Respiratory Acid–Base Disorders

Depressed Pump Secondary to Abnormal Central Drive

The [H ⁺ ] of body fluids is the main chemical stimulus for pulmonary ventilation acting on the central chemoreceptors (brainstem) and the peripheral arterial chemoreceptors (carotid and aortic bodies) (8). In normal humans there is a linear relationship between arterial PCO ₂ and minute ventilation and the slope becomes steeper in the presence of hypoxemia. In contrast, minute ventilation does not increase until arterial O ₂ tension (PaO ₂ ) falls below 60 mmHg, with further increases as hypoxemia worsens; yet, the hypocapnia resulting from the hypoxemia-induced hyperventilation blunts the ventilatory response.

Primary disturbances in the CNS comprise the classic forms of hypercapnia that result from an abnormal respiratory control system. Yet, a faulty respiratory drive is also involved in the development of respiratory failure in other clinical settings that are unrelated to a primary disorder of ventilatory control mechanism. The ventilatory response to hypoxia and hypercapnia in the normal population has a wide range, and genetic factors play a role in this variable response. In addition, an experimentally induced increase in the work of breathing caused by both an increased airway resistance and a decrease in thorax/lung compliance alters the ventilatory drive; this change points to a complex interaction between the mechanical load and the brainstem control of the respiratory muscles. Episodes of apnea occurring in patients with status asthmaticus have been linked to this interaction.

The pathogenesis of upper airway obstruction during sleep includes pharyngeal narrowing during both inspiration (caused by subatmospheric collapsing pressure) and expiration (caused by reduced ventilatory motor output due to central hypopnea).

Depressed Pump Secondary to Abnormal Function of Respiratory Muscles

Inadequate ventilation leading to CO ₂ retention may occur whenever the respiratory pump fails to adequately propel air through the respiratory conduits, in spite of a normal respiratory drive and the absence of lung disease. Primary disorders of the respiratory muscles and of the motor neurons responsible for pulmonary ventilation are classic examples of this pathophysiologic mechanism. However, an even larger and heterogeneous group of patients exists in which fatigue of the respiratory muscles plays a critical role in the development of respiratory acidosis. Such respiratory muscle fatigue is observed with poor nutrition, certain electrolyte disorders (potassium and phosphate depletion), an obligatory high level of ventilation, decreased compliance of the respiratory system, increased resistance to airflow, and alterations in thoracic configuration. Structural and functional changes in the respiratory muscles, as well as depletion of their energy stores, occur with malnutrition.

Increased Load Secondary to Abnormalities in the Lungs, and Pleural/Chest Wall Stiffness

A reduction in the effective alveolar ventilation (V _A ) causes respiratory acidosis in the presence of normal or even increased total minute ventilation (V _E ). The defect responsible for this condition is an increased dead space ventilation ( V _D ) caused by alveoli that remain ventilated but not perfused and from alveoli with excessive ventilation with respect to heir perfusion. In both cases, an increased ventilation to perfusion ratio ( V _A / Q ) exists. Advanced chronic obstructive pulmonary disease is the most typical condition in which this pathophysiologic defect dominates the CO ₂ retention observed. The maintenance of eucapnia in patients with less advanced disease results from an increased minute ventilation, which compensates for the inefficiency of the CO ₂ excretion imposed by the V _A /Q mismatch. Should the airway resistance increase, however, (because of bronchial spasm, edema of the bronchial wall, or retention of secretions), or if the minute ventilation needed to maintain eucapnia is too high, the PaCO ₂ will increase because of respiratory-muscle fatigue. The expanded V _D in patients with advanced pulmonary disease, pulmonary thromboembolism, and shock, results in ratios of V _D /V _E and V _D /V _T (dead space to tidal volume ventilation) that might be twice the normal value of 0.3; such ratios are frequently associated with CO ₂ retention. The nearly linear shape of the CO ₂ dissociation curve over the physiologic range greatly facilitates the excretion of carbon dioxide in patients with all types of V _A /Q inequalities, because blood leaving areas with low V _A /Q ratio (that has a relatively high PCO ₂ ) is counterbalanced when mixed with blood traversing high V _A /Q units (that has relatively low PCO ₂ values).

