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Annu. Rev. Med. 1976.27:465-484. Downloaded from www.annualreviews.org by WIB6242 - Universitaets- und Landesbibliothek Duesseldorf on 12/28/13. For personal use only.

Copyright 1976. All rights reserved

THE SLEEP APNEA

.:-7215

SYNDROMESl Christian Guillem inauIt, MD., Ara Tilkian, MD. and William C. Dement, M.D., Ph.D. Sleep Disorders Clinic, Stanford University School of Medicine, Stanford, California 94305

Department of Cardiology, Stanford University School of Medicine, Stanford, California 94305 Sleep Disorders Clinic, Stanford University School of Medicine, Stanford, California 94305

INTRODUCTION For many years pneumologists have conducted extensive studies of alveolar hypo­ ventilation syndromes whose hallmarks are a combination of hypercapnia and alveolar hypoxemia. Nonspecific alveolar hypoventilation can occur secondary to damaged respiratory centers in the brain,as seen in bulbar poliomyelitis (1), brain stem infarct (2, 3), bilateral cervical cordotomy (4), or the uncommon "primary" alveolar hypoventilation syndrome (Ondine's Curse syndrome), first reported by Severinghaus & Mitchell (5). A nonspecific alveolar hypoventilation can also be seen with drug intoxication (barbiturates and tranquilizers) (6) and with abnormalities of breathing apparatus, as in muscular dystrophy, kyphoscoliosis, Pierre Robin syndrome, obstructive lung disease, etc (7-10). During the 1950s another alveolar hypoventilation syndrome received much attention from respiratory specialists. This was the Pickwickian syndrome, a term coined by Sir William Osler (11) and classically described by Burwell et al (12). In its classic form the Pickwickian syndrome includes obesity,hypersomnolence,peri­ odic breathing with hypoventilation,and cor pulmonale. Several variants have also been described, depending chiefly on the presence or absence of cardiovascular problems and alveolar hypoventilation during wakefulness. For example, Alexander IThis research was supported by National Institute of Child Health and Human Develop­ ment Grant No. HD 08339, National Institute of Mental Health Grant No. MH 5804 to Dr. Dement, and bibliographic services of UCLA Brain Information Service. 465

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and his colleagues (13, 14) reported a "Joe" type of Pickwickian syndrome charac­ terized only by obesity and hypersomnolence. However, in contrast to the alveolar hypoventilation syndromes mentioned above, it was difficult to specify a common underlying physiopathology that would account for all the clinical symptoms and associations seen in the various "Pickwickian" syndromes. In 1965, Gastaut and his colleagues began to approach the Pickwickian syndrome with a different interest-sleep-and in so doing, they recorded multiple respiratory pauses during sleep (later to be called sleep-induced apnea) in Pickwickian patients (15). Their report inaugurated a new dimension in understanding the complex problems of the Pickwickian syndromes. Clinical sleep specialists began to investi­ gate respiratory changes as a function of sleep. This led to a greater emphasis on the daytime hypersomnolence, and patients began to be seen for sleep disorders rather than cardiorespiratory problems. This difference in patient recruitment gave new data, not previously available to pneumologists, on important interactions between respiration and sleep. Hallmark observations on sleep-induced respiratory dysrhythmias in nonobese patients were made by Duron et al (16), Lugaresi et al (17), and Kuhlo et al (18). At the suggestion of a respiratory specialist (P. Sadou!) and a neurologist-sleep researcher (E. Lugaresi), the first symposium on sleep-related respiratory problems that included specialists from both areas was held in Italy in 1972 (19). As a result of this intellectual confrontation, a new concept of "sleep-induced apnea syn­ dromes" with secondary cardiovascular consequences has rapidly evolved. In spite of crippling hypersomnolence or hemodynamic problems, the primary respiratory abnormality is typically completely undetectable when patients are fully alert, and obesity is not at all a necessary feature. This group of closely related syndromes has implications for neurologists, cardiologists, otolaryngologists, pneumologists, pedia­ tricians, and, particularly, physicians with a special interest in sleep disorders. Because many reports involving these syndromes have been published in the Eu­ ropean and Japanese literature, the primary goal of this review is to facilitate a greater familiarity with sleep apnea syndromes among American physicians. It is obvious that medical centers lacking a mechanism to ensure adequate labora­ tory evaluation of the sleep patient who presents a serious sleep disorder will not identify or diagnose a sleep apnea syndrome, since a reliable diagnosis is heavily dependent upon standard sleep recordings (20) combined with respiratory measure­ ments. Such a mechanism has been available at Stanford University for more than five years in the form of a sleep disorders clinic to which such patients can be referred for specialty evaluation. As a result, a uniquely large case series of sleep apnea patients has been evaluated, and a large reservoir of clinical experience with such patients has been accumulated. Because of this, and because most published reports have focused on limited areas of the problem, much of this review is based upon the Stanford University Sleep Disorders Clinic case series, particularly the clinical symptomatology, and unless otherwise specified, the reader may assume that this series is the source of specific descriptive material. Various subsamples of this case series have been described elsewhere (21-24).

