Metabolic Alkalosis
Metabolic alkalosis is a primary acid-base disorder characterized by an elevated serum bicarbonate concentration and increased arterial pH, often resulting from excessive loss of hydrogen ions or gain of bicarbonate.
Metabolic Alkalosis
Metabolic alkalosis is a primary acid–base disorder characterised by an increase in serum bicarbonate (HCO₃⁻) concentration ( > 26 mmol/L) with a consequent rise in arterial pH ( > 7.45), resulting from either a net gain of base (HCO₃⁻) or a net loss of acid (H⁺) from the extracellular fluid [1][2].
Terminology Precision — High Yield
Alkalosis = the ongoing process that removes H⁺ or adds HCO₃⁻. Alkalemia = the final measured state where pH > 7.45. You can have alkalosis without alkalemia if respiratory compensation (hypoventilation → ↑ pCO₂) is sufficient. Conversely, in a mixed disorder you may see alkalemia from metabolic alkalosis even alongside a concurrent metabolic acidosis [1][2].
A critically important concept — sometimes overlooked — is that metabolic alkalosis has two distinct phases [3]:
- Initiation (Generation): The event that creates the excess HCO₃⁻ (e.g., vomiting, diuretics).
- Maintenance: The reason the kidney fails to excrete the excess HCO₃⁻. This must always be present, because under normal circumstances the kidney has an enormous capacity to dump bicarbonate. If you correct the maintenance factor (e.g., replete volume, chloride, potassium), the alkalosis self-corrects.
"Think of metabolic alkalosis as a two-hit problem: something generates it, and something maintains it. Fixing only one won't always fix the patient."
Why is this important clinically?
- Metabolic alkalosis is the most common acid–base disorder in hospitalised patients (up to ~50% of all acid–base disturbances), yet receives far less teaching time than metabolic acidosis.
- Severe alkalemia (pH > 7.55) shifts the oxyhaemoglobin dissociation curve leftward (↑ Hb–O₂ affinity → ↓ tissue O₂ delivery), depresses ventilation (compensatory hypoventilation can worsen hypoxaemia), prolongs QT interval, and lowers the seizure threshold.
- In the context of hepatic encephalopathy, metabolic alkalosis promotes conversion of NH₄⁺ (charged, cannot cross BBB) into NH₃ (uncharged, crosses BBB freely), worsening encephalopathy [4].
2. Epidemiology and Risk Factors
| Setting | Key Points |
|---|---|
| Hospitalised adults | Most common acid–base disorder (~50%) — largely iatrogenic (diuretics, NG suction, IV fluids with lactate/citrate) |
| ICU patients | Up to 50% develop metabolic alkalosis; associated with increased ventilator days and mortality |
| Paediatrics | Pyloric stenosis classically presents with hypochloraemic hypokalaemic metabolic alkalosis [5]; gastroenteritis with vomiting |
| Outpatient | Chronic diuretic use (thiazide, loop); surreptitious vomiting (eating disorders); chronic liquorice ingestion |
| Hong Kong–specific considerations | High prevalence of traditional Chinese medicine containing liquorice (甘草, gān cǎo) — inhibits 11β-HSD2 → pseudo-hyperaldosteronism → hypokalaemic metabolic alkalosis [6][7]; high use of proton pump inhibitors; endemic Hepatitis B cirrhosis with diuretic use for ascites management |
- Volume depletion (any cause) — activates RAAS → secondary hyperaldosteronism → renal H⁺ and K⁺ loss.
- Diuretic use — thiazides and loop diuretics are the most common drug cause.
- Nasogastric suctioning / vomiting — loss of HCl-rich gastric fluid.
- Hypokalaemia (any cause) — drives intracellular H⁺ shift and ↑ renal ammoniagenesis.
- Mineralocorticoid excess — primary (Conn's) or secondary; or pseudo-hyperaldosteronism (liquorice, Cushing's).
- Bartter's and Gitelman's syndromes [1][2].
- Chronic respiratory acidosis with rapid mechanical ventilation correction — "post-hypercapnic alkalosis."
- Massive transfusion — citrate in stored blood is metabolised to HCO₃⁻ [8].
3. Anatomy and Physiology Review (Relevant Renal Acid–Base Handling)
To truly understand metabolic alkalosis, you must know how the kidney handles bicarbonate and hydrogen ions. Let's build this from first principles.
The kidney performs two main acid–base tasks daily:
- Reabsorbs filtered HCO₃⁻ (~4,320 mmol/day; ~24 mmol/L × 180 L GFR) — almost all in the proximal convoluted tubule (PCT, ~80–85%) via the Na⁺/H⁺ exchanger (NHE3) and carbonic anhydrase. The remaining ~15% is reabsorbed in the thick ascending limb (TAL) and distal nephron.
- Generates new HCO₃⁻ (~70 mmol/day) to replace that consumed buffering daily metabolic acid production — accomplished by:
- Titratable acid excretion (mainly H₂PO₄⁻) in the collecting duct.
- Ammonium (NH₄⁺) excretion — the quantitatively more important mechanism. Glutamine → NH₃ + H⁺ in the PCT → NH₄⁺ is trapped in the medullary interstitium → secreted into the collecting duct lumen.
| Segment | Transporter | Relevance to Metabolic Alkalosis |
|---|---|---|
| PCT | NHE3 (Na⁺/H⁺ exchanger) | ↑ activity in volume depletion and hypokalaemia → ↑ HCO₃⁻ reabsorption |
| PCT | Na⁺–HCO₃⁻ co-transporter (NBCe1) on basolateral side | Returns reabsorbed HCO₃⁻ to blood |
| TAL | NKCC2 (Na⁺/K⁺/2Cl⁻ co-transporter) | Inhibited by loop diuretics → ↑ distal Na⁺ delivery → ↑ K⁺/H⁺ loss |
| DCT | NCC (Na⁺/Cl⁻ co-transporter) | Inhibited by thiazides → similar downstream effect |
| Collecting duct (α-intercalated cells) | H⁺-ATPase and H⁺/K⁺-ATPase | Secrete H⁺ into lumen; H⁺/K⁺-ATPase reabsorbs K⁺ while secreting H⁺ |
| Collecting duct (β-intercalated cells) | Pendrin (Cl⁻/HCO₃⁻ exchanger) | Secretes HCO₃⁻ into the lumen in exchange for Cl⁻ — this is the kidney's main defence against alkalosis |
| Collecting duct (principal cells) | ENaC (epithelial Na⁺ channel), ROMK (K⁺ channel) | Aldosterone-sensitive; ↑ Na⁺ reabsorption → lumen-negative potential → drives K⁺ and H⁺ secretion |
Pendrin on β-intercalated cells requires luminal Cl⁻ to exchange for intracellular HCO₃⁻. When the patient is chloride-depleted (e.g., from vomiting, diuretics), there is insufficient Cl⁻ in the tubular lumen for this exchanger to work → the kidney cannot excrete excess HCO₃⁻ → alkalosis is maintained. This is why chloride repletion (saline) is therapeutic.
The Chloride Story — Must Know
Chloride depletion is the single most important maintenance factor in "saline-responsive" metabolic alkalosis. Without luminal Cl⁻, the β-intercalated cell's pendrin cannot dump HCO₃⁻. Additionally, chloride depletion impairs NaCl reabsorption proximally, causing more Na⁺ to reach the collecting duct where it is reabsorbed via ENaC in exchange for K⁺ and H⁺ → perpetuating both hypokalaemia and alkalosis [2][3].
This relationship is two-directional and is a favourite exam topic:
Hypokalaemia → Alkalosis:
- When extracellular K⁺ is low, K⁺ moves out of cells and H⁺ moves in (to maintain electroneutrality via the K⁺/H⁺ exchange) → intracellular acidosis in renal tubular cells → ↑ NHE3 activity in PCT → ↑ HCO₃⁻ reabsorption; ↑ ammoniagenesis → ↑ net acid excretion → generates and maintains alkalosis.
- At the collecting duct, when K⁺ is scarce, the H⁺/K⁺-ATPase is upregulated (trying to reabsorb every last K⁺) → more H⁺ is secreted → more HCO₃⁻ generated.
Alkalosis → Hypokalaemia:
- In alkalemia, H⁺ exits cells → K⁺ enters cells to maintain electroneutrality → serum K⁺ falls (transcellular shift).
- Additionally, filtered HCO₃⁻ that escapes proximal reabsorption acts as a non-reabsorbable anion in the collecting duct → increases electronegativity of the lumen → drives K⁺ secretion.
"Hypokalemia is the classical electrolyte abnormality associated with metabolic alkalosis" [1][2].
4. Etiology
Every cause of metabolic alkalosis can be understood through the dual-hit model:
Generation (↑HCO₃⁻ or ↓H⁺) + Maintenance (kidney can't excrete HCO₃⁻) = Sustained Metabolic AlkalosisMaintenance factors (must be present for sustained alkalosis):
- Chloride depletion (most common) — ↓ Cl⁻ delivery to pendrin
- Potassium depletion — intracellular acidosis in tubular cells → ↑ HCO₃⁻ reabsorption
- Effective circulating volume depletion (hypovolaemia) — ↑ proximal Na⁺ (and thus HCO₃⁻) reabsorption; ↑ RAAS
- Mineralocorticoid excess — directly stimulates H⁺ and K⁺ secretion in the collecting duct
- Reduced GFR — fewer nephrons to filter and excrete the excess HCO₃⁻
4.2 Aetiologies Classified by Saline Responsiveness
This is the clinically most useful classification and is directly from the GC lecture slides [1].
These patients are volume-depleted and chloride-depleted. The kidney is avidly retaining Na⁺ and Cl⁻, hence the low urinary Cl⁻. Giving normal saline (0.9% NaCl) corrects both volume and chloride deficits → the kidney can then excrete the excess HCO₃⁻.
| Mechanism | Causes | Pathophysiology |
|---|---|---|
| GI loss of H⁺ | Vomiting, NG tube drainage [1] | Gastric juice is rich in HCl (~150 mmol/L Cl⁻, ~80 mmol/L H⁺). Loss of HCl → loss of H⁺ (generates alkalosis) + loss of Cl⁻ (maintains alkalosis). Secondary volume depletion → RAAS activation → ↑ aldosterone → further renal K⁺ and H⁺ loss. HypoK from vomiting is actually largely a renal loss, not direct GI loss! [6][7] |
| Villous adenoma of colon | Rare; can secrete Cl⁻-rich, K⁺-rich fluid | |
| Renal loss of H⁺ (with volume depletion) | Diuretics (thiazide, furosemide) [1] | Loop diuretics block NKCC2 → ↑ Na⁺ delivery to collecting duct → ↑ K⁺/H⁺ secretion. Also cause volume contraction → ↑ proximal HCO₃⁻ reabsorption. Direct Cl⁻ loss in urine. NB: Urine Cl⁻ is high during diuretic action but low after the diuretic has worn off — timing of measurement matters! |
| Post-hypercapnic alkalosis | Chronic respiratory acidosis (e.g., COPD) → rapid correction with mechanical ventilation | During chronic respiratory acidosis, the kidney compensates by retaining HCO₃⁻. When you intubate and suddenly normalise pCO₂, the accumulated HCO₃⁻ remains → transient metabolic alkalosis. Maintenance: often concurrent Cl⁻ and K⁺ depletion from prior diuretic use |
| Contraction alkalosis | Diuresis, laxative abuse, vomiting, NG drainage, sweating in cystic fibrosis [3] | Loss of HCO₃⁻-poor fluid → ECF volume "contracts" around a relatively fixed total body HCO₃⁻ → concentration of HCO₃⁻ rises. (Think of it as the denominator shrinking while the numerator stays the same.) |
Vomiting and HypoK — Key Exam Point
"HypoK in vomiting is not due to direct GI loss but renal loss!" [6][7] Gastric juice contains only ~10 mmol/L K⁺ — not enough to cause significant hypokalaemia from vomiting alone. The mechanism is:
- Chloride deficiency → increased delivery of Na⁺ to distal tubules → increased K⁺ loss
- Metabolic alkalosis → bicarbonaturia → HCO₃⁻ acts as non-reabsorbable anion → drives K⁺ secretion
- Secondary hyperaldosteronism due to volume depletion → ↑ ENaC activity → ↑ K⁺ secretion
This triad is sometimes called "Pseudo-Bartter syndrome" [6][7]. Urine Cl⁻ is low (< 15–20 mEq/L) in this setting.
These patients have adequate or expanded ECF volume. Giving saline won't fix the problem because the maintenance factor is ongoing mineralocorticoid excess or severe K⁺ depletion rather than volume/chloride depletion.
Further subdivided by blood pressure:
A. Hypertensive (mineralocorticoid excess syndromes):
| Cause | Pathophysiology |
|---|---|
| Primary hyperaldosteronism (Conn's syndrome) [1][9] | Autonomous aldosterone secretion (adenoma 30–40%, bilateral hyperplasia 60–70%) → ↑ ENaC-mediated Na⁺ reabsorption → lumen-negative voltage → drives K⁺ and H⁺ secretion → hypokalaemic metabolic alkalosis + hypertension [9]. Biochemistry: ↓ renin, ↑ aldosterone. |
| Secondary hyperaldosteronism [1] | ↑ Renin → ↑ Aldosterone. Causes: renal artery stenosis, renin-secreting tumour, malignant hypertension. Same downstream effect on K⁺/H⁺. |
| Cushing's syndrome | Cortisol at very high levels overwhelms 11β-HSD2 → binds mineralocorticoid receptor → acts like aldosterone. Especially relevant in ectopic ACTH syndrome (e.g., oat cell/small cell lung CA) where cortisol levels are extremely high [6][7]. |
| Apparent mineralocorticoid excess (AME) / Liquorice ingestion | Liquorice contains glycyrrhizinic acid, an inhibitor of 11β-hydroxysteroid dehydrogenase (11β-HSD2). This enzyme normally converts cortisol → cortisone in the kidney. When inhibited, cortisol accumulates locally and binds the mineralocorticoid receptor → hypokalaemia and metabolic alkalosis [6][7]. "The enzyme can be overloaded by massive amounts of cortisol, leading to hypoK and alkalosis — a feature of oat cell lung CA" [6][7]. In Hong Kong, beware of 甘草 (gān cǎo) in TCM preparations. |
| Liddle syndrome | Gain-of-function mutation in ENaC → constitutive Na⁺ reabsorption independent of aldosterone → hypokalaemic alkalosis + hypertension with ↓ renin and ↓ aldosterone. Responds to amiloride (ENaC blocker), NOT spironolactone. |
| 11β-hydroxylase / 17α-hydroxylase deficiency (CAH) | Excess deoxycorticosterone (a mineralocorticoid) → similar downstream effects. |
B. Normotensive:
| Cause | Pathophysiology |
|---|---|
| Bartter's syndrome [1][2][10] | Autosomal recessive. Defect in NKCC2 (or ROMK or ClC-Kb) in the thick ascending limb of the loop of Henle → mimics the effect of a loop diuretic. Features: hypokalaemia, metabolic alkalosis, normal to low blood pressure, elevated renin and aldosterone [10]. Two subtypes: neonatal (severe, polyhydramnios) and classic. |
| Gitelman's syndrome [1][2][10] | Autosomal recessive. Defect in NCC (thiazide-sensitive Na⁺/Cl⁻ co-transporter) in the distal convoluted tubule → mimics thiazide diuretic. Milder than Bartter's. Features: hypokalaemic alkalosis + hypomagnesaemia + hypocalciuria (distinguishing features). |
| Severe hypokalaemia (any cause) [2] | Intracellular H⁺ shift → intracellular acidosis in renal tubular cells → ↑ ammoniagenesis and ↑ HCO₃⁻ reabsorption → metabolic alkalosis. |
| Alkali load | Intake of NaHCO₃, milk-alkali syndrome [1] (excessive calcium carbonate antacids → hypercalcaemia + metabolic alkalosis + renal impairment — the triad). |
| Ringer's lactate, massive blood transfusion (citrate), TPN (acetate) [3] | Lactate, citrate, and acetate are all metabolised by the liver to HCO₃⁻. In massive quantities → significant HCO₃⁻ load. |
Why Urine Na⁺ is Unreliable in Metabolic Alkalosis
Urine Na⁺ is inaccurate in determining volume status in metabolic alkalosis [2]. The reason: alkalemia increases filtered HCO₃⁻ that escapes proximal reabsorption → this negatively charged HCO₃⁻ obligates urinary Na⁺ excretion (to maintain electroneutrality) → urine Na⁺ may be spuriously high despite true volume depletion. Use urine Cl⁻ instead [2][3].
