Emergency physicians frequently encounter critically ill patients with acid–base disorders, and an accurate understanding of the underlying physiology behind these derangements and the body's attempt to compensate for them is essential to appropriately manage these patients.
Hydrogen ion concentration is typically not expressed directly but rather in terms of pH. Normal blood pH ranges from 7.36 to 7.44, with deviations above this range referred to as alkalemia and deviations below referred to as acidemia. Changes in [H+] may result from changes in volatile (Pco2) or nonvolatile (sulfuric, lactic, etc.) acids. An acidosis is any condition that increases the amount of acid in the blood and may be further characterized as respiratory (increased volatile acid) or metabolic (increased nonvolatile acid). Similarly, an alkalosis reduces the amount of acid in the blood and may also be characterized as respiratory or metabolic.
Several different buffer systems exist to help maintain a serum pH close to 7.4. The most important extracellular buffer system is the bicarbonate–carbonic anhydrase system, which converts CO2 from cellular metabolism to carbonic acid that subsequently dissociates into H+ and bicarbonate.
An isolated metabolic or respiratory process results in a primary acid–base disorder, and multiple processes result in a mixed acid–base disorder. Metabolic processes affect bicarbonate concentration, and respiratory processes affect Pco2. As the serum pH is shifted away from the normal range by a primary acid–base disorder, compensatory processes begin that attempt to restore a normal pH. A metabolic acidosis or alkalosis is compensated by changes in ventilation and a respiratory acidosis or alkalosis is compensated by adjusting renal acid excretion. These compensatory mechanisms will shift blood pH toward normal. In primary acid–base disorders, the underlying disorder will be evident from examination of the pH, Pco2, and serum bicarbonate (see Table 44–12).
Table 44–12. Primary Disorders and Compensatory Responses. ||Download (.pdf)
Table 44–12. Primary Disorders and Compensatory Responses.
|Disorder||Primary Abnormality||Compensation||pH||Pco2 (mm Hg)||Bicarbonate (mEq/L)|
|Respiratory acidosis||Increased Pco2||Increased [HCO3-]||<7.35||>45||>24|
|Respiratory alkalosis||Decreased Pco2||Decreased [HCO3-]||>7.45||<35||<24|
|Metabolic acidosis||Decreased [HCO3-]||Decreased Pco2||<7.35||<40||<22|
|Metabolic alkalosis||Increased [HCO3-]||Increased Pco2||>7.45||>40||>28|
Respiratory compensation for primary metabolic disorders begins within minutes as chemoreceptors sense the change in extracellular pH and signal the respiratory center to change minute ventilation. In a primary metabolic acidosis, the acidemia stimulates an increase in minute ventilation and subsequent decrease in Pco2; conversely, a metabolic alkalosis results in hypoventilation and increased Pco2. Renal compensation for primary respiratory disorders does not begin in earnest until after 6–12 hours of sustained acidemia or alkalemia. In a primary respiratory acidosis, the kidneys increase bicarbonate synthesis, excrete more protons, and reclaim more bicarbonate from the proximal tubule. Alkalemia promotes the retention of H+ and increased bicarbonate excretion. Compensatory mechanisms may take several days to reach maximal effect, and with the exception of compensation for chronic respiratory alkalosis never restore the pH to normal. The timing and limits of compensation are detailed in Table 44–13. A normal pH in the setting of an acid–base disturbance should alert the clinician to the presence of a mixed acid–base disorder.
