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 [email protected] VOLUME 8 | OCTOBER 2012 | 589 © 2012 Macmillan Publishers Limited. All rights reserved 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 www.nature.com/nrneph © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS 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 NATURE REVIEWS | NEPHROLOGY VOLUME 8 | OCTOBER 2012 | 591 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS 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. 592 | OCTOBER 2012 | VOLUME 8 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. www.nature.com/nrneph © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS 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. NATURE REVIEWS | NEPHROLOGY VOLUME 8 | OCTOBER 2012 | 593 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS 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 594 | OCTOBER 2012 | VOLUME 8 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. www.nature.com/nrneph © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS 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 NATURE REVIEWS | NEPHROLOGY VOLUME 8 | OCTOBER 2012 | 595 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS 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. www.nature.com/nrneph © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS 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 NATURE REVIEWS | NEPHROLOGY VOLUME 8 | OCTOBER 2012 | 597 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS 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 www.nature.com/nrneph © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS 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. VOLUME 8 | OCTOBER 2012 | 601 © 2012 Macmillan Publishers Limited. All rights reserved
© Copyright 2024