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TERMINOLOGY AND DEFINITIONS An apnea has been defined as a cessation of airflow at the nose and mouth lasting at least 10 sec (21); shorter respiratory pauses are discounted. A sleep apnea syn­ drome is diagnosed if, during seven hours of nocturnal sleep, at least 30 apneic episodes are observed both in rapid eye movement (REM) and non-rapid eye movement (NREM) sleep, some of which must appear in a repetitive sequence in NREM sleep. Apneic episodes at sleep onset or accompanying bursts of rapid eye movements in REM periods (25) are not considered pathologic. The foregoing criteria are based on more than 150 all-night polygraphic recordings in a control population of normal adult and child volunteers. Diagnosis is rarely a problem, however, since most patients have hundreds of repetitive apneas in a single night. Gastaut et al (26) have distinguished three types of sleep apnea with strain gauge and thermistor recording techniques. Central apnea is defined by cessation of air­ flow past nasal and buccal thermistors, accompanied by cessation of respiratory movements measured from abdominal and thoracic strain gauges. In upper airway apnea, airflow past nasal and buccal thermistors is absent in spite of persistent respiratory effort recorded by thoracic and abdominal strain gauges. Mixed apnea is defined by cessation of airflow and an absence of respiratory effort early in the episode, followed by resumption of unsuccessful respiratory effort in the latter part of the episode. Duron (27) has raised the possibility that mixed apnea can occur as an upper airway apnea, giving way to a central apnea. We have never observed this sequence. These terms and polygraphic definitions are used by nearly all investiga­ tors involved in the sleep apnea syndromes. Figures 1 and 2 illustrate the different types. COMMON CLINICAL SYMPTOMS AND OTHER FINDINGS IN THE SLEEP APNEA SYNDROMES At the Stanford University Sleep Disorders Clinic, between June 1972 and June 1975, we identified sleep apnea syndromes in sixty-two patients using the criteria outlined above. They were diagnosed from approximately 350 patients referred for evaluation of serious sleep problems. The patients included 50 adults; 38 male and 12 female ranging in age from 22-70 years; and 12 children, 1 1 male and 1 female, 3- 14 years old. The patients came from all walks of life and socioeconomic back­ grounds. Most were Caucasian, and 10% were black. All patients underwent the same initial diagnostic polysomnographic evaluation, which necessarily included continuous monitoring of EEG, eye movements, muscle tone, airflow, ECG, and respiratory effort during sleep. Additional studies were done on subsamples, depend­ ing on the specific questions we wished to assess and the willingness of the patients to participate. The patients were referred to the Sleep Disorders Clinic primarily for a sleep problem, chiefly daytime hypersomnolence and, less frequently, chronic insomnia.

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GUILLEMINAULT, TlLKIAN & DEMENT

ENDOESOPHAGEAL -----...\1 PRESSURE

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02 SATURATION

% C0 2

Figure 1

-----

EXPIRED

--

Example of a sleep-induced mixed apnea recorded on a Sanborn polygraph. On

the top tracing the endoesophageal pressure demonstrates the presence of a "central" or "diaphragmatic" component at the beginning of the apnea. No pressure change is recorded and there is no airflow through the upper airway, as demonstrated by the recording of expired

CO2 (bottom tracing). Diaphragmatic movements resume, and the first diaphragmatic swing produced normal pressure change (top tracing); however, no air passed through the upper airway (bottom tracing), and the second and third diaphragmatic swings produced larger endoesophageal pressure changes. This is due to a functional obstruction of the upper airway induced by sleep. In pure central apnea the recording is similar to the first part of the recording; in pure upper airway apnea the entire apneic period consists of increasing endoesophageal pressure swings and a flat expired CO2 tracing. During the absence of air exchange, the blood oxygen saturation declines.

Although the sleep problem was often the most troublesome symptom for the patients and frequently resulted in the first medical consultation, we have found that the sleep disorder complaint represents only one of the clinical symptoms of the sleep apnea syndrome. The following clinical descriptions have been derived from repeated questioning of our adult patients and their families, especially spouses of adult patients and parents of the younger patients. Some of these symptoms have been emphasized by other authors (28, 29).

Snoring In most patients the first clinical symptom was inordinately loud snoring. While many individuals with normal respiration during sleep may present light, intermit­ tent nasal snoring, sleep apnea patients have loud pharyngeal snoring, associated with snorting and interrupted by silences (apneic periods) of 20 sec or longer. The history of this symptom can be very difficult to trace, but appears to be essentially lifelong in many patients. For example, in studies of infants considered "near miss" for the Sudden Infant Death Syndrome (30), two infants gradually developed abnor­ mal snoring with apneic pauses during sleep. One child was 7 months old and the

SLEEP APNEA SYNDROMES [02

469

SATURATION

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OBSTRUCTIVE SLEEP. APNEA

30 seconds

..

