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The Control of Breathing in Clinical Practice^*

^* From the Pulmonary, Allergy, and Critical Care Section (Dr. Gleeson), The Penn State Geisinger Health System, Hershey, PA; St. Vincent’s Hospital (Dr. Caruana-Montaldo), St. Verona, Malta; and the Denver VA Medical Center (Dr. Zwillich), Denver, CO.

Correspondence to: Kevin Gleeson, MD, Pulmonary, Allergy, and Critical Care Section, The Penn State Geisinger Health System, 500 University Dr, Hershey, PA 17036

	Abstract

TOP Abstract Introduction Components of Respiratory... Integrated Responses of the... Control of Breathing in... Control of Breathing in... Drugs and the Control... Conclusion References

 
The control of breathing results from a complex interaction involving the respiratory centers, which feed signals to a central control mechanism that, in turn, provides output to the effector muscles. In this review, we describe the individual elements of this system, and what is known about their function in man. We outline clinically relevant aspects of the integration of human ventilatory control system, and describe altered function in response to special circumstances, disorders, and medications. We emphasize the clinical relevance of this topic by employing case presentations of active patients from our practice.

Key Words: carotid body • chemoreceptors • control of ventilation • pulmonary receptors

	Introduction

TOP Abstract Introduction Components of Respiratory... Integrated Responses of the... Control of Breathing in... Control of Breathing in... Drugs and the Control... Conclusion References

 
This review is intended as an overview of human respiratory control. The first section will briefly describe the physiology of respiratory control including the sensors, the central controllers, and the effector systems. Subsequently, the control of breathing under special conditions and in certain common disease states will be reviewed. Throughout this discussion, we will employ selected case histories from our current outpatient population to illustrate salient, clinically relevant concepts.

Ventilation is constantly monitored and adjusted to maintain appropriate arterial pH (pHa) and PaO₂. This homeostatic control system requires a system of sensors, a central controlling mechanism, and an effector system to carry out its commands (Fig 1 ). Its response to changes in blood chemistry, mechanical load, metabolic rate, and respiratory neural receptors enables the respiratory system to adapt to special physiologic circumstances such as sleep, exercise, and altitude, as well as to compensate for pathologic disorders such as asthma, COPD, drug use, Cheyne-Stokes respiration (CSR), and neurologic disease.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 1. A schematic of the respiratory control system. Information from the various peripheral sensors is fed to a central control mechanism, the output of which goes to the effector muscles. By changing ventilation, the respiratory muscles reduce perturbations of the sensors (negative feedback). Reprinted with permission from West.126

	Components of Respiratory Control

TOP Abstract Introduction Components of Respiratory... Integrated Responses of the... Control of Breathing in... Control of Breathing in... Drugs and the Control... Conclusion References

Peripheral Arterial Chemoreceptors:
The peripheral arterial chemoreceptors consist of the carotid and aortic bodies.The physiologic significance of the aortic bodies in humans is difficult to determine but likely to be small: the carotid bodies appear to have preeminent importance. The carotid bodies are located at the junction of the internal and external carotid arteries, and are small, measuring 1.5 x 2.0 x 3.7 mm each with a weight of 10.6 to 12.6 mg (Fig 2 ).^{1 2} They receive their blood supply from branches of the external carotid artery, and their sensory supply from the carotid sinus branch of the glossopharyngeal nerve.³

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 2. The location of the carotid and aortic bodies with respect to the common carotid arteries and aortic arch, respectively. Reprinted with permission from Ganong.1

View larger version (41K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Organization of the carotid body showing the two different cell types. Glomus cells (type I) contain catecholamines (norepinephrine and dopamine). When exposed to hypoxia, they release the stored neurotransmitters that stimulate the cuplike endings of the carotid sinus nerve fibers (Hering’s nerve) in the glossopharyngeal nerve. The glial-like sheath cells (type II) surround the type I cells and probably have a sustentacular function. Reprinted with permission from Ganong.1

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Figure 4. (Left, A: the carotid body responds to changes of PO2, PCO2, and pH in arterial blood. Impulses travel to the CNS through the carotid sinus nerve (Hering’s nerve). Right, B: the percent maximum response of the firing frequency of the carotid body to arterial PO2. Note that the maximum response occurs at a PO2 of < 50 mm Hg and that the response varies in a nonlinear fashion. Reprinted with permission from West.126

Case 1: Sequential Bilateral Carotid Endarterectomy in a COPD Patient.
A 69-year-old white woman was admitted for an elective right carotid endarterectomy. Her medical history was significant for 40 pack-years of cigarette smoking, severe COPD, two cerebrovascular accidents, and a left carotid endarterectomy 1 year prior. Her preoperative arterial blood gas values showed a pH of 7.43; PaCO₂, 48 mm Hg; PaO₂, 50 mm Hg; and bicarbonate (HCO₃^-), 31 mEq/L while breathing room air. After an uneventful procedure, she was extubated on postoperative day 2 and received oxygen by nasal cannula at a rate of 3 L. On postoperative day 3, the nurses noticed that the patient was increasingly somnolent, and by postoperative day 5 she had developed severely altered mental status characterized by lethargy and confusion, despite the absence of any narcotic or sedative medications. There was no detectable change in her chest examination or chest radiograph. Arterial blood gas values while breathing 2 L of oxygen demonstrated a pH of 7.28; PaCO₂, 69 mm Hg; PaO₂, 62 mm Hg; and HCO₃^-, 31 mEq/L. The pulmonary service was consulted at this point and recommended treating her with nasal bilevel positive airway pressure ventilation. The patient improved clinically; 2 days later, her arterial blood gases while breathing 2 L oxygen per nasal cannula were a pH of 7.38; PaCO₂, 54 mm Hg; PaO₂, 72 mm Hg; and HCO₃^-, 36 mEq/L.

This case report illustrates an example of the clinical importance of the carotid bodies in the control of ventilation. This patient developed acute respiratory acidemia following the inadvertent operative denervation of her sole remaining functional carotid body. Together with her severe COPD with baseline CO₂ retention, the acute loss of the carotid body input to the respiratory center resulted in further depression of E sufficient to produce CO₂ narcosis.

