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Bicarbonate therapy in lactic acidosis

Bicarbonate therapy in lactic acidosis
Literature review current through: Jan 2024.
This topic last updated: Mar 30, 2022.

INTRODUCTION — Lactic acidosis causes a decrease in serum bicarbonate concentration that is similar in magnitude to the increase in the lactate concentration. Lactate is a metabolizable organic anion that, when oxidized, will generate bicarbonate. Thus, if the stimulus to lactic acid production is eliminated by successful treatment of the underlying disease (eg, restoration of perfusion in a patient with shock), oxidative processes will metabolize the accumulated lactate and regenerate bicarbonate. This will correct the metabolic acidosis and reduce the anion gap.

The role of exogenous bicarbonate therapy in patients with lactic acidosis is controversial [1-5]. Most, but not all, experts believe that it is appropriate to use bicarbonate in acutely ill patients with profound lactic acidosis and acidemia (arterial pH less than 7.1). Such severe acidemia may produce hemodynamic instability as a result of reduced left ventricular contractility, arterial vasodilation, and impaired responsiveness to catecholamines [1,5-10].

The role of bicarbonate therapy and alternative buffering agents in patients with lactic acidosis will be discussed in this topic. The causes of lactic acidosis, the approach to the adult with metabolic acidosis, and the treatment of shock in adults are presented elsewhere:

(See "Causes of lactic acidosis".)

(See "Approach to the adult with metabolic acidosis".)

(See "Treatment of severe hypovolemia or hypovolemic shock in adults".)

The use of bicarbonate dialysis to correct lactic acidosis caused by metformin is discussed separately. (See "Metformin poisoning".)

OVERVIEW OF THERAPY — The following general approach applies to the use of bicarbonate therapy in patients with lactic acidosis:

Who should be treated – In our opinion, bicarbonate therapy should be initiated when lactic acidosis has generated severe acidemia (ie, pH less than 7.1). In patients with less severe acidemia (eg, pH 7.1 to 7.2) and severe acute kidney injury (ie, a twofold or greater increase in serum creatinine or oliguria), bicarbonate therapy can potentially prevent the need for dialysis and may improve survival [11]. (See 'Which patients should receive bicarbonate therapy' below.)

Goals of therapy – The primary therapy is reversal of the underlying disease (eg, shock). When using bicarbonate therapy in patients with lactic acidosis and severe acidemia, the aim is to maintain the arterial pH above 7.1 until the primary process causing the metabolic acidosis can be reversed. However, if the patient has severe acute kidney injury, then the goal is to raise the pH above 7.3. (See 'Therapeutic goal' below.)

Potential harms – Rapid infusions of sodium bicarbonate may increase the partial pressure of carbon dioxide (PCO2), accelerate the production of lactate, lower the ionized calcium, expand the extracellular space, and raise the serum sodium concentration. There is little evidence that any alternative buffering agents are superior to sodium bicarbonate therapy. (See 'Potential harms of bicarbonate and alternative agents' below.)

Approach – In adequately ventilated patients with lactic acidosis and severe acidemia, we give 1 to 2 mEq/kg sodium bicarbonate as an intravenous bolus. We repeat this dose after 30 to 60 minutes if the pH is still below 7.1. (See 'Approach' below.)

WHICH PATIENTS SHOULD RECEIVE BICARBONATE THERAPY — We suggest that patients with lactic acidosis and severe acidemia (pH less than 7.1 and serum bicarbonate level 6 mEq/L or less) receive bicarbonate therapy.

In addition, we suggest bicarbonate therapy for less severe acidosis (ie, pH 7.1 to 7.2) in patients who also have severe acute kidney injury (ie, a twofold or greater increase in serum creatinine or oliguria). Bicarbonate therapy in such patients may prevent the need for dialysis and improve survival [11].

If the patient's pH is 7.1 or lower and the serum bicarbonate level is greater than 6 mEq/L, then this indicates that the partial pressure of carbon dioxide (PCO2) is greater than 20 mmHg, which signifies inadequate ventilation. Such patients have mixed metabolic and respiratory acidosis, and rapid infusion of sodium bicarbonate may worsen the respiratory acidosis. Mechanical ventilation may be necessary to achieve a lower PCO2 level and raise the pH in these patients with severe acidemia due to mixed acidosis.

