Respiratory Acidosis, Respiratory Alkalosis, and Mixed Disorders

Etiology and Pathogenesis

The ventilatory system is responsible for eucapnia by adjustment of alveolar minute ventilation () to match the rate of CO₂ production. Its main elements are the respiratory pump, which generates a pressure gradient responsible for airflow, and the loads that oppose such action.

Carbon dioxide retention can occur from an imbalance between the strength of the respiratory pump and the extent of respiratory load (Fig. 14-1). When the respiratory pump is unable to balance the opposing load, respiratory acidosis develops. Respiratory acidosis may be acute or chronic (Tables 14-1 and 14-2). Life-threatening acidemia of respiratory origin can occur during severe, acute respiratory acidosis or during respiratory decompensation in patients with chronic hypercapnia.

A simplified form of the alveolar gas equation at sea level and on breathing of room air (FiO₂, 21%) is as follows:

where PAO₂ is alveolar O₂ tension (mm Hg). This equation demonstrates that patients breathing room air cannot reach PaCO₂ levels much greater than 80 mm Hg (10.6 kP) because the hypoxemia that would occur at greater values is incompatible with life. Therefore, extreme hypercapnia occurs only during O₂ therapy, and severe CO₂ retention is often the result of uncontrolled O₂ administration.

Secondary Physiologic Response

Adaptation to acute hypercapnia elicits an immediate increment in plasma [HCO₃⁻] due to titration of non-HCO₃⁻ body buffers; such buffers generate HCO₃⁻ by combining with H⁺ derived from the dissociation of carbonic acid, as follows:

CO2+H2O↔H2CO3↔HCO3−+H+ and H++B−↔HB

where B⁻ refers to the base component and HB refers to the acid component of non-HCO₃⁻ buffers. This adaptation is completed within 5 to 10 minutes from the increase in PaCO₂, and assuming a stable level of hypercapnia, no further change in acid-base equilibrium is detectable for a few hours.⁷ Moderate hypoxemia does not alter the adaptive response to acute respiratory acidosis. However, preexisting hypobicarbonatemia (whether it is caused by metabolic acidosis or chronic respiratory alkalosis) enhances the magnitude of the HCO₃⁻ response to acute hypercapnia; this response is diminished in hyperbicarbonatemic states, whether caused by metabolic alkalosis or chronic respiratory acidosis.^8,9

The adaptive increase in plasma [HCO₃⁻] observed in acute hypercapnia is amplified greatly during chronic hypercapnia as a result of HCO₃⁻ generation by the kidney.¹⁰ In addition, the renal response to chronic hypercapnia includes a reduction in the rate of Cl⁻ reabsorption, resulting in depletion of body Cl⁻ stores. Complete adaptation to chronic hypercapnia requires 3 to 5 days.⁷ Table 14-3 provides quantitative aspects of the secondary physiologic responses to acute and chronic hypercapnia. More recently, a substantially steeper slope for the change in plasma [HCO₃⁻] in chronic respiratory acidosis was reported (0.51 mmol/l for each 1 mm Hg chronic increase in PaCO₂), but the small number of arterial blood gas (ABG) measurements, one for each of 18 patients, calls in question the validity of the conclusion reached.¹¹ The renal response to chronic hypercapnia is not altered appreciably by dietary Na⁺ or Cl⁻ restriction, moderate K⁺ depletion, alkali loading, or moderate hypoxemia. However, recovery from chronic hypercapnia is crippled by a diet deficient in Cl⁻; in this circumstance, despite correction of the level of PaCO₂, plasma [HCO₃⁻] remains elevated as long as the state of Cl⁻ deprivation persists, leading to posthypercapnic metabolic alkalosis.

Clinical Manifestations

Because clinical hypercapnia almost always occurs in association with hypoxemia, it is often difficult to determine whether a specific manifestation is the consequence of elevated PaCO₂ or reduced PaO₂. Nevertheless, the clinician should bear in mind several characteristic manifestations of neurologic or cardiovascular dysfunction to diagnose the condition accurately and to treat it effectively.^4,7

Diagnosis

Whenever CO₂ retention is suspected, ABG values should be obtained.¹² If the patient's acid-base profile reveals hypercapnia in association with acidemia, at least an element of respiratory acidosis must be present. However, hypercapnia can be associated with a normal or even an alkaline pH if certain additional acid-base disorders are also present. Information from the patient history, physical examination, and ancillary laboratory data should be used to assess whether part or all of the increase in PaCO₂ reflects an adaptive response to metabolic alkalosis rather than being primary in origin.

