CONTENTS

• Diagnosis
• Symptoms
• Causes
• Investigation
• Treatment
  • When to treat?
  • Multimodal therapy
  • Hydrochloric acid
• Podcast
• Questions & discussion
• Pitfalls

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diagnosis

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Metabolic alkalosis may be diagnosed in two situations (red arrows above):

• (1) If the serum bicarbonate is elevated (>30 mM), this alone reveals a metabolic alkalosis.
• (2) If the anion gap is elevated but the reduction in bicarbonate is considerably less than would be expected for an isolated anion-gap metabolic acidosis (△AG >> △bicarb), this indicates the presence of a combination of an anion-gap metabolic acidosis plus metabolic alkalosis.

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symptoms

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In clinical practice, metabolic alkalosis is generally an asymptomatic laboratory finding. 

relationship of labs to symptoms?

• This is unclear.
• Bicarbonate levels <40 mM are typically asymptomatic. The likelihood of seizure may increase at levels >50 mM. (24766943)

potential symptoms

• Neurologic:
  • Delirium.
  • Seizures.
• Arrhythmia.
• Hypocalcemia (elevated pH shifts calcium ions onto albumin, thereby reducing ionized calcium levels).
  • Paresthesias, carpopedal spasm.
• Hypoventilation (due to respiratory compensation for the metabolic alkalosis).
  • This is generally not a significant issue.
  • For patients with a weak respiratory drive (e.g., obesity hypoventilation syndrome or COPD), severe metabolic alkalosis may promote hypoventilation.

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causes of metabolic alkalosis

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[1] Compensatory metabolic alkalosis (due to respiratory acidosis)

• Metabolic alkalosis may occur as a physiological response to chronic hypercapnic respiratory failure of any cause, most commonly:
  • Severe COPD.
  • OHS (obesity hypoventilation syndrome).
  • Chronic respiratory muscle weakness.
• Diagnosis of a compensatory metabolic alkalosis is based on ABG/VBG which shows acidemia.
• Further discussion of the evaluation and management of hypercapnia is here: 📖

[2] Chloride-depletion metabolic alkalosis (urine chloride <10-30 mM; usually patient is hypovolemic and this responds to saline therapy)

• Gastric acid loss:
  • Vomiting (e.g., gastric outlet obstruction).
  • Nasogastric or PEG tube suction.
• Post diuresis (after the diuretic action has dissipated).
• Post hypercapnic state. (35525634)
• Renal dysfunction (due to hypovolemia, heart failure, or cirrhosis) PLUS exogenous alkali:
  • TPN with excess acetate.
  • Citrate (massive transfusion, plasmapheresis).
  • Bicarbonate administration (e.g. milk-alkali syndrome, calcium carbonate intake).
• Chloride-wasting diarrhea:
  • Villous adenoma.
  • Laxative overuse.
  • High volume ileostomy output. (35525634)
• Cystic fibrosis with substantial sweating. (This is a multifactorial process involving increased sodium chloride loss in sweat, and impaired renal response to alkalosis because impaired CFTR function suppresses beta-intercalated cell function in the collecting duct. CF may also cause metabolic alkalosis with low urine chloride). (35525634)

[3] Non-chloride-depletion metabolic alkalosis (urine chloride >10-30 mM, often unresponsive to saline therapy)

• Active diuresis with thiazide or loop diuretics.
• Hypomagnesemia.
• Severe hypokalemia.
• Renal insufficiency PLUS exogenous alkali:
  • TPN with excess acetate.
  • Citrate (massive transfusion, plasmapheresis).
  • Bicarbonate administration
    • Milk-alkali syndrome related to calcium carbonate.
    • Sodium bicarbonate.
• High-dose sodium penicillin therapy. (High-dose sodium penicillin functions as a non-resorbable anion that promotes urinary potassium excretion, hypokalemia, and volume depletion.)
• Aminoglycosides (may cause hypokalemia and also inhibit the NKCC2 cotransporter in the thick ascending loop of Henle). (35525634)
• Hyperaldosteronism of any etiology (may be supported by presence of hypertension; usually causes chronic metabolic alkalosis with the exception of exogenous steroid administration).
  • Primary aldosteronism:
    • Aldosterone-secreting adenoma.
    • Bilateral adrenal hyperplasia.
  • Secondary aldosteronism:
    • Renin-secreting tumor.
    • Malignant hypertension, renal artery stenosis.
  • Severe Cushing syndrome (especially 2/2 ectopic ACTH production).
  • Exogenous mineralocorticoid:
    • Fludrocortisone.
    • Exogenous glucocorticoids.
    • Black licorice consumption. (Apparent mineralocorticoid excess due to inactivation of 11-beta hydroxysteroid dehydrogenase causing cortisol to stimulate mineralocorticoid receptors)

