Rational Treatment of Acid-Base Disorders

Practical Therapeutics

Margaret L. McLaughlin and Jerome P. Kassirer

Nephrology Division, Department of Medicine, New England Medical Center, and Department of Med icine, Tufts Un iversity School of Medi cine, Boston , Massachusetts, USA

Contents Summary , ,.., , ,.., ,.., ,..,.. 842 I. Metabolic Acidosis 843 1.1 Clinical Manifestations 843 1.2 Causes of Metabolic Acidosis 843 1.3 Treatment of Metabolic Acidosis 844 1.3.1 General Remarks 844 1.3.2 Loss of Alkaline Gastrointestinal Fluids 845 1.3.3 Carbonic Anhydrase Inhibitors 845 1.3.4 Urinary Diversion , 845 1.3.5 Lactic Acidosis 845 1.3.6 Diabetic Ketoacidosis 846 1.3.7 Alcoholic Ketoacidosis 846 1.3.8 Renal Tubular Acidosis ll47 1.3.9 Renal Acidosis (Uraemic Acidosis) 848 2. Metabolic Alkalosis , 848 2.1 Clinical Manifestations 848 2.2 Causes of Metabolic Alkalosis 848 2.3 Treatment of Metabolic Alkalosis 849 2.3.1 Milk-Alkali Syndrome 850 2.3.2 Combined Therapy with Nonabsorbabl e Alkali and Exchange Resins 850 2.3.3 Acute Alkali Loading 850 2.3.4 Gastric Fluid Losses 850 2.3.5 Diuretic Therapy , 851 2.3.6 Posthypercapnic Alkalosis 851 2.3.7 Primary Aldosteron ism 851 2.3.8 Bartter's Syndrom e 85I 2.3.9 Cushing's Syndrome 852 3. Respiratory Acidosis 852 3.1 Clinical Manifestations 852 3.2 Causes of Respiratory Acidosis , 852 3.3 Treatment of Respiratory Acidosis , 852 4. Respiratory Alkalosis 852 842 Drugs 39 (6) 1990

4.1 Clinical Manifestations 853 4.2 Causes of Respiratory Alkalosis 853 4.3 Treatment of Respiratory Alkalosis 853 5. Mixed Acid-Base Disturbances 853 5.1 Metabolic and Respiratory Acidosis 853 5.2 Metabolic and Respiratory Alkalosis 853 5.3 Metabolic Acidosis and Respiratory Alkalosis 854 5.4 Metabolic Alkalosis and Respiratory Acidosis 854 6. Conclusions 854

Summary Acid-base derangements are encountered frequently in clinical practice and many have life-threatening implications. Treatment is dependent on correctly identifying the acid base disorder and , whenever possible, repairing the underlying causal process. Bicarb onate is the agent of choice for the treatment of acute metabolic acidosis. Controversy surrounds the use of alkali therapy in lactic acidosis and diabetic ketoacidosis, but bi carbonate should clearly be administered for severe acidos is. In most patients with mild to moderate chloride-responsive metabolic alkalosis, providing an adequate amount of a chloride salt will restore acid-base balance to normal over a matter of days. In contrast, therapy of the chloride-resistant metabolic alkaloses is best directed at the underlying disease . When alkalaemia is severe, administering hydrochloric acid or a hydrochloric acid precursor may be necessary. Treatment of respiratory acidosis should be targeted at restoring ventilation; alkali should be administered only for superimposed metabolic acidosis . The therapy of res piratory alkalosis is centred on reversal of the root cause; short of this goal, there is no effective treatment of primary hypocapnia. The coexistence of more than one acid-base disorder (i.e. a mixed disorder) is not uncommon. When plasma bicarbonate concentration and arterial carbon dioxide tension (paCOl) are altered in opposite directions, extreme shifts in pH may occur. In such cases, it is imperative that the nature of the disturbance is identified early and therapy directed at both disorders.

Disturbances of acid-base balance are wide ical reactions rapidly achieve equilibrium condi spread in practice and many pose serious threats tions, allowing a simple expression of their rela to the well-being of patients. A rational approach tionship (Henderson 1908): to the treatment of acid-base disorders is depend (Eq. I) ent on an understanding of the basic pathophys iological mechanisms that give rise to them. Cor Thus, hydrogen ion concentration is a function rect identification of the underlying disturbance of the ratio of the arterial carbon dioxide tension may suggest new diagnostic avenues, as well as (paC02) to the bicarbonate concentration. It fol provide a guide to specific, and often life-saving, lows that changes in hydrogen ion concentration therapy. and, consequently, all acid-base disorders, result The carbonic acid-bicarbonate buffer system from changes in one or other of these 2 variables. plays a central role in acid-base balance because of Acid-base disturbances are classified into 4 pri its prevalence and its relation to physiological reg mary disorders - metabolic acidosis, metabolic al ulatory mechanisms. The hydration of dissolved kalosis, respiratory acidosis and respiratory alka C02 forms carbonic acid which then dissociates to losis - and various combinations of these disorders yield bicarbonate and hydrogen ions. These chem- categorised as mixed disturbances. Treatment of Acid-Base Disorders 843

