HYPOVENTILATION SYNDROMES

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HYPOVENTILATION SYNDROMES Samuel Krachman, DO, and Gerard J. Criner, MD

The respiratory control system normally is able to respond to changes in oxygen consumption and carbon dioxide (CO,) production to maintain homeostasis. That is accomplished by changes in minute ventilation (V,) that maintain arterial partial pressure of oxygen (Pao,) and CO, (Paco,) within a narrow range. Alveolar hypoventilation, an elevation in the Paco, to levels greater than 45 mm Hg, can occur with a number of disorders, referred to as the hypoventilation syndromes. Associated with hypercapnia is the development of hypoxemia, which adds to the clinical manifestations and morbidity found with the disorders. In addition, hypoventilation becomes more profound during sleep and can significantly worsen pre-existing hypercapnia and hypoxemia. In some, clinically significant hypercapnia and hypoxemia may develop only during sleep and may be unsuspected based on awake values. Mechanisms responsible for the development of hypoventilation include: (1) a decrease in central respiratory drive, (2) chest wall and lung parenchymal deformities, and (3) respiratory muscle weakness. In many disorders that provoke hypoventilation, more than o m ~ i ~ ' t i r ~ r i s ris1 rresponsible. This article reviews the normal control of breathing, including the changes that occur during sleep. In addition, it discusses the diagnostic work-up of hypoventilation, including the assessment of ventilatory control. Finally, individual hypoventilation syndromes,

including the pathophysiologic mechanisms and their treatment, are reviewed. DEFINITION OF ALVEOLAR HYPOVENTILATION

Only alveoli that are perfused can participate in gas exchange, including CO, elimination. If one disregards nitrogen, 0, and CO, are the predominant gases found within alveoli that diffuse across the interstitium, following a concentration gradient. Although diffusion of CO, is approximately 20 times that of 0,, the continued removal of CO, from the blood depends on adequate ventilation. That relationship is expressed in thd equation: Paco,

=

k Vco, / V,

(1) where Vco, is the metabolic production of CO,, k is a constant, and V, is alveolar ventilation. Pacq therefore decreases as V, increases and CO, is eliminated. Reciprocally, Paco, increases when V, decreases, and is referred to as alveolar hypoventilation. In addition, because the alveolus is a finite space, any increase in alveolar CO, leads to a decrease in O,, thereb-y causing hypoxemia. Alveolar hypoventilation can also occur when there is an increase in wasted ventilation to underperfused alveoli. Such increases in physiologic dead space (VJV,) are seen in disease states with increased ventilationperfusion (V/Q) inequality, such as chronic

From the Division of Pulmonary and Critical Care Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania

CLINICS IN CHEST MEDICINE VOLUME 19 * NUMBER 1 * MARCH 1998

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obstructive pulmonary disease (COPD). The contribution that physiologic dead space makes in alveolar hypoventilation is demonstrated in the following equation: Paco,

=

k V C O ~/

VE

(1 - VD/VT)

(2)

where VE is total expired ventilation, and 1 - VD/VT measures the portion of ventilation directly involved with gas exchange. Any increase in the amount of physiologic dead space without a corresponding increase in total ventilation will lead to an increase in Paco2. A decrease in tidal volume (VT) increases VJV, and leads to alveolar hypoventilation. The majority of the smaller V, is wasted ventilation of anatomic dead space and does not participate in effective alveolar gas exchange.

BRIEF REVIEW OF THE NORMAL CONTROL OF VENTILATION

The respiratory control system has metabolic and behavioral components that maintain homeostasis. The metabolic control system is an "automatic" system that responds to changes in gas exchange and afferent information received from chest wall and lung parenchymal receptors. The behavioral control system consists of higher cerebral centers that impose voluntary changes on respiration while awake and during spontaneous behaviors, such as speech or laughter.

Central Controller

The central controller is located in the medulla and is able to process information from adjacent chemoreceptors and from afferent neurons that terminate within it. It is composed of two aggregates of neurons-the dorsal respiratory group (DRG) and the ventral respiratory group (VRG)!7 Processed information from those two areas leads to a respiratory motor response, with projections from the DRG terminating in the diaphragm and those from the VRG, in the accessory muscles of respiration. There also seems to be input to the central controller from higher centers, including the pons, which tends to smooth out respiration, and the cerebral cortex, through the behavioral control center.

Sensors

Both chemo- and mechanoreceptors sense changes that require a response by the central controller to alter respiration and maintain homeostasis. Central chemoreceptors are located in the ventrolateral area of the medulla and respond to changes in hydrogen [H+] and Pco2in the extracellular fluid of the intracerebra1 interstitiurn.'* Respiratory acidosis, for example, leads to an increase in Pacq, with the C 0 2 freely diffusing across the bloodbrain barrier. That leads to an increase in [H'] and Pcq around the central chemoreceptors and causes a linear increase in V,. Overall, the ventilatory response to changes in Paco2 is the most important in regulating V,. Peripheral chemoreceptors include the carotid bodies, a group of cells located at the bifurcation of the carotid arteries, which sense changes in Pao,. They contain glomus cells, which contain neurotransmitters such as dopamine and serotonin, and sustentacular cells, which may be similar to glial cells in the central nervous system.30Glomus cells respond to hypoxemia and transmit afferent information by way of the carotid sinus nerve, which joins the glossopharyngeal nerve to reach the DRG. The carotid bodies are responsible for the ventilatory response to hypoxemia. They do not demonstrate increased activity until the P a q is less than 60 mm Hg, demonstrating a hyperbolic ventilatory response. They do not play a major role in response to changes in Paco2. Mechanoreceptors, located within the lungs, upper airway, and respiratory muscles, send important sensory information that affects ventilation and maintains homeostasis. The slowly adapting stretch receptors are located within airway smooth muscle and their stimulation helps terminate i n ~ p i r a t i o n . ~ ~ Rapidly adapting stretch receptors (irritant receptors) are located in the airways between epithelial cells and respond to the inhalation of noxious stimuli, leading to cough, bronchospasm, and tachypnea. C fibers are located in the lung parenchyma, blood vessels, and airways, and include the J receptors, the stimulation of which by interstitial edema leads to rapid, shallow breathing and the sensation of dyspnea. Upper airway receptors, when stimulated, cause bronchospasm, coughing, sneezing, and upper airway muscle stimulation. Muscle spindles, present in accessory muscles of respiration, are relatively lacking in the diaphragm.

