A meaningful analysis of fluid, electrolyte, and acid–base abnormalities is dependent on the history and physical examination of each patient. Although a rigorous appraisal of laboratory parameters often yields the correct differential diagnosis, the clinical characteristics provide an understanding of the extracellular fluid volume (ECFV) and pathophysiology. Thus, the evaluation always begins with an overall assessment of the patient.

History

The history should be directed toward clinical questions associated with fluid and electrolyte abnormalities. Xenobiotic exposure commonly results in fluid losses through the respiratory system (hyperpnea and tachypnea), gastrointestinal (GI) tract (vomiting and diarrhea), skin (diaphoresis), and kidneys (polyuria). Patients with ECFV depletion often complain of dizziness, thirst, and weakness. Usually the patients can identify the source of fluid loss.

A history of exposure to nonprescription and prescription medications, alternative or complementary therapies, and other xenobiotics can suggest the most likely electrolyte or acid–base abnormality. In addition, patient characteristics (race, gender, age), premorbid medical conditions, and the ambient temperature and humidity should always be considered.

Physical Examination

The vital signs are invariably affected by significant alterations in ECFV. Whereas hypotension and tachycardia often characterize life-threatening ECFV depletion, an increase of the heart rate and a narrowing of the pulse pressure are the earliest findings. Abnormalities are best recognized through an ongoing dynamic evaluation, realizing that the measurement of a single set of supine vital signs offers useful information only when markedly abnormal. Orthostatic pulse and blood pressure measurements provide a more meaningful determination of functional ECFV status (Chaps. 3 and 16).

The respiratory rate and pattern can give clues to the patient’s metabolic status. In the absence of lung disease, hyperventilation (manifested by tachypnea, hyperpnea, or both) is often either caused by a primary respiratory stimulus (respiratory alkalosis) or is a response to the presence of metabolic acidosis. Although hypoventilation (bradypnea or hypopnea or both) is present in patients with metabolic alkalosis, it is rarely clinically significant except in the presence of chronic lung disease or in combination with respiratory depressant xenobiotics. More commonly, hypoventilation is caused by a primary depression of consciousness and respiration with resulting respiratory acidosis. Unless the clinical scenario (eg, nature of the poisoning, presence of renal or pulmonary disease, and findings on physical examination or laboratory testing) is classic, arterial or venous blood gas analysis is recommended to determine the acid–base disorder associated with a change in ventilation.

The skin should be evaluated for turgor, moisture, and the presence or absence of edema. The moisture of the mucous membranes can also provide valuable information. These are nonspecific parameters and often fail to correlate directly with the status of hydration. This dissociation is especially true with xenobiotic exposure because many xenobiotics alter skin and mucous membrane moisture without necessarily altering ECFV status. For example, antimuscarinics commonly result in dry mucous membranes and skin without producing ECFV depletion. Conversely, patients exposed to sympathomimetics such as cocaine or cholinergics such as organic phosphorus compounds have moist skin and mucous membranes even in the presence of significant fluid losses. This dissociation of ECFV and cutaneous characteristics reinforces the need to assess patients meticulously.

The physical findings associated with electrolyte abnormalities are generally nonspecific. Hyponatremia, hypernatremia, hypercalcemia, and hypermagnesemia all produce a depressed level of consciousness. Neuromuscular excitability such as tremor and hyperreflexia occurs with hypocalcemia, hypomagnesemia, hyponatremia, and hyperkalemia. Weakness results from both hyperkalemia and hypokalemia. Also, multiple, concurrent electrolyte disorders can produce confusing clinical presentations, or patients can appear normal. Diagnostic findings, such as Chvostek and Trousseau signs (primarily found in hypocalcemia), are useful in assessing patients with potential xenobiotic exposures.

Rapid Diagnostic Tools

The electrocardiogram (ECG) is a useful tool for screening several common electrolyte abnormalities (Chap. 15). It is easy to perform, rapid, inexpensive, and routinely available. Unfortunately, because poor sensitivity (0.43) and moderate specificity (0.86) were demonstrated when ECGs were used to diagnose hyperkalemia, in actuality the test is of limited diagnostic value.¹⁵¹ However, the ECG is valuable for the evaluation of changes in serum potassium and calcium concentrations ([K⁺] and [Ca²⁺]) in an individual patient.

