18: Disorders of ventilatory control

involved. In some cases, hyperventilation is prominent, whereas in others hypoventilation is significant. In a third category, the most apparent change occurs in the pattern of breathing.

Presentation with hyperventilation

With certain acute disorders of the central nervous system (CNS), hyperventilation (i.e., decreased PCO2 and respiratory alkalosis) is relatively common. Acute infections (meningitis, encephalitis), strokes, and trauma affecting the CNS are notable examples. The exact mechanism of hyperventilation in these situations is not known with certainty. Patients with hyperthyroidism frequently present with hyperventilation that resolves after treatment. Increased sensitivity of the chemoreceptors in the brain due to hyperthyroidism appears to account for the effect. Hyperventilation frequently complicates advanced hepatic disease, presumably because of increased concentrations of circulating substances stimulating ventilation that normally are cleared by the healthy liver. Some proposed substances causing central stimulation of respiration in patients with hepatic disease include progesterone, ammonia, and glutamate.

Many acute disorders of the CNS are associated with hyperventilation.

Presentation with hypoventilation

A presentation with hypoventilation presumably results from a primary insult to the nervous system that affects centers involved with control of breathing. In such circumstances, patients have an elevated PCO2, but because the clinical problems are generally not acute, the pH level has returned closer toward normal due to renal compensation. When no specific etiologic factor or prior event can be found to explain the hypoventilation, the patient is said to have idiopathic hypoventilation or primary alveolar hypoventilation. Other patients have suffered a significant insult to the nervous system at some time in the past (e.g., encephalitis), and chronic hypoventilation presumably is a sequela of the past event.

Patients with these syndromes of hypoventilation are characterized by depressed ventilatory responses to the chemical stimuli of hypercapnia and hypoxia. Measurement of arterial blood gases reveals an elevation in arterial PCO2 accompanied by a decrease in PO2, the latter primarily attributable to hypoventilation. As in other disorders associated with these blood gas abnormalities, cor pulmonale may result and be the presenting problem in these syndromes. The term congenital central hypoventilation syndrome or Ondine’s curse (see Chapter 17) has been applied to a rare subset of patients with congenital alveolar hypoventilation. However, less severe decreases in ventilatory response to hypercapnia and hypoxia are commonly seen in clinical practice and probably represent a spectrum of abnormalities in ventilatory response.

The most common therapy for patients with clinically significant hypoventilation is noninvasive positive-pressure (i.e., assisted) ventilation, usually applied nocturnally. This topic is discussed in Chapter 30. In the past, treatment of alveolar hypoventilation generally centered around two modalities: drugs (most commonly the hormone progesterone) and electrical stimulation of the phrenic nerve. In the latter approach, the diaphragm can be induced to contract by repetitive electrical stimulation of the phrenic nerve, which can be achieved by intermittent current applied via an implanted electrode. Although both of these modalities are still used, noninvasive positive-pressure (i.e., assisted) ventilation, usually applied during sleep, is a more effective and better tolerated treatment in most cases.

Treatment of alveolar hypoventilation due to depressed central respiratory drive consists of:

1. Assisted ventilation, generally with nocturnal noninvasive ventilation

2. Pharmacotherapy (e.g., progesterone)

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3. Electrical stimulation of phrenic nerve

Abnormal patterns of breathing

In addition to disturbances in overall alveolar ventilation, patients with neurologic disease may demonstrate abnormal patterns of breathing. The term ataxic breathing is applied to a grossly irregular breathing pattern observed with some types of lesions in the medulla. In contrast, certain lesions in the pons result in a breathing pattern characterized by a prolonged inspiratory pause; this pattern is called apneustic breathing.

Another type of abnormal breathing pattern is termed Cheyne-Stokes breathing. Unlike the other patterns, Cheyne-Stokes breathing is common and warrants further description and discussion of what is known about its pathogenesis.

Cheyne-stokes breathing

Cheyne-Stokes breathing is a cyclic pattern in which periods of gradually increasing ventilation alternate with periods of gradually decreasing ventilation (sometimes to the point of apnea). This type of ventilation is shown schematically in Fig. 18.1. It has been known for many years that two main types of disorders are associated with this pattern of breathing: heart failure and some forms of CNS disease. Cheyne-Stokes breathing can also be seen under certain physiologic situations even in the absence of underlying disease. Examples include the onset of sleep and exposure to high altitude.