Data supporting the use of sodium bicarbonate therapy when the pH is below 7.1 are lacking. However, we suggest its use in such patients because it may treat or prevent the following adverse clinical effects of acidemia, each of which can produce hemodynamic instability [1,5-10,12]:

Reduced left ventricular contractility

Arrhythmias

Arterial vasodilation and venoconstriction

Impaired responsiveness to catecholamine vasopressors

In addition, relatively small bicarbonate concentration changes will have a large pH impact when the serum bicarbonate concentration is markedly reduced (doubling the bicarbonate concentration, for example from 2 to 4 mEq/L, without a change in PCO2 will raise the pH by 0.3 units). Sodium bicarbonate infusion will also expand the extracellular fluid (ECF) volume, an effect that can be beneficial or deleterious, depending upon the patient's preinfusion volume status.

We do not generally use bicarbonate therapy in patients with less severe acidosis (pH 7.1 or greater), unless the patient also has severe acute kidney injury. The best data come from a randomized trial of 389 critically ill patients with metabolic acidosis (mean serum bicarbonate, 13 mmol/L), elevated lactate (mean lactate, 5.8 mmol/L, and more than 80 percent of patients had levels greater than or equal to 2 mmol/L), and less severe acidemia (mean arterial pH, 7.15) who were assigned to either intravenous infusions of sodium bicarbonate (to maintain a pH greater than 7.3) or to no sodium bicarbonate [11]. Bicarbonate therapy had no statistically significant effect on mortality at 28 days (45 versus 54 percent) or organ failure at 7 days (62 versus 69 percent). However, among the subgroup of patients with severe acute kidney injury (defined as a twofold or greater increase in serum creatinine or oliguria), bicarbonate therapy reduced 28-day mortality (46 versus 63 percent) and the need for dialysis (51 versus 73 percent).

However, as discussed below, patients should generally be adequately ventilated before bicarbonate therapy is given. (See 'Potential harms of bicarbonate and alternative agents' below.)

The use of bicarbonate therapy in patients with cardiac arrest is discussed separately. (See "Advanced cardiac life support (ACLS) in adults", section on 'Medications used during CPR'.)

THERAPEUTIC GOAL — The primary aim of therapy is reversal of the underlying disease (eg, shock, sepsis). Tissue hypoxia may dramatically increase lactic acid production, often coupled with reduced metabolic clearance of lactate by the liver, heart, and kidneys. This combination of overproduction and underutilization can easily overwhelm any attempt to increase the serum bicarbonate with exogenously administered alkali. In fact, as discussed below, alkali therapy may accelerate lactic acid production. Thus, unless the pathologic process causing the excessive production of lactic acid can be reversed, any beneficial effect of exogenous bicarbonate will be transient. (See 'Potential harms of bicarbonate and alternative agents' below.)

When using bicarbonate therapy in patients with lactic acidosis and severe acidemia, we aim to maintain the arterial pH above 7.1 until the primary process causing the metabolic acidosis can be reversed. For the group of patients with severe acute kidney injury, the pH goal is 7.3 or higher.

POTENTIAL HARMS OF BICARBONATE AND ALTERNATIVE AGENTS

Potential harms of bicarbonate therapy — Rapid infusions of sodium bicarbonate have a number of potentially adverse effects:

Increased arterial and tissue capillary partial pressure of carbon dioxide (PCO2)

Acceleration of lactate generation

Reduced ionized calcium

Hypernatremia

Extracellular fluid (ECF) volume expansion

Increased PCO2 — The infused bicarbonate must undergo several metabolic steps to effectively raise the pH. First, it combines with a hydrogen ion to form carbonic acid (H2CO3). Second, H2CO3 dehydrates to carbon dioxide (CO2), and water (H2O). Then the CO2 must be removed from the tissue bed and from the body by circulation and respiration. If the CO2 generated by infused bicarbonate is not efficiently removed, then the resulting increase in PCO2 will prevent carbonic acid dehydration and the pH will not increase. Consequently, adequate perfusion and ventilation is a prerequisite to the effective use of exogenous bicarbonate.

