Salicylate Overdose

Quick Answer

Salicylate overdose is a life-threatening toxicological emergency characterized by a unique mixed acid-base disturbance (primary respiratory alkalosis with superimposed metabolic acidosis) due to direct stimulation of the respiratory center and uncoupling of oxidative phosphorylation. [1,2]

Pathophysiology:

• Uncoupling of oxidative phosphorylation in mitochondria produces heat (hyperthermia), inhibits ATP production, and shifts metabolism to anaerobic pathways with lactate and ketoacid accumulation [3,4]
• Direct stimulation of medullary chemoreceptors causes hyperventilation and respiratory alkalosis [5,6]
• Increased vascular permeability leads to non-cardiogenic pulmonary edema and cerebral edema [7,8]

Severity classification by serum salicylate level:

• Mild: below 300 mg/L (2.2 mmol/L) - tinnitus, nausea, vomiting
• Moderate: 300-600 mg/L (2.2-4.3 mmol/L) - hyperpnea, tachycardia, diaphoresis
• Severe: greater than 600 mg/L (greater than 4.3 mmol/L) - altered mental status, hyperthermia, pulmonary edema, seizures [9,10]

Treatment principles:

1. Volume resuscitation with dextrose-containing fluids (correct dehydration, provide glucose for cerebral metabolism) [11]
2. Urinary alkalinization with sodium bicarbonate (target urine pH greater than 7.5) - enhances renal salicylate excretion 10-20 fold through ion trapping [12,13]
3. Activated charcoal 50 g (1 g/kg) if within 2 hours or for enteric-coated preparations [14,15]
4. Hemodialysis for severe toxicity (EXTRIP criteria) [16]

Hemodialysis indications (EXTRIP 2015): [16]

• Salicylate level greater than 100 mg/dL (7.2 mmol/L) in acute overdose
• Altered mental status or seizures
• Acute kidney injury (creatinine greater than 2 mg/dL or 177 umol/L)
• Pulmonary edema requiring oxygen supplementation
• Failure of standard therapy or clinical deterioration

CRITICAL - Avoid intubation if possible:

• Loss of compensatory hyperventilation during induction causes rapid accumulation of CO2
• Rising PaCO2 allows more unionized salicylate to enter the CNS (ion trapping reversal)
• Case reports of cardiac arrest within minutes of intubation [17,18]
• If intubation unavoidable: Use the highest safe minute ventilation (RR 25-30, TV 8 mL/kg) and perform emergent hemodialysis [17]

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CICM Exam Focus

Key High-Yield Points

1. Unique acid-base pattern: Primary respiratory alkalosis (medullary stimulation) with superimposed high anion gap metabolic acidosis (HAGMA) from lactate, ketoacids, and salicylic acid itself [5,6,19]

2. Uncoupling of oxidative phosphorylation: Salicylates act as protonophores, dissipating the proton gradient across the inner mitochondrial membrane; this produces heat instead of ATP and triggers anaerobic metabolism [3,4,20]

3. CNS toxicity mechanism: Salicylates interfere with glucose utilization in the brain (neuroglycopenia) despite normal serum glucose; always give dextrose [7,21,22]

4. Urinary alkalinization target: Urine pH greater than 7.5 (ideally 8.0); each 1 unit increase in urine pH increases salicylate clearance 10-fold via ion trapping [12,13,23]

5. Potassium replacement essential: Alkalinization fails if the patient is hypokalemic (kidneys excrete K+ in exchange for H+ to maintain pH); target K+ greater than 4.0 mmol/L [24,25]

6. EXTRIP dialysis criteria (PMID 25272616): Level greater than 100 mg/dL (greater than 7.2 mmol/L), altered consciousness, renal failure, pulmonary edema, clinical deterioration despite therapy [16]

7. Intubation danger: Pre-intubation apnea allows CO2 accumulation and rapid acidosis; this shifts equilibrium toward unionized salicylic acid which crosses cell membranes including BBB more readily; can precipitate cardiac arrest [17,18,26]

8. Multi-dose activated charcoal (MDAC): Consider for enteric-coated aspirin or massive ingestions with ongoing absorption; standard dose 25-50 g every 4 hours [14,15,27]

9. Chronic vs acute toxicity: Chronic toxicity occurs at lower levels (300-400 mg/L) with more severe symptoms; elderly are at highest risk and often present with altered mental status at relatively low levels [28,29,30]

10. Done nomogram obsolete: Should NOT be used; poor correlation with clinical severity; treat based on clinical presentation, not just level [9,31]

Common Viva Themes

• Pathophysiology of salicylate toxicity and the dual acid-base disturbance
• Mechanism of urinary alkalinization and requirements for effective therapy
• EXTRIP criteria for hemodialysis initiation
• Dangers of intubation and ventilator management if intubation required
• Chronic vs acute salicylate poisoning - key differences
• Pharmacokinetics at toxic doses (volume of distribution expansion, protein binding saturation)
• Multi-dose activated charcoal - indications and contraindications
• Comparison of intermittent hemodialysis (IHD) vs continuous renal replacement therapy (CRRT)

Common Pitfalls

• Failure to recognize chronic salicylism (presents with confusion, tachypnea, metabolic abnormalities at lower levels)
• Using the Done nomogram for prognostication (unreliable, obsolete)
• Inadequate potassium replacement leading to failure of alkalinization
• Permitting hypoventilation after intubation (causes acute decompensation and death)
• Delaying hemodialysis while attempting alkalinization in severe poisoning
• Not providing dextrose (cerebral glucose utilization impaired despite normal serum glucose)
• Missing enteric-coated aspirin (delayed and prolonged absorption; levels may rise over 12-24 hours)
• Administering bicarbonate boluses instead of infusion (causes rebound acidemia)
• Forgetting to check serial levels (continued absorption common)

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Key Points

• Salicylate poisoning causes a mixed acid-base disturbance: respiratory alkalosis + metabolic acidosis [5,6,19]
• Uncoupling of oxidative phosphorylation produces hyperthermia and HAGMA [3,4,20]
• Severity: Mild below 300 mg/L, Moderate 300-600 mg/L, Severe greater than 600 mg/L [9,10]
• Urinary alkalinization with sodium bicarbonate (target urine pH greater than 7.5) increases salicylate clearance 10-20 fold [12,13,23]
• Potassium must be greater than 4.0 mmol/L for effective alkalinization [24,25]
• Hemodialysis indications (EXTRIP): Level greater than 100 mg/dL (7.2 mmol/L), altered mental status, pulmonary edema, renal failure, deterioration [16]
• AVOID intubation if possible - loss of hyperventilation causes rapid deterioration [17,18,26]
• If intubation required: Match pre-intubation minute ventilation (high RR, normal TV), emergent dialysis [17]
• Chronic poisoning is more dangerous at lower levels, especially in elderly [28,29,30]
• Always give dextrose - neuroglycopenia occurs despite normal serum glucose [7,21,22]
• Done nomogram is obsolete and should not be used [9,31]
• Multi-dose activated charcoal for enteric-coated preparations or massive ingestions [14,15,27]

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Pharmacokinetics and Toxicokinetics

Normal Pharmacokinetics

Aspirin (acetylsalicylic acid) is rapidly hydrolyzed to salicylic acid in the GI mucosa and bloodstream. The pharmacokinetics are dose-dependent and dramatically altered in overdose. [32,33]

