Alkalosis

(1)

Professor of Medicine, Department of Medicine, Chief, Division of Nephrology and Hypertension, Rutgers New Jersey Medical School, Newark, NJ, USA

Keywords

Respiratory acidosisAcute respiratory acidosisChronic respiratory acidosisAcute respiratory alkalosis

The physiology section of Chap. 12 applies to this chapter as well. Respiratory alkalosis, also called primary hypocapnia, is characterized by low pCO₂ (<35 mmHg) and elevated pH (>7.40). Primary hypocapnia reflects alveolar hyperventilation. The resultant alkalinization of body fluids is ameliorated by a decrease in serum [HCO₃ ⁻]. Secondary hypocapnia should be distinguished from primary hypocapnia, as the former occurs in response to metabolic acidosis. As soon as respiratory alkalosis develops, a decrease in serum [HCO₃ ⁻] occurs within minutes. This is due to nonbicarbonate buffering as well as H⁺ release from tissues. Lactate is also produced by alkalemia. This buffering from various sources persists for several hours, and the resultant acid–base disturbance is called acute respiratory alkalosis. During acute hypocapnia, the H⁺ secretion in both proximal tubule and cortical collecting duct is suppressed. When alkalemia persists, renal compensation starts with a decrease in both H⁺ secretion and basolateral exit of HCO₃ ⁻ in the proximal tubule. This lowers serum [HCO₃ ⁻] even further, due to which, the pH is maintained close to normal. The full renal compensation takes 2–3 days for completion, and a new steady state is established, which is called chronic respiratory alkalosis.

Pathophysiology

Arterial CO₂ tension represents the balance between its production, elimination, and the inspired CO₂. The inspired CO₂ is negligible. Reduced production of CO₂ can occur in hypothyroidism and hypothermia; however, parallel reduction in alveolar ventilation also occurs. Therefore, respiratory alkalosis is usually not seen in these conditions. For all practical purposes, primary hypocapnia and alkalemia develop due to elimination rather than reduced production of CO₂.

Primary hypocapnia results from alveolar hyperventilation due to increased ventilatory drive. Increased ventilatory drive arises from signals originating from lungs, the peripheral chemoreceptors (carotid and aortic), and the central chemoreceptors located in the medullary respiratory center. The response of central chemoreceptors to CO₂ is augmented by pain, anxiety, certain medications (progesterone, salicylates, etc.), and systemic diseases such as sepsis and liver failure. Although hypoxemia is a major stimulus for alveolar hyperventilation, pO₂ values <60 mmHg are required to cause this effect.

Patients on mechanical ventilation may develop respiratory alkalosis due to increased tidal volume and/or respiratory rate. Reduction in either or both may improve hypocapnia and respiratory alkalosis.

Thus, as stated in Chap. 12, both central and peripheral receptors, medullary respiratory center, and respiratory muscles sense change in pCO₂, O₂, and pH and respond appropriately to improve hypocapnia.

Secondary Physiologic Response to Respiratory Alkalosis (Hypocapnia)

As stated earlier, the renal and nonrenal mechanisms respond to a decrease in pCO₂ by lowering HCO₃ ⁻, so that dangerous increases in pH are avoided. Although acute respiratory alkalosis causes high pH, chronic respiratory alkalosis maintains pH at slightly high but near normal levels by further lowering serum [HCO₃ ⁻]. The secondary responses to both acute and chronic respiratory alkalosis are shown below:

Acute respiratory alkalosis

For each mmHg decrease in pCO₂, HCO₃ ⁻ decreases by 0.2 mEq/L.

Chronic respiratory alkalosis

For each mmHg decrease in pCO₂, HCO₃ ⁻ decreases by 0.4 mEq/L.

Table 13.1 shows the relationship between pCO₂, expected secondary response (compensation) and arterial pH in acute and chronic respiratory alkalosis.

Table 13.1

Relationship between hypocapnia, renal response, and pH

Type	pCO₂ (mmHg)	Expected renal response (compensation)	Expected serum [HCO₃ ⁻]	pH (calculated from Henderson equation) after compensation
Normal	40	–	24	7.40
Acute	20^a	For each mmHg decrease in pCO₂, HCO₃ ⁻ decreases by 0.2 mEq/L, ΔpCO₂ = 20 (40 − 20 = 20 × 0.2 = 4)	20 (24 − 4 = 20)	7.56
Chronic	20^a	For each mmHg decrease in pCO₂, HCO₃ ⁻ decreases by 0.4 mEq/L, ΔpCO₂ = 20(40 − 20 = 20 × 0.4 = 8)	16 (24 − 8 = 16)	7.50

^aArbitrary value

Mechanisms of Secondary Physiologic Response

Acute respiratory alkalosis

Hypocapnia decreases H⁺ concentration due to low H₂CO₃ concentration. As a result, the pH becomes dangerously high. Immediately the pH is reduced by a decrease in HCO₃ ⁻ concentration, which is accomplished by H⁺ release from hemoglobin and tissue buffers. Release of H⁺ from cells and production of organic acids such as lactic acid largely account for reduction in HCO₃ ⁻ concentration. These adaptive changes are complete within 15 min. As shown in Table 13.1, for each mmHg decrease in pCO₂, HCO₃ ⁻ decreases by 0.2 mEq/L.