The Central Chemoreceptors:
The fact that a ventilatory response to added CO₂ persists in experimental animals despite peripheral chemoreceptor denervation suggests that there are chemoreceptors in the brain that are sensitive to CO₂ or hydrogen ions.⁸ Although no definite chemoreceptors have been defined anatomically, results of experiments involving the local application of chemical, electrical, and thermal stimuli or the ablation of neural tissue suggest that the central chemoreceptors are located at or near the ventral surface of the medulla.⁸ Stimulation of these receptors increases both the rate of rise and the intensity of the inspiratory "ramp" signal, thereby increasing the frequency of the respiratory rhythm.⁹ The inspiratory ramp signal is a nervous signal transmitted to the respiratory muscles as a weak burst of action potentials that steadily increases in a ramp-like manner.^{10 11} Physiologically, these central chemoreceptors respond primarily to alterations of [H⁺] in the cerebrospinal fluid (CSF) and medullary interstitial fluid. The contribution of these central chemoreceptors to ventilation depends on the factors that alter hydrogen ion flux in their vicinity, causing changes in their intracellular pH. They are located in many different brainstem locations, including the ventral medullary surface, deeper sites near the nucleus tractus solitarius, and rostrally close to the locus ceruleus. Stimulation of these sites increases the whole respiratory control system output, suggesting that they respond to changes in brainstem pH via a ventilatory feedback loop. The sensing of acute pH changes, but not the steady-state ventilatory response, seems to require carbonic anhydrase. Imidazole-histidine appears to be an important molecule involved in central chemoreception and may be a pH sensor molecule. It is found in proteins located in pH-sensitive areas including ion channels, ion transport proteins, enzymes, and receptors. Thus, it may be involved in central chemoreception at sites within the ventrolateral surface of the medulla oblongata.¹²

Hydrogen ions enter and exit the CSF and extracellular fluid in the vicinity of the central chemoreceptors as a result of both CO₂ dissociation and by direct diffusion into and out of the bloodstream. Elevated arterial CO₂ rapidly penetrates the blood-brain barrier because CO₂ is highly membrane-permeable, is converted to carbonic acid (H₂CO₃), and rapidly dissociates into hydrogen ions and HCO₃^-. This causes [H⁺] in the CSF and interstitium to rise in parallel with PaCO₂. This increased [H⁺] stimulates respiration by a direct action on the central chemoreceptors. Conversely, a decreased PaCO₂ or [H⁺] inhibits ventilation.¹³

The ventilatory response to an increased PaCO₂ is divided into an initial rapid phase (within seconds) due to the relatively rapid acidification of the CSF, and a slower phase (within minutes) due to hydrogen ion buildup in the more highly buffered medullary interstitium. In addition, when compared with the highly membrane-permeable CO₂, hydrogen ions in the arterial blood penetrate the blood-brain barrier relatively slowly (minutes to hours). As a result, changes in pHa result in relatively slower and smaller changes in ventilation (Fig 5 ).¹⁴ Changes in PaCO₂ alone have a potent acute effect on ventilation but only a weak chronic effect. This occurs because a chronically elevated PaCO₂ is associated with renal compensation with the retention of HCO₃^-. This HCO₃^- gradually diffuses through the blood-brain barrier and into the CSF, where it binds to the excess hydrogen ions produced by the elevated PaCO₂ and negates their effect on ventilatory drive.¹³

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 5. Effects of increased arterial PCO2, both acute (continuous line) and chronic (dotted line), on the rate of alveolar ventilation. The second abscissa shows the relationship of decreased pHa (broken line) to alveolar ventilation. Note that an acute change in PCO2 has a greater effect on alveolar ventilation than a chronic change. Reprinted with permission from Guyton.9

Pulmonary Receptors:
Pulmonary receptors are present in the airways and lung parenchyma. They are all innervated by the vagus nerve, with myelinated fibers supplying the airway receptors and unmyelinated C fibers supplying the lung parenchyma.^{14 15} The airway receptors are subdivided into the slowly adapting receptors (SARs), also known to be the pulmonary stretch receptors, and the rapidly adapting receptors (RARs). The lung parenchyma receptors are called juxtacapillary receptors.

The SARs lie among the airway smooth muscle and are responsible for the Hering-Breuer inflation reflex in animals. Activation of these receptors also causes the tracheobronchial smooth muscle to relax, thus dilating the airways.¹⁶ The Hering-Breuer reflex is the prolongation of expiratory time and the decrease in respiratory rate in response to lung inflation.^{15 17} In humans, the Hering-Breuer reflex is manifest only at a VT of > 3 L and seems to play a protective role in preventing excessive lung inflation.^{10 17} The SARs do not accommodate to persistent stimulation such as prolonged distention.¹⁴ The SARs are thought to participate in ventilatory control by prolonging inspiration in conditions that reduce lung inflation, such as airway obstruction or decreased chest wall compliance, thereby allowing a normal VT to be achieved. Conversely, in conditions that prolong expiration, lung deflation is slow and the increased SAR activity increases the force of contraction of the expiratory muscles and also prolongs expiratory time. This prevents an increase in end-expiratory volume, thus decreasing the resting length of the inspiratory muscles and allowing them to function along the most advantageous portion of their length-tension curve.¹⁸

The RARs lie between the airway epithelial cells and are irritant receptors, responding to noxious stimuli such as dust, cigarette smoke, and histamine.¹⁹ They are concentrated in the carina and primary bronchi, and are also believed to be cough receptors.¹⁴ These RARs are innervated by myelinated fibers and have a more rapid rate of adaptation than SARs. During normal breathing, their discharge is independent of the phases of inspiration and expiration, and therefore these receptors do not seem to be an important influence on breathing at rest.²⁰ However, animal studies show that they are stimulated by conditions that increase airflow resistance and decrease lung compliance.²¹ Thus, their most important function may be to detect pathophysiologic changes in the airways. RARs also seem to be responsible for the augmented breathing and sighs that occur sporadically during normal breathing that helps to prevent atelectases.²² These receptors may be important in the sensations of chest tightness, dyspnea, bronchoconstriction, and the rapid and shallow breathing that occurs in asthma.^{16 23}

The pulmonary parenchymal receptors are innervated by the unmyelinated C fibers of the vagus nerve. They are called juxtacapillary receptors because of their location near capillaries in the alveolar walls. In animals, these receptors respond both to hyperinflation of the lungs and to chemicals present in the pulmonary circulation, and may be involved in the sensation of dyspnea in conditions causing interstitial congestion (eg, heart failure).^{17 24} Stimulation of these C fibers may also be associated with rapid shallow breathing, bronchoconstriction, and increased airway secretions.²⁵

The cumulative influence of lung receptors innervated by the vagus nerve on ventilation has been determined by blocking or interrupting the vagal tracts in animals. This intervention produces a reduced ventilatory response to hypercapnic and hypoxemic stimuli in conscious dogs at rest, and a decreased respiratory frequency response during exercise.²⁶ The mechanism for rapid shallow breathing and hyperventilation present during acute asthma has also been studied in dogs before and after vagotomy. Although vagotomy has no effect on baseline respiratory pattern, experimental bronchoconstriction after vagotomy does not produce the characteristic increase in respiratory rate and E present in dogs (and humans) with intact vagi, suggesting that the rapid shallow breathing pattern in response to bronchoconstriction is mediated by vagal afferent pathways.^{27 28} Another study in anesthetized dogs demonstrated that the rapid shallow breathing response to severe inspiratory resistive loading was abolished by bilateral vagectomy and was not mediated by diaphragm fatigue or hypoxia.²⁸ Similar results have been found in limited experiments in man.^{29 30}

Overall, these studies suggest that the abnormal breathing pattern associated with certain diseases (eg, asthma, pneumonia, heart failure, and pulmonary thromboembolism) in humans may be related primarily to lung receptor stimulation rather than derangements in lung mechanics or arterial blood gases.