Increased Carbon Dioxide Production

Overproduction of CO ₂ is seldom the sole cause of CO ₂ retention because enhanced V _{CO 2} stimulates ventilation thus increasing CO ₂ excretion. Yet, patients with marked reduction in pulmonary reserve and those receiving constant mechanical ventilation might develop respiratory acidosis caused by increased CO ₂ production. Relevant clinical conditions characterized by an increased V _CO2 include physical activity, increased work of breathing by the respiratory muscles, seizures, shivering, fever, and hyperthyroidism. The effect of hyperthermia may be substantial because CO ₂ production increases by approximately 13% for each 1°C-increase in body temperature above normal. The administration of large carbohydrate loads, orally or parenterally, is a potentially significant cause of enhanced CO ₂ production in patients with hypercapnic respiratory failure. In these cases, a larger portion of fat in the diet might properly supplement caloric intake without imposing the CO ₂ burden that results from carbohydrates. Additional causes of CO ₂ loading include the infusion of bicarbonate-containing solutions, hemodialysis with sorbent regenerative cartridge systems, and insufflation of the peritoneum with CO ₂ during endoscopic procedures.

Failure of Carbon Dioxide Transport

A large reduction in cardiac output and pulmonary blood flow caused by hemorrhage or pharmacologic vasodilation in the presence of constant pulmonary ventilation (i.e., fixed mechanical ventilation) leads to a reduction in PaCO ₂ and end-tidal PCO ₂ ; the latter is indicative of a reduction in pulmonary CO ₂ excretion which results in primary hypercapnia ( Figure 60.1 ). In fact, in states of severe circulatory failure, arterial hypocapnia can coexist with venous and therefore tissue, hypercapnia; however, the body CO ₂ stores have been enriched and respiratory acidosis rather than respiratory alkalosis is present. 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. The severely reduced pulmonary blood flow limits the CO ₂ delivered to the lungs for excretion, thereby increasing the venous PCO ₂ . On the other hand, the increased ventilation-to-perfusion ratio causes a larger than normal decrease of CO ₂ 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 PCO ₂ develops in two settings of cardiac dysfunction, namely, circulatory failure and cardiac arrest. ( Figure 60.2 ). Severe oxygen deprivation prevails in the tissues in these two conditions, and it can be completely disguised by the reasonably preserved arterial oxygen 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

The secondary increment in plasma [ ${\mathrm{HCO}}_3^{-}$ ] observed in acute and chronic hypercapnia is an integral part of the respiratory acidosis. Adaptation to acute hypercapnia elicits an immediate increment in plasma [ ${\mathrm{HCO}}_3^{-}$ ] due to titration of non- ${\mathrm{HCO}}_3^{-}$ body buffers; such buffers generate ${\mathrm{HCO}}_3^{-}$ by combining with H ⁺ derived from the dissociation of carbonic acid:

where B ⁻ refers to the base component and HB refers to the acid component of non- ${\mathrm{HCO}}_3^{-}$ buffers. This adaptation is completed within 5 to 10 minutes from the increase in PaCO ₂ , and assuming a stable level of hypercapnia, no further change in acid–base equilibrium is detectable for several hours. Observations in unanesthetized normal humans studied in an environmental chamber (inspired CO ₂ 7 and 10%) reveal a mean Δ[ ${\mathrm{HCO}}_3^{-}$ ]/ΔPaCO ₂ slope of 0.1 mEq/L per mm Hg. An essentially identical slope is obtained in humans in whom respiratory acidosis is induced by endogenous hypercapnia.

Moderate hypoxemia does not alter the adaptive response to acute respiratory acidosis. However, studies in dogs have shown that pre-existing hypobicarbonatemia (whether it is caused by metabolic acidosis or chronic respiratory alkalosis) enhances the magnitude of the plasma [ ${\mathrm{HCO}}_3^{-}$ ] response to acute hypercapnia; this response is diminished in hyperbicarbonatemic states (whether they are caused by metabolic alkalosis or chronic respiratory acidosis) ( Figure 60.3 ).