Treatment

As previously noted, CO₂ retention, whether acute or chronic, is always associated with hypoxemia in patients breathing room air. Consequently, O₂ administration represents a critical element in the management of respiratory acidosis.^1,13 However, supplemental O₂ may lead to worsening hypercapnia, especially in patients with chronic obstructive pulmonary disease (COPD). Although a depressed respiratory drive in CO₂ retention seems to play a role, other factors might account for the worsening hypercapnia in response to supplemental O₂ therapy. These include an increase in dead space ventilation and ventilation/perfusion () mismatch caused by the loss of hypoxic pulmonary vasoconstriction and the Haldane effect (decreased hemoglobin affinity for CO₂ in the presence of increased O₂ saturation), which mandates an increase in ventilation to eliminate the excess CO₂.⁷

Figures 14-2 and 14-3 outline the management of acute respiratory acidosis and chronic respiratory acidosis. Whenever possible, treatment must be directed at removal or amelioration of the underlying cause. Immediate therapeutic efforts should focus on securing a patent airway and restoring adequate oxygenation by delivery of an O₂-rich inspired mixture. Supplemental oxygen can be administered to the spontaneously breathing patient with nasal cannulas, Venturi masks, or non-rebreathing masks. Oxygen flow rates up to 5 l/min can be used with nasal cannulas; each increment of 1l/min increases the fraction of inspired O₂ concentration (FiO₂) by approximately 4%. Venturi masks, calibrated to deliver FiO₂ between 24% and 50%, are most useful in patients with COPD because the PO₂ can be titrated, thus minimizing the risk of CO₂ retention. Oxygen saturation of hemoglobin of approximately 80% to 90% can be achieved with nonbreathing masks.

If the target Po₂ is not achieved with these measures and the patient is conscious, cooperative, hemodynamically stable, and able to protect the lower airway, a method of noninvasive ventilation through a mask can be used, including bilevel positive airway pressure (BiPAP). With BiPAP, the inspiratory-pressure support decreases the work of breathing, and the expiratory-pressure support improves gas exchange by preventing alveolar collapse.

Endotracheal intubation and mechanical ventilatory support should be initiated if adequate oxygenation cannot be secured by noninvasive measures, if progressive hypercapnia or obtundation develops, or if the patient is unable to cough and clear secretions. Minute ventilation should be raised so that the PaCO₂ gradually returns to near its long-term baseline and excretion of excess HCO₃⁻ by the kidneys is accomplished (assuming that Cl⁻ is provided). By contrast, overly rapid reduction in the PaCO₂ risks the development of posthypercapnic alkalosis, with potentially serious consequences. If it develops, posthypercapnic alkalosis can be ameliorated by providing Cl⁻, usually as the potassium salt, and administering the HCO₃⁻-wasting diuretic acetazolamide at doses of 250 to 500 mg once or twice daily. Vigorous treatment of pulmonary infections, bronchodilator therapy, and removal of secretions can offer considerable benefit. Naloxone will reverse the suppressive effect of narcotic agents on ventilation. Avoidance of tranquilizers and sedatives, gradual reduction of supplemental oxygen, aiming at a PaO₂ of about 60 mm Hg (8 kP), and treatment of a superimposed metabolic alkalosis will optimize the ventilatory drive.