Therapeutic doses:

• Absorption: Rapid from stomach and small intestine; peak levels at 1-2 hours
• Volume of distribution (Vd): 0.1-0.2 L/kg (confined to plasma and ECF)
• Protein binding: 90% bound to albumin
• Metabolism: Hepatic conjugation with glycine (salicyluric acid) and glucuronic acid
• Elimination half-life: 2-3 hours
• Excretion: Renal; pH-dependent (ionized form cannot be reabsorbed)

Altered Kinetics in Overdose

At toxic concentrations, several critical changes occur that prolong toxicity and expand tissue distribution. [32,33,34]

Saturation of protein binding:

• At levels greater than 300 mg/L, albumin binding sites become saturated
• Free (unbound) salicylate fraction increases from 10% to greater than 50%
• Free drug crosses cell membranes including the blood-brain barrier (BBB)
• This explains why CNS toxicity increases disproportionately at higher levels

Volume of distribution expansion:

• Vd increases from 0.1-0.2 L/kg to 0.3-0.5 L/kg (up to 0.7 L/kg in severe cases)
• Increased tissue penetration, particularly CNS
• Larger pool of salicylate to eliminate

Saturation of hepatic metabolism:

• Conjugation pathways become saturated
• First-order kinetics shift to zero-order kinetics
• Elimination half-life extends from 2-3 hours to 15-30 hours (or longer)

Delayed gastric emptying:

• Salicylates cause pylorospasm and delayed gastric emptying
• Prolonged absorption phase with secondary peaks
• Enteric-coated preparations: Absorption may continue for 24-48 hours

Renal elimination becomes rate-limiting:

• At saturation, renal excretion of unchanged salicylate becomes the primary elimination route
• This is where urinary alkalinization is critical
• Non-ionized (HA) form is reabsorbed; ionized (A-) form is trapped in urine

Pharmacokinetic Implications for Treatment

Dialysis effectiveness:

• Low Vd (even when expanded) favors dialysis efficacy
• Increased free fraction at toxic levels makes dialysis highly effective
• Hemodialysis clearance: 50-100 mL/min (vs. endogenous clearance ~5 mL/min in overdose) [35,36]

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Pathophysiology

Overview of Toxicity Mechanisms

Salicylate toxicity involves multiple interconnected mechanisms affecting cellular metabolism, acid-base balance, and organ function. The severity of toxicity correlates with tissue (particularly CNS) salicylate concentrations rather than serum levels alone. [1,2,3]

Uncoupling of Oxidative Phosphorylation

This is the central mechanism of salicylate toxicity. [3,4,20,37]

Normal oxidative phosphorylation:

• Electrons from NADH/FADH2 pass through the electron transport chain (ETC)
• Protons (H+) are pumped from mitochondrial matrix to intermembrane space
• Proton gradient drives ATP synthase to produce ATP
• Energy from electron transport is coupled to ATP synthesis

Salicylate as a protonophore:

• Salicylic acid (weak acid, pKa 3.0) in its unionized form crosses the inner mitochondrial membrane
• In the alkaline matrix, it dissociates releasing H+ and collapses the proton gradient
• Protons bypass ATP synthase and return to the matrix via the salicylate carrier
• Energy is released as heat instead of driving ATP synthesis

Metabolic consequences:

1. Hyperthermia: Energy dissipated as heat; temperature may exceed 40C in severe cases
2. ATP depletion: Reduced ATP for cellular functions including Na+/K+-ATPase
3. Increased oxygen consumption: Cells attempt to maintain ATP production
4. Anaerobic glycolysis: Shift to less efficient metabolism with lactate production
5. Lipolysis and ketogenesis: Alternative fuel sources mobilized; ketoacids accumulate

Acid-Base Disturbances

Salicylate poisoning produces a characteristic mixed acid-base disturbance that evolves over time. [5,6,19,38]

Phase 1 - Primary Respiratory Alkalosis:

• Direct stimulation of medullary chemoreceptors
• Increased respiratory rate and depth (hyperpnea)
• Decreased PaCO2 (often 15-25 mmHg)
• Blood pH elevated or normal
• This phase may predominate in early/mild toxicity

Phase 2 - Mixed Respiratory Alkalosis + Metabolic Acidosis:

• Accumulation of organic acids:
  • Lactic acid (anaerobic metabolism)
  • Ketoacids (beta-hydroxybutyrate, acetoacetate)
  • Salicylic acid itself (contributes ~3-5 mmol/L to anion gap)
  • Pyruvic acid, citric acid intermediates
• High anion gap metabolic acidosis (HAGMA)
• Respiratory alkalosis partially compensates
• pH may be normal, low, or high depending on relative contributions

Phase 3 - Pure Metabolic Acidosis (Preterminal):

• Respiratory center depression (exhaustion or CNS toxicity)
• Loss of compensatory hyperventilation
• Profound metabolic acidosis (pH below 7.0)
• This phase indicates imminent cardiovascular collapse

Clinical importance of the acid-base pattern:

• Early recognition of respiratory alkalosis + HAGMA is diagnostic
• Pure respiratory alkalosis suggests early/mild poisoning
• Pure metabolic acidosis indicates severe/late poisoning with poor prognosis
• Maintaining alkalemia is critical (reduces CNS penetration)

Electrolyte Disturbances

Multiple electrolyte abnormalities accompany salicylate poisoning. [24,25,39]

Hypokalemia:

• Vomiting and diarrhea cause GI losses
• Respiratory alkalosis causes cellular K+ uptake
• Bicarbonate therapy promotes renal K+ wasting
• Critical: Hypokalemia must be corrected for effective alkalinization

Hyponatremia:

• Free water retention from SIADH-like effect
• Shift of water to intracellular compartment
• Pseudohyponatremia if hyperlipidemia present

Hypoglycemia (or perceived normoglycemia):

• Impaired gluconeogenesis
• Increased peripheral glucose utilization
• CNS glucose utilization impaired (neuroglycopenia) despite normal serum levels
• Always provide dextrose supplementation

Hypocalcemia:

• Alkalosis reduces ionized calcium
• May contribute to tetany and arrhythmias

Central Nervous System Toxicity

CNS manifestations are the primary determinant of mortality. [7,8,21,22,40]

Mechanisms:

1. Neuroglycopenia: Salicylates inhibit glucose transport into CNS cells; local glucose deficiency despite adequate serum levels
2. Direct neurotoxicity: Salicylate accumulation disrupts neurotransmitter synthesis and release
3. Cerebral edema: Increased vascular permeability; vasogenic and cytotoxic edema
4. Acid-base disruption: Brain pH falls; enzymatic dysfunction

Clinical manifestations (by severity):

• Mild: Tinnitus (earliest symptom), hearing loss, vertigo
• Moderate: Confusion, agitation, delirium, tremor
• Severe: Seizures, coma, cerebral edema

pH effect on CNS penetration:

• Salicylic acid (HA, unionized) crosses BBB readily
• Salicylate anion (A-, ionized) is trapped in blood
• Acidemia increases HA fraction and CNS penetration
• Alkalemia decreases CNS penetration (ion trapping in blood)
• This is why maintaining blood pH greater than 7.45 is critical [7,38,41]

