Metabolic alkalosis

Metabolic alkalosis is a primary rise in serum bicarbonate (over 26 mmol/L) with an arterial pH over 7.45 (or a rising pH with a compensatory rise in PaCO2). It is generated by loss of hydrogen ions (gastric or renal) or gain of bicarbonate, and maintained by volume depletion, chloride depletion, hypokalaemia and mineralocorticoid excess. Severe alkalosis reduces ionised calcium and causes arrhythmia, seizures and hypoventilation.

Clinical relevance. It is the commonest acid base disorder in hospital patients after metabolic acidosis, mainly from vomiting, nasogastric suction and diuretics. A pH over 7.55 is associated with high mortality.

Physiology. The kidney normally excretes excess bicarbonate. Alkalosis persists only if the kidney's ability to excrete bicarbonate is impaired, which happens when there is volume depletion with chloride loss (which promotes sodium and bicarbonate reabsorption), hypokalaemia, or aldosterone excess. Respiratory compensation by hypoventilation raises PaCO2 by about 0.7 mmHg for each 1 mmol/L rise in bicarbonate, rarely over 55 to 60 mmHg because hypoxia limits it.

Classification by severity.

• Mild: pH 7.46 to 7.49, bicarbonate 27 to 32 mmol/L.
• Moderate: pH 7.50 to 7.54, bicarbonate 33 to 40 mmol/L.
• Severe: pH over 7.55, or bicarbonate over 40 mmol/L.

Classification by urine chloride.

• Chloride responsive (urine chloride under 20 mmol/L): vomiting, nasogastric suction, remote diuretic use, post hypercapnic alkalosis, villous adenoma, chloride diarrhoea, and cystic fibrosis.
• Chloride resistant (urine chloride over 20 mmol/L): with hypertension (primary aldosteronism, Cushing syndrome, renal artery stenosis, liquorice, Liddle syndrome, congenital adrenal hyperplasia) or normal blood pressure (current diuretics, Bartter syndrome, Gitelman syndrome, severe hypokalaemia, hypomagnesaemia).
• Alkali load: milk alkali syndrome, sodium bicarbonate, citrate (massive transfusion), acetate (parenteral nutrition), and antacids with kidney failure.

Key distinctions. Urine chloride separates vomiting and diuretic related alkalosis from mineralocorticoid excess. Urine chloride is unreliable within hours of loop diuretics, when urine sodium and potassium are also high.

History.

• Vomiting, nasogastric suction, diarrhoea, diuretic use, laxative use, antacid and bicarbonate intake, calcium and vitamin D supplements, liquorice and chewing tobacco.
• Symptoms: weakness, cramps, tetany, paraesthesia, palpitations, confusion, seizures, and muscle twitching.
• Hypertension, hypokalaemia, family history of tubular disorders, adrenal disease, kidney disease, heart failure and cystic fibrosis.
• Chronic lung disease with recent ventilation (post hypercapnic alkalosis), recent transfusion, and parenteral nutrition.

Examination.

• Volume status: postural blood pressure, mucous membranes, skin turgor, weight, oedema.
• Blood pressure (high in mineralocorticoid excess, low in volume depletion), pulse, and respiratory rate (reduced).
• Neuromuscular: Chvostek and Trousseau signs, hyperreflexia, tetany, weakness.
• Signs of Cushing syndrome, heart failure, cirrhosis, and eating disorder (dental erosion, Russell sign).
• ECG: prolonged QT interval, arrhythmia, T wave flattening and U waves from hypokalaemia.

Red flags.

• pH over 7.55 or bicarbonate over 40 mmol/L.
• Seizures, tetany, confusion, or coma.
• Ventricular arrhythmia, QTc over 500 ms, or severe hypokalaemia (under 2.5 mmol/L).
• Hypoventilation with hypoxia or respiratory failure.
• Marked volume depletion or shock.
• Hypertension with hypokalaemia (aldosterone or cortisol excess).
• Massive transfusion or large alkali load.
• Digoxin therapy.

Special groups. Patients with chronic obstructive pulmonary disease who are rapidly ventilated develop post hypercapnic alkalosis with a risk of seizures. Infants with pyloric stenosis, cystic fibrosis or Bartter syndrome present with alkalosis. Patients with an eating disorder and surreptitious vomiting or laxative or diuretic use may conceal the history.

Chloride responsive alkalosis.

• Gastric loss: vomiting (hyperemesis, bulimia, pyloric stenosis, gastric outlet obstruction), nasogastric suction, and gastrocolic fistula.
• Renal loss: previous diuretic use, post hypercapnia, and sweat chloride loss in cystic fibrosis.
• Colonic loss: villous adenoma and congenital chloride diarrhoea.

