toxicologist.
3. Administer intravenous calcium.
4. Begin vasopressor support.
5. Use high-dose insulin with glucose and potassium monitoring.
6. Consider gastrointestinal decontamination for selected sustained-release ingestions when safe.
7. Consider extracorporeal life support for refractory cardiogenic shock.

AHA guidance recommends high-dose insulin and vasopressors for life-threatening calcium-channel blocker poisoning, while EXTRIP recommends against dialysis solely to remove amlodipine, diltiazem, or verapamil.

Clinical Pearl: Hyperglycemia in a profoundly hypotensive, bradycardic patient supports calcium-channel blocker toxicity.

NPLEX Trap: Atropine may be attempted, but severe poisoning commonly requires high-dose insulin and vasopressor therapy rather than atropine alone.

Diagnosis: Severe propranolol toxicity with cardiogenic shock, hypoglycemia, seizure, and sodium-channel blockade

Potential manifestations

• Bradycardia
• AV block
• Hypotension
• Cardiogenic shock
• Hypoglycemia
• Seizures
• Bronchospasm
• QRS widening
• Ventricular dysrhythmia

Treatment principles

• ABC stabilization
• Glucose correction

• Benzodiazepines for seizures
• Vasopressors
• High-dose insulin
• Glucagon as a possible adjunct
• Sodium bicarbonate for sodium-channel toxicity
• Extracorporeal life support for refractory shock

AHA recommendations support vasopressors and high-dose insulin for severe beta-blocker poisoning. Glucagon may improve contractility in some cases but can cause vomiting and should not replace complete resuscitative care.

Clinical Pearl: Hypoglycemia is more suggestive of beta-blocker poisoning, whereas hyperglycemia is commonly seen in severe calcium-channel blocker poisoning.

NPLEX Trap: Cardiac pacing may not correct the underlying loss of myocardial contractility.

Diagnosis: Methanol poisoning with optic toxicity and severe metabolic acidosis

Common sources

• Windshield-washer fluid
• Industrial solvents
• Contaminated or illicit alcohol
• Fuel products

Key investigations

• Blood gas
• Electrolytes and anion gap
• Measured serum osmolality
• Methanol concentration
• Glucose
• Renal function
• ECG
• Formal visual assessment when possible

Treatment principles

• Fomepizole
• Sodium bicarbonate for significant acidemia
• Folinic acid or folic acid to support formate metabolism
• Hemodialysis for severe poisoning
• Intensive supportive care

EXTRIP recommends extracorporeal treatment for severe methanol poisoning when findings include visual deficits, seizures, coma, pH at or below 7.15, persistent acidosis, or high methanol concentrations.

Clinical Pearl: The absence of an osmolal gap does not safely exclude a late presentation.

NPLEX Trap: Do not wait for blindness or a confirmed methanol concentration before starting an alcohol-dehydrogenase inhibitor when suspicion is high.

Diagnosis: Ethylene-glycol toxicity with metabolic acidosis and acute kidney injury

Clinical stages may include

• Initial intoxication and CNS depression
• Cardiopulmonary toxicity and acidosis
• Delayed acute kidney injury
• Cranial neuropathies in some delayed cases

Treatment principles

• Fomepizole
• Airway and circulatory support
• Sodium bicarbonate for severe acidosis
• Calcium treatment when symptomatic hypocalcemia is present
• Thiamine and pyridoxine as metabolic cofactors
• Hemodialysis when severe criteria are met
• Serial acid-base, renal, and electrolyte monitoring

EXTRIP recommends dialysis when severe clinical or biochemical features are present, including a very high anion gap, severe glycolate elevation, coma, seizure, or major kidney injury.

Clinical Pearl: Calcium-oxalate crystals support the diagnosis but may be absent.

NPLEX Trap: A declining osmolal gap may reflect metabolism into more dangerous acids rather than recovery.

Diagnosis: Severe salicylate toxicity

Major manifestations

• Tinnitus
• Nausea and vomiting
• Hyperventilation
• Diaphoresis
• Fever
• Hypokalemia
• Confusion
• Seizure
• Pulmonary edema
• Hypoglycemia within the CNS despite a normal serum glucose

Treatment principles

• Activated charcoal when appropriate
• Intravenous sodium bicarbonate
• Potassium correction
• Glucose administration when neurologic symptoms occur
• Serial salicylate concentrations
• Hemodialysis for severe poisoning
• Maintenance of high minute ventilation when intubation is unavoidable

EXTRIP recommends dialysis for severe salicylate poisoning, including altered mental status, new oxygen requirement, severe acidemia, renal impairment, or sufficiently high salicylate concentrations.

