Box 1.

Tests useful in the DD of metabolic acidosis

Box 2.

Causes of metabolic acidosis

Box 3.

Recommendations for the treatment of acute metabolic acidosis

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Jeffrey A. Kraut, MD

Professor of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California; Chief of Dialysis, Division of Nephrology, Greater Los Angeles Veterans Administration Healthcare System, Los Angeles, California; Investigator, UCLA Membrane Biology Laboratory, Los Angeles, California

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Disclosure: Jeffrey A. Kraut, MD, has disclosed no relevant financial relationships.

Nicolaos E. Madias, MD

Maurice S. Segal, M.D. Professor of Medicine, Tufts University School of Medicine, Boston, Massachusetts; Chairman, Department of Medicine, St. Elizabeth's Medical Center, Boston, Massachusetts

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Disclosure: Nicolaos E. Madias, MD, has disclosed no relevant financial relationships.

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Susan Allison

Editor, Nature Reviews Nephrology

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Disclosure: Susan Allison has disclosed no relevant financial relationships.

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Charles P. Vega, MD

Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

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Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

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CME

Metabolic Acidosis: Pathophysiology, Diagnosis and Management

Authors: Jeffrey A. Kraut, MD; Nicolaos E. Madias, MD
CME Released: 3/23/2010
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Describe the pathophysiology of metabolic acidosis
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Distinguish the causes of metabolic acidosis associated with an elevated anion gap
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Author(s)

Jeffrey A. Kraut, MD

Professor of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California; Chief of Dialysis, Division of Nephrology, Greater Los Angeles Veterans Administration Healthcare System, Los Angeles, California; Investigator, UCLA Membrane Biology Laboratory, Los Angeles, California

Disclosures

Disclosure: Jeffrey A. Kraut, MD, has disclosed no relevant financial relationships.

Nicolaos E. Madias, MD

Maurice S. Segal, M.D. Professor of Medicine, Tufts University School of Medicine, Boston, Massachusetts; Chairman, Department of Medicine, St. Elizabeth's Medical Center, Boston, Massachusetts

Disclosures

Disclosure: Nicolaos E. Madias, MD, has disclosed no relevant financial relationships.

Editor

Susan Allison

Editor, Nature Reviews Nephrology

Disclosures

Disclosure: Susan Allison has disclosed no relevant financial relationships.

CME Author(s)

Charles P. Vega, MD

Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosures

Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

Sarah Fleischman

CME Program Manager, Medscape, LLC

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Disclosure: Sarah Fleischman has disclosed no relevant financial relationships.

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Adverse Effects of Metabolic Acidosis

The adverse effects of metabolic acidosis are divided into those primarily associated with acute metabolic acidosis and those primarily associated with chronic metabolic acidosis (Figure 1).

Figure 1.

Enlarge

Adverse effects of a | acute metabolic acidosis and b | chronic metabolic acidosis.

Acute Metabolic Acidosis

Although acute metabolic acidosis can affect a number of organ systems, animal studies suggest that it affects the cardiovascular system most critically. Cardiac contractility and cardiac output are reduced^[70-72] and arterial vasodilatation develops, which contributes to the development of hypotension.^[73] The cardiovascular dysfunction that occurs varies depending on pH. When blood pH decreases from 7.4 to 7.2, cardiac output can increase due to increased catecholamine levels.^[70,72] When blood pH falls below 7.1-7.2, however, a fall in cardiac output is inevitable.^[70] There is also resistance to the inotropic and vasoconstrictive effects of infused catecholamines with severe acidemia.^[70,74] A predisposition to ventricular arrhythmias is often found in animal models of metabolic acidosis.^[75] Similar abnormalities in cardiovascular function might be expected in humans, as patients with severe metabolic acidosis are often hypotensive. However, the limited controlled studies in humans with severe lactic acidosis and ketoacidosis performed so far have been unable to demonstrate impaired cardiovascular function that is directly attributable to the metabolic acidosis.^[76-78] Further studies are warranted to resolve this disparity.

Mental confusion and lethargy are often observed in patients with acute metabolic acidosis, despite minor changes in cerebrospinal and brain pH.^[79] A pH-dependent reduction in the affinity of hemoglobin for oxygen (Bohr effect) is seen immediately.^[80] Within 8 h, a decrease in 2,3-diphosphoglycerate production occurs, which increases the affinity of hemoglobin for oxygen. Given that the time-dependent changes in pH and in 2,3-diphosphoglycerate have disparate effects on the affinity of hemoglobin for oxygen, the final effect on the affinity of hemoglobin for oxygen will depend on the duration of the acidosis.

