Acid/Base Disorders: Metabolic Alkalosis

Does this patient have metabolic alkalosis?

How does one make the diagnosis of metabolic alkalosis and differentiate simple from mixed disturbances?

Metabolic alkalosis is due either to a gain in bicarbonate or a bicarbonate precursor (HCO₃^–), loss of hydrogen ion (H⁺) or the loss of fluid that contains Cl^– in higher concentration and bicarbonate in lower concentration than serum. The brainstem is sensitive to interstitial and cellular H⁺changes and the decline in H⁺with metabolic alkalosis inhibits ventilation (respiratory compensation). In simple metabolic alkalosis the resultant compensatory alveolar hypoventilation leads to an increase in arterial carbon dioxide content (PaCO₂). For each 1 mEq/L rise in HCO₃^–, PaCO₂ rises about 0.7 mmHg (range 0.6-1.0 mmHg).

Based on the history, one can assess whether an increase in HCO₃^–is due to oral or intravenous alkali administration vs. H⁺ loss that results in addition of HCO₃^– to the body. The kidney plays a crucial role in maintaining HCO₃^–. Most often, the kidneys can excrete excess HCO₃^– and bicarbonaturia occurs. Factors that facilitate bicarbonaturia are adequate extracellular fluid (ECF) volume, dietary salt intake, potassium balance and appropriate mineralocorticoid activity.

In order for metabolic alkalosis to be maintained the kidneys ability to excrete excess bicarbonate must be impaired, most commonly as a result of ECF volume contraction. Patients can present with either simple or mixed acid-base disturbances. The evaluation of a patient with suspected metabolic alkalosis on a set of arterial blood gases involves four simple steps:

Step 1: Assess the arterial pH and identify the primary disturbance. An elevated serum HCO₃^–could be the result of metabolic alkalosis or may represent compensation for respiratory acidosis. The arterial pH will be elevated in the former and low in the latter. Compensation attempts to return arterial pH to normal but does not quite get there. A normal arterial pH with an abnormal PaCO₂ and HCO₃^–is a priori evidence of a mixed disturbance.

Step 2: Assess whether compensation is appropriate. Remember that for each 1 mEq/L rise in HCO₃^–, PaCO₂ rises about 0.7 mmHg (range 0.6-1.0 mmHg). If compensation is not appropriate (the change in PaCO₂ is either higher or lower than expected) then a superimposed respiratory acidosis (PaCO₂ higher than expected) or alkalosis (PaCO₂ lower than expected) is present.

Step 3: Assess the anion gap. This will help identify whether an elevated anion gap acidosis is also present. One needs to keep in mind, however, that a slight increase in the anion gap is often seen in the patient with severe metabolic alkalosis due to changes in the net anion charge and increased production of organic acids.

Step 4: If the anion gap is elevated, compare the increase in the anion gap to the decline in HCO₃^–. The increase in anion gap should roughly match the decline in HCO₃^–. If the decrease in HCO₃^–is much larger than the increase in the anion gap this suggests that both an anion gap and non-anion gap metabolic acidosis are present. This is where ΔAG/Δ HCO₃^–ratio becomes useful in the review of your patient’s laboratory data. Some clinical scenarios where mixed disturbances can occur are in the patient with renal failure and vomiting or the patient with diabetic ketoacidosis and vomiting.

Step 5: Remember a caveat to laboratory data interpretation. With severe metabolic alkalosis, one should rely on measurements of arterial pH and PaCO₂ to calculate serum bicarbonate concentration.

What is the cause of acid loss or alkali gain?

Extrinsic and intrinsic alkali gain

If your patient receives exogenous NaHCO₃orally for indigestion or intravenously during cardiopulmonary arrest, it adds HCO₃^– to the ECF, and can result in metabolic alkalosis. Similarly, large amounts of HCO₃^– precursors might be administered during massive blood transfusion or plasmapheresis. A lesser degree of alkalosis is observed when blood anticoagulated with citrate dextrose A formula (ACD-A) is used.

If you treat organic acidoses such as lactic acidosis or ketoacidosis, ketones and lactate are metabolized to HCO₃^– and add to ECF HCO₃^–. Following treatment of lactic acidosis or ketoacidosis, bicarbonaturia occurs and resolves metabolic alkalosis, unless the kidney’s ability to excrete HCO₃^– is impaired.

There is a rising incidence of milk-alkali syndrome especially in women taking calcium supplements for osteoporosis. It presents with nephrocalcinosis, declining renal function and metabolic alkalosis. In some Asian countries, betel nut chewing can cause this problem due to excessive calcium ingestion. Hypercalcemia and vitamin D excess increases proximal renal HCO₃^– reabsorption.

H⁺ loss

Patients may present with acid loss due to extra-renal or renal H⁺wasting. Redistribution of H⁺ from ECF to the ICF may also result in metabolic alkalosis. Vomiting and some forms of chloride-containing diarrhea cause proton loss and subsequent HCO₃^– generation. ECF volume contraction and hypokalemia maintain metabolic alkalosis once it has been initiated. Patients with nasogastric suctioning lose H⁺ produced by gastric parietal cells. In the process a gain in HCO₃^– with each proton secreted occurs, causing metabolic alkalosis.

Patients might lose H⁺ substantially from the kidneys. Remember, each milliequivalent of net acid excretion represents an equivalent gain in ECF HCO₃^–. When renal bicarbonate generation exceeds consumption, ECF HCO₃^– concentration rises. The process is maintained in the presence of activation of the renin-angiotensin-aldosterone system which increases both proximal and distal nephron bicarbonate reabsorption. Hence, this condition is different from alkalosis induced by diuretics, which is sensitive to effects of dietary NaCl intake.