Even with adequate ventilation, the PCO2 is likely to transiently rise at the local tissue level when bicarbonate is infused rapidly. Because CO2 readily penetrates cell membranes, this increase in tissue PCO2 may worsen intracellular acidosis even as arterial blood pH increases. This dissociation between tissue and systemic arterial acid-base parameters is magnified in patients with circulatory failure [13,14].

The cerebrospinal fluid (CSF) pH may also fall when bicarbonate is infused for two reasons: first, the mechanism described above increases the PCO2 locally in the brain and CSF; second, amelioration of systemic acidemia (ie, the rise in arterial blood pH) diminishes the drive for hyperventilation, causing the systemic PCO2 to increase. Any systemic and/or local increase in PCO2 will be quickly reflected within the CSF. By contrast, an increased blood bicarbonate concentration is only slowly transmitted to the CSF. Because CSF bicarbonate concentration does not rise as rapidly as the CSF PCO2, a "paradoxical" reduction in CSF pH may occur and this phenomenon has been associated with neurologic deterioration [15,16].

Acceleration of lactate generation — Acidemia will act as a "brake" on lactic acid generation by inhibiting glycolysis, largely mediated by a reduction in the activity of the enzyme, phosphofructokinase [17]. Thus, increasing pH with exogenous bicarbonate may accelerate the production of lactate.

Effects on calcium, sodium, and extracellular fluid volume — An increase in pH can decrease the ionized calcium concentration, which may adversely affect cardiac function [9,18]. Because sodium bicarbonate is usually infused as a hypertonic solution (8.4 percent), a 50 mL ampule containing 50 mEq of sodium bicarbonate (1000 mmol/L) will raise the serum sodium concentration of a 70 kg person by approximately 1 mEq/L and expand the ECF volume by approximately 250 mL.

Alternatives to bicarbonate therapy — The limitations and potential deleterious effects of sodium bicarbonate therapy in patients with lactic acidosis have prompted investigation of alternative buffering agents:

Tromethamine or tris-hydroxymethyl aminomethane (THAM) is an amino alcohol that buffers protons by virtue of its amine (NH2) moiety (pKa = 7.7). The potential advantage of THAM is that, unlike bicarbonate (HCO3), which generates CO2, this chemical reduces CO2 [19].

Carbicarb is an equimolar mixture of sodium carbonate (Na2CO3) and sodium bicarbonate (NaHCO3) that generates less CO2 than HCO3 [20].

Dichloroacetate (DCA) is an investigational drug that increases the activity of the enzyme pyruvate dehydrogenase and therefore accelerates mitochondrial oxidation of pyruvate and lactate metabolism [21].

Each of these alternatives to NaHCO3 has been studied and, despite certain theoretical advantages, none have been proven to be more effective or safer [20,22-28]. In addition, none of these agents are available for use in the United States.

APPROACH — In critically ill patients with severe lactic acidosis, which has resulted in severe acidemia (pH less than 7.1 and serum bicarbonate concentration 6 mEq/L or less), we suggest the following approach in regard to bicarbonate therapy:

Assure that the patient is adequately ventilated; this is a prerequisite to the effective use of exogenous bicarbonate in patients with lactic acidosis. In nonintubated patients with severe acidemia, an appropriate ventilatory response to the metabolic acidosis should reduce the partial pressure of carbon dioxide (PCO2) to at least 15 mmHg and often to 10 to 12 mmHg.

If bicarbonate administration raises the pH, this can reduce the ionized calcium concentration and have adverse hemodynamic consequences. Ideally, the ionized calcium should be measured and treated if it falls. However, in many facilities, this measurement may not be readily available within the required time frame. Under such circumstances, if the blood pressure falls or does not improve, and if the ionized calcium could be low, then empiric calcium infusion should be considered [5].

