Fluid, Electrolyte and Acid-Base Physiology

Fluid Balance

Fluid balance is the dynamic maintenance of total body water, intravascular volume and effective arterial blood volume, rather than simply matching intake to output. For MRCP Part 1, the key distinction is between osmolal homeostasis, which regulates water distribution across cell membranes, and volume homeostasis, which regulates renal sodium and water retention to preserve perfusion. These systems overlap but are physiologically separable: osmolality is sensed mainly by hypothalamic osmoreceptors, whereas effective circulating volume is sensed by arterial and cardiopulmonary baroreceptors.

Compartment	Approximate volume in 70 kg adult	Key features
Total body water	~42 L; ~60% body weight in men, ~50% in women, lower in elderly/adiposity	Falls with age and adipose mass; determines volume of distribution of water-soluble substances
Intracellular fluid	~28 L; two-thirds of total body water	Dominant intracellular osmoles include potassium salts and organic phosphates
Extracellular fluid	~14 L; one-third of total body water	Includes interstitial fluid and plasma; dominant osmoles are sodium salts
Plasma volume	~3 L; ~5% body weight	Clinically critical for preload, cardiac output and organ perfusion
Interstitial fluid	~11 L	Expansion produces oedema when lymphatic removal is exceeded

Water moves freely across most cell membranes according to osmotic gradients. A useful calculated plasma osmolarity is: 2 × Na⁺ + urea + glucose in mmol/L, with normal measured osmolality approximately 275–295 mOsm/kg. Tonicity refers only to effective osmoles that do not freely cross cell membranes; it therefore determines cell volume. Urea raises measured osmolality but is relatively ineffective as a sustained osmotic force across many membranes.

Intravascular-to-interstitial fluid exchange is described by the revised Starling principle. Fluid flux depends on hydrostatic pressure, oncotic pressure, capillary permeability and lymphatic drainage. The classic form is Jv = Kf[(Pc − Pi) − σ(πc − πi)], where Kf is filtration coefficient and σ the reflection coefficient. Increased venous pressure, reduced plasma oncotic pressure, increased permeability or lymphatic obstruction may produce oedema; however, oedema can coexist with reduced effective arterial volume, as in cirrhosis or heart failure.

Physiological regulation

The principal efferent mechanisms are thirst, arginine vasopressin and renal tubular sodium-water handling. Thirst is stimulated by a rise in plasma osmolality of approximately 2–3% and by hypovolaemia, angiotensin II and dry mouth. Vasopressin release begins at plasma osmolality around 280–285 mOsm/kg and increases steeply thereafter; severe hypovolaemia can override osmotic suppression. Vasopressin acts on renal collecting duct V2 receptors, increasing aquaporin-2 insertion and water reabsorption, producing urine osmolality that can rise to 800–1200 mOsm/kg in healthy adults.

Volume regulation is dominated by the renin–angiotensin–aldosterone system, sympathetic tone and natriuretic peptides. Reduced renal perfusion pressure, reduced macula densa chloride delivery or β₁-adrenergic stimulation increases renin release. Angiotensin II constricts efferent arterioles, stimulates proximal sodium reabsorption and aldosterone secretion, and promotes thirst and vasopressin release. Aldosterone increases distal nephron sodium reabsorption through epithelial sodium channels, with water following when antidiuretic hormone permits. Atrial and B-type natriuretic peptides are released by myocardial stretch and increase natriuresis by raising glomerular filtration and inhibiting renin, aldosterone and collecting duct sodium reabsorption.

Clinical classification of fluid states

State	Physiological problem	Typical clinical clues	Interpretative pitfalls
Hypovolaemia	Reduced extracellular and effective arterial volume	Postural hypotension, tachycardia, cool peripheries, oliguria, high urea:creatinine ratio	Blood pressure may remain normal until substantial loss; elderly patients may lack tachycardia
Euvolaemic water excess	Water gain with minimal overt ECF expansion	Absence of oedema or dehydration; concentrated urine if vasopressin-mediated	Clinical examination is insensitive for small volume changes
Hypervolaemia	Expanded ECF, often with reduced effective arterial volume	Peripheral oedema, raised JVP, pulmonary crackles, ascites, weight gain	In cirrhosis/nephrotic syndrome, total body fluid is high but arterial underfilling drives retention

Bedside assessment is imperfect. Capillary refill time >3 seconds, systolic pressure <90 mmHg, heart rate >100/min, respiratory rate >20/min and urine output <0.5 mL/kg/hour suggest clinically important hypovolaemia or shock, but must be integrated with context. Daily weights are often more reliable than fluid charts: 1 kg weight change approximates 1 L water. Central venous pressure poorly predicts fluid responsiveness; dynamic indices such as passive leg raise with stroke volume measurement are superior in ventilated or monitored patients.

