Salicylate, lithium and iron poisoning

• Three different toxins, one shared threat: oxidative phosphorylation and oxygen use. Salicylate stimulates breathing and uncouples mitochondria; lithium accumulates when the kidney cannot clear it; iron produces a corrosive gastroenteritis followed by a latent phase, then shock and liver failure.
• Salicylate classically produces a mixed picture of respiratory alkalosis plus high-anion-gap metabolic acidosis. Treatment is supportive care, urinary alkalinisation (bicarbonate) and, when severe, haemodialysis.
• Lithium has acute, acute-on-chronic and chronic patterns. Chronic poisoning causes neurotoxicity at modest levels, and nephrogenic diabetes insipidus is the common long-term renal complication. Severe poisoning is treated with haemodialysis using EXTRIP thresholds.
• Iron toxicity is predicted by the elemental dose (not toxic under 20 mg/kg; mild-moderate 20 to 60 mg/kg; severe over 60 mg/kg). Phases run from gastroenteritis to shock, liver failure and late bowel stricture. Severe cases get whole-bowel irrigation and intravenous desferrioxamine. ^[5]
• None of these has a specific antidote that fixes the basic problem: airway, breathing, circulation and early poison-centre contact come first, and dialysis is the definitive step for severe salicylate and lithium.

By the end of this page you should be able to:

1. Recognise the mixed acid-base disorder of salicylate poisoning and explain why each component occurs.
2. State the principles and doses of urinary alkalinisation and the indications for haemodialysis in salicylate poisoning.
3. Describe the three patterns of lithium poisoning and why symptoms can be delayed after an acute overdose.
4. Recognise nephrogenic diabetes insipidus from lithium and outline amiloride's role.
5. Apply the EXTRIP criteria and dialysis endpoints for lithium.
6. List the five phases of iron poisoning and their usual timing.
7. State the elemental iron thresholds and the indications and doses of desferrioxamine.
8. Interpret serum iron, abdominal radiograph and blood gas results in iron overdose.

Salicylates are found in aspirin and aspirin-containing compounds, bismuth subsalicylate, some liniments and muscle rubs (methyl salicylate), oil of wintergreen and certain keratolytic ointments. Topical absorption from large areas of skin, especially under occlusion, can cause systemic toxicity in children and adults.

The clinical picture is biphasic in time and mixed in physiology. Early on there is central stimulation with hyperventilation and respiratory alkalosis; later, uncoupling of oxidative phosphorylation and accumulation of organic acids produce a high-anion-gap metabolic acidosis. Acidosis matters because it drives salicylate into the brain and worsens toxicity.

Salicylate crosses into cells and interferes with oxidative phosphorylation, increasing oxygen consumption, generating lactic, keto- and salicylic acid, and producing heat. It also stimulates the medullary respiratory centre, giving the early hyperventilation. Several mechanisms disturb glucose metabolism, so hypoglycaemia (particularly in the central nervous system) can occur even when the blood glucose looks acceptable.

Acid-base changes classically occur in three stages, most easily seen in children but recognisable in adults:

• Phase 1: respiratory alkalosis from hyperventilation, with alkaline urine.
• Phase 2: paradoxical aciduria, with a urine pH below 6 despite blood alkalosis.
• Phase 3: metabolic acidosis with hypokalaemia, often with ongoing respiratory alkalosis.

The phases can overlap, and a patient with co-ingestion or respiratory depression may never show the early alkalosis.

History: formulation (immediate- or sustained-release aspirin), dose, time, co-ingestants, accidental or intentional. Symptoms may be minimal for several hours; severe toxicity can appear 6 to 12 hours after ingestion, later with enteric-coated preparations. ^[1]

Symptoms and signs: nausea and vomiting; tinnitus, vertigo and deafness; agitation, confusion, lethargy, seizures and coma; tachypnoea with deep respiration; tachycardia and diaphoresis; hyperthermia; gastrointestinal bleeding from gastritis. Non-cardiogenic pulmonary oedema occurs in severe cases. Severity generally tracks the acid-base status: respiratory alkalosis alone suggests mild toxicity, a near-normal pH (about 7.40 with combined alkalosis and acidosis behind it) moderate toxicity, and acidemia below 7.35 severe poisoning.

