Metabolic acidosis

Metabolic acidosis is a primary fall in serum bicarbonate (under 22 mmol/L) with an arterial pH under 7.35 (or a falling pH with a compensatory fall in PaCO2). It results from added acid, loss of bicarbonate, or failure of the kidney to excrete acid.

It is a sign of an underlying disorder, some immediately life threatening (diabetic ketoacidosis, sepsis with lactic acidosis, poisoning). The task is to find and treat the cause while supporting the circulation and ventilation.

Clinical relevance. Metabolic acidosis is present in about 30% of intensive care patients and in most patients with severe sepsis, kidney failure and diabetic emergencies. A pH under 7.20 is associated with reduced cardiac contractility, vasodilation, catecholamine resistance, arrhythmia and hyperkalaemia. A pH under 7.00 is associated with high mortality.

Physiology. Buffering by bicarbonate and proteins is followed within minutes by respiratory compensation through increased ventilation, and then by renal acid excretion over days.

The expected compensatory PaCO2 in a simple metabolic acidosis equals 1.5 multiplied by the bicarbonate plus 8 (plus or minus 2) mmHg. A PaCO2 higher than expected indicates a coexisting respiratory acidosis. A lower value indicates a coexisting respiratory alkalosis. One kPa equals 7.5 mmHg.

Classification by severity (arterial pH).

• Mild: 7.30 to 7.34.
• Moderate: 7.10 to 7.29.
• Severe: under 7.10 (life threatening).

Classification by anion gap. Anion gap equals sodium minus (chloride plus bicarbonate), with a normal value of 8 to 12 mmol/L (without potassium). Correct for albumin: add 0.25 multiplied by (40 minus albumin in g/L).

• High anion gap: ketoacidosis (diabetic, alcoholic, starvation), lactic acidosis, uraemia (acute and chronic kidney failure), and D-lactic acidosis in short bowel syndrome.
• High anion gap toxins: methanol, ethylene glycol, salicylate, propylene glycol, paracetamol in high dose with pyroglutamic acid, metformin, iron, isoniazid.
• Normal anion gap (hyperchloraemic): gastrointestinal bicarbonate loss (diarrhoea, intestinal fistula, ureterosigmoidostomy, ileal conduit), and renal tubular acidosis (types 1, 2 and 4).
• Other normal anion gap causes: carbonic anhydrase inhibitors (acetazolamide, topiramate), large volume isotonic saline, early kidney disease, hypoaldosteronism, post hypocapnic states, and recovery from diabetic ketoacidosis.

Key distinctions. The delta ratio (change in anion gap divided by change in bicarbonate) separates mixed disorders.

• Under 0.4: pure normal gap acidosis.
• 0.4 to 0.8: mixed high and normal gap acidosis (common in kidney failure).
• 1 to 2: pure high gap acidosis.
• Over 2: coexisting metabolic alkalosis or chronic respiratory acidosis.

History.

• Symptoms: breathlessness, rapid deep breathing, nausea, vomiting, abdominal pain, headache, drowsiness, confusion, weakness, and palpitations.
• Diabetes and insulin omission, alcohol intake, starvation, vomiting, diarrhoea, bowel surgery with urinary diversion, kidney disease, liver disease, sepsis, and shock.
• Ingestions: methanol, ethylene glycol (antifreeze), aspirin, paracetamol, iron, isoniazid, metformin overdose, and recreational substances. Time of ingestion and amount.
• Drugs: metformin, acetazolamide, topiramate, NRTIs, linezolid, propofol infusion (long), laxatives, trimethoprim, ACE inhibitors, and potassium sparing diuretics.
• Family history of tubular disease or metabolic disorders, and in children inherited metabolic disease.

Examination.

• Respiratory pattern (Kussmaul breathing: deep, regular and laboured), respiratory rate, oxygen saturation, temperature.
• Perfusion: pulse, blood pressure, capillary refill, urine output, mental state, peripheral vasodilation or shock.
• Dehydration, abdominal tenderness, ketone odour on the breath, and signs of sepsis, trauma or bowel ischaemia.
• Eyes: visual loss, papilloedema (methanol). Neurological signs: drowsiness, tremor, seizures.
• Signs of kidney failure (pericarditis, asterixis), liver failure, and malabsorption.

Red flags.