Assessment of urine specific gravity by dipstick analysis provides valuable information about ECFV status. A high urine specific gravity (>1.015) signifies concentrated urine and is often associated with ECFV depletion. However, urine specific gravity is often similarly elevated in conditions of ECFV excess, such as congestive heart failure or third spacing. Similarly, patients with excess antidiuretic hormone (ADH) secretion (eg, due to methylenedioxymethamphetamine {MDMA} exposure) excrete concentrated urine (specific gravity >1.015) even in the presence of a normal or expanded ECFV. Furthermore, when renal impairment or diuretic use is the source of the volume loss, the specific gravity is usually approximately 1.010 (known as isosthenuria). Finally, patients with lithium-induced diabetes insipidus (DI) excrete dilute urine (specific gravity <1.010) despite ongoing water losses and contraction of the ECFV.

The urine dipstick is highly reliable and rapidly available for determining the presence of ketones, which are often associated with common causes of metabolic acidosis (eg, diabetic ketoacidosis, salicylate poisoning, alcoholic ketoacidosis). The urine ferric chloride test rapidly detects exposure to salicylates with a high sensitivity and specificity although it is rarely used today in locations where salicylate concentrations can be obtained rapidly (Chap. 37).

Laboratory Studies

A simultaneous determination of the venous serum electrolytes, blood urea nitrogen (BUN), glucose, and arterial or venous blood gases are adequate to determine the nature of the most common acid–base, fluid, and electrolyte abnormalities. More complex clinical problems require determinations of urine and serum osmolalities, urine electrolytes, serum ketones, serum lactate, and other tests. A systematic approach to common problems is discussed in the following sections.

Definitions

The lack of a clear understanding and precise use of the terminology of acid–base disorders often leads to confusion and error. The following definitions provide the appropriate frame of reference for the remainder of the chapter and this textbook.

Whereas the terms acidosis and alkalosis refer to processes that tend to change pH in a given direction, acidemia and alkalemia only refer to the actual pH. By definition, a patient is said to have:

• 
  

  A metabolic acidosis if the arterial pH is less than 7.40 and serum bicarbonate concentration ([HCO₃⁻]) is less than 24 mEq/L. Because acidemia stimulates ventilation (respiratory compensation), metabolic acidosis is usually accompanied by a PCO₂ less than 40 mm Hg.

  
  
• 
  

  A metabolic alkalosis if the arterial pH is greater than 7.40 and serum [HCO₃⁻] is greater than 24 mEq/L. Because alkalemia inhibits ventilation (respiratory compensation), metabolic alkalosis is usually accompanied by a PCO₂ greater than 40 mm Hg.

  
  
• 
  

  A respiratory acidosis if the arterial pH is less than 7.40 and partial pressure of carbon dioxide (PCO₂) is greater than 40 mm Hg. Because an elevated PCO₂ stimulates renal acid excretion and the generation of HCO₃⁻ (renal compensation), respiratory acidosis is usually accompanied by a serum [HCO₃⁻] greater than 24 mEq/L.

  
  
• 
  

  A respiratory alkalosis if the arterial pH is greater than 7.40 and PCO₂ is less than 40 mm Hg. Because a decreased PCO₂ lowers renal acid excretion and increases the excretion of HCO₃⁻ (renal compensation), respiratory alkalosis is usually accompanied by a serum [HCO₃⁻] less than 24 mEq/L.

It is important to note that under many circumstances, a venous pH permits an approximation of arterial pH. However, when rigorously compared, the arterial blood gas analysis outperforms the venous blood gas analysis especially when findings are subtle.¹³¹ (See Chap. 28 for a further discussion of the relationship between arterial and venous pH.) Any combination of acidoses and alkaloses can be present in any one patient at any given time. The terms acidemia and alkalemia refer only to the resultant arterial pH of blood (acidemia referring to a pH <7.40 and alkalemia referring to a pH >7.40). These terms do not describe the processes that led to the alteration in pH. Thus, a patient with acidemia must have a primary metabolic or respiratory acidosis but potentially also has an alkalosis present at the same time. Clues to the presence of more than one acid–base abnormality include the clinical presentation, an apparent excess or insufficient “compensation” for the primary acid–base abnormality, a delta gap ratio {(Δ) anion gap/Δ[HCO₃⁻]} that significantly deviates from one, or an electrolyte abnormality that is uncharacteristic of the primary acid–base disorder.

