Regulation of normal pH (7.35-7.45) depends on both the lungs and kidneys. By the Henderson-Hasselbalch equation, pH is a function of the ratio of HCO3- (regulated by the kidney) to PCO2 (regulated by the lungs). The HCO3/PCO2 relationship is useful in classifying disorders of acid-base balance. Acidosis is due to gain of acid or loss of alkali; causes may be metabolic (fall in serum HCO3- ) or respiratory (rise in PCO2). Alkalosis is due to loss of acid or addition of base and is either metabolic (↑ serum [HCO3- ]) or respiratory (↓ PCO2) (Fig. 2-1. Nomogram Showing Bands for Uncomplicated Respiratory or Metabolic Acid-Base Disturbances in Intact Subjects).
To limit the change in pH, metabolic disorders evoke an immediate compensatory response in ventilation; full renal compensation for respiratory disorders is a slower process, such that “acute” compensations are of lesser magnitude than “chronic” compensations. Simple acid-base disorders consist of one primary disturbance and its compensatory response. In mixed disorders, a combination of primary disturbances is present.
The cause of simple acid-base disorders is usually obvious from history, physical examination, and/or basic laboratory tests. Initial laboratory evaluation depends on the dominant acid-base disorder, but for metabolic acidosis and alkalosis this should include electrolytes, BUN, creatinine, albumin, urinary pH, and urinary electrolytes. An arterial blood gas (ABG) is not always required for pts with a simple acid-base disorder, e.g., mild metabolic acidosis in the context of chronic renal failure. However, concomitant ABG and serum electrolytes are necessary to fully evaluate more complex acid-base disorders. The compensatory response should be estimated from the ABG; Winter's formula [PaCO2 = (1.5 × [HCO3- ]) + 8 ± 2] is particularly useful for assessing the respiratory response to metabolic acidosis. The anion gap should also be calculated; the anion gap = [Na+ ] - ([HCO3- ] + [Cl- ]) = unmeasured anions - unmeasured cations. The anion gap should be adjusted for changes in the concentration of albumin, a dominant unmeasured anion; the “adjusted anion gap” = anion gap + ∼2.5 × (4 - albumin mg/dL). Other supportive tests will elucidate the specific form of anion-gap acidosis (see below).
The low HCO3- in metabolic acidosis results from the addition of acids (organic or inorganic) or from a loss of HCO3- ; causes of metabolic acidosis are classically categorized by presence or absence of an increase in the anion gap (Table 2-1 Metabolic Acidosis). Increased anion-gap acidosis (>12 mmol/L) is due to addition of acid (other than HCl) and unmeasured anions to the body. Common causes include ketoacidosis (diabetes mellitus [DKA], starvation, alcohol), lactic acidosis, poisoning (salicylates, ethylene glycol, and methanol), and renal failure.
Rare and newly appreciated causes of anion-gap acidosis include D-lactic acidosis, propylene glycol toxicity, and 5-oxoprolinuria (also known as pyroglutamic aciduria). D-Lactic acidosis (an increase in the D-enantiomer of lactate) can occur in pts with removal, disease, or bypass of the short bowel, leading to increased delivery of carbohydrates to colon. Intestinal overgrowth of organisms that metabolize carbohydrate to D-lactate results in D-lactic acidosis; a wide variety of neurologic symptoms can ensue, with resolution following treatment with appropriate antibiotics to change the intestinal flora. Propylene glycol is a common solvent for IV preparations of a number of drugs, most prominently lorazepam. Pts receiving high rates of these drugs may develop a hyperosmolar anion-gap metabolic acidosis, due mostly to increased lactate, often accompanied by acute kidney failure. Pyroglutamic aciduria (5-oxoprolinuria) is a high anion-gap acidosis caused by dysfunction of the γ;-glutamyl cycle that replenishes intracellular glutathione; 5-oxoproline is an intermediate product of the cycle. Hereditary defects in the γ;-glutamyl cycle are associated with 5-oxoprolinuria; acquired defects occur in the context of acetaminophen therapy, due to derepression of the cycle by reduced glutathione and overproduction of 5-oxoproline. Resolution occurs after withdrawal of acetaminophen; treatment with N-acetyl cysteine to replenish glutathione stores may hasten recovery.
The differentiation of the various anion-gap acidoses depends on the clinical scenario and routine laboratory tests (Table 2-1 Metabolic Acidosis) in conjunction with measurement of serum lactate, ketones, toxicology screens (if ethylene glycol or methanol ingestion are suspected), and serum osmolality. D-Lactic acidosis can be diagnosed by a specific assay for the D-enantiomer; 5-oxoprolinuria can be diagnosed by the clinical scenario and confirmed by gas chromatographic/mass spectroscopic (GC/MS) analysis of urine, a widely available pediatric screening test for inborn errors of metabolism (typically “urine for organic acids”).