Table 44–13. Degree and Limits of Compensation. ||Download (.pdf)
Table 44–13. Degree and Limits of Compensation.
|Primary Disorder||Secondary Response||Time||Limit|
|Metabolic acidosis||Decreased Pco2 of 1 mm Hg for each 1 mEq/L decrease in [HCO3-]||24 h||Pco2 of 10 mm Hg|
|Metabolic alkalosis||Increased Pco2 of 0.7 mm Hg for each 1 mEq/L increase in [HCO3-]||24–36 h||Pco2 of 55 mm Hg|
| Acute||Increased [HCO3-] of 1 mEq/L for every 10 mm Hg in Pco2||5–10 min||[HCO3-] of 30 mEq/L|
| Chronic||Increased [HCO3-]of 3.5 mEq/L for every 10 mm Hg in Pco2||72–96 h||[HCO3-] of 45 mEq/L|
| Acute||Decreased [HCO3-] of 2 mEq/L for every 10 mm Hg in Pco2||5–10 min||[HCO3-] of 18 mEq/L|
| Chronic||Decreased [HCO3-] of 5 mEq/L for every 10 mm Hg in Pco2||48–72 h||[HCO3-] of 14 mEq/L|
Evaluation of Acid–Base Disorders
The patient's history and physical examination often provide important clues to the presence and etiology of acid–base disorders and are particularly valuable in the case of mixed disorders. Beyond the history and physical examination, initial assessment of acid–base disorders requires an electrolyte panel and blood gas. Values obtained via venous blood gas sampling (with the exception of Po2) are quite similar to those obtained via arterial sampling; pH is typically 0.01–0.03 lower, Pco2 is 6 mm Hg higher, and bicarbonate is 2 mEq/L higher in venous samples when compared to arterial samples. “Arterialization” of the venous blood specimen by warming the hand at 45°C for 10 minutes eliminates even these differences. Because of the decreased pain and morbidity associated with venous sampling, use of venous blood should be considered when oxygenation is not a concern.
The first step in analyzing the laboratory data in acid–base disorders is to ensure the internal consistency of that data using the Henderson-Hasselbalch equation (see Appendix). Following this, an anion gap should be calculated by adding the serum [Cl−] and [HCO3−] and subtracting this sum from the serum [Na+]. The anion gap represents the negative charge from unmeasured serum proteins and averages 10–12 mEq/L. The delta anion gap is the difference between the calculated anion gap and a normal anion gap, and when compared with the change in bicarbonate can be an important clue to the presence of a mixed disorder.
To determine the primary disorder, first examine the bicarbonate. Increased bicarbonate reflects either a primary metabolic alkalosis or metabolic compensation for a primary respiratory acidosis. Examination of the pH will then reveal the primary disorder: an elevated pH indicates a primary metabolic alkalosis, and a decreased pH indicates a primary respiratory acidosis. Decreased bicarbonate may result from a primary metabolic acidosis or as metabolic compensation for a respiratory alkalosis; decreased pH indicates a metabolic acidosis and increased pH indicates a respiratory alkalosis. Normal pH in the presence of either increased or decreased bicarbonate indicates a mixed disorder. In primary disorders, Pco2 and bicarbonate should deviate in the same direction, while in mixed disorders they deviate in opposite directions. Depending on the clinical setting, examination of serum and urine osmolality and urine electrolytes may be warranted to fully characterize the nature of the disorder.
Clinical Acid–Base Disorders
- Impairment in alveolar ventilation results in hypercapnia
- Alteration in consciousness may result
- Treatment is aimed at improving ventilation by treating the underlying disorder
Respiratory acidosis is defined as an elevated Pco2 (>45 mm Hg) and a decrease in serum pH below 7.36. Any condition that results in alveolar hypoventilation may cause respiratory acidosis (see Table 44–14).
Table 44–14. Causes of Respiratory Acidosis. ||Download (.pdf)
Table 44–14. Causes of Respiratory Acidosis.