ENDOESOPHAGEAL

PRESSURE

Figure 2 Recording of successive apneic cycles during sleep (on a Sanborn polygraph) in a 42-year-old adult male complaining of excessive daytime sleepiness. The endoesophageal pressure demonstrates the intricate relationship of central and upper airway apneas in mixed apnea episodes. The changes in endoesophageal pressure reached values of nearly 80 cm H20 in association with the large diaphragmatic swings against a closed upper airway. Oxygen saturation drops during each apneic episode. There is a delay between resumption of normal respiration and oxygen resaturation, due to physiological components and also to the inertia of the recording system. The oxygen saturation returns to near normal values, but during the course of the night an alveolar hypoventilation syndrome will gradually develop with repetitive sleep-induced apnea.

other 12 months old when the snoring was first noted. In addition, the mother of a young boy with sleep apnea reported the onset of loud nighttime snoring when the child was 4 months of age. Parents of the other children in the Stanford sleep apnea population have reported observing abnormal respiration and snoring during sleep in the first two years of life. In adult sleep apnea patients, the spouse or other bed partner is the best source of current information, and appropriate questioning always results in a vivid de­ scription of the loud snoring and unusual nocturnal respiratory pattern. In addition, patients commonly report that snoring has been a source of inconvenience and embarrassment for many years. Many patients are able to recall that family mem­ bers and friends have expressed amazement or concern about their snoring from adolescence or early adulthood, long before the sleep complaint appeared. In view of the ubiquity of snoring in sleep apnea patients, we feel that loud snoring, night after night, in children and adults even without an associated sleep complaint should strongly suggest a sleep apnea syndrome. Ear-nose-throat and all-night sleep evaluation should be considered in such instances. Abnormal Behavior During Sleep

It is apparent that abnormal behavior during sleep is a very prominent feature of the syndrome. Patients themselves seem to be generally unaware of these symptoms,

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which are reported only after specific questioning of the patient's spouse, bed part­ ner, or family members. Various abnormal movements are observed in association with repetitive sleep apneic episodes, occurring prior to resumption of respiration in each instance. These movements vary from a single, small movement of both hands or arms resembling a flapping tremor, to larger, more generalized movements of both upper and lower limbs. The movements can be extremely vigorous and in several cases injury to the bed partner has been reported. The spouses of several sleep apnea patients reported that they moved to a separate bed because they were unable to waken the patient and feared the large arm swings. In certain patients,movements include lifting the upper torso from the bed and then collapsing on the bed or the floor at the resump­ tion of respiration (31). Sleep apnea patients may also show somnambulism. This behavior generally appears after a series of repetitive apneic episodes, at which time the patient may arise and walk away from his bed, unresponsive to arousing stimuli. These episodes have been described by witnesses as ending abruptly when the patient collapses onto his bed or falls to the floor. Even after the patient falls to the floor, sleep is frequently uninterrupted and he may remain on the floor for the rest of the night. Injuries have been reported; one patient broke his wrist in this manner, and several bruised themselves repeatedly. Altered States 0/ Consciousness

Laboratory observations have confirmed an altered state of consciousness during the night in sleep apnea patients. When arousal is attempted, patients are often unre­ sponsive even to painful stimuli, and if the patient is finally aroused he typically exhibits temporal and spatial disorientation and difficulties with visual perception. Similar cognitive difficulties may also appear after waking in the morning, at which time patients complain of a "foggy mind" and an inability to remember events of the previous day. In children this abnormal state appears to be frequently associated with frightening hallucinations (31) that are not reported by adults, although they occasionally report "nightmares." Nocturnal Enuresis

In the Stanford series all children and three of the adults presented nightly enuretic episodes. One element appears to be peculiar to the nocturnal enuresis in all cases: bedwetting reappears after complete nocturnal toilet training. Complete urologic examinations were negative in those older children and adults who sought treatment for nocturnal enuresis prior to consulting the Sleep Clinic. Morning Headache

Approximately half of patients (both children and adults) with upper airway sleep apnea syndrome complain of repeated morning cephalgia, usually frontal, but some­ times diffuse. The headaches are present when patients awake in the morning and add to the "foggy" mind and general feeling of malaise. In general, the headaches dissipate several hours after arousal.

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Sleep Complaints

Daytime hypersomnolence is the usual reason that adult patients seek medical treatment. In children, however, hypersomnolence appears to be overlooked in spite of the heavy toll it exacts on learning and educational development. Adult patients complain of sudden, excessive drowsiness occurring inappropriately during the day and leading to an undeniable urge to sleep. They report falling asleep while driving, eating, talking, etc. The patients' lives and those of others are endangered because of these sudden sleep spells. For example, one patient in the Stanford series reported an incident that occurred while driving. He saw a railroad barrier closing about 300 yards ahead of him. The red blinkers were flashing, and he could hear the warning bell. The next thing he knew, his car had crashed into the barrier. Patients have also reported that daytime naps are not refreshing, but result in greater fatigue accom­ panied by "fogginess" and cephalgia. Two additional symptoms are often reported in close association with daytime hypersomnolence. The first of these is an automatic behavior syndrome (32), charac­ terized by complete retrograde amnesia lasting for as long as several hours. During such an episode it is possible for patients to complete simple, repetitive tasks, but complex behavior appears to be very difficult. This particularly includes the ability to speak coherently and appropriately. Polygraphic monitoring has revealed that frequent, repetitive microsleep episodes are directly related to the appearance and development of this syndrome (33). Hypnagogic hallucinations are also commonly experienced by adult patients when the urge to sleep arises in the daytime. Hallucinatory images have included seeing "a tree in the road." "a flashing red light," or "a dog driving a car." Characteristically, the images persist for a short time until recognized as such by the patient and dispelled. However, patients often react before realizing their hal­ lucinatory nature. For example, abrupt braking ora car to avoid "a tree" led to a serious accident in one of our cases. Although not necessarily associated with the daytime hypersomnolence, sleep paralysis and cataplexy typical of the narcolepsy syndrome were reported by 11 adult patients. Finally, in 14 cases in the Stanford series of sleep apnea patients, the chief complaint was of frequent and lengthy nighttime arousals, and many of the daytime symptoms were absent or less severe. Physical Examination