1. Metabolic Acidosis duced capacity of the kidneys to excrete acid (see table I). Metabolic acidosis is initiated by a reduction in Loss of bicarbonate-rich fluid results in deple plasma bicarbonate concentration. The most im tion of extracellular fluid volume and a reduction mediate consequence of a fall in bicarbonate con in bicarbonate concentration. At the same time, centration is an increase in plasma acidity. Cor chloride concentration rises as the remaining responding changes in cerebral hydrogen ion chloride is confined to a smaller volume of distri concentration are sensed by central chemorecep bution. Such a hyperchloraemic metabolic acidosis tors, giving rise to reflex hyperventilation, a fall in results from diarrhoea (Darrow et al. 1949), pan paC02, and a consequent attenuation in the degree creatic or biliary drainage, administration of car of acidification. bonic anhydrase inhibitors, and certain forms of urinary diversion . Administration of hydrochloric 1.1 Clinical Manifestations acid and substances which give rise to hydrochloric The clinical manifestations of metabolic acid acid when metabolised (e.g. ammonium chloride, osis include effects on the cardiovascular and pul monary systems, the circulation, oxygen transport, Table I. Causes of metabolic acidosis (from Kassirer et al. 1989. and potassium metabolism (Mitchell et al. 1972; with permission) Relman 1972). Hyperventilation, or Kussmaul res Normal anion gap pirations, is one of the most readily apparent Loss of bicarbonate manifestations of severe acidosis. Myocardial dys Diarrhoea function due to acidosis and a reduced threshold Small bowel losses for ventricular fibrillation also occur. Acidosis has Carbonic anhydrase inhibitors several effects on vascular tone, producing direct Ureterosigmoidostomy Ileal loop bladder arterial vasodilatation, indirect sympathetic-me Dilutional acidosis diated vasoconstriction, and direct venous vaso Addition of hydrochloric acid constriction. In addition, acute acidaemia shifts the Ammonium chloride haemoglobin dissociation curve to the right, but Arginine-HCI acidosis-induced depletion in cellular 2,3-diphos Lysine-HCI Total parenteral nutrition phoglycerate shifts the curve back in a matter of Disproportionate failure of renal tubular function hours (Mitchell et al. 1972). Hyperkalaemia is a Renal tubular acidosis frequent accompaniment of acute metabolic acid Mild renal failure osis and has been attributed to transcellular shifts Hyporeninaemic hypoaldosteronism Adrenal insufficiency ofpotassium in response to acidosis. However, cer tain types of metabolic acidosis due to organic acids Increased anion gap (e.g, lactic acid and acetoacetic acid) have little or Overproduction of organic acids no direct effect on serum potassium concentration Lactic acidosis (Fulop 1979). When hyperkalaemia does occur in Diabetic ketoacidosis Starvation ketosis these kinds of acidosis, decreased renal function or Alcoholic ketoacidosis insulin deficiency is probably more important in Methyl alcohol ingestion its genesis. Ethylene glycol ingestion Paraldehyde ingestion 1.2 Causes of Metabolic Acidosis Salicylate intoxication Infantile organic acidosis Three distinct pathological processes work alone Severe renal failure or in concert to produce metabolic acidosis: (a) loss Acute Chronic of bicarbonate; (b) addition of acid; and (c) re- 844 Drugs 39 (6) 1990

lysine-HC1, and arginine-HCl) also produce hy small additional decrement in bicarbonate concen perchloraemic acidosis. The normal kidney re tration or increase in paC02. In normal individ sponds to the reduction in plasma bicarbonate by uals, administered bicarbonate distributes through augmenting net acid excretion, resulting in the con a space of approximately 40 to 50%of bodyweight, servation of sodium with newly generated bicarb but the space of distribution may be more than onate and in the excretion of chloride and hydro twice that large when plasma bicarbonate is ex gen ion. tremely low (Garella et al. 1973). In addition , there Overproduction of organic acids results in a fall is often no way to assess the magnitude of organic in plasma bicarbonate concentration and an in acid production or on-going alkali loss. Conse crease in the plasma concentration of the anion of quently, estimates of bicarbonate space to predict that acid. In contrast to the pattern seen with direct a desired increment in plasma bicarbonate must be loss of bicarbonate or administration of substances considered a first approximation only. Given the that yield hydrochloric acid, the acidosis that re large number of variables, acid-base parameters sults from organic acid overproduction is charac should be assessed frequently and appropriate ad terised by a normal plasma chloride concentration justments made in the quantity of alkali admini and an increase in the concentration of plasma un stered. measured anions. The causes of metabolic acidosis Sodium bicarbonate is the agent of choice for with an increased anion gap include: lactic acid the treatment of acute metabolic acidosis. Sodium osis; diabetic ketoacidosis; starvation ketosis; al lactate, citrate and acetate require metabolic con coholic ketoacidosis; methyl alcohol, ethylene gly version to bicarbonate to exert their alkalinising col and paraldehyde intoxication; and salicylate effect, and hence their therapeutic effect may be overdose (Gabow 1985). Some degree of sodium delayed. For long term use, as in the treatment of and potassium depletion often accompanies this renal tubular acidosis, chronic diarrhoea, or end type of metabolic acidosis because these cations are stage renal disease, some patients find sodium cit excreted in the urine with the acid anions . rate more palatable than bicarbonate salts. The third type of metabolic acidosis results from In the acute setting, sodium bicarbonate should a failure of the kidney to excrete the daily acid load. be administered intravenously, either as a bolus or A hyperchloraemic metabolic acidosis develops added to a hyponatric solution and given contin with distal renal tubular acidosis and with mild uously. An ampoule of sodium bicarbonate con chronic renal insufficiency (Harrington & Cohen 1982), but when glomerular function is severely tains 50 mEq of sodium and bicarbonate. A readily impaired, anions (such as phosphate and sulphate) accessible oral form of alkali therapy is sodium bi are retained by the kidney and the plasma unmea carbonate tablets; a 650mg tablet contains 8 mEq sured anion concentration increases as well. of bicarbonate . Sodium citrate is available in a li quid form; Iml contains I mEcj of sodium and the 1.3 Treatment of Metabolic Acidosis equivalent of I mEq of bicarbonate . Hypernatraemia and volume overload are the 1.3.1 General Remarks major complications of administering large quan Whenever possible, efforts should be directed at tities of sodium bicarbonate. Metabolic alkalosis identifying and treating the underlying process may result after treatment of organic acidosis (e.g. which gave rise to the metabolic acidosis. No mat diabetic ketoacidosis, lactic acidosis) if bicarbonate ter what the cause, it is recommended that alkali is generated from the metabolism of retained or be administered for severe metabolic acidosis (i.e. ganic anions, and post-treatment respiratory alka plasma bicarbonate < 5 mmol/L). Patients with losis can occur in any form of metabolic acidosis plasma bicarbonate values in this range are at risk if hyperventilation persists as a consequence oflag of a sudden worsening in acidaemia with only a ging spinal fluid acidification. Transient hypoka- Treatment of Acid-Base Disorders 845

