Disorders of Ventilatory Control

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18

Disorders of Ventilatory Control

The finely tuned system of ventilatory control described in Chapter 17 is altered in a variety of clinical circumstances. In some cases, a primary disorder of the nervous system affects the neurologic network involved in ventilatory control and therefore may either diminish or increase the “drive” to breathe. In other instances the controlling system undergoes a process of adaptation in response to primary lung disease, so any alteration in function is a secondary phenomenon.

This chapter considers primary and secondary disturbances in ventilatory control. Of the secondary disorders, the most commonly seen is that associated with chronic obstructive pulmonary disease; therefore, the discussion of secondary disorders of ventilatory control focuses on this particular disorder. A common disturbance in the pattern of breathing, termed Cheyne-Stokes breathing, is covered, with a brief discussion of its pathogenesis. The final topic is ventilatory disorders associated with sleep, because alteration of ventilatory control may be an important component of the pathogenesis of sleep-related respiratory dysfunction.

Primary Neurologic Disease

Several diseases of the nervous system alter ventilation, apparently by affecting regions involved in ventilatory control. However, the results are variable, depending on the type of disorder and the region 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 during 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 metabolized 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 as a result of renal compensation with retention of bicarbonate. 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 generally 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, an element of decreased ventilatory response to hypercapnia and hypoxia is much more commonly seen in clinical practice and probably represents a spectrum of abnormalities in ventilatory response.

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. Progesterone is well known to be a respiratory stimulant and in some cases may improve respiratory drive and decrease CO2 retention. In the second 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, the most common current therapy for patients with clinically significant hypoventilation is noninvasive positive-pressure (i.e., assisted) ventilation, usually applied nocturnally. This topic is discussed in Chapter 29.

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

Cheyne-Stokes Breathing

Cheyne-Stokes breathing is a cyclic pattern in which periods of gradually increasing ventilation alternate with periods of gradually decreasing ventilation (even to the point of apnea). This type of ventilation is shown schematically in Figure 18-1. It has been known for many years that two main types of disorders are associated with this type 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.

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. For further discussion, the interested reader is referred to the references.

Prolongation in circulation time, which is one mechanism postulated to play a role in heart failure, results in an abnormal delay between events in the lung and sensing of PCO2 changes by the central chemoreceptors. Hence, 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 when hypoxia is driving the feedback system, as is seen on exposure to high altitude. 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 as a consequence of 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 chronic obstructive pulmonary disease (COPD) have variable levels of PCO2. Some patients with COPD do not demonstrate CO2 retention, whereas the condition of others is often characterized by hypercapnia (see Chapter 6). In the latter group, the ventilatory control mechanism appears to be recalibrated to operate at a higher setpoint for PCO2. When responsiveness to increased levels of PCO2 is measured in hypercapnic patients, it is apparent that their ventilatory response is diminished. However, these patients with chronic compensated respiratory acidosis have higher levels of plasma (as well as 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 attenuated by the increased buffering capacity available. A “chicken and egg” question then becomes important: Is CO2 retention secondary to an underlying ventilatory control abnormality in these patients, or is the diminution in ventilatory sensitivity merely secondary to chronic CO2 retention? Although this question remains unanswered, some evidence suggests that hereditary factors may be important and that CO2 retention is more likely to develop in patients with a genetically lower respiratory sensitivity.

Whatever the answer to this question, there is a clinically important corollary to this depression in CO2 sensitivity, irrespective of the cause of CO2 retention. When O2 is administered to the chronically hypoxemic and hypercapnic patient, PCO2 may rise even further. At the extreme, if very high levels of inspired O2 are administered, even life-threatening CO2 retention may occasionally be seen. In the past, this phenomenon was ascribed to loss of sensitivity to CO2 as a ventilatory stimulus, resulting from chronic CO2 retention. Such patients were thought to be primarily dependent on hypoxic drive as a ventilatory stimulus. Removal of the hypoxic stimulus by supplemental oxygen administration was thought to cause the observed increase in PCO2.

Administration of O2 to the chronically hypoxemic and hypercapnic patient may elevate PCO2.