• pH under 7.15 or bicarbonate under 10 mmol/L.
• Shock, hypotension, or lactate over 4 mmol/L.
• Reduced consciousness, seizures, or visual disturbance.
• Suspected toxic alcohol, salicylate, metformin or other poisoning, with a high anion gap or osmolar gap.
• Severe hyperkalaemia or ECG changes.
• Acute kidney injury or oliguria.
• Diabetic ketoacidosis with pH under 7.0.
• Suspected bowel ischaemia, necrotising infection or sepsis.
• Respiratory fatigue (falling respiratory rate or rising PaCO2 in a patient who has been hyperventilating).

Special groups. Children and infants: consider inherited metabolic disease, sepsis, dehydration, and poisoning. Pregnancy: acidosis from ketoacidosis occurs at lower glucose levels. Older adults have reduced compensatory capacity. Patients on metformin with kidney failure are at risk of lactic acidosis.

High anion gap metabolic acidosis.

• Ketoacidosis: diabetic ketoacidosis, alcoholic ketoacidosis, starvation ketosis, SGLT2 inhibitor associated euglycaemic ketoacidosis.
• Lactic acidosis: type A (shock, sepsis, hypoxia, cardiac arrest, mesenteric ischaemia, seizures, severe anaemia, carbon monoxide, cyanide) and type B (metformin, linezolid, NRTIs, liver failure, malignancy, thiamine deficiency, propofol infusion syndrome, beta agonists, short bowel D-lactate).
• Kidney failure: acute kidney injury and advanced chronic kidney disease.
• Toxins: methanol, ethylene glycol, propylene glycol (lorazepam infusion), salicylates, iron, isoniazid, toluene (mixed), paracetamol (pyroglutamic acidosis), and cyanide.

Normal anion gap metabolic acidosis.

• Gastrointestinal loss: diarrhoea, laxative abuse, pancreatic or biliary fistula, ileostomy, ureterosigmoidostomy, small bowel drainage, and cholestyramine.
• Renal tubular acidosis: type 1 distal (autoimmune disease, Sjogren syndrome, lithium, amphotericin, hypercalciuria), type 2 proximal (Fanconi syndrome, myeloma, tenofovir, acetazolamide), and type 4 (hypoaldosteronism, diabetic nephropathy, ACE inhibitors, NSAIDs, trimethoprim, heparin).
• Others: large volume 0.9% saline, parenteral nutrition with chloride, carbonic anhydrase inhibitors, early kidney failure, adrenal insufficiency, hyperparathyroidism, and recovery from diabetic ketoacidosis.

Compensation and mixed disorders to consider. Respiratory acidosis from fatigue or sedation, respiratory alkalosis from sepsis or salicylate (mixed with metabolic acidosis), and metabolic alkalosis from vomiting (mixed with high anion gap acidosis).

Step 1. Take an arterial blood gas (or venous gas). Confirm acidaemia (pH under 7.35), low bicarbonate, and the compensatory PaCO2.

Step 2. Laboratory tests: electrolytes with chloride, urea, creatinine, glucose, ketones (point of care beta hydroxybutyrate), lactate, albumin, liver tests, osmolality, calcium, magnesium, phosphate, full blood count, urinalysis (ketones, pH, glucose), and cultures.

Step 3. Calculate the anion gap (corrected for albumin) and the delta ratio. Divide into high and normal gap.

Step 4. High anion gap: measure lactate, ketones, creatinine, osmolality, salicylate level, paracetamol level, ethanol, and blood methanol and ethylene glycol if available.

Osmolar gap equals measured minus calculated osmolality, where calculated equals 2 multiplied by sodium plus glucose plus urea in mmol/L. An osmolar gap over 10 mOsm/kg suggests toxic alcohols. Review urine for calcium oxalate crystals (ethylene glycol).

Step 5. Normal anion gap: calculate the urine anion gap (urine sodium plus potassium minus chloride). A negative value suggests gastrointestinal bicarbonate loss (with normal ammonium excretion). A positive value suggests renal tubular acidosis.

Check urine pH (over 5.5 with a systemic acidosis suggests distal RTA), potassium (low in types 1 and 2, high in type 4), and fractional bicarbonate excretion.

Step 6. Search for the cause: chest radiograph, CT of the abdomen for ischaemia or collection, ECG, echocardiography, and toxicology screen.

Interpretation.

• A normal anion gap with hypokalaemia suggests diarrhoea or RTA.
• A high anion gap with an osmolar gap over 10 suggests toxic alcohols.
• A high anion gap with ketones suggests ketoacidosis; with lactate over 2 mmol/L, lactic acidosis.
• A pH under 7.15 with a normal compensatory PaCO2 means impending respiratory failure if the patient tires.

