1. health and fitness
2. disease

REVIEWS
Treatment of acute metabolic acidosis:
a pathophysiologic approach
Jeffrey A. Kraut and Nicolaos E. Madias
Abstract | Acute metabolic acidosis is associated with increased morbidity and mortality because of its
depressive effects on cardiovascular function, facilitation of cardiac arrhythmias, stimulation of inflammation,
suppression of the immune response, and other adverse effects. Appropriate evaluation of acute metabolic
acidosis includes assessment of acid–base parameters, including pH, partial pressure of CO 2 and HCO3–
concentration in arterial blood in stable patients, and also in central venous blood in patients with impaired
tissue perfusion. Calculation of the serum anion gap and the change from baseline enables the physician to
detect organic acidoses, a common cause of severe metabolic acidosis, and aids therapeutic decisions. A
fall in extracellular and intracellular pH can affect cellular function via different mechanisms and treatment
should be directed at improving both parameters. In addition to supportive measures, treatment has included
administration of base, primarily in the form of sodium bicarbonate. However, in clinical studies of lactic
acidosis and ketoacidosis, bicarbonate administration has not reduced morbidity or mortality, or improved
cellular function. Potential explanations for this failure include exacerbation of intracellular acidosis, reduction
in ionized Ca2+, and production of hyperosmolality. Administration of tris(hydroxymethyl)aminomethane
(THAM) improves acidosis without producing intracellular acidosis and its value as a form of base is worth
further investigation. Selective sodium–hydrogen exchanger 1 (NHE1) inhibitors have been shown to improve
haemodynamics and reduce mortality in animal studies of acute lactic acidosis and should also be examined
further. Given the important effects of acute metabolic acidosis on clinical outcomes, more intensive study of
the pathogenesis of the associated cellular dysfunction and novel methods of treatment is indicated.
Kraut, J. A. & Madias, N. E. Nat. Rev. Nephrol. 8, 589–601 (2012); published online 4 September 2012; doi:10.1038/nrneph.2012.186
Introduction
Acute metabolic acidosis is common in seriously ill
patients, 1 and when severe, can be associated with a
poor clinical outcome.1,2 Thus, rapid recognition of this
acid–base disorder and provision of effective therapy
are essential. Although disorder-specific therapy can be
efficacious in certain types of metabolic acidosis, such as
ketoacidosis or toxic alcohol ingestions,3 therapy is often
ineffective in other types, such as lactic acidosis.4
In this Review, we summarize the current approach
to the treatment of acute metabolic acidosis. We highlight the evidence for and against base therapy and
present evidence for the potential benefits of newer
targeted therapies that has been derived from advances
in the understanding of the pathophysiology of cellular
dysfunction.
Definition of acute metabolic acidosis
Acute metabolic acidosis has arbitrarily been defined as
an acid–base disorder initiated by a primary reduction in
serum HCO3– concentration and lasting a few minutes to
a few days. This definition differentiates it from chronic
metabolic acidosis, which is said to last weeks to years.5
Competing interests
The authors declare no competing interests.
Nonetheless, the time frame of acute metabolic acidosis
encompasses a sufficiently long period during which an
array of alterations in cellular function can occur even
in the absence of changes in the severity of the acidosis.
These alterations can affect the nature of the associated
adverse events and the response to therapy. There­
fore, an improved understanding of the time dependency of various cellular events occurring during acute
metabolic acidosis could result in the development of a
structured approach to treatment at various time points
of the disorder.
For purposes of assessing its severity, metabolic acid­
osis has been divided into three forms based on the level
of systemic arterial blood pH: mild (pH 7.30–7.36), moderate (pH 7.20–7.29), and severe (pH <7.20). Assuming
an appropriate ventilatory response, these arterial
blood pH levels are usually associated with a serum
HCO3– concentration of >20 mmol/l, 10–19 mmol/l, and
<10 mmol/l, respectively. Although this categorization is
arbitrary and its value in therapeutic decision-­making
has not been examined rigorously, it has frequently been
utilized by clinicians to make decisions about the requirement for and type of treatment. For example, clinicians
have often chosen a systemic pH of 7.20, corresponding to a serum HCO3– concentration of <10 mmol/l, as
NATURE REVIEWS | NEPHROLOGY Division of Nephrology,
Veterans Health
Administration Greater
Los Angeles Heathcare
System, 11301
Wilshire Boulevard,
Los Angeles, CA
90073, USA
(J. A. Kraut).
Department of
Medicine, Division
of Nephrology,
St Elizabeth’s Medical
Center, 736 Cambridge
Street Boston,
MA 02135, USA
(N. E. Madias).
Correspondence to:
J. A. Kraut
jkraut@ucla.edu
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REVIEWS
Key points
■■ Metabolic acidosis is a common acid–base disorder that can have a notable
impact on cellular function and can be associated with poor clinical outcomes
■■ Evaluation includes measurement of acid–base parameters in arterial blood in
stable patients, and in central venous blood in patients with markedly impaired
tissue perfusion, measurement of serum electrolytes, and calculation of anion
gap and osmolal gap
■■ As a fall in intracellular and extracellular pH affects cellular function, measures
should be taken to improve both parameters, particularly when pH is <7.1
■■ Administration of base in the form of sodium bicarbonate has not been shown
to improve cellular function or reduce mortality associated with lactic acidosis
or ketoacidosis and is associated with adverse effects
■■ Administration of other forms of base such as THAM, or use of other methods
of delivering base such as dialysis, might improve acid–base parameters
without the adverse effects of intravenous bicarbonate
■■ As acidosis could affect cellular function through additional mechanisms such
as activation of sodium–hydrogen exchanger 1, inhibition of this transporter
might be beneficial
a criterion for the urgent initiation of base therapy. The
putative justification for utilizing the level of systemic
arterial pH to initiate urgent therapy and the potential
pitfalls of such an approach will be discussed.
Epidemiology
Recognizing the disorders that commonly produce acute
metabolic acidosis is important for developing a targeted
approach to treatment. Acute metabolic acidosis occurs
most frequently in seriously ill patients, particularly
those in intensive care units (ICUs).1 The majority of
severe cases that might warrant aggressive therapy are
caused, at least in Western societies, by lactic acid­osis
or ketoacidosis.6 Thus, in one study, lactic acidosis and
ketoacidosis accounted for ~70% of patients with a blood
pH ≤7.10 and an elevated serum anion gap.7 Although
not rigorously examined, a review of the literature suggests that other organic acidoses, including those caused
by methanol, ethylene glycol, or diethylene glycol intoxication, pyroglutamic acidosis associated with acetaminophen toxicity, and salicylate intoxication account for
a minority of cases of acute metabolic acidosis.
On the other hand, non-gap (hyperchloraemic) acid­
osis have been reported to be present in between 19%1
and 45%8 of patients hospitalized in the ICU, presumed
to be caused by the administration of large quantities
of sodium chloride during treatment of hypotension.9
In both series, mortality associated with non-gap acid­
osis was lower than that associated with high anion
gap acidosis.
Some studies of acute metabolic acidosis found a
correlation between severity of acidaemia and clinical outcome,10 but other observational studies found
that clinical outcome correlated better with concentrations of unmeasured anions or serum chloride.11,12 This
finding has been interpreted by some as implying some
intrinsic detrimental effect on cellular function of certain
unmeasured anions (for example, lactate) or even chloride. The meaning and significance of these observations
are unclear.
At present, it seems most logical to utilize measures of
acidity to assess the severity of the metabolic acidosis in
590 | OCTOBER 2012 | VOLUME 8
order to determine the need for and type of therapy. Of
course, irrespective of the severity of the acute metabolic
acidosis, the clinical context of the metabolic acidosis has
important implications. For example, severe lactic acid­
osis (blood pH <7.00) can accompany vigorous exercise
or grand mal seizures without producing severe cellular
dysfunction.13 By contrast, a similar degree of acidaemia
in a patient with hypovolaemic shock or sepsis often has
dire consequences.
Monitoring the patient
The evaluation of the severity of metabolic acidosis
is usually based on examination of acid–base parameters measured in arterial blood14 or, less frequently, in
peripheral venous or arterialized venous blood.15 How­
ever, the deleterious effects of acute metabolic acidosis
on cell­ular function that necessitate treatment largely
result from events initiated by a decrease in the interstitial pH (pHe) and intracellular pH (pHi).16 Although
acid–base balance is monitored with systemic blood,
discordance between measures of tissue acidity and
acidity of systemic blood can occur under certain conditions, such as marked hypoperfusion.16–18 Moreover,
hetero­geneity can be present in the acid–base milieu
of dif­ferent cellular compartments. Therefore, it would
be ideal to directly monitor pHi (if possible in specific
cellular compartments) and pHe, or obtain surrogates
that reflect the acid–base milieu of these compartments.
Studies examin­ing these issues are in progress, but cur­
rent recom­mendations must be based on the available
monitoring modalities.
For patients with acute metabolic acidosis but stable
blood pressure and intact or only mild to moderate
decreases in tissue perfusion, measurement of acid–base
parameters in arterial blood, peripheral venous blood,
arterial­i zed venous blood, or central venous blood
can be used.14 However, under conditions of markedly
impaired tissue perfusion, as observed with circulatory
shock, acid–base parameters obtained from central
venous blood might more accurately reflect the acid–
base milieu of poorly perfused tissues, with pH being
substantially lower and partial pressure of CO2 (PCO2)
being substantially higher than in simultaneously
obtained arterial blood.17,19,20 In this regard, induction
of septic shock in rats, resulting in a fall of cardiac index
to approximately 30% of baseline, caused a threefold
increment in tissue PCO2 of liver, kidney, and brain and
a fourfold increment in veno-arterial PCO2 gradient;21
these findings show the inaccuracy of arterial blood
in reflecting the acid–base milieu of important tissues
during severe circulatory compromise.
