Metabolic acidosis may result from HCO3– loss, administration or ingestion of acid, or endogenous production and accumulation of acid. Loss of HCO3– occurs by externalization of intestinal contents (e.g., vomiting, enterocutaneous fistulae) and renal wasting of bicarbonate (e.g., renal tubular acidosis, carbonic anhydrase inhibitor therapy). Administration of acid, unlikely to be seen in the ED, occurs primarily with total parenteral nutrition, whereby patients receive hydrochloric salts of basic amino acids. Endogenous acids accumulate in renal tubular acidosis, ketoacidosis, and lactic acidosis. Acidosis from rapid infusion of normal saline, called dilutional acidosis, has been shown to involve endogenous accumulation from CO2 hydration.25
Unopposed metabolic acidosis results in a decreased serum [HCO3–] and an increase in serum [H+]. The increased [H+] stimulates the respiratory center, resulting in increased minute ventilation. The physiologically based "respiratory compensation" is an attempt to lower the [H+] by a reduction in Pco2 through increased ventilation. The steady-state relationship between the Pco2 and the [HCO3–] is shown in Eq. (8).‡‡ 12
While equation (8) expresses the steady-state values after 24 hour of metabolic acidosis, the respiratory response is almost immediate. When [HCO3–] is greater than ~8 mEq/L, the relationship between Pco2 and [HCO3–] is simpler. With normal respiratory compensation, Pco2 decreases by 1 mm Hg for every 1 mEq/L net decrease in [HCO3–]. Using these relationships allows the clinician to calculate the expected Pco2 from the measured [HCO3–], assuming respiratory compensation is normal. If the expected Pco2 value differs from the measured value in steady-state metabolic acidosis, then respiratory compensation is compromised, and a primary respiratory disorder exists in conjunction with the metabolic acidosis. As an example, if the [HCO3–] is 15 mEq/L, the expected Pco2 is ~30 mm Hg. If the actual measured value is higher than expected (e.g., 35 mm Hg), then by definition there is a concomitant respiratory acidosis (Figure 15–2A). If the measured value is lower than expected (e.g., 25 mm Hg), then there is a concomitant respiratory alkalosis. This latter case is not an example of overcompensation, but rather a second, simultaneous primary acid-base disturbance. These are important concepts. The body cannot tolerate metabolic and respiratory mechanisms for acidosis simultaneously, as one cannot buffer or compensate for the other.
Physiologic studies of otherwise healthy persons with acute metabolic acidosis caused by diarrhea found that the completeness of the respiratory response to metabolic acidosis depends on the duration of the acidosis, the time course of its development, and its severity. When [HCO3–] is held constant, steady-state Pco2 is reached in 11 to 24 hours. When acidosis develops slowly, there is no lag in respiratory compensation. If acidosis develops more quickly, the Pco2 is often higher than values observed in steady state; the more rapid and severe the acidosis, the larger is the difference between the observed Pco2 and the predicted steady-state CO2. The delay in full compensation again indicates the presence of concomitant respiratory acidosis, and the clinician must recognize the contribution of inadequate ventilation to the level of acidosis (e.g., [H+]). Thus, in the ED setting, the delay in reaching steady state is of passing interest as the labs results signify the reality of the moment. Unfortunately, the ED patient's illness can rarely be assumed to be in steady state.
There are limits to the adequacy of respiratory compensation during metabolic acidosis. Respiratory minute volume actually declines when pH decreases below 7.10. This finding has led clinicians to initiate bicarbonate therapy when pH falls below 7.10. It is particularly important to appreciate any contribution to the acidosis from inadequate respiratory response. Administration of HCO3– in the presence of hypoventilation may exacerbate the respiratory acidosis, because the HCO3– converts to CO2 and H2O.
The development of metabolic acidosis that drives the pH below 7.10 is likely associated with a very high risk of inadequate ventilation response, since there is a limit to respiratory compensation. The lowest Pco2 level achievable is ~12 mm Hg. This lower limit in obtainable Pco2 is due to resistance in airflow and increased CO2 generated by the exertion required for rapid ventilation, both offsetting the ventilator exhalation of CO2. The superimposition of respiratory acidosis on a patient in such a condition will result in a rapid decline of pH to levels at which organ function drops and pharmacotherapy will fail. Mechanical ventilation usually should be instituted in such situations to ensure the ventilatory rate and volume are sufficient to prevent an increase in Pco2 at this critical time.
