Attending Rounds

Lactic Acidosis in a Patient with Type 2Diabetes Mellitus

Lawrence S. Weisberg

AbstractLactic acidosis occurs when lactate production exceeds its metabolism. There are many possible causes of lacticacidosis, and in any given patient, several causes may coexist. This Attending Rounds presents a case in point.Metformin’s role in the pathogenesis of lactic acidosis in patients with diabetes mellitus is complex, as thepresent case illustrates. The treatment of lactic acidosis is controversial, except for the imperative to remedy itsunderlying cause. The use of sodium bicarbonate to treat the often alarmingmetabolic derangementsmay be quiteefficacious in that regard but is of questionable benefit to patients. Renal replacement therapies (RRTs) haveparticular appeal in this setting for a variety of reasons, but their effect on clinical outcomes is untested.

Clin J Am Soc Nephrol 10: 1476–1483, 2015. doi: 10.2215/CJN.10871014

IntroductionA 49-year-old man presented to the emergency depart-ment complaining of dyspnea for 2 days. He had a historyof hypertension, type 2 diabetesmellitus, atrial fibrillation,and a severe dilated cardiomyopathy. He had beenhospitalized several times in the previous year fordecompensated congestive heart failure (most recently,1month earlier). The plasma creatinine concentrationwas1.13 mg/dl on discharge.

Outpatient medications included insulin, digoxin,warfarin, spironolactone, metoprolol succinate, furose-mide (80 mg two times per day; increased from 40 mgdaily 1 month earlier), metolazone (2.5 mg daily; added1 month earlier), and metformin (2500 mg in three di-vided doses; increased from 1000 mg 1 month earlier).

Physical examination revealed an obese man in mod-erate respiratory distress. The temperature was 36.8°C,BP was 119/83 mmHg, and heart rate was 96 per min-ute. Peripheral hemoglobin oxygen saturation was 97%on room air, with a respiratory rate of 26 per minute.The heart rhythm was irregularly irregular; there was noS3 or murmur. Jugular venous pressure was about 8 cm.There was 11 edema at the ankles. A chest radiographshowed cardiomegaly and central venous prominence.The N-terminal pro-B-type natriuretic peptide level was5137 pg/ml (reference range 5 1–138 pg/ml). The pe-ripheral hemoglobin concentration was 12.5 g/dl, thewhite blood cell count was 12,500/ml (76% granulo-cytes), and the platelet count was 332,000/mL. Initialplasma chemistries are shown in Table 1.

The impression was decompensated congestive heartfailure. After administration of furosemide (160 mg intra-venously), the urine output increased to 320 ml over thenext 1 hour. There was no improvement in the dyspnea.Within 2 hours, the patient’s BP fell to 100/64 mmHg;he became agitated and more tachypneic. An endotra-cheal tube was inserted, and he was placed onmechanicalventilation. The BP fell to 80/42 mmHg, and continuous

intravenous infusions of dobutamine, epinephrine, andnorepinephrine were begun along with intravenous in-fusions of vancomycin, levofloxacin, and metronidazole.The urine output fell to ,5 ml/h. Repeat plasma chem-istry results are shown in Table 1. The nephrology ser-vice was consulted.

Patient SummaryA middle-aged man with a history of type 2 diabetes

mellitus and severe congestive heart failure presentedwith a 2-day history of dyspnea. Apart from tachypnea,he had normal vital signs and evidence of moderate fluidoverload with vascular congestion. Initial plasma chem-istries showed a plasma total CO2 and a small increasein the plasma creatinine concentration from hisknown baseline. The anion gap was high. Within 2hours, the patient became agitated, his BP fell, and herequired mechanical ventilation and medications tosupport his BP. Over the next several hours, he devel-oped oliguria and a severe metabolic acidosis, with ananion gap of 44 mmol/L and a plasma lactate concen-tration of 18.7 mmol/L.