Diuretics lead to NaCl loss and contraction of ECF volume. ECF HCO₃^– amount remains constant, which raises the HCO₃^–concentration, resulting in contraction alkalosis. Chronic diuretic use would lead to metabolic alkalosis, particularly on a low NaCl diet. Enhanced distal Na⁺ delivery results in increased K⁺ loss and increased net acid excretion, which sustains the metabolic alkalosis. Hypokalemia adds to net acid excretion and increases ammoniagenesis perpetuating the severity of metabolic alkalosis.

Intrinsic H⁺loss

Severe potassium depletion leads to redistribution of H⁺ from the ECF to ICF. In the process, ECF HCO₃^– is gained. There is partial correction with repletion of potassium in these patients, exchanging K⁺ with exiting H⁺ and titration of ECF HCO₃^–.

What is maintaining HCO3- accumulation in the ECF?

To illustrate the importance of the kidney in HCO₃^– excretion, take as an example a patient with a glomerular filtration rate (GFR) of 100 ml/min and HCO₃^–10 mEq/L above the plasma threshold. This patient would excrete 1 mEq/min of HCO₃^– in urine. In patients with metabolic alkalosis, either renal HCO₃^– excretion capacity is less than ECF HCO₃^– accumulation (urine pH would be alkaline), or renal HCO₃^– excretion capacity is compromised (urine pH is not alkaline). Factors that act to maintain a sustained metabolic alkalosis are further discussed below.

K⁺ depletion

Hypokalemia causes a decline in intracellular pH in renal tubular epithelial cells resulting in increased proximal tubular HCO₃^– reabsorption. Renal ammoniagenesis is increased and net acid excretion by the kidneys is increased. K⁺ depletion also leads to renal Cl^– wasting and ECF contraction/Cl^– depletion. These pathophysiologic processes perpetuate metabolic alkalosis. Severe K⁺ depletion can be found in patients with chronic diuretic use, laxative abuse and renal tubular disorders (Bartter and Liddle syndrome).

ECF volume depletion

This is the most common scenario seen in clinical practice. Loss of gastric HCl causes metabolic alkalosis (loss of H⁺ and volume resulting in increased mineralocorticoid activity and sustained metabolic alkalosis). Volume resuscitation with saline improves the kidney’s ability to excrete excess HCO₃^–. Volume depleted patients excrete less HCO₃^– than volume replete or volume expanded patients.

Volume depletion decreases GFR and results in stimulation of the renin-angiotensin-aldosterone axis. Increased catecholamines and angiotensin II levels increase HCO₃^– absorption in proximal and distal nephron. One may also encounter patients with hypertension, heart failure or cirrhosis on a low salt diet that have increased Na⁺/H⁺exchanger (NHE-3) activity in proximal tubules (more HCO₃^– reabsorption) and low delivery of Cl^– to distal nephron (decreased HCO₃^– excretion).

Excess mineralocorticoid activity

Increased angiotensin II or aldosterone activity increases net acid excretion in the distal nephron. Increased Na⁺ absorption due to increased expression of Na⁺/K⁺-ATPase generates higher luminal electronegativity, which enhances H⁺ excretion by alpha intercalated cells. Hence, pure mineralocorticoid excess causes metabolic alkalosis that is different from gastric or diuretic induced alkalosis due to a volume expanded state. This limits renal capacity to excrete a bicarbonate load. Primary aldosteronism, Cushing syndrome or licorice ingestion present with this abnormality.

Cl^–depletion

Cl^– depletion independent of ECF volume enhances proximal and distal HCO₃^– reabsorption. This condition is not commonly encountered in clinical practice.

Decreased GFR

Decline in GFR decreases the filtered load of HCO₃^– (GFR X HCO₃^–) and decreases absolute renal HCO₃^– reabsorption. An increase in GFR with crystalloids or infusion of atrial natriuretic peptide increases excess ECF HCO₃^– loss. It does not play a major role in sustaining chronic metabolic alkalosis in common clinical practice. On urinalysis, urine pH should still be alkaline in response to excess ECF HCO₃^–.

What are the symptoms of metabolic alkalosis?

The majority of metabolic alkalosis episodes are mild and self-limiting. Critically ill patients may exhibit pH >7.48 and increased overall mortality. Systemic alkalosis lowers the threshold for arrhythmia especially by decreasing ionized calcium levels. It causes vasoconstriction in various systemic vascular beds and manifests with masquerading CNS and peripheral nervous system symptoms.

Patients have increased predisposition for seizures and metabolic encephalopathy due to hypocalcemia. Many patients have accompanying hypokalemia and present with muscular cramps. At pH >7.6, severe ventricular arrhythmias and seizures can be seen.

Decline in interstitial H⁺affects the brain stem respiratory center, resulting in hypoventilation. Hypoxemia is never clinically severe. Tissue delivery of oxygen is reduced due to the greater oxygen affinity of hemoglobin. As a result, it facilitates anaerobic respiration with a slight increase in lactate production and high anion gap commonly seen in severe metabolic alkalosis. Albumin has higher electronegativity with increased arterial pH adding to the elevated anion gap. Digitalis toxicity is increased in alkalemic patients due to concomitant hypocalcemia and hypokalemia.

What other diseases and mixed disorders should I be cognizant of?

Metabolic alkalosis is first noticed by the clinician when HCO₃^– is elevated on serum chemistries. Elevated HCO₃^–is also found in chronic respiratory acidosis as compensation to the elevated PaCO₂. Note that patients on dialysis without renal function develop metabolic alkalosis only from alkali load and do not demonstrate elevated HCO₃^–with elevations in PaCO₂. Arterial blood gas (ABG) analysis can differentiate between these two conditions. In general, serum HCO₃^–does not increase above 38 mEq/L.

