Acid-Base Disorders

Metabolic Acidosis

Metabolic acidosis is a primary reduction in serum bicarbonate, usually with a fall in arterial pH, and secondary alveolar hyperventilation. Normal arterial pH is 7.35–7.45, bicarbonate 22–26 mmol/L, and PaCO₂ 4.7–6.0 kPa or 35–45 mmHg. In examinations, the key tasks are to confirm appropriate respiratory compensation, classify by anion gap, identify occult toxins or renal tubular acidosis, and treat the underlying disorder rather than the pH alone.

Physiological compensation and diagnostic confirmation

Respiratory compensation begins within minutes via peripheral and central chemoreceptor stimulation and is maximal by approximately 12–24 hours. The expected PaCO₂ is estimated by Winter’s formula: expected PaCO₂ in mmHg = 1.5 × [HCO₃⁻] + 8 ± 2. A measured PaCO₂ above this range indicates superimposed respiratory acidosis; below it indicates respiratory alkalosis, such as sepsis, pregnancy, salicylate poisoning, or liver failure.

Calculation	Formula / threshold	Interpretation
Anion gap	Na+ − (Cl− + HCO3−); normal approximately 8–12 mmol/L	Separates high anion gap from normal anion gap acidosis
Albumin correction	Add 2.5 mmol/L to anion gap for each 10 g/L albumin below 40 g/L	Prevents missing high-gap acidosis in hypoalbuminaemia
Delta ratio	ΔAG / ΔHCO3− = (AG − 12)/(24 − HCO3−)	<0.4: normal-gap process; 0.4–1: mixed; 1–2: typical high-gap; >2: concomitant alkalosis or chronic hypercapnia

Classification by anion gap

High anion gap metabolic acidosis

High-gap acidosis reflects accumulation of unmeasured anions: lactate, ketones, uraemic organic acids, or exogenous toxins. A practical mnemonic is GOLD MARK: glycols, oxoproline, L-lactate, D-lactate, methanol, aspirin, renal failure, ketoacidosis.

• Lactic acidosis: lactate is normally <2 mmol/L; levels >4 mmol/L are clinically significant and, with hypotension, define severe shock physiology in many sepsis pathways. Type A results from tissue hypoxia; type B occurs with metformin, malignancy, hepatic failure, thiamine deficiency, beta-agonists, nucleoside reverse transcriptase inhibitors, or mitochondrial disease. Metformin-associated lactic acidosis is more likely with acute kidney injury; metformin should be withheld when eGFR is <30 mL/min/1.73 m² or during hypoxic/septic illness.
• Ketoacidosis: diabetic ketoacidosis typically has capillary glucose >11 mmol/L, ketonaemia ≥3 mmol/L, pH <7.30 or bicarbonate <15 mmol/L. Euglycaemic DKA is associated with pregnancy, starvation, and SGLT2 inhibitors. Alcoholic ketoacidosis often has normal or low glucose and a high β-hydroxybutyrate:acetoacetate ratio.
• Renal failure: reduced ammoniagenesis and retention of sulphate, phosphate, hippurate and other organic anions; acidosis becomes common when eGFR falls below approximately 30 mL/min/1.73 m².
• Toxins: methanol causes visual symptoms and formic acid accumulation; ethylene glycol causes calcium oxalate crystalluria, hypocalcaemia and renal failure; salicylates classically cause mixed respiratory alkalosis plus high-gap metabolic acidosis. An osmolar gap >10–20 mOsm/kg supports toxic alcohol ingestion but may be absent late.

Normal anion gap metabolic acidosis

Normal-gap, hyperchloraemic acidosis arises from bicarbonate loss or impaired renal acid excretion with chloride retention. Causes include diarrhoea, pancreatic/ileal fistulae, acetazolamide, ureterosigmoidostomy, early renal failure, and renal tubular acidosis.