DiscussionClose examination of the initial plasma chemistries

reveals that he had an anion gap of 21 mmol/L onpresentation. The anion gap is well above the labo-ratory’s reference range of 8–14 mEq/L, and, withthat as a basis, could theoretically represent an in-crease of 7–13 mEq/L over baseline. In reality, thereis considerable variability in the usual anion gap of agiven individual (1), and the best way to assess thechange in the anion gap is to compare it not with thelaboratory’s reference range but with the patient’sown usual anion gap. In this patient, there were ampleold laboratory results to review, and his anion gapranged between 10 and 12 mEq/L. Thus, the anion gap

Division ofNephrology, CooperMedical School ofRowan University,Cooper UniversityHealth Care, Camden,New Jersey

Correspondence:Dr. Lawrence S.Weisberg, Division ofNephrology, CooperUniversity HealthCare, 401 HaddonAvenue, Camden, NJ08103. Email:Weisberg-Lawrence@CooperHealth.edu

www.cjasn.org Vol 10 August, 20151476 Copyright © 2015 by the American Society of Nephrology

on presentation represented an increase of 9–11 mEq/L overhis own baseline.Initially, there was no mention of the high anion gap—

clearly, an oversight. If one presumes that the high aniongap represents accumulation of the anion of an organicacid, which it does in most patients (2), then it is reason-able to expect the plasma total CO2 to fall concomitantly,because the accumulated protons titrate extracellularbicarbonate. Thus, the nearly normal total CO2 of 20mmol/L may be seen as paradoxical and may have ob-scured the diagnosis of a high anion gap metabolic aci-dosis. There are several possible explanations for adiscordance between the change in the anion gap and thechange in the total CO2 (1). The most obvious in this patientis a superimposed metabolic alkalosis. The patient deniedvomiting or alkali ingestion. Therefore, this is mostly likelycaused by the use of combination loop and thiazide diureticsfor the patient’s underlying congestive cardiomyopathy (3).The patient also had a respiratory acidosis, indicated bythe pCO2 above expected value, and this amplified hisacidemia.This patient quite clearly has a lactic acidosis. Common

criteria for the diagnosis of lactic acidosis include a plasmalactate concentration in excess of 4 mmol/L (4), usuallywith plasma pH ,7.35. By the time the nephrology ser-vice was consulted, the patient had a profound metabolicacidosis and extreme hyperlactatemia. The patient’s aniongap was high on presentation. Thus, he is likely to havehad a lactic acidosis on arrival, which worsened rapidly.Interestingly, the prominent dyspnea, out of proportion tothe physical manifestations of heart failure on presenta-tion, may have been caused by accumulated lactic acid,which seems to stimulate ventilatory drive in patientswith heart failure (5).The second set of laboratory results shows that the

change in the anion gap from the patient’s known baselinewas about 30 mEq/L, whereas the plasma lactate concentra-tion was about 19 mmol/L. Thus, the accumulated lactateaccounted for slightly over one half of the excess anion gap.This raises the possibility of other causes of the high anion gapacidosis in this patient. Diabetic ketoacidosis, toxic alcohols,

such as methanol and ethylene glycol, and salicylate in-toxication could cause an anion gap metabolic acidosis ofthis severity (6). Plasma ketones and salicylates were notdetected. A plasma osmolal gap (the difference betweenthe measured and the estimated plasma osmolality) .20mosmol/kg is a clue to the presence of an alcohol in thecirculation (7). The estimated plasma osmolality was 296mosmol/kg, and the measured plasma osmolality was311 mosmol/kg. Pyroglutamic acidosis (8) should be con-sidered in any patient presenting with a high anion gapacidosis. This is seen mostly in women (probably be-cause of sex-associated enzymatic differences) who in-gest acetaminophen regularly (8). Our patient gave nohistory of acetaminophen use.It should be noted, however, that, among patients with

an identified organic acidosis, much of the excess anion gapcannot be explained by the measured anions, even afterassiduous investigation (2). Likewise, in patients withwhat seems to be pure lactic acidosis, the lactate concen-tration explains less than one half of the change in theanion gap (9). (The contribution of pyroglutamic and otherorganic acids was investigated in a population of criticallyill patients with anion gap acidosis and found to be trivial[10].) Thus, although the large discrepancy between thechange in the anion gap and the lactate concentration in-troduces some ambiguity, it is quite typical of patientswith lactic acidosis.There were two important questions for the nephrology

consultant to answer. First, what is the likely cause of lacticacidosis in this patient? Second, what is the most effectivetreatment for the patient?