However, it now is known that hypoxic drive plays only a limited role in the frequently observed increase in PCO2 occurring in patients with underlying hypoventilation who are given supplemental oxygen. Three factors account for this well-recognized clinical event: changes in minute ventilation, changes in ventilation-perfusion matching, and the Haldane effect. To grasp this complicated phenomenon, each of these factors should be understood. The easiest factor to understand is the change in minute ventilation. If a patient is hypoxemic, low PaO2 is sensed by the peripheral chemoreceptors, causing stimulation of the respiratory center. When supplemental oxygen is given and the patient is no longer hypoxemic, this stimulation abates. As discussed, this was previously thought to be the sole explanation for the rise in PCO2 seen in hypoxic hypercapnic patients who were given supplemental oxygen. However, it now is known from a number of studies that the decrease in ventilation accounts for only a small proportion of the rise in PCO2. More important is a worsening of ventilation-perfusion matching. Recall that alveolar hypoxia results in decreased perfusion to the hypoxic lung segments, an effect that is mediated through hypoxic vasoconstriction of those pulmonary arterioles supplying hypoxic alveoli. However, administration of supplemental O2 may alleviate alveolar hypoxia in these poorly ventilated regions, thus aborting the compensatory localized vasoconstriction. Ventilation-perfusion mismatch becomes more marked in the absence of hypoxic vasoconstriction, leading to less efficient elimination of CO2 and increased levels of PCO2. The third factor contributing to the rise in PCO2 is the Haldane effect, in which deoxygenated hemoglobin has a higher affinity for CO2 (see Chapter 1). When supplemental oxygen is administered, the more oxygenated hemoglobin has a lower affinity for CO2, leading to enhanced release of CO2 from hemoglobin and a higher PCO2.

Significant elevations in PCO2 upon administration of supplemental O2 to the chronically hypercapnic patient can generally be prevented by avoiding excessive concentrations of supplemental O2 beyond those needed to raise oxygen saturation to approximately 90%. In the presence of significant hypoxemia, the clinician should not withhold supplemental O2 from patients who have chronic hypercapnia, because significant hypoxemia poses a greater risk than a further increase in PCO2. Nevertheless, such patients usually are given relatively limited amounts of supplemental O2 (often called “low-flow O2” because of the low flow rate of O2 given via nasal prongs) to minimize the degree of further hypercapnia. In the hospital setting, oxygen is frequently administered via noninvasive positive pressure ventilation, which generally attenuates any hypercapnia that may develop.

Sleep Apnea Syndrome

Sleep apnea syndrome is a comparatively recently recognized disorder of respiration during sleep. Although a number of factors contribute to its pathogenesis, sleep-related changes in ventilatory control, specifically control of upper airway muscle tone, constitute an important component.

In this syndrome, patients have repetitive periods of apnea (i.e., cessation of breathing) that occur during sleep. A period of more than 10 seconds without airflow is generally considered to constitute an apneic episode, and patients with this syndrome often have hundreds of such episodes during the course of a night’s sleep. The term hypopnea is used to describe a reduction in airflow of 50% or more but without the complete cessation of airflow implied by the term apnea. Because episodes of apnea and hypopnea commonly coexist, the broader term sleep apnea-hypopnea syndrome is sometimes used. Sleep apnea syndrome is surprisingly common; estimates suggest a prevalence of 2% to 9% in middle-aged adults. Men are affected more commonly than women, and affected women are typically postmenopausal.

Types

Sleep apnea syndrome is commonly divided into several types (obstructive, central, and mixed) depending on the nature of the episodes. In obstructive apnea, the drive to breathe still is present during the apneic episode, but transient obstruction of the upper airway prevents inspiratory airflow. Inspiratory muscles are active during obstructive apnea, but their attempts at initiating airflow are unsuccessful. In central apnea, there is no drive to breathe during the apneic period—that is, there is no signal from the respiratory center to initiate inspiration. Hence no respiratory muscle activity can be observed when airflow ceases. Frequently, patients may have episodes of apnea that have features of both central and obstructive apnea, a condition called mixed apnea. Typically, such episodes start without ventilatory effort (central apnea), but upper airway obstruction is present when ventilatory effort resumes (obstructive apnea). Because clinically significant episodes of obstructive apnea are more frequent than those of central apnea, the focus here is on the clinical features, pathophysiology, and treatment of obstructive apnea.

Categories of sleep apnea syndrome are:

Clinical Features

Patients with sleep apnea syndrome may seek medical consultation because of (1) symptoms or signs that they or their partner have noticed during a night’s sleep, (2) daytime symptoms, or (3) complications that arise from the repetitive apneic episodes. During sleep, patients with episodes of obstructive apnea are often noted to have a markedly deranged sleep pattern. Loud snoring is particularly prominent, and patients may have obvious snorting, gasping, and agitation as a result of trying to breathe against the obstructed airway. They also may have violent movements during periods of obstruction. Not uncommonly the sleep partner complains of being hit or injured as a result of these violent movements. On waking, patients often complain of a severe headache, presumably related to cerebral vasodilation associated with derangements in gas exchange that occur during the apneic episodes. It is important to note, however, that many patients, especially those with milder cases, will not report any problems to their physician. Symptoms may be noted only when the physician specifically inquires about sleep issues.

With such a disordered pattern of sleep, patients are effectively sleep deprived, and not surprisingly they may be overly somnolent during normal waking hours. Even though the patient is in bed and “asleep,” only the lightest phases of sleep are entered, and adequate amounts of the deeper phases of sleep are not achieved because of repeated “microarousals.” The degree of daytime hypersomnolence can be debilitating and even dangerous. Patients may fall asleep while driving, eating, working, or during a variety of other usual daytime activities. Patients are often considered to have a personality disorder, partially because of their extreme hypersomnolence and partially because of psychological changes that have presumably resulted from their disease. Inability to concentrate and depression are also seen.

