Respiratory Acidosis and Alkalosis

Pathophysiology

The ventilatory system is responsible for maintaining P co ₂ within normal limits by adjusting minute ventilation (˙V _E ) to match the rate of CO ₂ production. ˙V _E consists of two components: ventilation distributed in the gas-exchange units of the lungs (alveolar ventilation, ˙V _A ) and ventilation wasted in dead space (˙V _D ). Clinically important hypercapnia usually results from decreased ˙V _A and only rarely from increased CO ₂ production. Decreased ˙V _A can occur from a reduction in ˙V _E , an increase in ˙V _D , or a combination of the two. An increase in ˙V _D results from rapid and shallow ventilation or owing to an increase in “alveolar dead space” (ventilated alveoli with reduced perfusion). An increase in alveolar dead space is the main mechanism of hypercapnia in patients with parenchymal lung disease (asthma, pneumonia, COPD, cystic fibrosis, interstitial lung disease) and pulmonary vascular disease (thromboembolism, vasculitis).

Because the sum of P _co2 and PO ₂ in alveolar gas is constant in patients breathing room air (∼150 mm Hg at sea level), development of substantial hypercapnia is necessarily accompanied by equivalent hypoxemia. Estimation of the alveolar-arterial oxygen gradient (P _A O ₂ -P _a O ₂ ) allows distinguishing hypercapnic respiratory failure due to decreased ˙V _E from respiratory failure caused by intrinsic lung disease (hypercapnic and hypoxemic respiratory failure). The P _A O ₂ -P _a O ₂ should be calculated from a room-air arterial blood gas (ABG) and remains normal (<20 mm Hg) in hypercapnic respiratory failure caused by global hypoventilation but increases in respiratory failure resulting from intrinsic lung disease (abnormal gas exchange).

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 (CO ₂ production, O ₂ consumption), airway resistance, lung elastic recoil, and chest wall/abdominal resistance. Most frequently, primary hypercapnia develops from an imbalance between the strength of the respiratory pump and the weight of the respiratory loads, thereby resulting in a decreased ˙V _A . Impairment of the respiratory pump can occur because of depressed central drive, abnormal neuromuscular transmission, or muscle dysfunction. Causes of augmented respiratory loads include ventilation/perfusion mismatch (increased ˙V _D ), augmented airway flow resistance, lung/pleural/chest wall stiffness, impaired diaphragmatic function, and increased ventilatory demand. Overproduction of CO ₂ 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 experience respiratory acidosis due to increased CO ₂ production caused by increased muscle activity (agitation, myoclonus, shivering, and seizures), sepsis, fever, or hyperthyroidism. Increments in CO ₂ 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 treating metabolic acidosis.

The major threat to life from CO ₂ retention in patients who are breathing room air is the associated obligatory hypoxemia (in accordance with the alveolar gas equation). In the absence of supplemental oxygen, patients in respiratory arrest develop critical hypoxemia within a few minutes, long before extreme hypercapnia ensues. Because of the constraints of the alveolar gas equation, it is not possible for P co ₂ to reach values much higher than 80 mm Hg while the level of P o ₂ is still compatible with life. Extreme hypercapnia with P co ₂ values exceeding 100 mm Hg is occasionally seen in patients receiving oxygen therapy, and, in fact, it is often the result of unrestrained oxygen administration.

Secondary Physiologic Response

An immediate rise in plasma [HCO ₃ ⁻ ] owing to titration of nonbicarbonate body buffers occurs in response to acute hypercapnia. This adaptation is complete within 5 to 10 minutes of the increase in P co ₂ . On average, plasma [HCO ₃ ⁻ ] increases by about 0.1 mEq/L for each 1 mm Hg acute increment in P co ₂ ; as a result, the plasma hydrogen ion concentration [H ⁺ ] increases by about 0.75 nEq/L for each 1 mm Hg acute increment in P co ₂ . Therefore, the overall limit of adaptation of plasma [HCO ₃ ⁻ ] in acute respiratory acidosis is quite small; even when P co ₂ increases to levels of 80 to 90 mm Hg, the increment in plasma [HCO ₃ ⁻ ] 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 hypobicarbonatemia (from metabolic acidosis or chronic respiratory 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 phosphorus, 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 direct effects of the low tissue pH on skeletal muscle.

