Contents

Practical Therapeutics

Drugs 39 (6): 841-855, 19900012-6667/90/0006-0841/$07.50/0© ADlS Press LimitedAll rights reserved.DRUG03353

Rational Treatment of Acid-Base Disorders

Margaret L. McLaughlin and Jerome P. Kassirer

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

Summary , ,.., , ,.., ,.., ,..,.. 842I. Metabolic Acidosis 843

1.1 Clinical Manifestations 8431.2 Causes of Metabolic Acidosis 843

1.3 Treatment of Metabolic Acidosis 8441.3.1 General Remarks 844

1.3.2 Loss of Alkaline Gastrointestinal Fluids 8451.3.3 Carbonic Anhydrase Inhibitors 845

1.3.4 Urinary Diversion , 8451.3.5 Lactic Acidosis 8451.3.6 Diabetic Ketoacidosis 8461.3.7 Alcoholic Ketoacidosis 8461.3.8 Renal Tubul ar Acidosis ll471.3.9 Renal Acidosis (Uraem ic Acidosis) 848

2. Metabolic Alkalosis , 8482.1 Clinical Manifestations 848

2.2 Causes of Metabolic Alkalosis 8482.3 Treatment of Metabolic Alkalosis 849

2.3.1 Milk-Alkali Syndrome 8502.3.2 Combined Therapy with Nonabsorbabl e Alkali and Exchange Resins 8502.3.3 Acute Alkali Loading 8502.3.4 Gastric Fluid Losses 850

2.3.5 Diuretic Therapy , 8512.3.6 Posthypercapnic Alkalosis 8512.3.7 Primary Aldosteron ism 8512.3.8 Bartt er's Syndrom e 85I2.3.9 Cushing's Syndrome 852

3. Respiratory Acidosis 852

3.1 Clinical Manifestations 8523.2 Causes of Respiratory Acidosis , 852

3.3 Treatment of Respiratory Acidosis , 8524. Respiratory Alkalosis 852

842

Summary

Drugs 39 (6) 1990

4.1 Clinical Manifestations 8534.2 Causes of Respiratory Alkalosis 8534.3 Treatment of Respiratory Alkalosis 853

5. Mixed Acid-Base Disturbances 8535.1 Metabolic and Respiratory Acidosis 8535.2 Metabolic and Respiratory Alkalosis 8535.3 Metabolic Acidosis and Respiratory Alkalosis 8545.4 Metabolic Alkalosis and Respiratory Acidosis 854

6. Conclusions 854

Acid-base derangements are encountered frequently in clinical practice and many havelife-threatening implications. Treatment is dependent on correctly identifying the acid­base disorder and , whenever possible, repairing the underlying causal process. Bicarb­onate is the agent of choice for the treatment of acute metabolic acidosis. Controversysurrounds the use of alkali therapy in lactic acidosis and diabetic ketoacidosis, but bi­carbonate should clearly be administered for severe acidos is. In most patients with mildto moderate chloride-responsive metabolic alkalosis, providing an adequate amount ofa 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 underlyingdisease . When alkalaemia is severe , administering hydrochloric acid or a hydrochloricacid precursor may be necessary .

Treatment of respiratory acidosis should be targeted at restoring ventilation ; alkalishould be administered only for superimposed metabolic acidosis . The therapy of res­piratory alkalosis is centred on reversal of the root cause ; short of this goal, there is noeffective treatment of primary hypocapnia.

The coexistence of more than one acid-base disorder (i.e. a mixed disorder) is notuncommon. 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 directedat both disorders.

Disturbances of acid-base balance are wide­spread in practice and many pose serious threatsto the well-being of patients. A rational approachto the treatment of acid-base disorders is depend­ent on an understanding of the basic pathophys­iological mechanisms that give rise to them. Cor­rect identification of the underlying disturbancemay suggest new diagnostic avenues, as well asprovide a guide to specific, and often life-saving,therapy.

The carbonic acid-bicarbonate buffer systemplays a central role in acid-base balance because ofits prevalence and its relation to physiological reg­ulatory mechanisms. The hydration of dissolvedC02 forms carbonic acid which then dissociates toyield bicarbonate and hydrogen ions. These chem-

ical reactions rapidly achieve equilibrium condi­tions, allowing a simple expression of their rela­tionship (Henderson 1908):

(Eq. I)

Thus, hydrogen ion concentration is a functionof the ratio of the arterial carbon dioxide tension(paC02) to the bicarbonate concentration. It fol­lows that changes in hydrogen ion concentrationand, consequently, all acid-base disorders, resultfrom changes in one or other of these 2 variables.

Acid-base disturbances are classified into 4 pri­mary disorders - metabolic acidosis, metabolic al­kalosis, respiratory acidosis and respiratory alka­losis - and various combinations of these disorderscategorised as mixed disturbances.

Treatment of Acid-Base Disorders

1. Metabolic Acidosis

Metabolic acidosis is initiated by a reduction inplasma bicarbonate concentration. The most im­mediate consequence of a fall in bicarbonate con­centration is an increase in plasma acidity. Cor­responding changes in cerebral hydrogen ionconcentration are sensed by central chemorecep­tors, giving rise to reflex hyperventilation, a fall inpaC02, and a consequent attenuation in the degreeof acidification.

1.1 Clinical Manifestations

The clinical manifestations of metabolic acid­osis include effects on the cardiovascular and pul­monary systems, the circulation, oxygen transport,and potassium metabolism (Mitchell et al. 1972;Relman 1972). Hyperventilation, or Kussmaul res­pirations, is one of the most readily apparentmanifestations of severe acidosis. Myocardial dys­function due to acidosis and a reduced thresholdfor ventricular fibrillation also occur. Acidosis hasseveral effects on vascular tone, producing directarterial vasodilatation, indirect sympathetic-me­diated vasoconstriction, and direct venous vaso­constriction. In addition , acute acidaemia shifts thehaemoglobin dissociation curve to the right, butacidosis-induced depletion in cellular 2,3-diphos­phoglycerate shifts the curve back in a matter ofhours (Mitchell et al. 1972). Hyperkalaemia is afrequent accompaniment of acute metabolic acid­osis and has been attributed to transcellular shiftsofpotassium in response to acidosis. However, cer­tain types of metabolic acidosis due to organic acids(e.g, lactic acid and acetoacetic acid) have little orno direct effect on serum potassium concentration(Fulop 1979). When hyperkalaemia does occur inthese kinds of acidosis, decreased renal function orinsulin deficiency is probably more important inits genesis.

