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Respiratory Acidosis and AlkalosisNicolaos E. Madias | Horacio J. Adrogué

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RESPIRATORY ACIDOSIS

Respiratory acidosis, or primary hypercapnia, is the acid-base disturbance initiated by an increase in carbon dioxide tension of body fluids and in whole-body CO2 stores. Hyper-capnia acidifies body fluids and elicits an adaptive increment in the plasma bicarbonate concentration ([HCO3

−]) that should be viewed as an integral part of the respiratory acido-sis. Arterial CO2 tension (Pco2), measured at rest and at sea level, is greater than 45 mm Hg in simple respiratory acido-sis. Lower values of Pco2 might still signify the presence of primary hypercapnia in the setting of mixed acid-base disor-ders (e.g., eucapnia, rather than the expected hypocapnia, in the presence of metabolic acidosis). Another special case of respiratory acidosis is the presence of arterial eucapnia, or even hypocapnia, in association with venous hypercap-nia in patients who have an acute severe reduction in car-diac output but relative preservation of respiratory function (i.e., pseudorespiratory alkalosis).

PATHOPHYSIOLOGY

The ventilatory system is responsible for maintaining Pco2 within normal limits by adjusting minute ventilation ( V̇E) to match the rate of CO2 production. V̇E consists of two com-ponents: ventilation distributed in the gas-exchange units of the lungs (alveolar ventilation, V̇A) and ventilation wasted in dead space (V̇D). Hypercapnia can result from increased CO2 production, decreased V̇A, or both. Decreased V̇A can result from a reduction in V̇E, an increase in V̇D, or a com-bination of the two. The main elements of the ventilatory system are the respiratory pump, which generates a pressure gradient responsible for airflow, and the loads that oppose such action. The respiratory pump comprises the cerebrum, brainstem, spinal cord, phrenic and intercostal nerves, and the muscles of respiration. The respiratory loads include the ventilatory requirement (CO2 production, O2 consump-tion), airway resistance, lung elastic recoil, and chest-wall/abdominal resistance. Most frequently, primary hyper-capnia develops from an imbalance between the strength of the respiratory pump and the weight of the respiratory loads, thereby resulting in decreased V̇A. Impairment of the pump can occur because of depressed central drive, abnor-mal neuromuscular transmission, or muscle dysfunction. Causes of augmented respiratory loads include ventilation/perfusion mismatch (increased V̇D), augmented airway flow resistance, lung/pleural/chest-wall stiffness, and increased ventilatory demand. An increased V̇D occurs in many clini-cal conditions, including emphysema, cystic fibrosis, asthma,

and other intrinsic lung diseases, as well as chest-wall disor-ders. A less frequent cause of primary hypercapnia is failure of CO2 transport caused by decreases in pulmonary perfu-sion, a condition that occurs in cardiac arrest, circulatory collapse, and pulmonary embolism (thrombus, fat, air).

Overproduction of CO2 is usually matched by increased excretion, so that hypercapnia is prevented. However, patients with marked limitation in pulmonary reserve and those receiving constant mechanical ventilation might expe-rience respiratory acidosis due to increased CO2 production caused by increased muscle activity (agitation, myoclonus, shivering, seizures), sepsis, fever, or hyperthyroidism. Incre-ments in CO2 production might also be imposed by the administration of large carbohydrate loads (>2000 kcal/day) to nutritionally bereft, critically ill patients or during the decomposition of bicarbonate infused in the course of treat-ing metabolic acidosis.

The major threat to life from CO2 retention in patients who are breathing room air is the associated obligatory hypoxemia. When the arterial oxygen tension (Po2) falls to less than 40 to 50 mm Hg, harmful effects can occur, espe-cially if the fall is rapid. In the absence of supplemental oxygen, patients in respiratory arrest develop critical hypox-emia within a few minutes, long before extreme hypercap-nia ensues. Because of the constraints of the alveolar gas equation, it is not possible for Pco2 to reach values much higher than 80 mm Hg while the level of Po2 is still compat-ible with life. Extreme hypercapnia can be seen only during oxygen administration, and, in fact, it is often the result of uncontrolled oxygen therapy.