You should obtain an ABG and serum chemistries simultaneously, compare HCO₃^–on blood gas and chemistry for accuracy, calculate the anion gap and estimate compensations, compare Δ AG/Δ HCO₃^–and finally compare Δ Na and Δ Cl^–. Sometimes, chronic obstructive pulmonary disease (COPD) patients on diuretics can have mixed acid-base disturbances. Some examples are as follows:

• COPD can cause an elevation of bicarbonate due to CO₂retention and diuretics can cause contraction alkalosis: pH – 7.42, PaCO₂ – 67 mmHg, Na⁺ – 140 mEq/L, K⁺ – 3.5 mEq/L, Cl^– – 88 mEq/L, HCO₃^– – 42 mEq/L. Typically, bicarbonate rises 0.4 mEq/L for every mmHg rise in PaCO₂.

• Cirrhotics on diuretics can have respiratory alkalosis and metabolic alkalosis: pH – 7.55, PaCO₂ – 38 mmHg, Na⁺ – 140 mEq/L, K⁺ – 4.0 mEq/L, Cl^–– 91 mEq/L, HCO₃^–– 33 mEq/L. Typically, pure respiratory alkalosis would cause a decline in HCO₃^–0.4 mEq/L per mmHg decline in PaCO₂.

• Uremic patients with vomiting can have combined metabolic acidosis and metabolic alkalosis: pH – 7.42, PaCO₂ – 40 mmHg, Na⁺ – 140 mEq/L, K⁺ – 3.0 mEq/L, Cl^– – 95 mEq/L, HCO₃^– – 25 mEq/L.

• A patient with chronic alcohol abuse that has been vomiting may have: pH – 7.55, PaCO₂ – 48 mmHg, HCO₃^– – 40 mEq/L, Na⁺ – 135 mEq/L, Cl^– – 80 mEq/L, K⁺ – 2.8 mEq/L. If this patient develops ketoacidosis, pH may drop to 7.40, HCO₃^–becomes 25 mEq/L, and PaCO₂40 mmHg.

What should you expect to find on history and physical examination of patients with metabolic alkalosis?

You should take a careful history and physical exam in order to provide clues into initiating and maintenance factors for metabolic alkalosis. (Table I).

Table I.n

History should include:

• Medication use especially diuretics, laxative use and alkali intake, as well as ingestion of licorice.

• Family history should be sought regarding hypertension and electrolyte abnormalities to suggest inherited disorders such as Bartter and Liddle syndromes.

• GI symptoms of vomiting or diarrhea can explain metabolic alkalosis. Certain villous adenomas may be chloride secreting.

• Other diseases: obstructive sleep apnea, cirrhosis, COPD, cystic fibrosis also can be associated with mixed acid-base disturbances. One must also be cognizant of blood transfusions.

On physical examination it is very important to assess hypertension, signs of Cushing syndrome, volume status and other co-morbid conditions as mentioned in Table I. An orthostatic decrease in blood pressure and increase in heart rate, sunken eye balls, decreased skin turgor and thirst are signs of ECF volume depletion. Cushing syndrome would be suggested by signs of hypercortisolism such as moon facies, buffalo hump, striae and hypertension. After taking a detailed history and performing a physical examination, one should next order laboratory studies.

What tests to perform?

What laboratory studies should be ordered? What should one look for?

One should start with serum chemistries including calcium, magnesium and phosphorus levels. Low chloride and low potassium levels are common occurrences in patients with metabolic alkalosis. One should look for an anion gap as a small anion gap can be seen in severe metabolic alkalosis for reasons discussed earlier. High calcium levels should point towards milk alkali syndrome or hypercalcemia from other causes.

Magnesium depletion may be seen with diuretic use or renal tubular magnesium wasting. Low phosphorus concentration could be present in patients recovering from diabetic ketoacidosis or starvation ketoacidosis. Arterial blood gases may be obtained to rule out mixed disorders and chronic respiratory acidosis.

You should look at the urinalysis to assess urinary pH. Alkaline urine would be an appropriate response from the kidneys trying to excrete excess HCO₃^–. Volume depleted patients would have urine with high specific gravity. Finally, urine electrolytes are extremely helpful in differentiating a wide range of disorders. One would order urine chloride and urine K⁺ for developing a working algorithm to help sort out different disease entities. Some examples are as follows:

• Hypertension with hypokalemia can be seen in the hypertensive patient on diuretics or patients with primary aldosteronism state.

• High urinary pH with high urinary Na⁺ and K⁺ is seen in patients with diuretic abuse or active vomiting

• Low urinary pH with low urinary Na⁺ and Cl^– is seen in patients that used diuretics or vomited recently.

To aid in the differential diagnosis, metabolic alkalosis can be divided into chloride sensitive (urinary Cl^– <20 mEq/L) or chloride resistant (urinary Cl^– >20 mEq/L). Table II depicts some common causes of metabolic alkalosis.

Table II.n

If one is dealing with chloride-resistant metabolic alkalosis in a patient with hypertension, plasma hormone levels can aid in establishing a diagnosis. This will be discussed in detail in another section.

Some hypothetical examples of serum and urine electrolytes in different conditions are as follows:

• Patients treated with non-reabsorbable anions (Ticarcillin) may have metabolic alkalosis: serum Na⁺ – 138 mEq/L, K⁺ – 2.6 mEq/L, Cl^– – 90 mEq/L, HCO₃^– – 34; urinary Na⁺ – 35 mEq/L, K⁺ – 40 mEq/L, chloride – <10 mEq/L.

• Patients on diuretics may present with electrolytes as follows: serum Na⁺ – 138 mEq/L, K⁺ – 2.7 mEq/L, Cl^– – 95 mEq/L, HCO₃^– – 32, Mg²⁺ – 1.0; urinary Na⁺ – 56 mEq/L, K⁺ – 61 mEq/L, chloride – 67 mEq/L; urinary pH – 6.5, Mg²⁺ – 100 mg/dL, Ca²⁺ – 300 mg/dL.