| Feature | Saline-Responsive | Saline-Resistant |
|---|---|---|
| Urine Cl⁻ | < 15–20 mEq/L | > 15–20 mEq/L |
| ECF volume | Contracted | Normal or expanded |
| Blood pressure | Usually normal or low | Often hypertensive (if mineralocorticoid excess) |
| Key causes | Vomiting, NG suction, diuretics (remote use), post-hypercapnia, contraction alkalosis | Primary/secondary hyperaldosteronism, Cushing's, liquorice, Bartter's, Gitelman's, severe hypoK, alkali load |
| Treatment principle | Volume repletion with NS ± KCl | Treat underlying cause; spironolactone if mineralocorticoid excess |
5. Classification
As detailed in Section 4.2 above.
| Phase | Mechanism | Clinical Implication |
|---|---|---|
| Generation | Event that creates the initial ↑ HCO₃⁻ (or ↓ H⁺) | Must identify to prevent recurrence |
| Maintenance | Kidney's failure to excrete excess HCO₃⁻ (Cl⁻ depletion, K⁺ depletion, volume depletion, mineralocorticoid excess, ↓ GFR) | Must be corrected for the alkalosis to resolve [3] |
6. Clinical Features
| Symptom | Mechanism |
|---|---|
| Often asymptomatic (mild alkalosis) | pH 7.45–7.50 often well-tolerated; compensation (hypoventilation) keeps pH in near-normal range |
| Paraesthesiae (tingling, numbness — perioral, fingers) | Alkalemia → ↓ ionised (free) Ca²⁺ because more Ca²⁺ binds to albumin at higher pH (H⁺ normally competes with Ca²⁺ for albumin binding sites; when H⁺ ↓, more binding sites available for Ca²⁺). ↓ Ionised Ca²⁺ → neuronal hyperexcitability. Also partly due to Mg²⁺ loss [9]. |
| Muscle cramps, carpopedal spasm, tetany | Same mechanism — severe reduction in ionised Ca²⁺ → spontaneous motor nerve firing |
| Muscle weakness, especially proximal | Concurrent hypokalaemia — K⁺ is critical for maintaining resting membrane potential of skeletal muscle. HypoK → hyperpolarisation → muscle weakness/paralysis [6] |
| Fatigue, lethargy | Combination of hypokalaemia (impaired muscle energetics) and tissue hypoxia (left-shifted O₂-Hb curve) |
| Polyuria, polydipsia, nocturia | Hypokalaemia → nephrogenic diabetes insipidus (impaired aquaporin-2 expression in collecting duct; also ↓ medullary concentration gradient) [9] |
| Confusion, altered mental status | Severe alkalemia (pH > 7.55) → cerebral vasoconstriction → ↓ cerebral blood flow; also ↓ ionised Ca²⁺ → neuronal irritability. In liver disease: alkalosis promotes NH₃ crossing BBB → hepatic encephalopathy [4]. |
| Nausea, vomiting (if severe) | Central effect of severe alkalemia; also may be the cause rather than the consequence |
| Seizures (rare, severe alkalosis) | ↓ Ionised Ca²⁺ + ↓ cerebral blood flow → lowered seizure threshold |
| Respiratory symptoms: dyspnoea | Compensatory hypoventilation (↓ respiratory drive) may worsen pre-existing hypoxaemia; patients with lung disease may not tolerate this |
| Sign | Mechanism |
|---|---|
| Hypoventilation / shallow respirations | Respiratory compensation for metabolic alkalosis: ↑ pCO₂ to restore pH towards normal. Expected pCO₂ ≈ 0.7 × [HCO₃⁻] + 21 (± 2) [2]. However, compensation is limited — the body will not hypoventilate to the point of significant hypoxaemia (pCO₂ rarely exceeds 55 mmHg). |
| Chvostek's sign (tapping facial nerve → ipsilateral facial muscle twitch) | ↓ Ionised Ca²⁺ from alkalemia → increased neuromuscular excitability |
| Trousseau's sign (inflate BP cuff above systolic for 3 min → carpopedal spasm) | Same mechanism — ischaemia + ↓ ionised Ca²⁺ → spontaneous nerve firing |
| Hypotension, tachycardia (if volume depleted) | Underlying ECF volume depletion (saline-responsive causes) → ↓ preload → ↓ cardiac output |
| Hypertension (if mineralocorticoid excess) | Na⁺ and water retention from aldosterone/cortisol effect → volume expansion → hypertension [9] |
| ↓ Deep tendon reflexes, hypotonia, ileus | Hypokalaemia → hyperpolarisation of nerve and muscle membranes → ↓ excitability |
| Cardiac arrhythmias (ECG changes) | Hypokalaemia: flattened T waves, ST depression, U waves, prolonged QT, risk of torsades de pointes and VF. Alkalemia itself also prolongs QT. |
| ↓ Skin turgor, dry mucous membranes | Volume depletion in saline-responsive causes |
| Oedema | In saline-resistant causes with mineralocorticoid excess → Na⁺ retention [9] |
| Abdominal distension | Hypokalaemia-induced ileus (paralytic ileus) |
| Latent/overt tetany | Metabolic alkalosis causing ↓ ionised Ca²⁺ [9] |
Respiratory Compensation — Exam Favourite
Expected respiratory compensation in metabolic alkalosis:
- pCO₂ rises by ~0.7 mmHg for every 1 mEq/L rise in HCO₃⁻
- Expected pCO₂ ≈ 0.7 × [HCO₃⁻] + 21 (± 2)
- Compensation is limited — pCO₂ rarely exceeds 55 mmHg because hypoxaemia from hypoventilation eventually stimulates the peripheral chemoreceptors.
- If the measured pCO₂ is higher or lower than expected → suspect a concurrent respiratory acid–base disorder [1][2].
This deserves special emphasis as it is clinically important and repeatedly examined:
Metabolic alkalosis is a precipitating factor for hepatic encephalopathy [4].
Mechanism:
- Ammonia (NH₃) exists in equilibrium with ammonium (NH₄⁺): NH₃ + H⁺ ⇌ NH₄⁺
- At physiological pH, most ammonia exists as NH₄⁺ (charged → cannot cross BBB).
- In alkalosis, the equilibrium shifts towards NH₃ (uncharged → freely crosses BBB → enters brain → neurotoxicity → encephalopathy) [4].
- Additionally, hypokalaemia (frequently accompanies metabolic alkalosis) itself promotes ammonia production: intracellular acidosis in renal tubular cells from K⁺ depletion → ↑ ammoniagenesis → ↑ total body ammonia [4].
This is why in a cirrhotic patient, you must aggressively correct hypokalaemia and avoid metabolic alkalosis (be careful with diuretic doses!).
| Lab Finding | Explanation |
|---|---|
| ↑ pH ( > 7.45) | Defining feature (unless compensated or mixed disorder) |
| ↑ HCO₃⁻ ( > 26 mmol/L) | Primary disturbance |
| ↑ pCO₂ | Respiratory compensation (hypoventilation) |
| ↓ K⁺ | Classical association [1][2] — bidirectional relationship as above |
| ↓ Cl⁻ | Often the root cause of maintenance; also lost with H⁺ in vomiting (HCl) |
| ↓ Ionised Ca²⁺ | pH-dependent shift of Ca²⁺ onto albumin (total Ca²⁺ may be normal) |
| Urine Cl⁻ | Key discriminator: < 20 mmol/L = saline-responsive; > 20 mmol/L = saline-resistant [2][3] |
| ↓ Mg²⁺ | Often concurrent, especially with diuretics and Gitelman's |
ABG in pyloric stenosis: hypochloraemic hypokalaemic metabolic alkalosis [5].
- Why? Projectile, non-bilious vomiting of HCl-rich gastric juice → massive H⁺ and Cl⁻ loss → generation of metabolic alkalosis. Volume depletion → RAAS activation → aldosterone → renal K⁺/H⁺ loss → maintenance. The kidney eventually enters "paradoxical aciduria" — despite systemic alkalosis, the kidney excretes H⁺ (acidic urine) because it prioritises Na⁺ and volume reabsorption over correcting the alkalosis (Na⁺ is reabsorbed with HCO₃⁻ in the PCT when Cl⁻ is unavailable).
Let's tie everything together with a comprehensive pathophysiological diagram:
Key Pathophysiological Concepts Summarised
-
The kidney normally has a very high capacity to excrete HCO₃⁻ — you can infuse large amounts of NaHCO₃ into a healthy person and the kidney will dump it all. This is why a maintenance factor MUST be present for sustained metabolic alkalosis [3].
-
Chloride is king — Cl⁻ depletion prevents HCO₃⁻ excretion via pendrin and forces the kidney to reabsorb Na⁺ with HCO₃⁻ instead of Cl⁻ in the proximal tubule.
-
Volume depletion and hypokalaemia synergise — volume depletion increases proximal HCO₃⁻ reabsorption (the tubule reabsorbs "whatever it can" to hold onto volume); hypokalaemia drives intracellular acidosis in tubular cells → further ↑ HCO₃⁻ generation and reabsorption.
-
Mineralocorticoid excess is a self-perpetuating cycle — aldosterone → ↑ K⁺ loss → hypoK → intracellular acidosis → ↑ ammoniagenesis → more HCO₃⁻ generation, and simultaneously ↑ H⁺ secretion directly → alkalosis continues as long as the excess exists.
High Yield Summary
-
Definition: Metabolic alkalosis = primary ↑ HCO₃⁻ with ↑ pH; requires both a generation event and a maintenance factor.
-
Most common acid–base disorder in hospitalised patients.
-
Two-phase model: Generation (creates excess HCO₃⁻ or loses H⁺) + Maintenance (kidney fails to excrete HCO₃⁻ due to Cl⁻ depletion, K⁺ depletion, volume depletion, mineralocorticoid excess, or ↓ GFR).
-
Saline-responsive (UCl < 20): Vomiting, NG suction, diuretics (remote), post-hypercapnia, contraction alkalosis → treat with NS ± KCl.
-
Saline-resistant (UCl > 20): Mineralocorticoid excess (Conn's, Cushing's, liquorice), Bartter's, Gitelman's, severe hypoK, alkali load → treat underlying cause ± spironolactone.
-
Use urine Cl⁻ (NOT urine Na⁺) to classify — urine Na⁺ is unreliable due to bicarbonaturia.
-
Hypokalaemia is the classical electrolyte abnormality — bidirectional relationship.
-
Respiratory compensation: pCO₂ ↑ ~0.7 per 1 mEq/L ↑ HCO₃⁻; expected pCO₂ ≈ 0.7 × [HCO₃⁻] + 21 (±2); rarely > 55 mmHg.
-
Metabolic alkalosis precipitates hepatic encephalopathy by shifting NH₄⁺ → NH₃ (crosses BBB).
-
Pyloric stenosis (paeds): Classic presentation = hypochloraemic hypokalaemic metabolic alkalosis.
-
Vomiting-induced hypoK is a renal loss (not direct GI loss): Cl⁻ depletion → ↑ distal Na⁺ delivery → ↑ K⁺ secretion; metabolic alkalosis → bicarbonaturia → K⁺ loss; secondary hyperaldosteronism → further K⁺ loss.
-
Liquorice (甘草) inhibits 11β-HSD2 → cortisol acts on mineralocorticoid receptor → hypoK + metabolic alkalosis. Hong Kong relevant (TCM).
Active Recall - Metabolic Alkalosis (Definition, Aetiology, Pathophysiology, Clinical Features)
[1] Lecture slides: GC 044. Electrolyte and Acid-Base Disorders.pdf (Metabolic alkalosis slide) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf, p89 (Metabolic alkalosis section) [3] Senior notes: Ryan Ho Urogenital.pdf, p50 (Section 2.4.3 Metabolic Alkalosis) [4] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf, p464 (Hepatic encephalopathy precipitants) [5] Senior notes: Adrian Lui Pediatrics Notes.pdf, p253 (Pyloric stenosis) [6] Lecture slides: MBBS IV Electrolytes_2024.pdf, p21–22 (Liquorice/11beta-HSD2; Emetics mechanism) [7] Lecture slides: MBBS IV Electrolytes_2024 (1).pdf, p21–22 (Liquorice/11beta-HSD2; Emetics mechanism) [8] Senior notes: Ryan Ho Critical Care.pdf, p20 (Massive transfusion risks — metabolic alkalosis) [9] Senior notes: Ryan Ho Endocrine.pdf, p57 (Primary hyperaldosteronism — clinical features and biochemistry) [10] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf, p31 (Bartter syndrome)
Differential Diagnosis of Metabolic Alkalosis
When you encounter a patient with metabolic alkalosis (↑ HCO₃⁻, ↑ pH), the differential diagnosis is not simply a list to memorise. It is a logical algorithm driven by a few key discriminators that you can derive from first principles:
- Is this truly a primary metabolic alkalosis? (or is it compensation for chronic respiratory acidosis?)
- What is the urine Cl⁻? → separates saline-responsive from saline-resistant
- If saline-resistant: what is the blood pressure? → separates mineralocorticoid excess (hypertensive) from non-mineralocorticoid causes (normotensive)
- If hypertensive: what are the renin and aldosterone levels? → pinpoints the specific endocrine cause
This stepwise reasoning mirrors how you would work it up at the bedside. Let's walk through each layer systematically.
Before launching into the DDx of metabolic alkalosis, make sure you are not looking at compensatory metabolic alkalosis for chronic respiratory acidosis. The key is context and the pCO₂:
- In primary metabolic alkalosis, the pCO₂ rises as compensation (hypoventilation), but the pH remains > 7.40 (or at least at the alkalotic end).
- In compensatory metabolic alkalosis (i.e., chronic respiratory acidosis with renal HCO₃⁻ retention), the primary event is ↑ pCO₂ from lung disease, and the kidney retains HCO₃⁻ to bring pH towards normal. The pH is usually < 7.40 or at the acidotic side of normal.
Post-hypercapnic alkalosis is a hybrid: the patient had chronic respiratory acidosis (e.g., COPD), the kidneys compensated by retaining HCO₃⁻, and then the respiratory disorder was rapidly corrected (e.g., intubation and ventilation). Now the pCO₂ is normal but the excess HCO₃⁻ remains → transient metabolic alkalosis [1][2].
Also exclude a mixed disorder: concurrent metabolic alkalosis + respiratory alkalosis can produce severe alkalemia (pH > 7.55) out of proportion to either individual process.
High Yield — GC Slide Point
The workup for metabolic alkalosis centres on urine Cl⁻:
Do NOT use urine Na⁺ — it is unreliable in metabolic alkalosis because alkalemia increases filtered HCO₃⁻ above the resorptive threshold → the excess HCO₃⁻ (negatively charged) obligates Na⁺ co-excretion → urine Na⁺ is spuriously elevated despite true volume depletion [2].
Why urine Cl⁻ works: In a volume-depleted patient, the kidney avidly reabsorbs both Na⁺ and Cl⁻. However, in metabolic alkalosis the excess HCO₃⁻ forces some Na⁺ to be excreted (electroneutrality). Chloride is not affected by this phenomenon — it remains low if the patient is truly volume/chloride-depleted. Therefore urine Cl⁻ is a more reliable marker of volume status in this setting.
Caveat on timing: Diuretics cause renal Cl⁻ and K⁺ wasting, so urine Cl⁻ is high during active diuretic effect but low after the drug has worn off. Always consider timing relative to the last dose [3].