In the Stanford case series only 5% of the sleep apnea patients fit the description (12) of obese Pickwickian patients. In other cases series (34. 35) the percentage of Pickwickian patients has been much greater, presumably because the series did not originate in a sleep disorders clinic. Obesity and hypersomnolence, without the waking respiratory or cardiologic abnormalities, were seen in 34% of our patients. The remaining 61% were nonobese and without waking respiratory or cardiac symptoms. None of our patients showed the malformations that have been impli­ cated in other alveolar hypoventilation syndromes, including micrognathia, kypho-·

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scoliosis, functional atlanto-axio-occipital malformation (Dandy-Walker syndrome), and atlanto-axial dislocation (7, 8, 10, 36, 37). In all cases neurologic examination was normal, and EEG ruled out epileptic disorders. No endocrine disorders were found. The only significant finding from physical examination was elevated systolic and diastolic systemic blood pressure in 60% of the adults and 62% of the children. No specific causes could be found to explain this "essential" hypertension. It should be reemphasized that the majority of patients with sleep apnea syn­ dromes are not obese and have normal ventilation when awake. It is not likely that such patients will be referred to pulmonary specialists. We might infer. however. that such patients will begin to be identified in greater numbers in any center offering specialty evaluation during sleep for the complaints of daytime hypersomnolence and chronic insomnia. Sleep Structure

The data summarized below from the Stanford case series closely parallel the findings from other laboratories (35. 38-44). Apneic episodes during sleep are clearly related to a disruption of the ongoing sleep state. Most apneic pauses are associated with short EEG arousals characterized by the appearance of alpha rhythm and sometimes associated with slow eye movements. just prior to resump­ tion of respiration. When a clear EEG alpha arousal is not present. a K complex usually signals the appearance of the disturbing stimulus. In addition to these fine disturbances of sleep. the overall structural staging of sleep is abnormal. In adults, stages 3 and 4 NREM (i.e. slow-wave) sleep are always significantly reduced or completely absent. On the other hand. the percentage of stage 2 NREM sleep during the night is abnormally high. REM sleep is generally present in normal amounts. although it is infrequently reduced to 15% of total sleep in certain patients. Sleep structure in children is similarly disturbed, with the exception of the youngest children with fewest sleep apneic episodes. In these cases the percentage of stages 3 and 4 NREM sleep is abnormally high, and these sleep stages are not associated with apneic pauses. Another sleep structure anomaly is the occurrence of REM sleep periods at sleep onset in approximately one fourth of the patients. This particu­ lar sequence of sleep staging is usually associated with narcolepsy (45), although it has also been observed in normal individuals after selective REM sleep deprivation and in circadian rhythm disturbances (46. 47). RESPIRATION DURING SLEEP IN NORMALS

To fully appreciate the respiratory abnormalities found during sleep in sleep apnea patients. we first review the findings from studies of normal subjects. Respiration has been studied in normal adults during REM and NREM sleep using a number of techniques. These include simple polygraphic recordings (25. 48-50) and poly­ graphic recordings correlated with either oxygen consumption ( 5 1, 52) or spiro­ graphic techniques (53-57). Unfortunately. as summarized by Duron (57), several technical problems may develop with certain of these recording procedures.

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SLEEP APNEA SYNDROMES

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Nonetheless, clear respiratory irregularities during sleep have been noted in all the normal studies, and several general areas of agreement are apparent. Isolated, brief apneic episodes and spirographic abnormalities may appear normally at the onset of sleep and during REM sleep. Findings in our control population and those reported by Aserinsky (25, 49) showed that brief apneic pauses in REM sleep are generally associated with a burst of rapid eye movements. Respiratory pauses during sleep in normal adults are exceptional, and when they do appear they are not repetit ive and rarely exceed 30 sec. Furthermore, in a study of 18 normal subjects (ages 45-60 years), respiratory irregularities during sleep were more frequent in men than in women. This finding is in accordance with the sex distribution of the sleep apnea syndrome, in which men outnumbered women by a ratio of 6:1 or 10:1 (19, 21,34,35). Several in vesti gator s (58-60) have also reported increased carbon dioxide tension that appears to parallel sleep stages and seems to be associated with increased carbon dioxide threshold. In his normal subjects Bulow (55) distinguished two groups, based on carbon dioxide threshold during sleep. The first group was characterized by a very small, nonsignificant increase in carbon dioxide threshold during sleep; in the second group, the carbon dioxide threshold showed a large, significant in­ crease during sleep. Although Bulow (55) characterized the second group as having "unstable" respiratory regulation, Duron (57) denied the development of significant hypercapnia during sleep in his subjects. Furthermore, Duron (57) stated that hypercapnia was probably not related to the specific issue of respiratory pauses during sleep, citing Fink et al (61), who showed that certain subjects discretely hyperventilate at sleep onset, possibly inducing the physiologic hypocapnia respon­ sible for short apneic episodes at sleep onset. Two factors may have biased Duron's findings: first, he recorded only 12 subjects (compared to Bulow's 70 sub ject s) all of whom may have fallen into the first group described by Bulow. Second, Duron's subjects were all young adults ( 12-25 years). Although Bulow did not clearly state the age of the subjects in his "unstable" group, this factor may be significant, as indicated by the observations of Webb (51) and Webb & Hiestand (52), in which normal men over 50 were found to have significantly more respiratory irregularities during sleep than younger men. The foregoing data suggest the possibility that there are two constitutionally different populations, one with regular respiration and similar CO2 thresholds in waking and sleep, and the other presenting irregular respiratory functions during sleep. The suggestion that an underlying genetic predisposition for development of respiratory irregularities during sleep may exist is supported by a study in which Arkinstall et al (62) accounted for 80--90% of the variability in tidal volume re­ sponse to CO2 in terms of genetic factors. The existence of two such genetically different groups could have implications for the sleep apnea syndromes. It i s possible that an unstable respiratory regulation during sleep could gradually develop into overt pathology. On the other hand, the unstable group might represent a popula­ tion "at risk," in whom other factors, such as age, weight, mandibular position, and enlarged tonsils or adenoids might interact to produce a sleep apnea syndrome. ,

