Lactic acidosis - Medical School

Kidney International, Vol. 29 (1986), pp. 752—774
NEPHROLOGY FORUM
Lactic acidosis
Principal discussant: NIcoLAos F. MADIAS
New England Medical Center and Tufts University school of Medicine, Boston, Massachusetts
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, produced dramatic improvement of interstitial infiltrates. The subsequent
hospital course was complicated by a recurrence of pulmonary infiltrates, worsening dyspnea, disabling cough, severe inanition, myoclonus and tremors, abnormal liver function tests, hyponatremia, and
hostility and depression. Multiple cultures, including bone marrow,
revealed only Candida albicans in the sputum and urine. T-cell studies
showed a T4/T8 ratio of 0.4 (normal, 1.7—3.5), consistent with the
diagnosis of acquired immunodeficiency syndrome. A second course of
Editors
JORDAN J. COHEN
JOHN T. HARRINCTON
JEROME P. KASSIRER
NICOLAOS E. MADIAS
Managing Editor
CHERYL J. ZUSMAN
pentamidine isethionate was given for 14 days, 8 on an outpatient basis.
Following completion of the second course of treatment, the patient's
condition deteriorated and a third course of pentamidine isethionate
was started on an outpatient basis. For several days he refused to eat
and had repeated emesis. He was readmitted after a syncopal episode.
Physical examination revealed a chronically ill-appearing male in no
Michael Reese Hospital and Medical Center
University of Chicago Pritzker School of Medicine
and
distress. The temperature was 36.8°C and the blood pressure was 120/80
mm Hg supine and 66/40 mm Hg standing. The corresponding heart rate
New England Medical Center Hospitals
Tufts University School of Medicine
values were 68 and 72 beats/mm; the respiratory rate was 24/mm.
Positive findings included oral candidiasis and dullness at the right lung
base. No motor, sensory, or reflex abnormalities were present, with the
exception of previously known slight weakness of the right hip fiexors.
Case presentation
Laboratory data revealed: hemoglobin, 8.7 g/dl; mean corpuscular
A 33-year-old male was admitted to Michael Reese Hospital and
Medical Center for evaluation of weight loss, dyspnea, and fever. He
had factor Vill-deficient hemophilia and had been chronically ill over
several months with a cough productive of scanty sputum, weight loss
of 15 Ibs, low-grade fever, and progressive dyspnea on exertion. The
creatine kinase (CK), 437 units, The urinalysis was unremarkable.
volume, 93 pm3; white blood cell count, 1800/mm3 with 52% neutrophils, 10% band forms, and 21% lymphocytes; platelets, 97,000; serum
sodium, 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; and
medical history was notable for right total hip replacement and
splenomegaly.
Physical examination revealed a thin white male in no distress.
Temperature was 37.2°C; blood pressure, 115/80 mm Hg supine; heart
Chest x-ray was clear.
The clinical impression was that the patient had volume depletion and
probably esophageal candidiasis; endoscopy was negative, however.
Severe orthostatic hypotension persisted despite volume repletion.
Administration of 9-a-fluorocortisol was started on the eleventh hospital day and parenteral hyperalimentation with dextrose, vitamins, and
electrolyte solutions was initiated on the thirteenth day. Treatment with
rate, 120 beats/mm; and respiratory rate, 36/mm. There were white
plaques in the mouth, bilateral axillary lymphadenopathy, and splenomegaly. The lungs were clear and the remainder of the examination was
within normal limits. Laboratory findings disclosed: hemoglobin, 12.5
g/dl; mean corpuscular volume, 89 jsm3; white blood cell count, 7000/
mm3 with 78% neutrophils, 4% band forms, and 7% lymphocytes; and
normal platelets. Other routine chemistry tests were normal. Urinalysis
was unremarkable. Chest x-ray was suggestive of early, patchy intersti-
trimethoprim-sulfamethoxazole at a low dose was restarted on the
tial infiltrates. An arterial blood sample obtained with the patient
breathing room air revealed a pH of 7.48; PCO2, 32mm Hg; and P02, 63
mm Hg. The patient developed a hectic fever, and treatment with
ampicillin and gentamicin was started. Pulmonary function tests
showed reduced diffusing capacity and were consistent with a mild
restrictive defect. A gallium scan revealed diffuse uptake in the lungs,
and chest x-ray showed diffuse interstitial infiltrates. On the sixth
hospital day, bronchoscopy yielded biopsy material positive for Fneu-
fourteenth hospital day.
Two days later, the patient became abruptly tachypneic and had a
temperature of 38.2°C. The lungs were clear. An arterial blood sample
obtained 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, 17.7
mEq/liter; glucose, 408 mg/dl. A serum Acetest was negative. Tobramycm, cefazolin, ticarcillin, and amphotericin were administered. Hypotension, oliguria and refractory lactic acidosis developed. The patient
was intubated on the eighteenth hospital day and vasopressors were
required. After more than 250 mmol of sodium bicarbonate was
administered over 6 hours, the blood pH was 7.19, lactate concentration
33.5 mEq/liter, and serum carbon dioxide 8 mmol/liter. Hemofiltration
was performed for fluid removal. On the nineteenth hospital day the
patient died.
Presentation of the Forum is made possible by grants from CIBA
Pharmaceutical Company, GEIGY Pharmaceuticals, and Sandoz,
Discussion
DR. NIcOLAOS E. MADJAS (Chief, Division of Nephrology,
Incorporated.
© 1986 by the International Society of Nephrology
New England Medical Center, and Associate Professor of
752
753
Lactic acidosis
Medicine, Tufts University School of Medicine, Boston, Massachusetts): The terminal phase of the acquired immunodeficiency syndrome in this unfortunate young man illustrates several
prototypic features of what in my opinion represented lactic
acidosis in association with sepsis. Severe hyperlactatemia
accompanied by alkalemia, rather than acidemia, developed
along with the abrupt onset of pyrexia and hyperventilation. In
all probability, gram-negative or, less likely, fungal sepsis was
the culprit. The patient was at very high risk for sepsis in view
of his immunodeficiency, leukopenia, cachexia, lung injury,
and the presence of a central intravenous line. The lingering
hypotension, a known adverse effect of pentamidine isethionate
administration, might have contributed to the genesis of the
metabolic disturbance. Despite aggressive treatment, circulatory, renal, and respiratory failure developed; hyperlactatemia
persisted despite therapeutic efforts, including generous alkali
administration, and advanced to extreme levels during the
patient's agonal stage.
Definition of the contemporary clinical condition of lactic
acidosis is credited to Huckabee, who in 1961 pointed out that,
in addition to tissue hypoxia, hyperlactatemia might develop
under an array of other clinical circumstances [1, 2]. Nonethe-
less, tissue hypoxia secondary to circulatory failure and/or
hypoxemia constitutes the root cause of most clinical instances
of lactic acidosis.
Lactic acidosis is herein defined as the acid-base disorder,
originating from accumulation of lactic acid in the body fluids,
that is manifest by a plasma lactate concentration of at least 5
mEq/liter. Such an accumulation reflects disruption of the
normal balance between production and utilization of lactic acid
and could result from its overproduction, underutilization, or
both. Lactic acidosis is probably the most common cause of
metabolic acidosis in hospitalized patients. New knowledge
about the biochemistry and regulation of lactate metabolism
have allowed a better understanding of the pathophysiology of
the clinical disorder. Regretfully, progress in treatment has not
kept pace, and all too often the development of lactic acidosis
heralds a fatal outcome, as in the patient presented today.
Comprehensive treatises of various aspects of lactic acidosis
have been published recently [3—7]. In this Forum, I will
present an overview of the topic, highlighting recent advances
in the field.
Lactate metabolism
Metabolically produced lactate is accompanied by the generation of an equivalent number of protons that are released into
the body fluids. These protons, which are titrated by bicarbonate and non-bicarbonate body buffers, acidify the intracellular
and extracellular environments. By contrast, metabolic removal 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 biochemical and regulatory aspects of lactate production and utilization.
The sole biochemical reaction that generates or consumes
lactate in the organism is illustrated by Equation 1:
CH3COCOO + NADH +
(pyruvate)
LDH
H CH3CH(OH)C00
lactate)
+
NAD
(1)
This reversible reaction occurs in the cytosol and is catalyzed
by the enzyme lactate dehydrogenase (LDH), which is ubiquitous in the cytosol. Lactate is formed when pyruvate reacts
with reduced nicotinamide adenine dinucleotide (NADH) and is
converted back to pyruvate by reactions with the oxidized
counterpart of the dinucleotide (NAD). Lactate is a metabolic
end-product, its only metabolic fate being oxidation back to
pyruvate. The equilibrium of Equation 1 favors the formation of
lactate; thus, under normal conditions the concentration of
lactate is approximately tenfold greater than that of pyruvate.
Of the two optical isomers, L(+)-lactate is the natural form in
mammals; LDH is stereospecific for the L(+)-lactate reaction
and does not catalyze the processing of the levorotatory enantiomer D(—)-lactate.
Lactate production
The 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 concentration
of lactate yields Equation 2:
[Lactate] = Keq x [pyruvate]
[NADH]
[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 lactate
can be viewed as being determined by three variables: the
concentration of pyruvate; the [NADH]/[NAD] ratio, otherwise referred to as the redox (reductionloxidation) state; and
the intracellular hydrogen ion concentration.
Pyruvate concentration. Assuming no change in the other
two determinants, an increment in pyruvate concentration
should lead to a proportional increase in lactate concentration.
The cytosolic pyruvate concentration is the composite function
of a series of metabolic processes, some of which generate and
some of which consume pyruvate. The main pathway for
cellular production of pyruvate is anaerobic glycolysis (Emb-
den-Meyerhof pathway) (Fig. 1). Glycolysis occurs in the
cytosol, and its pace is controlled by the activities of three
functionally unidirectional enzymes that catalyze rate-limiting,
nonequilibrium steps in an irreversible mode: hexokinase (HK),
6-phosphofructokinase (PFK), and pyruvate kinase (PK). Different enzymes are required to catalyze these nonequilibrium
reactions in the "reverse" direction. ATP is an allosteric
inhibitor of the PFK reaction; thus, when ATP stores are
reduced, flux through this reaction is augmented and the rate of
glycolysis is increased. A key step in glycolysis is the oxidation
of glyceraldehyde 3-phosphate during which NAD is consumed and converted to NADH. Provision of NAD therefore
is essential to the maintenance of glycolysis. Anaerobic tissues
under normal conditions and aerobic tissues under hypoxic
conditions replenish NAD stores by the cytosolic conversion
of pyruvate to lactate (Equation 1). On the other hand, aerobic
tissues under normal conditions regenerate NAD largely via
mitochondrial oxidative reactions. Because the inner mitochon-
drial membrane is impermeable to both NADH and NAD,
reoxidation of cytosolic NADH in aerobic tissues is accomplished indirectly via transmitochondrial substrate "shuttles."
In essence, an oxidized substrate reacts with NADH in the
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Nephrology Forum
GLUCOSE
Glycogen
Glycogen
I + Glycogen
phosphoIase
synthetase
Hexokinase j 1Glucose-6-phosphatase
Glucose-6-Phosphate Phosphoglucomutase Glucose 1-phosphate
f Glucosephosphate
isomerase
Fructose 6-phosphate
6-Phosphofructokinase I Fructose-bisphosphatase
Fructose, 1 ,6-bisphosphate
_,j,dolase
Dihydroxyacetone
Glyceraldehyde 3-phosphate
phosphate
Triosephosphate
Glyceraldehyde-phosphate
isomerase
dehydrogenase
3-Phosphoglyceroyl phosphate
j Phosphoglycerate kinase
3-Phosphoglycerate
Phosphoglyceromutase
2-Phosphoglycerate
Et1cDl5S
Phosphoenolpyruvate
carboxykinase ________ Phosphoenolpyruvate
Pyruvate kinase
——
________
(cysoD
CMitochondrio7)
PYRUVATE
Pyruvat)ruvate
carboxylase
,—.- Alanine
__—
..- ianine
aminotransferase
-"ctate
dehydrogenase
-
LACTATE
dehydrogenase
Acetyl-C0A
Oxaloacetate
4 TCA
lcvcve0trate
Biosynthetic pathways
Fatty acids, Ketone bodies
Cholesterol, Steroid hormones
Acetyicholine
Fig. 1. Metabolic pathways of glycolysis and
gluconeo genesis.
The PDH reaction is a nonequilibrium reaction that commits
pyruvate to acetyl-CoA; that is, there is no way that acetyl-CoA
oxidized by the electron-transfer chain. The end result is the can be converted back to pyruvate. The resultant acetyl-CoA
effective transport of hydrogen ions, referred to as reducing can enter the tricarboxylic acid (TCA) cycle and the electron
equivalents, across the mitochondrial membrane and the reoxi- transfer/oxidative phosphorylation pathway for complete oxidation of cytosolic NADH. The two best-studied such systems dation to CO2 and water, or it can be utilized in various
are the malate/aspartate shuttle and the glycerol phosphate biosynthetic pathways (fatty acids, ketone bodies, cholesterol,
shuttle. Virtually all body tissues are equipped for glycolysis, steroid hormones, acetylcholine). The second aerobic mitobut particularly high rates are observed in brain, skeletal chondrial pathway for pyruvate is gluconeogenesis, that is, the
muscle, heart, and intestinal mucosa. An additional, although synthesis of glucose or glycogen, a process occurring exclusivequantitatively smaller, source of pyruvate is the transamination ly in the liver and the renal cortex. It is important to recognize
of alanine (released from muscle and small intestine) by the that gluconeogenesis is not a mere reversal of glycolysis; as I
enzyme alanine aminotransferase (AAT), a reaction that occurs have noted, three glycolytic reactions (HK, PFK, and PK) are
virtually exclusively in the liver. Finally, in the kidney, pyru- irreversibly catalyzed only in the "forward" direction. As
vate is formed from the metabolism of the carbon skeleton of Figure 1 illustrates, synthesis of glucose from pyruvate (as well
glutamine (aipha-ketoglutarate) following removal of the amide as from lactate and alanine) depends on bypassing these key,
and amino nitrogen groups of glutamine in the process of nonequilibrium reactions, The first step in this process, conversion of pyruvate to phosphoenolpyruvate, involves two compoammoniagenesis,
On the other hand, consumption of pyruvate in aerobic nents: (1) carboxylation of pyruvate to oxaloacetate within
tissues under normal conditions occurs by means of two mitochondria, a process catalyzed by pyruvate carboxylase
oxidative mitochondrial pathways and follows the transport of (PC); and (2) cytosolic conversion of oxaloacetate to phosphopyruvate across the mitochondrial membrane (Fig. 1). The first enolpyruvate, a process catalyzed by the enzyme phosphoenolof these is oxidative decarboxylation to acetyl-coenzyme A pyruvate carboxykinase (PEPCK). Both reactions require ATP.
cytosol, having converted thereby to its reduced form; this form
is transported into the mitochondrion where it is subsequently
(acetyl-CoA), a reaction catalyzed by a complex of three
The two additional steps requiring specific catalysis are affected
enzymes that are collectively referred to as pyruvate dehydrogenase (PDH) and that require a continuous supply of NAD.
by fructose-bisphosphatase (FBPase) and glucose-6-phospha-
tase (G-6-Pase). As is the case for the reactions unique to
Lactic acidosis
glycolysis, all those unique to gluconeogenesis are irreversible
(that is, functionally unidirectional); thus, they constitute the
rate-limiting steps of the gluconeogenesis pathway.
Formation of pyruvate (via the PK reaction) completes the
segment of the glycolytic pathway that is common to both
anaerobic and aerobic metabolism. The conversion of one
molecule of glucose to pyruvate or lactate is associated with the
755
Glucose
To Gluconeogenesis
ATP
NA
tcNAD+
Pyruvate
(ioso
Lactate
[NADI
net production of two molecules of ATP. The subsequent
aerobic oxidation of pyruvate generates 36 additional molecules
(Mitochondrion)
of ATP, for a total of 38 molecules per completely oxidized
molecule of glucose.