What Is the Likely Cause of Lactic Acidosis in ThisPatient?The conventional clinical laboratory assay for lactic

acid detects only L-lactic acid stereoisomer, and there-fore, D-lactic acidosis presents as an unexplained highanion gap metabolic acidosis. That is not the case here,and therefore, we will concern ourselves only with L-lacticacidosis.The causes of L-lactic acidosis (Table 2) can be divided

into those associated with delivery of oxygen insufficientto meet demands of metabolizing tissues (type A lacticacidosis) and all others (type B lactic acidosis), includingthose associated with excessive lactate generation unre-lated to oxygen delivery, impaired oxygen use, and im-paired lactate metabolism.In the patient at hand, obvious causes of type A lactic

acidosis seemed unlikely, at least initially. The patient wasnot hypotensive on arrival, and the peripheral oxygenationwas normal. He did meet several criteria for systemicinflammatory response syndrome, including rapid heartand respiratory rates and leukocytosis, but there was noobvious source of infection, and cultures of blood andurine proved later to be sterile. This made sepsis as a causeof lactic acidosis less likely but did not exclude it. Thepatient was sensibly covered with broad spectrum anti-biotics.Although he had no history of alcohol use, ingestion of

ethanol or another toxic alcohol should be considered in

Table 1. Initial plasma chemistry results

Analyte 1 moEarlier

OnPresentation 12 h

Glucose (mg/dl) 128 136 174BUN (mg/dl) 22 29 34Creatinine (mg/dl) 1.13 1.36 1.52Sodium (mmol/L) 140 136 137Potassium (mmol/L) 3.7 4.3 6.2Chloride (mmol/L) 97 95 89Total CO2 (mmol/L) 29 20 4Anion gap (mmol/L) 14 21 44Lactate (mmol/L) 18.7pH, arterial 6.97pCO2, arterial (torr) 26pO2, arterial (torr) 134HCO3, arterial(mmol/L)

8

Clin J Am Soc Nephrol 10: 1476–1483, August, 2015 Lactic Acidosis in Type 2 Diabetes Mellitus, Weisberg 1477

patients with lactic acidosis, and it was in this patient.Metabolism of alcohols by alcohol dehydrogenase lowersthe redox potential and may, thus, predispose to lacticacidosis, and propylene glycol may be metabolized tosome extent directly to lactate (11). Thus, lactate may con-tribute modestly to the high anion gap acidosis seen withtoxic alcohols but would not cause lactic acidosis of thisseverity. Additional evidence against a role for toxic alco-hols is the normal osmolal gap.Both types 1 and 2 diabetes mellitus seem to predis-

pose to the development of lactic acidosis (11,12). Onelarge population-based study has shown an incidence oflactic acidosis of 3% among all patients with diabetes mel-litus compared with 0.1% in the nondiabetic population(12). The causes of this predisposition are not known buthave been postulated to include a propensity for tissue hyp-oxia because of large and small vessel disease and alterationsin pyruvate metabolism (13). In the absence of anothercause, however, diabetes will not result in lactic acidosis ofthe degree seen in this patient.

The patient had been hospitalized several times in the recentpast, and there was no prior history of metabolic acidosis;therefore, a congenital error of metabolism can be confidentlyexcluded. Liver enzymes were initially normal, and the renalfunction had declined only slightly from baseline at the timeof presentation; therefore, liver and kidney failures are nottenable explanations for lactic acidosis. There was no exposureto medications other than those prescribed to him. Among thelatter, metformin should be considered as a cause of his lacticacidosis.

Metformin as a Cause of Lactic AcidosisGalega officinalis (goat’s rue or French lilac) was recog-

nized in medieval times as a treatment for diabetes mel-litus (14). On the basis of the discovery of its activeingredient, guanidine, several drugs of the biguanideclass were formulated to treat diabetes mellitus begin-ning in the 1950s (15). The first drug of this class inwide use, phenformin, was withdrawn from the UnitedStates market in the 1970s because of an unacceptably highincidence of lactic acidosis. Phenformin is highly lipid solubleand caused lactic acidosis by crossing the mitochondrial mem-brane and inhibiting mitochondrial oxidative phosphorylationand also, by inhibiting gluconeogenesis (11,16). Its descen-dent, metformin, lacks phenformin’s lipid solubility. It wasintroduced to the United States market in 1995 after studiesshowed a 10- to 20-fold reduction in the predisposition tolactic acidosis (17).Metformin is an insulin sensitizer (14,18); it is ineffec-