These patients are volume-contracted and chloride-depleted. The alkalosis will correct with normal saline (0.9% NaCl) ± KCl.
| Differential | Key History / Clue | Pathophysiology |
|---|---|---|
| Vomiting [1][4] | Nausea, retching; history of pregnancy, gastric outlet obstruction (GOO), eating disorder (bulimia nervosa), post-operative state | Loss of HCl-rich gastric fluid → H⁺ loss (generation) + Cl⁻ loss + volume depletion → RAAS activation → secondary hyperaldosteronism → renal K⁺/H⁺ loss (maintenance). HypoK in vomiting is predominantly renal loss, not GI loss — "Pseudo-Bartter syndrome" [6][7][14] |
| Nasogastric (NG) tube drainage [1][4] | Post-surgical, ICU setting; continuous NG suction | Identical mechanism to vomiting — continuous removal of gastric HCl |
| Diuretics — remote/past use [1][4] | History of thiazide or loop diuretic; urine Cl⁻ measured after drug has worn off | During active use → renal Na⁺/K⁺/Cl⁻ loss → volume depletion + Cl⁻ depletion + hypoK → generates and maintains alkalosis. After the drug wears off, the kidney starts retaining Cl⁻ → urine Cl⁻ falls < 20 |
| Contraction alkalosis [2] | History of massive diuresis, profuse vomiting, laxative abuse, sweating in cystic fibrosis [3] | Loss of HCO₃⁻-poor fluid → ECF volume "contracts" around a fixed amount of HCO₃⁻ → concentration of HCO₃⁻ rises (numerator stays same, denominator shrinks) |
| Post-hypercapnic alkalosis [2][3] | COPD patient recently intubated; sudden improvement after mechanical ventilation | Renal HCO₃⁻ retention was compensatory for chronic ↑ pCO₂. Rapid correction of pCO₂ leaves behind the excess HCO₃⁻. Usually concurrent Cl⁻/K⁺ depletion from prior diuretic use |
| Villous adenoma of colon [2][14] | Chronic watery diarrhoea with mucus, rectal bleeding | Secretes Cl⁻-rich and K⁺-rich fluid from the colonic mucosa → Cl⁻ and K⁺ depletion → metabolic alkalosis. This is an uncommon but classic exam answer. |
Paediatric DDx (Saline-Responsive):
| Differential | Key History / Clue | Pathophysiology |
|---|---|---|
| Pyloric stenosis [5] | 3–5 week-old infant, projectile non-bilious vomiting, palpable olive mass, visible peristalsis, M > F = 5:1 | ABG: hypochloraemic hypokalaemic metabolic alkalosis [5]. Massive HCl loss → H⁺/Cl⁻ depletion → RAAS activation → renal K⁺/H⁺ loss. Eventually "paradoxical aciduria" develops. |
| Congenital chloride diarrhoea [3] | Rare AR condition, profuse watery Cl⁻-rich diarrhoea from birth, polyhydramnios | Defective Cl⁻/HCO₃⁻ exchange in ileum and colon → massive faecal Cl⁻ loss → Cl⁻ depletion → metabolic alkalosis |
| Cystic fibrosis — sweat losses [3] | Recurrent respiratory infections, FTT, salty sweat | Excessive Cl⁻ (and Na⁺) loss in sweat → Cl⁻ depletion → metabolic alkalosis (especially in hot climates/febrile episodes) |
Step 3: Saline-Resistant Causes (Urine Cl⁻ > 15–20 mEq/L)
These patients have adequate or expanded ECF. The kidney is losing Cl⁻ despite not being volume-depleted — because there is an ongoing stimulus driving renal H⁺ and K⁺ secretion. Normal saline alone will NOT fix the alkalosis.
Now subdivide by blood pressure:
All of these share a common final pathway: excessive mineralocorticoid activity at the collecting duct → ↑ ENaC-mediated Na⁺ reabsorption → lumen-negative voltage → drives K⁺ and H⁺ secretion → hypokalaemic metabolic alkalosis + hypertension [1][9][12].
To differentiate within this group, measure plasma renin activity (PRA) and plasma aldosterone concentration (PAC):
| Differential | Renin | Aldosterone | Key Features / Clues |
|---|---|---|---|
| Primary hyperaldosteronism (Conn's syndrome) [1][2][9][12] | ↓ | ↑ | Most common endocrine cause of secondary HTN (~10% of HTN patients). Subtypes: adrenal adenoma (30–40%) vs bilateral adrenal hyperplasia (60–70%) [9]. Screening: aldosterone:renin ratio (ARR) [12]. HypoK is classical but present in only 9–37% in recent series [9]. |
| Glucocorticoid-remediable aldosteronism (FH type I) [9] | ↓ | ↑ | Rare AD condition; ectopic aldosterone secretion from zona fasciculata/reticularis in response to ACTH → dexamethasone-suppressible. Young patient with early-onset HTN + family history. |
| Secondary hyperaldosteronism [1][2] | ↑ | ↑ | Renin-driven. Causes: renal artery stenosis (RAS), renin-secreting tumour, malignant HTN. The hypertension and hypokalaemic alkalosis are consequences of RAAS over-activation from reduced renal perfusion [11]. |
| Cushing's syndrome [13] | ↓ | ↓ (or normal) | Excess cortisol overwhelms 11β-HSD2 → cortisol binds mineralocorticoid receptor → hypoK + metabolic alkalosis [6][7][13]. Clue: Cushingoid features (moon face, striae, proximal myopathy). Ectopic ACTH (e.g., oat cell lung CA) typically presents with hypoK rather than classical Cushingoid features due to rapid onset and massive cortisol [13]. |
| Liquorice / glycyrrhizinic acid ingestion [6][7][14] | ↓ | ↓ | Inhibits 11β-HSD2 → cortisol acts on mineralocorticoid receptor → pseudo-hyperaldosteronism [6][7]. In Hong Kong, beware 甘草 (gān cǎo) in TCM. Renin and aldosterone both suppressed (distinguishes from true hyperaldosteronism). |
| Liddle syndrome | ↓ | ↓ | Gain-of-function ENaC mutation → constitutive Na⁺ reabsorption. Young patient, family history of early HTN + hypoK. Responds to amiloride/triamterene (ENaC blockers), NOT spironolactone. |
| 11β-hydroxylase / 17α-hydroxylase deficiency (CAH) | ↓ | ↓ | Excess deoxycorticosterone (DOC, a mineralocorticoid). ± virilisation/ambiguous genitalia depending on enzyme. |
| Apparent mineralocorticoid excess (AME) | ↓ | ↓ | Congenital deficiency of 11β-HSD2 (same pathway as liquorice, but genetic). Very rare AR condition; childhood-onset severe HTN + hypoK. |
The Renin–Aldosterone Grid — Must Know for Exams
| Pattern | ↓ Renin, ↑ Aldo | ↑ Renin, ↑ Aldo | ↓ Renin, ↓ Aldo |
|---|---|---|---|
| Diagnosis | Primary hyperaldosteronism | Secondary hyperaldosteronism | Non-aldosterone mineralocorticoid excess (Cushing's, liquorice, Liddle, CAH, AME) [12] |
| Why renin is suppressed | Autonomous aldo suppresses renin via Na⁺ retention | Renin is the driver | Mineralocorticoid effect (from cortisol/DOC/ENaC gain-of-function) → Na⁺ retention → renin suppressed; aldo also suppressed because renin is low |
This grid is directly from the GC approach to investigating hypertension with hypokalaemic alkalosis [11][12].
| Differential | Key Features / Clues | Pathophysiology |
|---|---|---|
| Bartter's syndrome [1][4][10] | AR; presents neonatal (severe — polyhydramnios, prematurity) or classic (childhood/adolescence). Hypokalaemia, metabolic alkalosis, normal-to-low BP, elevated renin and aldosterone [10]. Hypercalciuria (→ nephrocalcinosis) in neonatal type. | Defect in NKCC2 / ROMK / ClC-Kb in thick ascending limb → mimics chronic loop diuretic. ↑ Distal Na⁺ delivery → ↑ K⁺/H⁺ secretion. Volume loss → secondary hyperaldosteronism → further K⁺/H⁺ loss. BP remains normal because prostaglandin-mediated vasodilation offsets RAAS activation. |
| Gitelman's syndrome [1][4][10] | AR; milder than Bartter's; older presentation (adolescence/adulthood). HypoK + metabolic alkalosis + hypomagnesaemia + hypocalciuria (the last two distinguish from Bartter's). | Defect in NCC (thiazide-sensitive co-transporter) in DCT → mimics chronic thiazide. ↑ Ca²⁺ reabsorption in DCT (paradoxically, because Na⁺ is not reabsorbed so electrochemical gradient favours passive Ca²⁺ reabsorption) → hypocalciuria; ↓ Mg²⁺ reabsorption via TRPM6 → hypomagnesaemia. |
| Severe hypokalaemia (any cause) [2] | Serum K⁺ very low ( < 2.5 mmol/L); may be from any aetiology of hypoK | Intracellular acidosis in renal tubular cells → ↑ NHE3 activity → ↑ HCO₃⁻ reabsorption; ↑ ammoniagenesis → net acid excretion → metabolic alkalosis |
| Alkali administration / ingestion [1][4] | History of NaHCO₃ intake, excessive calcium carbonate antacids, TPN (acetate), Ringer's lactate, massive blood transfusion (citrate) | Exogenous HCO₃⁻ load (or its metabolic precursors: lactate/citrate/acetate → hepatic metabolism → HCO₃⁻). Maintenance requires concurrent renal impairment or K⁺/Cl⁻ depletion; otherwise the kidney dumps the excess. Milk-alkali syndrome: excessive CaCO₃ → hypercalcaemia + metabolic alkalosis + AKI [1][4]. |
| Current diuretic use (timing matters) [14] | Patient still taking thiazide or loop diuretic; urine Cl⁻ is high because the drug is actively blocking Cl⁻ reabsorption right now | During active drug effect, Cl⁻ is being wasted renally → urine Cl⁻ > 20. This is technically saline-resistant while the drug is in the system. |
| Magnesium depletion [14] | Often co-exists with hypoK (diuretics, alcoholism, PPIs, Gitelman's) | Mg²⁺ is required for ROMK channel closure in the collecting duct. When Mg²⁺ is low, ROMK stays open → constitutive K⁺ secretion → refractory hypoK → metabolic alkalosis. Clinical pearl: if you can't correct the K⁺, check and replace Mg²⁺ first. |
| Penicillin, carbenicillin, ticarcillin [3] | High-dose IV penicillin antibiotics, ICU setting | These act as non-reabsorbable anions in the distal tubule → increase lumen electronegativity → drive K⁺ and H⁺ secretion. |
| Leukaemia [14] | Known haematological malignancy; lysozyme production (esp. AML) | Lysozyme causes renal tubular damage → K⁺ wasting → hypoK + metabolic alkalosis. Rare mechanism. |
Special Differential Diagnostic Scenarios
Bulimia nervosa can produce metabolic alkalosis through self-induced vomiting (pseudo-Bartter syndrome: hypoK + low urine Cl⁻ + metabolic alkalosis) [6][7][15]. Clue: young female, parotid enlargement, dental erosions, Russell's sign (calluses on knuckles). Some patients also abuse laxatives (which causes metabolic acidosis from GI HCO₃⁻ loss) — you may see a mixed picture.
In adults, GOO from peptic ulcer disease or gastric/pancreatic malignancy causes protracted vomiting → dehydration, hypoK, hypoCl metabolic alkalosis [16]. Key features: early satiety, vomiting of food eaten > 8 hours ago, succussion splash on exam.
Drugs are the most common cause of metabolic alkalosis in clinical practice [4]:
| Drug | Mechanism |
|---|---|
| Thiazide diuretics | Block NCC → ↑ distal Na⁺ delivery → K⁺/H⁺ wasting; Cl⁻ loss; volume contraction |
| Loop diuretics (furosemide) | Block NKCC2 → same downstream effect, more potent |
| Corticosteroids (high-dose) | Overwhelm 11β-HSD2 → mineralocorticoid effect |
| Fludrocortisone (exogenous mineralocorticoid) | Direct mineralocorticoid receptor activation |
| NaHCO₃ infusion | Exogenous alkali load |
| Antacids (CaCO₃) | Milk-alkali syndrome |
| Liquorice (甘草) | 11β-HSD2 inhibition [6][7] |
How to Differentiate Key Look-Alike Conditions
All three present with hypokalaemic metabolic alkalosis, high urinary K⁺, and normotension. How do you tell them apart?
| Feature | Bartter's | Gitelman's | Surreptitious Diuretic Abuse |
|---|---|---|---|
| Mimics | Loop diuretic (furosemide) | Thiazide diuretic | Actual diuretics |
| Urine Ca²⁺ | ↑ (hypercalciuria) | ↓ (hypocalciuria) — key distinguisher | Variable (depends on drug) |
| Serum Mg²⁺ | Normal or slightly low | ↓ (hypomagnesaemia) — key distinguisher | Variable |
| Severity | More severe; neonatal form → prematurity, polyhydramnios | Milder; often incidental finding in adolescence/adulthood | Variable |
| Urine diuretic screen | Negative | Negative | Positive — send urine for drug screen! |
| Genetic testing | NKCC2 / ROMK / ClC-Kb mutations | NCC mutation | N/A |
Exam Trap — Bartter vs. Gitelman
Both Bartter's and Gitelman's present with hypoK + metabolic alkalosis + normotension + high urine K. The distinguishing features are:
- Gitelman's = hypomagnesaemia + hypocalciuria (like thiazide effect)
- Bartter's = hypercalciuria ± nephrocalcinosis (like loop diuretic effect) [10]
If the question gives you a normotensive patient with hypoK + metabolic alkalosis + low urine Ca and low Mg → think Gitelman's.
| Feature | Conn's Syndrome | Liquorice / AME | Cushing's Syndrome |
|---|---|---|---|
| Renin | ↓ | ↓ | ↓ |
| Aldosterone | ↑ | ↓ | ↓ or normal |
| Cortisol | Normal | Normal (but cortisol not inactivated locally) | ↑ |
| Distinguishing clue | ↑ ARR; CT/MRI adrenal ± adrenal venous sampling | History of 甘草/liquorice; ↓ renin AND ↓ aldo | Cushingoid features; 24h UFC / LDDST / midnight cortisol |
A very high-yield exam point: whenever you see hypoK + metabolic alkalosis + hypertension with BOTH low renin AND low aldosterone, think of non-aldosterone mineralocorticoid excess — Cushing's, liquorice, Liddle, or CAH [6][7][12].
| Red Flag | Suggests |
|---|---|
| Young patient ( < 30) with unexplained HTN + hypoK + alkalosis | Genetic: Liddle, FH type I, CAH, congenital AME |
| Drug history of diuretics, corticosteroids, NaHCO₃, antacids | Drug-induced (most common in-hospital cause) |
| TCM use, candies, health supplements | Liquorice (甘草) — Hong Kong highly relevant [6][7][14] |
| Parotid enlargement, dental erosions, Russell's sign in young female | Bulimia nervosa [15] |
| Resistant hypertension ( ≥ 3 drugs) + hypoK | Screen for primary hyperaldosteronism (ARR) [12] |
| 3–5 week-old infant with projectile non-bilious vomiting | Pyloric stenosis [5] |
| Chronic lung disease (COPD) patient post-intubation | Post-hypercapnic alkalosis |
| Hypercalcaemia + alkalosis + renal impairment | Milk-alkali syndrome [1] |
| Persistent hypoK + metabolic alkalosis despite K replacement → check Mg | Magnesium depletion preventing K repletion [14] |
High Yield Summary — Differential Diagnosis of Metabolic Alkalosis
-
Confirm primary metabolic alkalosis vs. compensation for chronic respiratory acidosis — check the pH direction and clinical context.
-
Urine Cl⁻ is the master discriminator (NOT urine Na⁺): < 20 = saline-responsive; > 20 = saline-resistant [1][2].
-
Saline-responsive (low UCl): Vomiting, NG drainage, remote diuretics, post-hypercapnia, contraction alkalosis, villous adenoma, pyloric stenosis (paeds).
-
Saline-resistant (high UCl) + Hypertensive: Measure renin and aldosterone → ↓R ↑A = primary hyperaldosteronism; ↑R ↑A = secondary hyperaldosteronism; ↓R ↓A = non-aldo excess (Cushing's, liquorice, Liddle, CAH, AME).
-
Saline-resistant + Normotensive: Bartter's, Gitelman's, severe hypoK, alkali load, current diuretics, Mg depletion.
-
Bartter's vs. Gitelman's: Distinguish by urine Ca²⁺ and serum Mg²⁺.
-
Drugs are the most common overall cause — always take a thorough drug history including OTC, TCM, and supplements.
-
HypoK from vomiting is renal loss ("Pseudo-Bartter syndrome") — Cl⁻ depletion → ↑ distal Na⁺ → ↑ K⁺ secretion; metabolic alkalosis → bicarbonaturia → K⁺ loss; 2° hyperaldosteronism [6][7].
-
If hypoK is refractory to K⁺ replacement, check and correct Mg²⁺ [14].
