Reuben J. Strayer

Principles of Disease

Many basic cellular processes are sensitive to small changes in serum pH; the kidneys, lungs, and physiologic buffers therefore defend serum pH, which is normally between 7.36 and 7.44. Serum pH is determined by the relative concentrations of bicarbonate (HCO₃⁻) and carbon dioxide (PaCO₂); when two of these variables are known, the third may be calculated. Most blood gas analyzers measure pH and PaCO₂ and report a calculated [HCO₃⁻]; most laboratories, when they report a serum bicarbonate concentration, are reporting a measured total carbon dioxide concentration, which is the sum of the serum bicarbonate and dissolved carbon dioxide. The dissolved carbon dioxide usually contributes negligibly to total carbon dioxide concentration but can become significant in patients with hypercapnia.

An acidosis is a process that lowers HCO₃⁻ or raises PaCO₂ and tends to create an acidemia, which exists when serum pH is below 7.36. An alkalosis conversely represents a process that raises HCO₃⁻ or lowers PaCO₂ and tends to create an alkalemia, which is present when serum pH is above 7.44. The terms acidemia and acidosis are not interchangeable; acidosis (or alkalosis) describes a process that pushes serum pH down (or up); acidemia and alkalemia describe the serum pH itself. A patient who is acidemic has at least one acidosis but may have two or more acidoses and may also have one or more alkaloses. Patients with normal serum pH, that is, without acidemia or alkalemia, may have acidoses and alkaloses whose net effect is serum neutrality.

Bicarbonate concentration is predominantly regulated by the kidneys and PaCO₂ by lung ventilation. Diseases that affect kidney function may therefore produce a metabolic acidosis or alkalosis, for which the lungs will try to compensate by decreasing or increasing PaCO₂, respectively. Likewise, pulmonary insults cause a respiratory acidosis or alkalosis, for which the kidneys will try to compensate by raising or lowering serum HCO₃⁻, respectively.

In the majority of acid-base disturbances, the role of the emergency physician is to identify and manage dangerous causes of the disturbance. Uncommonly, the acid-base disorder is severe enough that the resulting acidemia or alkalemia itself is dangerous; serum pH below 6.7 or higher than 7.6 is considered unsustainable and may cause cardiac hypocontractility and irritability, seizures, cerebral edema, and a variety of metabolic disturbances. In these cases, empirical therapy directed at normalization of serum pH may be warranted simultaneously with a search for the underlying process or processes.

A reduced serum bicarbonate concentration defines a metabolic acidosis, which may be the primary disorder or a compensation for a primary respiratory alkalosis; an elevated serum bicarbonate concentration defines a metabolic alkalosis, which may be the primary disorder or a compensation for a primary respiratory acidosis. Likewise, a reduced PaCO₂ represents a respiratory alkalosis, and an elevated PaCO₂ represents a respiratory acidosis. When only a primary disturbance and its corresponding compensation are present, it is described as a simple acid-base disorder. A mixed acid-base disorder exists when more than one primary disturbance occurs simultaneously.

Alterations in serum pH are resisted initially by intracellular and extracellular physiologic buffers, followed by specific responses from the lungs and the kidneys. Peripheral and central chemoreceptors adjust pulmonary minute ventilation in response to changes in serum pH. In a primary metabolic acidosis, an increase in minute ventilation lowers PaCO₂ and pushes the serum pH closer to normal. A primary metabolic alkalosis likewise causes a reduction in minute ventilation to elevate PaCO₂ in an attempt to restore physiologic serum pH.

The response of the kidneys to alterations in serum pH occurs over hours to days. A sustained acidemia promotes renal excretion of H⁺ and retention of HCO₃⁻, whereas alkalemia causes renal HCO₃⁻ excretion and H⁺ retention. The kidney transports hydrogen ions in exchange for potassium, whose serum concentration must also be maintained within tight parameters. This may become clinically important when, for instance, correction of alkalemia is attempted: retention of H⁺ cannot occur unless potassium stores are sufficient to allow urinary K⁺ excretion. Potassium supplementation may therefore be necessary to alkalinize the urine in cases of, for example, heterocyclic antidepressant toxicity.