tive in the absence of insulin. It acts mainly by reducinghepatic gluconeogenesis (14,16,18), in large part by inhib-iting mitochondrial oxidative phosphorylation (19) andmitochondrial glycerophosphate dehydrogenase (20). Italso has some effect to increase peripheral glucose dis-posal (14,18). Unlike phenformin, metformin is not metab-olized and is eliminated entirely by the kidney. Its plasmaclearance is by glomerular filtration and to a greater ex-tent, tubular secretion through a variety of transporters(18). Despite a tremendous volume of distribution, itshalf-time of elimination is estimated to be only 2.7 hours(18).Because of its effect to reduce hepatic gluconeogenesis,

for which lactate is a substrate, and because it acts partlyby inhibiting mitochondrial oxidative phosphorylation andlowering the mitochondrial redox state (20), it is somewhatsurprising that metformin administration has been found tocause only a slight increase in basal and postprandial plasmalactate concentrations (14,18). Among the many studies cor-roborating metformin’s low potential to cause lactic acidosisare a systematic review of 347 clinical trials, finding no pa-tients with fatal or nonfatal lactic acidosis in 70,490 subject-years of metformin exposure (21), and a case-control study ofover 50,000 patients with type 2 diabetes mellitus, yieldingabout three cases of lactic acidosis per 100,000 patient-yearsof metformin use—an incidence no different from that amongpatients using sulfonylurea drugs (22). Nonetheless, veryshortly after the drug was marketed in the United States, acase series of metformin-associated lactic acidosis (MALA)was reported (23). This was followed by hundreds of case re-ports and a dozen case series over the past two decades (24).

Table 2. Causes of lactic acidosis

Type A lactic acidosis (oxygen supply: demandmismatch)

ShockSepsisSeizureRegional ischemia

Type B lactic acidosisExcessive lactate productionAlcoholsEthanolMethanolEthylene glycolPropylene glycol

Fructose metabolic defectsDiabetes mellitus

Impaired oxygen useDisruption of mitochondrial oxidative phosphorylationCyanide intoxicationCarbon monoxide intoxicationLinezolidBiguanidesNucleoside analog reverse transcriptioninhibitors

Acetaminophen intoxicationAcquired defects of the TCA cycleThiamine deficiencyNutritionalCancerAlcoholismGastrectomy

Congenital defects ofPyruvate transportTCA cycle enzymesPyruvate dehydrogenase complex

Impaired lactate useLiver diseaseKidney disease

TCA, tricarboxylic acid.

1478 Clinical Journal of the American Society of Nephrology

However, given the predisposition of patients with diabe-tes mellitus to hyperlactatemia and lactic acidosis (12),questions arose regarding metformin’s role in the reportedlactic acidosis. Does metformin cause lactic acidosis, or is itmerely associated with it?The fact that metformin is capable of causing lactic acidosis

is obvious from patients with pure metformin overdose (18).This serves to emphasize that, from both mechanistic andlogical standpoints, metformin accumulation is the risk forlactic acidosis (15), with studies suggesting that a metforminplasma level of at least 40 mg/L (10 times the therapeutic level)may be necessary to cause lactic acidosis (25). On this basis,there are three possible relevant conditions: (1) metformin-independent lactic acidosis (in which metformin cannot possi-bly be implicated), (2) metformin-induced lactic acidosis (inwhich no other possible cause of lactic acidosis is present),and (3) MALA (in which metformin is among the factorsthat might have caused lactic acidosis) (18). Strictly speaking,these defined conditions require measurement of plasma met-formin concentration; the latter two conditions may only beconsidered in the presence of a high metformin concentration.A plasma metformin concentration was not measured in thispatient. At our institution (and I suspect, most other large, ter-tiary referral centers), plasma metformin measurement cannotbe performed in-house. Specimens are sent to a reference lab-oratory, and results may take days to return. Thus, metforminlevels usually cannot help to guide acute management. Further-more, metformin levels correlate poorly with pH, plasma lac-tate levels, or clinical outcomes (26,27). A diagnosis of MALAin this patient is speculative and based on circumstantial evi-dence, but this working diagnosis may have important thera-peutic implications.Our patient had a number of risk factors forMALA (Table 3).

His plasma creatinine on arrival to the emergency departmentwas higher than his baseline, perhaps because of his increaseddiuretic regimen. He carried a diagnosis of severe congestiveheart failure, with frequent episodes of decompensation, andwas in decompensated congestive heart failure on admission.Whether a diagnosis of stable congestive heart failure shouldcontraindicate the use of metformin is a matter of some debate(28). Mechanistically, however, decompensated congestiveheart failure is likely to potentiate metformin’s contributionto lactic acidosis because of decreased tissue perfusion (5). Fi-nally, the patient’s dose of metformin had been increased tothe recommended maximum (even for patients with no riskfactors) a few weeks before admission. This combination offactors placed the patient at extremely high risk of lactic aci-dosis. Therefore, MALAwith heart failure and, possibly, sepsiswas the presumed diagnosis.