laemia, resulting from the shift of potassium into renal tubular damage due to obstruction and in cells, also may develop during the course of therapy. fection are the mechanisms which produce meta bolic acidosis. In contrast to ureterosigmoidos /.3.2 Loss ofAlkaline Gastrointestinal Fluids tomy, an ileal conduit permits continuous urinary Metabolic acidosis caused by loss of gastroin drainage to the outside, obviating prolonged con testinal fluid is often accompanied by large deficits tact with intestinal mucosa and reducing the op of sodium, potassium, chloride and water, in ad portunity for exchange. Hyperchloraemic meta dition to bicarbonate. The severity of the acidosis bolic acidosis, particularly if new in onset, should caused by stool loss varies with the aetiology of the direct attention toward the possibility that an ileal diarrhoea. Stool bicarbonate concentrations in ex loop has become partially obstructed. Few patients cess of 40 mrnol/L occur in patients with massive with ileal diversions need daily alkali therapy. watery diarrhoea (Watten et al. 1959) and villous adenomas of the rectum, and such losses can result 1.3.5 Lactic Acidosis in moderate to severe metabolic acidosis. The bi The therapy of lactic acidosis is controversial, carbonate concentration in pancreatic and biliary but all agree that effective treatment centres on the drainage always exceeds that in plasma, but severe identification and correction of the underlying pro metabolic acidosis rarely results unless drainage cess. Prompt treatment of low-cardiac-output states, volumes are unusually large. repletion of volume deficits, correction of shock In severe diarrhoea, volume repletion is an im and administration of antibiotics (in the septic portant target of initial therapy. Ideally, replace patient) should be given the highest priority. The ment therapy is guided by measurements of the use of vasoconstrictive substances should be min electrolyte composition of the diarrhoeal fluid. Be imised to avoid aggravation of ischaemia of peri cause such measurements are not very practical, pheral tissues. Invasive haemodynamic monitor however, a 0.45% saline solution containing 50 ing in an intensive care unit should be employed mfiq/L of sodium bicarbonate is a reasonable in to guide the use of volume replacement, cardio itial replacement fluid. Potassium losses are typi trophic agents and pressors (Madias 1986). cally large and should also be replaced. Acid-base Controversy surrounds the use of alkali therapy parameters and serum potassium should be as in the treatment of lactic acidosis. Experimental sessed frequently and therapy modified accord studies in dogs suggest that administering sodium ingly. bicarbonate may augment the accumulation of lac tic acid by stimulating its production or interfering 1.3.3 Carbonic Anhydrase Inhibitors with its metabolism by the liver (Grafet al. 1985). Carbonic anhydrase inhibitors such as aceta In addition, the evidence in humans of an adverse zolamide are only moderately potent in producing effect of alkali therapy in lactic acidosis is not con renal bicarbonate loss; thus, plasma bicarbonate vincing. We recommend that sodium bicarbonate concentrations rarely fall below 18 mrnol/L as a be administered for severe, life-threatening lactic result of their use (Harrington & Cohen 1982). acidosis, that is, when the pH falls below 7.20 Aside from discontinuing these agents, no other (which usually corresponds to a plasma bicarbon therapy is usually necessary. ate below 10 mrnol/L). Certainly, at a pH below this value, the negative inotropic and arrhythmo /.3.4 Urinary Diversion genic effects of acidaemia are substantial, and al Hyperchloraemic metabolic acidosis is seen less kali therapy gains time to address the principal dis frequently today with ureteroileostomies than when order. No specific guidelines can be given regarding ureterosigmoidostomies were the preferred ap the amount of alkali to be administered because proach to urinary diversion. Chloride-bicarbonate the rate of lactic acid production varies tremen exchange, reabsorption of urinary ammonium, and dously. As a general rule, however, it is desirable 846 Drugs 39 (6) 1990

to give sufficient alkali to maintain plasma bicarb as the major objections to the use of sodium bi onate concentration at 15 to 18 mmol/L, Acid-base carbonate. One recent randomised, prospective parameters should be assessed frequently and study in patients with severe diabetic ketoacidosis therapy modified accordingly. (arterial pH 6.9 to 7.14) found no significant dif Adjunctive or alternative therapy to sodium bi ference in the rate of decline of plasma glucose or carbonate in the treatment of lactic acidosis with ketone levels or in the rate of increase in pH or dichloroacetate also has been proposed. While plasma bicarbonate levels in patients who received dichloroacetate augments the oxidation of lactate bicarbonate or in those who did not (Morris et al. to acetyl-CoA, and evidence from human studies 1986). It is difficult to draw conclusions from this is promising (Stacpoole et al. 1983), toxicity may study because the number of subjects was small be a major drawback to its use. and the patients selected were free ofcomplicating illnesses. When acidosis is severe (plasma bicarb 1.3.6 Diabetic Ketoacidosis onate concentration less than 5 mmol/L), a small The mainstay of therapy of diabetic ketoacid additional loss ofbicarbonate, or an increase in en osis is insulin, but repletion offluid and electrolyte dogenous acid production from superimposed sep deficits and appropriate use of alkali are of equal sis and lactic acidosis, might easily result in life importance (Sanson & Levine 1989). In recent threatening acidosis. Likewise, any faltering in years, the effectiveness of physiological doses ofin ventilation because of fatigue, pneumonia or other sulin has been well established. Several insulin dos disorders could cause paC02 to rise (or to fail to age schedules have been shown to be effective. decrease) and the blood pH could fall below 7.00. Typically, a small loading dose of regular insulin Consequently, in patients with plasma bicarbonate (2 to 12 units) is administered intravenously, or a concentration less than 5 mmol/L, and particularly dose of 20 units is given intramuscularly followed in those with complicating illnesses, we believe that by a continuous infusion (2 to 12 units/hour). The the benefits ofadministering enough alkali to raise amount of insulin administered hourly is adjusted plasma bicarbonate by 3 to 4 mmol/L outweigh the to achieve a decrement in glucose concentration of risks. approximately 100 mg/dl/h (5.6 mrnol/L) [Kassi rer et al. 1989]. In the initial stages of treatment, 1.3.7 Alcoholic Ketoacidosis blood glucose levels and electrolytes should be This disorder is typically diagnosed in chronic measured hourly. Insulin therapy should be con alcoholics following a prolonged drinking bout. tinued until hyperglycaemia and ketonaemia have Profound acidosis is the rule, with plasma bicarb resolved. To avoid hypoglycaemia, glucose should onate concentrations frequently less than 10 mmol/ be added to the replacement fluids when the blood L (Miller et al. 1978). Accumulation of 3-hydroxy sugar level falls below 300 mg/dl (16.7 rnrnol/L). butyric acid is mainly responsible for the acidosis. Given the short half-life ofintravenous insulin, ap However, despite the severe acidaemia, alcoholic proximately one-halfto two-thirds ofthe usual daily ketoacidosis corrects with relative ease, and alkali insulin dose should be given subcutaneously as therapy or insulin administration is rarely neces intermediate-acting insulin one hour before dis sary. Infusion of glucose and saline frequently re continuing the insulin infusion . sults in rapid correction ofthe acidosis in a matter As with lactic acidosis, the use of endogenous of hours. alkali in the treatment of diabetic ketoacidosis is the subject of debate . Post-treatment alkalaemia, Intoxications worsening hypokalaemia due to an alkali-induced Methyl Alcohol: Ingestion of methyl alcohol may transcellular shift of potassium, and persistent hy result in serious consequences even when treat perventilation because of lagging equilibration of ment is promptly initiated (Jacobsen & McMartin arterial blood with the spinal fluid, have been cited 1986). The major manifestations are diminution in Treatment of Acid-Base Disorders 847