Determining the Primary Acid–Base Abnormality

It is helpful to begin by determining whether the patient has an acidosis or an alkalosis. This is followed by an assessment of the pH, PCO₂, and [HCO₃⁻]. With these 3 parameters defined, the patient’s primary acid–base disorder can be classified using the aforementioned definitions. Next it is important to determine whether the compensation of the primary acid–base disorder is appropriate. It is generally assumed that overcompensation cannot occur.¹⁰⁶ That is, if the primary process is metabolic acidosis, respiratory compensation tends to raise the pH toward normal but never to greater than 7.40. If the primary process is respiratory alkalosis, compensatory renal excretion of HCO₃⁻ tends to lower the pH toward normal but not to less than 7.40. The same is true for primary metabolic alkalosis and primary respiratory acidosis. As a rule, compensation for a primary acid–base disorder that appears inadequate or excessive is indicative of the presence of a second primary acid–base disorder.

Based on patient data, the Winters equation (Equation 12–1)⁷ predicts the degree of the respiratory compensation (the decrease in PCO₂) in metabolic acidosis as follows:

Thus, in a patient with an arterial [HCO₃⁻] of 12 mEq/L, the predicted PCO₂ is calculated as

or

If the actual PCO₂ is substantially lower than is predicted by the Winters equation, it can be concluded that both a primary metabolic acidosis and a primary respiratory alkalosis are present. If the PCO₂ is substantially higher than the predicted value, then both a primary metabolic acidosis and a primary respiratory acidosis are present.

An alternative to the Winters equation is the observation by Narins and Emmett that in compensated metabolic acidosis, the arterial PCO₂ is usually the same as the last 2 digits of the arterial pH.¹⁰⁶ For example, a pH of 7.26 predicts a PCO₂ of 26 mm Hg.

Guidelines are also available to predict the compensation for metabolic alkalosis,⁶⁴ respiratory acidosis, and respiratory alkalosis.⁸³ Patients with a metabolic alkalosis compensate by hypoventilating, resulting in an increase of their PCO₂ above 40 mm Hg. However, the concomitant development of hypoxemia limits this compensation so that respiratory compensation in the presence of a metabolic alkalosis usually results in a PCO₂ of 55 mm Hg or less. It is difficult to be more accurate about the expected respiratory compensation for a metabolic alkalosis, although the compensation, as in the case of metabolic acidosis, is nearly complete within hours of onset.

By contrast, the degree of compensation in primary respiratory disorders depends on the length of time the disorder has been present. In a matter of minutes, primary respiratory acidosis results in an increase in the serum [HCO₃⁻] of 0.1 times the increase in the PCO₂. This increase is a result of the production and dissociation of H₂CO₃. Over a period of days, respiratory acidosis causes the compensatory renal excretion of acid. This compensation increases the serum [HCO₃⁻] by 0.3 times the increase in PCO₂. Primary respiratory alkalosis acutely decreases the serum [HCO₃⁻] by 0.2 times the decrease in PCO₂. If a respiratory alkalosis persists for several days, renal compensation, by the urinary excretion of HCO₃⁻, decreases the serum [HCO₃⁻] by 0.4 times the decrease in PCO₂.

Calculating the Anion Gap

The concept of the anion gap is said to have arisen from the “Gamblegram” originally described in 1939⁵¹; however, its use was not popularized until the determination of serum electrolytes became routinely available. The law of electroneutrality states that the net positive and negative charges of all fluids must be equal. Thus, all of the negative charges present in the serum must equal all of the positive charges, and the sum of the positive charges minus the sum of the negative charges must equal zero. The problem that immediately arose (and produced an “anion gap”) was that all charged species in the serum are not routinely measured.

