Acid–base physiology

9 min read Last updated April 8, 2026

Clinical approach to an ABG (FRCA-safe structure)

  • Check internal consistency and context (FiO2, ventilation mode, haemodynamics, temperature, Hb, lactate, drugs/infusions).
    • pH, PaCO2, HCO3− should fit a primary process with appropriate compensation; if not, suspect mixed disorder or sampling/analysis error.
  • Step 1: Decide if acidemia or alkalemia (pH <7.35 or >7.45).
  • Step 2: Identify primary process (respiratory vs metabolic) using direction of PaCO2 and HCO3− relative to pH.
    • Respiratory: primary change in PaCO2; renal compensation changes HCO3− (hours–days).
    • Metabolic: primary change in HCO3−; respiratory compensation changes PaCO2 (minutes).
  • Step 3: Check expected compensation (is it appropriate?).
    • Metabolic acidosis: expected PaCO2 ≈ 1.5 × HCO3− + 8 (±2) (Winter’s formula).
    • Metabolic alkalosis: expected PaCO2 rises ~0.7 kPa per 10 mmol/L rise in HCO3− (or ~0.5–0.7 mmHg per 1 mmol/L).
    • Respiratory acidosis: acute HCO3− rises ~1 mmol/L per 10 mmHg PaCO2; chronic ~3–4 mmol/L per 10 mmHg.
    • Respiratory alkalosis: acute HCO3− falls ~2 mmol/L per 10 mmHg PaCO2; chronic ~4–5 mmol/L per 10 mmHg.
  • Step 4: Calculate anion gap (AG) and assess for mixed metabolic disorders.
    • AG = Na+ − (Cl− + HCO3−). Typical ~12 ± 4 mmol/L (lab dependent).
    • Correct for albumin: add ~2.5 mmol/L to AG for each 10 g/L albumin below 40 g/L (approx).
    • Delta ratio (high AG acidosis): (AG − normal AG) / (normal HCO3− − measured HCO3−).
    • Interpretation: <0.4 hyperchloraemic acidosis also; 0.4–0.8 mixed; 1–2 pure high AG acidosis; >2 concurrent metabolic alkalosis or chronic respiratory acidosis.
  • Step 5: Oxygenation and global context (A–a gradient if needed; lactate; ketones; renal function; toxins).

Renal handling of acid: high-yield clinical map

  • Kidney maintains acid–base by reabsorbing filtered HCO3− and generating new HCO3− while excreting H+ as titratable acid and NH4+.
  • Proximal tubule: reabsorbs ~80–90% filtered HCO3− (via carbonic anhydrase, Na+/H+ exchanger).
    • Filtered HCO3− combines with secreted H+ → H2CO3 → CO2 + H2O (luminal CA); CO2 diffuses in; intracellular CA reforms HCO3− which exits basolaterally.
  • Thick ascending limb: reabsorbs additional HCO3−; contributes to NH4+ handling.
  • Collecting duct (α-intercalated cells): secretes H+ (H+-ATPase, H+/K+-ATPase) and generates new HCO3−; urine pH can fall to ~4.5.
  • β-intercalated cells: secrete HCO3− (pendrin Cl−/HCO3− exchanger) in alkalosis.
  • Net acid excretion (NAE) = NH4+ excretion + titratable acid − HCO3− excretion.

Core concepts and definitions

  • Acids donate H+; bases accept H+. pH = −log10[H+]. Normal arterial pH ~7.35–7.45.
  • Henderson–Hasselbalch (bicarbonate buffer): pH = 6.1 + log10( [HCO3−] / (0.03 × PaCO2) ) (PaCO2 in mmHg).
    • Key relationship: pH depends on the ratio of metabolic component (HCO3−) to respiratory component (PaCO2).
  • Bicarbonate is not a closed buffer: lungs regulate CO2; kidneys regulate HCO3− and non-volatile acid excretion.
  • Volatile acid: CO2 (excreted by lungs). Non-volatile (fixed) acids: sulfuric/phosphoric acids from protein metabolism; organic acids (lactate, ketones).