Prescribing fluids

Intravenous fluid should be prescribed as a drug: indication, type, rate and endpoint. NICE guidance for adults recommends routine maintenance of approximately 25–30 mL/kg/day water, about 1 mmol/kg/day sodium, potassium and chloride, and 50–100 g/day glucose to limit starvation ketosis. Resuscitation is usually with 500 mL crystalloid over less than 15 minutes, reassessing after each bolus; smaller boluses such as 250 mL are prudent in frailty, heart failure or advanced kidney disease.

Crystalloids distribute across the extracellular fluid, so only about one-quarter of an isotonic crystalloid bolus remains intravascular after equilibration. Colloids exert greater short-term plasma expansion but have not shown general outcome superiority. The SAFE trial found 4% albumin and saline had similar 28-day mortality in ICU patients, with subgroup signals of harm in traumatic brain injury. Hydroxyethyl starch solutions are avoided in sepsis and critical illness because of increased renal replacement therapy and mortality signals. Balanced crystalloids reduce chloride load compared with 0.9% saline; SMART reported a modest reduction in major adverse kidney events in ICU patients with balanced crystalloids versus saline. These data support balanced crystalloids for many acutely unwell adults, while recognising that fluid choice must be individualised.

Electrolyte Homeostasis

Integrated renal and endocrine control

Electrolyte homeostasis is principally determined by renal tubular transport, effective arterial blood volume, and hormone-regulated exchange between extracellular fluid, intracellular fluid and bone. For examination purposes, distinguish concentration disorders, which often reflect water balance, from content disorders, which reflect total body electrolyte excess or deficit. Serum sodium is therefore mainly a marker of tonicity and water handling, whereas potassium, calcium, magnesium and phosphate more often indicate disordered intake, distribution, renal excretion or endocrine regulation.

Electrolyte	Usual adult reference range	Dominant regulation	Key exam concept
Sodium	135–145 mmol/L	ADH, thirst, renal medullary gradient, RAAS	Serum Na reflects water balance more than sodium stores
Potassium	3.5–5.0 mmol/L	Aldosterone, distal Na delivery, insulin, catecholamines, pH	Small extracellular changes may represent large total body shifts
Calcium	Total 2.2–2.6 mmol/L; ionised 1.12–1.32 mmol/L	PTH, vitamin D, renal calcium receptor	Interpret total calcium with albumin; ionised calcium is biologically active
Magnesium	0.7–1.0 mmol/L	Intestinal absorption, loop/DCT renal handling	Hypomagnesaemia causes refractory hypokalaemia and hypocalcaemia
Phosphate	0.8–1.5 mmol/L	PTH, FGF23, calcitriol, proximal tubular transport	Critical in CKD-mineral bone disorder and refeeding syndrome

Sodium disorders: tonicity first, volume second

Hyponatraemia is classified by severity: mild 130–134 mmol/L, moderate 125–129 mmol/L, severe <125 mmol/L; and by onset, acute <48 hours or chronic/unknown. The diagnostic sequence is: confirm hypotonicity, measure urine osmolality, then urine sodium. Serum osmolality is usually 275–295 mOsm/kg. Non-hypotonic hyponatraemia occurs with hyperglycaemia, mannitol, severe hyperlipidaemia or paraproteinaemia. Correct sodium for glucose: add approximately 2.4 mmol/L to measured Na for each 5.6 mmol/L glucose above normal.