Pulmonary Toxicity

Non-cardiogenic pulmonary edema (NCPE) is a major cause of morbidity and mortality. [7,8,42]

Mechanisms:

• Increased pulmonary capillary permeability
• Impaired alveolar fluid clearance (Na+/K+-ATPase dysfunction)
• Possible direct toxicity to type II pneumocytes
• Fluid overload may contribute (aggressive resuscitation)

Clinical features:

• Tachypnea out of proportion to level
• Hypoxemia
• Bilateral infiltrates on chest X-ray
• Usually occurs at levels greater than 500 mg/L but can occur at lower levels in chronic toxicity

Risk factors:

• Older age (greater than 70 years)
• Chronic toxicity
• Smoking
• Pre-existing lung disease
• Delayed presentation

Cardiovascular Effects

Cardiovascular instability occurs in severe poisoning. [43,44]

Mechanisms and manifestations:

• Initial: Tachycardia (sympathetic activation, fever, dehydration)
• Progressive: Vasodilation, decreased systemic vascular resistance
• Late: Myocardial depression (ATP depletion), arrhythmias
• Terminal: Cardiovascular collapse, asystole

ECG changes:

• Sinus tachycardia (most common)
• Prolonged QT interval
• ST-T wave changes
• Arrhythmias (VT, VF) in severe cases with electrolyte abnormalities

Other Organ Effects

Gastrointestinal:

• Direct GI irritation: Nausea, vomiting, abdominal pain
• GI bleeding: Inhibition of cyclooxygenase reduces protective prostaglandins
• Hepatotoxicity: Elevated transaminases (usually mild, reversible)

Renal:

• Acute kidney injury from dehydration, rhabdomyolysis, or direct toxicity
• Impairs drug elimination (clearance reduced)
• May precipitate need for dialysis

Coagulation:

• Inhibition of platelet function
• Prolonged bleeding time
• Rarely clinically significant unless massive overdose or pre-existing coagulopathy

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Clinical Presentation

Early Signs and Symptoms (Mild Toxicity)

Early features typically appear within 3-6 hours of acute ingestion. [9,10,45,46]

Cardinal early symptoms:

• Tinnitus: Earliest symptom; described as ringing, buzzing, or roaring
• Hearing impairment: Reversible sensorineural hearing loss
• Vertigo and nausea: Common, often with vomiting
• Tachypnea: May be subtle initially; patient often unaware

Other early features:

• Diaphoresis (sweating)
• Mild fever (37.5-38.5C)
• Lethargy or mild confusion
• Abdominal discomfort

Moderate Toxicity

Features of moderate toxicity generally correspond to levels 300-600 mg/L. [9,10,45]

Respiratory:

• Hyperpnea (increased depth and rate of breathing)
• Respiratory rate 25-40 breaths/min
• May appear as "air hunger" or "Kussmaul-like" breathing

Cardiovascular:

• Tachycardia (HR 100-130 bpm)
• Bounding pulses
• Warm, flushed skin (vasodilation)

Neurological:

• Confusion, disorientation
• Agitation, restlessness
• Tremor

Metabolic:

• Fever (38-39C)
• Dehydration (reduced skin turgor, dry mucous membranes)
• Hypoglycemia or low-normal glucose

Severe Toxicity

Severe toxicity occurs at levels greater than 600 mg/L in acute overdose, but at lower levels in chronic toxicity or elderly patients. [9,10,45,47]

Neurological (most important prognostic indicators):

• Altered level of consciousness
• Coma
• Seizures
• Signs of cerebral edema (papilledema, posturing)

Respiratory:

• Acute respiratory distress
• Non-cardiogenic pulmonary edema
• Hypoxemia despite high FiO2
• May develop ARDS

Cardiovascular:

• Hypotension
• Arrhythmias (sinus tachycardia, VT, VF)
• Cardiovascular collapse

Metabolic:

• Hyperthermia (greater than 40C)
• Severe metabolic acidosis (pH below 7.2)
• Profound electrolyte disturbances
• Acute kidney injury

Chronic Salicylism

Chronic salicylate toxicity is frequently unrecognized and carries higher morbidity and mortality than acute poisoning. [28,29,30,48]

High-risk populations:

• Elderly patients on regular aspirin or arthritis medications
• Patients with chronic pain syndromes
• Cognitive impairment (inadvertent repeat dosing)
• Renal impairment (decreased clearance)

Key differences from acute toxicity:

Clinical clues to chronic salicylism:

• Unexplained confusion in elderly patient
• Respiratory alkalosis with metabolic acidosis
• Persistent tachypnea
• Unexplained fever
• History of arthritis or chronic pain
• Recent increase in "pain medication" use

Differential Diagnosis

The presentation of salicylate toxicity mimics several other conditions. [1,49]

High anion gap metabolic acidosis (MUDPILES):

• Methanol
• Uremia
• Diabetic ketoacidosis
• Propylene glycol / Paraldehyde
• Isoniazid / Iron
• Lactic acidosis
• Ethylene glycol
• Salicylates

Other considerations:

• Sepsis (fever, tachypnea, altered mental status, metabolic acidosis)
• Thyroid storm (tachycardia, hyperthermia, altered mental status)
• Neuroleptic malignant syndrome (hyperthermia, rigidity, altered mental status)
• Serotonin syndrome (hyperthermia, agitation, tremor)

Key distinguishing features of salicylate toxicity:

• Primary respiratory alkalosis with metabolic acidosis (mixed pattern)
• Tinnitus (early, specific)
• History of aspirin access/use
• Elevated salicylate level

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Investigations

Essential Initial Investigations

A comprehensive workup is required for suspected salicylate poisoning. [1,9,50]

Serum salicylate level:

• Obtain immediately and repeat every 2-4 hours until declining
• Continue monitoring for 24+ hours with enteric-coated preparations
• Units: mg/L (mg/dL x 10 = mg/L) or mmol/L (mg/L / 138 = mmol/L)
• Note: Level alone does not predict severity (clinical status is paramount)

Arterial blood gas (ABG):

• Assess pH, PaCO2, PaO2, bicarbonate, lactate
• Typical pattern: Low PaCO2 (respiratory alkalosis) + low HCO3 (metabolic acidosis)
• Calculate anion gap: AG = Na - (Cl + HCO3); expected greater than 16-20 in significant toxicity
• Serial ABGs to monitor response to therapy

Electrolytes and renal function:

• Sodium, potassium, chloride, bicarbonate
• Creatinine, urea (assess renal function for dialysis decision)
• Glucose (may be low despite adequate serum level)
• Calcium, magnesium, phosphate

Full blood count:

• Usually unremarkable
• May show leukocytosis (stress response)
• Platelet function impaired but count typically normal

Coagulation studies:

• PT/INR, aPTT
• May be prolonged in severe cases
• Rarely clinically significant bleeding

Liver function tests:

• AST, ALT may be mildly elevated
• Significant elevation suggests Reye syndrome (paediatric) or severe toxicity

Additional Investigations

Chest X-ray:

• Assess for pulmonary edema
• Bilateral infiltrates suggest NCPE
• Obtain in all moderate-severe cases

ECG:

• Sinus tachycardia common
• Look for QT prolongation, ST-T changes
• Arrhythmia monitoring in severe cases