Limitations. Albumin, phosphate and paraproteins alter the anion gap. Lactate may be normal in early ischaemia. Toxic alcohols can produce a normal osmolar gap late, after metabolism to acids. Point of care ketone meters measure beta hydroxybutyrate only.

Principles. Treat the cause first, support circulation and ventilation, correct fluid and electrolyte deficits, and use alkali selectively.

Bicarbonate is not a routine treatment for acidosis from lactate or ketones, because it may lower ionised calcium, raise PaCO2 and cause sodium overload. It is useful when there is hyperkalaemia, poisoning with sodium channel blockade, salicylate toxicity, severe acidosis with acute kidney injury, or a bicarbonate loss state.

Airway, breathing and circulation. Give oxygen to keep saturation 94 to 98%. Do not intubate a hyperventilating acidotic patient without strong indication, because loss of respiratory compensation can precipitate a fatal drop in pH.

If intubation is needed, pre-oxygenate, maintain minute ventilation at the pre-intubation level with a high rate, and give a bicarbonate bolus beforehand where pH is under 7.1.

Fluids: isotonic crystalloid 500 mL to 1 litre boluses for shock. Prefer balanced solutions (lactated or acetate buffered solutions) over large volumes of 0.9% saline when hyperchloraemic acidosis is present.

Bicarbonate therapy (selective).

• Indications: pH under 7.00 to 7.10 with shock or organ failure, acute kidney injury with pH under 7.20, hyperkalaemia with ECG changes, sodium channel blocker or tricyclic overdose with QRS widening, salicylate or methanol poisoning, and normal anion gap acidosis from bicarbonate loss.
• Sodium bicarbonate 8.4% (1 mmol/mL) 1 mmol/kg (usual adult dose 50 to 100 mmol; maximum 150 mmol for each dose) IV over 30 to 60 minutes through a central line where possible. Peripheral use is acceptable in an emergency but with extravasation risk. Reassess pH and bicarbonate at 1 hour.
• Isotonic sodium bicarbonate 1.26% 500 mL (75 mmol) IV over 1 hour is an alternative that avoids hypertonic sodium and is safe peripherally.
• Monitoring: pH, bicarbonate, potassium (falls as pH rises), ionised calcium (falls; replace with calcium gluconate 10% 10 to 20 mL IV if symptomatic), sodium and osmolality, PaCO2 (rises, so ventilation must increase), and fluid status.
• Target pH over 7.20 and bicarbonate 15 to 18 mmol/L, not normalisation.
• Contraindications and cautions: heart failure and fluid overload, hypernatraemia, hypocalcaemia, hypokalaemia, and respiratory failure (cannot clear the carbon dioxide).

Diabetic ketoacidosis.

• Fixed rate insulin 0.1 units/kg/hour IV after 1 hour of fluid resuscitation and once potassium is over 3.3 mmol/L.
• Isotonic saline 1 litre over 1 hour, then 1 litre over 2 hours, 1 litre over 2 hours, 1 litre over 4 hours, and 1 litre over 4 hours (adjusted to volume status).
• Add glucose 10% at 125 mL/hour when glucose is under 14 mmol/L.
• Potassium chloride 40 mmol in each litre when potassium is 3.5 to 5.5 mmol/L. Give none if over 5.5. If under 3.3, hold insulin and give 20 to 40 mmol/hour.
• Bicarbonate only for pH under 6.9: sodium bicarbonate 8.4% 100 mmol (100 mL) in 400 mL of sterile water with 20 mmol of potassium chloride IV over 2 hours, repeated every 2 hours until pH is 7.0 or more. Evidence of benefit is limited; monitor potassium.
• Monitor capillary glucose and ketones hourly, venous gas and electrolytes every 2 hours, and fluid balance.

Lactic acidosis. Resuscitate (fluids, vasopressors, oxygen). Control the source (antibiotics within 1 hour, drainage, surgery). Treat hypoxia and stop causative drugs (metformin, linezolid). Give thiamine 100 to 300 mg IV daily when thiamine deficiency is possible. Use renal replacement therapy for metformin associated lactic acidosis with pH under 7.1, lactate over 20 mmol/L, or shock.

Toxic alcohol poisoning (methanol, ethylene glycol).

