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.
Metabolic Acidosis
Metabolic acidosis is a primary acid-base disorder characterised by a pathological process that leads to a net increase in plasma hydrogen ion concentration [H⁺] (or equivalently, a decrease in plasma bicarbonate [HCO₃⁻]), resulting in a tendency toward acidaemia (arterial pH < 7.35) [1][2].
Key distinction (from GC lecture material): Acidosis refers to the ongoing process causing an increase in plasma [H⁺]. Acidaemia refers to the end-result where [H⁺] is actually above normal (pH < 7.35). You can have acidosis without acidaemia if respiratory compensation is adequate [1][2].
Let's break the terminology down:
- "Metabolic" = the primary disturbance originates from a non-respiratory cause (i.e., not from CO₂ retention). It involves either gain of acid or loss of base (HCO₃⁻).
- "Acidosis" = a process driving pH downward.
The fundamental chemistry is governed by the Henderson-Hasselbalch equation:
In metabolic acidosis, the numerator (HCO₃⁻) falls, driving pH down. The body compensates by increasing ventilation (↓pCO₂ — Kussmaul breathing), which partially restores the ratio but does not fully normalise pH.
Normal Values — Must Know
2. Epidemiology and Risk Factors
Metabolic acidosis is among the most common acid-base disturbances encountered in clinical practice, particularly in acute care settings.
- Prevalence: Extremely common — virtually any critically ill patient may develop metabolic acidosis (lactic acidosis is the leading cause in ICU settings)
- In Hong Kong specifically:
- Diabetic ketoacidosis (DKA): rising incidence paralleling the increasing prevalence of Type 1 and poorly controlled Type 2 diabetes. HK has relatively lower T1DM incidence compared to Western countries, but DKA remains a common ED presentation.
- Chronic kidney disease (CKD): HK has a high prevalence of CKD (estimated ~10% of the population), making uraemic acidosis a very common cause of chronic metabolic acidosis.
- Diarrhoeal illness: common in paediatric populations and in travellers — leads to normal anion gap (NAGMA) metabolic acidosis through HCO₃⁻ loss.
- Poisoning: paracetamol overdose and methanol/ethylene glycol ingestion, though the latter are less common in HK than in Western settings.
| Risk Factor | Mechanism |
|---|---|
| Diabetes mellitus (esp. T1DM) | Insulin deficiency → unrestrained lipolysis → ketoacidosis |
| Chronic kidney disease | Impaired acid excretion (↓NH₄⁺ production, ↓titratable acid) + accumulation of sulphate, phosphate, hippurate |
| Sepsis / shock | Tissue hypoperfusion → anaerobic glycolysis → lactic acidosis |
| Alcohol use disorder | Alcoholic ketoacidosis + lactic acidosis (impaired hepatic lactate clearance) |
| Diarrhoea (acute/chronic) | Direct GI loss of HCO₃⁻ |
| Drugs: metformin, salicylates, topiramate, acetazolamide | Various mechanisms (see Aetiology) |
| Inborn errors of metabolism | Organic acidaemias, mitochondrial disorders — particularly in neonates/infants [3] |
| Renal tubular disorders | Impaired H⁺ secretion or HCO₃⁻ reabsorption (RTA types 1, 2, 4) |
| Toxin exposure | Methanol, ethylene glycol, iron, isoniazid |
| Starvation | Ketoacid accumulation from fatty acid oxidation |
3. Anatomy and Physiology of Acid-Base Homeostasis
To understand metabolic acidosis properly, you need to understand where acid comes from and how the body gets rid of it.
- Volatile acid (CO₂): ~15,000–20,000 mmol/day produced from aerobic metabolism. Eliminated entirely by the lungs. This is the respiratory component.
- Non-volatile (fixed) acids: ~50–100 mEq/day of H⁺ produced from:
- Protein metabolism → sulphuric acid (from sulphur-containing amino acids: methionine, cysteine)
- Phospholipid/nucleic acid metabolism → phosphoric acid
- Incomplete carbohydrate oxidation → lactic acid
- Fat metabolism → ketoacids (β-hydroxybutyric acid, acetoacetic acid)
- These must be eliminated by the kidneys.
3.2 Three Lines of Defence Against Acid
The body compensates via: (1) chemical buffers (immediate), (2) lungs (minutes–hours), (3) kidneys (hours–days) [2]
- Bicarbonate buffer system (most important extracellular buffer):
- H⁺ + HCO₃⁻ → H₂CO₃ → CO₂ + H₂O
- Open system: CO₂ is exhaled, preventing equilibrium from shifting back
- Haemoglobin (intracellular buffer in RBCs)
- Phosphate buffer (important intracellularly and in urine)
- Protein buffers (albumin, intracellular proteins)
- Bone: chronic acidosis leads to buffering by calcium carbonate and calcium phosphate in bone → chronic metabolic acidosis causes osteoporosis (this is why CKD patients develop bone disease partly from acidosis)
- Peripheral chemoreceptors (carotid and aortic bodies) detect ↑[H⁺] / ↓pH → stimulate the respiratory centre in the medulla
- Hyperventilation → ↓pCO₂ → partially restores pH
- This produces Kussmaul breathing: deep, laboured breathing — the body's attempt to "blow off" CO₂
- Expected pCO₂ in compensation (Winter's formula):
If measured pCO₂ is higher than expected → concomitant respiratory acidosis. If measured pCO₂ is lower than expected → concomitant respiratory alkalosis.
The kidney is the definitive mechanism for handling non-volatile acids. It does three things:
- Reabsorption of filtered HCO₃⁻: ~4,320 mmol/day of HCO₃⁻ is filtered at the glomerulus; >99% is reabsorbed, primarily in the proximal convoluted tubule (PCT) (~85%) via the Na⁺/H⁺ exchanger (NHE3) and carbonic anhydrase
- Regeneration of new HCO₃⁻: in the distal nephron (α-intercalated cells of the collecting duct), H⁺ is actively secreted via H⁺-ATPase and H⁺/K⁺-ATPase, and for each H⁺ secreted, one new HCO₃⁻ is generated and returned to the blood
- Excretion of H⁺ as titratable acid and ammonium (NH₄⁺):
- Titratable acid: H⁺ + HPO₄²⁻ → H₂PO₄⁻ (excreted in urine)
- Ammonium: glutamine → NH₃ + H⁺ → NH₄⁺ (predominant adaptive mechanism; takes 3-5 days to fully upregulate in chronic acidosis)
When you see "acidosis + hypokalemia → think underlying renal tubular acidosis (especially distal tubular pathology)" [4]
| Nephron Segment | Function in Acid-Base | Dysfunction → |
|---|---|---|
| Proximal tubule (PCT) | Reabsorbs ~85% of filtered HCO₃⁻; produces NH₄⁺ from glutamine | Type 2 (proximal) RTA: failure of HCO₃⁻ reabsorption |
| Thick ascending limb (TAL) | Reabsorbs some HCO₃⁻; NH₄⁺ recycling (countercurrent multiplication of NH₃) | Bartter syndrome (though primarily affects Na/K/Cl) |
| Distal tubule / Collecting duct (α-intercalated cells) | Active H⁺ secretion; generation of new HCO₃⁻ | Type 1 (distal) RTA: failure of H⁺ secretion → urine cannot be acidified below pH 5.5 |
| Collecting duct (principal cells) | Aldosterone-mediated Na⁺ reabsorption / K⁺ secretion; indirectly affects H⁺ secretion | Type 4 RTA: hypoaldosteronism or aldosterone resistance → hyperkalaemia + acidosis |
4. Aetiology and Pathophysiology
This is the core of understanding metabolic acidosis clinically. The approach centres on the anion gap (AG).
The anion gap is crucial in working up metabolic acidosis. You must differentiate between high and normal anion gap metabolic acidosis, since there are different differential diagnoses for each. [2]
Definition: The anion gap represents the difference between the principal measured cation (Na⁺) and the principal measured anions (Cl⁻ + HCO₃⁻):
Normal AG: 8–12 mmol/L (some references 10–14; check your lab's reference range)
What does the AG actually represent? It represents unmeasured anions in the plasma — principally albumin (the major contributor), phosphate, sulphate, and organic anions (lactate, ketoacids). In health, these account for the ~10 mmol/L gap.
From an electrolyte standpoint: In both HAGMA and NAGMA, HCO₃⁻ is reduced. In NAGMA, Cl⁻ rises to compensate (hence "hyperchloraemic metabolic acidosis"). In HAGMA, Cl⁻ stays normal, and the gap is filled by unmeasured anions (ketones, lactate, sulphate, toxin metabolites). [2]
Albumin Correction — Don't Forget!
Hypoalbuminaemia (very common in hospitalised patients) falsely lowers the anion gap. For every 10 g/L drop in albumin below 40 g/L, the AG decreases by ~2.5 mmol/L. Always calculate the corrected AG:
A patient with a "normal" AG of 10 but an albumin of 20 g/L may actually have a corrected AG of ~15 — i.e., a hidden HAGMA.
Once you identify a HAGMA, you should check whether there is a concomitant NAGMA or metabolic alkalosis hiding underneath.
| Δ/Δ Ratio | Interpretation |
|---|---|
| < 1 | Concurrent NAGMA (HCO₃⁻ has dropped more than the AG has risen → extra non-AG acid loss of HCO₃⁻) |
| 1–2 | Pure HAGMA |
| > 2 | Concurrent metabolic alkalosis (HCO₃⁻ hasn't dropped as much as expected → something is maintaining HCO₃⁻, e.g., concurrent vomiting) |
Corrected HCO₃⁻ / delta ratio can be used to rule out concomitant NAGMA [5]
4.3 Classification by Anion Gap
The classic mnemonic is MUDPILES + R [2][5]:
| Letter | Cause | Unmeasured Anion | Pathophysiology |
|---|---|---|---|
| M | Methanol | Formate | Methanol is metabolised by alcohol dehydrogenase → formaldehyde → formic acid (formate). Formate inhibits mitochondrial cytochrome c oxidase → cellular hypoxia. Also causes retinal toxicity (blindness) |
| U | Uraemia (CKD) | Sulphate, phosphate, hippurate | Failing kidneys cannot excrete the daily acid load. Accumulation of sulphate (from protein catabolism), phosphate, and organic anions (hippurate, urate) |
| D | Diabetic ketoacidosis (DKA) / Alcoholic ketoacidosis / Starvation ketoacidosis | β-hydroxybutyrate, acetoacetate | See detailed pathophysiology below |
| P | Paracetamol (in massive overdose) / Propylene glycol / Paraldehyde | Lactate (from hepatotoxicity), pyroglutamic acid (5-oxoproline) | Paracetamol → NAPQI → hepatic necrosis → lactic acidosis. Chronic paracetamol use can deplete glutathione → accumulation of pyroglutamic acid (5-oxoproline) |
| I | Iron / Isoniazid / Inborn errors of metabolism | Lactate, organic acids | Iron: direct GI mucosal injury + mitochondrial toxin → lactic acidosis. Isoniazid: inhibits pyridoxine → impairs GABA synthesis + causes seizures → lactic acidosis. IEMs: organic acidaemias, mitochondrial disorders [3] |
| L | Lactic acidosis | Lactate | See detailed pathophysiology below |
| E | Ethylene glycol | Glycolate, oxalate | Ethylene glycol → glycolaldehyde → glycolate → glyoxylate → oxalate. Calcium oxalate crystals deposit in renal tubules → AKI. Also causes cranial nerve palsies |
| S | Salicylates | Salicylate, lactate, ketoacids | Salicylates uncouple oxidative phosphorylation → ↑metabolic rate → mixed respiratory alkalosis (direct stimulation of respiratory centre) + metabolic acidosis (↑lactate, ↑ketoacids) |
| R | Rhabdomyolysis | Lactate, organic acids from muscle | Muscle necrosis → release of organic acids, phosphate, potassium → HAGMA [6] |
High Yield — HAGMA Causes for Exams
The mnemonic MUDPILES + R is commonly used to remember the causes of increased anion gap metabolic acidosis [2]:
- Methanol, Uraemia, DKA/Alcoholic/Starvation ketoacidosis, Paracetamol/Propylene glycol, Iron/Isoniazid/IEM, Lactic acidosis, Ethylene glycol, Salicylates, Rhabdomyolysis
- Also note: sulphate, phosphate, hippurate in renal failure contribute to the unmeasured anions [2]
Detailed Pathophysiology of Key HAGMA Causes
A. Lactic Acidosis [2]
Lactate is the end-product of anaerobic glycolysis. Normal plasma lactate is < 2 mmol/L [2]. Lactic acidosis is the most common cause of HAGMA in hospitalised patients.
Type A lactic acidosis: overproduction of L-lactate due to oxygen deficiency [2]
- Circulatory problem: e.g., hypotension in sepsis
- Respiratory problem: hypoxia
- Haemoglobin problem: e.g., CO poisoning
- Increased metabolic demand: e.g., grand mal seizure, severe exercise
Type B lactic acidosis: reduced metabolism of L-lactate, without hypoxaemia [2]
- Liver problems (liver is the main site of lactate clearance via gluconeogenesis)
- Alcoholism
- Thiamine deficiency (thiamine is a cofactor for pyruvate dehydrogenase; without it, pyruvate cannot enter the Krebs cycle and is shunted to lactate)
- Phenformin, metformin (metformin inhibits mitochondrial complex I → impairs oxidative phosphorylation)
Why is NaHCO₃ ineffective in Type A lactic acidosis? [2]
In lactic acidosis, the rate of production is massive — up to 72 mmol/min with total hypoxia in type A. So NaHCO₃ therapy is ineffective — you must control the root cause and control the rate of lactate production. NaHCO₃ has some utility in buying time to find and treat the root cause. Apart from not being effective, dumping that much sodium into the patient is also not good. [2]
B. Diabetic Ketoacidosis (DKA) [7][8]
Acute insulin deficiency leads to unrestrained lipolysis, ↑free fatty acids, excess hepatic ketone production and metabolic acidosis. [7]
Pathogenesis step by step:
- Insulin deficiency (± glucagon excess) → removes the "brake" on hormone-sensitive lipase in adipose tissue
- Unrestrained lipolysis → massive release of free fatty acids (FFAs) into the blood
- FFAs transported to the liver → undergo β-oxidation in mitochondria → generate acetyl-CoA
- Entry of acetyl-CoA into the Krebs cycle is rate-limited under conditions of low insulin/high glucagon (glucagon activates carnitine palmitoyltransferase I, which shuttles FFAs into mitochondria)
- Excess acetyl-CoA is diverted to ketogenesis → production of acetoacetate and β-hydroxybutyrate (the predominant ketone)
- These are strong acids → dissociate → release H⁺ → metabolic acidosis
Simultaneously:
- Hyperglycaemia causes osmotic diuresis, leading to dehydration and secondary loss of electrolytes [7]
- Insulin deficiency also causes impaired tubular sodium reabsorption [7]
- Net result: serum sodium and potassium usually normal on admission [7]
- Hypokalemia becomes evident after rehydration and insulin therapy (insulin-stimulated glucose transport into cell is accompanied by inward K⁺ shift) [7]
How to distinguish types of ketoacidosis by glucose level [5]:
- DKA: severe hyperglycaemia
- Alcoholic ketoacidosis: normo/hypoglycaemia + history of alcoholism
- Starvation ketoacidosis: hypoglycaemia
C. Uraemic Acidosis (CKD)
As nephrons are progressively destroyed:
- Early CKD (GFR 20-50): ↓NH₄⁺ production per nephron → remaining nephrons cannot generate enough NH₃ to buffer the daily acid load → NAGMA (the anion gap is initially normal because the retained acids are HCl-equivalent; the kidneys still excrete some organic anions)
- Late CKD (GFR < 15-20): retention of sulphate, phosphate, hippurate, and urate → these unmeasured anions accumulate → HAGMA
So CKD can present as either NAGMA (early) or HAGMA (late) — a commonly tested point.
D. Toxic Alcohols (Methanol, Ethylene Glycol)
Key diagnostic clue: elevated osmolar gap + HAGMA
Normal osmolar gap: < 10 mOsm/kg. Elevated osmolar gap suggests presence of unmeasured osmoles (alcohols).
Osmolar gap (elevated = toxic alcohol) is a key investigation in HAGMA workup [5]
In NAGMA, HCO₃⁻ is lost or not regenerated, and Cl⁻ rises to maintain electroneutrality. The anion gap remains normal because no new unmeasured anion is being added.
