Lactic Acidosis Update for Critical Care Clinicians

FRIEDRICH C. LUFTFranz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Medical Faculty of the CharitéHumboldt University of Berlin, Berlin, Germany.

Abstract.Lactic acidosis is a broad-anion gap metabolic aci-dosis caused by lactic acid overproduction or underutilization.The quantitative dimensions of these two mechanisms com-monly differ by 1 order of magnitude. Overproduction of lacticacid, also termed type A lactic acidosis, occurs when the bodymust regenerate ATP without oxygen (tissue hypoxia). Circu-latory, pulmonary, or hemoglobin transfer disorders are com-monly responsible. Overproduction of lactate also occurs withcyanide poisoning or certain malignancies. Underutilizationinvolves removal of lactic acid by oxidation or conversion toglucose. Liver disease, inhibition of gluconeogenesis, pyruvatedehydrogenase (thiamine) deficiency, and uncoupling of oxi-dative phosphorylation are the most common causes. Thekidneys also contribute to lactate removal. Concerns have beenraised regarding the role of metformin in the production oflactic acidosis, on the basis of individual case reports. The riskappears to be considerably less than with phenformin and

involves patients with underlying severe renal and cardiacdysfunction. Drugs used to treat lactic acidosis can aggravatethe condition. NaHCO3 increases lactate production. Treatmentof type A lactic acidosis is particularly unsatisfactory.NaHCO3 is of little value. Carbicarb is a mixture of Na2CO3

and NaHCO3 that buffers similarly to NaHCO3 but without netgeneration of CO2. The results from animal studies are prom-ising; however, clinical trials are sparse. Dichloroacetate stim-ulates pyruvate dehydrogenase and improves laboratory val-ues, but unfortunately not survival rates, among patients withlactic acidosis. Hemofiltration has been advocated for thetreatment of lactic acidosis, on the basis of anecdotal experi-ences. However, kinetic studies of lactate removal do notsuggest that removal can counteract lactate production in anymeaningful way. The ideal treatment is to stop acid productionby treating the underlying disorder.

Problems with acid-base balance and electrolyte distur-bances have been masterfully presented and explained byHalperin and colleagues (1–3) in a series of entertaining andenlightening books. I heartily encourage readers to profit fromthese delightful publications, as I have. An additional scholarlysource, which should always be within reach of critical careclinicians, is the monograph by Narinset al. (4). Briefly, lacticacid or lactate is a metabolic dead-end, because pyruvate, thesole immediate precursor, is also the only route of metabolictransformation. Approximately 1400 mmol of lactic acid areproduced daily, which are buffered by 1400 mmol of HCO3 toform sodium lactate. The liver is responsible for oxidizinglactate to restore this amount of HCO3. This task is formidable,because the lactate concentrations in plasma remain below 1mM. The role of the liver in lactate homeostasis is consider-able. However, total cessation of lactate clearance by the liverdoes not invariably lead to lactic acidosis. Extrahepatic tissuesmay compensate for loss of the normal contribution of theliver. The kidneys also contribute to lactate removal; estimatesvary but are approximately 10 to 20% of the total lactatemetabolized. The kidneys dispose of lactate in three ways:excretion, gluconeogenesis, and oxidation. Urinary excretion is

a very minor component, because the renal threshold is 6 to 10mM.

All tissues can produce lactic and pyruvic acid from glucose(Figure 1). Red blood cells produce lactic acid as a byproductof the regeneration of ATP during anaerobic glycolysis butcannot use lactic acid. All other tissues can use lactic acid toproduce acetyl-CoA via pyruvate dehydrogenase (PDH). Lac-tate dehydrogenase is located in the cytosol and catalyzes theinterconversion between lactate and pyruvate. The NADH/NAD1 cofactor system exchanges the hydrogen atoms re-leased or consumed. Therefore, the lactate/pyruvate ratio isalways proportional to the NADH/NAD1 ratio in the cytosol.Under normal conditions, the lactate/pyruvate ratio rangesfrom approximately 4:1 to 10:1. The lactate concentration inplasma is normally 0.4 to 1.0 mM but can increase to.20 mM.A high concentration of lactate is attributable to a high con-centration of pyruvate or a high level of NADH in the cytosol,or both. A high NADH/NAD1 ratio occurs as a result ofunderutilization of NADH with hypoxia or, less commonly,overproduction of NADH with hypoxia and/or oxidation ofethanol in the liver. Pyruvate levels increase if the compoundis produced more rapidly or utilized less rapidly. The formationof pyruvate has the greatest effect on pyruvate concentrations.The rate of production can increase 50-fold if either glucose orglycogen is required to generate ATP in the absence of oxygen.

