Which potential cause would the nurse associate with a patients diagnosis of metabolic acidosis?

Alkali Treatment of Metabolic Acidosis

Treatment of metabolic acidosis usually involves either sodium bicarbonate or citrate34 (Table 12.2). NaHCO3 can be taken orally as tablets or powder or given intravenously as a hypertonic bolus or an isotonic infusion, which can be created by adding 150 mmol NaHCO3 to 1 liter of 5% dextrose in water (D5W). This solution is useful if treatment requires both volume expansion and alkali administration.

Citrate may be taken orally as a liquid, as sodium citrate, potassium citrate, or citric acid, or a combination. Many patients find citrate-containing solutions more palatable than oral NaHCO3 as a source of oral alkali therapy. Oral citrate therapy should not be combined with medications that include aluminum. Citrate, which has a −3 charge under normal conditions, can complex with aluminum (Al3+) in the intestinal tract, resulting in an uncharged moiety that is rapidly absorbed across the intestinal tract and then can dissociate to release free aluminum. This can increase the rate of aluminum absorption dramatically and in some patients, particularly those with severe CKD, has resulted in acute aluminum encephalopathy.

The dose of alkali therapy administered is based on both the total body bicarbonate deficit and the desired rapidity of treatment. Under normal circumstances, the volume of distribution (VD) for bicarbonate is approximately 0.5 l/kg total body weight. Thus the bicarbonate deficit, in millimoles, can be estimated from the following formula:

Bicarbonate deficit=(0.5×LBWkg)×(24−HCO3−)

whereLBWkg is the lean body weight in kilograms and24 is the desired resultant bicarbonate concentration.

Several caveats regarding this equation should be understood. First, edema fluid contributes to the volume of distribution of bicarbonate. Accordingly, an estimation of the amount of edema fluid should be included in this calculation. Second, the volume of distribution for bicarbonate increases as the severity of the metabolic acidosis worsens. When serum [HCO3−] is 5 mmol/l or less, the volume of distribution may increase to 1 l/kg or more.

When acute treatment is desired, 50% of the bicarbonate deficit should be replaced during the first 24 hours. If hypertonic NaHCO3 is administered, the increase in serum [HCO3−] will be mirrored by an increase in serum [Na+]. After the initial 24 hours of therapy, the response to therapy and the patient's current clinical condition are reevaluated before future therapy is decided. Acute hemodialysis solely for the treatment of metabolic acidosis, other than that associated with renal failure, is rarely beneficial.

Renal Tubular Acidosis in Chronic Kidney Disease

Metabolic acidosis in advanced CKD is caused by failure of the tubular acidification process to excrete the normal daily acid load. As functional renal mass is reduced by disease, there is an adaptive increase in ammonia production and H+ secretion by the remaining nephrons. Despite increased production of ammonia from each remaining nephron, overall production may be decreased secondary to the decrease in total renal mass. In addition, there is less delivery of ammonia to the medullary interstitium secondary to a disrupted medullary anatomy.17 The ability to lower the urinary pH remains intact, reflecting the fact that the impairment in distal nephron H+ secretion is less than that in ammonia secretion. Quantitatively, however, the total amount of H+ secretion is small, and the acidic urine pH is the consequence of very little buffer in the urine. The lack of ammonia in the urine is reflected by a positive value for the UAG. Differentiation of RTA from type 4 RTA can be difficult as it is based on the clinician's determination of whether the severity of metabolic acidosis is out of proportion to the degree of renal dysfunction.

Patients with CKD may develop a hyperchloremic normal gap metabolic acidosis associated with normokalemia or mild hyperkalemia as GFR decreases to less than 30 ml/min. With more advanced CKD (GFR <15 ml/min), the acidosis may change to an anion gap metabolic acidosis, reflecting a progressive inability to excrete phosphate, sulfate, and various organic acids. At this stage, the acidosis is commonly referred to as uremic acidosis.