Severity correlates poorly with the serum salicylate level, and deterioration can occur even while the blood level falls, because salicylate redistributes into the central nervous system. ^[1]

• Serum salicylate concentration: at presentation, then repeated every 2 to 4 hours if symptomatic, or after sustained-release ingestion, until the level is falling. ^[1]
• Arterial (or venous) blood gas and pH: the acid-base picture guides severity and treatment.
• Urea, creatinine and electrolytes: renal function, sodium, potassium, glucose. Hypokalaemia is common and must be corrected.
• Glucose: beware hypoglycaemia.
• Abdominal radiograph: may show radiopaque tablets or concretions in large ingestions; not sensitive to dissolved tablets.

Rough blood-level benchmarks (adults; interpret clinically): 15 to 30 mg/dL is the therapeutic range, over 40 to 50 mg/dL indicates intoxication in most patients, and levels over 80 to 100 mg/dL are high enough that haemodialysis is often required. ^[6]

• Airway, breathing and circulation first. Hypovolaemia is common and often under-appreciated; give fluid to reach euvolaemia. Normal saline should be avoided once acidosis is a concern because it lowers pH; bicarbonate-containing fluids are preferred when pH is below 7.5. ^[6]
• In severe poisoning, hyperthermia and non-cardiogenic pulmonary oedema are life-threatening. Cooling and respiratory support are standard.
• Intubation is dangerous in mixed salicylism: hyperventilation is the patient's own compensation, and paralysis can collapse the pH. Avoid or delay if possible; give a 1 to 2 mEq per kg sodium bicarbonate load before intubation if it cannot be avoided, then ventilate vigorously to maximise minute ventilation until the acidosis is controlled. ^{[6] [1]}
• Glucose target: maintain mild to moderate hyperglycaemia (about 150 to 200 mg/dL, or around 8.3 to 11.1 mmol/L) in severe intoxication, because brain glucose is depleted before blood glucose is. ^[6]
• Repeated reassessment with serial neurology is the best reflection of tissue salicylate effect.

• Activated charcoal 1 g/kg, ideally within 1 hour of ingestion, when the airway is protected or the patient is cooperative. ^[1] Consider multi-dose charcoal for an ongoing rise in levels, and whole-bowel irrigation for an intubated patient with a large sustained-release ingestion.
• Beware aspiration risk with altered conscious level.

Urinary alkalinisation is the key non-dialysis method of enhancing elimination. It both traps salicylate in the urine and corrects the metabolic acidosis that drives the drug into the brain.

• Indications: a serum salicylate over 40 mg/dL (2.9 mmol/L), any symptomatic patient, or in chronic poisoning even when the level looks only modestly elevated. ^[6]
• Technique: 2 mmol per kg slow intravenous bolus of sodium bicarbonate, then an infusion at 1 mmol per kg per hour. ^[1] Monitor:
  • urine pH over 7.5; ^{[1] [6]}
  • serum pH around 7.5 to 7.55; ^[6]
  • serum potassium over 4.0 to 4.5 mEq/L (hypokalaemia prevents urinary alkalinisation). ^[6]
• Continue until salicylate falls below 40 mg/dL (2.9 mmol/L) and the patient is asymptomatic with a normal respiratory rate, then observe for 2 to 4 hours for rebound acidosis. ^{[6] [1]}
• Acetazolamide should not be used to alkalinise the urine: it can lower serum pH and displace salicylate from protein. ^[6]
• Urinary alkalinisation is ineffective where there is hypokalaemia, volume overload or renal failure. ^[1]

Haemodialysis is highly effective and should be considered early in severe or deteriorating poisoning, because it takes time to set up.