Normally present but not routinely measured cations include calcium and magnesium; normally present but not routinely measured anions include phosphate, sulfate, albumin, and organic anions (eg, lactate and pyruvate).⁴¹ Whereas Na⁺ and K⁺ normally account for 95% of extracellular cations, Cl⁻ and HCO₃⁻ account for 85% of extracellular anions. Thus, because more cations than anions are among the electrolytes usually measured, subtracting the anions from the cations normally yields a positive number, known as the anion gap. The anion gap is therefore derived as shown in Equation 12–2:

or

Because the serum [K⁺] varies over a limited range of perhaps 1 to 2 mEq/L above and below normal and therefore rarely significantly alters the anion gap, it is often deleted from the equation for simplicity. Most prefer this approach, yielding Equation 12–3:

Using Equation 12–3, the normal anion gap was initially determined to be 12 ± 4 mEq/L.⁴¹ However, because the normal serum [Cl⁻] is higher on current laboratory instrumentation, the current range for a normal anion gap is 7 ± 4 mEq/L.¹⁴⁹

A variety of pathologic conditions result in a rise or fall of the anion gap. High anion gaps result from increased presence of unmeasured anions or decreased presence of unmeasured cations (Table 12–1).^41,89 Conversely, a low anion gap results from an increase in unmeasured cations or a decrease in unmeasured anions (Table 12–2).^41,49,59,129

Anion Gap Reliability

Several authors have discussed the usefulness of the anion gap determination.^21,50,72 When 57 hospitalized patients were studied to determine the cause of elevated anion gaps in patients whose anion gap was greater than 30 mEq/L, the cause was always a metabolic acidosis with elevations of lactate or ketones.⁵⁰ In patients with smaller elevations of the anion gap, the ability to define the cause of the elevation diminished; in only 14% of patients with anion gaps of 17 to 19 mEq/L could the cause be determined. Another study determined that although the anion gap is often used as a screening test for hyperlactatemia (as a sign of poor perfusion), only patients with the highest serum lactate concentrations had elevated anion gaps.⁷² Finally, in a sample of 571 patients, those with greater elevations in anion gaps tended to have more severe illness. This logically correlated with higher admission rates, a greater percentage of admissions to intensive care units, and a higher mortality rate.²¹ Thus, although the absence of an increased anion gap does not exclude significant illness, a very elevated anion gap can generally be attributed to a specific cause (typically a disorder that is associated with elevated lactate or ketones) and usually indicates a relatively severe illness.

Metabolic Acidosis

After the diagnosis of metabolic acidosis is established by finding an arterial pH less than 7.40, [HCO₃⁻] <24 mEq/L, and PCO₂ <40 mm Hg, the serum anion gap should be analyzed. Indeed, the popularity of the anion gap is primarily based on its usefulness in categorizing metabolic acidosis as being of the high anion gap or normal anion gap type. This determination should be made after correcting the anion gap for the effect of hypoalbuminemia, a common and important confounding factor in chronically ill patients. The anion gap decreases approximately 3 mEq/L per 1 g/dL decrease in the serum [albumin].⁴⁷ In general, the electrolyte abnormalities that frequently accompany metabolic acidosis usually have only small and insignificant effects on the anion gap.

It should be noted that although many clinicians rely on the mnemonics MUDPILES (M, methanol; U, uremia; D, diabetic ketoacidosis; P, paraldehyde; I, iron; L, lactic acidosis; E, ethylene glycol; and S, salicylates) or KULT (K, ketones; U, uremia; L, lactate; T, toxins), to help remember this differential diagnosis, these mnemonics include rarely used drugs (phenformin, paraldehyde) and omit important others (eg, metformin, cyanide).