The approach to NAGMA uses the urine anion gap (UAG) to distinguish renal from extrarenal causes:
| UAG | Interpretation | Mechanism |
|---|---|---|
| Negative (e.g., -20 to -50) | Extrarenal cause (appropriate renal response) | Kidney is appropriately excreting NH₄⁺ (which carries Cl⁻ with it). The high urine Cl⁻ makes UAG negative |
| Positive (e.g., +20 to +40) | Renal cause (inappropriate renal response) | Kidney is NOT excreting enough NH₄⁺. This points to renal tubular acidosis |
Causes of NAGMA
A. Extrarenal Causes (Negative UAG)
- Diarrhoea (most common): GI secretions distal to the stomach are rich in HCO₃⁻. Loss of these fluids → direct HCO₃⁻ loss → NAGMA. The kidneys respond appropriately by ↑NH₄⁺ excretion → negative UAG
- Excretion of HCO₃⁻ in diarrhoeal fluid is a key mechanism [9]
- Pancreatic fistula / biliary drainage: pancreatic and biliary secretions are HCO₃⁻-rich
- Uretero-sigmoidostomy / ileal conduit: colonic/ileal mucosa absorbs Cl⁻ and secretes HCO₃⁻ → net HCO₃⁻ loss
- Cholestyramine: binds bile acids but also exchanges Cl⁻ for HCO₃⁻ in the gut lumen
B. Renal Causes (Positive UAG) — Renal Tubular Acidosis (RTA)
| Feature | Type 1 (Distal RTA) | Type 2 (Proximal RTA) | Type 4 RTA |
|---|---|---|---|
| Defect | Failure of H⁺ secretion by α-intercalated cells in collecting duct | Failure of HCO₃⁻ reabsorption in PCT | Aldosterone deficiency or resistance |
| Urine pH | > 5.5 (cannot acidify urine) | < 5.5 (once plasma HCO₃⁻ falls below the lowered reabsorptive threshold, the remaining H⁺ secretion is intact) | < 5.5 |
| Plasma K⁺ | Low (H⁺/K⁺-ATPase dysfunction → ↓K⁺ reabsorption) [10] | Low (↑Na⁺ in tubular fluid at DCT → cation exchange, Na⁺ reabsorbed in exchange for K⁺ secretion) [10] | High (aldosterone normally drives K⁺ secretion; deficiency → K⁺ retention) |
| Plasma HCO₃⁻ | Can be very low (< 10) | Usually 12–20 (stabilises once filtered load matches the lowered threshold) | Usually 15–20 (mild acidosis) |
| Associations | Sjögren syndrome, SLE, medullary sponge kidney, nephrocalcinosis, amphotericin B | Fanconi syndrome (generalised PCT dysfunction: glycosuria, aminoaciduria, phosphaturia, uricosuria), multiple myeloma, carbonic anhydrase inhibitors (acetazolamide), Wilson disease | Diabetic nephropathy (Type IV RTA) [11], adrenal insufficiency, ACEi/ARBs, K⁺-sparing diuretics, NSAIDs, heparin, calcineurin inhibitors |
| Complications | Nephrocalcinosis, renal stones (alkaline urine + hypocitraturia + ↑Ca excretion) | Rickets/osteomalacia (phosphate wasting) | Hyperkalaemia → cardiac risk |
| Treatment | Oral NaHCO₃ or Na citrate (1–2 mmol/kg/day) + K⁺ supplementation | Higher doses of NaHCO₃ (10–15 mmol/kg/day, because most is wasted in urine) + K⁺ supplementation. Thiazide diuretic can help (mild volume contraction → ↑proximal reabsorption) | Treat hyperkalaemia first (dietary K⁺ restriction, fludrocortisone if aldosterone deficiency, loop diuretic, Na⁺ polystyrene sulfonate). Correct acidosis with NaHCO₃ if needed |
Hypokalemia + metabolic acidosis → indicates underlying renal tubular acidosis, especially distal tubular pathology [4]
Type 1 RTA is due to a failure of H⁺/K⁺ exchanger in α-intercalated cells of distal tubules, resulting in ↓K⁺ reabsorption. Type 2 RTA is due to a failure of Na⁺/HCO₃⁻ co-transporter in PCT, resulting in cation exchange by K⁺ for the ↑Na⁺ in tubular fluid in DCT. [10]
C. Other Causes of NAGMA
- Acetazolamide (carbonic anhydrase inhibitor): inhibits HCO₃⁻ reabsorption in the PCT → bicarbonaturia → NAGMA
- Saline infusion (dilutional acidosis): large volumes of 0.9% NaCl (154 mmol/L Cl⁻ each) → relative excess of Cl⁻ → hyperchloraemic acidosis. This is why balanced crystalloids (Ringer's lactate, Hartmann's) are preferred for large-volume resuscitation
- Toluene inhalation: hippurate (metabolite) is rapidly excreted renally, so the anion gap may be normal despite it being an organic acid
- Coexisting NAGMA is common in DKA: urinary loss of ketone anions (β-hydroxybutyrate excreted as sodium/potassium salt → loss of potential HCO₃⁻) + HCl retention [5]
An alternative way to think about the causes uses the gain of acid vs. loss of base framework:
5. Classification
| HAGMA | NAGMA | |
|---|---|---|
| Anion gap | > 12 mmol/L | 8–12 mmol/L (normal) |
| Chloride | Normal | Elevated (hyperchloraemic) |
| Key unmeasured anion | Lactate, ketones, uraemic toxins, toxic metabolites | None (Cl⁻ replaces HCO₃⁻) |
| Mnemonic | MUDPILES + R | Diarrhoea, RTA, saline, acetazolamide, ureteral diversions |
| Acute | Chronic | |
|---|---|---|
| Onset | Hours to days | Weeks to months |
| Common causes | DKA, lactic acidosis, toxic ingestion | CKD, RTA, chronic diarrhoea |
| Compensation | Respiratory (immediate but limited) | Respiratory + renal (maximally upregulated NH₄⁺ production) |
| Consequences | Cardiovascular collapse, death | Muscle wasting, bone disease, growth retardation (children) |
6. Clinical Features
| Symptom | Pathophysiological Basis |
|---|---|
| Dyspnoea / air hunger | Respiratory compensation: peripheral chemoreceptors sense ↑[H⁺] → drive hyperventilation. Patients experience this as a subjective sensation of breathlessness even though the lungs are healthy |
| Fatigue / weakness / malaise | Acidosis impairs myocardial contractility and skeletal muscle function; enzymatic reactions function optimally at pH 7.4 |
| Nausea, vomiting, abdominal pain | Acidosis activates the chemoreceptor trigger zone in the area postrema; in DKA specifically, ketoacids cause gastric ileus → acute abdomen: diffuse abdominal pain, nausea, vomiting (due to ileus, usually only if severe acidosis) [8]. Also activates vagal afferents |
| Anorexia | Acidosis centrally suppresses appetite; in uraemia, accumulation of toxins adds to this |
| Confusion / drowsiness / coma | Severe acidosis (pH < 7.1) depresses CNS function. H⁺ crosses BBB → intracellular acidosis in neurons → impaired neurotransmission. In DKA: hyperosmolarity also contributes |
| Polyuria / polydipsia | In DKA: hyperglycaemia → osmotic diuresis → polyuria → polydipsia [7][8] |
| Bone pain (chronic) | Chronic acidosis → bone buffering → calcium carbonate dissolution → osteoporosis/osteomalacia |
| Muscle cramps | Electrolyte disturbances (K⁺, Ca²⁺, Mg²⁺) secondary to the acidotic state and underlying cause |
| Fruity breath | Specific to ketoacidosis: acetone (a volatile ketone) is exhaled → fruity smelling breath [8] |
| Leg cramps | Mentioned specifically in DKA [8] — likely from electrolyte derangement (K⁺, Mg²⁺, PO₄³⁻) |
| Growth failure (children) | Chronic metabolic acidosis impairs GH/IGF-1 axis and promotes protein catabolism |
| Sign | Pathophysiological Basis |
|---|---|
| Kussmaul breathing (deep, laboured respirations) | The hallmark sign. Peripheral chemoreceptors detect ↓pH → stimulate medullary respiratory centre → ↑rate AND ↑depth of breathing to ↓pCO₂. Named after Adolf Kussmaul. Classically seen in DKA but occurs in any cause of significant metabolic acidosis [2][8][12] |
| Tachypnoea | Milder form of respiratory compensation; may precede full Kussmaul pattern |
| Hypotension / tachycardia | (1) Acidosis causes peripheral vasodilation (H⁺ relaxes vascular smooth muscle → ↓SVR → hypotension). (2) Acidosis depresses myocardial contractility (↓Ca²⁺ sensitivity of troponin C). (3) In DKA/diarrhoea, concurrent hypovolaemia from fluid losses worsens hypotension. Tachycardia is a baroreceptor-mediated compensatory response |
| Dehydration signs | Dry mucous membranes, reduced skin turgor, sunken eyes, oliguria. In DKA: orthostatic hypotension or even shock [8]. Due to osmotic diuresis and/or GI losses |
| Warm, flushed peripheries | Acidosis-induced vasodilation (in the absence of shock) |
| Altered consciousness (drowsiness → stupor → coma) | Direct CNS depression from acidaemia; also from concurrent hyperosmolarity (DKA/HHS), uraemia, or toxic metabolites (methanol → formate) |
| Fruity/acetone breath | Acetone is volatile and exhaled — pathognomonic for ketoacidosis [8] |
| Uraemic fetor (ammoniacal/fishy breath) | In CKD/uraemic acidosis: breakdown of urea to ammonia by oral bacteria [12] |
| Scratch marks | In CKD: uraemic pruritus (from hyperphosphataemia and retained uraemic toxins) [12] |
| Café au lait complexion | In CKD: impaired excretion of urochromes + anaemia [12] |
| Muscle twitching / tetany / seizures | In late renal failure: neuromuscular irritability from hypocalcaemia and uraemic toxins. Seizures can be precipitated by overvigorous correction of acidosis [12] |
| Abdominal tenderness / guarding | In DKA: can mimic an acute surgical abdomen — always check glucose and ketones before rushing to theatre! The abdominal pain typically resolves with correction of acidosis |
| Clue | Points Toward |
|---|---|
| Fruity breath + hyperglycaemia + polyuria | DKA |
| History of alcoholism + normo/hypoglycaemia | Alcoholic ketoacidosis |
| Hypotension + tachycardia + warm peripheries + high lactate | Lactic acidosis (Type A — sepsis/shock) |
| Visual disturbance + elevated osmolar gap | Methanol poisoning (formate damages retinal ganglion cells) |
| Flank pain + oxalate crystals on urinalysis + elevated osmolar gap | Ethylene glycol poisoning |
| CKD history + elevated creatinine + normocytic anaemia | Uraemic acidosis |
| Profuse watery diarrhoea | GI HCO₃⁻ loss (NAGMA) |
| Recurrent nephrolithiasis + hypokalaemia + urine pH > 5.5 | Distal (Type 1) RTA |
| Diabetes + mild hyperkalaemia + mild acidosis | Type 4 RTA (hypoaldosteronism associated with diabetic nephropathy) [11] |
| Neonate/infant with metabolic crisis ± hyperammonaemia | Inborn errors of metabolism (IEM) [3] |
A systematic stepwise approach:
Investigations for HAGMA (KOLT approach) [5]:
- RFT, glucose
- CK (rhabdomyolysis)
- Plasma ketones (BOHB — β-hydroxybutyrate)
- Osmolar gap (elevated = toxic alcohol)
- Lactate: > 4 mmol/L is diagnostic (of significant lactic acidosis)
- Serum/urine toxicology
- ± Corrected HCO₃⁻ / delta ratio: to rule out concomitant NAGMA
8. Specific Paediatric Considerations
In children with acute gastroenteritis, metabolic acidosis develops through multiple mechanisms:
- Excretion of HCO₃⁻ in diarrhoeal fluid (primary mechanism) [9]
- Lactic acidosis due to decreased tissue perfusion (from hypovolaemia) [9]
- Ketoacidosis due to starvation or fasting ketosis [9]
- Decreased acid excretion by the kidney caused by a reduction in renal perfusion resulting from a reduction of effective circulatory perfusion due to hypovolaemia [9]
Metabolic diseases can present with life-threatening decompensation. Occurs in the neonatal period or in infancy, sometimes not until adulthood. Key metabolic emergencies include: hypoglycaemia, ketoacidosis, primary lactic acidosis, hyperammonaemia, intractable seizures, acute metabolic encephalopathy, acute liver failure. [3]
When a neonate or infant presents with unexplained HAGMA (especially with ketosis, hyperammonaemia, or hypoglycaemia), always consider IEM:
- Organic acidaemias (methylmalonic, propionic, isovaleric acidaemia): accumulation of organic acids → HAGMA
- Maple syrup urine disease: branched-chain amino acid accumulation
- Fatty acid oxidation defects: impaired ketogenesis but ↑organic acids
- Mitochondrial disorders (e.g., MELAS): primary lactic acidosis
| Condition | Type of Acidosis | Mechanism |
|---|---|---|
| CKD | NAGMA (early) → HAGMA (late) | ↓NH₄⁺ production → ↓acid excretion; accumulation of sulphate, phosphate [2][12] |
| DKA | HAGMA (±concurrent NAGMA) | Ketoacid accumulation; NAGMA component from urinary ketone loss [5][7] |
| Sepsis/shock | HAGMA (lactic) | Tissue hypoperfusion → anaerobic metabolism → lactate [2] |
| Diarrhoea | NAGMA | GI HCO₃⁻ loss [9] |
| Massive blood transfusion | HAGMA (initially from citrate; stored blood is acidic) [13] | Storage of citrated blood becomes progressively acidic → metabolic acidosis [13] |
| Rhabdomyolysis | HAGMA | Release of organic acids (lactate) from damaged muscle [6] |
| Tumour lysis syndrome | HAGMA | Cell lysis → release of organic acids → lactate → metabolic acidosis [14] |
| Ischaemic bowel | HAGMA (lactic) | Acute abdomen + metabolic acidosis = ischaemic bowel until proven otherwise [15] |
This is a critically important and frequently tested concept:
Metabolic acidosis → H⁺/K⁺ intracellular shift → often normokalaemia on admission (in DKA) [8]. But there is a net total body K⁺ deficit because of osmotic diuresis-driven K⁺ loss + secondary hyperaldosteronism.
The apparent K⁺ level on admission can be deceptively normal or even high, but once you give insulin + fluids:
- Insulin drives K⁺ into cells (via Na⁺/K⁺-ATPase stimulation)
- Correction of acidosis reverses the H⁺/K⁺ transcellular shift (K⁺ moves back into cells)
- Volume resuscitation dilutes K⁺
→ Hypokalaemia becomes evident after rehydration and insulin therapy [7]
This is why K⁺ monitoring is paramount during DKA treatment. You must replace K⁺ aggressively during correction.
Conversely, in Type 4 RTA, the aldosterone deficiency causes true hyperkalaemia that worsens with acidosis.