Mechanical ventilation with tidal volumes of 10 to 15 ml/kg body weight often leads to alveolar overdistention and volutrauma. Therefore, an alternative approach called permissive hypercapnia (or controlled mechanical hypoventilation) has been successfully applied to prevent barotrauma and cardiovascular collapse.^4,14 In this form of treatment, lower tidal volumes of less than 6 ml/kg and lower peak inspiratory pressures are used. Further, PaCO₂ is allowed to increase, but rarely exceeds 80 mm Hg, and blood pH can decrease to as low as 7.00 to 7.10, while adequate oxygenation is maintained. Because the patient usually requires neuromuscular blockade as well, accidental disconnection from the ventilator can cause sudden death. Contraindications to permissive hypercapnia include cerebrovas­cular disease, brain edema, increased ICP, convulsions, depressed cardiac function, arrhythmias, and severe pulmonary hypertension. Correction of acidemia attenuates the adverse hemodynamic effects of permissive hypercapnia.¹⁵ It appears prudent, although still controversial, to keep the blood pH at approximately 7.30 by the administration of intravenous alkali when controlled hypoventilation is prescribed.^1,16

Etiology and Pathogenesis

Respiratory alkalosis is the most frequent acid-base disorder encountered because it occurs in normal pregnancy and with high-altitude residence.^2,17,18 It is also the most common acid-base abnormality in critically ill patients, occurring either as the simple disorder or as a component of mixed disturbances; indeed, in such patients, its presence may constitute a serious prognostic sign, especially if PaCO₂ level is below 20 to 25 mm Hg (2.7 to 3.3 kP). The presence of hypocapnia signifies transient or persistent alveolar hyperventilation relative to the prevailing CO₂ production, thus leading to negative CO₂ balance. Primary hypocapnia might also originate from the extrapulmonary elimination of CO₂ by dialysis or other extracorporeal circulation (e.g., heart-lung machine).

Table 14-4 provides the major causes of respiratory alkalosis.¹² In most patients, primary hypocapnia reflects alveolar hyperventilation caused by increased ventilatory drive. This is a result of signals arising from the lung, the peripheral chemoreceptors (carotid and aortic), or the brainstem chemoreceptors, or signals originating in other brain centers.

The response of the brainstem chemoreceptors to CO₂ can be augmented by systemic diseases (e.g., liver disease, sepsis), pharmacologic agents, and volition. Hypoxemia is a major stimulus of alveolar ventilation, but PAO₂ values below 60 mm Hg (8 kP) are required to elicit this effect consistently. Alveolar hyperventilation can be the result of maladjusted mechanical ventilators, psychogenic hyperventilation, and lesions involving the central nervous system.

In states of severe circulatory failure, arterial hypocapnia may coexist with venous and therefore tissue hypercapnia; under these conditions, the body CO₂ stores have been enriched so that there is respiratory acidosis rather than respiratory alkalosis. This entity, which we have termed pseudorespiratory alkalosis, develops in patients with profound depression of cardiac function and pulmonary perfusion but relative preservation of alveolar ventilation, including patients with advanced circulatory failure and those undergoing cardiopulmonary resuscitation (CPR). The severely reduced pulmonary blood flow limits the CO₂ delivered to the lungs for excretion, thereby increasing the venous PCO₂. However, the increased ventilation-perfusion ratio causes a larger than normal removal of CO₂ per unit of blood traversing the pulmonary circulation, thereby giving rise to arterial eucapnia or frank hypocapnia. A progressive widening of the arteriovenous difference in pH and PCO₂ develops in two settings of cardiac dysfunction, circulatory failure and cardiac arrest (Fig. 14-4). In both situations, there is severe tissue O₂ deprivation, and it can be completely disguised by the reasonably preserved arterial O₂ values. Appropriate monitoring of acid-base composition and oxygenation in patients with advanced cardiac dysfunction requires mixed (or central) venous blood sampling in addition to the sampling of arterial blood.

Secondary Physiologic Response

Adaptation to acute hypocapnia is characterized by an immediate decrement in plasma [HCO₃⁻] that results totally from nonrenal mechanisms and is explained principally by alkaline titration of the non-HCO₃⁻ body buffers (see second equation under Respiratory Acidosis). This adaptation is completed within 5 to 10 minutes of the onset of hypocapnia, and if there is no further change in PaCO₂, no additional detectable changes in acid-base equilibrium occur for several hours.⁷

Adaptation to chronic hypocapnia entails an additional, larger decrease in plasma [HCO₃⁻] as a consequence of renal adjustments that reflect a dampening of H⁺ secretion by the renal tubule.¹⁰ Approximately 2 to 3 days are required for completion of the adaptation to chronic hypocapnia. Quantitative aspects of the secondary physiologic responses to acute and chronic hypocapnia are shown in Table 14-3.