SECONDARY PHYSIOLOGIC RESPONSE

An immediate rise in plasma [HCO3−] owing to titra-

tion of nonbicarbonate body buffers occurs in response to acute hypercapnia. This adaptation is complete within 5 to 10 minutes after the increase in Pco2. On average, plasma [HCO3

−] increases by about 0.1 mEq/L for each 1 mm Hg acute increment in Pco2; as a result, the plasma hydrogen ion concentration ([H+]) increases by about 0.75 nEq/L for each 1 mm Hg acute increment in Pco2. There-fore, the overall limit of adaptation of plasma [HCO3

−] in acute respiratory acidosis is quite small; even when Pco2 increases to levels of 80 to 90 mm Hg, the increment in plasma [HCO3

−] does not exceed 3 to 4 mEq/L. Moderate hypoxemia does not alter the adaptive response to acute respiratory acidosis. On the other hand, preexisting hypobi-carbonatemia (from metabolic acidosis or chronic respira-tory alkalosis) enhances the magnitude of the bicarbonate response to acute hypercapnia, whereas this response is

diminished in hyperbicarbonatemic states (from metabolic alkalosis or chronic respiratory acidosis). Other electrolyte changes observed in acute respiratory acidosis include mild increases in plasma sodium (1 to 4 mEq/L), potassium (0.1 mEq/L for each 0.1 unit decrease in pH), and phospho-rus, as well as small decreases in plasma chloride and lactate concentrations (the latter effect originating from inhibition of the activity of 6-phosphofructokinase and, consequently, glycolysis by intracellular acidosis). A small reduction in the plasma anion gap is also observed, reflecting the decline in plasma lactate and the acidic titration of plasma proteins. Acute respiratory acidosis induces glucose intolerance and insulin resistance that are not prevented by adrenergic blockade. These changes are likely mediated by the direct effects of the low tissue pH on skeletal muscle.

The adaptive increase in plasma [HCO3−] observed in

the acute phase of hypercapnia is amplified markedly dur-ing chronic hypercapnia as a result of the generation of new bicarbonate by the kidneys. Both proximal and distal acidi-fication mechanisms contribute to this adaptation, which requires 3 to 5 days for completion. The renal response to chronic hypercapnia includes chloruresis and the gen-eration of hypochloremia. On average, plasma [HCO3

−] increases by about 0.35 mEq/L for each 1 mm Hg chronic increment in Pco2; as a result, the plasma [H+] increases by about 0.3 nEq/L for each 1 mm Hg chronic increase in Pco2. More recently, a substantially steeper slope for the change in plasma [HCO3

−] was reported (0.51 mEq/L for each 1 mm Hg chronic increase in Pco2), but the small number of blood gas measurements, one for each of 18 patients, calls into question the validity of this conclusion. Empiric obser-vations indicate a limit of adaptation of plasma [HCO3

−] on the order of 45 mEq/L.

The renal response to chronic hypercapnia is not altered appreciably by dietary sodium or chloride restriction, mod-erate potassium depletion, alkali loading, or moderate hypoxemia. To what extent chronic kidney disease of vari-able severity limits the renal response to chronic hypercap-nia is currently unknown. Obviously, patients with end-stage kidney disease cannot mount a renal response to chronic hypercapnia, so they are more subject to severe acidemia. The degree of acidemia is more pronounced in patients who are receiving hemodialysis rather than peritoneal dialysis, because the former treatment maintains, on average, a lower plasma level [HCO3

−]. Recovery from chronic hypercapnia is crippled by a chloride-deficient diet. In this circumstance, despite correction of the level of Pco2, plasma [HCO3

−] remains elevated as long as the state of chloride deprivation persists, thus creating the entity of “posthypercapnic meta-bolic alkalosis.” Chronic hypercapnia is not associated with appreciable changes in the anion gap or in plasma concen-trations of sodium, potassium, or phosphorus.

ETIOLOGY

Respiratory acidosis can develop in patients who have nor-mal or abnormal airways and lungs. Tables 15.1 and 15.2 present, respectively, causes of acute and chronic respi-ratory acidosis. This classification accounts for the usual mode of onset and duration of the various causes, and it emphasizes the biphasic time course that characterizes the secondary physiologic response to hypercapnia. Primary

145 CHAPTER 15 — RESPIRATORY ACIDOSIS AND ALKALOSIS

hypercapnia can result from disease or malfunction within any element of the regulatory system that controls respira-tion, including the central and peripheral nervous system, respiratory muscles, thoracic cage, pleural space, airways, and lung parenchyma. Not infrequently, more than one cause contributes to the development of respiratory acidosis in a given patient. Chronic obstructive pulmonary disease (COPD) is the most common cause of chronic hypercapnia, a condition that includes emphysema, chronic bronchitis, and small-airway disease.