1.2 Causes of Metabolic Acidosis

Three distinct pathological processes work aloneor in concert to produce metabolic acidosis: (a) lossof bicarbonate; (b) addition of acid; and (c) re-

843

duced capacity of the kidneys to excrete acid (seetable I).

Loss of bicarbonate-rich fluid results in deple­tion of extracellular fluid volume and a reductionin bicarbonate concentration. At the same time,chloride concentration rises as the remainingchloride is confined to a smaller volume of distri­bution. Such a hyperchloraemic metabolic acidosisresults from diarrhoea (Darrow et al. 1949), pan­creatic or biliary drainage, administration of car­bonic anhydrase inhibitors, and certain forms ofurinary diversion . Administration of hydrochloricacid and substances which give rise to hydrochloricacid when metabolised (e.g. ammonium chloride,

Table I. Causes of metabolic acidosis (from Kassirer et al. 1989.with permission)

Normal anion gapLoss of bicarbonate

DiarrhoeaSmall bowel lossesCarbonic anhydrase inhibitorsUreterosigmoidostomyIleal loop bladderDilutional acidosis

Addition of hydrochloric acidAmmonium chlorideArginine-HCILysine-HCITotal parenteral nutrition

Disproportionate failure of renal tubular functionRenal tubular acidosisMild renal failureHyporeninaemic hypoaldosteronismAdrenal insufficiency

Increased anion gapOverproduction of organic acids

Lactic acidosisDiabetic ketoacidosisStarvation ketosisAlcoholic ketoacidosisMethyl alcohol ingestionEthylene glycol ingestionParaldehyde ingestionSalicylate intoxicationInfantile organic acidosis

Severe renal failure

AcuteChronic

844

lysine-HC1, and arginine-HCl) also produce hy­perchloraemic acidosis. The normal kidney re­sponds to the reduction in plasma bicarbonate byaugmenting net acid excretion, resulting in the con­servation of sodium with newly generated bicarb­onate and in the excretion of chloride and hydro­gen ion.

Overproduction of organic acids results in a fallin plasma bicarbonate concentration and an in­crease in the plasma concentration of the anion ofthat acid. In contrast to the pattern seen with directloss of bicarbonate or administration of substancesthat yield hydrochloric acid, the acidosis that re­sults from organic acid overproduction is charac­terised by a normal plasma chloride concentrationand an increase in the concentration of plasma un­measured anions. The causes of metabolic acidosiswith an increased anion gap include: lactic acid­osis; diabetic ketoacidosis; starvation ketosis; al­coholic ketoacidosis ; methyl alcohol, ethylene gly­col and paraldehyde intoxication; and salicylateoverdose (Gabow 1985). Some degree of sodiumand potassium depletion often accompanies thistype of metabolic acidosis because these cations areexcreted in the urine with the acid anions .

The third type of metabolic acidosis results froma failure of the kidney to excrete the daily acid load.A hyperchloraemic metabolic acidosis developswith distal renal tubular acidosis and with mildchronic renal insufficiency (Harrington & Cohen1982), but when glomerular function is severelyimpaired, anions (such as phosphate and sulphate)are retained by the kidney and the plasma unmea­sured anion concentration increases as well.

1.3 Treatment of Metabolic Acidosis

1.3.1 General RemarksWhenever possible, efforts should be directed at

identifying and treating the underlying processwhich gave rise to the metabolic acidosis. No mat­ter what the cause, it is recommended that alkalibe administered for severe metabolic acidosis (i.e.plasma bicarbonate < 5 mmol/L). Patients withplasma bicarbonate values in this range are at riskof a sudden worsening in acidaemia with only a

Drugs 39 (6) 1990

small additional decrement in bicarbonate concen­tration or increase in paC02. In normal individ­uals, administered bicarbonate distributes througha space of approximately 40 to 50%of bodyweight,but the space of distribution may be more thantwice that large when plasma bicarbonate is ex­tremely low (Garella et al. 1973). In addition , thereis often no way to assess the magnitude of organicacid production or on-going alkali loss. Conse­quently, estimates of bicarbonate space to predicta desired increment in plasma bicarbonate must beconsidered a first approximation only. Given thelarge number of variables, acid-base parametersshould be assessed frequently and appropriate ad­justments made in the quantity of alkali admini­stered.

Sodium bicarbonate is the agent of choice forthe treatment of acute metabolic acidosis. Sodiumlactate, citrate and acetate require metabolic con­version to bicarbonate to exert their alkalinisingeffect, and hence their therapeutic effect may bedelayed. For long term use, as in the treatment ofrenal tubular acidosis, chronic diarrhoea , or end­stage renal disease, some patients find sodium cit­rate more palatable than bicarbonate salts.

In the acute setting, sodium bicarbonate shouldbe administered intravenously, either as a bolus oradded to a hyponatric solution and given contin­uously. An ampoule of sodium bicarbonate con­tains 50 mEq of sodium and bicarbonate . A readilyaccessible oral form of alkali therapy is sodium bi­carbonate tablets; a 650mg tablet contains 8 mEqof bicarbonate . Sodium citrate is available in a li­quid form; Iml contains I mEcj of sodium and theequivalent of I mEq of bicarbonate .

Hypernatraemia and volume overload are themajor complications of administering large quan­tities of sodium bicarbonate. Metabolic alkalosismay result after treatment of organic acidosis (e.g.diabetic ketoacidosis, lactic acidosis) if bicarbonateis generated from the metabolism of retained or­ganic anions, and post-treatment respiratory alka­losis can occur in any form of metabolic acidosisif hyperventilation persists as a consequence oflag­ging spinal fluid acidification. Transient hypoka-

Treatment of Acid-Base Disorders

laemia, resulting from the shift of potassium intocells, also may develop during the course of therapy.