vision accompanied by peripapillary oedema and sion, but clinical experience with this agent is lim hyperaemia of the optic discs, severe metabolic ited (Baud et al. 1988). acidosis (with an increased anion gap), and abdom Salicylate: Salicylates affect acid-base equilib inal pain probably due to pancreatitis (Bennett et rium by directly stimulating alveolar ventilation al. 1953). Methyl alcohol is metabolised by the en and by increasing both carbon dioxide and endog zyme alcohol dehydrogenase to produce formal enous acid production. Consequently, mixed acid dehyde and formic acid, the latter being the pri base disturbances frequently result from salicylate mary toxin. overdose . Metabolic acidosis may be the present Dialysis is the mainstay of the treatment of ing feature of salicylate intoxication in children, but methyl alcohol intoxication. Haemodialysis effec it is less common in adults. In addition, the pres tively removes both the parent compound and its entation will vary depending on whether the inges metabolites and also rapidly corrects the metabolic tion is acute or chronic (Greer et al. 1965). acidosis. Peritoneal dialysis is less efficient but can Because of the likelihood of a mixed acid-base be used if haemodialysis is not feasible. The affin picture, it is essential that arterial blood gases be ity of alcohol dehydrogenase for ethyl alcohol used to guide therapy. If metabolic acidosis pre greatly exceeds that for methyl alcohol, and for this dominates, sodium bicarbonate should be admin reason administration of ethyl alcohol is com istered. In addition, treatment with sodium bi monly employed to interfere with the metabolism carbonate alkalinises the urine and augments the of methyl alcohol to its toxic metabolites. Ethyl al renal excretion of salicylate by inhibiting its reab cohol can be given either orally or intravenously. sorption. Of course, giving alkali in the presence Usually a loading dose of 0.6 g/kg followed by an of respiratory alkalosis may produce marked al infusion of 100 mg/kg/h is adequate to achieve the kalaemia, but alkali can be administered safely if desired blood ethyl alcohol level of 100 mg/dl (22 acid-base parameters are monitored carefully. Close rnmol/L). During haemodialysis the infusion rate attention should be paid to the patient's volume must be increased or ethyl alcohol added to the status because alkali therapy and its attendant sod dialysate at a concentration of 100 mg/dl (Garella ium load can aggravate the noncardiogenic pul 1988). Blood levels of ethyl alcohol must be mon monary oedema frequently seen in adults with sali itored carefully because its half-life varies consid cylate intoxication (Tweeddale 1974). Serum erably from individual to individual. Treatment potassium concentration must be carefully fol should cont inue until acidosis is corrected and lowed because alkali therapy can aggravate hypo serum methyl alcohol and formate levels are un kalaemia. detectable. In an otherwise healthy patient, administration Ethylene Glycol.' Like methyl alcohol, ingestion of intravenous fluids including alkali will enhance of ethylene glycol can result in profound metabolic renal excretion of salicylate and reduce blood sali acidosis (Jacobsen & McMartin 1986). Cardiopul cylate to the safe range in a matter of hours. When monary failure, coma and acute renal failure may the intoxication is unusually severe, or when renal evolve over a period of hours to days. As with failure or cardiac disease complicate the picture, methyl alcohol, administration of ethyl alcohol dialysis or haemoperfusion may be necessary. Of blocks the metabolism ofthe parent compound to these options, haemodialysis is preferred because its toxic metabolite, glycolic acid, by virtue of its it promptly corrects the metabolic acidosis as well greater affinity for alcohol dehydrogenase. Alkali as removing salicylate from the blood. therapy , haemodialysis and ethyl alcohol admin istration (see Methyl Alcohol) constitute appropri 1.3.8 Renal Tubular Acidosis (RTA) ate therapy. A pharmacological inhibitor of alcohol Patients with distal RTA (type I, gradient-lim dehydrogenase, 4-methylpyrazole, may prove to be ited) almost always require long term alkali therapy a safe and easier alternative to ethyl alcohol infu- to prevent severe acidosis, decrease renal potas- 848 Drugs 39 (6) 1990

