Kidney International, Vol. 29 (1986), pp. 752—774

NEPHROLOGY FORUM

Lactic acidosisPrincipal discussant: NIcoLAos F. MADIAS

New England Medical Center and Tufts University school of Medicine, Boston, Massachusetts

Case presentation

A 33-year-old male was admitted to Michael Reese Hospital andMedical Center for evaluation of weight loss, dyspnea, and fever. Hehad factor Vill-deficient hemophilia and had been chronically ill overseveral months with a cough productive of scanty sputum, weight lossof 15 Ibs, low-grade fever, and progressive dyspnea on exertion. Themedical history was notable for right total hip replacement andsplenomegaly.

Physical examination revealed a thin white male in no distress.Temperature was 37.2°C; blood pressure, 115/80 mm Hg supine; heartrate, 120 beats/mm; and respiratory rate, 36/mm. There were whiteplaques in the mouth, bilateral axillary lymphadenopathy, and spleno-megaly. The lungs were clear and the remainder of the examination waswithin normal limits. Laboratory findings disclosed: hemoglobin, 12.5g/dl; mean corpuscular volume, 89 jsm3; white blood cell count, 7000/mm3 with 78% neutrophils, 4% band forms, and 7% lymphocytes; andnormal platelets. Other routine chemistry tests were normal. Urinalysiswas unremarkable. Chest x-ray was suggestive of early, patchy intersti-tial infiltrates. An arterial blood sample obtained with the patientbreathing room air revealed a pH of 7.48; PCO2, 32mm Hg; and P02, 63mm Hg. The patient developed a hectic fever, and treatment withampicillin and gentamicin was started. Pulmonary function testsshowed reduced diffusing capacity and were consistent with a mildrestrictive defect. A gallium scan revealed diffuse uptake in the lungs,and chest x-ray showed diffuse interstitial infiltrates. On the sixthhospital day, bronchoscopy yielded biopsy material positive for Fneu-

Presentation of the Forum is made possible by grants from CIBAPharmaceutical Company, GEIGY Pharmaceuticals, and Sandoz,Incorporated.

© 1986 by the International Society of Nephrology

rnocystis carinii. Trimethoprim-sulfamethoxazole was administered,but was discontinued after 8 days because of leukopenia and rash.Pentamidine isethionate, 200 mg/day intramuscularly for 7 days, pro-duced dramatic improvement of interstitial infiltrates. The subsequenthospital course was complicated by a recurrence of pulmonary infil-trates, worsening dyspnea, disabling cough, severe inanition, myo-clonus and tremors, abnormal liver function tests, hyponatremia, andhostility and depression. Multiple cultures, including bone marrow,revealed only Candida albicans in the sputum and urine. T-cell studiesshowed a T4/T8 ratio of 0.4 (normal, 1.7—3.5), consistent with thediagnosis of acquired immunodeficiency syndrome. A second course ofpentamidine isethionate was given for 14 days, 8 on an outpatient basis.

Following completion of the second course of treatment, the patient'scondition deteriorated and a third course of pentamidine isethionatewas started on an outpatient basis. For several days he refused to eatand had repeated emesis. He was readmitted after a syncopal episode.

Physical examination revealed a chronically ill-appearing male in nodistress. The temperature was 36.8°C and the blood pressure was 120/80mm Hg supine and 66/40 mm Hg standing. The corresponding heart ratevalues were 68 and 72 beats/mm; the respiratory rate was 24/mm.Positive findings included oral candidiasis and dullness at the right lungbase. No motor, sensory, or reflex abnormalities were present, with theexception of previously known slight weakness of the right hip fiexors.Laboratory data revealed: hemoglobin, 8.7 g/dl; mean corpuscularvolume, 93 pm3; white blood cell count, 1800/mm3 with 52% neutro-phils, 10% band forms, and 21% lymphocytes; platelets, 97,000; serumsodium, 135 mEq/liter; potassium, 4.4 mEq/liter; chloride, 99 mEq/liter;carbon dioxide, 23 mmol/liter; glucose, 157 mg/dl; albumin, 3.3 g/dl;total calcium, 8.8 mg/dI; magnesium, 1.1 mg/dl; SGOT, 182 units; andcreatine kinase (CK), 437 units, The urinalysis was unremarkable.Chest x-ray was clear.

The clinical impression was that the patient had volume depletion andprobably esophageal candidiasis; endoscopy was negative, however.Severe orthostatic hypotension persisted despite volume repletion.Administration of 9-a-fluorocortisol was started on the eleventh hospi-tal day and parenteral hyperalimentation with dextrose, vitamins, andelectrolyte solutions was initiated on the thirteenth day. Treatment withtrimethoprim-sulfamethoxazole at a low dose was restarted on thefourteenth hospital day.

Two days later, the patient became abruptly tachypneic and had atemperature of 38.2°C. The lungs were clear. An arterial blood sampleobtained while the patient was breathing room air revealed a pH of 7.44;PCO2, 16 mm Hg; and P02, 90 mm Hg. Serum sodium was 135 mEq/liter; chloride, 97 mEq/liter; carbon dioxide, 11 mmol/liter; lactate, 17.7mEq/liter; glucose, 408 mg/dl. A serum Acetest was negative. Tobramy-cm, cefazolin, ticarcillin, and amphotericin were administered. Hypo-tension, oliguria and refractory lactic acidosis developed. The patientwas intubated on the eighteenth hospital day and vasopressors wererequired. After more than 250 mmol of sodium bicarbonate wasadministered over 6 hours, the blood pH was 7.19, lactate concentration33.5 mEq/liter, and serum carbon dioxide 8 mmol/liter. Hemofiltrationwas performed for fluid removal. On the nineteenth hospital day thepatient died.

Discussion

DR. NIcOLAOS E. MADJAS (Chief, Division of Nephrology,New England Medical Center, and Associate Professor of

752

EditorsJORDAN J. COHENJOHN T. HARRINCTONJEROME P. KASSIRERNICOLAOS E. MADIAS

Managing EditorCHERYL J. ZUSMAN

Michael Reese Hospital and Medical CenterUniversity of Chicago Pritzker School of Medicine

andNew England Medical Center Hospitals

Tufts University School of Medicine

Lactic acidosis 753

This reversible reaction occurs in the cytosol and is catalyzedby the enzyme lactate dehydrogenase (LDH), which is ubiqui-tous in the cytosol. Lactate is formed when pyruvate reactswith reduced nicotinamide adenine dinucleotide (NADH) and isconverted back to pyruvate by reactions with the oxidizedcounterpart of the dinucleotide (NAD). Lactate is a metabolic

of his immunodeficiency, leukopenia, cachexia, lung injury,and the presence of a central intravenous line. The lingeringhypotension, a known adverse effect of pentamidine isethionateadministration, might have contributed to the genesis of themetabolic disturbance. Despite aggressive treatment, circula-tory, renal, and respiratory failure developed; hyperlactatemiapersisted despite therapeutic efforts, including generous alkaliadministration, and advanced to extreme levels during thepatient's agonal stage.

Definition of the contemporary clinical condition of lacticacidosis is credited to Huckabee, who in 1961 pointed out that,in addition to tissue hypoxia, hyperlactatemia might developunder an array of other clinical circumstances [1, 2]. Nonethe-less, tissue hypoxia secondary to circulatory failure and/orhypoxemia constitutes the root cause of most clinical instancesof lactic acidosis.

Lactic acidosis is herein defined as the acid-base disorder,

Pyruvate concentration. Assuming no change in the othertwo determinants, an increment in pyruvate concentrationshould lead to a proportional increase in lactate concentration.The cytosolic pyruvate concentration is the composite functionof a series of metabolic processes, some of which generate andsome of which consume pyruvate. The main pathway forcellular production of pyruvate is anaerobic glycolysis (Emb-den-Meyerhof pathway) (Fig. 1). Glycolysis occurs in thecytosol, and its pace is controlled by the activities of threefunctionally unidirectional enzymes that catalyze rate-limiting,nonequilibrium steps in an irreversible mode: hexokinase (HK),6-phosphofructokinase (PFK), and pyruvate kinase (PK). Dif-ferent enzymes are required to catalyze these nonequilibriumreactions in the "reverse" direction. ATP is an allostericinhibitor of the PFK reaction; thus, when ATP stores arereduced, flux through this reaction is augmented and the rate ofglycolysis is increased. A key step in glycolysis is the oxidationof glyceraldehyde 3-phosphate during which NAD is con-sumed and converted to NADH. Provision of NAD thereforeis essential to the maintenance of glycolysis. Anaerobic tissuesunder normal conditions and aerobic tissues under hypoxicconditions replenish NAD stores by the cytosolic conversionof pyruvate to lactate (Equation 1). On the other hand, aerobictissues under normal conditions regenerate NAD largely viamitochondrial oxidative reactions. Because the inner mitochon-drial membrane is impermeable to both NADH and NAD,reoxidation of cytosolic NADH in aerobic tissues is accom-plished indirectly via transmitochondrial substrate "shuttles."In essence, an oxidized substrate reacts with NADH in the

Medicine, Tufts University School of Medicine, Boston, Massa-chusetts): The terminal phase of the acquired immunodeficien-cy syndrome in this unfortunate young man illustrates severalprototypic features of what in my opinion represented lacticacidosis in association with sepsis. Severe hyperlactatemiaaccompanied by alkalemia, rather than acidemia, developedalong with the abrupt onset of pyrexia and hyperventilation. Inall probability, gram-negative or, less likely, fungal sepsis wasthe culprit. The patient was at very high risk for sepsis in view

end-product, its only metabolic fate being oxidation back topyruvate. The equilibrium of Equation 1 favors the formation oflactate; thus, under normal conditions the concentration oflactate is approximately tenfold greater than that of pyruvate.Of the two optical isomers, L(+)-lactate is the natural form inmammals; LDH is stereospecific for the L(+)-lactate reactionand does not catalyze the processing of the levorotatory enan-tiomer D(—)-lactate.

Lactate productionThe presence of the enzyme LDH in sufficient quantities in

the cytosol ensures the near-equilibrium position of Equation 1.Recasting Equation ito highlight the equilibrium concentrationof lactate yields Equation 2:

[NADH] +[Lactate] = Keq x [pyruvate][NAD]

X [H ] (2)

where Keq is the equilibrium constant of the LDH reaction and[H] refers to the intracellular (cytosolic) hydrogen ion concen-tration. Consequently, the cytosolic concentration of lactatecan be viewed as being determined by three variables: theconcentration of pyruvate; the [NADH]/[NAD] ratio, other-wise referred to as the redox (reductionloxidation) state; andthe intracellular hydrogen ion concentration.

originating from accumulation of lactic acid in the body fluids,that is manifest by a plasma lactate concentration of at least 5mEq/liter. Such an accumulation reflects disruption of thenormal balance between production and utilization of lactic acidand could result from its overproduction, underutilization, orboth. Lactic acidosis is probably the most common cause ofmetabolic acidosis in hospitalized patients. New knowledgeabout the biochemistry and regulation of lactate metabolismhave allowed a better understanding of the pathophysiology ofthe clinical disorder. Regretfully, progress in treatment has notkept pace, and all too often the development of lactic acidosisheralds a fatal outcome, as in the patient presented today.Comprehensive treatises of various aspects of lactic acidosishave been published recently [3—7]. In this Forum, I willpresent an overview of the topic, highlighting recent advancesin the field.

Lactate metabolism

Metabolically produced lactate is accompanied by the gener-ation of an equivalent number of protons that are released intothe body fluids. These protons, which are titrated by bicarbon-ate and non-bicarbonate body buffers, acidify the intracellularand extracellular environments. By contrast, metabolic remov-al of lactate consumes an equivalent number of hydrogen ions,and thus replenishes the body's alkali reserve.