CLINICAL MANIFESTATIONS

Because hypercapnia almost always occurs with some degree of hypoxemia, it is often difficult to determine whether a specific manifestation is the consequence of the elevated Pco2 or the reduced Po2. Clinical manifestations of respira-tory acidosis arising from the central nervous system are col-lectively known as hypercapnic encephalopathy and include irritability, inability to concentrate, headache, anorexia, mental cloudiness, apathy, confusion, incoherence, com-bativeness, hallucinations, delirium, and transient psycho-sis. Progressive narcosis or coma might develop in patients receiving oxygen therapy, especially those with an acute exacerbation of chronic respiratory insufficiency in whom Pco2 levels of ≤100 mm Hg or even higher can occur. In addition, frank papilledema (pseudotumor cerebri) and motor disturbances, including myoclonic jerks, flapping tremor identical to that observed in liver failure, sustained myoclonus, and seizures may develop. Focal neurologic signs (e.g., muscle paresis, abnormal reflexes) might be observed. The neurologic symptom burden depends on the magnitude of hypercapnia, the rapidity with which it devel-ops, the severity of acidemia, and the degree of accompany-ing hypoxemia. Severe hypercapnia often is misdiagnosed as a cerebral vascular accident or an intracranial tumor.

The hemodynamic consequences of respiratory acidosis include a direct depressing effect on myocardial contrac-tility. An associated sympathetic surge, sometimes intense, leads to increases in plasma catecholamines; however, dur-ing severe acidemia (blood pH lower than about 7.20), receptor responsiveness to catecholamines is markedly blunted. Hypercapnia results in systemic vasodilatation via a direct action on vascular smooth muscle; this effect is most obvious in the cerebral circulation, where blood flow increases in direct relation to the level of Pco2. By contrast, CO2 retention can produce vasoconstriction in the pul-monary circulation as well as in the kidneys; in the latter case, the hemodynamic response may be mediated via an enhanced sympathetic activity. Mild to moderate hypercap-nia is usually associated with an increased cardiac output, normal or increased blood pressure, warm skin, a bounding pulse, and diaphoresis. However, if hypercapnia is severe or considerable hypoxemia is present, decreases in both car-diac output and blood pressure may be observed. Concomi-tant therapy with vasoactive medications (e.g., β-adrenergic receptor blockers) or the presence of congestive heart fail-ure may further impair the hemodynamic response. Cardiac arrhythmias, particularly supraventricular tachyarrhythmias not associated with major hemodynamic compromise, are common, especially in patients receiving digitalis. They do not result primarily from the hypercapnia, but rather reflect

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Table 15.1 Causes of Acute Respiratory Acidosis

Normal Airways and Lungs Abnormal Airways and Lungs

Central Nervous System Depression Upper Airway ObstructionGeneral anesthesia Coma-induced hypopharyngeal obstructionSedative overdosage Aspiration of foreign body or vomitusHead trauma Laryngospasm or angioedemaCerebrovascular accident Obstructive sleep apneaCentral sleep apnea Inadequate laryngeal intubationCerebral edema Laryngeal obstruction postintubationBrain tumorEncephalitis

Lower Airway ObstructionGeneralized bronchospasm

Neuromuscular Impairment Severe asthma (status—asthmaticus)High spinal-cord injury Bronchiolitis of infancy and adultsGuillain-Barré syndrome Disorders involving pulmonary alveoliStatus epilepticus Severe bilateral pneumoniaBotulism, tetanus Acute respiratory distress syndromeCrisis in myasthenia gravis Severe pulmonary edemaHypokalemic myopathyFamilial hypokalemic periodic paralysis

Pulmonary Perfusion DefectCardiac arrest*

Ventilatory Restriction Severe circulatory failure*Rib fractures with flail chest Massive pulmonary thromboembolismPneumothorax Fat or air embolusHemothoraxImpaired diaphragmatic function (e.g., peritoneal dialysis, ascites)

Iatrogenic EventsMisplacement or displacement of airway cannula during anesthesia or mechanical

ventilationBronchoscopy-associated hypoventilation or respiratory arrestIncreased CO2 production with constant mechanical ventilation (e.g., due to

high-carbohydrate diet or sorbent-regenerative hemodialysis)

From Madias NE, Adrogué HJ: Respiratory alkalosis and acidosis. In Seldin DW, Giebisch G, editors: The kidney: physiology and pathophysiology. Philadelphia, 2000, Lippincott Williams & Wilkins, pp 2131-2166.