Correction of the metabolic acidosis in patients with CKD is achieved by treatment with NaHCO3, 0.5 to 1.5 mmol/kg per day, beginning when the HCO3− level is less than 22 mmol/l. In some cases, non–sodium citrate formulations can be used. Loop diuretics are often used in conjunction with alkali therapy to prevent volume overload. If the acidosis becomes refractory to medical therapy, dialysis needs to be initiated. Recent evidence suggests that metabolic acidosis in the setting of CKD needs to be aggressively treated as chronic acidosis is associated with metabolic bone disease and may lead to an accelerated catabolic state in patients with chronic kidney disease.18,19

Step 3: Calculate the Anion Gap to Determine the Presence of a High AG Metabolic Acidosis

All evaluations of acid-base disorders should include a simple calculation of the AG since an elevated AG usually implies a metabolic acidosis. The AG is calculated from the serum electrolytes and is defined as follows:

(16.11)AG=Na+−(Cl−+HCO3−)=10±2mEq/L

The AG represents the unmeasured anions normally present in plasma and unaccounted for by the serum electrolytes exclusive of K+ that are measured on the electrolyte panel. Normal values for AG vary with the laboratory and analyte measurement techniques, but in general have declined with more precise measurement of serum electrolytes by ion selective electrodes. The normal value for AG ranges from 8-12 mEq/L, but the clinician should know the normal value for the AG in clinical laboratories used in their practice. Because of this range of normal values for the AG and for convenience, the following computations will use the value of 10 mEq/L as the “normal” anion gap. The unmeasured anions that contribute to this value are normally present in serum and include anionic proteins (principally albumin and, to lesser extent, α- and β-globulins), PO43–, SO42–, and organic anions. As already emphasized, interpretation of the anion gap requires either a normal serum albumin, or correction of the AG to a normal plasma albumin. In general, reduction in the serum albumin level by 1 g/dL from the normal value of 4.5 g/dL decreases the AG by 2.5 mEq/L. When acid anions, such as acetoacetate and lactate, are produced endogenously in excess and accumulate in ECF, the AG increases above the normal value. This is referred to as ahigh anion gap acidosis.27,28 Additionally, in a simple high AG metabolic acidosis, for each milliequivalent per liter increase in the corrected AG, there should be an equal decrease, measured as milliequivalent per liter, in the plasma HCO3− concentration.

A number of conditions other than metabolic acidosis can occasionally change the AG up or down (Table 16.3). An increase in the AG may be due to a decrease in unmeasured cations or an increase in unmeasured anions. Combined severe hypocalcemia and hypomagnesemia represent a decrease in the contribution of unmeasured cations. In addition, the AG may increase secondary to an increase in anionic albumin, as a consequence of either an increased albumin concentration or alkalemia.27,28 The increased AG in severe alkalemia can be explained in part by the effect of alkaline pH on the electrical charge of albumin.

Sepsis

Metabolic acidosis is common in patients with sepsis and septic shock; nevertheless, the exact incidence of metabolic acidosis in sepsis is largely unknown,52 with several small studies reporting temporal trends in specific populations.40,52 Lactic acidosis has been considered the hallmark of acid-base change in sepsis, but this is not the case. It has been more than 15 years since the strict association between anaerobiosis, hyperlactatemia, and sepsis was first questioned,34 and recent evidence points toward an acid-base profile in infection that is more complex than mere elevation in lactate levels. This does not mean that lactate is not important; in fact, lactate is related intrinsically to outcome in critically ill patients53 and has been incorporated into the new definitions of septic shock.54

In a prospective study of 60 patients with severe sepsis or septic shock admitted to a single tertiary ICU, Noritomi et al.40 highlighted the complexity and time trends of acid-base variables in sepsis. In brief, most of the acidosis was caused by hyperchloremia (and not because of high lactate levels, as may be presumed). Interestingly, survivors corrected their metabolic acidosis during their ICU stay through reduction of lactate levels and by reduction in SIG. Hypoalbuminemia had an important alkalizing effect in survivors and nonsurvivors.40