Acidosis: mechanism is transcellular shift of H⁺ → ↓K⁺ in ECF. Causes: DKA, renal failure, other acidosis. Important: apparent hyperK does not mean excessive body K stores. DKA results in osmotic diuresis → depletion of body's K reserve → apparent hyperK only a result of mobilization of intracellular K → normalization of ketone levels may result in hypokalemia → must monitor K level [16]
Acidosis causes a rightward shift of the oxygen-haemoglobin dissociation curve (Bohr effect):
- ↑[H⁺] decreases Hb's affinity for O₂ → O₂ is more readily released to tissues
- This is actually protective in the short term — it improves O₂ delivery to hypoxic tissues
- However, if you rapidly correct acidosis with NaHCO₃, you shift the curve leftward → Hb holds onto O₂ more tightly → tissue hypoxia can paradoxically worsen [17]
High Yield Summary
- Definition: Metabolic acidosis = process causing ↑[H⁺] / ↓[HCO₃⁻]; acidaemia ≠ acidosis (compensation can mask it)
- Anion gap is the key discriminating tool:
- HAGMA (MUDPILES + R): Methanol, Uraemia, DKA, Paracetamol/Propylene glycol, Iron/Isoniazid/IEM, Lactic acidosis, Ethylene glycol, Salicylates, Rhabdomyolysis
- NAGMA: Diarrhoea (most common), RTA (Types 1, 2, 4), saline infusion, acetazolamide, ureteral diversions
- Always correct AG for albumin (↓albumin = ↓AG = masked HAGMA)
- Delta-delta ratio to unmask concurrent disorders (< 1 = concomitant NAGMA; > 2 = concomitant met alkalosis)
- Urine anion gap separates renal vs extrarenal NAGMA (negative = GI loss; positive = RTA)
- Lactic acidosis: Type A (hypoxia/hypoperfusion) vs Type B (impaired clearance); NaHCO₃ is NOT a definitive treatment — treat the root cause
- DKA: insulin deficiency → lipolysis → ketogenesis → HAGMA; K⁺ is often deceptively normal on admission but total body K⁺ is depleted — watch for hypokalaemia during treatment
- Kussmaul breathing = deep laboured respiration = respiratory compensation for metabolic acidosis
- Winter's formula: Expected pCO₂ = 1.5 × [HCO₃⁻] + 8 (±2) — check for concurrent respiratory disorder
- NaHCO₃ risks: hypernatraemia, hypokalaemia, ↓ionised Ca²⁺, volume overload, paradoxical cerebral acidosis, leftward shift of O₂-Hb curve
- In children with diarrhoea, metabolic acidosis is multifactorial: HCO₃⁻ loss in stool, lactic acidosis from hypoperfusion, starvation ketosis, decreased renal acid excretion
- IEM must be considered in any neonate/infant with unexplained HAGMA + metabolic crisis
Active Recall - Metabolic Acidosis
[1] Lecture slides: Block A - Electrolyte and Acid-Base Disorders.pdf (Acid-base disorders section) [2] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (Anion Gap, Lactic Acidosis, Management sections) [3] Lecture slides: Chemical Pathology Seminar_Inherited metabolic disease 2025.pdf (Metabolic Emergency slide) [4] Senior notes: Block A - Introduction to Renal Investigations (RFT, urine tests and US kidneys).pdf (When to suspect renal tubular problems) [5] Senior notes: Maksim Medicine Notes.pdf (HAGMA section, p.213) [6] Senior notes: Ryan Ho Neurology.pdf (Rhabdomyolysis section, p.196) [7] Lecture slides: GC 078. Polyuria and polydipsia glucose metabolism, diabetes mellitus, diabetic ketoacidosis [Update 2025].pdf (DKA slide) [8] Senior notes: Ryan Ho Endocrine.pdf (DKA section, p.91); Adrian Lui Pediatrics Notes.pdf (DKA section, p.299) [9] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Dehydration complications, p.342) [10] Senior notes: Ryan Ho Chemical Path.pdf (Hypokalemia approach, p.18 — footnotes on RTA types) [11] Senior notes: Block A – Nephrology Data Interpretation.pdf (Type IV RTA and diabetic nephropathy, p.9) [12] Senior notes: Ryan Ho Fundamentals.pdf (General examination in renal patients, p.112) [13] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (Citrate toxicity, p.24) [14] Senior notes: Ryan Ho Haemtology.pdf (Tumour lysis syndrome, p.72) [15] Senior notes: Maksim Surgery Notes.pdf (Ischaemic bowel disease, p.91) [16] Senior notes: Ryan Ho Chemical Path.pdf (Hyperkalemia — disruption of K gradient, p.16) [17] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (Risks of NaHCO3 therapy)
Differential Diagnosis of Metabolic Acidosis
The differential diagnosis of metabolic acidosis is one of the most systematic and algorithmic exercises in clinical medicine. It hinges almost entirely on one calculation — the anion gap — and then branches from there using a handful of further discriminators (osmolar gap, urine anion gap, glucose level, lactate level, clinical context). Let's build this from first principles.
Before you can generate a differential, you must classify the metabolic acidosis. The anion gap is your primary fork in the road.
The anion gap is crucial in working up metabolic acidosis. You must differentiate between high and normal anion gap metabolic acidosis, since there are different differential diagnoses for each cause. [2]
Recall:
Normal anion gap = 8–14 mmol/L [2]. The AG represents unmeasured anions (principally albumin, phosphate, sulphate, organic anions). When new unmeasured anions appear (ketones, lactate, formate, glycolate, etc.), the AG rises. When the only process is HCO₃⁻ loss or impaired H⁺ excretion, Cl⁻ rises to maintain electroneutrality and the AG stays normal.
In metabolic acidosis with a normal anion gap: there is an increase in Cl⁻ to balance out the reduction in HCO₃⁻. In metabolic acidosis with an increased anion gap: there is no change in Cl⁻, and the gap increases, reflecting an increase in UNMEASURED ANIONS. [2]
Non-Acid-Base Conditions That Alter the Anion Gap
Altered anion gap can be seen in paraproteinaemia [2]:
- Reduced AG in IgG gammopathy (IgG is a cationic paraprotein → ↑unmeasured cations → ↓AG)
- Increased AG in IgA gammopathy (IgA is anionic)
Also remember: hypoalbuminaemia falsely lowers the AG (always correct for albumin — see Part 1). A "normal" AG in a patient with albumin of 20 g/L may actually be hiding a significant HAGMA.
2. Diagnostic Algorithm: Step-by-Step
The GC lecture slide provides the definitive exam-framing of the diagnostic approach [18]:
Diagnosis of metabolic acidosis [18]:
- Ensure this is Metabolic Acidosis
- Determine the Anion Gap (AG): high AG or normal AG
- If normal AG: Determine Urine AG [i.e. Urine Na + urine K – urine Cl] (Advanced). NaHCO₃ infusion or Acid loading test: proximal vs. distal RTA (Advanced)
- Look for any Osmolar Gap (OG): Measured osmol – calculated osmol
- Any mixed acid/base disorder (ΔAG vs. ΔHCO₃⁻)?
Let's flesh out each step.
- Check ABG: pH < 7.35 and HCO₃⁻ < 22 mmol/L
- Important: Low bicarbonate does not mean metabolic acidosis — it could be the compensatory mechanism to a primary respiratory alkalosis (e.g., something causing hyperventilation) [2]. You must look at the pH to distinguish the primary disorder.
- Apply Winter's formula to check if respiratory compensation is appropriate:
If pCO₂ is higher than expected → concomitant respiratory acidosis (e.g., a COPD patient with DKA). If pCO₂ is lower than expected → concomitant respiratory alkalosis (e.g., salicylate poisoning, which directly stimulates the respiratory centre).
- AG = Na⁺ − (Cl⁻ + HCO₃⁻)
- Correct for albumin if hypoalbuminaemic
- Fork: HAGMA vs. NAGMA
- UAG = Urine Na⁺ + Urine K⁺ − Urine Cl⁻
- Negative UAG → appropriate renal NH₄⁺ excretion → extrarenal cause (diarrhoea)
- Positive UAG → impaired renal NH₄⁺ excretion → renal tubular acidosis
- Further differentiation of RTA subtypes by urine pH, serum K⁺, and specialised tests (bicarbonate loading test)
- Osmolar gap = Measured osmolality − Calculated osmolality
- Calculated osmolality = 2[Na⁺] + [Urea] + [Glucose] (all mmol/L)
- Osmolal gap > 25 specific for toxic alcohol ingestion [19]
- If elevated → think methanol or ethylene glycol
- If normal → think DKA, lactic acidosis, uraemia, salicylates, etc.
Note that with time, methanol is gradually converted into formate: anion gap increases, osmolal gap decreases [19]. So a late-presenting methanol poisoning may have a high AG but a normal osmolar gap — the parent compound has already been metabolised.
- ΔAG/ΔHCO₃⁻ = (AG − 12) / (24 − HCO₃⁻)
- < 1 → concurrent NAGMA hiding underneath
- 1–2 → pure HAGMA
-
2 → concurrent metabolic alkalosis
3. Complete Differential Diagnosis by Category
Here is the comprehensive differential, organised by anion gap and then subcategorised.
| Cause | Unmeasured Anion | Key Discriminating Feature | Pathophysiology |
|---|---|---|---|
| Methanol | Formate | Elevated osmolar gap, visual disturbance ("snowstorm-like blurry vision"), fundoscopy shows hyperaemia or disc pallor [19] | Methanol → formaldehyde → formic acid; formate inhibits cytochrome c oxidase → tissue hypoxia + retinal toxicity |
| Uraemia (CKD) | Sulphate, phosphate, hippurate | Elevated creatinine and urea, small kidneys on US, normocytic anaemia | Failing kidneys cannot excrete daily acid load; accumulation of organic anions. Also sulphate, phosphate, hippurate in renal failure [2] |
| DKA | β-hydroxybutyrate, acetoacetate | Severe hyperglycaemia [20], positive plasma ketones/BOHB, history of T1DM or poorly controlled T2DM | Insulin deficiency → unrestrained lipolysis → ketogenesis → HAGMA |
| Alcoholic ketoacidosis | β-hydroxybutyrate | Normo/hypoglycaemia + history of alcoholism [20] | Alcohol metabolism consumes NAD⁺ → ↓gluconeogenesis → hypoglycaemia suppresses insulin → fasting state → ketogenesis. Also catecholamine surge in withdrawal favours fasting state [20] |
| Starvation ketoacidosis | β-hydroxybutyrate | Hypoglycaemia [20], usually minimal acidosis, takes 1–2 weeks of fasting to develop [20] | Prolonged fasting → ↓insulin → mobilisation of fat stores → ketogenesis |
| Paracetamol | Lactate, pyroglutamic acid (5-oxoproline) | Drug history, ↑ALT/AST, ± normal osmolar gap | Massive overdose → NAPQI → hepatic necrosis → ↓lactate clearance → lactic acidosis; chronic use → glutathione depletion → pyroglutamic acid accumulation |
| Propylene glycol | Lactate, D-lactate | Used as pharmaceutical solvent (e.g., IV lorazepam, phenytoin), elevated osmolar gap | Metabolised to L-lactate and D-lactate |
| Iron | Lactate | Serum Fe levels correlate with severity: > 90 μmol/L → severe toxicity [21] | Direct mitochondrial toxin + GI mucosal injury → lactic acidosis + haemorrhagic gastroenteritis |
| Isoniazid | Lactate | Drug history (TB treatment), seizures | Inhibits pyridoxine (vitamin B₆) → ↓GABA synthesis → seizures → ↑muscle activity → lactic acidosis; also directly impairs mitochondrial function |
| Inborn errors of metabolism | Organic acids, lactate | Neonatal/infant metabolic crisis; metabolic diseases can present with life-threatening decompensation — occurs in the neonatal period or in infancy, sometimes not until adulthood [3] | Organic acidaemias (methylmalonic, propionic, isovaleric), fatty acid oxidation defects, mitochondrial diseases, gluconeogenesis/glycogenolysis defects |
| Lactic acidosis (Type A) | Lactate | Normal lactate < 2 mmol/L; > 4 mmol/L diagnostic [18]; clinical shock, hypoxia | Overproduction of L-lactate due to oxygen deficiency: circulatory problem (e.g., hypotension in sepsis), respiratory problem (hypoxia), haemoglobin problem (e.g., CO poisoning), increased metabolic demand (e.g., grand mal seizure, severe exercise) [2][18] |
| Lactic acidosis (Type B) | Lactate | No hypoxaemia | Reduced metabolism of L-lactate without hypoxaemia: liver problems, alcoholism, thiamine deficiency, phenformin/metformin [2]. Metformin causes lactic acidosis in CKD patients (eGFR < 30 mL/min) [22] |
| D-lactic acidosis | D-lactate | Short bowel syndrome [23] | Carbohydrate malabsorption → colonic bacterial fermentation → D-lactate production; not detected by standard L-lactate assays |
| Ethylene glycol | Glycolate, oxalate | Elevated osmolar gap, calcium oxalate crystals in urine, AKI | Ethylene glycol → glycolaldehyde → glycolate → glyoxylate → oxalate; calcium oxalate crystals deposit in renal tubules → AKI |
| Salicylates | Salicylate, lactate, ketoacids | Mixed respiratory alkalosis + metabolic acidosis [21]; suspect salicylate poisoning in acid-base disorder of unknown origin [21] | Salicylates directly stimulate medullary respiratory centre → respiratory alkalosis; also uncouple oxidative phosphorylation → ↑metabolic rate → lactate + ketoacid accumulation → HAGMA |
| Rhabdomyolysis | Lactate, organic acids, phosphate | ↑↑↑CK (> 5× ULN), myoglobinuria (dipstick +ve, microscopy −ve), dark urine | Muscle necrosis → release of intracellular organic acids, K⁺, PO₄³⁻ |
The Ketoacidosis Sub-Differential — Glucose Level Is the Key
When you've identified ketoacidosis (positive ketones + HAGMA), the next question is: What is the glucose level? [20]
- DKA: severe hyperglycaemia (> 14 mmol/L)
- Alcoholic ketoacidosis: normo/hypoglycaemia + history of alcoholism
- Starvation ketoacidosis: hypoglycaemia
Also consider euglycaemic DKA — an emerging entity seen with SGLT2 inhibitors [22]. The glucose may be only mildly elevated or even normal because SGLT2i cause glycosuria, masking the hyperglycaemia. High index of suspicion needed in any patient on SGLT2i presenting with HAGMA + ketosis.
Osmolar Gap — Temporal Evolution in Toxic Alcohol Poisoning
A common exam pitfall: With time, methanol is gradually converted into formate — anion gap increases, osmolal gap decreases [19]. So:
- Early presentation: high osmolar gap, relatively normal AG (parent alcohol is present but hasn't been metabolised yet)
- Late presentation: high AG, normal osmolar gap (all parent alcohol has been converted to toxic metabolites)
You must check both OG and AG. Don't dismiss methanol/ethylene glycol just because the osmolar gap is normal in a late presenter.
3.2 Normal Anion Gap Metabolic Acidosis (NAGMA)
In NAGMA, there is an increase in Cl⁻ to balance out the reduction in HCO₃⁻ [2] — hence the term hyperchloraemic metabolic acidosis. The differential is separated by whether the problem is renal or extrarenal, using the urine anion gap.
| Cause | Mechanism | Key Clue |
|---|---|---|
| Diarrhoea | GI secretions below the stomach are HCO₃⁻-rich; their loss depletes HCO₃⁻ directly | History of diarrhoea; paired spot urine K < 20 mmol/L → acute diarrhoea [10]; negative UAG |
| Pancreatic / biliary fistula or drainage | Pancreatic juice contains ~100 mmol/L HCO₃⁻; loss = direct base loss | Post-surgical context |
| Uretero-sigmoidostomy / ileal conduit | Colonic or ileal mucosa absorbs Cl⁻ and secretes HCO₃⁻ in exchange; net HCO₃⁻ loss | History of urinary diversion surgery |
| Cholestyramine | Anion exchange resin: binds bile acids in GI lumen but also exchanges Cl⁻ for HCO₃⁻ | Drug history |
| Type | Defect | Serum K⁺ | Urine pH | Associations |
|---|---|---|---|---|
| Type 1 (Distal) RTA | Failure of H⁺ secretion by α-intercalated cells (H⁺-ATPase / H⁺/K⁺-ATPase defect) [10] | Low | > 5.5 (cannot acidify urine) | Sjögren's syndrome [24], SLE, medullary sponge kidney, nephrocalcinosis, amphotericin B |
| Type 2 (Proximal) RTA | Failure of HCO₃⁻ reabsorption in PCT (Na⁺/HCO₃⁻ co-transporter defect) [10] | Low | Variable (< 5.5 once plasma HCO₃⁻ drops below reabsorptive threshold) | Fanconi syndrome (glycosuria, aminoaciduria, phosphaturia, tubular proteinuria, uricosuria) [25], multiple myeloma, carbonic anhydrase inhibitors, Wilson disease |
| Type 4 (Hyperkalaemic) RTA | Aldosterone deficiency or resistance → ↓NH₄⁺ production (hyperkalaemia inhibits ammoniagenesis in PCT) | High | < 5.5 | Diabetic nephropathy [11], adrenal insufficiency, ACEi/ARBs, K⁺-sparing diuretics, NSAIDs, heparin, calcineurin inhibitors |
When should we suspect renal tubular problems? [24]:
- Severe and multiple electrolyte abnormalities (e.g., severe hypoK + hypoPO₄ → RTA)
- Unusual combination of acid-base and electrolyte abnormalities
- Usual situation: hypoK + metabolic alkalosis or hyperK + metabolic acidosis
- If hypoK + metabolic acidosis → ? RTA
- Presence of unusual substance in urine: glucose (without DM), amino acids
- Other clinical associations: e.g., Sjögren's syndrome with distal RTA
Fanconi Syndrome — The Proximal Tubular 'Leaky Pipe'
Fanconi syndrome is a syndrome of inadequate reabsorption in the proximal renal tubule [25]. Because the PCT handles reabsorption of HCO₃⁻, glucose, amino acids, phosphate, uric acid, and low-molecular-weight proteins simultaneously, a generalized PCT defect produces:
- NAGMA (Type 2 RTA) — HCO₃⁻ wasting
- Glycosuria (with normal blood glucose!)