*May produce “pseudorespiratory alkalosis.”

Table 15.2 Causes of Chronic Respiratory Acidosis

Normal Airways and Lungs Abnormal Airways and Lungs

Central Nervous System Depression Upper Airway ObstructionSedative overdosage Tonsillar and peritonsillar hypertrophyMethadone/heroin addiction Paralysis of vocal cordsPrimary alveolar hypoventilation (Ondine’s curse) Tumor of the cords or larynxObesity-hypoventilation syndrome (Pickwickian syndrome) Airway stenosis after prolonged intubationBrain tumor Thymoma, aortic aneurysmBulbar poliomyelitis Lower Airway ObstructionNeuromuscular ImpairmentPoliomyelitisMultiple sclerosisMuscular dystrophyAmyotrophic lateral sclerosisDiaphragmatic paralysisMyxedemaMyopathic disease

Chronic obstructive lung disease (bronchitis, bronchiolitis, bronchiectasis, emphysema)

Disorders Involving Pulmonary AlveoliSevere chronic pneumonitisDiffuse infiltrative disease (e.g., alveolar proteinosis)Interstitial fibrosis

Ventilatory RestrictionKyphoscoliosis, spinal arthritisObesityFibrothoraxHydrothoraxImpaired diaphragmatic function

From Madias NE, Adrogué HJ: Respiratory alkalosis and acidosis. In Seldin DW, Giebisch G, editors: The kidney: physiology and pathophysiology. Philadelphia, 2000, Lippincott Williams & Wilkins, pp 2131-2166.

the associated hypoxemia and sympathetic discharge, con-comitant medications, other electrolyte abnormalities, and underlying cardiac disease. Retention of salt and water is commonly observed in sustained hypercapnia, especially in the presence of cor pulmonale. In addition to the effects of heart failure on the kidney, multiple other factors may be involved, including the prevailing stimulation of the sympa-thetic nervous system and the renin-angiotensin- aldosterone axis, increased renal vascular resistance, and elevated levels of antidiuretic hormone and cortisol.

DIAGNOSIS

Whenever hypoventilation is suspected, arterial blood gases should be obtained. Alternatively, venous blood gases can be used to assess acid-base status and obtain information about tissue oxygenation. If the acid-base profile of the patient 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 an alkaline pH because of the simultaneous presence of additional acid-base disorders (see Chapter 12). Information from the patient’s history, physical examination, and ancillary labora-tory data should be used for an accurate assessment of the acid-base status.

THERAPEUTIC PRINCIPLES

Treatment of acute respiratory acidosis should focus on three critical steps: (1) ensuring a patent airway, (2) restoring adequate oxygenation by delivering an oxygen-rich inspired mixture, and (3) securing adequate ventilation to repair the abnormal blood gas composition. Indications for endotra-cheal intubation/mechanical ventilation include protection of the airway, relief of respiratory distress, improvement of pulmonary gas exchange, assistance with airway and lung healing, and application of appropriate sedation and neu-romuscular blockade. As noted, acute respiratory acidosis poses its major threat to survival, not because of hypercap-nia or acidemia, but because of the associated hypoxemia. The goal of oxygen therapy is to maintain a Po2 of at least 60 mm Hg and oxygen saturation of ≥90%; yet, a Po2 of 50 to 55 mm Hg might help prevent respiratory depression in patients with hypercapnia and chronic hypoxemia. Supple-mental oxygen can be administered to the spontaneously breathing patient with nasal cannulas, Venturi masks, or nonrebreathing masks. Oxygen flow rates ≤5 L/min can be used with nasal cannulas, each increment of 1 L/min increasing the Fio2 by approximately 4%. Venturi masks, calibrated to deliver Fio2 between 24% and 50%, are most useful in patients with COPD as they allow the Po2 to be titrated, thus minimizing the risk of CO2 retention.

