Acid-Base Disorders & Anion Gap

📋 Key Information Summary

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Systematic acid-base interpretation starts with pH, pCO₂, and HCO₃⁻ to identify the primary disorder and any compensatory response.
Metabolic acidosis is categorised by the anion gap (AG = Na⁺ – [Cl⁻ + HCO₃⁻]); normal AG is 8–12 mmol/L (with albumin correction).
High AG metabolic acidosis (HAGMA) is caused by unmeasured anions; use the MUDPILES mnemonic for common Australian causes.
Normal AG metabolic acidosis (NAGMA) is due to HCO₃⁻ loss or renal tubular acidosis; check urine anion gap and osmolar gap.
The delta-delta ratio (Δ/Δ) identifies mixed disorders: ratio <1 suggests coexisting NAGMA, >2 suggests coexisting metabolic alkalosis.
Metabolic alkalosis is often chloride-responsive (urine Cl⁻ <25 mmol/L) from vomiting or diuretics; saline infusion is first-line treatment.
Respiratory acidosis (↑pCO₂) indicates ventilatory failure; acute vs chronic distinction requires clinical correlation and HCO₃⁻ change.
Respiratory alkalosis (↓pCO₂) results from hyperventilation; consider pregnancy, liver disease, anxiety, salicylate poisoning.
Always correct albumin when calculating anion gap: corrected AG = calculated AG + 0.25 × (40 – albumin g/L).
Australian labs routinely report electrolytes, blood gases, and lactate; MBS item 66540 covers venous blood gas analysis.
Severe acidaemia (pH <7.1) may require IV sodium bicarbonate in critical care, but only after addressing the underlying cause.
Aboriginal and Torres Strait Islander populations have higher rates of type 2 diabetes and chronic kidney disease, increasing risk of ketoacidosis and renal tubular acidosis.
Pregnancy causes a normal respiratory alkalosis (pCO₂ ~30 mmHg); interpret blood gases with pregnancy-specific reference ranges.
Use the Henderson-Hasselbalch equation and Boston compensation rules to verify compensation adequacy and detect mixed disorders.

Introduction & Australian Epidemiology

Acid-base disorders are common in hospitalised patients and frequently encountered in primary care. A systematic approach involves analysis of pH, pCO₂, HCO₃⁻, and the anion gap (AG) to identify the primary disorder, assess compensation, and uncover mixed disturbances. In Australia, metabolic acidoses account for approximately 15–20% of all acid-base disorders in tertiary centres, with diabetic ketoacidosis and lactic acidosis being leading causes.

The anion gap, calculated as Na⁺ – (Cl⁻ + HCO₃⁻), is a critical tool for differentiating the causes of metabolic acidosis. Albumin correction is essential, as hypoalbuminemia can mask an elevated AG. Australian laboratories routinely provide electrolytes, venous/arterial blood gases, and lactate measurements, facilitating timely diagnosis. Respiratory disorders are often secondary to pulmonary, neurological, or iatrogenic conditions. Understanding these patterns is vital for appropriate management in both metropolitan and remote Australian settings.

Pathophysiology of Acid-Base Homeostasis

The body maintains pH between 7.35–7.45 via extracellular (bicarbonate) and intracellular (protein, phosphate) buffers, respiratory excretion of CO₂, and renal excretion/reabsorption of H⁺ and HCO₃⁻. Acidosis results from gain of acid or loss of base; alkalosis from gain of base or loss of acid.

Metabolic Acidosis: Primary reduction in HCO₃⁻ due to addition of non-volatile acid (increased AG) or loss of bicarbonate (normal AG). The anion gap represents unmeasured anions (albumin, phosphate, sulphate, organic acids).

Metabolic Alkalosis: Primary elevation in HCO₃⁻ from loss of H⁺ (vomiting, diuretics) or gain of HCO₃⁻ (exogenous alkali). Maintenance factors include volume depletion, hypokalaemia, and hypochloraemia.

Respiratory Disorders: Alveolar hypoventilation causes hypercapnia (respiratory acidosis); hyperventilation causes hypocapnia (respiratory alkalosis). Renal compensation occurs over 3–5 days.