In this section, I will present a brief account of the biochemi-cal and regulatory aspects of lactate production and utilization.The sole biochemical reaction that generates or consumeslactate in the organism is illustrated by Equation 1:

LDH

CH3COCOO + NADH + H CH3CH(OH)C00 + NAD(pyruvate) lactate) (1)

754 Nephrology Forum

GLUCOSE GlycogenGlycogen I + Glycogen

Hexokinase j 1Glucose-6-phosphatase phosphoIase synthetase

Glucose-6-Phosphate Phosphoglucomutase Glucose 1-phosphatef Glucosephosphate

isomeraseFructose 6-phosphate

6-Phosphofructokinase I Fructose-bisphosphataseFructose, 1 ,6-bisphosphate

_,j,dolaseDihydroxyacetone Glyceraldehyde 3-phosphate

phosphateTriosephosphate Glyceraldehyde-phosphate

isomerase dehydrogenase

3-Phosphoglyceroyl phosphate

j Phosphoglycerate kinase

3-Phosphoglycerate

Phosphoglyceromutase

2-Phosphoglycerate

cytosol, having converted thereby to its reduced form; this formis transported into the mitochondrion where it is subsequentlyoxidized by the electron-transfer chain. The end result is theeffective transport of hydrogen ions, referred to as reducingequivalents, across the mitochondrial membrane and the reoxi-dation of cytosolic NADH. The two best-studied such systemsare the malate/aspartate shuttle and the glycerol phosphateshuttle. Virtually all body tissues are equipped for glycolysis,but particularly high rates are observed in brain, skeletalmuscle, heart, and intestinal mucosa. An additional, althoughquantitatively smaller, source of pyruvate is the transaminationof alanine (released from muscle and small intestine) by theenzyme alanine aminotransferase (AAT), a reaction that occursvirtually exclusively in the liver. Finally, in the kidney, pyru-vate is formed from the metabolism of the carbon skeleton ofglutamine (aipha-ketoglutarate) following removal of the amideand amino nitrogen groups of glutamine in the process ofammoniagenesis,

On the other hand, consumption of pyruvate in aerobictissues under normal conditions occurs by means of twooxidative mitochondrial pathways and follows the transport ofpyruvate across the mitochondrial membrane (Fig. 1). The firstof these is oxidative decarboxylation to acetyl-coenzyme A(acetyl-CoA), a reaction catalyzed by a complex of threeenzymes that are collectively referred to as pyruvate dehydro-genase (PDH) and that require a continuous supply of NAD.

The PDH reaction is a nonequilibrium reaction that commitspyruvate to acetyl-CoA; that is, there is no way that acetyl-CoAcan be converted back to pyruvate. The resultant acetyl-CoAcan enter the tricarboxylic acid (TCA) cycle and the electrontransfer/oxidative phosphorylation pathway for complete oxi-dation to CO2 and water, or it can be utilized in variousbiosynthetic pathways (fatty acids, ketone bodies, cholesterol,steroid hormones, acetylcholine). The second aerobic mito-chondrial pathway for pyruvate is gluconeogenesis, that is, thesynthesis of glucose or glycogen, a process occurring exclusive-ly in the liver and the renal cortex. It is important to recognizethat gluconeogenesis is not a mere reversal of glycolysis; as Ihave noted, three glycolytic reactions (HK, PFK, and PK) areirreversibly catalyzed only in the "forward" direction. AsFigure 1 illustrates, synthesis of glucose from pyruvate (as wellas from lactate and alanine) depends on bypassing these key,nonequilibrium reactions, The first step in this process, conver-sion of pyruvate to phosphoenolpyruvate, involves two compo-nents: (1) carboxylation of pyruvate to oxaloacetate withinmitochondria, a process catalyzed by pyruvate carboxylase(PC); and (2) cytosolic conversion of oxaloacetate to phospho-enolpyruvate, a process catalyzed by the enzyme phosphoenol-pyruvate carboxykinase (PEPCK). Both reactions require ATP.The two additional steps requiring specific catalysis are affectedby fructose-bisphosphatase (FBPase) and glucose-6-phospha-tase (G-6-Pase). As is the case for the reactions unique to

Phosphoenolpyruvate Et1cDl5S

________ ,—.- Alaninecarboxykinase Phosphoenolpyruvate ..- ianinePyruvate kinase aminotransferase

________ -"ctate dehydrogenase(cysoD

PYRUVATE -LACTATE

Pyruvat)ruvate dehydrogenase

—— __—CMitochondrio7) carboxylase Acetyl-C0A

Biosynthetic pathwaysOxaloacetate

Cholesterol, Steroid hormonesFatty acids, Ketone bodies4 TCA

lcvcve0trateAcetyicholine Fig. 1. Metabolic pathways of glycolysis and

gluconeo genesis.

Lactic acidosis 755

glycolysis, all those unique to gluconeogenesis are irreversible(that is, functionally unidirectional); thus, they constitute therate-limiting steps of the gluconeogenesis pathway.

Formation of pyruvate (via the PK reaction) completes thesegment of the glycolytic pathway that is common to bothanaerobic and aerobic metabolism. The conversion of onemolecule of glucose to pyruvate or lactate is associated with thenet production of two molecules of ATP. The subsequentaerobic oxidation of pyruvate generates 36 additional moleculesof ATP, for a total of 38 molecules per completely oxidizedmolecule of glucose.

Impaired mitochondrial oxidative function, as occurs in hy-poxic states, leads to accumulation of pyruvate in the cytosoland thus to increased lactate production. The accumulation ofpyruvate reflects both overproduction of pyruvate and reducedutilization of pyruvate through its two pathways (note theNAD dependence of the PDH reaction and the ATP require-ment of the PC and PEPCK reactions). The former occursbecause a reduced supply of ATP to the cytosol stimulates thePFK reaction and results in augmented glycolysis (Fig. 2). Asnoted, ATP constitutes a potent external regulator of the PFKreaction. During anaerobic conditions, glycolysis becomes themain source of energy for the organism; despite the prevailingmitochondrial dysfunction, continuation of glycolysis (via oxi-dation of glyceraldehyde 3-phosphate) is assured by cytosolicregeneration of NAD via the conversion of pyruvate tolactate. Thus increased lactate production represents the tollpaid by the organism to maintain energy generation duringanaerobiosis.

The [NADH]/[NAD] ratio. This ratio is a measure of theredox state of cytosolic pyridine nucleotides. The ratio isaffected by the activity of the various cytosolic dehydrogenasesthat employ pyridine nucleotides for transferring H (mainlyduring the processes of glycolysis and gluconeogenesis), but inmitochondria-containing cells it is largely determined by therate of mitochondrial oxidative reactions; NADH is oxidized toNAD by the electron-transfer chain, which is coupled tooxidative phosphorylation. Suppression of mitochondrial func-tion through decreased oxygen availability or other mechanismsleads to reduced availability of NAD within the cytosol; asEquation 2 indicates, the resultant increase in the [NADH]/[NAD] ratio shifts the equilibrium of the LDH reaction towardlactate (Fig. 2).

Intracellular [it. According to Equation 2 and barring anychanges in pyruvate concentration and redox state, an incre-ment in intracellular [H] should lead to increased lactateconcentration in the cytosol. In isolated tissue preparations,however, this direct effect of intracellular [H] is ovemden bypH-mediated effects on PFK [8] and thus on pyruvate produc-tion (Fig. 1). Strong evidence indicates that the activity of PFKis inhibited by intracellular acidosis and stimulated by intracel-lular alkalosis; consequently, in tissue preparations, lactic acidproduction falls during acidosis and increases during alkalosis[9—13]. These effects of intracellular [H] on the glycolytic rateand on lactate production have been demonstrated duringaerobiosis as well as during anaerobiosis and may well servean important homeostatic function. Under conditions of tissuehypoxia, stimulation of glycolysis leads to augmented lacticacid production with a resultant decrement in intracellular PH;the acidosis in turn inhibits glycolysis and lactic acid production

0,,,,ENADH1ADP [NAD

Acetyl-CoA

— OxaloacetateG Citrate

Fig. 2. Mechanism of hypoxia-induced accumulation of lactate.

and thus moderates the acidification of the intracellular milieu.Conversely, this servomechanism blunts the increment in intra-cellular pH by augmenting lactic acid production during alkalo-sis [4, 9, 11, 14]. Acidosis and alkalosis thus influence lacticacid production in the direction of minimizing the acid-basedisruption. Given the ubiquity of the glycolytic process inmammalian tissues, the cellular machinery may well employpH-regulated production of lactic acid (and other organic acids)to buffer fluctuations in the prevailing pH, thereby maintaininga measure of stability in intracellular as well as extracellulardomains [4, 9, 11, 12].

In-vivo observations on the composition of extracellular fluidcorroborate the existence of such a negative feedback mecha-nism between net lactate production under basal or stimulatedconditions and acidity of body fluids. Several investigators havedocumented that plasma lactate concentration falls during acuterespiratory acidosis, thus contributing a small component to thewhole body's buffer response [15—19]. In addition, small decre-ments in plasma lactate have been observed in acute andchronic metabolic acidosis [20, 21]. On the other hand, smallrises in plasma lactate concentration occur during acute respira-tory or metabolic alkalosis [4, 9, 15, 16, 22—28]; however, anytendency for a substantial increase is probably tempered byaugmented lactate utilization. Whereas plasma lactate concen-tration is within normal limits during chronic hypocapnia evenin the presence of associated hypoxemia [29—34], a mild eleva-tion in lactate persists in chronic metabolic alkalosis [21, 35].An additional increment in plasma lactate is observed whenacute or chronic hypocapnia is superimposed on chronic meta-bolic alkalosis [36].

Several recent lines of evidence lend strong support to such ahomeostatic system of net lactic acid production under condi-tions of stimulated synthesis. Acute hypercapnia produced byelevating FiCO2 resulted in marked suppression of exercise-induced hyperlactatemia in volunteer subjects [37—40]. Similar-ly, administration of either NH4CI or NaHCO3 led to substan-tial suppression or augmentation, respectively, of the hyperlac-tatemia of exercise [39, 41]. Muscle lactate concentration andglycogen depletion were less in individuals ingesting NH4C1than in those given NaHCO3. In an experimental model of

To Gluconeogenesis

(ioso

GlucoseATP

tcNAD+NA LactatePyruvate

[NADI

(Mitochondrion)

756 Nephrology Forum

hypoxemia-induced lactic acidosis in the rat [42], superimposi-tion of either mild respiratory acidosis (PaCO2, 59 mm Hg) orHCI-induced metabolic acidosis (sufficient to decrease pH from7.27 to only 7.23) resulted in a dramatic blunting of the rise ofblood lactate; by contrast, superimposition of respiratory alka-losis (PaCO2, 15 mm Hg) led to an exaggerated rise in bloodlactate in the hypoxic animals. Moreover, findings in patientswith malignancy-induced chronic lactic acidosis [43, 44] as wellas extensive experience with experimental models of hypoxicand nonhypoxic lactic acidosis {45—52] clearly demonstratesthat bicarbonate administration augments lactate productionand blood lactate levels.

These observations are in full accord with previous findingsin fasting obese humans, another state of enhanced endogenousacid release, which revealed an exquisite sensitivity of ketoacidproduction to chronic mild changes in systemic pH produced byacid or alkali ingestion [12, 53, 54]; a fall in pH suppressed and arise increased ketoacid production. A similar effect has beenobserved on the degree of ketonuria in patients with diabetesmellitus [55, 56]. These clinical observations are amplifiedfurther by the demonstration of remarkable responsiveness ofketoacid production to acute changes in pH when HC1 orNaHCO3 is infused into rats or humans [57—59].

Taken together, these findings suggest the existence of amore generalized homeostatic system that regulates endoge-nous organic acid production via changes in systemic pH [12].What is truly remarkable is the impressive responsiveness ofthis system and the magnitude of the change elicited byrelatively small deviations in extracellular pH during probingexperimental maneuvers, Obviously, it would be of great inter-est to apply modern noninvasive technology to monitor theresponse of intracellular acidity to these relatively modestextracellular changes.

The role of this negative feedback system in the pathogenesisand evolution of clinical lactic acidosis is uncertain, and itrepresents an exciting area for future investigation. Such asystem might be crucial to survival during maximal exercise, astate characterized by marked hyperlactatemia and severeextracellular and intracellular acidosis [60, 61]. On the otherhand, this servomechanism is apparently overridden in cases ofsevere lactic acidosis. Indeed, in hypoxic lactic acidosis, al-though the prevailing acidemia can exert an inhibitory effect onthe magnitude of the evolving metabolic derangement, theacidemia eventually proves impotent in preventing escalation toextreme hyperlactatemia. It appears that any inhibitory effect ofacidemia is simply overridden by the hypoxic drive to augment-ed lactate production. Equally uncertain is whether a clinicallyrelevant interaction exists between this servomechanism andpH-mediated alterations in hepatic and renal gluconeogenesis(and, thus, lactate uptake).