If ventilation is adequate, the patient with severe lactic acidosis (pH less than 7.1) should be given an intravenous sodium bicarbonate bolus of 1 to 2 mEq/kg body weight. The serum electrolytes and blood pH should be measured 30 to 60 minutes later, and the dose of sodium bicarbonate can be repeated if severe lactic acidosis (pH less than 7.1) persists.

We prefer this empiric approach to the dosing of bicarbonate, rather than calculating the dose based upon the "bicarbonate distribution space." The bicarbonate distribution space is a virtual concept and not a true anatomic space. Its size varies markedly with the severity of the metabolic acidosis. In addition, since bicarbonate can be rapidly generated or decomposed, its apparent distribution space can change dramatically.

If several doses of NaHCO3 do not increase the pH above 7.1 and all other appropriate therapeutic interventions have been undertaken, then further NaHCO3 therapy should continue in the form of a near-isotonic solution of NaHCO3. This can be prepared by adding 3 ampules of NaHCO3 (8.4 percent) to a liter of 5% dextrose in water (D5W), which results in a solution of 150 mEq/L NaHCO3 in D5W. This has the advantage of being relatively isotonic but does increase the volume given to the patient. If volume overload is an issue and kidney function is compromised, then dialytic therapy can be instituted.

Dialytic therapy may be particularly effective in the treatment of otherwise refractory lactic acidosis [29]. Usually, a continuous form of dialytic therapy is used to minimize hemodynamic problems. Several advantages of such intervention include:

The administration of bicarbonate while maintaining or improving the patient's volume status

Avoidance of hypertonicity

Maintenance of a normal ionized calcium

Removal of toxins associated with lactic acidosis (eg, metformin, alcohols) (see "Metformin poisoning")

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)

SUMMARY AND RECOMMENDATIONS

The role of exogenous bicarbonate therapy in patients with lactic acidosis is controversial. Most experts believe that it is appropriate to use bicarbonate in acutely ill patients with profound lactic acidosis that has generated an arterial pH less than 7.1 and a serum bicarbonate of 6 mEq/L or less. Such severe acidemia may produce hemodynamic instability as a result of reduced left ventricular contractility, arterial vasodilation, and impaired responsiveness to catecholamines. (See 'Introduction' above.)

The following general approach applies to the use of bicarbonate therapy in patients with lactic acidosis (see 'Overview of therapy' above):

The primary therapy for lactic acidosis is reversal of the underlying disease (eg, shock). (See 'Therapeutic goal' above.)

In patients with lactic acidosis that has generated severe acidemia (arterial pH less than 7.1 [usually accompanied by a serum bicarbonate of 6 mEq/L or less]), we suggest sodium bicarbonate therapy rather than no alkali therapy (Grade 2C). (See 'Which patients should receive bicarbonate therapy' above.)

The goal of bicarbonate therapy in patients with lactic acidosis and severe acidemia is to maintain the arterial pH above 7.1 until the primary process causing the metabolic acidosis can be reversed. (See 'Therapeutic goal' above.)

In adequately ventilated patients with lactic acidosis and severe acidemia, we give 1 to 2 mEq/kg sodium bicarbonate as an intravenous bolus. We repeat this dose after 30 to 60 minutes if the pH is still less than 7.1. (See 'Approach' above.)

In patients with lactic acidosis that has generated less severe acidemia (ie, arterial pH 7.1 to 7.2), we suggest sodium bicarbonate therapy, rather than no alkali therapy, if severe acute kidney injury is also present (defined as a twofold or greater increase in serum creatinine or oliguria) (Grade 2B). We generally target a pH of 7.3 or higher in such patients. We do not typically give sodium bicarbonate to patients with arterial pH 7.1 or higher if they do not have severe acute kidney injury. (See 'Which patients should receive bicarbonate therapy' above.)

Rapid infusions of sodium bicarbonate may increase the partial pressure of carbon dioxide (PCO2), accelerate the production of lactate, lower the ionized calcium, expand the extracellular space, and raise the serum sodium concentration. (See 'Potential harms of bicarbonate and alternative agents' above.)

There is little evidence that any alternative buffering agents are superior to bicarbonate therapy. (See 'Potential harms of bicarbonate and alternative agents' above.)

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