Toxicology and Overdose Management — Part 2: Analgesic, Opioid, Benzodiazepine & Sedative Poisonings

1. Acetaminophen (Paracetamol) Poisoning

Acetaminophen is the most common cause of acute liver failure in the United States and many developed nations. The margin between the therapeutic ceiling (4 g/day in adults) and potentially hepatotoxic doses (> 150 mg/kg or 7.5 g in adults, whichever is less) is relatively narrow, making this a frequent and high-stakes toxicologic presentation.^{1 2 3}

1.1 Mechanism of Hepatotoxicity

At therapeutic doses, approximately 90% of acetaminophen is metabolized by glucuronidation and sulfation, with less than 5% oxidized by cytochrome P450 (primarily CYP2E1) to the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI is rapidly detoxified by conjugation with glutathione. In overdose, glucuronidation and sulfation pathways become saturated, a greater proportion is shunted to the CYP2E1 pathway, glutathione stores are depleted (below approximately 30% of normal), and NAPQI accumulates, binding covalently to hepatocellular proteins and causing centrilobular hepatic necrosis.^{1 2}

1.2 Toxic Doses

1.3 Clinical Stages of Acetaminophen Toxicity

1.4 The Rumack-Matthew Nomogram

The Rumack-Matthew nomogram is the standard tool for assessing hepatotoxicity risk after acute, single, timed ingestions of immediate-release acetaminophen.^{1 3}

How to use:

1. Obtain a serum acetaminophen level at 4 hours post-ingestion or later (levels drawn before 4 hours cannot be plotted)
2. Plot the level against the time since ingestion on the nomogram
3. If the level falls at or above the treatment line, initiate N-acetylcysteine (NAC)

Treatment line: The original “possible hepatotoxicity” line begins at 150 mcg/mL at 4 hours and follows a straight line (on a semi-logarithmic scale) to 4.7 mcg/mL at 24 hours. In the United States, the treatment line (150 mcg/mL at 4 hours) is used. Some countries use a lower, more conservative “treatment line” at 100 mcg/mL at 4 hours.

Key nomogram points:

When the nomogram CANNOT be used:

• Unknown or unreliable time of ingestion
• Chronic (repeated supratherapeutic) ingestion
• Staggered or repeated ingestions over > 8 hours
• Extended-release formulations (with a single level)
• Presentation > 24 hours after ingestion

In these situations, treat empirically with NAC if there is any reasonable concern for hepatotoxicity.

1.5 N-Acetylcysteine (NAC) — The Antidote

NAC is the specific antidote for acetaminophen poisoning. It works by: (1) replenishing glutathione stores, (2) providing an alternative substrate for NAPQI conjugation, (3) enhancing sulfate conjugation, and (4) potentially providing direct hepatoprotective effects. NAC is virtually 100% effective at preventing hepatotoxicity when administered within 8 hours of ingestion.^{1 2 4}

1.5.1 Intravenous NAC — 21-Hour Protocol (Preferred)

The standard IV NAC protocol consists of three sequential infusions over 21 hours total:⁴

Important notes:

• Use actual body weight; in obese patients, cap at 100 kg for dosing calculations (some protocols cap at 110 kg)
• For patients < 40 kg: reduce diluent volumes to avoid hyponatremia and fluid overload (use 3 mL/kg for Bag 1, 7 mL/kg for Bag 2, 14 mL/kg for Bag 3)
• The loading dose rate was historically 15 minutes; slowing to 60 minutes reduces anaphylactoid reactions

When to continue NAC beyond 21 hours:

• ALT or AST is elevated and rising
• INR > 1.5
• Acetaminophen level remains detectable
• Patient remains clinically ill
• Continue Bag 3 rate (6.25 mg/kg/hr) until: ALT is trending down AND INR < 2 AND acetaminophen level is undetectable AND patient is clinically improving

1.5.2 Oral NAC — 72-Hour Protocol

The oral protocol is an alternative when IV formulation is unavailable or when the clinical situation favors oral administration:^{1 4}

Practical considerations:

• Dilute in a carbonated cola beverage to improve palatability
• If patient vomits within 1 hour of a dose, repeat that dose
• Antiemetic (ondansetron 4 mg IV) before each dose if needed
• Oral NAC is often poorly tolerated due to taste and vomiting

1.5.3 Anaphylactoid Reactions to IV NAC

These are dose-rate-dependent, non-IgE-mediated histamine release reactions, not true anaphylaxis:⁴

Risk factors for anaphylactoid reaction: asthma, low initial acetaminophen level (less substrate for NAC to conjugate), rapid infusion rate.