Lactate utilizationAs I already have noted, the sole pathway for lactate utiliza-

tion is conversion back to pyruvate, its oxidized counterpart(Equation 1). Consequently, metabolic removal of lactate isequivalent to the metabolic removal of pyruvate. I will examinethe factors that influence lactate uptake and utilization in amoment.

Lactate is freely filtered at the glomerulus. At low concentra-tions it is reabsorbed virtually completely in the proximal

tubule. Under conditions of hyperlactatemia, renal excretioncontributes to lactate removal, the renal threshold for lactateexcretion being approximately 5 to 6 mEqlliter [20, 62]. In lacticacid-loading experiments in humans, rats, and sheep, renallactate excretion accounted for less than 1.2% of the infusedload [20, 62, 63]. In general, lactate excretion represents a smallfraction of total lactate uptake by the kidney.

Physiology and quantitative aspects of lactate metabolismPlasma lactate concentration is normally in the range of 1

mEqlliter and that of pyruvate about 0.1 mEqlliter. The normalratio of these two substances (known as the LIP ratio) isapproximately 10:1. Obviously, the stability of plasma lactateconcentration implies a precise equivalence between the proc-ess of releasing lactate to, and that of removing lactate from, theextracellular compartment. The average basal turnover rate innormal humans has been estimated at about 20 mEqlkgldaywith a range of 15 to 25 mEqlkglday [3, 6, 7, 63—66]. Thisamounts to approximately 1400 mEqlday per 70 kg subject orapproximately 1 mEqlmin. Such estimates have been obtainedthrough a variety of techniques including the disappearance ofinfused lactate, measurements of blood flow and arteriovenousdifferences for lactate across tissue beds, extrapolations fromin-vitro incubation data, and the kinetics of infused isotopicallylabeled lactate. Methodologic limitations make available esti-mates gross approximations at best. Estimates of the apparentvolume of distribution of lactate range from 270 to 340 mL/kg inhumans [63, 67] and about 360 mllkg in the rat [20]. Unfortu-nately, available information on quantitative aspects of lactateproduction and utilization by humans in health and disease isquite limited. Considerably more information is available fromstudies in experimental animals.

Although all tissues produce lactate during the course ofglycolysis, only some of them contribute substantial quantitiesto the extracellular fluid under normal aerobic circumstances.Table 1 lists the lactate-producing tissues. Whereas the renalmedulla normally produces lactate in spite of an adequatesubstrate and oxygen supply, the renal cortex has a high rate ofoxidative metabolism and lactate utilization [68]. Erythrocytesare obligatory producers of lactate because, in the absence ofmitochondria, they lack the apparatus for the metabolic proc-essing of pyruvate. During exercise, skeletal muscle is themajor source of circulating lactate. The maximal rates of lactateproduction by various tissues remain unknown. Yet estimatesfrom individuals undergoing short bursts of maximal exercise orhaving a grand-mal seizure indicate that lactate production canincrease by several hundredfold [4, 7, 69]. Under hypoxicconditions, virtually all tissues can release lactate into thecirculation. Indeed, during severe hypoxia and acidosis, eventhe liver—the predominant consumer of lactate under normalconditions—can add lactate to the blood [70, 71]; obviously,such a transition from net utilization of lactate to net productionis an ominous sign for the organism.

Liver and renal cortex, the major lactate-consuming organs,can use lactate (via pyruvate) as a substrate for gluconeogenesisand can oxidize it to CO2 and water. Animal studies indicatethat of the two pathways, gluconeogenesis is the primary modeof lactate processing in the liver. On the other hand, in thekidney the fraction of lactate that is extracted and converted toglucose as opposed to being oxidized remains unclear; variable

Lactic acidosis 757

Table 1. Lactate-producing and -consuming tissuesunder basal conditions

Producers ConsumersSkin LiverErythrocytes Renal cortexBrain HeartSkeletal muscle Salivary glands (?)Intestinal mucosaLeukocytesPlateletsRenal medullaTissues of the eye (cornea, lens, retina)

results have been obtained depending on the experimentalconditions employed. Available evidence suggests that about50% of the renal lactate uptake in the rat and dog is oxidized[11, 21, 72, 731. Although the interorgan apportioning of lactateutilization remains poorly defined, the relative contribution ofthe various organs to lactate uptake varies widely according tothe prevailing conditions (for example, basal state, exogenousinfusions of lactate at rest, vigorous exercise). Estimates for thefractional contribution of the liver to the total basal lactate loadin humans vary widely, ranging from 30% to 70%; 50% isprobably a reasonable figure [7, 74, 75]. Studies utilizing lacticacid loading in rats and sheep have estimated that the kidneyextracts approximately 20% to 30% of the load [20, 62, 761.Notably, the liver has a large reserve capacity for lactatemetabolism that is estimated to be higher than the basal rate byseveralfold [771. Hepatic uptake of lactate exhibits markedconcentration dependence [15, 62]. Recent lactate-loading ex-periments in sheep suggest that hepatic lactate uptake is asaturable process with second-order (Michaelis-Menten) kinet-ics [62]; whereas the basal rate of hepatic lactate removalaveraged 0.57 mEq.kg°75.h', the Vmax was estimated at 5.72mEq.kg°75.h', and the Km at 3.06 mEq/liter. Studies in theperfused rat liver have shown saturation of uptake at a plasmalactate concentration of approximately 4 mEqlliter [6]. Obser-vations in humans suggest that during mild exercise (about 30%to 60% of maximum 02 uptake, with plasma lactate levels up to2.3 mEqfliter) hepatic lactate uptake is augmented in proportionto the load [78—80]; in contrast, hepatic lactate uptake does notchange or even can decrease markedly during strenuous exer-cise [74, 81]. Despite the prevailing severe hyperlactatemiaduring maximal exercise, lactate uptake probably is suppressedby the marked diminution in hepatic blood flow that is known tooccur; an additional suppressive role might be exerted by theexisting, often severe, acidosis [15, 64, 70, 82—86]. Although thehepatic functional reserve for lactate removal is well docu-mented, the fact that hyperlactatemia develops during evenmild exercise indicates that the liver (as well as other lactate-consuming sites) cannot keep pace acutely with lactate-produc-ing organs; that is, lactate production at least transientlyoutstrips utilization.

Similarly, renal consumption of lactate is augmented inhyperlactatemia, thus contributing to the organism's reservecapacity (20, 72); the excess lactate enters both oxidative andbiosynthetic pathways [87]. As I already have noted, renalexcretion contributes to lactate removal under such circum-stances. In response to an exogenous lactic acid load in the ratand at a plasma lactate concentration of 10 mEqlliter, renal

lactate excretion accounted for approximately 12% of thecumulative renal contribution to lactate removal (the latterbeing about 25% to 30% of the administered load) [20]. Duringhyperlactatemia the heart's contribution to lactate removal alsoincreases [88]. Under these conditions, the lung can be involvedin lactate utilization [89].

Although normally a lactate-producing organ, resting skeletalmuscle also can extract lactate from the blood—and use itprimarily as fuel for oxidation—during hyperlactatemia pro-duced by exogenous infusion or by exercise of regional musclegroups [67, 90—92]. Indeed, several studies have shown conver-sion from lactate output to lactate uptake by resting skeletalmuscle following an infusion of a lactic acid load, with anestimated 25% to 35% of the load taken up by muscle [62, 67,90, 93]. Under such circumstances, skeletal muscle can disposeof more of the lactate load than does the liver [62, 90]. Whereassaturation of hepatic lactate uptake during relatively mildincreases in lactate level have been documented [6, 62], onestudy reported no saturation of extrasplanchnic lactate uptakeeven at the highest plasma lactate concentration, 20 mEqlliter[62]. In fact, deductions drawn from studies in the isolatedperfused rat hind limb, which showed a linear increase inmuscle lactate uptake with perfusate concentrations up to 27mEqlliter [94], suggest that the liver may contribute in only asmall way to lactate removal during recovery from maximalexercise. Further, the rate of plasma lactate recovery wasaugmented if the subject continued exercising at a submaximallevel rather than resting; this observation lends strong supportto the importance of skeletal muscle in extracting lactate undersuch circumstances [81]. Limited clinical data suggest a com-pensatory increase in lactate uptake by skeletal muscle whenhepatic lactate uptake is deranged [95]. Nonetheless, the contri-bution of skeletal muscle to lactate utilization during clinicallactic acidosis remains a matter of considerable debate [3, 6, 7,64, 67].

The importance of the liver as a lactate-consuming organ isexemplified by observations after functional hepatectomy in thediabetic dog. Functional hepatectomy was produced by divert-ing the portal circulation to the inferior vena cava and ligatingthe hepatic artery. Although lactate production due to surgicalstress might have contributed to acidosis, 2 and 3 hoursfollowing the procedure the plasma lactate increased from amean control value of 1.4 mEq/liter to average values of 6.0 and10.7 mEq/liter, respectively; corresponding values for blood pHwere 7.20 and 7.13 (mean control value, 7.42) [96].

Turning to the contribution of the kidney to lactate disposal,removal of an exogenous lactic acid load was slower in ratssubjected to bilateral nephrectomy as compared with animalssubjected to a sham operation; lactate elimination hall-lifeaveraged 5.3 minutes, and blood clearance for lactate (at aplasma concentration of 10 mEq/liter) was 45.3 mllmin/kg insham-operated animals; the corresponding values were 7.1minutes and 32 mllmin/kg in animals with bilateral nephrectomy[20]. Overall, nephrectomy resulted in approximately a 30%slowing of absolute lactate removal following an intravenouslactic acid load [20].

From the standpoint of the whole organism's economy,therefore, tissues with glycolytic activity under normal aerobicconditions metabolize glucose to lactate and relinquish it intothe circulation. In turn, lactate is extracted by the liver and

758 Nephrology Forum-into the body fluids must be removed. This task is achievedduring the metabolism of lactate via the two oxidative path-ways. When the liver and the renal cortex reconvert lactate toglucose during gluconeogenesis, Equation 5 is reversed and anumber of protons equivalent to the number of lactate ionsconsumed is removed from the body fluids (Equation 6):

2CH3CH(OH)C00 + 2W — C6H1206 (6)(lactate) (glucose)

Gluconeogenesis is an energy-requiring process and consumesATP and GTP; the aerobic repletion of these high-energy

____________________________ phosphate groups produces the net utilization of protons duringgluconeogenesis [97—99]. Similarly, during the combustion oflactate to CO2 and water, an equivalent number of protons areabstracted from the body fluids (Equation 7):

CH3CH(OH)C00 + H + 302 —* 3C02 + 3H20 (7)

In actuality, consumption of the proton occurs during aerobicmitochondrial ATP synthesis, which may be considered thereverse of ATP hydrolysis [97—99].

In the overall scheme, protons are generated in the cytosolvia hydrolysis of synthesized ATP and are consumed in themitochondria via aerobic reconstitution of high-energy phos-phate groups. The recapturing by the liver, and secondarily bythe kidney, of protons freed during glycolysis allows for regen-eration of bicarbonate and back-titration of the nonbicarbonatebuffers, so that no net input of hydrogen ion to body fluidsoccurs and acid-base balance remains undisturbed. In thissense, lactic acidosis is generated whenever an imbalancebetween ATP hydrolysis and ATP generation occurs, andresults in a net gain of hydrogen ions by the body fluids.

The importance of disposing of the protons produced duringglycolysis for the maintenance of acid-base equilibrium can bebetter appreciated when its magnitude—that is, 15 to 25 mEq ofH/kgfday under basal conditions, as much as the lactateproduced—is contrasted with the magnitude of net acid excre-tion by the kidney, approximately 1 mEq of H/kg!day. More-over, under conditions of lactate overproduction, an evengreater burden is placed on the liver and the kidney to maintainacid-base homeostasis. It is apparent therefore that from anacid-base perspective, the liver plays a pivotal, albeit notwidely appreciated, role in ensuring the daily miracle of theorganism's survival. This analysis is a sobering reminder tonephrologists, who usually are possessed by a nephrocentric

(3) view of acid-base balance.

Pat ho genesis of lactic acidosisLactic acidosis is generated whenever the production of

(4)lactic acid outstrips its utilization. The result of such animbalance is evidenced by the accumulation of lactate in thecirculation, often in the company of hypobicarbonatemia andacidemia. From a theoretical standpoint, as! have just stressed,the pathogenesis of this imbalance could reflect overproductionof lactic acid, underutilization, or both.