What Is the Most Effective Treatment for the Patient?Apart from supportive care, there are several possible

therapeutic approaches to patients with lactic acidosis ingeneral: treatment of the underlying cause, raising the systemicpH, and removal of lactate from the blood.Only thefirst of theseis not controversial. For patients with type A lactic acidosis,ameliorating the cause of lactic acidosis involves improvingtissue perfusion. Patients with shock should be treated withfluids and vasoactive medications to optimize their hemo-dynamics. To complicate even this straightforward recom-mendation, however, it must be noted that catecholamines

(epinephrine more than norepinephrine) cause an increase inplasma lactate concentration (29). Treatment of type B lacticacidosis may involve removal of the causative toxin as dis-cussed below.Alkali therapy often is used to treat the acidemia that

typically accompanies lactic acidosis. This practice is based,at least partly, on the recognition that acidemia has importanthemodynamic effects. It impairs myocardial contractility (30,31)and causes venoconstriction with central vascular congestion(32), arterial vasodilation and resistance to the vasoconstric-tive effects of catecholamines, especially when the pH is,7.10–7.20 (33). Although alkalinization has theoretical ap-peal, no animal or human studies of lactic acidosis haveshown an improvement in myocardial performance (33) orsurvival with sodium bicarbonate administration (34), evenamong patients with the most profound acidemia (35). In-deed, there is some evidence that sodium bicarbonate admin-istration for lactic acidosis may be harmful (36,37). There areseveral possible reasons for this. First, bicarbonate may causeparadoxical intracellular acidification because of the increasedgeneration of cell-permeant CO2 by mass action effect on thecarbonic acid equilibrium (38). Second, the increase in extra-cellular pH reduces ionized calcium concentration becauseof chelation by albumin (39), impairing myocardial contrac-tility (40). Third, alkalinization may reduce tissue oxygendelivery by the Bohr effect on hemoglobin oxygen affinity.Fourth, bicarbonate administration may increase lactate gen-eration by upregulating the pH-dependent rate-limiting stepin the glycolytic pathway. Fifth, administration of large vol-umes of sodium bicarbonate may cause intravascular fluidoverload. All this notwithstanding, international critical careguidelines for sepsis recommend giving sodium bicarbonate ifthe blood pH is ,7.15 (41).Precise calculation of bicarbonate deficit would require

an accurate estimate of the volume of distribution of bicarbon-ate. The apparent bicarbonate distribution space varies widely,however, and in inverse proportion to the bicarbonate concen-tration (42). Even if the deficit could be accurately calculated,the effect of administered bicarbonate on the final bicarbonateconcentration may be far from the predicted value becauseof ongoing acid generation and the contraction of the apparentbicarbonate distribution space as the bicarbonate concentrationrises. Therefore, it may be most practical to administer ashort-term or bolus infusion of sodium bicarbonate (e.g.,1–2 mmol/kg body wt intravenously), rechecking the arte-rial blood gases and pH at the end of the infusion andfrequently thereafter to guide additional therapy. Care mustbe taken to ensure the patient’s ventilation is appropriate atthe start of the infusion (i.e., pCO2 no greater than the plasma

Table 3. Contraindications to metformin use (14)

Impaired kidney functionAge .80 yrLiver diseaseCongestive heart failureRespiratory disease with risk for hypoxemiaHeavy ethanol useIntravascular radiocontrast administration

Clin J Am Soc Nephrol 10: 1476–1483, August, 2015 Lactic Acidosis in Type 2 Diabetes Mellitus, Weisberg 1479

bicarbonate concentration 115), because the bicarbonate infu-sion will lead to increased CO2 generation and may, thus,worsen the acidemia. Finally, continuous bicarbonate infusionscarry a risk of overshoot alkalemia, especially if the patient’sunderlying cause of lactic acidosis is improving and there ismetabolism of the lactate to bicarbonate.Tris-hydroxymethyaminomethane is an amino alcohol that