Pts with ethylene glycol, methanol, or propylene glycol toxicity may have an “osmolar gap,” defined as a >10-mosmol/kg difference between calculated and measured serum osmolality. Calculated osmolality = 2 × Na+ + glucose/18 + BUN/2.8. Of note, pts with alcoholic ketoacidosis and lactic acidosis may also exhibit a modest elevation in the osmolar gap; pts may alternatively metabolize ethylene glycol or methanol to completion by presentation, with an increased anion gap and no increase in the osmolar gap. However, the rapid availability of a measured serum osmolality may aid in the urgent assessment and management of pts with these medical emergencies.
Normal anion-gap acidosis can result from HCO3- loss from the GI tract. Diarrhea is by far the most common cause, but other GI conditions associated with external losses of bicarbonate-rich fluids may lead to large alkali losses-e.g., in ileus secondary to intestinal obstruction, in which liters of alkaline fluid may accumulate within the intestinal lumen. Various forms of kidney disease are associated with non-anion-gap acidosis due to reduced tubular reabsorption of filtered bicarbonate and/or reduced excretion of ammonium (NH4+ ). The early stages of progressive renal disease are frequently associated with a non-anion-gap acidosis, with development of an anion-gap component in more advanced renal failure. Non-anion-gap acidosis is also seen in renal tubular acidosis or in the context of tubulointerstitial injury, e.g., after acute tubular necrosis, allergic interstitial nephritis, or urinary tract obstruction. Finally, non-anion-gap acidosis due to exogenous acid loads may occur after rapid volume expansion with saline-containing solutions, the administration of NH4Cl (a component of cough syrup), lysine HCl, or treatment with the phosphate binder sevelamer hydrochloride.
Calculation of the urinary anion gap may be helpful in the evaluation of hyperchloremic metabolic acidosis, along with a measurement of urine pH. The urinary anion gap is defined as urinary ([Na+ ] + [K+ ]) - [Cl- ] = [unmeasured anions] - [unmeasured cations]); the NH4+ ion is the major unmeasured urinary cation in metabolic acidosis, wherein the urinary anion gap should be strongly negative. A negative anion gap thus suggests GI losses of bicarbonate, with appropriate renal response and increased NH4+ excretion; a positive anion gap suggests altered urinary acidification, as seen in renal failure or distal renal tubular acidoses. An important caveat is that the rapid renal excretion of unmeasured anions in anion-gap acidosis, classically seen in DKA, may reduce the serum anion gap and generate a positive value for the urinary anion gap, despite the adequate excretion of urinary NH4+ ; this may lead to misdiagnosis as a renal tubular acidosis.
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Metabolic AcidosisTreatment of metabolic acidosis depends on the cause and severity. DKA responds to insulin therapy and aggressive hydration; close attention to serum [K+ ] and administration of KCl is essential, given that the correction of insulinopenia can cause profound hypokalemia. The administration of alkali in anion-gap acidoses is controversial and is rarely appropriate in DKA. It is reasonable to treat severe lactic acidosis with IV HCO3- at a rate sufficient to maintain a pH >7.20; treatment of moderate lactic acidosis with HCO3- is controversial. IV HCO3 is however appropriate to reduce acidosis in D-lactic acidosis, ethylene glycol and methanol toxicity, and 5-oxoprolinuria. Chronic metabolic acidosis should be treated when HCO3- is <18-20 mmol/L. In pts with CKD, there is some evidence that acidosis promotes protein catabolism and may worsen bone disease. There is also evidence that correction of metabolic acidosis in CKD leads to a reduced rate of progression to end-stage renal disease (ESRD). Sodium citrate may be more palatable than oral NaHCO3. Oral therapy with NaHCO3 usually begins with 650 mg tid and is titrated upward to maintain serum [HCO3- ]. |
Metabolic alkalosis is due to a primary increase in serum [HCO3- ], distinguished from chronic respiratory acidosis-with a compensatory increase in renal HCO3- reabsorption-by the associated increase in arterial pH (normal or decreased in chronic respiratory acidosis). Administered, exogenous alkali (HCO3- , acetate, citrate, or lactate) may cause alkalosis if the normal capacity to excrete HCO3- is reduced or if renal HCO3- reabsorption is enhanced. A recently resurgent problem is “milk alkali syndrome,” a triad of hypercalcemia, metabolic alkalosis, and acute renal failure due to ingested calcium carbonate, typically taken for the treatment or prevention of osteoporosis or for symptomatic relief of peptic ulcer disease.