Furthermore, administration of bicarbonate under
these conditions might produce or exacerbate the
hypercarbic acidic environment of tissues, as any CO2
generated in the process of buffering will not be easily
dissipated. In the absence of appropriate studies, the role
of central venous blood gases in managing patients with
acute metabolic acidosis remains unclear. Even if central
venous blood gases prove to be valuable in the evaluation
of certain acid–base disorders, examination of arterial
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blood gases would still be required for evaluation of gas
exchange in the lungs.
Once a diagnosis of metabolic acidosis has been made,
determining the underlying cause will be valuable in
facilitating the design of disorder-specific therapy. A
complete history and physical examination will provide
important clues. In addition, serum Na+, Cl–, and HCO3–
levels should be measured to calculate the serum anion
gap. Determination of serum K+ is also essential, as its
level can change variably with acute metabolic acidosis.
When toxic alcohol exposure is suspected, serum osmolality should be measured and serum osmolal gap calculated. If suspicion remains high, even in the absence of
suggestive changes in the osmolal gap, determination of
serum methanol and ethylene glycol might be required
to exclude these alcohols. Because ketoacidosis and lactic
acidosis are common, serum lactate, serum ketone and
urine ketone levels should be measured. In patients suspected of acetaminophen overdose, 5‑­oxo­proline (pyroglutamic acid) should be measured in urine. Serum
aldosterone should be determined in patients with
non-gap acidosis suspected of adrenal insufficiency.
Acid–base status, serum electrolyte levels, and renal
func­tion should be measured at frequent intervals, both
to monitor the course of the acidosis and to assess the
effectiveness of therapy.
Serum anion gap
The serum anion gap and the change in anion gap from
its baseline (Δanion gap) are generally useful for detecting the presence of organic acidosis and mixed metabolic
acid–base disturbances, and for assessing their severity
both at the time of diagnosis and during the course of
treatment.22,23 Indeed, assessment of the Δanion gap/
ΔHCO3– relationship will enable the clinician to identify coexisting metabolic acid–base disturbances, such
as metabolic alkalosis, which will affect treatment decisions. Serum anion gap is occasionally insensitive in the
detection of organic acidosis because of the wide range
of normal values and the variation in baseline values
between patients and clinical laboratories.24 In one study,
the serum anion gap remained within the normal range
even when serum lactate concentration rose to 5 mEq/l.25
However, measurement of serum anion gap is an inex­
pen­sive method for indirectly assessing the severity of
acid load, following the natural course of high anion
gap metabolic acidosis, and for uncovering coexist­ing
meta­bolic acid–base disorders (for example, metabolic
alkalosis or normal anion gap metabolic acidosis). Since
the serum anion gap decreases by 2.3–2.5 mmol/l for
every 1 g reduction in serum albumin concentration (and
increases by a similar amount when serum albumin is
increased), the anion gap corrected for serum albumin
should always be used.24
Detection of an elevated serum anion gap that is primarily caused by accumulation of organic anions has an
important bearing on the decision to administer base
and the quantity of base to be given. For example, in
patients with ketoacidosis or lactic acidosis, reversal of
the processes that give rise to the excessive organic acid
production can lead to rapid generation of base. When
devising a specific base prescription for these patients,
the clinician must take into account the potential influx
of base resulting from the metabolism of circulating
organic anions in addition to any base synthesized by the
kidney or given to the patient. By contrast, in the case of
non-gap acidosis, improvement in acid–base balance will
depend solely on the quantity of base administered by
the clinician and the ability of the kidneys to sy­nthesize
new bicarbonate.
Serum creatinine and eGFR
Measurement of serum creatinine level and calculation
of estimated glomerular filtration rate (eGFR) is helpful
in detecting renal failure as a contributory factor to the
generation of metabolic acidosis. Moreover, because
renal failure constrains generation of new bicarbonate
and affects the excretion of organic acid anions (potential
sources of bicarbonate) and the ability to excrete admini­
stered sodium during treatment, eGFR should always be
calculated to help tailor therapy.
PaCO2
An increase in ventilation leading to a fall in arterial
partial pressure of CO2 (PaCO2) occurs within minutes
of the reduction in serum HCO 3 – concentration,
thereby attenuating the fall in blood pH.26 Establishing
whether the PaCO2 is appropriate for the level of hypo­
bicarbonataemia is important not only diagnostically,
but also therapeutically. If PaCO2 is not appropriately
depressed, the severity of the acidaemia and intra­cellular
acidosis at a given serum HCO3– concentration would be
greater. As a result, the clinician might elect to recom­
mend base administration at a higher serum HCO 3–
concentration than usual. Furthermore, in intubated
patients, measures designed to lower PaCO 2 might be
indicated as an ancillary therapeutic strategy.
Cellular effects of metabolic acidosis
Treatment of metabolic acidosis is indicated as the dis­
order is associated with dysfunction of various important
cellular processes. Acidosis has both beneficial and deleterious effects on cellular function (Box 1). Deleterious
effects include a decrease in cardiac contractility and
cardiac output,27,28 arterial vasodilatation29 (abnormalities contributing to development of hypotension), and
a predisposition to cardiac arrhythmias, which can contribute to sudden death.30 Although sympathetic stimulation accompanies the acidosis, responsiveness to both
endogenous and infused catecholamines is attenuated.31
Generalized venoconstriction also occurs, which can
displace blood into the central circulation leading to
increased pulmonary vascular volume and pressure and
predisposing to congestive heart failure.28 Tissue oxygen
delivery is impaired and cellular ATP production is
attenuated—two factors that will compromise important
organ functions.32 In addition, the immune response and
leukocyte function are suppressed,33,34 making patients
susceptible to infection. Paradoxically, proinflammatory
cytokines are stimulated and the inflammatory response
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Box 1 | Effects of acute metabolic acidosis
Deleterious effects
■■ Decreased cardiac contractility and cardiac output
■■ Predisposition to cardiac arrhythmias
■■ Peripheral vasodilatation
■■ Hypotension
■■ Decreased tissue oxygen delivery
■■ Decreased ATP generation
■■ Impairment in glucose regulation
■■ Stimulation of inflammatory mediators
■■ Impairment of the immune response
■■ Impaired phagocytosis
■■ Increased apoptosis
Beneficial effects
■■ Decreased affinity of haemoglobin for oxygen with
increased tissue oxygen delivery
■■ Vasodilatation of vessels with increased blood flow
to tissues
■■ Increased ionized Ca2+ with augmented myocardial
contractility
increases.35 Apoptosis in various tissues is enhanced, fur­
ther contributing to general organ dysfunction.36 Poten­tial
beneficial effects of acidosis include decreased haemo­
globin affinity for oxygen with increased oxygen deliv­ery,
vasodilatation with increased blood flow, and increased
ionized Ca2+ with enhanced myocardial contractility.28
Of the adverse effects on cellular function, the cardiovascular abnormalities seem to be the most influential
in affecting clinical outcome. Studies of phenformininduced lactic acidosis in dogs37 and in humans38 demon­
strated a marked reduction in cardiac index (~50%)
associated with a blood pH <7.10. Animal studies in
which systemic pH was reduced by infusion of lactic acid
(a model that does not share all of the abnormalities of
cellular function observed with hypoxic lactic acidosis
despite the presence of severe acidaemia) revealed that
as systemic pH fell from 7.40 to 7.20, cardiac output
actually rose; however, when pH fell below 7.20, cardiac
output began to fall.27 The initial rise in cardiac output
was prevented by pre-administration of β‑blockers, so
was probably caused by an endogenous catecholamine
surge. Also, in HCl-induced metabolic acidosis in rats,
blood pressure remained unchanged until systemic pH
fell to ~7.20.39 Factors contributing to cardiac arrhythmias are also more prominent when acidaemia is severe
(that is, pH ≤7.10).30 As similar studies demonstrating a strict relationship between blood pH level and
cardiac function impairment in humans are not available, clinicians have extrapolated from these observations in animals to provide the rationale for choosing a
systemic pH of 7.10–7.20 as the threshold for initiating
base therapy. Of course, the clinical context in which
acute metabolic acidosis arises is often much more
complex than in these experimental models. Also, the
patient often has several important comorbidities that
can modify the response to the acidosis. However, in
the absence of available studies that better mimic the
clinical situation, information derived from the animal
ex­periments must guide therapy.
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Mechanisms of cellular dysfunction
When selecting an appropriate therapeutic regimen
for metabolic acidosis, it is valuable to understand the
mechanisms producing cellular dysfunction as well as
the impact of various therapies on these mechanisms.
In this regard, many clinicians have presumed that the
impact of the acid load on pHi of various organs is primarily responsible for cellular dysfunction. However,
although a fall in pHi usually accompanies the development of acute metabolic acidosis, it is unclear whether
pHi remains persistently and uniformly depressed. Also,
evidence indicates that pHe alterations can have independent effects on cellular function.16 As a consequence,
although a rise in the pH of both compartments would
be beneficial, increasing pHe even in the absence of
improvement in pHi could theoretically be helpful. On
the other hand, a rise in pHe could potentially be deleterious by enhancing Na+–H+ exchange, thereby increasing
intracellular Na+ and Ca2+ concentrations. The eventual impact of changes of pHe on cellular function will
depend upon the interplay of these effects and remains
to be determined.
The available data suggest that decreases in both pHe
and pHi plays a critical role in producing cellular dysfunction (Figure 1), as will be described in more detail.
It seems that factors activated by acidosis could be targets
for treatment.
Interstitial pH
In vitro experiments have documented that a reduction in
external pH independent of any changes in pHi can have
important effects on cellular function. Such a decrease
reduces the binding of insulin40 and catecholamines41 to
their cognate receptors, attenuating the action of these
hormones. It also alters the opening of proton-gated K+
channels in both the myocardium, enhancing arrhythmo­
genicity,42–45 and in blood vessels, perhaps contributing
to their vasodilatation. These effects are most prominent
at an external pH of ≤7.10. At a much lower pH (≤6.50),
proton-gated G‑protein-coupled receptors and transient receptor potential vanilloid 1 (TRPV1) might be
activated,46 possibly contributing to cellular dysfunction.