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RESPIRATION DURING SLEEP IN SLEEP APNEA PATIENTS

The typical sleep apnea patient has hundreds of repetitive or periodic apneic epi­ sodes in a single night. Depending upon the length of the sleep period and the duration of individual episodes, the usual range is between 200 and 500 (21, 63). Accurate determination of blood gases is extremely difficult because the levels are continuously changing. The peak and trough values of PaOz and PaCOz depend mainly upon the duration of an apneic episode and also upon the type of the apnea. It has become clear that PaO? drops more rapidly in upper airway sleep apnea than in central sleep apnea (21, 30). A primary consideration in various studies has been to determine whether respira­ tory patterns during sleep differed among Pickwickian patients, obese sleep apnea patients, and nonobese sleep apnea patients (64). At present, the Stanford series comprises 23 adult male patients, whose sleep studies include blood gas determina­ tions, ear oximetry, and precise quantitative measurement of respiratory variables. Table I summarizes sleep apnea variables in terms of the above three subgroups. As can be readily appreciated, there is no great difference in any value as a function of obesity or additional cardiopulmonary problem (e.g. Pickwickianism). All patients showed repeated oxygen desaturation in association with apneic episodes. PaOz values did not differ among the groups. In the non-Pickwickian patients, alveolar hypoventilation was seen during sleep, and values quickly returned to normal when patients were fully awakened. During the night patients in all three groups presented cycles in which PaOz gradually changed from one series of repeti­ tive apneic episodes to another. For example, during 10 or 15 min, the PaOz was 20-30 mm Hg at the end of an apnea and 30-40 mm Hg after resumption of respiration; this pattern might be followed by one in which, for no apparent reason (i.e. no change in sleep stage, body position, or pattern of apnea), the PaOz levels were 40-60 mm Hg at the end of an apnea and 55-85 mm Hg after resumption of respiration. In REM sleep periods individual differences appeared, although these differences were independent of the patient group. In certain patients REM sleep was associated with a marked increase in the duration of apneic episodes from 90 to 130 sec. In other patients REM sleep periods were relatively free of apnea. Koo et al (65) have Table 1

Apneic episodes during sleep in patients8 Obese, non­

Number of patients Mean number of apneas per night Mean duration of apneic episodes (sec) Mean apneas in NREM sleep (%) Mean upper airway apnea (%)

a Results based

Pickwickian,

Nonobese

Pickwickian

sleep apnea

sleep apnea

3 346 25.0 82.2 96.8

10 429 27.2 87.0 92.0

10 449 29.1 84.2 86.3

on averages from 8 hr of nocturnal sleep.

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SLEEP APNEA SYNDROMES

475

recently shown that patients with chronic obstructive pulmonary disease showed a worsening of arterial blood gas values, taken as an index of alveolar hypoventilation, in REM sleep. Similar results were seen in 15 of the patients included in Table 1, with no apparent relationship to patient group. These data, as well as a report by Lugaresi et al (41), suggest that obesity is not a requisite for severe sleep-induced apnea and that alveolar hypo ventilation may develop to a similar degree during sleep in both obese and nonobese patients. The relationship of changes in respiratory function to changes in sleep state suggests another factor that may be important in understanding the sleep apnea syndrome. As mentioned above, we have found certain patients in whom the respira­ tory irregularities are aggravated by REM sleep and others in whom respiration appears relatively normal in REM sleep. (A third group, uninfluenced by REM sleep, may also exist, but was not apparent in our sample.) The marked changes in respiratory pattern from wakefulness to sleep, and within sleep states themselves, underline the significance of brain mechanisms in the sleep apnea syndrome. De­ scribing patient groups by these sleep state-related changes may provide more information than categories based on clinical findings such as obesity. Another significant factor is the type of apnea patients present during sleep. In our sleep apneic patients all three types of apnea (central, upper airway, and mixed) are seen during each night, although the ratio of the types of apnea varies from patient to patient. There has been a tendency to assume that apneas involving diaphragmatic cessation result directly from a CNS defect, while upper airway apneas result from a peripheral obstruction. Several investigators (26, 42, 66, 67) have shown that upper airway sleep apnea may exist in patients in whom no cause of obstruction can be detected during wakefulness. In patients in the Stanford series who have had direct and indirect laryngoscopic examinations, no cause of obstruc­ tion was found in most cases. This may allow us to question the general role of physical obstruction: Why is upper airway sleep apnea present in only certain patients with micrognathia (10), obesity, Prader-Willi syndrome (68), and enlarged tonsils and adenoids (69-72)1 Do CNS abnormalities interact with peripheral prob­ lems in these cases? Is a CNS defect the prime determinant of mixed and upper airway apneas that involve no peripheral factor? Are mixed apneas related to secondary hypoxia, hypercapnia, and acidosis, inducing a disruption of central respiratory regulation? These questions cannot be answered conclusively, but suggestive evidence is available. Schwartz & Escande (73) demonstrated that a sudden "collapse" of the pharyngeal walls occurred during upper airway sleep apnea in Pickwickian patients. Using serial X rays, Smirne & Comi (74) found a slightly abnormal thickness and length of the soft palate of two Pickwickian patients during wakefulness. In sleep the pharyngeal wall collapsed slightly, interrupting the air column at the level of the soft palate between the base of the tongue and the pharyngeal walls. During upper airway apnea and associated with successive intrathoracic depression second­ ary to ineffective respiratory attempts, Smirne & Comi observed a progressive collapse of the lower portion of the pharyngeal walls and the upper pharynx. We attempted to abort the upper airway apnea by positioning a pharyngeal tube during