- Aminoaciduria
- Phosphaturia → hypophosphataemic rickets (children) / osteomalacia (adults)
- Tubular proteinuria (↑urine β2-microglobulin)
- Uricosuria
- Hypokalaemia (compensatory K⁺ secretion in DCT for ↑Na⁺ in tubular fluid)
Diagnosis of proximal RTA confirmed by bicarbonate loading test: fractional excretion of HCO₃⁻ > 15% after IV NaHCO₃ infusion → Type 2 RTA [25].
| Cause | Mechanism |
|---|---|
| Acetazolamide | Carbonic anhydrase inhibitor → blocks HCO₃⁻ reabsorption in PCT → bicarbonaturia → NAGMA (pharmacological Type 2 RTA) |
| Saline infusion (dilutional) | Large-volume 0.9% NaCl (154 mmol/L Cl⁻) → hyperchloraemia → NAGMA |
| Toluene inhalation | Metabolised to hippurate → rapidly excreted renally (as Na/K salt) → AG may be normal at presentation; the "missing anion" has already left the body [23] |
| Post-hypocapnia | Rapid correction of chronic respiratory alkalosis → renal HCO₃⁻ excretion was already low to compensate; sudden ↑CO₂ → ↑H₂CO₃ with inadequate HCO₃⁻ reserve |
| Topiramate | Inhibits carbonic anhydrase (similar to acetazolamide) → HCO₃⁻ wasting |
4. Specific Differential Diagnosis Scenarios
Agonising epigastric pain but insignificant signs — differential diagnoses: acute pancreatitis, mesenteric thrombosis (often accompanied by a high anion gap metabolic acidosis caused by lactate, pain out of proportion to clinical findings), diabetic ketoacidosis [26]
This is a classic exam scenario. All three can present with severe pain and relatively benign examination initially. The metabolic acidosis is the discriminating lab clue: lactate points to mesenteric ischaemia, ketones + hyperglycaemia points to DKA.
Severe high anion gap metabolic acidosis in a neonate suggests severe energy deficiency — consider: fatty acid oxidation defect, mitochondrial diseases, gluconeogenesis/glycogenolysis defects, neonatal hyperinsulinism, cortisol/GH deficiency [3]
In the HKUMed Chemical Pathology Seminar case, a neonate born at 40 weeks presented with cardiac arrest, undetectable H'stix, severe HAGMA, and seizures. The differential of metabolic emergencies in neonates must always include inborn errors of metabolism [3].
Salicylate overdose classically produces a mixed respiratory alkalosis + metabolic acidosis [21]. The respiratory alkalosis comes from direct stimulation of the medullary respiratory centre by salicylate; the metabolic acidosis comes from uncoupled oxidative phosphorylation generating lactate and ketoacids.
In acute respiratory alkalosis, immediate bicarbonate buffer compensation can only result in ~2 mmol/L drop in HCO₃⁻ per each 1.33 kPa drop in pCO₂. If the observed HCO₃⁻ is lower than expected from compensation alone, an underlying metabolic acidosis is present. This can be verified by anion gap. [21]
CKD can cause either NAGMA or HAGMA depending on the stage:
- Early (GFR 20–50 mL/min): ↓NH₄⁺ excretion per nephron, but remaining nephrons still excrete some organic anions → HCl-equivalent acid retained → NAGMA (sometimes called "Type 4 RTA of CKD" or hyperchloraemic acidosis of CKD)
- Late (GFR < 15–20 mL/min): inability to excrete sulphate, phosphate, hippurate, urate → accumulation of unmeasured anions → HAGMA
Typical electrolytes and acid-base abnormalities in kidney failure: usually metabolic acidosis [24]
DDx of Kussmaul breathing: rapid/deep breathing → metabolic acidosis. Point-of-care (POC) arterial blood gas: severe metabolic acidosis [27]
When you see Kussmaul breathing at the bedside, the DDx is essentially the DDx of metabolic acidosis itself, most importantly:
- DKA
- Lactic acidosis (sepsis/shock)
- Uraemic acidosis
- Toxic ingestion (methanol, ethylene glycol, salicylates)
| HAGMA (↑AG) | NAGMA (Normal AG, ↑Cl⁻) |
|---|---|
| MUDPILES + R | Extrarenal (UAG −) |
| M — Methanol | Diarrhoea |
| U — Uraemia (late CKD) | Pancreatic/biliary fistula |
| D — DKA / AKA / Starvation KA | Ureteral diversion |
| P — Paracetamol / Propylene glycol | Cholestyramine |
| I — Iron / Isoniazid / IEM | Renal (UAG +) |
| L — Lactic acidosis (A and B) | Type 1 (distal) RTA |
| E — Ethylene glycol | Type 2 (proximal) RTA / Fanconi |
| S — Salicylates | Type 4 (hyperkalaemic) RTA |
| R — Rhabdomyolysis | Other |
| D-lactic acidosis (short bowel) | Saline infusion / Acetazolamide / Topiramate / Toluene |
| SGLT2i — euglycaemic DKA | Early CKD |
High Yield Summary — Differential Diagnosis of Metabolic Acidosis
- Step 1: Confirm metabolic acidosis (pH < 7.35 AND ↓HCO₃⁻; not just compensation for respiratory alkalosis)
- Step 2: Calculate the anion gap (correct for albumin!)
- HAGMA → MUDPILES + R: Methanol, Uraemia, DKA/AKA/Starvation KA, Paracetamol/Propylene glycol, Iron/Isoniazid/IEM, Lactic acidosis, Ethylene glycol, Salicylates, Rhabdomyolysis
- NAGMA → UAG: Negative UAG = extrarenal (diarrhoea); Positive UAG = renal (RTA)
- Osmolar gap > 25 → toxic alcohols (methanol, ethylene glycol). Remember temporal evolution: early = high OG/normal AG; late = normal OG/high AG
- Ketoacidosis sub-differential by glucose: DKA (high), AKA (normal/low), starvation (low), SGLT2i-associated euglycaemic DKA (normal/mildly high)
- CKD causes both NAGMA (early) and HAGMA (late)
- HypoK + metabolic acidosis = think RTA (especially distal); HyperK + metabolic acidosis = think Type 4 RTA or CKD
- Delta-delta ratio catches hidden concurrent NAGMA (< 1) or metabolic alkalosis ( > 2)
- Salicylate poisoning = classic mixed respiratory alkalosis + HAGMA
Active Recall - Differential Diagnosis of Metabolic Acidosis
References
[2] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (Anion Gap, Lactic Acidosis sections) [3] Lecture slides: Chemical Pathology Seminar_Inherited metabolic disease 2025.pdf (Metabolic Emergency slide; Neonatal cardiac arrest case) [5] Senior notes: Maksim Medicine Notes.pdf (HAGMA section, p.213) [10] Senior notes: Ryan Ho Chemical Path.pdf (Hypokalemia approach, p.18 — footnotes on RTA types) [11] Senior notes: Block A – Nephrology Data Interpretation.pdf (Type IV RTA and diabetic nephropathy, p.9) [18] Lecture slides: GC 044. Electrolyte and Acid-Base Disorders.pdf (Diagnosis of metabolic acidosis slide, p.8; L-lactic acidosis slide, p.15) [19] Senior notes: Ryan Ho Chemical Path.pdf (Methanol section, p.41) [20] Senior notes: Ryan Ho Urogenital.pdf (Ketoacidosis section, p.47) [21] Senior notes: Ryan Ho Chemical Path.pdf (Salicylate section, p.42; Iron section, p.42) [22] Senior notes: Block A - Drugs and the Kidney.pdf (Metformin side effect, p.19; SGLT2i euglycaemic ketoacidosis, p.19) [23] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Causes of metabolic acidosis table, p.87) [24] Lecture slides: Introduction-kidney-Ix.pdf (When to suspect renal tubular problems, p.29; Typical abnormalities in kidney failure, p.28) [25] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (Fanconi syndrome case, p.23–25; Distal RTA case, p.25–27) [26] Senior notes: Block A - Upper abdominal pain_ peptic ulcer; pancreatitis and gallstone.pdf (Agonising epigastric pain DDx, p.6) [27] Lecture slides: CFB (MED02) Clinical Demonstration on general examination.pdf (DDx Kussmaul breathing, p.19)
Diagnostic Criteria, Algorithm, and Investigations for Metabolic Acidosis
1. Diagnostic Criteria — Confirming Metabolic Acidosis
Metabolic acidosis is fundamentally a laboratory diagnosis confirmed by arterial (or venous) blood gas analysis combined with a basic metabolic panel. There is no single "diagnostic criterion" in the way we diagnose, say, rheumatoid arthritis with classification criteria — instead, it is a biochemical diagnosis with a subsequent algorithmic workup to identify aetiology.
| Parameter | Criterion | Why This Value? |
|---|---|---|
| Arterial pH | < 7.35 | Defines acidaemia — the end-result of the acidotic process. Note: compensated metabolic acidosis may have pH 7.35–7.40 if respiratory compensation is intact |
| Plasma [HCO₃⁻] | < 22 mmol/L | HCO₃⁻ is consumed buffering the excess H⁺, or is lost directly (diarrhoea, RTA). This is the primary disturbance in metabolic acidosis |
| pCO₂ | < 40 mmHg (< 5.3 kPa) | Must be low (or at least not elevated) to confirm that the low HCO₃⁻ is a primary metabolic process rather than compensation for respiratory alkalosis |
Confirm metabolic acidosis: [HCO₃⁻] < 22 mmol/L with pCO₂ < 40 mmHg [28]
The Most Common Diagnostic Pitfall
Low bicarbonate does not mean metabolic acidosis — it could be the compensatory mechanism to a primary respiratory alkalosis (e.g., something causing hyperventilation) [2]. You must look at the pH first. If pH > 7.45, the primary disorder is alkalosis, and the low HCO₃⁻ is renal compensation. Only if pH < 7.35 (or 7.35–7.40 with a clear metabolic story) can you call it metabolic acidosis.
Once metabolic acidosis is confirmed, assess whether the respiratory compensation is appropriate:
Or in kPa: 1 mmol/L ↓ in HCO₃⁻ ≈ 0.17 kPa ↓ in pCO₂ (minimum 1.3 kPa in acute, 2–2.7 kPa in chronic) [29]
| Measured pCO₂ vs Expected | Interpretation |
|---|---|
| Within ±2 of expected | Simple (compensated) metabolic acidosis — respiratory system is doing its job |
| Higher than expected | Concurrent respiratory acidosis (e.g., COPD + DKA; exhaustion of respiratory muscles in severe sepsis). The patient cannot blow off enough CO₂ |
| Lower than expected | Concurrent respiratory alkalosis (e.g., salicylate poisoning directly stimulating the medullary respiratory centre on top of metabolic acidosis) |
If pCO₂ is higher than expected, then there may be concurrent respiratory acidosis. May consider to intubate and hyperventilate patient if inadequate [28]
1.3 Diagnostic Criteria for Specific Aetiologies
While metabolic acidosis itself is diagnosed purely biochemically, specific causes have their own formal diagnostic criteria. The most important for exams:
Diagnostic criteria for DKA [8]:
- Blood glucose > 14 mmol/L (AND)
- Arterial pH < 7.3 (AND)
- Plasma HCO₃⁻ < 15 mmol/L (High anion gap metabolic acidosis) (AND)
- Moderate ketonuria or ketonaemia (OR) high serum β-hydroxybutyric acid
| DKA Severity (ADA) | pH | HCO₃⁻ (mmol/L) | Mental Status |
|---|---|---|---|
| Mild | 7.25–7.3 | 15–18 | Alert |
| Moderate | 7.0–7.25 | 10–15 | Mild drowsiness |
| Severe | < 7.0 | < 10 | Stupor/coma |
| Test | Confirms | Method | Diagnostic Finding |
|---|---|---|---|
| Acid loading test (NH₄Cl) | Type 1 (Distal) RTA | Oral ammonium chloride 0.1 g/kg to induce acidosis [28][23] | Failure to acidify urine (pH > 5.3–5.5) after metabolic acid loading is diagnostic of Type 1 RTA [23] |
| Fractional excretion of HCO₃⁻ (FEHCO₃⁻) | Type 2 (Proximal) RTA | NaHCO₃ infusion 0.5–1.0 mmol/kg/h to raise serum [HCO₃⁻] above normal [28] | FEHCO₃⁻ > 15% (especially when done after NaHCO₃ infusion) = proximal RTA; < 5% = distal RTA/normal [28] |
| Alternative: Furosemide with fludrocortisone test | Type 1 (Distal) RTA | Furosemide + fludrocortisone administered; measure urine pH | Urine pH > 5.3 = distal RTA |
The FEHCO₃⁻ formula:
Since fractional excretion of bicarbonate ion is 21.9% > 15% — the diagnosis of proximal RTA (type II) is made [25]
This integrates the GC lecture slide framework [18] with the detailed stepwise approach from senior notes [2][28][23].
GC Lecture Slide — Diagnosis of metabolic acidosis [18]:
- Ensure this is Metabolic Acidosis
- Determine the Anion Gap: high AG or normal AG
- If normal AG: Determine Urine AG [Urine Na + urine K – urine Cl]. NaHCO₃ infusion or Acid loading test: proximal vs. distal RTA
- Look for any Osmolar Gap: Measured osmol – calculated osmol
- Any mixed acid/base disorder (ΔAG vs. ΔHCO₃⁻)?
3. Investigation Modalities — Detailed Guide
Here we go through every investigation you would order, why you order it, and how to interpret the results.
Consider VBG: less painful, difference is not clinically significant [30]. In practice, VBG is increasingly used as the first-line test because it avoids arterial puncture complications. The pH difference is only ~0.03, HCO₃⁻ is essentially identical, and pCO₂ is ~6 mmHg (0.8 kPa) higher on VBG than ABG. For an initial screen, VBG is often sufficient.
| Parameter | Normal | Interpretation in Metabolic Acidosis |
|---|---|---|
| pH | 7.35–7.45 | < 7.35 confirms acidaemia (< 7.1 is life-threatening) [2] |
| pCO₂ | 35–45 mmHg (4.7–6.0 kPa) | Should be low (respiratory compensation). If not → mixed disorder |
| pO₂ | 75–100 mmHg (10–13 kPa) | Relevant if considering Type A lactic acidosis (hypoxia) |
| HCO₃⁻ | 22–26 mmol/L | < 22 = metabolic acidosis |
| Base excess (BE) | -2 to +2 | Negative = base deficit = metabolic acidosis. Note: BE does not give extra info over [HCO₃⁻] [21] |
| Lactate | < 2 mmol/L | > 4 mmol/L diagnostic of lactic acidosis [5][18] |
High Yield — ABG Interpretation Systematic Approach
- Look at pH → acidaemia or alkalaemia?
- Look at pCO₂ → respiratory component (high = respiratory acidosis, low = compensation or respiratory alkalosis)
- Look at HCO₃⁻ → metabolic component (low = metabolic acidosis, high = compensation or metabolic alkalosis)
- Apply Winter's formula → is compensation appropriate?
- Calculate anion gap from accompanying electrolytes
This is your workhorse investigation — ordered simultaneously with or as part of the ABG workup.
| Test | Key Findings | Interpretation & Pathophysiological Basis |
|---|---|---|
| Sodium (Na⁺) | Variable | In DKA: pseudohyponatraemia (hyperglycaemia pulls water from ICF → dilutes Na⁺; also ↑Glc/ketones → hyperosmolar hypoNa) [8]. In dehydration: may be high. Used to calculate AG and osmolality |
| Potassium (K⁺) | Often deceptively normal in DKA | K⁺ may be normal or even elevated on admission despite total body K⁺ depletion [8][30]. Acidosis shifts K⁺ extracellularly (H⁺/K⁺ exchange). In RTA: hypoK in Type 1 and 2; hyperK in Type 4 [28] |
| Chloride (Cl⁻) | ↑ in NAGMA; Normal in HAGMA | In NAGMA, Cl⁻ rises to replace lost HCO₃⁻ (hyperchloraemic acidosis) [2]. Critical for AG calculation |
| Bicarbonate (HCO₃⁻) | ↓ | Defines the metabolic acidosis. Degree of reduction correlates with severity |
| Urea | May be ↑ | Elevated in pre-renal AKI (dehydration in DKA), CKD (uraemic acidosis), upper GI bleed |
| Creatinine | May be ↑ | Elevated in renal failure (both AKI and CKD). Used in FEHCO₃⁻ calculation |
| Calcium (Ca²⁺) | May be ↓ | In CKD: ↓Ca²⁺ (↓1,25-vit D + hyperPO₄). In rhabdomyolysis: ↓Ca²⁺ (entry into damaged myocytes). In ethylene glycol: ↓Ca²⁺ (oxalate chelation) |
| Phosphate (PO₄³⁻) | Variable | In CKD: ↑PO₄. In DKA: may be initially high but total body depleted. In Fanconi: ↓PO₄ (phosphaturia) |
| Magnesium (Mg²⁺) | May be ↓ | In alcoholism, DKA, cisplatin nephrotoxicity |
Anion gap calculation from this panel:
Normal AG = 8–14 mmol/L [2]. Significant if > 20 mmol/L [19].