sium losses, and prevent bone disease. The main and the resulting hypercapnia attenuates the in tenance dose of alkali required varies considerably, crease in systemic pH. primarily because the degree of bicarbonate wast ing that may accompany the distal defect is also 2.1 Clinical Manifestations highly variable. In the absence of appreciable bi carbonate wasting, approximately I mliq/kg/day of Even in the absence of underlying lung disease, alkali should suffice. In practice, however, most secondary hypoventilation is accompanied by some adults and older children require 2 to 3 mfiq/kg,' degree of hypoxia. With plasma bicarbonate con day of supplemental alkali because of some bi centrations greater than 60 mrnol/L, values for carbonate wasting (Kassirer et al. 1989). pa02 as low as 45 to 50mm Hg may occur in Occasionally these patients may present with patients even with normal pulmonary function profound metabolic acidosis and severe hypoka (Tuller & Meddi 1971). In patients with pre-exist laemia. The deficits of bicarbonate and potassium ing pulmonary disease, the hypoxia may be even may be several hundred milli-equivalents each. more severe. Two other prominent manifestations Rapid simultaneous administration of sodium bi of alkalaemia are hypokalaemia and central nerv carbonate and potassium chloride is required in ous system dysfunction. The hypokalaemia that is such individuals. frequently associated with metabolic alkalosis is In contrast, patients with proximal RTA (type multifactorial. While substantial potassium losses II, bicarbonate-wasting) rarely develop severe acid often accompany the processes that generate al osis yet they may need to ingest alkali in the range kalosis (e.g. diuretic administration, gastric fluid of 5 to 15 mliq/kg/day to achieve normal plasma losses), transcellular shifts of potassium and renal bicarbonate concentrations because of huge renal potassium wasting also play an important part in bicarbonate losses (Kassirer et al. 1989). While al the genesis of hypokalaemia. kali therapy tends to ameliorate the hypokalaemia The common central nervous system manifes in distal RTA, the increased delivery of bicarb tations of alkalaemia include lethargy and confu onate to the distal nephron promotes potassium sion. In severe alkalaemia muscle twitching and secretion in proximal RTA. generalised seizures can occur. Whether alkalaemia per se is responsible for these derangements or 1.3.9 Renal Acidosis (Uraemic Acidosis) whether they can be ascribed to the hypoxia and Some degree of acidosis is usually present in volume depletion that often accompanies the patients with chronic renal insufficiency when the metabolic alkalosis remains speculative. glomerular filtration rate is reduced to 25 ml/min or less (Harrington et al. 1982), but the degree of 2.2 Causes of Metabolic Alkalosis acidosis is not usually severe enough to warrant treatment. However, when plasma bicarbonate falls The causes of metabolic alkalosis can be di below 15 mmol/L, alkali should be provided in a vided into 4 groups (table II). The first group con dose of I to 2 mliq/kg/day. Patients with severe sists of alkaloses secondary to alkali administra renal insufficiency should be monitored carefully tion. Administration of exogenous alkali at rates for signs of volume overload because of the accom greater than endogenous acid production will in panying increase in sodium intake. crease plasma bicarbonate concentration, but when the alkali is discontinued prompt excretion of an 2. Metabolic Alkalosis alkaline urine restores plasma bicarbonate to nor mal. Examples of metabolic alkalosis that fall into Metabolic alkalosis is initiated by an increase in this category are the milk-alkali syndrome and acute plasma bicarbonate. This alkalinisation gives rise sodium bicarbonate or sodium acetate loading. to a compensatory decrease in alveolar ventilation, The second group consists of chloride-respon- Treatment of Acid-Base Disorders 849

Table II. Causes of metabolic alkalosis (from Kassirer et al. 1989, ing's syndrome, and primary aldosteronism fall into with permission) this category. Urinary chloride excretion is often

Alkalosis secondary to alkali administration high and the alkalosis persists despite chloride Continuous alkali administration administration. Milk-alkali syndrome The disorders that fall into the last category Ingestion of large quantities of sodium bicarbonate (idiopathic alkalosis) are not well defined, although Ingestion of soybean formula diet at least some have been attributed to extreme po Combined therapy with nonabsorbable alkali and exchange resins tassium depletion. Recovery from organic acidosis Acute alkali loading 2.3 Treatment of Metabolic Alkalosis Chloride-responsive alkalosis Gastric fluid losses The treatment of metabolic alkalosis also centres Diuretic therapy Posthypercapnic state on the prompt identification and removal of the Stool losses underlying process that caused the alkalosis. If the Congenital chloridorrhoea cause is not obvious or if surreptitious vomiting or Villous adenoma self-administration of diuretics are being enter Chloride-resistant alkalosis tained as aetiologies, measurement of urinary Primary aldosteronism chloride and pH may be useful. A low urine chlor Bartter's syndrome Cushing's syndrome ide (less than 10 to 20 mmol/L) points toward a Disorders that simulate adrenocortical excess chloride-responsive alkalosis, whereas a higher Idiopathic value suggests the recent administration of a di Miscellaneous uretic, or less commonly, a chloride-resistant form Secondary aldosteronism of metabolic alkalosis. The presence of a persist Malignant hypertension Renovascular hypertension ently alkaline urine should raise the possibility of Renin-secreting tumours excessive alkali intake, as in the milk-alkali syn Mineralocorticoid excess (other than aldosterone) drome. Penicillin therapy In most cases of mild to moderate chloride-re Parathyroid disease and hypercalcaemia sponsive metabolic alkalosis, when adequate chlor Refeeding fof/owing fasting ide is provided the kidney excretes the surplus al kali and restores acid-base balance to normal over sive alkaloses. In this variety, alkalosis is perpet a matter of days. The alkalosis associated with the uated by sodium avidity and disproportionate chloride-resistant disorders is not generally severe chloride depletion. Common examples are the al and therapy should be directed at the primary de kalosis due to diuretic therapy and gastric fluid fect. When severe alkalaemia is present (plasma bi losses. Typically, little or no sodium chloride is ex carbonate greater than 40 mmol/L), the adminis creted in the urine because losses of sodium chlor tration of hydrochloric acid or a hydrochloric acid ide and water during the development of the al precursor may be required . In the same fashion as kalosis have induced mild to moderate volume estimating the quantity of alkali to administer to depletion. This type of metabolic alkalosis is cor severely acidotic patients, the quantity of acid re rected promptly by either sodium or potassium quired in mEq can be calculated by assuming that chloride administration. the volume of distribution of bicarbonate is roughly In contrast, in the third group, chloride-resist equivalent to 50% of bodyweight and by multiply ant alkaloses, alkalosis is maintained in the ab ing this figure by the desired decrement in bicarb sence of volume contraction and in the face of onate concentration. abundant dietary (and urinary) chloride. The al Hydrochloric acid, ammonium chloride and ar kalosis accompanying Bartter's syndrome, Cush- ginine monohydrochloride infusions are useful for 850 Drugs 39 (6) 1990

