Acid-Base Disorders

Last updated 19 August 2026.

Key points

Four primary disorders: metabolic acidosis, metabolic alkalosis, respiratory acidosis and respiratory alkalosis - defined by the pH, the PaCO₂ (respiratory component) and the bicarbonate (metabolic component).
Compensation is never complete: the pH does not return fully to normal by compensation alone. A normal pH with abnormal CO₂ and bicarbonate means a mixed disorder, not perfect compensation.
The anion gap: Na⁺ − (Cl⁻ + HCO₃⁻), normally 8-12 mmol/L. It divides metabolic acidosis into raised anion gap (added acid) and normal anion gap / hyperchloraemic (bicarbonate loss).
Correct the gap for albumin: add ~2.5 mmol/L to the anion gap for every 10 g/L the albumin is below 40. Albumin is the main unmeasured anion, so hypoalbuminaemia masks a raised gap.
Raised anion gap causes: lactate, ketones, urate (renal failure) and toxins - remember GOLDMARK or the classic MUDPILES.
Normal anion gap causes: diarrhoea, renal tubular acidosis, acetazolamide, ureteric diversion and large-volume 0.9% saline.
Renal tubular acidosis: type 1 (distal) - cannot acidify urine, urine pH >5.5, low K⁺, stones. Type 2 (proximal) - bicarbonate wasting, low K⁺. Type 4 - hypoaldosteronism, HIGH K⁺.
Metabolic alkalosis: use the urinary chloride: <20 mmol/L = chloride-responsive (vomiting, diuretics) and corrects with saline; >20 = chloride-resistant (hyperaldosteronism, Bartter, Gitelman).

Introduction

Normal arterial pH is tightly maintained between 7.35 and 7.45, despite the body producing large quantities of acid every day. This is achieved by three lines of defence acting over very different timescales, and understanding them makes the disorders far easier to reason about.¹

Chemical buffers - immediate (seconds). The bicarbonate-carbonic acid system is the most important extracellular buffer, alongside haemoglobin, phosphate and protein
Respiratory compensation - rapid (minutes to hours). Altering alveolar ventilation changes PaCO₂, and therefore carbonic acid
Renal compensation - slow (hours to days), but the most powerful. The kidney reabsorbs filtered bicarbonate in the proximal tubule and generates new bicarbonate in the distal nephron by excreting hydrogen ions as ammonium and titratable acid

The relationship is captured by the Henderson-Hasselbalch equation, in which pH depends on the ratio of bicarbonate to PaCO₂. This is why compensation works: a primary change in one component can be partly offset by a change in the other in the same direction, restoring the ratio even though both values are abnormal.

Compensation never fully corrects the pH

This single rule identifies most mixed disorders and is very commonly tested.

Compensation moves the pH towards normal but does not reach or cross it. If the pH is acidaemic, the primary disorder is an acidosis, whatever else is going on
A completely normal pH with a clearly abnormal PaCO₂ and bicarbonate indicates a MIXED disorder - two primary processes pulling in opposite directions - not exquisite compensation
Over-correction is impossible by compensation alone. If the pH has moved past normal in the opposite direction, there is a second primary disorder
Respiratory compensation is fast; renal compensation takes 2-5 days. So an acute respiratory acidosis will show little bicarbonate rise, whereas a chronic one shows a substantially raised bicarbonate - which is how you date the disorder

Acid-base nomogram plotting bicarbonate concentration against arterial pH with overlaid PaCO2 isopleths, showing labelled bands for acute and chronic respiratory acidosis and alkalosis and for metabolic acidosis and alkalosis. — An **acid-base nomogram**. Plotting the **pH against the bicarbonate**, with **PaCO₂ isopleths** overlaid, places the patient within a labelled band corresponding to a specific primary disorder and its expected degree of compensation. **Values falling outside any band indicate a mixed disorder** - the same conclusion reached arithmetically using the expected-compensation formulae.Huckfinne, public domain, via Wikimedia Commons