Buffer systems (what matters in exams)

  • Extracellular: bicarbonate is dominant; phosphate minor in plasma but important in urine (titratable acid).
  • Intracellular: proteins and phosphate; haemoglobin is a major non-bicarbonate buffer in blood.
  • Isohydric principle: all buffer pairs in a solution are in equilibrium with the same [H+]; changing one affects others.

Renal mechanisms in detail

  • Reabsorption of filtered HCO3− (mainly proximal tubule): prevents loss of base; does not generate new HCO3−.
  • Generation of new HCO3− requires net H+ excretion (as titratable acid or NH4+). For each H+ excreted with a urinary buffer, one new HCO3− is added to blood.
  • Titratable acid: mainly H2PO4− formed from filtered HPO42−. Limited by phosphate availability and urine pH.
  • Ammoniagenesis (proximal tubule): glutamine → NH4+ + HCO3−. NH4+ excreted in urine; HCO3− returned to blood (new bicarbonate).
    • NH3 diffuses into lumen and traps H+ as NH4+ (diffusion trapping), especially in collecting duct.
    • NH4+ excretion is the major adaptive mechanism in chronic metabolic acidosis.
  • Minimum urine pH ~4.5 limits free H+ excretion; therefore buffering (phosphate, NH3) is essential.
  • Hormonal/physiological influences: aldosterone increases H+ secretion (α-intercalated cells) and K+ secretion; hypokalaemia promotes H+ secretion and HCO3− reabsorption; hyperkalaemia impairs ammoniagenesis.

Respiratory–renal integration and time course

  • Respiratory compensation is rapid (minutes): changes PaCO2 via alveolar ventilation.
  • Renal compensation is slower (hours to days): changes HCO3− reabsorption, H+ secretion, NH4+ production.
  • In chronic respiratory disorders, kidneys adjust plasma HCO3− substantially; in acute disorders, HCO3− change is small.

Anion gap and strong ions (exam-relevant comparisons)

  • Anion gap (traditional): reflects unmeasured anions (albumin, phosphate, sulfate, lactate, ketones, toxins).
  • High anion gap metabolic acidosis causes: lactate, ketoacidosis, renal failure (uremia), toxins (e.g., methanol, ethylene glycol, salicylate), others (e.g., 5-oxoproline with chronic paracetamol).
  • Normal anion gap (hyperchloraemic) metabolic acidosis: GI HCO3− loss (diarrhoea), renal tubular acidosis, saline load, ureteric diversions.
  • Stewart approach (conceptual): pH determined by 3 independent variables: PaCO2, strong ion difference (SID), and total weak acids (Atot: albumin, phosphate).
    • 0.9% saline reduces SID (raises Cl− relative to Na+) → metabolic acidosis.
    • Hypoalbuminaemia reduces Atot → metabolic alkalosis tendency and lowers measured anion gap.

Renal tubular acidosis (RTA): patterns worth knowing

  • Type 1 (distal) RTA: impaired H+ secretion in distal nephron → inability to acidify urine (urine pH typically >5.5), hypokalaemia, risk of calcium phosphate stones.
  • Type 2 (proximal) RTA: impaired HCO3− reabsorption → bicarbonaturia; urine pH may be high initially then can fall <5.5 once plasma HCO3− is low; hypokalaemia.
  • Type 4 RTA: hypoaldosteronism or aldosterone resistance → reduced NH4+ excretion and hyperkalaemia; urine pH often <5.5.