Overproduction of lactic acid is clearly recognized as themechanism of transient lactic acidosis in subjects undergoingvigorous exercise and in those who have generalized convul-sions [3, 4, 7, 65]. Similarly, for reasons I already have noted,hypoxia constitutes a potent stimulus for lactic acid production.However, given the extensive reserve capacity for lactate

)Gluconeogenesis Lactate

Liver, renal cortex

Skin, erythrocytes, brain,/ skeletal muscle, intestinal mucosaleukocytes, platelets, renal medulla, tissues of the eye

Anaerobic glycolysisGlucose Lactate

Fig. 3. The Con cycle.

renal cortex and is either reconverted to glucose or becomesfuel for oxidation to CO2 and water. The cyclical relationshipbetween glucose and lactate, embodied in the Cori cycle (Fig.3), ensures a continuous supply of glucose to tissues requiringthis substrate as fuel, such as brain and erythrocytes.

Another important dividend to the body's economy from theunperturbed function of the Cori cycle is that the cycle providesfor the recapturing of hydrogen ions released into the bodyfluids during glycolysis and thus allows for acid-base balance tobe maintained. What follows is a short overview of the acid-base consequences of lactate metabolism.

Exogenously administered lactic acid is virtually completelydissociated in body fluids, because its pK' is 3.86. However,lactic acid as such is not produced at any step in the glycolyticprocess; rather lactate, its conjugate base, is the actual end-product of anaerobic glycolysis. Nonetheless the glycolyticprocess also results in the release of protons in numbersequivalent to the lactate produced, and the net effect is as iflactic acid were released into the body fluids.

Conversion of glucose to lactate is coupled to the synthesis oftwo molecules of ATP. The most simplified description of thestoichiometry of this conversion is as follows (Equation 3):

C6111206 + 2ADP3 + 2Pi2 — 2CH3CH(OH)C00 + 2ATr + 2H20(gtucose) (lactate)

Under steady-state conditions, the ratio of AlP to ADP re-mains unchanged; consequently, all ATP synthesized in Equa-tion 3 is promptly consumed (Equation 4):

2ATP + 21120 —* 2ADP3 + 2Pi2 + 2W

Summing up Equations 3 and 4 we obtain Equation 5:

C6H1206 —* 2CH3CH(OH)COO + 2W(glucose) (lactate)

Thus, protons are released via the hydrolysis of ATP generatedduring anaerobic glycolysis and not via dissociation of thelactic acid species [97—99]. Protons freed from this process aretitrated by bicarbonate and nonbicarbonate buffers residing inthe intracellular and extracellular compartments. For acid-base balance to be maintained, however, the protons released

Lactic acidosis 759

extraction in normal individuals, as evidenced by observationsduring lactate infusion or transient overproduction by exercis-ing muscle, it has become increasingly apparent that defectiveutilization must be involved in the pathogenesis of most types ofpersistent lactic acidosis. Observations in patients in circula-tory shock have revealed substantial negative arteriovenousdifferences for lactate across muscle, liver, and kidney; thesefindings attest to a failure of the hepatic and renal mechanismsfor lactate removal [100]. Indeed, in view of the fact that bothpathways of lactate utilization depend critically on intact mito-chondrial function, it is not surprising that tissue hypoxiaproduces defective lactate processing (Fig. 2). Furthermore, theevidence in support of the contention that nonhypoxic forms oflactic acidosis are secondary to lactate overproduction [2] isextremely weak [6, 7, 64]. In addition, observations fromexperimental models of hypoxic [45, 101, 102] and nonhypoxic[103] forms of lactic acidosis have clearly implicated bothoverproduction and underutilization of lactate in the pathogene-sis of the disorder. Thus, although we are far from being able toquantitatively apportion the lactate load into overproductionand underutilization columns, it appears likely that both limbsof lactate metabolism might be defective in most forms ofclinical lactic acidosis. Accordingly, I should like to addressbriefly some factors that are known to affect lactate utilizationby the liver and kidney. This knowledge has been derived fromexperimental studies and its clinical relevance remains uncer-tain; nonetheless, it allows for the formulation of an insightfulperspective of the pathogenesis of the disorder.

As I already have noted, hyperlactatemia produced by exoge-nous infusion elicits increased utilization of lactate by the liverand kidney [15, 20, 62, 72, 871. On the other hand, gradedhypoxia of the hepatic parenchyma leads to a progressivediminution in hepatic lactate uptake; this reduction converts theliver from a lactate-consuming to a lactate-producing organ [45,71, 104, 105]. Thus, in early studies in the isolated perfused ratliver, a reduction in hepatic blood flow by 40% to 67% resultedin conversion from lactate uptake to lactate production [45,105]. By contrast, in a more recent study of the same experi-mental preparation [1061, lactate uptake was reduced onlymodestly when hepatic blood flow was decreased by 67% ofnormal; this finding of course reflects an increase in the hepaticextraction ratio of lactate as hepatic blood flow decreases. Atmore advanced degrees of hypoperfusion, however, severereductions in uptake were noted. Yet, even when blood flowwas reduced by 93%, minimal lactate uptake, but not output,was still observed. At that point, liver intracellular pH averaged7.03 as compared to a mean value of 7.25 during basal flow[106]. Similarly, in-vivo studies in the dog have suggested alarge hepatic functional reserve for lactate disposal even duringsevere ischemia [20]. At plasma lactate concentrations up to 4.2mEq/liter, reductions in total hepatic blood flow by 70% or lessdid not elicit a significant decrease in hepatic uptake. However,further hypoperfusion markedly depressed lactate uptake andeven caused net lactate production [104]. The weight of theevidence thus suggests that a reduction in hepatic blood flow toless than 30% of normal cannot be compensated for and resultsin decreased lactate utilization. Indeed, less severe degrees ofhypoperfusion might lead to substantial impairment of lactateuptake if accompanied by greater degrees of hyperlactatemia.Additional in vivo studies in the dog have shown that reduction

—2

Fig. 4. Relationship between extracellular pH (PHe) and lactate uptakein the isolated perfused rat liver during simulated metabolic acidosis(reprinted by permission from Clinical Science and Molecular Medi-cine, vol 45, pp 543—549, copyright © 1973, The Biochemical Society,London).

in oxygen tension to a mean Pa02 of 47 mm Hg decreasedhepatic lactate uptake by an average of —5.3 tEq/kgImin (meancontrol value of 1.7 Eq/kgImin); this change indicated aconversion to net lactate production. When more severe hypox-emia was established (mean Pa02 of 35 mm Hg), net lactateproduction by the liver was increased (mean of —9.2 Eq/kgImm) [1041. In addition to hypoxia, reduction of the hepaticredox state induced by other means (for example, biguanides,fructose, alcohol) has been shown to lead to impaired lactateremoval.

In studies of graded hemorrhage in the dog, renal lactateuptake remained stable up to a blood loss of 30% of the basalvolume. Following a 40% blood loss, which resulted in a meanarterial blood pressure of 72 mm Hg and a reduction in renalblood flow by 66% of the prehemorrhage value, renal lactateuptake decreased sharply; lactate production occurred duringhemorrhagic shock from a 45% to 50% blood loss at a meanarterial blood pressure of 38 mm Hg and a 94% reduction inrenal blood flow [107, 108]. Following reinfusion of shed blood,renal lactate uptake remained below baseline levels, probablyreflecting hypoxic tissue damage.

Moreover, strong evidence indicates that either severe meta-bolic or respiratory acidosis impairs hepatic lactate uptake [15,64, 70, 82—84, 109, 1101. Lactate uptake by the isolated perfusedrat liver decreased progressively at a perfusate pH of less than7.10; indeed, when the perfusate pH was lowered below 7.0,and liver intracellular pH fell to below 7.05, lactate output,rather than uptake, occurred (Figs. 4 and 5) [70]. Additionalstudies have revealed that gluconeogenesis from lactate ismarkedly depressed in the isolated perfused rat liver when theperfusate pH is lowered below 7.10 [83]. By contrast, in-vivoand in-vitro studies have shown that moderate degrees ofacidosis do not significantly change hepatic lactate uptake [15,62, 64, 70]. The suppressive effect of acidosis on lactate uptakehas been attributed to decreased gluconeogenesis from lactatethat occurs as a result of a fall in oxaloacetate concentration;the latter could reflect inhibition of pyruvate carboxylase (PC)enzymatic activity, increase in the [malate]/[oxaloacetate] ratio,or both [84, 111]. It is interesting that myocardial lactate uptakedecreased by 30% in anesthetized dogs when blood pH was

(10)

I

+3

+2

+1

0

—1

0E

0.

7.2 7.1

760 Nephrology Forum

lowered to 7.16 to 7.20 by the infusion of hydrochloric acid[112].

Experiments in the isolated perfused rat liver have examinedthe effects of combined hypoperfusion and acidosis on lactateuptake and gluconeogenesis [85]. The conditions were selectedto simulate those prevailing during moderate to severe exerciseor during circulatory collapse; in addition, acidosis itself isknown to decrease hepatic blood flow [113]. Ischemia andacidosis have separate inhibitory effects on hepatic lactateuptake; thus, both could contribute to the defect in lactateutilization characteristic of those settings [85]. Notably, epi-nephrine exerted a marked ameliorating effect on lactate uptakeunder these experimental conditions [86]. This observationmight have clinical relevance, in view of the high levels ofcirculating epinephrine during acidemic states, such as strenu-ous exercise and shock.

As expected from Equations 6 and 7, the metabolic process-ing of lactate by gluconeogenesis or oxidation should increasethe hepatocyte pH by abstracting intracellular hydrogen ions;by contrast, decreased lactate consumption should decreaseintracellular pH. This formulation assumes that at least part ofthe lactate entering the hepatocyte is not accompanied by anequivalent number of protons; support for this mechanism hasbeen obtained [6, 114]. Experiments in the isolated perfusedliver from several species indicate a direct relationship betweenlactate consumption and a change in intracellular pH [106, 115,116]. These interrelationships make it evident that the genera-tion of severe acidemia during lactic acidosis carries in itself thepotential of initiating a vicious cycle in which the resultantdepressed hepatic intracellular pH would suppress lactate up-take, thus leading to further aggravation of intracellular as wellas extracellular acidosis (Fig. 6). This ominous cycle would bereinforced further by the depressive effects of acidosis onhepatic blood flow [113].

A potent defense mechanism against a maladaptive positive-feedback system such as this resides in the kidney. Evidencefrom in-vitro and in-vivo studies suggests that acidosis substan-tially increases renal lactate uptake and utilization via gluconeo-genesis by stimulating the activity of the key gluconeogenicenzyme PEPCK [11, 20, 76, 117]. This adaptation is apparentwithin 2 to 4 hours from the onset of acidosis [118]. Theaugmented renal contribution to lactate utilization during acido-sis occurs despite the accompanying substantial decrease inrenal blood flow [113]. The mechanism underlying the oppositeeffects of acidosis on lactate utilization by the liver and kidneyremains obscure. The overall impact of these responses on thebody's ability to handle a lactic acid load was quantified in ratssubjected to either bilateral nephrectomy or to a sham operationand then made acidotic with NH4CI, Lactate removal wasslowed in nephrectomized animals by approximately 50% dur-ing extracellular acidemia at pH 6,75; this result reflected boththe suppressed hepatic uptake and the absence of the renalcontribution. It was estimated that whereas the contribution ofthe kidney to lactate removal was 16% at pH 7.45, it rose to 44%at pH 6.75. Consequently, the enhanced ability of the kidney toremove lactate during acidemia was sufficient to compensatefor approximately one-half of the concomitant fall in the extra-renal (primarily hepatic) capacity for lactate extraction; the netresult was a relatively slight decrease in whole-body lactateremoval in the sham-operated animals [20]. It thus appears that

(8)

÷3

+2

+1

0

(9)

(14)

0)

E0E

0

(8)

I(3)

—2

—3

—4

-57.4 7.3 7.2 7.1 7.0 6.9 6.8

pH1

Fig. 5. Relationship between intracellular pH (pI-fj) and lactate uptakein the isolated perfused rat liver during simulated metabolic acidosis(reprinted by permission from Clinical Science and Molecular Medi-cine, vol 45, pp 543—549, copyright © 1973, The Biochemical Society,London).