Clinical Presentation & Diagnostic Criteria

Symptoms are non-specific and depend on severity and chronicity. Severe acidaemia (pH <7.2) may cause hyperventilation (Kussmaul respiration), nausea, vomiting, lethargy, confusion, and haemodynamic instability. Alkalosis can cause paraesthesia, carpopedal spasm, tetany, and seizures.

Diagnostic Criteria:

Metabolic Acidosis: pH <7.35, HCO₃⁻ <22 mmol/L, pCO₂ compensatory decrease (Winter's formula: expected pCO₂ = 1.5 × HCO₃⁻ + 8 ± 2).
Metabolic Alkalosis: pH >7.45, HCO₃⁻ >28 mmol/L, pCO₂ compensatory increase (expected pCO₂ = 0.7 × HCO₃⁻ + 21 ± 2).
Respiratory Acidosis: pH <7.35, pCO₂ >45 mmHg. Acute: HCO₃⁻ ↑1 mmol/L per 10 mmHg pCO₂. Chronic: HCO₃⁻ ↑3.5 mmol/L per 10 mmHg pCO₂.
Respiratory Alkalosis: pH >7.45, pCO₂ <35 mmHg. Acute: HCO₃⁻ ↓2 mmol/L per 10 mmHg pCO₂. Chronic: HCO₃⁻ ↓5 mmol/L per 10 mmHg pCO₂.

Investigations (Australian Lab Availability & MBS Items)

ESSENTIAL

Venous Blood Gas (VBG)

pH, pCO₂, HCO₃⁻, lactate, electrolytes. MBS item 66540. Available in most Australian EDs and rural hospitals.

ESSENTIAL

Serum Electrolytes, Creatinine, eGFR

Calculate anion gap; correct for albumin. MBS items 66509, 66510.

AVAILABLE

Serum Lactate

Critical for identifying type A/B lactic acidosis. MBS item 66545.

AVAILABLE

Serum Beta-Hydroxybutyrate (βOHB)

Preferred for diagnosing diabetic and alcoholic ketoacidosis. MBS item 66557.

AVAILABLE

Urine Electrolytes & Osmolality

Urine anion gap (Na⁺ + K⁺ – Cl⁻) distinguishes renal from extra-renal HCO₃⁻ loss.

SPECIALIST

Serum Osmolal Gap

Measured osmolality – calculated osmolality. Elevated >10 suggests toxic alcohol ingestion (methanol, ethylene glycol).

Risk Stratification / Severity Scoring

Mild

pH 7.30–7.35

HCO₃⁻ 18–22 mmol/L. Often asymptomatic. Manage underlying cause in outpatient setting.

Setting: Primary care, GP follow-up

Moderate

pH 7.20–7.29

HCO₃⁻ 10–17 mmol/L. Kussmaul respiration, mild confusion. Requires urgent investigation and treatment.

Setting: Emergency department, short stay

Severe

pH <7.20

HCO₃⁻ <10 mmol/L. Haemodynamic compromise, obtundation, multi-organ failure risk.

Setting: ICU/HDU admission, consider bicarbonate therapy

⚠️

Clinical Pearl: Mortality rises sharply when pH <7.0. In severe metabolic acidosis, the mortality rate in Australian ICUs is 40–50%, primarily driven by the underlying aetiology rather than the acidaemia itself.

Metabolic Acidosis: High vs Normal Anion Gap

Metabolic acidosis is classified by the anion gap (AG), calculated as Na⁺ – (Cl⁻ + HCO₃⁻). Always correct for albumin: corrected AG = calculated AG + 0.25 × (40 – albumin g/L).

Feature	High Anion Gap (HAGMA)	Normal Anion Gap (NAGMA)
Anion Gap	>12 mmol/L (corrected)	8–12 mmol/L (corrected)
Primary Mechanism	Addition of non-volatile acid (unmeasured anions)	Loss of HCO₃⁻ or failure to excrete H⁺ (hyperchloraemia)
Common Causes	Lactic acidosis, ketoacidosis, renal failure, toxic ingestions	Diarrhoea, renal tubular acidosis (RTA), ureteric diversions, early renal failure
Urinary AG	Variable	Positive in RTA; negative in extra-renal loss (diarrhoea)
Key Investigation	Lactate, βOHB, creatinine, osmolal gap	Urine pH, urine electrolytes, serum potassium

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Australian Context: Diabetic ketoacidosis (DKA) is a leading cause of HAGMA in Australia, with an estimated 2,500–3,000 hospital admissions annually. Type 2 DKA is increasingly recognised, particularly in Indigenous Australians.