Although the increment in plasma [ ${\mathrm{HCO}}_3^{-}$ ] during acute hypercapnia originates virtually exclusively from body buffering, evidence exists for a renal adjustment even during this early phase of the disorder. A fall in urine pH and a small increase in urine NH ₄ ⁺ and titratable acid excretion have been observed within minutes after induction of hypercapnia. Moreover, ${\mathrm{HCO}}_3^{-}$ reabsorption rate in the proximal convoluted tubule increases in response to acute hypercapnia. Sustained hypercapnia causes an additional, larger increase in plasma [ ${\mathrm{HCO}}_3^{-}$ ] owing to stimulation of renal acidification. As a consequence, net acid excretion (largely in the form of NH ₄ ⁺ ) transiently exceeds endogenous acid production, effecting negative H ⁺ balance and generation of new ${\mathrm{HCO}}_3^{-}$ for the body fluids. Conservation of the new ${\mathrm{HCO}}_3^{-}$ is ensured by an increased rate of renal ${\mathrm{HCO}}_3^{-}$ reabsorption, which reflects the hypercapnia-induced increase in H ⁺ secretory rate. Observations during the provision of exogenous alkali indicate that this increase in renal ${\mathrm{HCO}}_3^{-}$ reabsorption occurs roughly in parallel with the spontaneous increase in plasma [ ${\mathrm{HCO}}_3^{-}$ ]. A new steady state emerges for any given level of hypercapnia when the augmented filtered load of ${\mathrm{HCO}}_3^{-}$ is balanced by the increase in ${\mathrm{HCO}}_3^{-}$ reabsorption and when net acid excretion returns to the level that offsets daily endogenous acid production. In the new steady state, however, the mix of the net acid constituents differs from the normal baseline: Excretion of NH ₄ ⁺ remains increased, but is balanced by increased ${\mathrm{HCO}}_3^{-}$ excretion and decreased titratable acidity. Urine pH is also increased compared to baseline. As ${\mathrm{HCO}}_3^{-}$ stores are being augmented by the transient increase in net acid excretion, Cl ⁻ stores are correspondingly depleted by a transient increase in renal Cl ⁻ excretion. Chloruresis appears to outstrip net acid excretion during the first 1–2 days of exposure to hypercapnia, the difference being accounted for by an increase in the excretion of Na ⁺ and K ⁺ . Consequently, some degree of Na ⁺ and K ⁺ depletion typically accompanies adaptation to chronic hypercapnia. The hypochloremia that results from the transient chloruresis is sustained by a persistently depressed renal Cl ⁻ reabsorption. In dogs, a new steady state emerges within three to five days. Whether this temporal pattern applies to humans is unknown. In patients, chronic hypercapnia often reflects gradual deterioration in pulmonary function; consequently, the secondary response might keep pace with the slowing rising PaCO ₂ without a perceptible delay.

Studies in dogs indicate that a highly predictable curvilinear relationship exists between the degree of chronic hypercapnia and the levels at which plasma [ ${\mathrm{HCO}}_3^{-}$ ] and blood [H ⁺ ] stabilize following full physiological adaptation. Over the range of PaCO ₂ values between 40 and 90 mm Hg, which would encompass most values encountered clinically, this curvilinear relationship between plasma [ ${\mathrm{HCO}}_3^{-}$ ] and PaCO ₂ is closely approximated by a straight line with a mean Δ[ ${\mathrm{HCO}}_3^{-}$ ]/ΔPaCO ₂ slope of 0.3 mEq/L per mm Hg. The corresponding relationship between blood [H ⁺ ] and PaCO ₂ is strikingly linear, [H ⁺ ] rising on average by 0.32 nEq/L per mm Hg chronic elevation in PaCO ₂ . Careful observations of patients with chronic hypercapnia as a result of chronic obstructive pulmonary disease allowed estimation of a mean Δ[ ${\mathrm{HCO}}_3^{-}$ ]/ΔPaCO ₂ slope of 0.35 mEq/L per mm Hg. This slope functions up to a PaCO ₂ of approximately 70 mm Hg. Beyond that level, the slope of Δ[ ${\mathrm{HCO}}_3^{-}$ ]/ΔPaCO ₂ seems to flatten. More recently, a substantially larger slope was reported, but the small number of blood gas measurements, one for each of 18 patients, calls into question the validity of the conclusion reached. Notably, there is no information in humans on the effects of pre-existing metabolic acidosis or metabolic alkalosis on the Δ[ ${\mathrm{HCO}}_3^{-}$ ]/ΔPaCO ₂ slope of superimposed chronic hypercapnia. In dogs, the background presence of metabolic disorders alters this slope substantially.