/.3.2 Loss ofAlkaline Gastrointestinal FluidsMetabolic acidosis caused by loss of gastroin­

testinal fluid is often accompanied by large deficitsof sodium, potassium, chloride and water, in ad­dition to bicarbonate. The severity of the acidosiscaused by stool loss varies with the aetiology of thediarrhoea. Stool bicarbonate concentrations in ex­cess of 40 mrnol/L occur in patients with massivewatery diarrhoea (Watten et al. 1959) and villousadenomas of the rectum, and such losses can resultin moderate to severe metabolic acidosis. The bi­carbonate concentration in pancreatic and biliarydrainage always exceeds that in plasma, but severemetabolic acidosis rarely results unless drainagevolumes are unusually large.

In severe diarrhoea, volume repletion is an im­portant target of initial therapy . Ideally, replace­ment therapy is guided by measurements of theelectrolyte composition of the diarrhoeal fluid. Be­cause such measurements are not very practical,however, a 0.45% saline solution containing 50mfiq/L of sodium bicarbonate is a reasonable in­itial replacement fluid. Potassium losses are typi­cally large and should also be replaced. Acid-baseparameters and serum potassium should be as­sessed frequently and therapy modified accord­ingly.

1.3.3 Carbonic Anhydrase InhibitorsCarbonic anhydrase inhibitors such as aceta­

zolamide are only moderately potent in producingrenal bicarbonate loss; thus, plasma bicarbonateconcentrations rarely fall below 18 mrnol/L as aresult of their use (Harrington & Cohen 1982).Aside from discontinuing these agents, no othertherapy is usually necessary.

/.3.4 Urinary DiversionHyperchloraemic metabolic acidosis is seen less

frequently today with ureteroileostomies than whenureterosigmoidostomies were the preferred ap­proach to urinary diversion. Chloride-bicarbonateexchange, reabsorption of urinary ammonium, and

845

renal tubular damage due to obstruction and in­fection are the mechanisms which produce meta­bolic acidosis. In contrast to ureterosigmoidos­tomy, an ileal conduit permits continuous urinarydrainage to the outside, obviating prolonged con­tact with intestinal mucosa and reducing the op­portunity for exchange. Hyperchloraemic meta­bolic acidosis, particularly if new in onset, shoulddirect attention toward the possibility that an ilealloop has become partially obstructed. Few patientswith ileal diversions need daily alkali therapy.

1.3.5 Lactic AcidosisThe therapy of lactic acidosis is controversial,

but all agree that effective treatment centres on theidentification and correction of the underlying pro­cess. Prompt treatment of low-cardiac-output states,repletion of volume deficits, correction of shockand administration of antibiotics (in the septicpatient) should be given the highest priority. Theuse of vasoconstrictive substances should be min­imised to avoid aggravation of ischaemia of peri­pheral tissues. Invasive haemodynamic monitor­ing in an intensive care unit should be employedto guide the use of volume replacement, cardio­trophic agents and pressors (Madias 1986).

Controversy surrounds the use of alkali therapyin the treatment of lactic acidosis. Experimentalstudies in dogs suggest that administering sodiumbicarbonate may augment the accumulation of lac­tic acid by stimulating its production or interferingwith its metabolism by the liver (Graf et al. 1985).In addition, the evidence in humans of an adverseeffect of alkali therapy in lactic acidosis is not con­vincing. We recommend that sodium bicarbonatebe administered for severe, life-threatening lacticacidosis, that is, when the pH falls below 7.20(which usually corresponds to a plasma bicarbon­ate below 10 mrnol/L). Certainly, at a pH belowthis value, the negative inotropic and arrhythmo­genic effects of acidaemia are substantial, and al­kali therapy gains time to address the principal dis­order. No specific guidelines can be given regardingthe amount of alkali to be administered becausethe rate of lactic acid production varies tremen­dously. As a general rule, however, it is desirable

846

to give sufficient alkali to maintain plasma bicarb­onate concentration at 15 to 18 mmol/L, Acid-baseparameters should be assessed frequently andtherapy modified accordingly.

Adjunctive or alternative therapy to sodium bi­carbonate in the treatment of lactic acidosis withdichloroacetate also has been proposed. Whiledichloroacetate augments the oxidation of lactateto acetyl-CoA, and evidence from human studiesis promising (Stacpoole et al. 1983), toxicity maybe a major drawback to its use.

1.3.6 Diabet ic KetoacidosisThe mainstay of therapy of diabetic ketoacid­

osis is insulin, but repletion of fluid and electrolytedeficits and appropriate use of alkali are of equalimportance (Sanson & Levine 1989). In recentyears, the effectiveness of physiological doses of in­sulin has been well established. Several insulin dos­age schedules have been shown to be effective.Typically, a small loading dose of regular insulin(2 to 12 units) is administered intravenously, or adose of 20 units is given intramuscularly followedby a continuous infusion (2 to 12 units/hour). Theamount of insulin administered hourly is adjustedto achieve a decrement in glucose concentration ofapproximately 100 mg/dl/h (5.6 mrnol/L) [Kassi­rer et al. 1989]. In the initial stages of treatment,blood glucose levels and electrolytes should bemeasured hourly. Insulin therapy should be con­tinued until hyperglycaemia and ketonaemia haveresolved . To avoid hypoglycaemia, glucose shouldbe added to the replacement fluids when the bloodsugar level falls below 300 mg/dl (16.7 rnrnol/L).Given the short half-life of intravenous insulin, ap­proximately one-half to two-thirds of the usual dailyinsulin dose should be given subcutaneously asintermediate-acting insulin one hour before dis­continuing the insulin infusion .

As with lactic acidosis , the use of endogenousalkali in the treatment of diabetic ketoacidosis isthe subject of debate . Post-treatment alkalaemia,worsening hypokalaemia due to an alkali-inducedtranscellular shift of potassium, and persistent hy­perventilation because of lagging equilibration ofarterial blood with the spinal fluid, have been cited

Drugs 39 (6) 1990

as the major objections to the use of sodium bi­carbonate. One recent randomised, prospectivestudy in patients with severe diabeti c ketoacidosis(arterial pH 6.9 to 7.14) found no significant dif­ference in the rate of decline of plasma glucose orketone levels or in the rate of increase in pH orplasma bicarbonate levels in patients who receivedbicarbonate or in those who did not (Morris et al.1986). It is difficult to draw conclusions from thisstudy because the number of subjects was smalland the patients selected were free of complicatingillnesses. When acidosis is severe (plasma bicarb­onate concentration less than 5 mmol/L), a smalladditional loss of bicarbonate, or an increase in en­dogenous acid production from superimposed sep­sis and lactic acidosis , might easily result in life­threatening acidosis. Likewise, any faltering inventilation because of fatigue, pneumonia or otherdisorders could cause paC02 to rise (or to fail todecrease) and the blood pH could fall below 7.00.Consequently, in patients with plasma bicarbonateconcentration less than 5 mmol/L, and particularlyin those with complicating illnesses, we believe thatthe benefits of administering enough alkali to raiseplasma bicarbonate by 3 to 4 mmol/L outweigh therisks.