HYPOVENTILATION SYNDROMES

This complex respiratory control system maintains homeostasis. Disease states that affect one or more of its components can significantly affect the pattern of respiration, in many instances leading to the development of hypoventilation. EFFECT OF SLEEP ON VENTILATION

Normal sleep is generally categorized as nonrapid eye movement (NREM) and rapid eye movement (REM) sleep based on differences in a number of physiologic parameters.%NREM sleep is further subdivided into stages 1 through 4, representing a continuum of sleep, with stages 3 and 4 (also referred to as delta or slow wave sleep [SWS]) being a deeper and more restful sleep, with a higher 37 Although brain activity arousal threshold.32, is great during REM sleep, it is characterized by inhibition of spinal motor neurons, leading to muscle atonia (referred to as tonic REM), with intermittent bursts of REMs and distal muscle twitches (referred to as phasic REM). REM sleep is also considered to be restful sleep, with a variable arousal threshold. The majority of SWS occurs during the first third of the night. The first REM period occurs 70 to 90 minutes into sleep and then cycles every 90 minutes throughout the night. Control of Breathing During Sleep

During the transition from wakefulness to NREM sleep, input from the behavioral control system, a source of nonrespiratory input to the metabolic control system during wakefulness, decreases. During NREM sleep, the hypoxic drive to breathe is decreased and the ventilatory response to Paco2 is dampened.8, Many of the observed changes are sleep-stage specific, with hypoxic and hypercapnic ventilatory responses being the least during REM sleep. Normal sleep onset can be associated with an alteration in the respiratory pattern. Minute ventilation decreases, primarily because a decrease in V, and, as a consequence, Paco2 increases 3 to 10 mm Hg and Pao2 decreases 2 to 8 mm Hg.40 In addition, the apneic threshold for Paco2 increases 1 to 3 mm Hg above the awake level. The breathing pattern can be periodic in stages 1 and 2 of sleep, as one fluctuates between wakefulness and stages 1 and 2. During an arousal, the ele-

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vated Paco2associated with sleep precipitates hyperventilation to drive the Paco2 down to the awake set point, commonly below the sleeping apneic threshold. As sleep is re-entered, an apnea occurs until Paco2 increases again above the sleep-related threshold. In contrast, the breathing pattern appears to be more regular during SWS. During REM, the breathing pattern is very irregular, with periods of hypoventilation noted during phasic REM. ASSESSMENT OF HYPOVENTILATION SYNDROMES Clinical Presentation

The signs and symptoms secondary to the disorder causing hypoventilation are usually nonspecific and of limited value. In the early stages of the disorder, the patient may be totally asymptomatic, but, as the syndrome progresses, dyspnea on exertion, followed by dyspnea at rest, is the most common symptom encountered by patients who suffer from hypoventilation. Disturbed sleep and daytime hypersomnolence resulting from nocturnal hypoventilation may progress and, if a disorder causes respiratory muscle weakness, impaired cough and repeated lower respiratory tract infections may also complicate the patient's course. If hypoventilation becomes more severe, hypercapnia or hypoxemia becomes more evident and respiratory failure may ensue, requiring ventilatory support. The value of the physical examination is both in characterizing the cause of hypoventilation (i.e., chest wall deformity, morbid obesity, severe COPD) and detailing the severity of the complications that result from it (i.e., the presence of cor pulmonale). Moreover, carefuI history taking can allow one to determine the rate of progression of the underlying disorder, such that potential therapies can be undertaken based on full knowledge of the severity of the presentation and its pattern of progression. Arterial Blood Gas Analysis

Hypoxemia is usually mild and may occur as a result of microatelectasis and subsequent intrapulmonary shunting or V / Q imbalance. In addition, patients with neuromuscular disease who have hypoventilation may have im-

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paired cough and retain secretions that further contribute to the development of hypoxemia. Measurement of hemoglobin saturation by pulse oximetry, a commonly used laboratory test for oxygenation, is an insensitive indicator of hypoventilation and should be discouraged. Alhough an elevation of Paco, values during daytime spontaneous breathing is a helpful clue to the presence of hypoventilation, in almost all cases, it is preceded by more severe and earlier derangements in gas exchange during sleep. The presence of daytime hypercapnia should prompt investigation into the breathing pattern and gas exchange during sleep so that appropriate therapy (i.e., nocturnal supplemental 0, or noninvasive ventilation) can be implemented. Bicarbonate and pH values should also be studied to help determine whether an acute or chronic respiratory acidosis is present.

Evaluation of Ventilatory Control

A number of tests have been developed to evaluate the responsiveness of the respiratory control system. They include the use of chemical stimulation, such as with hypercapnia or hypoxia. In addition, mouth occlusion techniques have been used as a measure of central respiratory drive. Hypoxic Challenge To measure the ventilatory response to hypoxia, a subject breathes from a bag initially containing enriched 0,. Nitrogen is added to the bag to produce hypoxia, with CO, added to bag as well to prevent fluctuations in CO, levels from influencing the ventilatory response. The ventilatory response curve for hypoxia normally is hyperbolic, with no significant change in ventilation until the Pao2 decreases to below 60 mm Hg, a level at which V, abruptly increases (Fig. 1)/3 With hypercapnia, the ventilatory response is greater at any given level of Pao2.43A normal response, when expressed as a comparison of V, to oxyhemoglobin saturation (Sao,), is a 1-L increase in ventilation for each 1%decrease in Sao,. The response decreases normally with age41and can become significantly attenuated in persons chronically exposed to hypoxia, such as those living at high altit~de.6~

Hypercapnic Challenge The CO, rebreathing test measures the ventilatory response to increasing concentrations of CO,. During the test, the subject rebreathes from a prefilled bag that contains 7% to 8% CO,. In addition to CO,, the bag also contains excess O,, to prevent hypoxia from influencing the ventilatory response. The ventilatory response to an increasing Paco, is linear, with the slope of the line reflecting CO, sensitivity (Fig. 2).” The normal response is 2 to 5 L/minute/mm Hg Pacop. The presence of hypoxia increases the central controller’s sensitivity to Paco,, with a response greater than would occur with either stimuli al0ne.4~

Mouth Occlusion Pressure In patients with underlying chest wall deformities, neuromuscular disease, or intrinsic lung disease, it becomes more difficult to measure a change in ventilation as a reflection of central respiratory drive. Because of those limitations, the mouth occlusion pressure test was developed to more accurately measure central respiratory drive.68 During the test, while breathing through a mouthpiece, the inspiratory valve is selectively closed, with the subject unaware of the maneuver. The following breath is then performed against an occluded airway. The pressure generated during the first 0.1 second (Po.l) while the subject is still unaware of the occlusion and under semi-isometric conditions, is unaffected by mechanical limitations. Because it represents central drive to the muscles of inspiration and the contractile properties of those muscles, however, its accuracy in measuring central respiratory drive has been debated.