• Thiazide diuretic use or Gitelman syndrome can present with similar labs: serum Na⁺ – 138 mEq/L, K⁺ – 2.8 mEq/L, Cl^– -95 mEq/L, HCO₃^– – 32, Mg²⁺ -1.0, osmolality – 287; urinary Na⁺ – 10 mEq/L, K⁺ – 10 mEq/L, chloride – <10 mEq/L, Mg²⁺ – 25 mg/dL, Ca²⁺ – 100 mg/dL, osmolality – 580.

• Liddle syndrome would present with young hypertensive patient with following labs: serum Na⁺ – 140 mEq/L, K⁺ – 2.8 mEq/L, Cl^– – 90 mEq/L, HCO₃^– -32, ABG pH – 7.48; urinary Na⁺ – 50 mEq/L, K⁺ – 80 mEq/L, chloride – 140 mEq/L, plasma aldosterone concentration – 4 ng/dL, plasma rennin activity – 0.5 pmol/L, and cortisol normal.

• Gentamicin use can present with acute rise in serum creatinine and/or the following labs: serum Na⁺ – 131 mEq/L, K⁺ – 1.9 mEq/L, Cl^– – 85 mEq/L, HCO₃^– – 34, Mg²⁺0.9, ionized Ca²⁺ – 2.5 mg/dl, and arterial pH – 7.49; urinary Na⁺ – 30 mEq/L, K⁺ – 25 mEq/L, chloride – >20 mEq/L, Mg²⁺ – 25 mg/dL, Ca²⁺ -200 mg/dL.

How does one make the diagnosis of primary aldosteronism?

An adrenal adenoma or bilateral adrenal hyperplasia cause increased production of aldosterone. Increased mineralocorticoid activity is a main mechanism for initiating and maintaining metabolic alkalosis. Increased Na reabsorption and H⁺/K⁺-ATPase activity with resultant increased reclamation of HCO₃^– and volume expansion cause hypertension, hypokalemia and metabolic alkalosis found in primary aldosteronism.

In some families, glucocorticoid remediable aldosteronism occurs due to a genetic defect in the aldosterone synthase gene. There is a family history of difficult to control hypertension that is amenable to steroid therapy. It can be diagnosed by the presence of elevated 18-OH-cortisol and 18-oxocortisol in urine. One can differentiate primary aldosteronism from other chloride-resistant metabolic alkaloses based on renin and aldosterone levels (Table III).

Table III.n

What are the genetic causes of metabolic alkalosis?

You should be aware of five inherited diseases that can cause metabolic alkalosis.

Bartter syndrome

Bartter syndrome presents in childhood without hypertension. It results from various abnormalities that impair NaCl reabsorption in the thick ascending limb. NaCl delivery to the distal nephron is increased, the renin-angiotensin-aldosterone system is activated and hypokalemic metabolic alkalosis that is chloride resistant occurs. Urine electrolytes reveal high urine Na⁺, K⁺, Cl^–, Mg²⁺, Ca²⁺ and high urinary osmolality.

Gitelman syndrome

Gitelman syndrome presents in adults and is more common than Bartter syndrome. It is caused by mutations in the thiazide-sensitive NaCl cotransporter in the distal convoluted tubule. Surreptitious diuretic use should always be considered and screening for diuretics in urine should be part of the work up.

Liddle syndrome

Liddle syndrome is a rare autosomal dominant disease resulting from mutations in the epithelial sodium channel in collecting duct. Severe hypertension is often present.

Glucocorticoid remediable aldosteronism

Glucocorticoid remediable aldosteronism (GRA) is an autosomal dominant disorder presenting similarly to primary aldosteronism with volume dependent hypertension and hypokalemic metabolic alkalosis. It occurs due to chimerism between the glucocorticoid responsive promoter regions of 11-β-hydroxylase and aldosterone synthase genes. Excess aldosterone is produced that is not responsive to K⁺or renin, but responsive to glucocorticoids.

Apparent mineralocorticoid excess

Apparent mineralocorticoid excess (AME) mimics licorice ingestion. The 11-β-hydroxysteroid dehydrogenase enzyme is inhibited allowing glucocorticoids to occupy type 1 renal mineralocorticoid receptors, mimicking aldosterone. It is characterized by low renin and aldosterone levels with salt-sensitive hypertension accompanied by metabolic alkalosis/hypokalemia. Hypertension responds to thiazides and spironolactone.

How should patients with metabolic alkalosis be managed?

If you decide your patient has primary metabolic alkalosis, what therapy should you administer immediately?

One should treat the underlying mechanism that initiates and maintains metabolic alkalosis. Chloride-sensitive metabolic alkalosis responds to volume resuscitation and restoration of ECF potassium. Specific treatments are required for chloride-resistant metabolic alkalosis.

Patients with cirrhosis and congestive heart failure pose challenges in management as a low urinary Cl^– would usually imply saline infusion for the correction of metabolic alkalosis. This is not well tolerated in these patients since they have an excess of total body salt and water. Acetazolamide (carbonic anhydrase inhibitor) causes bicarbonaturia in patients with adequate renal function. Hypokalemia may worsen, however, with its use.

In life threatening conditions with metabolic alkalosis (pH ≥7.6), dilute hydrochloric acid (0.1 N HCl) can be infused centrally to buffer excess ECF HCO₃^–. Caution is warranted as it may cause hemolysis. Titration should be done to bring arterial pH to approximately 7.5. Hemodialysis using low HCO₃^– bath and high Cl^– bath can be performed.

In general, some treatment options are summarized in Table IV.

Table IV.n

What happens to patients with metabolic alkalosis?

How does H+ loss lead to addition of HCO3- to the ECF? How does chloride depletion have an added effect?

Gastrointestinal losses from vomiting and nasogastric suction lead to proton loss that triggers metabolic alkalosis. Secretion of a proton into the lumen of the stomach results in addition of HCO₃^– to the ECF. Chloride is actively transported from the parietal cell into the lumen and sodium ions are absorbed. This generates a negative potential of -40 to -70 millivolts in the canaliculus.

