CURRENT REVIEW * ACTUALITES
Clinical features and treatment of obstructive sleep apnea R. John Kimoff, MD, FRCPC; Manuel G. Cosio, MD; Maurice McGregor, MD, FRCP Objective: To review the clinical features and treatment of obstructive sleep apnea
(OSA).
Data source and selection: All articles on OSA published in French and English between 1970 and 1990 and indexed in Index Medicus were reviewed. Studies addressing the epidemiologic features and clinical aspects of OSA were selected, and special emphasis was given to articles reporting the effects of treatment on morbidity and mortality rates. Main results: OSA is characterized by episodes of upper airway obstruction during sleep that result in repetitive hypoxemia and sleep disruption. OSA leads to various neuropsychologic and cardiovascular complications, including daytime hypersomnolence, cognitive impairment, systemic and pulmonary hypertension and cardiac arrhythmias. There is suggestive evidence that the death rate among affected people is increased. The true incidence of OSA is unknown, but estimates have varied from 1% upwards among men. The current treatment with the greatest overall effectiveness and acceptability is nasal continuous positive airway pressure. Conclusion: This common, readily treatable disorder is associated with serious complications and therefore must be widely recognized by health professionals.
Objectif: Examiner les caracteristiques cliniques et le traitement de l'apnee obstructive du sommeil (AOS). Source des donnees et selection: Tous les articles sur I'AOS publies en francais et en anglais entre 1970 et 1990 et figurant dans l'Index Medicus ont ete examines. Les etudes sur les caracteristiques epidemiologiques et les aspects cliniques de l'AOS ont ete selectionnees, avec insistance speciale sur les articles precisant les effets du traitement sur les taux de morbidite et de mortalite. Principaux resultats: L'AOS se caracterise par des episodes d'occlusion des voies respiratoires superieures pendant le sommeil, occlusion resultant en hypoxemie repetitive et troubles du sommeil. L'AOS conduit a diverses complications neuropsychologiques et cardiovasculaires, notamment l'hypersomnolence diume, les handicaps cognitifs, l'hypertension systemique et pulmonaire et l'arythmie. Les preuves laissent penser que les taux de deces ont augmente chez les personnes touchees. L'incidence reelle de 1'AOS est inconnue, mais les estimations varient de 1 % et plus chez les hommes. Le traitement actuel le plus efficace et le plus acceptable globalement est la pression nasale continue positive sur les voies aeriennes superieures. Conclusion: Ce problbme courant et de traitement facile est associe A des complications graves et doit donc etre largement reconnu par les specialistes de la sante. From the Department ofMedicine, McGill University, and the Desmond N. Stoker Pulmonary and Sleep Laboratory, Royal Victoria
Hospital, Montreal, Que.
Based on a report prepared at the request of the Conseil d'evaluation des technologies de la sante du Quebec. Dr.
Kimoff was supported by a research fellowship of the Canadian Lung Association.
Dr.
Kimoff is assistant professor, Dr. Cosio professor and Dr. McGregor professor emeritus, Department ofMedicine, McGill University.
Reprint requests to: Dr. Manuel G. Cosio, Rm. L4.09, Royal Victoria Hospital, 687 Pine Ave. W, Montreal, PQ H3A JAI -
For prescribing information see page 81 0
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In recent years there has been increasing awareness of the prevalence and significance of respiratory disorders during sleep. One of these, obstructive sleep apnea (OSA), was only recently recognized but has already been found to occur frequently in the population. Because it is associated with significant complications that are treatable this disorder must be widely recognized. We therefore decided to review articles published in French and English between 1970 and 1990 that were indexed in Index Medicus. Studies addressing the epidemiologic features and clinical aspects of OSA were selected, and special emphasis was given to articles reporting the effects of treatment on morbidity and mortality rates.
Etiologic features OSA is due to temporary obstruction of the oropharynx or hypopharynx during sleep. It is characterized by loud snoring that is repeatedly interrupted by episodes of complete upper airway obstruction and resolves with temporary arousal. A commonly used definition is a condition in which 10 or more episodes of obstruction, each lasting more than 10 seconds, are detected per hour of sleep.1 The OSA syndrome refers to the constellation of neuropsychologic and cardiovascular complications resulting from the recurrent episodes of hypoxemia or the repetitive interruption of sleep or both. The cause of OSA is poorly defined but appears to be multifactorial; upper airway tract malformation, oropharyngeal muscle dysfunction and abnormal respiratory drive each play a greater or lesser part. Obesity and alcohol consumption are well recognized as aggravating factors.