1.6 Massive Acetaminophen Ingestion

Massive ingestion (generally defined as > 500 mg/kg or acetaminophen level > 500 mcg/mL at 4 hours) carries special risks:^{1 5}

• Early metabolic acidosis (elevated lactate) before hepatotoxicity develops — due to impaired mitochondrial function
• Elevated lactate may be an early marker of severity
• Coma may occur from acetaminophen itself (not liver failure) at very high levels
• Standard 21-hour NAC protocol may be insufficient — consider higher infusion rates or additional loading doses
• Some toxicologists recommend doubling the Bag 1 dose (300 mg/kg loading) for levels > 500 mcg/mL
• Recheck acetaminophen levels at 4-hour intervals until declining
• Hemodialysis may be considered for levels > 900 mcg/mL with metabolic acidosis, or when NAC cannot keep pace with NAPQI production⁶

1.7 Extended-Release Acetaminophen

Extended-release formulations (e.g., Tylenol ER) have a delayed absorption profile:¹

• Check a second acetaminophen level at 8 hours post-ingestion (in addition to the 4-hour level)
• If either level plots above the treatment line, initiate NAC
• If the 4-hour level is below the line but the 8-hour level is above, begin NAC

1.8 Late-Presenting Acetaminophen Overdose

Patients presenting > 24 hours after ingestion with evidence of hepatotoxicity:^{1 2}

• Initiate IV NAC immediately regardless of acetaminophen level
• NAC provides benefit even in established hepatotoxicity (reduces mortality from approximately 58% to 37% in Stage III patients)
• Continue until criteria for discontinuation are met (see Section 1.5.1)
• Evaluate for liver transplant if King’s College Criteria are met:
  • pH < 7.30 after fluid resuscitation (single criterion is sufficient)
  • OR all three of: INR > 6.5 (PT > 100 sec) AND creatinine > 3.4 mg/dL AND Grade III–IV hepatic encephalopathy

2. Salicylate Poisoning

Salicylate toxicity (primarily from aspirin ingestion) is a potentially lethal poisoning that is frequently under-recognized. The pathophysiology is complex, involving uncoupling of oxidative phosphorylation, stimulation of the medullary respiratory center, disruption of the Krebs cycle, and interference with hemostasis.^{7 8}

2.1 Toxic Doses

2.2 Clinical Manifestations

Critical concept — the “salicylate trapping” principle:

• Salicylate is a weak acid (pKa ≈ 3.0)
• In acidemic blood, salicylate becomes un-ionized and crosses the blood-brain barrier freely
• Even small decreases in blood pH dramatically increase CNS salicylate penetration
• Any intervention that worsens acidemia (intubation with inadequate minute ventilation, sedation reducing respiratory drive) can cause rapid clinical deterioration and death

2.3 Diagnostic Evaluation

• Salicylate level: obtain immediately and repeat every 2–4 hours until consistently declining
  • Therapeutic: 10–30 mg/dL
  • Toxic: > 40 mg/dL (chronic) or > 60 mg/dL (acute)
  • Severe: > 80 mg/dL (acute) — hemodialysis likely indicated
  • Critical: > 100 mg/dL — immediate hemodialysis
• ABG/VBG: assess acid-base status (mixed respiratory alkalosis + metabolic acidosis pattern is characteristic)
• BMP: anion gap, bicarbonate level
• Lactate: marker of severity

Done nomogram limitations: The Done nomogram (which plots salicylate level against time to predict severity) is unreliable and should NOT be used to guide management. It does not account for chronic ingestion, co-ingestants, acid-base status, or clinical deterioration. Clinical assessment and serial levels are superior.⁷

2.4 Salicylate — Alkalinization Protocol

Urinary alkalinization (also called “alkaline diuresis”) is the primary enhanced elimination strategy for moderate salicylate poisoning. It exploits the ion-trapping principle: alkalinizing the urine increases the proportion of ionized (charged) salicylate in renal tubular fluid, preventing reabsorption and accelerating urinary excretion.^{7 8 9}

Protocol

1. Solution preparation: Add 150 mEq sodium bicarbonate (three 50-mEq ampules) to 1 liter of D5W. Add 40 mEq KCl to each liter (hypokalemia prevents urinary alkalinization because the kidney preferentially reabsorbs potassium and excretes hydrogen ions).