Active Recall - Differential Diagnosis of Metabolic Alkalosis
References
[1] Lecture slides: GC 044. Electrolyte and Acid-Base Disorders.pdf (Metabolic alkalosis slide) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf, p89 (Metabolic alkalosis section) [3] Senior notes: Ryan Ho Urogenital.pdf, p50 (Section 2.4.3 Metabolic Alkalosis) [4] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf, p16 (Metabolic alkalosis causes and treatment) [5] Senior notes: Adrian Lui Pediatrics Notes.pdf, p253 (Pyloric stenosis) [6] Lecture slides: MBBS IV Electrolytes_2024.pdf, p21–22 (Liquorice/11beta-HSD2; Emetics mechanism) [7] Lecture slides: MBBS IV Electrolytes_2024 (1).pdf, p21–22 (Liquorice/11beta-HSD2; Emetics mechanism) [9] Senior notes: Ryan Ho Endocrine.pdf, p57 (Primary hyperaldosteronism) [10] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf, p27–31 (Bartter syndrome) [11] Senior notes: Block A - High blood pressure_ hypertension.pdf, p27 (Renovascular/mineralocorticoid HTN) [12] Senior notes: Ryan Ho Fundamentals.pdf, p433 (Approach to primary hyperaldosteronism) [13] Senior notes: Ryan Ho Endocrine.pdf, p61 (Cushing's syndrome) [14] Senior notes: Ryan Ho Chemical Path.pdf, p18 (Hypokalemia approach and causes) [15] Senior notes: Ryan Ho Psychiatry.pdf, p216 (Bulimia nervosa) [16] Senior notes: Ryan Ho GI.pdf, p81 (Ulcer-related GOO)
Diagnostic Criteria, Diagnostic Algorithm and Investigations for Metabolic Alkalosis
1. Diagnostic Criteria — Defining Metabolic Alkalosis on ABG/VBG
There is no single "diagnostic criterion" for metabolic alkalosis in the way that, say, the Jones criteria define rheumatic fever. Instead, metabolic alkalosis is diagnosed by a characteristic pattern on arterial (or venous) blood gas analysis combined with clinical context. The diagnosis is established when all three of the following are present:
| Parameter | Finding | Explanation |
|---|---|---|
| pH | > 7.45 (alkalemia) | The Henderson–Hasselbalch equation tells us: pH ∝ HCO₃⁻ / pCO₂. When HCO₃⁻ rises, pH rises. Exception: in a mixed disorder or well-compensated state, pH can be near-normal despite an ongoing metabolic alkalosis process [17]. |
| Serum HCO₃⁻ | > 26 mmol/L (primary elevation) | This is the defining metabolic component. HCO₃⁻ is elevated because of H⁺ loss or HCO₃⁻ gain [17]. |
| pCO₂ | Appropriately elevated (compensatory hypoventilation) | The respiratory system compensates by reducing ventilation → retaining CO₂. If pCO₂ is NOT elevated as expected, suspect a concurrent respiratory alkalosis. If pCO₂ is MORE elevated than expected, suspect a concurrent respiratory acidosis. |
Expected Respiratory Compensation Formula — Must Know
Expected pCO₂ ≈ 0.7 × [HCO₃⁻] + 21 (± 2 mmHg)
Alternative form: pCO₂ rises by ~0.7 mmHg for every 1 mEq/L rise in HCO₃⁻
Compensation is limited: pCO₂ rarely exceeds 55 mmHg — the body will not hypoventilate to the point of dangerous hypoxaemia [2][3].
If the measured pCO₂ does not match the expected value, a mixed acid–base disorder is present.
This is worth rehearsing because exams love to give you an ABG and ask you to interpret it. The systematic approach is:
- Look at the pH: > 7.45 → alkalemia (the primary process is an alkalosis).
- Look at the HCO₃⁻: > 26 mmol/L → metabolic component is responsible.
- Check if pCO₂ is appropriately compensated: Use the formula above. If it matches → simple metabolic alkalosis. If not → mixed disorder.
- Check the electrolytes: Expect hypokalaemia and hypochloraemia [1][4] — their absence does not exclude metabolic alkalosis, but their presence strongly supports it and the degree helps guide management.
Reminder from the GC lecture: "Change in pH follows the direction of change of the HCO₃⁻:CO₂ ratio" [17]. If HCO₃⁻ goes up and CO₂ goes up proportionally less, pH rises → metabolic alkalosis confirmed.
- Mixed disorder: Concurrent metabolic acidosis (e.g., a cirrhotic patient on diuretics who also has lactic acidosis from sepsis) can normalise the pH while the metabolic alkalosis process is still present. In this case, look for ↑ HCO₃⁻ alongside an elevated anion gap.
- Adequate compensation: Compensation alone cannot fully normalise pH in metabolic alkalosis (unlike chronic respiratory alkalosis where complete compensation is possible) [17]. So if pH is perfectly 7.40 with ↑ HCO₃⁻, think mixed disorder.
The diagnostic algorithm for metabolic alkalosis follows a logical sequence that can be derived from first principles. The goal is threefold:
- Confirm the diagnosis (ABG interpretation)
- Classify the cause (saline-responsive vs. saline-resistant)
- Identify the specific aetiology (targeted investigations)
2.1 Master Algorithm (Mermaid Diagram)
3. Investigation Modalities — Detailed Guide
Below is a systematic, investigation-by-investigation breakdown. For each test, I explain what it is, why you order it, what the key findings are, and how to interpret them.
3.1 First-Line Investigations (Every Patient with Suspected Metabolic Alkalosis)
What: Measures pH, pCO₂, pO₂, HCO₃⁻ (calculated), base excess.
Why: This is the defining investigation for any acid–base disorder. Without it, you cannot confirm metabolic alkalosis [17][18][20].
Key findings and interpretation:
| Parameter | Expected in Metabolic Alkalosis | Interpretation |
|---|---|---|
| pH | > 7.45 | Alkalemia confirms an alkalotic process is dominant |
| HCO₃⁻ | > 26 mmol/L | Primary metabolic component; the higher the HCO₃⁻, the more severe |
| pCO₂ | Elevated (compensatory) | Expected pCO₂ ≈ 0.7 × [HCO₃⁻] + 21. If measured pCO₂ does not match → mixed disorder |
| Base excess | Positive (> +2) | Reflects the metabolic component; a large positive BE confirms significant metabolic alkalosis |
| pO₂ | May be slightly low | Compensatory hypoventilation → mild hypoventilation-related hypoxaemia (usually not clinically significant unless pre-existing lung disease) |
VBG vs ABG
In practice, VBG is often used instead of ABG for acid–base assessment (less painful, fewer complications). VBG pH is ~0.03–0.04 lower than ABG pH, and VBG pCO₂ is ~3–8 mmHg higher than ABG pCO₂. VBG HCO₃⁻ correlates well with ABG HCO₃⁻. For screening purposes, VBG is adequate; ABG is needed if precise pO₂ or when mixed respiratory disorder is suspected.
What: Serum Na⁺, K⁺, Cl⁻, HCO₃⁻ (or total CO₂), Mg²⁺, Ca²⁺ (adjusted or ionised), creatinine, urea.
Why: Electrolyte disturbances are both the cause and the consequence of metabolic alkalosis. You need these to: (a) identify the classical pattern, (b) assess severity, (c) guide treatment [1][14][18].
Key findings and interpretation:
| Electrolyte | Expected Finding | Why |
|---|---|---|
| K⁺ | ↓ (< 3.5 mmol/L) | "Hypokalemia is the classical electrolyte abnormality associated with metabolic alkalosis" [1][4]. Bidirectional relationship explained in prior sections. |
| Cl⁻ | ↓ (< 98 mmol/L) | HCl loss (vomiting/NG) or renal Cl⁻ wasting (diuretics). Chloride depletion is the key maintenance factor in saline-responsive alkalosis. |
| Na⁺ | Normal or slightly elevated | In mineralocorticoid excess: Na⁺ tends to be at upper end of reference range [9][12]. |
| Mg²⁺ | Often ↓ | Co-depleted with K⁺ (diuretics, Gitelman's). If you cannot correct hypoK despite aggressive replacement → check and correct Mg²⁺ first [14]. |
| Ca²⁺ (ionised) | ↓ | Alkalemia shifts Ca²⁺ onto albumin → ↓ ionised Ca²⁺ → tetany risk [9]. Total Ca²⁺ may be normal. |
| Creatinine / Urea | Variable | Urea ↑ with dehydration (pre-renal). Creatinine ↑ if AKI from severe volume depletion or underlying CKD (reduces ability to excrete HCO₃⁻). |
From the GC vomiting workup slide: "RFT, CaPO₄: Cr ↑, Ca ↑, electrolyte disturbances (particularly K ↓, Na ↓ or Na ↑), AKI" [18]. "Venous blood gas: metabolic acidosis, metabolic alkalosis" [18].
What: Standard electrocardiogram.
Why: Hypokalaemia causes characteristic and potentially lethal ECG changes. You must do an ECG in every patient with metabolic alkalosis because concurrent hypoK is expected [18][20].
Key findings:
| ECG Finding | Serum K⁺ Level | Mechanism |
|---|---|---|
| Flattened or inverted T waves | < 3.0 mmol/L | ↓ K⁺ prolongs phase 3 repolarisation |
| ST segment depression | < 3.0 mmol/L | Altered repolarisation |
| Prominent U waves | < 2.5 mmol/L | Delayed repolarisation of Purkinje fibres or papillary muscles |
| Prolonged QT / QU interval | < 2.5 mmol/L | U wave merges with T wave → apparent QT prolongation |
| Arrhythmias (PACs, PVCs, VT, VF, TdP) | < 2.0 mmol/L | Altered automaticity and re-entry circuits |
GC slide: "ECG: U wave, flat T wave, long QTc, myocardial ischaemia" [18].
What: Random (spot) urine sample measuring Cl⁻ concentration.
Why: This is THE investigation that classifies metabolic alkalosis into saline-responsive vs. saline-resistant [1][2][3][19].
How to interpret:
| Urine Cl⁻ | Classification | Implications |
|---|---|---|
| < 15–20 mEq/L | Saline-responsive | Patient is volume/chloride-depleted; kidney avidly retains Cl⁻. Causes: vomiting, NG suction, remote diuretics, post-hypercapnia. Treatment: NS ± KCl [1][2]. |
| > 15–20 mEq/L | Saline-resistant | Adequate/expanded ECF; ongoing renal Cl⁻ wasting. Causes: current diuretics, mineralocorticoid excess, Bartter's, Gitelman's. Treatment: address underlying cause [1][2]. |
Timing Caveat with Diuretics
Diuretics cause HIGH urine Cl⁻ while active but LOW urine Cl⁻ after the drug has worn off. A patient who took furosemide this morning will have UCl > 20 right now; if you measure tomorrow morning (drug cleared), UCl will be < 20. Always consider the timing of last diuretic dose when interpreting urine Cl⁻ [3][14].
3.2 Second-Line Investigations (Guided by Urine Cl⁻ and Clinical Context)
What: Spot urine K⁺ (or 24-hour urine K⁺) measured before K⁺ replacement, paired with plasma K⁺ and HCO₃⁻.
Why: This is the core approach to working up hypokalaemia and simultaneously informs the metabolic alkalosis aetiology [2][14][21].
Key findings and interpretation (the "HCO₃⁻ + Urine K⁺ Grid"):
This grid is directly from the Chemical Pathology and senior note approach [2][14][21]:
| Plasma HCO₃⁻ | Spot Urine K⁺ | Differential Diagnosis | Mechanism |
|---|---|---|---|
| ↑ (Alkalosis) | > 20 mmol/L (renal loss) | Vomiting (renal K wasting via 2° hyperAld + bicarbonaturia), current diuretics, mineralocorticoid excess, Mg depletion, gentamicin, leukaemia [14] | Ongoing renal K⁺ secretion despite hypoK → indicates a tubular or hormonal drive pushing K⁺ out |
| ↑ (Alkalosis) | < 20 mmol/L (extrarenal) | Chronic diarrhoea, laxative abuse, previous/remote diuretics, villous adenoma of colon [14] | K⁺ is being lost via GI tract or was lost renally in the past but renal conservation has now kicked in |
| ↓ (Acidosis) | > 20 mmol/L | Renal tubular acidosis (Type 1 or 2) [14] | Renal K⁺ wasting with concurrent inability to excrete acid |
| ↓ (Acidosis) | < 20 mmol/L | Acute diarrhoea [14] | Direct GI loss of both K⁺ and HCO₃⁻ |
High Yield — GC & Medicine Lecture Case
Case 3 from MBBS IV Electrolytes lecture: "F/29, Plasma K = 1.5 mmol/L, Hx of persistent hypokalaemia and metabolic alkalosis, Plasma Na = 135 mmol/L (on the low side), Spot urine K = 56 mmol/L, Spot urine Na = 32 mmol/L" [6][7].
This is a classic presentation of either Bartter's/Gitelman's syndrome or surreptitious diuretic abuse. The spot urine K of 56 mmol/L (> 20) confirms renal K⁺ wasting. Combined with persistent metabolic alkalosis and normotension → think inherited tubulopathy. Further workup: serum Mg²⁺, urine Ca²⁺, urine diuretic screen.
What: Spot urine sodium.
Why you should be cautious: Urine Na⁺ is inaccurate in determining volume status in metabolic alkalosis because alkalemia increases HCO₃⁻ excretion (negatively charged) which obligates Na⁺ excretion (positively charged) → urine Na⁺ is spuriously elevated despite true volume depletion [2].
When it IS useful: If urine Na⁺ is very low (< 10 mmol/L), it strongly suggests volume depletion. However, a "normal" or "high" urine Na⁺ in the setting of alkalosis is uninterpretable.
Bottom line: always prefer urine Cl⁻ over urine Na⁺ for metabolic alkalosis workup [2][3].
What: TTKG = (Urine K / Plasma K) × (Plasma Osmolality / Urine Osmolality)
Why: It estimates the K⁺ concentration in the cortical collecting duct fluid, reflecting the "drive" for K⁺ secretion. TTKG > 7 in the setting of hypoK indicates inappropriate renal K⁺ wasting [21].
Caveats: TTKG has fallen out of favour in some centres because it assumes equilibration of osmolality in the CCD, which may not hold in certain states (e.g., water diuresis). Spot urine K/Cr ratio (> 2.5 mmol/mmol = renal loss) is increasingly used as an alternative [21].
3.3 Investigations for Saline-Resistant Causes
Once urine Cl⁻ > 15–20 mEq/L is confirmed, the next branch depends on blood pressure.
3.3.1 For Hypertensive Patients: Endocrine Workup
What: Simultaneous measurement of basal PRA and PAC, and calculation of the aldosterone:renin ratio (ARR) [9][12][22].
Why: This is the screening test for primary hyperaldosteronism and allows you to sort the patient into one of three diagnostic buckets:
| Pattern | Interpretation | Differential |
|---|---|---|
| ↓ PRA (< 1 ng/mL/h), ↑ PAC (≥ 10–20 ng/dL), ARR > 30 | Primary hyperaldosteronism [9][12][22] | Conn's adenoma, bilateral adrenal hyperplasia, GRA |
| ↑ PRA, ↑ PAC, ARR < 10 | Secondary hyperaldosteronism [9][12] | Renal artery stenosis, renin-secreting tumour, malignant HTN |
| ↓ PRA, ↓ PAC | Non-aldosterone mineralocorticoid excess [12] | Cushing's, liquorice, Liddle, CAH, AME |
Precautions before testing (this is high yield and frequently tested) [9][12][22]:
- Exclude other causes of hypoK first: diuretics, GI loss, RTA [22].
- Document excessive urinary K⁺ loss (spot or 24h urine K⁺) [22].
- Ensure reasonable Na⁺ intake: low Na⁺ intake protects against hypoK by ↓ tubular Na⁺ available for exchange, but can falsely elevate aldosterone via RAAS stimulation [22].
- Stop interfering drugs for ≥ 2 weeks (MRA ≥ 6 weeks) before dynamic testing:
- Diuretics → ↑ renin (false negative for primary hyperaldo)
- β-blockers → ↓ renin (false positive for primary hyperaldo)
- ACEI/ARBs → ↓ aldosterone (false negative)
- MRA (spironolactone) → blocks aldo action → ↑ renin (false negative)
- Safe drugs that don't interfere: α-blockers (prazosin, doxazosin), non-DHP CCBs (verapamil) [9][12][22]
From the screening for mineralocorticoid HT slide: "Plasma: Increased aldosterone (PAC), Decreased renin (PRA), Decreased potassium, Elevated or normal sodium, Decreased or normal magnesium, Metabolic alkalosis" [11].