Chest Wall and Muscle Mechanoreceptors:
Mechanoreceptors are sensors that respond to changes in length, tension, or movement. The primary mechanoreceptors in the chest are the muscle spindle endings and tendon organs of the respiratory muscles and the joint proprioceptor. Muscle spindles are primarily influenced by changes in length and are responsible for reflex contraction of the skeletal muscles in response to stretching. Afferent information from these receptors is carried in the anterior columns of the spinal reticular pathway and terminates in the region of the respiratory centers in the medulla.³¹ Muscle receptor afferents are involved in the level and timing of respiratory activity.³² These receptors may also play a role in the increase in ventilation occurring during the early stages of exercise.

Tendon organs sense changes in the force of contraction exerted by the muscles of respiration. Tendon organ receptors are involved in monitoring the force of muscle contraction and have an inhibiting effect on inspiration. They may be important in coordinating respiratory muscle contraction during breathing at rest or with a respiratory load.³²

Joint proprioceptors sense the degree of chest wall movement and may also influence the level and timing of respiratory activity. Proprioceptor afferents project to the phrenic motor neurons and affect their firing rate. They also ascend to the medullary respiratory neurons in the dorsal respiratory group and nucleus retroambiguus, where they affect the timing of inspiration and expiration.³²

These mechanoreceptors may also be important in the sensation of dyspnea when respiratory effort is increased by the mechanism of length-tension inappropriateness.¹⁶ This is illustrated by the following case history.

Case 2: Large Pleural Effusion Associated With Dyspnea.
A 74-year-old white man presented with dyspnea on minimal exertion for several weeks. His medical history was significant for stage IV non-Hodgkin’s lymphoma treated with radiation and chemotherapy several years previously. Physical examination demonstrated left cervical lymphadenopathy and decreased vocal fremitus, dullness to percussion, and poor air entry on the right side of the chest. A chest radiograph showed a large (> 50% of the hemithorax) right pleural effusion with mediastinal shift to the contralateral side. Spirometry showed an FVC of 3.0 L (60% of predicted) and a FEV₁ of 2.4 L (82% of predicted). Arterial oxygen saturation (SaO₂) on room air was 94% at rest, with mild desaturation (SaO₂ < 88%) occurring with informal exercise testing (1 to 2 min of ambulation in the clinic hallway). A 1.5-L therapeutic thoracentesis was performed, with dramatic improvement in the patient’s symptoms. The patient returned to the clinic several weeks later with recurrence of his symptoms of shortness of breath with minimal exertion. Physical examination confirmed reaccumulation of the pleural fluid. Right-sided pleurodesis was ultimately performed with no pleural fluid recurrence and excellent long-term relief of his dyspnea.

This patient had dyspnea primarily resulting from the presence of a large pleural effusion. This appears to arise primarily by the mechanism of length-tension inappropriateness caused by a pleural effusion stretching the chest wall.³³ According to this hypothesis, inspiratory muscle activation produces muscle contraction and a degree of tension in the muscles that is sensed by the tendon organs. If the respiratory muscles are inefficient for mechanical reasons (in this case because of the thoracic distention produced by the pleural effusion), the magnitude of tension in the muscle produced by a given amount of muscle contraction is proportionately lower than in the normal state. This discrepancy between the degree of neural input to and contraction of the respiratory muscles and the tension produced by that muscle contraction is sensed by the cerebral cortex as dyspnea. Removal of the pleural fluid in this case had the effect of reducing end-expiratory muscle fiber length and restoring the relationship of muscle contraction and muscle tension to normal, thereby immediately reducing dyspnea.³³ This scenario does not exclude the possibility that other mechanisms may be contributing to this patient’s symptoms. It is possible that the relief of dyspnea following thoracentesis may have resulted from the decreased work of breathing (WOB) that occurs because of the removal of the mechanical load of the pleural effusion, or possibly because of improved gas exchange from improved ventilation/perfusion (/) matching.

The Central Respiratory Controllers
The central respiratory controllers are divided into the brainstem group (involuntary) and the cerebral cortex group (voluntary). The former is further subdivided into pneumotaxic, apneustic, and medullary centers.

The pneumotaxic center consists of the nucleus parabrachialis and the Kolliker-Fuse nucleus in the pons. This center is important in influencing the timing of the inspiratory cut-off by providing a tonic input to the respiratory pattern generators located in the inspiratory center. Thus, this center may modulate the respiratory response to stimuli such as hypercapnia, hypoxia, and lung inflation, and is of importance in regulating the duration of inspiration.^{31 34}

The apneustic center is found in the lower pons and seems to function as the source of impulses that terminate inspiration, an "inspiratory cut-off switch."³⁴ Inactivation of this center results in apneustic breathing, which is rhythmic respiration with a marked increase in inspiratory time and a short expiration phase.³⁵ Apneustic breathing can be experimentally induced in animals by transecting the spinal cord between the pneumotaxic center and the lower brainstem in combination with bilateral vagotomy. Clinical information from patients with multiple sclerosis with brainstem involvement and clinical pathologic correlations suggest that the pneumotaxic center may function similarly in man.^{35 36}

The medullary center is divided into an inspiratory dorsal respiratory group (DRG) of neurons and an expiratory ventral respiratory group (VRG). The DRG is located in the nucleus of tractus solitarius in the medulla and is important in integrating impulses from visceral afferents from the upper airways, intra-arterial chemoreceptors, and lung parenchyma through the fifth, ninth and 10th cranial nerves, respectively.³⁴ It may also be the site of projection of proprioceptive afferents from the respiratory muscles and chest wall. The DRG is a processing center for respiratory reflexes and is the site of origin of the normal rhythmic respiratory drive consisting of repetitive bursts of inspiratory action potentials.³⁴ The exact mechanism by which this rhythm is generated is unknown.