Clinical features of sleep apnea syndrome are:

Secondary cardiovascular complications of obstructive sleep apnea are believed to be mediated in part by increased sympathetic nervous system activity. During the episodes of apnea, patients may have a variety of cardiac arrhythmias or conduction disturbances, although they rarely are life threatening. As a result of episodes of prolonged hypoxemia at night, pulmonary hypertension can result, and unexplained cor pulmonale may be the presenting clinical problem. Systemic hypertension appears to be associated with and perhaps is a consequence of obstructive sleep apnea, and there is increasing evidence that links obstructive sleep apnea with an elevated risk of coronary artery disease and stroke.

Pathophysiology

During the last 2 decades, a great deal has been learned about the pathogenesis and risk factors leading to obstructive sleep apnea syndrome. Normally, inspiration is characterized not only by contraction of the diaphragm, resulting in negative airway pressure, but also by increased activity of a number of upper airway muscles acting to keep the pharynx patent. The genioglossus muscle is particularly important in this regard because it prevents the tongue from falling against the posterior pharyngeal wall and occluding the pharynx.

In patients with obstructive sleep apnea, structural and functional factors often work together to allow the upper airway to close during inspiration. In most patients, an excess of soft tissue in the upper airway, often as a consequence of obesity, compromises the size of the pharyngeal opening. During sleep, particularly rapid eye movement sleep, loss of activity of the upper airway muscles allows inspiratory collapse of the soft tissues and obstruction of the upper airway. Airflow eventually resumes after each episode of obstruction as the patient arouses (although these microarousals often are not evident to the patient), when activity of the upper airway muscles is restored, and when the airway temporarily becomes patent. However, as the patient falls asleep again, inspiratory muscle activity is again lost, and the cycle repeats itself. Because of the importance of structural factors contributing to a small upper airway, patients who are obese (with short, fat necks) or who have a small jaw (micrognathia), a large tongue, or large tonsils are at particular risk for obstructive sleep apnea.

During an episode of central apnea, monitoring of chest wall motion reveals no movement, corresponding to cessation of airflow and a fall in O2 saturation (Fig. 18-2, A). With obstructive apnea, chest wall and abdominal movement can be detected during a fruitless attempt to move air through the obstructed airway. Airflow measured simultaneously is found to be absent (tidal volume = 0) and O2 saturation drops, often to profoundly low levels (Fig. 18-2, B). When O2 saturation drops significantly during sleep, disturbances in cardiac rhythm can occur, and elevation of pulmonary artery pressure may be seen as a consequence of hypoxia-induced pulmonary vasoconstriction.

Treatment

In patients with central sleep apnea, treatment generally consists of the use of respiratory stimulants, an electrical implanted phrenic nerve pacemaker to stimulate the diaphragm, or mechanical ventilation, either invasive via a tracheostomy tube or noninvasive via a face mask. In obstructive sleep apnea, a variety of forms of therapy have been used. With patients who are markedly obese, an attempt at significant weight loss is often made. Although weight loss can sometimes dramatically improve the number and severity of apneic episodes, long-term weight reduction is difficult for most patients to maintain, making other forms of therapy necessary. In all patients, respiratory depressants, including alcohol and sedative-hypnotic drugs, should be avoided because they may worsen obstructive sleep apnea.

The first-line therapy used in most patients with obstructive sleep apnea syndrome is nasal continuous positive airway pressure, commonly called nasal CPAP. A mask connected to an air compressor is placed over the nose of the patient at bedtime. The compressor maintains positive pressure in the upper airway throughout the respiratory cycle, thus providing a pneumatic splint to keep the airway open.

An alternative but less common form of therapy involves nocturnal use of an oral appliance to maintain the tongue and/or the jaw in a relatively anterior position. This mechanical form of therapy facilitates airway patency by keeping the tongue away from the posterior pharyngeal wall.

Nasal CPAP is often applied at night to patients with obstructive sleep apnea to prevent upper airway closure.

Because nasal CPAP and oral appliances are so often effective, other forms of therapy now are used less frequently. Nevertheless, surgical modes of therapy may be beneficial in selected patients. For example, some patients are treated by a surgical procedure called uvulopalatopharyngoplasty, which involves removal of redundant soft tissue in the upper airway. However, the procedure is not without a risk of complications. Patients with particularly severe obstructive apnea whose disease is refractory to other forms of therapy can be treated with a tracheostomy, which involves placement of a tube in the trachea to allow air to bypass the site of upper airway obstruction. Despite the drastic nature of tracheostomy as a form of treatment, the therapeutic response often is quite significant. Patients may have a dramatic reversal of symptoms and a striking improvement in their lifestyle, which previously was limited by intractable daytime sleepiness.

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