• Fomepizole 15 mg/kg IV (in 100 mL isotonic saline or 5% glucose over 30 minutes) as a loading dose, then 10 mg/kg IV every 12 hours for 4 doses, then 15 mg/kg every 12 hours until the alcohol level is under 200 mg/L (0.2 g/L) and acidosis has resolved.
• Give fomepizole every 4 hours during haemodialysis (or an infusion). Monitor liver function, rash, and phlebitis.
• Ethanol is an alternative if fomepizole is not available: loading 0.6 g/kg IV then infusion to a blood level of 1 g/L, with close glucose and level monitoring.
• Folinic acid 50 mg IV every 6 hours (or folic acid 50 mg IV every 6 hours) for methanol, for 24 hours.
• Thiamine 100 mg IV once daily and pyridoxine 50 mg IV every 6 hours for ethylene glycol.
• Haemodialysis for pH under 7.25, visual or neurological signs, kidney injury, methanol level over 500 mg/L (15.6 mmol/L), ethylene glycol level over 500 mg/L (8 mmol/L), or severe acidosis. Give bicarbonate 1 mmol/kg IV for pH under 7.3.
• Do not delay antidote while waiting for levels.

Salicylate poisoning.

• Sodium bicarbonate 8.4% 1 to 2 mmol/kg IV bolus (50 to 100 mmol) over 15 to 30 minutes.
• Then give an infusion (150 mmol in 1 litre of 5% glucose at 1.5 to 2 times maintenance) to achieve a urine pH of 7.5 to 8.0 and a serum pH of 7.45 to 7.55.
• Replete potassium (target potassium over 4.0 mmol/L, as hypokalaemia prevents alkaline urine). Monitor salicylate level every 2 hours.
• Avoid intubation unless essential, as loss of hyperventilation can be lethal.
• Haemodialysis for level over 7.2 mmol/L (about 1000 mg/L) in acute poisoning, level over 6.5 mmol/L with kidney impairment, altered mental state, pulmonary oedema, or pH under 7.2.

Kidney failure. Dialysis for refractory acidosis. Chronic metabolic acidosis in kidney disease: sodium bicarbonate 500 mg to 1 g (6 to 12 mmol) orally two to three times daily, titrated to a serum bicarbonate of 22 mmol/L or more (maximum 6 g daily; monitor blood pressure, oedema and calcium).

Renal tubular acidosis.

• Distal (type 1): sodium bicarbonate or potassium citrate to supply 1 to 2 mmol/kg/day of alkali orally in 3 to 4 divided doses (adults), adjusted to a bicarbonate of 22 mmol/L or more and normal potassium. Give potassium citrate 10 to 20 mmol orally two to three times daily for hypokalaemia and stones (monitor potassium).
• Proximal (type 2): larger alkali doses of 5 to 15 mmol/kg/day with potassium and thiazide, under nephrology.
• Type 4: treat hyperkalaemia (low potassium diet, loop diuretic, sodium zirconium cyclosilicate 5 to 10 g orally once daily). Give fludrocortisone 50 to 200 micrograms orally once daily if hypoaldosteronism, monitoring blood pressure and potassium.

Gastrointestinal bicarbonate loss. Give oral or IV fluid replacement and oral sodium bicarbonate 500 mg to 1 g (6 to 12 mmol) two to three times daily. Treat diarrhoea (stop laxatives; loperamide 4 mg then 2 mg after each loose stool, maximum 16 mg daily, if infection is excluded). Replace potassium.

Monitoring. Check arterial or venous gas, electrolytes, lactate and glucose every 1 to 4 hours initially, then every 6 to 12 hours. Use continuous ECG, oxygen saturation, blood pressure and urine output. Repeat anion gap and delta ratio on repeat tests.

Referral and escalation. Critical care for pH under 7.15, shock or ventilatory support. Nephrology for dialysis, RTA and kidney failure. Toxicology for poisoning. Endocrinology for diabetic ketoacidosis. Metabolic specialists for inherited disorders.

Admission criteria. Admit for pH under 7.30 or bicarbonate under 18 mmol/L, or any acidosis with a serious cause (sepsis, ketoacidosis, poisoning, kidney failure, shock). Stable mild chronic acidosis from kidney disease or RTA can be managed in the community.

Discharge and safety netting. Discharge when pH and bicarbonate are normal or stable, the cause is controlled, and oral alkali or treatment is established. Check electrolytes and bicarbonate in 3 to 7 days. Patients return for rapid breathing, vomiting, confusion, abdominal pain, reduced urine output, or palpitations.