However, given the pH level at which these receptors and
channels are activated, their actions are unlikely to have
any significant role in cellular dy­sfunction except in the
most extreme cases of lactic acidosis.
Under experimental conditions of central nervous
system (CNS) ischaemia that results in lactic acidosis,
Na+-permeable and Ca2+-permeable acid-sensing ion
channels (ASICs) are activated by the fall in external
pH and increase in lactate concentration producing
increments in the intracellular concentrations of both
cations, 47,48 which can contribute to tissue damage.
Paradoxically, a reduction in pHi actually inhibits activation of this channel.49 Reducing the activity of this
channel lessens the extent of CNS damage in various
experimental models.47 Thus, activation of this channel
could contribute to the extension of cerebral damage in
individuals with acute metabolic acidosis associated with
ischaemic insult to the CNS.
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Metabolic acidosis
pHe and/or pHi
Activity of
K+ channels
Na+-dependent
H+/base transporters
Na+
Activity of
ASIC1a
Activity of
TRPV1
Na+–Ca2+ exchange
Activity of
H+-sensing GPCR
Activity of
MAPK
Cai2+
Cellular dysfunction and injury
Figure 1 | Potential pathways through which a reduction in pHe and pHi could contribute to cellular dysfunction and injury.
The reduction in pHe and pHi associated with metabolic acidosis activates certain channels and increases the activity of
certain transporters, which can lead to deleterious increments in cellular Na + and/or Ca2+. These changes in pH also affect
the activity of enzymes that cause cellular injury. Targeting one or more of these moieties might reduce cellular injury and
be used as adjunctive therapy to amelioration of the acidosis. Abbreviations: ASIC1a, acid-sensing ion channel 1a; GPCR,
G‑protein-coupled receptor; MAPK, mitogen activated protein kinase; pHe, interstitial pH; pHi, intracellular pH; TRPV1,
transient receptor potential vanilloid receptor 1.
Simulated metabolic acidosis increased the adhesiveness of endothelial cells to leukocytes and augmented
the expression of vascular adhesion molecules,35 effects
mediated by activation of a proton-sensing G‑proteincoupled receptor (GPCR4).35 These changes were postulated as an additional mechanism whereby metabolic
acidosis could promote inflammation and tissue injury.
Intracellular pH
A relatively stable pHi of 7.10–7.30 is necessary for the
optimal function of cells.50 A reduction in pHi can impair
cellular function by several mechanisms. In myocardial
cells, it can reduce cardiac contractility by competitive
inhibition of Ca2+ binding to troponin. In myocardial
cells and in cells of other tissues, it decreases ATP production, possibly by inhibiting phosphofructokinase.32
Also, a reduction in pHi decreases potassium flux into
myocardial cells and blood vessels by reducing the
opening of pH-gated potassium channels, such as Kir,
and promotes apoptosis in myocardial and possibly
other cells either directly or acting synergistically with
hypoxia.36 The pHi at which these effects are observed
has been evaluated primarily using in vitro systems. For
several K+ channels, 50% inhibition occurs at a pH i of
6.70–7.00.51 The optimum pH for phosphofructokinase
is 7.20 and its activity is inhibited at lower values.52
In vivo studies of pHi in which acidaemia was produced by infusion of HCl or lactic acid (models of normal
anion gap and high-anion gap acidosis, respectively)
yielded minimal or no change in pHi.53 By contrast, lactic
acid­osis produced by ischaemia caused profound reductions in pHi.54 The stabilization of pHi despite persistent
acidaemia with some models of metabolic acidosis suggests that myocardial dysfunction might be related to
additional factors (such as activation of NHE1, as will
be discussed) besides a lingering reduction in pHi.
In this regard, a reduction in pHi also activates several
regulatory H+/base transporters, including the Na+–H+
exchanger 1, NHE1, the Na+–HCO3– co-transporter,
NBC1, and H+–ATPase;55,56 such activation is designed
to return pHi to baseline levels. In the presence of lactic
acidosis, a monocarboxylic proton transporter, which
transports lactate and a proton,56 is also active. Activation
of the Na+-dependent transporters causes an increase in
the cellular concentration of Na+ that can produce cell
swelling. Also, the rise in cell Na+ can slow or reverse the
Na+–Ca2+ exchanger, and thereby increase the cellular
concentration of Ca2+, which is injurious to the cell. In
the heart, these changes lead to cardiac stunning and promotion of arrhythmogenicity;57 in the brain and kidney,
they can contribute to cellular injury. Reperfusion of the
myocardium after a period of ischa­emia further exacerbates the cellular injury possibly in part by raising
interstitial pH thereby accelerating Na+-dependent
H+/base transport. Normalization of pHi slows the activity of these transporters and reduces cellul­ar Na+ and
Ca2+ concentrations.
Treatment
Treatment of acute metabolic acidosis can be divided into
that specific to a particular disorder and that applicable
to all metabolic acidoses (general therapy). The benefits
and complications of the various methods designed to
improve acid–base parameters are summarized (Table 1)
and our recommendations for the treatment of various
causes of acute metabolic acidosis are shown (Boxes 2–5).
It is worth emphasizing that the value of each measure
in the treatment of acute lactic acidosis or non-gap acidosis has never been tested in randomized controlled
studies, although bicarbonate therapy has been examined in a rigo­rous fashion in the treatment of ketoacidosis. There­fore, except for the treatment of ketoacidosis, all
recommen­dations represent our opinions as gleaned from
examination of the literature and remain open to debate.
Disorder-specific therapy
In many cases, acute metabolic acidosis can be corrected with therapy tailored to the specific disorder.
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Table 1 | Base administration in the treatment of acute metabolic acidosis
Modality of base
administration
Advantages
Disadvantages
Comments
Intravenous sodium
bicarbonate
Inexpensive; simple to use
Might exacerbate intracellular
acidosis; can provide large
sodium load
Should be given slowly as isosmotic solution to
avoid hyperosmolality and minimize extent of
intracellular acidosis; estimate magnitude of
bicarbonate deficit so as to administer minimum
quantity necessary to achieve desired blood pH
Intravenous THAM
Buffers protons without generating CO2;
penetrates cells to buffer pHi
Reports of hyperkalaemia,
hypercapnia, and liver necrosis
in newborns; requires intact
renal function or dialysis
Given as 0.3 M solution (best via central vein);
serum potassium and PCO2 should be
monitored carefully during therapy
Intravenous
carbicarb
Buffers pHe and pHi without generating significant
quantities of CO2; preserves cardiac contractility
in animal studies
None
Never introduced into practice but studies to
re-examine its potential use are planned
Dialysis
Can provide large quantities of base while
preventing volume overload or hyperosmolality;
CRRT can deliver base over 24 h period at low rate
Requires use of dialysis
equipment and personnel; risk
of hypotension with procedure
Intermittent haemodialysis or CRRT modalities
can be utilized; if available, CRRT is preferred
Abbreviations: CRRT, continuous renal replacement therapy; PCO2, partial pressure of CO2; pHe, interstitial pH; pHi, intracellular pH.
For example, administration of insulin and fluids can
eliminate metabolic acidosis in most cases of ketoacid­
osis. Administration of fomepizole, an inhibitor of
alcohol dehydrogenase, and/or dialysis is effective in
the treatment of acidosis associated with toxic alcohols
such as methanol, ethylene glycol, or diethylene glycol.3
Administration of mineralocorticoid corrects acidosis
associated with adrenal insufficiency. If these approaches
are not successful, treatment with base or other general
therapies are often required.
General therapy
Sodium bicarbonate
On the basis of evidence that reductions in pHe and pHi
can cause cellular dysfunction, it seems self evident that
base therapy would be beneficial. Sodium bicarbonate is
the most common form of base recommended by physicians. However, the value of bicarbonate administration
remains controversial,4,58,59 as exemplified by the disparity
of opinion among polled nephrologists and critical care
physicians concerning its use in the treatment of acute
organic acidosis.60 In that survey, directors of nephrology
training programs were more likely than directors of critical care training programs to recommend administration
of base to patients with lactic acidosis and ketoacidosis
(86% versus 67% and 60% versus 28%, respectively). The
blood pH at which therapy should be initiated was also
a matter of controversy, with 40% of critical care physicians stating that they would give base only at a blood pH
<7.00, whereas only 6% of nephrologists stated that they
would wait until that degree of acidaemia was reached. By
contrast, the majority of both groups would administer
bicarbonate to patients with non-gap acidosis. The blood
pH at which clinicians would recommend bicarbonate
to these patients was not specified, although it is likely
to be similar to or higher than that for organic acidosis
(pH 7.10).
Clinicians offer several reasons for why they might
not routinely recommend bicarbonate administration
for lactic acidosis and ketoacidosis. First, even in the
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absence of exogenous bicarbonate, if the abnormality
producing ketoacidosis or lactic acidosis can be corrected, the organic anion(s) of the offending acid(s) will
be rapidly metabolized thereby generating equivalent
quantities of bicarbonate.
Also, data on the effect of bicarbonate administration on mortality and cardiovascular function has
been conflicting. In one small study in dogs with
­phenformin-induced lactic acidosis, bicarbonate did
not reduce mortality.61 By contrast, in a hypoxic model
of lactic acid­osis in rats,62 survival time was increased
(albeit only for a short time) but ultimate survival was
not affected. Controlled studies in humans have not been
performed. However, observational studies of patients
with diverse causes of lactic acidosis, including sepsis,
shock, and metformin toxicity, did not demonstrate that
bicar­bonate administration either prolonged survival or
reduced mortality.63,64
In terms of cardiovascular function, administration of
sodium bicarbonate to pigs with lactic acidosis induced
by lactic acid infusion did not improve cardiac contractility more than administration of similar quantities of
sodium chloride.65 Indeed, bicarbonate administration
to dogs with hypoxia-induced lactic acidosis actually
caused cardiac output to fall.66 Similarly, administration
of bicarbonate to rats with hypoxic lactic acidosis caused
a fall, albeit transient, in cardiac output.62 In studies of
patients with severe lactic acidosis due to diverse causes
(blood pH ~7.10), bicarbonate administration did not
cause a fall in cardiac output, but also did not improve
cardiac output or stabilize blood pressure more than
administration of equivalent quantities of sodium
chloride did, at least within the 30–60 min period after
infusion.67,68 On the other hand, administration of bicarbonate to individuals with heart disease (NYHA Class III
or IV congestive heart failure) but normal acid–base
parameters69 was associated with reduced myocardial
oxygen consumption, enhanced glycolysis, increased
blood lactate concentration, and in a small subgroup of
the patients, decreased cardiac output.