Acid–base effects of common perioperative fluids and drugs

  • 0.9% saline: hyperchloraemic metabolic acidosis (reduced SID) and possible renal vasoconstriction with high chloride loads.
  • Balanced crystalloids (e.g., Hartmann’s/Plasma-Lyte): less hyperchloraemia; lactate/acetate/gluconate are metabolised to bicarbonate equivalents (requires hepatic/extrahepatic metabolism).
  • Diuretics: loop/thiazide can cause metabolic alkalosis (volume contraction, increased distal Na+ delivery → H+ and K+ loss).
  • Acetazolamide: proximal carbonic anhydrase inhibition → bicarbonaturia → metabolic acidosis; can be used to treat metabolic alkalosis.
  • Vomiting/NG suction: loss of HCl → metabolic alkalosis; kidney maintains alkalosis with volume depletion and chloride depletion (chloride-responsive alkalosis).
Explain the Henderson–Hasselbalch equation and how the lungs and kidneys regulate pH.

Aim: link equation to physiology and time course.

  • pH = 6.1 + log10( [HCO3−] / (0.03 × PaCO2) ).
  • Lungs regulate PaCO2 (volatile acid) rapidly by changing alveolar ventilation.
  • Kidneys regulate [HCO3−] and net acid excretion slowly by reabsorbing filtered HCO3− and generating new HCO3− via H+ excretion as NH4+ and titratable acid.
  • Clinical implication: acute respiratory disorders show minimal HCO3− change; chronic respiratory disorders show significant renal compensation.
Describe how the kidney reabsorbs filtered bicarbonate in the proximal tubule.

Common viva: must mention carbonic anhydrase and Na+/H+ exchange.

  • Tubular H+ secretion via Na+/H+ exchanger (NHE3) combines with filtered HCO3− → H2CO3.
  • Luminal carbonic anhydrase converts H2CO3 → CO2 + H2O; CO2 diffuses into the cell.
  • Intracellular carbonic anhydrase reforms H2CO3 → H+ + HCO3−; HCO3− exits basolaterally (e.g., Na+/HCO3− cotransporter).
  • Net effect: reclaim filtered HCO3− without net H+ loss (H+ is recycled).
How does the kidney generate ‘new’ bicarbonate? Distinguish this from bicarbonate reabsorption.

Key discriminator: new HCO3− requires net H+ excretion.

  • Reabsorption of filtered HCO3− prevents loss of base but does not add new base to the body.
  • New HCO3− is generated when H+ is excreted with urinary buffers (phosphate as titratable acid, or NH3 as NH4+). Each H+ excreted this way adds one HCO3− to blood.
  • Net acid excretion (NAE) = NH4+ + titratable acid − urinary HCO3−.
What is ammoniagenesis and why is it important in chronic metabolic acidosis?

Expect mention of glutamine metabolism and adaptive increase.

  • Proximal tubule metabolises glutamine → NH4+ (excreted) + HCO3− (returned to blood).
  • NH3/NH4+ system allows large amounts of H+ to be excreted despite minimum urine pH limitation.
  • In chronic metabolic acidosis, ammoniagenesis upregulates markedly and becomes the major component of net acid excretion.
  • Hyperkalaemia suppresses ammoniagenesis → predisposes to metabolic acidosis (notably type 4 RTA).
Define titratable acidity. What limits it?

Often asked alongside ammonium excretion.

  • Titratable acidity is the amount of H+ excreted buffered mainly by phosphate (HPO42− → H2PO4−), measured by titrating urine back to plasma pH.
  • Limited by availability of urinary buffers (especially phosphate) and by urine pH (buffer pKa and minimum urine pH).
  • Does not include NH4+ (which is measured separately).
A patient has metabolic acidosis. How do you assess whether respiratory compensation is appropriate?

This is a common data interpretation viva.

  • Use Winter’s formula: expected PaCO2 (mmHg) ≈ 1.5 × HCO3− + 8 (±2).
  • If measured PaCO2 is higher than expected → concurrent respiratory acidosis (hypoventilation).
  • If measured PaCO2 is lower than expected → concurrent respiratory alkalosis (hyperventilation).
Explain the anion gap. How do you correct it for albumin and why does it matter perioperatively?