The diffusion potential causes potassium to move into the canalicular lumen. The canalicular membrane exchanges potassium with protons mediated by an H⁺/K⁺ exchanger. Protons required for this reaction are generated from water breakdown. The hydroxyl group generated combines with CO₂ and forms HCO₃^– which exits the parietal cell across the basolateral membrane. This mechanism is illustrated in Figure 1.

GI losses increase gastric pH which triggers more proton secretion by gastric parietal cells resulting in further proton loss and ECF HCO₃^– addition. Induction of Cl^– depletion contributes to chloride depletion metabolic alkalosis (CDMA). This may be the reason why certain lower GI losses present with metabolic alkalosis (villous adenomas or congenital chloridorrhea).

To prove the CDMA concept, Schwartz et al. conducted balance studies in humans and dogs. They induced CDMA by gastric aspiration or diuretics. They showed Cl^– repletion by NaCl or KCl (but not Na⁺/K⁺ repletion) fully corrected CDMA in the maintenance phase. During correction, net acid excretion (NH₄⁺ excretion + urinary titratable acid – bicarbonaturia) is decreased by bicarbonaturia. Sodium phosphate replacement worsened metabolic alkalosis when compared to KCl replacement in such patients.

Intercalated cells in cortical collecting duct (CCD) secrete HCO₃^– as soon as Cl^– is repleted. This is mediated by a Cl^–/HCO₃^– exchanger. In CDMA, this transporter is activated aiding in bicarbonaturia. CDMA is not always accompanied by volume contraction as in the case in heart failure or cirrhotics with mixed acid-base disorders. In such clinical scenarios, Cl^– repletion is not possible. Acetazolamide can be used to increase renal HCO₃^– excretion if metabolic alkalosis is severe.

What are the actions of the renin-angiotensin-aldosterone system in maintaining metabolic alkalosis?

To understand the physiology of renin and aldosterone in maintaining metabolic alkalosis, one first needs to review renal HCO₃^– excretion. Assuming ECF HCO₃^– = 24 mEq/L and GFR = 180 L/day, 4320 mEq of HCO₃^– is filtered by the kidneys. Eighty-five percent is absorbed in the proximal tubules, 10% in thick ascending loop of Henle, and >5% in the distal nephron resulting in 1 mEq/day of bicarbonate excretion under normal conditions. Carbonic anhydrase (CA) is an important zinc metalloenzyme involved in the reabsorption of HCO₃^– in kidney. It catalyzes the following reaction:

CO₂ + OH^–⇔ HCO₃^–

In the proximal tubule, cytosolic CA Type II catalyzes the reaction to extrude H⁺from apical membrane (H⁺ extrusion coupled by Na⁺/H⁺ exchanger [NHE-3] or H⁺-ATPase) and HCO₃^– leaves the cell across the basolateral membrane (HCO₃^– exit is coupled with Na+ by NBC transporter). The extruded proton combines with luminal HCO₃^– to form H₂O + CO₂(Figure 2).

Figure 2.

Proton and HCO₃^– formation in the cell is catalyzed by cytosolic CA. CA inhibition markedly reduces trans-epithelial HCO₃^–reabsorption. HCO₃^–is reabsorbed with secretion of H⁺ into the lumen. Na⁺/H⁺ exchanger (NHE-3) is the major mode of proximal HCO₃^–and Na⁺absorption (~2/3). The remaining 1/3 of HCO₃^–reabsorption is carried out by H^₊-ATPase.

Potassium depletion increases expression of NHE-3 and NBC transporters resulting in increased proximal HCO₃^–reabsorption. Similarly, angiotensin II increases NHE-3 and NBC transporters via cAMP/protein kinase C-tyrosine kinase pathways.

In the thick ascending loop of Henle (TAL), 10-20% of the filtered HCO3- load is reabsorbed. Regulation of HCO₃^–absorption in TAL is more sensitive to metabolic acidosis as compared to alkalosis. NH4+ is absorbed in TAL and helps maintain high medullary NH4⁺ which is important for regulating acid secretion in the collecting duct. The physiological role of angiotensin II on HCO₃^–absorption in TAL is unclear.

In the distal nephron, final regulation of acid excretion occurs. Five to ten percent of remaining HCO₃^–is absorbed in this segment. Cortical collecting duct (CCD) and outer medullary collecting duct (OMCD) have intercalated cells that play a major role in acid excretion and are unique in secreting HCO₃^–. The major functions of different parts of the distal nephron are shown in Figure 3.

H⁺-ATPase and H⁺/K⁺-ATPase are present in the intercalated cells of CCD and OMCD shown in Figure 4. Increased activity of H⁺/K⁺-ATPase is the major mode of increased acid secretion (effective net HCO₃^–absorption). Mineralocorticoids are important determinants of net acid excretion. They directly stimulate H⁺-ATPase and increase H⁺ secretion. Hypokalemia increases H⁺ secretion in the distal nephron. Both result in increased HCO₃^–resorption and maintain metabolic alkalosis.

Figure 4.

CCD and OMCD are unique in secreting HCO₃^–directly via Cl^–/ HCO₃^–exchange. Luminal flow rate and NaCl delivery also affect HCO₃^–absorption. Volume depletion can maintain metabolic alkalosis as high angiotensin II levels increases HCO₃^–reclamation.

How does one diagnose primary aldosteronism?

Patients with hypertension and easily provoked hypokalemia with urine electrolytes consistent with kaliuresis raises a suspicion of primary aldosteronism. There is accompanied metabolic alkalosis and hypomagnesemia on laboratory examination, with the absence of peripheral edema on physical exam. Many patients have resistant hypertension that is difficult to control. One can develop a stepwise approach to diagnose primary hyperaldosteronism.