A high anion gap metabolic acidosis results from the absorption or generation of an acid that dissociates into an anion other than Cl⁻ that has neither been excreted nor metabolized at the time the anion gap is determined. The retention of this “unmeasured” anion (eg, glycolate in ethylene glycol poisoning) increases the anion gap. By contrast, a normal anion gap metabolic acidosis results from the absorption or generation of an acid that dissociates into H⁺ and Cl⁻. In this case, the “measured” Cl⁻ is retained as HCO₃⁻, is titrated, and its concentration reduced during the acidosis, and no increase in anion gap is produced. Normal anion gap acidosis, also referred to as hyperchloremic metabolic acidosis, is typically caused by intestinal or renal bicarbonate losses as in diarrhea or renal tubular acidosis, respectively. Other causes of high and normal anion gap metabolic acidoses are described elsewhere^3,4 and shown in Tables 12–3 and 12–4.

Narrowing the Differential Diagnosis of a High Anion Gap Metabolic Acidosis

The ability to diagnose the etiology of a high anion gap metabolic acidosis is an essential skill in clinical medicine. The following discussion provides a rapid and cost-effective approach to the problem. As always, the clinical history and physical examination provide essential clues to the diagnosis. For example, iron poisoning is virtually always associated with significant GI symptoms, the absence of which essentially excludes the diagnosis (Chap. 45). Furthermore, when iron overdose is suspected, an abdominal radiograph often shows the presence of iron-containing tablets. The acidosis associated with isoniazid (INH) toxicity results from seizures, the absence of which excludes INH as the cause of a metabolic acidosis (Chap. 56). Methanol poisoning is classically associated with visual complaints or abnormal finding on funduscopic examination (Chap. 106). Methyl salicylate has a characteristic wintergreen odor (Chap. 37). When these findings are absent, the laboratory analysis must be relied on, as follows:

1. 
   

   Begin with the serum electrolytes, BUN, creatinine, and glucose. A rapid blood glucose reagent test should be performed to help confirm or exclude hyperglycemia. Although hyperglycemia should raise the possibility of diabetic ketoacidosis, the absence of an elevated serum glucose does not exclude the possibility of euglycemic diabetic ketoacidosis,^11,27,74 alcoholic or starvation ketoacidosis, which are often associated with normal or even low serum glucose concentrations. An elevated BUN and creatinine are essential to diagnose acute or chronic kidney failure.

   
   
2. 
   

   Proceed to the urinalysis. If there is a suspicion of a high anion gap metabolic acidosis and only the arterial or venous blood gas analysis is completed, the evaluation can easily begin here while the electrolyte determinations are pending. A urine dipstick for glucose and ketones helps with the diagnosis of diabetic ketoacidosis and other ketoacidoses. However, the absence of urinary ketones does not exclude a diagnosis of alcoholic ketoacidosis⁴⁸ (Chap. 76), and ketones are often present in patients with severe salicylism (Chap. 37) and biguanide-associated metabolic acidosis (Chap. 47). If timed properly, the urine of a patient who has ingested fluorescein-containing antifreeze (ethylene glycol) fluoresces when exposed to a Wood lamp. Also, because ethylene glycol is metabolized to oxalate, calcium oxalate crystals are present in the urine of approximately half of poisoned patients. Although the presence of a fluorescent urine and calcium oxalate crystals are useful findings, their absence does not exclude ethylene glycol poisoning (Chap. 106). When clinically available, a urine ferric chloride test should be performed. Although highly sensitive and specific for the presence of salicylates, this test is not specific for the diagnosis of salicylism because small amounts of salicylate will be detected in the urine even days after its last use (Chap. 37). Thus, a serum salicylate concentration must be obtained to quantify the findings of a positive urine ferric chloride test result. A negative urine ferric chloride test result essentially excludes a diagnosis of salicylism.

   
   
3. 
   

   A blood lactate concentration can be helpful. In theory, if the lactate (measured in mEq/L) can entirely account for the fall in serum [HCO₃⁻], the cause of the high anion gap can be attributed to lactic acidosis. In practicality we know that this unfortunately does not work largely because the volumes of distribution of bicarbonate and lactate are not identical, with the bicarbonate volume of distribution being very dependent on pH.¹¹⁹ Another important example is that glycolate (a metabolite of ethylene glycol) can produce a false-positive elevation of the lactate concentration with many current laboratory techniques.^100,150

When the above analysis of a high anion gap metabolic acidosis is nondiagnostic, the diagnosis is usually toxic alcohol ingestion, starvation, or alcoholic ketoacidosis (with minimal urine ketones), or a multifactorial process involving small amounts of lactate and other anions. One approach is to provide the patient with 1 to 2 hours of intravenous (IV) hydration, dextrose, and thiamine. If the acidosis improves, the etiology is either ketoacidosis or metabolic acidosis with hyperlacatemia. In the absence of improvement, a more detailed search for the toxic alcohols, involving measurement of either the osmol gap or actual methanol and ethylene glycol concentrations, should be initiated (discussed later).