The four primary disorders and expected compensation

The primary acid-base disorders, their compensation and their expected values.
Disorder	Primary change	Compensation	Expected compensation
Metabolic acidosis	↓ HCO₃⁻	Hyperventilation → ↓ PaCO₂	Winter's formula: expected PaCO₂ (kPa) ≈ 0.16 × HCO₃⁻ + 1.1 (in mmHg: 1.5 × HCO₃⁻ + 8 ± 2). A higher CO₂ than expected means a coexisting respiratory acidosis; a lower one a coexisting respiratory alkalosis
Metabolic alkalosis	↑ HCO₃⁻	Hypoventilation → ↑ PaCO₂	PaCO₂ rises ~0.09 kPa (0.7 mmHg) per 1 mmol/L rise in HCO₃⁻. Compensation is limited by hypoxia, which eventually drives ventilation
Respiratory acidosis	↑ PaCO₂	Renal HCO₃⁻ retention	Acute: HCO₃⁻ rises ~1 mmol/L per 1.3 kPa (10 mmHg) rise in PaCO₂. Chronic (2-5 days): rises ~4 mmol/L per 1.3 kPa. The bicarbonate therefore dates the disorder
Respiratory alkalosis	↓ PaCO₂	Renal HCO₃⁻ excretion	Acute: HCO₃⁻ falls ~2 mmol/L per 1.3 kPa fall in PaCO₂. Chronic: falls ~5 mmol/L per 1.3 kPa

A practical example of why this matters: a patient with COPD and a PaCO₂ of 8 kPa who has a bicarbonate of 26 has an acute respiratory acidosis (the kidney has not had time to retain bicarbonate) and is decompensating now. The same PaCO₂ with a bicarbonate of 36 indicates chronic CO₂ retention with established renal compensation - a very different clinical situation and a very different urgency.

Metabolic acidosis and the anion gap

Metabolic acidosis arises either because acid has been added to the body or because bicarbonate has been lost. The anion gap distinguishes the two and is the single most useful calculation in acid-base medicine.

Calculating and correcting the anion gap

Anion gap = Na⁺ − (Cl⁻ + HCO₃⁻), normally 8-12 mmol/L. (Some laboratories include potassium: (Na⁺ + K⁺) − (Cl⁻ + HCO₃⁻), normal 12-16 - check which your lab reports.)

The 'gap' represents unmeasured anions - principally albumin, plus phosphate, sulphate and organic acids
A raised gap means an unmeasured acid has been added (lactate, ketones, toxins)
A normal gap means bicarbonate has been lost and replaced by chloride - hence the alternative name hyperchloraemic acidosis
Always correct for albumin: add ~2.5 mmol/L to the anion gap for every 10 g/L that albumin falls below 40 g/L. A critically ill patient with an albumin of 20 g/L has an anion gap approximately 5 mmol/L lower than it should be, so a 'normal' gap of 11 is really 16 - clearly raised. Missing this is a common error in exactly the patients most likely to have a lactic acidosis

Raised anion gap metabolic acidosis

The traditional mnemonic is MUDPILES; the more modern GOLDMARK reflects current practice better.

Causes of a raised anion gap metabolic acidosis (GOLDMARK).
Letter	Cause	Clinical notes
G	Glycols - ethylene glycol, propylene glycol	Antifreeze ingestion; raised osmolar gap, calcium oxalate crystals in urine, AKI
O	Oxoproline (5-oxoproline)	Chronic paracetamol use, especially in malnourished women
L	L-lactate	Type A - tissue hypoperfusion: sepsis, shock, ischaemia, hypoxia. Type B - without hypoperfusion: metformin, liver failure, malignancy, thiamine deficiency, alcohol
D	D-lactate	Short bowel syndrome with bacterial overgrowth; causes encephalopathy and is missed by standard lactate assays
M	Methanol	Raised osmolar gap; causes blindness through optic nerve injury
A	Aspirin (salicylates)	Classically a mixed picture: respiratory alkalosis (direct respiratory centre stimulation) plus raised anion gap metabolic acidosis
R	Renal failure	Accumulation of urate, sulphate and phosphate
K	Ketoacidosis	Diabetic, alcoholic, or starvation ketoacidosis