Fig. 6. Theoretical positive-feedback mechanism operating to decreasesystemic pH under conditions of severe lactic acidosis.

Lactic acidosis 761

Table 2. Synopsis of acid-base effects on lactate metabolisma

Acidosis Alkalosis

Lactate synthesis I t(Glycolysis)

Lactate utilization(Gluconeogenesis)Liver IKidney

Net lactate production in vivot

ta Adapted from Ref. 12.

the role of the kidney as a lactate-consuming organ becomesprogressively more important as extracellular pH falls; insevere acidemia, liver and muscle fall very short of compensat-ing for the absence of kidneys.

The role, if any, of this renal adaptation in the pathogenesis ofthe many forms of clinical lactic acidosis remains undefined.However, it is intriguing to note that renal dysfunction is oftenpresent in patients who develop either hypoxic or non-hypoxictypes of lactic acidosis as well as in those with phenformin-induced lactic acidosis [3—7, 65, 77, 119]. Phenformin has beenshown to inhibit renal gluconeogenesis both in vivo and in vitro,in addition to its suppressive effect on hepatic gluconeogenesis[4, 120, 1211.

Table 2 presents a synopsis of the currently known effects ofchanges in systemic pH on lactate metabolism. Acidosis inhib-its lactate synthesis, retards hepatic lactate uptake, but pro-motes renal lactate extraction and utilization. On the otherhand, alkalosis stimulates lactate generation; no consistenteffect of alkalosis on lactate utilization has been identified. As Ihave noted, experimental observations under basal conditionsas well as during stimulated lactate production (exercise, hy-poxemia, phenformin administration) reveal suppression of netlactate production in vivo by acidosis and augmentation byalkalosis. Nonetheless, additional research is required to definethe aggregated effect of the multitude of influences of acidosison lactate metabolism. The level of severity of the acidosis, itsoften rapidly evolving course, and the associated—primary and!or secondary—hemodynamic disturbances are among the fac-tors that add special complexity to this task. It is possible, forexample, that during severe acidosis the aggregate effect ofthese various influences might lead to a pH-induced increase innet lactate production because of the overriding importance ofimpaired hepatic lactate utilization.

Clinical featuresThe clinical presentation of lactic acidosis is extremely

variable and heavily influenced by the manifestations of theunderlying disease. Nonetheless, its development is often her-alded by the sudden onset of malaise, weakness, anorexia,vomiting, and a deterioration in mental status. Hyperventila-tion, tachycardia, hypotension, and circulatory instability arecommon associated findings [3, 4, 65]. The diagnosis of lacticacidosis frequently is strongly suspected on clinical groundsand is supported by the finding of an otherwise unaccounted-forelevation in the concentration of plasma undetermined anions(anion gap), often in the company of hypobicarbonatemia andacidemia. Of course, confirmation of the diagnosis rests withthe finding of an elevated plasma lactate level. The clinical

significance of lactate levels in the range of 2 to 4 mEq/literremains unclear. On the other hand, lactate levels of 5 mEq!literor greater usually point to the seriousness of the clinicalcondition: the higher the level, the greater the gravity of thepatient's status and the worse the prognosis [122]. I would liketo discuss some general aspects of the clinical presentation oflactic acidosis.

Acid-baseAlthough substantial hypobicarbonatemia is a regular accom-

paniment of lactic acidosis, this need not be the case. If lacticacidosis is superimposed on a preexisting hyperbicarbonatemicstate, the accumulated lactic acid may not be sufficient to drivethe plasma bicarbonate to frankly subnormal levels. The onlylaboratory clue to the coexistence of lactic acidosis in thissetting is the inappropriately elevated plasma anion gap.

It generally has been assumed that in uncomplicated lacticacidosis (and, in fact, in all types of organic acidosis) reciprocalstoichiometry is maintained between the decrement in plasmabicarbonate and the increment in anion gap. This assumptionoriginates from the expectation that titration precisely replacesbicarbonate with the anion of the offending acid, that is, lactate.Consequently, plasma chloride concentration, unaffected bytitration, is assumed to remain normal. As a corollary, whenlactic acidosis is found to be associated with hypochloremia(that is, when the increment in anion gap is greater than thedecrement in bicarbonate from normal), it has been argued thatan antecedent metabolic alkalosis might have been present butpresumably is now hidden by the overriding impact of theacidosis. Undoubtedly, in the untreated patient, close corre-spondence often exists between the decrement in plasma bicar-bonate and the increment in anion gap, as well as the rise inplasma lactate. Yet on several occasions we have been puzzledby the occurrence of moderate hypochloremia (in the absenceof corresponding hyponatremia) in patients with lactic acidosisbut without an identifiable cause for the putative underlyingalkalosis. Recent experiments in our laboratory have suggestedthat some degree of hypochloremia might be an integral part ofthe prevailing acidosis [1231. A stable degree of lactic acidosiswas produced in nephrectomized rats by infusing the racemicmixture of L(+)- and D(—)-lactic acid over a 3-hour period. AsFigure 7 illustrates, a decrement in plasma chloride concentra-tion accounted, on average, for 38% and 48% of the incrementin plasma anion gap at 1 and 3 hours, respectively. Wetheorized that this acidosis-induced hypochloremia was due toexpansion of the extracellular compartment secondary to theextrusion of cellular cations that occurs in the process ofbuffering [123]. Although this mechanism provides a plausibleexplanation for the puzzling hypochloremia I already havereferred to, its relevance to the clinical setting remains to bedetermined. Assuming that this mechanism is operative, onemight not expect the generation of acidosis-induced hypochlo-remia at the very onset of acidosis before substantial ionic shiftshave occurred; this prediction is supported by studies ofhyperacute, transient lactic acidosis secondary to a singlegrand-mal seizure in which hypochloremia was not present [691and by observations in humans following maximal exercise ofshort duration [60]. By contrast, acidosis of several hoursduration might feature this abnormality unless offsetting factorswere involved [123].

acidosis, and its spontaneous recovery is not accompanied by asignificant change in plasma potassium [69]. Although hyperka-lemia occurs commonly in patients with various types of lacticacidosis, the level of plasma potassium correlates poorly withthe degree of acidemia; moreover, most of the hyperkalemicpatients are hypercatabolic, have renal dysfunction, or both[136]. It is doubtful whether organic acidemia in general is acause of hyperkalemia at all [136]. Despite various hypotheses,the reasons for the disparate response of plasma potassium tolactic acidosis as compared to mineral acidosis remain unknown[132, 133].

Miscellaneous laboratory findingsSerum phosphate concentration is usually increased in pa-

tients with lactic acidosis [130, 137, 138]. The pathogenesis ofthis abnormality is unclear but in all probability reflects arelease of inorganic phosphate from cells [139],

Hyperurieemia, another regular feature of lactic acidosis,results from decreased renal excretion of urate owing to com-petitive inhibition of tubule urate secretion by the lactate ion[140].

Finally, the plasma levels of certain amino acids are frequent-ly increased in patients with lactic acidosis; the most notableincrease corresponds to alanine, but proline, valine, lysine, andleucine are also increased substantially [141].

Causes of lactic acidosisThe causes of acquired lactic acidosis are catalogued in Table

3. Increased oxygen demand arises from intense voluntaryexercise, which is certainly the most common cause of transientlactic acidosis. Substantial hyperlactatemia also occurs in gen-eralized convulsions, the clinical equivalent of strenuous volun-tary exercise. Tissue hypoxia is by far the most common causeof clinically significant lactic acidosis. The decrease in oxygenavailability in the tissues results from reduced tissue perfusion,reduced arterial oxygen content, or both. On the other hand, anumber of drugs and toxic substances can cause lactic acidosisin the absence of tissue hypoxia. Certain clinical disordersincluding diabetes mellitus, liver failure, sepsis, and neoplasticdiseases predispose the patient to lactic acidosis. Detaileddescriptions of the causes of lactic acidosis can be foundelsewhere [3—7, 65, 135, 142]. Congenital lactic acidosis resultsfrom a variety of relatively rare, congenital enzymatic defectsthat affect the metabolism of pyruvate and lactate (Table 4).

Treatment

Management of lactic acidosis must be directed at promptidentification and aggressive treatment of the underlying causeor predisposing disorder whenever possible. Although judiciousadministration of alkali might be warranted to ameliorate theprevailing acidemia and thus possibly prevent catastrophiccardiovascular sequelae, such maneuvers should only be re-garded as temporizing and adjunctive to cause-specific mea-sures. Critical tissue hypoxia is the underlying culprit in mostcases of clinical lactic acidosis; therapeutic measures thereforeshould be directed at augmenting oxygen delivery to the tissues.Indeed, focusing one's efforts on merely treating the acidemiaby alkali infusion can be likened to treating diabetic ketoacido-sis with bicarbonate while neglecting insulin administration.

762 Nephrology Forum

Anion• gapR [Nat]

[KIEU [HCOj]D [cl-I

ll

lh 3h

20

10 -

5)

15-0wE

—10 -

—20

—30

Time from control

Fig. 7. Contribution of hypochloremia to the increment in plasma aniongap during lactic acidosis produced by infusion of the racemic mix-ture of L(+)- and D(—)-lactic acid in the nephrectomized rat (from Ref.123).

The degree of acidemia generated by a given level of lacticacidosis-induced hypobicarbonatemia is, of course, determinedby the attendant level of PaCO2. No systematic observations onthe magnitude of the ventilatory adaptation to lactic acidosis areavailable. Retrospective studies have variably reported that thisresponse is greater than, equal to, or less than that associatedwith other types of metabolic acidosis [3, 124—127]. In an animalmodel of lactic acidosis, the degree of ventilatory adaptationwas virtually identical to that observed in mineral acid-inducedmetabolic acidosis [123]. Stimulation of carotid and aorticchemoreceptor activities in response to lactic acid-inducedmetabolic acidosis has been shown in the cat [128]. Althoughhypocapnia regularly occurs in clinical lactic acidosis [129], itoften is difficult to ascribe it entirely to the adaptive response inview of the frequent coexistence of other processes known tostimulate alveolar ventilation, for example, hypoxemia, hypo-tension, sepsis, pulmonary disease, and hepatic failure. On theother hand, processes that lead to ventilatory failure can limitthe ventilatory response to lactic acidosis or superimpose frankhypercapnia; of course, acidemia is compounded under suchcircumstances.

Plasma potassium concentrationIn contrast to mineral acid-induced acidosis, lactic acidosis of

comparable severity induced by exogenous infusion of lacticacid is not associated with a significant change in plasmapotassium concentration [130—135]. Similarly, hyperkalemia isnot observed in patients with grand mal seizure-induced lactic

Lactic acidosis 763

Table 3. Causes of acquired lactic acidosisa

Increased oxygen demand1. Vigorous voluntary exercise2. Generalized convulsions

Reduced oxygen availability (tissue hypoxia)1. Reduced tissue perfusion

a. Shock or incipient shockb. Acute left ventricular failurec. Low cardiac output

2. Reduced arterial 02 contenta. Asphyxiab. Hypoxemia (Pa02 <35 mm Hg)c. Carbon monoxide poisoningd. Very severe anemia

Drugs and toxins1. Ethanol2. Biguanides (phenformin, metformin, buformin)3. Various intoxications (e.g., methanol, ethylene glycol,

salicylates, isoniazid, streptozotocin, cyanide, nitroprusside,papaverine, paracetamol, nalidixic acid)

4. Fructose, sorbitol, and xylitol5. Epinephrine, norepinephrine

Certain disorders1. Diabetes mellitus2. Liver failure3. Sepsis4. Neoplastic diseases5. Renal failure6. Iron deficiency7. Short-bowel syndrome [D(—)-lactic acidosis}

Idiopathic (spontaneous) lactic acidosis

Adapted from Refs. 3, 4, and 65.

Table 4. Causes of congenital lactic acidosisa

Defects in gluconeogenesisI. Glucose-6-phosphatase deficiency (type I glycogen storage

disease—von Gierke's disease)2. Fructose-bisphosphatase deficiency3. Pyruvate carboxylase deficiencyDefects in pyruvate oxidation1. Pyruvate dehydrogenase deficiency2. Oxidative phosphorylation defects

a Adapted from Refs. 4 and 65.

