Salicylate poisoning acid-base: a classic mixed disorder
Salicylate hits the brain and the mitochondria, so two primary disorders appear together. Use the anion gap and Winters' expected PaCO₂ to recognise the mix.
Chapters (9)
Explain why salicylate toxicity produces an early respiratory alkalosis followed by a high anion gap metabolic acidosis, and recognise the mixed pattern on a blood gas.
The short version
- Salicylate stimulates the respiratory centre in the brain early, causing hyperventilation and a primary respiratory alkalosis.
- It uncouples oxidative phosphorylation, so lactate and ketoacids accumulate and produce a high anion gap metabolic acidosis.
- Salicylate itself is only a small part of the gap; the gap is mostly the body's own acids.
- The pH depends on the balance of the two disorders: often near normal or alkalaemic in adults, more acidaemic in children and in late or severe poisoning.
- A PaCO₂ below the Winters window with a high anion gap is the mixed pattern.
Salicylate poisoning acid-base: two separate hits
A young man is breathing fast and has ringing in his ears. His pH is 7.48, yet his bicarbonate is 16. He is alkalaemic and acidotic at the same time.
That is the salicylate poisoning acid-base picture. Salicylate acts at two different places, and each hit produces its own primary disorder.[1][3][4]
The tools: anion gap, Winters' formula and the delta ratio
Normal is about 12 mEq/L (K⁺ excluded).
Valid in metabolic acidosis; mm Hg.
About 1 to 2 suggests a pure high anion gap acidosis; above 2 suggests an additional metabolic alkalosis.
The anion gap and Winters' formula are the two tools that expose this mix.[5] The delta ratio thresholds are carried from the series lesson on the delta ratio (EP 04).
Hit one: the brain and respiratory alkalosis
Salicylate directly stimulates the respiratory centre in the brain. The patient hyperventilates, PaCO₂ falls, and a respiratory alkalosis results.[1][3][4]
This is a primary event, not compensation. It appears early, at lower doses.[2][3]
Hit two: the mitochondria and the high anion gap
Salicylate uncouples oxidative phosphorylation. The electron transport chain keeps running, but it no longer makes ATP efficiently, and the energy is lost as heat.[1][2]
Cells shift to anaerobic metabolism, so lactate rises. Fat breakdown also rises, and ketoacids appear. These unmeasured anions raise the gap: a high anion gap metabolic acidosis.[2][3]
Salicylate itself is only a small part of the gap. The gap is mostly the body's own acids.[3][4]
The order of events and what the pH does
First comes the respiratory alkalosis. Later the metabolic acidosis builds up.[2][3]
What the pH does depends on the balance of the two disorders.[2][4][6]
| Patient | Typical pattern |
|---|---|
| Adults | Usually a mixed picture; pH can sit near normal, or even alkalaemic |
| Children | Mostly a metabolic acidosis |
| Late or severe poisoning | The pH tends to tip toward acid as the metabolic acidosis builds |
The recognition trick: the Winters window
Calculate Winters' expected PaCO₂. If the measured PaCO₂ is lower than expected, a respiratory alkalosis sits on top of the metabolic acidosis.[5][6]
- Bicarbonate is 16
- Expected PaCO₂ = 1.5 × 16 + 8 = 32, give or take 2
- Measured PaCO₂ is 22
- 22 is far below the window: a second disorder
Treatment, briefly
- Acidaemia pushes salicylate into the brain, so acidaemia is avoided.[2][3]
- Sodium bicarbonate alkalinises the urine, with potassium replacement, which speeds salicylate excretion.[2][3][4]
- Intubation is dangerous, because losing the fast breathing makes the acidaemia worse. If it is unavoidable, the ventilator must keep the minute ventilation high.[2][3]
- Severe poisoning needs haemodialysis.[3][4]
Practice question
Original · USMLE styleA 19-year-old woman is brought to the emergency department 4 hours after ingesting an unknown number of tablets from a bottle in her bathroom. She has had repeated vomiting and reports ringing in her ears. Temperature is 37.9 °C (100.2 °F), pulse is 118/min, respirations are 30/min and deep, and blood pressure is 112/68 mm Hg. She is alert but anxious. Laboratory studies show:
| Serum Na⁺ | 140 mEq/L |
|---|---|
| Serum Cl⁻ | 104 mEq/L |
| Serum HCO₃⁻ | 14 mEq/L |
| Serum glucose | 92 mg/dL |
| Arterial pH (room air) | 7.47 |
| Arterial PCO₂ (room air) | 20 mm Hg |
Common questions
Why does salicylate poisoning cause respiratory alkalosis?