If screening is positive (PRA < 1, PAC ≥ 10, ARR > 30), the diagnosis must be confirmed by one of the following salt-loading tests [2][9][22]:
| Test | Method | Positive Result |
|---|---|---|
| Saline infusion test | IV 0.9% NS over 4 hours, seated/recumbent | PAC remains ≥ 10 ng/dL (normally suppressed to < 5) [9] |
| Oral sodium loading test | High-Na diet (200 mmol/day) × 3 days + 24h urine aldosterone | 24h urinary aldosterone > 12 μg/day |
| Fludrocortisone suppression test | Fludrocortisone 0.1 mg QID × 4 days | PAC > 6 ng/dL at day 4 |
| Captopril challenge test | Captopril 25–50 mg PO, measure PAC at 1–2h | PAC fails to suppress < 30% from baseline |
Exception: "Spontaneous hypoK with Ald ≥ 20 → practically diagnostic" — confirmatory testing may be unnecessary [9].
| Investigation | Method | Interpretation |
|---|---|---|
| CT / MRI adrenal [22] | Thin-slice CT preferred | Unilateral hypodense nodule → suggests adenoma; bilateral enlargement → hyperplasia. Caveat: CT alone is insufficient — non-functioning incidentalomas are common; small adenomas can be missed. |
| Postural (balance) test [9][22] | Measure PRA + PAC at 8AM supine (after overnight recumbence) and 12 noon erect (after 4h ambulation) | Adenoma: ACTH-dependent → higher Ald in morning, paradoxical fall at noon. Hyperplasia: RAAS-dependent → higher Ald at noon. Caveat: not reliable enough alone for definitive differentiation [9]. |
| Adrenal venous sampling (AVS) [22] | Bilateral adrenal vein catheterisation; simultaneous cortisol + aldosterone from each adrenal vein + IVC | Gold standard for lateralisation. Cortisol-corrected Ald ratio > 4:1 between adrenal veins = lateralises (→ adenoma, consider surgery). < 3:1 = bilateral (→ hyperplasia, medical Mx) [22]. |
| 131-Iodocholesterol scintigraphy [22] | Nuclear medicine scan | Low sensitivity for small lesions; largely superseded by AVS. |
When you see ↓ renin AND ↓ aldosterone with hypertension + hypoK + metabolic alkalosis, the mineralocorticoid effect is NOT from aldosterone. Workup:
| Investigation | Purpose | Key Finding |
|---|---|---|
| 24h urinary free cortisol (UFC) | Screening for Cushing's | > 3× upper limit of normal is strongly suggestive |
| Low-dose dexamethasone suppression test (LDDST) | Screening | Failure of cortisol suppression to < 50 nmol/L at 8AM after 1 mg dexa at 11PM |
| Midnight salivary cortisol | Screening | Loss of diurnal cortisol rhythm |
| Drug history: liquorice (甘草), TCM, corticosteroids | Pseudo-mineralocorticoid excess | "Target search crucial for finding the causative drug" [14]. Liquorice inhibits 11β-HSD2 [6][7]. |
| Genetic testing | Liddle syndrome, congenital AME, CAH | If young patient with early-onset HTN + hypoK + ↓R ↓A and no drug cause found |
3.3.2 For Normotensive Patients: Tubulopathy and Other Workup
What: Serum Mg²⁺ and 24h urine Ca²⁺ (or spot urine Ca/Cr ratio).
Why: These are the key discriminators between Bartter's and Gitelman's syndromes [10][23]:
| Finding | Bartter's | Gitelman's |
|---|---|---|
| Serum Mg²⁺ | Normal or slightly low | ↓ (hypomagnesaemia) |
| 24h urine Ca²⁺ | ↑ (hypercalciuria) → risk of nephrocalcinosis | ↓ (hypocalciuria) |
Why this pattern? Gitelman's affects the DCT (NCC defect). Loss of Na⁺ reabsorption in DCT paradoxically enhances paracellular Ca²⁺ reabsorption (because the low intracellular Na⁺ drives more Na⁺/Ca²⁺ exchange on the basolateral side) → hypocalciuria. Mg²⁺ reabsorption via TRPM6 in the DCT is also impaired → hypomagnesaemia. Bartter's affects the TAL where most Ca²⁺ is reabsorbed paracellularly alongside Na⁺ — loss of Na⁺ reabsorption → loss of Ca²⁺ → hypercalciuria.
What: Urine screen for loop diuretics, thiazides, and their metabolites.
Why: Surreptitious diuretic abuse is a common mimic of Bartter's/Gitelman's. If the patient denies diuretic use but has a classic tubulopathy picture, send a urine drug screen [6][7].
Case 4 from MBBS IV Electrolytes lecture: "M/72, HT on amlodipine and indapamide, Persistent and severe hypoK (K 2.1 mmol/L), metabolic alkalosis, despite K replacement and stopping indapamide. Claimed no herbs or other drugs. Extensive work up but all non-informative" [6][7]. This case illustrates that sometimes the cause is occult drug ingestion (TCM, herbal preparations) — the lesson is to always perform a targeted drug search and take a careful medication/supplement history including over-the-counter and TCM.
Even without hypertension, plasma renin and aldosterone can help:
What: Targeted gene panels (or whole exome sequencing) for specific channelopathies.
When: Suspected inherited tubulopathy (young patient, consanguinity, family history, persistent unexplained hypoK + alkalosis) [10][23].
| Gene | Syndrome | Segment |
|---|---|---|
| SLC12A1 (NKCC2) | Bartter type I | TAL |
| KCNJ1 (ROMK) | Bartter type II | TAL |
| CLCNKB (ClC-Kb) | Bartter type III | TAL/DCT |
| BSND (Barttin) | Bartter type IV | TAL (with deafness) |
| SLC12A3 (NCC) | Gitelman | DCT |
| SCNN1B/SCNN1G (ENaC) | Liddle | CD |
What: Ultrasound of kidneys.
Why: Look for nephrocalcinosis (medullary calcification — suggests chronic hypercalciuria, as in Bartter's) [10]. Also assess kidney size and morphology for underlying CKD.
| Investigation | When to Order | Key Finding |
|---|---|---|
| CXR | Post-vomiting (aspiration risk); ICU (post-intubation alkalosis) | Aspiration pneumonia [18]; cardiomegaly if HF (secondary hyperaldo cause) |
| USS abdomen (pylorus) | Neonate 3–5 weeks with projectile vomiting | Elongated and hypertrophied pylorus (muscle thickness > 4 mm, length > 16 mm) [5] |
| CT/MRI adrenal | Suspected primary hyperaldosteronism | Adrenal adenoma vs hyperplasia [22] |
| Renal duplex USS / CTA / MRA | Suspected renovascular HTN | Renal artery stenosis → secondary hyperaldo [11] |
| 24h urine cortisol / LDDST | Suspected Cushing's | Elevated UFC; failure of cortisol suppression |
| AXR | Vomiting patient to r/o obstruction | Dilated bowel, air-fluid levels |
| Serum ammonia | Cirrhotic with confusion + alkalosis | ↑ NH₃; alkalosis shifts NH₄⁺ → NH₃ (crosses BBB) |
| Step | Action | Purpose |
|---|---|---|
| 1 | ABG/VBG | Confirm metabolic alkalosis (pH > 7.45, HCO₃⁻ > 26); check compensation |
| 2 | Serum electrolytes (Na⁺, K⁺, Cl⁻, Mg²⁺, Ca²⁺, Cr, urea) | Identify pattern: hypoK + hypoCl is classical; check Mg²⁺; assess renal function |
| 3 | ECG | Screen for hypoK cardiac effects (U waves, flat T, long QT) |
| 4 | Spot urine Cl⁻ | Classify: < 20 = saline-responsive; > 20 = saline-resistant |
| 5 | Spot urine K⁺ (before replacement) | Renal K⁺ loss (> 20) vs. extrarenal ( < 20) |
| 6a | If saline-responsive: Clinical assessment | Identify cause (vomiting? NG? diuretics? COPD?) → treat with NS ± KCl |
| 6b | If saline-resistant: Check BP | Hypertensive → endocrine workup; Normotensive → tubulopathy workup |
| 7 | If hypertensive: PRA + PAC + ARR | ↓R ↑A = primary hyperaldo; ↑R ↑A = secondary; ↓R ↓A = non-aldo excess |
| 8 | If normotensive: Serum Mg²⁺, urine Ca²⁺, urine drug screen | Gitelman (low Mg, low urine Ca) vs Bartter (high urine Ca) vs diuretic abuse |
| 9 | Confirmatory + subtype Ix as needed | Salt-loading test, CT adrenal, AVS, genetic testing, Cushing's workup |
High Yield Summary — Diagnosis & Investigations
-
Diagnostic criteria: pH > 7.45 + HCO₃⁻ > 26 + appropriately elevated pCO₂. Verify compensation: expected pCO₂ = 0.7 × [HCO₃⁻] + 21 (±2).
-
Urine Cl⁻ is the single most important investigation to classify metabolic alkalosis. UCl < 20 = saline-responsive; UCl > 20 = saline-resistant. Do NOT rely on urine Na⁺.
-
Spot urine K⁺ + plasma HCO₃⁻ paired assessment identifies renal vs. extrarenal K⁺ loss and narrows the differential.
-
ECG is mandatory — screen for hypoK-related arrhythmia risk (U waves, flat T, long QT).
-
For saline-resistant + hypertensive: measure PRA + PAC → classify into primary hyperaldo (↓R ↑A), secondary hyperaldo (↑R ↑A), or non-aldo excess (↓R ↓A) → targeted confirmatory Ix.
-
For saline-resistant + normotensive: serum Mg²⁺ + urine Ca²⁺ distinguish Bartter's (hypercalciuria) from Gitelman's (hypocalciuria + hypoMg) → urine drug screen to r/o surreptitious diuretic use → genetics if indicated.
-
Stop interfering drugs ≥ 2 weeks before ARR testing (diuretics, β-blockers, ACEI/ARB, MRA).
-
Adrenal venous sampling is the gold standard for lateralisation in primary hyperaldosteronism.
-
Always take a thorough drug and supplement history — including TCM (liquorice/甘草) — as drugs are the most common cause of metabolic alkalosis in hospitalised patients.
Active Recall - Diagnosis & Investigations of Metabolic Alkalosis
References
[1] Lecture slides: GC 044. Electrolyte and Acid-Base Disorders.pdf (Metabolic alkalosis slide) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf, p89 (Metabolic alkalosis section) [3] Senior notes: Ryan Ho Urogenital.pdf, p50–52 (Section 2.4.3 Metabolic Alkalosis) [4] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf, p16 (Metabolic alkalosis) [5] Senior notes: Adrian Lui Pediatrics Notes.pdf, p253 (Pyloric stenosis) [6] Lecture slides: MBBS IV Electrolytes_2024.pdf, p14, p18 (Case 3, Case 4) [7] Lecture slides: MBBS IV Electrolytes_2024 (1).pdf, p14, p18 (Case 3, Case 4) [9] Senior notes: Ryan Ho Endocrine.pdf, p57–58 (Primary hyperaldosteronism approach) [10] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf, p19, p27 (Gitelman, Bartter) [11] Senior notes: Block A - High blood pressure_ hypertension.pdf, p27 (Mineralocorticoid HTN screening) [12] Senior notes: Ryan Ho Fundamentals.pdf, p433 (Approach to primary hyperaldosteronism) [14] Senior notes: Ryan Ho Chemical Path.pdf, p18 (Hypokalemia approach — HCO₃/urine K grid) [17] Senior notes: Adrian Lui Pediatrics Notes.pdf, p310 (Acid–base approach) [18] Lecture slides: GC 068. Indigestion and 'heartburn'.pdf, p34 (Workup for acute vomiting) [19] Senior notes: Maksim Medicine Notes.pdf, p215 (Metabolic alkalosis concept) [20] Senior notes: Block A - Indigestion and 'heartburn'_ nausea and vomiting.pdf, p23 (Workup vomiting) [21] Senior notes: Ryan Ho Urogenital.pdf, p25 (Hypokalemia diagnostic evaluation) [22] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours.pdf, p8 (Conn's investigations) [23] Senior notes: Block A - Introduction to Renal Investigations (RFT, urine tests and US kidneys).pdf, p6 (Tubular problems)
Management of Metabolic Alkalosis
Before diving into specific treatments, let's establish the conceptual foundation. Everything in the management of metabolic alkalosis flows from the two-hit model you already know:
- Remove the generation event — stop whatever is creating the excess HCO₃⁻ or losing H⁺.
- Correct the maintenance factor(s) — this is the part that actually allows the kidney to dump the excess HCO₃⁻.
The kidney has an enormous innate capacity to excrete HCO₃⁻ (it filters ~4,320 mmol/day). The reason alkalosis persists is that something is preventing the kidney from doing its job. Fix that "something" — chloride depletion, potassium depletion, volume depletion, or mineralocorticoid excess — and the kidney self-corrects [1][3][4][19].
High Yield — GC Lecture Treatment Principles
GC slide treatment of metabolic alkalosis [1]:
- "If ECF contracted, expand with saline, HCO₃⁻ will fall with expansion"
- "Correct hypoK⁺"
- "If ECF expanded, correct alkalosis with IV HCl or oral NH₄Cl"
Senior note treatment principles [4]:
- "Depends on patient's ECF status"
- "Correction of hypokalemia, and: If ECF is contracted [→ saline]; if ECF is expanded [→ acid therapy]"
Detailed Treatment Modalities
Before you think about the specific aetiology, address the immediate life threats. Metabolic alkalosis itself is rarely acutely lethal, but the concurrent hypokalaemia can kill.
| Action | Indication | Rationale |
|---|---|---|
| Cardiac monitoring | K⁺ < 3.0 mmol/L or any ECG changes (U waves, long QT) | HypoK → arrhythmias (VT/VF, torsades de pointes). Continuous telemetry needed to catch and treat arrhythmias immediately. |
| IV KCl replacement | K⁺ < 2.5 mmol/L or symptomatic hypoK or ECG changes | Peripheral IV: max 40 mmol/L concentration, max 10–20 mmol/h rate. Central line: up to 40 mmol/h in ICU with monitoring. Always give KCl (not K⁺ with other anions) — the Cl⁻ component treats both the hypoK and the Cl⁻ depletion simultaneously [3]. |
| IV MgSO₄ | Mg²⁺ < 0.5 mmol/L or refractory hypoK | If you cannot correct hypoK despite aggressive replacement → check and correct Mg²⁺ [14]. Mg²⁺ deficiency keeps ROMK channels open → constitutive K⁺ secretion → K⁺ replacement is futile until Mg²⁺ is repleted. |
| IV calcium gluconate | Symptomatic hypocalcaemia (tetany, seizures) from alkalemia | Alkalemia shifts Ca²⁺ onto albumin → ↓ ionised Ca²⁺. 10% calcium gluconate 10 mL IV over 10 min stabilises the neuronal membrane. |
Why KCl, Not K-citrate or K-acetate?
In metabolic alkalosis, the goal is to replete both K⁺ AND Cl⁻. KCl provides both. Potassium citrate or potassium acetate are metabolised to HCO₃⁻ by the liver, which would worsen the alkalosis. Exception: In RTA (metabolic acidosis), potassium citrate IS appropriate because the citrate generates the HCO₃⁻ you need [4].
This seems obvious but is often forgotten in the rush to correct electrolytes. If the generation event continues, you are fighting a losing battle.
| Generation Event | Action | Details |
|---|---|---|
| Vomiting | Anti-emetics + treat underlying cause [20] | Ondansetron (5-HT₃ antagonist), metoclopramide (D₂ antagonist/prokinetic). Treat the cause: e.g., GOO → OGD ± balloon dilatation; pyloric stenosis → Ramstedt pyloromyotomy (after electrolyte correction) |
| NG suction | Minimise or discontinue if clinically safe; add PPI [2] | "PPIs if alkalosis is due to NG drainage" [2] — PPIs reduce gastric acid secretion → less HCl in the aspirate → less H⁺/Cl⁻ loss per unit volume drained. H₂ blockers (e.g., ranitidine) are an alternative. |
| Diuretics | Stop or dose-reduce the offending diuretic [3][19] | Often the single most important intervention in hospitalised patients. If ongoing diuresis is needed (e.g., heart failure), switch to a K⁺-sparing diuretic or add one (see below). |
| Alkali administration | Stop NaHCO₃ infusion, reduce CaCO₃ intake | In milk-alkali syndrome: stop all calcium carbonate antacids; hydrate; treat hypercalcaemia. |
| Liquorice / TCM / exogenous steroids | Identify and cease offending agent [6][7][14] | "Target search crucial for finding the causative drug" [14]. In Hong Kong: 甘草 (gān cǎo). |
3. Saline-Responsive Metabolic Alkalosis (UCl < 15–20 mEq/L)
These patients are volume-depleted, chloride-depleted, and usually potassium-depleted. The treatment logic is straightforward: replete what is missing.