Indications combine concentration, renal function, clinical and acid-base factors:

• Serum salicylate over 100 mg/dL (7.2 mmol/L) for acute poisoning, or over 90 mg/dL (6.5 mmol/L) if renal function is impaired, or 80 mg/dL (5.8 mmol/L) with renal dysfunction despite supportive care (EXTRIP). ^{[2] [1]}
• Altered mental status (including suspected cerebral oedema, need for intubation). ^[2]
• Non-cardiogenic pulmonary oedema. ^[2]
• Systemic pH below 7.2 despite bicarbonate. ^[2]
• Standard therapy failing, including urinary alkalinisation that cannot be achieved (for example in renal failure or fluid overload). ^[2]
• Poison-centre practice also uses the treatment thresholds of over 7.2 mmol/L (100 mg/dL) or rising above 4.4 mmol/L (60 mg/dL) despite alkalinisation, plus severe features (coma, refractory acidosis or electrolyte upset, hyperthermia over 39 °C despite cooling, renal failure). ^[1]

Cessation: continue dialysis until clinical improvement is clear and the salicylate is below 1.4 mmol/L (19 mg/dL), or for at least 4 to 6 hours if levels are unavailable. ^[2] Recheck levels for rebound, because redistribution occurs.

Lithium is still a first-line mood stabiliser for bipolar disorder, with a narrow therapeutic index and wholly renal elimination. Poisoning presents in three patterns:

• Acute: a lithium-naïve patient takes an overdose.
• Acute on chronic: a patient on maintenance lithium takes an acute overdose on top of their body burden.
• Chronic: a patient on long-term lithium accumulates it because of rising dose, declining kidney function or a drug-drug interaction.

Chronic poisoning is the most dangerous clinically: brain lithium is already high while the blood level may look only modestly elevated, so toxicity can be severe at concentrations that fall inside or just above the therapeutic range.

Lithium is a 7 Da monovalent cation (similar to sodium), freely filtered and about 60 to 80% reabsorbed with sodium in the proximal tubule (with smaller fractions in the loop of Henle and collecting duct). Protein binding is zero and the volume of distribution is 0.7 to 0.9 L/kg. The usual half-life is 12 to 27 hours, but in older adults and chronic users it can reach 58 hours. Peak after immediate-release ingestion is 30 minutes to 2 hours (4 to 5 hours for modified-release preparations). Absorption can be prolonged by clumping of lithium carbonate. ^[3]

Conditions that increase proximal reabsorption - volume depletion, thiazide diuretics, NSAIDs and ACE inhibitors or ARBs - raise lithium levels predictably. Lithium is not bound by activated charcoal. ^[3]

The central nervous system is the organ most affected, especially in chronic poisoning:

• Mild: drowsiness, nausea, vomiting, tremor, hyperreflexia, agitation, muscle weakness, ataxia.
• Moderate: stupor, rigidity, hypertonia, hypotension.
• Severe: coma, convulsions, myoclonus, cardiopulmonary collapse.

Gastrointestinal symptoms characterise acute poisoning (they are prominent) but are usually absent in chronic poisoning, where neurotoxicity dominates. Cardiac effects include transient ST depression, bradycardia, sinus node dysfunction and inverted T waves. Acute kidney injury on presentation is common, particularly in chronic toxicity. ^[3]

A rare neurological aftermath is the syndrome of irreversible lithium-effectuated neurotoxicity (SILENT): persistent cerebellar and cognitive deficits even after lithium has been cleared, with no definitive treatment other than prevention. ^[3]

• Therapeutic steady-state concentration: 0.6 to 1.2 mEq/L (or mmol/L; the conversion is 1 to 1). ^[3]
• Mild toxicity: 1.5 to 2.5 mEq/L. ^[3]
• Moderate toxicity: 2.5 to 3.5 mEq/L. ^[3]
• Severe toxicity: over 3.5 mEq/L. ^[3]

These numbers are only a guide. Acute poisoning can produce very high levels with few symptoms because brain distribution lags by about 24 hours; chronic poisoning can be severe at 1.5 mEq/L or just above. Clinical picture and kidney function always override the number. Acute ingestions of more than 1 gram of elemental lithium are potentially serious (300 mg lithium carbonate contains 8 mEq, equivalent to 56.4 mg elemental lithium). ^[3]

Lithium is the commonest pharmacological cause of nephrogenic diabetes insipidus (NDI):

