METABOLIC ALKALOSIS

Ricardo M Heguilén MD

Unidad de Nefrología. Hospital Juan A Fernández

Universidad de Buenos Aires. ARGENTINA

The problem in perspective

Metabolic alkalosis (MA) is one of the most common electrolyte disturbances observed in hospitalized patients, and accounts for nearly half of all acid-base disorders.

Metabolic alkalosis, when severe, represents a serious and life-threatening medical condition with mortality rates ranging from 50% for pHs higher than 7.55 to almost 80% at pHs in excess of 7.65

• Severe alkalosis predisposes to refractory arrhythmias by reducing coronary blood flow. • Tissue perfusion is severely compromised as a consequence of diffuse arteriolar constriction and by decreasing the cerebral blood flow MA may lead to altered consciousness and seizures. • In patients with poor respiratory status, the normal compensatory decrease in the ventilatory response to MA may cause severe hypoxemia. • Alkalosis leads to hypokalemia which can cause arrhythmias, neuromuscular dysfunction and by increasing the production of ammonia can precipitate hepatic encephalopathy in patients with preexistent chronic liver disease. • In MA hydrogen ions are released from the anionic binding sites of albumin, calcium is then taken up resulting in a dramatic reduction in the serum concentration of ionized calcium.

Definitions

Metabolic alkalosis refers to a condition that leads to a primary increase in serum - - bicarbonate concentration ([HCO3 ]) occurring as a consequence of a gain in HCO3 to, or a loss of H+ from the body. MA manifests as alkalemia (pH >7.40). As compensatory mechanism, MA yields to alveolar hypoventilation with the consequent increase in arterial

carbon dioxide tension (PaCO2). This compensatory rise in PaCO2, minimize the change in pH that might otherwise occur.

Arterial PaCO2 quickly increases by roughly 0.7 mm Hg for every 1 mmol/L increase in - plasma [HCO3 ]. One should suspect a complex or mixed acid-base disturbance when the

change in PaCO2 is not within the expected range. A PaCO2 that increases more than 0.7 times the rise in bicarbonate indicates the coexistence of MA with primary respiratory

acidosis. Similarly, if the rise in PaCO2 is of a lesser amount than the expected change, primary respiratory alkalosis is also present.

Compensation of respiratory alkalosis occurs as shown below

‐ ⇑ Plasma [HCO3 ]

‐ ⇑ [HCO3 ] of the interstitial fluid around the respiratory center

⇑ in pH of the interstitial fluid

Around the respiratory center ⇓ respiratory rate

⇑ Arterial pCO2

An elevated serum bicarbonate concentration is the hallmark for suspecting that MA does - exist, however, an elevated serum [HCO3 ] (no greater than 35 mmol/L) is often observed as a compensatory response to primary respiratory acidosis.

The serum anion gap, calculated as the difference between serum Na concentration and the sum of serum chloride plus bicarbonate, help to discriminate between primary MA and the metabolic compensation for respiratory acidosis. Definite diagnosis is made through the blood gas analysis which reveals and elevation of pH and pCO2 along with an - increased calculated serum [HCO3 ]

Pathophysiology

Pathophysiologically, MA depends on the serial occurrence of two main processes; 1. Generation and 2. Maintenance. Thus

METABOLIC ALKALOSIS: Generation + Maintenance

Generation of metabolic alkalosis

Generation of MA depends upon the gain of alkali, the loss of acid or the contraction of the ECF which leads to the concentration of a “constant” bicarbonate pool.

In this setting, the normal renal response involves the excretion of a considerable amount of bicarbonate by 1. Diminishing the fraction of sodium and bicarbonate reabsorbed in the - - PT and 2. Secretion of bicarbonate against chloride (Cl /HCO3 antiporter) by the B- intercalated cells in the collecting duct.

Metabolic alkalosis may be generated by one of the mechanisms discussed below:

1. Loss of hydrogen ions:

+ - Losses of H represent a net gain of HCO3 . Hydrogen ions can be lost from the ECF through: a. The gastrointestinal tract (vomiting, nasogastric suction) b. The kidneys: increased distal sodium delivery in the presence of aldosterone stimulates sodium reabsorption and H+ secretion in the collecting duct c. Hydrogen shifting to the ICF as occurs in hypokalemia

2. Gain of bases. Bicarbonate (alkali) administration

Often in the presence of an impaired ability of the kidney to excrete the excess bicarbonate as occurs when the GFR is reduced or when there is an increased tubular reabsorption as in real or effective volume depletion

3. Contraction alkalosis:

Contraction of the ECF volume secondary to the loss of bicarbonate-poor NaCl - fluid along with a constant bicarbonate pool increases plasma [HCO3 ](usually 2-3 mmol/L). This phenomenon is termed contraction alkalosis.