General measuresSwift steps should be taken to evaluate and treat cardiovascu-

lar collapse, low-cardiac-output states, hypoxemia, and sepsis.As a general rule, aggressive hemodynamic monitoring in anintensive care setting should be employed in directing therapeu-tic measures. Hypovolemia requires prompt extracellular fluidvolume repletion. Every effort should be made to limit the useof vasoconstrictor agents in treating low-cardiac-output states;such agents aggravate the ischemia of peripheral tissues, wors-en the severity of lactic acidosis and, in turn, prove counterpro-ductive for the patient's hemodynamic status [3, 4, 65, 1431.Rather, administration of inotropic compounds along withafterload reducing agents should be used. Extreme vigilanceshould be exercised for the early detection of fatigue of theventilatory apparatus and the presence of critical hypoxemiaand/or hypercapnia; if necessary, artificial ventilation should be

implemented promptly [144]. The outcome of lactic acidosisdepends on the severity and reversibility of the underlyingcondition. If the cause cannot be corrected, lactic acidosis isvirtually certain to advance, and the overall prognosis is grim.By contrast, successful treatment of the underlying conditionleads to prompt improvement of the systemic acid-base statusas the metabolism of the accumulated lactate generates anequivalent amount of endogenous bicarbonate. Typically, themild to moderate degrees of lactic acidosis accompanyinguncomplicated acute alcoholism, acute pulmonary edema, self-limited grand-mal seizures, and diabetic ketoacidosis abate withcause-specific and general supportive measures without theneed for treatment of the acidosis itself.

Alkali therapyCause-specific measures should be complemented by alkali

therapy whenever the prevailing acidemia is severe, that is,when the pH falls below approximately 7.20 [3, 4, 6, 65, 145]. Inthe absence of a complicating element of respiratory acidosis(which, if present, warrants prompt efforts at increasing alveo-lar ventilation), such degrees of acidemia usually imply decre-ments in plasma bicarbonate concentration below 10 mEq/liter.Intravenous sodium bicarbonate should be administered toraise the plasma bicarbonate concentration to 10 to 12 mEq/literand to maintain blood pH at or above 7.20. This recommenda-tion is based on strong evidence indicating that severe acide-mia—that is, pH below 7.20—exerts adverse hemodynamiceffects, including impairment of cardiac contractility; reductionof cardiac output, arteriolar dilation, dangerous degrees ofhypotension, and diminution in hepatic and renal blood flow;peripheral venoconstriction leading to central redistribution ofblood volume, thereby augmenting the workload of a depressedmyocardium; increased pulmonary vascular resistance leadingto "shock lung"; and bradycardia and sensitization to variousmalignant ventricular arrhythmias [75, 113, 145—148]. Althoughacidemia stimulates the release of catecholamines, it alsoprogressively attenuates the inotropic and chronotropic effectsof these sympathetic mediators on the heart; thus, at pH valuesbelow 7.20, the direct negative inotropic effect of acidemiabecomes dominant. A recent study, which revealed rapiddesensitization and uncoupling of human /3-adrenergic recep-tors in an in-vitro model of lactic acidosis, provides a plausibleexplanation for the characteristic lack of responsiveness tosympathetic mediators [149]. These observations, which sug-gest that pretreatment with /3-adrenergic blocking agents sensi-tizes the myocardium to the adverse hemodynamic effects ofacidemia, might have clinical relevance. It therefore should beevident that alkali therapy must be administered (1) to possiblyavoid the superimposition of severe acidemia-related hemody-namic compromise on that already caused by the underlyingdisease; and (2) to reinstate cardiac reactivity to endogenous aswell as exogenous catecholamines until the underlying condi-tion can be identified and treated. Beyond its direct beneficialeffects, such treatment provides a certain measure of safetyagainst the superimposition of additional acidifying stresses; atvalues below 10 mEq/liter, a further small decline in plasmabicarbonate concentration and/or a small increment in PaCO2can cause catastrophic acidemia.

The utility of this time-honored, adjunctive measure in treat-ing lactic acidosis has been criticized strongly in recent years [7,

No treatment NaCI NaHCO37.37.2 1a 7.11 47.0 1 ______

47, 49—5 1, 142]. Critics have argued that despite the establishedpractice of vigorously treating severe lactic acidosis with sodi-um bicarbonate, mortality rates continue to be overwhelming.This is hardly a persuasive criticism in itself, since the underly-ing clinical entities—and root causes of the tactic acidosis—often are of grave severity. Alkali administration, althoughdesigned to potentially limit the gravity of the metabolic distur-bances and their hemodynamic epiphenomena, is not expectedto alter materially the course of the background disorder. As Ialready have emphasized, alkali is used as symptomatic treat-ment directed at severe, life-threatening acidemia; unless spe-cific measures prove successful in relieving critical tissuehypoperfusion and hypoxia, the outcome is certain to bedismal.

Notwithstanding, an even more serious indictment of bicar-bonate therapy has been handed down recently. Its criticscharge that such therapy, far from being beneficial, actuallyexerts a detrimental effect on the course of lactic acidosis [7, 47,49—51, 142]. I should like to review the chief pieces of experi-mental evidence supporting this charge.

Hypoxic lactic acidosis was induced in anesthetized dogswith fixed ventilation at an Fi02 of 8%, with resulting Pa02values of 25 to 30 mm Hg [51]. The impact of three treatmentoptions—no therapy, administration of 1 M NaCl at 2.5 mmol/kg/hr, or an equivalent amount of 1 M NaHCO3—applied for 60minutes was studied with regard to blood acid-base status,lactate metabolism, and systemic hemodynamics. As Figure 8shows (left panel), animals in all three treatment groups experi-enced significant and similar decrements in pH and in plasmabicarbonate concentration during the experimental period.Moreover, although plasma lactate rose further in all groupsafter one hour of observation, the plasma lactate level wassignificantly higher in the NaHCO3 group as compared to theremaining two groups. Skeletal muscle lactate production didnot change significantly in any of the three groups. Gut lactateproduction remained unchanged in the groups receiving eitherno treatment or NaHCO3, but it decreased significantly in the

NaC1 group (Fig. 8, middle panel). Hepatic lactate extractionremained unchanged in all three groups. The baseline meanaortic pressure and blood flow to the gut and liver were normalin all groups, whereas the cardiac index was 130% higher thanthat in the control animals. No significant changes in bloodpressure and cardiac index were noted in the NaC1 group duringthe course of treatment; by contrast, both these parameters fellin the animals receiving either no treatment or NaHCO3, moreso in the latter group (Fig. 8, right panel). Observations on thefate of blood flow to the gut and liver were not provided.

Although interesting, the relevance of these observations toclinical hypoxic lactic acidosis remains unclear. After all, theclinical entity is usually characterized by a decreased, notincreased, cardiac output, and by decreased, rather than nor-mal, blood pressure and organ perfusion. In addition, thepathogenesis of the augmentation in the plasma lactate levelduring NaHCO3 treatment is somewhat puzzling when viewedin the context of the remaining evidence. Thus, the observedhemodynamic deterioration in the NaHCO3 group apparentlywas insufficient to alter either lactate production by gut andskeletal muscle (the main sources of lactate in this model) orhepatic lactate extraction; nonetheless, an exaggerated aggra-vation of hyperlactatemia was noted. The investigators ob-served that although systemic acid-base status did not changeduring the course of the experiment, portal PCO2 averaged 55mm Hg after NaHCO3 treatment—a value significantly higherthan the 45 mm Hg after NaC1 treatment, It is unclear to whatextent the fixed ventilation of the animals affected this result.Assuming that the basal values of this parameter did not differbetween the NaCI- and NaHCO3-treated groups, it is possiblethat this degree of portal hypercapnia might have producedexcessive intrahepatic acidification, thus adversely affectinghepatic lactate uptake [70]. Yet extraction of lactate by liverremained unaltered by treatment in all groups. Furthermore,the disparate hemodynamic response between the NaCI- andNaHCO3-treated groups of animals,despite the similarity in theamount of sodium and volume administered and the prevailing

764 Nephrology Forum

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Fig. S. Effect of 3 treatment options (no treatment, NaG!, or NaHCO3) on hypoxemia-induced lactic acidosis in the dog. Left panel, changes inblood pH, and bicarbonate and lactate concentrations. Middle panel, production of gut lactate in animals treated with NaCI (clear bars) orNaHCO3 (hatched bars). Right panel, hemodynamie changes in dogs receiving NaCI (open circles), NaHCO, (closed circles), or no treatment(open triangles) (from Ref. 51, copyright 1985 by the AAAS).

Lactic acidosis 765

acid-base status, is intriguing but puzzling. No mortality wasreported in any of the studied groups [511.

Using a different experimental model, the same group ofinvestigators has produced evidence supporting their thesis ofan adverse role of bicarbonate therapy in lactic acidosis [49].Lactic acidosis was induced in diabetic dogs (having undergonesurgical pancreatectomy) via infusion of intravenous phenfor-mm. Following 90 minutes of treatment with either NaHCO3 (1mmollmin as a 1 M solution) or equivalent amounts of NaCl,systemic acid-base status remained unchanged in both groups;however, plasma lactate remained essentially unaltered in theNaCI-treated group but increased twofold in the NaHCO3-treated animals. Lactate production by the gut doubled in theNaHCO3 group and remained unchanged in the NaC1 group;hepatic lactate uptake was unaffected by either treatment.Moreover, cardiac output, hepatic portal venous blood flow,and liver and erythrocyte intracellular pH all decreased in theNaHCO3-treated animals but remained essentially unchangedin the animals given NaCl. However, muscle intracellular pHfell significantly in the NaCl, but not in the NaHCO3, animals.After 4 hours of observation, the same mortality rate, 83%, wasseen in both groups.

Again, the relevance of these experimental observations tothe clinical disorder is uncertain. Intravenous phenformin inhigh doses is cardiotoxic and produces consistent decreases incardiac output and systemic hemodynamics even before anychanges in systemic acid-base status are detectable [96, 103].Why NaHCO3 administration would increase phenformin'scardiotoxicity as compared to equimolar amounts of NaC1remains unclear. It has been suggested that because phenforminis a strong base, alkalinization would intensify its diffusionacross plasma membranes to intracellular binding sites [150].

Despite some inconsistencies, the evidence derived fromthese [49, 51] and other studies supporting the notion thatbicarbonate administration or, in general, alkalinization (rela-tive or absolute) of body fluids stimulates lactate production isstrong. Even massive doses of alkali may not succeed insubstantially increasing the plasma bicarbonate level in malig-nancy-associated chronic lactic acidosis; indeed, a direct stoi-chiometric relationship between alkali administration and acidproduction, presumably by the malignancy, has been demon-strated [43, 44]. Moreover, there is a dynamic inverse relation-ship between the prevailing acidity of body fluids and eitherketoacid production during ketoacidosis [12, 53, 54] or lactateproduction during hypoxemia-induced lactic acidosis [42]. Acentral difference between clinical hypoxic lactic acidosis andthe hypoxemia-induced experimental counterpart is that thelatter is a model of relatively controlled lactic acidosis in whichthe tendency toward continued lactate production apparently iscompensated for by salutary hemodynamic adjustments as wellas by the negative feedback exerted by the prevailing acidemia.By contrast, clinical hypoxic lactic acidosis is often a precipi-tous, explosive state in which the prevailing hemodynamicdisarray gives rise to rapidly advancing lactic acidosis that, inturn, aggravates the circulatory compromise, diminishes hepat-ic and renal blood flow, and leads to more severe acidemia byaccelerating production and decreasing uptake of lactate. It isthus clear that the negative feedback control system betweensystemic pH and organic acid production (suggested by experi-mental studies) is overriden during clinical hypoxic lactic

acidosis, and that it gives way to an all-too-familiar lethalvicious cycle. Consequently, I reject any extrapolations of theexisting experimental findings to the clinical setting, and Idispute the implication that the clinical use of bicarbonateshould be abandoned. Nonetheless, the cumulative experimen-tal evidence has reinforced the clinical dictum that bicarbonateshould be administered wisely and cautiously.

I believe strongly, therefore, that judicious administration ofbicarbonate along the guidelines given here is imperative. Byreturning systemic pH above the hemodynamically criticallevel, the clinician "buys time" that might allow control of theunderlying causative illness. This relative alkalinization proba-bly tends to increase lactate production, but this tendencyshould be offset by the improved state of tissue perfusion and,possibly, by the augmentation of hepatic lactate extraction. Forthis reason the clinician should take pains to use the smallestpossible amounts of bicarbonate that will allow the return ofsystemic pH to hemodynamically safe levels [144].

