Metabolic alkalosis is an absolute or relative increase in extracellular HCO3- that has not been initiated by pulmonary disease-associated changes in PaCO2. Respiratory disease may likewise cause a relative increase in extracellular HCO3-, but via excess expiration of CO2 and thus decreased PaCO2. Alkalosis may occur without alkalemia: alkalosis is the process itself which results in HCO3- excess, whereas alkalemia is the rise in pH above reference range. Alkalemia occurs only with incomplete respiratory compensation, in the presence of concurrent metabolic abnormalities which inhibit homeostatic mechanisms, or with mixed-acid base disorders. The objectives of this presentation are to review the body's normal response to alkalosis (focusing on the kidney), the essential pathophysiologic processes thought to result in and perpetuate alkalemia, and the differential diagnoses associated with alkalosis and alkalemia in dogs, cats, and people.
Normal Response to Metabolic Alkalosis
In normal animals almost all filtered HCO3- is reabsorbed, as cellular processes result in net production of acid, and HCO3- retention is required to maintain normal pH. Reabsorption of HCO3- occurs primarily in the proximal convoluted tubule, with the remainder exiting the ultrafiltrate in all distal portions of the nephron. Filtered HCO3- combines with H+ excreted by tubular cells to form H2CO3 which then spontaneously produces H2O and CO2; CO2 then passes back into the tubular epithelial cell where carbonic anhydrase drives the reaction back to H+ and HCO3-. The H+ is again re-excreted, while the HCO3- passes into the ECF. However, the physiologic requirement for maintenance of electroneutrality means that for every resorbed molecule of HCO3- some cation must be resorbed in parallel, or some anion must be excreted. Depending on the specific transporter and which cell type in the nephron, the ions most commonly exchanged between the lumen and tubular epithelial cells are Na+ and Cl-.
When normal renal mechanisms for coping with alterations in pH are overwhelmed or inhibited, ECF pH may be maintained via changes in carbon dioxide excretion through exhalation. Metabolic alkalosis may result in compensatory respiratory acidosis: an increase in CO2 retention via hypoventilation. Experimental studies have shown that a 1 mEq/L increase in serum HCO3- should result in a 0.7 mm Hg increase in PaCO2. This change is not immediate--in healthy dogs up to 24 hrs may be required for full compensation to occur. The same 1 mEq/0.7 mm Hg balance has been demonstrated in healthy kittens. Alterations in PaCO2 outside of the expected range may imply a mixed acid-base disorder, although the caveat exists that the numbers above were generated in healthy animals of limited age ranges.
Pathophysiologic Causes of Alkalosis
Development of metabolic alkalosis may be multifactorial, and is different in various disease processes. However the most common underlying metabolic derangements which result in significant alkalosis are H+ loss, Cl- loss, and possibly K+ loss. Other conditions, including Mg+ loss or hypoalbuminemia are either rare or do not apparently cause significant alkalosis and thus will not be discussed here. Loss of H+ is the most common cause of alkalosis in veterinary patients, either through loss of gastric contents or excretion of excess H+ in urine. In the former, loss of large amounts of HCl directly results in alkalosis by direct H+ loss. Increased urinary H+ excretion is most commonly associated with diuretic therapy, specifically those associated with inhibition of sodium resorption. The resultant increased sodium avidity in the more distal portions of the tubule results in increased Na+/H+ countertransport and thus excretion of H+; therefore, the more proximally acting a diuretic, the more likely the development of metabolic alkalosis.
Hypochloremia is a common aggravating factor in establishment of metabolic alkalosis, but more importantly is the most common cause of persistent alkalosis. In veterinary patients the most common causes of metabolic alkalosis are also associated with hypovolemia. Sodium resorption increases throughout the renal tubule and secondary hyperaldosteronism occurs via upregulation of the RAAS. However, because of electroneutrality, sodium must be resorbed in conjunction with an anion, or an alternative cation must be excreted. Normally Na+/Cl- cotransport is the primary mechanism for sodium resorption. However in the face of hypochloremia, and thus reduced ultrafiltrate Cl-, Na+ resorption occurs primarily via Na+/H+ and Na+/K+ countertransporters. The loss of H+ thus perpetuates metabolic alkalosis by causing a continued relative increase in HCO3-.