Respiratory Mechanics Measurements of respiratory mechanics in patients who present with hypoventilation may give important clues to the cause and severity of the disease underlying hypoventilation. The tests include measurements of respiratory muscle pressures, spirometry, and lung volumes. Respiratory Muscle Pressures Measurement of maximum static inspiratory and expiratory mouth pressures mea-

HYPOVENTILATION SYNDROMES

.r 40 50

E

143

k

1 .- 30 .-m

-

-c -L

>” 20

-

10 -

0 20

Paco, = 48.7rnrn 48.7 rnrn

. . . . - - .Paco, Pace, . - -= 43.7mrn 35.8 43.7 - - mrn rnrn Paco, = 35.8rnrn

40

60 PAO,

ao

100 120 140 (mrn Hg)

Figure 1. The ventilatory response to hypoxia. Note that the response is hyperbolic, with an increase in ventilation not seen until the Paon is less than 60 mm Hg in the setting of normocapnia. With hypercapnia, the ventilatory response is greater at any given level of Paon. (From Loeschcke HH, Gertz KH: lntracranielle chemorezeptoren rnit wirkung out die atmug. Pflugers Arch 267:469, 1958; with permission.)

sured at the airway opening during a voluntary contraction against an occluded airway is the simplest and most commonly performed test of respiratory muscle strength. In the technique, mouth pressures are measured with a pressure transducer in-line with the patient seated upright with a nose clip on. Maximum inspiratory pressure is measured near residual volume (RV) after maximal expiration, whereas maximum expiratory pressure is measured near total lung capacity (TLC).In each case, efforts are maintained for at least 1second and are repeated three to six times, with the maximum value recorded. The major factor affecting measurement of respiratory muscle pressures is lung volume. Maximum inspiratory pressure is greatest at RV, a lung volume at which the inspiratory muscles are at their greatest mechanical advantage and respiratory system outward elastic recoil is maximal. Conversely, measurement of maximum expiratory pressure is greatest at TLC, a lung volume at which the expiratory muscles are at their greatest mechanical advantage and inward elastic recoil of the respiratory system is greatest. Changes in lung volume because of chest wall or lung pathology have an important effect on generation of maximum respiratory pressures. It therefore is important to realize that, in pa-

tients with pathologically altered lung volumes, all or a significant portion of the respiratory muscle pressures measured may be because of inspiratory and expiratory muscle mechanical disadvantage, rather than skeletal muscle weakness. Measurement of Transdiaphragmatic Pressure

Although measurements of maximum airway pressures are useful measures of global respiratory muscle strength, they fail to assess individual respiratory muscle function. Because the diaphragm is the major muscle of inspiration and may be susceptible to isolated injury in specific conditions (i.e., idiopathic diaphragm paralysis or phrenic nerve injury during open heart surgery), specific testing of diaphragm strength is required in some patients. Diaphragm strength can be assessed by measuring gastric (Pga) and endoesophageal (Pes) pressures with balloon-tipped catheters placed in the stomach and midesophagus, respectively. Transdiaphragmatic pressure (Pdi) is measured as the algebraic subtraction of Pes from Pga (Pdi = Pga Pes). Maneuvers to elicit maximum and reproducible Pdi have been the subject of recent

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- 40 t

.-C

Pao, = 4 7 mm H g

E

2 35

100mmHg

20

15 10

5

-

0

Figure 2. The ventilatory response to hypercapnia. Note the linear response in ventilation with increasing PACO?.The slope of the line reflects the sensitivity or gain of the central respiratory controller. The presence of hypoxia increases the central ventilatory response, more than would occur with either stimuli alone. (From Neilson M, Smith H: Studies on the regulation of respiration in acute hypoxia, with an appendix on respiratory control during prolonged hypoxia. Acta Physiol Scand 24:293, 1951; with permission.)

intense study. Earlier studies that measured Pdi during maximum static inspiratory efforts during a closed airway at functional residual capacity (FRC) or RV suffered from a significant degree of intrasubject variability and submaximal diaphragm activation. A combined maneuver of active expulsion with superimposed Mueller maneuver has been shown to yield the most reproducible maximal Pdi when subjects use a visual oscilloscopic cue of Pes and Pga.42Another recently explored technique is electrophrenic stimulation to measure Pdi during a single unfused twitch contraction (Pdi twitch). The technique has also been used to assess maximal static Pdi indirectly by the twitch occlusion techn i q ~ e In . ~ that method, single twitches are superimposed on progressively stronger volitional Pdi contractions. As voluntary effort and Pdi increase, the increment in Pdi produced during the twitch (i.e., the twitch deflection superimposed on the volitional Pdi) decreases. When no discemible Pdi twitch deflection is seen, it is assumed that the dia-

phragm is maximally activated and volitional Pdi represents maximum Pdi. Although this technique is more objective, its requirements for expertise and equipment, and its relative discomfort, have mainly relegated it to use as a research tool. The measurements of maximum respiratory pressures during more natural acts were studied recently. Maximum Pdi during a forcible sniff has been used as an index of maximum Pdi because of its relative ease of performance and reproducibility. In the technique, the subject performs a vigorous sniff, with the nose acting as a Starling resistor, thereby generating intrathoracic pressures against a semi-occluded airway. This maneuver approaches a more natural act and is more easily mastered by both patients and technicians. Spirometry

Spirometry is an easily performed, reproducible test that helps characterize whether

HYPOVENTILATION SYNDROMES

the hypoventilation a patient suffers is from a restrictive or obstructive ventilatory disorder, and characterizes the severity of the impairment. Respiratory muscle weakness induced by neuromuscular disease or chest wall disorders produces restrictive patterns on spirometric testing, manifested by reductions in vital capacity (VC) that are mirrored by similar reductions in force expiratory volume in 1 second (FEV,). A reduction in VC is commonly out of proportion to the reduction in maximum respiratory muscle forces because of the curvilinear contour of the pressurevolume curve. A decrease in VC greater than 25% on changing from the upright to supine posture has been used as a sign of diaphragmatic weakness and portends a greater likelihood of sleep-related hypoventilation.', l5 FEV, and mid-expiratory flow rates are often greater than predicted in patients with neuromuscular disease (elastic recoil of the respiratory system is enhanced) and less than normally predicted in patients with obstructive ventilatory disorders. Changes in the configuration of the flowvolume curve may also be helpful, either to confirm the presence of an obstructive ventilatory disorder or to diagnose respiratory muscle weakness or a malfunction of the upper airway muscles. Saw-toothing of the inspiratory limb contour is seen in patients with extrapyramidal disorders affecting the upper airway muscles. Similarly, a plateauing of the inspiratory flow wave form may be indicative of extrathoracic airways obstruction. Several features of an abnormal flow-volume loop configuration correlate with neuromuscular disease. They include a reduced peak expiratory flow, a decreased slope of the descending limb of the maximum expiratory flow curve, a drop off of FEV, near residual volume, and a reduction in forced inspiratory flow at 50% of VC.66 Measurement of lung volumes in patients with hypoventilation may either confirm the presence of hyperinflation in patients with obstructive ventilatory disorders or reveal a reduction of lung volumes consistent with patients with restrictive ventilatory patterns caused by neuromuscular disease, kyphoscoliosis, or obesity. A reduced TLC and a normal or reduced FRC are common in patients with neuromuscular disease, whereas RV is elevated. That usually indicates the presence of expiratory muscle weakness. Similar findings are found in patients with morbid obesity and obesity hypoventilation syndrome