The serum [K+] level is affected by metabolic acidosis. The movement of H+ into cells is associated with extrusion of K+. Changes in [K+] are more substantial during inorganic acidosis, although elevated serum [K+] is typically seen in diabetic ketoacidosis. In general, for each 0.10 change in the pH, serum [K+] will change by approximately 0.5 mEq/L, in an inverse relationship. Whatever the mechanism of the acidosis, it is important to remember that normal values as well as low serum [K+] likely reflect severe intracellular K+ depletion. As the acidosis is corrected, serum [K+] should fall, possibly to levels that may produce clinical symptoms, dysrhythmias, and other adverse outcomes.
CLINICAL FEATURES AND PHYSIOLOGIC CONSEQUENCES OF ACIDOSIS
Symptoms of the primary disorder causing metabolic acidosis dominate the clinical presentation; however, several symptoms are common to various etiologies. Patients may complain of abdominal pain, headache, nausea with or without vomiting, and generalized weakness, and because acidosis stimulates the respiratory center, the patient may complain of dyspnea.
Acidemia has numerous negative physiologic consequences that impair the function of enzymes as well as many different organs through mechanisms not yet well understood. Cardiac contractile function is reduced, likely due to impaired oxidative phosphorylation, intracellular acidosis, and alterations in intracellular calcium concentrations. The threshold for ventricular fibrillation falls as the defibrillation threshold rises. Hepatic and renal perfusion and systemic blood pressure decline, and pulmonary vascular resistance increases. The physiologic effects of catecholamines are attenuated, and when acidosis is sufficiently severe, vascular collapse may result. A catabolic state develops, including a generalized increase in metabolism, resistance to insulin, and inhibition of anaerobic glycolysis. The effect of hypoxia on all organs is aggravated.26
CAUSES OF METABOLIC ACIDOSIS
The causes of elevated AG metabolic acidosis are listed in Table 15–2. A comparison with the patient's steady-state AG should be made whenever possible. Measurement and detection of specific anions may be indicated.
Differential Diagnosis of Wide AG Acidosis
The differential diagnoses to be considered in emergency practice fall into four broad categories: renal failure (uremia), ketoacidosis (diabetic ketoacidosis, alcoholic ketoacidosis, starvation ketoacidosis), lactic acidosis, and ingestions (methanol, ethylene glycol, salicylates, and many others).
Renal failure should be evident from the serum chemistries. Acidosis seen in initial stages of renal failure may be severe, but tends to be stable, with [HCO3–] ~15 mEq/L in cases of chronic renal failure.
Positive serum ketones point to one of the ketoacidoses. In instances of known insulin-dependent diabetes mellitus, diabetic ketoacidosis is likely, although there is usually a component of lactic acidosis. In alcoholics who have recently stopped heavy drinking, alcoholic ketoacidosis should be considered; ketoacids contribute far less to the acidosis in ketoacidosis than lactate. Starvation ketosis will be found in patients with recent oral intake that is inadequate, such as in cases of fasting, dieting, or protracted vomiting, although the magnitude of acid-base disturbance in starvation ketosis should be small. The major ketone present in the serum of a patient with untreated diabetic or alcoholic ketoacidosis may be β-hydroxybutyrate. A specific test is now available. The older nitroprusside test yields a false-negative result for β-hydroxybutyrate. See chapter 223, "Type 1 Diabetes Mellitus for a detailed discussion.
Lactic acidosis occurs whenever lactate production exceeds lactate metabolism and is classified into two types. The first, in which tissue hypoxia is present and lactate production is elevated, is referred to as type A. Normal tissue oxygenation and impairment of lactate metabolism define the second, called type B. Severe acidosis that is resistant to treatment is seen in various type B lactic acidoses and ingestions. Lactic acidosis is not a diagnosis, but a syndrome with its own differential diagnosis. Causes of lactic acidosis include renal failure, shock, sepsis, cardiac arrest, trauma, seizures, tissue ischemia, diabetic ketoacidosis, thiamine deficiency, malignancy (e.g., leukemia), liver dysfunction, genetic disorders (e.g., metabolic diseases), toxins (e.g., methanol), and medications (e.g., metformin, salicylates, iron, isoniazid) (Table 15–2).