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investigation

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[#1] history, physical, and review of archival data

• Review of available information will usually reveal the cause of the metabolic alkalosis.
• Hypovolemia (e.g., on bedside echocardiography) suggests chloride deficiency.
• Hypertension suggests excess aldosterone activity.
• Chronicity may be helpful (e.g., a chronic metabolic alkalosis may suggest chronic compensation for COPD).

[#2] if the cause remains unclear: basic lab evaluation

• Complete electrolytes (including Ca/Mg/Phos).
  • Hypercalcemia may suggest milk-alkali syndrome.
  • Hypokalemia and hypomagnesemia may cause metabolic alkalosis (so these require aggressive management).
  • Hypophosphatemia might suggest refeeding syndrome as an etiology. (32586924)
• Urine potassium and chloride levels:
  • Urine potassium <20-30 mM suggests that hypokalemia may be contributory.
  • Urine chloride concentration is the most important:
    • Chloride <10-30 mM suggests saline responsive.
    • Chloride >10-30 mM suggests saline unresponsive.
    • Chloride between 10-30 mM lies in a grey area that doesn't provide reliable diagnostic information. (24766943)
• VBG/ABG to evaluate for compensatory metabolic alkalosis.
  • [1] If the pCO2 is severely elevated (e.g., >>50 mm), this may suggest that there is a primary respiratory acidosis with secondary metabolic compensation.
  • [2] Expected respiratory compensation for a primary metabolic alkalosis involves a mild degree of hypercapnia as shown below (e.g., pCO2 ~40-50 mm). However, this response is highly variable. Hypokalemia may cause diaphragmatic weakness which further elevates the pCO2. (32586924)

[#3] evaluation of the renin-angiotensin-aldosterone system (RAAS)

• Generally, this isn't useful in critical care. However, this may be considered if:
  • Patient has a persistent alkalosis with urine chloride >10-30 mM, and/or is refractory to normal saline infusion.
  • Other clinical features suggest excessive activity of the renin-angiotensin-aldosterone system (e.g., hypertension, hypokalemia).
• Investigation of the RAAS involves measurement of renin & aldosterone levels.
• These may be interpreted as follows: (30369299)
  • Low renin & high aldosterone ➡️ Primary hyperaldosteronism (aldosterone-secreting adenoma, bilateral adrenal hyperplasia).
  • High renin & high aldosterone ➡️ Secondary hyperaldosteronism (renin-secreting tumor, renal artery stenosis).
  • Low renin & low aldosterone ➡️ State of apparent mineralocorticoid excess (Cushing syndrome, exogenous mineralocorticoid, licorice ingestion).

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when to treat?

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compensatory metabolic alkalosis (due to chronic respiratory acidosis) should usually be left alone

• Patients with chronic hypercapneic respiratory failure will develop a chronic compensatory metabolic alkalosis.
• This is a compensatory mechanism that is generally beneficial. The metabolic alkalosis allows patients to have a fairly normal pH, despite hypoventilation.
  • Without metabolic compensation, these patients would be acidemic and have an increased respiratory drive. This could cause dyspnea, respiratory exhaustion, and eventually full-on respiratory failure.
• One exception is that if a chronic compensatory alkalosis is exacerbated (e.g., by diuresis), then it may be reasonable to attempt to return the patient to their chronic baseline bicarbonate level.

the ideal treatment is to resolve the cause

• Most cases of metabolic alkalosis don't require specific therapy directed at immediately reducing the bicarbonate. Instead, resolving the underlying cause is generally sufficient. For example, a patient with hypovolemia may be treated with volume resuscitation.
• However, specific treatment of the alkalosis may be indicated in the following situations:
  • Alkalosis is moderate to severe (either causing symptoms).
  • The process causing the alkalosis can't be easily reversed (e.g., patient develops contraction alkalosis from diuretics, but you need to continue diuretic therapy to achieve volume control).

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multimodal therapy

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If a decision is made to treat the alkalosis, potential treatments are listed below. Depending on the severity of the alkalosis and the clinical scenario, either one or several simultaneous therapies may be utilized.

[1] aggressive correction of hypokalemia with KCl electrolyte repletion if hypokalemic and/or hypomagnesemic

• Potassium chloride should be supplemented aggressively to target a potassium >4.5 mM (unless the patient has renal failure, which places them at increased risk of hyperkalemia).
• Don't use other types of potassium salts (e.g. potassium citrate or potassium acetate), as the citrate or acetate anions may worsen the alkalosis.
• Underlying physiology: Hypokalemia functions to maintain alkalosis via several mechanisms:
  • Hypokalemia increases bicarbonate absorption in the proximal tubule.
  • Hypokalemia increases ammoniagenesis with subsequent acid excretion.
  • Hypokalemia increases H+ secretion by alpha-intercalated cells in the cortical collecting duct.
  • Hypokalemia reduces pendrin activity, thereby decreasing bicarbonate reabsorption by beta-intercalated cells in the cortical collecting duct. 

[2] aggressive correction of hypomagnesemia

• Hypomagnesemia may contribute to alkalosis and make it difficult to successfully treat the hypokalemia.
• Further discussion of magnesium pharmacology: 📖

[3] if hypovolemic, give normal saline

• Volume depletion will perpetuate the metabolic alkalosis.
• Resuscitation with normal saline may be helpful among patients with hypovolemia (“saline-responsive alkalosis”).
• Urine chloride <10-30 mM predicts improvement following normal saline.
• This is one situation where normal saline is superior to a balanced crystalloid (because you're looking for an acidotic fluid).

[4] if hypervolemic, give diuretics that promote bicarbonate excretion

• (a) Acetazolamide: 💉
  • IV acetazolamide is generally felt to be the front-line diuretic for management of metabolic alkalosis in critical care (probably since it is the most effective).
  • For patients who are continuing to receive diuretics, dosing of acetazolamide should be aggressive (to avoid worsening the metabolic alkalosis).
  • Make sure to monitor potassium levels carefully (acetazolamide may induce hypokalemia, which will aggravate treatment of the metabolic alkalosis).
• (b) Amiloride: 💉
  • Amiloride isn't commonly used for metabolic alkalosis, but it may be helpful (especially among patients with volume overload who require ongoing diuresis to achieve euvolemia).
  • Benefits of amiloride may include:
    • (a) Limiting potassium losses.
    • (b) Treatment of metabolic alkalosis.
    • (c) Mild promotion of overall diuretic efficacy (for patients with ongoing volume overload).
• (Spironolactone) 💉
  • ⚠️ The main drawback of spironolactone is that it takes ~24-48 hours to work. This limits its use in acute care medicine, since patient condition will often change within 1-2 days prior to the effect of the spironolactone.
  • Increased mineralocorticoid activity is often a primary or secondary cause of metabolic alkalosis.
  • Spironolactone may be useful for patients with volume overload (e.g., congestive heart failure) or hyperaldosteronism.

[5] hold or decrease the dose of alkalosis-inducing diuretics (e.g., furosemide)

• If the patient is close to euvolemic, then simply discontinuing alkalosis-inducing diuretics makes sense.
• In patients with mild alkalosis plus persistent volume overload, diuresis should be continued in combination with treatments for alkalosis. Further discussion of this situation here: 📖

[6] proton pump inhibitor in patients with ongoing vomiting or nasogastric suction

• Loss of acidic gastric contents will cause a metabolic alkalosis.
• Administration of a proton pump inhibitor neutralizes the pH of gastric secretions, preventing loss of acid via the stomach.

[7] for intubated patients, adjust ventilator to target mildly alkalemic pH

• Hypercapnia will tend to impair the correction of metabolic alkalosis. Specifically, if the pCO2 is high enough to produce a normal or acidemic pH, this will impair renal bicarbonate excretion.
• To facilitate renal bicarbonate excretion, consider targeting a mildly alkalotic pH (e.g., 7.45-7.50).

[8] reformulate total parenteral nutrition (TPN)

• For patients on TPN, adjust the formulation to remove any sodium acetate.