Clinical Pearl: Clinical deterioration is more important than a single declining salicylate concentration.

NPLEX Trap: Do not interpret an alkalemic pH as evidence that severe salicylate toxicity is absent.

Diagnosis: Amitriptyline poisoning with anticholinergic toxicity, seizure, and sodium-channel blockade

Important ECG findings

• QRS widening
• Terminal R wave in aVR
• Right-axis deviation
• Ventricular dysrhythmias
• QT prolongation

Treatment principles

• Airway stabilization
• Sodium bicarbonate
• Benzodiazepines for seizures

• Intravenous fluids
• Norepinephrine for persistent hypotension
• Continuous ECG monitoring
• Consider lipid emulsion or extracorporeal support in selected refractory cases

AHA guidance supports sodium bicarbonate for life-threatening cardiotoxicity caused by sodium-channel blocking poisons.

Clinical Pearl: A QRS duration above approximately 100 milliseconds increases seizure risk; greater widening is associated with ventricular dysrhythmia risk.

NPLEX Trap: Do not administer a class IA or IC antiarrhythmic to treat tricyclic-induced wide-complex dysrhythmia.

Diagnosis: Severe organophosphate-induced cholinergic crisis

Muscarinic findings

• Salivation
• Lacrimation
• Urination
• Diarrhea
• Vomiting
• Bronchorrhea
• Bronchospasm
• Bradycardia
• Miosis

Nicotinic findings

• Fasciculations
• Weakness
• Paralysis
• Variable tachycardia or hypertension

Treatment principles

• Rescuer protection and decontamination
• Airway suction and ventilation
• Atropine titrated to respiratory findings
• Pralidoxime
• Benzodiazepines for seizure or severe agitation
• Prolonged observation for recurrent weakness or intermediate syndrome

ATSDR resources identify atropine as treatment for muscarinic toxicity and pralidoxime as an acetylcholinesterase reactivator that can improve neuromuscular and respiratory function.

Clinical Pearl: The immediate cause of death is commonly respiratory failure from bronchorrhea, bronchospasm, central depression, and neuromuscular weakness.

NPLEX Trap: Do not stop atropine merely because the heart rate becomes elevated if dangerous respiratory secretions remain.

Diagnosis: Suspected cyanide toxicity associated with enclosed-space fire

Clinical manifestations

• Altered consciousness
• Seizure
• Hypotension
• Cardiovascular collapse
• Severe lactic acidosis
• Respiratory arrest
• Normal-appearing arterial oxygen saturation

Treatment principles

• Immediate airway and ventilation support
• High-concentration oxygen
• Hydroxocobalamin
• Treatment for concurrent carbon monoxide exposure
• Burn and inhalation-injury management
• Seizure and shock treatment

CDC material notes that cyanide can be generated by structural fires and that AHA recommendations identify hydroxocobalamin as the antidote of choice for suspected severe cyanide toxicity.

Clinical Pearl: A high venous oxygen concentration can occur because tissues cannot extract and use oxygen effectively.

NPLEX Trap: Do not wait for a blood cyanide concentration, which is generally unavailable rapidly enough to guide emergency treatment.

Diagnosis: Malignant hyperthermia triggered by anesthetic exposure

Common triggers

• Volatile inhalational anesthetics
• Succinylcholine

Important findings

• Rising end-tidal CO₂
• Tachycardia
• Masseter or generalized rigidity
• Mixed metabolic and respiratory acidosis
• Hyperkalemia
• Rhabdomyolysis
• Myoglobinuria
• Rapidly increasing core temperature

Treatment principles

• Stop triggering agents
• Call for the malignant-hyperthermia cart and assistance
• Administer dantrolene
• Use 100% oxygen at high flow
• Cool the patient

• Treat hyperkalemia and acidosis
• Monitor CK, potassium, coagulation, renal function, temperature, and urine output
• Continue post-crisis monitoring because recurrence can occur

MHAUS recommends an initial intravenous dantrolene dose of 2.5 mg/kg using actual body weight, repeated until hypermetabolism and rigidity are controlled.

Clinical Pearl: Hyperthermia is an important finding but may not be the earliest manifestation.

NPLEX Trap: Dantrolene does not treat ordinary exertional or environmental heat stroke.