Chloride resistant alkalosis.

• Mineralocorticoid excess with hypertension: primary aldosteronism (Conn adenoma, adrenal hyperplasia), Cushing syndrome, ectopic ACTH, renal artery stenosis, renin secreting tumour, congenital adrenal hyperplasia, Liddle syndrome, apparent mineralocorticoid excess, and liquorice.
• Normal or low blood pressure: current loop and thiazide diuretics, Bartter syndrome, Gitelman syndrome, severe magnesium or potassium depletion, and refeeding alkalosis.

Exogenous alkali. Sodium bicarbonate, milk alkali syndrome (calcium carbonate with absorbable alkali), citrate (transfusion, plasma exchange, regional anticoagulation), acetate (parenteral nutrition, dialysis), lactate (large volumes), and carbenicillin and penicillin derivatives.

Hypoventilation and others. Post hypercapnic alkalosis, contraction alkalosis (loss of chloride rich fluid), severe hypokalaemia, hypomagnesaemia, and hypoalbuminaemia (reduces anion gap and raises pH).

Step 1. Take a blood gas and confirm alkalaemia with a raised bicarbonate. Estimate the compensation (PaCO2 should rise by about 0.7 mmHg for each 1 mmol/L increase in bicarbonate). A lower than expected PaCO2 indicates a coexisting respiratory alkalosis; a higher value, a coexisting respiratory acidosis.

Step 2. Laboratory tests: electrolytes with chloride, potassium, magnesium, calcium (ionised), phosphate, urea, creatinine, glucose, albumin, and urine electrolytes.

Step 3. Measure urine chloride on a spot sample, ideally before diuretic or saline therapy.

• Urine chloride under 20 mmol/L: chloride responsive (vomiting, nasogastric loss, remote diuretics, post hypercapnia).
• Urine chloride over 20 mmol/L with normal or low blood pressure and urine sodium and potassium raised: current diuretics, Bartter or Gitelman syndrome (check urine diuretic screen), or severe hypokalaemia.
• Urine chloride over 20 mmol/L with hypertension: measure plasma renin and aldosterone (aldosterone to renin ratio), cortisol, and imaging of the adrenals and renal arteries.

Step 4. Further tests: urinary potassium, magnesium, 24 hour urinary cortisol or overnight dexamethasone suppression test, genetic tests (Bartter, Gitelman, Liddle), sweat test (cystic fibrosis), calcium and PTH (milk alkali syndrome), and imaging for gastric outlet obstruction.

Interpretation. Urine chloride under 20 mmol/L means that chloride depletion is the maintaining factor and the alkalosis will respond to chloride (saline). A bicarbonate over 40 mmol/L with hypertension and hypokalaemia suggests aldosterone excess.

Limitations. Urine chloride is unreliable within 24 hours of loop diuretic therapy or large saline loads. Compensatory hypoventilation can raise PaCO2 so that pH is mildly raised only. Albumin changes can affect the anion gap in mixed disorders.

Principles. Remove the cause, restore volume, chloride and potassium, and reverse the maintaining factors. Most patients need only saline and potassium. Severe alkalosis (pH over 7.55 or symptomatic) needs additional measures in a monitored area.

Chloride responsive alkalosis (vomiting, nasogastric suction, diuretic related).

• Isotonic saline 0.9% 1 to 2 litres IV over 2 to 4 hours, then 100 to 150 mL/hour, continuing until urine chloride exceeds 20 mmol/L and bicarbonate falls (monitor volume status, sodium and weight; avoid fluid overload in heart failure and kidney failure).
• Potassium chloride 20 to 40 mmol in each litre of isotonic saline IV (maximum 10 mmol/hour peripherally and 20 mmol/hour centrally with ECG monitoring; reduce in kidney impairment; recheck potassium every 4 to 6 hours), aiming for potassium of 4.0 mmol/L or more. Replace magnesium: magnesium sulphate 2 g (8 mmol) IV over 20 minutes to 2 hours when magnesium is under 0.7 mmol/L (monitor reflexes and respiratory rate; reduce by half in kidney impairment).
• Stop the cause: antiemetics for vomiting (ondansetron 4 mg IV every 8 hours, maximum 16 mg for each IV dose; monitor QTc), reduce nasogastric losses with a proton pump inhibitor (omeprazole 40 mg IV once daily, or 80 mg bolus then 8 mg/hour in high output; monitor magnesium), relieve gastric outlet obstruction, and stop or reduce diuretics.
• Patients who cannot tolerate saline because of oedema (heart failure, cirrhosis, nephrotic syndrome): acetazolamide 250 to 500 mg IV or orally once or twice daily (maximum 1 g daily for 1 to 3 days; monitor potassium, phosphate, bicarbonate, sodium and kidney function; avoid in sulphonamide allergy, severe liver disease with encephalopathy, and low potassium until repleted).