- Respiratory center depression
- Narcotic/sedative overdose
- Cardiac arrest
- Paralysis of respiratory muscles
- Anticholinesterases, anesthetics
- Cerebral, brain stem, or high spinal cord infarct
- Primary neuromuscular diseases: Guillain-Barré, myasthenia gravis, amyotrophic lateral sclerosis, poliomyelitis, botulism, tetanus
- Myopathy of respiratory muscles: muscular dystrophy, hypokalemic myopathy, electrolyte imbalance (decreased phosphorus, magnesium), familial periodic paralysis
- Primary hypoventilation
- Diaphragmatic paralysis
- Airway obstruction
- Upper: laryngeal edema/spasm, tracheal edema/stenosis, obstructive sleep apnea
- Lower: mechanical (foreign body, aspirated fluid, neoplasm, bronchospasm)
- Pulmonic/musculoskeletal abnormalities
- Pneumonia, pulmonary edema, acute respiratory disease syndrome, restrictive lung disease, pulmonary embolism
- Pneumothorax, hemothorax, chest wall trauma, flail chest smoke inhalation iatrogenic (mechanical ventilation)
- Chronic airway disease (chronic obstructive pulmonary disease, emphysema)
- Extreme kyphoscoliosis
- Extreme obesity (Pickwickian syndrome)
The hallmark of respiratory acidosis is an alteration in level of consciousness. The characteristic features of hypercapnia range from fatigue, irritability, headache, confusion, stupor, and obtundation to coma and are dependent on the severity and chronicity of the hypercapnia. A Pco2 of 70 may result in coma when secondary to an acute respiratory acidosis, while a person with chronic respiratory acidosis may tolerate Pco2 levels higher than this without a decrease in mental status.
Acute Respiratory Acidosis
Acutely, the increased protons resulting from a respiratory acidosis are buffered by intracellular proteins. This results in a rise in [HCO3−] of 1 mEq/L for every 10 mm Hg increase in Pco2 up to a maximum [HCO3−] of 30 mEq/L and a decrease in pH of 0.08. This compensation is complete within minutes and no further compensation is possible until renal excretion of acid begins, which may take 72–96 hours.
Chronic Respiratory Acidosis
Chronic respiratory acidosis commonly results from COPD and extreme obesity. Renal compensation reaches a steady state after 3–4 days and involves the excretion of chloride in addition to acid, with retention of bicarbonate. An increase in the Pco2 of 10 mm Hg is expected to result in an increase in [HCO3−] of 3.5 mEq/L (to a maximum of 45 mEq/L) and a decrease in pH of 0.03.
Treatment and Disposition
Treatment consists primarily of reversing and stabilizing the underlying process that generated the respiratory acidosis. Bronchodilators, reversal of opioids, and support of ventilation using either BiPAP or intubation may be warranted depending on the clinical picture. Care should be taken not to decrease the Pco2 too rapidly in the setting of chronic respiratory acidosis, as the shift in pH may result in electrolyte abnormalities with dysrhythmias or seizure. Patients with acute respiratory acidosis requiring therapy should be admitted. Admission for patients with chronic respiratory acidosis is more commonly warranted by other findings such as hypoxemia.
- Hypocapnia may be generated by many common causes
- Chronic respiratory alkalosis may be completely compensated
- Treat the underlying cause
Respiratory alkalosis is defined as a Pco2 below 35 mm Hg with an increase in serum pH above 7.44. Acutely, respiratory alkalosis is most commonly caused by hyperventilation secondary to other causes (see Table 44–15). These causes may reduce Pco2 to 25–35 mm Hg, with further decreases resulting from concurrent metabolic acidosis or hypoxia.
Table 44–15. Causes of Respiratory Alkalosis. ||Download (.pdf)
Table 44–15. Causes of Respiratory Alkalosis.
- Early shock
- Early sepsis
- Pulmonary disease
- Pulmonary embolism
- CNS infection
- Liver disease
- Acute salicylate ingestion
The clinical findings of respiratory alkalosis vary depending on the severity and acuity of the process. Acutely, symptoms attributable to hypocalcemia (such as circumoral and digital paresthesia and carpopedal spasm) may occur from the rapid shift in pH. More severe hypocapnia may result in cerebral vasoconstriction with lightheadedness, dizziness, confusion, and altered consciousness. Chronically, respiratory alkalosis may result in hypophosphatemia and a lowered seizure threshold.