In acute metabolic acidosis, macrophage production of interleukins is stimulated and lymphocyte function is suppressed, leading to increased inflammation and an impaired immune response.^[81] The chemotactic properties and bactericidal capacity of leukocytes are dampened,^[82] potentially making patients with acute metabolic acidosis more susceptible to infection. In addition, the cellular response to insulin is impaired, partly as a result of a pH-dependent decrease in the binding of insulin to its receptor.^[83]

Cellular energy production can be compromised in metabolic acidosis^[84] as the activity of 6-phosphofructokinase, a critical enzyme in glycolysis, is pH dependent. Apoptosis is stimulated by metabolic acidosis predisposing to cellular death.^[85]

Chronic Metabolic Acidosis

Chronic metabolic acidosis does not seem to have a significant effect on cardiovascular function, although mortality is increased in patients with CKD when serum HCO₃^- concentration is <22 mmol/l.^[86] Chronic metabolic acidosis exerts its most prominent effects on the musculoskeletal system. Metabolic acidosis can produce or exacerbate pre-existing bone disease,^[87,88]accelerate muscle degradation leading to muscle loss,^[89]and retard growth in children.^[90] Glucose tolerance can be impaired because of interference with the actions of insulin,^[91] albumin synthesis can be reduced,^[2] progression of CKD can be accelerated,^[92] and production of ( β₂-microglobulin can be augmented, which predisposes patients to amyloidosis.^[93] Although once disputed, the concept that metabolic acidosis represents an important factor in accelerating the progression of CKD is gaining support.^[92]

Underlying the clinical abnormalities reported with chronic metabolic acidosis are the direct effects of metabolic acidosis on bone and muscle, and possibly kidney, as well as indirect effects on these tissues emanating from alterations in the secretion and/or action of several hormones, including corticosteroids,^[89] thyroid hormone,^[94]and parathyroid hormone.^[95] A generalized stimulation of inflammation also seems to contribute to the adverse effects of chronic metabolic acidosis.^[4] These abnormalities are more frequent and severe with greater degrees of metabolic acidosis, but even mild metabolic acidosis might contribute to the development of bone disease and muscle degradation,^[96,97] a finding that has important implications for treatment.

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Page 6 of 9

Management of Metabolic Acidosis

CME Information

Abstract and Introduction
Pathophysiology of Metabolic Acidosis
Diagnosis of Metabolic Acidosis
Additional Diagnostic Studies
Causes of Metabolic Acidosis
Adverse Effects of Metabolic Acidosis
Management of Metabolic Acidosis
Conclusions
Key Points

References

Box 1.

Box 2.

Box 3.

CME

Metabolic Acidosis: Pathophysiology, Diagnosis and Management

Target Audience and Goal Statement

Disclosures

Author(s)

Jeffrey A. Kraut, MD

Nicolaos E. Madias, MD

Editor

Susan Allison

CME Author(s)

Charles P. Vega, MD

CME Reviewer(s)

Sarah Fleischman

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Metabolic Acidosis: Pathophysiology, Diagnosis and Management: Adverse Effects of Metabolic Acidosis

Adverse Effects of Metabolic Acidosis

Figure 1.

Acute Metabolic Acidosis

Chronic Metabolic Acidosis

Table of Contents

Box 1.

Box 2.

Box 3.

References

Faculty and Disclosures

Author(s)

Jeffrey A. Kraut, MD

Nicolaos E. Madias, MD

Editor

Susan Allison

CME Author(s)

Charles P. Vega, MD

CME Reviewer(s)

Sarah Fleischman

CME

Metabolic Acidosis: Pathophysiology, Diagnosis and Management

Target Audience and Goal Statement

Disclosures

Author(s)

Jeffrey A. Kraut, MD

Nicolaos E. Madias, MD

Editor

Susan Allison

CME Author(s)

Charles P. Vega, MD

CME Reviewer(s)

Sarah Fleischman

Accreditation Statements

For Physicians

Instructions for Participation and Credit

Metabolic Acidosis: Pathophysiology, Diagnosis and Management: Adverse Effects of Metabolic Acidosis

Adverse Effects of Metabolic Acidosis

Figure 1.

Acute Metabolic Acidosis

Chronic Metabolic Acidosis

Table of Contents