Disorder	Core defect	Typical findings
Distal RTA type 1	Impaired distal H+ secretion	Urine pH persistently >5.5, hypokalaemia, nephrocalcinosis, calcium phosphate stones; associated with Sjögren’s, amphotericin B
Proximal RTA type 2	Reduced proximal bicarbonate reabsorption	Urine pH initially high then <5.5 once plasma bicarbonate falls; Fanconi syndrome, myeloma, tenofovir, ifosfamide
Type 4 RTA	Hypoaldosteronism or aldosterone resistance	Hyperkalaemia, mild acidosis; diabetes, ACE inhibitors, ARBs, spironolactone, trimethoprim, heparin

The urinary anion gap = urine Na⁺ + K⁺ − Cl⁻. A negative value suggests appropriate NH₄⁺ excretion, supporting gastrointestinal bicarbonate loss; a positive value suggests renal acidification failure. It is unreliable with volume depletion, very low urine sodium, or unmeasured urinary anions such as ketoacids.

Management principles

Treatment is directed at the cause: restore perfusion and source control in shock; insulin and fluids for ketoacidosis; renal replacement therapy for severe uraemia, refractory hyperkalaemia, pulmonary oedema, or toxin removal; and specific antidotes for toxic alcohols. Fomepizole inhibits alcohol dehydrogenase and is given as 15 mg/kg IV loading, then 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours; dosing is increased during haemodialysis.

Intravenous sodium bicarbonate is not routine in lactic acidosis or DKA, as it may increase CO₂ generation, reduce ionised calcium, worsen intracellular acidosis and cause sodium/volume overload. Consider it when pH is <7.1 with haemodynamic compromise, life-threatening hyperkalaemia, severe non-gap bicarbonate loss, or selected acute kidney injury. A common estimate of bicarbonate deficit is 0.5 × body weight kg × (target HCO₃⁻ − measured HCO₃⁻), targeting partial correction, often to 10–12 mmol/L or pH >7.20, rather than normalisation.

The BICAR-ICU trial studied critically ill patients with severe metabolic acidaemia, pH ≤7.20 and bicarbonate ≤20 mmol/L. Overall, bicarbonate did not significantly reduce the composite endpoint of death by day 28 or organ failure at day 7, but in the prespecified acute kidney injury subgroup it reduced mortality and need for renal replacement therapy. This underpins current cautious, targeted use rather than blanket correction of acidaemia.

Metabolic Alkalosis

Metabolic alkalosis is defined by a primary rise in plasma bicarbonate, typically HCO₃⁻ >28 mmol/L, with alkalemia if pH >7.45. Respiratory compensation is hypoventilation, limited by hypoxaemia: expected PaCO₂ ≈ 0.7 × [HCO₃⁻] + 20 ± 5 mmHg. A PaCO₂ substantially above this implies concomitant respiratory acidosis; substantially below implies respiratory alkalosis. Severe alkalemia, especially pH ≥7.55, is associated with arrhythmias, seizures, reduced cerebral blood flow, reduced ionised calcium, and increased mortality in ICU cohorts.

Pathophysiology: generation and maintenance

Metabolic alkalosis requires both generation of excess bicarbonate or hydrogen ion loss and maintenance by impaired renal bicarbonate excretion. The kidney normally excretes an alkali load efficiently; persistence therefore implies one or more of: extracellular fluid contraction, chloride depletion, potassium depletion, reduced GFR, mineralocorticoid excess, or ongoing alkali administration.

• Hydrogen ion loss: gastric loss from vomiting or nasogastric suction removes HCl, generating “new” bicarbonate. Urine may paradoxically contain bicarbonate early, but once chloride depleted, distal sodium reabsorption occurs with H⁺/K⁺ secretion.
• Renal H⁺ loss: loop and thiazide diuretics increase distal sodium delivery and activate RAAS, enhancing collecting duct H⁺ secretion via α-intercalated cells.
• Mineralocorticoid excess: aldosterone or aldosterone-like states increase ENaC-mediated sodium reabsorption, generating a lumen-negative potential that drives K⁺ and H⁺ secretion.
• Hypokalaemia: shifts H⁺ intracellularly, stimulates ammoniagenesis, increases proximal bicarbonate reabsorption, and promotes H⁺ secretion. It is both cause and consequence.
• Alkali load: calcium carbonate, sodium bicarbonate, citrate from massive transfusion, or milk-alkali syndrome, especially with reduced GFR.
• Post-hypercapnic alkalosis: after rapid correction of chronic hypercapnia, renal-retained bicarbonate persists while PaCO₂ falls.