The adaptive increase in plasma [HCO ₃ ⁻ ] observed in the acute phase of hypercapnia is amplified markedly during chronic hypercapnia as a result of the generation of new bicarbonate by the kidneys. Both proximal and distal acidification mechanisms contribute to this adaptation, which requires 3 to 5 days for completion. The kidney response to chronic hypercapnia includes chloruresis and the generation of hypochloremia. Retrospective studies in the 1960s in hospitalized patients with hypercapnic respiratory failure estimated that, on average, plasma [HCO ₃ ⁻ ] increases by approximately 0.35-0.4 mEq/L for each 1 mm Hg chronic increment in P co ₂ , while recent studies in outpatients with stable hypercapnic respiratory failure reported a substantially steeper slope for the change in plasma [HCO ₃ ⁻ ] of 0.5 mEq/L for each 1 mm Hg chronic increase in P co ₂ . This slope is sufficient to maintain systemic acidity between the mid-normal range and mild acidemia, highlighting a remarkably effective secondary response to chronic hypercapnia. Thus, in uncomplicated steady-state chronic hypercapnia at a Paco ₂ of 70 mm Hg, the 95% prediction interval for blood pH is 7.32–7.38. Empiric observations indicate a limit of adaptation of plasma [HCO ₃ ⁻ ] on the order of 45 mEq/L.

The kidney response to chronic hypercapnia is not altered appreciably by dietary sodium or chloride restriction, moderate potassium depletion, alkali loading, or moderate hypoxemia. The extent to which chronic kidney disease of variable severity limits the kidney response to chronic hypercapnia remains unknown. Obviously, patients with end-stage kidney disease cannot mount a kidney response to chronic hypercapnia (i.e., generation of new bicarbonate by the kidneys), making them 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, lower plasma [HCO ₃ ⁻ ]. Recovery from chronic hypercapnia is crippled by a chloride-deficient diet. In this circumstance, despite correction of the level of P co ₂ , plasma [HCO ₃ ⁻ ] remains elevated as long as the state of chloride deprivation persists, thus creating the entity of “posthypercapnic metabolic alkalosis.” Chronic hypercapnia is not associated with appreciable changes in the anion gap or in plasma concentrations of sodium, potassium, or phosphorus.

Etiology

Primary hypercapnia can result from disease or malfunction within any element of the ventilatory system, including the central and peripheral nervous system, respiratory muscles, thoracic cage, pleural space, airways, and lung parenchyma. Commonly used clinical expressions are linked to certain etiologies: Patients with absent or depressed respiratory drive caused by CNS dysfunction “won’t breathe”; those with abnormalities of the peripheral nervous system, respiratory muscles, chest wall and pleura, and upper airways exhibit respiratory effort and complain that they “can’t breathe”; and patients with abnormal gas exchange owing to lung dysfunction report shortness of breath and that they “can’t breathe enough”. Tables 15.1 and 15.2 present causes of acute and chronic respiratory acidosis, respectively. 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. Some conditions can cause acute, acute on chronic, or chronic hypercapnia. COPD, including emphysema, chronic bronchitis, and small-airway disease, is the most common cause of chronic hypercapnia. Importantly, certain causes of chronic respiratory acidosis (e.g., COPD) can superimpose an element of acute respiratory acidosis during periods of decompensation (e.g., pneumonia, major surgery, heart failure).

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 P co ₂ or the reduced P o ₂ . Clinical manifestations of respiratory acidosis arising from the CNS are collectively known as hypercapnic encephalopathy . Mild to moderate hypercapnia (up to 70 mm Hg) is associated with irritability, inability to concentrate, headache, anorexia, mental cloudiness, apathy, and confusion. Higher P co ₂ values or rapidly developing hypercapnia is characterized by incoherence, combativeness, hallucinations, delirium, transient psychosis, seizures, and coma. Progressive narcosis develops at P co ₂ >75-80 mm Hg, but if chronic hypercapnia is present, levels >90-100 mm Hg are required. Neurological examination might reveal asterixis, myoclonus, and papilledema (pseudotumor cerebri). Severe hypercapnia can be misdiagnosed as a cerebral vascular accident or an intracranial tumor.

The hemodynamic consequences of respiratory acidosis include a direct depressing effect on myocardial contractility. An associated sympathetic surge, sometimes intense, leads to increases in plasma catecholamines; however, during severe acidemia (blood pH lower than approximately 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 P co ₂ . By contrast, CO ₂ retention can produce vasoconstriction in the pulmonary circulation resulting in pulmonary hypertension and right-sided heart failure (cor pulmonale). Similarly, CO ₂ retention can lead to vasoconstriction in the renal circulation that may be the result, at least in part, of enhanced sympathetic activity. Mild to moderate hypercapnia 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 cardiac output and blood pressure may be observed.

Concomitant therapy with vasoactive medications (e.g., β-adrenergic receptor blockers) or the presence of congestive heart failure 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 the associated hypoxemia and sympathetic discharge, concomitant medication, other electrolyte abnormalities, and underlying cardiac disease. Cardiac arrhythmias are also observed after initiation of mechanical ventilation and likely result from sudden correction of acidemia. 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 sympathetic nervous system and the renin-angiotensin-aldosterone axis, increased renal vascular resistance, and elevated levels of antidiuretic hormone and cortisol.