No simple prescription exists for predetermining the amountof bicarbonate necessary for achieving this goal in the individ-ual patient. The only recourse available to the clinician is toperform an individual titration for each patient. Frequent moni-toring of the acid-base status during bicarbonate therapy isessential for a cogent appraisal of additional bicarbonate re-quirements. That the goal of raising plasma bicarbonate byadministering alkali can be achieved is well documented inmany forms of clinical lactic acidosis, but widely variable ratesof bicarbonate administration are required [3, 65]. This variabil-ity in dose requirement largely reflects the fact that the rate oflactic acid production is itself extremely variable. The clinicianalso should note that the apparent space of distribution forbicarbonate is enlarged in hypobicarbonatemic states [151];thus, calculating bicarbonate doses on the basis of the normalvalue of the apparent space of distribution for bicarbonate of40% to 50% body weight will underestimate the bicarbonaterequirements. Indeed, when lactic acid production proceedsextremely rapidly, administered bicarbonate can fail to effectdetectable changes in plasma bicarbonate concentration, theapparent space of distribution for bicarbonate becoming essen-tially infinite.

Administration of large and occasionally massive amounts ofbicarbonate entails certain risks [3, 4, 65, 144]. Hypernatremiaand marked hyperosmolality, and volume overload are commonproblems. Establishment of adequate diuresis with potent loopdiuretics allows the infusion of large doses of alkali withoutsuperimposing iatrogenic circulatory compromise. On the otherhand, if renal failure is present, peritoneal dialysis, hemodialy-sis, or hemofiltration may be required [152—154]. "Overshoot"alkalosis is an extremely undesirable complication of aggressivealkali dosing and underscores the strong recommendation forjudicious bicarbonate administration; the swift transition fromsevere acidemia to alkalemia can produce tetany, altered men-tal status, generalized convulsions, and cardiac arrhythmias.These complications arise from two mechanisms. The first isthe persistence of hyperventilation at levels inappropriate forthe newly prevailing plasma bicarbonate concentration—eitherbecause of the known delay of medullary chemoreceptors toregister the amelioration of acidity in the systemic circulation,or because of pH-independent stimuli of alveolar ventilation.Second, substantial elevations in plasma bicarbonate, occasion-

766 Nephrology Forum

ally to frankly supranormal levels, can result from the compos-ite effect of inordinately large exogenous alkali loads and fromthe regeneration of endogenous alkali from the metabolism ofthe accumulated lactate [3, 4, 65, 144]. Special attention shouldbe paid to the level of plasma potassium to prevent hypokalemiaduring treatment, especially in patients receiving digitalis. Ad-ministration of bicarbonate produces increments in PaCO2 thatoriginate both from the release of CO2 during the internaltitration of bicarbonate and from pH-mediated suppression ofalveolar ventilation [151, 155]. In patients with adequate gasexchange, this small effect is usually inconsequential, but it canbe clinically important in patients with borderline oxygenation.Bicarbonate administration during resuscitative efforts in pa-tients with cardiorespiratory arrest prior to the reestablishmentof gas exchange may compound the often severe acidemia. Thiseffect occurs due to complete retention of the CO2 releasedduring the rapid titration of infused bicarbonate by the ongoinglactic acid production [1561. Finally, concerns that the changesin pH induced by judicious alkali administration will produce aclinically significant decrease in tissue oxygen delivery byenhancing hemoglobin's affinity for oxygen (Bohr effect) areunfounded [144, 157].

Additional measuresInsulin administration has been suggested as a therapeutic

measure in diabetic patients with lactic acidosis, whether or notbiguanide agents are involved [158, 159]. Theoretically, insulincould exert a beneficial effect by stimulating the oxidation ofpyruvate through the pyruvate dehydrogenase (PDH) pathwayand by limiting the flow of gluconeogenic amino acids to theliver. Although the evidence supporting this therapy is tenuous,it is probably advisable to include insulin in the treatment planin this setting [4, 7, 160].

In a single patient with lactic acidosis in association withcongestive heart failure, normal cardiac output, and normoten-sion but clinical evidence of severe peripheral vasoconstriction,afterload reduction with sodium nitroprusside led to strikingresolution of the metabolic abnormality [161]. No additionalexperience has been documented in such a setting, however,and the efficacy of this modality thus remains unproven. As Ialready have mentioned, afterload reducing agents should beused in preference to vasoconstrictors in the treatment of low-cardiac-output states [162, 1631.

Methylene blue, an oxidizing agent, was proposed as treat-ment for lactic acidosis on the premise that it promotes theconversion of NADH to NADt and thus restores the cellularredox state; however, clinical application of this therapy hasnot proved successful [164].

Thiamine and lipoic acids, agents that act as coenzymes forthe PDH enzyme complex, have been utilized occasionally inthe treatment of patients with lactic acidosis, but experience islimited and therefore their utility remains uncertain [3, 4, 165].However, thiamine represents remarkably effective specifictherapy in patients with lactic acidosis in association withfulminant beriberi [165, 166].

Peritoneal dialysis, hemodialysis, or hemofiltration is a usefuladjunctive measure in the management of patients with im-paired renal function who require large alkali loads [152—154,167, 1681. In addition to preventing or treating the associatedvolume overload, dialysis conveniently and reliably provides

the needed alkali. Obviously, in view of impaired lactateutilization there is no sense in employing lactate-buffereddialysate. Acetate-buffered dialysate has been used effectivelybut should be avoided in patients with hemodynamic insuffi-ciency or instability and in those prone to acetate intolerance.Bicarbonate-buffered peritoneal dialysis or hemodialysis hasbeen employed successfully in the management of patients withlactic acidosis [153, 167, 168]. Its attractions include provisionof bicarbonate as such, rather than of alkali precursors; avoid-ance of the risk of further hypobicarbonatemia due to animbalance between the diffusive losses of bicarbonate in thedialysate and alkali generation from the acetate; the preventionof acetate dialysis-induced hypoxemia; and probably a betterhemodynamic profile. Bicarbonate-buffered peritoneal dialysisis particularly suitable in the management of patients withcirculatory failure. In addition, dialysis can remove drugs andtoxins such as methanol and salicylates; hemodialysis does notremove appreciable quantities of phenformin, however [169].Finally, dialysis can remove lactate from the body fluids andthus often prevent rebound hyperbicarbonatemia. Recent evi-dence suggests that hyperlactatemia per se (independent ofchanges in systemic pH) exerts adverse effects on myocardialcontractility. In-vitro studies have shown that increased lactateconcentration impairs frog atrial muscle contractility [170],leads to swelling and reduction in oxidative phosphorylation inisolated beef heart mitochondria [171], and inhibits glucoseutilization by ischemic rat myocardium at the glyceraldehyde 3-phosphate dehydrogenase step [172]. In addition, hyperlactate-mia per se decreased exercise tolerance in normal rats [173]. Bycontrast, increased lactate concentration did not decrease thecontractility of the papillary muscle of the cat [147]. If anadverse hemodynamic effect of hyperlactatemia were con-firmed, it would provide a plausible explanation for evidence ofhemodynamic deterioration following bicarbonate administra-tion independent of changes in systemic pH [49, 51, 96]. Suchconfirmation would support therapeutic strategies specificallyaimed at reducing plasma lactate.

Finally, dichloroacetate (DCA) is an exciting investigationalagent that holds promise as a therapeutic tool in lactic acidosis.Because DCA stimulates PDH activity in many tissues, itaugments the oxidation of pyruvate to acetyl-CoA [174, 175].This effect directs lactate, alanine, and pyruvate into theformation of carbon dioxide, fatty acids, and ketone bodies(Fig. 1) and consequently inhibits hepatic gluconeogenesis fromthese 3-carbon precursors. Decreases in the plasma levels oflactate, alanine, pyruvate, and glucose occur, whereas plasmaketone-body concentration increases [176—179]. In nonacidoticdiabetic patients, DCA decreases lactate levels [180], and it canimprove the disordered lactate metabolism in experimentallactic acidosis produced by functional hepatectomy, phenfor-mm administration, exercise, epinephrine infusion, or hypoxe-mia [52, 175, 177, 181—184]. In one study [52], administration ofDCA to diabetic dogs with phenformin-induced lactic acidosissignificantly lowered plasma lactate and significantly raisedplasma bicarbonate concentration and pH as compared to asimilarly prepared group of animals that received NaHCO3treatment (Fig. 9). Moreover, whereas treatment with NaHCO3could not arrest the progressive fall in the cardiac index,treatment with DCA returned cardiac index to the control value(Fig. 10); mortality during a 4-hour treatment period with either

Lactic acidosis 767

210 270 330 390 450

Time, minutes

Fig. 9. Effect of dichloroacetate (DCA) or NaHCO3 treatment on bloodacid-base composition and lactate level during phenformin-inducedlactic acidosis in the diabetic dog (reproduced from The Journal ofClinical Investigation, 1982, vol. 70, pp. 853—862 by copyright permis-sion of The American Society for Clinical Investigation).

modality averaged 91% in dogs receiving NaHCO3, as com-pared with 22% in dogs treated with DCA [52]. It is interestingthat treatment with DCA resulted in increased liver lactateuptake in association with increased liver intracellular PH; thus,the decreased hyperlactatemia noted could be the compositeeffect of decreased lactate production due to improved cardiacperformance and increased lactate utilization. These authorsmade similar observations about DCA treatment in dogs withfunctional hepatectomy and lactic acidosis [52]. The decisivelybetter outcome of DCA therapy compared to NaHCO3 adminis-tration in this study often has been quoted as a potent argumentagainst the utility of NaHCO3 therapy [7, 49, 51]. I find thisargument unconvincing, however. To attempt to draw a paral-lel, I do not think it valid to conclude that NaHCO3 has no rolein the management of diabetic ketoacidosis on the basis ofimproved outcome of patients treated with insulin as comparedto outcome in those treated with alkali alone.

Two studies have provided evidence in support of a beneficialrole of DCA in the treatment of hypoxemia-induced lactic

Time, hours

Fig. 10. Effect of dichioroacetate (DCA) or NaHCO3 treatment oncardiac index during phenformin-induced lactic acidosis in the diabeticdog (reproduced from The Journal of Clinical Investigation, 1982, vol.70, pp. 853—862 by copyright permission of The American Society forClinical Investigation).

acidosis in rats and dogs [183, 184]. Unlike treatment withsodium chloride, DCA administration resulted in attenuation ofthe hyperlactatemia, hypobicarbonatemia, and acidemia in hyp-oxemic rats; moreover, the animals receiving DCA maintainedhigher mean blood pressures and greater rates of urine flow andsodium excretion [183]. Similarly, administration of DCA tohypoxemic dogs significantly increased plasma bicarbonate andpH, and stabilized plasma lactate concentration; by contrast,progression of hypobicarbonatemia, acidemia, and hyperlacta-temia was noted in the group receiving sodium chloride. Addi-tionally, animals given DCA, but not those given NaCl, experi-enced increased hepatic lactate extraction, decreased liver andmuscle lactate levels, and elevated muscle intracellular pH[184].