Classification: urine chloride is the key bedside discriminator

Category	Urine chloride	Typical causes	Clinical clues
Chloride-responsive	<10–20 mmol/L	Vomiting, nasogastric suction, prior diuretic use, post-hypercapnic state, chloride-depletion alkalosis	Volume contraction, low urinary chloride despite alkalosis; responds to NaCl and KCl
Chloride-resistant	>20 mmol/L	Current diuretics, primary hyperaldosteronism, Cushing syndrome, apparent mineralocorticoid excess, Liddle syndrome, Bartter/Gitelman syndromes, severe hypokalaemia	Hypertension suggests mineralocorticoid excess; normotension suggests diuretics or tubulopathy

Interpret urine chloride with caution after recent diuretic exposure, when it may be high transiently. Urine potassium helps assess renal K⁺ wasting: urine K⁺ >20 mmol/L or transtubular K⁺ gradient >4 during hypokalaemia supports renal loss, although TTKG is less reliable in non-steady states.

Diagnostic approach

1. Confirm primary disorder: ABG/VBG pH, HCO₃⁻, PaCO₂; assess compensation using the formula above.
2. Assess severity: pH 7.45–7.54 mild/moderate; ≥7.55 severe; ≥7.60 urgent, particularly with arrhythmia, hypoventilation, seizures, or low ionised calcium.
3. Measure electrolytes: K⁺, Mg²⁺, Cl⁻, creatinine. Hypomagnesaemia perpetuates renal potassium wasting.
4. Use urine chloride: differentiates saline-responsive from saline-resistant causes.
5. If hypertensive with urine Cl⁻ >20 mmol/L: check plasma renin and aldosterone. Primary aldosteronism screening uses aldosterone-renin ratio; many guidelines consider ARR positive when aldosterone is ≥10–15 ng/dL with suppressed renin, though assay-specific thresholds apply.

Management

Treatment targets the maintaining mechanism rather than the bicarbonate number alone. Stop offending agents: diuretics, alkali, liquorice, excessive bicarbonate, calcium carbonate. Correct K⁺ aggressively because alkalosis is rarely corrected without potassium repletion; typical replacement is oral KCl 40–100 mmol/day in divided doses, or IV KCl 10 mmol/hour peripherally, up to 20 mmol/hour via central line with ECG monitoring in severe deficits. Aim for serum K⁺ >4.0 mmol/L in arrhythmia-prone patients. Replace magnesium if low, e.g. magnesium sulfate 2 g IV over 20–60 min, repeated as required.

Scenario	Preferred treatment	Key cautions
Chloride-responsive, volume depleted	0.9% saline plus KCl; restores GFR, distal chloride delivery, and bicarbonaturia	Avoid fluid overload in heart failure or advanced CKD
Oedematous states requiring diuresis	Acetazolamide 250–500 mg PO/IV once or twice daily	Promotes bicarbonaturia but may worsen hypokalaemia; reduced efficacy in severe CKD
Mineralocorticoid excess	Spironolactone 25–100 mg/day or eplerenone 25–50 mg twice daily; adrenalectomy for unilateral aldosterone-producing adenoma	Monitor K+ and renal function; eplerenone has fewer antiandrogenic effects
Liddle syndrome	Amiloride 5–20 mg/day or triamterene	Spironolactone ineffective because aldosterone is suppressed
Life-threatening alkalemia, pH ≥7.55–7.60, unable to give saline	Consider ICU therapy: acetazolamide, renal replacement therapy, or rarely dilute hydrochloric acid via central line	HCl typically 0.1–0.2 mol/L, central venous only, specialist supervision

In ventilated COPD patients with post-hypercapnic alkalosis, avoid excessive rapid reduction of PaCO₂; acetazolamide can lower bicarbonate, although the DIABOLO trial did not show a significant reduction in duration of invasive ventilation despite biochemical improvement. For MRCP, the recurring principle is: urine chloride classifies the alkalosis, potassium depletion maintains it, and treatment follows volume/chloride status and mineralocorticoid activity.