1.3.7 Alcoholic KetoacidosisThis disorder is typically diagnosed in chronic

alcoholics following a prolonged drinking bout.Profound acidosis is the rule, with plasma bicarb­onate concentrations frequently less than 10 mmol/L (Miller et al. 1978). Accumulation of 3-hydroxybutyric acid is mainly responsible for the acidosis.However, despite the severe acidaemia, alcoholicketoacidosis corrects with relative ease, and alkalitherapy or insulin administration is rarely neces­sary. Infusion of glucose and saline frequently re­sults in rapid correction of the acidosis in a matterof hours .

IntoxicationsMethyl Alcohol: Ingestion of methyl alcohol may

result in serious consequences even when treat­ment is promptly initiated (Jacobsen & McMartin1986). The major manifestations are diminution in

Treatment of Acid-Base Disorders

vision accompanied by peripapillary oedema andhyperaemia of the optic discs, severe metabolicacidosis (with an increased anion gap), and abdom­inal pain probably due to pancreatitis (Bennett etal. 1953). Methyl alcohol is metabolised by the en­zyme alcohol dehydrogenase to produce formal­dehyde and formic acid, the latter being the pri­mary toxin .

Dialysis is the mainstay of the treatment ofmethyl alcohol intoxication. Haemodialysis effec­tively removes both the parent compound and itsmetabolites and also rapidly corrects the metabolicacidosis. Peritoneal dialysis is less efficient but canbe used if haemodialysis is not feasible. The affin­ity of alcohol dehydrogenase for ethyl alcoholgreatly exceeds that for methyl alcohol, and for thisreason administration of ethyl alcohol is com­monly employed to interfere with the metabolismof methyl alcohol to its toxic metabolites. Ethyl al­cohol can be given either orally or intravenously.Usually a loading dose of 0.6 g/kg followed by aninfusion of 100 mg/kg/h is adequate to achieve thedesired blood ethyl alcohol level of 100 mg/dl (22rnmol/L). During haemodialysis the infusion ratemust be increased or ethyl alcohol added to thedialysate at a concentration of 100 mg/dl (Garella1988). Blood levels of ethyl alcohol must be mon­itored carefully because its half-life varies consid­erably from individual to individual. Treatmentshould cont inue until acidosis is corrected andserum methyl alcohol and formate levels are un­detectable.

Ethylene Glycol.' Like methyl alcohol, ingestionof ethylene glycol can result in profound metabolicacidosis (Jacobsen & McMartin 1986). Cardiopul­monary failure, coma and acute renal failure mayevolve over a period of hours to days. As withmethyl alcohol, administration of ethyl alcoholblocks the metabolism of the parent compound toits toxic metabolite, glycolic acid, by virtue of itsgreater affinity for alcohol dehydrogenase . Alkalitherapy , haemodialysis and ethyl alcohol admin­istration (see Methyl Alcohol) constitute appropri­ate therapy. A pharmacological inhibitor of alcoholdehydrogenase, 4-methylpyrazole, may prove to bea safe and easier alternative to ethyl alcohol infu-

847

sion, but clinical experience with this agent is lim­ited (Baud et al. 1988).

Salicylate: Salicylates affect acid-base equilib­rium by directly stimulating alveolar ventilationand by increasing both carbon dioxide and endog­enous acid production. Consequently, mixed acid­base disturbances frequently result from salicylateoverdose . Metabolic acidosis may be the present­ing feature of salicylate intoxication in children, butit is less common in adults . In addition, the pres­entation will vary depending on whether the inges­tion is acute or chronic (Greer et al. 1965).

Because of the likelihood of a mixed acid-basepicture , it is essential that arterial blood gases beused to guide therapy. If metabolic acidosis pre­dominates, sodium bicarbonate should be admin­istered. In addition, treatment with sodium bi­carbonate alkalinises the urine and augments therenal excretion of salicylate by inhibiting its reab­sorption. Of course, giving alkali in the presenceof respiratory alkalosis may produce marked al­kalaemia, but alkali can be administered safely ifacid-base parameters are monitored carefully. Closeattention should be paid to the patient's volumestatus because alkali therapy and its attendant sod­ium load can aggravate the noncardiogenic pul­monary oedema frequently seen in adults with sali­cylate intoxication (Tweeddale 1974). Serumpotassium concentration must be carefully fol­lowed because alkali therapy can aggravate hypo­kalaemia.

In an otherwise healthy patient, administrationof intravenous fluids including alkali will enhancerenal excretion of salicylate and reduce blood sali­cylate to the safe range in a matter of hours. Whenthe intoxication is unusually severe, or when renalfailure or cardiac disease complicate the picture ,dialysis or haemoperfusion may be necessary. Ofthese options, haemodialysis is preferred becauseit promptly corrects the metabolic acidosis as wellas removing salicylate from the blood.

1.3.8 Renal Tubular Acidosis (RTA)Patients with distal RTA (type I, gradient-lim­

ited) almost always require long term alkali therapyto prevent severe acidosis, decrease renal potas-

848

sium losses, and prevent bone disease. The main­tenance dose of alkali required varies considerably,primarily because the degree of bicarbonate wast­ing that may accompany the distal defect is alsohighly variable. In the absence of appreciable bi­carbonate wasting, approximately I mliq/kg/day ofalkali should suffice. In practice, however, mostadults and older children require 2 to 3 mfiq/kg,'day of supplemental alkali because of some bi­carbonate wasting (Kassirer et al. 1989).

Occasionally these patients may present withprofound metabolic acidosis and severe hypoka­laemia. The deficits of bicarbonate and potassiummay be several hundred milli-equivalents each.Rapid simultaneous administration of sodium bi­carbonate and potassium chloride is required insuch individuals.