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who have a 20% reduction in TLC, 40% reductions in VC, FEV1, and maximal voluntary ventilation, and 40% to 65% reductions in expiratory reserve volume (ERV), leading to a 20% reduction in FRC.61,64

DISORDERS ASSOCIATED WITH ALVEOLAR HYPOVENTILATION Central Alveolar Hypoventilation

In patients with primary alveolar hypoventilation (PAH), hypercapnia and hypoxemia develop in the absence of any underlying chest wall, neuromuscular, or lung parenchymal disease. Although rare, the disorder affects predominantly male patients, occasionally recognized in infancy but more commonly during early adulthood. Despite the presence of hypercapnia and hypoxemia, most patients are free of respiratory complaints, but may complain of excessive daytime sleepiness, disrupted sleep, and morning headaches. On examination, patients show evidence of secondary pulmonary hypertension with cor pulmonale and rightsided heart failure. In some patients, the diagnosis is made only after they present in respiratory failure, such as following general anesthesia for elective surgery. Most patients with PAH have a normal alveolar-arterial O2 gradient and are able to voluntarily hyperventilate and normalize their arterial blood gases. Spirometry shows no evidence of airflow obstruction, and lung volume measurements are normal. At rest, patients with PAH demonstrate similar respiratory rates but decreased V, and V, compared with age-matched contro1s,52and ventilatory responses to hypercapnic or hypoxic challenges that are absent or severely attenuated.51On exercise, patients demonstrate an increase in V, with increasing CO, production, but with an attenuated slope. The defect in PAH appears to be the inability to centrally integrate chemoreceptor signals. When patients with PAH are exposed to fractional inspiratory oxygen level of loo%, they hypoventilate further compared with baseline. That suggests that the peripheral chemoreceptors are functional. It may be that transmitted signals from central and peripheral chemoreceptors are not being processed correctly, possibly at a central intermediate location. An incorrect signal therefore is re-

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layed to the central respiratory controller, leading to an inappropriate response. During sleep, hypoventilation increases, leading to worsening hypoxemia and hyper~apnia.,~,This is most marked during stages 3 and 4 of with an intermediate decrease or no change reported during REM.60 This may be because of the increased input from the behavioral control system noted to be present during wakefulness and REM sleep. The term central alveolar hypoventilation has been used in patients whose PAH is caused by an underlying central neurologic disease. That includes patients with Shy-Drager syndrome, meningitis or encephalitis, multiple sclerosis, and primary brainstem lesions, such as those caused by infarction or malignancy. Obesity Hypoventilation Syndrome

Obesity can be associated with the development of hypoventilation. There are a number of ways to define obesity, including the use of percent ideal body weight, body weight-toheight index (BW/Ht), and body mass index (BMI), which is the quotient BW/Ht2. The upper normal value for BMI is 28 kg/m2, with values greater than 40 kg/m2 consistent with severe obesity. Yet, although obesity is quite common, obesity-related hypoventilation is less prevalent, despite similar BMIs noted in those with and without the condition. As a result, there appear to be factors other than obesity that lead t o the development of hypoventilation. Pulmonary function studies show that patients with obesity hypoventilation syndrome (OHS) have a TLC 20% smaller and M W 40% lower compared with subjects with simple obesity.61,64 In addition, chest wall and lung parenchymal compliances are both substantially lower in OHS. Whereas it is normal in subjects with simple obesity, inspiratory muscle strength is decreased by 40% in patients with OHS. Work of breathing is 250% higher in OHS compared with normal controls, and associated with that is an increase in CO, production. At rest, patients with OHS have a higher respiratory rate but a lower VT compared with eucapnic obese subjects. Although all the aforementioned factors may contribute to the elevated Pace, seen in patients with OHS, a defect in the central respiratory controller appears to be most important in causing the observed hypoventila-

tion. A decreased ventilatory response to CO, rebreathing has been observed.57In addition, there are reports of patients with a normal response to CO, but an attenuated ventilatory response to h y p o ~ i a .Overall, ~~ a decreased central ventilatory responsiveness to appropriate chemical stimuli, associated with the mechanical changes that occur with obesity, leads to the development of OHS. During sleep, patients with OHS have a tendency to develop obstructive apneas that worsen pre-existing hypoxemia and hypercapnia.@ On the other hand, most patients with obstructive sleep apnea (OSA) do not have daytime hypercapnia. The combination of the two disorders, commonly referred to as the Pickwickian syndrome, helps explain the daytime hypersomnolence experienced by patients with OHS, and the morning headaches in patients with OSA. Full-night polysomnogram studies should be performed on all patients with OHS to quantitate the severity of nocturnal 0, desaturation and to rule out associated sleep-disordered breathing (i.e., OSA). Chest Wall Deformities

Patients with chest wall deformities, such as kyphoscoliosis, fibrothorax, and thoracoplasty, often develop respiratory insufficiency or failure. That often occurs in conjunction with the development of hypoventilation. Of those disorders, kyphoscoliosis is one chest wall deformity most frequently associated with respiratory complications. Such patients have the lowest lung volumes, with a decrease in VC and ERV, whereas RV is reduced only modestly. Decreases in lung volume are primarily a result of a decrease in chest wall compliance associated with the deformity. Patients are usually asymptomatic until the Cobb angle (used to measure spinal curvature) increases greater than 120", at which point dyspnea with exertion is seen and the patient becomes at risk for the development of respiratory failure. Hypoventilation occurs because of a decrease in V , the result of a decrease in chest wall compliance. As a consequence of the lower Vb V,/V, increases despite the lack of any real change in alveolar dead space.39That raises Paco, and accounts for most of the hypoxemia that develops; V/Q inequality and diffusion abnormalities contribute only minimally to the resultant hypoxemia.

HYPOVENTILATION SYNDROMES

The pulmonary circulation is also affected in patients with chest wall deformities, both structurally and functionally. In patients with kyphoscoliosis, pulmonary vascular resistance (PVR) increases because of compression of the pulmonary vasculature and medial hypertrophy of the pulmonary vessels. The latter is thought to result from deflated lung compressing the pulmonary vascular bed and increased blood flow through the vessels. In addition, the hypoxemia that develops leads to a functional vasoconstriction that also raises PVR. During sleep, patients with kyphoscoliosis hypoventilate, with significant decreases in Sao, and increases in end-tidal C0,.19,33, 45, 59 This appears to be worse during REM sleep, when the accessory muscles of respiration are less active. The severity of the decrease in Sao, during sleep appears to correlate with awake value of Sao,; the lower the awake resting Sao2,the greater the decrease in Sao, during sleep. Although some earlier studiesI9,33 reported obstructive apneas during the night in such patients, a more recent report, involving a larger number of patients,59 showed the events to be rare. More commonly, such patients predominantly hypoventilate, with occasional central apneas being noted, mostly during REM sleep.59

Central Sleep Apnea Syndromes.