Urine:

• Urine pH: Target for alkalinization
• Urine salicylate (ferric chloride test): Purple colour indicates presence

Toxicology screen:

• Consider co-ingestants (paracetamol, opioids, ethanol)
• Paracetamol level essential in all overdose presentations

Interpretation of Salicylate Levels

Severity classification (acute single ingestion): [9,10]

Important caveats:

• These thresholds apply to acute single ingestions only
• Chronic toxicity occurs at much lower levels
• Clinical severity often does not correlate with level
• Falling level with worsening clinical status indicates tissue distribution
• Always treat the patient, not the number

Done nomogram (historical, now obsolete):

• Developed in 1960 for acute pediatric ingestions
• Does not account for chronic toxicity, enteric-coated preparations, or protein binding saturation
• Should NOT be used for clinical decision-making [31]

Serial Monitoring

Frequency of repeat levels:

• Every 2 hours initially in severe cases
• Every 4 hours in moderate cases
• Continue until levels are clearly declining AND patient is improving
• Enteric-coated aspirin: Monitor for 24+ hours (delayed absorption)

Indicators of continued absorption:

• Rising salicylate level over time
• Increasing anion gap despite therapy
• Failure to respond to alkalinization
• Consider bezoar formation (CT abdomen if suspected)

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Management

Resuscitation and Initial Stabilization

Initial management follows a systematic approach with attention to the unique dangers of salicylate poisoning. [1,2,17]

Airway Management

AVOID INTUBATION IF POSSIBLE [17,18,26,51]

This is a critical teaching point for CICM examinations. The dangers include:

Mechanism of deterioration:

1. Pre-intubation apnea during RSI causes immediate CO2 retention
2. Rising PaCO2 (from 20 to 40 mmHg in seconds) causes:
   • Fall in blood pH (respiratory acidemia)
   • Shift of salicylate equilibrium toward unionized (HA) form
   • Rapid CNS penetration of salicylate
3. Result: Cardiac arrest within minutes of intubation

Case reports:

• Leatherman and Schmitz (1988) reported cardiac arrests immediately following intubation in patients with "stable" salicylate toxicity who lost compensatory hyperventilation [17]
• Similar cases continue to be reported, emphasizing this remains an under-recognized danger

If intubation is absolutely required:

• Recognize it as a high-risk procedure
• Pre-oxygenate with BVM at high respiratory rate
• Use rapid sequence intubation with fastest acting agents
• Immediately ventilate at high minute ventilation (RR 25-30, TV 8 mL/kg)
• Target PaCO2 below 25 mmHg (match pre-intubation level)
• Arrange emergent hemodialysis
• Avoid paralysis if possible (patient-triggered ventilation safer)

Breathing

Oxygenation:

• Provide supplemental oxygen
• Monitor SpO2 and ABG
• Be alert for development of pulmonary edema

Ventilation (non-intubated patient):

• Allow and encourage hyperventilation
• Do NOT give sedation that may impair respiratory drive
• Monitor respiratory fatigue (indication for dialysis)

Circulation

Fluid resuscitation: [11,52]

• IV access with large bore cannulae
• Assess volume status (usually dehydrated)
• Initial bolus: 20 mL/kg crystalloid
• Continue resuscitation to achieve adequate urine output (greater than 2 mL/kg/h target for alkalinization)
• Include dextrose: D5W or D10W to maintain glucose greater than 5 mmol/L
• Monitor for fluid overload (pulmonary edema risk)

Vasopressors:

• Noradrenaline if hypotensive despite fluids
• Vasodilation is common in severe cases

Disability

Dextrose supplementation:

• Give D50W 50 mL (25 g dextrose) empirically if altered mental status
• Continue dextrose infusion to maintain glucose greater than 5 mmol/L
• Remember: CNS glucose utilization impaired despite normal serum levels

Seizure management:

• Benzodiazepines first-line
• Avoid phenytoin (ineffective, may worsen acidosis)
• Persistent seizures indicate severe toxicity requiring dialysis

Decontamination

Gastrointestinal decontamination can reduce absorption if performed early. [14,15,27,53]

Activated Charcoal

Indications:

• Within 2 hours of ingestion (standard formulations)
• May be effective beyond 2 hours for:
  • Enteric-coated preparations
  • Large ingestions (greater than 300-500 mg/kg)
  • Delayed gastric emptying

Dosing:

• 1 g/kg (50 g in adults) as single dose
• Mix with water or sorbitol

Contraindications:

• Altered level of consciousness without airway protection
• Significant vomiting
• GI obstruction or perforation

Multi-Dose Activated Charcoal (MDAC)

Indications:

• Enteric-coated aspirin ingestion
• Massive ingestion (greater than 500 mg/kg)
• Rising salicylate levels despite therapy
• Evidence of bezoar on imaging

Dosing:

• 25-50 g every 4 hours
• Continue until levels declining

Monitoring:

• Bowel sounds (ileus may develop)
• Aspiration risk
• Electrolytes (may cause hypomagnesemia, hypokalemia)

Gastric Lavage

Rarely indicated:

• Consider only if massive ingestion within 1 hour
• Enteric-coated tablets are too large for lavage tube
• Risk of aspiration, esophageal injury

Whole Bowel Irrigation

Consider for:

• Massive ingestion of enteric-coated aspirin
• Evidence of bezoar on imaging
• Dosing: Polyethylene glycol solution 1-2 L/h until clear rectal effluent

Urinary Alkalinization

This is the mainstay of enhanced elimination for moderate salicylate toxicity. [12,13,23,24,25,54]

Mechanism

Ion trapping:

• Salicylic acid is a weak acid (pKa 3.0)
• In alkaline urine: HA dissociates to H+ + A- (ionized form)
• Ionized A- cannot be reabsorbed from renal tubule
• Net effect: Enhanced urinary excretion

Mathematical relationship:

• At urine pH 5.0: Salicylate mostly unionized (HA) and reabsorbed
• At urine pH 7.0: ~50% ionized
• At urine pH 8.0: greater than 90% ionized
• Each 1-unit increase in urine pH increases clearance ~10-fold

Protocol for Urinary Alkalinization

Sodium bicarbonate infusion:

1. Bolus: NaHCO3 1-2 mmol/kg IV (100-150 mL of 8.4% solution)

2. Infusion: 150 mmol NaHCO3 in 1 L D5W at 150-250 mL/h

   • Alternative: 100-150 mmol/L NaHCO3 added to maintenance fluids

3. Potassium supplementation: Add 20-40 mmol KCl to each liter

   • ESSENTIAL: Hypokalemia prevents alkalinization

4. Targets:

   • Blood pH: 7.45-7.55 (avoid greater than 7.60)
   • Urine pH: greater than 7.5 (ideally 8.0)
   • Urine output: greater than 2-3 mL/kg/h

5. Monitoring:

   • Urine pH hourly (dipstick or pH meter)
   • Serum potassium every 2-4 hours
   • ABG every 4 hours
   • Fluid balance (avoid overload)

Requirements for Effective Alkalinization

Potassium must be adequate (greater than 4.0 mmol/L):

• Hypokalemia causes renal H+ excretion (in exchange for K+)
• This prevents alkalinization of urine despite bicarbonate therapy
• Aggressive K+ replacement is essential