Salicylate directly stimulates the respiratory centre in the brain. The patient hyperventilates and PaCO₂ falls. It is a primary event, not compensation, and it appears early, at lower doses.
Why does salicylate cause a high anion gap metabolic acidosis?
It uncouples oxidative phosphorylation, so cells shift to anaerobic metabolism and lactate rises, and ketoacids appear. These unmeasured anions raise the gap. Salicylate itself is only a small part of the gap.
Can the pH be normal or alkalaemic in salicylate poisoning?
Yes. The pH depends on the balance of the respiratory alkalosis and the metabolic acidosis. Adults often have a mixed picture with a near-normal or alkalaemic pH, while children and late or severe poisoning tend toward acidaemia.
How do you spot the mixed disorder on a blood gas?
Calculate Winters' expected PaCO₂ (1.5 × HCO₃⁻ + 8 ± 2). A measured PaCO₂ below that window, with a high anion gap, means a respiratory alkalosis on top of the metabolic acidosis.
Transcript
Read the full narration, by chapter669 words
0:00Alkaemic and acidotic at the same time?
A young man is breathing fast, with ringing in his ears. His pH is 7.48, but his bicarbonate is 16. Alkalaemic, and acidotic, at the same time? That is salicylate poisoning, and today we learn why. The objective: explain the early respiratory alkalosis, then the high anion gap metabolic acidosis, and spot the mixed pattern on a blood gas.
0:27The tools: anion gap, Winters' formula, delta ratio
First, the tools we already have. The anion gap is sodium, minus chloride and bicarbonate together. Normal is about 12. In a metabolic acidosis, Winters' formula gives the expected PaCO2: 1.5 times bicarbonate, plus eight, give or take two. And the delta ratio compares how far the gap rose with how far bicarbonate fell.
0:53Two separate hits
Now, salicylate. Think of two separate hits, at two different places. Hit one: the brain. Salicylate directly stimulates the respiratory centre. The patient hyperventilates, PaCO2 falls, and we get a respiratory alkalosis. This is a primary event, not compensation, and it appears early, at lower doses.
1:16Hit two: the mitochondria and the high anion gap
Hit two: the mitochondria. Salicylate uncouples oxidative phosphorylation. The electron transport chain keeps running, but it no longer makes ATP efficiently, and the energy is lost as heat. Cells shift to anaerobic metabolism, so lactate rises. Fat breakdown also rises, and ketoacids appear. These unmeasured anions raise the gap, so this is a high anion gap metabolic acidosis. A detail worth knowing: salicylate itself is only a small part of the gap. The gap is mostly the body's own acids.
1:54The order of events and what the pH does
So the order matters. First comes the respiratory alkalosis. Later the metabolic acidosis builds up. What does the pH do? That depends on the balance of the two. Adults usually have a mixed picture, and the pH can sit near normal, or even alkaemic. Children mostly show a metabolic acidosis, and a late or severe poisoning also tips the pH toward acid.
2:22The recognition trick: the Winters window
Here is the recognition trick. Calculate Winters' expected PaCO2. If the measured PaCO2 is lower than expected, a respiratory alkalosis sits on top. Our patient: bicarbonate 16, so expected PaCO2 is 32, give or take two. His is 22. Far below the window. A second disorder.
2:45Treatment, briefly
Treatment, briefly. Acidaemia pushes salicylate into the brain, so we avoid it. We give sodium bicarbonate to alkalinise the urine, with potassium replacement, which speeds salicylate excretion. Intubation is dangerous, because losing the fast breathing makes the acidaemia worse. If it is unavoidable, the ventilator must keep the minute ventilation high. And severe poisoning needs haemodialysis.