Diagnosis: Bupivacaine-associated local-anesthetic systemic toxicity

Possible early findings

• Circumoral numbness
• Metallic taste
• Tinnitus
• Dizziness
• Agitation
• Visual disturbance
• Muscle twitching

Severe findings

• Seizure
• Reduced consciousness
• Hypotension
• Bradycardia
• Wide-complex dysrhythmia
• Ventricular fibrillation

• Cardiac arrest

Treatment principles

• Stop local-anesthetic administration
• Call for the LAST kit and resuscitation team
• Maintain airway and oxygenation
• Use benzodiazepines for seizures
• Administer 20% lipid emulsion
• Apply modified resuscitation principles
• Continue observation after recovery

ASRA maintains a dedicated checklist for LAST and emphasizes prompt lipid-emulsion treatment rather than delaying until all standard resuscitative measures fail.

Clinical Pearl: LAST can present primarily with cardiovascular collapse without a clearly recognized neurologic warning phase.

NPLEX Trap: Do not use additional lidocaine as the first antiarrhythmic treatment for local-anesthetic toxicity.

Diagnosis: HIT complicated by proximal DVT

Important features

• Platelet reduction usually greater than 50%

• Typical onset five to ten days after heparin initiation
• Venous or arterial thrombosis
• Skin necrosis at injection sites
• Acute reaction after intravenous heparin bolus
• Thrombosis may occur despite only moderate thrombocytopenia

Treatment principles

• Calculate the 4Ts score
• Stop all heparin
• Begin a non-heparin anticoagulant when indicated
• Order PF4-heparin immunoassay
• Obtain a functional assay when appropriate
• Evaluate for asymptomatic thrombosis
• Avoid routine platelet transfusion unless clinically necessary
• Delay warfarin until platelet recovery

ASH recommends using the 4Ts score, avoiding unnecessary testing in low-probability patients, and using a non-heparin anticoagulant for suspected or confirmed clinically significant HIT.

Clinical Pearl: The percentage fall in platelet count is often more important than whether the absolute count falls below the laboratory reference range.

NPLEX Trap: HIT is primarily a thrombotic disorder, not a bleeding disorder.

Diagnosis: Life-threatening warfarin-associated retroperitoneal hemorrhage

Major-bleeding features

• Hemodynamic instability
• Critical-site bleeding
• Major hemoglobin decrease
• Need for transfusion
• Ongoing or uncontrolled hemorrhage

Treatment principles

• Stop warfarin
• Resuscitate airway and circulation
• Administer four-factor PCC
• Administer intravenous vitamin K
• Control the bleeding source
• Transfuse blood products when indicated
• Review interacting drugs and illnesses
• Reassess future anticoagulation after stabilization

ACC guidance recommends a reversal agent for life-threatening or critical-site bleeding and identifies four-factor PCC plus vitamin K as the preferred approach for major warfarin-associated hemorrhage.

Clinical Pearl: Retroperitoneal bleeding may initially present with back, hip, groin, or flank pain without visible external bleeding.

NPLEX Trap: Vitamin K alone does not reverse life-threatening warfarin bleeding rapidly enough.

Diagnosis: Massive long-acting insulin overdose with recurrent hypoglycemia

Potential complications

• Seizure
• Coma
• Aspiration
• Cerebral injury
• Hypokalemia
• Hypomagnesemia
• Hypophosphatemia
• Fluid overload from prolonged dextrose administration

Treatment principles

• Immediate dextrose
• Continuous titrated glucose infusion
• Frequent bedside glucose testing
• Electrolyte monitoring
• Oral complex carbohydrate when safe
• Glucagon when intravenous access is temporarily unavailable
• Prolonged monitored observation
• Psychiatric safety assessment after medical stabilization

Published reviews identify intravenous glucose as the central treatment for insulin overdose and emphasize that hypoglycemia can be prolonged for days following massive long-acting insulin exposure.

Clinical Pearl: The duration of hypoglycemia after a massive injection may greatly exceed the usual therapeutic duration of the insulin product.

NPLEX Trap: Do not stop dextrose after a single normal glucose measurement.