Malaria is an infectious disease in which acidosis and its components have been studied in greater detail. In this population, despite a high prevalence of hyperlactatemia,55 SIG was a more important determinant of mortality than lactate.56 An increase in SIG was associated with illness severity and encephalopathy, with many anions contributing to SIG (mostly hydroxyphenyllactic acid, α-hydroxybutyric acid, and β-hydroxybutyric acid).57 In children with meningococcemia, hyperchloremia accounts for the majority of metabolic acidosis occurring after the first 12 hours.58

Treatment of Metabolic Acidosis

As the number of functioning nephrons declines, CKD leads to net retention of hydrogen ions, which begins when GFR falls below 40 to 50 mL/min/1.73 m2.199 Among persons in whom GFR decreases from 90 to less than 20 mL/min/1.73 m2, the prevalence of metabolic acidosis rises from 2% to 39% and is higher among younger persons and those with diabetes.200 As the patient approaches ESKD, the plasma bicarbonate concentration tends to stabilize between 15 and 20 mEq/L. Chronic metabolic acidosis has multiple adverse consequences, including increased protein catabolism, increased bone turnover, induction of inflammatory mediators, insulin resistance, and increased production of corticosteroids and parathyroid hormone. Several observational studies, including the CRIC study, have identified low serum bicarbonate as a risk factor for CKD progression,201 although post hoc analysis of data from persons with diabetic kidney disease enrolled in the RENAAL and IDNT studies found that an association between lower serum bicarbonate and renal outcomes was not maintained after adjustment for baseline GFR.202

The first study to show convincing renoprotection with bicarbonate supplementation was from a single center and involved 134 persons with advanced CKD (creatinine clearance rates between 15 and 30 mL/min/1.73 m2) and baseline serum bicarbonate concentrations of 16 to 20 mEq/L. The participants were randomly assigned to receive treatment with oral bicarbonate or no treatment.203 After 2 years of follow-up, there was a lower mean rate of decline in creatinine clearance (1.88 vs. 5.93 mL/min/1.73 m2) and a lower risk of ESKD among the persons who received the bicarbonate treatment than among the controls (6.5% vs. 33%). In a subsequent randomized, placebo-controlled trial in persons with a mean eGFR of 75 mL/min/1.73 m2, treatment with sodium bicarbonate for 5 years was associated with a slower rate of decline in eGFR (derived from plasma cystatin C measurements) compared with placebo or treatment with sodium chloride.204 Western diets are typically acid producing, but the addition of significant portions of fruits and vegetables can move this to a base-producing state. Further studies have reported that correction of acidosis with a diet rich in fruits and vegetables was as effective as sodium bicarbonate in ameliorating kidney damage in early (stage 1 or 2 CKD)205 and more advanced (stage 4 CKD) disease.206 Furthermore, a recent trial has reported benefit even in people with mild acidosis. People with stage 3 CKD and serum bicarbonate 22 to 24 mmol/L were randomized to oral bicarbonate supplementation, a diet rich in fruits and vegetables, or “usual care.” All participants received treatment with an RAAS inhibitor, and SBP was controlled to lower than 130 mm Hg. Both interventions achieved an increase in serum bicarbonate and were associated with a decrease in urinary angiotensinogen. After 3 years, both interventions were associated with less albuminuria and GFR decline than the “usual care” group.207 The KDIGO guidelines recommend bicarbonate supplementation for persons with levels below 22 mEq/L,3 but further studies are required to further investigate whether this may also be beneficial in the setting of less severe acidosis.

Clinical Presentation

The clinical presentation of metabolic acidosis is dominated by the signs and symptoms of the underlying illness. However, there are some features common to many of these illnesses. In particular, deep, rapid respirations are often present. The paradigm for this is Kussmaul's respirations seen in children with diabetic ketoacidosis.10 Dehydration, nausea, abdominal pain, vomiting, lethargy, and malaise are also common features in many cases of metabolic acidosis. In cases of inborn errors of metabolism, coma may dominate the presentation to the emergency department.7 In some cases, such as seen with septic shock, the signs and symptoms of metabolic acidosis and those of septic shock are intimately intertwined.18 As septic shock resolves, so does the metabolic acidosis. Determining if there are symptoms solely attributable to metabolic acidosis is of no clinical significance and not feasible.