buffers without generating CO2. It has the theoretical advan-tage, therefore, of avoiding both the superimposed respiratoryacidosis that may accompany bicarbonate administration andits consequent intracellular acidification (32). There is no evi-dence to support the use of Tris-hydroxymethyaminomethanein this situation.Renal replacement therapy (RRT) offers a number of theo-

retical and practical advantages over alkali infusion for thetreatment of lactic acidosis. First, RRT can deliver largequantities of base without the risk of volume overload. Second,RRT may reduce plasma lactate concentration. (This may notnecessarily be a benefit, because lactate serves as a preferredenergy substrate for some tissues under conditions of metabolicstress and may, thus, confer an adaptive advantage [34].) Third,RRT has the potential to maintain the plasma ionized calciumconcentration while raising pH, thus potentially improvingmyocardial contractility (43). There are few studies of RRT rel-evant to the treatment of lactic acidosis, and most are in thesetting of sepsis with hemodynamic instability (44). Almost allinvolve continuous RRT (CRRT). Early uncontrolled studiesshowed the feasibility of CRRT modalities in the treatment ofpatients with renal failure and lactic acidosis (45–47) and em-phasized the metabolic advantage of bicarbonate- over lactate-buffered dialysate (46). A recent single-center observationalcohort study of 116 patients with AKI and lactic acidosisshowed that CRRT using bicarbonate-buffered fluids can re-duce blood lactate levels and raise pH (48). The effect of CRRTon survival in patients with lactic acidosis has never beenassessed, and therefore, the use of RRT in this patient cannotbe considered evidence based.Our patient had lactic acidosis in association with suspec-

ted metformin intoxication. Some investigators (49) (but notall [18]) have shown a correlation between plasma metforminconcentration and severity of acidosis, and most patients withMALA have impaired renal function. Thus, metformin re-moval by dialysis has figured prominently in the managementof patients with MALA (50). Metformin is readily dialyzable,owing to its low molecular weight and lack of protein binding(44). Because of its very high volume of distribution andtwo-compartment elimination kinetics (50), metformin’s re-moval may be best accomplished with prolonged extracor-poreal therapy, either intermittent (49) or continuous (51).In one series, it took an average of 15 hours of conventionalhemodialysis to reduce metformin levels to ,20% of pre-dialysis levels (49). CRRT may be the preferred modalityfor patients with hemodynamic instability, such as in thispatient. The ambiguities regarding the most efficacious mo-dality of RRT in MALA and lactic acidosis in general pointto the need for future controlled clinical trials in this area.

Back to the PatientFigure 1 shows the patient’s biochemical course. He was

receiving sodium bicarbonate intravenously at the time ofthe consultation, and the pH had risen from 6.97 to 7.08,

with a concomitant fall in ionized calcium. During that time,there was a sharp decline in arterial pressure, promptinginfusions of maximum doses of dopamine, dobutamine, epi-nephrine, phenylephrine, norepinephrine, and vasopressin.There was a sharp increase in transaminase concentrations(peak aspartate transaminase 514,650 IU/L), which werefelt to be caused by passive hepatic congestion.Because of the profound acidemia and hyperkalemia with

oliguria in this hemodynamically unstable patient—and thepossibility that metformin may have been implicated—weinitiated continuous venovenous hemodialysis with a bicar-bonate bath, as noted in Figure 1. With that, the anion gapand plasma lactate concentration fell, and the plasma totalCO2, the pH, and with some delay, the ionized calciumrose. Despite the biochemical improvement, there wasonly a slight improvement in the BP, which remained inthe range of 105/75 mmHg on maximum inotropic andpressor support. All biochemical parameters showed max-imum improvement by about 24 hours of CRRT, afterwhich they began to deteriorate along with the patient’shemodynamics. The patient died on the third hospital day.

QuestionsRon Zanger, MD, Attending Nephrologist, CooperUniversity Health CareGiven this patient’s only modest renal impairment on

presentation, significant metformin accumulation seemsunlikely, even with his relatively high prescribed dose.Do you think metformin was likely to be the sole causeof his severe lactic acidosis?

Dr. Lawrence WeisbergOn arrival, the patient had impaired renal function, the

duration of which was unclear. Therefore, it is unclear towhat extent themetformin, prescribed at a very high dose, hadaccumulated. His lactic acidosis seemed out of proportion tothe severity of his heart failure on presentation, suggestingan additional cause, the most likely of which is metformin. Inthe absence of a plasma metformin level, it is impossible todefinitely assess the drug’s contribution. Having said that,however, our patient, like the majority of patients who pres-ent with lactic acidosis while taking metformin, had other riskfactors for lactic acidosis (25,52), the most important of whichmay have been his decompensated congestive heart failure.The severe lactic acidosis, therefore, was probably the resultof a nefarious synergy between the metformin and his decom-pensated congestive heart failure.