3:13Practice question
Your turn. A 19-year-old woman is brought in after taking an unknown number of tablets 4 hours ago. She has vomiting, ringing in her ears, and a respiratory rate of 30. Sodium 140, chloride one oh four, bicarbonate 14. Arterial blood gas on room air: pH 7.47, PaCO2 20. Which best describes her acid-base status? A, respiratory alkalosis alone. B, high anion gap metabolic acidosis with appropriate compensation. C, high anion gap metabolic acidosis with a concomitant respiratory alkalosis. D, high anion gap metabolic acidosis with a concomitant metabolic alkalosis. E, normal anion gap metabolic acidosis with respiratory compensation. Pause here and decide. The gap is 140 minus one oh four plus 14, which is 22. E is out: the gap is high, not normal. A is out: an acute respiratory alkalosis alone does not lower bicarbonate to 14, and does not raise the gap to 22. B is out: appropriate compensation would give a PaCO2 near 29, and hers is 20. D is out: the gap rose by 10 and bicarbonate fell by 10, a delta ratio of one, so no extra metabolic alkalosis. So the answer is C: a high gap metabolic acidosis with a respiratory alkalosis on top, the classic salicylate pattern.
4:59High-yield recap and next lesson
Three things to keep. One: salicylate stimulates the respiratory centre early, causing respiratory alkalosis. Two: it uncouples oxidative phosphorylation, so lactate and ketoacids cause a high anion gap metabolic acidosis. Three: a PaCO2 below the Winters window, with a high gap, is the mixed pattern, and the pH may be near normal. Next up: lactic acidosis, type A versus type B.
Sources
Numbers in the text, e.g. [1], point here- Nickson C. Salicylate toxicity. Life in the Fast Lane (LITFL). litfl.com/salicylate-toxicity/
- Salicylates. WikEM. wikem.org/wiki/Salicylates
- Deranged Physiology. Salicylate toxicity (Chapter 5.1.9). derangedphysiology.com/main/required-reading/pharmacology-and-toxicology/Chapter%205.1.9/salicylate-toxicity
- Brandis K. Acid-Base Physiology, 8.06 Metabolic Acidosis due to Drugs and Toxins. med.libretexts.org/Bookshelves/Anatomy_and_Physiology/Book%3A_Acid-base_Physiology_(Brandis)/08%3A_Major_Types_of_Metabolic_Acidosis/8.06%3A_Metabolic_Acidosis_due_to_Drugs_and_Toxins
- Lewis JL III. Acid-Base Disorders. MSD Manual Professional Version. msdmanuals.com/professional/endocrine-and-metabolic-disorders/acid-base-regulation-and-disorders/acid-base-disorders
- Deranged Physiology. CICM 2013 Paper 1, Question 3.2 (salicylate case). derangedphysiology.com/main/cicm-fellowship-exam/past-papers/2013-paper-1-saqs/question-32
The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.
Image credits. Illustrations: Servier Medical Art (smart.servier.com), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/); adapted (recoloured, outlined, resized): brain, mitochondrion, lungs. All other diagrams are original; example lab values are illustrative.
Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-REN-016.
For exam study only, not medical advice. Read the medical disclaimer.
In this series
Playlist on YouTube- EP 01ABG interpretation, made simple5:35
- EP 02Anion gap explained: high vs normal gap metabolic acidosis5:25
- EP 03Winters' formula: the expected PaCO₂ in metabolic acidosis5:10
- EP 04Delta ratio: find the hidden second acid–base disorder5:09
- EP 05New bicarbonate: how the kidney excretes acid with ammonium5:23
- EP 06High anion gap metabolic acidosis causes, sorted by the anion5:54
- EP 07Osmolar gap: how toxic alcohols hide from the anion gap5:31
- EP 08Urine anion gap: telling diarrhea from RTA5:33
- EP 09Renal tubular acidosis: tell RTA types 1, 2 and 4 apart5:24
- EP 10Metabolic alkalosis: generation, maintenance and urine chloride5:30
- EP 11Vomiting metabolic alkalosis: why the urine turns acid5:36
- EP 12Bartter vs Gitelman: NKCC2, NCC and urine calcium5:21
- EP 13Respiratory acidosis compensation: acute vs chronic5:22
- EP 14Respiratory alkalosis compensation: acute vs chronic5:33
- EP 15Metabolic alkalosis compensation: the expected PaCO₂5:12
- EP 16Salicylate poisoning acid-base: a classic mixed disorder5:31
- EP 17Type A vs type B lactic acidosis: split it by mechanism5:33
- EP 18DKA anion gap explained: from high gap to hyperchloraemic acidosis5:42
- EP 19Acidosis and hyperkalemia: how pH shifts potassium5:43
- EP 20ABG interpretation in 6 steps: the acid-base algorithm5:32
- EP 21Acid-base practice cases: three ABG vignettes, one algorithm5:44