the treatment of severe metabolic alkalosis. Hy patients with severe renal insufficiency, metabolic drochloric acid solutions must be administered alkalosis may result (Schroeder 1969). As the resin through a central line to avoid severe corrosive re absorbs the ingested cation, intestinal bicarbonate actions. One litre of 0.1N HC! contains 100 mEq is made available for absorption. Discontinuing ofhydrogen ions; the rate ofadministration of this either one or both of these agents results in dissi solution should not exceed 300 to 500 ml/h (Kas pation of the alkalosis, but because of the under sirer et al. 1989). Alternatively, a 2.14% solution lying renal impairment it may take several days for of ammonium chloride containing approximately plasma bicarbonate concentration to return to con 400 mEq of hydrogen ion/L can be made from a trol levels. 26.75% stock solution. Ammonium chloride should not be administered at rates greater than 300 to 2.3.3 Acute Alkali Loading 400 ml/h, Hepatic conversion of ammonium Rapid administration of sodium bicarbonate or chloride yields urea and hydrochloric acid. The sodium acetate results in metabolic alkalosis when major contraindication to administering a solution the rate of infusion exceeds the capacity ofthe kid containing ammonia is liver disease. The third op ney to excrete the excess alkali. In addition to an tion for acidification is the use of arginine mono immediate increase in plasma bicarbonate concen hydrochloride. 300ml of a 10% solution contains tration, plasma carbon dioxide tension will in approximately 150 mEq of hydrogen ions; this crease acutely because carbonic acid is generated amount can be given over I hour, if necessary from the titration of nonbicarbonate buffers. This (Kassirer et al. 1989). Dangerous hyperkalaemia can effect is only relevant clinically when ventilation occur during the course ofarginine administration, is controlled by artificial means. In such patients presumably from displacement of intracellular po arterial blood gases should be monitored during al tassium by the arginine cation (Bushinsky & Gen kali infusion. nari 1978). This effect seems to be more common in patients with abnormal renal function . Serum 2.3.4 Gastric Fluid Losses potassium should always be monitored carefully The primary therapy of metabol ic alkalosis in during and after an arginine monochloride infu duced by vomiting or nasogastric suctioning is to sion. provide an adequate supply of chloride salt and thus to curtail renal bicarbonate generation. In this 2.3.1 Milk-Alkali Syndrome regard, urinary chloride excretion is a valuable in In its classic form, the milk-alkali syndrome de dex of whether chloride intake is sufficient. Values velops in patients who ingest large quantities of of at least 50 mliq/day generally signify adequate milk and absorbable alkali, but it occurs in patients replacement. When large amounts of gastric fluid who have ingested only calcium carbonate. The are being lost, it may be useful to measure the elec syndrome is characterised by the triad ofmetabolic trolyte composition of the fluid, and estimate the alkalosis, hypercalcaemia and renal insufficiency. hydrogen ion concentration (as the difference be In most cases, therapy consists of eliminating the tween the sum of the sodium and potassium con alkali load. When the milk-alkali syndrome occurs centrations and the chloride concentration). Re in the setting of vomiting or gastric suction, ade placement of hydrogen ion losses with hydrochloric quate chloride must also be provided. acid or a hydrochloric acid precursor will prevent metabolic alkalosis from developing, but this ap 2.3.2 Combined Therapy with Nonabsorbable proach is generally not needed unless gastric losses Alkali and Exchange Resins are unusually large. Alternatively, histamine H2 When nonabsorbable alkali (e.g. magnesium hy receptor antagonists, by inhibiting gastric acid se droxide, aluminium hydroxide) and cation-ex cretion, may be effective in preventing the gener change resins are administered simultaneously to ation of metabolic alkalosis. These agents are not Treatment of Acid-Base Disorders 851

effective, of course, in the correction of established times it may be necessary to lower plasma bicarb alkalosis. onate concentration with hydrochloric acid or a hydrochloric acid precursor. Reducing the plasma 2.3.5 Diuretic Therapy bicarbonate concentration to a value unsuitably low Diuretic-induced metabolic alkalosis falls into for the prevailing paCOz in patients with chronic the chloride-responsive category. The agents typi lung disease may result in acidaemia, however, cally responsible include furosemide (frusemide), when the patient is removed from the ventilator. ethacrynic acid, bumetanide and metolazone. Di uretics cause metabolic alkalosis by 3 mechanisms: 2.3.7 Primary Aldosteronism (a) an increase in renal acid excretion; (b) a dis Hypersecretion of aldosterone by the adrenal proportionate loss of chloride-rich fluid; and (c) a cortex induces sodium retention, hypertension, and transcellular shift of hydrogen ions. As with gastric metabolic alkalosis of the chloride-resistant type. alkalosis, administering sufficient chloride salt will Administration of sodium chloride to patients with prevent metabolic alkalosis from developing dur the syndrome of primary aldosteronism does not ing diuretic therapy. In the majority of patients, correct the alkalosis and aggravates hypokalaemia potassium chloride is the appropriate therapy, but by increasing urinary potassium losses. In contrast, in the presence of volume depletion sodium chlor spironolactone, an aldosterone antagonist, promptly ide should be provided as well. By inhibiting sod corrects the hypertension and hypokalaemia, and ium reabsorption and hydrogen secretion, distal restores acid-base balance to normal. Amiloride, a blocking agents (e.g. spironolactone, triamterene, nonspecific distal blocking agent with properties amiloride), are effective in preventing diuretic-in similar to spironolactone, is also effective. duced alkalosis. Caution should be exercised when these agents are administered to patients with renal 2.3.8 Bartter's Syndrome insufficiency because of the danger of severe hyper Bartter's syndrome is a rare disorder character kalaemia. Acetazolamide, a carbonic anhydrase in ised by hypokalaemia, metabolic alkalosis and nor hibitor, is effective in the treatment of metabolic mal blood pressure. Histologically the juxtaglom alkalosis particularly when used on alternate days. erular apparatus of the kidney is hyperplastic and Severe hypokalaemia may occur, however, if care hyperreninaemic hyperaldosteronism is a charac is not taken to replete potassium stores during teristic finding. The exaggerated synthesis and ex administration of the drug. cretion of renal prostaglandins that accompany the hyperreninaemic state are probably a secondary ef 2.3.6 Posthypercapnic Alkalosis fect (Halushka et al. 1977). Posthypercapnic metabolic alkalosis occurs when Hypokalaemia and alkalosis in these patients can hypercapnia is corrected acutely with mechanical be difficult to treat. Prostaglandin inhibitors are ventilation and the plasma bicarbonate concentra dramatically effective in some patients, but in tion remains inappropriately high. Care should be others the defects are only partially responsive and taken to lower the paCOz gradually in the presence the beneficial effect is short-lived (Verberckmoes of chronic hypercapnia, and adequate chloride et al. 1976). Indomethacin, at a dose of 150 to 200 should be provided to permit bicarbonate excre mg/day, is an appropriate starting regimen. Addi tion. If severe alkalosis develops acutely, the re tional potassium chloride may be needed. Should spirator should be adjusted to allow the paCOz to the response to indomethacin not be sustained, an rise. Persistent metabolic alkalosis can reduce the other prostaglandin inhibitor may be successful. In ventilatory drive and impede weaning. Acetazol patients in whom prostaglandin inhibitors are amide may be of value in augmenting bicarbon otherwise contraindicated, potassium sparing agents aturia, but it should be used as an adjuvant to ad in combination with potassium chloride may im ministering chloride salts, not as a substitute. At prove the alkalosis and hypokalaemia. Clearly, the 852 Drugs 39 (6) 1990