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Taken together, the data do not reveal any improvement in cardiac function in response to bicarbonate
administration either in animals or humans with lactic
acidosis. Indeed, under certain circumstances, it could
depress cardiovascular function. Furthermore, prolonged survival was shown in only a single rat study, and
even in that case, for less than 1 h.62
Similarly with ketoacidosis, despite theoretical reasons
indicating that bicarbonate administration would
benefit patients (for example, raising pH improves cellular responsiveness to insulin70), several retrospective
and prospective controlled studies found that addition
of bicarbonate to conventional therapy (insulin and
fluids) in patients with moderate to severe ketoacidosis (blood pH 6.80–7.00) did not improve blood pressure, accelerate the rate of recovery from ketoacidosis,
or reduce the number of days of hospitalization.4,71–73
Controlled studies of cardiovascular response to bicarbonate admini­stration in ketoacidosis have not been
performed. A single study in patients with ketoacidosis
demonstrated no increase in cardiac function after metabolic acid­osis was corrected by treatment with insulin
and fluids without bicarbonate.74
Thus, studies examining the effect of sodium bicarbonate administration on cardiovascular function and mortality in the two most common forms of acute metabolic
acidosis, when available, have not shown any beneficial
effects in humans. Unfortunately, no well-­controlled randomized studies of lactic acidosis have been performed.
Moreover, the studies examining the impact of bicarbonate on cardiovascular function in patients with lactic
acidosis involved a small numbers of patients and a very
short time frame. However, there seems to be sufficient
data in studies of ketoacidosis to indicate that bicarbonate therapy is not beneficial when blood pH is >6.80.
Studies of more severe acidaemia are limited.
The impact of bicarbonate therapy on organic acid­
osis other than ketoacidosis or lactic acidosis has not
been examined in any rigorous fashion. Although base
therapy is routinely recommended in the treatment of
many toxic alcohol ingestions, including methanol or
ethylene glycol, the benefits of this treatment remain
unclear. It has been suggested that in addition to the
expected generic benefits of base, its administration can
reduce cellular toxicity by diminishing the concentration
of the undissociated acids.75 Similarly, base therapy has
a place in the treatment of salicylate intoxication when
dialysis is not recommended. Under these circumstances,
administration of sufficient base to alkalinize the urine
(pH 7.50–8.00) will facilitate the urinary excretion of the
salicylate ion and thereby hasten recovery.
As noted, clinicians are more likely to recommend
bicarbonate administration for acute non-gap acidosis
than for organic acidoses, perhaps reflecting the perception that complications of therapy might be less frequent (although this idea has not been examined in any
rigorous fashion).60 Determining the optimal therapy
for this type of acidosis is becoming increasing important, as some studies have indicated that it occurs in
as many as 49% of patients with acidosis in the ICU. 8
Box 2 | Recommendations for treatment of lactic acidosis
■■ Actively attempt to address and/or eliminate major cause of disorder
(for example, sepsis, hypovolaemia, circulatory depression)
■■ Consider base therapy when systemic blood pH ≤7.10 or at levels ≤7.20 in the
presence of underlying cardiovascular disease or evidence of haemodynamic
compromise
■■ Calculate bicarbonate requirements using this formula: bicarbonate
requirement = desired [HCO3–] – present serum [HCO3–] × HCO3– space, where
HCO3– space = [0.4 + (2.6/[HCO3–]) × body weight (kg)
■■ To minimize potential complications of bicarbonate administration, initiate
therapy based on calculation using bicarbonate space of 50% body weight (kg);
if not successful in achieving desired serum [HCO3–], administer larger
quantities of bicarbonate based on bicarbonate space calculated from
above formula
■■ Consider potential delivery of new bicarbonate from metabolism of lactate if the
disorder producing lactic acidosis has improved; use changes in serum anion
gap as a rough estimate of potential bicarbonate generated from metabolism
of lactate
■■ Administer sodium bicarbonate as an isosmotic solution and infuse it at a slow
rate (~0.1 mEq/kg per min)
■■ Consider administration of calcium intravenously to prevent fall in Ca2+ after
base treatment
■■ If patient is intubated and there is evidence of inadequate ventilatory response
to acidosis, consider measures to increase ventilation
■■ Assess course and response to therapy with measurement of acid–base
parameters every 2–4 h
■■ Consider use of THAM in patients with present or incipient CO2 retention
■■ Estimate THAM requirements using the following formula: 0.3 M THAM
requirement (in ml) = body dry weight (kg) × base deficit (mEq/l) × 1.1, where
base deficit = desired serum [HCO3–] – actual serum [HCO3–]
■■ Consider continuous renal replacement therapy in presence of significant renal
impairment as a means of delivering base while controlling volume
and osmolality
Box 3 | Recommendations for treatment of diabetic ketoacidosis
■■ Actively attempt to correct acidosis with insulin and fluid replacement; if this is
unsuccessful within a few hours and blood pH ≤7.00, consider base therapy
■■ Calculate bicarbonate requirements using the formula: bicarbonate
requirement = desired [HCO3–] – present serum [HCO3–] × bicarbonate space,
where bicarbonate space = [0.4 + (2.6/[HCO3–]) × body weight (kg)
■■ To minimize potential complications of bicarbonate administration, initiate
therapy based on calculation using bicarbonate space of 50% body weight (kg);
if not successful in achieving desired serum [HCO3–], administer larger
quantities of bicarbonate based on bicarbonate space calculated from
above formula
■■ Consider administration of calcium intravenously to prevent fall in Ca2+ after
base treatment
■■ Consider potential delivery of new bicarbonate from metabolism of ketones so
be conservative in estimate of base needs
■■ Use changes in serum anion gap as rough estimate of potential bicarbonate
generated from metabolism of ketones
■■ Administer sodium bicarbonate as an isosmotic solution and infuse it at a slow
rate (~0.1 mEq/kg per min)
■■ If patient is intubated and there is evidence of inadequate ventilatory response
to acidosis, consider measures to increase ventilation
■■ Assess course and response to therapy with measurement of acid–base
parameters every 2–4 h
■■ Consider use of THAM in patients with present or incipient CO2 retention
■■ If giving base to children monitor carefully for evidence of cerebral oedema
However, whether there is any urgency for the treatment of this acid–base pattern remains unclear. In fact,
in one observational study, mortality associated with
this electrolyte pattern was substantially lower than that
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Box 4 | Recommendations for treatment of toxic alcohol ingestion
■■ Actively attempt to treat intoxication with administration of fomepizole
and dialysis
■■ Consider administration of base only with severe acidosis, blood pH <7.10
and no access to fomepizole or dialysis
■■ Follow recommendations for use of base in treatment of lactic acidosis (Box 2)
Box 5 | Recommendations for treatment of non-gap metabolic acidosis
■■ Consider administration of base when blood pH ≤7.20
■■ Calculate bicarbonate requirements using the formula: bicarbonate
requirement = desired [HCO3–] – present serum [HCO3–] × bicarbonate space,
where bicarbonate space = [0.4 + (2.6/[HCO3–]) × body weight (kg)
■■ To minimize potential complications of bicarbonate administration, initiate
therapy based on calculation using bicarbonate space of 50% body weight (kg);
if not successful in achieving desired serum [HCO3–], administer larger
quantities of bicarbonate based on bicarbonate space calculated from
above formula
■■ Administer sodium bicarbonate as an iso-osmotic solution designed to raise
blood pH >7.20
■■ If patient is intubated and there is evidence of inadequate ventilatory response,
to acidosis consider measures to increase ventilation
■■ Consider administration of calcium intravenously to prevent fall in Ca2+ after
base treatment
■■ Assess course and response to therapy with measurement of acid–base
parameters every 2–4 h
■■ Consider use of THAM in patients with present or incipient CO2 retention
associated with lactic acidosis (29% versus 58%).1 This
difference could be a consequence of less severe hypobicarbonataemia occurring with this pattern, even when
the non-gap acidosis is present in seriously ill patients
in the ICU.8
However, when severe, it seems that non-gap acid­osis
produces similar adverse effects as organic acid­oses:
infusion of HCl to rats produced hypotension when
blood pH fell <7.10,76,77 and also increased the levels of
inflammatory mediators. Indeed, acidification of the cell
culture media with HCl actually causes greater release
of inflammatory molecules than a similar acidification
with lactic acid.78
Unfortunately, only a few studies have specifically
examined the benefits or complications of base therapy
given to patients with non-gap acidosis. In one study
of 24 patients who developed moderate metabolic
acidosis while receiving saline during surgery (mean
blood pH 7.28, mean serum HCO 3– concentration
18 mmol/l), administration of sodium bicarbonate or
tris(hydroxymethyl)aminomethane (THAM) successfully restored blood acid–base parameters without inducing either a fall in blood pressure or a significant increase
in PaCO2.79 However, larger controlled studies would be
helpful for establishing guidelines on the administration
of base in patients with non-gap acidosis.