With sleep onset, ventilatory control is no longer influenced by the behavioral control system. In addition, the stimulatory effect of wakefulness on ventilation is also no longer present. In patients with alveolar hypoventilation, defects are often present in the central respiratory controller, causing hypercapnia while awake. With sleep onset and the loss of the awake neural drive, the manifestations of the defective metabolic control system become even more pronounced. That includes worsening hypoventilation and hypercapnia, and the development of central hypopneas and apneas. Central sleep apnea (CSA) can also occur in the setting of a normal or slightly low awake Paco,. This can occur normally as one fluctuates between wakefulness and stages 1 and 2 at sleep onset, until sleep is finally maintained. CSA and periodic breathing can also occur at high altitude, with hyperventilation secondary to the hypoxia driving the

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Paco, down to levels well below the sleeprelated apneic threshold. In addition, CSA with a normal or low awake Paco2 can be seen in patients with an increased central controller gain; in other words, an increased sensitivity to changes in Paco,. This can occur in the setting of medical disorders such as congestive heart failure (CHF) and stroke, or as an idiopathic form, with no associated underlying disorder.

Idiopathic Central Sleep Apnea

The clinical presentation of patients with idiopathic central sleep apnea (ICSA) is much different from those with OSA. Although there is a similar male predominance, patients with ICSA are generally of a normal body habitus. In addition, patients may complain less of daytime sleepiness and more of insomnia, with frequent awakenings during the night.I0 Depression also seems to be a common finding in such patients. Although predominantly central in nature, obstructive events are also commonly seen, with a history of snoring frequently being present. It recently was demonstrated that patients with ICSA have a lower awake Paco, and nocturnal transcutaneous Pco, compared with a normal control group.69In addition, the ventilatory response to CO, while awake was significantly greater in the patients with ICSA. That seems to indicate that patients with ICSA chronically hyperventilate, both while awake and asleep, secondary to an increased central ventilatory drive. The onset of periodic breathing in the majority of patients appears to be triggered by one or more large breaths, associated with an arousa170(Fig. 3). It therefore appears that patients chronically hyperventilate, with their Paco, closer to both the awake and sleep apneic threshold compared with normal controls. An increase in VT associated with a transient arousal decreases the Paco, to below the sleeping apneic threshold, causing a central apnea (see Fig. 3). An increased central controller gain leads to exaggerated ventilatory responses after the termination of the apnea and propagates the periodic breathing. Hypoxemia probably does not play a major role because oxyhemoglobin desaturation associated with the events is minimal.

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Figure 3. Polysomnogram recording in a patient with idiopathic central sleep apnea. An arousal (arrow) is associated with an abrupt increased tidal volume (V,) in the subsequent breaths. This increase in ventilation decreases the Paco2 and triggers a central apnea. (From Xie A, Wong B,Phillipson EA, et al: Interaction of hyperventilation and arousal in the pathogenesis of idiopathic central sleep apnea. Am J Respir Crit Care Med 150:489, 1994; with permission.)

Cheyne-Stokes Respiration

Cheyne-Stokes respiration (CSR) is a form of sleep-disordered breathing characterized by a crescendo-decrescendo alteration in V,, separated by periods of apnea or hypopnea. In patients with neurologic disease, CSR is seen when higher cortical injury has occurred, possibly reflecting loss of input from the behavioral control system. In CHF, CSR is seen in approximately 40% of patients with an ejection fraction of less than 40%. Sleep is often disrupted, with frequent nocturnal arousals. Clinically, patients present with complaints of excessive daytime sleepiness, paroxysmal nocturnal dyspnea, insomnia, and snoring. Proposed mechanisms include an increased central controller gain, similar to that noted in patients with ICSA. The increased central sensitivity to CO, might be one of the mechanisms involved in the development of the baseline hypocapnia noted in patients with CSR.48 Another proposed mechanism involves underdampening. Because of differences in binding affinity, a large amount of CO, but a small amount of 0, is stored in the body. A larger store of gas acts as a better buffer to maintain arterial blood gas tension when there is a change in ventilation. The ratio of the volume of stored gas in the body to change in gas tension in the blood is known as the dampening ratio. In patients with pulmonary vascular congestion and a reduced

FRC, the CO, and 0, stores are decreased. As a result, the respiratory system becomes much more unstable (underdampened), exaggerating the changes in Paco, and Pao, during transient changes in ventilation. A circulatory time delay between the alveolar capillary membranes of the lungs and the peripheral chemoreceptors has been proposed as a mechanism leading to CSR. It recently was shown, however, that the circulation time correlates with the CSR cycle length rather than with the presence or absence of periodic breathi11g.4~ Whatever the mechanism(s) causing CSR in patients with CHF, the mortality rate appears to be increased in those patients compared with control subjects with a similar degree of left ventricular dy~function.~~ Neuromuscular Disorders

Patients with neuromuscular disease have an abnormal breathing pattern manifested by a low V, and high respiratory rate that persists even in response to hypoxic or hypercapnic challenges.2, The rapid and shallow breathing pattern appears to be caused by severe muscle weakness or disordered afferent and efferent output in motor neurons that are impaired by the underlying neuromuscular d i ~ e a s e . ~ It was previously hypothesized that decreased ventilatory response to hypoxic or hypercapnic challenges in patients with neu-