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the night in a small series of four patients. Only one patient showed any change at all as a result of this approach. Direct electromyographic recording of muscles such as the middle constrictor of the pharynx may give more clues to the mechanisms underlying upper airway apnea. The likelihood of CNS involvement in all threc types of sleep apnea seems reasonable at this time. There is some evidence that the secondary hypoxia, hypercapnia, and acidosis may aggravate the perturbation of respiratory function during sleep. One of the most effective treatments of sleep apnea syndromes involving a predominance of upper airway apnea is the insertion of a permanent tracheal valve, closed during the day and opened at night to bypass the pharyngolaryngeal problem (18, 21, 75-77). One would assume a priori that such a procedure, while eliminating upper airway apnea, would have little effect on pure central apnea or the diaphragmatic (central) compo­ nent of mixed apneas. Recordings conducted on nine patients (two children and seven adults) at four weeks following tracheostomy showed no upper airway apnea, although central apneas continued. On subsequent recordings conducted up to 12 months following surgery there was a significant decrease in central apneas during sleep. These data suggest the presence of a feedback loop in which impairment of the respiratory drive leads to sleep-induced apnea; resultant hypoxia, hypercapnia, and acidosis interact secondarily with the "respiratory neuronal network" (in its very broadest meaning) to increase the possibility of disturbance in eNS respiratory regulation. WAKING RESPIRATORY FUNCTION IN THE SLEEP APNEA SYNDROMES

Respiratory abnormalities in Pickwickian patients have been reported extensively (IS, 38, 40, 78). In collaboration with Drs. Fred Eldridge and James Phillips at Stanford, we have evaluated waking respiratory function in six nonobese and five obese adult sleep apnea patients. Some of these essentially negative data have been reported (21). Pulmonary function tests included spirometric tests, studies of lung volume, elastic recoil, flow resistance, and arterial blood gases. An exercise study compared rest and three grades of exercise. CO2 response curve and post-hyperven­ tilation breathing tests as described by Plum et al (79) were also conducted. During full alertness these tests were all within normal limits, but rapid deterioration of values was noted when patients became drowsy. Without proper evaluation of the patient's state of vigilance, sleepiness may produce erroneous interpretation of daytime pulmonary evaluations in these patients. SLEEP COMPLAINT AND PREDOMINANT TYPE OF SLEEP APNEA

In the Stanford case series the majority of patients showed a predominance of upper airway sleep apnea associated with a complaint of excessive daytime hypersomno­ lence (21, 23). In the remaining patients there was a predominance of central apnea associated with the complaint of daytime fatigue and disturbed nocturnal sleep

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(insomnia) (63, 80). Patients in the latter group did not snore continuously, but heavy snoring was always present at some point in the night. The sleep of these patients was characterized by an essentially normal sleep latency, several lengthy nocturnal arousals, and premature morning awakenings. Hypoxia and hypercapnia were less pronounced than in patients with upper airway apnea. (Differences in oxygen consumption due to muscular effort may explain this finding.) Hemody­ namic changes were also less marked in these patients. HEMODYNAMICS IN NORMAL SLEEP Arterial Pressure Changes During Normal Sleep

Using indirect methods, Snyder e( al (48, 81) and Richardson et al (82) have shown that significant hemodynamic changes occur during sleep in normal human volun­ teers. Khatri & Freis (83), Bristow et al (50), and Coccagna et al (84) generally confirmed these earlier reports by cannulating the brachial artery for direct, continu­ ous recording of the arterial pressure during sleep in association with standard sleep and respiratory recording parameters. These latter investigators showed that the arterial pressure decreases rapidly during the first hour of sleep and gradually increases in the second part of the night. All three reports agreed that there is a direct relationship between sleep stages and arterial pressure; the lowest systolic and diastolic values were noted in stages 3 and 4 NREM sleep. Bristow et al (50) also reported very low values in REM sleep, but this finding was not confirmed by either Khatri & Freis (83) or by Coccagna et al (84). Snyder et al (48, 81) reported consistently higher values of arterial pressure in REM sleep than in stages 3 and 4 REM sleep, sometimes exceeding even the highest values recorded in the same subject during the waking hours. This finding was confirmed by Coccagna et al (84), who also found that the arterial pressure values recorded during the early part of sleep (NREM) were significantly lower than the values recorded during wakefulness. The results of Khatri & Freis (83) and Bristow et al (50) did not show a statistically significant decrease. Finally, Coccagna et al (84) speculate that an uItradian variation of arterial pressure may be superim­ posed on the pressure variations linked to sleep stages. Pulmonary Arterial Pressure Changes During Normal Sleep