The signs and symptoms of many of the conditions that cause metabolic acidosis are nonspecific and overlap. Given this, the emergency physician will encounter very ill patients for whom a metabolic acidosis has been identified, but for whom a specific diagnosis is not readily apparent.

One approach to refine the differential diagnosis for conditions presenting with a metabolic acidosis is to assess the serum for “unmeasured” anions. The term unmeasured is primarily of historical significance given that the measurement of important anions such as lactate is now routine. One approach to assessing serum for these excess anions is the anion gap.13,20,21 The anion gap is calculated as follows:

Anion gap = [Na+] + [K+] − [Cl−] − [HCO3 −]

where [Na+], [K+], and [Cl−] are the serum sodium, potassium, and chloride concentrations respectively.13,20 The numerical values for these electrolytes are the same whether conventional units (mEq/L) or Systéme International d'Unites (SI) (mmol/L) are used. An alternative form of the anion gap does not include potassium in the sum.22,23 There is not a universally agreed upon normal anion gap.23 A reasonable approximation for a normal anion gap is in the range of 8 to 16.24 Given differences in how individual hospital laboratories perform their electrolyte analyses, the exact values constituting a normal anion gap will vary.24 Fortunately, many hospital laboratories report an anion gap along with their report on electrolyte measurements. The anion gap is useful in differentiating some relatively common and serious conditions that present to the emergency department with a metabolic acidosis (Table 111-1). One of the limitations of the anion gap is its inappropriate normalization in the setting of hypoalbuminemia.13,20,25–28 Adjustments to the anion gap calculation to take abnormalities of serum albumin into account have been proposed.26,27

One alternative to the anion gap that adjusts for abnormalities in serum albumin is the strong ion gap.20,29,30 The strong ion gap is calculated as follows:

Strong ion gap = [Na+] + [K+] − [Cl−] − [HCO3−] − 2.8 [albumin (g/dL)] − 0.6 [phosphate (mg/dL)]

A normal strong ion gap is zero. A falsely negative strong ion gap occurs in the setting of an elevated serum chloride. The role, if any, of the strong ion gap in evaluating children in the emergency department has not been determined. Another proposed alternative is the chloride: sodium ratio.31

Evaluation of Urinary Acidification

The cause of metabolic acidosis is often evident from the clinical situation. However, because the kidney is responsible for both the reclamation of filtered HCO3− and the excretion of the daily production of fixed acid, to evaluate a metabolic acidosis it may be necessary to assess whether the kidney is appropriately able to reabsorb HCO3−, secrete H+ against a gradient, and excrete NH4+ (Box 13.1). The simplest test is to measure urine pH. Although urine pH can be measured using a dipstick, the lack of precision of this technique prevents it from being useful in clinical decision-making. Ideally the urine should be collected under oil and the pH measured using a pH electrode. Under conditions of acid loading, urine pH should be below 5.5. A pH higher than 5.5 usually reflects impaired distal hydrogen ion secretion. Measuring the pH after challenging the patient with the loop diuretic, furosemide, will increase the sensitivity of this test by providing Na+ to the distal tubule for reabsorption. The reabsorption of Na+ creates a negative electrical potential in the lumen and enhances H+ secretion. It is important, however, to rule out urinary infections with urea-splitting organisms, which will increase pH. An elevated urine pH may also be misleading in conditions associated with volume depletion and hypokalemia, as can occur in diarrhea. In contradistinction to furosemide, volume depletion with decreased sodium delivery to the distal tubule impairs distal H+ secretion. Furthermore, hypokalemia, by enhancing ammoniagenesis, raises the urine pH.