A theory to explain the breathing rhythmicity of the central pattern generator is as follows. Inspiration begins by the abrupt removal of inhibitory impulses to the DRG. This is followed by increased inspiratory motoneuron activity in the form of a slowly augmenting ramp of signals that is suddenly terminated by an off-switch mechanism. This termination of inspiratory activity occurs when a critical threshold is attained. During early expiration, there is another burst of inspiratory neuronal activity that is referred to as postinspiration inspiratory activity (PIIA). PIIA does not prolong inspiration, but rather slows down the rate of exhalation during the first part of the expiratory phase. The neurons that generate the PIIA may depend on mechanisms that are different from those responsible for the main inspiratory ramp activity.¹¹

The VRG consists of both inspiratory and expiratory neurons and is located within the nucleus ambiguus rostrally and nucleus retroambiguus caudally. The VRG innervates respiratory effector muscles through the phrenic, intercostal, and abdominal respiratory motoneurons.³⁴ Its output increases with the need for forceful expiration such as in exercise or in any condition of increased airway resistance to breathing (eg, COPD or asthma).³⁷

The cerebral cortex plays a role in ventilatory control and can also influence or bypass the central respiratory control mechanism in order to accomplish behavior-related respiratory activity such as cough, speech, singing, voluntary breath holding, and other such activities.³⁸

Effector System
The effector system consists of those pathways and muscles that are involved in the actual performance of inspiration and expiration. The spinal pathways connect the respiratory centers in the brain and spinal cord to the respiratory muscles and are divided into the descending and ascending pathways. The descending pathways connect the DRG and VRG to the ventrolateral columns of the spinal cord, the phrenic nerves, and the intercostal and abdominal muscles of respiration. These pathways are used for the inhibition of the expiratory muscles during inspiration and inhibition of inspiratory muscles during expiration to prevent opposing muscles from contracting at the same time.³⁴ The ascending pathways connect the respiratory muscles to the higher brainstem levels. Impairment of the ascending spinal pathways (eg, following bilateral percutaneous cervical cordotomy or anterior spinal operations) may lead to respiratory dysfunction in the form of apnea during sleep that is reversed by arousal. This condition may be caused by damage of ascending spinoreticular fibers, lessening brainstem reticular formation activity and causing a general depression of respiration.³⁴

The respiratory muscles consist of the diaphragm and the intercostal, abdominal, and accessory muscles of respiration. The diaphragm is responsible for the majority (75%) of air movement during quiet inspiration, while the intercostal, abdominal, and accessory muscles (sternocleidomastoid and other neck muscles) account for the remainder.³⁹ Inspiration at rest is active and expiration is a passive event in patients with normal lungs. During exercise or in patients with airway obstruction, both inspiration and expiration become active, with expiratory contraction of the abdominal wall and internal intercostal muscles.⁴⁰ The clinical importance of the diaphragm is illustrated by the following case history.

Case 3: Bilateral Hemidiaphragm Weakness.
A 77-year-old white man was transferred to the medical ICU for failure to wean off mechanical ventilation after the repair of a type 1 thoracic aortic dissection. His postoperative course had been uncomplicated until he was extubated 48 h later. Within 15 min of extubation, he became tachypneic, hypercapnic, and acidotic (pHa of 7.13; PaCO₂, 85 mm Hg; and PaO₂, 66 mm Hg), and required reintubation. Initial evaluation included a brief interval of spontaneous breathing off the ventilator, during which paradoxical inward inspiratory motion of the abdomen was observed. A chest radiograph showed bilateral small but clear lung fields with minimal pleural effusions. Fluoroscopy of the diaphragm demonstrated bilateral failure to descend with rapid inspiratory efforts (sniff test).

This patient has respiratory failure due to bilateral hemidiaphragm paralysis, presumably caused by intraoperative phrenic nerve injury.⁴¹ Less common than previously believed, this is nevertheless an easily overlooked cause of ventilator dependence after thoracic surgery. One reason it may be overlooked is that positive pressure ventilation masks the characteristic paradoxical diaphragm/abdominal wall movement and the pulmonary restriction, which would otherwise be obvious. In our experience, it presents as prolonged postoperative ventilator dependence following either complex or multiple intrathoracic operations. Typically, the patient has good gas exchange and a favorable clinical course until the ventilator is totally discontinued, when acute ventilatory decompensation occurs within a short time. Once the diagnosis is considered, measuring maximal inspiratory pressure (PImax), maximum voluntary ventilation (MVV), and supine and sitting vital capacities (VCs) will confirm it. In bilateral diaphragm paralysis, both PImax and MVV are decreased and there is a > 50% reduction in VC in the supine vs the upright position.⁴²

	Integrated Responses of the Ventilatory Control System

TOP Abstract Introduction Components of Respiratory... Integrated Responses of the... Control of Breathing in... Control of Breathing in... Drugs and the Control... Conclusion References

 
The categorization of the respiratory control system employed above is a useful means of organizing and outlining the anatomic and physiologic information available regarding its various components. However, all normal physiologic functions and derangements of respiratory control must consider the integrated function of the entire system. Considerable information of clinical significance is best understood as it relates to the integrated ventilatory response to the various chemical stimuli.

Respiratory Response to Increased CO₂
The integration of the central respiratory centers is normally coordinated, and thus arterial CO₂ is maintained constant with relatively little variation. Therefore, ventilation increases in a directly proportional manner to increasing CO₂ production. This response is reflected in the ventilatory response to experimentally induced arterial hypercapnia (Fig 5) . During exercise, this occurs without arterial hypercapnia occurring. There is an important interaction between hypercapnic and hypoxemic ventilatory responses. The slope of the ventilatory response to increases in PaCO₂ is greater in the presence of a lower PaO₂ (Fig 6 ).⁴³ Although the majority of normal subjects maintain a resting PaCO₂ of 40 mm Hg, there is substantial genetic variation in CO₂ and oxygen sensitivity.⁴⁴ Genetic variation in drive may explain some of the differences in blood gas tensions in patients with COPD.⁴⁵ Both hypercapnic and hypoxemic ventilatory responses tend to decrease with increasing age or formal exercise training.^{46 47} Pregnancy is associated with an increase in resting E primarily because of an increased VT. This begins in the first trimester but then remains relatively constant thereafter. The hyperventilation is thought to be secondary to the rise in progesterone blood levels.⁴⁸

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 6. Fan of lines showing the difference in ventilatory response to PaCO2 at various fixed values for alveolar PO2. Note that hypoxemia increases the slope of the ventilatory response to PaCO2. BTPS = corrected for physiologic body temperature, pressure, and water saturation. Reprinted with permission from Ganong1 ; see original source for references within Figure .