Clinical Manifestations

A rapid decrease in PaCO₂ to half-normal values or lower is typically accompanied by numbness and paresthesias of the extremities, chest discomfort (especially in patients manifesting increased airway resistance), circumoral numbness, lightheadedness, and mental confusion. Muscle cramps, increased deep tendon reflexes, carpopedal spasm, and generalized seizures occur infrequently. Cerebral vasoconstriction and reduced cerebral blood flow have been well documented during acute hypocapnia; in severe cases, cerebral blood flow might decrease to below 50% of normal values. Hypocapnia can have deleterious effects on the brain of premature infants; in patients with traumatic brain injury, acute stroke, or general anesthesia; and after sudden exposure to very high altitude.¹⁹ Long-term neurologic sequelae can develop when immature brains are exposed to PaCO₂ levels below 15 mm Hg (2 kP) for even short periods. Furthermore, abrupt correction of hypocapnia in these patients leads to cerebral vasodilation, which might cause reperfusion injury or intraventricular hemorrhage.

Brain injury caused by hypocapnia probably results from cerebral ischemia. Other factors include hypocapnia itself, alkalemia, pH-induced shift of the oxyhemoglobin (HbO₂) dissociation curve, decreased levels of ionized calcium and potassium, depletion of the antioxidant glutathione by cytotoxic excitatory amino acids, increases in anaerobic metabolism, cerebral oxygen demand, neuronal dopamine, and seizure activity. If sepsis is present, brain damage worsens with the release of lipopolysaccharide, interleukin-1β, and tumor necrosis factor α.¹⁹

The cardiovascular manifestations of respiratory alkalosis differ in passive and active hyperventilation. The induction of acute hypocapnia in anesthetized patients (i.e., passive hyperventilation) results in a decrease in cardiac output, an increase in peripheral resistance, and a decrease in the systemic blood pressure. By contrast, active hyperventilation does not change or might even increase cardiac output and leaves systemic blood pressure virtually unchanged. The discrepant response of cardiac output during hyperventilation probably reflects the decrease in venous return caused by mechanical ventilation in passive hyperventilation and the reflex tachycardia consistently observed in active hyperventilation. Sustained hypo­capnia induced by exposure to high altitude for several weeks results in a cardiac output within control values or higher. Although it does not lead to cardiac arrhythmias in normal individuals, acute hypocapnia appears to contribute to the generation of both atrial and ventricular tachyarrhythmias in patients with ischemic heart disease; such arrhythmias are frequently resistant to standard forms of therapy. Chest pain and ischemic ST-T wave changes have been observed in acutely hyperventilating patients with no evidence of fixed lesions on coronary angiography.

Diagnosis

Evaluation of the patient history, physical examination, and ancillary laboratory data are required to establish the diagnosis of respiratory alkalosis.^12,17 Careful observation can detect abnormal patterns of breathing in some patients, although marked hypocapnia can occur without a clinically evident increase in respiratory effort. ABG determinations are required to confirm the presence of hyperventilation.

The diagnosis of respiratory alkalosis, especially the chronic form, is frequently missed; physicians often misinterpret the electrolyte pattern of hyperchloremic hypobicarbonatemia as indicative of normal anion gap metabolic acidosis. If the patient's acid-base profile reveals hypocapnia in association with alkalemia, at least an element of respiratory alkalosis must be present. However, hypocapnia might be associated with a normal or an acidic pH because of the concomitant presence of additional acid-base disorders. The clinician should also note that mild degrees of chronic hypocapnia leave blood pH within the high-normal range. The diagnosis of respiratory alkalosis can have important clinical implications; it often provides a clue to the presence of an unrecognized, serious disorder or signals the threat of a known underlying disease.