The possible causes of lactic acidosis are self-evident. Ox-ygen deficits (tissue hypoxia) are the most common and oftenrefractory causes, including pulmonary problems (low PO2),circulatory problems (poor delivery of O2), and hemoglobin

Correspondence to Dr. Friedrich C. Luft, Wiltberg Strasse 50, 13125 Berlin,Germany. Phone: 49-30-9417-2202; Fax: 49-30-9417-2206; E-mail:luft@fvk-berlin.de

1046-6673/1202-0015Journal of the American Society of NephrologyCopyright © 2001 by the American Society of Nephrology

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problems (low O2-carrying capacity, for various reasons). Lac-tic acidosis caused by oxygen deficits is generally termed typeA (fast) lactic acidosis. Also possible is compromised lactatemetabolism without hypoxia, which is frequently termed typeB (slow) lactic acidosis. In the latter case, the causes includehigh glycolysis rates attributable to low cytosolic ATP levels(violent exercise), uncoupled oxidative phosphorylation, de-creased breakdown of lactate because of deficiencies in PDH(thiamine deficiency), high levels of ATP production from fator low rates of ATP synthesis, and low levels of conversion oflactate to glucose. The latter problem occurs with hepaticdestruction or replacement or defects in gluconeogenesis re-sulting from side effects of drugs or inborn errors of metabo-lism. Malignant cells produce more lactate than normal cells,even under aerobic conditions. This phenomenon is enhancedif the tumor outstrips the blood supply or if the amount ofavailable thiamine is insufficient. Decreased lactate removal isusually hepatic in origin. Patients with renal failure are atincreased risk.

Treatment of Lactic AcidosisType A Lactic Acidosis

The only effective treatment for type A lactic acidosis iscessation of acid production via the improvement of tissueoxygenation. Appropriate measures include treatment of shock,

restoration of the circulating fluid volume, improvement oraugmentation of cardiac function, resection of ischemic areas,and amelioration of sepsis. Sepsis causes a series of circulatorydisturbances that lead to tissue hypoxia. This fact should al-ready be well known to readers, and little has changed regard-ing this issue.

NaHCO3 and CarbicarbNaHCO3 therapy is of little value for type A lactic acidosis.

The hydrogen ion loads, which may be produced at 72 mmol/min, make NaHCO3 therapy of doubtful value. However, suchtherapy may possibly “buy time.” Carbicarb is a mixture ofNa2CO3 and NaHCO3 that buffers similarly to NaHCO3 butwithout the net generation of CO2. The results from clinicaltrials are sparse. Bersin and Arieff (5) studied ventilated dogsmade hypoxic. They found that muscle O2 consumption in-creased with carbicarb and decreased with NaHCO3. Arterialpressure decreased less with carbicarb (212 versus 246mmHg, P , 0.006), and the cardiac output was stable withcarbicarb but decreased with NaHCO3 (from 143 to 98 ml/kgper min, P , 0.004). Stroke volume also improved withcarbicarb, without a change in pulmonary capillary wedgepressure, suggesting that carbicarb has beneficial effects onmyocardial contractility. Rheeet al. (6) administered carbi-carb, NaHCO3, and NaCl, in random order, to dogs withhypoxic lactic acidosis. NaHCO3 increased PCO2 and lactateproduction. Carbicarb increased pH and the cardiac index,without increasing lactate levels. The stoke volume index wasalso increased, and the heart rate was decreased. However, inanother dog study, Blecicet al.(7) found that carbicarb was notsuperior to other regimens in a model of cardiac arrest. I am notaware of any controlled human carbicarb trials.