Case 4: Primary Alveolar Hypoventilation.
A 47-year-old woman was referred for asymptomatic respiratory acidosis with a pH of 7.35; PaCO₂, 49 mm Hg; and PaO₂, 67 mm Hg. Her medical history included sick sinus syndrome, for which a pacemaker was inserted, and postural hypotension secondary to autonomic dysfunction. The physical examination revealed a nonobese patient with a BP of 110/80 mm Hg supine and 80/60 mm Hg standing, but the findings were otherwise normal. A urine toxicology screen showed no illicit drug use, and thyroid function tests and chest radiograph were normal. Spirometry, lung volumes, diffusing capacity, MVV, and negative inspiratory pressure were normal. A nocturnal polysomnogram demonstrated minimal central apneas/hypopneas associated with mild desaturation by pulse oximetry. A neurologic workup (including a CT scan of the brain) was normal, and a provisional diagnosis of primary alveolar hypoventilation was made by exclusion. This was confirmed by the arterial blood gas values after 5 min of voluntary hyperventilation: pH of 7.52; PaCO₂, 29 mm Hg; and PaO₂, 93 mm Hg.

The diagnosis of primary alveolar hypoventilation is ordinarily based on finding hypercapnia, hypoxemia, and chronic respiratory acidosis in the absence of respiratory muscle weakness, mechanical ventilatory defects, or an underlying neurologic disease.⁴⁹ These patients, although often asymptomatic, may have symptoms secondary to the combination of hypercapnia and resulting hypoxemia. These may include symptoms of cor pulmonale, morning headaches, daytime fatigue, somnolence, confusion, and sleep disturbances. However, alveolar-arterial gradient, airflow rates, and lung volumes are usually normal, as are MVV and PImax. In contrast, patients’ ventilatory and occlusion pressure responses to hypercapnia are reduced or absent, and they have an abnormal ventilatory response to exercise associated with further increases in their PaCO₂ and a decrease in PaO₂.⁴⁹ Their breath-holding time is also markedly prolonged without the accompanying sensation of dyspnea.⁵⁰ Typically, these patients can voluntarily hyperventilate to a normal or low PaCO₂.

This case illustrates an important method that may be useful to differentiate the cause of hypercapnia in a patient. If the patient can, during voluntary hyperventilation, lower PaCO₂ to normal or below, then a central mechanism depressing ventilation is at least partially responsible for the hypercapnia. However, if voluntary hyperventilation fails to lower PaCO₂ to normal, an alternative cause of the hypercapnia should be sought. Primary alveolar hypoventilation was diagnosed in this patient, as she effectively hyperventilated on command, and no central lesions effecting her central respiratory drive were identified.

Respiratory Response to Decreased Oxygen
The ventilatory response to hypoxemia varies depending on the level of CO₂ and also varies between individuals on a genetically determined basis.^{43 45} It also decreases with age and training.^{46 47} The response to a falling PaO₂ demonstrates an exponential type of curve rather than the linear relationship of increasing ventilation in response to increasing PaCO₂ (Fig 7 ). There is little increase in E until the PaO₂ falls to < 60 mm Hg.⁵¹ At this point, any further decrease in PaO₂ causes a marked increase in E. However, if CO₂ is added to the inspired gas during testing to cause hypercapnia, then the resultant ventilatory response is markedly increased (Fig 7) . Conversely, if the PaCO₂ is decreased during testing, the ventilatory response to hypoxemia is blunted.⁴³ The clinician should be alerted when the patient is not dyspneic in the face of significant hypoxemia, particularly when hypercapnia is also present. In these patients, a low ventilatory drive should be suspected, and reversible abnormalities (eg, ventilatory-depressant drug use—opiates and sedatives) or hypothyroidism should be considered.

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Figure 7. Shown are the ventilatory response curves at three different levels of alveolar CO2. Note that when PACO2 is 36 mm Hg, almost no increase in ventilation occurs until the PaO2 is reduced to about 50 mm Hg. Reprinted with permission from West.126

In metabolic alkalosis, respiratory compensation for the increased serum HCO₃^- occurs with a decrease in minute alveolar ventilation. This elevates PaCO₂ to cause a respiratory acidosis, and tends to normalize pH. This compensation is ultimately limited by the carotid chemoreceptors once PaO₂ begins to decrease.⁵²

	Control of Breathing in Special Physiologic Circumstances

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Sleep
At sleep onset, the behavioral and cognitive influences on ventilatory control are largely eliminated. E and respiratory responses to exogenous (and presumably endogenous) stimuli such as the response to hypoxia and hypercapnia are generally reduced.^{53 54} In addition, an increase in airflow resistance typically occurs at sleep onset because of relative hypotonia of the upper airway dilatory muscles.⁵⁵ Ventilatory compensation to both added and intrinsic resistance to breathing is also severely reduced during rapid eye movement (REM) sleep; this explains why the majority of sleep-related ventilatory disturbances are most severe during this phase of sleep.⁵⁶ These effects are summarized in Table 1 . Hypoventilation during slow-wave sleep is a product of a decreased VT and respiratory rate resulting in a 2- to 7-mm Hg increase in PaCO₂ and a reciprocal fall in PaO₂. A periodic breathing pattern following sleep onset commonly occurs in stages 1 and 2 of sleep. The respiratory pattern is notably most regular in stages 3 and 4.⁵⁷ Another notable change related to the sleep state is the marked reduction in skeletal muscle tone during REM sleep, sparing only the diaphragm and ocular muscles. This decreased muscle activity is thought to be caused by REM-related supraspinal inhibition of the alpha motor drive and the specific depression of fusimotor function, causing attenuation of the stretch and polysynaptic reflexes with decreased muscle tone.⁵⁸ The diaphragm is relatively spared because it contains very few muscle spindles and is therefore much less affected by these inhibitory impulses.⁵⁹ However, during phasic REM sleep, the contraction of the diaphragm becomes uncoordinated (so-called "diaphragmatic fragmentation").⁶⁰ In fact, respiration during phasic REM sleep is very irregular and consists of sudden changes in both respiratory amplitude and frequency, which are linked to the rapid eye movements. SaO₂ is also lowest during this period.⁶¹ Ventilation during REM sleep is primarily maintained through diaphragmatic contraction. It follows that any respiratory impairment in which diaphragmatic dysfunction is prominent (eg, paralysis, weakness, or the hyperinflation of severe COPD) can cause severe nocturnal hypoventilation, especially during REM sleep.