Chronic respiratory alkalosis

If hypocapnia persists for few hours, adaptation occurs with further decrease in HCO₃ ⁻ concentration. As a result, the pH returns to near normal or slightly above normal. The mechanisms for this change in pH are twofold: (1) net acid excretion, particularly titratable acidity, decreases with no change in NH₄ ⁺ excretion; and (2) HCO₃ ⁻ excretion increases. These two mechanisms increase urine pH (alkaline pH). After several days, net acid excretion increases, and HCO₃ ⁻ excretion decreases with return of urine pH to control level. As shown in Table 13.1, for each mmHg decrease in pCO₂, HCO₃ ⁻ decreases by 0.4 mEq/L in chronic respiratory alkalosis.

Both the decrease and stabilization of HCO₃ ⁻ in chronic hypocapnia are related to inhibition of luminal Na/H exchanger and basolateral Na/HCO₃ cotransporter in the proximal tubule. Also, it has been shown that H-ATPase activity throughout the nephron segments is decreased in chronic hypocapnia.

Usually serum Cl⁻ concentration is increased in chronic respiratory alkalosis. This increase is not due to a decrease in serum HCO₃ ⁻ concentration. Studies have attributed the increase in Cl⁻ to Na⁺ excretion without accompanying Cl⁻ excretion. Also, ECF volume decreases due to Na⁺ excretion, which raises Cl⁻ concentration.

Causes of Acute and Chronic Respiratory Alkalosis

With few exceptions, all causes are associated with both acute and chronic respiratory alkalosis. Acute respiratory alkalosis is generally caused by anxiety–hyperventilation syndrome, pain, pneumonia, acute asthmatic attack, septicemia, pulmonary embolism, pulmonary edema, salicylate ingestion, or increased minute ventilation in mechanically ventilated patients. Therefore, acute respiratory alkalosis is rather common in general wards and intensive care units. Chronic respiratory alkalosis is rather common in patients with central nervous system disorders, interstitial lung diseases, and chronic liver failure. Pregnancy is a condition of chronic respiratory alkalosis. Table 13.2 shows the most important causes of respiratory alkalosis.

Table 13.2

Causes of respiratory alkalosis

Direct stimulation of medullary respiratory center

Anxiety–hyperventilation syndrome

Stroke

CNS infection, tumor, or trauma

Gram-negative sepsis

Liver failure

Pregnancy

Hypermetabolic state (fever, thyrotoxicosis)

Drugs (salicylates, progesterone, nicotine, xanthine derivatives, catecholamines, antipsychotic drug quetiapine)

Pain

Hypoxemic stimulation of medullary respiratory center

Pulmonary diseases (pneumonia, asthma, pulmonary edema, pulmonary embolus, interstitial lung disease, high altitude, hypotension, severe anemia)

Mechanical ventilation

High minute ventilation

Selected Conditions of Respiratory Alkalosis

Anxiety–Hyperventilation Syndrome

Some individuals overbreathe in response to stressful situations and develop hypocapnia and respiratory alkalosis. Anxiety and or panic disorders (symptoms may overlap between the two conditions) may provoke hyperventilation. Patients present with symptoms such as dyspnea, circumoral numbness, paresthesias of lower extremities, and chest tightness or pain. Interestingly, these anxious individuals with dyspnea are not hypoxemic, and they have adequate oxygenation. Hyperventilation syndrome can be either acute or chronic. Arterial blood gasses are extremely important to exclude other causes of hyperventilation and hypoxia. In particular, subclinical asthma should be ruled out based on blood gas measurements.

The pathogenesis of hyperventilation syndrome is not completely understood. However, certain factors such as sodium lactate, CO₂, caffeine, isoproterenol, and emotional stress have been implicated in provoking hyperventilation.

Treatment for acute episodes includes anxiolytic drugs, psychiatric counseling, and reassurance. Serotonin reuptake inhibitors are frequently used for chronic patients.

High Altitude

As the person climbs from sea level to high altitude, both alveolar and arterial O₂ pressure fall, and hypoxemia develops. Within few minutes, alveolar ventilation increases with a slight reduction in pCO₂. In hours to 2–3 days, adaptation to high altitude occurs by progressive increase in ventilation. This increase in ventilation is related to stimulation of peripheral chemoreceptors located in the carotid and aortic arch bodies (carotid body receptors are more sensitive than aortic arch body receptors to hypoxemia), which send signals to the medullary respiratory centers. Hyperventilation does not continue forever because the stimulatory effect of peripheral chemoreceptors to hypoxemia is slowly reduced. Either low pCO₂ or low concentration of bicarbonate in cerebrospinal fluid seems to desensitize the peripheral chemoreceptors. As a result, long-term residents living in high altitude areas maintain low alveolar ventilation and high pCO₂ for any given pO₂ level compared to short-term dwellers. Figure 13.1 shows the mechanism of hypoxia-induced alveolar hyperventilation.