The Δ Anion Gap-to-Δ[HCO₃⁻] Ratio

Many patients have mixed acid–base disorders such as metabolic acidosis and respiratory alkalosis. Depending on the relative effects of the acid–base disorders, the patient may have significant acidemia or alkalemia, minor alterations in pH, or even a normal pH. Although the clinical presentation, degree of compensation for the primary acid–base disorder, or the presence of unexpected electrolyte abnormalities suggest whether more than one primary acid–base disorder is present, comparing the Δ anion gap (ΔAG) with the Δ[HCO₃⁻] provides additional information to help establish the correct diagnosis.

In a patient with a simple high anion gap metabolic acidosis, each 1 mEq/L decrease in the serum [HCO₃⁻] should (at least initially) be associated with a 1 mEq/L rise in the anion gap.¹⁰⁶ This occurs because the unmeasured anion is paired with the acid that is titrating the HCO₃⁻. Any deviation from this direct relationship may be an indication of a mixed acid–base disorder.^60,106,111 Thus, the ratio of the change in the anion gap (ΔAG) to the deviation of the serum [HCO₃⁻] from normal (Equation 12–4) evolved:

A ratio close to one would suggest a pure high anion gap metabolic acidosis. When the ratio is greater than one, there is a relative increase in [HCO₃⁻] that can result only from a concomitant metabolic alkalosis or renal compensation such as renal generation of HCO₃⁻ for a respiratory acidosis. Alternatively, when the ratio is less than one, the additional presence of either hyperchloremic (normal anion gap) metabolic acidosis or compensated respiratory alkalosis is suggested. Although the usefulness of this relationship has been supported strongly by some authors,^109,111 others suggest that it is often flawed and frequently misleading.^34,125

After reviewing the arguments, the statements of one author³⁴ are reasonable in concluding that “the exact relationship between the ΔAG and Δ[HCO₃⁻] in a high anion gap metabolic acidosis is not readily predictable and deviation of the ΔAG/Δ[HCO₃⁻] ratio from unity does not necessarily imply the diagnosis of a second acid–base disorder.” Regardless, very large deviations from a value of one usually are associated with the presence of a second primary acid–base disorder.

The Osmol Gap

The osmol gap, which is sometimes used to screen for toxic alcohol ingestion, is defined as the difference between the values for the measured serum osmolality and the calculated serum osmolarity. Osmolarity is a measure of the total number of particles in one liter of solution. Osmolality differs from osmolarity in that it represents the number of particles per kilogram of solution. Thus, osmolarity and osmolality represent molar and molal concentrations of solutes, respectively. In clinical medicine, osmolarity is usually calculated whereas osmolality is measured.

Calculating osmolarity requires a summing of the known particles in solution. Because molarity and milliequivalents are particle-based measurements, unlike weight or concentration, the known constituents of serum that are measured in the latter units (such as mg/dL) have to be converted to molar values. Assumptions are required based on the extent of dissociation of polar compounds (eg, NaCl), the water content of serum, and the contributions of various other solutes such as Ca²⁺ and Mg²⁺. The nature and limitations of these assumptions are beyond the scope of this chapter. Readers are referred to several reviews for more details.^67,110 Many equations have been used and evaluated for calculating serum osmolarity. One investigation that used 13 different methods to evaluate sera from 715 hospitalized patients³⁶ concluded that Equation 12–5 provided the most accurate calculation:

Obvious sources of potential error in this calculation include laboratory error in determining the measured parameters and the failure to account for a number of osmotically active particles.