Maintenance of metabolic alkalosis

The main factors that contribute to the maintenance of the alkalosis are:

• Decrease in renal perfusion • Chloride depletion (even without volume depletion) o Via the GI tract or the kidneys (loop or thiazide-like diuretics o Stimulation of the renin-angiotensin-aldosterone system (RAAS) - o Impaired collecting duct B-type intercalated cells Cl/HCO3 exchanger • Hypokalemia o By reducing the GFR o Intracellular shifting of hydrogen ions o Increased renal ammoniogenesis o Stimulation of collecting duct apical H/K-ATPase o Impaired distal nephron chloride reabsorption

• Increased PaCO2 o Increases the insertion of cytoplasmic-formed proton ATPases into the apical membrane of CCD cells probably favoring H+ secretion

Clinical manifestations

Most of the symptoms and clinical manifestations associated with MA derive from the causative disease, thus a detailed medical history and physical examination may help to establish the etiology (vomiting in GI losses; renal failure for alkali-loading alkalosis, use of loop or thiazide-like diuretics, glucocorticoids/fluodrocortisone, calcium carbonate/Al- OH/antiacid abuse, carbenoxolone, etc for drug-associated conditions). The age of onset and the heritance may orientate to some familial disorders (Bartter or Gitelman syndrome). Manifestations associated with coexistent electrolyte disturbances such as hypokalemia (myalgia and weakness) and/or hypocalcemia (muscle contractions, peribucal tingling, tetany, Chvostek and Trousseau signs, mental obtundation and seizures) are quite frequent. The assessment of blood pressure and the evaluation of the volume status help to anticipate the 2 most common forms of MA, those that will respond to chloride repletion (salt responsive) and those that will not (salt resistant).

Some phenotypic characteristics at presentation (obesity, hirsutism, acne, growth retardation, sexual ambiguity, infantilism, etc) may be indicative of congenital or acquired hormonal conditions.

Causes

The most common causes of MA are associated with the use of thiazide-like or loop diuretics or as a consequence of loss of gastric secretions. MA can be divided into chloride (salt)-responsive alkalosis (urine chloride <20 mEq/L), chloride (salt)-resistant alkalosis (urine chloride >20 mEq/L), and other causes like alkali-loading alkalosis.

Chloride (salt)-responsive alkalosis (UCl <20 mmol/L)

Loss of gastric fluid

The mechanism by which it produces MA is rather complex but is mainly due to net gain of bicarbonate which is maintained by volume contraction, activation of the RAAS and the consequent renal hydrogen loss.

Thiazide or loop diuretics

Both diuretics reduce NaCl reabsorption in the DCT or the thick ascending loop of Henle and cause MA by chloride depletion and by increased H+ and K+ secretion in the CD subsequent to an increased local reabsorption of sodium. While diuretics are still acting, urine chloride excretion is somewhat high and decrease after discontinuation of the drug

Non-absorbable antacids

Which lead to an excess absorption of intestinal bicarbonate while hydrogen ions are buffered by the hydroxide anion and lost by the feces

Other causes

Congenital chloridorrhea (defective Cl/HCO3 exchange in colon and ilium)

Villous adenomas may cause MA by increasing fecal loss of potassium.

Posthypercapnic alkalosis which is frequently observed in individual recovering from a precedent status of respiratory acidosis.

Cystic fibrosis causes loss of chloride in sweat and MA which may be aggravated by concurrent volume depletion.

Chloride (salt)-resistant alkalosis (UCl >20 mEq/L) With hypertension

Just to remember!!!!! The use of diuretics (both thiazides or loop acting), as prescribed in hypertensive individuals is the most common cause of MA in patients suffering from hypertension.

Primary aldosteronims (usually associated with adrenal adenoma, bilateral adrenal hyperplasia, adrenal carcinoma, glucocorticoid-remediable aldosteronism –GRA-, syndrome of apparent mineralocorticoid excess –AME- by deficiency of the enzyme 11- beta OH- dehydrogenase or its inactivation by licorice or carbenoxolone consumption)

Cushing syndrome or disease caused by ectopic ACTH production and associated with high concentration of cortisol.

Liddle syndrome, an autosomal dominant condition characterized by an increased reabsorption of sodium through an apparently always opened ENaC in the CCD despite the suppression of aldosterone

Secondary hyperaldosteronism due to significant unilateral or bilateral renal artery stenosis or renin or deoxycorticosterone-secreting tumors.