Chloride resistant alkalosis.

• Primary aldosteronism: spironolactone 25 mg orally once daily, increased every 4 weeks to 100 mg (maximum 400 mg daily; monitor potassium, creatinine, blood pressure and gynaecomastia), or eplerenone 25 mg once daily increased to 50 mg twice daily, with surgery for a unilateral adenoma.
• Cushing syndrome: treat the cause, with potassium replacement and spironolactone 25 to 100 mg daily.
• Liddle syndrome: amiloride 5 to 10 mg orally once daily (maximum 20 mg daily) or triamterene 100 mg twice daily, with a low sodium diet.
• Bartter and Gitelman syndromes: potassium chloride 40 to 100 mmol/day orally in divided doses, magnesium, amiloride 5 to 10 mg daily, high salt diet, and indomethacin 25 mg two to three times daily in Bartter syndrome, under specialist care.
• Diuretic related with continuing need: reduce the dose or add amiloride 5 to 10 mg orally once daily or spironolactone 25 to 50 mg once daily; replace potassium and magnesium.
• Milk alkali syndrome: stop calcium carbonate and alkali, give isotonic saline, and treat hypercalcaemia and kidney injury.

Severe alkalosis (pH over 7.55, bicarbonate over 40 mmol/L, or arrhythmia, seizures or ventilatory compromise).

• Admit to a monitored area. Correct volume, potassium, chloride, magnesium and calcium. Ionised calcium low with tetany: calcium gluconate 10% 10 to 20 mL IV over 10 minutes with ECG monitoring.
• Acetazolamide 500 mg IV once or twice daily in volume overloaded patients (monitor potassium, phosphate and bicarbonate).
• Hydrochloric acid 0.1 to 0.2 mol/L (100 to 200 mmol/L) in sterile water or 5% glucose, infused through a central vein at a maximum of 20 mmol/hour (maximum 0.2 mmol/kg/hour), in the intensive care unit, when other measures fail. The hydrogen ion deficit equals 0.5 multiplied by weight (kg) multiplied by (measured bicarbonate minus desired bicarbonate of 24 mmol/L); give half the calculated dose and recheck gas at 4 hours. Monitor pH, bicarbonate and potassium every 4 hours, and watch for haemolysis and tissue necrosis if extravasated.
• Dialysis or haemofiltration with a low bicarbonate, chloride rich replacement fluid for kidney failure or refractory alkalosis.
• Post hypercapnic alkalosis: reduce ventilation to allow PaCO2 to rise toward the patient's baseline; give acetazolamide 250 to 500 mg IV; replace chloride and potassium.
• Seizures: lorazepam 4 mg IV (0.1 mg/kg, maximum 4 mg, repeated once after 10 minutes) and correction of alkalosis and ionised calcium.

Alkali load. Stop bicarbonate, citrate and alkali sources. Reduce citrate anticoagulation rates and replace ionised calcium in massive transfusion or regional citrate anticoagulation.

Monitoring. Venous or arterial gas, bicarbonate, potassium, ionised calcium, magnesium and chloride every 4 to 6 hours initially, then daily; urine output and urine chloride; volume status and daily weight; ECG until normal; and blood pressure for hyperaldosteronism.

Referral and escalation. Critical care for severe alkalosis, arrhythmia, seizures or hydrochloric acid infusion. Endocrinology for aldosterone and cortisol excess. Nephrology for tubular disorders and renal replacement therapy. Gastroenterology or surgery for gastric outlet obstruction. Respiratory medicine for post hypercapnic alkalosis. Psychiatry for eating disorders.

Admission criteria. pH over 7.50 or bicarbonate over 35 mmol/L with symptoms, any seizure, arrhythmia or severe hypokalaemia, unable to maintain oral intake, gastric outlet obstruction, or an unexplained cause. Mild asymptomatic alkalosis from diuretics can be managed in the community.

Discharge and safety netting. Discharge when pH and bicarbonate are normal or stable, potassium is 3.5 mmol/L or more, the cause is controlled, and oral intake is adequate, with electrolytes and bicarbonate checked in 3 to 7 days. Advise on diuretic review and eating disorder support if relevant. Patients return for cramps, tingling, palpitations, persistent vomiting, confusion or fits.