Impaired mitochondrial oxidative function, as occurs in hy-
poxic states, leads to accumulation of pyruvate in the cytosol
and thus to increased lactate production. The accumulation of
pyruvate reflects both overproduction of pyruvate and reduced
utilization of pyruvate through its two pathways (note the
NAD dependence of the PDH reaction and the ATP requirement of the PC and PEPCK reactions). The former occurs
because a reduced supply of ATP to the cytosol stimulates the
PFK reaction and results in augmented glycolysis (Fig. 2). As
noted, ATP constitutes a potent external regulator of the PFK
reaction. During anaerobic conditions, glycolysis becomes the
main source of energy for the organism; despite the prevailing
mitochondrial dysfunction, continuation of glycolysis (via oxidation of glyceraldehyde 3-phosphate) is assured by cytosolic
regeneration of NAD via the conversion of pyruvate to
lactate. Thus increased lactate production represents the toll
paid by the organism to maintain energy generation during
ADP
0,,,,ENADH1
[NAD
Acetyl-CoA
— Oxaloacetate
G 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 intracellular pH by augmenting lactic acid production during alkalosis [4, 9, 11, 14]. Acidosis and alkalosis thus influence lactic
acid production in the direction of minimizing the acid-base
disruption. Given the ubiquity of the glycolytic process in
mammalian tissues, the cellular machinery may well employ
anaerobiosis.
pH-regulated production of lactic acid (and other organic acids)
to buffer fluctuations in the prevailing pH, thereby maintaining
The [NADH]/[NAD] ratio. This ratio is a measure of the
redox state of cytosolic pyridine nucleotides. The ratio is
a measure of stability in intracellular as well as extracellular
domains [4, 9, 11, 12].
affected by the activity of the various cytosolic dehydrogenases
In-vivo observations on the composition of extracellular fluid
corroborate the existence of such a negative feedback mechanism between net lactate production under basal or stimulated
conditions and acidity of body fluids. Several investigators have
documented that plasma lactate concentration falls during acute
respiratory acidosis, thus contributing a small component to the
whole body's buffer response [15—19]. In addition, small decre-
that employ pyridine nucleotides for transferring H (mainly
during the processes of glycolysis and gluconeogenesis), but in
mitochondria-containing cells it is largely determined by the
rate of mitochondrial oxidative reactions; NADH is oxidized to
NAD by the electron-transfer chain, which is coupled to
oxidative phosphorylation. Suppression of mitochondrial function through decreased oxygen availability or other mechanisms
leads to reduced availability of NAD within the cytosol; as
Equation 2 indicates, the resultant increase in the [NADH]/
[NAD] ratio shifts the equilibrium of the LDH reaction toward
lactate (Fig. 2).
Intracellular [it. According to Equation 2 and barring any
changes in pyruvate concentration and redox state, an incre-
ment in intracellular [H] should lead to increased lactate
concentration in the cytosol. In isolated tissue preparations,
however, this direct effect of intracellular [H] is ovemden by
pH-mediated effects on PFK [8] and thus on pyruvate production (Fig. 1). Strong evidence indicates that the activity of PFK
is inhibited by intracellular acidosis and stimulated by intracellular alkalosis; consequently, in tissue preparations, lactic acid
production falls during acidosis and increases during alkalosis
[9—13]. These effects of intracellular [H] on the glycolytic rate
and on lactate production have been demonstrated during
aerobiosis as well as during anaerobiosis and may well serve
an important homeostatic function. Under conditions of tissue
hypoxia, stimulation of glycolysis leads to augmented lactic
acid production with a resultant decrement in intracellular PH;
the acidosis in turn inhibits glycolysis and lactic acid production
ments in plasma lactate have been observed in acute and
chronic metabolic acidosis [20, 21]. On the other hand, small
rises in plasma lactate concentration occur during acute respiratory or metabolic alkalosis [4, 9, 15, 16, 22—28]; however, any
tendency for a substantial increase is probably tempered by
augmented lactate utilization. Whereas plasma lactate concentration is within normal limits during chronic hypocapnia even
in the presence of associated hypoxemia [29—34], a mild elevation in lactate persists in chronic metabolic alkalosis [21, 35].
An additional increment in plasma lactate is observed when
acute or chronic hypocapnia is superimposed on chronic metabolic alkalosis [36].
Several recent lines of evidence lend strong support to such a
homeostatic system of net lactic acid production under conditions of stimulated synthesis. Acute hypercapnia produced by
elevating FiCO2 resulted in marked suppression of exerciseinduced hyperlactatemia in volunteer subjects [37—40]. Similarly, administration of either NH4CI or NaHCO3 led to substantial suppression or augmentation, respectively, of the hyperlac-
tatemia of exercise [39, 41]. Muscle lactate concentration and
glycogen depletion were less in individuals ingesting NH4C1
than in those given NaHCO3. In an experimental model of
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Nephrology Forum
hypoxemia-induced lactic acidosis in the rat [42], superimposition of either mild respiratory acidosis (PaCO2, 59 mm Hg) or
HCI-induced metabolic acidosis (sufficient to decrease pH from
7.27 to only 7.23) resulted in a dramatic blunting of the rise of
blood lactate; by contrast, superimposition of respiratory alkalosis (PaCO2, 15 mm Hg) led to an exaggerated rise in blood
lactate in the hypoxic animals. Moreover, findings in patients
with malignancy-induced chronic lactic acidosis [43, 44] as well
as extensive experience with experimental models of hypoxic
and nonhypoxic lactic acidosis {45—52] clearly demonstrates
that bicarbonate administration augments lactate production
and blood lactate levels.
These observations are in full accord with previous findings
tubule. Under conditions of hyperlactatemia, renal excretion
contributes to lactate removal, the renal threshold for lactate
excretion being approximately 5 to 6 mEqlliter [20, 62]. In lactic
acid-loading experiments in humans, rats, and sheep, renal
lactate excretion accounted for less than 1.2% of the infused
load [20, 62, 63]. In general, lactate excretion represents a small
fraction of total lactate uptake by the kidney.
Physiology and quantitative aspects of lactate metabolism
Plasma lactate concentration is normally in the range of 1
mEqlliter and that of pyruvate about 0.1 mEqlliter. The normal
ratio of these two substances (known as the LIP ratio) is
approximately 10:1. Obviously, the stability of plasma lactate
concentration implies a precise equivalence between the process of releasing lactate to, and that of removing lactate from, the
extracellular compartment. The average basal turnover rate in
normal humans has been estimated at about 20 mEqlkglday
rise increased ketoacid production. A similar effect has been with a range of 15 to 25 mEqlkglday [3, 6, 7, 63—66]. This
observed on the degree of ketonuria in patients with diabetes amounts to approximately 1400 mEqlday per 70 kg subject or
mellitus [55, 56]. These clinical observations are amplified approximately 1 mEqlmin. Such estimates have been obtained
further by the demonstration of remarkable responsiveness of through a variety of techniques including the disappearance of
ketoacid production to acute changes in pH when HC1 or infused lactate, measurements of blood flow and arteriovenous
NaHCO3 is infused into rats or humans [57—59].
differences for lactate across tissue beds, extrapolations from
Taken together, these findings suggest the existence of a in-vitro incubation data, and the kinetics of infused isotopically
more generalized homeostatic system that regulates endoge- labeled lactate. Methodologic limitations make available estinous organic acid production via changes in systemic pH [12]. mates gross approximations at best. Estimates of the apparent
What is truly remarkable is the impressive responsiveness of volume of distribution of lactate range from 270 to 340 mL/kg in
this system and the magnitude of the change elicited by humans [63, 67] and about 360 mllkg in the rat [20]. Unforturelatively small deviations in extracellular pH during probing nately, available information on quantitative aspects of lactate
experimental maneuvers, Obviously, it would be of great inter- production and utilization by humans in health and disease is
est to apply modern noninvasive technology to monitor the quite limited. Considerably more information is available from
response of intracellular acidity to these relatively modest studies in experimental animals.
Although all tissues produce lactate during the course of
extracellular changes.
The role of this negative feedback system in the pathogenesis glycolysis, only some of them contribute substantial quantities
and evolution of clinical lactic acidosis is uncertain, and it to the extracellular fluid under normal aerobic circumstances.
represents an exciting area for future investigation. Such a Table 1 lists the lactate-producing tissues. Whereas the renal
system might be crucial to survival during maximal exercise, a medulla normally produces lactate in spite of an adequate
state characterized by marked hyperlactatemia and severe substrate and oxygen supply, the renal cortex has a high rate of
extracellular and intracellular acidosis [60, 61]. On the other oxidative metabolism and lactate utilization [68]. Erythrocytes
hand, this servomechanism is apparently overridden in cases of are obligatory producers of lactate because, in the absence of
severe lactic acidosis. Indeed, in hypoxic lactic acidosis, al- mitochondria, they lack the apparatus for the metabolic procthough the prevailing acidemia can exert an inhibitory effect on essing of pyruvate. During exercise, skeletal muscle is the
the magnitude of the evolving metabolic derangement, the major source of circulating lactate. The maximal rates of lactate
acidemia eventually proves impotent in preventing escalation to production by various tissues remain unknown. Yet estimates
extreme hyperlactatemia. It appears that any inhibitory effect of from individuals undergoing short bursts of maximal exercise or
acidemia is simply overridden by the hypoxic drive to augment- having a grand-mal seizure indicate that lactate production can
ed lactate production. Equally uncertain is whether a clinically increase by several hundredfold [4, 7, 69]. Under hypoxic
relevant interaction exists between this servomechanism and conditions, virtually all tissues can release lactate into the
pH-mediated alterations in hepatic and renal gluconeogenesis circulation. Indeed, during severe hypoxia and acidosis, even
the liver—the predominant consumer of lactate under normal
(and, thus, lactate uptake).
conditions—can add lactate to the blood [70, 71]; obviously,
Lactate utilization
such a transition from net utilization of lactate to net production
As I already have noted, the sole pathway for lactate utiliza- is an ominous sign for the organism.
Liver and renal cortex, the major lactate-consuming organs,
tion is conversion back to pyruvate, its oxidized counterpart
(Equation 1). Consequently, metabolic removal of lactate is can use lactate (via pyruvate) as a substrate for gluconeogenesis
equivalent to the metabolic removal of pyruvate. I will examine and can oxidize it to CO2 and water. Animal studies indicate
the factors that influence lactate uptake and utilization in a that of the two pathways, gluconeogenesis is the primary mode
of lactate processing in the liver. On the other hand, in the
moment.
Lactate is freely filtered at the glomerulus. At low concentra- kidney the fraction of lactate that is extracted and converted to
tions it is reabsorbed virtually completely in the proximal glucose as opposed to being oxidized remains unclear; variable
in fasting obese humans, another state of enhanced endogenous
acid release, which revealed an exquisite sensitivity of ketoacid
production to chronic mild changes in systemic pH produced by
acid or alkali ingestion [12, 53, 54]; a fall in pH suppressed and a
Lactic acidosis
Table 1. Lactate-producing and -consuming tissues
under basal conditions
Producers
Skin
Erythrocytes
Brain
Skeletal muscle
Intestinal mucosa
Leukocytes
Platelets
Renal medulla
Tissues of the eye (cornea, lens, retina)
Consumers
Liver
Renal cortex
Heart
Salivary glands (?)
results have been obtained depending on the experimental
conditions employed. Available evidence suggests that about
50% of the renal lactate uptake in the rat and dog is oxidized
[11, 21, 72, 731. Although the interorgan apportioning of lactate
utilization remains poorly defined, the relative contribution of
the various organs to lactate uptake varies widely according to
the prevailing conditions (for example, basal state, exogenous
infusions of lactate at rest, vigorous exercise). Estimates for the
fractional contribution of the liver to the total basal lactate load
in humans vary widely, ranging from 30% to 70%; 50% is
757
lactate excretion accounted for approximately 12% of the
cumulative renal contribution to lactate removal (the latter
being about 25% to 30% of the administered load) [20]. During
hyperlactatemia the heart's contribution to lactate removal also
increases [88]. Under these conditions, the lung can be involved
in lactate utilization [89].
Although normally a lactate-producing organ, resting skeletal
muscle also can extract lactate from the blood—and use it
primarily as fuel for oxidation—during hyperlactatemia produced by exogenous infusion or by exercise of regional muscle
groups [67, 90—92]. Indeed, several studies have shown conver-
sion from lactate output to lactate uptake by resting skeletal
muscle following an infusion of a lactic acid load, with an
estimated 25% to 35% of the load taken up by muscle [62, 67,
90, 93]. Under such circumstances, skeletal muscle can dispose
of more of the lactate load than does the liver [62, 90]. Whereas
saturation of hepatic lactate uptake during relatively mild
increases in lactate level have been documented [6, 62], one
study reported no saturation of extrasplanchnic lactate uptake
even at the highest plasma lactate concentration, 20 mEqlliter
[62]. In fact, deductions drawn from studies in the isolated
perfused rat hind limb, which showed a linear increase in
probably a reasonable figure [7, 74, 75]. Studies utilizing lactic
acid loading in rats and sheep have estimated that the kidney
muscle lactate uptake with perfusate concentrations up to 27
mEqlliter [94], suggest that the liver may contribute in only a
small way to lactate removal during recovery from maximal
extracts approximately 20% to 30% of the load [20, 62, 761.
exercise. Further, the rate of plasma lactate recovery was
Notably, the liver has a large reserve capacity for lactate
augmented if the subject continued exercising at a submaximal
level rather than resting; this observation lends strong support
to the importance of skeletal muscle in extracting lactate under
such circumstances [81]. Limited clinical data suggest a compensatory increase in lactate uptake by skeletal muscle when
hepatic lactate uptake is deranged [95]. Nonetheless, the contribution of skeletal muscle to lactate utilization during clinical
lactic acidosis remains a matter of considerable debate [3, 6, 7,
metabolism that is estimated to be higher than the basal rate by
severalfold [771. Hepatic uptake of lactate exhibits marked
concentration dependence [15, 62]. Recent lactate-loading ex-
periments in sheep suggest that hepatic lactate uptake is a
saturable process with second-order (Michaelis-Menten) kinet-
ics [62]; whereas the basal rate of hepatic lactate removal
averaged 0.57 mEq.kg°75.h', the Vmax was estimated at 5.72
mEq.kg°75.h', and the Km at 3.06 mEq/liter. Studies in the
perfused rat liver have shown saturation of uptake at a plasma
lactate concentration of approximately 4 mEqlliter [6]. Observations in humans suggest that during mild exercise (about 30%
to 60% of maximum 02 uptake, with plasma lactate levels up to
2.3 mEqfliter) hepatic lactate uptake is augmented in proportion
to the load [78—80]; in contrast, hepatic lactate uptake does not
change or even can decrease markedly during strenuous exercise [74, 81]. Despite the prevailing severe hyperlactatemia
during maximal exercise, lactate uptake probably is suppressed
by the marked diminution in hepatic blood flow that is known to
occur; an additional suppressive role might be exerted by the
64, 67].
The importance of the liver as a lactate-consuming organ is
exemplified by observations after functional hepatectomy in the
diabetic dog. Functional hepatectomy was produced by diverting the portal circulation to the inferior vena cava and ligating
the hepatic artery. Although lactate production due to surgical
stress might have contributed to acidosis, 2 and 3 hours
following the procedure the plasma lactate increased from a
mean control value of 1.4 mEq/liter to average values of 6.0 and
10.7 mEq/liter, respectively; corresponding values for blood pH
were 7.20 and 7.13 (mean control value, 7.42) [96].
Turning to the contribution of the kidney to lactate disposal,
ing organs; that is, lactate production at least transiently
removal of an exogenous lactic acid load was slower in rats
subjected to bilateral nephrectomy as compared with animals
subjected to a sham operation; lactate elimination hall-life
averaged 5.3 minutes, and blood clearance for lactate (at a
plasma concentration of 10 mEq/liter) was 45.3 mllmin/kg in
sham-operated animals; the corresponding values were 7.1
outstrips utilization.
minutes and 32 mllmin/kg in animals with bilateral nephrectomy
Similarly, renal consumption of lactate is augmented in
hyperlactatemia, thus contributing to the organism's reserve
[20]. Overall, nephrectomy resulted in approximately a 30%
slowing of absolute lactate removal following an intravenous
lactic acid load [20].
existing, often severe, acidosis [15, 64, 70, 82—86]. Although the
hepatic functional reserve for lactate removal is well documented, the fact that hyperlactatemia develops during even
mild exercise indicates that the liver (as well as other lactateconsuming sites) cannot keep pace acutely with lactate-produc-
capacity (20, 72); the excess lactate enters both oxidative and
biosynthetic pathways [87]. As I already have noted, renal
excretion contributes to lactate removal under such circumstances. In response to an exogenous lactic acid load in the rat
and at a plasma lactate concentration of 10 mEqlliter, renal
From the standpoint of the whole organism's economy,
therefore, tissues with glycolytic activity under normal aerobic
conditions metabolize glucose to lactate and relinquish it into
the circulation. In turn, lactate is extracted by the liver and
758
-
/
Nephrology Forum
Skin, erythrocytes, brain,
skeletal muscle, intestinal mucosa
leukocytes, platelets, renal medulla, tissues of the eye
Anaerobic glycolysis
Glucose
Lactate
into the body fluids must be removed. This task is achieved
)
during the metabolism of lactate via the two oxidative pathways. When the liver and the renal cortex reconvert lactate to
glucose during gluconeogenesis, Equation 5 is reversed and a
number of protons equivalent to the number of lactate ions
consumed is removed from the body fluids (Equation 6):
2CH3CH(OH)C00 + 2W — C6H1206
(6)
(lactate)
(glucose)
Gluconeogenesis is an energy-requiring process and consumes
ATP and GTP; the aerobic repletion of these high-energy
Gluconeogenesis
____________________________
phosphate groups produces the net utilization of protons during
gluconeogenesis [97—99]. Similarly, during the combustion of
lactate to CO2 and water, an equivalent number of protons are
abstracted from the body fluids (Equation 7):
Lactate
Liver, renal cortex
CH3CH(OH)C00 +
Fig. 3. The Con cycle.