Adequate urine output:

• Cannot trap ionized salicylate without urine flow
• Target greater than 2-3 mL/kg/h
• Volume resuscitation may be needed

Adequate renal function:

• Alkalinization ineffective if AKI present
• Consider dialysis if creatinine rising or oliguria develops

When Alkalinization is Ineffective

Consider hemodialysis if:

• Unable to achieve urine pH greater than 7.5 despite adequate therapy
• Serum potassium cannot be maintained
• Oliguria or AKI
• Clinical deterioration despite treatment
• Level continues to rise

Hemodialysis

Hemodialysis is highly effective for salicylate removal and is the definitive treatment for severe toxicity. [16,35,36,55,56]

EXTRIP Recommendations (PMID: 25272616)

The Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup published evidence-based guidelines in 2015. [16]

Extracorporeal treatment is RECOMMENDED if:

1. Salicylate level greater than 100 mg/dL (greater than 7.2 mmol/L, greater than 1000 mg/L) in acute overdose

   • Even without symptoms, dialysis should be initiated

2. Altered mental status attributable to salicylate

   • Regardless of level
   • Confusion, agitation, lethargy, seizures, coma

3. Acute kidney injury

   • Creatinine greater than 2 mg/dL (177 umol/L)
   • Or rapid rise in creatinine

4. Pulmonary edema requiring supplemental oxygen

   • Non-cardiogenic pulmonary edema
   • Hypoxemia

5. Failure of standard therapy

   • Clinical deterioration despite appropriate treatment
   • Inability to achieve urinary alkalinization
   • Rising level despite decontamination

6. Severe acid-base disturbance

   • pH below 7.2 despite bicarbonate therapy

Additional considerations for dialysis:

• Chronic toxicity with level greater than 60 mg/dL (600 mg/L) and clinical findings
• Elderly patient with confusion at lower levels
• Need for intubation (compensatory hyperventilation will be lost)

Intermittent Hemodialysis vs CRRT

Intermittent hemodialysis (IHD) is PREFERRED: [35,36,55]

Advantages of IHD:

• Higher clearance rates (3-5x greater than CRRT)
• Faster reduction of salicylate levels
• Corrects metabolic acidosis rapidly
• Can often be completed in single session

When to use CRRT instead:

• Hemodynamic instability precluding IHD
• IHD unavailable
• As adjunct after IHD to prevent rebound

Duration:

• Continue until salicylate level below 20-30 mg/dL (below 200-300 mg/L)
• Clinical improvement essential
• May need repeat sessions for massive ingestions or enteric-coated preparations

Post-Dialysis Management

Rebound phenomenon:

• Salicylate redistributes from tissues after dialysis
• Levels may rise 20-30% after dialysis
• Re-check level 2-4 hours post-dialysis
• May need repeat dialysis session

Continue standard therapy:

• Urinary alkalinization during and after dialysis
• Serial levels until clearly declining
• Watch for delayed absorption (enteric-coated)

Algorithm: Salicylate Overdose Management

SALICYLATE OVERDOSE MANAGEMENT ALGORITHM

Initial Assessment
├── ABG, salicylate level, electrolytes, glucose
├── ECG, chest X-ray
├── Calculate anion gap
└── Assess mental status

Severity Classification
├── MILD (below 300 mg/L)
│   ├── Activated charcoal if below 2 hours
│   ├── IV fluids with dextrose
│   ├── Monitor serial levels
│   └── Consider alkalinization
│
├── MODERATE (300-600 mg/L)
│   ├── Activated charcoal
│   ├── IV fluids with dextrose
│   ├── URINARY ALKALINIZATION
│   │   ├── NaHCO3 1-2 mmol/kg bolus
│   │   ├── Infusion 150 mmol in 1L D5W
│   │   ├── Target urine pH greater than 7.5
│   │   └── Maintain K+ greater than 4.0 mmol/L
│   ├── Serial levels every 2-4 hours
│   └── Monitor for deterioration
│
└── SEVERE (greater than 600 mg/L or any EXTRIP criteria)
    ├── Activated charcoal (if safe)
    ├── Aggressive resuscitation
    ├── Urinary alkalinization
    ├── HEMODIALYSIS
    │   ├── Level greater than 100 mg/dL (7.2 mmol/L)
    │   ├── Altered mental status
    │   ├── Pulmonary edema
    │   ├── AKI
    │   └── Clinical deterioration
    ├── AVOID INTUBATION if possible
    │   └── If required: High MV, emergent dialysis
    └── Repeat dialysis if rebound

Post-Treatment Monitoring
├── Serial levels until below 200 mg/L and declining
├── Clinical improvement
└── Watch for delayed absorption (enteric-coated)

---

Specific Scenarios

Enteric-Coated Aspirin Ingestion

Enteric-coated aspirin presents unique challenges. [53,57]

Key differences:

• Absorption delayed by 4-12 hours (may extend to 24-48 hours)
• Peak levels occur much later
• Tablets may form bezoar in stomach
• Standard decontamination window extended

Management modifications:

• Activated charcoal may be effective beyond 2-hour window
• Multi-dose activated charcoal indicated
• Serial levels for at least 24 hours
• Consider whole bowel irrigation
• CT abdomen if levels continue to rise (bezoar formation)
• Lower threshold for dialysis

Topical Salicylate Toxicity

Significant systemic absorption can occur from topical salicylate products. [58]

Products implicated:

• Methyl salicylate (oil of wintergreen) - extremely concentrated
• Salicylic acid preparations (keratolytics, acne treatments)
• Topical analgesic creams/balms

Risk factors:

• Damaged or inflamed skin
• Large surface area application
• Occlusive dressings
• Chronic/repeated application

Clinical features:

• Same as oral ingestion
• Often delayed presentation
• May not be recognized as salicylate toxicity

Management:

• Remove topical source
• Skin decontamination
• Standard treatment as for oral ingestion

Pediatric Considerations

Children may present with different features. [59,60]

Differences from adults:

• Metabolic acidosis may predominate (less respiratory compensation)
• Hypoglycemia more common
• Dehydration develops rapidly
• Hyperthermia more pronounced
• Seizures more common

Management modifications:

• Weight-based activated charcoal (1 g/kg)
• Careful fluid management
• Lower threshold for dextrose supplementation
• Age-appropriate dialysis catheter

Pregnancy

Salicylate overdose in pregnancy is complex. [61]

Fetal considerations:

• Salicylates cross the placenta freely
• Fetal levels may equal or exceed maternal levels
• Fetal acidemia increases CNS penetration
• Associated with premature closure of ductus arteriosus, IUGR

Management:

• Standard maternal treatment
• Fetal monitoring
• Left lateral position
• Low threshold for dialysis (also helps fetus)
• Multidisciplinary involvement (toxicology, obstetrics, neonatology)

---

Prognosis and Outcomes

Mortality

Overall mortality: [28,29,62]

• Acute overdose: 1-5% with appropriate treatment
• Chronic toxicity: 15-25% (often unrecognized, delayed treatment)
• Progressed to requiring dialysis: 5-10%
• Cardiac arrest from respiratory failure/acidosis: Nearly 100% if not immediately corrected

Predictors of Poor Outcome

Clinical features associated with mortality: [28,29,62,63]