Treatment

Figure 14-5 provides a synopsis of the management of patients with respiratory alkalosis. The view that hypocapnia poses minimal risk to health under most conditions is not accurate. Substantial hypocapnia in hospitalized patients, whether spontaneous or deliberately induced, may result in transient or permanent damage in the brain as well as the respiratory and cardiovascular systems.¹⁹ Furthermore, rapid correction of severe hypocapnia leads to vasodilation of ischemic areas, resulting in reperfusion injury in the brain and lung. Consequently, severe hypocapnia in hospitalized patients must be prevented whenever possible, and if it is present, abrupt correction should be avoided. Severe alkalemia caused by acute primary hypocapnia requires corrective measures that depend on whether serious clinical manifestations are present. Such measures can be directed at reducing plasma [HCO₃⁻], increasing PaCO₂, or both. Even if baseline plasma [HCO₃⁻]is moderately decreased, reducing it further can be particularly rewarding in these patients because this maneuver combines effectiveness with relatively little risk. For patients with the anxiety-hyperventilation syndrome, in addition to reassurance or sedation, rebreathing into a closed system (e.g., paper bag) might prove helpful by interrupting the vicious cycle that can result from the reinforcing effects of the symptoms of hypocapnia.

Respiratory alkalosis resulting from severe hypoxemia requires O₂ therapy. The oral administration of 250 to 500 mg acetazolamide twice daily can be beneficial in the management of signs and symptoms of high-altitude sickness, a syndrome characterized by hypoxemia and respiratory alkalosis.¹⁷ Patients undergoing mechanical ventilation can facilitate effective correction of hypocapnia, whether from maladjusted ventilator or other factors, by resetting the device.

Etiology and Pathogenesis

Mixed acid-base disturbances are usually observed in hospitalized patients, especially those in critical care units.²¹ Characterization of these disorders and proper identification of their pathogenesis can be challenging and are a prerequisite for taking sound corrective action. Certain clinical settings are often associated with mixed acid-base disorders, including cardiorespiratory arrest, sepsis, drug intoxications, diabetes mellitus, and organ failure (especially renal, hepatic, and pulmonary failure). Patients with severe renal impairment or end-stage renal disease (ESRD) are prone to mixed acid-base disturbances of great complexity and severity.²² In these conditions, metabolic acidosis of the high anion gap type is frequently accompanied by a component of hyperchloremic acidosis, inability to mount an appropriate secondary response to chronic respiratory acidosis or alkalosis, inability to respond to a load of fixed acids (e.g., lactic acid) or a primary loss of alkali (e.g., diarrhea) with the expected increase in net acid excretion, and inability to respond to an alkali load with bicarbonaturia despite the presence of increased plasma [HCO₃⁻]. As a result, these patients are particularly vulnerable to the development of both extreme acidemia and extreme alkalemia.

A practical classification of mixed acid-base disorders recognizes three main groups of disturbances in accordance with the preceding definition (Fig. 14-6). Representative examples are depicted in Table 14-5, and some of these mixed disorders are reviewed next.

Metabolic Acidosis and Respiratory Acidosis

The expected hypocapnia secondary to metabolic acidosis is estimated by ΔPaCO₂/Δ[HCO₃⁻] = 1.2 mm Hg/mEq/l (Δ indicates change). If measured PaCO₂ exceeds 5 mm Hg of the estimated value, respiratory acidosis is also present. Clinical examples of metabolic acidosis combined with respiratory acidosis include untreated cardiopulmonary arrest, circulatory failure in patients with COPD, severe renal failure associated with hypercapnic respiratory failure, various intoxications, and hypokalemic (or less frequently hyperkalemic) paralysis of respiratory muscles in patients with diarrhea or renal tubular acidosis (RTA) (Fig. 14-7 and Table 14-5, example 4).

Metabolic Alkalosis and Respiratory Alkalosis

Metabolic alkalosis combined with respiratory alkalosis might be encountered in patients with primary hypocapnia associated with chronic liver disease who develop metabolic alkalosis from a variety of causes, including vomiting, nasogastric drainage, diuretics, profound hypokalemia, and alkali administration (e.g., absorption of antacids; infusion of lactated Ringer solution, alimentation solutions, citrated blood products), especially in the patient with renal impairment. Mixed metabolic/respiratory alkalosis also occurs in critically ill patients, particularly those undergoing mechanical ventilation, and in patients with respiratory alkalosis, caused by either pregnancy or heart failure, who experience metabolic alkalosis attributable to diuretics or vomiting (Fig. 14-8 and Table 14-5, example 6).