Some data on DCA are available in humans as well. Thirteengravely sick, hypotensive patients with lactic acidosis in associ-ation with various predisposing illnesses (such as renal andhepatic disease, sepsis, leukemia or lymphoma, arrhythmias)were given DCA [185]. Of the 11 who did not receive concur-rent treatment with bicarbonate, each of 7 experienced at least a20% decrease in plasma lactate (Fig. 11); this subgroup had asignificant, mean reduction of lactate of 80% (from an averagevalue of 14.2 to 2.8 mEq/liter) and significant increases inplasma bicarbonate and pH (from 14 to 21 mEq/liter and from7.24 to 7.39, respectively). The fall in plasma lactate persistedfor several hours after treatment with DCA was terminated. In10 of the 13 treated patients, increases in systolic bloodpressure of 10 to 40 mm Hg were noted soon after the initiationof DCA treatment; in 4 patients whose cardiac output wasmonitored, the increase in systolic blood pressure was accom-panied by a significant mean increase in cardiac output of 21%(from 6.2 to 8.4 liters/mm). These findings are in accord withprevious observations indicating that DCA improves cardiacfunction in dogs with experimentally induced myocardial isch-emia or lactic acidosis [52, 186]. Because the drug is known toaugment aerobic oxidative metabolism in cardiac tissue [187], it

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768 Nephrology Forum

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might improve myocardial contractility. These hemodynamiceffects might complement the metabolic action of DCA indecreasing the plasma lactate level. Unfortunately, despitethese favorable metabolic and hemodynamic consequences, allbut one of the patients in that study died of their underlyingdisease [185]. Additional human experience with DCA includesobservations in 8 adult patients with severe lactic acidosis inassociation with biguanide therapy, hypotension, sepsis, ormalignancy; 3 of the 8 had a greater than 20% reduction inplasma lactate levels, and 2 of the 3 survived [185, 188, 1891.Moreover, of 7 children with congenital forms of lactic acidosis,DCA produced biochemical and/or clinical improvement in 4[190—194]. In general, no appreciable drug toxicity has beenobserved in studies of short-term administration of DCA [180,185, 188, 189, 190—193, 1951. By contrast, serious side effectshave been noted with long-term administration, including limbparalysis, cataracts, increased urinary oxalate excretion, testic-ular degeneration, neuropathy, mutagenicity, and changes inthe white matter of the central nervous system [175]; obviouslythese findings make DCA unsuitable for extended use [196].

One would hope that the encouraging results of the humanstudies coupled with those from experimental models wouldprompt prospective controlled trials of this agent to define itsproper role in the management of lactic acidosis. In one sense,augmentation of lactate utilization during lactic acidosis byDCA resembles restoration by insulin of the disordered metabo-lism during diabetic ketoacidosis. Although the underlyingdisease is clearly the main determinant of the eventual outcomeof the patient, alleviation of the lactic acidemia by DCA or ananalogue coupled with judicious administration of alkali forsevere acidemia should at least allow the clinician the opportu-nity to apply other therapeutic measures directed at the inciting

disorder. It is currently unknown whether the beneficial effectof DCA on lactic acidosis would be translated into a favorablealteration of the natural course of the underlying disease andthus to decreased mortality. Indeed, the so-far disappointingsurvival data with DCA therapy should restrain the critics ofNaHCO3 therapy who have denounced bicarbonate therapy onthe charge that high mortality rates from lactic acidosis persistdespite alkali provision.

ConclusionAdvances in the understanding of lactate metabolism have

allowed insights into the pathogenesis of lactic acidosis. Despitethis progress, however, the development of hyperlactatemiaremains an index of the gravity of the patient's condition and iscommonly the harbinger of the patient's impending demise. Themainstay of therapy for lactic acidosis continues to centeraround efforts to improve or eradicate the underlying cause orpredisposing condition, coupled with the careful and restrainedadministration of sodium bicarbonate to prevent or treat criticalacidemia. Clinical research should continue with the promisinginvestigational agent DCA to define its proper role in thetreatment of the various forms of lactic acidosis.

Questions and answers

DR. JOHN T. HARRINGTON: You alluded to the hyperlactate-mia of respiratory alkalosis. Could you be a little more quantita-tive on this issue?

DR. MADIAS: Several investigators have attributed a majorcomponent of the reduction in plasma bicarbonate during acuterespiratory alkalosis to the accumulation of lactic acid (on theorder of 50% to 75%). This conclusion was based on studies inanesthetized animals subjected to mechanical ventilation suffi-cient to achieve severe hypocapnia (PaCO, less than 15 mm Hg)[18, 197, 198]. By contrast, studies in unanesthetized animalsand in humans subjected to milder degrees of hypocapnia(PaCO, of 20 to 30 mm Hg) have reported only a slight andshort-lived elevation in plasma lactate concentration (in therange of 0.5 to 1.5 mEq/liter). Indeed, the hyperlactatemiavanishes within 8 hours despite the persistent hypocapnia [23,24, 28]. Additional studies in anesthetized animals and humansconfirm the presence of only a mild degree of hyperlactatemiaduring moderate grades of acute respiratory alkalosis [22, 25—271. Moreover, during chronic hypocapnia, plasma lactateconcentration is within normal limits even in the presence ofassociated hypoxemia [29—34]. The large increase in lactateobserved by some probably reflected a degree of circulatoryinsufficiency consequent to the cardiovascular effects of anes-thesia and vigorous mechanical ventilation.

DR. VINCENT J. CANzANELLO (Division of Nephrology,NEMCH): Do changes in hormones affecting the transcellulardistribution of potassium account for the lack of hyperkalemiaduring experimental lactic acidosis?

DR. MAmAs: To my knowledge, this attractive possibility hasnot been investigated systematically. In this regard, recentobservations have uncovered a role of the endocrine pancreasto account for the different response of plasma potassium toexperimental ketoacidosis (normokalemia or hypokalemia) ascompared to mineral acidosis (hyperkalemia): Whereas ketoaci-dosis was associated with hyperinsulinemia, HC1-induced aci-dosis was accompanied by elevated glucagon levels [199].

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Lactic acidosis 769

Da. RICHARD L. TANNEN (Director, Division of Nephrology,the University of Michigan Medical Center, Ann Arbor, Michi-gan): Dr. Madias, I agree with your comments and yourrecommendations about bicarbonate administration in patientswith acute lactic acidosis. However, in considering the adverseeffects on the circulation that clearly have been shown to attendtreatment with bicarbonate in studies of experimental lacticacidosis [49, 51], I would like to propose that factors other thanbicarbonate itself or changes in the hydrogen ion concentrationmight be at fault. It seems quite possible, for example, thatthese adverse effects might be caused by metabolic intermedi-ates, the concentrations of which are stimulated by the adminis-tration of bicarbonate.

DR. MADIAS: I agree that changes in acid-base status conse-quent to bicarbonate administration cannot explain the adversehemodynamic effects reported in these studies [49, 51, 96, 103].These reports have implied that the hemodynamic deteriorationmight arise from bicarbonate-induced intracellular acidosis. Butthis suggestion runs counter to available experimental evi-dence. First, whole-body intracellular pH increases followingsodium bicarbonate infusion in the dog [200]. Second, cardiacand skeletal muscle intracellular pH of the rabbit increases inresponse to sodium bicarbonate infusion [201]. Moreover,myocardial contractility and cardiac output increase consistent-ly following an intravenous or intracoronary infusion of sodiumbicarbonate in the dog [112, 202, 203]. Your suggestion that oneor more metabolic intermediates of stimulated glycolysis mightbe at fault is an attractive one and deserving of futureinvestigation.

I should like to reemphasize the important insights in thephysiology of lactic acid metabolism that these studies haveprovided [47—51]. The findings on the hemodynamic effects ofbicarbonate treatment have raised important questions thatmerit further investigation. On the other hand, I maintainstrongly at present that any extrapolation from the findings ofthese studies to patients is inappropriate. I have presented indetail the reasons for my position, chief of which are thequestionable relevance of the experimental models to theclinical circumstances and the strong evidence indicating thatsevere acidemia triggers a series of adverse hemodynamiceffects. I should add that regarding mortality, even no treatmentat all appears to make no difference in these experimentalmodels [49, 51]. I suggest that leaving severe lactic acidosisuntreated is not a viable option in the clinical setting.

DR. ANDREW S. LEVEY (Division of Nephrology, NEMCH):Could you expand your comments about the potential toxicityof the lactate ion itself?

DR. MADIAS: Our thinking has been dominated by theconcept that the deleterious effects of lactic acidosis stemexclusively from the outpouring of hydrogen ions into the bodyfluids, whereas the lactate ions themselves are thought to beinnocuous. Yet, some [170—173] but not all [147] of the recentpieces of evidence I have reviewed cast doubt on this conceptand argue for a direct adverse effect of the lactate ion onmyocardial contractility. I believe that this may be an issue ofgreat importance, and it certainly warrants intensiveinvestigation.

DR. CANZANELLO: A number of recent studies suggest thatadministration of either NH4C1 or NaHCO3 induces a substan-tial decrease or rise, respectively, of the hyperlactatemia of

exercise. Have these maneuvers affected exercise tolerance?DR. MADIAS: Careful studies have documented that treat-

ment with oral NH4C1 is associated with markedly diminishedendurance during high-intensity, cycle-ergometer exercise; bycontrast, treatment with oral NaHCO3 led to enhanced endur-ance [41, 204, 205]. In contrast to these studies of prolongedexercise, changes in acid-base status induced by these maneu-vers have not produced appreciable effects on maximal poweroutput and fatigue during short-term, maximal exercise [39]. Inboth types of exercise however, NH4C1-induced acidosis hasdecreased the post-exercise plasma lactate concentration,whereas NaHCO3 has augmented the hyperlactatemia. In addi-tion to inducing changes in net lactate production, alterations inacid-base status probably influence plasma lactate levels byaffecting the rate of lactate efflux from muscle; several observa-tions suggest that acidosis impairs and alkalosis promotes theeffiux of lactate [206—2081.

DR. RONALD D. PERRONE (Division of Nephrology,NEMCII): Would you comment on the treatment of the lacticacidosis associated with malignancies?

DR. MADIAs: Although lactic acidosis in the company ofcirculatory insufficiency, liver failure, or sepsis is a commonoccurrence in the preterminal stage of many neoplastic dis-eases, it occasionally develops in the absence of such factorsand may pursue a relatively chronic course [3, 4, 65]. Such a"paraneoplastic" metabolic derangement usually is seen inpatients with leukemia or other myeloproliferative disorders; italso occurs in association with lymphomas and with severalsolid tumors. Overproduction of lactic acid by the neoplastictissue has been implicated in the pathogenesis of this syndrome.Because leukocytes and neoplastic cells have a high glycolyticrate, increased production of lactate would be expected if thetumor burden were large. In some instances, lactic acidosis hasdeveloped only in association with high-glucose, total parenter-al nutrition. In addition, rapidly proliferating tumors may sufferfrom an inadequate blood supply, producing severe hypoxiaand an increased dependence on anaerobic glycolysis. Also,oxygenation can be decreased in a tightly packed bone marrow,thus favoring the accumulation of lactate. The pathogenetic roleof lactate overproduction is supported by the observation thatlactic acidosis resolves with successful treatment of the under-lying malignancy [209—2111. Furthermore, a role for hepaticunderutilization of lactate has been suggested in some cases oflactic acidosis in patients with massive replacement of the liverby tumor [3, 4, 65, 2111.

With regard to alkali administration, the general restraint Isuggested for its use in hypoxic states should be exercised alsoin this setting, As I have mentioned, even massive doses ofalkali may not succeed in substantially increasing plasma bicar-bonate in these patients because of a direct stoichiometricrelationship between alkali administration and acid production,presumably by the malignancy [43, 44]. In addition to the well-known risks stemming from the administration of large bicar-bonate loads, aggravation of the prevailing cachexia may alsooccur in the patient with cancer and poor dietary intake becausethe body's glycogen and protein stores may be depleted as aconsequence of stimulated lactate production [44]. Consequent-ly, such patients should receive the smallest possible amount ofbicarbonate that is sufficient to prevent or treat life-threatening

770 Nephrology Forum

acidemia and always in the company of an adequate nutrientsupply.

DR. HARRINGTON; What is your opinion regarding the phe-nomenon referred to as idiopathic lactic acidosis?

DR. MADrAS: As you know, the terms "idiopathic" and"spontaneous" have been applied to cases of lactic acidosisthat develop presumably in the absence of evidence for anestablished cause or associated condition [1, 2, 212]. Althoughas yet unrecognized cause(s) may be at play, well-foundedreservations have been raised about the validity of this designa-tion [4, 213]. Close scrutiny of published reports suggests thatmany such patients probably suffered from circulatory insuffi-ciency too subtle for clinical detection [135, 213, 214]. Inaddition, a substantial fraction of patients classified as having"idiopathic" lactic acidosis were taking phenformin. Indeed, inthe great majority of cases, the clinical picture quickly ad-vanced to overt circulatory collapse, often in the company ofsepsis or liver failure, and had a catastrophic outcome [4, 215,216]. It therefore appears that the development of so-calledidiopathic lactic aeidosis is usually a warning sign presaging theappearance of circulatory failure. Although I have included it inTable 3 for completion, I suspect that idiopathic lactic acidosisdoes not exist.

Reprint requests to Dr. N. P. Madias, Division of Nephrology, Box172, New England Medical Center, 17] Harrison Avenue, Boston,Massachusetts 02111, USA

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