MUDPILES Mnemonic & Delta-Delta Ratio

The MUDPILES mnemonic aids recall of causes of high anion gap metabolic acidosis:

M – Methanol (methylated spirits ingestion)
U – Uraemia (acute or chronic kidney injury)
D – Diabetic ketoacidosis
P – Paracetamol (propylene glycol toxicity) or Propofol infusion syndrome
I – Isoniazid, Iron, Inhalants (e.g., glue sniffing – toluene)
L – Lactic acidosis (type A: hypoxic; type B: metformin, liver disease)
E – Ethylene glycol (antifreeze) – look for calcium oxalate crystals
S – Salicylates (aspirin overdose – mixed respiratory alkalosis & metabolic acidosis)

Delta-Delta Ratio (Δ/Δ): Helps identify mixed disorders when anion gap is elevated. Calculate: ΔAG = AG – 12; ΔHCO₃⁻ = 24 – HCO₃⁻. Ratio = ΔAG / ΔHCO₃⁻.

Delta-Delta Ratio	Interpretation	Example
< 1	Concurrent normal AG acidosis	DKA + diarrhoea
1–2	Pure HAGMA	Pure lactic acidosis
> 2	Concurrent metabolic alkalosis	DKA + vomiting

Metabolic Alkalosis

Metabolic alkalosis is the most common acid-base disorder in hospitalised patients. It is generated by loss of H⁺ (vomiting, NG suction) or gain of HCO₃⁻ (excessive bicarbonate, citrate in transfusions), and maintained by volume depletion, hypokalaemia, or hyperaldosteronism.

Type	Urine Cl⁻	Common Causes	Treatment
Chloride-responsive	< 25 mmol/L	Vomiting, diuretics, post-hypercapnia	IV 0.9% NaCl ± KCl
Chloride-resistant	> 40 mmol/L	Hyperaldosteronism, Cushing's, severe hypokalaemia, Bartter/Gitelman	Treat underlying cause; spironolactone

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Sodium Chloride 0.9%

Normal Saline · Isotonic crystalloid

Adult dose 500–2000 mL IV over 4–8 hours, based on volume status and urine output

Paediatric dose 20 mL/kg IV bolus for dehydration; maintenance with 0.9% NaCl + KCl

PBS status ✔ PBS General Benefit

Respiratory Acidosis & Alkalosis

Respiratory Acidosis (Hypercapnia)

pCO₂ >45 mmHg, pH <7.35

Acute: CNS depression (opioids, benzodiazepines), severe asthma/COPD exacerbation, neuromuscular disease (Guillain-Barré).
Chronic: COPD, obesity hypoventilation syndrome, kyphoscoliosis.
Compensation: Kidneys retain HCO₃⁻ (3.5 mmol/L ↑ per 10 mmHg pCO₂).

Respiratory Alkalosis (Hypocapnia)

pCO₂ <35 mmHg, pH >7.45

Acute: Anxiety/panic, pain, hypoxia, salicylate poisoning, sepsis.
Chronic: Pregnancy (progesterone), liver disease, high altitude, central sleep apnoea.
Compensation: Kidneys excrete HCO₃⁻ (5 mmol/L ↓ per 10 mmHg pCO₂).

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Critical: In acute respiratory acidosis, if pH falls below 7.20, consider mechanical ventilation. In salicylate poisoning, respiratory alkalosis is often followed by metabolic acidosis – check salicylate levels and anion gap.

Empirical Therapy

Empirical management focuses on stabilising the patient while identifying the underlying cause:

1

Assess & Stabilise

Secure airway, breathing, circulation. Check glucose and treat hypoglycaemia. Administer oxygen if hypoxic.

2

Fluid Resuscitation

For volume-depleted states (DKA, diarrhoea): IV 0.9% NaCl 1–2 L over 1–2 hours, then adjust.