The serum anion gap = Unmeasured anion – Unmeasured cation = Measured cation – Measured anion. Na⁺ is the primary measured cation; Cl⁻ and HCO₃⁻ are the primary measured anions. Unmeasured anions include albumin, ketones, lactic acids, and PO₄³⁻. [23]
Albumin-corrected AG:
Plasma ketones (BOHB) are a key HAGMA investigation [5]
- Why BOHB over urine dipstick ketones? The urine dipstick (nitroprusside reaction) only detects acetoacetate but not BOHB, and 75% of ketones in DKA is BOHB → underestimates ketosis [30]. Serum BOHB is the preferred assay.
- Interpretation: Moderate ketonaemia ≥ 3 mmol/L supports DKA diagnosis [30]
- Monitoring: BOHB is better for monitoring DKA resolution than urine ketones, because as DKA is treated, BOHB is converted back to acetoacetate (paradoxically increasing urine ketone positivity even as the patient improves)
Normal: < 2 mmol/L. Lactate > 4 mmol/L is diagnostic [18][5]
- Most modern ABG machines report lactate simultaneously — so you often get this with your first blood gas
- In the context of HAGMA: elevated lactate identifies lactic acidosis as the cause
- Caution: PD (peritoneal dialysis) fluid contains high lactate [5], so if a PD patient has lactic acidosis, haemodialysis with bicarbonate dialysate is preferred over PD
Osmolar gap = Measured osmolality − Calculated osmolality [19][23]
Calculated osmolality (all in mmol/L):
| Finding | Interpretation |
|---|---|
| Normal osmolar gap (< 10 mOsm/kg) | Most HAGMA causes (DKA, lactic acidosis, uraemia, salicylates) [23] |
| Elevated OG (> 10; > 25 specific for toxic alcohols) [19] | Methanol, ethylene glycol, propylene glycol, isopropyl alcohol |
Elevated osmolar gap suggests ingestion but lacks specificity since it can be elevated in lactic acidosis, diabetic ketoacidosis and alcoholic ketoacidosis [23]. Use in combination with clinical context.
Note that with time, methanol is gradually converted into formate — anion gap increases, osmolal gap decreases [19]. A normal OG does NOT exclude toxic alcohol ingestion in late presentations.
3.7 Urine Investigations
NH₄⁺ is the primary unmeasured cation so the urine anion gap is an indirect measure of urinary H⁺ excretion in the form of NH₄⁺ [23]
| UAG | Interpretation | Why? |
|---|---|---|
| Negative | Increased urinary excretion of NH₄⁺ — appropriate response to acidaemia → Type 2 (Proximal) RTA / GI loss of HCO₃⁻ (diarrhoea) [23] | NH₄⁺ is excreted with Cl⁻; the high urine Cl⁻ drives UAG negative |
| Positive | Failure of kidneys to excrete NH₄⁺ → Type 1 (Distal) RTA / Type 4 (Hyperkalaemic) RTA [23] | Kidneys cannot generate sufficient NH₄⁺; urine Cl⁻ is low |
Why Does Proximal RTA Have a Negative UAG?
In proximal RTA, the defect is in HCO₃⁻ reabsorption in the PCT, not in distal H⁺ secretion. The distal nephron is intact and can still acidify urine (once plasma HCO₃⁻ drops below the lowered threshold) and excrete NH₄⁺ normally. So the UAG is negative (appropriate NH₄⁺ excretion), just like in diarrhoea. To distinguish proximal RTA from diarrhoea, you need the clinical context (no diarrhoea history) and confirmatory tests (FEHCO₃⁻, look for Fanconi syndrome features).
| Urine pH | Significance |
|---|---|
| > 5.5 (cannot be acidified) | Distal (Type 1) RTA — the α-intercalated cells cannot secrete H⁺ [28] |
| < 5.5 | Normal distal acidification; seen in diarrhoea, proximal RTA (once threshold is exceeded), Type 4 RTA |
| Finding | Significance |
|---|---|
| Glucose (with normal blood glucose) | Renal glycosuria — points to proximal tubule dysfunction (Fanconi syndrome) [25] |
| Ketones (dipstick) | Supports ketoacidosis; but remember dipstick detects acetoacetate only, not BOHB |
| Blood (dipstick +ve, microscopy −ve for RBCs) | Myoglobinuria in rhabdomyolysis (myoglobin cross-reacts with dipstick peroxidase) |
| Calcium oxalate crystals | Ethylene glycol poisoning — pathognomonic finding |
| Proteinuria (low-molecular-weight) | Tubular proteinuria (↑urine β2-microglobulin) — Fanconi syndrome [25] |
- Generalised aminoaciduria seen in Fanconi syndrome [25]
- CK is a key investigation in HAGMA workup [5]
- Massively elevated CK (> 5× ULN, often > 10,000 U/L) = rhabdomyolysis
- Release of intracellular muscle contents → K⁺, PO₄, organic acids, myoglobin → HAGMA + AKI
Serum/urine toxicology [5]
| Test | Detects |
|---|---|
| Serum salicylate level | Salicylate poisoning (suspect in unexplained mixed respiratory alkalosis + HAGMA) |
| Serum paracetamol level | Paracetamol overdose |
| Serum ethanol | Alcohol intoxication; also needed to calculate osmolar gap accurately (ethanol itself elevates OG) |
| Methanol screening test | Available in labs of major hospitals; +ve → confirmed by quantitative serum methanol assay (limited availability) [19] |
| Serum iron | Iron poisoning (> 90 μmol/L = severe toxicity) |
| Urine drug screen | Broader screen for illicit substances |
This is especially important in DKA:
Look for precipitating infections: respiratory, gastrointestinal, septicaemia, meningitis [30][8]
| Investigation | Looking For |
|---|---|
| CBC with differential | Leukocytosis (infection, stress response in DKA — note WBC may be elevated in DKA even without infection) |
| Blood cultures | Sepsis/bacteraemia |
| Urine culture | UTI (common precipitant of DKA) |
| CXR | Pneumonia, pulmonary oedema |
| ECG | Hypokalaemia (U waves, flat T, long QTc) or hyperkalaemia (tall peaked T, widened QRS). Also MI as precipitant of DKA [30] |
| Amylase/lipase | Elevated in DKA even without pancreatitis [31]; but also to exclude pancreatitis as precipitant |
| Cardiac enzymes (troponin) | Silent MI, especially in elderly diabetics |
In a case of suspected acutely presenting metabolic disease [32]:
- Basic metabolic investigations: ABG and plasma electrolytes, plasma glucose, plasma lactate, plasma ammonium, urine and blood ketones, creatine kinase
- Special metabolic investigations: acylcarnitine on dried blood spots, plasma amino acids, urinary organic acids, insulin
- Store frozen plasma and urine samples for further investigations, e.g., in death
Investigations for HAGMA (KOLT approach) [5]:
| Investigation | Mnemonic Letter | What It Tells You |
|---|---|---|
| Plasma ketones (BOHB) | K | Ketoacidosis (DKA, AKA, starvation) |
| Osmolar gap | O | Toxic alcohols if > 25 |
| Lactate | L | Lactic acidosis if > 4 mmol/L |
| Serum/urine toxicology | T | Salicylates, paracetamol, methanol, ethylene glycol, iron |
| + RFT, glucose | — | Uraemia, DKA |
| + CK | — | Rhabdomyolysis |
| + Corrected HCO₃⁻ / delta ratio | — | Rule out concomitant NAGMA [5] |
| Feature | Type 1 (Distal) | Type 2 (Proximal) | Type 4 (Hyperkalaemic) |
|---|---|---|---|
| Serum K⁺ | Low | Low | High |
| Urine pH | Always > 5.5 | Variable (< 5.5 once below threshold) | < 5.5 |
| Urine AG | Positive (increased) | Normal | Positive |
| FEHCO₃⁻ | < 5% | > 15% | < 5% |
| NH₄Cl acid loading test | Urine pH > 6.0 | Variable | Urine pH < 5.5 |
| Stones | Often (nephrocalcinosis) | Seldom | No |
| Bone disease | Osteomalacia/rickets | Osteomalacia/rickets | No |
| Acidosis severity | Progressive, can be severe (HCO₃⁻ < 10) | Self-limiting (HCO₃⁻ ~12–20) | Mild (HCO₃⁻ 15–20) |
(Adapted from [28])
Renal loss of potassium can be evaluated by calculating the transtubular potassium gradient (TTKG): TTKG > 4 confirms renal K⁺ wasting. Renal loss of phosphate evaluated by TRP%: TRP < 85% confirms renal phosphate wasting [25]
Once the aetiology is identified and treatment initiated, ongoing monitoring is critical (using DKA as the paradigm):
Investigations for DKA — subsequent monitoring [31]:
| Parameter | Frequency | Why |
|---|---|---|
| Blood glucose | Hourly | Guide insulin infusion rate; target glucose fall ~3–5 mmol/L/hr |
| RFT (Na, K, Cl, HCO₃⁻, urea, Cr) | Hourly until BG < 14 [31], then 2–4 hourly | K⁺ can plummet with insulin; Na⁺ correction reveals true Na⁺ as glucose falls |
| ABG | Repeat PRN; intensive monitoring in 24–48 hours [31] | Confirm resolution of acidosis (HCO₃⁻ ≥ 18, pH > 7.3, AG normalised) |
| Urine output | Continuous (catheter in severe cases) | Guide fluid resuscitation; detect AKI |
| Vital signs (T, BP, HR, RR, GCS) | T 2-hourly; others hourly [31] | Detect haemodynamic instability, cerebral oedema (children), infection |
| CVP | If indicated (severe dehydration, elderly, cardiac comorbidity) | Guide fluid resuscitation |
High Yield Summary — Diagnostic Criteria, Algorithm and Investigations
- Confirm metabolic acidosis: pH < 7.35 + HCO₃⁻ < 22 + pCO₂ < 40. Low HCO₃⁻ alone is NOT sufficient — must exclude compensation for respiratory alkalosis
- Winter's formula: Expected pCO₂ = 1.5 × [HCO₃⁻] + 8 (±2). Deviations indicate mixed disorders
- GC 5-step algorithm: (1) Confirm MA, (2) AG, (3) UAG if NAGMA, (4) Osmolar gap, (5) Delta-delta for mixed disorders
- HAGMA workup — KOLT: Ketones, Osmolar gap, Lactate, Toxicology + RFT/glucose/CK/delta ratio
- NAGMA workup: UAG → negative = diarrhoea; positive = RTA → then urine pH + serum K⁺ to subtype
- DKA criteria: glucose > 14 + pH < 7.3 + HCO₃⁻ < 15 + moderate ketonuria/ketonaemia
- Lactic acidosis: lactate > 4 mmol/L diagnostic
- Toxic alcohols: OG > 25 highly specific; confirm with specific assays
- RTA confirmatory: NH₄Cl acid loading (distal: urine pH > 5.5); FEHCO₃⁻ > 15% (proximal)
- Serum BOHB is superior to urine dipstick ketones (dipstick misses 75% of DKA ketones which are BOHB)
- DKA amylase: can be elevated even without pancreatitis — don't overcall pancreatitis
Active Recall - Diagnostic Criteria, Algorithm and Investigations
References
[2] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (Diagnosis of metabolic acidosis, Anion Gap sections) [5] Senior notes: Maksim Medicine Notes.pdf (HAGMA investigations — KOLT, p.213–215) [8] Senior notes: Ryan Ho Endocrine.pdf (DKA section, p.91); MBBS Final MB (Medicine) (Felix PY Lai).pdf (DKA diagnostic criteria, p.1502) [10] Senior notes: Ryan Ho Chemical Path.pdf (Hypokalemia approach with paired urine K and HCO3, p.18) [18] Lecture slides: GC 044. Electrolyte and Acid-Base Disorders.pdf (Diagnosis of metabolic acidosis slide, p.8; L-lactic acidosis slide, p.15) [19] Senior notes: Ryan Ho Chemical Path.pdf (Methanol section — osmolar gap, screening test, p.41) [23] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Serum AG, UAG, osmolar gap definitions, p.86–88; causes of metabolic acidosis table, p.87; acid loading test and FEHCO3, p.1039) [25] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (Fanconi syndrome workup — TTKG, TRP%, FEHCO3, bicarbonate loading test, p.23; Distal RTA case, p.25–27) [28] Senior notes: Ryan Ho Urogenital.pdf (Approach to metabolic acidosis, p.39; FEHCO3 and NH4Cl test, p.44; RTA comparison table, p.44) [29] Senior notes: Maksim Medicine Notes.pdf (Acid-base compensation table, p.211–213) [30] Senior notes: Maksim Medicine Notes.pdf (DKA lab features, VBG note, p.83–85) [31] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (DKA investigations — initial and subsequent hours, p.1503) [32] Senior notes: Ryan Ho Chemical Path.pdf (Investigations of IEM, p.56)
Management of Metabolic Acidosis
The overarching philosophy of managing metabolic acidosis is deceptively simple — find the cause and fix it. Bicarbonate infusion is a temporising measure, not a cure. Let's build this systematically from first principles.
Management of metabolic acidosis: Determine the cause of acidosis and treat the underlying cause. Some causes have independent threat to life, e.g., methanol poisoning. There may be specific treatment for certain causes, e.g., methanol poisoning. Correction of HCO₃⁻ by NaHCO₃. [2][18]
Three pillars of management:
- Identify and treat the underlying cause — this is the definitive treatment
- Ensure adequate respiratory compensation — if failing, consider intubation
- Correct the acidosis directly with NaHCO₃ — only as a bridge, and only in severe cases
Identify and treat the underlying disorder. Some causes have independent threat to life, e.g., methanol poisoning. Some causes may have specific treatment, e.g., ethanol administration in methanol poisoning [28]
Before anything else, check whether the patient's lungs are keeping up:
Confirm adequate respiratory compensation: if pCO₂ is higher than expected, then there may be concurrent respiratory acidosis. May consider to intubate and hyperventilate patient if inadequate [28]
- Apply Winter's formula: Expected pCO₂ = 1.5 × [HCO₃⁻] + 8 (±2) mmHg
- If measured pCO₂ is above the expected range → the patient has concurrent respiratory acidosis → they are not compensating adequately
- This can occur in:
- COPD patients (cannot increase ventilation)
- Respiratory muscle fatigue (severe sepsis, neuromuscular disease)
- CNS depression (drug overdose, encephalopathy)
- Consider mechanical ventilation if acute pulmonary oedema (APO) to remove CO₂ [5]
Ventilation Pitfall in Metabolic Acidosis
If you intubate a patient with severe metabolic acidosis, you must set the ventilator to maintain the same minute ventilation they were achieving spontaneously (i.e., replicate their Kussmaul breathing). If you put them on "normal" ventilator settings with a lower respiratory rate, you will suddenly reduce their CO₂ elimination → pCO₂ rises → pH plummets → cardiac arrest. Always match or exceed the pre-intubation minute ventilation.
4. Sodium Bicarbonate (NaHCO₃) Therapy
This is the most commonly examined treatment modality for metabolic acidosis per se. Understanding its role, dosing, and — most importantly — its risks and limitations is critical.
IV 8.4% NaHCO₃ infusion: consider if pH < 7.1 [5]
Administration of NaHCO₃: indication usually only limited to severe metabolic acidosis (pH < 7.1) unless associated with severe renal impairment [28]
| Scenario | Role of NaHCO₃ |
|---|---|
| pH < 7.1 (life-threatening acidosis) | Bridge therapy to buy time while treating the underlying cause |
| Refractory hyperkalaemia | NaHCO₃ shifts K⁺ intracellularly (as H⁺ comes out in exchange) |
| Salicylate poisoning | Urine and serum alkalinisation (see below) |
| Tricyclic antidepressant overdose | Alkalinisation prevents Na⁺ channel blockade → treats QRS widening |
| Chronic metabolic acidosis (CKD, RTA) | Oral NaHCO₃ for chronic replacement |
| Rhabdomyolysis | Urine alkalinisation to prevent myoglobin cast formation in tubules [6] |
When NOT to Give NaHCO₃ — or Use It Cautiously
- Lactic acidosis (Type A): NaHCO₃ therapy is ineffective unless production of lactate is controlled. Its use may buy time for life-saving treatment. The Na⁺ load limits its massive use [18][2]. The rate of lactate production can reach up to 72 mmol/min with total hypoxia [2] — no amount of bicarbonate can keep up.
- DKA: Insulin is the definitive treatment; NaHCO₃ is generally not recommended unless pH < 6.9–7.0 (ADA guidelines). Bicarbonate may worsen hypokalaemia and cerebral oedema.