• Prevalence of impaired concentrating ability ranges from about 20 to 70% depending on definition and duration, and clinically significant polyuria (over 3 L per day) occurs in roughly 40% of long-term users. ^[4]
• Mechanism: lithium enters collecting-duct principal cells through the epithelial sodium channel (ENaC) and down-regulates aquaporin-2, making the kidney resistant to antidiuretic hormone despite high or normal vasopressin levels. ^[4]
• Diagnosis: a water-deprivation test followed by desmopressin (DDAVP) fails to raise the urine osmolality in NDI, whereas central diabetes insipidus responds to DDAVP. ^[4]
• Treatment: amiloride, which blocks ENaC and reduces lithium entry into principal cells, is the mechanistically targeted drug and improves concentrating ability in clinical studies. Thiazides and NSAIDs can reduce urine volume but increase lithium levels, so if used, lithium must be monitored closely. ^[4]
• NDI both causes polyuria and polydipsia and creates a constant vulnerability to dehydration. Any intercurrent illness (vomiting, diarrhoea, fever) can then produce volume depletion, rising lithium levels and acute kidney injury. Sick-day rules and hydration advice are therefore standard.
• Chronic exposure is also associated with tubulointerstitial nephropathy, microcysts visible on renal MRI, and, in a minority, progressive chronic kidney disease; episodes of acute toxicity are one of the strongest predictors of long-term renal decline. ^[4]

Drug interactions that precipitate chronic toxicity: thiazides raise steady-state lithium by 30 to 50%; NSAIDs and ACE inhibitors or ARBs reduce renal clearance via different mechanisms. ^[4]

• Stop lithium and any interacting drugs (thiazides, NSAIDs, ACE inhibitors or ARBs). ^[3]
• Volume resuscitation with intravenous isotonic saline is the foundation; lithium clearance depends on euvolaemia. ^[3]
• Activated charcoal is not useful (it does not bind lithium). If required, gastric lavage or whole-bowel irrigation with polyethylene glycol may be used, especially with modified-release preparations; there is no evidence that decontamination improves outcome. ^[3]
• Sodium polystyrene sulfonate has been suggested to enhance lithium elimination but its role is unproven. ^[3]
• Careful monitoring of lithium levels, renal function, electrolytes and cardiac rhythm. Clinical improvement often lags the fall in serum level because of delayed brain equilibration.

Lithium is one of the most effectively dialysed toxins (intermittent haemodialysis clearance roughly 100 mL per minute, versus 10 to 40 mL per minute endogenously). ^[3] EXTRIP defines the thresholds: ^[3]

• Recommended (level 1D) if any:
  • kidney function is impaired and the lithium concentration is over 4.0 mEq/L; or
  • decreased level of consciousness, seizures or life-threatening dysrhythmias, regardless of the concentration.
• Suggested (level 2D) if any:
  • concentration over 5.0 mEq/L;
  • significant confusion;
  • the expected time to reduce the concentration below 1.0 mEq/L with optimal treatment is over 36 hours.
• "Impaired kidney function" in this context means stage 3B to 5 chronic kidney disease (eGFR below 45 mL per minute per 1.73 m²), Kidney Disease Improving Global Outcomes stage 2 or 3 acute kidney injury, or, without a baseline, creatinine over 2 mg/dL (176 µmol/L) in adults (over 1.5 mg/dL or 132 µmol/L in older or low-muscle-mass patients). ^[3]
• Cessation when the level is below 1.0 mEq/L or clinical improvement is clear; if levels are unavailable, continue for at least 6 hours. After stopping, repeat levels over 12 hours to catch rebound, which is maximal at 6 to 12 hours and can reach 0.5 to 1.0 mEq/L; ongoing absorption (especially modified-release tablets) can cause a larger, symptomatic rebound. ^[3]
• Intermittent haemodialysis is the preferred modality; continuous renal replacement therapy is an acceptable alternative when haemodialysis is unavailable or the patient is haemodynamically unstable. Peritoneal dialysis gives poor clearance and is not recommended. Maximising blood and effluent flow during haemodialysis improves lithium removal. ^[3]
• For asymptomatic patients with massive ingestion, close monitoring and early liaison with a dialysis team are prudent even before criteria are met.