HYPOVENTILATION SYNDROMES

romuscular disease was responsible for hypoventilation, but ventilation is not a good index of respiratory motor activity in patients with significant respiratory muscle weakness. Recently it has been demonstrated that measured mouth occlusion pressure (Po.,), is maintained or increased in patients with neuromuscular disease, despite substantial muscle weakness. Those studies indicate that central respiratory drive is usually well preserved in patients with neuromuscular disease. Hypoventilation is more likely to be caused by respiratory muscle weakness in patients with neuromuscular disease. The pattern, prognosis, and degree of respiratory impairment attributable to a specific neuromuscular disease are varied and depend on the level of neuromuscular system impairment and the prognosis of the underlying disease. Despite profound respiratory muscle weakness, a significant number of patients with severe neuromuscular disease do not complain of dyspnea or other respiratory complaint^.'^, 65 Explanations for the lack of pulmonary symptoms despite the presence of significant respiratory muscle weakness are not clear, but patients with chronic and severe neuromuscular diseases often are sedentary and do not usually stress their respiratory status, which may explain their lack of symptoms. The characteristic hallmark of neuromuscular disease is decreased VC, as a consequence of respiratory muscle weakness. The decrease in VC parallels the progression of the underlying disease. The magnitude of reduction in VC is greater than expected, however, based solely on the reduction in respiratory muscle strength. This has led some investigators to believe that the decreased VC in patients with neuromuscular disease is caused both by respiratory muscle weakness and decreased lung and chest wall compliance. That appears to be supported by the data of DeTroyer and colleag~es,'~who found, on average, a 45% decrease in lung compliance in 25 patients with moderate to severe neuromuscular disease. Moreover, others have shown that chest wall compliance is decreased by approximately 30% in patients with chronic neuromuscular diseases.2o,n The mechanisms for the decrease in lung and chest wall compliance in patients with chronic neuromuscular diseases are unknown, but several hypotheses have been put forth, such as the development of micro- and macroatelectasis, a reduction in lung tissue elasticity, or a decrease in visco-

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elasticity of chest wall structures because of chronic limitations in respiratory excursions. Regardless of the mechanism(s), however, it appears that patients with chronic neuromuscular diseases have moderate reductions in VC and TLC associated with decreases in FRC and a normal RV. Characteristic changes in respiratory mechanics in patients with neuromuscular disease include: Central drive Rapid, shallow breathing pattern Decreased ventilatory responses to chemical challenges Normal or increased Po., upon chemical challenge Lung volumes Decreased VC Decreased expiratory reserve volume RV maintained Patients with neuromuscular disease have significant and numerous episodes of nocturnal desaturation that are most prevalent during REM sleep and are characterized by hypoventilation rather than episodes of upper airway obstruction. It appears that the degree of oxygen desaturation correlates with the severity of underlying diaphragm dysfunction.ll Several hypotheses have been put forth to explain nocturnal desaturation in patients with neuromuscular disease. Such patients develop a rapid and shallow breathing pattern that leads to dead-space ventilation, which promotes hypercapnia and worsened oxygenation. With sleep, reductions in ventilatory drive, especially in those with pre-existing abnormalities of ventilatory control, may further contribute to worsened nocturnal hypoventilation. Furthermore, patients with neuromuscular diseases characterized by diaphragm dysfunction may be more prone to nocturnal desaturation during REM sleep. During REM sleep with depression of intercostal and accessory muscle activity, the diaphragm must make a greater contribution to maintain ventilation. Support for that hypothesis comes from studies that have found diaphragm dysfunction to be highly correlated with the presence and magnitude of O2desaturation that occurs during REM sleep." Abnormalities in nocturnal gas exchange are usually early indicators of problems in daytime gas exchange. Patients with the most impaired gas exchange during REM sleep have the greatest degree of daytime hypercapnia. In contrast, patients with normal noc-

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turnal gas exchange are unlikely to have any daytime abnormalities such as hypoxemia or hypercapnia. Chronic Obstructive Pulmonary Disease Hypoventilation manifesting itself as CO, retention has been variably demonstrated in patients with severe airflow obstruction. It is usually not observed unless the FEV, is less than 1 L or 35% of predicted. Even with substantial decreases in FEV,, many patients remain normocapnic. Why CO, retention develops in some COPD patients and not others, despite comparable degrees of airflow obstruction, is unknown, but several factors have been proposed. One factor may be that an individual patient's intrinsic hypoxic responsiveness is important in determining whether patients hypoventilate in response to similar degrees of airflow obstruction. Depressed chemical responsiveness occurs in hypercapnic COPD patients, attributed to longstanding h y p o ~ i or a ~elevations ~ in serum b i ~ a r b o n a t e Moreover, .~~ investigators have shown that hypoxic and hypercapnic responses may be abnormal in blood relatives of patients who retain C0,.22,% Besides chemical responsiveness, an alteration in breathing pattern may be essential to the development of hypercapnia in severe COPD. Hypercapnic COPD patients breathe more rapidly and shallowly, a . pattern that contributes to increased dead-space ventilation and CO, retention. A more rapid and shallow breathing pattern is thought to be a compensatory mechanism that reduces inspiratory time, thereby decreasing the work of breathing and defending against the development of inspiratory muscle fatigue in individuals who are severely obstructed and hyperinflated. Evidence that patients with severe COPD develop electromyographic evidence of diaphragm fatigue when asked to voluntarily prolong inspiratory time or increase V, appears to support that supposition.6 Whether inspiratory muscle fatigue develops is determined by the duration of inspiratory muscle contraction and by pressure generated with each breath as a percentage of the maximum pressure that the muscle can generate.55Hyperinflation has been shown to be more severe in hypercapnic patients, and impairs inspiratory muscle function by requiring that greater pressure be developed

with each breath and simultaneously decreasing the maximum pressure that the inspiratory muscles can generate. Indeed, the reduction in inspiratory muscle strength in COPD patients has been found to correlate with the development of hypercapnia, such that once maximum inspiratory pressure falls to less than 50% of predicted, PCO, rises in a linear fashion.55Furthermore, a ratio of lung resistance to maximum inspiratory pressure recently was described as a predictor of hypercapnia in COPD patient^.^ Finally, a significant correlation has been demonstrated between measured intrinsic positive end-expiratory pressure (PEEP) and arterial Pco, in patients with severe COPD.% This suggests that intrinsic PEEP and its inherent inspiratory threshold loading effect further impair already burdened respiratory muscles, thereby fostering hypercapnia by precipitating inspiratory muscle fatigue or provoking a change to a more rapid and shallow breathing pattern that avoids fatigue. It appears that the need to maintain effective gas exchange is counterbalanced in severe COPD patients by breathing strategies adopted to minimize inspiratory muscle effort. Those effects result in the complex development of CO, retention in patients with severe COPD. During sleep, patients with COPD may demonstrate worsening gas exchange, with significant hypoxemia developing, especially during REM sleep. Nocturnal 0, desaturation (NOD) during REM can occur in patients with an awake Pao, greater than 60 mm Hg, with a reported incidence of 27?'oZ7 (Fig. 4). Hypoventilation appears to be the main mechanism responsible for the development of NOD. Pulmonary artery pressures are significantly higher in patients with NOD.25In addition, such patients have a reported higher mortality rate compared with those who do not de~aturate.,~ TREATMENT OF ALVEOLAR HYPOVENTILATION Oxygen The hypoxemia that develops in patients with alveolar hypoventilation most commonly is associated with hypercapnia. The administration of supplemental O2 therefore will not necessarily correct the underlying cause of the hypoxemia, but may prevent