• Altered level of consciousness on presentation
• Age greater than 70 years
• Delayed presentation (greater than 24 hours)
• Chronic toxicity (vs. acute)
• Hyperthermia greater than 40C
• Pulmonary edema
• Seizures
• pH below 7.2 on presentation
• Cerebral edema

Laboratory markers of severity:

• Level greater than 100 mg/dL (greater than 7.2 mmol/L) in acute overdose
• Profound metabolic acidosis
• Rising creatinine
• Hypokalemia refractory to replacement

Long-Term Sequelae

Most survivors of salicylate poisoning recover completely. [62]

Potential sequelae:

• Sensorineural hearing loss (usually reversible)
• Tinnitus (usually resolves)
• Chronic kidney disease (if prolonged AKI)
• Neurological deficits (rare, if cerebral edema occurred)

Follow-up recommendations:

• Audiology if persistent tinnitus/hearing loss
• Renal function if AKI occurred
• Psychiatric evaluation if intentional overdose
• Medication review to prevent future toxicity

---

Formulary

Quick Reference: Salicylate Toxicity Treatment

Target Parameters

Dialysis Parameters

---

Australian and New Zealand Context

Poison Information Services

Australia:

• Poisons Information Centre: 13 11 26 (24 hours)
• State Toxicology Services for ICU consultation

New Zealand:

• National Poisons Centre: 0800 POISON (0800 764 766)

Dialysis Access

• All major teaching hospitals have intermittent hemodialysis capability
• CRRT available in ICU settings
• Some regional centres may require retrieval to tertiary centre
• Telehealth consultation with toxicologists available nationally

Common Salicylate Products

Prescription:

• Aspirin 100 mg, 300 mg tablets
• Aspirin/dipyridamole (Asasantin)
• Compound analgesics containing aspirin

Over-the-counter:

• Aspirin (various brands)
• Disprin, Aspro
• Cold and flu preparations (some contain aspirin)

Topical:

• Dencorub, Deep Heat (methyl salicylate)
• Salicylic acid preparations (wart treatments, acne products)

---

Key Clinical Pearls

Ten Key Teaching Points

1. Mixed acid-base disturbance is diagnostic: Primary respiratory alkalosis with superimposed HAGMA - look for low PaCO2 with low HCO3

2. Chronic toxicity is deadlier than acute: Mortality 15-25% vs 1-5%; occurs at lower levels in elderly

3. Never trust the Done nomogram: Obsolete and unreliable; treat the patient not the number

4. Potassium must be replete for alkalinization to work: Hypokalemia causes renal H+ excretion, preventing urine alkalinization

5. Intubation can kill: Pre-intubation apnea allows CO2 accumulation, acidemia, and rapid CNS salicylate penetration

6. If you must intubate: Match pre-intubation minute ventilation, arrange emergent dialysis, use highest safe respiratory rate

7. Give dextrose to all altered patients: Neuroglycopenia occurs despite normal serum glucose

8. EXTRIP criteria for dialysis: Level greater than 100 mg/dL (7.2 mmol/L), altered mental status, AKI, pulmonary edema, deterioration

9. Watch for rebound after dialysis: Tissue redistribution causes levels to rise 20-30% after initial dialysis

10. Enteric-coated aspirin is different: Delayed absorption for 24-48 hours; extended monitoring and MDAC needed

Common Examination Questions

"Describe the acid-base abnormality in salicylate poisoning."

• Primary respiratory alkalosis (direct medullary stimulation causing hyperventilation)
• Superimposed high anion gap metabolic acidosis (lactate, ketoacids, salicylate)
• Early: Respiratory alkalosis predominates
• Late: Metabolic acidosis predominates (poor prognosis)

"What are the indications for dialysis?"

• EXTRIP criteria: Level greater than 100 mg/dL (greater than 7.2 mmol/L), altered mental status, pulmonary edema, AKI, deterioration despite therapy

"Why is intubation dangerous?"

• Compensatory hyperventilation maintains low PaCO2 and systemic alkalemia
• Apnea during intubation causes rapid CO2 rise
• Acidemia shifts equilibrium to unionized salicylic acid
• Unionized form crosses BBB rapidly
• Can cause cardiac arrest within minutes

---

Nursing Considerations

Key Nursing Priorities

1. Respiratory monitoring: Continuous SpO2, respiratory rate, work of breathing; alert physician to tiring patient

2. Neurological assessment: GCS every 1-2 hours; early detection of deterioration

3. Fluid balance: Strict I/O charting; monitor for overload (pulmonary edema)

4. Urine pH monitoring: Hourly dipstick; target greater than 7.5; alert if unable to achieve

5. Electrolyte awareness: Potassium needs frequent monitoring; replace aggressively

6. Temperature monitoring: Hyperthermia common; external cooling may be needed

7. Medication administration: Ensure bicarbonate infusion running correctly; potassium added

8. Safety: Confusion and agitation common; fall precautions; 1:1 supervision if needed

Red Flags Requiring Immediate Physician Notification

• Decreasing level of consciousness
• Respiratory fatigue or tachypnea greater than 40/min
• New seizure activity
• Hypotension (SBP below 90 mmHg)
• Urine pH persistently below 7.0 despite therapy
• Temperature greater than 40C
• Oxygen requirement increasing

---

Pharmacist Pearls

Drug Interactions and Considerations

Medications affecting salicylate toxicity:

• Carbonic anhydrase inhibitors (acetazolamide): May worsen CNS penetration by causing systemic acidosis
• Antacids: Alkaline urine from antacid use may actually aid elimination
• Warfarin: Aspirin displaces warfarin from albumin, increasing anticoagulant effect

Medications to avoid:

• Probenecid: Decreases renal salicylate excretion
• Further NSAIDs: Additive renal toxicity

Bicarbonate compatibility:

• Do not mix with calcium-containing solutions (precipitation)
• Separate from catecholamine infusions
• Compatible with potassium chloride

TGA/PBS Considerations

• Aspirin is available OTC without restriction
• Topical methyl salicylate products available OTC
• No specific reversal agent available
• Bicarbonate, activated charcoal readily available

---

SAQ Practice Questions

SAQ 1: Pathophysiology and Acid-Base

A 52-year-old woman is brought to the emergency department after ingesting an unknown quantity of aspirin tablets 4 hours ago. Her ABG shows: pH 7.48, PaCO2 22 mmHg, HCO3 16 mmol/L, lactate 4.2 mmol/L. Salicylate level is 520 mg/L.

a) Describe the acid-base disturbance and explain its pathophysiology. (50%)

Model Answer:

This patient has a mixed respiratory alkalosis with high anion gap metabolic acidosis (HAGMA).