Iron supplements and prenatal multivitamins are the common sources; children's chewable multivitamins usually contain too little to cause serious toxicity. Iron is sold as different salts, so the elemental iron content matters:

• Ferrous sulfate: about 20% elemental iron. ^[5]
• Ferrous gluconate: about 12% elemental iron.
• Ferrous fumarate: about 33% elemental iron.

Tablets may be radiopaque on abdominal radiograph. Parenteral iron overdose is rarely significant.

Iron is directly corrosive to the gastrointestinal mucosa and, in excess, disrupts mitochondrial oxidative phosphorylation, catalyses free-radical formation and, once transferrin is saturated, combines with water to form iron hydroxide and release hydrogen ions, worsening the metabolic acidosis. Coagulopathy occurs early by interference with the clotting cascade and later from liver injury. ^[5]

Toxicity is determined by the elemental iron dose: ^[5]

• Up to 20 mg/kg: not toxic. ^[5]
• 20 to 60 mg/kg: mild to moderate toxicity. ^[5]
• Over 60 mg/kg: possible severe toxicity. ^[5]

The severity of phase 1 features usually mirrors overall severity, and late phases develop only after moderate or severe early features. ^[5] If no symptoms appear within 6 hours, serious toxicity is unlikely; shock and coma within 6 hours carry a mortality of roughly 10%. ^{[5] [4]}

Acute gastroenteritis with vomiting (often haematemesis), colicky abdominal pain and diarrhoea; lethargy, irritability, tachypnoea, tachycardia, hypotension, metabolic acidosis and coma in severe cases. Delayed presentation may already be in phase 2 or 3, when the gastroenteritis has settled and the patient can look deceptively well.

• Serum iron measured 3 to 4 hours after ingestion: toxicity is suggested above 350 mcg/dL (63 µmol/L). A level over 500 mcg/dL (89.5 µmol/L) signifies severe toxicity. ^[5]
• Abdominal radiograph: detects intact tablets or concretions but misses chewed or dissolved tablets, liquid preparations and the small amounts in multivitamins. ^[5]
• Blood gas and anion gap: metabolic acidosis supports severe toxicity.
• Total iron-binding capacity is unreliable and not recommended. ^[5] Diagnosis rests on correlating serum iron, acid-base status and clinical findings over time.
• Desferrioxamine challenge urine test is no longer recommended. ^[5]
• Poisoning should be considered in children with access to iron and unexplained metabolic acidosis or haemorrhagic gastroenteritis, in mixed ingestions, and in siblings and playmates of the index child. ^[5]

• Airway, breathing and circulation; hydration; treat shock.
• Whole-bowel irrigation with polyethylene glycol until no iron is visible on repeat radiograph: 1 to 2 L per hour in adults, or 25 to 40 mL per kg per hour in children, delivered via nasogastric tube if needed, with airway protection (intubation if necessary). Gastric lavage is usually unhelpful; activated charcoal does not bind iron and is used only for co-ingestants. ^[5]
• Hospitalise all patients with more than mild gastroenteritis. ^[5]
• Intravenous desferrioxamine for severe toxicity (metabolic acidosis, shock, severe gastroenteritis or serum iron over 500 mcg/dL, 89.5 µmol/L): infused at up to 15 mg per kg per hour, titrated until hypotension occurs, with concurrent intravenous hydration. Desferrioxamine and iron poisoning both lower blood pressure, so patients need close monitoring. ^[5]
• Haemodialysis, haemofiltration or exchange transfusion are adjuncts in selected severe cases. ^[5]
• Discharge or observe patients with minimal symptoms and no acidosis or high iron levels.

Salicylate poisoning in pregnancy is serious for both mother and fetus; alkalinisation and early haemodialysis follow the same criteria, with a low threshold for involving senior and obstetric input. Iron overdose in pregnancy is treated the same as in non-pregnant adults, including desferrioxamine when indicated. Lithium is teratogenic in the first trimester and acute toxicity in pregnancy is an emergency requiring standard maternal resuscitation and sodium chloride and, if indicated, dialysis.