Acute Respiratory Alkalosis
Compensation for acute hypocapnia begins within minutes and involves the movement of protons from the intracellular to the extracellular space. For every decrease in Pco2 of 10 mm Hg, [HCO3−] should decrease by 2.5 mEq/L and pH should increase by 0.08.
Chronic Respiratory Alkalosis
Renal compensation for chronic respiratory alkalosis results in decreased proton excretion and the retention of chloride for bicarbonate. Chronically, a decrease in Pco2 of 10 mm Hg will result in a decrease in [HCO3−] of 5 mEq/L. With prolonged hypocapnia (2 weeks or more), pH may be normal.
Treatment and Disposition
Treatment for respiratory alkalosis focuses on treating the underlying disorder, with disposition based on the precipitating cause rather than the alkalosis itself.
- Commonly divided into anion gap and nongap causes
- Cardiovascular effects are most immediately life-threatening
- Calculate the anion gap and delta gaps
- Use Winter's formula to identify respiratory compensation
- Treat the underlying cause
Metabolic acidosis occurs due to an imbalance between the plasma concentration of H+ and HCO3− and is defined as a decrease in [HCO3−] to below 22 with a decrease in pH below 7.36. It may result from overproduction of organic acids (most commonly lactate or ketones), loss of bicarbonate through intestinal or renal wasting, or the inability to excrete acids from normal metabolism or toxin ingestion.
Metabolic acidosis results in a variety of impairments regardless of the underlying etiology (see Table 44–16). The anion gap is commonly used to help determine the etiology; however, the anion gap can be misleading in patients with low albumin and in the rare patients with an anion gap acidosis who are euvolemic. Winter's formula can be used to predict the Pco2 expected for the measured serum bicarbonate to determine if appropriate respiratory compensation is in place (Pco2 = 1.5 × [HCO3−] + 8 ± 2).
Table 44–16. Effects of Metabolic Acidosis. ||Download (.pdf)
Table 44–16. Effects of Metabolic Acidosis.
- Decreased contractility
- Decreased renal and hepatic blood flow
- Decreased fibrillation threshold
- Decreased cardiac responsiveness to catecholamines
- Increased cerebral blood flow
- Increased minute ventilation
- Respiratory muscle fatigue
- Inhibition of anaerobic metabolism
- Increased metabolic rate
- Increased protein catabolism
An elevated anion gap is synonymous with the presence of a metabolic acidosis and implies an overproduction of acids or a decrease in acid clearance by the kidney. The accumulation of acidic anions that are not measured by routine laboratory testing lowers the serum bicarbonate via buffering, thus generating an increased anion gap. An increased anion gap is associated with the following conditions:
- renal failure
- lactic acidosis
- exogenous toxins metabolized to lactate—cyanide, carbon monoxide, ibuprofen, INH, iron, strychnine, toluene
- exogenous toxins metabolized to acids—aspirin, methanol, ethylene glycol, paraldehyde.
A metabolic acidosis with a normal anion gap is generated by the loss of bicarbonate with a reciprocal increase in chloride concentration, giving it its alternate name of hyperchloremic acidosis. The serum potassium concentration can be used to divide hyperchloremic acidosis into hypo- and hyperkalemic forms. Causes associated with hypokalemia include diarrhea, small bowel or pancreatic fistula, ureteral diversion, ileal loop, type 1 renal tubular acidosis (RTA), and the use of carbonic anhydrase inhibitors. Normal and hyperkalemic causes include type 4 RTA, early renal failure, hydronephrosis, tubulointerstitial renal disease, and hypoaldosteronism. Nongap acidosis may also result from rapid hydration with normal saline.
Calculation of the urinary anion gap can help identify the source of a nongap acidosis. The urinary anion gap is calculated by adding [Na+] and [K+] and subtracting [Cl−] and is used to determine urine ammonium excretion, which is difficult to measure directly. A positive value indicates that the renal ammonium production is impaired, pointing toward a renal source for the acidosis. A negative value is consistent with GI losses.