DichloroacetateDichloroacetate has received much attention for the treat-

ment of lactic acidosis (8). Dichloroacetate exerts multipleeffects on pathways of intermediate metabolism. The drugstimulates peripheral glucose utilization and inhibits glucone-ogenesis, thus reducing hyperglycemia in animals and humansubjects with diabetes mellitus. Dichloroacetate inhibits lipo-genesis and cholesterol genesis, thus decreasing circulatinglipid and lipoprotein levels in short-term studies of patientswith acquired or hereditary disorders of lipoprotein metabo-lism. By stimulating the activity of PDH, dichloroacetate fa-cilitates oxidation of lactate and decreases morbidity in ac-quired and congenital forms of lactic acidosis (Figure 1).However, in a randomized controlled trial in patients withlactic acidosis, dichloroacetate was disappointing. Stacpooleetal. (9) studied the compound in patients with severe type Alactic acidosis. Those authors observed that dichloroacetatedecreased the lactate concentrations in the treated patients buthad no beneficial effects on outcomes. The authors concludedthat dichloroacetate treatment of patients with severe lacticacidosis results in statistically significant but clinically unim-portant changes in arterial blood lactate concentrations and pHand fails to alter either hemodynamics or survival rates.

Figure 1. (A) L-Lactic acid synthesis. Lactic acid accumulates ifpyruvate or NADH accumulates. G6P, glucose-6-phosphate; LDH,lactate dehydrogenase. (B) Dichloroacetate effects. Dichloroacetate(DCA) activates pyruvate dehydrogenase (PDH), favoring lactateoxidation. Thiamine is a coenzyme for PDH.

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HemofiltrationHemofiltration and “continuous renal replacement thera-

pies” have been advocated as treatments for lactic acidosis.Schetz (10) mentioned lactic acidosis as an indication for suchtreatment and, indeed, critical care physicians in Europe areinsistent on such therapies for patients with lactic acidosis.However, controlled studies are lacking. Hiltonet al. (11)recently presented their observational experience. Theyclaimed that they corrected lactic acidosis without inducingeither extracellular volume expansion or hypernatremia. For 89of 200 patients (45%) with lactic acidosis, the lactic acidosisresolved during treatment with bicarbonate-based hemofiltra-tion. Fifty-seven patients (29%) survived. Significant differ-ences at presentation for the group of patients who survived,compared with those who died, were observed in age, meanarterial pressure, and Acute Physiology and Chronic HealthEvaluation II scores. Neither the severity of the presentingacidosis nor the arterial blood lactate concentrations appearedto predict outcomes in that series. Patients who developedacute renal failure and lactic acidosis after cardiac surgeryexhibited a low survival rate. The authors suggested that thecombination of acute renal failure and lactic acidosis thatcannot be safely treated with hemofiltration using lactate-basedreplacement fluids can be managed with bicarbonate-basedhemofiltration. Marianoet al. (12) reported success in usingcontinuous renal replacement therapy for the management ofphenformin-induced lactic acidosis. However, there is amplereason for skepticism regarding these anecdotal reports.Levraut et al. (13) investigated the effects of continual renalreplacement therapy on lactate clearance. They studied 10critically ill patients with acute renal failure and stable bloodlactate concentrations, in a two-stage investigation. They mea-sured lactate concentrations in samples of serum and ultrafil-trate from patients receiving continuous venovenous hemofil-tration with dialysis, to calculate lactate clearance by thehemofilter. In addition, they conducted an evaluation of totalplasma lactate clearance by infusing sodium lactate (1mmol/kg body wt) in 15 min. They found that, at the end of thelactate infusion, the median blood lactate concentration in-creased despite renal replacement therapy. The median totalplasma lactate clearance was 1379 ml/min (range, 754 to 1881ml/min), and the median filter lactate clearance was 24 ml/min(range, 7 to 36 ml/min). Therefore, filter lactate clearanceaccounted for,3% of total lactate clearance. The authorsconcluded that continuous venovenous hemofiltration with di-alysis cannot meet lactate overproduction. The data suggestthat a randomized controlled trial of this treatment for lacticacidosis, as was performed for dichloroacetate, is probably notworth the effort.

Type B Lactic AcidosisType B lactic acidosis does not have the same treatment

urgency as type A lactic acidosis, because the condition is notassociated with a primary problem in generating ATP. There-fore, the rate at which hydrogen ions accumulate is muchlower. An important cause of type B lactic acidosis involvesethanol intoxication. Ethanol metabolism generates NADH and

leads to the conversion of pyruvate to lactate (Figure 2).Ethanol metabolism must be ongoing for this type of lacticacidosis to occur, and the condition is mild even withouttreatment. However, the situation may be different in cases ofthiamine deficiency. Thiamine (vitamin B1) is a cofactor forPDH. When thiamine is absent, glucose cannot be oxidizedanaerobically. The major danger is not lactic acidosis but,rather, the central nervous system injury that is caused whenglycolysis is accelerated to supply ATP that can no longer besupplied by the oxidation of ketoacids. This condition (Wer-nicke-Korsakoff syndrome) can be ameliorated or avoided bysupplying thiamine.