What: 0.9% NaCl ("normal saline") contains 154 mmol/L Na⁺ and 154 mmol/L Cl⁻.
Why it works:
- Provides volume → corrects hypovolaemia → reduces proximal NaHCO₃ reabsorption → allows the kidney to start excreting HCO₃⁻.
- Provides chloride → re-enables pendrin (Cl⁻/HCO₃⁻ exchanger on β-intercalated cells) to secrete HCO₃⁻ into the tubular lumen.
- Suppresses RAAS → reduces aldosterone → less renal H⁺/K⁺ secretion.
"If ECF contracted, expand with saline, HCO₃⁻ will fall with expansion" [1].
Dosing: Typically 1–2 L over the first 2–4 hours, then titrated to clinical response (urine output, vital signs, electrolytes q4–6h). In elderly or heart failure patients, give more cautiously with monitoring for fluid overload.
Contraindications / Cautions:
- Heart failure / fluid overload: Do NOT volume-load a patient in acute decompensated HF. Use acetazolamide or cautious KCl instead.
- Severe liver disease with ascites: Aggressive saline can worsen ascites and dilutional hyponatraemia. In these patients, the alkalosis is often secondary to diuretics (spironolactone + furosemide for ascites management) — dose-reduce the diuretic and add KCl cautiously.
What: IV or oral KCl.
Why it works:
- Corrects hypokalaemia → removes the intracellular acidosis in renal tubular cells that drives excess HCO₃⁻ reabsorption and ammoniagenesis.
- The Cl⁻ component contributes to Cl⁻ repletion.
- "Correction of hypokalemia" is a core treatment principle on the GC slide [1].
Dosing:
- Mild hypoK (3.0–3.5 mmol/L): Oral KCl 40–80 mmol/day (Slow-K 600 mg tablets = 8 mmol K⁺ each; or KCl liquid).
- Moderate (2.5–3.0): IV KCl 20–40 mmol in 1 L NS over 2–4 hours; oral supplementation as tolerated.
- Severe ( < 2.5 or symptomatic): IV KCl via central line at up to 40 mmol/h with continuous cardiac monitoring.
Contraindications:
- Renal failure (GFR < 20): Risk of iatrogenic hyperkalaemia. Give cautiously with frequent monitoring.
- Hyperkalaemia: Obviously do not give K⁺ if K⁺ is already high (this can happen in mixed disorders, e.g., Type 4 RTA + concurrent metabolic alkalosis — unusual but possible).
What: Omeprazole 20–40 mg IV/PO daily, pantoprazole 40 mg IV, etc.
Why it works: By suppressing gastric parietal cell H⁺/K⁺-ATPase → less HCl produced → less H⁺ and Cl⁻ lost in NG drainage → slows the generation of alkalosis.
Indication: "PPIs if alkalosis is due to NG drainage" [2]. Also useful in ongoing vomiting that cannot be immediately controlled.
Contraindications: Generally well tolerated. Long-term PPI use is associated with Mg²⁺ depletion, C. difficile risk, osteoporosis — but these are not relevant in the acute setting.
What: Acetazolamide (Latin roots: "acet-" = acetyl; "-azol-" = azole ring; "-amide" = NH₂ group) — a carbonic anhydrase (CA) inhibitor.
Why it works: Carbonic anhydrase in the PCT catalyses: CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻. By inhibiting CA, acetazolamide blocks proximal HCO₃⁻ reabsorption → forces the kidney to dump HCO₃⁻ in the urine → directly lowers serum HCO₃⁻.
Dosing: Acetazolamide 250 mg QID PO or IV [2][19].
Indication: Adjunct when saline + KCl alone are insufficient, or when volume loading is contraindicated (e.g., heart failure, post-cardiac surgery patients on diuretics who cannot receive large volumes of NS).
Contraindications / Cautions:
- May promote K⁺ loss [2] — because ↑ HCO₃⁻ and Na⁺ delivery to the distal tubule → more Na⁺/K⁺ exchange → more K⁺ secretion. Always co-administer KCl with acetazolamide.
- Hepatic encephalopathy: Acetazolamide causes metabolic acidosis → in theory might help the alkalosis, but it also increases renal NH₃ production and can worsen HE in cirrhotic patients. Use with extreme caution.
- Sulfonamide allergy: Acetazolamide is a sulfonamide derivative. True cross-reactivity is rare but listed as a relative contraindication.
Acetazolamide — The 'Volume-Sparing' Option
Acetazolamide is your friend when the patient has metabolic alkalosis but you cannot give large volumes of NS — e.g., a heart failure patient on furosemide who has developed contraction alkalosis. Acetazolamide dumps HCO₃⁻ in the urine without requiring volume loading. Just remember to supplement K⁺ [2][3][19].
4. Saline-Resistant Metabolic Alkalosis (UCl > 15–20 mEq/L)
Normal saline alone will NOT fix these patients. You must treat the underlying cause that is driving ongoing renal H⁺ and K⁺ loss.
4A. Mineralocorticoid Excess — Hypertensive Causes
The management depends on subtype differentiation [22][24]:
| Subtype | Treatment | Rationale |
|---|---|---|
| Adrenal adenoma (Conn's) | Unilateral laparoscopic adrenalectomy [22][24] | Localised pathology → curative excision. "Remember to pre-medicate to optimise electrolyte balance before surgery" [22] — correct hypoK with spironolactone + KCl pre-operatively for at least 4–6 weeks. |
| Bilateral adrenal hyperplasia | Medical therapy: Spironolactone 100–400 mg daily PO [1][2][22][24] | "Generalised pathology, cannot remove all" [22]. Spironolactone = competitive antagonist at the mineralocorticoid receptor → blocks aldosterone's effect → ↓ Na⁺ reabsorption, ↓ K⁺/H⁺ secretion → corrects both HTN and hypoK-alkalosis. |
Spironolactone — Key Drug Details:
| Property | Detail |
|---|---|
| Mechanism | Competitive antagonist at the mineralocorticoid receptor (MR) in the collecting duct principal cells. Blocks aldosterone → ↓ ENaC expression → ↓ Na⁺ reabsorption → ↓ lumen-negative voltage → ↓ K⁺ and H⁺ secretion → corrects hypoK and alkalosis |
| Dose | 100–400 mg daily PO [2] |
| Side effects | Gynaecomastia (binds androgen receptor — anti-androgen effect), breast tenderness, menstrual irregularities, hyperkalaemia, GI upset |
| Contraindications | Hyperkalaemia (K⁺ > 5.5), severe renal impairment (eGFR < 30 — risk of lethal hyperK), concurrent K⁺-sparing drugs or K⁺ supplements without monitoring, Addison's disease |
Eplerenone — Alternative MRA:
| Property | Detail |
|---|---|
| Mechanism | Selective MR antagonist — less gynaecomastia than spironolactone because minimal anti-androgen activity [22][24] |
| Dose | 25–50 mg daily PO |
| When to use | Spironolactone-intolerant patients (gynaecomastia, breast pain). "Eplerenone — less gynaecomastia, more expensive" [24] |
Amiloride / Triamterene — Second-line:
| Property | Detail |
|---|---|
| Mechanism | Blocks ENaC (epithelial sodium channel) in the distal tubular cells → blocks Na⁺ reabsorption and K⁺ excretion independent of aldosterone [24] |
| When to use | "Second line if patient can't tolerate spironolactone, and cannot afford eplerenone" [24]. Also the drug of choice for Liddle syndrome (gain-of-function ENaC mutation — spironolactone won't work because the channel is constitutively active regardless of aldosterone). |
| Contraindications | Hyperkalaemia, renal impairment, concurrent K⁺-sparing drugs |
Treat the underlying cause:
| Cause | Treatment |
|---|---|
| Renal artery stenosis | Renal artery revascularisation (angioplasty ± stenting) for fibromuscular dysplasia; medical Mx (ACEI/ARB + antihypertensives) for atherosclerotic RAS unless specific indications for intervention (flash pulmonary oedema, resistant HTN, ischaemic nephropathy) [11] |
| Heart failure | Guideline-directed medical therapy (ACEI/ARB/ARNI + β-blocker + MRA + SGLT2i); adjust diuretic doses to minimise alkalosis |
| Cirrhosis | Reduce diuretic doses; careful KCl supplementation; avoid excessive paracentesis without albumin replacement |
Treat according to the underlying cause (pituitary adenoma → transsphenoidal surgery; ectopic ACTH → treat primary tumour; adrenal adenoma/carcinoma → adrenalectomy; iatrogenic → taper steroids). While awaiting definitive treatment, spironolactone or amiloride can partially correct the hypoK-alkalosis.
4B. Normotensive Causes
Management of Bartter syndrome [10][25]:
| Treatment | Rationale |
|---|---|
| Sodium, chloride and potassium supplementation | Replace the ongoing renal losses. "Medically supervised NaCl + KCl supplementation is necessary" [10]. |
| Spironolactone | Reduces urinary K⁺ loss by blocking the secondary hyperaldosteronism effect at the collecting duct [10][25]. |
| NSAIDs (indomethacin) | In severe cases where supplementation alone cannot maintain biochemical homeostasis [10]. Mechanism: prostaglandins sustain high GFR in Bartter's → NSAIDs ↓ GFR → ↓ filtered Na⁺/K⁺ → ↓ losses. Must be given alongside stomach acid suppression (PPI) to prevent GI irritation [10]. |
| Free access to water | "Prevent dehydration" [10] — these patients have an impaired concentrating ability. |
| Surveillance renal USS | Monitor for nephrocalcinosis (from hypercalciuria) [10][25]. |
| Calcium carbonate + Vitamin D | If nephrocalcinosis or hypocalcaemia develop [25]. |
Case management from RTD: "Indomethacin + Spironolactone + sodium + potassium supplement + calcium carbonate + vitamin D" [25].
| Treatment | Rationale |
|---|---|
| Oral KCl supplementation | Usually the mainstay; high doses often required (40–80+ mmol/day) |
| Oral MgCl₂ or Mg oxide | Hypomagnesaemia is a hallmark — must be supplemented. MgCl₂ preferred over Mg oxide (better bioavailability). |
| Amiloride ± spironolactone | If K⁺ supplementation alone is insufficient — reduces renal K⁺ wasting |
| NSAIDs | Rarely needed (Gitelman's is milder than Bartter's) |
Aggressively replete K⁺ (and Mg²⁺). The alkalosis will correct once K⁺ normalises (removes the intracellular acidosis that drives HCO₃⁻ retention and ammoniagenesis).
Stop the CaCO₃ intake. IV NS hydration to treat hypercalcaemia and provide volume for renal HCO₃⁻ excretion. Loop diuretics (furosemide) to enhance calciuria if severe hypercalcaemia. Monitor renal function (AKI is part of the triad).
5. Severe / Refractory Metabolic Alkalosis (pH > 7.55 or Renal Failure)
When the above measures fail or pH is dangerously high ( > 7.55), more aggressive interventions are needed.
5A. Acid Therapy
"If ECF expanded, correct alkalosis with IV HCl or oral NH₄Cl" [1].
What: IV HCl 100 mmol/L — dilute solution infused via central venous catheter [3].
Why it works: Directly provides H⁺ ions → neutralises excess HCO₃⁻: H⁺ + HCO₃⁻ → H₂CO₃ → CO₂ + H₂O.
Indication: Severe alkalosis (pH > 7.55) or non-dialysed renal failure where the kidney cannot excrete HCO₃⁻ [3].
How: Typically 0.1 N (100 mmol/L) HCl in sterile water or D5W. Infuse at 50–100 mL/h via central line (peripheral infusion causes phlebitis/tissue necrosis). Monitor ABG q2–4h.
Contraindications / Cautions:
- Must use central line (sclerosant if peripheral).
- Risk of overcorrection → metabolic acidosis.
- Requires ICU-level monitoring.
- Not widely available in all centres.
What: NH₄Cl 1–2 g PO q6h.
Why it works: NH₄Cl is metabolised by the liver: NH₄⁺ + Cl⁻ → urea + HCl. The HCl generated neutralises HCO₃⁻.
Indication: Mild-to-moderate alkalosis when IV HCl is unavailable or not indicated. Oral alternative.
Contraindications:
- Hepatic impairment / cirrhosis — the liver cannot metabolise NH₄⁺ → risk of hyperammonaemia and encephalopathy. This is an absolute contraindication.
- Renal failure (cannot excrete urea generated).
NH₄Cl Is Contraindicated in Liver Disease!
NH₄Cl relies on hepatic conversion to urea. In liver failure, NH₃ accumulates → worsens encephalopathy. Never use NH₄Cl in cirrhotics. Use IV HCl via central line or dialysis instead.
What: Standard haemodialysis with a low-bicarbonate / acetate-free dialysate.
Why it works: Directly removes HCO₃⁻ from the blood across the dialysis membrane. Also corrects volume overload and electrolyte disturbances simultaneously.
Indication: "Dialysis in those with acute or chronic kidney diseases (cannot excrete HCO₃⁻)" [3]. Also for refractory alkalosis when saline, KCl, and acetazolamide have all failed, or when the patient cannot tolerate volume loading.
Contraindications: Haemodynamic instability (consider CRRT instead); vascular access issues.
| Scenario | Key Management Points |
|---|---|
| Vomiting-induced metabolic alkalosis | Anti-emetics + IV NS + IV KCl. Treat cause (e.g., GOO: OGD ± balloon dilatation). HypoK is renal loss → will not correct until volume and Cl⁻ are repleted [6][7]. |
| NG-drainage alkalosis (ICU) | PPI to reduce gastric H⁺ output [2] + IV NS + KCl + acetazolamide if volume-restricted. |
| Diuretic-induced alkalosis | Stop/dose-reduce diuretic. NS + KCl. If diuretic must continue (e.g., HF): add spironolactone or amiloride + acetazolamide [3][19]. |
| Post-hypercapnic alkalosis | NS + KCl to allow renal HCO₃⁻ excretion. Avoid over-ventilating COPD patients — target mild permissive hypercapnia initially so the kidneys have time to adjust. Acetazolamide may help. |
| Pyloric stenosis (paeds) | Correct electrolytes FIRST (NS + KCl) → surgery (Ramstedt pyloromyotomy) only after biochemical normalisation [5]. The anaesthetist will not accept a profoundly alkalotic infant. |
| Conn's adenoma | Pre-operative spironolactone + KCl (4–6 weeks) → laparoscopic unilateral adrenalectomy [22][24]. |
| Bilateral adrenal hyperplasia | Long-term spironolactone 100–400 mg/day (or eplerenone if intolerant) [2][22][24]. |
| Bartter syndrome | NaCl + KCl + spironolactone ± indomethacin (with PPI) + surveillance renal USS [10][25]. |
| Gitelman syndrome | Oral KCl + MgCl₂ ± amiloride |
| Liquorice / AME | Cease offending agent + KCl supplementation; effects reversible [6][7][14] |
| Liddle syndrome | Amiloride (ENaC blocker) — NOT spironolactone (MR is not the problem; ENaC is constitutively active) |
| Milk-alkali syndrome | Stop CaCO₃. IV NS hydration ± loop diuretics for hypercalcaemia. Monitor RFT. |
| Cirrhotic on diuretics | Dose-reduce furosemide/spironolactone; careful KCl supplementation; avoid NH₄Cl (hepatic encephalopathy risk); avoid excessive paracentesis. |
| Parameter | Frequency | Target / Purpose |
|---|---|---|
| Serum K⁺ | q4–6h during acute correction; q12–24h once stable | Target K⁺ > 3.5 mmol/L (ideally > 4.0 to ensure stability) |
| Serum Cl⁻ | q6–12h | Normalisation of Cl⁻ indicates adequate repletion |
| ABG/VBG | q4–6h during active treatment | Monitor pH, HCO₃⁻ towards normalisation; check pCO₂ to assess compensation adequacy |
| Urine output | Hourly (if catheterised) or q4h | Ensure adequate diuresis (aim > 0.5 mL/kg/h) — indicates kidneys are perfused and can excrete HCO₃⁻ |
| ECG / telemetry | Continuous if K⁺ < 3.0 | Monitor for resolution of U waves, QT normalisation; detect arrhythmias |
| Serum Mg²⁺ | Daily | Correct if low — refractory hypoK often due to hypoMg |
| Serum Cr / Urea | Daily | Monitor renal function, especially if receiving NS (volume status) or acetazolamide |
| Classification | First-Line | Second-Line / Adjuncts | Severe / Refractory |
|---|---|---|---|
| Saline-responsive (UCl < 20) | IV NS 0.9% + KCl [1][2] | PPI (if NG drainage) [2]; Acetazolamide 250 mg QID [2][19] | IV HCl via central line; dialysis |
| Saline-resistant — Hypertensive | Spironolactone 100–400 mg/day [1][2] | Eplerenone; amiloride/triamterene [24]; surgery for adenoma [22] | Dialysis if renal failure |
| Saline-resistant — Normotensive | KCl + MgCl₂ supplementation | Spironolactone/amiloride; NSAIDs (Bartter) [10]; genetic counselling | Dialysis if renal failure |
| ECF-expanded states | "IV HCl or oral NH₄Cl" [1] | Acetazolamide; dialysis | Haemodialysis |
High Yield Summary — Management of Metabolic Alkalosis
-
Two overarching principles: (a) Remove the generation event; (b) Correct the maintenance factor(s) — Cl⁻, K⁺, volume, or mineralocorticoid excess.