Additional reasons for concern about bicarbonate
administration are potential complications besides
the possible changes in cardiac function previously
described. These include exacerbation of intracellular
acidosis,80 volume overload, overshoot metabolic alkalosis, stimulation of organic acid production, reduction in ionized Ca 2+ and resultant impaired cardiac
596 | OCTOBER 2012 | VOLUME 8
contractility,67 hyperosmolality (if bicarbonate is given
as a hyperosmolal solution81), and cerebral oedema in
children with ketoacidosis.82
The exacerbation of intracellular acidosis has been
ascribed to the rapid permeation into cells of CO 2
formed from reaction of administered bicarbonate with
protons.83 Factors that theoretically predispose to this
intracellular acidosis include rapid administration of
bicarbonate, a high haematocrit, and impaired clearance
of CO2 from tissues as observed in low flow states.17,84 It is
important to emphasize that exacerbation of intracellular
acidosis is not inevitable with bicarbonate administration. A few animal studies of experimentally produced
metabolic acidosis have demonstrated that bicarbonate
administration can actually raise pHi.80
Despite the lack of strong clinical evidence in support
of its benefit, and the potential complications of its
administration, many clinicians still recommend bicarbonate therapy, particularly for a blood pH <7.10.59 To
the extent that cellular dysfunction and/or injury with
metabolic acidosis is primarily related to a reduction
in pH in critical compartments, administration of base
seems justified, if it is capable of improving the acid–base
milieu of these compartments. Perhaps, providing conditions to ensure dissipation of generated CO2, such as
adequate blood flow to tissues and adequate pulmonary
ventilation (thereby minimizing intracellular acidosis),
and to maintain a normal ionized Ca2+, would facilitate
the positive effects of bicarbonate administration, thus
strengthening the rationale for its use in the treatment
of acute metabolic acidosis.
At present, in the absence of evidence that provides
a strong argument for administration of bicarbonate,
the decision to recommend it is an individual one. If
it is given, it should be administered as an infusion of
isosmotic sodium bicarbonate, rather than one of the
hypertonic sodium bicarbonate preparations available
(4.2%, 7.5% or 8.4%), since giving it in such a manner
will prevent the hyperosmolality that might ensue from
use of the hypertonic solutions.81,85 On the other hand,
administering it as an isosmotic solution can provide a
large volume load, and this possibility should be factored
in when assessing the volume status of the patient.81,85
Giving it as an infusion will lessen the generation of CO2
that promotes intracellular acidosis.86 Sodium bicarbonate infused at a rate of 0.1 mEq/kg/min over 10 min to
dogs subjected to ventricular fibrillation-induced cardiac
arrest produced less CO2 and a relatively similar increment in serum HCO3– concentration than did a bolus
injection (1 mmol/kg over 20 s).86
Based on animal studies (which showed that cardiac
function was improved when systemic pH was >7.10–
7.20), we suggest sufficient base be given to raise blood
pH >7.10 and maintain it at least at that level.27 Whether
any benefit will accrue from raising it above this level
is unclear. However, as systemic acidosis even of a mild
degree seems to induce catecholamine release,27 a higher
blood pH might theoretically be targeted in patients susceptible to arrhythmias. Again, controlled studies are
indicated to precisely determine goals of therapy.
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Preceding its administration, the clinician should
estimate the quantity of bicarbonate required to raise
serum [HCO3–] by a given amount. To estimate bicarbonate requirements necessitates an estimate of bicarbonate
space (volume of distribution of administered HCO3–).
This value is not static, but increases as the hypo­
bicarbonataemia becomes more severe.87 One derived
formula frequently used is shown (Box 2).
In other estimates of bicarbonate requirements, the
bicarbonate space used is not altered as serum bicarbonate concentration changes, but rather is kept at a fixed
value of 50% body weight.59 Since the bicarbonate space
using the former formula can be ≥90% when serum
HCO3– concentration is ≤5 mmol/l, it might be prudent
to initially administer the quantity of bicarbonate calculated using the lower bicarbonate space, in order
to minimize potential complications of bicarbonate
therapy. If this approach is not successful in achieving
the desired serum [HCO3–], then larger quantities of
bicarbonate can be given. In both instances, the estimate
does not take into account other sources of acid or base
and therefore acid–base parameters should be carefully
monitored during bicarbonate therapy (approximately
every 2–4 h). Potential base delivery from metabolism
of retained organic anions can be estimated from their
actual measure­ment or from examination of the serum
anion gap.
THAM
Owing to concerns about bicarbonate therapy further
reducing pHi, alternative buffers have been developed.
THAM was introduced into clinical practice in 1959.88
It buffers protons by virtue of the ammonia moiety.
Because 30% of the compound exists in the nonionized
form, a portion can penetrate cells and thereby raise pHi.
One drawback of the use of this agent is that elimination
of protons only occurs when the buffer is excreted in the
urine. Therefore, its usefulness is constrained in the presence of significant renal impairment (GFR <30 ml/min).
Indeed, since it is provided as a 300–389 mmol/l solution,
significant retention of THAM in extracellular fluid compartments may ensue under these circumstances, leading
to hyperosmolality. However, as it is a small molecule it
can be removed by dialysis and can therefore be used in
patients with severe renal failure on dialysis.
Experimental studies in dogs with lactic acidosis
produced by infusion of lactic acid demonstrated that
administration of THAM caused cardiac contractility to
rise in concert with improvement in extracellular acid–
base parameters.27 Moreover, administration of THAM
to patients with mild lactic acidosis in the ICU was as
effec­tive as sodium bicarbonate in improving extracellular
acid–base parameters, without any negative sequelae.89
In patients with acute respiratory acidosis given
THAM, the decline in cardiac contractility was blunted
in association with improvement of acid–base para­
meters. 90 Similarly, administration of THAM to six
patients with acute metabolic acidosis and acute lung
injury improved acid–base parameters while causing
PaCO2 to fall from 63 ± 19 mmHg to 50 ± 16 mmHg.91 By
contrast, bicarbonate administration failed to improve
acid–base parameters, while causing PaCO2 to rise by an
average of 9 mmHg.
Reported complications of THAM therapy include respiratory depression (with increase in PCO2) and hyperkalemia,88 although the incidence of these complications
is not clear. However, THAM is not thought to generate
CO2 in the buffering process, and as mentioned has been
administered to patients with hypercapnia and caused
PCO2 to fall.91 Moreover, administration of THAM did
not result in a significant rise in serum potassium in
formal studies in both animals and humans.89,92 An additional potential complication of THAM includes vascular
irritation if it is administered through a peripher­al vein,
particularly if extravasation occurs.
In light of its apparent effectiveness, further examination of the use of THAM in the treatment of acute
metabolic acidosis, particularly under circumstances in
which CO2 retention is present or anticipated, should
be considered. Randomized controlled studies in which
cardiovascular function is also evaluated would be useful
in determining the role of this buffer in the treatment of
acute metabolic acidosis.
THAM is administered as a 0.3 M solution (300 mEq/l).
A formula is used to estimate the quantity of THAM
required to raise serum concentration of HCO3– by a
given amount (Box 2). As with bicarbonate administration, this estimate does not take into account continuing
acid production or base synthesis. Therefore, acid–base
parameters should be monitored carefully (at least every
2 h) during its administration as should serum potassium
concentration.
Carbicarb
Carbicarb is a 1:1 mixture of sodium bicarbonate and
sodium carbonate. It generates less carbon dioxide
during buffering than does bicarbonate alone and would
therefore theoretically cause a smaller decrease in pHi.
Experimental studies in animals demonstrated its superiority over sodium bicarbonate in preserving or improving cardiac output and pHi.93 In a study of 36 patients
undergoing surgery who developed mild metabolic
acidosis (mean pH 7.31) and were randomly assigned
to bicarbonate or carbicarb treatment, response to base
treatment and change in hemodynamic para­meters of
the groups as a whole were not different.94 Studies of the
impact of carbicarb on more severe metabolic acid­osis
are not available and the drug is not currently available
for commercial use. However, the drug does have intriguing potential and one of the authors is re-­examining its
use as a buffer in the treatment of acidosis.
Dialysis
Hyperosmolality and volume overload are potential
complications of sodium bicarbonate administration.
To avoid these complications, various modes of dialytic
therapy have been suggested for the treatment of lactic
acidosis. Small observational studies and individual case
reports of metformin-induced or phenformin-induced
metabolic acidosis seemed to demonstrate a decrease in
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Table 2 | Experimental therapies for treatment of acute metabolic acidosis
Experimental therapy
Target
Outcomes and stage of development
Dichloroacetate
Pyruvate
dehydrogenase
Animal studies promising in treatment of lactic acidosis; clinical studies in
humans with lactic acidosis showed no decrease in mortality
Administration of selective inhibitors
of NHE1 or amiloride analogues
NHE1
Small animal studies of various models of shock and lactic acidosis
demonstrated improved cardiac function, reduced mortality, and
decreased generation of proinflammatory cytokines; human studies yet to
be performed
Administration of selective inhibitors
of ASIC1a
ASIC1a
In vitro studies and studies in animals demonstrated reduced cellular
damage and extension of cerebral infarct; human studies yet to be
performed
Administration of inhibitors of MAPK
MAPK pathway
Only cell culture studies have been performed; animal studies exploring
this treatment need to be performed
Administration of inhibitors of
TRPV1
TRPV1
Cell culture studies demonstrate exposure to selective inhibitor of TRPV1
decreases cell death
Abbreviations: ASIC1a, acid-sensing ion channel 1a; MAPK, mitogen activated protein kinase; NHE1, Na +–H+ exchanger; TRPV1, transient receptor potential
vanilloid 1.
mortality with dialysis.95 In addition, continuous haemo­
filtration, using a locally prepared bicarbonate-based
replacement fluid, resulted in rapid resolution of the
acidosis in 45% of 200 patients with acute lactic acidosis, although eventual mortality remained extremely high
(72%).96 Thus although dialysis seems attractive, particularly in patients with renal dysfunction, randomized
controlled studies are needed to prove the benefits of this
treatment strategy in patients with lactic acidosis.