The renal response to chronic hypercapnia is not altered appreciably by dietary Na ⁺ or Cl ⁻ restriction, moderate K ⁺ depletion, alkali loading, moderate hypoxemia (PaO ₂ , 45–55 mm Hg), or adrenalectomy. However, recovery from chronic hypercapnia is crippled by a diet deficient in Cl ⁻ ; in this circumstance, despite correction of the level of PaCO ₂ , plasma [ ${\mathrm{HCO}}_3^{-}$ ] remains elevated so long as the state of Cl ⁻ deprivation persists, leading to posthypercapnic metabolic alkalosis. On the other hand, moderate potassium depletion does not interfere with full repair of acid–base equilibrium following the return to eucapnia.

Available information implicates essentially the entire nephron and its acidification apparatus in the renal response to chronic hypercapnia. Micropuncture observations in the proximal tubule of the rat indicate that, whereas absolute ${\mathrm{HCO}}_3^{-}$ reabsorption is increased only mildly in acute hypercapnia, a substantial rise is observed during the chronic phase of the disorder. Total CO ₂ absorption was unchanged in microperfused cortical collecting tubules obtained from rabbits exposed to hypercapnia for 3–6 hr, but it was substantially increased in tubules derived from animals that had been exposed to hypercapnia for a 24-hr period. Other microperfusion studies in the rabbit have shown, however, stimulation of acidification in cortical and medullary collecting tubules within 20 min from the onset of hypercapnia. Parallel increases in the rates of the luminal Na ⁺ /H ⁺ exchanger (presumably the NHE-3) and the basolateral Na ⁺ /3 ${\mathrm{HCO}}_3^{-}$ cotransporter in the proximal tubule have been described; these adaptations reflect an increase in the V _max of each transporter but no change in the K _m for sodium. However, other investigators have not been able to reproduce the finding of a stimulated Na ⁺ /H ⁺ exchanger in chronic hypercapnia. Additionally, several studies have shown that acute or chronic hypercapnia induces exocytotic insertion of H ⁺ -ATPase-containing subapical vesicles to the luminal membrane of both proximal tubule cells and type A intercalated cells of cortical and medullary collecting ducts. Such a redistribution of H ⁺ -ATPase pumps during hypercapnia is not associated with a detectable increase in their quantity in either cortex or medulla. A transient increase in cell calcium appears to be important in this exocytotic event. Rat tubule microdissection studies revealed that by 24 hr of hypercapnia, but not at earlier times, the activity of H ⁺ -ATPase along the entire nephron (i.e., proximal tubule, thick ascending limb of Henle, and cortical and medullary collecting tubules) and that of the H ⁺ -K ⁺ -ATPase in the cortical and medullary collecting tubules were increased. Similar increases in the activities of the H ⁺ -ATPase and the H ⁺ -K ⁺ -ATPase were observed in adrenalectomized rats replaced with physiological doses of aldosterone. Further, chronic hypercapnia increases the steady-state abundance of mRNA coding for the basolateral Cl ⁻ / ${\mathrm{HCO}}_3^{-}$ exchanger (band 3 protein) of type A intercalated cells in rat renal cortex and medulla. Whether this change is translated into increased levels of protein and activity of the exchanger remains unknown.