2. Infusion rate: 250 mL/hour initially (1.5–2 times maintenance), then adjust to target.

3. Bolus: 1–2 mEq/kg sodium bicarbonate IV push if severe acidemia present.

4. Monitoring targets:

   • Urine pH: 7.5–8.0 (check hourly with urine dipstick or pH meter)
   • Serum pH: 7.45–7.55 (do NOT exceed 7.60)
   • Serum potassium: maintain ≥ 4.0 mEq/L (supplement aggressively)
   • Serial salicylate levels every 2–4 hours

5. Continue until: salicylate level is < 30 mg/dL and trending down, symptoms are resolving, and acid-base status is normalizing.

Indications for Alkalinization

• Salicylate level > 30 mg/dL (acute) with symptoms
• Any symptomatic salicylate poisoning
• Acute ingestion > 150 mg/kg

Precautions

• Monitor for hypernatremia, hypokalemia, fluid overload
• Avoid in patients with renal failure (cannot excrete bicarbonate load; hemodialysis preferred)
• Avoid in patients with pulmonary edema (fluid administration may worsen)

2.5 Salicylate — Hemodialysis Criteria

Hemodialysis is the definitive treatment for severe salicylate poisoning and should not be delayed when indicated. Recommendations from the extracorporeal treatments workgroup:¹⁰

Intubation in salicylate poisoning — EXTREME CAUTION:

• If intubation becomes necessary, the patient MUST be hyperventilated to maintain the compensatory respiratory alkalosis
• Target minute ventilation should match or exceed the patient’s pre-intubation minute ventilation (often 20–30 L/min)
• Use the highest respiratory rate and tidal volume feasible
• Failure to hyperventilate the intubated salicylate patient can cause rapid acidemia → increased CNS salicylate penetration → death
• Consider hemodialysis as an alternative to intubation in the deteriorating salicylate patient

3. Opioid Poisoning — Complete Management

3.1 Diagnosis

The classic opioid toxidrome consists of respiratory depression, miosis, and decreased level of consciousness. However, several caveats exist:^{11 12}

• Mydriasis may occur with meperidine, tramadol, propoxyphene, or when hypoxia or co-ingestants are present
• Seizures may occur with meperidine (normeperidine metabolite), tramadol, and propoxyphene
• QRS prolongation/sodium channel blockade occurs with methadone, propoxyphene, and loperamide (massive doses)
• QTc prolongation is prominent with methadone and loperamide
• Serotonin syndrome may occur with meperidine, tramadol, and fentanyl (when combined with serotonergic agents)

3.2 Naloxone — Detailed Titration Protocol

See Part 1, Section 1.3 for the full naloxone dosing algorithm. Key additional points:^{11 12}

• Titrate to adequate ventilation, not consciousness — waking an opioid-dependent patient fully will precipitate withdrawal (vomiting, aspiration risk, agitation, departure against medical advice)
• Naloxone duration: approximately 30–90 minutes (much shorter than most opioids)
• Re-sedation is expected and common — plan for observation and possible repeat dosing or infusion
• Buprenorphine and pentazocine have high receptor affinity; higher naloxone doses (10–15 mg) may be needed

3.3 Opioid-Specific Considerations

3.4 Post-Reversal Observation

• Minimum 4–6 hours after last naloxone dose for short-acting opioids
• Minimum 12–24 hours for long-acting opioids (methadone, extended-release formulations)
• Patients who require a naloxone infusion generally require ICU admission
• Consider re-dosing or infusion if any recurrence of respiratory depression