- Volume overloaded patients: NaHCO₃ carries a massive Na⁺ load → worsens pulmonary oedema
- Patients with concurrent hypokalaemia: NaHCO₃ shifts K⁺ into cells → can precipitate fatal arrhythmia
NaHCO₃ required (mmol) = (ideal HCO₃⁻ − measured HCO₃⁻) × BW × 0.5 [5]
1 mmol = 1 mL if 8.4% NaHCO₃ [5]
Practical approach: give half of the calculated deficit initially, then recheck ABG:
Dosing: give half of body deficit. Deficit = (24 − [HCO₃⁻]) × BW × 0.5 [28]
The reason you only give half: (1) avoid overcorrection, (2) allow time to reassess, (3) the underlying cause may be resolving simultaneously (e.g., insulin correcting DKA).
Example: 70 kg patient, measured HCO₃⁻ = 8 mmol/L
- Deficit = (24 − 8) × 70 × 0.5 = 560 mmol
- Give half = 280 mmol = 280 mL of 8.4% NaHCO₃
- Administer slowly over 1–2 hours with serial ABG monitoring
| Complication | Mechanism | Clinical Significance |
|---|---|---|
| Hypokalaemia | NaHCO₃ shifts K⁺ into cells by raising pH, particularly in patients with existing hypokalaemia or loss of K⁺ with contracted ECF resulting in normokalaemia (e.g., DKA) [2][28] | Can precipitate fatal arrhythmia. Must monitor K⁺ closely and replace as needed |
| Decreased ionic calcium | Raising pH frees albumin binding sites for Ca²⁺ → ↓ionised Ca²⁺. Especially a problem in CRF with pre-existing hypocalcaemia [2][28] | Can cause tetany, seizures, cardiac arrhythmia |
| Volume overload | 1 mmol HCO₃⁻ carries 1 mmol Na⁺. If 200 mmol NaHCO₃ given, 200 mmol Na⁺ is given = more than 1 litre of normal saline (154 mmol Na⁺) [2] | Volume overload → acute pulmonary oedema [5] |
| Paradoxical cerebral acidosis | Bicarbonate in blood breaks down to form CO₂ → CO₂ diffuses past BBB to enter brain → converted by carbonic anhydrase to acid → paradoxical drop in CSF pH [2][28] | Worsening confusion, obtundation. Particularly dangerous if patient cannot increase ventilation to blow off the extra CO₂ |
| Tissue hypoxia | Alkalinisation shifts O₂-Hb dissociation curve leftward → Hb holds O₂ more tightly → less O₂ delivery to tissues [5] | Counterproductive in shock states |
| Hypernatraemia | Excessive Na⁺ load from the NaHCO₃ solution | Osmotic demyelination risk if corrected too rapidly |
| Overshoot alkalosis | Over-correction, especially in DKA/AKA where ketone metabolism regenerates HCO₃⁻ once insulin/glucose is given | Late metabolic alkalosis after resolution of underlying cause |
Monitor ABG after infusion: risk of ↑CO₂ if poorly ventilated → paradoxical respiratory acidosis [5]
5. Renal Replacement Therapy (Dialysis)
Dialysis is the ultimate safety net when metabolic acidosis (and its complications) are refractory to medical therapy.
Indications of urgent dialysis (AEIOU) [33][34][35]:
- A = Acidosis: Refractory metabolic acidosis with HCO₃⁻ < 10 mmol/L [34]
- E = Electrolyte disturbance: Uncontrolled hyperkalaemia > 6 mmol/L [34]
- I = Intoxication: Drug removal in overdose (alcohol, NSAIDs, paracetamol, metformin, methanol, ethylene glycol) [34]
- O = Oedema: Refractory fluid overload / uncontrolled pulmonary oedema [34]
- U = Uraemia: Uraemic pericarditis / uraemic encephalopathy / intractable uraemic symptoms [34]
Haemodialysis: last-resort treatment for renal support. Indications: acidosis with pH < 7.1 refractory to bicarbonate infusion, hyperK > 6.5 or rapidly rising K refractory to medical Rx, intoxication (drug removal), fluid overload refractory to diuretics, features of uraemia [33]
| Modality | Mechanism | Advantages | Disadvantages |
|---|---|---|---|
| Intermittent haemodialysis (IHD) | Solute removal by diffusive transport (down diffusion gradient into dialysate) [36] | Rapid removal of toxins — especially useful for emergencies (severe hyperK, intoxication, TLS). Restricted treatment period allows downtime for other interventions. Less expensive [36] | Considerable haemodynamic instability and fluid shifts with hypotension, cerebral oedema [36] |
| Continuous renal replacement therapy (CRRT) | Solute removal by convective transport (pressure gradient across membrane + replacement fluid) [36] | More haemodynamic stability due to slower fluid removal. Less fluctuations and fluid shifts — better for patients with cerebral oedema, ↑ICP [36] | Need for prolonged anticoagulation + immobilisation. Risk of hypothermia [36] |
Consider dialysis if volume overload / CKD / poisoning [5]
Lactic acidosis: HD if renal failure (PD has high lactate) [5]. This is because peritoneal dialysate contains lactate as a buffer, which would worsen lactic acidosis. Always use haemodialysis with bicarbonate dialysate for lactic acidosis.
6. Aetiology-Specific Management
DKA: Insulin infusion until acidosis fully corrected (i.e., all ketone bodies metabolised). Coexisting NAGMA common: urinary loss of ketone + HCl retention [5]
The four pillars of DKA management:
| Pillar | Details | Rationale |
|---|---|---|
| 1. IV Fluids | NS 1L in first hour → 500 mL/hr for next 4 hours → then 250 mL/hr. Switch to dextrose-saline once glucose < 14 mmol/L | Replace massive fluid deficit (average 5–8L); restore circulating volume and renal perfusion; prevent hypoglycaemia once insulin starts working |
| 2. IV Insulin | Fixed-rate insulin infusion (typically 0.1 U/kg/hr) | Insulin suppresses ketogenesis — this is the definitive treatment. Insulin also promotes glucose uptake and stops gluconeogenesis |
| 3. Potassium replacement | Add KCl to IV fluids once K⁺ < 5.5 mmol/L (20–40 mmol/L of fluid). Do NOT give insulin until K⁺ is ≥ 3.5 | Insulin causes simultaneous uptake of K⁺ from extracellular to intracellular compartment → chance of lethal hypokalaemia [37]. Total body K⁺ is depleted despite normal serum K⁺ on admission |
| 4. Bicarbonate | Only if pH < 7.0 (or < 6.9 per ADA) [37] | Controversial and generally avoided. Risks include worsening hypokalaemia, cerebral oedema, and overshoot alkalosis once ketones are metabolised |
Administer LOW DOSE insulin and fluids immediately, and potentially bicarbonate if pH < 7.0. However, insulin will cause simultaneous uptake of potassium → so there is a chance of lethal hypokalaemia — be aware, supplement potassium if needed [37]
Monitoring: Target glucose reduction ~3–5 mmol/L/hr. Resolution criteria: pH > 7.3, HCO₃⁻ > 15, AG normalised, BOHB < 0.6.
Target normalisation of AG as an indication of suppression of ketogenesis [20]
Transition: Once DKA resolved and patient eating → overlap IV insulin with subcutaneous insulin by ≥1 hour before stopping IV.
Alcoholic ketoacidosis: Glucose infusion + thiamine [5]
| Treatment | Mechanism |
|---|---|
| Dextrose-saline | Dextrose → ↑↑insulin level → suppress ketosis. Saline → replace fluid deficit due to vomiting and osmotic diuresis (ketonuria) [20] |
| Thiamine (before or with glucose) | Alcoholics are thiamine-depleted. Glucose load without thiamine → Wernicke encephalopathy (thiamine is a cofactor for pyruvate dehydrogenase; giving glucose without it diverts remaining thiamine away) |
| K⁺, PO₄³⁻, Mg²⁺ replacement | Common deficiencies in alcoholics [20] |
Note: no insulin is needed in AKA (unlike DKA). The glucose infusion itself stimulates enough endogenous insulin to shut down ketogenesis.
Treatment of Type A L-lactic acidosis: most effective is to improve O₂ delivery to tissue. Correct hypotension, hypoxaemia. NaHCO₃ therapy ineffective unless production of lactate is controlled [18][2]
| Type | Treatment |
|---|---|
| Type A (hypoxia/hypoperfusion) | Correct hypotension (IV fluids, vasopressors), correct hypoxaemia (supplemental O₂, mechanical ventilation), treat underlying sepsis (antibiotics, source control). NaHCO₃ is a temporiser only |
| Type B (impaired clearance) | Treat underlying cause: stop offending drug (metformin), correct liver failure, replace thiamine. Haemodialysis with bicarbonate dialysis for refractory cases [2] |
Haemodialysis with bicarbonate dialysis is the appropriate modality [2][5]. PD has high lactate in the dialysate, so it would worsen the problem [5].
Some causes have independent threat to life, e.g., methanol poisoning. There may be specific treatment for certain causes, e.g., methanol poisoning, use ethanol (VODKA) [2]
| Treatment | Mechanism | Indication |
|---|---|---|
| Fomepizole (4-methylpyrazole) — preferred | Competitive inhibitor of alcohol dehydrogenase (ADH), which is the enzyme that converts methanol → formaldehyde and ethylene glycol → glycolaldehyde. By blocking ADH, you prevent formation of the toxic metabolites | First-line antidote. Given as loading dose 15 mg/kg IV, then 10 mg/kg Q12H |
| Ethanol (IV or oral) | Also a competitive inhibitor of ADH (has higher affinity than methanol/EG). Binds ADH preferentially → methanol/EG is excreted unchanged by kidneys | Used when fomepizole is unavailable. Difficult to dose (need to maintain serum ethanol 100–150 mg/dL). More side effects (sedation, hypoglycaemia) |
| Haemodialysis | Removes both parent alcohol and toxic metabolites directly | Severe poisoning: pH < 7.15, visual disturbance (methanol), renal failure, very high serum levels, refractory acidosis |
| Folinic acid (leucovorin) | Enhances metabolism of formate → CO₂ + H₂O | Adjunct in methanol poisoning |
| Pyridoxine + thiamine | Enhance metabolism of glyoxylate → non-toxic metabolites | Adjunct in ethylene glycol poisoning |
Treatment of salicylate poisoning [20]:
| Step | Details | Mechanism |
|---|---|---|
| Resuscitation | ABCs, IV fluids | Stabilise the patient |
| GI decontamination | Activated charcoal to bind GI aspirin | Reduces ongoing absorption (effective if within 1–2 hours of ingestion, or in enteric-coated/sustained-release preparations) |
| Urine and serum alkalinisation by NaHCO₃ | Alkalinisation of serum → ionic trapping into blood → ↓intracellular salicylate level. Alkalinisation of urine → ionic trapping into tubular fluid → ↑salicylate excretion [20] | Salicylate is a weak acid; in alkaline pH it becomes ionised and cannot cross cell membranes (trapped in blood/urine). Target urine pH 7.5–8.0 |
| Glucose supplementation | Supplemental glucose if altered mental status [20] | CNS hypoglycorrhachia can occur even with normal blood glucose |
| Haemodialysis | If contraindication to NaHCO₃ (fluid overload) or renal failure or severe intoxication [20] | Directly removes salicylate |
Treatment: GI decontamination (gastric lavage, emesis, bowel irrigation — activated charcoal should NOT be used as it does not adsorb Fe). Fluid resuscitation. Desferoxamine (iron chelator) [21]
Metabolic acidosis in CKD: low protein diet (0.6–0.8 g/kg/day), IV NaHCO₃ (beware volume overload and worsening of hypocalcaemia) [33]
| Treatment | Details |
|---|---|
| Oral NaHCO₃ (chronic) | Standard long-term treatment in CKD stages 3–5 to maintain HCO₃⁻ > 22 mmol/L. Typical dose: 1–2 g TDS |
| Low protein diet | Reduces endogenous acid production from protein catabolism |
| Control hyperkalemic acidosis: low K diet, oral bicarbonate, oral K binders (calcium resonium, patiromer, sodium zirconium cyclosilicate), adjust medications (ACEI/ARB dose) [34] | |
| Dialysis | When medical management fails or at CKD Stage 5 |
Management of Type 1 and Type 2 RTA: Correct acidosis by oral NaHCO₃. Very high dose is required in proximal RTA because of loss of HCO₃⁻ in urine. Potassium citrate is a better alternative for distal RTA (citrate → HCO₃⁻ by liver). Potassium supplement for hypoK⁺ [2]
| Type | Treatment | Key Notes |
|---|---|---|
| Type 1 (Distal) RTA | Oral NaHCO₃ or potassium citrate 1–2 mEq/kg/day [28] | Lower doses needed (distal acidification is impaired but there's no proximal wasting). Potassium citrate is preferred because it simultaneously replaces K⁺ and provides alkali. Higher doses given in children for growing skeleton [28]. Sjögren's syndrome-induced Type 1 RTA responds to steroids [2] |
| Type 2 (Proximal) RTA | Oral NaHCO₃ 10–15 mEq/kg/day [28] + potassium supplement | Bicarbonate requirement is higher in proximal RTA despite less marked metabolic acidosis, because any increase in bicarbonate concentration in blood would lead to ↑bicarbonate excretion (above Tm), jeopardising efficacy [28]. Consider adding thiazide diuretic (mild volume contraction → ↑proximal reabsorption → less HCO₃⁻ wasting) |
| Type 4 (Hyperkalaemic) RTA | Stop or reduce inciting drugs. Loop diuretics + low K diet → excrete K⁺. Fludrocortisone if aldosterone deficiency [2] | Hyperkalaemia is the hallmark [2]. Treat the K⁺ first, then address acidosis. Also: dietary K⁺ restriction, Na⁺ polystyrene sulfonate / patiromer / sodium zirconium cyclosilicate for chronic K⁺ binding |
Treatment of Fanconi syndrome mainly consists of replacement of substances lost in the urine (mainly fluid and bicarbonate) [25]
- Oral rehydration solution (ORS): replaces fluid, electrolytes, and provides glucose (co-transport with Na⁺ facilitates absorption)
- IV fluids: Hartmann's solution preferred over NS (Hartmann's contains lactate which is metabolised to HCO₃⁻ → helps correct acidosis; NS worsens hyperchloraemic acidosis)
- Potassium replacement as needed
Treat/prevent AKI: aggressive hydration IV NS ~100–200 mL/h. Bicarbonate infusion to prevent/treat metabolic acidosis. Treatment of electrolyte disturbance (hypoCa, hyperK). Dialysis if necessary [6]
Urine alkalinisation with NaHCO₃ targets urine pH > 6.5 to prevent myoglobin precipitation in renal tubules (myoglobin is more soluble and less nephrotoxic at alkaline pH).
Management: aggressive hydration 3L/m²/d, correction of hyperK + ECG monitoring, rasburicase, RRT if necessary. Urine alkalinisation only in those with acidosis [14]
| Aetiology | Definitive Treatment | Role of NaHCO₃ | Role of Dialysis |
|---|---|---|---|
| DKA | IV insulin + fluids + K⁺ | Only if pH < 6.9–7.0 | Rarely needed |
| AKA | Dextrose-saline + thiamine | Usually unnecessary | Rarely needed |
| Lactic acidosis Type A | Restore O₂ delivery: correct hypotension, hypoxaemia | Bridge only; ineffective as standalone | HD with bicarbonate dialysate if refractory |
| Lactic acidosis Type B | Remove offending agent, treat liver failure, thiamine | Bridge if severe | HD with bicarbonate dialysate |
| Methanol / EG | Fomepizole (or ethanol) + HD | May help with acidosis correction | Definitive for severe cases |
| Salicylates | Activated charcoal + urine alkalinisation (NaHCO₃) | Therapeutic (alkalinisation) | If refractory / renal failure |
| Iron | Desferoxamine + GI decontamination | May assist | If renal failure |
| Uraemia (CKD) | Oral NaHCO₃ long-term + low protein diet | Primary treatment | When medical Mx fails |
| Type 1 RTA | Potassium citrate or NaHCO₃ 1–2 mEq/kg/d | Primary treatment | Not needed |
| Type 2 RTA | NaHCO₃ 10–15 mEq/kg/d + thiazide + K⁺ | Primary treatment | Not needed |
| Type 4 RTA | Stop offending drugs + fludrocortisone + loop diuretics + low K diet | Adjunct if needed | Rarely needed |
| Diarrhoea | ORS / Hartmann's solution + K⁺ replacement | Usually unnecessary if IV Hartmann's used | Not needed |
| Rhabdomyolysis | Aggressive IV NS + urine alkalinisation | Therapeutic (renal protection) | If AKI/refractory hyperK |
| TLS | Hydration + rasburicase + treat hyperK | Only if acidotic | If refractory AKI/hyperK |
8. Special Considerations
Principles of management of AKI: treat underlying cause, general measures (diet, stop nephrotoxic drugs — especially NSAIDs, ACEI, metformin), treat complications (fluid overload, hyperK, metabolic acidosis), renal replacement therapy if indicated [36][33]
Metabolic acidosis in AKI: NaHCO₃ as 1st line, dialysis if severe [36]
Stepped approach:
- Stop nephrotoxic drugs (NSAIDs, aminoglycosides, ACEI/ARB, metformin)
- Volume management based on clinical status
- IV NaHCO₃ for acidosis
- Dialysis if refractory (AEIOU criteria)
Hyperkalemic acidosis management in CKD: low K diet, control acidosis with oral bicarbonate, oral potassium binders (calcium resonium, patiromer, sodium zirconium cyclosilicate), adjust medications (ACEI/ARB) [34]
Oral potassium binders have onset time in the hours — for long-term control only. Acute hyperkalemia: use normal treatment — IV calcium gluconate to stabilise rhythm first, then insulin-dextrose, inhaled beta-2 agonist [34]
| Agent | Onset | Notes |
|---|---|---|
| Calcium resonium (sodium polystyrene sulfonate) | Hours | Rare but serious side effect: colonic necrosis [34] |
| Patiromer | 4–7 hours | Newer agent; can cause hypomagnesaemia |
| Sodium zirconium cyclosilicate | 2 hours | Fastest onset among oral binders; can cause oedema |
Normal saline: risk of hyperchloraemic acidosis. Lactated Ringer's (Hartmann's): ↓↓risk of hyperchloraemic acidosis. Probably prefer Hartmann's in states of acidosis [38]
For large-volume resuscitation in any cause of metabolic acidosis, Hartmann's solution is physiologically superior to NS because:
- Lower chloride content (112 vs 154 mmol/L) → less hyperchloraemia
- Contains lactate (29 mmol/L) → metabolised in the liver to HCO₃⁻ → partially corrects acidosis
- Exception: in DKA, some centres prefer NS initially because Hartmann's contains potassium (5 mmol/L) and the lactate is contraindicated if hepatic function is impaired
High Yield Summary — Management of Metabolic Acidosis
- Treat the underlying cause — this is ALWAYS the priority. NaHCO₃ is a bridge, not a cure
- NaHCO₃ indications: severe acidosis pH < 7.1, refractory hyperK, salicylate/TCA poisoning, chronic RTA/CKD
- NaHCO₃ dosing: deficit = (24 − measured HCO₃⁻) × BW × 0.5; give half the deficit first; 1 mL of 8.4% = 1 mmol
- NaHCO₃ risks (5 key ones): hypokalaemia, ↓ionised Ca²⁺, volume overload, paradoxical cerebral acidosis, tissue hypoxia
- Dialysis indications — AEIOU: Acidosis (refractory, pH < 7.1, HCO₃⁻ < 10), Electrolytes (hyperK > 6), Intoxication, Oedema (refractory), Uraemia
- DKA: insulin + fluids + K⁺; NaHCO₃ only if pH < 6.9–7.0; target AG normalisation
- AKA: dextrose-saline + thiamine (no exogenous insulin needed)
- Lactic acidosis Type A: restore O₂ delivery — NaHCO₃ cannot keep up with production (72 mmol/min at total hypoxia)
- Toxic alcohols: fomepizole (or ethanol) + HD
- Salicylates: activated charcoal + urine alkalinisation + HD if severe
- RTA Type 1: potassium citrate 1–2 mEq/kg/d; Type 2: high-dose NaHCO₃ 10–15 mEq/kg/d + thiazide; Type 4: treat hyperK, fludrocortisone
- Fluid choice: Hartmann's preferred over NS in acidosis (less hyperchloraemic acidosis, lactate regenerates HCO₃⁻)
- Lactic acidosis + dialysis: use HD with bicarbonate dialysate, NOT PD (PD contains lactate)
Active Recall - Management of Metabolic Acidosis
References
[2] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (Management of metabolic acidosis; Risks of NaHCO₃; Lactic acidosis treatment; RTA management, p.7–8, 16) [5] Senior notes: Maksim Medicine Notes.pdf (HAGMA management, NaHCO₃ dosing and complications, dialysis indications, aetiology-specific Mx, p.213–215, 217) [6] Senior notes: Ryan Ho Neurology.pdf (Rhabdomyolysis management, p.196) [14] Senior notes: Ryan Ho Haemtology.pdf (TLS management, p.72) [18] Lecture slides: GC 044. Electrolyte and Acid-Base Disorders.pdf (Management of metabolic acidosis slide, p.16; L-lactic acidosis treatment, p.15) [20] Senior notes: Ryan Ho Urogenital.pdf (AKA management, salicylate treatment, p.47–48) [21] Senior notes: Ryan Ho Chemical Path.pdf (Iron poisoning treatment, p.42) [25] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (Fanconi syndrome treatment, p.25) [28] Senior notes: Ryan Ho Urogenital.pdf (Management of metabolic acidosis — NaHCO₃ indication, risks, dosing, RTA comparison, p.39, 44) [33] Senior notes: Ryan Ho Critical Care.pdf (AKI management — metabolic acidosis, dialysis indications, p.26); Ryan Ho Urogenital.pdf (AKI management, p.98) [34] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (AKI/CKD treatment — AEIOU indications, p.932, 1034); Block A - Chronic Kidney Disease and its Complications.pdf (Hyperkalemic acidosis management, K binders, p.28) [35] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (Dialysis indications — AEIOU, p.863) [36] Senior notes: Ryan Ho Urogenital.pdf (IHD vs CRRT comparison, AKI volume management, p.98); Adrian Lui Pediatrics Notes.pdf (AKI management principles, p.332) [37] Senior notes: Block A - Polyuria and polydipsia_ glucose metabolism; diabetes mellitus; diabetic ketoacidosis.pdf (DKA treatment — insulin + K⁺ awareness, p.12–13) [38] Senior notes: Ryan Ho Fluids and Nutrition.pdf (NS vs Hartmann's — hyperchloraemic acidosis risk, p.4)
Complications of Metabolic Acidosis
Metabolic acidosis is not merely a laboratory abnormality — it is a systemic derangement that, if severe or prolonged, damages virtually every organ system. The complications arise from two sources: (1) the direct effects of acidaemia on cellular function, and (2) complications of the underlying cause and of the treatment itself. Let's work through each systematically from first principles.
1. Cardiovascular Complications
The heart and vasculature are exquisitely pH-sensitive. Acidaemia directly impairs the molecular machinery of cardiac contraction and vascular tone.
Severe metabolic acidosis is associated with multisystem consequences — Heart: ↓contractility, arrhythmias, ↓response to catecholamines [28]
- Mechanism: H⁺ ions compete with Ca²⁺ for binding to troponin C on the actin–myosin complex. When [H⁺] is high, Ca²⁺ is displaced → the sensitivity of the contractile apparatus to calcium is reduced → ↓myocardial contractility (negative inotropic effect)
- Additionally, intracellular acidosis inhibits sarcoplasmic reticulum Ca²⁺ release → further impairs contraction
- Clinical consequence: reduced cardiac output → hypotension → worsening tissue perfusion → more lactic acid → vicious cycle
- Acidosis causes hyperkalaemia via H⁺/K⁺ transcellular shift → K⁺ moves out of cells into the ECF as H⁺ moves in [16]
- Hyperkalaemia depolarises the resting membrane potential of cardiomyocytes → inactivates Na⁺ channels → slows conduction → peaked T waves → widened QRS → VF/asystole
- Concurrently, acidosis itself destabilises cardiac membrane potential, increasing susceptibility to both ventricular and supraventricular arrhythmias
Hyperkalaemia: symptoms (arrhythmia, weakness) usually only when K > 6 [33]
Vascular: ↓response to catecholamines, arterial dilatation, venoconstriction, ↑pulmonary vascular resistance [28]
- Arterial dilatation: H⁺ directly relaxes vascular smooth muscle → ↓systemic vascular resistance → hypotension
- Catecholamine resistance: acidosis impairs the binding affinity of catecholamines (adrenaline, noradrenaline) to their receptors → vasopressors become less effective. This is why septic shock patients with severe lactic acidosis are notoriously difficult to resuscitate — the acidosis itself sabotages the treatment
- Venoconstriction: paradoxically, venous smooth muscle constricts under acidosis → shifts blood centrally → contributes to pulmonary congestion
- ↑Pulmonary vascular resistance: H⁺ causes pulmonary arteriolar vasoconstriction → increases right ventricular afterload → right heart failure in severe cases
2. Respiratory Complications
Respiratory: hyperventilation [28]
- The immediate compensation for metabolic acidosis is Kussmaul breathing — deep, rapid respirations to blow off CO₂
- Kussmaul's breathing → hyperventilation in an attempt to expel as much pCO₂ as possible [2]
- However, sustained hyperventilation is exhausting for the respiratory muscles (diaphragm, intercostals). In prolonged or severe acidosis, the patient's respiratory muscles fatigue → pCO₂ starts to rise → pH plummets → respiratory arrest
- This is a pre-terminal sign — a patient who was hyperventilating and then "quietens down" is getting worse, not better
- If a patient with severe metabolic acidosis is intubated and the ventilator is set to inadequate minute ventilation (i.e., lower than their pre-intubation Kussmaul breathing), the sudden loss of respiratory compensation → acute rise in pCO₂ → precipitous pH drop → cardiac arrest
3. Neurological Complications
- Severe acidaemia (pH < 7.1) directly depresses CNS function
- H⁺ crosses the blood–brain barrier → intracellular neuronal acidosis → impaired neurotransmitter synthesis and release → reduced synaptic transmission → altered mental status, coma [28]
- In DKA, the hyperosmolarity from hyperglycaemia compounds this by causing osmotic water shifts out of brain cells → neuronal dehydration → further obtundation
Neurological disturbances: mental obtundation, hemianopsia, hemiparesis, seizure, coma [8]
- May be caused by:
- Severe acidaemia itself (disruption of neuronal membrane stability)
- Concurrent electrolyte disturbances: hypocalcaemia (lowers seizure threshold), hyponatraemia (cerebral oedema)
- Specific toxins: methanol (formate is directly neurotoxic), isoniazid (inhibits pyridoxine → ↓GABA)
Seizures can be precipitated by overvigorous correction of acidosis (e.g., by bicarbonate infusions) [12]
Paradoxical Cerebral Acidosis — A Complication of Treatment
When you give IV NaHCO₃, the bicarbonate reacts with H⁺ in the blood to form CO₂ + H₂O. CO₂ is a small, lipophilic molecule that crosses the blood–brain barrier freely and rapidly. However, HCO₃⁻ itself crosses the BBB very poorly. So the blood pH improves but the CSF pH paradoxically drops (because CO₂ accumulates in the CSF and is converted back to H₂CO₃ by carbonic anhydrase → H⁺ rises in CSF). This can worsen neurological status and precipitate seizures.
Too rapid correction may result in paradoxical cerebral acidosis — bicarbonate in blood breaks down to form CO₂ → CO₂ diffuses past BBB to enter brain → converted by carbonic anhydrase to acid [2]
- Most feared complication of DKA treatment in children (mortality 20–25%)
- Mechanism: rapid correction of hyperosmolarity (with insulin + fluids) → osmotic gradient favours water entry into brain cells → cerebral oedema → ↑ICP → herniation
- Risk factors: younger age, new-onset DKA, rapid fluid administration, rapid glucose correction, bicarbonate use
- Clinical signs: headache, altered consciousness, bradycardia, hypertension, pupil changes (Cushing triad)
4. Electrolyte Disturbances
Metabolic acidosis never occurs in isolation — it invariably drags electrolytes along with it. These electrolyte derangements are often more immediately dangerous than the pH change itself.
Acidosis: mechanism is transcellular shift of H⁺ → K⁺ moves out of cells. Causes: DKA, renal failure, other acidosis. Important: apparent hyperK does not mean excessive body K stores. DKA results in osmotic diuresis → depletion of body's K reserve → apparent hyperK only a result of mobilisation of intracellular K → normalisation of ketone levels may result in hypokalaemia → must monitor K level [16]
Two scenarios:
| Setting | K⁺ on Admission | Actual Total Body K⁺ | Risk |
|---|---|---|---|
| DKA | Normal or high | Depleted (osmotic diuresis + secondary hyperaldosteronism) | Hypokalaemia becomes evident after rehydration and insulin [7] → arrhythmia |
| CKD / Type 4 RTA | Truly high | Truly excessive (impaired K⁺ excretion) | Hyperkalaemia → arrhythmia, cardiac arrest |
- As covered above, treatment of DKA unmasks the underlying K⁺ depletion
- Insulin drives K⁺ into cells; correction of acidosis reverses the H⁺/K⁺ shift; volume resuscitation dilutes K⁺
- Hypokalaemia (K⁺ < 3.5) → flat T waves, U waves, prolonged QT → risk of torsades de pointes and VF
- Ionised (free) calcium decreases in the setting of alkalinisation (e.g., NaHCO₃ therapy) because H⁺ is consumed → more albumin binding sites freed → Ca²⁺ binds albumin → ↓ionised Ca²⁺
- In CKD: hypocalcaemia is pre-existing (↓1,25-vitamin D + hyperphosphataemia) — worsened by NaHCO₃ treatment
NaHCO₃ decreases ionic calcium — problem in chronic renal failure with hypocalcaemia [2]
- Clinical consequences: paraesthesiae, tetany (Chvostek and Trousseau signs), seizures, laryngospasm, QT prolongation → arrhythmia
- In CKD: failing kidneys cannot excrete phosphate
- In rhabdomyolysis and TLS: intracellular phosphate is released from damaged cells
Tumour lysis syndrome: hyperK, hyperPO₄, hyperuricaemia, metabolic acidosis (lactate), hypoCa [14]
Hyperphosphataemia worsens hypocalcaemia (PO₄³⁻ chelates Ca²⁺) and contributes to renal tubular calcium phosphate deposition → acute nephrocalcinosis → AKI.
5. Metabolic Complications
Metabolic: insulin resistance, inhibition of glycolysis, ↓ATP synthesis, hyperK [28]
- Acidosis impairs insulin receptor signalling → peripheral tissues become resistant to insulin's effects
- This is particularly problematic in DKA: the very condition that caused the acidosis (insulin deficiency) is compounded by the acidosis making insulin less effective
- Clinical implication: higher insulin doses may be needed initially until pH improves
- H⁺ directly inhibits phosphofructokinase-1 (PFK-1), the rate-limiting enzyme of glycolysis
- Reduced glycolysis → ↓ATP production → impaired cellular function across all tissues
- This creates a vicious cycle in lactic acidosis: tissue hypoxia → lactate → acidosis → ↓glycolysis → ↓ATP → cell death → more lactate
- Chronic metabolic acidosis (as in CKD) activates the ubiquitin-proteasome proteolytic pathway in skeletal muscle → accelerated muscle protein breakdown
- This is why CKD patients with chronic acidosis develop sarcopenia and are in a catabolic state despite adequate caloric intake
- Additionally, chronic acidosis suppresses albumin synthesis in the liver → contributes to hypoalbuminaemia
- The skeleton serves as a buffer reservoir: chronic acidosis mobilises calcium carbonate and calcium phosphate from bone to buffer the excess H⁺
- Over months to years: dissolution of bone mineral → osteopenia and osteoporosis
- In children: growth plate impairment → rickets and growth failure
- In adults: osteomalacia (impaired mineralisation)
- This is particularly relevant in:
- CKD: chronic acidosis compounds the bone disease already caused by secondary hyperparathyroidism and vitamin D deficiency → renal osteodystrophy
- Type 1 and Type 2 RTA: chronic acidosis + hypocitraturia → nephrocalcinosis, renal stones, and bone disease
Clinical features of proximal RTA include: hypophosphataemic rickets (in children) and osteomalacia (in adults), growth failure [25]
7. Renal Complications
Metabolic acidosis both causes and is caused by AKI — a bidirectional relationship:
- Acidosis → renal vasoconstriction → ↓renal blood flow → pre-renal AKI
- Specific aetiological AKI:
- Rhabdomyolysis: myoglobin precipitates in renal tubules at low pH → ATN (AKI occurs in 15–50% of rhabdomyolysis, due to ATN [6])
- Ethylene glycol: calcium oxalate crystal deposition in tubules → obstructive ATN
- DKA: severe dehydration from osmotic diuresis → pre-renal AKI
- TLS: uric acid nephropathy and nephrocalcinosis → AKI (AKI due to uric acid nephropathy and acute nephrocalcinosis [14])
- In Type 1 (distal) RTA: urine cannot be acidified → alkaline urine promotes calcium phosphate crystallisation; hypocitraturia (citrate is consumed as a buffer) removes a key inhibitor of stone formation → bilateral medullary nephrocalcinosis and recurrent renal stones
- In ethylene glycol poisoning: calcium oxalate crystals deposit in tubules and parenchyma
- Chronic acidosis accelerates CKD progression through:
- Increased tubular ammoniagenesis (compensatory) → ammonia activates complement → tubulointerstitial inflammation and fibrosis
- Endothelin-1 and aldosterone upregulation
- This is why oral bicarbonate supplementation in CKD to maintain HCO₃⁻ > 22 mmol/L has been shown to slow CKD progression
The complications of the specific underlying condition often dominate the clinical picture:
| Underlying Cause | Major Complications |
|---|---|
| DKA | Cerebral oedema (children); venous thromboembolism (dehydration + hypercoagulability); aspiration pneumonia (reduced consciousness + vomiting); hypokalaemia during treatment |
| Lactic acidosis / Sepsis | Multi-organ failure; DIC; ARDS |
| Methanol poisoning | Permanent blindness (formate destroys retinal ganglion cells); basal ganglia necrosis |
| Ethylene glycol poisoning | AKI from calcium oxalate deposition; cranial nerve palsies; myocarditis |
| Salicylate overdose | Non-cardiogenic pulmonary oedema; hyperthermia; coagulopathy; GI bleeding |
| Rhabdomyolysis | AKI (ATN); compartment syndrome; DIC |
| CKD | Renal osteodystrophy, normocytic anaemia, secondary hyperparathyroidism [39] |
9. Complications of Treatment (Iatrogenic)
We must not only treat the acidosis — we must not make things worse. These iatrogenic complications are extremely high-yield for exams.