Normal anion gap (hyperchloraemic) metabolic acidosis

Diarrhoea - the commonest cause; loss of bicarbonate-rich intestinal fluid
Renal tubular acidosis - types 1, 2 and 4 (see below)
Acetazolamide - a carbonic anhydrase inhibitor causing bicarbonate wasting
Ureteric diversion - ileal conduit or ureterosigmoidostomy, where bowel mucosa absorbs chloride and secretes bicarbonate
Large-volume 0.9% sodium chloride infusion - a genuinely iatrogenic cause. 'Normal' saline has a chloride concentration of 154 mmol/L, well above plasma, and large volumes produce a dilutional hyperchloraemic acidosis. This is a principal argument for balanced crystalloids such as Hartmann's or Plasma-Lyte in resuscitation
Pancreatic or biliary fistulae
Addison's disease and early renal failure
Ammonium chloride and parenteral nutrition

The renal tubular acidoses

The renal tubular acidoses are a group of disorders in which the kidney fails to acidify the urine or to reabsorb bicarbonate normally, producing a normal anion gap metabolic acidosis with normal or near-normal GFR. They are heavily examined because the pattern of potassium and urine pH distinguishes them cleanly.

The renal tubular acidoses.
Feature	Type 1 (distal)	Type 2 (proximal)	Type 4 (hyperkalaemic)
Defect	Failure to excrete H⁺ in the distal tubule	Failure to reabsorb HCO₃⁻ in the proximal tubule	Aldosterone deficiency or resistance (hyporeninaemic hypoaldosteronism)
Serum potassium	LOW	LOW	HIGH - the key discriminator
Urine pH	Always > 5.5 - cannot acidify urine even when systemically acidotic	Variable: >5.5 while bicarbonate is being wasted, but <5.5 once serum bicarbonate falls below the reabsorptive threshold	Usually < 5.5
Serum bicarbonate	Can be very low (often <10)	Moderately low (12-20), stabilises at the new threshold	Mildly low (>17)
Causes	Autoimmune - Sjögren syndrome, SLE, rheumatoid arthritis; hypercalciuria; drugs (amphotericin B, lithium); genetic	Fanconi syndrome (with glycosuria, aminoaciduria, phosphaturia); myeloma; Wilson disease; acetazolamide; tenofovir	Diabetic nephropathy (classic); drugs - ACE inhibitors, ARBs, spironolactone, NSAIDs, trimethoprim, heparin, calcineurin inhibitors; Addison's disease; obstructive uropathy
Complications	Nephrocalcinosis and renal stones (calcium phosphate, due to alkaline urine and hypocitraturia); rickets/osteomalacia; growth failure	Osteomalacia and rickets; stones are uncommon	Hyperkalaemia and its cardiac consequences
Treatment	Oral bicarbonate or potassium citrate	Large doses of bicarbonate plus potassium; thiazides may help	Fludrocortisone; stop culprit drugs; dietary potassium restriction; loop diuretic

Note that type 3 RTA is a rare hybrid with features of both types 1 and 2 and is not usually required knowledge. A useful shortcut for exams: the RTA with a high potassium is type 4, and the RTA that causes stones is type 1.

Metabolic alkalosis

Metabolic alkalosis requires both a generating process (loss of acid or gain of bicarbonate) and a maintaining process - normally the kidney would simply excrete excess bicarbonate, so alkalosis persists only if something prevents this. The maintaining factor is usually volume depletion, chloride depletion, hypokalaemia or mineralocorticoid excess, and identifying it is what directs treatment.

Use the urinary chloride to classify metabolic alkalosis

Urinary chloride is more reliable than urinary sodium here, because bicarbonate excretion obligates sodium loss and can make urinary sodium misleadingly high even in volume depletion.