Step 1: Screen individuals who meet any one of the following clinical scenarios:

• Hypertension with spontaneous or low-dose diuretic induced hypokalemia

• Patients with resistant hypertension (three antihypertensive agents of different classes)

• Hypertension with known adrenal mass

• All hypertensive patients with first degree relative diagnosed with primary aldosteronism

Step 2: To screen for primary aldosteronism, spironolactone and eplerenone must be stopped for 6 weeks prior to checking plasma aldosterone concentration (PAC) and plasma renin activity (PRA).

Ideally, angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), diuretics, and non-steroidal anti-inflammatory drugs (NSAIDS) should be stopped 2 weeks prior to the test. However, most of these drugs are reasonable to continue for the first screen.

Random PAC/PRA or ARR (aldosterone-to-renin activity ratio) is used as the screening test (Table V). It is drawn in the early morning to stimulate renin production (diurnal pattern). ARR cutoff is arbitrary ranging from 20 to 100 ([ng/dL]/[ng/mL/hr]). Primary aldosteronism is suggested by a high ARR. Requiring higher cutoff for ARR or PAC increases specificity but decreases sensitivity of the test.

Table V.n

Step 3: Other disorders that present with hypertension, metabolic alkalosis and hypokalemia include:

• Deoxy-cortisone excess: Tumor or 17-OH deficiency or 11-OH deficiency

• Glucocorticoid remediable aldosteronism (GRA)

• Apparent mineralocorticoid excess (AME)

• Cushing syndrome

• Liddle syndrome

Step 4: Confirmatory tests can be done in several ways:

• 24 hr urine collection for urinary sodium, potassium and aldosterone is performed after 3 days of dietary salt supplementation (3 salt tablets = 24 mEq Na per day + 10 mEq KCl TID-QID). PAC level >14 ng/dL + urinary Na >200 mEq/day + normal serum potassium levels confirms primary aldosteronism. Higher PAC level suggests an adenoma.

• Saline suppression test is performed by administering 2000 ml of 0.9% normal saline over 4 hrs in the morning (0800-1200) and bringing serum potassium to normal range. If PAC >10 ng/dL, primary aldosteronism is confirmed.

• Fludrocortisone suppression test is performed by administering 0.1 mg fludrocortisone every 6 hours with salt supplements. PAC >8 ng/dL confirms primary aldosteronism.

Step 5: What is the etiology of the primary aldosteronism?

• Computed tomography (CT) with fine cuts of the adrenal glands is a very sensitive diagnostic tool. CT scan finds 5% incidental nodules and has 53% accuracy. If the glands are lumpy, it is hard to rule out an adenoma. Usually, young patients with age <40 years and >1 cm nodule and a normal contralateral adrenal gland is an adenoma.

• Adrenal vein sampling: Administer 250 mcg ACTH in 500 ml D5W at 100 ml/hr. Right and left adrenal vein, inferior vena cava and portal vein are sampled to measure aldosterone and cortisol levels. A/C ratio >4 lateralizes an adenoma. This test is considered valid if adrenal vein to inferior vena cava cortisol level >3:1 (often >10:1). It is an invasive method and has 25% failure rate to cannulate the right adrenal vein.

Step 6: Refer to surgery as it is the best management option available for an aldosterone-producing adenoma. Medical management with spironolactone 100-200 mg/day or eplerenone 50 mg daily or twice daily can be done. Medical management is limited by compliance. PAC levels typically rise with medical management.

What does one need to know about genetic causes of metabolic alkalosis?

There are six genetic diseases that cause metabolic alkalosis. The pathophysiology behind each disease gives a detailed understanding of HCO₃^– balance in the body.

Bartter syndrome

Bartter syndrome presents with normotensive chloride-resistant metabolic alkalosis. It closely mimics loop diuretic abuse. This is a rare disorder due to a defect in chloride absorption in TAL as shown in Figure 5. It results in high NaCl delivery to the distal nephron, renin-angiotensin-aldosterone activation and development of hypokalemic metabolic alkalosis.

Figure 5.

Bartter’s syndrome occurs due to one of six genetic defects: loss of function mutation in NKCC2 (type 1), ROMK (type 2), CLC-Kb (type 3), bartin (a protein necessary for Cl^– channel trafficking to the basolateral membrane: defective in type 4), and simultaneous mutations in both CLC-Ka and CLC-Kb (type 6). A gain-of-function mutation in the basolateral membrane Ca²⁺-sensing receptor can result in the same phenotype secondary to inhibition of apical membrane K⁺ channels (type 5).

Gitelman syndrome

As discussed earlier, Gitelman syndrome presents in adults and is more common than Bartter syndrome. It is caused by mutations in the thiazide-sensitive NaCl cotransporter in the distal convoluted tubule. Most mutations result in reduced trafficking of the transporter to the luminal membrane.

Urinary calcium excretion is low in patients with Gitelman syndrome. This may be the result of increased calcium reabsorption in the proximal or distal nephron (Figure 6). Thiazide diuretics can be used to attempt to clinically differentiate Bartter from Gitelman syndrome.

There is no change expected in urinary chloride excretion with the administration of thiazide diuretics in patients with Gitelman syndrome (defective thiazide-sensitive NaCl cotransporter). This is in contrast to patients with Bartter syndrome where there is an exaggerated response (increase in urinary chloride excretion) to the administration of thiazide diuretics (distal nephron hypertrophy with high NaCl delivery).