[9] dialysis

• This is a potential treatment of metabolic alkalosis among patients with renal failure.
• Alkalosis alone is an exceedingly uncommon indication for dialysis. However, dialysis could be reasonable in a patient with other indications as well.
• In a patient with numerous profound electrolyte abnormalities (electrolytic disarray), dialysis will fix all problems simultaneously. This is an artless, yet effective, approach.

[10] intravenous hydrochloric acid

• Hydrochloric acid be used if the above therapies fail or aren't working fast enough (see below).
• Hydrochloric acid is generally safe and effective, but also usually not worth the enormous volume of calls and anxiety that this will generate.

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hydrochloric acid

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usual indications for IV hydrochloric acid

• Severe metabolic alkalosis (pH over ~7.55 or bicarbonate over ~38 mM), plus one of the following:
  • (a) Failure of more conservative modalities.
  • (b) Alkalosis is so profound that immediate control is needed (insufficient time to use more conservative treatments). Clinical manifestations such as delirium, seizure, or arrhythmia may support a need for immediate therapy.
  • (c) Patient remains volume overloaded, requiring ongoing therapy with diuretics. In this context, HCl may allow for ongoing diuresis with simultaneous management of acid-base status. (29359573)
• Hydrochloric acid is effective and safe (if monitored and dosed properly). However, it's generally avoided due to unfamiliarity with this therapy.
• HCl must be given via central line, ideally via the distal port of the line (if line gets pulled back a bit, the distal port will remain intravascular).
  • Central line position should be confirmed with chest X-ray and should lie in the superior vena cava or right atrium.

estimate dosage of acid required

• Shoot for a desired bicarbonate above normal (e.g., ~35 mEq/L).
  • This is a safe bicarbonate level, but if you overshoot the patient won't be rendered acidemic.
  • The goal isn't to normalize the bicarbonate, but rather merely to remove the patient from immediate danger due to alkalemia.
• Calculate bicarbonate excess:
  • Formula for bicarb excess = (0.5)(lean body weight) (plasma bicarb – desired bicarbonate)
  • If we're shooting for a bicarbonate level of ~35 mEq/L, then…
  • Bicarb excess = (0.5)(lean body weight)(plasma bicarbonate – 35 mEq/L)
• These formulas are only very rough estimates. (29359573)
• In a recent published series, the mean amount of HCl infused was 300 mEq.
• This represents a starting point only. It doesn't negate the need to monitor electrolytes & pH during infusion.

administration

• Hydrochloric acid is supplied as 0.1-0.2 Normal solution of HCl (0.1-0.2 mEq/ml). Ideally this should be formulated in sterile water, to avoid volume overload.
  • 0.1 Normal = 100 mEq/L
  • 0.2 Normal = 200 mEq/L
• The maximum safe infusion rate is 0.2 mEq/kg/hr.
  • For 0.1 Normal, this is equal to 2 ml/kg/hr (i.e. ~150 ml/hr).
  • For 0.2 Normal, this is equal to 1 ml/kg/hr (i.e. ~75 ml/hr).
• In practice, the average infusion rate is ~10 mEq/hour. (29359573)
  • For 0.1 Normal, this is equal to 100 ml/hour.
  • For 0.2 Normal, this is equal to 50 ml/hour.
• Monitor electrolytes (including Ca/Mg/Phos) and ABG/VBG (e.g., after every ~75 mEq administered).

risks

• If central line is displaced, it may necrose tissue.
• Electrolyte abnormalities.

continue conventional therapy for metabolic alkalosis!

• In addition to hydrochloric acid, also simultaneously pursue additional treatments to decrease the patient's bicarbonate level (see #1-#9 above).
• The goal of hydrochloric acid is to accelerate treatment, to more rapidly move the patient out of danger from severe alkalemia. However, this isn't really intended as the definitive (or sole) treatment.

protocol

• The approach below isn't necessarily optimal for every patient (it might be too conservative in some situations, or a bit aggressive for very small patients). However, it's simple and represents a good place to start in most cases.

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podcast

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Metabolic alkalosis commonly occurs during diuresis. This isn't a contraindication to further diuresis. Ongoing diuresis may be performed if needed, but this must be done with simultaneous treatment of the metabolic alkalosis (e.g., using acetazolamide, spironolactone, and potassium chloride supplementation).
• For severe metabolic alkalosis, don't rely on a single treatment (e.g., normal saline). Rather, a multimodal strategy may be most effective, with attention to all factors which may be perpetuating the metabolic alkalosis.

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