HYPOVENTILATION SYNDROMES

151

Wake REM Stage 1 Stage 2 Stage 3 Stage 4

100 02

SAT

80 Figure 4. REM-associated nocturnal oxygen desaturation (NOD) in a COPD patient with an awake Paoz greater than 60 mm Hg. Note that before the final REM episodes, supplemental oxygen was added, preventing any further episodes of NOD during REM.

sis and thereby increases ventilation. In pasome of its sequelae. In patients with COPD tients with idiopathic CSA, acetazolamide has and hypoxemia, continuous low-flow O2 has been shown to significantly affect m~rtality.~" been shown to decrease both the central apnea index and the arousal index. This was Yet the use of nocturnal O2in COPD patients noted with initial use, with a further decrease with REM-associated NOD has been shown noted at 1 month.l3 Theophylline has also to decrease pulmonary hypertension but have been used for the treatment of CSR. Proposed no significant effect on mortalityz6In patients mechanisms include improvement in cardiac with CSR secondary to CHF, O2 therapy has function and therefore circulation time, and a been shown to significantly decrease the apcentral effect on hypoxic drive.58Theophylnea-hypopnea index, the arousal index, and the degree of oxyhemoglobin de~aturation.~~line is also known to compete for adenosine, a known central respiratory depressant. It reIn other disorders, such as neuromuscular cently was shown to decrease the apneadisease or chest wall deformities, 0, adminishypopnea index and severity of oxyhemoglotration may worsen existing hypercapnia and bin desaturation without a change in left other treatment modalities may be more benventricular function, suggesting a more ceneficial. tral Respiratory Stimulants

Respiratory stimulants have been used with limited success in patients with alveolar hypoventilation. Medroxyprogesterone has been shown to be effective in patients with obesity-related hypoventilation, mainly by increasing central respiratory drive.63In patients with COPD, medroxyprogesterone decreases Paco2 and increases Pao,, both while awake and during sleep.62This appears to be secondary to an increase in V, and, therefore, V,. Almitrine bismesylate works peripherally on the carotid bodies, enhancing their ventilatory response to hypoxemia. In patients with COPD, it has been shown to improve gas exchange, during wakefulness and sleep.31 Unfortunately, almitrine can cause pulmonary hypertension by enhancing the pulmonary vasoconstriction response to hypoxemia. Acetazolamide produces a metabolic acido-

Assisted Ventilation

In patients with severe hypoventilation, mechanical ventilation may be indicated to augment spontaneous breathing. Indications for mechanical ventilation are: Symptoms of nocturnal hypoventilation (e.g., morning headaches, decreased energy, nightmares, enuresis) Dyspnea at rest or increased work of breathing with sleep Hypoventilation that induces cor pulmonale (Pco, > 45 mm Hg; pH < 7.32 after treating reversible causes) Nocturnal hypoventilation (S,O, < 88%) despite supplemental O2therapy Comparison of invasive versus noninvasive forms of mechanical ventilation to treat hypoventilation are shown in Table 1. The advan-

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Table 1. INVASIVE VERSUS NONINVASIVE VENTILATION IN HYPOVENTILATION lnvasive Ventilation (Tracheostomy 81 PositivePressure Ventilation) Increased secretions Uncontrolled upper airway Impaired cognition Failed noninvasive ventilation

Noninvasive Ventilation Minimal secretions Upper airway intact Awake, alert

tages and disadvantages of different forms of ventilation are shown in Table 2. Noninvasive Mechanical Ventilation

In most patients with chronic hypoventilation, the onset of progressive respiratory failure is insidious. In most circumstances, noninvasive forms of ventilatory support should be considered first. Negative-Pressure Ventilation. Negativepressure ventilators were the first forms of noninvasive ventilation used during the polio epidemics in the 1930s to 1950s. Negativepressure ventilators function by intermittently applying subatmospheric pressure around the thorax and abdomen, thereby increasing transpulmonary pressure and inflating the lung. The efficacy of negative-pressure ventilation is determined by the magnitude of negative pressure applied, thoracic and abdominal compliances, and the surface area over which the negative pressure is applied. Tank ventilators are the most efficient form of negative-pressure ventilators; cuirass and pulmowrap ventilators surround smaller thoracic and abdominal surface areas and are therefore less efficient. Tank ventilators, although reliable, are large, cumbersome, im-

mobile, and can induce claustrophobia. Chest cuirasses and pulmowrap ventilators, although less efficient, are more portable than tank ventilators. All forms of negative-pressure ventilation can induce upper airway obstruction, which is a potential limitation in patients with decreased upper airway tone. Noninvasive Positive-Pressure Ventilation. Noninvasive positive-airway pressure applied to the nose or mouth by a variety of nasal and facial masks and lip seals recently has been shown to be beneficial in treating the symptoms of hypoventilation. Improvements in gas exchange (daytime and nocturnal), sleep quality, and quality of life, have been described, simultaneously avoiding upper airways obstruction. Because noninvasive positive-pressure ventilation appears to be better tolerated than negative pressure ventilation, its equipment simpler, its trigger is patient initiated, and ventilation leak is compensated, it is now the preferred modality for noninvasive ventilation. lnvasive Mechanical Ventilation The use of positive-pressure ventilation by way of tracheostomy to treat chronic hypoventilation has also been reported as a successful modality. In patients with chronic, stable neuromuscular disease or chest wall disorders, the use of chronic nocturnal positive-pressure ventilation has been shown to restore effective nocturnal and daytime gas exchange, reverse pulmonary hypertension, and restore functional well-being. The indications, advantages, and disadvantages of invasive ventilation over noninvasive forms are shown in Table 2. Although more costly, morbid, and complex to apply, in patients with significant secretions, loss of upper airway

Table 2. ADVANTAGES AND DISADVANTAGES OF VENTILATION AND TECHNIQUES USED TO TREAT HYPOVENTILATION Technique Negative pressure ventilation Tank Cuirass Pulmowrap Noninvasive positive pressure lnvasive ventilation Tracheostomy and positivepressure ventilation Glossopharyngeal breathing Diaphragm pacing

Advantages

Disadvantages

Dependable, familiar, no airway intubation, simplicity, can significantly augment ventilation

Cumbersome, can cause upper airway obstruction, bulky, constraints on nursing care

Avoids upper airway obstruction, leak compensated, patient triggered Reliable ventilation, can suction secretions, controls upper airway

Mask, mouth leaks, aerophagia, skin breakdown Tracheostomy, expensive, increased respiratory infections, limitations on speech and swallowing Learning curve, limited ventilation Expensive, upper airway obstruction, surgery, possible diaphragm fatigue

Decreases ventilatory dependency Decreases ventilatory dependency

HYPOVENTILATION SYNDROMES

muscle tone, or upper airways obstruction, intermittent ventilation by way of tracheostomy remains a valuable treatment option. Other Therapy

