Metabolic Acidosis

Introduction

What is metabolic acidosis?

• Metabolic acidosis is a pathologic process characterized by an increase in hydrogen ions (H⁺) and a decrease in serum bicarbonate (HCO₃^–).
  • Acidemia is defined as low arterial pH (less than 7.35) and may or may not be present in patients with metabolic acidosis, depending on the presence of other acid-base disorders and compensatory mechanisms.
  • Therefore, patients with metabolic acidosis may have low, normal, or high pH.
• Most commonly, metabolic acidosis results from increased pathologic anions, leading to an increased anion gap; however, it may also occur with a normal or low anion gap.¹
• These changes may be characterized as acute or chronic.
• Please refer to the OA Summaries “Normal Acid-Base Balance” and “Acid-Base Buffer Systems” for further discussion of normal physiology and compensatory mechanisms.

When to suspect?

• Metabolic acidosis is common in critically ill patients, with one study demonstrating that approximately 64% of patients in intensive care units (ICUs) in the United States are affected.²
• Metabolic acidosis may also be seen with toxic ingestions and excessive IV fluid treatment.
• Chronic metabolic acidosis is less common but should be considered in patients with chronic kidney disease (CKD), renal tubular acidosis, and chronic diarrhea.

Why do we care?

Acute Metabolic Acidosis

• Acute metabolic acidosis, occurring within minutes to hours, primarily impacts the cardiovascular system and is a significant cause of mortality.
  • Cardiac contractility and cardiac output are reduced.
  • Arterial vasodilation leads to hypotension.
  • Patients with severe acidosis also develop a resistance to the inotropic and vasoconstrictive effects of infused catecholamines.
  • Mental confusion and lethargy are often observed. Other physiological effects are shown in Figure 1.

• Interestingly, evidence suggests that it is the cause of acidosis, and not the pH itself, that leads to adverse events.
  • For example, a pH less than 6.9 in lactic acidosis is a strong predictor of mortality, whereas the same pH in diabetic ketoacidosis (DKA) is not associated with cardiac dysfunction or mortality.¹
  • Lactic acidosis associated with trauma, sepsis, or cardiogenic shock had the highest mortality. Mortality from severe acidosis (pH less than 7.2) in ICU patients, excluding DKA, was 57%.¹

Chronic Metabolic Acidosis

• Chronic metabolic acidosis, occurring over time, primarily affects the musculoskeletal system, including bone resorption and muscular wasting. Other physiologic effects are demonstrated in Figure 2.
• Patients may also experience chronic compensatory hyperventilation and dyspnea.

Evaluation

Compensatory Mechanisms

• Metabolic acidosis induces both acute and chronic compensatory patterns. Though discussed briefly here, please refer to OA Summary “Acid-Base Buffer Systems” for further information.
• Metabolic processes that increase plasma hydrogen ion concentration shift the equation below to the left, thereby decreasing both plasma hydrogen ion and bicarbonate concentrations.

• • The resulting increase in PaCO₂ increases minute ventilation, except in patients with respiratory failure or on mechanical ventilation.
  • Chronic metabolic (renal) compensation takes hours to days, leading to increased acid excretion and decreased bicarbonate loss.
  • The liver assists in management via metabolism of anions responsible for the metabolic acidosis (e.g., lactate, acetate, citrate) and metabolism of glutamate into ammonia (Park).

Common Etiologies

• Management of metabolic acidosis relies on accurate assessment of its cause and mechanism.
• Metabolic acidosis may be classified based on mechanism:
  • Increased endogenous acids (lactic acids, ketoacids, urates, etc.)
  • Ingestion or infusion of exogenous acids (toxic alcohols, salicylates, etc.)
  • Relative increase of chloride compared to sodium (gastrointestinal losses, 0.9% NaCl, etc.)
• Alternatively, metabolic acidosis may be classified based on whether there is a relative increase in unmeasured anions.
  • Increased acid production (endogenous or exogenous) lead to a relative increase in unmeasured anions creating a high anion gap metabolic acidosis (HAGMA).
  • The relative increase of chloride leads to a non-anion gap metabolic acidosis (NAGMA).
    • Note: There are situations in which an anion gap may appear normal despite having a high anion gap, discussed in Key Equations.¹
  • Common causes of HAGMA and NAGMA are listed below. Further discussion of causes and management is detailed in Table 2.

Diagnostic Approach

• Generally, a detailed history and physical examination, along with serum electrolytes and a calculation of the anion gap, are sufficient to determine the etiology (traditional/ Henderson-Hasselbach approach).
• In more complicated situations, a stepwise approach should be used to determine the underlying cause of metabolic acidosis (physicochemical). The flowchart below offers one such method for analysis.¹
• Please refer to the OA Summary on normal acid-base balance (Link) for further consideration of the details, strengths, and weaknesses of physicochemical vs traditional (Henderson-Hasselbach) evaluation methods.

Key Equations

Anion Gap

• Anion gap (AG) is the difference in the concentrations of major cations and anions in plasma.

• A normal anion gap is 6-12 mEq/L, comprised primarily of albumin (the predominant plasma anion buffer) and phosphate.
• Based on the anion gap, metabolic acidosis may be classified as HAGMA or NAGMA.
  • There are limitations to using the anion gap for classifying metabolic acidosis. HAGMA can occur in conjunction with NAGMA. Secondly, HAGMA can be present despite a normal or low anion gap if there is concurrent hypoalbuminemia.¹

Expected Anion Gap

• Given that albumin is the predominant anion in the anion gap, hypoalbuminemia may result in a normal or low anion gap despite the presence of pathologic anions leading to an acidosis.
• Therefore, the expected anion gap may be calculated using:

Strong Ion Gap (SIG)

• SIG is a simplified method for quantifying the presence of unmeasured anions, including organic and inorganic acids and exogenous anions, even in the setting of hypoalbuminemia. The SIG is equivalent to HAGMA corrected for albumin, simplified below.