This test has been used in a cohort of patients where the investigators demonstrated higher fractional excretion of chloride with the use of 50 mg of hydrochlorothiazide in patients with Bartter syndrome. It should be noted, however, that very few of these patients had mutations in CLC-Kb and that this subtype of Bartter syndrome often has a clinical presentation similar to that of Gitelman syndrome

Liddle syndrome

As discussed earlier, Liddle syndrome is a rare autosomal dominant disease resulting in mutation of epithelial sodium channels in the collecting duct. Na⁺ reabsorption in the collecting duct occurs in the principle cell. This process is mediated by ENaC (epithelial Nachannel) present on the apical membrane of principal and inner medullary collecting duct (IMCD) cells. It is different from Na⁺channels present on nerves and muscles. It is comprised of 3 sub-units: a (required for channel function), b and g (increase magnitude of ion movement).

In Liddle syndrome, the carboxy-terminus of either b or g subunits (area known as a PY motif) is mutated or deleted preventing its binding to a protein that normally inhibits channel activity (the ubiquitin ligase Nedd4-2). The PY motif in the b and g subunits is involved in protein-protein interaction with Nedd4-2 (protein that ubiquitinates ENaC resulting in internalization of the transporter). Thus, mutated channels do not interact with Nedd4-2 and are not internalized (Figure 7). Sodium reabsorption is increased as are potassium and proton secretion, leading to the phenotype (hypertension with hypokalemia and metabolic alkalosis).

Apparent mineralocorticoid excess

As discussed earlier, Apparent mineralocorticoid excess (AME) is an autosomal dominant disorder presenting with volume dependent hypertension and hypokalemic metabolic alkalosis. To understand the pathophysiology behind this phenotype, one needs to understand the mechanism of aldosterone action.

Aldosterone is a key hormone in controlling Na⁺ and K⁺ transport in CCD. It is produced in the adrenal gland (zona glomerulosa of the adrenal cortex), and regulated by ECF volume and plasma potassium levels (hyperkalemia and volume contraction increase aldosterone secretion). It activates apical ENaC and the basolateral membrane Na⁺/K⁺-ATPase in CCD/OMCD, which results in Na⁺ retention and kaliuresis.

One surprising finding that resulted from the cloning and expression of the mineralocorticoid receptor was that it had equal affinity for glucocorticoids and mineralocorticoids. Since glucocorticoids circulate at 100-1000 times the concentration of mineralocorticoids, end organs that are sensitive to aldosterone need an enzyme to inactivate intracellular glucocorticoids or the receptor will always be occupied by glucocorticoids. This role is served by the enzyme type II 11-b-hydroxysteroid dehydrogenase (HSD). It degrades cortisol to the cortisone, which has much lower affinity for the receptor, allowing aldosterone to bind to the mineralocorticoid receptor (Figure 8). This enzyme is absent in AME, can be inhibited by licorice ingestion or can be overwhelmed in Cushing syndrome.

AME presents with low renin and aldosterone levels with salt-sensitive hypertension accompanied by metabolic alkalosis/hypokalemia. Hypertension responds to thiazides and spironolactone. The urinary free cortisol to cortisone ratio measured in 24-hour urine is a standard diagnostic test. A normal ratio is 0.3-0.5, where as in AME the ratio is elevated, commonly to levels as high as 18 in adults. The diagnosis is confirmed by genetic testing, which is commercially available.

Figure 8.

Figure 9.

Glucocorticoid remediable aldosteronism

Glucocorticoid remediable aldosteronism (GRA) is an autosomal dominant disorder with a phenotype of aldosteronism (volume dependent hypertension and hypokalemic metabolic alkalosis). On chromosome 8, the genes encoding aldosterone synthase and 11-hydroxylase are close together. The chimerism results in a hybrid aldosterone synthase gene that is now regulated by ACTH. This results in increased production of aldosterone (in normal subjects, ACTH has no role in aldosterone synthase activity). Treatment of such subjects is accomplished by suppressing ACTH by administering corticosteroids.

KCNJ5 mutation

Recently, mutations in the KCNJ5 gene were reported in patients with primary aldosteronism presenting as massive adrenal hyperplasia. KCNJ5 is an inwardly rectifying K⁺ channel that sets the resting membrane potential of glomerulosa cells in the adrenal cortex. Mutations in the channel result in increased sodium conductance. Sodium entry depolarizes the cell and increases Ca²⁺ entry, which subsequently signals aldosterone production and cellular proliferation. Mutations in KCNJ5 genes were also noted in adrenal adenoma specimens of 22 patients with primary aldosteronism.

Pseudo-Bartter syndrome has been reported in patients with cystic fibrosis. Cystic fibrosis is an autosomal recessive disease that occurs due to either the abnormal synthesis, transport or function of the cystic fibrosis transmembrane regulator (CFTR) which is a chloride channel. Patients lose large amounts of NaCl in their sweat during hot weather resulting in hypovolemia, ADH release and secondary aldosteronism. Patients can present with hyponatremia and metabolic alkalosis.

It is hypothesized that the CFTR mutation may impair proximal and distal NaCl reabsorption in some patients generating metabolic alkalosis of renal origin. However, many of these patients present with concomitant vomiting that generates alkalosis of gastric origin. Clinicians can distinguish this from true Bartter syndrome by checking urinary chloride.

Aminoglycosides can also mimic Bartter syndrome. Stimulation of the calcium-sensing receptor on the basolateral membrane of TAL inhibits apical ROMK channel activity and possibly NKCC2 as well. This results in NaCl wasting and decreased Ca²⁺ and Mg²⁺ reabsorption across the paracellular pathway.

What are controversies related to correction of metabolic alkalosis in critically ill patients?

Metabolic alkalosis is a common acid-base disturbance in hospitalized and critically ill patients. It is thought to increase morbidity and mortality in ICU patients, increase length of stay and prolong weaning in patients with chronic obstructive pulmonary disease (COPD) on mechanical ventilation.

High arterial pH decreases cardiac output and alters the oxyhemoglobin dissociation curve, delaying weaning in mechanically ventilated patients, especially in COPD patients. H⁺ in the ECF of the brain controls ventilator drive. Compensation for metabolic alkalosis is alveolar hypoventilation with a resultant rise in PaCO₂. It is believed that decreasing HCO₃^– levels may decrease PaCO₂and aid weaning.