In patients with toxic alcohol ingestion (Box 4), in
addition to provision of base, dialysis can remove both
the parent alcohol and the potentially toxic organic acid
metabolite(s).3 Dialysis has been restricted to the treatment of patients with very high levels of the offending
alcohol although one author has advocated a more liberal
approach.3
Increased respiratory excretion of CO2
As decreases in pHe and pHi seem to be the major factors
contributing to cellular dysfunction and injury, methods
to raise their levels other than the administration of base
might be beneficial. In patients who are intubated and
maintained on ventilatory support, reducing PaCO2 by
increasing the rate and/or depth of ventilation could be
helpful. The decrease in PCO2, if expressed in peripheral
tissues, can reduce the intracellular acidosis rapidly and
might therefore provide an additional benefit to other
methods of alkalinizing the body fluids.97 The benefits
of this approach should be weighed against the possible
risk of barotrauma.
Stabilization of ionized calcium
Myocardial function is affected by levels of ionized
Ca2+.98 The acidaemia-induced rise in ionized Ca2+ counteracts the depressive effects of acidosis on cardiac function. Administration of base reduces ionized Ca2+ levels
and might prevent improvement in cardiac function
arising from amelioration of the acidosis.67 Therefore,
consideration should be given to administering calcium
during base therapy. If given, it should be administered
through a line separate from that in which bicarbonate
is given, to prevent its precipitation.
598 | OCTOBER 2012 | VOLUME 8
Experimental therapies
Because base therapy alone fails to eliminate many of the
complications of acute metabolic acidosis and because
of the potential adverse effects of this therapy, a great
deal of interest has been generated in developing novel
methods of treatment to either complement base therapy
or substitute for it (Table 2).37
For example, dichloroacetate, a compound that lowers
blood lactate levels by increasing pyruvate oxidation via
activation of pyruvate dehydrogenase, was proposed for
treating lactic acidosis.37 Studies in dogs with hypoxic
lactic acidosis revealed that therapy with this compound
resulted in stabilization of cardiac index, a fall in blood
lactate, and a decrease in mortality to 17% (versus 67%
in dogs receiving bicarbonate).37 However, ran­domized
controlled studies in humans failed to demonstrate
that dichloroacetate treatment reduced mortality,
even though it caused a greater increment in blood pH
and serum HCO3– concentration than did traditional
measures alone. 99 Therefore, use of this compound
in the treatment of acute lactic acidosis has largely
been abandoned.
Other targeted therapies that emerged from studies of
the factors contributing to cellular dysfunction have been
examined using simulated metabolic acidosis in vitro or
in animal models of acute metabolic acidosis.
Targeting NHE1 is the first experimental therapy that
has been studied extensively using animal models. As
noted, activation of NHE1 in response to ischaemiainduced lactic acidosis was shown to cause deleterious
increments in cellular Na+ and Ca2+.57 Administration of
selective inhibitors of NHE1 to pigs with haemorrhageinduced lactic acidosis attenuated the metabolic acidosis
and hypovolaemic hypotension, improved myocardial
performance, tissue oxygen delivery, and cardiac function during resuscitation, and reduced mortality by
80%.100,101 This treatment also improved oxygen delivery,
reduced generation of proinflammatory cytokines, and
reduced mortality in a pig model in which a period of
hypoperfusion (produced by controlled haemorrhage)
was followed by an infusion of lactic acid to produce
severe lactic acidosis.102
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Amiloride given in high doses also inhibits NHE1.
Administration of amiloride to rats with sepsis prevented the decline in cardiac function in association
with an attenuation of a rise in intracellular Na + and
Ca2+.103 In addition, administration of amiloride to rats
with haemor­rhagic shock attenuated the inflammatory response, as reflected by TNF levels.104 As selective
inhibitors of NHE1 and compounds such as amiloride
are available and have been approved for use in humans,
clinical studies to determine their effectiveness in lactic
acidosis or other forms of metabolic acidosis in humans
seem warranted. Also, as base therapy is often prescribed
to patients with acute metabolic acidosis, the impact of
the combination of base therapy and inhibition of NHE1
needs to be explored to determine whether combined
therapy has any value.
Examination of other targeted treatments is at an
earlier stage of investigation. Cerebral ischaemia is
accompanied by intense lactic acidosis. Attenuating the
activity of ASC1a (the Na+ and Ca2+–-permeable channel
present in the CNS) either by intraventricular injection
of specific inhibitors of the channel or by rendering the
gene nonfunctional reduced the infarct size produced
by transient occlusion of the middle cerebral artery in
mice by 50%.47,105 Although not necessarily useful in all
cases of metabolic acidosis, these findings suggest that
administration of selective inhibitors of ASIC1a might
prevent CNS damage in individuals with metabolic acid­
osis accompanied by impaired cerebral perfusion. The
role of targeting this channel in the treatment of acute
metabolic acidosis remains under investigation.
In vitro studies have shown that stimulation of p38
mitogen activated protein kinase (MAPK) by acidosis
contributes to hypoxic cell death in cardiac myocytes.106
Also, the cell death is abrogated by exposure to selective inhibitors of MAPK; these observations suggest that
this approach might be useful clinically. Animal studies
examining the impact of targeting this pathway in cell
dysfunction and injury arising with metabolic acidosis
are needed.
The TRPV1 channels, which are activated by a pHe
<6.0,107 have been postulated as possible factors contributing to myocardial cell death and development of arrhythmias,108 as well as cell death of cortical neurons.46 In vitro
studies demonstrate that cell death induced by activation
of the channel can be completely prevented by exposure
1.
2.
3.
4.
Gunnerson, K. J., Saul, M., He, S. & Kellum, J.
Lactate versus non-lactate metabolic acidosis:
a retrospective outcome evaluation of critically
ill patients. Crit. Care Med. 10, R22–R32
(2006).
Khosravani, H., Shahpori, R., Stelfox, H. T.,
Kirkpatrick, A. W. & Laupland, K. B. Occurrence
and adverse effect on outcome of
hyperlactatemia in the critically ill. Crit. Care 13,
(2009).
Kraut, J. A. & Kurtz, I. Toxic alcohol ingestions:
clinical features, diagnosis, and management.
Clin. J. Am. Soc. Nephrol. 3, 208–225 (2008).
Kraut, J. A. & Kurtz, I. Use of base in the
treatment of severe acidemic states. Am. J.
Kidney Dis. 38, 703–727 (2001).
5.
6.
7.
8.
9.
to the TRPV1 antagonist capsazepine.46 Again, animal
studies examining the benefits of targeting this channel
are necessary.
Finally, ongoing research studies examining the mecha­
nisms of cellular injury and dysfunction with acute
metabolic acidosis might reveal other potential targets.
Once identified, studies of the feasibility of target­ing
these factors in the treatment of acute metabolic acid­osis
are warranted.
Conclusions
Despite extensive research examining the optimal
methods for evaluation and treatment of acute metabolic
acidosis, several major questions remain unanswered.
For example, what is the best means of monitoring
patients before and after initiation of therapy? What is
the impact of bicarbonate and other base therapy on
pHe and pHi of various tissues in humans? What criteria
should be used to decide on what base should be admini­
stered and when should it be given in various types of
metabolic acidosis? What is the best method of preventing complications of therapy of metabolic acidosis?
Finally, which factors contribute to cellular dysfunction
with metabolic acidosis, and what is the impact of targeted treatment directed against these factors? Finding
answers to these questions should improve the effectiveness of treatment of acute metabolic acidosis and thereby
improve clinical outcomes of seriously ill patients with
this acid–base disorder.
Review criteria
This Review was based on a comprehensive search of
the literature from 1975 to 2011 using the MEDLINE
database. In addition, references included in articles
retrieved during the search were examined. With one
exception, only full-text papers published in English
were included. Search terms utilized included:
“acid–base disorders”, “metabolic acidosis”, “high
anion gap acidosis”, “normal anion gap metabolic
acidosis”, “hyperchloremic acidosis”, “treatment
of metabolic acidosis”, “acid–base emergencies”,
“bicarbonate”, “bicarbonate space”, “THAM”, “carbicarb”,
“dichloroacetate”, “adverse effects of metabolic acidosis”,
“NHE1”, “lactic acidosis”, “ketoacidosis”, “toxic alcohols”,
“methanol intoxication”, and “ethylene glycol intoxication”.
Kraut, J. A. & Madias, N. E. Metabolic acidosis:
pathophysiology, diagnosis and management.
Nat. Rev. Nephrol. 6, 274–285 (2010).
Gabow, P. A. Disorders associated with an
abnormal anion gap. Kidney Int. 27, 472–483
1985.
Gabow, P. A. et al. Diagnostic importance of
increased serum anion gap. N. Engl. J. Med. 303,
854–858 (1980).
Brill, S. A., Stewart, T. R., Brundage, S. I. &
Schreiber, M. A. Base deficit does not predict
mortality when secondary to hyperchloremic
acidosis. Shock 17, 459–462 (2002).
Kellum, J. A. Saline-induced hyperchloremic
metabolic acidosis. Crit. Care Med. 30, 259–261
(2002).
NATURE REVIEWS | NEPHROLOGY 10. Day, N. P. J. et al. The pathophysiologic and
prognostic significance of acidosis in severe
adult malaria. Crit. Care Med. 28, 1833–1840
(2000).
11. Martin, M., Murray, J., Berne, T., Demetriades, D.
& Belzberg, H. Diagnosis of acid-base
derangements and mortality prediction in the
trauma intensive care unit: the physiochemical
approach. J. Trauma 58, 238–243 (2005).
12. Noritomi, D. T. et al. Metabolic acidosis in
patients with severe sepsis and septic shock:
a longitudinal quantitative study. Crit. Care Med.
37, 2733–2739 (2009).
13. Orringer, C. E., Eustace, J. C., Wunsch, C. D. &
Gardner, L. B. Natural history of lactic acidosis
after grand mal seizures—model for study of an
VOLUME 8 | OCTOBER 2012 | 599
© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
anion gap acidosis not associated with
hyperkalemia. N. Engl. J. Med. 297, 796–799
(1977).