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 (e.g., bilevel positive airway pressure [BiPAP]). With BiPAP, the inspiratory-pressure support decreases the patient’s work of breathing, and the expiratory-pressure support improves gas exchange by preventing alveolar collapse.

Endotracheal intubation with mechanical ventilatory sup-port should be initiated if adequate oxygenation cannot be

147 CHAPTER 15 — RESPIRATORY ACIDOSIS AND ALKALOSIS

secured by noninvasive measures, if progressive hypercapnia or obtundation develops, or if the patient is unable to cough and clear secretions. Large tidal volumes during mechani-cal ventilation often lead to alveolar overdistention, which results in hypotension and barotrauma, two life-threatening complications. To overcome these complications, prescrip-tion of tidal volumes of 6 mL/kg body weight (instead of the conventional level of 12 mL/kg body weight) to achieve pla-teau airway pressures of <30 cm H2O, has been proposed. Because an increase in Pco2 develops (but rarely exceeds 80 mm Hg), this approach is termed permissive hypercapnia or controlled mechanical hypoventilation. If the resultant hyper-capnia reduces the blood pH to less than 7.20, many phy-sicians would prescribe bicarbonate; however, this strategy is controversial, and others would intervene only for pH values on the order of 7.00. Several studies indicate that permissive hypercapnia affords improved clinical outcomes. Heavy sedation and neuromuscular blockade are frequently needed with this therapy. After discontinuation of neu-romuscular blockade, some patients develop prolonged weakness or paralysis. Contraindications to permissive hypercapnia include cerebrovascular disease, brain edema, increased intracranial pressure, and convulsions; depressed cardiac function and arrhythmias; and severe pulmonary hypertension. Notably, most of these entities can develop as adverse effects of permissive hypercapnia itself, especially if it is associated with substantial acidemia.

The presence of a concurrent metabolic acidosis is the primary indication for alkali therapy in patients with acute respiratory acidosis. Administration of sodium bicarbonate to a spontaneously breathing patient with simple respiratory acidosis is not only of questionable efficacy but also involves considerable risk. Concerns include pH-mediated depres-sion of ventilation, enhanced CO2 production because of bicarbonate decomposition, and volume expansion; how-ever, alkali therapy may have a role in patients with severe bronchospasm by restoring the responsiveness of the bron-chial musculature to β-adrenergic agonists. Successful man-agement of intractable asthma in patients with blood pH lower than 7.00 by administering sufficient sodium bicarbon-ate to raise blood pH to greater than 7.20 has been reported.

Patients with chronic respiratory acidosis frequently develop episodes of acute decompensation that can be seri-ous or life threatening. Common culprits include pulmo-nary infections, use of narcotics, and uncontrolled oxygen therapy. In contrast to acute hypercapnia, injudicious use of oxygen therapy in patients with chronic respiratory acido-sis can produce further reductions in alveolar ventilation. Respiratory decompensation superimposes an acute ele-ment of CO2 retention and acidemia on the chronic baseline. Only rarely can one remove the underlying cause of chronic respiratory acidosis, but maximizing alveolar ventilation with relatively simple maneuvers is often successful in the management of respiratory decompensation. Such maneu-vers include treatment with antibiotics, bronchodilators, or diuretics; avoidance of irritant inhalants, tranquilizers, and sedatives; elimination of retained secretions; and gradual reduction of supplemental oxygen, aiming at a Po2 of about 50 to 55 mm Hg. Administration of adequate quantities of chloride (usually as the potassium salt) prevents or corrects a complicating element of metabolic alkalosis (commonly diuretic-induced) that can further dampen the ventilatory

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drive. Acetazolamide may be used as an adjunctive measure, but care must be taken to avoid potassium depletion. Potas-sium and phosphate depletion should be corrected, as they can contribute to the development or maintenance of respi-ratory failure by impairing the function of skeletal muscles. Restoration of the Pco2 of the patient to near its chronic baseline should proceed gradually, over a period of many hours to a few days. Overly rapid reduction in Pco2 in such patients risks the development of sudden, posthypercapnic alkalemia with potentially serious consequences, including reduction in cardiac output and cerebral blood flow, cardiac arrhythmias (including predisposition to digitalis intoxica-tion), and generalized seizures. In the absence of a compli-cating element of metabolic acidosis, and with the possible exception of the severely acidemic patient with intense gen-eralized bronchoconstriction who is undergoing mechani-cal ventilation, there is no role for alkali administration in chronic respiratory acidosis.