Metabolic Alkalosis and Respiratory Acidosis

Metabolic alkalosis with respiratory acidosis is one of the most frequently encountered mixed acid-base disorders. The usual clinical setting involves COPD in conjunction with diuretic therapy, but it can occur with other causes of metabolic alkalosis (e.g., vomiting, administration of corticosteroids) (Fig. 14-9 and Table 14-5, example 5). Critically ill patients with respiratory failure caused by acute respiratory distress syndrome and occasionally those with profound hypokalemia with diaphragmatic muscle weakness also might develop mixed metabolic alkalosis and respiratory acidosis.

Metabolic Acidosis and Respiratory Alkalosis

As with respiratory acidosis and metabolic alkalosis, the combination of metabolic acidosis and respiratory alkalosis is characterized by normal or near-normal blood pH; its two components exert offsetting effects on systemic acidity (Fig. 14-10). This disorder is common in intensive care unit patients and is generally associated with high mortality. Causes of the primary hypocapnia include fever, hypotension, gram-negative septicemia, pulmonary edema, hypoxemia, and mechanical hyperventilation. The component of metabolic acidosis in turn might be lactic acidosis (e.g., complicating shock, hepatic failure) or renal acidosis. A considerable fraction of adults and children develop respiratory alkalosis and lactic acidosis in the course of acute severe asthma. In some patients, the lactic acidosis appears to be caused by excessive use of β₂-adrenergic agonists and corticosteroids. The resulting increased ventilatory demands might worsen abnormal lung mechanics and precipitate ventilatory failure.^23,24 Salicylate intoxication is another cause of mixed metabolic acidosis and respiratory alkalosis. Stimulation of the ventilatory center in the brainstem accounts for the respiratory alkalosis, whereas the accelerated production of organic acids, including pyruvic, lactic, and keto acids, and to a lesser extent the accumulation of salicylic acid itself are responsible for the metabolic acidosis.

Clinical Manifestations

The symptoms and signs of the underlying disease that give rise to the observed mixed acid-base disorder dominate the clinical picture, but the development of severe abnormalities in either PaCO₂ (severe hypocapnia or hypercapnia) or systemic acidity (profound acidemia or alkalemia) might be responsible for the superimposition of additional clinical manifestations. On the one hand, profound hypocapnia might induce obtundation, generalized seizures, and occasionally even coma or death as a result of a critical reduction in cerebral blood flow and other mechanisms. Rarely, angina pectoris also might occur. On the other hand, severe hypercapnia might generate a profound encephalopathy with the classic features of pseudotumor cerebri, including headaches, obtundation, vomiting, and bilateral papilledema, caused by increased ICP. Extreme acidemia results in depression of the central nervous system as well as the cardiovascular system.⁷ Reduction in myocardial contractility and peripheral vascular resistance triggered by acidemia might result in severe hypotension. Profound alkalemia might elicit paresthesias, tetany, cardiac dysrhythmias, or generalized seizures.

Diagnosis

The basic principles underlying the diagnosis of mixed acid-base disorders are identical to those required for the identification of simple acid-base disturbances. These include assessment of the accuracy of the acid-base data by ensuring that the available values for pH, PaCO₂, and plasma [HCO₃⁻] satisfy the mathematical constraints of the Henderson-Hasselbalch equation; a careful history and performance of a complete physical examination; analysis of the plasma anion gap and other ancillary laboratory data; and knowledge of the quantitative aspects of the adaptive response to each of the four simple acid-base disturbances. Adherence to these principles cannot be overemphasized. Even experienced clinicians risk misdiagnosis of the prevailing acid-base status by bypassing this systematic approach.³

Normality of the acid-base parameters is not in itself sufficient for diagnosis of normal acid-base status; indeed, normal acid-base values might be the fortuitous result of mixed acid-base disorders (e.g., high anion gap acidosis treated with alkali infusion, diarrhea-induced metabolic acidosis in conjunction with vomiting-induced metabolic alkalosis). A given set of acid-base parameters is never diagnostic of a particular acid-base disorder, whether it is simple or mixed in nature; rather, it is consistent with a range of acid-base abnormalities. What on the surface appears to be a clear-cut simple acid-base disorder might actually reflect the interplay of a number of coexisting acid-base disturbances. The patient history and physical examination frequently provide important insights into the prevailing acid-base status as well as useful clues to the differential diagnosis.