Diagnostic Strategies

An acid-base disturbance is often first identified when the results of laboratory tests ordered to evaluate the patient’s symptoms demonstrate alterations in bicarbonate, pH, or PaCO₂. The possibility of an acid-base disorder is suggested by clinical events such as toxic ingestions, severe vomiting, or diarrhea as well as in patients with diseases affecting the organs responsible for maintenance of acid-base balance—primarily the lungs and kidney. All critically ill patients and certainly all patients being mechanically ventilated require an assessment of acid-base status.

When an acid-base disturbance is identified or suspected, elucidation of its underlying cause or causes is central to appropriate management. When the cause of an acid-base disturbance is not evident, the emergency evaluation begins with a full history and physical examination and proceeds with targeted laboratory studies.

Simple acid-base disorders are categorized by the serum pH, PaCO₂, and HCO₃⁻ concentrations (Table 124-1). When the primary disturbance is identified, the next step is to determine its etiology and whether an appropriate compensation has occurred. An inappropriate compensation suggests that the process underlying the primary disturbance has hindered an appropriate response or that more than one primary disturbance is present. Simple formulas allow the calculation of an appropriate response once the primary disturbance has been categorized. Compensatory processes generally return pH toward normal but not to normal and never beyond normal; such an exaggerated “compensation” actually represents a second primary disorder.

Blood gas and serum chemistry analysis allows calculation and interpretation of the serum anion gap.

Plasma must remain electrically neutral: the sum of anions and cations must be equal. Because routinely measured cations exceed routinely measured anions, the anion gap represents the concentration of anions other than chloride and bicarbonate in the blood. A variety of these anions are normally present, but serum albumin accounts for most of the physiologic (normal) anion gap, which is usually between 9 and 15. The higher the anion gap, the more likely that one or more unmeasured anions is generating a metabolic acidosis. Besides albumin, classic unmeasured anions such as lactate and ketones are now also routinely measured and can be incorporated into a diagnostic pathway (albumin concentration reported in grams per deciliter must be corrected by multiplying by 2.5 to be included in anion gap calculations). Unmeasured cations are also present and may account for an elevated anion gap in cases of hypomagnesemia or hypocalcemia, often in combination with hypokalemia (because serum potassium concentration varies so little, it is usually left out of anion gap calculations and is therefore functionally an unmeasured cation). Elevated concentrations of unmeasured cations may cause a low anion gap (<3 mEq/L), such as in cases of lithium toxicity and hypergammaglobulinemia seen in multiple myeloma. Bromide toxicity and hypertriglyceridemia may confound electrolyte measurements and also cause a low or negative anion gap.

Hypoalbuminemia is common and consequential from an acid-base perspective because as albumin is the primary contributor to the “normal” anion gap, significant depression of serum albumin will reduce the anion gap, which could mask the presence of an important unmeasured anion. For example, a chronically malnourished alcoholic may present with alcoholic ketoacidosis but also long-standing hypoalbuminemia, which causes a substantial increase in serum bicarbonate (hypoalbuminemia is in fact a state of metabolic alkalosis). The acute ketonemia therefore reduces serum bicarbonate to “normal,” and no anion gap is present. Patients at risk for hypoalbuminemia who present with any significant illness should have serum albumin measured, and if it is low, a normal serum bicarbonate concentration represents a metabolic acidosis. The anion gap can be adjusted to reflect hypoalbuminemia, when albumin is measured in grams per deciliter, by the following formula:

A normal anion gap does not exclude clinically significant acidosis or high concentrations of unmeasured anions. Direct measurement of compounds that often produce an elevated anion gap (e.g., lactate, ketones, toxic alcohols) should still be pursued when there is clinical concern despite a normal anion gap.