FIGURE 18.1 Cheyne-Stokes breathing shows cyclic pattern of ventilation. In

patients with prolonged circulation time, delay between signal to chemoreceptor

(PCO2 at chemoreceptor) and ventilatory output (reflected by alveolar PCO2) is shown.

Common causes of Cheyne-Stokes ventilation are heart failure and some forms of CNS disease.

Central to the pathogenesis of Cheyne-Stokes ventilation is a problem with the feedback system of ventilatory control. Normally, the controlling system can adjust its output to compensate for arterial blood gas values that differ from the ideal or desired state. For example, with an elevated arterial PCO2, the

central chemoreceptor signals the medullary respiratory center to increase its output to augment ventilation and restore PCO2 to normal. Similarly, the peripheral chemoreceptor responds to hypoxemia by increasing its output, signaling the medullary respiratory center to augment ventilation and restore PO2 to normal.

At times, this feedback system may fail, especially if there is a delayed response to the signal or if the system responds more than necessary and overshoots the mark. Such defects in the feedback process appear to be at work in Cheyne-Stokes breathing. This section touches on a few aspects of theories proposed to explain Cheyne-Stokes ventilation, but for further discussion, the interested reader is referred to the Suggested Readings.

Decreased cardiac output produces a slowed circulation time, which results in an abnormal delay between events in the lung and sensing of PCO2 changes by the central chemoreceptor. This is one mechanism postulated to play a role in generating Cheyne-Stokes breathing in heart failure. Due to this abnormal delay, medullary respiratory output is out of phase with gas exchange at the lungs, and oscillations in ventilation occur as the central chemoreceptor and the medullary respiratory center make belated attempts to maintain a stable PCO2 (see Fig. 18.1).

An alternative explanation for Cheyne-Stokes breathing that occurs with heart failure is an accentuated ventilatory response to hypercapnia. This type of heightened responsiveness of the feedback system produces “instability” of respiratory control and a cyclic overshooting and undershooting of ventilation. Such increased responsiveness of the ventilatory control system may also play a role in patients with CNS disease who exhibit periods of Cheyne-Stokes respiration.

A similar type of instability of ventilatory control occurs at high altitude, when hypoxia is driving the feedback system. The ventilatory response to hypoxia is nonlinear. For the same drop in PO2, the increment in ventilation is larger at a lower absolute PO2 (see Fig. 17.3). This means that at a relatively high initial PO2, the system is less likely to respond to small changes in PO2 but then is apt to overshoot as PO2 falls further. This instability of the respiratory control system results in a widely oscillating output from the respiratory center and thus a cyclic pattern of ventilation.

Control abnormalities secondary to lung disease

Ventilatory control mechanisms often respond to various forms of primary lung disease by altering respiratory center output. Either stimulation of peripheral chemoreceptors by hypoxemia or stimulation of receptors by diseases affecting the airways or pulmonary interstitium can induce the respiratory center to increase its output, resulting in respiratory alkalosis. For example, patients with asthma commonly demonstrate increased respiratory drive and hyperventilation during acute attacks, due to stimulation of airway receptors. Similarly, patients with acute pulmonary embolism, pneumonia, or chronic interstitial lung disease often hyperventilate, presumably as a result of stimulation of one or more types of intrathoracic receptors, with or without the additional ventilatory stimulus contributed by hypoxemia.

In contrast, patients with COPD have variable levels of PCO2. The development of hypercapnia is inconsistent in patients with COPD (see Chapter 6). In patients with COPD who demonstrate elevated levels of carbon dioxide, the ventilatory control mechanism appears to be recalibrated to operate at a higher set point for PCO2, rather than the hypercapnia being solely due to reduced function of the lung. When responsiveness to increased levels of PCO2 is measured in hypercapnic patients, it is apparent that their ventilatory response is diminished. Patients with chronic compensated respiratory acidosis have higher levels of plasma and cerebrospinal fluid bicarbonate because of bicarbonate retention by the

kidneys. Therefore, for any increment in PCO2, the effect on pH at the medullary chemoreceptor is

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