Treger, R., Pirouz, S., Kamangar, N. & Corry, D.
Agreement between central venous and arterial
blood gas measurements in the intensive care
unit. Clin. J. Am. Soc. Nephrol. 5, 390–394
(2010).
Toftegaard, M., Rees, S. E. & Andreassen, S.
Correlation between acid-base parameters
measured in arterial blood and venous blood
sampled peripherally, from vena cavae superior,
and from the pulmonary artery. Eur. J. Emerg.
Med. 15, 86–91 (2008).
Venkatesh, B., Morgan, T. J. & Cohen, J.
Interstitium: the next diagnostic and therapeutic
platform in critical illness. Crit. Care Med. 38,
S630–S636 (2010).
Adrogue, H. J. et al. Assessing acid-base status
in circulatory failure differences between arterial
and central venous blood. N. Engl. J. Med. 320,
1312–1316 (1989).
Bakker, J. et al. Veno-arterial carbon dioxide
gradient in human septic shock. Chest 101,
509–515 (1992).
Vonplanta, M., Weil, M. H., Gazmuri, R. J. &
Bisera, J. Myocardial acidosis associated with
CO2 production during cardiac arrest and
resuscitation. Circulation 80, 684–692 (1989).
Sato, Y., Weil, M. H. & Tang, W. Tissue
hypercarbic acidosis as a marker of acute
circulatory failure (shock). Chest 114, 263–274
(1998).
Desai, V. S., Weil, M. H., Tang, W., Gazmuri, R. &
Bisera, J. Hepatic, renal, and cerebral tissue
hypercarbia during sepsis and shock in rats.
J. Lab. Clin. Med. 125, 456–461 (1995).
Emmett, M. & Narins, R. G. Clinical use of anion
gap. Medicine (Baltimore) 56, 38–54 (1977).
Emmett, M. Anion-gap interpretation: the old
and the new. Nat. Clin. Pract. Nephrol. 2, 4–5
(2006).
Kraut, J. A. & Madias, N. E. Serum anion gap: Its
uses and limitations in clinical medicine. Clin. J.
Am. Soc. Nephrol. 2, 162–174 (2007).
Adams, B. D., Bonzani, T. A. & Hunter, C. J. The
anion gap does not accurately screen for lactic
acidosis in emergency department patients.
Emerg. Med. J. 23, 179–182 (2006).
Wiederseiner, J. M., Muser, J., Lutz, T.,
Hulter, H. N. & Krapf, R. Acute metabolic
acidosis: Characterization and diagnosis of the
disorder and the plasma potassium response.
J. Am. Soc. Nephrol. 15, 1589–1596 (2004).
Wildenthal, K., Mierzwiak, D. S., Myers, R. W. &
Mitchell, J. H. Effects of acute lactic acidosis on
left ventricular performance. Am. J. Physiol. 214,
1352–1359 (1968).
Mitchell, J. H., Wildenthal, K. & Johnson, R. L. Jr.
The effects of acid-base disturbances on
cardiovascular and pulmonary function. Kidney
Int. 375–379 (1972).
Kellum, J. A., Song, M. C. & Venkataraman, R.
Effects of hyperchloremic acidosis on arterial
pressure and circulating inflammatory molecules
in experimental sepsis. Chest 125, 243–248
(2004).
Orchard, C. H. & Cingolani, H. E. Acidosis and
arrhythmias in cardiac muscle. Cardiovasc. Res.
28, 1312–1319 (1994).
Huang, Y. G., Wong, K. C., Yip, W. H.,
Mcjames, S. W. & Pace, N. L. Cardiovascular
responses to graded doses of 3 catecholamines
during lactic and hydrochloric acidosis in dogs.
Br. J. Anaesth. 74, 583–590 (1995).
Halperin, M. L., Cheema-Dhadli, S.,
Halperin, F. A. & Kamel, K. S. Rationale for the
use of sodium bicarbonate in a patient with
600 | OCTOBER 2012 | VOLUME 8
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
lactic acidosis due to a poor cardiac output.
Nephron 66, 258–261 1994.
Kellum, J. A., Song, M. C. & Li, J. Y. Extracellular
acidosis and the immune response: clinical and
physiologic implications. Crit. Care 8, 331–336
(2004).
Lardner, A. The effects of extracellular pH on
immune function. J. Leukoc. Biol. 69, 522–530
(2001).
Chen, A. et al. Activation of GPR4 by acidosis
increases endothelial cell adhesion through the
cAMP/Epac pathway. PLoS ONE 6, e27586
(2011).
Graham, R. A. et al. A unique pathway of cardiac
myocyte death caused by hypoxia-acidosis.
J. Exp. Biol. 207, 3189–3200 (2004).
Park, R. & Arieff, A. I. Treatment of lactic acidosis
with dichloroacetate in dogs. J. Clin. Invest. 70,
853–862 (1982).
Latif, M. A. A. & Weil, M. H. Circulatory defects
during phenformin lactic acidosis. Intensive Care
Med. 5, 135–139 (1979).
Pedoto, A. et al. Acidosis stimulates nitric oxide
production and lung damage in rats. Am. J.
Respir. Crit. Care Med. 159, 397–402 (1999).
Sonne, O., Gliemann, J. & Linde, S. Effect of pH
on binding kinetics and biological effect of
insulin in rat adipocytes. J. Biol. Chem. 256,
6250–6254 (1981).
Davies, A. O. Rapid desensitization and
uncoupling of human beta adrenergic receptors
in an in vitro model of lactic acidosis. J. Clin.
Endocrinol. Metab. 59, 398–404 (1984).
Claydon, T. W. et al. Inhibition of the K+ channel
Kv1.4 by acidosis: protonation of an extracellular
histidine slows the recovery from N‑type
inactivation. J. Physiol. 526, 253–264 (2000).
Fan, Z. & Makielski, J. C. Intracellular H+ and
Ca2+ modulation of trypsin modified ATPsensitive K+ channels in rabbit ventricular
myocytes. Circ. Res. 72, 715–722 (1993).
Fan, Z., Furukawa, T., Sawanobori, T.,
Makielski, J. C. & Hiraoka, M. Cytoplasmic
acidosis induces multiple conductance states in
atp sensitive potassium channels of cardiac
myocytes. J. Membr. Biol. 136, 169–179 (1993).
Funckbrentano, C. Potassium channels and
arrhythmias. Arch. Mal. Coeur Vaiss. 85, 9–13
(1992).
Shirakawa, H. et al. TRPV1 stimulation triggers
apoptotic cell death of rat cortical neurons.
Biochem. Biophys. Res. Commun. 377,
1211–1215 (2008).
Benveniste, M. & Dingledine, R. Limiting strokeinduced damage by targeting an acid channel.
N. Engl. J. Med. 352, 85–86 (2005).
Xiong, Z. G., Chu, X. P. & Simon, R. P. Acid
sensing ion channels—novel therapeutic targets
for ischemic brain injury. Front. Biosci. 12,
1376–1386 (2007).
Xiong, Z. G. et al. Neuroprotection in ischemia:
blocking calcium-permeable acid-sensing ion
channels. Cell 118, 687–698 (2004).
Madshus, I. H. Regulation of intracellular pH in
eukaryotic cells. Biochem. J. 250, 1–8 (1988).
Jiang, C., Qu, Z. Q. & Xu, H. X. Gating of inward
rectifier K+ channels by proton-mediated
interactions of intracellular protein domains.
Trends Cardiovasc. Med. 12, 5–13 (2002).
Trivedi, B. & Danforth, W. H. Effect of pH on the
kinetics of frog muscle phosphofructokinase.
J. Biol. Chem. 241, 4110–4114 (1966).
Zahler, R., Barrett, E., Majumdar, S., Greene, R. &
Gore, J. Lactic acidosis: effect of treatment on
intracellular pH and energetics in living rat heart.
Am. J. Physiol. 262, H1572–H1578 (1992).
Rehring, T. F. et al. Mechanisms of pH
preservation during global ischemia in
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
preconditioned rat heart: roles for PKC and NHE.
Am. J. Physiol. 275, H805–H813 (1998).
Gottlieb, R. A., Gruol, D. L., Zhu, J. Y. &
Engler, R. L. Preconditioning in rabbit
cardiomyocytes—role of pH, vacuolar proton
ATPase, and apoptosis. J. Clin. Invest. 97,
2391–2398 (1996).
Vaughan-Jones, R. D. et al. pH regulated Na+
influx into the mammalian ventricular myocyte:
the relative role of Na+‑H+ exchange and Na+HCO3 co-transport. J. Cardiovasc. Electrophysiol.
17, 134–140 (2006).
Wu, D. M. & Kraut, J. A. Potential role of NHE1
(sodium-hydrogen exchanger 1) in the cellular
dysfunction of lactic acidosis: implications for
treatment. Am. J. Kidney Dis. 57, 781–787
(2011).
Kraut, J. A. & Kurtz, I. Controversies in the
treatment of acute metabolic acidosis. NephSAP
5, 1–9 (2006).
Sabatini, S. & Kurtzman, N. A. Bicarbonate
therapy in severe metabolic acidosis. J. Am. Soc.
Nephrol. 20, 692–695 (2009).
Kraut, J. A. & Kurtz, I. Use of base in the
treatment of acute severe organic acidosis by
nephrologists and critical care physicians:
results of an online survey. Clin. Exp. Nephrol.
10, 111–117 (2006).
Arieff, A. I., Leach, W., Park, R. & Lazarowitz, V. C.
Systemic effects of NaHCO3 in experimental
lactic acidosis in dogs. Am. J. Physiol. 242,
F586–F591 (1982).
Halperin, F. A., Cheema-Dhadli, S., Chen, C. B. &
Halperin, M. I. Alkali therapy extends the period
of survival during hypoxia:studies in rats. Am. J.
Physiol. 271, R381–R387 (1996).