The body buffers an acute metabolic acidosis by using intracellular and extracellular proteins, increasing H+ elimination by the kidney, and stimulating the respiratory drive. Respiratory compensation for a metabolic acidosis involves hyperventilation, and may take 12–24 hours to be fully effective. Under ordinary circumstances, a Pco2 of 10 mm Hg is the lower limit of compensation, with Pco2 falling by 1.0–1.3 for every 1 mEq/L decrease in [HCO3−].
Treatment of metabolic acidosis requires treatment of the underlying cause. In many cases, reversing the underlying causes (e.g., DKA) and replacing volume will allow for the metabolism of organic acids back to bicarbonate or for the kidneys to regenerate bicarbonate. Maintaining adequate tissue perfusion and oxygenation is essential to avoid worsening the acidosis. The use of alkalinizing agents is controversial, as multiple studies have failed to demonstrate benefit from sodium bicarbonate administration and it could theoretically impair oxygen unloading in the tissues as well as result in increased CO2 formation, thereby worsening the acidosis. In severe cases (dysrhythmias, catecholamine insensitivity, hemodynamic instability), sodium bicarbonate may be used to raise the pH to 7.1 at a dose of 0.5 mEq/L/kg. Disposition depends on the severity of the underlying disorder, although nongap acidosis is rarely life threatening.
- Commonly results from vomiting or volume depletion secondary to diuretics
- Evaluate urine chloride concentration to help guide therapy
Metabolic alkalosis is defined as a primary elevation of serum [HCO3−] above 28 mEq/L with an elevation in pH above 7.44. A primary metabolic alkalosis results from the loss of acid or, more rarely, the gain of base. Gastric losses via vomiting or NG suctioning and diuretic use are common causes of metabolic alkalosis, with the resultant volume contraction maintaining the alkalosis. Various other medical conditions can result in a metabolic alkalosis, and determination of the urine chloride can help guide therapy (see Table 44–17).
Table 44–17. Causes of Metabolic Alkalosis. ||Download (.pdf)
Table 44–17. Causes of Metabolic Alkalosis.
|Saline Responsive (Urine [Cl] <10 mEq/L)||Saline Resistant (Urine [Cl] >20 mEq/L)||Other Causes|
- Gastrointestinal: vomiting, nasogastric suction, Cl diarrhea, villous adenoma
- Diuretic therapy
- Cystic fibrosis
- Alkali syndrome
- Mineralocorticoid excess: primary aldosteronism
- Secondary causes: congestive heart failure, cirrhosis, Bartter syndrome, licorice, renin tumor, tobacco
- Cushing syndrome, severe K+ depletion
- Congenital adrenal hyperplasia
- Refeeding alkalosis
- Massive blood transfusion
- Hypercalcemia (bone metastases)
Metabolic alkalosis produces hypokalemia, hypocalcemia, and hypomagnesemia. With severe alkalosis, signs of hypocalcemia may predominate. Decreased cerebral blood flow may result in lethargy and confusion, ultimately progressing to coma and seizures. A history of gastric losses or diuretic use may be obtained and signs of volume contraction on physical examination may be evident. Hypertension should raise the suspicion of primary aldosteronism. Patients with chronic hypercapnia may experience a metabolic alkalosis following correction of the hypercapnia.
Respiratory compensation for a metabolic alkalosis consists of hypoventilation. For every increase of 1 mEq/L in the [HCO3−], Pco2 will rise by 0.7 mm Hg and pH increase by 0.015. Pco2 typically will not increase above 55 mm Hg because of the hypoxemia that ensues at that level of ventilation.
Urine chloride concentration should be measured to guide initial therapy. Patients with a urine [Cl−] below 10 mEq/L are characterized as chloride responsive and should be treated with volume expansion using normal saline. Patients with a urine [Cl−] above 20 mEq/L may be chloride resistant; a urine [Cl−] above 40 mEq/L always indicates that sufficient volume expansion has occurred. Potassium replacement (up to 100–500 mEq) may be needed to correct the alkalosis in certain settings. Acetazolamide may be used in posthypercapnic metabolic alkalosis if volume status is normal. Disposition depends on the severity of the precipitating cause.
