Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Treatment of acute metabolic acidosis: a pathophysiologic approach

Nature Reviews Nephrology volume 8, pages 589–601 (2012)Cite this article

Subjects

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 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.

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

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Potential pathways through which a reduction in pHe and pHi could contribute to cellular dysfunction and injury.

References

  1. 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).

    Google Scholar 

  2. 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).

  3. Kraut, J. A. & Kurtz, I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin. J. Am. Soc. Nephrol. 3, 208–225 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Kraut, J. A. & Kurtz, I. Use of base in the treatment of severe acidemic states. Am. J. Kidney Dis. 38, 703–727 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Kraut, J. A. & Madias, N. E. Metabolic acidosis: pathophysiology, diagnosis and management. Nat. Rev. Nephrol. 6, 274–285 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Gabow, P. A. Disorders associated with an abnormal anion gap. Kidney Int. 27, 472–483 1985.

    Article  CAS  PubMed  Google Scholar 

  7. Gabow, P. A. et al. Diagnostic importance of increased serum anion gap. N. Engl. J. Med. 303, 854–858 (1980).

    Article  CAS  PubMed  Google Scholar 

  8. 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).

    Article  PubMed  Google Scholar 

  9. Kellum, J. A. Saline-induced hyperchloremic metabolic acidosis. Crit. Care Med. 30, 259–261 (2002).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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 anion gap acidosis not associated with hyperkalemia. N. Engl. J. Med. 297, 796–799 (1977).

    Article  CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    Article  PubMed  Google Scholar 

  16. Venkatesh, B., Morgan, T. J. & Cohen, J. Interstitium: the next diagnostic and therapeutic platform in critical illness. Crit. Care Med. 38, S630–S636 (2010).

    Article  PubMed  Google Scholar 

  17. 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).

    Article  CAS  PubMed  Google Scholar 

  18. Bakker, J. et al. Veno-arterial carbon dioxide gradient in human septic shock. Chest 101, 509–515 (1992).

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. Sato, Y., Weil, M. H. & Tang, W. Tissue hypercarbic acidosis as a marker of acute circulatory failure (shock). Chest 114, 263–274 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. 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).

    CAS  PubMed  Google Scholar 

  22. Emmett, M. & Narins, R. G. Clinical use of anion gap. Medicine (Baltimore) 56, 38–54 (1977).

    Article  CAS  Google Scholar 

  23. Emmett, M. Anion-gap interpretation: the old and the new. Nat. Clin. Pract. Nephrol. 2, 4–5 (2006).

    Article  PubMed  Google Scholar 

  24. 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).

    Article  CAS  PubMed  Google Scholar 

  25. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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).

    CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  Google Scholar 

  28. 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).

  29. 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).

    Article  CAS  PubMed  Google Scholar 

  30. Orchard, C. H. & Cingolani, H. E. Acidosis and arrhythmias in cardiac muscle. Cardiovasc. Res. 28, 1312–1319 (1994).

    Article  CAS  PubMed  Google Scholar 

  31. 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).

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Lardner, A. The effects of extracellular pH on immune function. J. Leukoc. Biol. 69, 522–530 (2001).

    CAS  PubMed  Google Scholar 

  35. Chen, A. et al. Activation of GPR4 by acidosis increases endothelial cell adhesion through the cAMP/Epac pathway. PLoS ONE 6, e27586 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Graham, R. A. et al. A unique pathway of cardiac myocyte death caused by hypoxia-acidosis. J. Exp. Biol. 207, 3189–3200 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Park, R. & Arieff, A. I. Treatment of lactic acidosis with dichloroacetate in dogs. J. Clin. Invest. 70, 853–862 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Latif, M. A. A. & Weil, M. H. Circulatory defects during phenformin lactic acidosis. Intensive Care Med. 5, 135–139 (1979).

    Article  CAS  PubMed  Google Scholar 

  39. Pedoto, A. et al. Acidosis stimulates nitric oxide production and lung damage in rats. Am. J. Respir. Crit. Care Med. 159, 397–402 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. 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).

    CAS  PubMed  Google Scholar 

  41. 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).

    Article  CAS  PubMed  Google Scholar 

  42. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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).

    Article  CAS  PubMed  Google Scholar 

  44. 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).

    Article  CAS  PubMed  Google Scholar 

  45. Funckbrentano, C. Potassium channels and arrhythmias. Arch. Mal. Coeur Vaiss. 85, 9–13 (1992).

    Google Scholar 

  46. Shirakawa, H. et al. TRPV1 stimulation triggers apoptotic cell death of rat cortical neurons. Biochem. Biophys. Res. Commun. 377, 1211–1215 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Benveniste, M. & Dingledine, R. Limiting stroke-induced damage by targeting an acid channel. N. Engl. J. Med. 352, 85–86 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. 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).

    Article  CAS  PubMed  Google Scholar 

  49. Xiong, Z. G. et al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell 118, 687–698 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Madshus, I. H. Regulation of intracellular pH in eukaryotic cells. Biochem. J. 250, 1–8 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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).

    Article  CAS  PubMed  Google Scholar 

  52. Trivedi, B. & Danforth, W. H. Effect of pH on the kinetics of frog muscle phosphofructokinase. J. Biol. Chem. 241, 4110–4114 (1966).

    CAS  PubMed  Google Scholar 

  53. 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).

    CAS  PubMed  Google Scholar 

  54. 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).

    CAS  PubMed  Google Scholar 

  55. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 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).