H + 302 —* 3C02 + 3H20
(7)
In actuality, consumption of the proton occurs during aerobic
mitochondrial ATP synthesis, which may be considered the
reverse of ATP hydrolysis [97—99].
renal cortex and is either reconverted to glucose or becomes
fuel for oxidation to CO2 and water. The cyclical relationship
between glucose and lactate, embodied in the Cori cycle (Fig.
3), ensures a continuous supply of glucose to tissues requiring
this substrate as fuel, such as brain and erythrocytes.
Another important dividend to the body's economy from the
unperturbed function of the Cori cycle is that the cycle provides
for the recapturing of hydrogen ions released into the body
fluids during glycolysis and thus allows for acid-base balance to
be maintained. What follows is a short overview of the acidbase consequences of lactate metabolism.
Exogenously administered lactic acid is virtually completely
dissociated in body fluids, because its pK' is 3.86. However,
lactic acid as such is not produced at any step in the glycolytic
process; rather lactate, its conjugate base, is the actual endproduct of anaerobic glycolysis. Nonetheless the glycolytic
In the overall scheme, protons are generated in the cytosol
via hydrolysis of synthesized ATP and are consumed in the
mitochondria via aerobic reconstitution of high-energy phosphate groups. The recapturing by the liver, and secondarily by
the kidney, of protons freed during glycolysis allows for regeneration of bicarbonate and back-titration of the nonbicarbonate
buffers, so that no net input of hydrogen ion to body fluids
occurs and acid-base balance remains undisturbed. In this
sense, lactic acidosis is generated whenever an imbalance
between ATP hydrolysis and ATP generation occurs, and
results in a net gain of hydrogen ions by the body fluids.
The importance of disposing of the protons produced during
glycolysis for the maintenance of acid-base equilibrium can be
better appreciated when its magnitude—that is, 15 to 25 mEq of
H/kgfday under basal conditions, as much as the lactate
process also results in the release of protons in numbers
produced—is contrasted with the magnitude of net acid excretion by the kidney, approximately 1 mEq of H/kg!day. More-
equivalent to the lactate produced, and the net effect is as if
lactic acid were released into the body fluids.
greater burden is placed on the liver and the kidney to maintain
Conversion of glucose to lactate is coupled to the synthesis of
two molecules of ATP. The most simplified description of the
stoichiometry of this conversion is as follows (Equation 3):
C6111206 + 2ADP3
+
2Pi2
— 2CH3CH(OH)C00
+
2ATr + 2H20
(lactate)
(gtucose)
(3)
over, under conditions of lactate overproduction, an even
acid-base homeostasis. It is apparent therefore that from an
acid-base perspective, the liver plays a pivotal, albeit not
widely appreciated, role in ensuring the daily miracle of the
organism's survival. This analysis is a sobering reminder to
nephrologists, who usually are possessed by a nephrocentric
view of acid-base balance.
Under steady-state conditions, the ratio of AlP to ADP re-
mains unchanged; consequently, all ATP synthesized in Equation 3 is promptly consumed (Equation 4):
2ATP + 21120 —* 2ADP3 + 2Pi2 + 2W
(4)
Summing up Equations 3 and 4 we obtain Equation 5:
C6H1206 —* 2CH3CH(OH)COO
(glucose)
+ 2W
(lactate)
Thus, protons are released via the hydrolysis of ATP generated
during anaerobic glycolysis and not via dissociation of the
lactic acid species [97—99]. Protons freed from this process are
titrated by bicarbonate and nonbicarbonate buffers residing in
the intracellular and extracellular compartments. For acidbase balance to be maintained, however, the protons released
Pat ho genesis of lactic acidosis
Lactic acidosis is generated whenever the production of
lactic acid outstrips its utilization. The result of such an
imbalance is evidenced by the accumulation of lactate in the
circulation, often in the company of hypobicarbonatemia and
acidemia. From a theoretical standpoint, as! have just stressed,
the pathogenesis of this imbalance could reflect overproduction
of lactic acid, underutilization, or both.
Overproduction of lactic acid is clearly recognized as the
mechanism of transient lactic acidosis in subjects undergoing
vigorous exercise and in those who have generalized convulsions [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
759
Lactic acidosis
extraction in normal individuals, as evidenced by observations
during lactate infusion or transient overproduction by exercising muscle, it has become increasingly apparent that defective
utilization must be involved in the pathogenesis of most types of
persistent lactic acidosis. Observations in patients in circulatory shock have revealed substantial negative arteriovenous
differences for lactate across muscle, liver, and kidney; these
findings attest to a failure of the hepatic and renal mechanisms
for lactate removal [100]. Indeed, in view of the fact that both
pathways of lactate utilization depend critically on intact mito-
chondrial function, it is not surprising that tissue hypoxia
produces defective lactate processing (Fig. 2). Furthermore, the
evidence in support of the contention that nonhypoxic forms of
lactic acidosis are secondary to lactate overproduction [2] is
extremely weak [6, 7, 64]. In addition, observations from
experimental models of hypoxic [45, 101, 102] and nonhypoxic
[103] forms of lactic acidosis have clearly implicated both
overproduction and underutilization of lactate in the pathogenesis of the disorder. Thus, although we are far from being able to
quantitatively apportion the lactate load into overproduction
and underutilization columns, it appears likely that both limbs
+3
(10)
+2
+1
I
0
E
0
7.2
7.1
0.
—1
—2
Fig. 4. Relationship between extracellular pH (PHe) and lactate uptake
in the isolated perfused rat liver during simulated metabolic acidosis
(reprinted by permission from Clinical Science and Molecular Medicine, vol 45, pp 543—549, copyright © 1973, The Biochemical Society,
London).
in oxygen tension to a mean Pa02 of 47 mm Hg decreased
of lactate metabolism might be defective in most forms of hepatic lactate uptake by an average of —5.3 tEq/kgImin (mean
clinical lactic acidosis. Accordingly, I should like to address control value of 1.7 Eq/kgImin); this change indicated a
briefly some factors that are known to affect lactate utilization
by the liver and kidney. This knowledge has been derived from
experimental studies and its clinical relevance remains uncertain; nonetheless, it allows for the formulation of an insightful
perspective of the pathogenesis of the disorder.
As I already have noted, hyperlactatemia produced by exogenous infusion elicits increased utilization of lactate by the liver
and kidney [15, 20, 62, 72, 871. On the other hand, graded
hypoxia of the hepatic parenchyma leads to a progressive
diminution in hepatic lactate uptake; this reduction converts the
liver from a lactate-consuming to a lactate-producing organ [45,
71, 104, 105]. Thus, in early studies in the isolated perfused rat
liver, a reduction in hepatic blood flow by 40% to 67% resulted
in conversion from lactate uptake to lactate production [45,
105]. By contrast, in a more recent study of the same experimental preparation [1061, lactate uptake was reduced only
modestly when hepatic blood flow was decreased by 67% of
normal; this finding of course reflects an increase in the hepatic
extraction ratio of lactate as hepatic blood flow decreases. At
more advanced degrees of hypoperfusion, however, severe
reductions in uptake were noted. Yet, even when blood flow
was reduced by 93%, minimal lactate uptake, but not output,
was still observed. At that point, liver intracellular pH averaged
7.03 as compared to a mean value of 7.25 during basal flow
[106]. Similarly, in-vivo studies in the dog have suggested a
large hepatic functional reserve for lactate disposal even during
severe ischemia [20]. At plasma lactate concentrations up to 4.2
mEq/liter, reductions in total hepatic blood flow by 70% or less
did not elicit a significant decrease in hepatic uptake. However,
further hypoperfusion markedly depressed lactate uptake and
even caused net lactate production [104]. The weight of the
evidence thus suggests that a reduction in hepatic blood flow to
less than 30% of normal cannot be compensated for and results
in decreased lactate utilization. Indeed, less severe degrees of
hypoperfusion might lead to substantial impairment of lactate
uptake if accompanied by greater degrees of hyperlactatemia.
Additional in vivo studies in the dog have shown that reduction
conversion to net lactate production. When more severe hypox-
emia was established (mean Pa02 of 35 mm Hg), net lactate
production by the liver was increased (mean of —9.2 Eq/kgI
mm) [1041. In addition to hypoxia, reduction of the hepatic
redox state induced by other means (for example, biguanides,
fructose, alcohol) has been shown to lead to impaired lactate
removal.
In studies of graded hemorrhage in the dog, renal lactate
uptake remained stable up to a blood loss of 30% of the basal
volume. Following a 40% blood loss, which resulted in a mean
arterial blood pressure of 72 mm Hg and a reduction in renal
blood flow by 66% of the prehemorrhage value, renal lactate
uptake decreased sharply; lactate production occurred during
hemorrhagic shock from a 45% to 50% blood loss at a mean
arterial blood pressure of 38 mm Hg and a 94% reduction in
renal blood flow [107, 108]. Following reinfusion of shed blood,
renal lactate uptake remained below baseline levels, probably
reflecting hypoxic tissue damage.
Moreover, strong evidence indicates that either severe metabolic or respiratory acidosis impairs hepatic lactate uptake [15,
64, 70, 82—84, 109, 1101. Lactate uptake by the isolated perfused
rat liver decreased progressively at a perfusate pH of less than
7.10; 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]. Additional
studies have revealed that gluconeogenesis from lactate is
markedly depressed in the isolated perfused rat liver when the
perfusate pH is lowered below 7.10 [83]. By contrast, in-vivo
and in-vitro studies have shown that moderate degrees of
acidosis do not significantly change hepatic lactate uptake [15,
62, 64, 70]. The suppressive effect of acidosis on lactate uptake
has been attributed to decreased gluconeogenesis from lactate
that 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 uptake
decreased by 30% in anesthetized dogs when blood pH was
760
Nephrology Forum
÷3
lowered to 7.16 to 7.20 by the infusion of hydrochloric acid
(9)
[112].
Experiments in the isolated perfused rat liver have examined
the effects of combined hypoperfusion and acidosis on lactate
uptake and gluconeogenesis [85]. The conditions were selected
to simulate those prevailing during moderate to severe exercise
or during circulatory collapse; in addition, acidosis itself is
known to decrease hepatic blood flow [113]. Ischemia and
acidosis have separate inhibitory effects on hepatic lactate
uptake; thus, both could contribute to the defect in lactate
utilization characteristic of those settings [85]. Notably, epi-
(8)
+2
(14)
+1
0)
0
nephrine exerted a marked ameliorating effect on lactate uptake
under these experimental conditions [86]. This observation
might have clinical relevance, in view of the high levels of
circulating epinephrine during acidemic states, such as strenuous exercise and shock.
As expected from Equations 6 and 7, the metabolic processing of lactate by gluconeogenesis or oxidation should increase
the hepatocyte pH by abstracting intracellular hydrogen ions;
by contrast, decreased lactate consumption should decrease
intracellular pH. This formulation assumes that at least part of
the lactate entering the hepatocyte is not accompanied by an
equivalent number of protons; support for this mechanism has
been obtained [6, 114]. Experiments in the isolated perfused
liver from several species indicate a direct relationship between
lactate consumption and a change in intracellular pH [106, 115,
116]. These interrelationships make it evident that the generation of severe acidemia during lactic acidosis carries in itself the
potential of initiating a vicious cycle in which the resultant
depressed hepatic intracellular pH would suppress lactate uptake, thus leading to further aggravation of intracellular as well
as extracellular acidosis (Fig. 6). This ominous cycle would be
reinforced further by the depressive effects of acidosis on
hepatic blood flow [113].
A potent defense mechanism against a maladaptive positive-
(8)
E
0
E
0
(3)
I
—2
—3
—4
-5
7.4
7.3
7.2
7.1
7.0
6.9
6.8
pH1
Fig. 5. Relationship between intracellular pH (pI-fj) and lactate uptake
in the isolated perfused rat liver during simulated metabolic acidosis
(reprinted by permission from Clinical Science and Molecular Medicine, vol 45, pp 543—549, copyright © 1973, The Biochemical Society,
London).
feedback system such as this resides in the kidney. Evidence
from in-vitro and in-vivo studies suggests that acidosis substantially increases renal lactate uptake and utilization via gluconeo-
genesis by stimulating the activity of the key gluconeogenic
enzyme PEPCK [11, 20, 76, 117]. This adaptation is apparent
within 2 to 4 hours from the onset of acidosis [118]. The
augmented renal contribution to lactate utilization during acido-
sis occurs despite the accompanying substantial decrease in
renal blood flow [113]. The mechanism underlying the opposite
effects of acidosis on lactate utilization by the liver and kidney
remains obscure. The overall impact of these responses on the
body's ability to handle a lactic acid load was quantified in rats
subjected to either bilateral nephrectomy or to a sham operation
and then made acidotic with NH4CI, Lactate removal was
slowed in nephrectomized animals by approximately 50% during extracellular acidemia at pH 6,75; this result reflected both
the suppressed hepatic uptake and the absence of the renal
contribution. It was estimated that whereas the contribution of
the 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 to
remove lactate during acidemia was sufficient to compensate
for approximately one-half of the concomitant fall in the extrarenal (primarily hepatic) capacity for lactate extraction; the net
result was a relatively slight decrease in whole-body lactate
removal in the sham-operated animals [20]. It thus appears that
Fig. 6. Theoretical positive-feedback mechanism operating to decrease
systemic pH under conditions of severe lactic acidosis.
Lactic acidosis
Table 2. Synopsis of acid-base effects on lactate metabolisma
Acidosis
Alkalosis
Lactate synthesis
I
t
(Glycolysis)
Lactate utilization
(Gluconeogenesis)
Liver
Kidney
I
t
Net lactate production in vivo
761
significance of lactate levels in the range of 2 to 4 mEq/liter
remains unclear. On the other hand, lactate levels of 5 mEq!liter
or greater usually point to the seriousness of the clinical
condition: the higher the level, the greater the gravity of the
patient's status and the worse the prognosis [122]. I would like
to discuss some general aspects of the clinical presentation of
lactic acidosis.
t
a Adapted from Ref. 12.
the role of the kidney as a lactate-consuming organ becomes
progressively more important as extracellular pH falls; in
severe acidemia, liver and muscle fall very short of compensating for the absence of kidneys.
The role, if any, of this renal adaptation in the pathogenesis of
the many forms of clinical lactic acidosis remains undefined.
However, it is intriguing to note that renal dysfunction is often
present in patients who develop either hypoxic or non-hypoxic
types of lactic acidosis as well as in those with phenformininduced lactic acidosis [3—7, 65, 77, 119]. Phenformin has been
shown 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 of
changes in systemic pH on lactate metabolism. Acidosis inhib-
its lactate synthesis, retards hepatic lactate uptake, but promotes renal lactate extraction and utilization. On the other
hand, alkalosis stimulates lactate generation; no consistent
effect of alkalosis on lactate utilization has been identified. As I
have noted, experimental observations under basal conditions
as well as during stimulated lactate production (exercise, hypoxemia, phenformin administration) reveal suppression of net
lactate production in vivo by acidosis and augmentation by
alkalosis. Nonetheless, additional research is required to define
the aggregated effect of the multitude of influences of acidosis
on lactate metabolism. The level of severity of the acidosis, its
often rapidly evolving course, and the associated—primary and!
or secondary—hemodynamic disturbances are among the factors that add special complexity to this task. It is possible, for
example, that during severe acidosis the aggregate effect of
these various influences might lead to a pH-induced increase in
net lactate production because of the overriding importance of
impaired hepatic lactate utilization.
Clinical features
The clinical presentation of lactic acidosis is extremely
variable and heavily influenced by the manifestations of the
underlying disease. Nonetheless, its development is often her-
alded by the sudden onset of malaise, weakness, anorexia,
vomiting, and a deterioration in mental status. Hyperventilation, tachycardia, hypotension, and circulatory instability are
common associated findings [3, 4, 65]. The diagnosis of lactic
acidosis frequently is strongly suspected on clinical grounds
and is supported by the finding of an otherwise unaccounted-for
elevation in the concentration of plasma undetermined anions
(anion gap), often in the company of hypobicarbonatemia and
acidemia. Of course, confirmation of the diagnosis rests with
the finding of an elevated plasma lactate level. The clinical
Acid-base
Although substantial hypobicarbonatemia is a regular accompaniment of lactic acidosis, this need not be the case. If lactic
acidosis is superimposed on a preexisting hyperbicarbonatemic
state, the accumulated lactic acid may not be sufficient to drive
the plasma bicarbonate to frankly subnormal levels. The only
laboratory clue to the coexistence of lactic acidosis in this
setting is the inappropriately elevated plasma anion gap.
It generally has been assumed that in uncomplicated lactic
acidosis (and, in fact, in all types of organic acidosis) reciprocal
stoichiometry is maintained between the decrement in plasma
bicarbonate and the increment in anion gap. This assumption
originates from the expectation that titration precisely replaces
bicarbonate with the anion of the offending acid, that is, lactate.