In contrast, patients with proximal RTA (typeII, bicarbonate-wasting) rarely develop severe acid­osis yet they may need to ingest alkali in the rangeof 5 to 15 mliq/kg/day to achieve normal plasmabicarbonate concentrations because of huge renalbicarbonate losses (Kassirer et al. 1989). While al­kali therapy tends to ameliorate the hypokalaemiain distal RTA, the increased delivery of bicarb­onate to the distal nephron promotes potassiumsecretion in proximal RTA.

1.3.9 Renal Acidosis (Uraemic Acidosis)Some degree of acidosis is usually present in

patients with chronic renal insufficiency when theglomerular filtration rate is reduced to 25 ml/minor less (Harrington et al. 1982), but the degree ofacidosis is not usually severe enough to warranttreatment. However, when plasma bicarbonate fallsbelow 15 mmol/L, alkali should be provided in adose of I to 2 mliq/kg/day. Patients with severerenal insufficiency should be monitored carefullyfor signs of volume overload because of the accom­panying increase in sodium intake .

2. Metabolic Alkalosis

Metabolic alkalosis is initiated by an increase inplasma bicarbonate. This alkalinisation gives riseto a compensatory decrease in alveolar ventilation,

Drugs 39 (6) 1990

and the resulting hypercapnia attenuates the in­crease in systemic pH.

2.1 Clinical Manifestations

Even in the absence of underlying lung disease,secondary hypoventilation is accompanied by somedegree of hypoxia. With plasma bicarbonate con­centrations greater than 60 mrnol/L, values forpa02 as low as 45 to 50mm Hg may occur inpatients even with normal pulmonary function(Tuller & Meddi 1971). In patients with pre-exist­ing pulmonary disease, the hypoxia may be evenmore severe. Two other prominent manifestationsof alkalaemia are hypokalaemia and central nerv­ous system dysfunction. The hypokalaemia that isfrequently associated with metabolic alkalosis ismultifactorial. While substantial potassium lossesoften accompany the processes that generate al­kalosis (e.g. diuretic administration, gastric fluidlosses), transcellular shifts of potassium and renalpotassium wasting also play an important part inthe genesis of hypokalaem ia.

The common central nervous system manifes­tations of alkalaemia include lethargy and confu­sion. In severe alkalaemia muscle twitching andgeneralised seizures can occur. Whether alkalaemiaper se is responsible for these derangements orwhether they can be ascribed to the hypoxia andvolume depletion that often accompanies themetabolic alkalosis remains speculative.

2.2 Causes of Metabolic Alkalosis

The causes of metabolic alkalosis can be di­vided into 4 groups (table II). The first group con­sists of alkaloses secondary to alkali administra­tion. Administration of exogenous alkali at ratesgreater than endogenous acid production will in­crease plasma bicarbonate concentration, but whenthe alkali is discontinued prompt excretion of analkaline urine restores plasma bicarbonate to nor­mal. Examples of metabolic alkalosis that fall intothis category are the milk-alkali syndrome and acutesodium bicarbonate or sodium acetate loading.

The second group consists of chloride-respon-

Treatment of Acid-Base Disorders

Table II. Causes of metabolic alkalosis (from Kassirer et al. 1989,with permission)

Alkalosis secondary to alkali administrationContinuous alkali administration

Milk-alkali syndromeIngestion of large quantities of sodium bicarbonateIngestion of soybean formula dietCombined therapy with nonabsorbable alkali and exchangeresinsRecovery from organic acidosis

Acute alkali loadingChloride-responsive alkalosisGastric fluid lossesDiuretic therapyPosthypercapnic stateStool losses

Congenital chloridorrhoeaVillous adenoma

Chloride-resistant alkalosisPrimary aldosteronismBartter's syndromeCushing's syndromeDisorders that simulate adrenocortical excessIdiopathicMiscellaneousSecondary aldosteronism

Malignant hypertensionRenovascular hypertensionRenin-secreting tumours

Mineralocorticoid excess (other than aldosterone)Penicillin therapyParathyroid disease and hypercalcaemiaRefeeding fof/owing fasting

sive alkaloses. In this variety , alkalosis is perpet­uated by sodium avidity and disproportionatechloride depletion. Common examples are the al­kalosis due to diuretic therapy and gastric fluidlosses. Typically, little or no sodium chloride is ex­creted in the urine because losses of sodium chlor­ide and water during the development of the al­kalosis have induced mild to moderate volumedepletion. This type of metabolic alkalosis is cor­rected promptly by either sodium or potassiumchloride administration.

In contrast, in the third group, chloride-resist­ant alkaloses, alkalosis is maintained in the ab­sence of volume contraction and in the face ofabundant dietary (and urinary) chloride . The al­kalosis accompanying Bartter's syndrome, Cush-

849

ing's syndrome, and primary aldosteronism fall intothis category. Urinary chloride excretion is oftenhigh and the alkalosis persists despite chlorideadministration.

The disorders that fall into the last category(idiopathic alkalosis) are not well defined, althoughat least some have been attributed to extreme po­tassium depletion.

2.3 Treatment of Metabolic Alkalosis

The treatment of metabolic alkalosis also centreson the prompt identification and removal of theunderlying process that caused the alkalosis. If thecause is not obvious or if surreptitious vomiting orself-administration of diuretics are being enter­tained as aetiologies, measurement of urinarychloride and pH may be useful. A low urine chlor­ide (less than 10 to 20 mmol/L) points toward achloride-responsive alkalosis, whereas a highervalue suggests the recent administration of a di­uretic, or less commonly, a chloride-resistant formof metabolic alkalosis. The presence of a persist­ently alkaline urine should raise the possibility ofexcessive alkali intake, as in the milk-alkali syn­drome.

In most cases of mild to moderate chloride-re­sponsive metabolic alkalosis, when adequate chlor­ide is provided the kidney excretes the surplus al­kali and restores acid-base balance to normal overa matter of days. The alkalosis associated with thechloride-resistant disorders is not generally severeand therapy should be directed at the primary de­fect. When severe alkalaemia is present (plasma bi­carbonate greater than 40 mmol/L), the adminis­tration of hydrochloric acid or a hydrochloric acidprecursor may be required . In the same fashion asestimating the quantity of alkali to administer toseverely acidotic patients, the quantity of acid re­quired in mEq can be calculated by assuming thatthe volume of distribution of bicarbonate is roughlyequivalent to 50% of bodyweight and by multiply­ing this figure by the desired decrement in bicarb­onate concentration.