View larger version (11K): [in this window] [in a new window] [Download PPT slide]   Figure 8. The ventilatory response to exercise showing the initial rapid increase that occurs at the onset (phase I), followed by the slower and exponential increase (phase II), the steady state (phase III), and the rapid decrease that occurs with cessation of activity. Reprinted with permission from Wasserman et al.71

Phase II of the ventilatory response to exercise occurs within 20 to 30 s of exercise initiation, an interval that approximates the circulation time for venous blood from the exercising muscles to reach the respiratory centers. This phase consists of a slower and exponential increase in E, oxygen uptake (O₂), and CO₂ elimination. This increased ventilation lags behind CO₂ production, and consequently the respiratory exchange ratio and PaO₂ decrease in association with an increase in PaCO₂ during this period.⁶⁶

Phase III of the respiratory response to exercise is a steady state characterized by pulmonary gas exchange that matches the metabolic rate to maintain a stable arterial PaCO₂, pHa, PaO₂, and respiratory exchange ratio that are similar to resting values.⁶⁷ It normally occurs within 4 min of exercise initiation and is characterized by a generally constant respiratory frequency and VT, and a ventilatory response to exercise that is linearly related to CO₂ output. The magnitude of the steady-state ventilatory response appears to be inversely related to the resting PaCO₂, and the lower the PaCO₂, the greater the ventilatory response to a given level of exercise. There is little change in blood lactate concentration during this phase. Patients who have undergone carotid body resection show no impairment in their ability to regulate PaCO₂ during phase III.⁶⁸ Phase III ends once the anaerobic threshold is reached.

Phase IV is the final ventilatory response to exercise. It begins at the point at which the anaerobic threshold is reached. It is also known as the first ventilatory threshold. At this point, oxygen consumption exceeds oxygen delivery, and lactic acid accumulates in arterial blood as a product of anaerobic metabolism. This lactic acidosis produces an exponential rise in E, which is usually accompanied by a decrease in PaCO₂.^{69 70} The second ventilatory threshold is a second nonlinear increase in ventilation that occurs when the subject reaches 70 to 90% of their maximal O₂. At this point, ventilation increases disproportionately to both O₂ and CO₂ elimination. This threshold is accompanied by prominent arterial hypocapnia until exhaustion finally occurs.⁶⁷

Termination of exercise is associated with an abrupt decrease in ventilation followed by an exponential decay to resting levels. This abrupt decrease is usually of a lesser magnitude than the abrupt increase seen at the onset of exercise. It may be secondary to the removal of neural stimuli from the higher neural centers and exercising limbs, while the slow decay may be related to the removal of the remaining stimuli (hypoxia, hypercapnia, and short-term potentiation) present during steady-state exercise.⁶⁷ The measurement of the ventilatory response to exercise is a useful clinical tool that is often used to evaluate the cause of dyspnea or exercise limitation.

Altitude
The ventilatory response to altitude is largely dependent on the degree of altitude and rate of ascent. As altitude increases, barometric pressure decreases; although the partial pressures of oxygen and nitrogen remain unchanged, their absolute pressures decrease. Inspired oxygen tension is 150 mm Hg at sea level and approximately 120 mm Hg at 5,200 feet; thus, the expected arterial PaO₂ decreases from 100 to 70 mm Hg. This mild hypoxemia results in an increase in alveolar ventilation and a lower arterial PaCO₂ (respiratory alkalosis).⁷¹

Acute mountain sickness may develop following rapid ascent to moderate altitude as a result of hypoxemia that causes cerebral vasodilatation with increased perfusion pressure, leading to the development of cerebral edema. Symptoms include headache, nausea and vomiting, lethargy, and sleep disturbances. Hypoxemia-induced hyperventilation and pulmonary hypertension are probably important in the common complaint of dyspnea at altitude. Twenty-five percent of visitors to Rocky Mountain ski resorts developed symptoms of acute mountain sickness, usually within the first 12 h of arrival. Persons who are younger, are less physically fit, live at sea level, have a history of acute mountain sickness, or have underlying lung problems are more likely to develop this syndrome.⁷² Symptoms may be diminished or abolished either by slow ascent, (eg, over a 5-day period) or by 2 days of prophylaxis with acetazolamide. This drug induces a HCO₃^- and sodium diuresis, causing a hyperchloremic metabolic acidosis. This leads to compensatory hyperventilation with subsequent improvement in oxygenation and normalization of breathing pattern during sleep.⁷³

High-altitude pulmonary edema is a form of noncardiogenic pulmonary edema secondary to hypoxia of high altitudes that may develop in normal subjects without preexisting cardiac or pulmonary disease. It occurs after 6 to 48 h at altitudes of > 8,000 feet and is more common with cold exposure and after exercise. The symptoms of this illness consist of cough, severe dyspnea, chest pain, and fatigue. On examination, these patients may be febrile, tachypneic, tachycardic, and cyanotic; their chest examination may reveal crackles and wheezes. A chest radiograph initially shows prominent pulmonary arteries and patchy, diffuse infiltrates. The ECG shows sinus tachycardia and a right ventricular strain pattern. Pulmonary artery catheterization reveals elevated pulmonary artery pressures, with a low pulmonary capillary wedge pressure. SaO₂ is 40 to 70%, and the mortality rate is 4 to 11%. Treatment is centered on increasing the fraction of inspired oxygen with supplemental oxygen or increasing barometric pressure by rapid descent. Nifedipine, a calcium-channel antagonist, may be utilized in acute treatment and also for prophylaxis in susceptible subjects.⁷⁴

Normal Adaptations to Stress
Important insight into the capacity of the integrated respiratory control system to respond to acute disease states can be gained by experimentally inducing acute respiratory muscle fatigue in subjects with a normal respiratory apparatus. Following a brief interval of breathing against a high resistance, normal subjects develop respiratory muscle fatigue, measured by a reduction in their ability to reach or sustain normal high (negative) inspiratory pressures.⁷⁵ When exposed to the stimulus of CO₂ rebreathing while in this fatigued state, these subjects maintain their ventilatory response to CO₂, but do so at lower inspiratory pressures with smaller, more frequent breaths (ie, rapid shallow breathing).⁷⁵ In addition, if these subjects with experimentally induced acute respiratory muscle fatigue are subjected to heavy exercise, ventilation is also maintained at prefatigue exercise values, but again with smaller, more frequent breaths.⁷⁶ This is accomplished by recruitment of abdominal muscles to augment the efforts of the fatigued respiratory apparatus.⁷⁷ As can be surmised by this information, these experimental observations correspond to the well-known pattern of rapid shallow breathing and accessory muscle use employed to sustain E in acute asthmatics. Thus, the ventilatory control system rapidly employs a variety of compensatory mechanisms in the service of its ultimate function.