Pattern	Typical findings	Examples
Urine osmolality <100 mOsm/kg	Appropriate ADH suppression	Primary polydipsia, low-solute intake, beer potomania
Urine osmolality >100 mOsm/kg; urine Na <30 mmol/L	Low effective arterial volume	Vomiting, diarrhoea, heart failure, cirrhosis
Urine osmolality >100 mOsm/kg; urine Na >30 mmol/L	Renal sodium loss or SIADH phenotype	Diuretics, adrenal insufficiency, cerebral salt wasting, SIADH

SIADH requires hypotonic hyponatraemia with inappropriately concentrated urine, clinical euvolaemia, urine Na typically >30 mmol/L, normal thyroid/adrenal/renal function and no recent diuretic use. Severe symptomatic hyponatraemia with seizures, coma or impending herniation requires 3% hypertonic saline 150 mL over 20 minutes, repeated up to twice aiming for an initial 4–6 mmol/L rise, not normalisation. Chronic hyponatraemia correction should generally not exceed 8–10 mmol/L in 24 hours and 18 mmol/L in 48 hours; use lower targets, about 6 mmol/L/day, in alcoholism, malnutrition, advanced liver disease or hypokalaemia because of osmotic demyelination risk. Tolvaptan, an oral V2 antagonist, increases aquaresis; trial evidence from SALT-1 and SALT-2 showed improved sodium at days 4 and 30, but it is avoided in hypovolaemia, severe symptoms requiring hypertonic saline, and significant liver disease.

Hypernatraemia implies water deficit relative to sodium. Causes include unreplaced extrarenal water loss, osmotic diuresis, diabetes insipidus and impaired thirst. Urine osmolality >800 mOsm/kg suggests intact ADH response; <300 mOsm/kg suggests diabetes insipidus. Desmopressin responsiveness distinguishes central from nephrogenic diabetes insipidus. Chronic hypernatraemia should be corrected slowly, generally ≤10–12 mmol/L/day, to avoid cerebral oedema.

Potassium homeostasis

Approximately 98% of potassium is intracellular. The distal nephron determines excretion via principal cell potassium secretion, driven by aldosterone, luminal electronegativity, sodium delivery and flow. Insulin and β2-agonists shift potassium into cells; acidaemia, hyperosmolality, tissue breakdown and non-selective β-blockade shift it out.

Emergency	Treatment	Typical dose and key point
Hyperkalaemia with ECG changes or K ≥6.5 mmol/L	Membrane stabilisation	10 mL of 10% calcium gluconate IV over 2–5 min; repeat after 5–10 min if ECG persists
Intracellular shift	Insulin-glucose	10 units soluble insulin IV with 25 g glucose; onset 15 min, duration 4–6 h; monitor hypoglycaemia
Intracellular shift	Nebulised salbutamol	10–20 mg nebulised; additive to insulin, less reliable in β-blocked patients
Potassium removal	Dialysis or binders	Urgent dialysis for renal failure/refractory cases; patiromer onset 4–7 h, sodium zirconium cyclosilicate onset about 1 h

Hypokalaemia is mild 3.0–3.4, moderate 2.5–2.9 and severe <2.5 mmol/L. Evaluate urinary potassium: urine K >20 mmol/L or transtubular gradient historically >4 suggests renal loss. Causes include diuretics, mineralocorticoid excess, Bartter/Gitelman syndromes, renal tubular acidosis, diarrhoea, insulin and β-agonists. Replace orally if possible; IV potassium chloride is typically 10 mmol/hour peripherally, up to 20 mmol/hour via central access with continuous ECG monitoring. Correct magnesium or potassium will remain refractory.

Calcium, magnesium and phosphate

Calcium is regulated by PTH, 1,25-dihydroxyvitamin D and the calcium-sensing receptor. Albumin-adjusted calcium is commonly estimated by: corrected calcium = measured calcium + 0.02 × (40 − albumin g/L), though ionised calcium is preferred in critical illness. Hypercalcaemia is mild 2.6–3.0, moderate 3.0–3.5 and severe >3.5 mmol/L. Primary hyperparathyroidism and malignancy predominate. Severe or symptomatic hypercalcaemia is treated with 0.9% saline rehydration, followed by IV bisphosphonate such as zoledronic acid 4 mg IV over at least 15 minutes or pamidronate 30–90 mg IV; onset is 2–4 days. Calcitonin 4 IU/kg subcutaneously or intramuscularly every 12 hours gives faster but tachyphylactic reduction. Denosumab is useful in bisphosphonate-refractory or renal impairment-associated malignancy hypercalcaemia.