Stacpoole, P. W. et al. Natural history and course
of acquired lactic acidosis in adults. Am. J. Med.
97, 47–54 (1994).
Luft, D., Schmulling, R. M. & Eggstein, M. Lactic
acidosis in biguanide-treated diabetes: a review
of 330 cases. Diabetologia 14, 75–87 (1978).
Cooper, D. J., Hebertson, M. J., Werner, H. A. &
Walley, K. R. Bicarbonate does not increase left
ventricular contractility during L‑lactic acidemia
in pigs. Am. Rev. Resp. Dis. 148, 317–322
(1993).
Graf, H., Leach, W. & Arieff, A. I. Evidence for a
detrimental effect of bicarbonate therapy in
hypoxic lactic acidosis. Science 227, 754–756
(1985).
Cooper, D. J., Walley, K. R., Wiggs, B. R. &
Russell, J. A. Bicarbonate does not improve
hemodynamics in critically ill patients who have
lactic acidosis. Ann. Intern. Med. 112, 492–498
(1990).
Mathieu, D., Neviere, R., Billard, V., Fleyfel, M. &
Wattel, F. Effects of bicarbonate therapy on
hemodynamics and tissue oxygenation in
patients with lactic acidosis:a prospective,
controlled clinical study. Crit. Care Med. 19,
1352–1356 (1991).
Bersin, R. M., Chatterjee, K. & Arieff, A. I.
Metabolic and hemodynamic consequences of
sodium bicarbonate administration in patients
with heart disease. Am. J. Med. 87, 7–13 (1989).
Cuthbert, C. & Alberti, K. G. Acidemia and insulin
resistance in the diabetic ketoacidotic rat.
Metabolism 27, 1903–1916 (1978).
Gamba, G., Oseguera, J., Castrejon, M. & GomezPerez, F. J. Bicarbonate therapy in severe
diabetic ketoacidosis. A double blind,
randomized placebo controlled study. Rev. Invest.
Clin. 43, 234–238 (1991).
Green, S. M. et al. Failure of adjunctive
bicarbonate to improve outcome in severe
pediatric diabetic ketoacidosis. Ann. Emerg.
Med. 31, 41–48 (1998).
www.nature.com/nrneph
© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
73. Hale, P. J., Crase, J. & Nattrass, M. Metabolic
effects of bicarbonate in the treatment of
diabetic ketoacidosis. Br. Med. J. 289,
1035–1038 1984.
74. Maury, E., Vassal, T. & Offenstadt, G. Cardiac
contractility during severe ketoacidosis. N. Engl.
J. Med. 341, 1938 (1999).
75. Barceloux, D. G., Bond, G. R., Krenzelok, E. P.,
Cooper, H. & Vale, J. A. American Academy of
Clinical Toxicology practice guidelines on the
treatment of methanol poisoning. J. Toxicol. Clin.
Toxicol. 40, 415–446 (2002).
76. Kellum, J. A., Song, M. C. & Almasri, E.
Hyperchloremic acidosis increases circulating
inflammatory molecules in experimental sepsis.
Chest 130, 962–967 (2006).
77. Pedoto, A. et al. Role of nitric oxide in acidosisinduced intestinal injury in anesthetized rats.
J. Lab. Clin. Med. 138, 270–276 (2001).
78. Kellum, J. A., Song, M. C. & Li, J. Y. Lactic and
hydrochloric acids induce different patterns of
inflammatory response in LPS-stimulated RAW
264.7 cells. Am. J. Physiol. 286, R686–R692
(2004).
79. Rehm, M. & Finsterer, U. Treating intraoperative
hyperchloremic acidosis with sodium
bicarbonate or tris-hydroxymethyl
aminomethane: a randomized prospective study.
Anesth. Analg. 96, 1201–1208 (2003).
80. Forsythe, S. & Schmidt, G. A. Sodium
bicarbonate for the treatment of lactic acidosis.
Chest 117, 260–267 (2000).
81. Mattar, J. A., Weil, M. H., Shubin, H. & Stein, L.
Cardiac arrest in critically ill hyperosmolal states
following cardiac arrest. Am. J. Med. 56,
162–168 (1974).
82. Glaser, N. et al. Risk factors for cerebral edema
in children with diabetic ketoacidosis. N. Engl. J.
Med. 344, 264–269 (2001).
83. Levraut, J. et al. Effect of sodium bicarbonate on
intracellular pH under different buffering
conditions. Kidney Int. 49, 1262–1267 (1996).
84. Levraut, J. et al. Initial effect of sodium
bicarbonate on intracellular pH depends on the
extracellular nonbicarbonate buffering capacity.
Crit. Care Med. 29, 1033–1039 (2001).
85. Huseby, J. S. & Gumprecht, D. G. Hemodynamic
effects of rapid bolus hypertonic sodium
bicarbonate. Chest 79, 552–554 (1981).
86. Bleske, B. E., Chow, M. S. S., Hong, Z., Kluger, J.
& Fieldman, A. Effects of different dosages and
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
modes of sodium bicarbonate administration
during cardiopulmonary resuscitation. Am. J.
Emerg. Med. 10, 525–532 (1992).
Fernandez, P. C., Cohen, R. M. & Feldman, G. M.
The concept of bicarbonate distribution space
—the crucial role of body buffers. Kidney Int. 36,
747–752 (1989).
Nahas, G. G., Sutin, K. M. & Fermon, C.
Guidelines for the treatment of acidaemia with
THAM. Drugs 55, 191–194 (1998).
Hoste, E. A. et al. Sodium bicarbonate versus
THAM in ICU patients with mild metabolic
acidosis. J. Nephrol. 18, 303–307 (2005).
Weber, T. et al. Tromethamine buffer modifies
the depressant effect of permissive hypercapnia
on myocardial contractility in patient with acute
respiratory distress syndrome. Am. J. Resp. Crit.
Care Med. 162, 1361–1365 (2000).
Kallet, R. H., Jasmer, R. M., Luce, J. M.,
Lin, L. H. & Marks, J. D. The treatment of
acidosis in acute lung injury with trishydroxymethyl aminomethane (THAM). Am. J.
Resp. Crit. Care Med. 161, 1149–1153 (2000).
Waters, J. H., Howard, R. S. & Lesnik, I. K.
Plasma potassium response after
tromethamine (THAM) or sodium bicarbonate in
the acidotic rabbit. Anesth. Analg. 83, 789–792
(1996).
Bersin, R. M. & Arieff, A. I. Improved
hemodynamic function during hypoxia with
carbicarb, a new agent for the management of
acidosis. Circulation 77, 227–233 (1988).
Leung, J. M. et al. Safety and efficacy of
intravenous Carbicarb in patients undergoing
surgery: comparison with sodium bicarbonate in
the treatment of metabolic acidosis. Crit. Care
Med. 22, 1540–1549 (1994).
Heaney, D., Majid, A. & Junor, B. Bicarbonate
haemodialysis as a treatment of metformin
overdose. Nephrol. Dial. Transplant. 12,
1046–1047 (1997).
Hilton, P. J., Taylor, L. G., Forni, L. G. &
Treacher, D. F. Bicarbonate-based
haemofiltration in the management of acute
renal failure with lactic acidosis. Q. J. Med. 91,
279–283 (1998).
Bettice, J. A. Effect of hypocapnia on intracellular
pH during metabolic acidosis. Respir. Physiol. 38,
257–266 (1979).
Lang, R. M., Fellner, S. K., Neumann, A.,
Bushinsky, D. A. & Borow, K. M. Left ventricular
NATURE REVIEWS | NEPHROLOGY contractility varies directly with blood ionized
calcium. Ann. Intern. Med. 108, 524–529 (1988).
99. Stacpoole, P. W. et al. A controlled clinical trial of
dichloroacetate for treatment of lactic acidosis in
adults. N. Engl. J. Med. 327, 1564–1569 (1992).
100.Wu, D. M., Bassuk, J., Arias, J., Doods, H. &
Adams, J. A. Cardiovascular effects of Na+/H+
exchanger inhibition with BIIB513 following
hypovolemic circulatory shock. Shock 23,
269–274 (2005).
101.Wu, D. M. et al. Na+/H+ exchange inhibition
delays the onset of hypovolemic circulatory
shock in pigs. Shock 29, 519–525 (2008).
102.Wu, D. M., Kraut, J. A. & Abraham, W. M. Na+/H+
exchanger (NHE1) inhibition in an experimental
model of lactic acidosis in pigs [abstract
MO007]. Presented at the World Congress of
Nephrology 2011.
103.Sikes, P. J., Zhao, P., Maass, D. L., White, J. &
Horton, J. W. Sodium/hydrogen exchange activity
in sepsis and in sepsis complicated by previous
injury: 31P and 23Na NMR study. Crit. Care Med.
33, 605–615 (2005).
104.Soliman, M. Dimethyl amiloride, a Na+‑H+
exchange inhibitor, and its cardioprotective
effects in hemorrhagic shock in in vivo
resuscitated rats. J. Physiol. Sci. 59, 175–180
(2009).
105.Pignataro, G., Simon, R. P. & Xiong, Z. G.
Prolonged activation of ASIC1a and the time
window for neuroprotection in cerebral
ischaemia. Brain 130, 151–158 (2007).
106.Zheng, M. et al. Intracellular acidosis-activated
p38 MAPK signaling and its essential role in
cardiomyocyte hypoxic injury. FASEB J. 19,
109–111 (2005).
107.Ryu, S. J., Liu, B. Y., Yao, J., Fu, Q. & Qin, F.
Uncoupling proton activation of vanilloid receptor
TRPV1. J. Neurosci. 27, 12797–12807 (2007).
108.Watanabe, H., Murakami, M., Ohba, T., Ono, K. &
Ito, H. The pathological role of transient receptor
potential channels in heart disease. Circ. J. 73,
419–427 (2009).
Acknowledgements
The authors’ work is supported in part by research
funds from the Veterans Administration.
Author contributions
The authors contributed equally to all aspects of
this manuscript.
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