	Control of Breathing in Various Disease States

TOP Abstract Introduction Components of Respiratory... Integrated Responses of the... Control of Breathing in... Control of Breathing in... Drugs and the Control... Conclusion References

 
Asthma
Symptomatic asthmatics normally breathe at a normal or increased frequency.⁷⁸ Their ventilatory drive (as measured by mouth occlusion pressure) increases during exacerbations, probably in response to the resistive load imposed by increased airflow resistance.⁷⁹ This compensation is usually excellent, as most asthmatics hyperventilate during an episode of wheezing with dyspnea. Although asthmatics are usually hypoxemic during attacks, supplemental oxygen does not significantly raise the low PaCO₂, suggesting that hypoxemia is not the cause of the hypocapnia. The hyperventilation during acute asthma attacks is primarily caused by an increased respiratory rate and is not accompanied by an increased VT.⁷⁹ This is the reverse of the respiratory pattern response seen in asthmatics during bronchoconstriction iatrogenically induced by either methacholine or exercise, where E increases because of increases in VT alone, with no increase in the respiratory rate. A possible explanation for these different responses is the presence of severe airway inflammation during an acute asthma attack that is absent in the bronchoconstrictor challenge induced by methacholine or exercise.⁷⁹

The clinical importance of increased respiratory drive in severe asthma is well known to physicians, as the majority of asthmatics have a low PaCO₂ on presentation for emergency care. A normal or increased PaCO₂ signifies severe airway obstruction, patient fatigue, and incipient ventilatory failure. These attacks may be fatal and mandate careful observation and monitoring of the patient.

A final issue of potentially life-saving clinical importance is that asthmatic patients with histories of acute asthma and respiratory failure (near-fatal asthma) may have an inherently blunted perception of the resistance to their breathing imposed by worsening bronchospasm. Thus, they are unable to sense when they are reaching the point of critical airflow obstruction.⁸⁰ It is of utmost importance that these patients routinely monitor some objective measure of lung function, such as peak expiratory flow rate, to determine when their airflow obstruction is progressing. In this way, they can modify their treatment early and prevent life-threatening exacerbations.

COPD
The clinical importance of the ventilatory response to CO₂ in COPD is illustrated by the following cases of normocapnic vs hypercapnic COPD patients. In this section, we will also discuss several other ventilatory control issues unique to these patients.

Case 5: Severe COPD Without CO₂ Retention.
A 50-year-old white woman presented to the pulmonary clinic with complaints of progressive dyspnea on exertion and weight loss for the past 5 years. She denied any cough, phlegm, or peripheral edema. Her medical history was significant for a 60–pack-year history of cigarette smoking. Examination of her chest revealed hyperinflation with poor air entry bilaterally but no wheezing. Extremities showed no clubbing, cyanosis, or edema. Her chest radiograph showed evidence of hyperinflation with bullous changes and a small heart. Spirometry demonstrated an FEV₁ of 0.47 L (18% of predicted) and an FVC of 2.8 L (86% of predicted). Arterial blood gas analysis on room air showed a pH of 7.42; PaCO₂, 36 mm Hg; PaO₂, 68 mm Hg; and serum HCO₃^-, 24 mEq/L.

This woman has severe COPD, yet nonetheless manages to maintain a normal PaCO₂ and pH. She can be contrasted to the following patient from our practice.

Case 6: Severe COPD With CO₂ Retention.
A 72-year-old white woman with a 40–pack-year history of cigarette smoking presented with cough, increasingly purulent sputum, dyspnea and paroxysmal nocturnal dyspnea, worsening lower extremity edema, and weight gain. Physical examination revealed cyanosis, increased jugular venous pressure, decreased breath sounds, wheezing, prolonged expiration, and bilateral lower extremity edema. Her chest radiograph showed increased bronchovascular markings and an enlarged heart. Spirometry demonstrated an FEV₁ of 0.74 L (31% of predicted) and an FVC of 2.43 L (73% of predicted). Arterial blood gas analysis on room air showed a pH of 7.35; PaCO₂, 52 mm Hg; PaO₂, 60 mm Hg; and serum HCO₃^-, 29 mEq/L. These values were consistent with a compensated respiratory acidosis.

These cases juxtapose two patients from our practice with severe COPD. The most notable fact is that the first patient (case 5) with the greater airflow obstruction (FEV₁, 0.46 L) has a normal arterial CO₂, while the second, with less severe obstruction (FEV₁, 0.74 L), has hypoventilation and a respiratory acidosis. The causes of hypercapnia in COPD are multiple and complex, and include the degree of airflow obstruction, inspiratory muscle function, the native ventilatory response to CO₂, the coexistence of nocturnal hypoventilation, and other less well-defined features. The most important determinant of arterial CO₂ retention in these patients is the magnitude of airflow obstruction. This has been studied previously in a group of COPD patients.⁸¹ Very few patients with an FEV₁ of 1 L had PaCO₂ values > 40 mm Hg. However, this study also demonstrated great variability in the degree of CO₂ retention for any level of FEV₁ reduction of < 1 L. Therefore, the degree of CO₂ retention in patients with COPD with lung function in this range seems to be determined by other factors.

Another possible explanation for chronic hypercapnia is inspiratory muscle dysfunction or weakness in association with an increase in lung resistance.⁸² This decrease in inspiratory muscle strength is probably caused by a combination of increased lung volumes together with shortening of the diaphragm and other inspiratory muscles or generalized muscle weakness affecting the respiratory muscles. This combination of inspiratory muscle weakness and increased lung resistance is associated with hypercapnia and may be a protective strategy to avoid overloading the inspiratory muscles, thereby causing fatigue and ultimately irreversible respiratory failure.⁸³

One interindividual factor that may contribute to this variable hypercapnia in COPD patients is the native ventilatory response to PaCO₂. This concept of inherent differences in the ventilatory response to CO₂ arose from the observation that considerable variability existed in the magnitude of the ventilatory response to experimentally induced increases in arterial PCO₂ in normal subjects. In accord with this concept, subjects with high ventilatory responses to abnormal blood gases who went on to develop even severe COPD would adapt to their disease by maintaining normal blood gases by increasing total E, thereby preserving alveolar ventilation and reasonable blood gas values. Those with native low ventilatory responses to CO₂ would, alternatively, adapt to increasing airflow obstruction by tolerating arterial CO₂ retention, and therefore hypoventilate and develop respiratory acidosis. According to this paradigm, COPD patients have been classified into those with high ventilatory responses to abnormal blood gases (type A; pink puffers) and those with low responses (type B; blue bloaters), with additional distinguishing characteristics (Table 2 ). A genetic basis for attenuated respiratory drive is supported by the observation that adult children of pink puffers have higher ventilatory chemosensitivity than offspring of blue bloaters do.⁴⁵