Consequently, plasma chloride concentration, unaffected by
titration, is assumed to remain normal. As a corollary, when
lactic acidosis is found to be associated with hypochloremia
(that is, when the increment in anion gap is greater than the
decrement in bicarbonate from normal), it has been argued that
an antecedent metabolic alkalosis might have been present but
presumably is now hidden by the overriding impact of the
acidosis. Undoubtedly, in the untreated patient, close correspondence often exists between the decrement in plasma bicar-
bonate and the increment in anion gap, as well as the rise in
plasma lactate. Yet on several occasions we have been puzzled
by the occurrence of moderate hypochloremia (in the absence
of corresponding hyponatremia) in patients with lactic acidosis
but without an identifiable cause for the putative underlying
alkalosis. Recent experiments in our laboratory have suggested
that some degree of hypochloremia might be an integral part of
the prevailing acidosis [1231. A stable degree of lactic acidosis
was produced in nephrectomized rats by infusing the racemic
mixture of L(+)- and D(—)-lactic acid over a 3-hour period. As
Figure 7 illustrates, a decrement in plasma chloride concentration accounted, on average, for 38% and 48% of the increment
in plasma anion gap at 1 and 3 hours, respectively. We
theorized that this acidosis-induced hypochloremia was due to
expansion of the extracellular compartment secondary to the
extrusion of cellular cations that occurs in the process of
buffering [123]. Although this mechanism provides a plausible
explanation for the puzzling hypochloremia I already have
referred to, its relevance to the clinical setting remains to be
determined. Assuming that this mechanism is operative, one
might not expect the generation of acidosis-induced hypochloremia at the very onset of acidosis before substantial ionic shifts
have occurred; this prediction is supported by studies of
hyperacute, transient lactic acidosis secondary to a single
grand-mal seizure in which hypochloremia was not present [691
and by observations in humans following maximal exercise of
short duration [60]. By contrast, acidosis of several hours
duration might feature this abnormality unless offsetting factors
were involved [123].
762
Nephrology Forum
Anion
• gap
R [Nat]
[KI
20
EU [HCOj]
D [cl-I
10 -
acidosis, and its spontaneous recovery is not accompanied by a
significant change in plasma potassium [69]. Although hyperkalemia occurs commonly in patients with various types of lactic
acidosis, the level of plasma potassium correlates poorly with
the degree of acidemia; moreover, most of the hyperkalemic
patients are hypercatabolic, have renal dysfunction, or both
[136]. It is doubtful whether organic acidemia in general is a
cause of hyperkalemia at all [136]. Despite various hypotheses,
the reasons for the disparate response of plasma potassium to
lactic acidosis as compared to mineral acidosis remain unknown
[132, 133].
5)
15-0
w
Miscellaneous laboratory findings
Serum phosphate concentration is usually increased in patients with lactic acidosis [130, 137, 138]. The pathogenesis of
E
this abnormality is unclear but in all probability reflects a
—10 -
release of inorganic phosphate from cells [139],
ll
—20
Hyperurieemia, another regular feature of lactic acidosis,
results from decreased renal excretion of urate owing to competitive 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 notable
increase corresponds to alanine, but proline, valine, lysine, and
leucine are also increased substantially [141].
—30
lh
3h
Time from control
Fig. 7. Contribution of hypochloremia to the increment in plasma anion
Causes of lactic acidosis
The causes of acquired lactic acidosis are catalogued in Table
gap during lactic acidosis produced by infusion of the racemic mix-
3. Increased oxygen demand arises from intense voluntary
ture of L(+)- and D(—)-lactic acid in the nephrectomized rat (from Ref.
exercise, which is certainly the most common cause of transient
lactic acidosis. Substantial hyperlactatemia also occurs in generalized convulsions, the clinical equivalent of strenuous voluntary exercise. Tissue hypoxia is by far the most common cause
of clinically significant lactic acidosis. The decrease in oxygen
availability in the tissues results from reduced tissue perfusion,
reduced arterial oxygen content, or both. On the other hand, a
number of drugs and toxic substances can cause lactic acidosis
123).
The degree of acidemia generated by a given level of lactic
acidosis-induced hypobicarbonatemia is, of course, determined
by the attendant level of PaCO2. No systematic observations on
the magnitude of the ventilatory adaptation to lactic acidosis are
available. Retrospective studies have variably reported that this
response is greater than, equal to, or less than that associated
with other types of metabolic acidosis [3, 124—127]. In an animal
model of lactic acidosis, the degree of ventilatory adaptation
was virtually identical to that observed in mineral acid-induced
metabolic acidosis [123]. Stimulation of carotid and aortic
chemoreceptor activities in response to lactic acid-induced
metabolic acidosis has been shown in the cat [128]. Although
hypocapnia regularly occurs in clinical lactic acidosis [129], it
often is difficult to ascribe it entirely to the adaptive response in
view of the frequent coexistence of other processes known to
stimulate alveolar ventilation, for example, hypoxemia, hypotension, sepsis, pulmonary disease, and hepatic failure. On the
other hand, processes that lead to ventilatory failure can limit
the ventilatory response to lactic acidosis or superimpose frank
hypercapnia; of course, acidemia is compounded under such
circumstances.
in the absence of tissue hypoxia. Certain clinical disorders
including diabetes mellitus, liver failure, sepsis, and neoplastic
diseases predispose the patient to lactic acidosis. Detailed
descriptions of the causes of lactic acidosis can be found
elsewhere [3—7, 65, 135, 142]. Congenital lactic acidosis results
from a variety of relatively rare, congenital enzymatic defects
that affect the metabolism of pyruvate and lactate (Table 4).
Treatment
Management of lactic acidosis must be directed at prompt
identification and aggressive treatment of the underlying cause
or predisposing disorder whenever possible. Although judicious
administration of alkali might be warranted to ameliorate the
prevailing acidemia and thus possibly prevent catastrophic
cardiovascular sequelae, such maneuvers should only be regarded as temporizing and adjunctive to cause-specific mea-
Plasma potassium concentration
sures. Critical tissue hypoxia is the underlying culprit in most
In contrast to mineral acid-induced acidosis, lactic acidosis of cases of clinical lactic acidosis; therapeutic measures therefore
comparable severity induced by exogenous infusion of lactic should be directed at augmenting oxygen delivery to the tissues.
acid is not associated with a significant change in plasma Indeed, focusing one's efforts on merely treating the acidemia
potassium concentration [130—135]. Similarly, hyperkalemia is by alkali infusion can be likened to treating diabetic ketoacidonot observed in patients with grand mal seizure-induced lactic sis with bicarbonate while neglecting insulin administration.
Lactic acidosis
Table 3. Causes of acquired lactic acidosisa
Increased oxygen demand
1. Vigorous voluntary exercise
2. Generalized convulsions
Reduced oxygen availability (tissue hypoxia)
1. Reduced tissue perfusion
a. Shock or incipient shock
b. Acute left ventricular failure
c. Low cardiac output
2. Reduced arterial 02 content
a. Asphyxia
b. Hypoxemia (Pa02 <35 mm Hg)
c. Carbon monoxide poisoning
d. Very severe anemia
Drugs and toxins
1. Ethanol
2. 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 xylitol
5. Epinephrine, norepinephrine
Certain disorders
1. Diabetes mellitus
2. Liver failure
3. Sepsis
4. Neoplastic diseases
5. Renal failure
6. Iron deficiency
7. Short-bowel syndrome [D(—)-lactic acidosis}
Idiopathic (spontaneous) lactic acidosis
763
implemented promptly [144]. The outcome of lactic acidosis
depends on the severity and reversibility of the underlying
condition. If the cause cannot be corrected, lactic acidosis is
virtually certain to advance, and the overall prognosis is grim.
By contrast, successful treatment of the underlying condition
leads to prompt improvement of the systemic acid-base status
as the metabolism of the accumulated lactate generates an
equivalent amount of endogenous bicarbonate. Typically, the
mild to moderate degrees of lactic acidosis accompanying
uncomplicated acute alcoholism, acute pulmonary edema, selflimited grand-mal seizures, and diabetic ketoacidosis abate with
cause-specific and general supportive measures without the
need for treatment of the acidosis itself.
Alkali therapy
Cause-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]. In
the absence of a complicating element of respiratory acidosis
(which, if present, warrants prompt efforts at increasing alveolar ventilation), such degrees of acidemia usually imply decrements in plasma bicarbonate concentration below 10 mEq/liter.
Intravenous sodium bicarbonate should be administered to
raise the plasma bicarbonate concentration to 10 to 12 mEq/liter
and to maintain blood pH at or above 7.20. This recommendation is based on strong evidence indicating that severe acidemia—that is, pH below 7.20—exerts adverse hemodynamic
effects, including impairment of cardiac contractility; reduction
of cardiac output, arteriolar dilation, dangerous degrees of
Adapted from Refs. 3, 4, and 65.
Table 4. Causes of congenital lactic acidosisa
Defects in gluconeogenesis
I. Glucose-6-phosphatase deficiency (type I glycogen storage
disease—von Gierke's disease)
2. Fructose-bisphosphatase deficiency
3. Pyruvate carboxylase deficiency
Defects in pyruvate oxidation
1. Pyruvate dehydrogenase deficiency
2. Oxidative phosphorylation defects
a
Adapted from Refs. 4 and 65.
General measures
Swift steps should be taken to evaluate and treat cardiovascular collapse, low-cardiac-output states, hypoxemia, and sepsis.
As a general rule, aggressive hemodynamic monitoring in an
intensive care setting should be employed in directing therapeutic measures. Hypovolemia requires prompt extracellular fluid
volume repletion. Every effort should be made to limit the use
of vasoconstrictor agents in treating low-cardiac-output states;
such agents aggravate the ischemia of peripheral tissues, worsen the severity of lactic acidosis and, in turn, prove counterproductive for the patient's hemodynamic status [3, 4, 65, 1431.
hypotension, and diminution in hepatic and renal blood flow;
peripheral venoconstriction leading to central redistribution of
blood volume, thereby augmenting the workload of a depressed
myocardium; increased pulmonary vascular resistance leading
to "shock lung"; and bradycardia and sensitization to various
malignant ventricular arrhythmias [75, 113, 145—148]. Although
acidemia stimulates the release of catecholamines, it also
progressively attenuates the inotropic and chronotropic effects
of these sympathetic mediators on the heart; thus, at pH values
below 7.20, the direct negative inotropic effect of acidemia
becomes dominant. A recent study, which revealed rapid
desensitization and uncoupling of human /3-adrenergic receptors in an in-vitro model of lactic acidosis, provides a plausible
explanation for the characteristic lack of responsiveness to
sympathetic mediators [149]. These observations, which suggest that pretreatment with /3-adrenergic blocking agents sensi-
Rather, administration of inotropic compounds along with
afterload reducing agents should be used. Extreme vigilance
should be exercised for the early detection of fatigue of the
ventilatory apparatus and the presence of critical hypoxemia
tizes the myocardium to the adverse hemodynamic effects of
acidemia, might have clinical relevance. It therefore should be
evident that alkali therapy must be administered (1) to possibly
avoid the superimposition of severe acidemia-related hemodynamic compromise on that already caused by the underlying
disease; and (2) to reinstate cardiac reactivity to endogenous as
well as exogenous catecholamines until the underlying condition can be identified and treated. Beyond its direct beneficial
effects, such treatment provides a certain measure of safety
against the superimposition of additional acidifying stresses; at
values below 10 mEq/liter, a further small decline in plasma
bicarbonate concentration and/or a small increment in PaCO2
can cause catastrophic acidemia.
The utility of this time-honored, adjunctive measure in treat-
and/or hypercapnia; if necessary, artificial ventilation should be
ing lactic acidosis has been criticized strongly in recent years [7,
764
Nephrology Forum
7.3
A
No treatment NaCI NaHCO3
120
'I)
1
a 7.2
7.11
4
7.0 1 ______
L 1000
14
40
ii
c'
to
'3 Io
a 12
00 10
500
B
•0
0
' 150
'OS
C-
0
600
600
Time, minutes
60
SF
0
60
Time, minutes
100
50
0
30
60
Time, minutes
Fig. S. Effect of 3 treatment options (no treatment, NaG!, or NaHCO3) on hypoxemia-induced lactic acidosis in the dog. Left panel, changes in
blood pH, and bicarbonate and lactate concentrations. Middle panel, production of gut lactate in animals treated with NaCI (clear bars) or
NaHCO3 (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).
47, 49—5 1, 142]. Critics have argued that despite the established
practice of vigorously treating severe lactic acidosis with sodium bicarbonate, mortality rates continue to be overwhelming.
This is hardly a persuasive criticism in itself, since the underlying clinical entities—and root causes of the tactic acidosis—
often are of grave severity. Alkali administration, although
designed to potentially limit the gravity of the metabolic disturbances and their hemodynamic epiphenomena, is not expected
to alter materially the course of the background disorder. As I
already have emphasized, alkali is used as symptomatic treatment directed at severe, life-threatening acidemia; unless spe-
cific measures prove successful in relieving critical tissue
hypoperfusion and hypoxia, the outcome is certain to be
dismal.
NaC1 group (Fig. 8, middle panel). Hepatic lactate extraction
remained unchanged in all three groups. The baseline mean
aortic pressure and blood flow to the gut and liver were normal
in all groups, whereas the cardiac index was 130% higher than
that in the control animals. No significant changes in blood
pressure and cardiac index were noted in the NaC1 group during
the course of treatment; by contrast, both these parameters fell
in the animals receiving either no treatment or NaHCO3, more
so in the latter group (Fig. 8, right panel). Observations on the
fate of blood flow to the gut and liver were not provided.
Although interesting, the relevance of these observations to
clinical hypoxic lactic acidosis remains unclear. After all, the
clinical entity is usually characterized by a decreased, not
increased, cardiac output, and by decreased, rather than nor-
Notwithstanding, an even more serious indictment of bicar- mal, blood pressure and organ perfusion. In addition, the
bonate therapy has been handed down recently. Its critics pathogenesis of the augmentation in the plasma lactate level
charge that such therapy, far from being beneficial, actually during NaHCO3 treatment is somewhat puzzling when viewed
exerts a detrimental effect on the course of lactic acidosis [7, 47,
49—51, 142]. I should like to review the chief pieces of experimental evidence supporting this charge.
Hypoxic lactic acidosis was induced in anesthetized dogs
with fixed ventilation at an Fi02 of 8%, with resulting Pa02
values of 25 to 30 mm Hg [51]. The impact of three treatment
options—no therapy, administration of 1 M NaCl at 2.5 mmol/
kg/hr, or an equivalent amount of 1 M NaHCO3—applied for 60
minutes was studied with regard to blood acid-base status,
lactate metabolism, and systemic hemodynamics. As Figure 8
shows (left panel), animals in all three treatment groups experienced significant and similar decrements in pH and in plasma
bicarbonate concentration during the experimental period.
Moreover, although plasma lactate rose further in all groups
after one hour of observation, the plasma lactate level was
significantly higher in the NaHCO3 group as compared to the
remaining two groups. Skeletal muscle lactate production did
not change significantly in any of the three groups. Gut lactate
production remained unchanged in the groups receiving either
no treatment or NaHCO3, but it decreased significantly in the
in the context of the remaining evidence. Thus, the observed
hemodynamic deterioration in the NaHCO3 group apparently
was insufficient to alter either lactate production by gut and
skeletal muscle (the main sources of lactate in this model) or
hepatic lactate extraction; nonetheless, an exaggerated aggravation of hyperlactatemia was noted. The investigators observed that although systemic acid-base status did not change
during the course of the experiment, portal PCO2 averaged 55
mm Hg after NaHCO3 treatment—a value significantly higher
than the 45 mm Hg after NaC1 treatment, It is unclear to what
extent the fixed ventilation of the animals affected this result.
Assuming that the basal values of this parameter did not differ
between the NaCI- and NaHCO3-treated groups, it is possible
that this degree of portal hypercapnia might have produced
excessive intrahepatic acidification, thus adversely affecting
hepatic lactate uptake [70]. Yet extraction of lactate by liver
remained unaltered by treatment in all groups. Furthermore,
the disparate hemodynamic response between the NaCI- and
NaHCO3-treated groups of animals,despite the similarity in the
amount of sodium and volume administered and the prevailing
Lactic acidosis
acid-base status, is intriguing but puzzling. No mortality was
reported in any of the studied groups [511.
Using a different experimental model, the same group of
investigators has produced evidence supporting their thesis of
an adverse role of bicarbonate therapy in lactic acidosis [49].
Lactic acidosis was induced in diabetic dogs (having undergone
surgical pancreatectomy) via infusion of intravenous phenformm. Following 90 minutes of treatment with either NaHCO3 (1
mmollmin 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 the
NaCI-treated group but increased twofold in the NaHCO3treated animals. Lactate production by the gut doubled in the
NaHCO3 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 the
NaHCO3-treated animals but remained essentially unchanged
in the animals given NaCl. However, muscle intracellular pH
fell significantly in the NaCl, but not in the NaHCO3, animals.
After 4 hours of observation, the same mortality rate, 83%, was
seen in both groups.
Again, the relevance of these experimental observations to
the clinical disorder is uncertain. Intravenous phenformin in
high doses is cardiotoxic and produces consistent decreases in
cardiac output and systemic hemodynamics even before any
changes in systemic acid-base status are detectable [96, 103].
Why NaHCO3 administration would increase phenformin's
cardiotoxicity as compared to equimolar amounts of NaC1
remains unclear. It has been suggested that because phenformin
is a strong base, alkalinization would intensify its diffusion
across plasma membranes to intracellular binding sites [150].
