The immediate response to the low pH generated by the increased PaCO₂ and H₂CO₃ is to buffer (or bind) hydrogen ions with nonbicarbonate buffers. Bicarbonate does not work as an effective buffer in this situation because it reacts with hydrogen ions to form H₂CO₃, which is the original culprit. In the extracellular fluid (ECF) space, proteins constitute the only buffer, whereas within the cells, hemoglobin, phosphate, proteins, and lactate are the major nonbicarbonate buffers; 97% of the buffering of H₂CO₃ derives from intracellular rather than extracellular fluid buffers (6).

The definitive compensation for respiratory acidosis resides solely in the kidneys. The kidneys respond to the increased systemic PCO₂ by increasing the production and excretion of ammonium (NH₄⁺). The renal tubular cells metabolize glutamine to produce two NH₃ molecules and α-ketoglutarate (AKG). The AKG goes to the liver, where metabolism produces two HCO₃^–. The kidney excretes the NH₃ as NH₄⁺, which marks the addition of the new HCO₃^– to the body stores by the liver. If the kidneys fail to excrete the NH₄⁺, it travels to the liver, and metabolism generates H⁺, which negates the addition of the HCO₃^– to the body. Thus, increased renal excretion of NH₄⁺ is a crucial component of the generation of new HCO₃^–. The increased urinary NH₄⁺ excretion is balanced by increased Cl^– excretion, with a resultant fall in plasma (Cl^–). When a steady state of hypercapnia is reached, chloride excretion returns to normal and equals intake. NH₄⁺ excretion also returns to normal, even though H⁺ secretion remains increased. The persistently increased H⁺ secretion is needed to reclaim the increased filtered HCO₃^– load that results from the increase in plasma concentration (7, 8). Experimental evidence has shown that both the proximal tubule and the distal tubule participate in adaptation to
respiratory acidosis. In the proximal tubule, increases in PaCO₂ cause corresponding activation of the luminal Na/H exchanger and basolateral Na/HCO₃ exchanger, leading to net reabsorbtion of bicarbonate (9). There also appears to be increased activity of H⁺/ATPase in the distal tubule (10). The chemical buffering and renal compensation that occur with chronic respiratory acidosis are diagramed in Figure 4-1.

The third, or corrective, response to respiratory acidosis is the restoration of effective ventilation. Correction or amelioration of an acute neurologic process causing hypoventilation or a ventilatory or gas-exchange defect may be possible. Unfortunately, many processes that result in chronic hypercapnia are caused by irreversible parenchymal lung damage and thus can be corrected only partially at best.

In metabolic acidosis, the corrective agent, the kidney, is sometimes a cause of the disorder, as in uremic acidosis, but at other times is not, as in diabetic ketoacidosis. In respiratory acidosis, however, the respiratory system, which includes neural control—mechanical, circulatory, and membrane exchange components—always is involved as the cause of the disorder and is also the corrective agent.

The acute onset of hypercapnia is invariably accompanied by hypoxemia, which usually dominates the clinical picture. Depending on the underlying disorder and the state of consciousness, the patient may present with the signs and symptoms of acute respiratory distress, including marked restlessness, tachypnea, and marked dyspnea. As the process worsens, stupor and eventually coma develop. CO₂ has vasodilating properties, and thus hypercapnia is associated with increased cerebral blood flow (13, 14). This increase in blood flow to the brain probably accounts for the headaches and occasional signs of increased intracranial pressure that can occur with both acute and chronic hypercapnia (15, 16). Severe acute respiratory acidosis can cause refractory hypotension through two mechanisms (17). First, cardiac contractility is reduced and cardiac output falls. Second, peripheral arterial smooth muscle relaxes, causing vasodilation and decreased systemic vascular resistance. Modest acute increases in PaCO₂ (13-19 mm Hg) actually increase cardiac output as well as pulmonary artery pressure (18).

In intensive care units, hypoventilation is frequently induced in patients with severe lung injury and acute respiratory distress syndrome (ARDS). This strategy was shown to reduce mortality and ventilator time in the ARDSNet trial (19). Although the difference in PaCO₂ was not large (5 mm Hg), this trial did suggest that the benefits of low tidal volume ventilation outweigh the risks of mild acute hypercapnia. It should be noted that many patients in the trial were treated with bicarbonate therapy to minimize the fall in blood pH.