Options for treatment aimed at correcting metabolic alkalosis are potassium replacement and administration of ammonium chloride, hydrochloric acid, or acetazolamide. These therapeutic interventions potentially increase minute ventilation, potentially allowing patients to be weaned more rapidly. Although there is controversy about the effectiveness of these interventions, multiple observational and a recent randomized controlled trial, report improvement in serum bicarbonate concentration with changes in PaCO₂with use of intravenous acetazolamide in critically ill intubated patients, without reduction in the duration of invasive ventilation or improvement in ventilator weaning.

In a case series of eight patients from Toronto General Hospital, acetazolamide (500 mg IV per day) or ammonium chloride (1-2 grams oral TID or QID) improved arterial pH and subsequent PaCO₂. No controls were employed and the effect on ventilation was unclear.

In a French case control study matched to historical controls (for serum HCO₃^–levels, arterial pH, age and severity of illness), 26 intubated patients with COPD and mixed metabolic alkalosis (HCO₃^– >26 mmol/L and arterial pH >7.38) were treated with acetazolamide 500 mg IV daily for 4 days during the initial 11 days of weaning. There was a statistically significant rise in PaO₂/FiO₂ ratio, decline in serum HCO₃^–and arterial pH. PaCO₂remained unchanged and there was no difference in ventilator weaning. A retrospective study in critically ill pediatric patients confirmed these findings (Bar et al. 2015). Finally, the best evidence comes from a randomized-controlled double-blind trial in 380 critically ill COPD patients that reported no difference in the duration of invasive mechanical ventilation with use of intravenous acetazolamide compared to placebo despite greater changes in the serum bicarbonate concentration and rapid correction of metabolic alkalosis in the acetazolamide group (Faisy et al. JAMA 2016).

Belgian investigators reviewed the role of hydrochloric acid in a case series of 15 critically ill patients admitted for mixed respiratory acidosis and metabolic alkalosis, and a pH of between 7.35 and 7.45. Hydrochloric acid infusion at 25 mmol/hr to a goal HCO₃^– <26 mmol/L or pH <7.35 led to a mean decline in arterial pH from 7.41 to 7.33 and PaCO₂from 54 to 48 mm Hg. The authors concluded that even in the absence of alkalemia, active correction of metabolic alkalosis by HCl infusion can improve PaCO₂and oxygen exchange in critically ill patients with mixed respiratory acidosis and metabolic alkalosis.

In summary, there is insufficient evidence to suggest that the use of acetazolamide facilitates weaning from the ventilator or decreases the morbidity/mortality in patients with metabolic alkalosis and respiratory acidosis. Ammonium chloride and hydrochloric acid infusions are reasonable options but their clinical utility still remains unclear.

When can we encounter metabolic alkalosis in hemodialysis patients?

Patients on dialysis experience metabolic alkalosis following events that increase serum bicarbonate concentration. These patients do not experience secondary increase in serum bicarbonate concentration due to respiratory acidosis. In addition, dialysis patients encounter sustained metabolic alkalosis independent of chloride stores due to lack of kidney function. A hemodialysis patient can experience severe metabolic alkalosis (arterial blood pH >7.6) with low serum chloride concentration (<80 mEq/L) and high calculated serum bicarbonate concentration (>50 mEq/L) from a few days of profuse vomiting and can clinically manifest as lethargy and confusion (Huber et al. 2011). Serum bicarbonate concentration can reach beyond the laboratory standard range that is seen in patients with intact kidney function. As a result, laboratory measurements may be difficult and direct electrode measurements of arterial pH and PaCO₂ should be performed. Subsequently, serum bicarbonate concentration can be calculated from the following equation: Change in PaCO₂ (mm Hg) = 0.7 times change in serum bicarbonate concentration (mEq/L).

The primary management of such a patient will be dialysis with low bicarbonate bath (30 mEq/L). Severe metabolic alkalosis in dialysis patients have been reported with crack cocaine use, therapeutic plasma exchange, massive blood transfusions that provide massive citrate load and pica ingestion.

What is the evidence?

Nishizaka, MK, Pratt-Ubunama, M, Zaman, MA, Cofield, S. “Validity of plasma aldosterone-to-renin activity ratio in African American and white subjects with resistant hypertension”. Am J Hypertens. vol. 18. 2005 Jun. pp. 805-812.

Wilson, RF, Gibson, D, Percinel, AK, Ali, MA. “Severe alkalosis in critically ill surgical patients”. Arch Surg. vol. 105. 1972 Aug. pp. 197-203.

Bear, R, Goldstein, M, Phillipson, E, Ho, M. “Effect of metabolic alkalosis on respiratory function in patients with chronic obstructive lung disease”. Can Med Assoc J. vol. 117. 1977 Oct. pp. 900-903.

Faisy, C, Mokline, A, Sanchez, O, Tadié, JM. “Effectiveness of acetazolamide for reversal of metabolic alkalosis in weaning COPD patients from mechanical ventilation”. Intensive Care Med. vol. 36. 2010 May. pp. 859-863.

Brimioulle, S, Berre, J, Dufaye, P, Vincent, JL. “Hydrochloric acid infusion for treatment of metabolic alkalosis associated with respiratory acidosis”. Crit Care Med. vol. 17. 1989 Mar. pp. 232-236.

Young, WF, Stanson, AW, Thompson, GB, Grant, CS. “Role for adrenal venous sampling in primary aldosteronism”. Surgery. vol. 36. 2004 Dec. pp. 1227-35.

Bar, A, Cies, J, Stapleton, K, Tauber, D. “Acetazolamide therapy for metabolic alkalosis in critically ill pediatric patients”. Pediatr Crit Care Med. vol. 16. 2015 Feb. pp. e34-40.

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