Despite some inconsistencies, the evidence derived from
these [49, 51] and other studies supporting the notion that
bicarbonate administration or, in general, alkalinization (relative or absolute) of body fluids stimulates lactate production is
strong. Even massive doses of alkali may not succeed in
substantially increasing the plasma bicarbonate level in malignancy-associated chronic lactic acidosis; indeed, a direct stoichiometric relationship between alkali administration and acid
production, presumably by the malignancy, has been demonstrated [43, 44]. Moreover, there is a dynamic inverse relationship between the prevailing acidity of body fluids and either
ketoacid production during ketoacidosis [12, 53, 54] or lactate
production during hypoxemia-induced lactic acidosis [42]. A
central difference between clinical hypoxic lactic acidosis and
the hypoxemia-induced experimental counterpart is that the
latter is a model of relatively controlled lactic acidosis in which
the tendency toward continued lactate production apparently is
compensated for by salutary hemodynamic adjustments as well
as 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 hemodynamic
disarray gives rise to rapidly advancing lactic acidosis that, in
765
acidosis, and that it gives way to an all-too-familiar lethal
vicious cycle. Consequently, I reject any extrapolations of the
existing experimental findings to the clinical setting, and I
dispute the implication that the clinical use of bicarbonate
should be abandoned. Nonetheless, the cumulative experimental evidence has reinforced the clinical dictum that bicarbonate
should be administered wisely and cautiously.
I believe strongly, therefore, that judicious administration of
bicarbonate along the guidelines given here is imperative. By
returning systemic pH above the hemodynamically critical
level, the clinician "buys time" that might allow control of the
underlying causative illness. This relative alkalinization proba-
bly tends to increase lactate production, but this tendency
should be offset by the improved state of tissue perfusion and,
possibly, by the augmentation of hepatic lactate extraction. For
this reason the clinician should take pains to use the smallest
possible amounts of bicarbonate that will allow the return of
systemic pH to hemodynamically safe levels [144].
No simple prescription exists for predetermining the amount
of bicarbonate necessary for achieving this goal in the individual patient. The only recourse available to the clinician is to
perform an individual titration for each patient. Frequent moni-
toring of the acid-base status during bicarbonate therapy is
essential for a cogent appraisal of additional bicarbonate requirements. That the goal of raising plasma bicarbonate by
administering alkali can be achieved is well documented in
many forms of clinical lactic acidosis, but widely variable rates
of bicarbonate administration are required [3, 65]. This variability in dose requirement largely reflects the fact that the rate of
lactic acid production is itself extremely variable. The clinician
also should note that the apparent space of distribution for
bicarbonate is enlarged in hypobicarbonatemic states [151];
thus, calculating bicarbonate doses on the basis of the normal
value of the apparent space of distribution for bicarbonate of
40% to 50% body weight will underestimate the bicarbonate
requirements. Indeed, when lactic acid production proceeds
extremely rapidly, administered bicarbonate can fail to effect
detectable changes in plasma bicarbonate concentration, the
apparent space of distribution for bicarbonate becoming essentially infinite.
Administration of large and occasionally massive amounts of
bicarbonate entails certain risks [3, 4, 65, 144]. Hypernatremia
and marked hyperosmolality, and volume overload are common
problems. Establishment of adequate diuresis with potent loop
diuretics allows the infusion of large doses of alkali without
superimposing iatrogenic circulatory compromise. On the other
hand, if renal failure is present, peritoneal dialysis, hemodialysis, or hemofiltration may be required [152—154]. "Overshoot"
alkalosis is an extremely undesirable complication of aggressive
alkali dosing and underscores the strong recommendation for
judicious bicarbonate administration; the swift transition from
severe acidemia to alkalemia can produce tetany, altered men-
turn, aggravates the circulatory compromise, diminishes hepatic and renal blood flow, and leads to more severe acidemia by
accelerating production and decreasing uptake of lactate. It is
thus clear that the negative feedback control system between
systemic pH and organic acid production (suggested by experi-
tal status, generalized convulsions, and cardiac arrhythmias.
These complications arise from two mechanisms. The first is
the persistence of hyperventilation at levels inappropriate for
the newly prevailing plasma bicarbonate concentration—either
because of the known delay of medullary chemoreceptors to
register the amelioration of acidity in the systemic circulation,
or because of pH-independent stimuli of alveolar ventilation.
mental studies) is overriden during clinical hypoxic lactic
Second, substantial elevations in plasma bicarbonate, occasion-
766
Nephrology Forum
ally to frankly supranormal levels, can result from the composite effect of inordinately large exogenous alkali loads and from
the regeneration of endogenous alkali from the metabolism of
the accumulated lactate [3, 4, 65, 144]. Special attention should
be paid to the level of plasma potassium to prevent hypokalemia
during treatment, especially in patients receiving digitalis. Administration of bicarbonate produces increments in PaCO2 that
originate both from the release of CO2 during the internal
titration of bicarbonate and from pH-mediated suppression of
alveolar ventilation [151, 155]. In patients with adequate gas
exchange, this small effect is usually inconsequential, but it can
be clinically important in patients with borderline oxygenation.
Bicarbonate administration during resuscitative efforts in patients with cardiorespiratory arrest prior to the reestablishment
of gas exchange may compound the often severe acidemia. This
effect occurs due to complete retention of the CO2 released
during the rapid titration of infused bicarbonate by the ongoing
lactic acid production [1561. Finally, concerns that the changes
in pH induced by judicious alkali administration will produce a
clinically significant decrease in tissue oxygen delivery by
enhancing hemoglobin's affinity for oxygen (Bohr effect) are
unfounded [144, 157].
Additional measures
Insulin administration has been suggested as a therapeutic
measure in diabetic patients with lactic acidosis, whether or not
biguanide agents are involved [158, 159]. Theoretically, insulin
could exert a beneficial effect by stimulating the oxidation of
pyruvate through the pyruvate dehydrogenase (PDH) pathway
and by limiting the flow of gluconeogenic amino acids to the
liver. Although the evidence supporting this therapy is tenuous,
it is probably advisable to include insulin in the treatment plan
in this setting [4, 7, 160].
In a single patient with lactic acidosis in association with
congestive heart failure, normal cardiac output, and normotension but clinical evidence of severe peripheral vasoconstriction,
afterload reduction with sodium nitroprusside led to striking
resolution of the metabolic abnormality [161]. No additional
experience has been documented in such a setting, however,
and the efficacy of this modality thus remains unproven. As I
already have mentioned, afterload reducing agents should be
used in preference to vasoconstrictors in the treatment of lowcardiac-output states [162, 1631.
Methylene blue, an oxidizing agent, was proposed as treat-
the needed alkali. Obviously, in view of impaired lactate
utilization there is no sense in employing lactate-buffered
dialysate. Acetate-buffered dialysate has been used effectively
but should be avoided in patients with hemodynamic insufficiency or instability and in those prone to acetate intolerance.
Bicarbonate-buffered peritoneal dialysis or hemodialysis has
been employed successfully in the management of patients with
lactic acidosis [153, 167, 168]. Its attractions include provision
of bicarbonate as such, rather than of alkali precursors; avoid-
ance of the risk of further hypobicarbonatemia due to an
imbalance between the diffusive losses of bicarbonate in the
dialysate and alkali generation from the acetate; the prevention
of acetate dialysis-induced hypoxemia; and probably a better
hemodynamic profile. Bicarbonate-buffered peritoneal dialysis
is particularly suitable in the management of patients with
circulatory failure. In addition, dialysis can remove drugs and
toxins such as methanol and salicylates; hemodialysis does not
remove appreciable quantities of phenformin, however [169].
Finally, dialysis can remove lactate from the body fluids and
thus often prevent rebound hyperbicarbonatemia. Recent evi-
dence suggests that hyperlactatemia per se (independent of
changes in systemic pH) exerts adverse effects on myocardial
contractility. In-vitro studies have shown that increased lactate
concentration impairs frog atrial muscle contractility [170],
leads to swelling and reduction in oxidative phosphorylation in
isolated beef heart mitochondria [171], and inhibits glucose
utilization by ischemic rat myocardium at the glyceraldehyde 3phosphate dehydrogenase step [172]. In addition, hyperlactatemia per se decreased exercise tolerance in normal rats [173]. By
contrast, increased lactate concentration did not decrease the
contractility of the papillary muscle of the cat [147]. If an
adverse hemodynamic effect of hyperlactatemia were confirmed, it would provide a plausible explanation for evidence of
hemodynamic deterioration following bicarbonate administration independent of changes in systemic pH [49, 51, 96]. Such
confirmation would support therapeutic strategies specifically
aimed at reducing plasma lactate.
Finally, dichloroacetate (DCA) is an exciting investigational
agent that holds promise as a therapeutic tool in lactic acidosis.
Because DCA stimulates PDH activity in many tissues, it
augments the oxidation of pyruvate to acetyl-CoA [174, 175].
This effect directs lactate, alanine, and pyruvate into the
formation of carbon dioxide, fatty acids, and ketone bodies
(Fig. 1) and consequently inhibits hepatic gluconeogenesis from
ment for lactic acidosis on the premise that it promotes the these 3-carbon precursors. Decreases in the plasma levels of
conversion of NADH to NADt and thus restores the cellular lactate, alanine, pyruvate, and glucose occur, whereas plasma
redox state; however, clinical application of this therapy has ketone-body concentration increases [176—179]. In nonacidotic
not proved successful [164].
Thiamine and lipoic acids, agents that act as coenzymes for
the PDH enzyme complex, have been utilized occasionally in
the treatment of patients with lactic acidosis, but experience is
limited and therefore their utility remains uncertain [3, 4, 165].
diabetic patients, DCA decreases lactate levels [180], and it can
However, thiamine represents remarkably effective specific
therapy in patients with lactic acidosis in association with
DCA to diabetic dogs with phenformin-induced lactic acidosis
significantly lowered plasma lactate and significantly raised
fulminant beriberi [165, 166].
Peritoneal dialysis, hemodialysis, or hemofiltration is a useful
plasma bicarbonate concentration and pH as compared to a
similarly prepared group of animals that received NaHCO3
adjunctive measure in the management of patients with im-
treatment (Fig. 9). Moreover, whereas treatment with NaHCO3
paired renal function who require large alkali loads [152—154,
167, 1681. In addition to preventing or treating the associated
volume overload, dialysis conveniently and reliably provides
treatment with DCA returned cardiac index to the control value
(Fig. 10); mortality during a 4-hour treatment period with either
improve the disordered lactate metabolism in experimental
lactic acidosis produced by functional hepatectomy, phenformm administration, exercise, epinephrine infusion, or hypoxemia [52, 175, 177, 181—184]. In one study [52], administration of
could not arrest the progressive fall in the cardiac index,
767
Lactic acidosis
)
mM/L
15
10-
125
.,. ;,.
(5
(5
100
x
V
C
1
-n
0(5
0-
20
00
75
(5
10-
(5
50
NaHCO3
N\r__L_1 NaHCO
0
1
2
4
5
6
7
8
Time, hours
0)
C
Fig.
10. Effect of dichioroacetate (DCA) or NaHCO3 treatment on
cardiac index during phenformin-induced lactic acidosis in the diabetic
dog (reproduced from The Journal of Clinical Investigation, 1982, vol.
70, pp. 853—862 by copyright permission of The American Society for
Clinical Investigation).
0•
7.40 -
N
. 7.20
acidosis in rats and dogs [183, 184]. Unlike treatment with
-
0)
NaHCO3
C
7.00
therapy
phenformin
N N.
p
C
0
0
210
270
330
390
450
Time, minutes
Fig. 9. Effect of dichloroacetate (DCA) or NaHCO3 treatment on blood
acid-base composition and lactate level during phenformin-induced
lactic acidosis in the diabetic dog (reproduced from The Journal of
Clinical Investigation, 1982, vol. 70, pp. 853—862 by copyright permission of The American Society for Clinical Investigation).
modality averaged 91% in dogs receiving NaHCO3, as compared with 22% in dogs treated with DCA [52]. It is interesting
that treatment with DCA resulted in increased liver lactate
uptake in association with increased liver intracellular PH; thus,
the decreased hyperlactatemia noted could be the composite
effect of decreased lactate production due to improved cardiac
performance and increased lactate utilization. These authors
made similar observations about DCA treatment in dogs with
functional hepatectomy and lactic acidosis [52]. The decisively
better outcome of DCA therapy compared to NaHCO3 administration in this study often has been quoted as a potent argument
against the utility of NaHCO3 therapy [7, 49, 51]. I find this
argument unconvincing, however. To attempt to draw a parallel, I do not think it valid to conclude that NaHCO3 has no role
in the management of diabetic ketoacidosis on the basis of
improved outcome of patients treated with insulin as compared
to outcome in those treated with alkali alone.
Two studies have provided evidence in support of a beneficial
role of DCA in the treatment of hypoxemia-induced lactic
sodium chloride, DCA administration resulted in attenuation of
the hyperlactatemia, hypobicarbonatemia, and acidemia in hypoxemic rats; moreover, the animals receiving DCA maintained
higher mean blood pressures and greater rates of urine flow and
sodium excretion [183]. Similarly, administration of DCA to
hypoxemic dogs significantly increased plasma bicarbonate and
pH, and stabilized plasma lactate concentration; by contrast,
progression of hypobicarbonatemia, acidemia, and hyperlactatemia was noted in the group receiving sodium chloride. Additionally, animals given DCA, but not those given NaCl, experienced increased hepatic lactate extraction, decreased liver and
muscle lactate levels, and elevated muscle intracellular pH
[184].
Some data on DCA are available in humans as well. Thirteen
gravely sick, hypotensive patients with lactic acidosis in associ-
ation with various predisposing illnesses (such as renal and
hepatic disease, sepsis, leukemia or lymphoma, arrhythmias)
were given DCA [185]. Of the 11 who did not receive concurrent treatment with bicarbonate, each of 7 experienced at least a
20% decrease in plasma lactate (Fig. 11); this subgroup had a
significant, mean reduction of lactate of 80% (from an average
value of 14.2 to 2.8 mEq/liter) and significant increases in
plasma bicarbonate and pH (from 14 to 21 mEq/liter and from
7.24 to 7.39, respectively). The fall in plasma lactate persisted
for several hours after treatment with DCA was terminated. In
10 of the 13 treated patients, increases in systolic blood
pressure of 10 to 40 mm Hg were noted soon after the initiation
of DCA treatment; in 4 patients whose cardiac output was
monitored, the increase in systolic blood pressure was accompanied by a significant mean increase in cardiac output of 21%
(from 6.2 to 8.4 liters/mm). These findings are in accord with
previous observations indicating that DCA improves cardiac
function in dogs with experimentally induced myocardial ischemia or lactic acidosis [52, 186]. Because the drug is known to
augment aerobic oxidative metabolism in cardiac tissue [187], it
768
Nephrology Forum
disorder. It is currently unknown whether the beneficial effect
of DCA on lactic acidosis would be translated into a favorable
alteration of the natural course of the underlying disease and
thus to decreased mortality. Indeed, the so-far disappointing
survival data with DCA therapy should restrain the critics of
NaHCO3 therapy who have denounced bicarbonate therapy on
the charge that high mortality rates from lactic acidosis persist
despite alkali provision.
DCA OCA
26
24
22
20
16
Ii
a-
16
14
'2
10
Conclusion
Advances in the understanding of lactate metabolism have
8
allowed insights into the pathogenesis of lactic acidosis. Despite
6
this progress, however, the development of hyperlactatemia
4
remains an index of the gravity of the patient's condition and is
commonly the harbinger of the patient's impending demise. The
2
0
0
1
2 3 4 5 6 7 8 9 10 11
15 16 17 20
60
Cu
—
8<8
50
40
30
01
2 3 4 5 6 7 8 9 10
mainstay of therapy for lactic acidosis continues to center
around efforts to improve or eradicate the underlying cause or
predisposing condition, coupled with the careful and restrained
administration of sodium bicarbonate to prevent or treat critical
acidemia. Clinical research should continue with the promising
investigational agent DCA to define its proper role in the
treatment of the various forms of lactic acidosis.
Time, hours
Questions and answers
and plasma drug concentration in a patient with tactic acidosis in
DR. JOHN T. HARRINGTON: You alluded to the hyperlactateassociation with hypotension, sepsis, hepatic disease, and severe mia of respiratory alkalosis. Could you be a little more quantitaanemia [reprinted by permission of The New England Journal of
Fig. 11. Effect of dichloroacetate (DCA) treatment on plasma lactate
Medicine (vol 309, pp 390—396, 1983)1.
might improve myocardial contractility. These hemodynamic
effects might complement the metabolic action of DCA in
decreasing the plasma lactate level. Unfortunately, despite
these favorable metabolic and hemodynamic consequences, all
but one of the patients in that study died of their underlying
disease [185]. Additional human experience with DCA includes
tive on this issue?