3

Specific Antidotes

If suspect toxic ingestion: fomepizole for methanol/ethylene glycol (if available), N-acetylcysteine for paracetamol.

4

Recheck Blood Gas

Repeat VBG in 1–2 hours to assess response. Monitor anion gap and delta-delta.

Directed / Pathogen- or Mechanism-Specific Therapy

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Insulin (Actrapid®)

Novo Nordisk · For DKA

Adult dose 0.1 units/kg/h IV infusion (max 10 units/h) until ketosis clears

Paediatric dose 0.05–0.1 units/kg/h IV for DKA

PBS status ✔ PBS General Benefit

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Sodium Bicarbonate

For severe acidaemia (pH <7.1)

Adult dose 50–100 mmol IV over 15–30 minutes if pH <7.1; only in ICU setting

Caution May worsen intracellular acidosis, cause hypokalaemia, hypernatraemia

PBS status ✔ PBS General Benefit

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Potassium Chloride

For hypokalaemia in metabolic alkalosis

Adult dose 20–40 mmol in 1 L IV fluid (max 10 mmol/h IV via central line)

Oral replacement Slow-K® 600 mg PO BD-TDS

PBS status ✔ PBS General Benefit

Monitoring

0–1 hours

Continuous pulse oximetry, cardiac monitoring if severe. Repeat VBG at 1 hour if initial pH <7.2.

1–4 hours

Check electrolytes (especially K⁺, Cl⁻), glucose, and lactate. Titrate IV fluids and insulin if applicable.

4–12 hours

Repeat VBG and electrolytes. Aim to close anion gap in HAGMA. Watch for over-correction in alkalosis.

12–24 hours

Transition to oral intake. Educate on prevention (e.g., sick-day rules for diabetics).

Special Populations

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Pregnancy

Normal pCO₂ is ~30 mmHg due to progesterone-driven hyperventilation; interpret blood gases accordingly.

Hyperemesis gravidarum can cause hypochloraemic metabolic alkalosis; rehydrate with IV NaCl + KCl.

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Paediatrics

Higher AG normal range (up to 16 mmol/L in neonates). Corrected AG = AG + (40 – albumin) × 0.25.

Diarrhoeal illness is a leading cause of NAGMA in children; ORS (Gastrolyte®) is first-line.

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Elderly & CKD

Reduced renal acid excretion predisposes to NAGMA. Avoid high-dose IV NaHCO₃ if oedematous.

Metformin-associated lactic acidosis is rare but more common in eGFR <30 mL/min.

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Immunocompromised

Lactic acidosis may indicate sepsis or ischaemic bowel; maintain a high index of suspicion.

Antiretroviral therapy (e.g., tenofovir) can cause RTA; monitor bicarbonate.

📚 References

1. Berend K, de Vries AP, Gans RO. Physiological approach to assessment of acid-base disturbances. N Engl J Med. 2014;371(15):1434-1445.
2. Reddy P, Mooradian AD. Diagnosis and management of metabolic acidosis in hospitalised patients. Intern Med J. 2019;49(2):150-158.
3. Australian Institute of Health and Welfare (AIHW). Diabetes: Australian facts. Canberra: AIHW; 2023.
4. Kraut JA, Madias NE. Metabolic acidosis: pathophysiology, diagnosis and management. Nat Rev Nephrol. 2010;6(5):274-285.
5. Royal Australian College of General Practitioners (RACGP). Management of type 2 diabetes: A handbook for general practice. Melbourne: RACGP; 2020.
6. Galla JH. Metabolic alkalosis. J Am Soc Nephrol. 2000;11(2):369-375.
7. Department of Health. MBS Online. Canberra: Australian Government; 2024. Available from: www.mbsonline.gov.au.
8. Palmer BF, Clegg DJ. Respiratory acid-base disorders. Endocrinol Metab Clin North Am. 2019;48(4):685-697.
9. Kidney Health Australia. Chronic kidney disease management in primary care. 4th ed. Melbourne: Kidney Health Australia; 2020.
10. Aboriginal and Torres Strait Islander Health Practice Board of Australia. Cultural safety framework. 2022.