Mutation in the mineralocorticoid receptor which turned to be responsible to progesterone. Exacerbations of hypertension during pregnancy characterize this condition

Without hypertension

MA may also be produced by the Bartter syndrome, an inherited autosomal recessive condition characterized by hypokalemic MA, stimulated RAAS, increased prostaglandin activity, hypercalciuria and normal BP. It is caused by an impaired NaCl reabsorption in the tALH. The disease in due to mutations in the CLCNKB gene that codifies the basolateral chloride channel (classic Bartter) or in the NKCC2 or in the ROMK1 genes which codifies the luminal Na-2Cl-K cotransport or the apical K channel (antenatal Bartter)

Gitelman syndrome is an inherited autosomal recessive disorder characterized by a defective activity of the thiazide-sensitive sodium/chloride transporter (NCCT) located in the distal convoluted tubule. The disease mimics the effect of an acting thiazide diuretic. Therefore, patients with this condition present salt wasting, hyperactivity of the RAAS and hypokalemic metabolic alkalosis along with hypocalciuria and hypomagnesemia.

Magnesium depletion can provoke MA probably as a consequence of the concurrent association with hipokalemia.

- Hypokalemia may “per se” cause MA by enhancing proximal HCO3 reabsorption, reduced GFR, impaired chloride reabsorption, increased ammonia genesis and distal nephron intracellular acidosis.

Other causes Alkali-loading alkalosis

The presence of moderate-severe renal excretory failure or some other conditions that contribute to the maintenance of MA impairs the ability of the kidney to eliminate an alkaline load. Commonly encountered examples are bicarbonate-based dialysate for ESRD, citrate administration to prevent clotting in blood lines or bags or massive blood transfusions.

- The administration of HCO3 in patients with lactic or ketoacidosis could potentially lead to overshooting alkalosis once these bicarbonate-forming anions are metabolized.

The milk alkali syndrome, not uncommon before the advent of H2-receptor blockers or gastric proton pump inhibitors.

Refeeding after prolonged fasting, (especially with carbohydrate-rich diets).

Hypercalcemia

Hypercalcemia impairs fluid reabsorption in the tALH causing volume depletion; thus - enhancing PT HCO3 reabsorption and producing MA.

Administration of non-reabsorbable anions

The distal delivery of certain anions, such as penicillin or penicillin-derivatives, in the presence of avid sodium reabsorption enhances distal proton secretion and produces MA.

Hypoalbuminemic conditions

The probable mechanism is the loss of negative charges of albumin.

Finding the cause

• Once suspected, the definite diagnosis of MA is obtained by measuring serum electrolytes and ABG. • The assessment of urine chloride concentration may help to discriminate those causes of MA associated with innaparent or subtle volume contraction ([UCl < 20 mmol/L) from those that aren´t ([UCl > 20 mmol/L). Urine sodium is not always low in MA associated with volume contraction because the elimination of the excess bicarbonate as sodium or potassium salts • In patients with hypertension and hypokalemic MA, measurement of plasma renin activity and serum aldosterone can be useful to differenciate primary or secondary hyperaldosteronic states as well as other endocrine-related conditions. • CT or MRI scanning, doppler US, renal scintigraphy or renal angiography are useful tools to localize adrenal masses or renovascular disease respectively. • Plasma and urine free cortisol levels,cortisol metabolites and other specific tests (dexametasone suppresion test) are useful for the valuation of Cushing syndrome, 11B-HSD deficiency, or the syndrome of apparent mineralocorticoid excess • Urine sampling to screen surretitious diuretic use is sometimes of great value.

Other Tests

• Gene analysis is helpful to diagnose inherited causes of hypokalemic alkalosis. GRA, Liddle syndrome, Bartter and Gitelman syndrome, AME, or CAH can be appropriately diagnosed using this approach.

TREATMENT, (WHEN, WHY and HOW)

The rational approach and management of MA depends initially on the underlying etiology and on the volume status of the patient.

When to begin and why to treat

- Mild metabolic alkalosis ([HCO3 ] 32-34 mmol/L)

At this stage plasma [K+] is usually within the normal range (3.5 – 4.0 mmol/L) therefore no specific treatment is necessary. It is mandatory however to maintain vigilance aimed at detecting further changes.

- Moderate metabolic alkalosis ([HCO3 ] 34-40 mmol/L)

At this stage symptoms may appear and compensatory hypoventilation could potentially cause hypoxemia in individual with poor respiratory reserve. Potassium deficit (typically 250-500 mmol) is reflected by plasma [K+] in the range of 2.5-3.5 mmol/L. Treatment should be started without further delay.

- Severe metabolic alkalosis ([HCO3 ] 40-45 mmol/L)

At plasma pH >7.6 the likelihood of seizures, cardiac arrhythmia, or other major alkalemic symptoms is extremely high therefore treatment is mandatory. Typically [K+] is close to 2.0-2.4 mmol/L reflecting an almost 1000 mmol potassium deficit. Severe hypoxemia is highly probable in patients with pre-existent lung dysfunction.