DR. MADIAS: Several investigators have attributed a major
component of the reduction in plasma bicarbonate during acute
respiratory alkalosis to the accumulation of lactic acid (on the
order of 50% to 75%). This conclusion was based on studies in
anesthetized animals subjected to mechanical ventilation sufficient to achieve severe hypocapnia (PaCO, less than 15 mm Hg)
[18, 197, 198]. By contrast, studies in unanesthetized animals
observations in 8 adult patients with severe lactic acidosis in
association with biguanide therapy, hypotension, sepsis, or
malignancy; 3 of the 8 had a greater than 20% reduction in
plasma lactate levels, and 2 of the 3 survived [185, 188, 1891.
and in humans subjected to milder degrees of hypocapnia
(PaCO, of 20 to 30 mm Hg) have reported only a slight and
short-lived elevation in plasma lactate concentration (in the
range of 0.5 to 1.5 mEq/liter). Indeed, the hyperlactatemia
Moreover, of 7 children with congenital forms of lactic acidosis,
vanishes within 8 hours despite the persistent hypocapnia [23,
24, 28]. Additional studies in anesthetized animals and humans
confirm the presence of only a mild degree of hyperlactatemia
during moderate grades of acute respiratory alkalosis [22, 25—
DCA produced biochemical and/or clinical improvement in 4
[190—194]. In general, no appreciable drug toxicity has been
observed in studies of short-term administration of DCA [180,
185, 188, 189, 190—193, 1951. By contrast, serious side effects
have been noted with long-term administration, including limb
paralysis, cataracts, increased urinary oxalate excretion, testicular degeneration, neuropathy, mutagenicity, and changes in
the white matter of the central nervous system [175]; obviously
these findings make DCA unsuitable for extended use [196].
One would hope that the encouraging results of the human
studies coupled with those from experimental models would
prompt prospective controlled trials of this agent to define its
proper role in the management of lactic acidosis. In one sense,
augmentation of lactate utilization during lactic acidosis by
DCA resembles restoration by insulin of the disordered metabolism during diabetic ketoacidosis. Although the underlying
disease is clearly the main determinant of the eventual outcome
of the patient, alleviation of the lactic acidemia by DCA or an
analogue coupled with judicious administration of alkali for
severe acidemia should at least allow the clinician the opportunity to apply other therapeutic measures directed at the inciting
271. Moreover, during chronic hypocapnia, plasma lactate
concentration is within normal limits even in the presence of
associated hypoxemia [29—34]. The large increase in lactate
observed by some probably reflected a degree of circulatory
insufficiency consequent to the cardiovascular effects of anesthesia and vigorous mechanical ventilation.
DR. VINCENT J. CANzANELLO (Division of Nephrology,
NEMCH): Do changes in hormones affecting the transcellular
distribution of potassium account for the lack of hyperkalemia
during experimental lactic acidosis?
DR. MAmAs: To my knowledge, this attractive possibility has
not been investigated systematically. In this regard, recent
observations have uncovered a role of the endocrine pancreas
to account for the different response of plasma potassium to
experimental ketoacidosis (normokalemia or hypokalemia) as
compared to mineral acidosis (hyperkalemia): Whereas ketoacidosis was associated with hyperinsulinemia, HC1-induced acidosis was accompanied by elevated glucagon levels [199].
Lactic acidosis
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 your
recommendations about bicarbonate administration in patients
with acute lactic acidosis. However, in considering the adverse
effects on the circulation that clearly have been shown to attend
treatment with bicarbonate in studies of experimental lactic
acidosis [49, 51], I would like to propose that factors other than
bicarbonate itself or changes in the hydrogen ion concentration
might be at fault. It seems quite possible, for example, that
769
exercise. Have these maneuvers affected exercise tolerance?
DR. MADIAS: Careful studies have documented that treatment with oral NH4C1 is associated with markedly diminished
endurance during high-intensity, cycle-ergometer exercise; by
contrast, treatment with oral NaHCO3 led to enhanced endurance [41, 204, 205]. In contrast to these studies of prolonged
exercise, changes in acid-base status induced by these maneuvers have not produced appreciable effects on maximal power
output and fatigue during short-term, maximal exercise [39]. In
both types of exercise however, NH4C1-induced acidosis has
these adverse effects might be caused by metabolic intermediates, the concentrations of which are stimulated by the administration of bicarbonate.
DR. MADIAS: I agree that changes in acid-base status consequent to bicarbonate administration cannot explain the adverse
hemodynamic effects reported in these studies [49, 51, 96, 103].
These reports have implied that the hemodynamic deterioration
might arise from bicarbonate-induced intracellular acidosis. But
decreased the post-exercise plasma lactate concentration,
this suggestion runs counter to available experimental evi-
NEMCII): Would you comment on the treatment of the lactic
acidosis associated with malignancies?
DR. MADIAs: Although lactic acidosis in the company of
circulatory insufficiency, liver failure, or sepsis is a common
occurrence in the preterminal stage of many neoplastic diseases, it occasionally develops in the absence of such factors
and may pursue a relatively chronic course [3, 4, 65]. Such a
dence. First, whole-body intracellular pH increases following
sodium bicarbonate infusion in the dog [200]. Second, cardiac
and skeletal muscle intracellular pH of the rabbit increases in
response to sodium bicarbonate infusion [201]. Moreover,
myocardial contractility and cardiac output increase consistently following an intravenous or intracoronary infusion of sodium
bicarbonate in the dog [112, 202, 203]. Your suggestion that one
or more metabolic intermediates of stimulated glycolysis might
be at fault is an attractive one and deserving of future
investigation.
I should like to reemphasize the important insights in the
physiology of lactic acid metabolism that these studies have
provided [47—51]. The findings on the hemodynamic effects of
whereas NaHCO3 has augmented the hyperlactatemia. In addition to inducing changes in net lactate production, alterations in
acid-base status probably influence plasma lactate levels by
affecting the rate of lactate efflux from muscle; several observations suggest that acidosis impairs and alkalosis promotes the
effiux of lactate [206—2081.
DR. RONALD D. PERRONE (Division of Nephrology,
"paraneoplastic" metabolic derangement usually is seen in
patients with leukemia or other myeloproliferative disorders; it
also occurs in association with lymphomas and with several
solid tumors. Overproduction of lactic acid by the neoplastic
tissue has been implicated in the pathogenesis of this syndrome.
Because leukocytes and neoplastic cells have a high glycolytic
exclusively from the outpouring of hydrogen ions into the body
rate, increased production of lactate would be expected if the
tumor burden were large. In some instances, lactic acidosis has
developed only in association with high-glucose, total parenteral nutrition. In addition, rapidly proliferating tumors may suffer
from an inadequate blood supply, producing severe hypoxia
and 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 role
of lactate overproduction is supported by the observation that
lactic acidosis resolves with successful treatment of the underlying malignancy [209—2111. Furthermore, a role for hepatic
underutilization of lactate has been suggested in some cases of
lactic acidosis in patients with massive replacement of the liver
by tumor [3, 4, 65, 2111.
With regard to alkali administration, the general restraint I
suggested for its use in hypoxic states should be exercised also
in this setting, As I have mentioned, even massive doses of
alkali may not succeed in substantially increasing plasma bicar-
fluids, whereas the lactate ions themselves are thought to be
bonate in these patients because of a direct stoichiometric
innocuous. Yet, some [170—173] but not all [147] of the recent
pieces of evidence I have reviewed cast doubt on this concept
relationship between alkali administration and acid production,
presumably by the malignancy [43, 44]. In addition to the wellknown risks stemming from the administration of large bicarbonate loads, aggravation of the prevailing cachexia may also
occur in the patient with cancer and poor dietary intake because
bicarbonate treatment have raised important questions that
merit further investigation. On the other hand, I maintain
strongly at present that any extrapolation from the findings of
these studies to patients is inappropriate. I have presented in
detail the reasons for my position, chief of which are the
questionable relevance of the experimental models to the
clinical circumstances and the strong evidence indicating that
severe acidemia triggers a series of adverse hemodynamic
effects. I should add that regarding mortality, even no treatment
at all appears to make no difference in these experimental
models [49, 51]. I suggest that leaving severe lactic acidosis
untreated 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 toxicity
of the lactate ion itself?
DR. MADIAS: Our thinking has been dominated by the
concept that the deleterious effects of lactic acidosis stem
and argue for a direct adverse effect of the lactate ion on
myocardial contractility. I believe that this may be an issue of
great importance, and it certainly warrants intensive
investigation.
DR. CANZANELLO: A number of recent studies suggest that
administration of either NH4C1 or NaHCO3 induces a substan-
tial decrease or rise, respectively, of the hyperlactatemia of
the body's glycogen and protein stores may be depleted as a
consequence of stimulated lactate production [44]. Consequently, such patients should receive the smallest possible amount of
bicarbonate that is sufficient to prevent or treat life-threatening
770
Nephrology Forum
acidemia and always in the company of an adequate nutrient
supply.
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 acidosis
that develop presumably in the absence of evidence for an
established cause or associated condition [1, 2, 212]. Although
15. GOLDSTEIN PT, SIMMON D, TA5HKIN D: Effect of acid-base
alterations on hepatic lactate utilization. I Physiol 233:261—278,
1972
ANREP GV, CANNAN RK: The concentration of lactic acid in the
blood in experimental alkalaemia and acidaemia. I Physiol 58:244—
258, 1924
17. COHEN JJ, BRACKETT NC JR, SCHWARTZ WB: The nature of the
16.
carbon dioxide titration curve in the normal dog. I Clin Invest
43:777—786, 1964
18.
as yet unrecognized cause(s) may be at play, well-founded
reservations have been raised about the validity of this designation [4, 213]. Close scrutiny of published reports suggests that
many such patients probably suffered from circulatory insuffi-
34:23 1—245,
the great majority of cases, the clinical picture quickly advanced to overt circulatory collapse, often in the company of
sepsis or liver failure, and had a catastrophic outcome [4, 215,
216]. It therefore appears that the development of so-called
idiopathic lactic aeidosis is usually a warning sign presaging the
appearance of circulatory failure. Although I have included it in
Table 3 for completion, I suspect that idiopathic lactic acidosis
does not exist.
1955
K, MA5UKO K, NI5HISAKA N, MAT5UKI M, H0RIKAwA H, WATANABE R: Acid-base changes of arterial plasma
19. ICHIYANAGI
during exogenous and endogenous hypercapnia in man. Respir
ciency too subtle for clinical detection [135, 213, 214]. In
addition, a substantial fraction of patients classified as having
"idiopathic" lactic acidosis were taking phenformin. Indeed, in
GIEBISCH G, BERGER L, PIns RE: The extrarenal response to
acute acid-base disturbances of respiratory origin. I Clin Invest
Physiol 7:310—325,
20. YUDKIN
J,
1969
COHEN RD: The contribution of the kidney to the
removal of a lactic acid load under normal and acidotic conditions
in the
conscious rat. Clin
Sci Mol Med 48:121—131,
1975
21. LEAL-PINTO E, PARK BC, KING F, MACLEOn M, Pins RE:
Metabolism of lactate by the intact functioning kidney of the dog.
Am J Physiol 224:1463—1467, 1973
HEBERT LA, LEVESQUE PR, ET5TEN BE, SCHWARTZ
22. Aiuius GS,
WB: Characterization and clinical application of the "significance
band" for acute respiratory alkalosis. N Engl I Med 280:117—123,
1969
23. CAIN SM, DUNN JE I!: Transient arterial lactic acid changes in
unanesthetized dogs at 21,000 feet. Am I Physiol 206:1437—1440,
1964
Reprint requests to Dr. N. P. Madias, Division of Nephrology, Box
172, New England Medical Center, 17] Harrison Avenue, Boston,
Massachusetts 02111, USA
24. ELDRIDGE F, SALZER J: Effect of respiratory alkalosis on blood
lactate and pyruvate in humans. I Appl Physiol 22:461—468, 1967
25. MANFREDI F: Effects of hypoeapnia and hypercapnia on intracellular acid-base equilibrium in man. J Lab Clin Med 69:304—312,
References
26. PRYS-ROBERTS C, KELMAN GR, NUNN iF: Determination of the
1967
1. HUCKABEE WE: Abnormal resting blood lactate. I. The signifi-
cance of hyperlactatemia in hospitalized patients. Am J Med
30:833—839, 1961
2. HUCKABEE WE: Abnormal resting blood lactate. II. Lactic acido-
sis. Am J Med 30:840—848, 1961
3. COHEN RD, Woons HF: Clinical and Biochemical Aspects of
in vivo carbon dioxide titration curve of anaesthetized man. Br J
Anaesth 38:500, 1966
27. SYKES MK, COOKE PM: The effect of hyperventilation on "excess
lactate" production during anaesthesia. Br I Anaesth 37:372—379,
1965
28. TAKANO
N: Blood lactate accumulation and its causative factors
during passive hyperventilation in dogs. Jpn J Physiol 16:481—496,
Lactic Acidosis. Oxford: Blackwcll Scientific Publications, 1976
4. RELMAN AS: Lactic acidosis, in Acid-Base and Potassium Ho-
meostasis, edited by BRENNER BM, STEIN JH, New York,
moderate
PARK R, ARIEFF A!: Lactic acidosis, in Advances in Internal
Medicine, edited by STOLLERMAN GH, Chicago, Yearbook Medical Publishers, 1980, vol 25, pp 33—68
666, 1937
31. FOR5TER HV, DEMPSEY JA, CHOSY LW: Incomplete compensa-
65—100
6. COHEN RD, Woons HF: Lactic acidosis revisited. Diabetes
32:181—191, i983
7. KREIsBERG RA: Pathogenesis
Annu Rev Med 35:181—193,
8.
tion of CSF[Ht] in man during acclimatization to high altitude
(4,300 m). I Appl Physiol 38:1067—1072,
and management of lactic acidosis.
renal adaptation
1984
hypocapnia. J Clin Invest 51:1722—
33. GENNARI Fi, KAEHNY WD, LEvESQUE PR, COHEN JJ: Acid-base
response
9. RELMAN AS: Metabolic consequences of acid-base disorders.
to chronic hypocapnia in man (abstract). Clin Res
28:533A, 1980
Kidney mt 1:347—359, 1972
HALPERIN ML, CONNORS HP, RELMAN AS, KARNOvSKY ML:
34. GLEDHILL N, BEIRNE GJ, DEMPSEY JA: Renal response to shortterm hypoeapnia in man. Kidney mt 8:376—386, 1975
Factors that control the effect of pH on glycolysis in leukocytes. J
35.
Biol Chem 244:384—390,
DAwSON AG: Contribution ofpH sensitive metabolic processes to
Acta 499:85—98, 1977
12. Moon VL, TANNEN RL: pH control of lactic acid and keto acid
production: A mechanism of acid-base regulation. Miner Electrolyte Metab 9:317—325, 1983
B, DANFORTH WH: Effect of pH on the kinetics of frog
muscle phosphofructokinase. J Biol Chem 241:4110—4112, 1966
PARK R, LEACH Wi, ARIEFF A!: Determination of liver intracellular pH in vivo and its homeostasis in acute acidosis and alkalosts.
Am I Physiol 236:F240-F245, 1979
13. TRIvEDI
ADROGUE Hi, BREN5ILvER i, MADIAS NE: Changes
anion
1969
pH homeostasis in isolated rat kidney tubules. Biochim Biophys
14.
to chronic
1730, 1972
1968
11.
1975
32. GENNARI FJ, GOLDsTEIN MB, SCHWARTZ WB: The nature of the
SCRUTTON MC, UTTER ME: The regulation of glycolysis and
gluconeogenesis in animal tissues. Annu Rev Biochem 37:249—302,
10.
hypoxemia and hypocapnia on CSFIHI and ventilation
in man. J Appl Physiol 38:665—674, 1975
30. DILL DB, TALBOTT ill, CoNsoLAzIo WV: Blood as a physicochemical system. XII. Man at high altitudes. I Biol Chem 118:649—
Edinburgh, London, Churchill Livingstone, 1978, chapter 3, pp
5.