Diagnosis: Severe low-dose methotrexate toxicity from daily administration error and impaired clearance

Major manifestations

• Stomatitis and mucositis
• Diarrhea
• Pancytopenia
• Neutropenic infection
• Bleeding
• Hepatic injury
• Acute kidney injury
• Skin ulceration
• Pulmonary toxicity

Treatment principles

• Stop methotrexate
• Administer leucovorin
• Treat neutropenic sepsis immediately
• Support blood counts and bleeding complications

• Correct dehydration and renal dysfunction
• Monitor CBC, renal function, liver tests, and methotrexate concentration when relevant
• Consider glucarpidase in appropriate high-dose delayed-clearance situations
• Review medication-dispensing and dosing systems

FDA prescribing information warns that renal dysfunction markedly increases methotrexate toxicity. Leucovorin is indicated to counteract toxicity from impaired elimination or overdose, while EXTRIP recommends glucarpidase rather than extracorporeal removal when it is indicated and available.

Clinical Pearl: Weekly methotrexate prescribed for inflammatory disease is a major medication-safety risk when patients mistakenly take it daily.

NPLEX Trap: A low or undetectable serum methotrexate concentration does not reliably exclude serious toxicity after repeated low-dose exposure.

Diagnosis: Clozapine-associated severe neutropenia complicated by septic shock

Warning symptoms

• Fever
• Sore throat
• Mouth ulcers
• Chills
• Flu-like symptoms
• Weakness
• Signs of focal or systemic infection

Treatment principles

• Stop or withhold clozapine
• Emergency sepsis management
• Broad-spectrum antibiotics
• Blood cultures and source assessment
• Hematology and psychiatry consultation
• Consider granulocyte colony-stimulating factor in selected patients
• Continue serial ANC monitoring
• Make any future rechallenge decision through specialist risk-benefit assessment

In February 2025, FDA removed mandatory participation in the clozapine REMS program but continued to recommend ANC monitoring because severe neutropenia remains potentially fatal, particularly during the first several months of treatment.

Clinical Pearl: Serious infection may produce minimal pus or local inflammation when the ANC is extremely low.

NPLEX Trap: Removal of an administrative REMS requirement does not mean that hematologic monitoring is unnecessary.

Diagnosis: Carbon monoxide poisoning from indoor generator use

Key investigations

• Carboxyhemoglobin by co-oximetry
• Blood gas and lactate
• ECG and cardiac biomarkers
• Glucose

• Neurologic assessment
• Pregnancy testing when relevant

Treatment principles

• Remove the patient from the source
• Administer high-concentration oxygen
• Treat seizures, dysrhythmias, and hypotension
• Consider hyperbaric oxygen in severe cases
• Evaluate everyone exposed to the same environment
• Warn about delayed neurologic complications

Clinical Pearl: Carboxyhemoglobin may decrease before blood is collected, particularly after oxygen treatment.

NPLEX Trap: Do not use a normal conventional pulse-oximetry reading to rule out carbon monoxide poisoning.

Reference basis: CDC clinical guidance recommends immediate 100% oxygen and consideration of hyperbaric treatment for neurologic impairment, cardiac involvement, severe acidosis, loss of consciousness, or high carboxyhemoglobin.

Common causes

• Dapsone
• Benzocaine
• Prilocaine

• Phenazopyridine
• Nitrates and nitrites
• Aniline compounds

Diagnostic clues

• Cyanosis that does not improve normally with oxygen
• Saturation gap between pulse oximetry and calculated arterial saturation
• Chocolate-brown blood
• Confirmation through co-oximetry

Clinical Pearl: PaO₂ measures dissolved oxygen and may be normal even when hemoglobin cannot deliver oxygen effectively.

NPLEX Trap: Do not repeatedly increase oxygen alone without considering dyshemoglobinemia when cyanosis and saturation remain unexplained.

Reference basis: AHA guidance recommends methylene blue for life-threatening methemoglobinemia and notes risks of ineffectiveness and hemolysis in G6PD deficiency.

Potential stages

1. Gastrointestinal injury

1. Apparent latent improvement
2. Shock and metabolic acidosis
3. Hepatic failure
4. Delayed gastrointestinal scarring

Treatment principles

• Emergency toxicology consultation
• Airway and circulatory stabilization
• Intravenous fluids and vasopressors when required
• Serial blood gases, glucose, renal and hepatic tests
• Deferoxamine for systemic toxicity
• Whole-bowel irrigation in selected cases

Clinical Pearl: A temporary reduction in gastrointestinal symptoms does not guarantee recovery.

NPLEX Trap: Activated charcoal does not adequately adsorb iron.

Reference basis: FDA prescribing information identifies deferoxamine as treatment for acute iron intoxication and emphasizes that it supplements rather than replaces standard resuscitative care.