Hypocalcaemia with tetany, seizures or QT prolongation requires 10 mL of 10% calcium gluconate IV over 10 minutes, followed by infusion if needed. Always check magnesium, phosphate, vitamin D and PTH. Hypomagnesaemia impairs PTH secretion and action; causes include proton pump inhibitors, aminoglycosides, cisplatin, amphotericin, loop/thiazide diuretics, diarrhoea and alcohol. Symptomatic or severe hypomagnesaemia is treated with magnesium sulfate, commonly 2 g IV over 10–20 minutes in torsades de pointes, or slower replacement for non-arrhythmic deficiency.

Phosphate is governed by proximal tubular reabsorption, inhibited by PTH and FGF23. Hypophosphataemia is severe below 0.3 mmol/L and may cause rhabdomyolysis, haemolysis, respiratory failure and myocardial dysfunction; refeeding syndrome is the classic MRCP association, with insulin-driven cellular uptake of phosphate, potassium and magnesium after carbohydrate reintroduction. Hyperphosphataemia in CKD contributes to secondary hyperparathyroidism and vascular calcification; management includes dietary phosphate restriction, dialysis optimisation and binders such as calcium acetate, sevelamer or lanthanum according to calcium level and vascular calcification risk.

Acid-Base Balance

Normal arterial pH is tightly maintained at 7.35–7.45, reflecting the ratio of bicarbonate to dissolved carbon dioxide in the Henderson–Hasselbalch equation: pH = 6.1 + log([HCO₃⁻]/0.03 × PaCO₂). Thus acid-base status is determined by a metabolic component, chiefly plasma bicarbonate, and a respiratory component, PaCO₂. Normal arterial values are approximately PaCO₂ 4.7–6.0 kPa or 35–45 mmHg, HCO₃⁻ 22–26 mmol/L, and base excess −2 to +2 mmol/L.

Physiological buffering and compensation

Immediate buffering is mediated by bicarbonate, haemoglobin, intracellular proteins and phosphate. The bicarbonate system is open and therefore dominant because CO₂ is eliminated by alveolar ventilation. Carbonic anhydrase catalyses CO₂ hydration in erythrocytes and renal tubular cells. Respiratory compensation occurs within minutes by altering alveolar ventilation; renal compensation takes hours to days and involves proximal bicarbonate reclamation, distal hydrogen secretion, titratable acid excretion and ammoniagenesis.

The kidney filters approximately 4,000–5,000 mmol/day of bicarbonate, normally reclaiming nearly all of it: 80–90% in the proximal tubule via Na⁺/H⁺ exchange, the remainder in the thick ascending limb and collecting duct. Net acid excretion is mainly as NH₄⁺, generated from glutamine in the proximal tubule, and as titratable phosphate. Aldosterone promotes distal H⁺ secretion by type A intercalated cells, explaining the association of mineralocorticoid excess with metabolic alkalosis and hypokalaemia.

Primary disorder	Expected compensation	Exam use
Metabolic acidosis	PaCO2 ≈ 1.5 × HCO3− + 8 ± 2 mmHg	Winter’s formula; higher PaCO2 implies respiratory failure
Metabolic alkalosis	PaCO2 rises ≈ 0.7 mmHg per 1 mmol/L rise in HCO3−	Hypoventilatory compensation limited by hypoxaemia
Acute respiratory acidosis	HCO3− rises ≈ 1 mmol/L per 10 mmHg PaCO2 rise	Minutes to hours
Chronic respiratory acidosis	HCO3− rises ≈ 3.5–4 mmol/L per 10 mmHg PaCO2 rise	Renal adaptation over 3–5 days
Acute respiratory alkalosis	HCO3− falls ≈ 2 mmol/L per 10 mmHg PaCO2 fall	Early hyperventilation
Chronic respiratory alkalosis	HCO3− falls ≈ 4–5 mmol/L per 10 mmHg PaCO2 fall	Pregnancy, high altitude, chronic liver disease

Systematic interpretation

1. Confirm pH: acidaemia <7.35, alkalaemia >7.45.
2. Identify the primary process from PaCO₂ and HCO₃⁻.
3. Check whether compensation is appropriate; inappropriate values imply a mixed disorder.
4. Calculate anion gap: AG = Na⁺ − (Cl⁻ + HCO₃⁻); normal approximately 8–12 mmol/L but falls by about 2.5 mmol/L for each 10 g/L fall in albumin below 40 g/L.
5. In high anion gap metabolic acidosis, calculate delta ratio: ΔAG/ΔHCO₃⁻. A ratio <0.8 suggests additional normal-gap acidosis; >2 suggests concurrent metabolic alkalosis or chronic respiratory acidosis.