Jason A. Kline, MD, Attending Nephrologist, CooperUniversity Health CareThis patient had a dreadful clinical course. Is this typical

of patients with MALA?

Dr. Lawrence WeisbergThe prognosis of patients with lactic acidosis, in general,

is quite variable and depends on the underlying comorbid-ities, with mortality approaching 100% in patients withlactic acidosis after cardiac arrest (53). The mortality ofpatients with MALA seems to be lower than that of pa-tients with lactic acidosis of other causes (54), but again, it

1480 Clinical Journal of the American Society of Nephrology

depends on the circumstances. Patients whose lactic aci-dosis is caused by intentional metformin overdose have avery low mortality rate, whereas those for whom metfor-min is one of several causes of lactic acidosis—as is the casewith our patient—have a mortality rate around 50%(49,54). Our patient’s course is perhaps best appreciatedin two phases. In the first phase, he presented with rapidlyprogressive lactic acidosis out of proportion to his conges-tive heart failure, likely as a result of high metformin levels.The second phase was entered when the acidemiareached a critical level. At that point, the patient’s hemo-dynamics deteriorated drastically. This further reduced hisorgan perfusion and increased the generation of lactate, theclearance of which was impaired by acute kidney failureand hepatic congestion. The combination of severely im-paired myocardial contractility and maximum doses of cat-echolamines, causing intense peripheral vasoconstriction,likely led to additional tissue hypoperfusion, establishing avicious, downward spiral. This patient serves to emphasizethat most patients with MALA have additional causes oflactic acidosis, the nature and severity of which determinetheir prognosis.

Christopher B. McFadden, Attending Nephrologist, CooperUniversity Health CareIs metformin strictly contraindicated in patients with CKD,

or can its dose be adjusted for renal function?

Dr. Lawrence WeisbergThe metformin package insert contraindicates the use of

the drug when the plasma creatinine concentration is $1.4mg/dl in women and $1.5 mg/dl in men (55). Some in-vestigators worry that such an absolute restriction

deprives too many patients of a medication with a highlyfavorable risk to benefit profile (18,25). Several large stud-ies suggest that an adjusted dose of metformin may beprescribed safely to patients whose eGFR is as low as 30ml/min (15,56). Adam and O’Brien (25) have gone so faras to propose a dose-adjustment scheme for patients acrossthe full range of kidney function, including dialysis depen-dence. However, such liberalization of metformin use iscontroversial (57). Furthermore, it must be borne in mindthat CKD is the single biggest risk for AKI, which in turn,seems to pose the greatest risk for MALA (15).

William D. Sirover, MD, Attending Nephrologist, CooperUniversity Health CareWhy did the patient’s plasma potassium concentration

rise acutely with development of the severe lactic acidosis?

Dr. Lawrence WeisbergAt first blush, this is somewhat unexpected, given the

conventional wisdom that efflux of cellular potassium, withconsequent hyperkalemia, accompanies mineral (hyper-chloremic) acidosis but not organic acidosis, like lactic orketoacidosis (58). Of note, however, is Fulop’s original caseseries (59), which is widely cited in support of this contention,revealed that some patients with organic acidoses did develophyperkalemia. Indeed, among patients with the highestpotassium concentrations in that series were those withphenformin-associated lactic acidosis (59). It is, therefore,plausible, although speculative, that the biguanide-inducedfailure of ATP generation impairs Na,K-ATPase and allowsnet K efflux from cells. As with diabetic ketoacidosis, theacidemia per se does not cause the hyperkalemia; rather, thereis a common cause of the acidosis and the hyperkalemia.

Figure 1. | Plasma chemistries over time. Top panel shows arterial pH,middle panel shows ionized calcium (reference range54.4–5.0mg/dl),and bottom panel shows total CO2 (blue line), anion gap (magenta line), and lactate (green line). CRRT, continuous RRT.

Clin J Am Soc Nephrol 10: 1476–1483, August, 2015 Lactic Acidosis in Type 2 Diabetes Mellitus, Weisberg 1481

DisclosuresNone.

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