-
Saline-responsive (UCl < 20): IV NS ± KCl → HCO₃⁻ will fall with ECF expansion. Add PPI if NG drainage, acetazolamide if volume-restricted [1][2].
-
Saline-resistant + hypertensive: Spironolactone 100–400 mg daily (blocks MR → ↓ K⁺/H⁺ secretion). Adenoma → adrenalectomy. Bilateral hyperplasia → lifelong MRA. Eplerenone if gynaecomastia; amiloride for Liddle syndrome [1][2][24].
-
Saline-resistant + normotensive: KCl + MgCl₂ supplementation. Bartter: add indomethacin + spironolactone. Gitelman: KCl + MgCl₂ ± amiloride [10].
-
Acetazolamide (250 mg QID): CA inhibitor → forces renal HCO₃⁻ excretion. Volume-sparing option. Caution: promotes K⁺ loss (always co-give KCl) [2][19].
-
Severe alkalosis (pH > 7.55) or renal failure: IV HCl 100 mmol/L via central line, or oral NH₄Cl (contraindicated in liver disease), or haemodialysis [1][3].
-
Always use KCl (not K-citrate/acetate) in metabolic alkalosis — Cl⁻ component is therapeutic; citrate/acetate → HCO₃⁻ → worsens alkalosis.
-
Always check and correct Mg²⁺ — refractory hypoK is often due to hypoMg.
-
Pyloric stenosis: Correct electrolytes FIRST → surgery SECOND.
-
NH₄Cl is absolutely contraindicated in liver disease (NH₃ → encephalopathy).
Active Recall - Management of Metabolic Alkalosis
References
[1] Lecture slides: GC 044. Electrolyte and Acid-Base Disorders.pdf (Metabolic alkalosis treatment slide) [2] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf, p89 (Treatment of metabolic alkalosis) [3] Senior notes: Ryan Ho Urogenital.pdf, p50–52 (Section 2.4.3 Metabolic Alkalosis — treatment) [4] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf, p16 (Treatment principles) [5] Senior notes: Adrian Lui Pediatrics Notes.pdf, p253 (Pyloric stenosis) [6] Lecture slides: MBBS IV Electrolytes_2024.pdf, p21–22 (Liquorice mechanism) [7] Lecture slides: MBBS IV Electrolytes_2024 (1).pdf, p21–22 (Liquorice mechanism) [10] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf, p31 (Bartter syndrome management) [11] Senior notes: Block A - High blood pressure_ hypertension.pdf, p27 (Renovascular HTN treatment) [14] Senior notes: Ryan Ho Chemical Path.pdf, p18 (Target drug search) [19] Senior notes: Maksim Medicine Notes.pdf, p215 (Metabolic alkalosis management) [20] Senior notes: Block A - Indigestion and 'heartburn'.pdf, p24 (Management of acute vomiting) [22] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours.pdf, p8–12 (Conn's management) [24] Senior notes: Block A - I have fluctuating BP_ cushing syndrome; adrenal diseases and tumours.pdf, p12 (Management of aldosteronism — spironolactone, eplerenone, amiloride) [25] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf, p29 (Bartter case management)
Complications of Metabolic Alkalosis
Metabolic alkalosis is not just a laboratory curiosity — it has real, organ-specific consequences. Many complications arise not from the alkalosis itself but from the concurrent electrolyte derangements (especially hypokalaemia and hypochloraemia) that invariably accompany it. Others result directly from the shift in pH affecting enzyme function, protein binding, and cellular excitability. Let's work through each complication systematically, explaining the mechanism from first principles.
1. Cardiac Complications
This is the most immediately life-threatening complication and arises almost entirely from the concurrent hypokalaemia rather than from the alkalosis per se [4][26].
Mechanism:
- K⁺ is the principal determinant of the resting membrane potential (RMP) of cardiomyocytes. Normal RMP ≈ −90 mV, largely set by the K⁺ equilibrium potential (Nernst equation: E_K = −61.5 × log [K⁺]ᵢ / [K⁺]ₒ).
- When extracellular K⁺ falls (hypoK), the ratio [K⁺]ᵢ/[K⁺]ₒ increases → E_K becomes more negative → the RMP hyperpolarises. You might think this makes cells harder to excite, but paradoxically:
- Hyperpolarisation increases the voltage difference that must be traversed during the upstroke of the action potential → cells take longer to repolarise.
- Phase 3 repolarisation (K⁺ efflux via IKr and IKs channels) is slowed because the electrochemical gradient for K⁺ efflux is reduced.
- This prolongs the action potential duration (APD) → prolonged QT interval → early afterdepolarisations (EADs) → triggered activity → risk of torsades de pointes (TdP) and ventricular fibrillation.
- Additionally, hypoK enhances automaticity of pacemaker cells and promotes re-entrant circuits.
ECG changes of hypokalaemia [4][18][26]:
| ECG Finding | K⁺ Level | Mechanism |
|---|---|---|
| Flattened T waves | < 3.0 | Prolonged phase 3 repolarisation |
| ST segment depression | < 3.0 | Altered repolarisation currents |
| Prominent U waves | < 2.5 | Delayed repolarisation of Purkinje fibres or mid-myocardial M cells |
| Prolonged QT/QU interval | < 2.5 | U wave merges with T wave; true QT prolongation from slowed IKr |
| Arrhythmias: PACs, PVCs, VT, VF, TdP | < 2.0 | EADs + enhanced automaticity + re-entry |
"Cardiac arrhythmia, particularly when [K⁺] < 2.0" [26]. "ECG: U wave, flat T wave, long QTc" [18].
Alkalemia itself independently prolongs the QT interval and lowers the fibrillation threshold, compounding the arrhythmia risk from hypoK.
Clinical Pearl — Digoxin Toxicity
Patients on digoxin are at extreme risk. Digoxin and K⁺ compete for the same binding site on the Na⁺/K⁺-ATPase. When K⁺ is low, digoxin binds more avidly → enhanced digoxin effect → toxicity (arrhythmias) at "therapeutic" serum digoxin levels. Always check K⁺ urgently in a digitalised patient with new arrhythmias.
Severe alkalemia (pH > 7.55) can directly impair myocardial contractility through several mechanisms:
- Altered intracellular Ca²⁺ handling (↓ ionised Ca²⁺ reduces Ca²⁺ available for the contractile apparatus).
- Shifts in enzyme kinetics of Ca²⁺-dependent ATPases.
- This is usually only clinically significant in patients with pre-existing cardiac dysfunction.
2. Respiratory Complications
Mechanism: The body compensates for metabolic alkalosis by hypoventilating — retaining CO₂ to bring the HCO₃⁻/pCO₂ ratio (and therefore pH) back towards normal [4][17].
- Expected pCO₂ = 0.7 × [HCO₃⁻] + 21 (±2); compensation can raise pCO₂ up to ~55 mmHg [4].
- Hypoventilation → ↓ alveolar ventilation → ↓ PAO₂ → hypoxaemia (by the alveolar gas equation: PAO₂ = FiO₂ × (P_atm − P_H₂O) − PaCO₂/RQ).
- In a healthy person, this mild hypoxaemia is well tolerated. However, in patients with pre-existing lung disease (COPD, pulmonary fibrosis, post-operative atelectasis), the compensatory hypoventilation can cause clinically significant desaturation and respiratory failure.
This is why metabolic alkalosis is particularly dangerous in ICU patients already on borderline ventilation.
Mechanism (the Bohr effect in reverse):
- ↑ pH → haemoglobin's affinity for O₂ increases → the O₂-Hb dissociation curve shifts leftward.
- This means Hb picks up O₂ more readily in the lungs (good) but releases O₂ less readily in the peripheral tissues (bad).
- Net result: tissue hypoxia despite apparently adequate SaO₂ and PaO₂.
- Particularly relevant in critically ill patients where tissue O₂ demand is high (sepsis, post-operative states).
In ICU, metabolic alkalosis suppresses the central respiratory drive (medullary chemoreceptors sense pH, not HCO₃⁻ directly). A patient on mechanical ventilation with concurrent metabolic alkalosis will have reduced spontaneous respiratory effort → difficulty weaning → prolonged ventilator days → increased risk of ventilator-associated pneumonia and other ICU complications.
3. Neurological Complications
Mechanism: Alkalemia → ↓ ionised Ca²⁺.
The key concept: albumin has multiple binding sites for both H⁺ and Ca²⁺. At normal pH, H⁺ ions occupy many of these sites, leaving a portion of Ca²⁺ "free" (ionised) in the plasma. When pH rises:
- H⁺ concentration falls → H⁺ dissociates from albumin → binding sites open up → Ca²⁺ moves onto albumin → ionised Ca²⁺ falls.
- Total calcium may remain normal, but it is the ionised fraction that determines neuromuscular excitability.
- ↓ Ionised Ca²⁺ → lowered threshold for neuronal and muscle fibre depolarisation → spontaneous firing → paraesthesiae (tingling), carpopedal spasm, Chvostek's sign, Trousseau's sign, and in severe cases, generalised seizures.
"Latent/overt tetany due to metabolic alkalosis causing ↓ ionised Ca" [9].
Mechanism: Alkalemia causes cerebral arteriolar vasoconstriction → ↓ cerebral blood flow (CBF) → cerebral hypoperfusion.
- This is because cerebrovascular smooth muscle is exquisitely pH-sensitive. ↑ pH → constriction (the opposite of the CO₂-mediated vasodilation seen in hypercapnia).
- Clinical consequence: confusion, dizziness, light-headedness, and in severe cases (pH > 7.6), obtundation or coma.
This is a critically important and repeatedly examined complication [27].
Mechanism:
- Ammonia exists in equilibrium: NH₃ + H⁺ ⇌ NH₄⁺.
- At physiological pH, ~98% is in the NH₄⁺ form (charged → cannot cross the blood-brain barrier).
- In alkalosis, ↓ H⁺ shifts the equilibrium towards NH₃ (uncharged → freely crosses the BBB → enters astrocytes → neurotoxicity → encephalopathy) [27].
- Additionally, hypokalaemia itself increases renal ammoniagenesis (intracellular acidosis in renal tubular cells from K⁺ depletion → ↑ glutamine metabolism → ↑ total body ammonia production) [27].
- This creates a vicious cycle: hypokalaemia → ↑ ammonia production AND alkalosis → ↑ NH₃ entry into brain → worsening encephalopathy.
Metabolic alkalosis is a listed precipitant of hepatic encephalopathy: "Promote conversion of NH₄⁺ into NH₃. NH₄ is a charged particle which cannot cross the BBB into NH₃ which can enter the brain" [27].
Clinical Significance in Cirrhosis
Cirrhotic patients on diuretics (furosemide + spironolactone for ascites) are at constant risk of developing metabolic alkalosis (from the furosemide component) + hypokalaemia. This combination precipitates hepatic encephalopathy. Always monitor K⁺ and pH carefully in cirrhotics and be aggressive about KCl supplementation. If encephalopathy develops, reduce/stop the diuretic and correct the alkalosis.
4. Musculoskeletal Complications
Mechanism: K⁺ is critical for maintaining the RMP of skeletal muscle cells. When extracellular K⁺ falls:
- The RMP hyperpolarises (becomes more negative).
- A greater depolarising stimulus is required to reach threshold → muscle cells become less excitable → weakness.
- Characteristically affects proximal muscles (LL > UL) first, progressing distally with worsening hypoK [26].
- Severe hypoK ( < 2.0) → respiratory muscle paralysis → respiratory failure [26].
"Muscle weakness, paralysis (proximal muscle myopathy)" [26]. "Generalised weakness → especially of the proximal musculature. Respiratory failure. Fatal arrhythmia." [28]
Mechanism: In normal muscle, contraction releases local K⁺ which mediates a vasodilatory response to increase blood flow. When systemic K⁺ is very low, this local K⁺ release is insufficient → the vasodilatory response is lost → muscle ischaemia → myocyte necrosis → rhabdomyolysis [21][26][29].
- Clinical features: intense myalgia, dark (tea-coloured) urine (myoglobinuria), markedly elevated CK ( > 5× ULN).
- Complications of rhabdomyolysis itself: AKI from myoglobin-induced ATN (15–50%), compartment syndrome, DIC, hyperK (paradoxically — from release of intracellular K⁺ from dying muscle cells) [29].
"Rhabdomyolysis" is listed as a complication of hypokalaemia [26][29].
Mechanism: Smooth muscle of the GI tract is also K⁺-dependent. HypoK → hyperpolarisation of smooth muscle cells → reduced contractility → adynamic (paralytic) ileus → abdominal distension, absent bowel sounds, vomiting (which further worsens the alkalosis in a vicious cycle).
"Ileus, constipation" [26].
5. Renal Complications
Mechanism: Chronic K⁺ depletion (sustained > 2–3 weeks) impairs:
- Aquaporin-2 (AQP2) expression in the collecting duct — AQP2 is the ADH-responsive water channel. Without it, the collecting duct becomes impermeable to water despite ADH stimulation.
- Medullary concentration gradient — hypoK interferes with the countercurrent mechanism in the medullary interstitium.
- Net result: the kidney cannot concentrate urine → polyuria, polydipsia, nocturia despite adequate or even elevated ADH levels → nephrogenic DI.
"Polyuria" [26]. "Polydipsia, polyuria, nocturia due to nephrogenic DI" [9].
Mechanism: In severe metabolic alkalosis with volume depletion and chloride depletion:
- The kidney prioritises volume preservation over acid–base correction.
- In the proximal tubule, Na⁺ must be reabsorbed to maintain volume. Normally, Na⁺ is co-transported with Cl⁻. When Cl⁻ is depleted, the only available anion for Na⁺ co-transport is HCO₃⁻ → the kidney avidly reabsorbs NaHCO₃ to save volume.
- Meanwhile, in the collecting duct, the H⁺/K⁺-ATPase is upregulated (trying to conserve the last remaining K⁺) → H⁺ is secreted into the urine despite systemic alkalosis.
- Urine pH is paradoxically acidic (pH < 5.5) despite serum alkalosis.
- This is classically described in pyloric stenosis (paediatrics) and severe vomiting-induced alkalosis.
Paradoxical Aciduria — Exam Favourite
Despite being systemically alkalotic, the kidney produces acidic urine because:
- Volume preservation (NaHCO₃ reabsorption) takes priority over pH correction.
- K⁺ conservation (H⁺/K⁺-ATPase upregulation) forces H⁺ secretion. This worsens the alkalosis systemically — a vicious cycle broken only by providing Cl⁻ (saline) and K⁺.
Mechanism specific to Bartter's: The NKCC2 defect in the thick ascending limb causes loss of the lumen-positive voltage that normally drives paracellular Ca²⁺ reabsorption → hypercalciuria → calcium precipitates in the renal medulla → nephrocalcinosis → further impairs concentrating ability → worsens polyuria [10][25].
"Surveillance renal ultrasound should be employed to monitor for the development of nephrocalcinosis, a common complication which further augments urinary concentrating difficulty" [10].