With acute respiratory acidosis, the arterial blood reflects the pathophysiologic state with an elevated PCO₂, a moderately elevated plasma [HCO₃^–] (<30 mmol/L), and a low pH. If the patient is breathing room air, then the PaO₂ is decreased. The venous serum electrolytes reveal a modestly elevated total CO₂ content, with usually normal plasma concentrations of sodium, potassium, and chloride.

Some of the causes of acute respiratory failure, which leads to acute CO₂ retention, are listed in Table 4-1.

The key to treatment of acute respiratory acidosis is the restoration of effective ventilation. Modest amounts of sodium bicarbonate (NaHCO₃) may be given intravenously to mitigate severe acidosis; the latter is only
a holding measure to prevent the serious cardiovascular effects of marked acidemia until definitive therapy is established (20). Because equilibration of HCO₃^– across the blood-brain barrier is markedly slower than that of CO₂ with bicarbonate administration, a delay in the correction of the cerebral pH may occur, and cerebrospinal fluid pH falls initially (21).

Patients with chronic respiratory acidosis exhibit few, if any, signs or symptoms related directly to CO₂ retention and acidosis. However, papilledema and other neurologic disturbances have been described in several patients (22, 23). These findings are not caused by the hypercapnia per se nor by the pH changes that mediate cerebral vascular reactivity through intracellular calcium. Rather, secondary changes in catecholamines are the likely causes (13). The signs and symptoms of the chronic pulmonary disease, with or without cor pulmonale, usually predominate. Chronic respiratory acidosis causes decreased bone mineralization, although to a lesser degree than does metabolic acidosis (24, 25, 26). This effect does not appear to be mediated by altered function of bone osteoclasts or osteoblasts and is not accompanied by hypercalciuria (27, 28).

Arterial blood examination reveals a low pH (not <7.25 even with severe chronic CO₂ retention), an elevated PaCO₂, and an elevated plasma [HCO₃^–]. Thus, a blood pH <7.25 is a marker of imposed acute hypercapnia or metabolic acidosis. Plasma sodium and potassium concentrations are usually normal. Total plasma CO₂ content is elevated, and plasma chloride concentration is reciprocally decreased. The anion gap is usually normal (22). In the absence of diuretic use or vomiting, these serum electrolyte findings should lead the clinician to check arterial blood gas values. The urine pH is usually acid.

Chronic respiratory acidosis is seen most commonly in patients with chronic obstructive pulmonary disease (COPD). However, any condition that can lead to chronic retention of CO₂ (27) will cause the same acid-base disturbance. Examples of such conditions are given in Table 4-2.

The epidemic of obesity has led to an increased prevalence of the obesity hypoventilation syndrome (OHS). Patients with OHS exhibit hypercapnia while awake (PaCO₂ > 45 mm Hg), obesity (BMI > 30 kg/m²), and absence of alternative causes of hypoventilation. Most patients with OHS have sleep-disordered breathing and obstructive sleep apnea. The hypoventilation may be secondary to altered respiratory muscle mechanics and decreased ventilator drive (29, 30). Patients with OHS commonly develop hypoxemia, pulmonary hypertension, and signs of right-sided congestive heart failure. In patients with nocturnal hypercapnia due to sleep apnea but daytime normocapnia, metabolic alkalosis may actually develop. Nocturnal hypercapnia can lead to renal generation of bicarbonate. People on low-salt diets (low chloride) are unable to excrete this bicarbonate and thus develop posthypercapnic metabolic alkalosis.

Chronic respiratory acidosis can be corrected effectively only by restoring or improving the ability of the respiratory system to excrete CO₂. Often, this is impossible because of an irreversible pathologic condition. However, adequate airway drainage, relief of bronchospasm, and treatment of pulmonary infections and congestive heart failure may lead to significant improvement. Because the arterial pH remains >7.25 even with chronic PaCO₂ elevations to 110 mm Hg (31), the acidosis per se is not dangerous, although the patient is at more risk for serious acidemia if metabolic acidosis occurs. Attention to the maintenance of adequate O₂ tension (PO₂) is the critical need.

People with end-stage renal disease (ESRD) who also have COPD or another cause of chronic hypercapnia are unable to generate the usual amounts of bicarbonate for compensation in chronic respiratory acidosis. Thus, they may benefit from dialysis using a higher bicarbonate dialysate.