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 CO2 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.
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
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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).
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).
Day, N. P. J. et al. The pathophysiologic and prognostic significance of acidosis in severe adult malaria. Crit. Care Med. 28, 1833–1840 (2000).
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).
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).
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 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 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 ATP-sensitive 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 stroke-induced 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 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. & Gomez-Perez, 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).
Hale, P. J., Crase, J. & Nattrass, M. Metabolic effects of bicarbonate in the treatment of diabetic ketoacidosis. Br. Med. J. 289, 1035–1038 1984.
Maury, E., Vassal, T. & Offenstadt, G. Cardiac contractility during severe ketoacidosis. N. Engl. J. Med. 341, 1938 (1999).
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).
Kellum, J. A., Song, M. C. & Almasri, E. Hyperchloremic acidosis increases circulating inflammatory molecules in experimental sepsis. Chest 130, 962–967 (2006).
Pedoto, A. et al. Role of nitric oxide in acidosis-induced intestinal injury in anesthetized rats. J. Lab. Clin. Med. 138, 270–276 (2001).
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).
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).
Forsythe, S. & Schmidt, G. A. Sodium bicarbonate for the treatment of lactic acidosis. Chest 117, 260–267 (2000).
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).
Glaser, N. et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N. Engl. J. Med. 344, 264–269 (2001).
Levraut, J. et al. Effect of sodium bicarbonate on intracellular pH under different buffering conditions. Kidney Int. 49, 1262–1267 (1996).
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).
Huseby, J. S. & Gumprecht, D. G. Hemodynamic effects of rapid bolus hypertonic sodium bicarbonate. Chest 79, 552–554 (1981).
Bleske, B. E., Chow, M. S. S., Hong, Z., Kluger, J. & Fieldman, A. Effects of different dosages and 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 tris-hydroxymethyl 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 contractility varies directly with blood ionized calcium. Ann. Intern. Med. 108, 524–529 (1988).
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).
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).
Wu, D. M. et al. Na+/H+ exchange inhibition delays the onset of hypovolemic circulatory shock in pigs. Shock 29, 519–525 (2008).
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.
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).
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).
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).
Zheng, M. et al. Intracellular acidosis-activated p38 MAPK signaling and its essential role in cardiomyocyte hypoxic injury. FASEB J. 19, 109–111 (2005).
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).
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).
The authors' work is supported in part by research funds from the Veterans Administration.
The authors declare no competing financial interests.
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Kraut, J., Madias, N. Treatment of acute metabolic acidosis: a pathophysiologic approach. Nat Rev Nephrol 8, 589–601 (2012). https://doi.org/10.1038/nrneph.2012.186
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