6. Metabolic and Electrolyte Complications
The relationship between metabolic alkalosis and hypokalaemia is bidirectional and self-perpetuating:
- Alkalosis → HypoK: H⁺ exits cells → K⁺ enters cells (transcellular shift); ↑ filtered HCO₃⁻ acts as non-reabsorbable anion in DCT → drives K⁺ secretion.
- HypoK → Alkalosis: K⁺ exits cells → H⁺ enters cells → intracellular acidosis in renal tubular cells → ↑ NHE3 activity → ↑ HCO₃⁻ reabsorption; ↑ ammoniagenesis → ↑ net acid excretion → generates more HCO₃⁻.
This means you cannot fully correct the alkalosis without correcting the K⁺, and you cannot fully correct the K⁺ without correcting the alkalosis — they must be addressed simultaneously [4][14].
Chloride depletion is the key maintenance factor for saline-responsive metabolic alkalosis. It also:
- Impairs gastric acid regeneration (Cl⁻ is needed for HCl production by parietal cells — though this is a minor issue compared to the renal effects).
- Prevents pendrin-mediated HCO₃⁻ excretion (see pathophysiology section).
Often co-exists with hypoK in the setting of diuretic use, Gitelman syndrome, or chronic vomiting. As discussed, Mg²⁺ depletion keeps ROMK channels constitutively open → K⁺ is continuously secreted → refractory hypokalaemia that cannot be corrected until Mg²⁺ is repleted [14].
Mechanism as described above (pH-dependent shift of Ca²⁺ onto albumin). Total Ca²⁺ may be normal but the biologically active ionised fraction is reduced → tetany risk [9].
| Treatment | Complication | Mechanism |
|---|---|---|
| Overly rapid saline infusion | Volume overload, pulmonary oedema | Especially in elderly, HF, or CKD patients |
| Overly rapid K⁺ replacement | Hyperkalaemia → arrhythmias | If infusion rate exceeds renal excretory capacity (especially in CKD) |
| Acetazolamide | Worsening hypoK | ↑ HCO₃⁻ and Na⁺ delivery to DCT → drives K⁺ secretion; must co-supplement KCl |
| IV HCl | Overcorrection → metabolic acidosis; tissue necrosis if extravasated | Must use central line; monitor ABG q2–4h |
| NH₄Cl | Hyperammonaemia → hepatic encephalopathy | Absolutely contraindicated in liver disease |
| Spironolactone | Hyperkalaemia; gynaecomastia | Monitor K⁺; switch to eplerenone if anti-androgen side effects intolerable |
| pH Range | Severity | Key Complications |
|---|---|---|
| 7.45–7.50 | Mild | Usually well tolerated; mild hypoK changes on ECG |
| 7.50–7.55 | Moderate | Paraesthesiae, muscle cramps, compensatory hypoventilation becoming clinically significant, arrhythmia risk ↑ |
| 7.55–7.60 | Severe | Confusion, significant arrhythmias, impaired tissue O₂ delivery, seizure risk, tetany |
| > 7.60 | Critical | Lethal: pH > 7.7 is incompatible with life [4]. Refractory arrhythmias, cardiopulmonary arrest, multi-organ failure |
"Lethal → all cellular function become disrupted: > 7.7" [4].
| System | Complication | Mechanism |
|---|---|---|
| Cardiac | Arrhythmias (VT, VF, TdP) | HypoK → prolonged QT, EADs, enhanced automaticity [18][26] |
| Impaired contractility | ↓ Ionised Ca²⁺ → ↓ Ca²⁺ for contractile apparatus | |
| Respiratory | Hypoventilation → hypoxaemia | Compensatory CO₂ retention [4][17] |
| ↓ O₂ delivery to tissues | Left shift of O₂-Hb curve (Bohr effect) | |
| Ventilator weaning difficulty | Suppressed central respiratory drive | |
| Neurological | Paraesthesiae, tetany, seizures | ↓ Ionised Ca²⁺ → neuronal hyperexcitability [9] |
| Confusion, coma | Cerebral vasoconstriction → ↓ CBF | |
| Hepatic encephalopathy | NH₄⁺ → NH₃ shift; ↑ renal ammoniagenesis from hypoK [27] | |
| Musculoskeletal | Proximal muscle weakness → respiratory failure | HypoK → hyperpolarisation → ↓ muscle excitability [26][28] |
| Rhabdomyolysis | HypoK → impaired local vasodilatory response → muscle ischaemia [26][29] | |
| Paralytic ileus | HypoK → smooth muscle hyperpolarisation [26] | |
| Renal | Nephrogenic DI (polyuria) | Chronic hypoK → ↓ AQP2, ↓ medullary gradient [9] |
| Paradoxical aciduria | Volume/K⁺ conservation overrides pH correction | |
| Nephrocalcinosis (Bartter) | Hypercalciuria → medullary Ca²⁺ deposition [10] | |
| Metabolic | Self-perpetuating hypoK–alkalosis cycle | Bidirectional: alkalosis → hypoK → more alkalosis [4][14] |
| Hypomagnesaemia → refractory hypoK | ROMK stays open → K⁺ wasting continues [14] | |
| ↓ Ionised Ca²⁺ | pH-dependent shift onto albumin [9] |
High Yield Summary — Complications of Metabolic Alkalosis
-
Cardiac arrhythmias are the most immediately life-threatening complication — driven by concurrent hypoK (flat T, U waves, prolonged QT → TdP, VF). K⁺ < 2.0 is the danger zone.
-
Compensatory hypoventilation → mild hypoxaemia in healthy individuals; can cause respiratory failure in patients with pre-existing lung disease. Also impairs ICU ventilator weaning.
-
Left shift of the O₂-Hb dissociation curve → tissue hypoxia despite normal SaO₂ (Bohr effect in reverse).
-
Neuromuscular irritability (tetany, paraesthesiae, seizures) from ↓ ionised Ca²⁺ due to pH-dependent shift onto albumin.
-
Hepatic encephalopathy — alkalosis shifts NH₄⁺ → NH₃ (crosses BBB); hypoK increases renal ammoniagenesis → ↑ total body ammonia. Critical in cirrhotics on diuretics.
-
Proximal muscle weakness → respiratory failure from hypoK; rhabdomyolysis from impaired local muscle vasodilation in severe hypoK.
-
Paralytic ileus from hypoK → worsens vomiting → worsens alkalosis (vicious cycle).
-
Nephrogenic DI (chronic hypoK → polyuria) and paradoxical aciduria (kidney prioritises volume over pH).
-
Self-perpetuating hypoK-alkalosis cycle: must treat both simultaneously.
-
pH > 7.7 is lethal — all cellular functions disrupted.
Active Recall - Complications of Metabolic Alkalosis
References
[4] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf, p2–3, p16, p27 (Lethal pH, compensation, hypoK complications) [9] Senior notes: Ryan Ho Endocrine.pdf, p57 (Tetany, ionised Ca, polyuria from hyperaldosteronism) [10] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf, p31 (Bartter — nephrocalcinosis) [14] Senior notes: Ryan Ho Chemical Path.pdf, p18 (HypoK approach; Mg depletion) [17] Senior notes: Adrian Lui Pediatrics Notes.pdf, p310 (Acid–base compensation) [18] Lecture slides: GC 068. Indigestion and 'heartburn'.pdf, p34 (ECG changes in hypoK from vomiting workup) [21] Senior notes: Ryan Ho Urogenital.pdf, p25 (HypoK clinical features — rhabdomyolysis mechanism) [25] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf, p29 (Bartter case — nephrocalcinosis management) [26] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf, p27 (Hypokalemia complications list) [27] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf, p464 (Hepatic encephalopathy precipitants — from prior section reference) [28] Senior notes: Block A - Two cases of polyuria and polydipsia.pdf, p3 (HypoK complications — weakness, respiratory failure, fatal arrhythmia) [29] Senior notes: Ryan Ho Neurology.pdf, p196 (Rhabdomyolysis — aetiology including hypoK, clinical features, complications)
High Yield Summary
-
Definition: Metabolic alkalosis = primary ↑ HCO₃⁻ with ↑ pH; requires both a generation event and a maintenance factor.
-
Most common acid–base disorder in hospitalised patients.
-
Two-phase model: Generation (creates excess HCO₃⁻ or loses H⁺) + Maintenance (kidney fails to excrete HCO₃⁻ due to Cl⁻ depletion, K⁺ depletion, volume depletion, mineralocorticoid excess, or ↓ GFR).
-
Saline-responsive (UCl < 20): Vomiting, NG suction, diuretics (remote), post-hypercapnia, contraction alkalosis → treat with NS ± KCl.
-
Saline-resistant (UCl > 20): Mineralocorticoid excess (Conn's, Cushing's, liquorice), Bartter's, Gitelman's, severe hypoK, alkali load → treat underlying cause ± spironolactone.
-
Use urine Cl⁻ (NOT urine Na⁺) to classify — urine Na⁺ is unreliable due to bicarbonaturia.
-
Hypokalaemia is the classical electrolyte abnormality — bidirectional relationship.
-
Respiratory compensation: pCO₂ ↑ ~0.7 per 1 mEq/L ↑ HCO₃⁻; expected pCO₂ ≈ 0.7 × [HCO₃⁻] + 21 (±2); rarely > 55 mmHg.
-
Metabolic alkalosis precipitates hepatic encephalopathy by shifting NH₄⁺ → NH₃ (crosses BBB).
-
Pyloric stenosis (paeds): Classic presentation = hypochloraemic hypokalaemic metabolic alkalosis.
-
Vomiting-induced hypoK is a renal loss (not direct GI loss): Cl⁻ depletion → ↑ distal Na⁺ delivery → ↑ K⁺ secretion; metabolic alkalosis → bicarbonaturia → K⁺ loss; secondary hyperaldosteronism → further K⁺ loss.
-
Liquorice (甘草) inhibits 11β-HSD2 → cortisol acts on mineralocorticoid receptor → hypoK + metabolic alkalosis. Hong Kong relevant (TCM).
High Yield Summary — Differential Diagnosis of Metabolic Alkalosis
-
Confirm primary metabolic alkalosis vs. compensation for chronic respiratory acidosis — check the pH direction and clinical context.
-
Urine Cl⁻ is the master discriminator (NOT urine Na⁺): < 20 = saline-responsive; > 20 = saline-resistant [1][2].
-
Saline-responsive (low UCl): Vomiting, NG drainage, remote diuretics, post-hypercapnia, contraction alkalosis, villous adenoma, pyloric stenosis (paeds).
-
Saline-resistant (high UCl) + Hypertensive: Measure renin and aldosterone → ↓R ↑A = primary hyperaldosteronism; ↑R ↑A = secondary hyperaldosteronism; ↓R ↓A = non-aldo excess (Cushing's, liquorice, Liddle, CAH, AME).
-
Saline-resistant + Normotensive: Bartter's, Gitelman's, severe hypoK, alkali load, current diuretics, Mg depletion.
-
Bartter's vs. Gitelman's: Distinguish by urine Ca²⁺ and serum Mg²⁺.
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Drugs are the most common overall cause — always take a thorough drug history including OTC, TCM, and supplements.
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HypoK from vomiting is renal loss ("Pseudo-Bartter syndrome") — Cl⁻ depletion → ↑ distal Na⁺ → ↑ K⁺ secretion; metabolic alkalosis → bicarbonaturia → K⁺ loss; 2° hyperaldosteronism [6][7].
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If hypoK is refractory to K⁺ replacement, check and correct Mg²⁺ [14].
High Yield Summary — Diagnosis & Investigations
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Diagnostic criteria: pH > 7.45 + HCO₃⁻ > 26 + appropriately elevated pCO₂. Verify compensation: expected pCO₂ = 0.7 × [HCO₃⁻] + 21 (±2).
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Urine Cl⁻ is the single most important investigation to classify metabolic alkalosis. UCl < 20 = saline-responsive; UCl > 20 = saline-resistant. Do NOT rely on urine Na⁺.
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Spot urine K⁺ + plasma HCO₃⁻ paired assessment identifies renal vs. extrarenal K⁺ loss and narrows the differential.
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ECG is mandatory — screen for hypoK-related arrhythmia risk (U waves, flat T, long QT).
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For saline-resistant + hypertensive: measure PRA + PAC → classify into primary hyperaldo (↓R ↑A), secondary hyperaldo (↑R ↑A), or non-aldo excess (↓R ↓A) → targeted confirmatory Ix.
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For saline-resistant + normotensive: serum Mg²⁺ + urine Ca²⁺ distinguish Bartter's (hypercalciuria) from Gitelman's (hypocalciuria + hypoMg) → urine drug screen to r/o surreptitious diuretic use → genetics if indicated.
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Stop interfering drugs ≥ 2 weeks before ARR testing (diuretics, β-blockers, ACEI/ARB, MRA).
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Adrenal venous sampling is the gold standard for lateralisation in primary hyperaldosteronism.
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Always take a thorough drug and supplement history — including TCM (liquorice/甘草) — as drugs are the most common cause of metabolic alkalosis in hospitalised patients.
High Yield Summary — Management of Metabolic Alkalosis
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Two overarching principles: (a) Remove the generation event; (b) Correct the maintenance factor(s) — Cl⁻, K⁺, volume, or mineralocorticoid excess.
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Saline-responsive (UCl < 20): IV NS ± KCl → HCO₃⁻ will fall with ECF expansion. Add PPI if NG drainage, acetazolamide if volume-restricted [1][2].
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Saline-resistant + hypertensive: Spironolactone 100–400 mg daily (blocks MR → ↓ K⁺/H⁺ secretion). Adenoma → adrenalectomy. Bilateral hyperplasia → lifelong MRA. Eplerenone if gynaecomastia; amiloride for Liddle syndrome [1][2][24].
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Saline-resistant + normotensive: KCl + MgCl₂ supplementation. Bartter: add indomethacin + spironolactone. Gitelman: KCl + MgCl₂ ± amiloride [10].
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Acetazolamide (250 mg QID): CA inhibitor → forces renal HCO₃⁻ excretion. Volume-sparing option. Caution: promotes K⁺ loss (always co-give KCl) [2][19].
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Severe alkalosis (pH > 7.55) or renal failure: IV HCl 100 mmol/L via central line, or oral NH₄Cl (contraindicated in liver disease), or haemodialysis [1][3].
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Always use KCl (not K-citrate/acetate) in metabolic alkalosis — Cl⁻ component is therapeutic; citrate/acetate → HCO₃⁻ → worsens alkalosis.
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Always check and correct Mg²⁺ — refractory hypoK is often due to hypoMg.
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Pyloric stenosis: Correct electrolytes FIRST → surgery SECOND.
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NH₄Cl is absolutely contraindicated in liver disease (NH₃ → encephalopathy).
High Yield Summary — Complications of Metabolic Alkalosis
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Cardiac arrhythmias are the most immediately life-threatening complication — driven by concurrent hypoK (flat T, U waves, prolonged QT → TdP, VF). K⁺ < 2.0 is the danger zone.
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Compensatory hypoventilation → mild hypoxaemia in healthy individuals; can cause respiratory failure in patients with pre-existing lung disease. Also impairs ICU ventilator weaning.
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Left shift of the O₂-Hb dissociation curve → tissue hypoxia despite normal SaO₂ (Bohr effect in reverse).
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Neuromuscular irritability (tetany, paraesthesiae, seizures) from ↓ ionised Ca²⁺ due to pH-dependent shift onto albumin.
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Hepatic encephalopathy — alkalosis shifts NH₄⁺ → NH₃ (crosses BBB); hypoK increases renal ammoniagenesis → ↑ total body ammonia. Critical in cirrhotics on diuretics.
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Proximal muscle weakness → respiratory failure from hypoK; rhabdomyolysis from impaired local muscle vasodilation in severe hypoK.
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Paralytic ileus from hypoK → worsens vomiting → worsens alkalosis (vicious cycle).
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Nephrogenic DI (chronic hypoK → polyuria) and paradoxical aciduria (kidney prioritises volume over pH).
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Self-perpetuating hypoK-alkalosis cycle: must treat both simultaneously.
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pH > 7.7 is lethal — all cellular functions disrupted.
Metabolic Acidosis
Metabolic acidosis is a clinical disturbance characterized by a decrease in blood pH due to a primary reduction in serum bicarbonate concentration, resulting from acid accumulation or bicarbonate loss.
Renal Tubular Acidosis
Renal tubular acidosis is a group of disorders characterized by normal anion gap (hyperchloremic) metabolic acidosis resulting from defective renal tubular acid secretion or bicarbonate reabsorption despite relatively preserved glomerular filtration.