Lactate levels should be measured and accounted for in an adjustment of the AG. Ethanol is frequently cited as a cause of wide AG acidosis, but ethanol should never be considered the etiologic source of any significant metabolic acidosis; look for other causes. Although ethyl alcohol metabolism may lead indirectly to very mild lactic acidosis, usually due to the same mechanism as alcoholic ketoacidosis, in which lactic acidosis is more substantial, neither the alcohol nor its metabolites directly contribute to the acidosis.
Determination of the osmolal gap will help identify methanol and ethylene glycol from other etiologies. Although methanol is measured in most hospital laboratories, determination of ethylene glycol levels is performed off-site in many institutions. A widened osmolal gap without clear evidence of methanol ingestion may determine the diagnosis long before confirmatory laboratory evidence is available. Calculated adjustments to the osmolal gap may need to be made if ethanol is a co-ingestant (see chapter 185, "Alcohols" for detailed discussion).
Concomitant acid-base disturbance may further assist in determining the etiology. The triple acid-base disturbance of wide AG metabolic acidosis, metabolic alkalosis, and respiratory alkalosis is seen with sepsis (lactic acidosis) and salicylate poisoning. The latter also may be associated with a mild temperature elevation.
The relation of [HCO3–] to the AG and the [HCO3–] to the expected Pco2 compensation must be examined in every patient with wide AG acidosis to determine whether other acid-base disturbances, metabolic or respiratory, exist (Figure 15–2A).
Differential Diagnosis of Unchanged (Normal) AG Acidosis
The non-AG type of acidosis is often referred to as "normal" AG acidosis.3 Some texts refer to this as hyperchloremic metabolic acidosis, but not all cases of normal AG acidosis are associated with hyperchloremia. If the patient has hyponatremia with a normal AG acidosis, the chloride may be in the normal range. Abnormal chloride levels alone usually signify a more serious underlying metabolic disorder, such as metabolic acidosis (elevated chloride) or metabolic alkalosis (low chloride).27
Normal AG acidosis results from loss of HCO3–, failure to sufficiently excrete H+, or administration of H+. Bicarbonate may be lost from the urine or GI tract and is usually accompanied by K+ loss. However, potassium-sparing diuretics, hypoaldosteronism, urinary tract obstruction, and type IV renal tubular acidosis result in loss of HCO3– with retention of K+ (Table 15–3). Acetazolamide exerts its effect through carbonic anhydrase inhibition, inducing a functional renal tubular acidosis.
Causes of Normal Anion Gap Metabolic Acidosis
||Download (.pdf) Table 15–3
Causes of Normal Anion Gap Metabolic Acidosis
|With a Tendency to Hyperkalemia ||With a Tendency to Hypokalemia |
|Subsiding diabetic ketoacidosis ||Renal tubular acidosis, type I (classical distal acidosis) |
|Early uremic acidosis ||Renal tubular acidosis, type II (proximal acidosis) |
|Early obstructive uropathy ||Acetazolamide |
|Renal tubular acidosis, type IV ||Acute diarrhea with losses of HCO3– and K+ |
|Hypoaldosteronism (Addison's disease) ||Ureterosigmoidostomy with increased resorption of [H+] and [Cl–] and losses of HCO3– and K+ |
|Infusion or ingestion of HCl, NH4Cl, lysine-HCl, or arginine-HCl ||Obstruction of artificial ileal bladder |
|Potassium-sparing diuretics ||Dilution acidosis (may occur with 0.9% NaCl infusion) |
One should be wary of traditional classification based on [K+], because serum [K+] itself is dependent on the actual pH. Thus, in severe acidosis, a normal range [K+] value may be falsely reassuring. As the acidosis is corrected and acidemia resolves, the [K+] will concordantly fall.
Because all diuretics may cause a contraction alkalosis, the metabolic acidosis that occurs simultaneously with potassium-sparing diuretics may not be evident, as the two may simply cancel each other out (Figure 15–2C). Because the AG is unchanged, there is no indication that two distinct opposing processes may be occurring. As with wide AG–type acidosis, the expected Pco2 compensation must be examined in every patient with normal AG acidosis to determine whether other respiratory acid-base disturbances exist (Figure 15–2A).