Hydrochloric acid, ammonium chloride and ar­ginine monohydrochloride infusions are useful for

850

the treatment of severe metabolic alkalosis. Hy­drochloric acid solutions must be administeredthrough a central line to avoid severe corrosive re­actions. One litre of 0.1N HC! contains 100 mEqof hydrogen ions; the rate of administration of thissolut ion should not exceed 300 to 500 ml/h (Kas­sirer et al. 1989). Alternatively, a 2.14% solutionof ammonium chloride containing approximately400 mEq of hydrogen ion/L can be made from a26.75% stock solution. Ammonium chloride shouldnot be administered at rates greater than 300 to400 ml/h, Hepatic conversion of ammoniumchloride yields urea and hydrochloric acid. Themajor contraindication to administering a solutioncontaining ammonia is liver disease. The third op­tion for acidification is the use of arginine mono­hydrochloride. 300ml of a 10% solution containsapproximately 150 mEq of hydrogen ions; thisamount can be given over I hour, if necessary(Kassirer et al. 1989). Dangerous hyperkalaemia canoccur during the course ofarginine administration,presumably from displacement of intracellular po­tassium by the arginine cation (Bushinsky & Gen­nari 1978). This effect seems to be more commonin patients with abnormal renal function . Serumpotassium should always be monitored carefullyduring and after an arginine monochloride infu­sion.

2.3.1 Milk-Alkali SyndromeIn its classic form, the milk-alkali syndrome de­

velops in patients who ingest large quantities ofmilk and absorbable alkali, but it occurs in patientswho have ingested only calcium carbonate. Thesyndrome is characterised by the triad of metabolicalkalosis, hypercalcaemia and renal insufficiency.In most cases, therapy consists of eliminating thealkali load. When the milk-alkali syndrome occursin the setting of vomiting or gastric suction, ade­quate chloride must also be provided.

2.3.2 Combined Therapy with NonabsorbableAlkali and Exchange ResinsWhen nonabsorbable alkali (e.g. magnesium hy­

droxide, aluminium hydroxide) and cation-ex­change resins are administered simultaneously to

Drugs 39 (6) 1990

patients with severe renal insufficiency, metabolicalkalosis may result (Schroeder 1969). As the resinabsorbs the ingested cation, intestinal bicarbonateis made available for absorption. Discontinuingeither one or both of these agents results in dissi­pation of the alkalosis, but because of the under­lying renal impairment it may take several days forplasma bicarbonate concentration to return to con­trol levels.

2.3.3 Acute Alkali LoadingRapid administration of sodium bicarbonate or

sodium acetate results in metabolic alkalosis whenthe rate of infusion exceeds the capacity of the kid­ney to excrete the excess alkali. In addition to animmediate increase in plasma bicarbonate concen­tration, plasma carbon dioxide tension will in­crease acutely because carbonic acid is generatedfrom the titration of nonbicarbonate buffers. Thiseffect is only relevant clinically when ventilationis controlled by artificial means. In such patientsarterial blood gases should be monitored during al­kali infusion.

2.3.4 Gastric Fluid LossesThe primary therapy of metabol ic alkalosis in­

duced by vomiting or nasogastric suctioning is toprovide an adequate supply of chloride salt andthus to curtail renal bicarbonate generation. In thisregard, urinary chloride excretion is a valuable in­dex of whether chloride intake is sufficient. Valuesof at least 50 mliq/day generally signify adequatereplacement. When large amounts of gastric fluidare being lost, it may be useful to measure the elec­trolyte composition of the fluid, and estimate thehydrogen ion concentration (as the difference be­tween the sum of the sodium and potassium con­centrations and the chloride concentration). Re­placement of hydrogen ion losses with hydrochloricacid or a hydrochloric acid precursor will preventmetabolic alkalosis from developing, but this ap­proach is generally not needed unless gastric lossesare unusually large. Alternatively, histamine H2­receptor antagonists, by inhibiting gastric acid se­cretion, may be effective in preventing the gener­ation of metabolic alkalosis. These agents are not

Treatment of Acid-Base Disorders

effective, of course, in the correction of establishedalkalosis.

2.3.5 Diuretic TherapyDiuretic-induced metabolic alkalosis falls into

the chloride-responsive category. The agents typi­cally responsible include furosemide (frusemide),ethacrynic acid, bumetanide and metolazone. Di­uretics cause metabolic alkalosis by 3 mechanisms:(a) an increase in renal acid excretion; (b) a dis­proportionate loss of chloride-rich fluid; and (c) atranscellular shift of hydrogen ions. As with gastricalkalosis, administering sufficient chloride salt willprevent metabolic alkalosis from developing dur­ing diuretic therapy . In the majority of patients ,potassium chloride is the appropriate therapy, butin the presence of volume depletion sodium chlor­ide should be provided as well. By inhibiting sod­ium reabsorption and hydrogen secretion, distalblocking agents (e.g. spironolactone, triamterene,amiloride), are effective in preventing diuretic-in­duced alkalosis. Caution should be exercised whenthese agents are administered to patients with renalinsufficiency because of the danger of severe hyper­kalaemia. Acetazolamide, a carbonic anhydrase in­hibitor, is effective in the treatment of metabolicalkalosis particularly when used on alternate days.Severe hypokalaemia may occur, however, if careis not taken to replete potassium stores duringadministration of the drug.

2.3.6 Posthypercapnic AlkalosisPosthypercapnic metabolic alkalosis occurs when

hypercapnia is corrected acutely with mechanicalventilation and the plasma bicarbonate concentra­tion remains inappropriately high. Care should betaken to lower the paCOz gradually in the presenceof chronic hypercapnia, and adequate chlorideshould be provided to permit bicarbonate excre­tion. If severe alkalosis develops acutely, the re­spirator should be adjusted to allow the paCOz torise. Persistent metabolic alkalosis can reduce theventilatory drive and impede weaning. Acetazol­amide may be of value in augmenting bicarbon­aturia, but it should be used as an adjuvant to ad­ministering chloride salts, not as a substitute. At

851

times it may be necessary to lower plasma bicarb­onate concentration with hydrochloric acid or ahydrochloric acid precursor. Reducing the plasmabicarbonate concentration to a value unsuitably lowfor the prevailing paCOz in patients with chroniclung disease may result in acidaemia, however,when the patient is removed from the ventilator.