Metabolic alkalosis is primarily caused by renal retention of HCO3- and is due to a variety of underlying mechanisms. Pts are typically separated into two major subtypes: Cl- -responsive and Cl- -resistant. Measurement of urine Cl- affords this separation in the clinical setting (Fig. 2-2. The Diagnostic Approach to Metabolic Alkalosis). The quintessential causes of Cl- -responsive alkalosis are GI induced from vomiting or gastric aspiration through a nasogastric tube, and renal induced from diuretic therapy. Hypovolemia, chloride deficiency, activation of the RAA axis, and hypokalemia play interrelated roles in the maintenance of this hypochloremic or “contraction” alkalosis. The various syndromes of true or apparent mineralocorticoid excess cause Cl- -resistant metabolic alkalosis (Fig. 2-2. The Diagnostic Approach to Metabolic Alkalosis); most of these pts are hypokalemic, volume expanded, and/or hypertensive.
Common forms of metabolic alkalosis are generally diagnosed from the history, physical examination, and/or basic laboratory tests. ABGs will help determine whether an elevated [HCO3- ] is reflective of metabolic alkalosis or chronic respiratory acidosis; ABGs are required for the diagnosis of mixed acid-base disorders. Measurement of urinary electrolytes will aid in separating Cl- -responsive and Cl- -resistant forms. Urinary [Na+ ] may thus be >20 meq/L in Cl- -responsive alkalosis despite the presence of hypovolemia; however, urinary [Cl- ] will typically be very low, except in pts with severe hypokalemia. Notably, urinary [Cl- ] may be variable in pts with diuretic-associated alkalosis, depending on the temporal relationship to diuretic administration. Other diagnostic tests-e.g., plasma renin, aldosterone, cortisol-may be appropriate in Cl- -resistant forms with high urinary [Cl- ] (Fig. 2-2. The Diagnostic Approach to Metabolic Alkalosis).
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Metabolic AlkalosisThe acid-base disorder in Cl- -responsive alkalosis will typically respond to saline infusion; however, the associated hypokalemia should also be corrected. Pts with true or apparent mineralocorticoid excess require specific treatment of the underlying disorder. For example, hyperactive amiloride-sensitive ENaC channels cause Liddle's syndrome, which can respond to therapy with amiloride and related drugs; pts with hyperaldosteronism may in turn respond to blockade of the mineralocorticoid receptor with spironolactone or eplerenone. Finally, severe alkalosis in the critical care setting may require treatment with acidifying agents such as acetazolamide. |
Respiratory acidosis is characterized by CO2 retention due to ventilatory failure. Causes include sedatives, stroke, chronic pulmonary disease, airway obstruction, severe pulmonary edema, neuromuscular disorders, and cardiopulmonary arrest. Symptoms include confusion, asterixis, and obtundation.
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Respiratory AcidosisThe goal is to improve ventilation through pulmonary toilet and reversal of bronchospasm. Intubation or noninvasive positive pressure ventilation (NPPV) may be required in severe acute cases. Acidosis due to hypercapnia is usually mild; however, combined respiratory and metabolic acidosis may cause a profound reduction in pH. Respiratory acidosis may accompany low tidal volume ventilation in ICU pts and may require metabolic “overcorrection” to maintain a neutral pH. |
Excessive ventilation causes a primary reduction in CO2 and ↑ pH in pneumonia, pulmonary edema, interstitial lung disease, and asthma. Pain and psychogenic causes are common; other etiologies include fever, hypoxemia, sepsis, delirium tremens, salicylates, hepatic failure, mechanical overventilation, and CNS lesions. Pregnancy is associated with a mild respiratory alkalosis. Severe respiratory alkalosis may acutely cause seizures, tetany, cardiac arrhythmias, or loss of consciousness.
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Respiratory AlkalosisTreatment should be directed at the underlying disorders. In psychogenic cases, sedation or a rebreathing bag may be required. |
In many circumstances, more than a single acid-base disturbance exists. Examples include combined metabolic and respiratory acidosis with cardiogenic shock; metabolic alkalosis and anion-gap acidosis in pts with vomiting and diabetic ketoacidosis; and anion-gap metabolic acidosis with respiratory alkalosis in pts with salicylate toxicity. The diagnosis may be clinically evident and/or suggested by relationships between the PCO2 and [HCO3- ] that diverge from those found in simple disorders. For example, the PCO2 in a pt with metabolic acidosis and respiratory alkalosis will be considerably less than that predicted from the [HCO3- ] and Winter's formula [PaCO2 = (1.5 × [HCO3- ]) + 8 + 2].
In “simple” anion-gap acidosis, the anion gap increases in proportion to the fall in [HCO3- ]. A lesser drop in serum [HCO3- ] than in the anion gap suggests a coexisting metabolic alkalosis. Conversely, a proportionately larger drop in [HCO3- ] than in the anion gap suggests the presence of a mixed anion-gap and non-anion-gap metabolic acidosis. Notably, however, these interpretations assume 1:1 relationships between unmeasured anions and the fall in [HCO3- ], which are not uniformly present in individual pts or as acidoses evolve. For example, volume resuscitation of pts with DKA will typically increase glomerular filtration and the urinary excretion of ketones, resulting in a decrease in the anion gap in the absence of a supervening non-anion-gap acidosis.