Components:

• Primary respiratory alkalosis: pH 7.48, PaCO2 22 mmHg

  • Caused by direct stimulation of medullary respiratory centre by salicylate [5,6]
  • Results in hyperventilation

• Superimposed HAGMA:

  • Expected HCO3 for chronic respiratory alkalosis = 24 - (40-22)/5 = 20.4 mmol/L
  • Actual HCO3 = 16 mmol/L (lower than expected)
  • Anion gap = Na - (Cl + HCO3) = elevated (calculate with electrolytes)
  • Elevated lactate (4.2 mmol/L) confirms metabolic component

Pathophysiology of HAGMA:

• Uncoupling of oxidative phosphorylation: Salicylate acts as a protonophore, dissipating the proton gradient across inner mitochondrial membrane, producing heat instead of ATP [3,4]
• Anaerobic metabolism: Reduced ATP production shifts cells to glycolysis with lactate accumulation [20]
• Ketogenesis: Lipolysis and beta-oxidation produce ketoacids [37]
• Salicylate anion: Contributes directly to anion gap (3-5 mmol/L) [19]

Clinical significance:

• Early/moderate poisoning: Respiratory alkalosis predominates (as in this case)
• Late/severe poisoning: Metabolic acidosis predominates (indicates decompensation)
• Maintaining systemic alkalemia is protective (reduces CNS penetration)

b) Outline your management of this patient, including targets for therapy. (50%)

Model Answer:

Immediate management:

1. Resuscitation:

   • IV access, continuous monitoring
   • Do NOT sedate or intubate unless absolutely necessary (risk of losing compensatory hyperventilation) [17,18]
   • IV fluids with dextrose (D5W or D10W) - correct dehydration, maintain glucose greater than 5 mmol/L [11]

2. Decontamination:

   • Activated charcoal 50 g (1 g/kg) if safe airway [14,15]
   • Consider MDAC if enteric-coated aspirin suspected

3. Urinary alkalinization: [12,13,23]

   • Bolus: NaHCO3 1-2 mmol/kg IV
   • Infusion: 150 mmol NaHCO3 in 1L D5W at 150-250 mL/h
   • Targets:
     • Urine pH: greater than 7.5 (ideally 8.0)
     • Blood pH: 7.45-7.55
     • Serum K+: greater than 4.0 mmol/L (essential for effective alkalinization) [24,25]
     • Urine output: greater than 2-3 mL/kg/h

4. Potassium replacement:

   • Add 20-40 mmol KCl per liter of bicarbonate solution
   • Monitor K+ every 2-4 hours
   • Replace aggressively

5. Monitoring:

   • Serial salicylate levels every 2-4 hours
   • ABG every 4 hours
   • Hourly urine pH
   • Continuous cardiac monitoring

6. Hemodialysis preparation: [16]

   • This patient's level (520 mg/L) is moderate but approaching severe
   • Indications for dialysis (EXTRIP criteria):
     • Level greater than 100 mg/dL (greater than 1000 mg/L)
     • Altered mental status
     • Pulmonary edema
     • AKI
     • Deterioration despite therapy
   • Currently not meeting criteria but prepare for escalation

7. Investigations:

   • Check paracetamol level (co-ingestion)
   • Renal function, electrolytes
   • Chest X-ray
   • Consider psychiatry referral when stable

---

SAQ 2: Hemodialysis Decision-Making

A 72-year-old man with osteoarthritis has been confused for 3 days. His family reports he has been taking "extra" aspirin for back pain. On examination he is febrile (38.8C), tachypnoeic (RR 32/min), and disoriented. ABG: pH 7.28, PaCO2 18 mmHg, HCO3 8 mmol/L. Salicylate level is 450 mg/L. Creatinine 210 umol/L.

a) This patient has chronic salicylate toxicity. Explain why this carries a worse prognosis than acute toxicity. (30%)

Model Answer:

Chronic salicylate toxicity carries mortality of 15-25% compared to 1-5% for acute toxicity. [28,29,30]

Reasons for worse prognosis:

1. Delayed diagnosis: [28,29]

   • Symptoms develop insidiously over days
   • Confusion in elderly often attributed to other causes (sepsis, dementia, stroke)
   • Diagnosis frequently delayed greater than 24-48 hours

2. Lower levels produce severe toxicity: [30]

   • Chronic exposure allows tissue accumulation
   • Protein binding sites saturated at lower total levels
   • Higher free salicylate fraction

3. Elderly vulnerability: [48]

   • Reduced renal function (decreased clearance)
   • Lower albumin (higher free fraction)
   • Cognitive impairment (continued dosing despite symptoms)
   • Multiple comorbidities
   • Polypharmacy (drug interactions)

4. Greater tissue penetration: [7,34]

   • Prolonged exposure allows equilibration with tissues
   • CNS accumulation despite relatively lower serum levels

5. More pronounced metabolic derangement: [28,29]

   • This patient has pH 7.28 (severe acidosis)
   • Indicates respiratory centre decompensation
   • Loss of protective hyperventilation

b) Outline the indications for hemodialysis in this patient based on EXTRIP criteria. Does this patient require dialysis? (40%)

Model Answer:

EXTRIP 2015 Dialysis Indications (PMID 25272616): [16]

Extracorporeal treatment is recommended if ANY of the following:

This patient MEETS criteria for hemodialysis based on:

1. Altered mental status - primary indication
2. Acute kidney injury (Cr 210 umol/L) - will impair drug clearance and alkalinization efficacy
3. Chronic toxicity in elderly - higher mortality at any given level
4. Severe metabolic acidosis (pH 7.28, HCO3 8) - indicates decompensation

Additional considerations:

• Loss of respiratory compensation suggested by pH 7.28 with PaCO2 18 (appropriate compensation would be pH closer to 7.35)
• Age greater than 70 is additional poor prognostic factor
• Alkalinization will be ineffective with creatinine 210

Conclusion: Immediate hemodialysis indicated

c) Describe how you would manage this patient's airway if intubation becomes necessary. (30%)

Model Answer:

The principle: AVOID INTUBATION IF POSSIBLE [17,18,26,51]

Dangers of intubation:

• Pre-intubation apnea causes immediate CO2 retention
• PaCO2 rises from 18 to 40+ mmHg within seconds
• Resulting acidemia shifts equilibrium to unionized salicylic acid
• Unionized form rapidly crosses BBB
• Risk of cardiac arrest within minutes of intubation

If intubation is UNAVOIDABLE (e.g., coma, respiratory arrest, aspiration):

1. Pre-intubation:

   • Bag-valve-mask ventilation at high rate (RR 30-35)
   • Pre-oxygenate to maximum
   • Call for dialysis NOW
   • Have vasopressors ready

2. Induction:

   • Ketamine 1-2 mg/kg (maintains respiratory drive if patient arousing)
   • Avoid propofol or thiopentone boluses (apnea, cardiovascular depression)
   • Rocuronium 1.2 mg/kg for rapid paralysis
   • Minimize apnea time

3. Post-intubation ventilation:

   • Match pre-intubation minute ventilation
   • Target PaCO2 15-20 mmHg (same as pre-intubation)
   • Settings: RR 25-30, TV 6-8 mL/kg
   • Avoid hypoventilation at all costs
   • Target pH 7.45-7.55

4. Emergent hemodialysis:

   • Do not delay
   • Patient now at extreme risk
   • IHD preferred for rapid clearance

5. Post-intubation monitoring:

   • ABG immediately post-intubation
   • Repeat at 15 minutes
   • Adjust ventilation to maintain alkalemia

---

Viva Scenarios

Viva 1: Approach to Salicylate Overdose

Examiner: A 25-year-old woman is brought in by ambulance after ingesting 50 aspirin tablets (325 mg each) 2 hours ago. She is alert and vomiting. Describe your approach.

Candidate Response Structure:

Initial assessment: "I would approach this as a potentially life-threatening overdose requiring urgent assessment and management."