In selected patients with hypoventilation, glossopharyngeal breathing and diaphragmatic pacing may also be important aids to augment ventilation. Intermittent glossopharyngeal breathing, using oral or pharyngeal muscles, has been shown to augment ventilation. Short periods of spontaneous ventilation are possible once patients have mastered the technique. During glossopharyngeal breathing, the patient gulps in air by intermittently contracting the tongue against the palate in a piston-like fashion, thereby, injecting air into the trachea. After sufficient practice, the patient is able to gulp approximately 50 to 150 mL of air every halfsecond. With repeated gulping of air in series, patients may finally achieve V, of approximately 500 to 600 mL. Although this technique is somewhat difficult, some patients have successfully used it to maintain short periods of time off mechanical ventilation. In selected patients, diaphragmatic pacing may also be an important treatment option for severe hypoventilation. Although external stimulation of the phrenic nerve has been well documented since the late 1940s, longterm phrenic nerve stimulation did not become a reality until the development of implantable electrodes and receivers in the late 1960s. Diaphragmatic pacing requires a radiofrequency transmitter and an antenna to discharge stimulatory signals to a receiver, which, when activated by radio-frequency waves, transmits electrical impulses to an electrode over the phrenic nerve. Diaphragmatic pacing has several potential limitations, including its high cost (approximately $20,000), the potential to fail abruptly, the development of upper airway obstruction, and the potential for the induction of diaphragm fatigue. Moreover, the technique requires surgery to implant the electrodes and receiver. On the other hand, successful implantation allows patients to be free from mechanical ventilation for prolonged periods and to speak more freely. The main group of patients that appears to benefit from diaphragmatic pacing are those with central alveolar hypoventilation or those with high cervical spinal cord injury. It is thought that approximately one third of patients with high

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cervical cord injuries may be suitable for this type of treatment.29 Intermittent positive-pressure breathing and respiratory muscle training have also been used in select patient groups with hypoventilation. Despite initial enthusiasm for its use, there is no substantial evidence that intermittent positive-pressure breathing has a beneficial effect on respiratory system compliance or lung volumes in patients with chronic hypoventilation. Inspiratory muscle training may be helpful in some patients who exhibit hypoventilation because of respiratory muscle weakness. By strengthening weakened respiratory muscles, cough may be enhanced, secretion clearance improved, and ventilatory capacity increased, so as to avert the development of respiratory tract infections and respiratory failure. Respiratory muscle training has been shown to increase strength and ventilatory endurance in both normal subjects and in COPD patients. Uncontrolled studies performed in patients with muscular dystrophy have also shown that inspiratory muscle training may improve respiratory muscle endurance and strength.16 Although the aforementioned studies have shown a beneficial physiologic effect of respiratory muscle training, none has correlated the physiologic improvements with improved clinical outcome. SUMMARY

In summary, alveolar hypoventilation can be associated with a diverse group of disorders, collectively referred to as the hypoventilation syndromes. Most have associated hypercapnia and hypoxemia while awake, with a significant worsening in gas exchange during sleep. In some disorders, gas exchange abnormalities are manifested only during periods of sleep. Signs and symptoms suggestive of the underlying disorder leads one to investigate for associated hypoventilation. Proper diagnosis allows the implementation of appropriate therapy, which may both improve gas exchange and associated symptoms, and impact overall survival. References 1. Allen SM, Hunt B, Green M Fall in vital capacity with posture. British Journal of Diseases of the Chest 79:267, 1985

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2. Baydur A: Respiratory muscle strength and control of ventilation in patients with neuromuscular disease. Chest 99:330, 1991 3. Begin R, Grassino A: Inspiratory muscle dysfunction and chronic hypercapnia in chronic obstructive pulmonary disease. American Review of Respiratory Disease 143:905, 1991 4. Begin R, Bureau MA, Lupien L, et a1 Control and modulation of respiration in Steinert’s myotonic dystrophy. American Review of Respiratory Disease 121:281, 1980 5. Bellemare F, Bigland-Ritchie B Assessment of human diaphragm strength and activation using phrenic nerve stimulation. Respir Physiol 58:263, 1984 6. Bellemare F, Grassino A: Force reserve of the diaphragm in patients with chronic obstructive pulmonary disease. J Appl Physiol55:8, 1983 7. Bergofsky EH, Turino GM, Fishman AP: Cardiorespiratory failure in kyphoscoliosis. Medicine (Baltimore) 38:263, 1959 8. Berthon-Jones M, Sullivan CE: Ventilatory and arousal responses to hypoxia in sleeping humans. American Review of Respiratory Disease 125:632, 1982 9. Berthon-Jones M, Sullivan CE: Ventilation and arousal responses to hypercapnia in normal sleeping humans. J Appl Physiol57(1):59, 1984 10. Bradley TD, Phillipson EA: Central sleep apnea. Clin Chest Med 13:493, 1992 11. Bye PTF‘, Ellis ER, Issa FG, et al: Respiratory failure and sleep in neuromuscular disease. Thorax 45:241, 1990 12. Davis J, Goldman M, Loh L, et al: Diaphragm function and alveolar hypoventilation. QJM177k37, 1976 13. Debacker WA, Verbraecken J, Willemen M, et al: Central apnea index decreases after prolonged treatment with acetazolamide. Am J Resp Crit Care Med 151:87, 1995 14. Demedts M, Beckers J, Rochette F, et al: Pulmonary function in moderate neuromuscular disease without respiratory complaints. European Journal of Respiratory Disease 63:62, 1982 15. DeTroyer A: Lung volume restriction in patients with respiratory muscle weakness. Thorax 35:603, 1980 16. Dih4arco AF, Kellig JS, M a r c 0 MS, et al: The effects of inspiratory muscle training on respiratory muscle function in patients with muscular dystrophy. Muscle Nerve 8:284,1985 17. Dolly FR, Block AJ: Medroxyprogesterone acetate and COPD Effects on breathing and oxygenation in sleeping and awake patients. Chest 84394,1983 18. Eldridge FL, Kiley JF’, Millhorn DE: Respiratory responses to medullary hydrogen ion changes in cat: Different effects of respiratory and metabolic acidoses. J Physiol 358:286, 1985 19. Ellis ER, Grunstein RR, Chan S, et a 1 Noninvasive ventilatory support during sleep improves respiratory failure in kyphoscoliosis. Chest 94811, 1988 20. Estenne M, Detroyer A The effects of tetraplegia on chest wall statics. American Review of Respiratory Disease 134121,1986 21. Estenne M, Heilpom A, Delhez L, et al: Chest wall stiffness in patients with chronic respiratory muscle weakness. American Review of Respiratory Disease 128:1002, 1983 22. Fleetham JA, Amup ME, Anthonisen N R Familial aspects of ventilatory control in patients with chronic obstructive pulmonary disease. American Review of Respiratory Disease 1293,1984

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