    Article  Google Scholar 

  57. 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).

    Article  CAS  PubMed  Google Scholar 

  58. Kraut, J. A. & Kurtz, I. Controversies in the treatment of acute metabolic acidosis. NephSAP 5, 1–9 (2006).

    Google Scholar 

  59. Sabatini, S. & Kurtzman, N. A. Bicarbonate therapy in severe metabolic acidosis. J. Am. Soc. Nephrol. 20, 692–695 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. 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).

    Article  PubMed  Google Scholar 

  61. 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).

    CAS  PubMed  Google Scholar 

  62. 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).

    CAS  PubMed  Google Scholar 

  63. Stacpoole, P. W. et al. Natural history and course of acquired lactic acidosis in adults. Am. J. Med. 97, 47–54 (1994).

    Article  CAS  PubMed  Google Scholar 

  64. Luft, D., Schmulling, R. M. & Eggstein, M. Lactic acidosis in biguanide-treated diabetes: a review of 330 cases. Diabetologia 14, 75–87 (1978).

    Article  CAS  PubMed  Google Scholar 

  65. 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).

    Article  CAS  PubMed  Google Scholar 

  66. Graf, H., Leach, W. & Arieff, A. I. Evidence for a detrimental effect of bicarbonate therapy in hypoxic lactic acidosis. Science 227, 754–756 (1985).

    Article  CAS  PubMed  Google Scholar 

  67. 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).

    Article  CAS  PubMed  Google Scholar 

  68. 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).

    Article  CAS  PubMed  Google Scholar 

  69. 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).

    Article  CAS  PubMed  Google Scholar 

  70. Cuthbert, C. & Alberti, K. G. Acidemia and insulin resistance in the diabetic ketoacidotic rat. Metabolism 27, 1903–1916 (1978).

    Article  CAS  PubMed  Google Scholar 

  71. 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).

    CAS  PubMed  Google Scholar 

  72. Green, S. M. et al. Failure of adjunctive bicarbonate to improve outcome in severe pediatric diabetic ketoacidosis. Ann. Emerg. Med. 31, 41–48 (1998).

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  74. Maury, E., Vassal, T. & Offenstadt, G. Cardiac contractility during severe ketoacidosis. N. Engl. J. Med. 341, 1938 (1999).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  76. Kellum, J. A., Song, M. C. & Almasri, E. Hyperchloremic acidosis increases circulating inflammatory molecules in experimental sepsis. Chest 130, 962–967 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Pedoto, A. et al. Role of nitric oxide in acidosis-induced intestinal injury in anesthetized rats. J. Lab. Clin. Med. 138, 270–276 (2001).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  80. Forsythe, S. & Schmidt, G. A. Sodium bicarbonate for the treatment of lactic acidosis. Chest 117, 260–267 (2000).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  82. Glaser, N. et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N. Engl. J. Med. 344, 264–269 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Levraut, J. et al. Effect of sodium bicarbonate on intracellular pH under different buffering conditions. Kidney Int. 49, 1262–1267 (1996).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  85. Huseby, J. S. & Gumprecht, D. G. Hemodynamic effects of rapid bolus hypertonic sodium bicarbonate. Chest 79, 552–554 (1981).

    Article  CAS  PubMed  Google Scholar 

  86. 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).

    Article  CAS  PubMed  Google Scholar 

  87. 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).

    Article  CAS  PubMed  Google Scholar 

  88. Nahas, G. G., Sutin, K. M. & Fermon, C. Guidelines for the treatment of acidaemia with THAM. Drugs 55, 191–194 (1998).

    Article  CAS  PubMed  Google Scholar 

  89. Hoste, E. A. et al. Sodium bicarbonate versus THAM in ICU patients with mild metabolic acidosis. J. Nephrol. 18, 303–307 (2005).

    CAS  PubMed  Google Scholar 

  90. 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).

    Article  CAS  PubMed  Google Scholar 

  91. 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).

    Article  CAS  PubMed  Google Scholar 

  92. 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).

    Article  CAS  PubMed  Google Scholar 

  93. 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).

    Article  CAS  PubMed  Google Scholar 

  94. 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).

    Article  CAS  PubMed  Google Scholar 

  95. Heaney, D., Majid, A. & Junor, B. Bicarbonate haemodialysis as a treatment of metformin overdose. Nephrol. Dial. Transplant. 12, 1046–1047 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. 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).

    Article  CAS  Google Scholar 

  97. Bettice, J. A. Effect of hypocapnia on intracellular pH during metabolic acidosis. Respir. Physiol. 38, 257–266 (1979).

    Article  CAS  PubMed  Google Scholar 

  98. 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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  101. Wu, D. M. et al. Na+/H+ exchange inhibition delays the onset of hypovolemic circulatory shock in pigs. Shock 29, 519–525 (2008).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors' work is supported in part by research funds from the Veterans Administration.

Author information

Authors and Affiliations

  1. Division of Nephrology, Veterans Health Administration Greater Los Angeles Heathcare System, 11301 Wilshire Boulevard, Los Angeles, 90073, CA, USA

    Jeffrey A. Kraut

  2. Department of Medicine, Division of Nephrology, St Elizabeth's Medical Center, 736 Cambridge Street, Boston, 02135, MA, USA

    Nicolaos E. Madias

Authors
  1. Jeffrey A. Kraut
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicolaos E. Madias
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of this manuscript.

Corresponding author

Correspondence to Jeffrey A. Kraut.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2012.186

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing