• 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.

1. Volatile acid (CO₂): ~15,000–20,000 mmol/day produced from aerobic metabolism. Eliminated entirely by the lungs. This is the respiratory component.
2. 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.

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]

Once you identify a HAGMA, you should check whether there is a concomitant NAGMA or metabolic alkalosis hiding underneath.

Corrected HCO₃⁻ / delta ratio can be used to rule out concomitant NAGMA ^[5]

An alternative way to think about the causes uses the gain of acid vs. loss of base framework:

(DKA severity classification from ADA uses similar thresholds: Mild: pH 7.25–7.3, HCO₃ 15–18; Moderate: pH 7.0–7.25, HCO₃ 10–15; Severe: pH < 7.0, HCO₃ < 10 ^[7][8])

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

• 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

MUDPILES + R ^[2][5]

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)

Confirm metabolic acidosis: [HCO₃⁻] < 22 mmol/L with pCO₂ < 40 mmHg ^[28]

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]

If pCO₂ is higher than expected, then there may be concurrent respiratory acidosis. May consider to intubate and hyperventilate patient if inadequate ^[28]

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.

This is your workhorse investigation — ordered simultaneously with or as part of the ABG workup.

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):

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.

• 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]

This is especially important in DKA:

Look for precipitating infections: respiratory, gastrointestinal, septicaemia, meningitis ^[30][8]

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]:

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]

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

Risks of NaHCO₃ therapy ^[2][5][28]:

Monitor ABG after infusion: risk of ↑CO₂ if poorly ventilated → paradoxical respiratory acidosis ^[5]

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]

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.

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:

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]

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]

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 of salicylate poisoning ^[20]:

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]

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]

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)
  • Lactated Ringer's (Hartmann's): ↓↓risk of hyperchloraemic acidosis (contains lactate → regenerate bicarb). Probably prefer Hartmann's in states of acidosis ^[38]
  • Normal saline risk: causes hyperchloraemic acidosis ^[38]
• 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]

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:

1. Stop nephrotoxic drugs (NSAIDs, aminoglycosides, ACEI/ARB, metformin)
2. Volume management based on clinical status
3. IV NaHCO₃ for acidosis
4. 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]

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:

1. Lower chloride content (112 vs 154 mmol/L) → less hyperchloraemia
2. Contains lactate (29 mmol/L) → metabolised in the liver to HCO₃⁻ → partially corrects acidosis
3. 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

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

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

• 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]

• 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)

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:

• 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.

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

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

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]