1966
29. DEMPSEY JA, FOR5TER HV, GLEDHILL N, D0PIC0 GA: Effects of
36.
in the plasma
gap during chronic metabolic acid-base disturbances. Am I
Physiol 235:F291—F297, 1978
ADROGUE Hi, MAmAs NE, COHEN ii: The
influence of acute and
chronic hypocapnia on acid-base equilibrium in dogs with chronic
metabolic alkalosis (abstract). Clin Res 26:455A, 1978
37. GRAHAM T, WILSON BA, SAMPLE M, VANDIJK i, BONEN A: The
effects of hypercapnia on metabolic responses to progressive
exhaustive work. Med Sci Sports Exerc 12:278—284, 1980
38. GRAHAM TE, WILSON BA, SAMPLE M, DuK JV, G05LIN B: The
effects of hypercapnia on the metabolic response to steady-state
exercise, Med Sci Sports Exerc 14:286—291, 1982
39. MCCARTNEY N, HEIGENHAU5ER GTE, ioNEs NL: Effects of pH
771
Lactic acidosis
on maximal power output and fatigue during short-term dynamic
exercise. JAppi Physiol (Resp Environ Exerc Physiol) 55:225—229,
1983
40. EHRSAM RE, HEIGENHAU5ER GJF, JONES NL: Effect of respira-
tory acidosis on metabolism in exercise. J App! Physiol (Resp
Environ Exerc Physiol) 53:63—69, 1982
JT, COHEN JJ: Metabolic acidosis, in Acid-Base,
edited by COHEN JJ, KASSIRER JP, Boston, Little, Brown, 1982,
chapter 8, pp 140—149
66. KREISBERG RA: Glucose-lactate inter-relations in man. N Engl J
65. HARRINGTON
Med 287:132—137, 1972
67. WOLL PJ, RECORD CO:
Lactate elimination in man: Effects of
lactate concentration and hepatic dysfunction. Eur J Clin Invest
41. SUTTON JR, JONES NL, TOEWS CJ: Effect of pH on muscle
glycolysis during exercise. Clin Sci 61:33 1—338, 1981
42. ABU-ROMEH S, TANNEN RL: Amelioration of lactic acidosis by
9:397—404, 1979
68.
superimposed respiratory or inorganic metabolic acidosis. Proc
COHEN JJ, KAMM DE: Renal metabolism: Relation to renal
function, in The Kidney, edited by BRENNER BH, RECTOR FC JR,
Philadelphia, Saunders, 1981, vol 1, pp 144—248
Am Soc Nephro! 17:32A, 1984
43. FRALEY DS, ADLER S, BURNS FJ, ZErr B: Stimulation of lactate
69. ORRINGER CE, EUSTACE JC, WUNSCH CD, GARDNER LB: Natural
production by administration of bicarbonate in a patient with a
history of lactic acidosis after grand-mal seizures. N Engi J Med
solid neoplasm and lactic acidosis. N Engi J Med 303:1100—1102,
1980
44. FIELDS AL, WALMAN SL, HALPERIN ML: Chronic lactic acidosis
297:796—799, 1977
70. LLOYD MH, ILE5 RA, SIMPSON BR, STRUNIN JM, LAYTON JM,
COHEN RD: The effect of simulated metabolic acidosis on intracel-
in a patient with cancer: Therapy and metabolic consequences.
lular pH and lactate metabolism in the isolated perfused rat liver.
Clin Sci Mo! Med 45:543—549, 1973
Cancer 47:2026—2029, 1981
45. BERRY MN, SCHEUER J: Splanchnic lactic acid metabolism in
71. WOODS HF, KREBS HA: Lactate production in the perfused rat
hyperventilation, metabolic alkalosis and shock. Metabolism
liver. Biochem J 125:129—139, 1971
72. BRAND PH, COHEN JJ, BIGNALL MC: Independence of lactate
16:537—547, 1967
oxidation from net Na reabsorption in dog kidney in vivo. Am J
46. ARIEFF A, KERIAN A: Lactic acidosis: An experimental model.
Metabolism 25:307—312, 1976
47. ARIEFF A, LEACH WJ, LAZAROWITZ VC: Effects of NaHCO3 in
Physiol 227:1255—1262, 1974
73. DIES F, VALDEZ
14:645, 1978
48. ARIEFF Al, LEACH W, PARK R: Production and recovery from
type A hypoxic lactic acidosis: Studies on mechanisms (abstract).
Clin Res 30:522A, 1982
49, ARIEFF Al, LEACH WJ, PARK R, LAZAROWITZ VC: Systemic
effects of NaHCO3 in experimental lactic acidosis in dogs. Am J
Physiol 242:F586—F591, 1982
50. LEACH WJ, ARIEFF Al: Systemic effects of bicarbonate in experi-
mental lactic acidosis in diabetic rabbits (abstract). Clin Res
29:411A, 1981
51. GRAF H, LEACH W, ARIEFF Al: Evidence for a detrimental effect
of bicarbonate therapy in hypoxic lactic acidosis. Science
227:754—756, 1985
PARK R, ARIEFF A!: Treatment of lactic acidosis with dichloroacetate in dogs. J Clin Invest 70:853—862, 1982
53. Hoor VL, DANFORTH E JR, HORTON ES, TANNEN RL: Impact of
hydrogen ion on fasting ketogenesis: Feedback regulation of acid
production. Am J Physiol 242:F238—F245, 1982
54. Hooc VL: pH regulation of endogenous acid production in
subjects with chronic ketoacidosis. Am J Physiol 249:F220—F226,
240:F343—F351, 1981
74. ROWELL LB, KEANING KK, EVANS TO, KENNEDY JW, BLACK-
MON JR, KUSUMI F: Splanchnic removal of lactate and pyruvate
during prolonged exercise in man. J App! Physiol 21:1773—1778,
1966
75. COHEN RD: Some acid problems. J Roy Coi Phys Lond 16:69—77,
1982
76. YUDKIN J, COHEN RD: The effect of acidosis on lactate removal
by the perfused rat kidney. C!in Sd Mo! Med 50:185—194, 1976
77. BERRY MN: The liver and lactic acidosis. Proc Roy Soc Med
60:1260—1262, 1967
78. SESTOFT L, TRAP-JENSEN J, LYNGSdE J, CLAUSEN JP, HOLST JJ,
NIELSEN SL, REHFELD JF, SCHAFFALITZKY DE MUCKADELL 0:
Regulation of gluconeogenesis and ketogenesis during rest and
exercise in diabetic subjects and normal men. Clin Sc! Mol Med
52.
53:411—418, 1977
79. AHLBORG G, FELIG P, HAGENFELDT
Substrate turnover
L, HENDLER R, WAHREN J:
during prolonged exercise
in man. J Clin invest
53:1080—1090, 1974
80. AHLBORG G, FELIG P: Lactate and glucose exchange across the
1985
forearm, legs, and splanchnic bed during and after prolonged leg
exercise. J Clin Invest 69:45—54, 1982
55. STAUBLI C: Beitrage zur Pathologic und Therapie des Diabetes
Mellitus. Dtsch Arch Kiln Med 93:107—160, 1908
56. ADLERSBERG D: Acetonurie und acidose. Biochem Z 143:527—532,
JM, VILET R, GARZA R: Lactate oxidation and
sodium reabsorption by dog kidney in vivo. Am J Physiol
therapy of experimental lactic acidosis (abstract). Kidney mt
HERMANSEN L, STENSVOLD I: Production and removal of lactate
during exercise in man. Acta Physiol Scand 86:191—201, 1972
1923
82. BARON PG, ILES RA, COHEN RD: Effect of varying pCO2 on
57. MACKAY EM, WICK AN, CARNE HO, BARNUM CP: The influence intracellular pH and lactate consumption in the isolated perfused
of alkalosis and acidosis upon fasting ketosis. JBiol Chem 138:63—
rat liver. Ciin Sd 55:175—181, 1978
83. HEMS R, Ross BD, BERRY MN, KREBS HA: Gluconeogenesis in
68, 1941
the perfused rat liver. Biochem J 101:284—292, 1966
58. STINEBAUGH BJ, MARLI55 EB, GOLDSTEIN MB, Fox IH,
84. ILES RA, COHEN RD, RIsr AH, BARON PG: The mechanism of
SCHLOEDER FX, HALPERIN ML: Mechanism for the paradoxical
inhibition by acidosis of gluconeogenesis from lactate in rat liver.
aciduria following alkali administration to prolonged-fasted patients. Metabolism 24:915—922, 1975
BiochemJ 164:185—191, 1977
85. ILES RA, COHEN RD, BARON PG: The effect of combined ischae59. Hooc VL, LAGRANGE BM: pH regulation of ketoacid production
mia and acidosis on lactate uptake and gluconeogenesis in the
contributes to acid-base homeostasis in rats (abstract). Clin Res
perfused rat liver. C!in Sci 60:537—542, 1981
33:486A, 1985
86. ILE5 RA, COHEN RD, BARON PG, SMITH JA, HENDERSON RM:
60. OsNEs J-B, HERMANSEN L: Acid-base balance after maximal
The effect of adrenaline on hepatic lactate uptake in the acidotic
exercise of short duration. J App! Physiol 32:59—63, 1972
partially ischaemic rat liver. Ciin Sc! 60:543—548, 1981
61. SAHLIN K: Intracellular pH and energy metabolism in skeletal
87. COHEN JJ, MERKENS LS, PETERSON OW: Relation of Na reabmuscle of man, with special reference to exercise. Acta Physiol
sorption to utilization of 02 and lactate in the perfused rat kidney.
Scand (Suppl 455): 1—56, 1978
Am J Physiol 238:F4l5—F427, 1980
62. NAYLOR JM, KRONFELD DS, FREEMAN DE, RICHARDSON D:
88. SPITZER JJ: Effects of lactate infusion on canine myocardial free
Hepatic and extrahepatic lactate metabolism in sheep: Effects of
fatty acid and metabolism in vivo. Am JPhysiol 226:213—217, 1974
lactate loading and pH. Am J Physio! 247:E747—E755, 1984
89. WOLFE RR, HOCHACHKA PW, TRELSTAD RL, BURKE JF: Lactate
63. CONNOR H, WOODS HF, LEDINGHAM JGG, MURRAY JD: A model
of L(+)-lactate metabolism in normal man. Ann Nutr Metab
oxidation in perfused rat lung. Am J Physiol 236:E276—E282, 1979
90. AHLBORG G, HAGENFELDT L, WAHREN J: Influence of lactate
26:254—263, 1982
infusion on glucose and FFA metabolism in man. Scand J C!in
64. COHEN RD, SIMPSON R: Lactate metabolism. Anesthesiology
43:661—673, 1975
81.
Lab Invest 36: 193—201, 1976
772
Nephrology Forum
91. FREYSCHUSS U, STRANDELL T: Limb circulation during arm and
117. ALLEYNE GAO, FLORES H, RooBoL A: The interrelationship of
leg exercise in the supine position. J App! Physiol 23:163—170,
the concentration of hydrogen ions, bicarbonate ions, carbon
1967
92. BRooKs GA, GAES5ER GA: End points of lactate and glucose
metabolism after exhausting exercise. J App! Physiol (Resp Environ Exerc Physiol) 49:1057—1069, 1980
93. BRUCE GL, YATES JW: Lactic acid infusion in dogs: Effects of
varying infusate pH. J App! Physiol (Resp Environ Exerc Physiol)
dioxide and calcium ions in the regulation of renal gluconeogenesis
in the rat. Biochem J 136:445—453, 1973
118. ALLEYNE GAO: Renal metabolic response to acid-base changes.
II. The early effects of metabolic acidosis on renal metabolism in
the rat. J Clin Invest 49:943—95 1, 1970
119. COHEN RD, WARD JD, BRAIN AJS, MURRAY CR, SAvEGE TM,
ILES RA: The relation between phenformin therapy and lactic
54:1254—1260, 1983
94. MCLANE JA, HoLLoszY JO: Glycogen synthesis from lactate in
three types of skeletal muscle. J Biol Chem 254:6548—6553, 1979
95. RECORD CO, CHASE RA, WIwAM5 R, APPLETON D: Disturbances in lactate metabolism in patients with liver damage due to
paracetamol overdose. Metabolism 30:638—643, 1981
96.
573—580, 1983
97. GEVERS W: Generation
cells. J Mo! Cell Cardiol 9:867—874, 1977
Biochem 15:40—43, 1978
99. JOHNSTON DG, ALBERT KGMM: Acid-base balance in metabolic
acidosis. Clin Endocrinol Metab 12:267—285, 1983
SRIU55ADAP0RN S, COHN JN: Regional lactate metabolism in
clinical and experimental shock. Circulation (suppl VI)37: 187,
1968
101. ARIEFF Al, PARK R, LEACH W: Pathogenesis of lactic acidosis in
dogs (abstract). Kidney mt 21:143, 1982
ELDRIDGE FL: Relationship between lactate turnover rate and
blood concentration in hemorrhagic shock. JAppl Physiol 37:321—
323, 1974
103. ARIEFF Al, PARK R, LEACH WJ, LAZAROWITZ VC: Pathophysiol-
ogy of experimental lactic acidosis in dogs. Am J Physiol
239:F135—F142, 1980
104.
TASHKIN DP, GOLDSTEIN PJ, SIMMONS DH: Hepatie lactate
uptake during decreased liver perfusion and hypoxemia. Am J
Physiol 223:968—974, 1972
SCHIMASSEK H: Lactate metabolism in the isolated perfused rat
liver. Ann NYAcadSci 119:1013—1028, 1965
106. ILEs RA, BARON PG, COHEN RD: The effect of reduction of
perfusion rate on lactate and oxygen uptake, glucose output and
105.
energy supply in the isolated perfused liver of starved rats,
Biochem J 184:635—642, 1979
107. NELIMARKKA 0: Renal oxygen and lactate metabolism in hemor-
rhagic shock: An experimental study. Acta Chir Scand
(suppl)518:1—44, 1984
108. NELIMARKKA 0, HALKOLA L, NIINIKOSKI J: Renal hypoxia and
lactate metabolism in hemorrhagic shock in dogs. Crit Care Med
12:656—660, 1984
109.
ethyl biguanide in vivo and in vitro on gluconeogenesis and
ammonia production in rats. Clin Sci 40:107—115, 1971
122. LoFT D, DEICHSEL G, SCHMULLING R-M, STEIN W, EGGSTEIN
M: Definition of clinically relevant lactic aeidosis in patients with
internal diseases. Am J Clin Pathol 80:484—489, 1983
of protons by metabolic processes in heart
98. ZILvA JF: The origin of acidosis in hyperlactataemia. Ann Clin
102.
121. ALLEYNE GAO, BESTERMAN HS, FLORES H: The effect of phenyl
ARIEFF Al, GERTZ EW, PARK R, LEACH W, LAZAROWITZ VC:
Lactic acidosis and the cardiovascular system in the dog. Clin Sd
100.
120.
ILE5 RA, BARON RG, COHEN RD: Mechanism of the effect of
varying pCO2 on gluconeogenesis from lactate in the perfused rat
liver. Clin Sci Mo! Med 55:183—188, 1978
110. FINE A, BROSNAN JT, HERZBERG GR: Release of lactate by the
liver in metabolic acidosis in vivo. Metabolism 33:393—396, 1984
111. KLEINEKE J, SOLING HD: Comparative studies with pyruvate
carboxylase from rat and guinea pig liver, in Regulation of
Gluconeogenesis, edited by SOLING HD, WILLMS B, New York,
London, Academic Press, 1971, pp 20—24
112. GOOnYER AVN, ECKHARDT WE, O5TBERG RH, G00DKIND MJ:
Effects of metabolic acidosis and alkalosis on coronary blood flow
123. MADIAS NE, HOMER SM, JOHNS CA, COHEN JJ: Hypochloremia
as a consequence of anion gap metabolic acidosis. fLab Clin Med
104:15—23, 1984
124. RELMAN AS: Lactic acidosis.
200:628—632, 1961
The effect of changes in lactate uptake on the intracellular pH of
the perfused rat liver, Clin Sci 41:159—170, 1971
116. LLOYD MH, ILE5 RA, WALTON B, HAMILTON CA, COHEN RD:
Effect of phenformin on gluconeogenesis from lactate and intracellular pH in the isolated perfused guinea pig liver. Diabetes 24:6 18—
624,
1975
Trans
Am Clin Climatol Assoc
82:70—76, 1970
125.
FULOP M: The ventilatory response in severe metabolic acidosis.
Clin Sci Mol Med 50:367, 1976
126. EHLERS SM, PETZEL RA, BROWN DC: Ventilatory response in
lactic acidosis and diabetic ketoacidosis. Miner Electrolyte Metab
3:200, 1980
127. FULOP M: Ventilatory response in patients with acute lactic
acidosis. Crit Care Med 10:173—175, 1982
128. P0K0R5KI M, LAHIRI 5: Aortic and carotid chemoreceptor responses to metabolic aeidosis in the cat. Am f Physiol 244:R652—
R658, 1983
129. PERRET C, ENRICO JF: Lactate in acute circulatory failure, in
Lactate in Acute Conditions, edited by PERRET C, BOSSART H,
Basel, Karger, 1978, pp 69—82
130. OSTER JR, PEREZ GO, VAAMONDE CA: Relationship between
blood pH and potassium and phosphorus during acute metabolic
acidosis. Am J Physiol 235:F345—F351, 1978
131. OSTER JR, PEREZ GO, CASTRO A, VAAMONDE CA: Plasma
potassium response to acute metabolic acidosis induced by mineral and nonmineral acids. Miner Electrolyte Metab 4:28—36, 1980
132. ADROGUE HJ, MADIA5 NE: Changes in plasma potassium concentration during acute acid-base disturbances. Am f Med 71:456—
467,
1981
133. PEREZ
GO, O5TER JR, VAAMONDE CA: Serum potassium concen-
tration in acidemic states. Nephron 27:233—243,
134.
1981
PEREZ GO, KEM DC, O5TER JR, VAAMONDE CA: Effect of acute
metabolic acidosis on the renin-aldosterone system. Mechanism of
increases in plasma aldosterone in dogs infused with lactic acid. f
Lab Clin Med 96:371—378, 1980
135. FULOP M: Lactic aeidosis. NY State f Med 82:712—717, 1982
136. FULOP M: Serum potassium in lactic acidosis and ketoacidosis. N
Engl J Med 300:1087—1089, 1979
137. TRANQUADA RE, GRANT WJ, PETERSON CR: Lactic acidosis.
Arch Intern Med 117:192—202, 1966
138. O'CONNOR LR, KLEIN KL, BETHUNE JE: Hyperphosphatemia in
lactic acidosis. N EngI J Med 297:707—709, 1977
139. O5TER JR, ALPERT HC, VAAMONDE CA: Effect of acid-base
Status on plasma phosphorus response to lactate. Can J Physiol
and myocardial metabolism in the intact dog. Am J Physiol
113. YUDKIN J, COHEN RD, SLACK B: The haemodynamic effects of
metabolic acidosis in the rat. Clin Sci Mol Med 50:177—184, 1976
114. M0N50N JP, SMITH JA, COHEN RD, ILE5 RA: Evidence for a
lactate transporter in the plasma membrane of the rat hepatocyte.