Children are more vulnerable to tissue hypoxia and to salicylate and iron toxicity at lower doses. Paediatric iron ingestion often follows access to adult tablets or prenatal vitamins stored within reach. Salicylate chewable aspirin can mislead because small tablets still reach toxic doses. Desferrioxamine and whole-bowel irrigation doses are weight-based.

Older adults have reduced renal clearance and a higher brain-to-serum lithium ratio, so chronic toxicity presents earlier and more severely. Combine sick-day rules (hold ACE inhibitors, ARBs, NSAIDs and thiazides when volume depleted, maintain fluids) with 3 to 6 monthly lithium and renal monitoring. ^[4]

• Salicylate: the antidote is bicarbonate and fluid; haemodialysis may be unavailable, so early urinary alkalinisation plus good supportive care is the realistic mainstay. A salicylate assay may not be available; treat on clinical and acid-base grounds.
• Lithium: supportive care, isotonic saline and withdrawal of interacting drugs are universal first steps. Where haemodialysis is unavailable, continuous renal replacement or peritoneal dialysis is inferior but may be the only option; contact a poison centre for dosing guidance. Amiloride for NDI is cheap and worth stocking.
• Iron: whole-bowel irrigation can be done with nasogastric polyethylene glycol and serial radiographs; desferrioxamine is the key stocked antidote. Without it, aggressive supportive and dialytic supportive care and early referral are the options.
• Poison centres and toxicologists provide dosing guidance for all three; their 24-hour advice numbers should be known locally.

• Salicylate poisoning produces a mixed respiratory alkalosis and high-anion-gap metabolic acidosis; early phase 1 alkalosis, phase 2 paradoxical aciduria, phase 3 acidosis with hypokalaemia. ^[1]
• Treat salicylates with supportive care, urinary alkalinisation (2 mmol/kg bolus then 1 mmol/kg/h, urine pH over 7.5, potassium over 4.0-4.5 mEq/L) and haemodialysis for severe or criteria-based disease. ^{[1] [6] [2]}
• Haemodialysis criteria for salicylates include altered mental status, pulmonary oedema, pH under 7.2, levels over 100 mg/dL (7.2 mmol/L) or over 90 mg/dL with renal impairment, or failure of standard therapy. ^[2]
• Lithium patterns: acute, acute on chronic and chronic. Chronic poisoning causes neurotoxicity at levels near the therapeutic range because brain concentrations are higher than serum. ^[3]
• Lithium is not bound by charcoal; management is saline, stopping interacting drugs and dialysis for severe disease using EXTRIP thresholds. ^[3]
• Nephrogenic diabetes insipidus affects roughly 20 to 70% of long-term lithium users, with polyuria over 3 L/day in about 40%; amiloride is the targeted ENaC-blocking treatment, but thiazides and NSAIDs worsen lithium accumulation. ^[4]
• Iron toxicity depends on elemental dose: under 20 mg/kg non-toxic, 20 to 60 mg/kg mild to moderate, over 60 mg/kg severe. The five phases run from gastroenteritis to shock and liver failure, with a dangerous latent phase at 6 to 48 hours. ^[5]
• Serum iron 3 to 4 hours after ingestion: toxic above 350 mcg/dL (63 µmol/L), severe above 500 mcg/dL (89.5 µmol/L). TIBC is unreliable; abdominal radiograph may show tablets. ^[5]
• Desferrioxamine up to 15 mg/kg/h IV for severe iron poisoning, with whole-bowel irrigation (PEG 1 to 2 L/h adult or 25 to 40 mL/kg/h child) until no iron is visible; activated charcoal does not bind iron. ^[5]
• For all three toxins, airway, breathing, circulation and early poison-centre contact are non-negotiable first steps.

Emergency medicine: approach to the poisoned patient, acute kidney injury, metabolic acidosis, respiratory alkalosis, coma and seizures, non-cardiogenic pulmonary oedema. Nephrology: chronic kidney disease, diabetes insipidus, renal replacement therapy. Psychiatry: bipolar disorder, mood stabilisers. Paediatrics: accidental poisoning and ingestions. Dermatology: topical salicylate absorption, psoriasis and ichthyosis. Toxicology: toxidromes and antidotes.