NaHCO₃ complications: volume overload → acute pulmonary oedema, hypokalaemia, hypocalcaemia, cerebral acidosis (increased CO₂ readily passes intracellularly), tissue hypoxia (shift of O₂ dissociation curve) [5]
- When DKA or AKA is treated, the ketone anions (β-hydroxybutyrate, acetoacetate) are metabolised back to HCO₃⁻ by the liver
- If NaHCO₃ was also given during treatment, the patient now has exogenous + endogenous HCO₃⁻ → overshoot alkalosis
- Alkalosis itself has complications: ↓ionised Ca²⁺ → tetany; leftward shift O₂-Hb curve → tissue hypoxia; hypokalaemia
Use of bicarbonate in lactic acidosis and ketoacidosis is likely to give rise to late-onset metabolic alkalosis when the underlying cause is removed by treatment [28]
Seizures + coma if overvigorous correction of acidosis (e.g., by bicarbonate infusions) [12]
- Paradoxical cerebral acidosis (see above) and rapid osmolality shifts can trigger seizures
- Always correct slowly, recheck ABG frequently, give only half the calculated deficit
- Metformin must be stopped in renal failure → lactic acidosis in CKD patients (eGFR < 30 mL/min) [22]
- Metformin must be stopped before contrast CT → contrast nephrotoxicity may cause metformin retention → fatal lactic acidosis [40]
- Acetazolamide (Diamox): RFT must be checked before using systemic acetazolamide as it may precipitate metabolic acidosis in a patient with poor renal function [41]
| System | Complication | Mechanism |
|---|---|---|
| Cardiovascular | ↓Contractility, arrhythmias, vasodilatation, catecholamine resistance | H⁺ displaces Ca²⁺ from troponin C; K⁺ shifts; smooth muscle relaxation |
| Respiratory | Kussmaul breathing → respiratory muscle fatigue → respiratory arrest | Compensation via chemoreceptors; diaphragm exhaustion |
| Neurological | Confusion, coma, seizures; cerebral oedema (paediatric DKA) | Neuronal intracellular acidosis; osmotic shifts; paradoxical cerebral acidosis from NaHCO₃ |
| Electrolytes | HyperK (apparent or real), hypoK (unmasked by treatment), hypoCa, hyperPO₄ | H⁺/K⁺ shift; osmotic diuresis; NaHCO₃-induced Ca²⁺ binding; impaired renal excretion |
| Metabolic | Insulin resistance, ↓ATP synthesis, protein catabolism, muscle wasting | H⁺ inhibits PFK-1 and insulin signalling; ubiquitin-proteasome activation |
| Bone | Osteoporosis, rickets, osteomalacia, renal osteodystrophy | Chronic buffering mobilises bone CaCO₃ and CaPO₄ |
| Renal | AKI (from myoglobin, oxalate, urate, dehydration); nephrocalcinosis; CKD progression | Tubular crystal deposition; complement activation from ↑ammoniagenesis |
| Iatrogenic | Overshoot alkalosis, paradoxical cerebral acidosis, seizures from rapid correction | Ketone metabolism regenerates HCO₃⁻; CO₂ crosses BBB; rapid osmolality shifts |
High Yield Summary — Complications of Metabolic Acidosis
- Cardiovascular: ↓contractility + arrhythmias (from hyperK) + vasodilatation + catecholamine resistance → haemodynamic collapse
- Hyperkalaemia is the most immediately life-threatening electrolyte complication — acidosis shifts K⁺ out of cells. But in DKA, total body K⁺ is DEPLETED; hypokalaemia emerges during treatment
- CNS: confusion → coma (pH < 7.1); seizures from acidosis itself, electrolyte disturbances, or overvigorous NaHCO₃ correction
- Paradoxical cerebral acidosis: NaHCO₃ → CO₂ crosses BBB → CSF pH drops despite blood pH improvement
- Respiratory fatigue: prolonged Kussmaul breathing exhausts respiratory muscles → sudden decompensation (rising pCO₂ = pre-terminal sign)
- Chronic bone disease: skeleton buffers chronic acidosis → osteoporosis/rickets/osteomalacia (CKD, RTA)
- Chronic metabolic acidosis accelerates CKD progression (ammonia-driven tubulointerstitial inflammation)
- AKI: myoglobin (rhabdomyolysis), oxalate (ethylene glycol), urate (TLS), dehydration (DKA) all cause tubular injury
- Insulin resistance: acidosis impairs insulin signalling → worsens hyperglycaemia in DKA → vicious cycle
- Treatment complications: NaHCO₃ → hypokalaemia, hypocalcaemia, volume overload, paradoxical cerebral acidosis, tissue hypoxia; overshoot alkalosis when DKA/AKA treated with NaHCO₃ + insulin resolves ketosis
Active Recall - Complications of Metabolic Acidosis
References
[2] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (Risks of NaHCO₃ therapy; compensatory mechanisms, p.3, 8) [5] Senior notes: Maksim Medicine Notes.pdf (NaHCO₃ complications, p.213–215) [6] Senior notes: Ryan Ho Neurology.pdf (Rhabdomyolysis complications — AKI 15–50%, p.196) [7] Lecture slides: GC 078. Polyuria and polydipsia glucose metabolism, diabetes mellitus, diabetic ketoacidosis [Update 2025].pdf (DKA electrolyte shifts) [8] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (DKA clinical manifestations — neurological disturbances, p.1502) [12] Senior notes: Ryan Ho Fundamentals.pdf (General examination in renal patients — seizures from overvigorous correction, Kussmaul breathing, p.112) [14] Senior notes: Ryan Ho Haemtology.pdf (Tumour lysis syndrome pathophysiology and complications, p.72) [16] Senior notes: Ryan Ho Chemical Path.pdf (Hyperkalemia — acidosis mechanism, transcellular shift, DKA K⁺ depletion, p.16) [22] Senior notes: Block A - Drugs and the Kidney.pdf (Metformin — lactic acidosis in CKD, p.19) [25] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (Proximal RTA clinical features — rickets, osteomalacia, growth failure, p.23–25) [28] Senior notes: Ryan Ho Urogenital.pdf (Severe metabolic acidosis multisystem consequences — heart, vascular, respiratory, metabolic, cerebral, p.39; late-onset metabolic alkalosis from NaHCO₃ in ketoacidosis, p.50) [33] Senior notes: Ryan Ho Critical Care.pdf (AKI management — hyperK threshold, p.26) [39] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (CKD complications — metabolic acidosis, anaemia, bone disease, p.23) [40] Senior notes: Ryan Ho Diagnostic Radiology.pdf (Metformin retention after contrast CT → fatal lactic acidosis, p.38) [41] Senior notes: Ryan Ho Opthalmology.pdf (Acetazolamide — check RFT before use, may precipitate metabolic acidosis, p.50)
High Yield Summary
- Definition: Metabolic acidosis = process causing ↑[H⁺] / ↓[HCO₃⁻]; acidaemia ≠ acidosis (compensation can mask it)
- Anion gap is the key discriminating tool:
- HAGMA (MUDPILES + R): Methanol, Uraemia, DKA, Paracetamol/Propylene glycol, Iron/Isoniazid/IEM, Lactic acidosis, Ethylene glycol, Salicylates, Rhabdomyolysis
- NAGMA: Diarrhoea (most common), RTA (Types 1, 2, 4), saline infusion, acetazolamide, ureteral diversions
- Always correct AG for albumin (↓albumin = ↓AG = masked HAGMA)
- Delta-delta ratio to unmask concurrent disorders (< 1 = concomitant NAGMA; > 2 = concomitant met alkalosis)
- Urine anion gap separates renal vs extrarenal NAGMA (negative = GI loss; positive = RTA)
- Lactic acidosis: Type A (hypoxia/hypoperfusion) vs Type B (impaired clearance); NaHCO₃ is NOT a definitive treatment — treat the root cause
- DKA: insulin deficiency → lipolysis → ketogenesis → HAGMA; K⁺ is often deceptively normal on admission but total body K⁺ is depleted — watch for hypokalaemia during treatment
- Kussmaul breathing = deep laboured respiration = respiratory compensation for metabolic acidosis
- Winter's formula: Expected pCO₂ = 1.5 × [HCO₃⁻] + 8 (±2) — check for concurrent respiratory disorder
- NaHCO₃ risks: hypernatraemia, hypokalaemia, ↓ionised Ca²⁺, volume overload, paradoxical cerebral acidosis, leftward shift of O₂-Hb curve
- In children with diarrhoea, metabolic acidosis is multifactorial: HCO₃⁻ loss in stool, lactic acidosis from hypoperfusion, starvation ketosis, decreased renal acid excretion
- IEM must be considered in any neonate/infant with unexplained HAGMA + metabolic crisis
High Yield Summary — Differential Diagnosis of Metabolic Acidosis
- Step 1: Confirm metabolic acidosis (pH < 7.35 AND ↓HCO₃⁻; not just compensation for respiratory alkalosis)
- Step 2: Calculate the anion gap (correct for albumin!)
- HAGMA → MUDPILES + R: Methanol, Uraemia, DKA/AKA/Starvation KA, Paracetamol/Propylene glycol, Iron/Isoniazid/IEM, Lactic acidosis, Ethylene glycol, Salicylates, Rhabdomyolysis
- NAGMA → UAG: Negative UAG = extrarenal (diarrhoea); Positive UAG = renal (RTA)
- Osmolar gap > 25 → toxic alcohols (methanol, ethylene glycol). Remember temporal evolution: early = high OG/normal AG; late = normal OG/high AG
- Ketoacidosis sub-differential by glucose: DKA (high), AKA (normal/low), starvation (low), SGLT2i-associated euglycaemic DKA (normal/mildly high)
- CKD causes both NAGMA (early) and HAGMA (late)
- HypoK + metabolic acidosis = think RTA (especially distal); HyperK + metabolic acidosis = think Type 4 RTA or CKD
- Delta-delta ratio catches hidden concurrent NAGMA (< 1) or metabolic alkalosis ( > 2)
- Salicylate poisoning = classic mixed respiratory alkalosis + HAGMA
High Yield Summary — Diagnostic Criteria, Algorithm and Investigations
- Confirm metabolic acidosis: pH < 7.35 + HCO₃⁻ < 22 + pCO₂ < 40. Low HCO₃⁻ alone is NOT sufficient — must exclude compensation for respiratory alkalosis
- Winter's formula: Expected pCO₂ = 1.5 × [HCO₃⁻] + 8 (±2). Deviations indicate mixed disorders
- GC 5-step algorithm: (1) Confirm MA, (2) AG, (3) UAG if NAGMA, (4) Osmolar gap, (5) Delta-delta for mixed disorders
- HAGMA workup — KOLT: Ketones, Osmolar gap, Lactate, Toxicology + RFT/glucose/CK/delta ratio
- NAGMA workup: UAG → negative = diarrhoea; positive = RTA → then urine pH + serum K⁺ to subtype
- DKA criteria: glucose > 14 + pH < 7.3 + HCO₃⁻ < 15 + moderate ketonuria/ketonaemia
- Lactic acidosis: lactate > 4 mmol/L diagnostic
- Toxic alcohols: OG > 25 highly specific; confirm with specific assays
- RTA confirmatory: NH₄Cl acid loading (distal: urine pH > 5.5); FEHCO₃⁻ > 15% (proximal)
- Serum BOHB is superior to urine dipstick ketones (dipstick misses 75% of DKA ketones which are BOHB)
- DKA amylase: can be elevated even without pancreatitis — don't overcall pancreatitis
High Yield Summary — Management of Metabolic Acidosis
- Treat the underlying cause — this is ALWAYS the priority. NaHCO₃ is a bridge, not a cure
- NaHCO₃ indications: severe acidosis pH < 7.1, refractory hyperK, salicylate/TCA poisoning, chronic RTA/CKD
- NaHCO₃ dosing: deficit = (24 − measured HCO₃⁻) × BW × 0.5; give half the deficit first; 1 mL of 8.4% = 1 mmol
- NaHCO₃ risks (5 key ones): hypokalaemia, ↓ionised Ca²⁺, volume overload, paradoxical cerebral acidosis, tissue hypoxia
- Dialysis indications — AEIOU: Acidosis (refractory, pH < 7.1, HCO₃⁻ < 10), Electrolytes (hyperK > 6), Intoxication, Oedema (refractory), Uraemia
- DKA: insulin + fluids + K⁺; NaHCO₃ only if pH < 6.9–7.0; target AG normalisation
- AKA: dextrose-saline + thiamine (no exogenous insulin needed)
- Lactic acidosis Type A: restore O₂ delivery — NaHCO₃ cannot keep up with production (72 mmol/min at total hypoxia)
- Toxic alcohols: fomepizole (or ethanol) + HD
- Salicylates: activated charcoal + urine alkalinisation + HD if severe
- RTA Type 1: potassium citrate 1–2 mEq/kg/d; Type 2: high-dose NaHCO₃ 10–15 mEq/kg/d + thiazide; Type 4: treat hyperK, fludrocortisone
- Fluid choice: Hartmann's preferred over NS in acidosis (less hyperchloraemic acidosis, lactate regenerates HCO₃⁻)
- Lactic acidosis + dialysis: use HD with bicarbonate dialysate, NOT PD (PD contains lactate)
High Yield Summary — Complications of Metabolic Acidosis
- Cardiovascular: ↓contractility + arrhythmias (from hyperK) + vasodilatation + catecholamine resistance → haemodynamic collapse
- Hyperkalaemia is the most immediately life-threatening electrolyte complication — acidosis shifts K⁺ out of cells. But in DKA, total body K⁺ is DEPLETED; hypokalaemia emerges during treatment
- CNS: confusion → coma (pH < 7.1); seizures from acidosis itself, electrolyte disturbances, or overvigorous NaHCO₃ correction
- Paradoxical cerebral acidosis: NaHCO₃ → CO₂ crosses BBB → CSF pH drops despite blood pH improvement
- Respiratory fatigue: prolonged Kussmaul breathing exhausts respiratory muscles → sudden decompensation (rising pCO₂ = pre-terminal sign)
- Chronic bone disease: skeleton buffers chronic acidosis → osteoporosis/rickets/osteomalacia (CKD, RTA)
- Chronic metabolic acidosis accelerates CKD progression (ammonia-driven tubulointerstitial inflammation)
- AKI: myoglobin (rhabdomyolysis), oxalate (ethylene glycol), urate (TLS), dehydration (DKA) all cause tubular injury
- Insulin resistance: acidosis impairs insulin signalling → worsens hyperglycaemia in DKA → vicious cycle
- Treatment complications: NaHCO₃ → hypokalaemia, hypocalcaemia, volume overload, paradoxical cerebral acidosis, tissue hypoxia; overshoot alkalosis when DKA/AKA treated with NaHCO₃ + insulin resolves ketosis
Hypernatremia
Hypernatremia is a serum sodium concentration greater than 145 mEq/L, typically resulting from a deficit of total body water relative to sodium, leading to hyperosmolality and cellular dehydration.
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.