Metabolic acidosis

High anion gap metabolic acidosis reflects accumulation of unmeasured anions. Important causes include lactate, ketoacids, uraemic sulphates/phosphates, salicylate, methanol, ethylene glycol, propylene glycol and pyroglutamate. Lactic acidosis is usually defined as lactate >2 mmol/L; levels ≥4 mmol/L in sepsis indicate high risk and mandate urgent resuscitation. Type A lactic acidosis follows tissue hypoxia; type B occurs with metformin, malignancy, liver failure, thiamine deficiency and beta-agonists.

Normal anion gap metabolic acidosis is usually due to bicarbonate loss or impaired renal acidification: diarrhoea, pancreatic/intestinal fistulae, renal tubular acidosis, acetazolamide, ureterosigmoidostomy and early renal failure. Urinary anion gap, Na⁺ + K⁺ − Cl⁻, is negative in diarrhoea due to high NH₄⁺ excretion, but positive in distal renal tubular acidosis.

Renal tubular acidosis	Defect	Typical features
Type 1 distal	Impaired distal H+ secretion	Urine pH >5.5, hypokalaemia, nephrocalcinosis, Sjögren’s
Type 2 proximal	Impaired bicarbonate reabsorption	Fanconi syndrome, hypokalaemia, urine pH variable
Type 4	Hypoaldosteronism or resistance	Hyperkalaemia, diabetes, ACE inhibitors, heparin

Sodium bicarbonate is not routine in metabolic acidosis because CO₂ generation may worsen intracellular acidosis and volume/sodium load. It is considered for severe acidemia, commonly pH ≤7.1, particularly with haemodynamic compromise or hyperkalaemia. A pragmatic dose is 1–2 mmol/kg IV initially, reassessing gases and ionised calcium. The BICAR-ICU trial suggested no overall mortality benefit but reduced need for renal replacement therapy and improved outcomes in the subgroup with acute kidney injury.

Metabolic alkalosis

Metabolic alkalosis requires generation and maintenance. Generation follows H⁺ loss, alkali gain, or intracellular H⁺ shift with hypokalaemia. Maintenance requires impaired bicarbonate excretion, usually from extracellular volume depletion, chloride depletion, hypokalaemia, reduced GFR or mineralocorticoid excess. Urine chloride distinguishes chloride-responsive alkalosis, typically urine Cl⁻ <10–20 mmol/L after vomiting or diuretics, from chloride-resistant alkalosis, urine Cl⁻ >20 mmol/L, due to hyperaldosteronism, Cushing’s, Bartter or Gitelman syndromes. Treatment is mechanism-based: isotonic saline and potassium chloride for volume/chloride depletion; spironolactone/eplerenone or adrenal-directed therapy for mineralocorticoid excess; acetazolamide may be useful in oedematous states but can worsen hypokalaemia.

Respiratory acid-base disorders

Respiratory acidosis results from alveolar hypoventilation: COPD, severe asthma, CNS depression, neuromuscular weakness, chest wall disease or ventilatory failure. Acute hypercapnia causes rapid acidaemia; chronic hypercapnia is partially buffered by renal bicarbonate retention. Oxygen therapy in chronic CO₂ retainers should generally target saturations 88–92% to reduce worsening hypercapnia from V/Q effects and the Haldane effect.

Respiratory alkalosis is caused by hyperventilation: hypoxaemia, pulmonary embolism, sepsis, pregnancy, liver failure, salicylate toxicity and anxiety. Salicylate poisoning classically produces early respiratory alkalosis followed by high anion gap metabolic acidosis; severity correlates poorly with a single level, but concentrations >500 mg/L in adults are serious and alkalinisation of urine with IV sodium bicarbonate is standard in significant poisoning.