2.3.7 Primary AldosteronismHypersecretion of aldosterone by the adrenal

cortex induces sodium retention, hypertension, andmetabolic alkalosis of the chloride-resistant type.Administration of sodium chloride to patients withthe syndrome of primary aldosteronism does notcorrect the alkalosis and aggravates hypokalaemiaby increasing urinary potassium losses. In contrast,spironolactone, an aldosterone antagonist, promptlycorrects the hypertension and hypokalaemia, andrestores acid-base balance to normal. Amiloride, anonspecific distal blocking agent with propertiessimilar to spironolactone, is also effective.

2.3.8 Bartter's SyndromeBartter's syndrome is a rare disorder character­

ised by hypokalaemia, metabolic alkalosis and nor­mal blood pressure. Histologically the juxtaglom­erular apparatus of the kidney is hyperplastic andhyperreninaemic hyperaldosteronism is a charac­teristic finding. The exaggerated synthesis and ex­cretion of renal prostaglandins that accompany thehyperreninaemic state are probably a secondary ef­fect (Halushka et al. 1977).

Hypokalaemia and alkalosis in these patients canbe difficult to treat. Prostaglandin inhibitors aredramatically effective in some patients, but inothers the defects are only partially responsive andthe beneficial effect is short-lived (Verberckmoeset al. 1976). Indomethacin, at a dose of 150 to 200mg/day, is an appropriate starting regimen. Addi­tional potassium chloride may be needed. Shouldthe response to indomethacin not be sustained, an­other prostaglandin inhibitor may be successful. Inpatients in whom prostaglandin inhibitors areotherwise contraindicated, potassium sparing agentsin combination with potassium chloride may im­prove the alkalosis and hypokalaemia. Clearly, the

852

combination of a potassium sparing diuretic and apotassium salt is potentially dangerous and shouldonly be used with careful monitoring of plasma po­tassium concentration.

2.3.9 Cushing 's SyndromeThe metabolic alkalosis that accompanies Cush­

ing's syndrome is typically mild and occurs in onlyone-third of patients. In contrast, severe alkalosisand hypokalaemia are more common in patientswith carcinoma of the adrenal cortex and in thosewith adrenal hyperplasia associated with cortico­trophin (ACTH)-producing tumours (particularlylung cancer). Administration of potassium chlorideis appropriate, but therapy is best directed at theunderlying process.

3. Respiratory Acidosis

Respiratory acidosis is initiated by an increasein carbon dioxide tension. The immediate conse­quence of an increase in arterial carbon dioxidetension (paC02) is an increase in plasma acidity.Acutely, titration of nonbicarbonate buffers resultsin a small increase in plasma bicarbonate concen­tration, but when hypercapnia is sustained, en­hanced renal reabsorption of bicarbonate furtherincreases plasma bicarbonate concentration.

3.1 Clinical Manifestations

Central nervous system manifestations are themost important clinical consequences of hypercap­nia. The factors correlated with cerebral dysfunc­tion are the magnitude of the hypercapnia, the rap­idity with which it develops, the severity of theacidaemia and the degree of attendant hypoxia .Acute hypercapnia induces peripheral vasodilata­tion, stimulates the sympathetic nervous systemand increases cardiac output. Arrhythmias fre­quently occur during acute and chronic hypercap­nia. Whether the absolute level of hypercapnia isarrhythmogenic or whether rapid change in paC02,hypoxia or acidaemia is the culprit remains to bedetermined.

Drugs 39 (6) 1990

3.2 Causes of Respiratory Acidosis

Airway obstruction or dysfunction of the regu­latory system controlling ventilation can result inalveolar hypoventilation and hypercapnia. Causesof respiratory acidosis include obstruction of largeor small airways , respiratory centre depression, cir­culatory catastrophes, or neuromuscular and re­strictive defects.

3.3 Treatment of Respiratory Acidosis

The treatment of respiratory acidosis should bedirected at prompt correction of the underlyingcausal process. The major insult of acute respira­tory acidosis is hypoxaernia, and oxygen must beadministered at the onset. If ventilatory support isnecessary in acute hypercapnia, the paC02 can berapidly dropped to normal without adverse con­sequences. Alkali administration should be givenonly for superimposed metabolic acidosis .

In chronic respiratory acidosis efforts to correctthe cause are often less fruitful because of the ir­reversible nature of the underlying disease process.Careful attention to volume status, nutrition, chestphysiotherapy and the administration of broncho­dilators and antibiotics are often effective in im­proving ventilation. In view of the chronic natureof the hypercapnia, it is prudent to decrease paC02toward normal over a period of hours to days andsimultaneously to provide sufficient chloride to al­low the kidneys to excrete previously retained bi­carbonate. As described above, more rapid repairmay result in posthypercapnic alkalosis. Likewise,any coexisting metabolic alkalosis should bepromptly treated because alkalosis may blunt ven­tilation and induce hypoxia.

4. Respiratory Alkalosis

Respiratory alkalosis is initiated by a reductionin arterial carbon dioxide tension, which alkalin­ises the body fluids. Titration of nonbicarbonatebuffers results in a small decrement in plasma bi­carbonate concentration. Over time, changes in the

Treatm ent of Acid-Base Disorders

renal absorption of bicarbonate serve to attenuatethe degree of alkalinisation.

4.1 Clinical Manifestations

As with respiratory acidosis, central nervoussystem dysfunction is the most prominent clinicalfeature of respiratory alkalosis. Acute hypocapniainduces lightheadedness, confusion and, on occa­sion, seizures. These manifestations are mediatedthrough a decrease in cerebral blood flow: for ex­ample , a 40% reduction in flow is observed at apaC02 of 20mm Hg. In fact, this effect on bloodflow provides the rationale for inducing acute hy­pocapnia in selected settings to reduce cerebraloedema. Chronic respiratory alkalosis appears tobe better tolerated in terms of cerebral dysfunction.