RESPIRATORY ALKALOSIS

Respiratory alkalosis, or primary hypocapnia, is the acid-base disturbance initiated by a reduction in carbon dioxide tension of body fluids. Hypocapnia alkalinizes body fluids and elicits an adaptive decrement in plasma [HCO3

−] that should be viewed as an integral part of the respiratory alka-losis. The level of Pco2 measured at rest and at sea level is lower than 35 mm Hg in simple respiratory alkalosis. Higher values of Pco2 may still indicate the presence of an element of primary hypocapnia in the setting of mixed acid-base dis-orders (e.g., eucapnia, rather than the anticipated hyper-capnia, in the presence of metabolic alkalosis).

PATHOPHYSIOLOGY

Primary hypocapnia most commonly reflects pulmonary hyperventilation caused by increased ventilatory drive. The latter results from signals arising from the lung, from the peripheral (carotid and aortic) or brainstem chemorecep-tors, or from influences originating in other centers of the brain. Hypoxemia is a major stimulus of alveolar ventilation, but Po2 values lower than 60 mm Hg are required to elicit this effect consistently. Additional mechanisms for the genera-tion of primary hypocapnia include maladjusted mechani-cal ventilators, the extrapulmonary elimination of CO2 by a dialysis device or extracorporeal circulation (e.g., heart-lung machine), and decreased CO2 production (e.g., sedation, skeletal muscle paralysis, hypothermia, hypothyroidism) in patients receiving constant mechanical ventilation.

A condition termed pseudorespiratory alkalosis occurs in patients who have profound depression of cardiac function and pulmonary perfusion but have relative preservation of alveolar ventilation, including patients with advanced cir-culatory failure and those undergoing cardiopulmonary resuscitation. In such patients, venous (and tissue) hyper-capnia is present because of the severely reduced pulmo-nary blood flow that limits the amount of CO2 delivered to the lungs for excretion. On the other hand, arterial blood reveals hypocapnia because of the increased ventila-tion-to-perfusion ratio, which causes a larger than normal removal of CO2 per unit of blood traversing the pulmonary

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circulation. However, absolute CO2 excretion is decreased, and the body CO2 balance is positive. Therefore, respiratory acidosis, rather than respiratory alkalosis, is present. Such patients may have severe venous acidemia (often resulting from mixed respiratory and metabolic acidosis) accompa-nied by an arterial pH that ranges from mild acidemia to frank alkalemia. In addition, arterial blood may show nor-moxia or hyperoxia, despite the presence of severe hypox-emia in venous blood. Therefore, both arterial and mixed (or central) venous blood sampling is needed to assess the acid-base status and oxygenation of patients with critical hemodynamic compromise.

SECONDARY PHYSIOLOGIC RESPONSE

Adaptation to acute hypocapnia is characterized by an imme-diate drop in plasma [HCO3

−], principally as a result of titration of nonbicarbonate body buffers. This adaptation is completed within 5 to 10 minutes after the onset of hypocap-nia. Plasma [HCO3

−] declines, on average, by approximately 0.2 mEq/L for each 1 mm Hg acute decrement in Pco2; con-sequently, the plasma [H+] decreases by about 0.75 nEq/L for each 1 mm Hg acute reduction in Pco2. The limit of this adap-tation of plasma [HCO3

−] is on the order of 17 to 18 mEq/L. Concomitant small increases in plasma chloride, lactate, and other unmeasured anions balance the decline in plasma [HCO3

−]; each of these components accounts for about one third of the bicarbonate decrement. Small decreases in plasma sodium (1 to 3 mEq/L) and potassium (0.2 mEq/L for each 0.1 unit increase in pH) may be observed. Severe hypophosphatemia can occur in acute hypocapnia because of the translocation of phosphorus into the cells.