Drug-induced lactic acidosis can be caused by oxidativephosphorylation uncouplers or drugs that interfere with glu-cogenesis. Although the lactic acidosis may be severe, thechances for survival are good. The measures required areneutralization of the excess hydrogen ions with NaHCO3,slowing of hydrogen ion production with insulin (in the case ofmetformin-induced lactic acidosis), acceleration of lactate me-tabolism (perhaps with dichloroacetate), and elimination of theoffending drug by renal excretion or other means.

The Biguanide DilemmaType 2 diabetes mellitus is increasing dramatically in inci-

dence, and the glycemic treatment is unsatisfactory. Insulin,sulfonylureas, and thiazolidinediones all have various danger-ous side effects, and all three lead to additional weight gain ingenerally already obese patients. The biguanides have appealbecause they at least do not engender further weight gain.However, many well documented cases of lactic acidosis indiabetic patients using the biguanide phenformin were reported(14). The association caused phenformin to be removed fromthe market in the United States in 1978. Metformin is a far lessdangerous biguanide and has been widely used in Europe.Putative risk factors for lactic acidosis with biguanide treat-ment are as follows: age of.60 yr; decreased cardiac, hepatic,or renal function; diabetic ketoacidosis; surgery; respiratoryfailure; ethanol intoxication; and fasting. Biguanides may in-hibit oxidative metabolism and thus increase the concentration

Figure 2.Ethanol-inducedL-lactic acidosis. The metabolism of etha-nol increases the NADH/NAD1 ratio, which favors the conversion ofpyruvate to lactate rather than to glucose (figures adapted fromreferences 1 and 3).

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of NADH, reduce gluconeogenesis, and suppress the gastroin-testinal absorption of glucose.

Stanget al. (15) determined the incidence of lactic acidosisin a geographically defined population of metformin users. Thestudy included 11,797 Saskatchewan residents who receivedone or more metformin prescriptions, resulting in 22,296 per-son-yr of exposure. There were 10 subjects with hospitaldischarges with a diagnosis of acidosis. However, primaryrecord review revealed only two cases with laboratory findingsof elevated blood lactate levels, for an incidence of 9 cases/100,000 person-yr of metformin exposure. In both cases, fac-tors other than metformin could have contributed to the lacticacidosis. No additional cases were found in a review of deathregistrations in their study. The authors concluded that the rateof lactic acidosis among metformin users in a population withcomplete ascertainment of hospitalizations and deaths wassimilar to previously published rates calculated on the basis ofpassive reporting of cases. The rate of metformin-inducedlactic acidosis was well below the lactic acidosis rate of 40 to64 cases/100,000 patient-yr for patients prescribed phenformin.

The reports of metformin-induced lactic acidosis are neces-sarily anecdotal. For instance, Reekeret al. (16) described atypical patient. A 62-yr-old woman had been found uncon-scious in her bed. She was resuscitated several times in theambulance on the way to the hospital. Her rectal temperaturewas 28°C. She was a diabetic being treated with metformin andglimepiride and had decreased renal function (serum creatinineconcentration, 1.5 mg/dl). The patient also had heart failureattributable to heart disease. She exhibited marked lactic aci-dosis (lactate concentration, 45 mM; pH 6.6). Continuousvenovenous hemodialysis with bicarbonate-buffered solutionswas performed. The authors concluded that metformin wasresponsible and suggested that the drug should be prescribedonly if the contraindications (in particular, renal failure) arecarefully monitored. They also indicated that severe lacticacidosis should be treated early with continuous venovenoushemodialysis with bicarbonate-buffered substitution fluids.The authors may be correct in their assumptions, because“clinical success is always unassailable.” However, multiplefactors interacted in the case of this critically ill woman, anddoubt remains regarding the pathogenesis and the value of thetreatments.