The measurement of serum osmolality also has the potential for error stemming from the use of different laboratory technique.⁴⁰ It is essential to ensure that the freezing point depression technique or osmometry is used because when the boiling point elevation method is used, xenobiotics with low boiling points (ethanol, isopropanol, methanol) will not be detected.

Conceptual errors may also result. In methanol poisoning, the methanol molecule has osmotic activity that is measured but not calculated, and no increase in the anion gap is present until it is metabolized to formate. Although the metabolite also has osmotic activity, its activity is accounted for by Na⁺ in the osmolarity calculation because it is largely dissociated, existing as Na⁺ formate. Thus, shortly after a methanol ingestion, the patient will have an elevated osmol gap and a normal anion gap; later, the anion gap will increase, and the osmol gap will decrease (Fig. 106–4). This effect is highlighted by several case reports.^9,30

Using Equation 12–5 to calculate osmolarity, it is often stated that the “normal” osmol gap is 10 ± 6 mOsm/L.³⁶ However, when more than 300 adult samples were studied with a more commonly used equation (Eq. 12–6),

normal values for the osmol gap were –2 ± 6 mOsm/L.⁶⁷ Almost identical results are reported in children.⁹⁶

The largest limitation of the osmol gap calculation is due to the documented large standard deviation around a small “normal” number.^36,67 An error of 1 mEq/L (<1.0%) in the determination of the serum [Na⁺] will result in an error of 2 mOsm/L in the calculation of the osmol gap. Considering this variability, the molecular weights (MWs) and relatively modest serum concentrations of the xenobiotics in question (eg, ethylene glycol; MW, 62 Da; at a concentration of 50 mg/dL theoretically contributes only 8.1 mOsm/L) and the predicted fall in the osmol gap as metabolism occurs, small or even negative osmol gaps can never be used to exclude toxic alcohol ingestion.⁶⁷ This overall concept is illustrated by an actual patient with an osmol gap of 7.2 mOsm (well within the normal range) who ultimately required hemodialysis for severe ethylene glycol poisoning.¹³⁸ An additional error may result when including ethanol in the determination of the osmol gap. When present, ethanol is osmotically active and should be included in the calculated osmolarity. In theory, because the MW of ethanol is 46 g/mol, dividing the serum ethanol concentration (in mg/dL) by 4.6 will yield the osmolar contribution in mmol/L. However, because the physical interaction of ethanol with water is complex, it is more scientifically accurate to divide by lower numbers as the ethanol concentration increases.^26,115 Therefore because the osmol gap is a screening tool, we suggest continuing to use the 4.6 divisor (or if in SI units using the unmodified molar concentration) in an attempt to reduce clinical false-negative test results.

Finally, although exceedingly large serum osmol gaps are suggestive of toxic alcohol ingestions, common conditions such as alcoholic ketoacidosis, metabolic acidosis with elevated lactate, kidney failure, and shock are all associated with elevated osmol gaps.^73,128,134 This may be surprising because lactate, acetoacetate, and β-hydroxybutyrate should not account for any increase in the osmol gap because they are charged (and accounted for in the osmolarity calculation). Apparently, these conditions are associated with the accumulation of small uncharged, unmeasured molecules in the serum.

Thus, although the negative and positive predictive values of the osmol gap are too poor to recommend this test to routinely screen for xenobiotic ingestion, the presence of very high osmol gaps (>50–70 mOsm/L) usually indicates a diagnosis of toxic alcohol ingestion (Chap. 106).

Differential Diagnosis of a Normal Anion Gap Metabolic Acidosis

Although the differential diagnosis of a normal anion gap metabolic acidosis is extensive (Table 12–4), most cases result from either urinary or GI HCO₃⁻ losses: renal tubular acidosis (RTA) or diarrhea, respectively. A number of xenobiotics also cause this disorder, including toluene,²⁵ which also may cause a high anion gap metabolic acidosis. When the findings of the history and physical examination cannot be used to narrow the differential diagnosis, the use of a urinary anion gap is suggested.^15,120

The urinary anion gap is calculated as shown in Equation 12–7:

The size of this gap is inversely related to the urinary ammonium (NH₄⁺) excretion.⁵⁸ As NH₄⁺ elimination increases, the urinary anion gap decreases and can actually become negative because NH₄⁺ serves as an unmeasured urinary cation and is predominantly accompanied by Cl⁻.