The signal that triggers the renal acidification response to hypercapnia remains undefined, but present evidence favors the increase in PaCO ₂ itself rather than the decrease in systemic pH. Indeed, observations in dogs indicate that a decrement in systemic pH is not a prerequisite to the augmentation of renal ${\mathrm{HCO}}_3^{-}$ reabsorption required for sustaining the secondary hyperbicarbonatemia characteristic of chronic hypercapnia. Subsequent in vitro studies in rabbit proximal tubule have provided plausible validation of these whole-animal observations. Much more work is required in this area as well as the role of the filtered ${\mathrm{HCO}}_3^{-}$ load, and that of changes in hemodynamics and hormonal factors (such as stimulated β-adrenergic tone, renin-angiotensin-aldosterone system, cortisol, and arginine vasopressin).

There is currently no information on the impact of graded degrees of chronic renal insufficiency on the renal acidification response to respiratory acidosis. In a patient with hyporeninemic hypoaldosteronism, hyperkalemia, and an eGFR on the order of 20–25 ml/min/1.73 m ² , the secondary response to chronic hypercapnia was suppressed; correction of the hyperkalemia allowed expression of an essentially normal secondary response . These events were ascribed to the fact that the renal response to chronic hypercapnia largely entails stimulation of ammoniagenesis and increased ammonium excretion, processes that are impaired by hyperkalemia. This case also suggests that in the absence of hyperkalemia, advanced renal insufficiency would be required to adversely impact this response. Obviously, patients with end-stage renal disease cannot mount a renal response to chronic hypercapnia and, thus, they are more subject to severe acidemia. The degree of acidemia is more pronounced in patients receiving hemodialysis rather than peritoneal dialysis because the former treatment maintains, on average, a lower plasma [ ${\mathrm{HCO}}_3^{-}$ ].

Plasma Electrolyte Composition during Respiratory Acidosis

Mild hypernatremia (Δ[Na ⁺ ], 2–4 mEq/liter) is typically seen in both acute and chronic hypercapnia. Hypochloremia is a consistent finding in chronic hypercapnia, and it reflects both a shift of chloride into erythrocytes and a loss of chloride in the urine during the adaptive process. Plasma potassium concentration increases (by only approximately 0.1 mEq/liter for each 0.1 unit fall in pH) during acute hypercapnia, probably because of a shift of this ion out of cells; plasma potassium does not change appreciably during chronic hypercapnia. Hyperphosphatemia is a characteristic feature of acute hypercapnia and probably reflects a release of phosphate from tissues; a rise in plasma phosphate is not observed during chronic hypercapnia. Consistent changes in plasma calcium and magnesium have not been noted in response to hypercapnia in limited observations in humans. Plasma lactate and pyruvate concentrations fall during acute hypercapnia, but they are not significantly altered by chronic hypercapnia, even in the presence of moderately severe hypoxemia. No appreciable changes in plasma unmeasured anions occur in either acute or chronic hypercapnia.

Intracellular pH during Respiratory Acidosis

Increases in extracellular PCO ₂ both in vivo and in vitro exert a prompt acidifying effect on intracellular pH. Efforts at estimating the magnitude of intracellular acidification during acute hypercapnia using the “whole-body” DMO method have yielded variable results. In vivo estimates of intracellular pH of various tissues (using the DMO method or ³¹ P-NMR spectroscopy) have yielded variable responses to acute hypercapnia. Whereas intracellular pH falls in skeletal muscle and kidney by a magnitude similar to that in the extracellular compartment, smaller changes or no changes in intracellular pH have been noted in cardiac muscle, cerebral cortex, and liver (54). Renal intracellular pH returns to the normal level during the chronic phase of respiratory acidosis. There is currently no information regarding the impact of chronic hypercapnia on the intracellular acidity of other tissues.

Neurologic

Hypercapnia causes vasodilation and increased cerebral perfusion when autoregulation pathways of cerebral blood flow are intact. This effect amounts to approximately 6% blood flow increase per 1 mm Hg rise in PCO ₂ , and is less pronounced in women than in men presumably because of differences in prostaglandin levels. Maximal hypercapnic vasodilation occurs at PCO ₂ levels of about 80 mm Hg. Experimental studies in humans demonstrated increases in cerebral blood flow up to 200% in response to hypercapnia. Aging impairs the vasodilatory response, an effect that may be dependent on a lower concentration of oxyhemoglobin or on derangements in the arterial wall.