FRCA often tests albumin correction and hidden high AG acidosis.

  • AG = Na+ − (Cl− + HCO3−); reflects unmeasured anions (albumin is a major contributor).
  • Correct for low albumin: add ~2.5 mmol/L to AG for each 10 g/L albumin below 40 g/L (approx).
  • Perioperative relevance: hypoalbuminaemia can mask a high AG acidosis (e.g., lactate, ketones), so an apparently ‘normal’ AG may be misleading unless corrected.
What is the delta ratio and how does it identify mixed metabolic disorders?

Classic FRCA calculation question.

  • Delta ratio = (AG − normal AG) / (normal HCO3− − measured HCO3−).
  • Interpretation: ~1–2 suggests isolated high AG metabolic acidosis; <1 suggests additional normal AG acidosis; >2 suggests concurrent metabolic alkalosis (or pre-existing raised HCO3− e.g., chronic respiratory acidosis).
  • Use corrected AG (for albumin) for best accuracy.
Why does 0.9% saline cause metabolic acidosis? Compare with balanced crystalloids.

Frequently examined in physiology and perioperative medicine.

  • 0.9% saline has high chloride relative to plasma; chloride rise reduces strong ion difference (SID) → metabolic acidosis (hyperchloraemic).
  • Balanced crystalloids have chloride closer to plasma and include metabolizable anions (lactate/acetate) that generate bicarbonate equivalents → less acidosis.
  • Clinical context: large-volume saline resuscitation can produce a normal AG acidosis that may coexist with lactic acidosis (mixed picture).
Outline renal tubular acidosis types 1, 2 and 4, including potassium and urine pH patterns.

High-yield classification question.

  • Type 1 (distal): impaired distal H+ secretion → urine pH typically >5.5; hypokalaemia; stones (calcium phosphate).
  • Type 2 (proximal): impaired HCO3− reabsorption → bicarbonaturia; urine pH variable (often >5.5 initially, can become <5.5 after steady state); hypokalaemia.
  • Type 4: hypoaldosteronism/resistance → reduced NH4+ excretion; hyperkalaemia; urine pH often <5.5.
Previous FRCA-style data interpretation: ABG pH 7.25, PaCO2 3.0 kPa, HCO3− 10 mmol/L, Na 140, Cl 112, albumin 20 g/L. Interpret fully.

Work through: primary disorder, compensation, AG (corrected), mixed disorders.

  • pH 7.25 = acidemia; HCO3− 10 low → primary metabolic acidosis.
  • Compensation: HCO3− 10 → expected PaCO2 (mmHg) ≈ 1.5×10+8 = 23 (±2) mmHg ≈ 3.1 (±0.3) kPa. Measured PaCO2 3.0 kPa → appropriate respiratory compensation.
  • AG = 140 − (112 + 10) = 18 mmol/L (appears mildly high).
  • Albumin correction: albumin 20 (20 below 40) → add ~2.5×2 = 5. Corrected AG ≈ 23 → significant high AG acidosis present.
  • Also chloride is high (112) consistent with concurrent hyperchloraemic (normal AG) acidosis (mixed metabolic acidosis possible). Consider delta ratio to refine.
Previous FRCA-style viva: Explain why hypokalaemia is associated with metabolic alkalosis and how the kidney contributes.

Link K+ shifts, H+/K+ exchange, and renal handling.

  • Cellular shift: hypokalaemia promotes K+ movement out of cells and H+ into cells → extracellular alkalosis.
  • Renal: hypokalaemia increases proximal HCO3− reabsorption and stimulates H+ secretion (including via H+/K+-ATPase in α-intercalated cells), sustaining alkalosis.
  • Common clinical setting: diuretics/vomiting cause both K+ depletion and alkalosis; correction often requires chloride and potassium repletion.

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