Primary survey:

• Airway: Currently intact (alert)
• Breathing: Assess respiratory rate and pattern - expect tachypnea if absorption has begun
• Circulation: IV access, fluids, continuous monitoring
• Disability: GCS, glucose

Ingested dose calculation: "50 tablets x 325 mg = 16.25 g. For a 60 kg person, this is approximately 270 mg/kg, which is a potentially severe ingestion (greater than 300 mg/kg is severe by some criteria)."

Immediate investigations:

• Salicylate level (baseline)
• ABG (look for respiratory alkalosis, metabolic acidosis)
• Electrolytes, renal function, glucose
• Paracetamol level (rule out co-ingestion)
• ECG

Examiner: Her initial salicylate level is 280 mg/L. ABG: pH 7.45, PaCO2 28, HCO3 20.

Candidate: "This shows early salicylate toxicity with primary respiratory alkalosis and minimal metabolic acidosis. The level of 280 mg/L is in the mild-moderate range, but levels will likely rise over the next 2-4 hours as absorption continues."

Management:

1. Decontamination: "Activated charcoal 50 g is indicated - she is alert and within 2 hours of ingestion. This can reduce absorption by up to 50%." [14,15]

2. IV fluids: "D5W to maintain glucose and hydration. Target urine output greater than 2 mL/kg/h."

3. Urinary alkalinization: "I would start sodium bicarbonate infusion - 150 mmol in 1L D5W with 20 mmol KCl at 150-250 mL/h. Target urine pH greater than 7.5." [12,13]

4. Serial levels: "Repeat salicylate level every 2 hours until declining, as absorption may continue."

Examiner: Four hours later, her level is now 580 mg/L. She is more tachypnoeic and becoming confused. ABG: pH 7.38, PaCO2 22, HCO3 12.

Candidate: "This is very concerning. She has deteriorated clinically with:

• Rising level (280 to 580 mg/L) indicating ongoing absorption
• Worsening acid-base (HCO3 dropped from 20 to 12)
• Altered mental status (confusion)
• Loss of respiratory alkalosis compensation (pH falling despite low PaCO2)"

"This patient now meets EXTRIP criteria for hemodialysis due to altered mental status and clinical deterioration despite therapy." [16]

Actions:

1. Urgent nephrology consultation for hemodialysis
2. Continue alkalinization
3. Consider MDAC if bowel sounds present
4. Avoid intubation if at all possible
5. ICU admission

Examiner: She needs intubation. What are the risks and how would you manage this?

Candidate: "Intubation in salicylate toxicity is extremely high risk because of the danger of losing compensatory hyperventilation." [17,18]

Risks:

• Pre-intubation apnea causes rapid CO2 accumulation
• Systemic acidemia develops within seconds
• This shifts salicylate to its unionized form
• Unionized salicylic acid crosses BBB readily
• Can cause cardiac arrest within minutes of intubation

If intubation unavoidable:

1. "Pre-oxygenate with BVM at high respiratory rate"
2. "Call for dialysis now - this is an emergency"
3. "Use rapid sequence induction with short apnoea time"
4. "Immediately ventilate at high minute ventilation - RR 25-30, TV 6-8 mL/kg"
5. "Target PaCO2 to match pre-intubation level (~20-25 mmHg)"
6. "ABG immediately post-intubation and every 15 minutes initially"
7. "Emergent hemodialysis"

---

Viva 2: Chronic Salicylate Toxicity

Examiner: An 82-year-old nursing home resident is transferred to your ICU with confusion and respiratory distress. She has a history of osteoarthritis and has been taking regular aspirin. Her nurse noticed she was "a bit off" for 3 days before becoming acutely unwell today. How would you approach this?

Candidate Response Structure:

Initial concerns: "This presentation raises strong concern for chronic salicylate toxicity, which carries significantly higher mortality (15-25%) than acute overdose. Key red flags include:

• Elderly patient
• Chronic aspirin use for arthritis
• Insidious symptom onset over days
• Confusion plus respiratory symptoms" [28,29,30]

Differential diagnosis: "While considering salicylate toxicity, I would also consider:

• Sepsis (common in elderly, causes confusion)
• Acute coronary syndrome
• Stroke
• Metabolic derangement
• Drug toxicity (other medications)"

"The key distinguishing feature of salicylism would be the acid-base pattern: respiratory alkalosis with metabolic acidosis."

Examiner: Her ABG shows pH 7.22, PaCO2 15, HCO3 6. Salicylate level 380 mg/L. What is your interpretation?

Candidate: "This is very concerning. Despite a relatively modest level of 380 mg/L, she has:

• Severe metabolic acidosis (HCO3 6)
• Profound respiratory compensation (PaCO2 15)
• Decompensating pH (7.22)

The relatively low level with severe clinical presentation is typical of chronic toxicity where tissue accumulation exceeds serum levels." [28,29,30]

Expected compensation calculation: "For HCO3 of 6, expected PaCO2 = 1.5 x 6 + 8 = 17. Her PaCO2 of 15 shows she is maximally compensating, possibly even hypercompensating, which suggests a superimposed respiratory alkalosis from salicylate."

Examiner: Does this patient need dialysis?

Candidate: "Yes, absolutely. This patient meets multiple EXTRIP criteria for hemodialysis:" [16]

Indications present:

1. "Altered mental status (confusion)"

• Primary indication

2. "Severe acidosis (pH 7.22)"

• Indicates decompensation

3. "Chronic toxicity in elderly"

• Higher risk

4. "Will likely have renal impairment" (should check creatinine)

"The level of 380 mg/L would not typically mandate dialysis in acute overdose, but in chronic toxicity with this clinical picture, dialysis is life-saving."

Dialysis parameters:

• "Intermittent hemodialysis preferred for rapid clearance"
• "Continue until level below 200 mg/L and clinical improvement"
• "Watch for rebound - repeat level 2-4 hours post-dialysis"
• "May need repeat sessions" [35,36]

Examiner: Her nursing home reports she was also taking ibuprofen "when needed." Does this affect your management?

Candidate: "NSAID co-ingestion has several important implications:

1. Additive renal toxicity: Both aspirin and ibuprofen inhibit prostaglandins needed for renal blood flow; higher risk of AKI

2. Decreased salicylate clearance: Ibuprofen may compete for renal excretion pathways

3. GI bleeding risk: Both agents inhibit protective prostaglandins; check hemoglobin and stool occult blood

4. Albumin displacement: Both compete for albumin binding; may increase free salicylate fraction

Management implications:

• Check renal function urgently
• Lower threshold for dialysis
• GI prophylaxis
• Avoid further nephrotoxins"

Examiner: The patient survives. What follow-up would you recommend?

Candidate: "Post-discharge management should include:

1. Medication review: Identify all aspirin-containing products; consider alternatives for arthritis pain

2. Renal function monitoring: AKI may lead to chronic kidney disease

3. Audiology: If tinnitus or hearing loss persists

4. Nursing home education: Recognition of salicylate toxicity; safe prescribing practices

5. Family discussion: Ensure understanding of what happened; medication safety

6. Pharmacy involvement: Medication reconciliation; blister pack for compliance monitoring

7. Geriatric review: Cognitive assessment; polypharmacy review"

---

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