A larger decrement in plasma [HCO3−] occurs in chronic

hypocapnia as a result of renal adaptation to the disorder, which involves suppression of both proximal and distal acidi-fication mechanisms. Completion of this adaptation requires 2 to 3 days. Plasma [HCO3

−] decreases, on average, by about 0.4 mEq/L for each 1 mm Hg chronic decrement in Pco2; as a consequence, plasma [H+] decreases by approximately 0.4 nEq/L for each 1 mm Hg chronic reduction in Pco2. The limit of this adaptation of plasma [HCO3

−] is on the order of 12 to 15 mEq/L. About two thirds of the decline in plasma [HCO3

−] is balanced by an increase in plasma chloride con-centration, and the remainder reflects an increase in plasma unmeasured anions; part of the remainder results from the alkaline titration of plasma proteins, but most remains unde-fined. Plasma lactate does not increase in chronic hypocap-nia, even in the presence of moderate hypoxemia. Similarly, no appreciable change in the plasma concentration of sodium occurs. In sharp contrast with acute hypocapnia, the plasma concentration of phosphorus remains essentially unchanged in chronic hypocapnia. Although plasma potas-sium is in the normal range in patients with chronic hypo-capnia at sea level, hypokalemia and renal potassium wasting have been described in subjects in whom sustained hypocap-nia was induced by exposure to high altitude. Patients with end-stage kidney disease are obviously at risk for develop-ment of severe alkalemia in response to chronic hypocap-nia, because they cannot mount a renal response. This risk is higher in patients receiving peritoneal dialysis rather than hemodialysis, because the former treatment maintains, on average, a higher plasma level [HCO3

−].

ETIOLOGY

Primary hypocapnia is the most frequent acid-base distur-bance encountered; it occurs in normal pregnancy and with high-altitude residence. Box 15.1 lists the major causes of respiratory alkalosis. Most are associated with the abrupt appearance of hypocapnia, but in many instances the pro-cess is sufficiently prolonged to permit full chronic adapta-tion. Consequently, no attempt has been made to separate these conditions into acute and chronic categories. Some of the major causes of respiratory alkalosis are benign, whereas others are life threatening. Primary hypocapnia is particu-larly common among the critically ill, occurring either as the simple disorder or as a component of mixed distur-bances. Its presence constitutes an ominous prognostic sign, with mortality increasing in direct proportion to the severity of the hypocapnia.

CLINICAL MANIFESTATIONS

Rapid decrements in Pco2 to half the normal values or lower are typically accompanied by paresthesias of the extremities, chest discomfort (especially in patients mani-festing increased airway resistance), circumoral numbness,

149 CHAPTER 15 — RESPIRATORY ACIDOSIS AND ALKALOSIS

lightheadedness, confusion, and, rarely, tetany or general-ized seizures. These manifestations are seldom present in the chronic phase. Acute hypocapnia decreases cerebral blood flow, which in severe cases may reach values <50% of normal, resulting in cerebral hypoxia. This hypoperfu-sion has been implicated in the pathogenesis of the neuro-logic manifestations of acute respiratory alkalosis along with other factors, including hypocapnia per se, alkalemia, pH-induced shift of the oxyhemoglobin dissociation curve, and decrements in the levels of ionized calcium and potassium. Some evidence indicates that cerebral blood flow returns to normal in chronic respiratory alkalosis.

Patients who are actively hyperventilating manifest no appreciable changes in cardiac output or systemic blood pressure. By contrast, acute hypocapnia in the course of pas-sive hyperventilation, as typically observed during mechani-cal ventilation in patients with a depressed central nervous system or receiving general anesthesia, frequently results in a major reduction in cardiac output and systemic blood pres-sure, increased peripheral resistance, and substantial hyper-lactatemia. This discrepant response probably reflects the decline in venous return caused by mechanical ventilation in passive hyperventilation versus the reflex tachycardia con-sistently observed in active hyperventilation. Although acute

Hypoxemia or Tissue Hypoxia

Decreased inspired O2 tensionHigh altitudeBacterial or viral pneumoniaAspiration of food, foreign body,or vomitusLaryngospasmDrowningCyanotic heart diseaseSevere anemiaLeft shift deviation of the HbO2 curveHypotension*Severe circulatory failure*Pulmonary edema