Mixed Acid–Base Disorders
- Up to three disorders can coexist
- Analyze the data in a stepwise fashion
- Calculate delta gaps and determine if appropriate compensation exists
- Metabolic acidosis and respiratory alkalosis commonly coexist
Respiratory acidosis and respiratory alkalosis can never coexist, but any other combination of processes is possible. Consider a mixed disorder whenever the degree of compensation is inadequate, or if an acid–base disorder causes no shift in pH (except in chronic respiratory alkalosis), or if the clinical picture is not consistent with a primary process.
Combined Metabolic Acidosis and Respiratory Acidosis
This is an ominous combination and is found in patients in cardiopulmonary arrest. Once a metabolic acidosis has been identified, determine if the Pco2 is appropriate; if it is higher than expected, a superimposed respiratory acidosis exists. In chronic respiratory acidosis, [HCO3−] should increase by 3.5 mEq/L for every increase of 10 mm Hg in Pco2. A smaller increase in [HCO3−] implies incomplete compensation or a superimposed metabolic acidosis.
Combined Metabolic Alkalosis and Respiratory Alkalosis
This mixed disorder is commonly encountered and may result from congestive heart failure, early sepsis, liver disease, or salicylate ingestion. It is identified by a respiratory compensation that is greater than expected for the degree of metabolic acidosis. In patients with chronic respiratory alkalosis, [HCO3−] should be decreased by 5 mEq/L for every 10 mm Hg decrease in Pco2. A greater decrease in [HCO3−] implies a superimposed metabolic acidosis.
Combined Metabolic Alkalosis and Respiratory Acidosis
This mixed disorder may occur in patients with chronic respiratory acidosis who develop a metabolic alkalosis from diuretic use. Appropriate compensation for a metabolic alkalosis is an increase in Pco2 of 0.7 mm Hg for each 1 mEq/L increase in [HCO3−]. A greater increase in Pco2 implies a superimposed respiratory acidosis. For patients with chronic respiratory acidosis, [HCO3−] should increase by 3.5 mEq/L for each increase in Pco2 of 10 mm Hg. Greater increases in [HCO3−] imply a superimposed metabolic alkalosis.
Combined Metabolic Alkalosis and Respiratory Alkalosis
This mixed disorder may result in patients with hepatic failure who are taking diuretics and in patients who require mechanical ventilation and are taking diuretics or undergoing NG suctioning. An increase in Pco2 of less than 0.7 mm Hg for each 1 mEq/L increase in [HCO3−] implies a superimposed respiratory alkalosis. In chronic respiratory alkalosis, [HCO3−] should be decreased by 5 mEq/L for every 10 mm Hg decrease in Pco2, with smaller decreases indicating a superimposed metabolic alkalosis.
Use of Delta Gaps to Identify Mixed Disorders
The use of the delta anion gap and delta bicarbonate can help identify mixed acid–base disorders that would not otherwise be readily apparent, including those with a normal pH. The delta anion gap is derived by subtracting 10 from the calculated anion gap. The delta bicarbonate is derived by subtracting the measured [HCO3−] from 24. For most commonly encountered anion gap acidoses, there will be a 1:1 relationship between the delta anion gap and the delta bicarbonate. When the delta bicarbonate exceeds the delta anion gap, a mixed anion gap and nongap acidosis is likely. When the delta bicarbonate is below the delta anion gap, a mixed anion gap acidosis with a metabolic alkalosis is likely (see Table 44–18).
Table 44–18. Use of the Delta Gaps to Detect Mixed Disorders. ||Download (.pdf)
Table 44–18. Use of the Delta Gaps to Detect Mixed Disorders.
|Blood Chemistry||Normal||Anion Gap Acidosis||Anion Gap and Nongap Acidosis||Metabolic Alkalosis||Anion Gap Acidosis and Metabolic Alkalosis|
|Delta anion gap||10||10||2||16|
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