A critical component of the diagnostic process is the examination of the plasma anion gap (Table 14-6). This derived parameter provides important insights into the nature of the prevailing changes in plasma [HCO₃⁻]. An elevated plasma anion gap might offer the first clue to the presence of disordered acid-base status despite normal acid-base parameters. With a plasma HCO₃⁻ concentration deficit (Δ[HCO₃⁻]_p), a normal or subnormal value for the plasma anion gap denotes that the entire decrease in HCO₃⁻ can be attributed to acidifying processes resulting in the loss of alkali (e.g., diarrhea, RTA) or to respiratory alkalosis. By comparison, with a high anion gap metabolic acidosis, there is usually a close reciprocal stoichiometry between the decrease in serum HCO₃⁻ and the increase in the anion gap, termed the Δ(anion gap). A reduction in serum HCO₃⁻ of 10 mmol/l is therefore associated with a Δ(anion gap) of 10 mmol/l. Addition of the value for the Δ(anion gap) to the prevailing level of serum HCO₃⁻ allows the derivation of the basal value of HCO₃⁻ existing before the development of the high anion gap metabolic acidosis. Appreciation of this reciprocal relationship between the Δ[HCO₃⁻]_p and the Δ(anion gap) is important in distinguishing between a pure high anion gap metabolic acidosis and a mixed high and normal anion gap metabolic acidosis and in detecting a mixed high anion gap metabolic acidosis and metabolic alkalosis. Additional diagnostic insights are often obtained by examination of other laboratory data, including the serum potassium, glucose, urea nitrogen, and creatinine concentrations; semiquantitative measures for ketonemia or ketonuria; screening of blood or urine for toxins; and estimation of the serum osmolar gap.

Mild acid-base disorders pose particular diagnostic difficulty because of the overlap of values for the simple disturbances near the normal range. In such patients, any of several simple disorders or a variety of mixed disturbances might fully account for the acid-base data under evaluation. Again, careful correlation of all available clinical information should guide the diagnostic process.

Treatment

The management of mixed acid-base disturbances is aimed at restoration of the altered acid-base status by treatment of each simple acid-base disorder involved.^1,2,20,26 Figures 14-7 to 14-10 provide recommendations for treatment of patients with some common mixed acid-base disturbances.

Given the variable response time to therapy of the individual components, it is crucial to be aware of the effect that graded correction might have on systemic acidity. The asynchronous reversal of the individual components might be used at times to therapeutic advantage; on other occasions, such a practice might prove catastrophic. For example, extreme acidemia caused by metabolic acidosis and respiratory acidosis, or extreme alkalemia caused by metabolic alkalosis and respiratory alkalosis, might be safely corrected by a rapid return of PaCO₂ toward normal. By comparison, an asynchronous return of PaCO₂ to normal in a patient with profound metabolic acidosis and superimposed respiratory alkalosis might prove disastrous. Similarly, extreme caution should be exercised in treating patients with respiratory acidosis and metabolic alkalosis, one of the most common mixed acid-base disorders. Although therapeutic measures intended to improve alveolar ventilation should be instituted, an abrupt decrease in PaCO₂ risks development of severe alkalemia. Therefore, aggressive measures should be taken to treat metabolic alkalosis, making certain that reversal of the metabolic component does not lag behind treatment of the respiratory element. In fact, because the ventilatory drive in patients with chronic respiratory acidosis depends in part on the prevailing acidemia, reversal of a complicating element of metabolic alkalosis regularly results in improved alveolar ventilation, thus achieving a decrease in PaCO₂ and an increase in PaO₂.