4.2 Causes of Respiratory Alkalosis

Respiratory alkalosis is associated with manyserious illnesses. In an intensive care unit , respi­ratory alkalosis appears to be the most commonacid-base derangement. In such patients, a paC02of 15mm Hg or less has been associated with amortality rate of almost 90% (Mazzara et al. 1974).The causes of hypocapnia are many , including hy­poxia, pulmonary disease and various central nerv­ous system disorders.

4.3 Treatment of Respiratory Alkalosis

As in treating all acid-base disorders, the therapyof respiratory alkalosis is centred on reversal of theroot cause. Short of this goal, there is no effectivetreatment of primary hypocapnia. Hypoxia itself isa frequent cause of hypocapnia, and administra­tion of oxygen alone often suffices to correct thealkalosis. If the cause is not immediately apparent,consideration should be given to salicylate intox­ication , early Gram-negative sepsis and meningitis ,because early intervention may be life-saving.

5. Mixed Acid-Base Disturbances

The coexistence of more than one acid-base dis­order is a frequent occurrence and is termed amixed disturbance. Virtually any combination of

853

simple disorders can arise. When plasma bicarb­onate concentration and paC02 are altered in op­posite directions extreme shifts in hydrogen ionconcentration may ensue, whereas changes in thesame direction tend to ameliorate the change inpH. Some common mixed disorders are discussed.

5.1 Metabolic and Respiratory Acidosis

A mixed metabolic and respiratory acidosis isreadily apparent whenever the plasma bicarbonateis low and the paC02 is high. A more subtle ver­sion of this mixed disorder is present in patientswith respiratory acidosis and a normal rather thanelevated plasma bicarbonate concentration. Simi­larly, when metabolic acidosis is not accompaniedby an appropriate decrease in paC02, a mixed dis­order exists. Common examples of mixed meta­bolic and respiratory acidosis are untreated cardio­pulmonary arrest , chronic obstructive lung diseasecomplicated by septic shock, and poisoning withvarious drugs and toxins. Because an extreme de­gree of acidosis can occur with mixed metabolicand respiratory acidosis, it is imperative that themixed nature of the disturbance is identified earlyand therapy is directed at both disorders.

5.2 Metabolic and Respiratory Alkalosis

Similarly, a mixed metabolic and respiratory al­kalosis can be diagnosed whenever the plasma bi­carbonate is high and the paC02 is low. Here, too,the extreme shift in hydrogen ion concentration thatoccurs makes recognition of vital importance.Mixed metabolic and respiratory alkalosis can oc­cur when patients with respiratory alkalosis (e.g.from congestive heart failure) are treated with po­tent diuretics . Another setting where this disturb­ance may occur is when patients with primary hy­pocapnia associated with liver disease are treatedwith diuretics or gastric drainage. Clearly, therapyshould be directed at removing the underlyingcause, if possible. In view of the difficulty in treat­ing primary hypocapnia , efforts to reduce the ele­vated plasma bicarbonate concentration are morefruitful.

854

5.3 Metabolic Acidosis and RespiratoryAlkalosis

The mixed disturbance comprised of metabolicacidosis and respiratory alkalosis can be diagnosedwhen plasma bicarbonate concentration and paC02are both low and the pH is normal or near normal.This disturbance can occur when severe metabolicacidosis is rapidly corrected, when lactic acidosiscomplicates septic shock, in salicylate intoxication,and in the hepatorenal syndrome. Treatment mustbe directed at the specific acid-base disorders andthe underlying process.

5.4 Metabolic Alkalosis and RespiratoryAcidosis

A diagnosis of mixed metabolic alkalosis andrespiratory acidosis can be made when plasma bi­carbonate concentration and paC02 are both ele­vated and the pH is normal or near normal. Thisdisturbance is commonly seen in patients withchronic lung disease who are treated with diuretics.Gastric drainage, vomiting or various other causesof metabolic alkalosis will produce a similar pic­ture when superimposed on respiratory failure. Ef­forts should be directed at improving ventilationand specifically treating the metabolic alkalosis.Even a small component of coexisting metabolicalkalosis will decrease ventilation and interfere withweaning efforts. As noted previously, administra­tion of carbonic anhydrase inhibitors (e.g. aceta­zolamide) may be useful in this setting. When sev­ere alkalaemia is present, hydrochloric acid or ahydrochloric acid precursor should be admini­stered.

6. Conclusions

Prompt and appropriate therapy reduces oreliminates many morbid effects of acid-base dis­turbances.

In many forms of metabolic acidosis, admin­istration of sodium bicarbonate increases plasmabicarbonate concentration predictably. In disord­ers characterised by rapid alkali loss or rapid acid

Drugs 39 (6) 1990

accumulation, the amount of alkali needed will beincreased, and the quantity to be administered canbe determined only by repeated monitoring of apatient's acid-base status. Excessiveadministrationof alkali has its own dangers.

Therapy in metabolic alkalosis also depends onthe nature of the underlying cause. Those disorderscharacterised by depletion of body chloride storeswill respond well to treatment with sodium or po­tassium chloride; those unassociated with chloridedeficiency (principally hyperadrenal states) requireelimination of the root cause. In both forms,administration of hydrochloric acid or a hydro­chloric acid precursor may be needed when alka­laemia is particularly severe.

In acute respiratory acidosis and acute respira­tory alkalosis, prompt restoration of carbon diox­ide tension to normal immediately restores normalacid-base equilibrium and avoids the complica­tions of hypercapnia or hypocapnia.

The therapy of chronic respiratory acidosis musttake into account the increase in plasma bicarb­onate concentration that occurs during adaptationto chronic hypercapnia . When carbon dioxide ten­sion in such patients is reduced abruptly, plasmabicarbonate concentration must be reduced simul­taneously, so as to avoid posthypercapnic meta­bolic alkalosis. Administration of the sodium orpotassium salts of chloride is usually sufficient toavoid this complication .

Elimination of the cause of the sustained hy­pocapnia is the only approach to the treatment ofchronic respiratory alkalosis. Attempts to treat theacid-base disorder per se are usually futile.

In all acid-base disturbances, therapy is an it­erative process. No therapeutic algorithm existswhich offers a prospective, preset therapeutic pack­age. Repeated, and sometimes continuous observ­ation of the patient and repeated measurements ofthe patient's acid-base parameters are required foroptimal therapy.

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