Urinary chloride < 20 mmol/L - 'chloride-responsive': vomiting or nasogastric aspiration (the classic hypokalaemic hypochloraemic metabolic alkalosis of pyloric stenosis), diuretics after they have worn off, post-hypercapnia, laxative abuse, cystic fibrosis. These respond to 0.9% sodium chloride and potassium replacement
Urinary chloride > 20 mmol/L - 'chloride-resistant': primary hyperaldosteronism (Conn syndrome), Cushing syndrome, liquorice excess, Bartter and Gitelman syndromes, severe hypokalaemia, and current diuretic use. These do NOT respond to saline - treat the underlying cause, use potassium-sparing diuretics or spironolactone, and replace potassium and magnesium
A practical clue: chloride-responsive causes are usually associated with hypovolaemia, chloride-resistant causes with normal or expanded volume and often hypertension

Respiratory disorders

Respiratory acidosis (raised PaCO₂)

Reduced respiratory drive - opiates, benzodiazepines, anaesthetics, head injury, stroke, oxygen-induced hypercapnia in chronic type 2 respiratory failure
Neuromuscular disease - Guillain-Barré syndrome, myasthenia gravis, motor neurone disease, muscular dystrophy, cervical cord injury
Airway and lung disease - COPD (the commonest cause), severe asthma (a rising CO₂ in acute asthma is an ominous, life-threatening sign), pneumonia, ARDS, pulmonary oedema, obstructive sleep apnoea
Chest wall and pleural - kyphoscoliosis, obesity hypoventilation, flail chest, large pneumothorax or effusion
Inadequate mechanical ventilation

Respiratory alkalosis (low PaCO₂)

Anxiety and hyperventilation - and remember that this lowers ionised calcium, producing perioral paraesthesiae, carpopedal spasm and tetany with a normal total calcium
Hypoxia - pulmonary embolism, pneumonia, pulmonary oedema, high altitude, anaemia
Pain and fever
Sepsis - often an early feature, before lactic acidosis supervenes
Drugs - salicylates (early), doxapram, progesterone
Central causes - stroke, meningitis, encephalitis, head injury
Pregnancy - progesterone-driven hyperventilation causes a chronic compensated respiratory alkalosis, which is normal
Liver failure, and excessive mechanical ventilation

Management principles

The governing principle is to treat the underlying cause rather than the number. Acid-base abnormalities are almost always a manifestation of a disease process, and correcting the pH without addressing the cause achieves little and may cause harm.²

Metabolic acidosis - treat the cause: fluid resuscitation and antibiotics for sepsis, insulin and fluids for DKA, stop metformin in metformin-associated lactic acidosis, antidotes and dialysis for toxic alcohols, fluids and steroids in Addison's disease
Sodium bicarbonate - controversial and not routinely recommended in lactic acidosis or DKA. It may worsen intracellular acidosis (CO₂ crosses membranes more readily than bicarbonate), causes hypernatraemia, volume overload and hypokalaemia, and shifts the oxygen dissociation curve. It has a clearer role in severe hyperchloraemic acidosis, renal tubular acidosis, hyperkalaemia with acidosis, and tricyclic antidepressant overdose (where it is genuinely indicated for cardiotoxicity)
Renal replacement therapy - for severe refractory acidosis (pH <7.1), particularly with renal failure, fluid overload, hyperkalaemia or a dialysable toxin
Metabolic alkalosis - 0.9% saline and potassium if chloride-responsive; treat the endocrine cause and use spironolactone if chloride-resistant. Acetazolamide is occasionally used, and dilute hydrochloric acid via a central line very rarely
Respiratory acidosis - improve ventilation: treat the underlying lung disease, reverse opiates or benzodiazepines, use controlled oxygen therapy targeting 88-92% in those at risk of hypercapnia, and escalate to NIV or invasive ventilation where indicated
Respiratory alkalosis - treat the underlying cause; reassurance and rebreathing in anxiety-driven hyperventilation, but always exclude hypoxia, PE and sepsis before attributing hyperventilation to anxiety
Correct associated electrolytes - potassium, magnesium, calcium and phosphate are frequently deranged and interact with the acid-base state
Recheck the gas after intervention to confirm the direction of travel