There is only one study of pulmonary arterial pressure (PAP) changes during sleep in normals. Lugaresi et al (85) continuously monitored PAP in three normal sub­ jects by means of a microcatheter positioned in the pulmonary artery using Grand­ jean's technique (86). Polygraphic recording of EEG, electro-oculogram (EOG), chin electromyogram (EM G), ECG, and respiration was conducted simultaneously. Cyclic variations of PAP with a period of approximately 20-30 Sec were noted during states 1 and 2 NREM sleep. The variation in PAP reached a maximum of 2-4 mm Hg above the baseline value obtained during wakefulness. Stages 3 and 4 NREM sleep seemed to be the most stable periods, with no significant PAP fluctua­ tions (E: Lugaresi, personal communication, 1973).

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HEMODYNAMIC AND CARDIAC ABNORMALITIES IN SLEEP

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APNEA SYNDROMES

Right heart hypertrophy and congestive heart failure are considered part of the Pickwickian syndrome. Similarly, chronic nasopharyngeal obstruction or adenoid and tonsillar hypertrophy can lead to cor pulmonale in children (69-72, 87, 88). From nocturnal recordings of pulmonary and systemic arterial pressure, Coccagna et al (89) suggested that sleep-induced apnea with hypersomnia ("hypersomnia with periodic breathing") occurring regularly during sleep over a period of years, may be responsible for the development of cor pulmonale. We have also continuously monitored pulmonary arterial pressure (using a Swan-Ganz ® catheter) during 16-18 hr in insomniac patients with sleep-induced apnea (80, 90) and in nonobese hypersomniac patients with sleep-induced apnea (21). Recently, in collaboration with Drs. Ara Tilkian and John Schroeder, we performed more complex monitoring in 12 sleep apnea patients who were obese but did not show other characteristics of the Pickwickian syndrome (91). Fifteen hours of continuous monitoring, begin­ ning in the late afternoon, included pulmonary arterial pressure, systemic arterial pressure, and Pa02 with a femoral arterial oxygen electrode (in addition to standard sleep parameters and respiratory variables). Prior to the continuous monitoring, intracardiac e1ectrophysiologic studies were performed. These included His bundle recordings, atrial pacing, and sinus node recovery time. Cardiac output determina­ tions were made during sleep after the onset of hemodynamic abnormalities, and blood gases were measured intermittently throughout the day and night. One or two continuous 24-hr periods of ECG monitoring (Holter recording) were also carried out. The data from Stanford are concordant with the findings of Coccagna et al (75); that is, significant hemodynamic abnormalities developed during nocturnal sleep secondary to the repetitive apneic episodes. Such abnormalities were directly related to the total number of sleep apneic episodes during the night. Increased pulmonary arterial pressure appeared with the vigorous inspiratory efforts performed against a closed airway during upper airway sleep apneic episodes. Very large intrathoracic pressure swings developed, ranging from 5 to -85 mm Hg. At the onset of ventilation, these pressure swings immediately dropped to a normal range, but rises in pulmonary arterial pressure were typically sustained. It should be noted that pulmonary arterial pressure was also elevated in insomniacs with central sleep apnea (63). Coccagna et al (89) reported a correlation of sleep stages with PAP and systemic pressure, including a gradual increase from wakefulness to stages 1-4 NREM sleep and a great rise with REM sleep. In our patients the increase in arterial pressure was closely related to the distribution of apneic episodes. In patients who presented no sleep apnea during REM sleep, PAP measurements were almost normal at that time. The onset of rises in systemic pressure occurred following the lowest point of oxygen saturation of an apneic cycle at the onset of ventilation and sinus tachycardia. In several patients cardiac output was determined at various intervals. No significant changes were seen in cardiac output (A. Tilkian et ai, in preparation). Continuous ECG monitoring (Holter recording) showed a

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variety of arrhythmias, some potentially life threatening, during the night in associa­ tion with repetitive sleep apneas (91). Episodes of sinus arrest, asystoles up to 6.4 sec, heart block, and ventricular tachycardia were seen. No arrhythmias were seen during wakefulness. In 50 cardiac patients (without sleep apnea) who had under­ gone similar electrocardiographic recording, none presented these arrhythmias, associated only with nocturnal sleep (9\). Kryger et al (44) also noted atrial flutter fibrillation with a slow ventricular response and prolonged asystole during sleep­ induced apnea in one patient. We have already mentioned the very important observations of Lugaresi et al (29), who found that eight normal volunteers who were "heavy" snorers all showed a typical sleep apnea syndrome with associated hemodynamic abnormalities. COMMENTARY