Independent of bicarbonate levels, sodium and chloride play an important role in acid-base status. When [Na⁺] − [Cl⁻], the so-called strong ion difference, is significantly less than 38, an acidosis is present. An alternative to using the anion gap to identify both the presence and cause of acid-base disorders has the clinician start with the base excess (as calculated by a blood gas analyzer), subtract the sodium chloride effect,* and subtract the albumin effect.^† What remains is, in the case of metabolic acidosis, the unmeasured anions (e.g., lactate, ketones, uremic acids, toxic alcohols, or other toxins; see later).¹

Painful arterial blood sampling is unnecessary for the evaluation of acid-base disturbances. PaCO₂, HCO₃⁻, and pH values taken from peripheral venous, central venous, intraosseous, and capillary blood are all suitable for acid-base assessment.2–4

Respiratory Acidosis

Respiratory acidosis occurs when hypoventilation leads to an inappropriately elevated PaCO₂ and resulting acidemia. Any condition that reduces minute ventilation may cause respiratory acidosis (Box 124-1). This commonly occurs acutely in the setting of airway embarrassment, pulmonary insults, major trauma, intracranial catastrophe, or central nervous system (CNS) depressants and chronically in progressive lung disease, neurologic muscle weakness conditions, or obesity hypoventilation syndrome. Respiratory acidosis may be accompanied by hypoxemia, which, depending on its pace and severity, will cause end-organ effects such as headache, ischemic chest pain, altered mental status (usually agitation), bradycardia, and circulatory collapse. When tissue oxygenation is adequate, hypercapnia—which is better tolerated than hypoxemia—tends to produce somnolence and obtundation with cerebral vasodilation and resulting elevation of intracranial pressure.

Beginning 6 to 12 hours after onset of the insult and progressing for 3 to 5 days, the kidneys respond to a respiratory acidosis by retaining bicarbonate; the resulting compensatory metabolic alkalosis, with an elevated serum bicarbonate level, partially corrects serum pH. Chloride ions are excreted in the urine to increase serum HCO₃⁻; patients with chronic respiratory acidosis (e.g., as seen in chronic obstructive pulmonary disease) are therefore often noted to have hypochloremia. An appropriate metabolic compensation for respiratory acidosis is an increase of approximately 3.5 mEq/L in serum HCO₃⁻ concentration for every increase of 10 mm Hg in PaCO₂; a patient with chronic respiratory disease resulting in a baseline PaCO₂ of 60 mm Hg would therefore be expected to have a serum bicarbonate level of approximately 30 mEq/L (and a slight acidemia).

Acute respiratory acidosis is the most immediately dangerous of the acid-base disturbances; fortunately, it is usually also the most readily treatable, as pulmonary ventilation deficits are quickly addressed by therapies commonly used by emergency physicians. Relief of airway obstruction and provision of either noninvasive or mechanical ventilation will often correct imminently dangerous hypoxemia or hypercapnia as treatments directed at the underlying disorder are initiated.

Patients with chronic respiratory acidosis are often hypoxemic at baseline and may be susceptible to further hypoventilation if normal oxygen saturation levels are promptly restored.⁵ Typically, a patient with chronic obstructive pulmonary disease being treated for an acute exacerbation receives high-flow oxygen and is later found to be obtunded with profound hypercapnia. It is therefore prudent to target a lower than normal oxygen saturation in patients thought to be so habituated; SpO₂ fractions in the low 90s and high 80s are usually well tolerated in this population.⁶ However, supplemental oxygen must not be withheld from patients with dangerously low oxygen saturation or patients with end-organ hypoxic insults, such as myocardial or cerebral ischemia. In these cases, aggressive oxygenation therapies must be instituted, with preparations made to initiate mechanical ventilation if it is needed.

Patients with chronic respiratory acidosis who have been intubated should receive frequent blood gas analyses; standard ventilator settings applied to patients who chronically hypoventilate may precipitate posthypercapnic metabolic alkalosis. Correction of PaCO₂ to normal levels (40 mm Hg) in this group can cause dangerous alkalemia; clinicians should target a slightly acidemic serum pH (~7.35), which, depending on the severity and chronicity of the patient’s baseline respiratory acidosis, may correspond to remarkably high PaCO₂ levels.

Respiratory Alkalosis

Respiratory alkalosis occurs when increased minute ventilation causes a decreased PaCO₂ and subsequent increase in serum pH. It is often associated with hysterical hyperventilation; however, as always, the emergency physician must consider dangerous conditions before arriving at a psychiatric diagnosis (Box 124-2).