Stimulation of Chest Receptors

PneumoniaAsthmaPneumothoraxHemothoraxFlail chestAcute respiratory distress syndromeCardiac failureNoncardiogenic pulmonary edemaPulmonary embolismInterstitial lung disease

Central Nervous System Stimulation

VoluntaryPainAnxiety

PsychosisFeverSubarachnoid hemorrhageCerebrovascular accidentMeningoencephalitisTumorTrauma

Drugs or Hormones

Nikethamide, ethamivanDoxapramXanthinesSalicylatesCatecholaminesAngiotensin IIVasopressor agentsProgesteroneMedroxyprogesteroneDinitrophenolNicotine

Miscellaneous

PregnancySepsisHepatic failureMechanical hyperventilationAcetate hemodialysisHeart-lung machineExtracorporeal membrane oxygenation (ECMO)Heat exposureRecovery from metabolic acidosis

From Madias NE, Adrogué HJ: Respiratory alkalosis and acidosis. In Seldin DW, Giebisch G, editors: The kidney: physiology and pathophysiology. Philadelphia, 2000, Lippincott Williams & Wilkins, pp 2131-2166.

HbO2, Oxyhemoglobin.*May produce “pseudorespiratory alkalosis.”

Box 15.1 Causes of Respiratory Alkalosis

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hypocapnia does not lead to cardiac arrhythmias in normal volunteers, it appears that it contributes to the generation of both atrial and ventricular tachyarrhythmias in patients with ischemic heart disease. Chest pain and ischemic ST-T wave changes have been observed in acutely hyperventilating subjects with or without coronary artery disease. Coronary vasospasm and Prinzmetal angina can be precipitated by acute hypocapnia in susceptible subjects. The pathogenesis of these manifestations has been attributed to the same fac-tors that are incriminated in the neurologic manifestations of acute hypocapnia.

DIAGNOSIS

Careful observation can detect abnormal patterns of breath-ing in some patients, yet marked hypocapnia may be pres-ent without a clinically evident increase in respiratory effort. Therefore, an arterial blood gas analysis should be obtained whenever hyperventilation is suspected. In fact, the diagno-sis of respiratory alkalosis, especially the chronic form, is fre-quently missed; physicians often misinterpret the electrolyte pattern of hyperchloremic hypobicarbonatemia as indicative of a normal anion gap metabolic acidosis. If the acid-base profile of the patient reveals hypocapnia in association with alkalemia, at least an element of respiratory alkalosis must be present; however, primary hypocapnia may be associated with a normal or an acidic pH as a result of the concomitant presence of other acid-base disorders. Notably, mild degrees of chronic hypocapnia commonly leave blood pH within the high-normal range. As always, proper evaluation of the acid-base status of the patient requires careful assessment of the history, physical examination, and ancillary laboratory data (see Chapter 12). After the diagnosis of respiratory alkalo-sis has been made, a search for its cause should ensue. The diagnosis of respiratory alkalosis can have important clinical implications, often providing a clue to the presence of an unrecognized, serious disorder (e.g., sepsis) or indicating the severity of a known underlying disease.

THERAPEUTIC PRINCIPLES

Management of respiratory alkalosis must be directed when-ever possible toward correction of the underlying cause. Respiratory alkalosis resulting from severe hypoxemia requires oxygen therapy. The widely held view that hypo-capnia, even if severe, poses little risk to health is inaccu-rate. In fact, transient or permanent damage to the brain, heart, and lungs can result from substantial hypocapnia. In addition, rapid correction of severe hypocapnia can lead to reperfusion injury in the brain and lung. Therefore, severe hypocapnia in hospitalized patients must be prevented whenever possible, and, if it is present, a slow correction is most appropriate.

Rebreathing into a closed system (e.g., a paper bag) may prove helpful for the patient with the anxiety-hyperventila-tion syndrome because it interrupts the vicious cycle that can result from the reinforcing effects of the symptoms of hypo-capnia. Administration of 250 to 500 mg acetazolamide can be beneficial in the management of signs and symptoms of

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high-altitude sickness, a syndrome characterized by hypox-emia and respiratory alkalosis. Considering the risks of severe alkalemia, sedation or, in rare cases, skeletal muscle paralysis and mechanical ventilation may be required tempo-rarily to correct marked respiratory alkalosis. Management of pseudorespiratory alkalosis must be directed at optimizing systemic hemodynamics.

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