Because renal excretion of NH4+ accounts for the majority of acid excretion, measurement of urine NH4+ provides important information. Urinary NH4+ excretion can be decreased by a variety of mechanisms, including a primary decrease in ammoniagenesis by the proximal tubule as seen in chronic kidney disease (CKD), or by decreased trapping in the distal tubule either secondary to decreased H+ secretion or increased delivery of HCO3−, which will preferentially buffer H+, making it unavailable to form NH4+. Although direct measurement of NH4+ is becoming more readily available in clinical laboratories and is the true gold standard, many laboratories still do not perform this assay. Fortunately, an estimate of NH4+ excretion is easily obtained by calculating the urine anion gap (UAG) or urine osmole gap. If, as is usual, the anion balancing the charge of the NH4+ is Cl−, then

should be negative, because the chloride is greater than the sum of Na+ and K+ (Fig. 13.3). Although the measurement of the UAG in conditions of acid loading is often reflective of NH4+ excretion, the presence of anions other than Cl− (such as keto anions or hippurate) makes it a less reliable assessment of NH4+ than the urine osmole gap. The urine osmole gap, from the measured urine osmolality, is calculated as follows:

The osmole gap is composed primarily of NH4+ salts. Thus, half of the gap represents NH4+. An osmole gap greater than 100 mmol/L signifies normal NH4+ excretion.

Another test of distal H+ ion secretory ability is measurement of urine PCO2 during bicarbonate loading. Distal delivery of HCO3− in the presence of normal H+ secretory capacity results in elevated PCO2 in the urine. When there is a secretory defect, urine PCO2 does not increase. Accurate measurement of urine PCO2 requires that the urine be collected under oil to prevent the loss of CO2 into the air.

Lactic Acid

Excess lactic acid is the most common cause of metabolic acidosis in the pediatric population. Table 133-4 lists some of the many causes of lactic acidosis. Lactic acid and pyruvic acid are formed by glycolysis. Lactate and pyruvate are maintained at an approximate 10:1 molar ratio. The normal lactate range varies among laboratories but is generally 0.5 to 2 mEq/L (the alternative unit mmol/L is equal to mEq/L for lactate). Interpretation of a lactate result requires knowledge of the patient's age and fasting or fed state, as well as the conditions under which the sample was obtained. Because glycolysis is the primary energy metabolism pathway when oxygen is in short supply, it is not surprising that most cases of lactic acidosis are due to temporary tissue hypoperfusion and hypoxia. Lactic acidosis may also be a clue to an inborn error of metabolism and can occur due to decreased utilization of pyruvate by downstream enzymes (see Table 133-4). Note that lactic acidosis may be present without frank acidemia or an anion gap. Serum lactate measurement may reveal an elevated lactate level in the context of a normal blood pH and only a mild increase in the anion gap.

A departure from the normal 10:1 ratio of lactate to pyruvate can help narrow the differential diagnosis for lactic acidosis. For example, if a lactic acidosis is due to a respiratory chain defect, lactate and pyruvate should be measured simultaneously and usually have a ratio greater than 10:1. By contrast, pyruvate dehydrogenase deficiency is often associated with increases in both lactate and pyruvate, yielding a normal ratio. Whenever possible, an arterial sample should be collected for lactate and pyruvate measurements. Blood collected distal to the capillary bed often results in a falsely elevated lactate level and lactate-pyruvate ratio. The use of a tourniquet can also cause false-positive results.

Metabolic Acidosis

Metabolic acidosis, usually but not invariably with a modest increase in the anion gap, occurs when the serum creatinine exceeds 4 mg/dL. Patients with advanced renal failure caused by diabetes typically display a less severe degree of metabolic acidosis compared with individuals with other forms of renal failure.63 The majority of patients with stage 4 and 5 stable CKD have a serum bicarbonate level of 12 to 18 mEq/L, with a blood pH of 7.3 or higher.64 Thus more severe metabolic acidosis in the ICU (bicarbonate concentration <15 mEq/L) mandates a workup for superimposed disease processes associated with metabolic acidosis. The mild metabolic acidosis of CKD rarely requires specific alkalization therapy.