The treatment of acidosis reflects that of the underlying disorder but particularly emphasizes restoration of normal tissue perfusion and oxygenation. The most important step is to determine whether there is a respiratory component to the acidosis (i.e., a primary respiratory acidosis), because the treatment approach differs. If there is inadequate respiratory compensation, the most appropriate treatment will be to first correct the respiratory problem. Address electrolyte disturbances, administer antidotes for toxins as appropriate, and initiate treatment for underlying causes such as sepsis (see chapter 150, "Toxic Shock Syndromes") or diabetic ketoacidosis (see chapter 225, "Diabetic Ketoacidosis").
Buffer Therapy in Acidosis
Slow replacement of sodium bicarbonate in patients with sodium bicarbonate loss due to diarrhea or proximal renal tubular acidosis is useful.28 The adverse effects of acidemia make the concept of buffer therapy teleologically appealing, but its role in instances of cardiac arrest and severe metabolic acidosis is unclear. A small 2013, single-center, randomized controlled trial showed mortality benefit in the treatment of sepsis patients; this study needs confirmation.29 The traditional therapeutic buffer, sodium bicarbonate, may have negative effects in the treatment of acidosis. Bicarbonate therapy results in the generation of significant quantities of CO2, which diffuses readily into cells, in particular those of the CNS, which may cause paradoxical worsening of intracellular acidosis. An abrupt CO2 increase may exceed the ventilatory capacity of a patient already at maximum minute ventilation, thereby producing abrupt and worsening respiratory acidosis. After successful treatment with bicarbonate, "overshoot" alkalosis may result. Bicarbonate therapy imposes an osmotic and sodium load (1000 mEq/L of typical 1 N solution). These concerns suggest that bicarbonate therapy should not be used in the ED treatment of mild to moderate metabolic acidosis.
Concerning use of buffer therapy for cardiac arrest, diabetic ketoacidosis, and lactic acidosis, several studies of HCO3– use in adult and pediatric cases, including patients with severe acidosis, failed to show any improvement in speed of recovery or decrease in complication rates with buffer therapy.26,28,30,31,32,33 There has been some suggestion of harmful effects, particularly an increased rate of development of cerebral edema in pediatric patients with diabetic ketoacidosis who were treated with bicarbonate. However, it remains unclear whether certain subgroups of patients (for example, those with cardiac or other disease) may benefit from bicarbonate therapy and dialysis.
The goal of bicarbonate and dialysis therapy in lactic acidosis may be to "bridge" the patient physiologically to definitive treatment of the etiology of the acidosis. Bicarbonate therapy may be appropriate for limited indications (Table 15–4).26,28,30,31,32,33,34
Potential Indications for Bicarbonate Therapy in Metabolic Acidosis
||Download (.pdf) Table 15–4
Potential Indications for Bicarbonate Therapy in Metabolic Acidosis
|Indication ||Rationale |
|Severe hypobicarbonatemia (<4 mEq/L) ||Insufficient buffer concentrations may lead to extreme increases in acidemia with small increases in acidosis. |
|Severe acidemia (pH <7.00 to 7.15)* in cases of wide anion gap acidosis, with signs of shock or myocardial irritability that has not responded to supportive measures including adequate ventilation and fluid resuscitation as indicated by the patient's clinical characteristics ||Therapy for the underlying cause of acidosis depends on adequate organ perfusion. |
|Severe hyperchloremic acidemia† ||Lost bicarbonate must be regenerated by kidneys and liver, which may require days. |
When given, HCO3– can be dosed 0.5 mEq/kg for each milliequivalent per liter rise in [HCO3–] desired.26 The goal is to restore adequate buffer capacity ([HCO3–] >8 mEq/L) or to achieve clinical improvement in shock or dysrhythmias. Bicarbonate should be given as slowly as the clinical situation permits. Seventy-five milliliters of 8.4% sodium bicarbonate in 500 mL of dextrose 5% in water produces a nearly isotonic solution for infusion. Adequate time should be allowed for the desired effect to be achieved, and close monitoring of acid-base balance, especially in patients with organic acidosis, is critical. Other buffers appeared promising in the treatment of metabolic acidosis during early studies but have failed to provide improvement in clinical outcomes, including carbicarb, and tris-hydroxymethyl amino-methane.