The precise mechanism of CO ₂ -induced cerebral vasodilation in humans remains undefined. The increase in cerebral blood flow appears to originate from the associated acidosis, because normalization of pH by administering bicarbonate reverses the vasodilation. Studies in healthy volunteers demonstrated that hypercapnia increased cerebral release of nitric oxide accompanied by an increase in venous-arterial difference for nitrite. In contrast hypoxemia (FiO ₂ 10 and 12%) caused a net cerebral uptake of nitrite. Release of CNP (C-natriuretic peptide) was also observed in hypercapnia. Animal studies have shown that two mechanisms, namely, activation of K _ATP channels in vascular smooth muscle and release of nitric oxide participate in hypercapnic vasodilation. Conversely, some studies in humans have shown that CO ₂ -induced cerebral vasodilation is independent of nitric oxide. Animal studies have also demonstrated that hypercapnia increases optic disc PO ₂ and this effect is prevented with systemic nitric oxide synthase inhibition; thus, nitric oxide seems to mediate CO ₂ -vasodilation in retinal arterioles.

It is a widely held view that hypercapnia should be avoided in patients suffering from ischemic brain injury because it may lead to uncontrolled intracranial hypertension. However, recently published experimental studies in rats have demonstrated that moderate to severe hypercapnia (PaCO ₂ 60–100 mm Hg) is neuroprotective after transient global cerebral ischemia-reperfusion injury; this protection was proposed to be mediated by a hypercapnia-induced promotion of survival of neurons by modulating apoptosis-regulating proteins. In contrast, rats exposed to very severe hypercapnia (PaCO ₂ 100–120 mm Hg) had increased brain injury and more cerebral edema. Whether a similar response occurs in humans remains unknown.

Most of the important clinical manifestations of hypercapnia result from its effects on the central nervous system (CNS). Factors that influence the CNS disturbances in respiratory acidosis are the magnitude of the hypercapnia, the rapidity with which it develops the severity of the acidemia, and the degree of attendant hypoxemia. Acute hypercapnia is often associated with marked anxiety, severe breathlessness, disorientation, confusion, incoherence, and combativeness. The alterations in the level of consciousness observed in hypercapnia are accompanied by reductions in brain glutamate and aspartate and increases in glutamine and gammaaminobutyric acid (GABA). In unusually severe hypercapnia, stupor or coma can result. Hypercapnic coma characteristically occurs in patients with acute exacerbations of chronic respiratory insufficiency, who are treated injudiciously with “high-flow” oxygen. Motor disturbances, including tremor, myoclonic jerks, and asterixis, are frequent accompaniments of both acute and chronic hypercapnia. Sustained myoclonus and seizure activity can also develop. Signs and symptoms of increased intracranial pressure (pseudotumor cerebri) are occasionally evident in patients with either acute or chronic hypercapnia, and they appear to be related to the vasodilating effects of CO ₂ on cerebral blood vessels. Headache is a frequent complaint. Blurring of the optic discs and frank papilledema can be found when hypercapnia is severe. The plantar response can be extensor. It is not surprising, given this broad range of possible CNS findings, that respiratory acidosis often is diagnosed erroneously as a cerebral vascular accident or as an intracranial tumor.

Cardiovascular

Animal studies in cardiac myocytes and in intact isolated hearts have demonstrated that the decrease in tissue pH observed in ischemia, if maintained during reperfusion, may have a protective effect against irreversible tissue injury. The large decrease in tissue pH is accounted for by the combined effects of respiratory and metabolic acidosis in association with hypoxia. This protection has been called the “pH paradox” since the rapid correction of acidosis observed during reperfusion precipitates irreversible tissue injury. Correction of ischemia induced-acidosis during reperfusion increases cytosolic free calcium that leads to cellular injury. Administration of inhibitors of Na ⁺ /H ⁺ exchange have been shown to prevent a rapid rise in tissue pH during reperfusion and this effect ameliorates ischemia/reperfusion injury.