How to treat

• Chloride (Volume)-responsive alkalosis

Whenever possible, the underlying cause/s (generating factor/s) must be removed (stop nasogastric sucction or supress gastric acid secretion with H2-blockers or proton pump inhibitors; consider the safety of removing or reducing the dosage of diuretics if they are suspected to be the cause)

The next step is to pay attention to those factors that maintain the alkalosis (volume depletion, hypokalemia, aldosterone excess) Sodium chloride solutions should be administered along with potassium suplementation providing that salt-responsive alkalosis is almost always associated with K+ depletion. Potassium should be administered as chloride salts instead of preparations containing organic anions.

As aldosterone excess is secondary to volume depletion, it self- corrects once the ECF is restored

When chloride-responsive MA occurs in the scenario of edematous conditions (CHF, cirrhosis, nephrotic syndrome, etc) the following strategies can be useful:

Administer KCl but not saline solution because repairing hypokalemia may to some extent correct MA.

- Reducing the diuretic dosage may help lower serum [HCO3 ] while retaining a satisfactory therapeutic effect in terms of fluid balance.

Add acetazolamide, which reduce proximal bicarbonate reabsorption, but give KCl prophylactically due to the possible massive kaliuresis associated with it bicarbonaturic effect.

Give spirolactone. This K+ sparing diuretic block the mineralocorticoid effect in the distal nephron.

Chloride (Volume)-resistant alkalosis

The main goal is to remove the underlying cause or to interfere with it mechanism (surgical removal of adrenal or pituitary adenoma, spirolactone, dexametasone for GRA, or other K+ sparing diuretics for AME or Liddle syndrome, etc) Bartter or Gitelman syndromes may be alleviated with KCl supplements, K+ sparing diuretics, NSAIDs or ACEis.In case of licorice abuse, this offending drug should be immediatly removed.

Aggressive treatment of Metabolic Alkalosis

- On rare occasions it is mandatory to aggresively and rapidly lower plasma [HCO3 ]. In such instances the following measures can be used:

Carbonic anhydrase inhibitors (acetazolamide)

Intravenous infusion of HCl (through a central venous line) or acid precursors

(NH4Cl, arginine monohydrochloride). When calculating the amount of acid to be given to - decrease serum [HCO3 ].to a target level it is useful to compute the apparent volume of distribution of bicarbonate (almost 50% of body weight) and the mmol/L of bicarbonate to - be reduced. For example: if you wish to lower [HCO3 ] by 12 mmol/L in a 75 kg patient:

(0.5 x 75) x 12= 450 mmol of acid are necessary Dialysis: Both hemodialysis or peritoneal dialysis with reduced buffer contain as well as acetate-free biofiltration are of value. This therapeutic approach is almost always reserved for patients with severe MA and associated advanced renal failure.

References

• DuBose TD Jr. Metabolic alkalosis. In: Brenner and Rector's The Kidney. 6th ed. Philadelphia: WB Saunders; 2000: 971-997 • Adrogue HJ, Madias NE. Management of life-threatening acid-base disorders. Second of two parts. N Engl J Med. 1998; 338 (2):107-11 • Galla JH. Metabolic Alkalosis. J Am Soc Nephrol. 2000;11:369- 75. • Rose BD. Metabolic alkalosis. In: Clinical Physiology of Acid-Base and Electrolyte Disorders. 4th ed. New York: McGraw-Hill; 1994: 515-35. • Scheinman SJ, Guay-Woodford LM, Thakker RV. Genetic disorders of renal electrolyte transport. N Engl J Med. 1999; 340 (15): 1177-87. • Leblanc M, Farah A. Severe metabolic alkalosis corrected by hemodialysis. Clin Nephrol. 1997; 48 (1): 65. • Hixson R, Christmas D. Use of omeprazole in life-threatening metabolic alkalosis. Intensive Care Med. 1999; 25 (10): 1201. • Geller DS, Farhi A, Pinkerton N. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science. 2000;89 (5476): 119-23. • Hodgkin JE, Soeprono FF, Chan DM: Incidence of metabolic alkalemia in hospitalized patients. Crit Care Med 1980; 8: 725–732 • Tannen RL: Effect of potassium on renal acidification and acidbase homeostasis. Semin Nephrol 1987; 7: 263–273 • Verlander JW, Madsen KM, Galla JH, Luke RG, Tisher CC: Response of intercalated cells to chloride depletion metabolic alkalosis. Am J Physiol 1991; 262: F309–F319 • Warnock DG: Liddle syndrome: An autosomal dominant from of human hypertension. Kidney Int 1998; 53: 18–24 • Kurtz I: Molecular pathogenesis of Bartter’s and Gitelman’s syndromes. Kidney Int 1998; 54: 1396–1410