Clin Sci Mo! Med 62:411—420, 1982
115. COHEN RD, ILES RA, BARNETT D, HOWELL MEO, STRUNIN J:
acidosis. Diabetologia 9:43—46, 1973
MEYER F, IPAKTCHI M, CLAUSER H: Specific inhibition of gluconeogenesis by biguanides. Nature 213:203—204, 1967
140.
Pharmacol 62:939—942, 1984
YU TF, SIROTA JH, BERGER L, HALPERIN M, GUTMAN AB:
Effect of sodium lactate infusion on urate clearance in man. Proc
Soc Exp Biol Med 96:809, 1957
141. MARLI55 EB, A0KI TT, TOEWS CJ, FELIG F, CANNON JJ, KYNER
J, HUCHABEE WE, CAHILL GE JR: Amino acid metabolism in
lactic acidosis. Am J Med 52:474—481, 1972
142. PARK R, ARIEFF Al: Lactic acidosis: Current concepts. Clin
Endocrinol Metab 12:339—358,
143.
1983
HARDAWAY RM III: Metabolic acidosis produced by vasopressors. Surg Gynecol Obstet 151:203—204, 1980
144. MACKLEM PT: The
Med 99:601—610,
diaphragm in health and disease. J Lab
1982
Clin
773
Lactic acidosis
145. NARINS RG, JONES ER, DORNFELD LP: Alkali therapy of the
organic acidoses: A critical assessment of the data and the case for
judicious use of sodium bicarbonate, in Controversies in Nephrology and Hypertension, edited by NARINS RG, New York, Edinburgh, London, Churchill Livingstone, 1984, chapter 10, pp 359—
376
146. NARINS RG, BASTL CP, RUDNICK MR, JAVAHERI S, STOM MC,
JONES ER: Acid-base metabolism, in Current Nephrology, edited
169. TOBIN M, MOOKERJEE BK: Hemodialysis for phenformin associated lactic acidosis. J Dial 2:273—285, 1978
170. YATANI A, FUJINO T, KINOsHITA K, GoTo M: Excess lactate
modulates ionic currents and tension components in frog atrial
muscle. J Mo! Cell Cardiol 13:147—161, 1981
171. JuRKowITz M, Scorr KM, ALTSCHULD RA, MEROLA AJ, BRIER-
LEY GP: Ion transport by heart mitochondria: Retention and loss
of energy coupling in aged heart mitochondria. Arch Biochem
by G0NIcK HC, New York, 1982, Wiley, volume 5, chapter 3, pp
Biophys 165:98—1 13,
147. MITCHELL JH, WILDENTHAL K, JOHNSON RL JR: The
effects of
acid-base disturbances on cardiovascular and pulmonary function.
Kidney mt 1:375—389, 1972
148. CluE Si, WILDENTHAL K, ADCOCK R, TEMPLETON G, WILLER-
dehydrogenase in heart muscle. Recent Adv
Cardiac Struct Metab 12:175—182, 1978
173. FINCH CA, GOLLNICK PD, HLASTALA MP, MILLER LR, DILLMANN E, MACKLER B: Lactic acidosis as a result of iron deficienglyceraldehyde-3-P
Stud
cy. J Clin
SON J:
Inhibition of inotropic effect of hypersomotic mannitol by
lactate in vitro, Am JPhysiol 231:1209—1213, 1976
149. DAVIES
AO:
Rapid desensitization and uncoupling
adrenergic receptors in an in vitro model
Endocrinol Metab 59:398—405, 1984
150.
174.
653, 1973
175. CRABB DW, YOUNT EA, HARRIS RA:
DAVIDOFF F: Guanidine derivatives in medicine. N EngI J Med
dichioroacetate. Metabolism
176.
ADROGUE Hi, BRENSILVER J, COHEN JJ, MADIAS NE:
Invest 64:129—137, 1979
WHITEHOUSE 5, RANDLE PJ: Activation of pyruvate dehydrogen-
ase in perfused rat heart by dichioroacetate. Biochem
of human 13-
of lactic acidosis. J Clin
289:141—145, 1973
151.
1974
172. MOCHIZUKI 5, KOBAYASHI K, NEELY JR: Effects of L-lactate on
79—130
Influence
J 134:651—
The metabolic effects of
30:1024—1039, 1981
STACPOOLE PW, FELTS JM: Diisopropylammonium dichloroacetate (DIPA) and sodium dichloroacetate (DCA): Effect on glucose
steady-state alterations in acid-base equilibrium on the fate of
administered bicarbonate in the dog. J Clin Invest 71:867—883,
in normal and diabetic tissue. Metabolism
of
and fat metabolism
1983
19:71, 1970
BLACKSHEAR-PJ, HOLLOWAY PAH, ALBERTI KGMM: The meta-
177.
RL, WEISFELDT ML: Sodium bicarbonate administration
during caridac arrest. JAMA 235:506, 1976
153. VAZIRI ND, NESS R, WELLIKSON L, BARTON C, GREEP N:
Bicarbonate-buffered peritoneal dialysis: An effective adjunct in
the treatment of lactic acidosis. Am J Med 67:392—396, 1979
bolic effects of sodium dichioroacetate in the starved rat. Biochem
152. BIsHoP
J 142:279—286, 1974
178.
interaction of dichloracetate and insulin in experimental diabetic
ketoacidosis: Studies on whole animals and after functional hepa-
154. GUDIS SM, MANGI S, FEINROTH M, RuBIN JE, FRIEDMAN EA,
BERLYNE GM:
Rapid correction of severe lactic acidosis with
tectomy. Biochem J 146:447, 1975
179.
tion. Nephron 33:65—66, 1983
RC, CLARK JK: The
acute effects in man of
Metabolism 29:997—1002, 1980
180. STACPOOLE PW, MooRE GW, KORNHAUSER DM: Metabolic ef-
fects of dichioroacetate in patients with diabetes mellitus and
a rapid intravenous infusion of hypertonic sodium bicarbonate
solution.
H. Changes
in respiration and output of carbon dioxide. J
Clin Invest 35:245—253, 1956
156. OSTREA EM, ODELL GB: The influence of bicarbonate administra-
tion on blood pH in a "closed system": Clinical implications. J
Pediatr 80:671—680, 1972
hyperlipoproteinemia. N Eng! J Med 298:526—530, 1978
181. HOLLOWAY PAH, ALBERTI KGMM: Phenformin-induced lactic
acidosis: Prevention by dichioroacetate. C/in Sd Mo! Med 50:33,
1976
182. LOUBATIERES
KOPYT N, JONES ER, NARINS RG: Tissue 02
delivery is stable despite rapid correction of chronic metabolic acidosis (abstract). Proc Am Soc Nephrol 15: 136A, 1982
157. BENJAMIN
HULTER NH, GLYNN RD. SEBASTIAN A: Renal and systemic acid-
base effects of chronic dichloracetate administration in dogs.
massive isotonic bicarbonate infusion and simultaneous ultrafiltra-
155. SINGER RB, DEERING
BLACKSHEAR Pi, HOLLOWAY PAH, ALBERTI KGMM: Metabolic
AL, RIBES G, VALETTE G: Reduction par le dich-
loroacétate de sodium et par l'insuline des hyperlactatémies
i,
graves consecutives chez Ic Chien anesthésié ou éveillé a l'administration de phenformine. C R Acad Sci [D] (Paris) 284:325—327,
MI5BIN RI: Phenformin-associated lactic acidosis: Pathogenesis
and treatment. Ann Intern Med 87:591—595, 1977
159. DEMBO Ai, MARLISS EB, HALPERIN ML: Insulin therapy in
phenformin-associated lactic acidosis. Diabetes 24:28—35, 1975
1977
183. SCHEID J, ABU-ROMEH 5, TANNEN RL: Effect of Na dichloroace-
160. COLEMAN RA, SOMMERvILLE HM, FRIEDMAN HS, FALLETTA
JM, KINNEY TR: Insulin therapy for ketolactic acidosis complicat-
184.
158.
ing malignancy. J Pediatr
100:584—587, 1982
TARADASH MR, JACOBSON LB: Vasodilator therapy of idiopathic
lactic acidosis. N Eng! J Med 293:468—471, 1975
162. MASON DT: Afterload reduction and cardiac performance: Physio161.
logic basis of systemic vasodilators as a new approach to treatment of congestive heart failure. Am J Med 65:106—125, 1978
163. BREzI5 M, ROWE M, SHALER 0: Reversal of lactic acidosis
associated with heart failure by nitroprusside administration. Br
MedJ 1:1399—1400,
tate in hypoxic lactic acidosis in rats. Proc Am Soc Nephrol
1979
185.
17:54A, 1984
GRAF H, LEACH W, ARIEFF Al: Effects of dichloroacetate in the
treatment of hypoxic lactic acidosis in dogs. J Clin Invest 76:919—
923, 1985
STACPOOLE PW, HARMAN EM, CURRY SH, BAUMGARTNER TG,
MI5BIN RI:
Engi J
Treatment of lactic acidosis with dichloroacetate. N
Med 309:390—396, 1983
186. MjØs OD, MILLER NE, RIEMERSMA RA, OLIVER MF: Effects of
dichioroacetate on myocardial substrate extraction, epicardial STsegment elevation, and ventricular blood flow following coronary
occlusion in dogs. Cardiovasc Res 10:427—436, 1976
187. MCALLISTER A, ALLISON SP, RANDLE Pi: Effects of dichioroace-
164. TRANQUADA RE, BERNSTEIN 5, GRANT WJ: Intravenous methylene blue in the therapy of lactic acidosis. Arch Intern Med 114:13—
25, 1964
tate on the metabolism of glucose, pyruvate, acetate, 3-hydroxybutyrate and palmitate in rat diaphragm and heart muscle in vitro
165. MAJOOR CLH: Alcoholism as a cause of ben-ben heart disease. J
Roy CoiPhysLond 12:143—152, 1978
166. CAMPBELL CH: The severe lactic acidosis of thiamine deficiency:
acids by dog heart in vivo. Biochem
Lancet 2:446—449, 1984
167. CHALOPIN JM, TANGER Y, BESANCENOT JF, CABANNE JF, RIFLE
Acute pernicious or fulminating beriberi.
G:
and on extractions of glucose, lactate, pyruvate and free fatty
J 134:1067—1081,
1973
188. IRSIGLER K, BRANDLE J, KASPAR L, KRITZ H, LAGEDER H,
Treatment of biguanide-induced lactic acidosis with
dichloroacetate: 3 case histories. Arzneimitielforsch 29:555—559,
REGAL H:
1979
Treatment of metformin-associated lactic acidosis with closed
recirculation bicarbonate-buffered hemodialysis. Arch Intern Med
189. BLACKSHEAR Pi, FANG LS-T, AXELROD L: Treatment of severe
lactic acidosis with dichloracetate. Diabetes Care 5:391—394, 1982
144:203—205, 1984
168. FOULKS Ci, WRIGHT LF: Successful repletion of bicarbonate
190. COUDE FX, SAUDUBRAY JM, DEMAUGRE F, MARSAC C, LEROUX
stores in ongoing lactic acidosis: A role for bicarbonate-buffered
pentoneal dialysis. South Med J 74:1162—1163, 1981
JP: Dichloroacetate as treatment for congenital lactic acidosis. N
Eng! J Med 299:1365—1366, 1978
191. EVANS OB, STACPOOLE PW: Brief treatment with dichioroaceta
774
Nephrology Forum
does not modify suspected subacute necrotizing encephalomyelitis, Ann Neurol 8:647—648, 1980
192. MCKHANN G, FRANc0I5 B, EVRARD P: Long-term use of low
doses of sodium dichloroacetate in a child with congenital lactic
acidosis (abstract). Pediatr Res 14:167, 1980
193. HALWORTH JC, RoBINsoN BH, PERRY TL: Lactic acidosis due to
pyruvate carboxylase deficiency. J Inherit Metab Dis 4:57—58,
1981
194. AYNSLEY-GREEN A, WEINDLING AM, SOLTESZ 0, Ross B, JEN-
KINS PA: Dichloroacetate in the treatment of congenital lactic
acidosis. J inherit Metab Dis 7:26, 1984
204.
performance. Am J Physiol 212:917—923, 1967
SUTTON JR, JONES NL, ToEws CJ: Growth hormone secretion in
acid-base alterations at rest and during exercise. C/in Sci 50:241—
247,
1976
205. JONES NL, SUTTON JR, TAYLOR R, Toaws CJ: Effect of pH on
eardiorespiratory and metabolic responses to exercise.
Physiol (Respir Environ Exerc Physiol) 43:959—964, 1977
J
App!
206. MAINWOOD OW, WORSLEY-BROWN P, PATERSON RA: The meta-
bolic changes in frog sartorius muscles during recovery from
fatigue at different external bicarbonate concentrations. Can J
Physio!Pharmaco! 50:143—155,
1972
195. WELLS PG. MOORE OW, RABKIN D, WILKINSON OR, OATES JA,
207. HIRCHE H, HOMBACH V, LANGOHR HD, WAcKER U, BussE J:
STACPOOLE PW: Metabolic effects and pharmacokinetics of intra-
Lactic acid permeation rate in working gastrocnemii of dogs
venously administered dichloroacetate in humans. Diabetologia
during
19:109—113, 1980
metabolic alkalosis and acidosis. Pfluegers Arch 356:209—
222, 1975
196. STACPOOLE PW, MOORE OW, KORNHAUSER DM: Toxicity of
chronic dichloroacetate. N Engi J Med 300:372, 1979
208. SPENCER TL, LEHNINGER AL: L-lactate transport in Ehrlich
197. EICHENHOLZ A, MULHAUSEN RU, ANDERSON WE, MACDONALD
209, NADIMINTI Y, WANG JC, CHOU S-Y, PINELES E, TOBIN MS:
FM: Primary hypocapnia: A cause of metabolic acidosis. J Appi
Lactic acidosis associated with Hodgkin's disease: Response to
Physiol 17:283, 1962
198. ENGEL K, KILDEBERG P, WINTERS RW: Quantitative displacement of blood acid-base Status in acute hypocapnia. Scand J C/in
210. GROSSMAN L, HOLLOWAY R, D'COSTA M, RONCARI D, LAZAROVITS A, BAKER M, PANTALONY D: Lactic aeidosis in a patient with
Lab invest 23:5, 1969
199. ADROGUE HJ, CHAP Z, ISHIDA T, FIELD JB: Role of the endocrine
pancreas in the kalemic response to acute metabolic acidosis in
ascites-tumour cells. Biochem J 154:405—414, 1976
chemotherapy. N Eng! J Med 303:15—17,
1980
acute leukemia. C/in invest Med 6:85—88, 1983
211. SCULlER JP, NICAISE C, KLASTERSKY J: Lactic acidosis: A
metabolic complication of extensive metastatic cancer. Eur J Can
conscious dogs. J C/in Invest 75:798—808, 1985
200. COHEN RD, SIMPSON BR, GOODWIN FJ, STRUNIN L: The early
C/in Onco! 19:597—601, 1983
212. WATERS WC III, HALL JD, SCHWARTZ WB: Spontaneous lactic
effects of infusion of sodium bicarbonate and sodium lactate on
intracellular hydrogen ion activity in dogs. C/in Sci 33:233—247,
acidosis: The nature of the acid-base disturbance and consider-
1967
201. PooLE-WILsoN PA, CAMERON IR: Intracellular pH and K of
cardiac and
skeletal muscle in acidosis and alkalosis. Am J Physiol
229:1305—1310, 1975
202. ANDERSON LG, SNYDER DD, CAMPBELL FS: Effects of sodium
bicarbonate on myocardial contractile
Surg Forum 14:287—289, 1963
203. CLANCY
force and cardiac output.
RL, CINGOLANI HE, TAYLOR RR, GRAHAMTP
JR,
GILMORE JP: Influence of sodium bicarbonate on myocardial
ations in diagnosis and management. Am J Med 35:781—793, 1963
213. FULOP M, HOaERMAN HD: Is lactic acidosis "spontaneous"? NY
State J Med 77:24—26, 1977
214. PHILLIP50N EA, SPROULE BJ: The clinical significance of elevated
blood lactate. Can Med Assoc J 92:1334, 1965
215. LUFT D, SCHMULLING R-M, EGG5TEIN M: Lactic aeidosis in
biguanide treated diabetics: a review of 330 cases. Diabetologia
14:75—87, 1978
216, OLIvA PB, SCHWARTZ HA: Survival
lactic acidosis.
Ann
of a patient
intern Med 71:587,
1969
with spontaneous