An assessment of myocardial contractility and blood flow in response to short term moderate respiratory acidosis and alkalosis have been reported in anesthetized patients with coronary artery disease. It was concluded that changes in PaCO ₂ lead to hemodynamic effects largely due to alterations in systemic vascular resistance rather than by alterations in myocardial contractility.

The hemodynamic consequences of respiratory acidosis can reflect a variety of mechanisms, including a depressing effect on myocardial contractility, systemic vasodilation resulting from an action of hypercapnia on vascular smooth muscle, stimulation of the sympathetic nervous system leading to increased plasma catecholamine levels, and blunting of receptor responsiveness to catecholamines. The composite effect of these inputs is such that acute hypercapnia of mild to moderate degree is usually characterized by warm, flushed skin, a bounding pulse, diaphoresis, increased cardiac output, and normal or increased blood pressure. On the other hand, severe hypercapnia might be attended by decreases in both cardiac output and blood pressure. The vasodilatory effect of acute hypercapnia is most apparent in the cerebral circulation, where blood flow increases in direct relation to the level of PaCO ₂ . Chronic respiratory acidosis is associated with normal cardiac output and blood pressure, unless a complicating disorder such as cor pulmonale supervenes. Cerebral blood flow remains increased in chronic hypercapnia, but the increment appears to be less than that occurring in comparable levels of acute hypercapnia.

Cardiac arrhythmias occur frequently in patients with either acute or chronic hypercapnia, especially those receiving digitalis as therapy for cor pulmonale. Particularly common are supraventricular tachyarrhythmia’s with ventricular rates of 120–160 beats/min. Yet the role of the elevated PaCO ₂ per se in the generation of cardiac arrhythmias is unclear. Indeed, remarkably little cardiac irritability occurs in extreme hypercapnia in the absence of accompanying hypoxemia and, by way of contrast, rapid restoration of normal PaCO ₂ from very high levels is known to trigger cardiac arrhythmias, including those of ventricular origin. Of interest is the reported striking increase in myocardial PCO ₂ (e.g., up to 346 mmHg) and [H ⁺ ] (e.g., 440 nEq/liter, pH 6.38) after ventricular fibrillation. Such hypercapnia greatly reduces cardiac resuscitability. Because bicarbonate administration can aggravate PCO ₂ leading to further circulatory depression, this agent should be used with caution in the presence of respiratory acidosis.

Respiratory

The normally dry alveolar space results from active sodium transport across the epithelial barrier mediated by the Na, K-ATPase. A reduced alveolar fluid reabsorption caused by mechanical stress, endothelial activation, or hypoxia can lead to pulmonary edema. Hypercapnia, independent of acidosis, has been shown to impair alveolar fluid reabsorption by decreasing Na, K-ATPase activity in the alveolar epithelial cells. This CO ₂ -induced effect results from stimulation of Na, K-ATPase endocytosis. Recent investigations have demonstrated that in rat lungs, hypercapnia leads to extracellular signal-regulated kinase (ERK) activation which in turn may mediate the CO ₂ -induced Na,K-ATPase down regulation and endocytosis.

Complex shifts in the oxyhemoglobin dissociation curve occur during hypercapnia, because increased PaCO ₂ tends to shift the curve to the right (Bohr effect), and acidemia (by decreasing intracellular 2,3-DPG) tends to shift the curve to the left. Further complexity is introduced if chronic hypoxemia is present, because of an augmented intracellular 2,3-DPG level, which tends to shift the curve to the right. In addition to the effects of hypercapnia on P ₅₀ , erythropoietin production in response to hypoxia is inhibited by respiratory acidosis.

Contradictory evidence has been obtained about the effects of acute hypercapnia on pulmonary vascular resistance and pulmonary artery pressure; some studies indicate an increase in these parameters, whereas others have failed to demonstrate any significant effect. Respiratory acidosis does not significantly influence the pulmonary vasoconstriction in response to hypoxia whereas respiratory alkalosis blunts this response. Diaphragm performance decreases during respiratory acidosis in anesthetized dogs, but such an effect was not observed in other skeletal muscles.