Base Excess/Deficit

• Like anion gap, base excess (or base deficit) can be used to approach metabolic acidosis. Base deficit is the amount of strong base required to titrate a liter of whole blood to a pH of 7.40 at 37°C at a PaCO₂ of 40 mmHg.
• Metabolic acidosis is associated with an abnormally large negative base excess (less than -2 mEq/L).
  • A key limitation of the base deficit is that it does not distinguish among the contributions of hypoalbuminemia, chloride excess, and unmeasured anions to metabolic acidosis.

Strong Ion Difference (SID)

• Strong ion difference is another concept arising from the physicochemical approach to acid-base disturbances. Please see the OA summary on normal acid-base balance for more details. Link

Apparent Strong Ion Difference (SIDa)

• SIDa is the simplified difference in ionic strength between the dominant cation (sodium) and the dominant anion (chloride) and allows the practitioner to determine whether chloride is contributing to metabolic acidosis.

• A normal SID_a value is 35mEq/L.
  • A low value indicates NAGMA, as indicated by a relative increase in chloride relative to sodium.
  • A high value indicates that alkalosis may coexist with HAGMA if renal compensation is present.

Expected PaCO₂

• Multiple rules exist for the consideration of metabolic acidosis respiratory compensation, including:

1. Expected PaCO₂ (mmHg)=1.5[HCO₃^–] + 8 ± 2 (Winter’s formula)
2. Expected PaCO₂ (mmHg)= [HCO₃^–] + 15
3. Expected PaCO₂ should approximate the decimal digits of arterial pH (e.g., if pH = 7.25, then pCO₂ should approximate 25mmHg).
4. If severe metabolic acidosis (HCO₃^– less than 7 mEq/L) then pCO₂ should be maximally reduced to 8-12mmHg

Management

• Acid-base status must be considered in anesthesiology, particularly with respect to ventilation, carbon dioxide management, anesthetic agents, fluid therapy, and blood products.
• Management for common (and less common) etiologies of acute metabolic acidosis is summarized in the table below.
• Most importantly, management of metabolic acidosis should focus on treating the underlying condition rather than the pH or bicarbonate itself.

Additional Management Strategies

Bicarbonate supplementation in acute metabolic acidosis

• Administration of bicarbonate has not been shown to decrease cardiovascular events or mortality and is generally avoided due to possible adverse effects.³
• Adverse effects include paradoxical intracellular acidosis, increased lactate production, myocardial depression, hypertonicity of the extracellular fluid due to hypertonic solution administration, volume overload, overshoot that can cause metabolic alkalosis, potentiation of organic acid synthesis, and effects on sodium and calcium concentrations.
• Some recommend administration of bicarbonate when there is severe acidemia (pH less than 7.1) that does not improve rapidly or in those with pH 7.1-7.2 with severe AKI. May decrease the need for dialysis and mortality.⁴
• A relative hyperchloremic pattern lacks bicarbonate precursors; therefore, patients with this pattern depend on base administration by the clinician and bicarbonate generation by the kidneys, making patients with this pattern more likely to benefit from bicarbonate.²
• Also beneficial in the management of toxicities, including salicylates, methanol, and ethylene glycol, as it can reduce the formation of soluble toxins and enhance urinary clearance.¹

Bicarbonate supplementation in chronic metabolic acidosis

• In chronic metabolic acidosis, increased bicarbonate supplementation may reduce compensatory hyperventilation and dyspnea, as well as other adverse effects of chronic metabolic acidosis.
• Oral supplementation may be useful in patients with CKD when serum bicarbonate is less than 22mEq/L to slow the decline of glomerular filtration rate (GFR).¹

Trishydroxymethyl Aminomethane (THAM)

• THAM is an amino alcohol that has been investigated as an alternative to bicarbonate, as it has been shown to increase extracellular pH without reducing intracellular pH.
• Pros: THAM buffers hydrogen ions, may reduce carbon dioxide, and generates bicarbonate via the following equation:

• Cons: THAM must have intact renal function to excrete, or THAM-NH₃ molecules require dialysis to remove; other potential adverse effects are also possible.²

Potential Benefits of Metabolic Acidosis

• Metabolic acidosis may not be entirely harmful, as acidotic conditions may:¹
  • Fuel monocyte differentiation into macrophages
  • Use acetoacetate to maintain mitochondrial function and allow for mitochondrial remodeling
  • Delay cell death in hepatocytes in anoxic environments
  • Minimize infarct size during reperfusion after myocardial infarction
• Correcting pH abrogates these protective effects, underscoring the importance of correcting the underlying cause rather than the pH itself.

Conclusion

• Multiple approaches exist for evaluating metabolic acidosis, including traditional and physicochemical models.
• Acute metabolic acidosis is a potentially lethal consequence of acute illness or toxicity, primarily affecting the cardiovascular system; management addresses the underlying cause with bicarbonate or THAM as therapies in case of severe acidemia.
• Chronic metabolic acidosis primarily affects the musculoskeletal system in the context of chronic disease; oral bicarbonate supplementation may help alleviate dyspnea and slow the decline of GFR.