Some COPD patients with CO₂ retention will develop worsening respiratory acidosis when given supplemental oxygen that raises their PaO₂ to > 70 mm Hg, an effect that is usually attributed to the loss of their hypoxic stimulus to breathe. However, reduction in hypoxic ventilatory drive may not be the sole mechanism causing increasing hypercapnia in this group. A second potential explanation for the arterial hypercapnia associated with supplemental oxygen administration in this patient group is worsening / mismatch resulting in a significant increase in the dead space–to-VT ratio.^{86 87}

/ mismatch occurring under these circumstances may be explained as follows. Before supplemental oxygen use, areas of local alveolar hypoxia produce pulmonary hypoxic vasoconstriction, thereby diverting the flow of CO₂-rich blood from poorly ventilated to better ventilated lung segments. When supplemental oxygen reverses local hypoxemia, pulmonary hypoxic vasoconstriction reverses and allows for perfusion of very poorly ventilated lung segments, increasing the proportionate amount of dead space and reducing effective alveolar ventilation, thus allowing arterial CO₂ to rise. Finally, PaCO₂ may increase with supplemental oxygen administration because of a concurrent decrease of the CO₂ carrying capacity of the hemoglobin molecule secondary to the increasing oxygenation. This results in an altered steady-state relationship between carboxyhemoglobin and PaCO₂, which raises the latter by several millimeters of mercury. This is known as the Haldane effect.⁸⁸

COPD patients have an increased neural drive to their respiratory muscles, as measured by surface electromyographic activity of the diaphragm associated with an increased respiratory rate and low VT.⁸⁹ This increased drive seems to be greater in hypercapnic COPD patients than in normocapnic patients, and may be related to mechanical (pulmonary and chest wall) and chemical (hypoxic) afferents. This theory is in contrast to the concept of an inherited decreased ventilatory response to CO₂ in patients who develop CO₂ retention.⁴⁵ This increased respiratory drive is probably needed to overcome both increased airway resistance and mechanically disadvantaged respiratory muscles. The latter is a product of several factors: flattening of the diaphragm (muscle shortening) causes the muscle to operate on a less favorable portion of its length-tension curve. There is also a decreased radius of curvature of the diaphragm, which requires an increased motor input to generate the same transdiaphragmatic pressure. Lastly, hyperinflation of the lungs and chest wall reverses the normally outwardly directed chest wall recoil forces, which assist inspiration. These factors together contribute to a reduction in inspiratory muscle strength that can be measured as a decrease in the PImax.^{83 90} For these reasons, an increased neural drive to breathe is required to maintain the same level of alveolar ventilation in patients with COPD compared with normal subjects.⁸⁹

Obesity-Hypoventilation Syndrome
Obesity-hypoventilation syndrome is another sleep-related disorder affecting the control of ventilation. This is illustrated by the following case history.

Case 7: Obesity-Hypoventilation Syndrome.
A 65-year-old woman was evaluated for bilateral knee replacement surgery. During her preoperative assessment, she was noted to be cyanotic with an SaO₂ of 80% by pulse oximetry. The patient admitted to cough, shortness of breath with exertion, and swollen ankles for several years. She had daytime hypersomnolence but was not noted to be a loud snorer. Her medical history included hypertension and gout, for which she was taking medications. She was a nonsmoker and had no previous history of pulmonary disease. On examination, she was 5 feet, 2 inches tall, and weighed 252 lb. Mental status, chest, cardiovascular system, and abdominal examinations were normal. She had 2+ pitting edema of both lower extremities up to the level of the knees associated with venous stasis dermatitis. Initial laboratory data included a hematocrit of 58%; arterial blood gas assessment showed a pH of 7.36; PCO₂, 55 mm Hg; PaO₂, 45 mm Hg; and HCO₃^-, 34 mEq/L. Spirometry showed mild obstruction with an FEV₁ of 1.3 L (70% of predicted) and an FEV₁/FVC of 0.68. A chest radiograph showed prominent pulmonary arteries bilaterally. An echocardiogram showed a severely dilated right atrium and right ventricle with an estimated pulmonary artery systolic pressure of 80 mm Hg. A diagnosis of obesity-hypoventilation syndrome was made. The patient was treated with nocturnal bilevel continuous positive airway pressure (CPAP) ventilation by nasal mask and dramatically improved over a period of 3 months.

Patients with obesity-hypoventilation (pickwickian) syndrome usually have hypersomnolence, daytime hypoventilation, hypoxemia with the development of pulmonary hypertension, and subsequent right-sided cardiac failure.⁹¹ The daytime hypersomnolence is related to their disturbed sleep.⁹² These patients have marked depression of both their hypercapnic and hypoxic respiratory drives, accompanied by an abnormal and irregular pattern of breathing during sleep that persists during the waking state.⁹³ They have an increased respiratory rate (25%) and a decreased VT (25%) compared with subjects with simple obesity. In contrast to subjects with simple obesity, the inspiratory muscles are weak and ventilatory drive is not increased to meet the extra WOB. Both VC and expiratory reserve volume are reduced.⁹⁴ The cause of their daytime arterial hypercapnia is believed to be increased mechanical impedance to breathing related to severe obesity combined with a decreased central respiratory drive.^{95 96} This daytime hypercapnia differentiates them from OSA patients. Although obesity-hypoventilation syndrome is often associated with OSA or central sleep apnea, this is not always the case; this combination is associated with worse hypoxemia and hypercapnia. The primary treatment involves weight loss combined with improving oxygenation through the use of supplemental nocturnal oxygen and the relief of any concurrent OSA through the use of nocturnal nasal CPAP or tracheostomy.^{97 98} Weight loss is effective by reducing the mechanical impedance to breathing. Nasal CPAP alone or bilevel CPAP ventilation corrects abnormal ventilatory drive and nocturnal hypoventilation with subsequent improvement in daytime blood gases.^{99 100} The enhancement of central respiratory drive by drugs such as medroxyprogesterone is sometimes effective.¹⁰¹

CSR
CSR is a disorder of breathing pattern characterized by a progressive increase in VT followed by a decrease, occurring in a cyclical pattern associated with intervening periods of apnea. It is a form of periodic breathing that may occur in a variety of situations in adults, such as neurologic disease, congestive heart failure, and ascent to altitude.¹⁰² CSR is illustrated by the following case history.

Case 8: CSR in a Patient With Neurologic Disease.</