Holsteinet al. (17) indicated that physicians largely ignorethe dangers of metformin. They performed a cross-sectionalanalysis of 308 consecutive patients with type 2 diabetes mel-litus (mean age, 66 yr) who had been previously treated withmetformin on an outpatient basis and were admitted to aGerman general hospital between January 1995 and May 1998,because of acute disease or for optimization of their diabetesmellitus management. All patients underwent a basic investi-gation, including documentation of the medical history, a phys-ical examination, an electrocardiogram, and an extensive lab-oratory profile. At the time of admission to the hospital, 73%of the patients were found to have contraindications, riskfactors, or intercurrent illnesses necessitating discontinuationof metformin administration; 51% of these patients had severalof these conditions. As major contraindications to metformin,

renal impairment was present in 19% of all cases, heart failurein 25%, respiratory insufficiency in 6.5%, and hepatic impair-ment in 1.3%. Additional risk factors included advanced heartdisease in 51% of cases, atrial fibrillation in 9.8%, chronicalcohol abuse in 3.3%, advanced peripheral vascular disease in2%, and pregnancy in 0.7%. As intercurrent illnesses, cerebralischemia occurred in 9.8% of cases with metformin treatment,and malignancies were diagnosed in 6.5%. The patients withrelative or absolute contraindications to metformin were olderand had been previously treated with more cardiovascularmedications. Most interestingly, despite the considerable riskfor lactic acidosis of many patients, no cases of lactic acidosiswere observed.

It is not my intention to minimize the potential of metforminto cause lactic acidosis. However, patients with type 2 diabetesmellitus who develop this complication are ill and have nu-merous concomitant problems, and the literature is difficult tointerpret. Prudent physicians should monitor renal function,withhold the drug from patients with renal and/or hepaticinsufficiency, and consider severe cardiac failure with poorhepatic and renal perfusion a relative contraindication. Met-formin has been used for.40 yr as an effective glucose-lowering agent in type 2 diabetes mellitus. The life-threateningrisks associated with metformin are rare and could mostly beavoided by strict adherence to the prescribing guidelines.Given the four decades of clinical experience with metformin,the antihyperglycemic efficacy of the drug, and its benefits inthe metabolic syndrome, metformin offers a favorable risk/benefit profile, compared with the chronic morbidity and pre-mature death observed among patients with type 2 diabetesmellitus.

Miscellaneous IssuesHow good are we in making the diagnosis of acid-base

disturbances in critically ill patients? Arterial blood gases areconsidered the key to diagnosing acid-base disturbances. Weilet al. (18) showed that differences in acid-base status betweenmixed venous blood and arterial blood exist in critically illpatients undergoing resuscitation. Their study was subse-quently supported by animal data showing that mixed venousblood gases were superior to arterial blood gases for the as-sessment of acid-base status (19). The problem of CO2 accu-mulation in the tissues may be exacerbated by the administra-tion of NaHCO3 to treat lactic acidosis (20). No data have beenpresented to show that disparities between mixed venous andarterial PCO2 and pH occur in lactic acidosis attributable toseptic shock or other causes. CO2 elimination cannot be ac-complished without increasing pulmonary blood flow. Studiescomparing mixed venous and arterial blood gas values invarious forms of lactic acidosis and the inclusion of suchmeasurements in studies of lactic acidosis are warranted. Anexample of such an investigation is the report by Levyet al.(21), who found that hemodynamically unstable patients withsepsis requiring catecholamine therapy exhibited lactic acido-sis with an elevated lactate/pyruvate ratio and decreased arte-rial ketone body levels, suggesting decreases in the cytoplas-mic and mitochondrial redox states. The duration of lactic

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acidosis was associated with the development of multiple or-gan failure and death in their patients. Mixed venous acid-baseassessments permitted elucidation of the findings.

D-Lactic AcidosisA favorite for board examination questions, this unique form

of lactic acidosis can occur in patients with jejunoileal by-passes, small bowel resections, or other forms of short-bowelsyndrome (22). Bacteria are responsible for metabolizing glu-cose and carbohydrate toD-lactic acid, which is then system-ically absorbed. Lactate dehydrogenase can effectively metab-olize only L-lactate;D-lactate is only slowly metabolized byhuman subjects. Clues to the condition are a short bowel orother causes of malabsorption, acidosis with a broad anion gapthat cannot be explained, and neurologic symptoms. The aniongap is commonly smaller than expected on the basis of theHCO3 decrease, becauseD-lactate is not very well absorbed byrenal tubules. The increased anion gap may be the result ofD-lactate or some as yet unknown absorbed toxin. A discrep-ancy between the calculated urine osmolality and the measuredurine osmolality (urine osmolal gap) is expected. Treatmentconsists of fluid resuscitation, restriction of simple sugars,NaHCO3 administration as necessary, and the judicious use ofantibiotics (such as metronidazole). The latter requires somecaution, because antibiotics can precipitate the syndrome bypermitting overgrowth of lactobacilli (23).

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