Historically, it is understandable that the most complete form of sleep apnea syn­ drome reported by Burwell et al (12), was the first to be recognized as a pathological entity. We now recognize, however, that most of the symptoms reported by Burwell et al (12) are secondary to an abnormal respiratory pattern during sleep. Depending on the type, frequency, and intensity of the abnormal sleep-related respiratory pattern, the clinical symptomatology will differ. Abnormalities induced by a devel­ oping sleep apnea syndrome are first done during sleep, and only gradually affect the waking period. The time course of the illness depends on several factors, includ­ ing the severity of the nocturnal respiratory problem, the patient's age, the presence of obesity, upper airway obstruction, and so forth. The sequence in which symptoms appear may also vary. For example, we have seen one patient with an upper airway sleep apnea syndrome who shows cardiac arrhythmia, hypertension, and increased pulmonary arterial pressure with each repetitive apnea. Although this patient has developed "essential" hypertension during wakefulness and is progressively devel­ oping right ventricle impairment, his weight is entirely normal and he is without daytime hypersomnolence Other patients present profound daytime sleepiness, but no other clinical findings, and a variety of other combinations may be found. The common factor in all patients, however, is the sleep-induced apnea syndrome. Although many questions about the sleep apnea syndromes remain unanswered, a few points are now very clear. These include the role of sleep-induced apnea as a primary cause of multiple clinical symptoms, the relationship of a Pickwickian syndrome to the evolution of a sleep apnea syndrome, and the important therapeutic role of chronic tracheostomy that bypasses the upper airway obstructions and protects the patient from the secondary deleterious clinical symptoms. This treat­ ment was first reported by Kuhlo et al ( 18) and Coccagna et al (75). The Stanford case series of upper airway sleep apnea patients now includes 12 patients successfully treated with this approach by Dr. F. Blair Simmons (21, 67). One interesting problem for sleep researchers is why patients complain of fatigue and daytime somnolence. Two schools of thought have arisen from sleep studies in Pickwickian patients: The first suggests that the hypersomnolence is secondary to an accruing sleep deprivation caused by repeated disturbance of sleep by the respira,

.

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tory difficulties (15, 35, 66); the second suggests that the hypersomnolence may result from a defect of the CNS structures that control sleep (la, 22, 66). Recent sleep studies of nonobese sleep apnea patients with and without excessive daytime sleepiness, and obese sleep apneics without daytime sleepiness, have called into question both hypotheses, chiefly because similar abnormalities of sleep structure have been found in all cases. Further knowledge derives from the finding that hypersomnolence disappears within 24 hr after tracheal intubation or permanent tracheostomy, either of which resolves the respiratory abnormality and consequent sleep disturbance. This finding seems to rule out a purely central origin of the hypersomnolence. On the other hand, the concept of hypersomnia resulting solely from the sleep disturbance is difficult to reconcile with recent findings from heavy snorers with sleep apnea who present no daytime sleepiness (29) and from two patients in our population who presented a typical sleep-induced apnea syndrome with no daytime complaints. In addition, we have also studied ten patients in whom closure of tracheostomy for one night instantaneously produced reappearance of the daytime symptoms of such severity as is never seen in normals who undergo a full night of sleep deprivation. Lugaresi and his colleagues (66) have suggested that the nocturnal hypercapnia and continu­ ous oscillation in the PaC02 that result from repetitive sleep apneic episodes may "alter the reactivity of the reticular activating system" in such a way as to affect daytime vigilance. We feel that simultaneous changes in other blood gases should also be considered. While it appears certain that sleep apnea, disturbed nocturnal sleep, and excessive daytime sleepiness are related, the exact mechanisms that lead to the daytime sleepiness are not clear. The symptom of daytime hypersomnolence apparently develops gradually during the course of the disease, and the available data do not support the conclusion that any factor is wholly responsible. The hypoxemia, hyper­ capnia, and acidosis that occur during sleep are not sufficient to explain the hyper­ somnolence, since patients with chronic lung disease and chronic alveolar hypoventilation do not necessarily present this symptom. In addition, Cole & Alex­ ander (14) reported hypersomnia in obese patients with no carbon dioxide retention. In our opinion, the daytime hypersomnolence in sleep apnea patients may result from the fluctuating nature of all these changes. In the sleep apnea syndromes it i� clear that blood gas values fluctuate repeatedly and abruptly many times throughout the night. Thus the patients are in a very unstable state during sleep, in contrast to normal individuals, or even patients with continuous alveolar hypoventilation in whom there is a stable state, either normal or pathological. Metabolic changes induced by the unstable state in sleep apnea may be of greater significance and severity than those seen in the pathological, but stable state. Other factors that have received little attention include the impact of the blood gas changes on neurotransmitters in the brain and the effects of the hemodynamic changes on cerebral blood flow. Hypoxia may interact with monoamine synthesis (92) and may significantly increase the cerebral content of y-aminobutyric acid as well (93). Thus, alteration of neurotransmitters involved in sleep processes may also play a role in the daytime hypersomnoience.

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ACKNOWLEDGMENT

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We wish to acknowledge the colleagueship of Dr. John Schroeder, Dr. F. Blair Simmons, Dr. Frederic Eldridge, Dr. Michael Hill, and Dr. James Phillips for their contributions to the evaluation of various patients in the sleep apnea case series at Stanford. Literature Cited

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The sleep apnea syndromes.

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