The normal anion gap metabolic acidosis associated with diarrhea results from HCO₃⁻ loss. During this process, the ability of the kidney to eliminate NH₄⁺ is undisturbed; in fact, it increases as a normal response to the acidemia. Thus, with gastrointestinal HCO₃⁻ losses, the urinary anion gap should decrease and may become negative. By contrast, a patient with RTA has lost the ability to either reabsorb HCO₃⁻ (type 2 RTA) or increase NH₄⁺ excretion in response to metabolic acidosis (types 1 and 4 RTA) and the urinary anion gap should become more positive. Indeed, when the urinary anion gap was calculated in patients with diarrhea or RTA, it was found that patients with diarrhea had a mean negative gap (–20 ± 5.7 mEq/L) compared with a positive gap (23 ± 4.1 mEq/L) in those with RTA.⁵⁸ Therefore, when evaluating the patient with a normal anion gap metabolic acidosis, the determination of a urinary anion gap is helpful to determine the source of the disorder when the history and physical examination are unclear.

Adverse Effects of Metabolic Acidosis

The acuity of onset and severity of metabolic acidosis determine the consequences of this disorder. Acute metabolic acidosis is usually characterized by obvious hyperventilation (caused by respiratory compensation). At arterial pH values less than 7.20, cardiac and central nervous system abnormalities are often present. These include decreases in blood pressure and cardiac output, cardiac dysrhythmias, and progressive obtundation.^3,4 Chronic metabolic acidosis is often not accompanied by overt clinical symptoms. The nonspecific symptoms of anorexia and fatigue are the most typical manifestations of chronic acidosis, and compensatory hyperventilation although present is often not evident. Because the consequences of even severe metabolic acidosis are nonspecific, the presence of metabolic acidosis is most often suggested by the history and physical examination and subsequently confirmed by laboratory testing.

Management Principles in Patients with Metabolic Acidosis

The treatment of metabolic acidosis depends on its severity and cause. In most cases of severe poisoning, with a serum [HCO₃⁻] concentration less than 8 mEq/L and an arterial pH value less than 7.20, we recommend treating with HCO₃⁻ to increase the pH to greater than 7.20, as described in detail elsewhere.^3,4 As an example, to raise the serum [HCO₃⁻] by 4 mEq/L in a 70-kg person with an apparent HCO₃⁻ distribution space of 50% of body weight, approximately 140 mEq must be administered. Unfortunately, because the apparent volume of distribution of HCO₃⁻ increases as the pH and serum [HCO₃⁻] fall, any given dose of exogenous HCO₃⁻ will have less of an effect on pH. When ECFV overload (caused by heart failure, kidney failure, or the sodium bicarbonate therapy itself) cannot be prevented or managed by administering loop diuretics, hemofiltration or hemodialysis will be necessary.

In patients with arterial pH values greater than 7.20, the cause of the acidosis should guide therapy. Metabolic acidosis primarily caused by the overproduction of acid, as in the case of ketoacidosis and toxic alcohol poisoning, requires very large quantities of HCO₃⁻ and typically does not respond well to sodium bicarbonate therapy. Treatment in these patients should be directed at the cause of acidosis (eg, insulin and IV fluids in diabetic ketoacidosis; fomepizole in methanol, ethylene glycol, and DEG poisonings (Antidotes in Depth: A33), fluids, dextrose, and thiamine in alcoholic ketoacidosis; fluid resuscitation, antibiotics, and vasopressors in sepsis-induced hyperlactatemia). Patients with metabolic acidosis primarily caused by insufficient excretion of acid (eg, acute or chronic kidney failure, RTA) should be treated with a low-protein diet (if feasible) and oral sodium bicarbonate or substances that generate HCO₃⁻ during metabolism. We recommended an oral sodium citrate solution such as Shohl solution, which yields 1 mEq base/mL. The goal of therapy is to increase the serum [HCO₃⁻] to 20 to 22 mEq/L and the pH to 7.30.