Classic triad

• Refractory seizures
• Severe metabolic acidosis
• Coma

Treatment principles

• Immediate pyridoxine
• Benzodiazepines

• Airway protection
• Ventilation
• Correction of severe acidosis
• Serial glucose, lactate, electrolytes, and blood gases
• Toxicology consultation

Clinical Pearl: Hyperglycemia may occur and should not mislead the examiner toward diabetic ketoacidosis when the exposure history and refractory seizures indicate isoniazid toxicity.

NPLEX Trap: Conventional antiseizure medication alone may fail unless pyridoxine is administered.

Reference basis: Current FDA isoniazid labeling describes severe refractory seizures, metabolic acidosis, and pyridoxine-based emergency management.

Key manifestations

• CNS and respiratory depression
• Hyperammonemia
• Cerebral edema
• Hypotension
• Acidosis
• Hypernatremia
• Thrombocytopenia

• Hepatic injury

Treatment principles

• Support airway and circulation
• Activated charcoal in selected protected-airway cases
• L-carnitine
• Serial valproate and ammonia concentrations
• Hemodialysis for severe toxicity
• Monitor for delayed absorption from enteric-coated products

Clinical Pearl: Hyperammonemic encephalopathy can occur even without dramatic liver-enzyme elevation.

NPLEX Trap: Do not attribute reduced consciousness solely to a psychiatric medication’s sedating effect without checking ammonia and valproate concentrations.

Reference basis: EXTRIP recommends extracorporeal treatment for severe valproate poisoning, particularly with shock, cerebral edema, or extreme concentrations.

Key findings

• Repeated vomiting
• Tremor and agitation
• Severe tachycardia

• Supraventricular and ventricular dysrhythmias
• Hypokalemia
• Hyperglycemia
• Seizures

Treatment principles

• Activated charcoal when safe
• Benzodiazepines for seizures
• Electrolyte correction
• Careful dysrhythmia management
• Hemodialysis in severe toxicity
• Serial concentrations after sustained-release exposure

Clinical Pearl: Chronic toxicity can be severe at lower concentrations than a single acute overdose, particularly in older patients.

NPLEX Trap: Do not dismiss persistent vomiting as a minor medication adverse effect when tachycardia and neurologic symptoms are present.

Reference basis: EXTRIP recommends extracorporeal treatment for theophylline poisoning complicated by seizure, life-threatening dysrhythmia, shock, or rising concentrations.

Clinical progression

1. Severe gastrointestinal fluid loss
2. Cardiovascular collapse and multiorgan failure
3. Bone-marrow suppression
4. Recovery with possible alopecia

Patient-safety concerns

• Narrow therapeutic index
• Renal or hepatic impairment
• Strong CYP3A4 inhibitors
• P-glycoprotein inhibitors

• Repeated dosing errors

Clinical Pearl: Severe diarrhea may be the first warning of a potentially fatal systemic poisoning.

NPLEX Trap: Do not prescribe colchicine without reviewing kidney function and interacting medications.

Reference basis: Current colchicine labeling describes early gastrointestinal toxicity followed by multiorgan failure, marrow suppression, and possible alopecia, with particularly dangerous interactions in renal or hepatic impairment.

Potential manifestations

• Coma mimicking brain death
• Respiratory depression
• Hypotonia
• Hyporeflexia
• Bradycardia
• Myoclonus or seizure
• Hypothermia

Treatment principles

• Stop baclofen
• Support ventilation
• Treat seizure when present
• Consult toxicology and nephrology
• Consider hemodialysis in severe toxicity with kidney impairment

Clinical Pearl: Baclofen toxicity can produce both flaccidity and abnormal movements.

NPLEX Trap: Do not prescribe routine baclofen doses without considering renal clearance.

Reference basis: EXTRIP identifies a role for extracorporeal treatment in severe baclofen toxicity associated with kidney impairment, especially when prolonged ventilation is required.

Key manifestations

• Drowsiness or coma
• Miosis
• Bradycardia
• Hypotension
• Respiratory depression
• Hypothermia
• Reduced reflexes

Treatment principles

• Airway and ventilation support
• Intravenous fluids
• Vasopressor support when required
• Atropine for selected symptomatic bradycardia
• Trial of naloxone
• Observation for extended-release exposure or patches

Clinical Pearl: Clonidine toxicity can closely resemble opioid poisoning.

NPLEX Trap: A partial response to naloxone does not prove that an opioid caused the presentation.

