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