combination of a potassium sparing diuretic and a 3.2 Causes of Respiratory Acidosis potassium salt is potentially dangerous and should only be used with careful monitoring ofplasma po Airway obstruction or dysfunction of the regu tassium concentration. latory system controlling ventilation can result in alveolar hypoventilation and hypercapnia. Causes 2.3.9 Cushing 's Syndrome of respiratory acidosis include obstruction of large The metabolic alkalosis that accompanies Cush or small airways, respiratory centre depression, cir ing's syndrome is typically mild and occurs in only culatory catastrophes, or neuromuscular and re one-third of patients. In contrast, severe alkalosis strictive defects. and hypokalaemia are more common in patients with carcinoma of the adrenal cortex and in those 3.3 Treatment of Respiratory Acidosis with adrenal hyperplasia associated with cortico trophin (ACTH)-producing tumours (particularly The treatment of respiratory acidosis should be lung cancer). Administration ofpotassium chloride directed at prompt correction of the underlying is appropriate, but therapy is best directed at the causal process. The major insult of acute respira underlying process. tory acidosis is hypoxaernia, and oxygen must be administered at the onset. If ventilatory support is 3. Respiratory Acidosis necessary in acute hypercapnia, the paC02 can be rapidly dropped to normal without adverse con Respiratory acidosis is initiated by an increase sequences. Alkali administration should be given in carbon dioxide tension. The immediate conse only for superimposed metabolic acidosis. quence of an increase in arterial carbon dioxide In chronic respiratory acidosis efforts to correct tension (paC02) is an increase in plasma acidity. the cause are often less fruitful because of the ir Acutely, titration of nonbicarbonate buffers results reversible nature of the underlying disease process. in a small increase in plasma bicarbonate concen Careful attention to volume status, nutrition, chest tration, but when hypercapnia is sustained, en physiotherapy and the administration of broncho hanced renal reabsorption of bicarbonate further dilators and antibiotics are often effective in im increases plasma bicarbonate concentration. proving ventilation. In view of the chronic nature ofthe hypercapnia, it is prudent to decrease paC02 3.1 Clinical Manifestations toward normal over a period of hours to days and simultaneously to provide sufficient chloride to al Central nervous system manifestations are the low the kidneys to excrete previously retained bi most important clinical consequences of hypercap carbonate. As described above, more rapid repair nia. The factors correlated with cerebral dysfunc may result in posthypercapnic alkalosis. Likewise, tion are the magnitude ofthe hypercapnia, the rap any coexisting metabolic alkalosis should be idity with which it develops, the severity of the promptly treated because alkalosis may blunt ven acidaemia and the degree of attendant hypoxia . tilation and induce hypoxia. Acute hypercapnia induces peripheral vasodilata tion, stimulates the sympathetic nervous system 4. Respiratory Alkalosis and increases cardiac output. Arrhythmias fre quently occur during acute and chronic hypercap Respiratory alkalosis is initiated by a reduction nia. Whether the absolute level of hypercapnia is in arterial carbon dioxide tension, which alkalin arrhythmogenic or whether rapid change in paC02, ises the body fluids. Titration of nonbicarbonate hypoxia or acidaemia is the culprit remains to be buffers results in a small decrement in plasma bi determined. carbonate concentration. Over time, changes in the Treatm ent of Acid-Base Disorders 853