Hypokalemia likewise aggravates and perpetuates metabolic alkalosis. Reduced ultrafiltrate further upregulates Na+/H+ countertransport. Additionally hypokalemia leads to H+/K+ countertransport throughout the body in an effort to maintain intravascular K+ within reference range. The shift of H+ intracellularly further aggravates metabolic alkalosis.
As detailed above, it is most useful to divide the differential diagnoses for metabolic alkalosis into hypochloremic (i.e., chloride-responsive) and normochloremic (i.e., non-chloride responsive) conditions. The recognized causes of metabolic alkalosis in dogs and cats are fewer than in people; however clinicians should be alert as to these 'oddball' differentials, as in theory these undocumented diseases may still sporadically occur. Again, metabolic alkalosis is not the same as alkalemia, and some of the differentials listed below are likely rarely associated with clinically significant alterations in systemic pH. Conditions most commonly associated with alkalemia in dogs and cats are indicated by an asterisk (*).
Differential Diagnoses in Dogs and Cats
Acute correction of long-standing respiratory acidosis (due to delay in reversal of compensatory metabolic alkalosis)
Diuretic therapy: most likely with loop diuretics* and thiazides
Excessive loss of gastric fluid: gastric outflow obstruction via gastric dilatation/volvulus, pyloric outflow obstruction (foreign body, mass, hypertrophy, etc.)*
Aggressive bicarbonate administration
Organic anion excess (lactate, gluconate, acetate, citrate)
Additional Differential Diagnoses in People
Congenital chloridorrhea (excess fecal loss of Cl-)
High doses of renally-excreted nonresorbable anions, particularly sodium-penicillin salts
Villous adenoma (i.e., rectal polyps; occurs in a subset of patients, presumptively via secretory diarrhea and secondary hypokalemia)
Barter syndrome (a rare child-onset inherited renal tubular disease)
Gittelman syndrome (a rare adult-onset inherited renal tubular disease)
Hypercalcemia unassociated with hyperparathyroidism
Abuse of drugs/foods which result in hyperaldosteronism (most commonly licorice)
Chronic aspiration of gastric contents
Milk-alkali syndrome (excess milk or antacids)
As with all acid-base disorders, treatment of metabolic alkalosis should primarily be focused on treatment or elimination of the underlying cause. Clinical signs associated with metabolic alkalosis in people include altered mentation and other central neurologic abnormalities such as seizures, muscle cramps, and tetany. These have not been recognized in veterinary patients. Nevertheless in some cases severity of alkalosis is severe enough that despite adequate compensation specific therapy is indicated.
Treatment of hypochloremic alkalosis is via administration of Cl- in the form of intravenous saline. Because maintenance of alkalosis in these conditions is primarily due to insufficient Cl- to allow Na+ reabsorption without HCO3- in the distal tubule, administration of free acid alone is insufficient--there is an absolute requirement for Cl-. Intravenous 0.45% or 0.9% NaCl solution is the treatment of choice, but because the volume to be administered depends on whole-body chloride concentration the amount required may vary widely. In people efficacy of therapy can be monitored by measurement of urine pH. Once chloride has been adequately replenished urine pH should become alkaline as HCO3- excretion is allowed to resume. Additionally, because hypokalemia may play a role in some patients both with initiation and maintenance of metabolic alkalosis, low serum potassium concentrations should be concurrently treated. Intravenous fluids should be supplemented with KCl, as any other potassium salt results in renal excretion of the salt anion with H+, which may prolong or prevent correction of alkalosis. In those rare cases where clinical signs are attributable to alkalosis, acidification may be required. Ammonium chloride should be used in these cases, as dilute HCl has a low therapeutic index and may cause intravascular hemolysis.
Treatments of normochloremic alkalosis is much more variable. In dogs and cats these diseases are usually either readily corrected by fluid therapy or are rarely associated with clinically significant alkalemia. In people those diseases which cannot be readily treated and which require intervention a number of agents may be used to minimize H+ loss or HCO3- reabsorption. H2-blockers decrease acidity of gastric contents, and thus may be of some help. Acetazolamide, which inhibits carbonic anhydrase, reduces HCO3- reabsorption in tubule epithelial cells. Spironolactone, an aldosterone antagonist, is used in diseases associated with mineralocorticoid excess. Hemodialysis may be used in cases associated with renal dysfunction.
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2. Rose BD, Post TW. (ED). Clinical physiology of acid-base and electrolyte disorders, 5th