4. Benzodiazepine Poisoning

4.1 Clinical Presentation

Pure benzodiazepine overdose is rarely fatal. The classic presentation includes CNS depression (drowsiness to coma), ataxia, slurred speech, and respiratory depression. Significant morbidity and mortality typically occur with co-ingestion (opioids, ethanol, barbiturates, other sedatives) or in elderly patients with comorbidities.¹³

4.2 Supportive Management

• Airway protection and respiratory support (intubation if GCS ≤ 8)
• Activated charcoal if within 1–2 hours and airway is protected
• Observation and supportive care is the mainstay
• Most patients can be safely observed and recover without specific intervention

4.3 Flumazenil — The Benzodiazepine Antagonist

Flumazenil is a competitive antagonist at the GABA-A benzodiazepine receptor. Its use in acute overdose is limited and controversial due to significant risks.^{13 14}

Dosing Protocol (When Used)

Contraindications to Flumazenil — CRITICAL

Appropriate Uses of Flumazenil

• Iatrogenic over-sedation from procedural sedation in patients with no history of chronic benzodiazepine use and no seizure risk
• Pediatric accidental ingestion of isolated benzodiazepine in a child with no seizure history and no other ingestions
• Diagnostic tool: in selected cases to clarify the contribution of benzodiazepines to altered mental status (use only after careful risk assessment)

5. Ethanol Intoxication and Co-Ingestion

5.1 Acute Ethanol Intoxication

Clinical correlation of blood alcohol concentration (BAC):

Note: Chronic heavy drinkers may appear minimally symptomatic at levels that would be lethal in non-tolerant individuals.

5.2 Management

• Supportive care: airway, glucose, thiamine (100 mg IV before or with glucose in at-risk patients)
• Evaluate for co-ingestants, trauma (head CT if altered beyond expected for BAC), hypoglycemia
• Obtain acetaminophen and salicylate levels
• Monitor for withdrawal if chronic heavy use (may develop 6–24 hours after cessation)

6. GHB (Gamma-Hydroxybutyrate) Poisoning

6.1 Clinical Features

• Rapid onset of CNS depression (dose-dependent: drowsiness → unresponsive coma)
• Bradycardia
• Respiratory depression
• Miosis (may mimic opioid toxicity)
• Hypothermia
• Myoclonus, agitation during recovery
• Abrupt awakening is characteristic — patients may transition from deep coma to agitated wakefulness

6.2 Management

• Purely supportive: airway management, respiratory support
• No specific antidote
• Naloxone and flumazenil are NOT effective
• Short duration of action (2–4 hours); most patients recover with observation
• Avoid intubation if possible — consider temporizing with bag-valve-mask ventilation given the short duration
• Monitor for co-ingestants

7. Barbiturate Poisoning

7.1 Clinical Presentation

Barbiturates cause dose-dependent CNS depression progressing from sedation to coma, respiratory depression, hypotension, and hypothermia. Unique features include:¹⁵

• Absence of deep tendon reflexes in severe cases
• Fixed, dilated pupils may occur (mimicking brain death)
• Cutaneous bullae (“barb blisters”) at pressure points
• Cardiovascular depression with hypotension

7.2 Classification by Duration of Action

7.3 Management

8. Isopropanol (Isopropyl Alcohol) Poisoning

8.1 Key Features

Isopropanol is the most commonly ingested toxic alcohol but the least toxic of the toxic alcohols. It is metabolized to acetone (not a toxic organic acid), so it produces an elevated osmol gap and ketonemia/ketonuria WITHOUT metabolic acidosis (a unique pattern).¹⁷

8.2 Clinical Presentation

• CNS depression (roughly twice as potent as ethanol)
• Abdominal pain, hemorrhagic gastritis
• Hypotension (vasodilation, myocardial depression)
• Characteristic fruity breath (acetone)
• Laboratory hallmark: elevated osmol gap + ketones WITHOUT anion gap metabolic acidosis

8.3 Management

• Supportive care (airway, fluids, vasopressors if needed)
• Fomepizole is NOT indicated (acetone is not a toxic metabolite)
• Hemodialysis only for refractory hypotension or very high levels (> 400 mg/dL) with clinical deterioration
• Most patients recover with supportive care alone