renal absorption of bicarbonate serve to attenuate simple disorders can arise. When plasma bicarb the degree of alkalinisation. onate concentration and paC02 are altered in op posite directions extreme shifts in hydrogen ion 4.1 Clinical Manifestations concentration may ensue, whereas changes in the same direction tend to ameliorate the change in As with respiratory acidosis, central nervous pH. Some common mixed disorders are discussed. system dysfunction is the most prominent clinical feature of respiratory alkalosis. Acute hypocapnia 5.1 Metabolic and Respiratory Acidosis induces lightheadedness, confusion and, on occa sion, seizures. These manifestations are mediated A mixed metabolic and respiratory acidosis is through a decrease in cerebral blood flow: for ex readily apparent whenever the plasma bicarbonate ample, a 40% reduction in flow is observed at a is low and the paC02 is high. A more subtle ver paC02 of 20mm Hg. In fact, this effect on blood sion of this mixed disorder is present in patients flow provides the rationale for inducing acute hy with respiratory acidosis and a normal rather than pocapnia in selected settings to reduce cerebral elevated plasma bicarbonate concentration. Simi oedema. Chronic respiratory alkalosis appears to larly, when metabolic acidosis is not accompanied be better tolerated in terms of cerebral dysfunction. by an appropriate decrease in paC02, a mixed dis 4.2 Causes of Respiratory Alkalosis order exists. Common examples of mixed meta bolic and respiratory acidosis are untreated cardio Respiratory alkalosis is associated with many pulmonary arrest, chronic obstructive lung disease serious illnesses. In an intensive care unit, respi complicated by septic shock, and poisoning with ratory alkalosis appears to be the most common various drugs and toxins. Because an extreme de acid-base derangement. In such patients, a paC02 gree of acidosis can occur with mixed metabolic of 15mm Hg or less has been associated with a and respiratory acidosis, it is imperative that the mortality rate of almost 90% (Mazzara et al. 1974). mixed nature of the disturbance is identified early The causes of hypocapnia are many, including hy and therapy is directed at both disorders. poxia, pulmonary disease and various central nerv ous system disorders. 5.2 Metabolic and Respiratory Alkalosis

4.3 Treatment of Respiratory Alkalosis Similarly, a mixed metabolic and respiratory al kalosis can be diagnosed whenever the plasma bi As in treating all acid-base disorders, the therapy carbonate is high and the paC02 is low. Here, too, of respiratory alkalosis is centred on reversal of the the extreme shift in hydrogen ion concentration that root cause. Short of this goal, there is no effective occurs makes recognition of vital importance. treatment of primary hypocapnia. Hypoxia itself is Mixed metabolic and respiratory alkalosis can oc a frequent cause of hypocapnia, and administra cur when patients with respiratory alkalosis (e.g. tion of oxygen alone often suffices to correct the from congestive heart failure) are treated with po alkalosis. If the cause is not immediately apparent, tent diuretics . Another setting where this disturb consideration should be given to salicylate intox ance may occur is when patients with primary hy ication, early Gram-negative sepsis and meningitis, pocapnia associated with liver disease are treated because early intervention may be life-saving. with diuretics or gastric drainage. Clearly, therapy 5. Mixed Acid-Base Disturbances should be directed at removing the underlying cause, if possible. In view of the difficulty in treat The coexistence ofmore than one acid-base dis ing primary hypocapnia , efforts to reduce the ele order is a frequent occurrence and is termed a vated plasma bicarbonate concentration are more mixed disturbance. Virtually any combination of fruitful. 854 Drugs 39 (6) 1990

5.3 Metabolic Acidosis and Respiratory accumulation, the amount of alkali needed will be Alkalosis increased, and the quantity to be administered can be determined only by repeated monitoring of a The mixed disturbance comprised of metabolic patient's acid-base status. Excessiveadministration acidosis and respiratory alkalosis can be diagnosed of alkali has its own dangers. when plasma bicarbonate concentration and paC02 Therapy in metabolic alkalosis also depends on are both low and the pH is normal or near normal. the nature of the underlying cause. Those disorders This disturbance can occur when severe metabolic characterised by depletion of body chloride stores acidosis is rapidly corrected, when lactic acidosis will respond well to treatment with sodium or po complicates septic shock, in salicylate intoxication, tassium chloride; those unassociated with chloride and in the hepatorenal syndrome. Treatment must deficiency (principally hyperadrenal states) require be directed at the specific acid-base disorders and elimination of the root cause. In both forms, the underlying process. administration of hydrochloric acid or a hydro chloric acid precursor may be needed when alka 5.4 Metabolic Alkalosis and Respiratory laemia is particularly severe. Acidosis In acute respiratory acidosis and acute respira tory alkalosis, prompt restoration of carbon diox A diagnosis of mixed metabolic alkalosis and ide tension to normal immediately restores normal respiratory acidosis can be made when plasma bi acid-base equilibrium and avoids the complica carbonate concentration and paC02 are both ele tions of hypercapnia or hypocapnia. vated and the pH is normal or near normal. This The therapy of chronic respiratory acidosis must disturbance is commonly seen in patients with take into account the increase in plasma bicarb chronic lung disease who are treated with diuretics. onate concentration that occurs during adaptation Gastric drainage, vomiting or various other causes to chronic hypercapnia. When carbon dioxide ten of metabolic alkalosis will produce a similar pic sion in such patients is reduced abruptly, plasma ture when superimposed on respiratory failure. Ef bicarbonate concentration must be reduced simul forts should be directed at improving ventilation taneously, so as to avoid posthypercapnic meta and specifically treating the metabolic alkalosis. bolic alkalosis. Administration of the sodium or Even a small component of coexisting metabolic potassium salts of chloride is usually sufficient to alkalosis will decrease ventilation and interfere with avoid this complication . weaning efforts. As noted previously, administra Elimination of the cause of the sustained hy tion of carbonic anhydrase inhibitors (e.g. aceta pocapnia is the only approach to the treatment of zolamide) may be useful in this setting. When sev chronic respiratory alkalosis. Attempts to treat the ere alkalaemia is present, hydrochloric acid or a acid-base disorder per se are usually futile. hydrochloric acid precursor should be admini In all acid-base disturbances, therapy is an it stered. erative process. No therapeutic algorithm exists which offers a prospective, preset therapeutic pack 6. Conclusions age. Repeated, and sometimes continuous observ ation ofthe patient and repeated measurements of Prompt and appropriate therapy reduces or the patient's acid-base parameters are required for eliminates many morbid effects of acid-base dis optimal therapy. turbances. In many forms of metabolic acidosis, admin References istration of sodium bicarbonate increases plasma Baud FJ. Galliot M. Astier A. Bien DV. Garnier R. et al. Treat bicarbonate concentration predictably. In disord ment of eth ylene glycol poisoning with intravenous 4-meth ers characterised by rapid alkali loss or rapid acid ylpyrazole. New England Journal ofMedicine 319: 97-100.1988 Treatment of Acid-Base Disorders 855

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