Red flags

Act on these

pH below 7.2 - severe acidaemia; impairs myocardial contractility, causes vasodilatation and arrhythmia, and reduces the response to catecholamines. Escalate urgently
A raised lactate with hypotension - sepsis or shock until proven otherwise; start the sepsis six and resuscitate. Lactate clearance is a key marker of response
A rising PaCO₂ in acute severe asthma - a life-threatening sign indicating the patient is tiring; call for critical care immediately
A raised anion gap acidosis with a raised osmolar gap - suspect methanol or ethylene glycol poisoning; contact TOXBASE and treat urgently with fomepizole or ethanol and dialysis before blindness or renal failure develops
Mixed respiratory alkalosis and raised anion gap metabolic acidosis - the classic salicylate poisoning picture; check a salicylate level
A 'normal' anion gap in a hypoalbuminaemic critically ill patient - correct for albumin; a significant acidosis may be concealed
A normal pH with markedly abnormal CO₂ and bicarbonate - a mixed disorder; do not report it as compensated
A metabolic acidosis with hyperkalaemia and a urine pH below 5.5 - consider type 4 RTA, and review ACE inhibitors, spironolactone and trimethoprim
Persistent hypokalaemic metabolic alkalosis with hypertension - investigate for primary hyperaldosteronism
Large-volume 0.9% saline resuscitation - anticipate hyperchloraemic acidosis; consider a balanced crystalloid
Severe acidosis with renal failure or a dialysable toxin - involve renal and critical care early for haemodialysis
Attributing hyperventilation to anxiety without excluding pulmonary embolism, sepsis and hypoxia - a recurrent and dangerous error

Prognosis

Acid-base disturbances are almost never the primary determinant of outcome; the underlying disease is. Their prognostic value lies in what they reveal about the severity of that disease, and in this respect they are among the most useful markers available at the bedside. A lactate above 4 mmol/L in suspected sepsis, for example, identifies patients at substantially increased risk of death and mandates aggressive resuscitation - and serial lactate clearance over the first hours is one of the better predictors of survival.

Severe acidaemia is independently harmful once the pH falls below about 7.2. It depresses myocardial contractility, causes systemic vasodilatation with pulmonary vasoconstriction, predisposes to arrhythmia and blunts the response to catecholamines and inotropes - creating a self-reinforcing cycle of shock and worsening acidosis. Recognising and interrupting that cycle by restoring perfusion is far more effective than attempting to correct the pH directly with bicarbonate, which is why routine bicarbonate administration has largely fallen out of favour.

Prognosis by cause varies enormously. Diabetic ketoacidosis has an excellent outlook with prompt treatment, mortality now well under 1% in the UK. Metformin-associated lactic acidosis and toxic alcohol poisoning carry high mortality but are highly responsive to timely dialysis. Chronic compensated disorders - the raised bicarbonate of long-standing COPD, or the chronic respiratory alkalosis of pregnancy - are physiologically appropriate adaptations requiring no correction at all, and attempting to normalise them causes harm. The renal tubular acidoses generally have a good prognosis with alkali therapy, though type 1 carries a lifelong risk of nephrocalcinosis, stones and progressive renal impairment if untreated, and childhood-onset disease can cause growth failure and rickets. In every case, the practical message is the same: the acid-base result is a window onto the underlying process, and it is that process which should be treated.

References

Berend K, de Vries APJ, Gans ROB. Physiological approach to assessment of acid-base disturbances. New England Journal of Medicine. 2014. Available here
NICE CG174. Intravenous fluid therapy in adults in hospital. 2013, updated 2017. Available here
Joint British Diabetes Societies. The Management of Diabetic Ketoacidosis in Adults. Available here
NICE NG51. Sepsis: recognition, diagnosis and early management. 2016, updated 2024. Available here
TOXBASE (National Poisons Information Service). Methanol and ethylene glycol poisoning. Available here
British Thoracic Society. Guideline for oxygen use in healthcare and emergency settings. Available here
Huckfinne, public domain, via Wikimedia Commons. Available here

This article is written for revision and education. It is not clinical guidance and must not be used to make decisions about the care of a patient. Always check current NICE guidance and local protocols.