Reference basis: Current clonidine labeling describes early hypertension followed by hypotension, bradycardia, respiratory depression, hypothermia, miosis, and coma.

Common causes

• Antihistamines
• Tricyclic antidepressants
• Atropine and scopolamine
• Antipsychotics
• Antispasmodics
• Certain plants

Treatment principles

• Supportive care
• Benzodiazepines
• External cooling
• Bladder decompression when necessary
• Sodium bicarbonate for cardiac sodium-channel toxicity
• Toxicology consultation before physostigmine

Clinical Pearl: Dry skin helps distinguish anticholinergic toxicity from sympathomimetic toxicity, in which diaphoresis is common.

NPLEX Trap: Do not give physostigmine reflexively to every delirious patient with dilated pupils.

Reference basis: AHA poisoning guidance supports sodium bicarbonate for life-threatening sodium-channel blockade and emphasizes toxidrome-specific resuscitation.

Potential complications

• Acute coronary syndrome
• Aortic dissection
• Stroke
• Seizure
• Hyperthermia
• Rhabdomyolysis
• Metabolic acidosis
• Ventricular dysrhythmia

Clinical Pearl: Diaphoresis favors a sympathomimetic toxidrome over a classic anticholinergic toxidrome.

NPLEX Trap: Do not treat severe stimulant agitation with physical restraint alone; sustained muscle activity can worsen hyperthermia and acidosis.

Reference basis: AHA guidance describes cocaine-associated sodium- and potassium-channel blockade, QRS widening, QT prolongation, and potentially fatal ventricular dysrhythmias.

Treatment principles

• Airway and ventilation
• Naloxone for opioid effect
• Glucose assessment
• ECG and co-ingestant evaluation
• Cautious use or avoidance of flumazenil
• Observation for recurrent respiratory depression

Clinical Pearl: Isolated benzodiazepine poisoning often produces sedation with relatively preserved vital signs; severe respiratory depression should raise concern for opioids or another co-ingestant.

NPLEX Trap: Do not administer flumazenil routinely in an unknown mixed overdose.

Reference basis: Current benzodiazepine labeling warns that combination with opioids may cause profound sedation, respiratory depression, coma, and death.

Potential complications

• Withdrawal seizures
• Delirium
• Hyperthermia
• Rhabdomyolysis
• Aspiration
• Electrolyte abnormalities
• Dysrhythmias
• Wernicke encephalopathy

Treatment principles

• Benzodiazepines
• Thiamine
• Fluids and electrolyte correction
• Treat concurrent infection or trauma
• Continuous monitoring in severe cases
• Long-term alcohol-use-disorder treatment after stabilization

Clinical Pearl: A concurrent illness may precipitate withdrawal and independently contribute to fever and delirium.

NPLEX Trap: Do not assume every symptom is caused by withdrawal; investigate sepsis, head injury, hypoglycemia, hepatic encephalopathy, and other causes.

Reference basis: ASAM recommends benzodiazepines as first-line therapy for moderate-to-severe alcohol withdrawal and intensive monitored treatment for withdrawal delirium.

Risk factors

• Alcohol-use disorder
• Starvation
• Hyperemesis
• Bariatric surgery
• Malabsorption
• Cancer
• Prolonged intravenous nutrition without vitamins

Treatment principles

• Parenteral thiamine
• Magnesium correction
• Nutritional rehabilitation
• Treatment of hypoglycemia
• Investigation of competing neurologic diagnoses

Clinical Pearl: A normal blood thiamine result does not safely exclude a clinical emergency.

NPLEX Trap: Do not wait for all three classic features before treating.

Reference basis: Nutrition guidance recognizes acute thiamine deficiency and Wernicke–Korsakoff disease as major risks when malnourished patients receive carbohydrate without adequate vitamin replacement.

Treatment and prevention

• Identify high-risk patients before feeding
• Administer thiamine
• Start nutrition cautiously
• Monitor phosphate, potassium, magnesium, glucose, and fluids
• Avoid sodium and fluid overload
• Escalate calories progressively

Clinical Pearl: Electrolyte concentrations may initially appear normal despite severe total-body depletion.

NPLEX Trap: Do not start full-calorie feeding immediately in a severely malnourished patient.

Reference basis: NICE nutrition guidance identifies prolonged minimal intake, very low BMI, weight loss, and low phosphate, potassium, or magnesium as major refeeding risks and recommends close electrolyte monitoring.