Complications Neuropsychologic Neuropsychologic disturbance is marked by excessive daytime sleepiness or hypersomnolence. It is the result of major disruption of normal sleep patterns because of repetitive arousal from sleep. Patients experience episodes of falling asleep while seated quietly and even while performing purposeful activities. These episodes can occur during work or social functions and can lead to embarrassment, domestic discord, decreased work productivity, loss of employment and an increased incidence of accidents. I6 Hypersomnolence is the single most important presenting symptom and frequently identifies which patients will require, and accept, specific therapy. It is not, however, a symptom physicians have learned to elicit in their training. Hypersomnolence is not 690
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tiredness, fatigue or lassitude but, rather, clearcut sleepiness. It develops over a long period and is first experienced by a person as sleep onset when his or her attention is not demanded (e.g., when watching television, listening to a dull speaker at a meeting, reading quietly or waiting at a traffic light). Eventually more alerting situations are affected, such as long-distance driving or quiet conversation. The recording of specific historical details from the subject and his or her spouse is crucial to the diagnosis, particularly since patients sometimes do not realize the severity of their sleepiness. This is perhaps because they find it socially unacceptable or have slipped into it so gradually. Impairment of intellectual performance such as decreased concentration and memory loss is reported by most patients.'-3 Such personality changes as irritability and moodiness are seen in about 50% of subjects,'3 and more severe psychiatric disturbances such as major depression and psychosis have been reported.' In one study' 42% of patients reported decreased libido and impotence, and 30% experienced nocturnal enuresis. Cognitive impairment can be objectively detected in patients who become hypoxemic during sleep. Measurement of attention concentration, complex problem-solving and shortterm recall has been found to give scores in the impaired range.7'8 OSA in children can present as inattention at school and unexplained cor pulmonale. Physicians should pay attention to mothers' complaints of children snoring between colds. Automobile accidents have been reported to occur 2.0 to 2.6 times more frequently among patients with OSA than among others.9"'0 In the latter series one-third of OSA patients had been involved in an automobile accident within the preceding 5 years. Of 150 patients found to have OSA in a sleep laboratory 54% had had automobile accidents, 45% had had problems at work, and 14% were unable to work.' CMA guidelines recognize that untreated patients who drive are a threat to themselves and others."
Cardiovascular Hemodynamic and cardiac abnormalities are felt to be due to the repeated episodes of hypoxemia and hypercapnia and to fluctuations in intrathoracic pressure and autonomic tone during the periods of obstructed breathing; they are associated with various neurohumoral changes, including a persistently elevated catecholamine level.'2-16 Systemic and pulmonary artery pressures increase progressively to varying degrees depending on the duration of apnea and the degree of oxygen desaturation.'2-'4 In severely affected people systemic pressures may remain
M-
elevated day and night. Systemic hypertension has been reported in 50% to 60% of OSA patients."' 71'8 Conversely, sleep studies involving unselected patients with essential hypertension revealed that 20% to 30% of them had OSA.'9-2' Sustained pulmonary hypertension, often associated with clinical evidence of right ventricular failure, has been observed in about 20% of OSA patients.22-24 In such patients it has usually been associated with obstructive airways disease or morbid obesity.22-24 However, Fletcher and associates,25 in a study involving patients with chronic obstructive pulmonary disease, OSA and pulmonary hypertension, found that treatment of OSA substantially lowered the pulmonary artery pressures and improved right ventricular function. Thus, OSA, as well as pulmonary impairment, contributes significantly to the genesis of sustained pulmonary hypertension in such cases. Cardiac arrhythmias have been reported to be a significant complication of OSA in several series.18,26-28 Gf 400 OSA patients examined during sleep with a Holter monitor 11% had sinus arrest, 8% had second-degree heart block, and 20% had various other arrhythmias.26 The arrhythmias occurred predominantly during apneic episodes.26 In a study by Miller27 and in a recent report from our laboratory28 the main finding of concern was prolonged sinus pauses during apneic episodes in 9% and 8% of patients respectively. These three studies showed that the prevalence rate of ventricular arrhythmias was not significantly higher among patients with apnea than among control subjects. However, Shepard and collaborators,'8 in a study involving people with more severe apnea, found a significant increase in ventricular ectopy when the oxygen saturation fell below 60%.18
Death rate The death rate may be higher among people with OSA than among others because of the cardiovascular abnormalities described previously. Several early studies reported high death rates in small groups of patients with pickwickian syndrome who had severe OSA.2930 Two recent retrospective case series strongly suggested an increased death rate among men with OSA.3'32 A causal relation is suggested by the observation that 55% of deaths in one series occurred during sleep.33 Even though women are less commonly affected by OSA than men they may be at greater risk of death.34 He and colleagues3' retrospectively assessed the deaths in a group of 246 untreated men with OSA. Patients with an apnea index (Al [number of apneic episodes per hour]) greater than 20 had a probability of an 8-year cumulative survival of 0.63 (standard
deviation [SD] 0.17). The probability of 8-year survival in patients with an AI below 20 was 0.96 (SD 0.02). None of 58 patients who received tracheostomy or nasal continuous positive airway pressure (CPAP) died. The Stanford Sleep Group assessed the deaths among 198 OSA patients;32 71 had "more severe" apnea (mean AI 69 [SD 23]) and underwent tracheostomy, and 127 had "less severe" apnea (mean AI 43 [SD 30.5]) and were instructed only to lose weight. Over 5 years the age-adjusted mean cardiovascular death rate was 5.9 per 100 patients (95% confidence interval 2.1 to 11.6) in the conservatively treated group. There were no deaths in the tracheostomy group. In a third retrospective study, involving 91 patients with OSA and 35 control subjects followed for approximately 2.5 years, there were nine and four deaths respectively; this difference was not statistically significant.35 Similarly, Thorpy and coworkers36 found no difference in the 5-year and 10-year survival rates between OSA patients who underwent tracheostomy and untreated control subjects. However, the AI was not recorded in the former study and was only 5 in the latter. Thus, some or possibly all of these patients were much less severely affected than those in the previous studies.3",32
Prevalence rate The prevalence of OSA is unknown. The condition affects older children and adults, predominantly middle-aged men. Over 60% of patients are obese.",2 Women account for 12% to 35% of OSA patients, and most are postmenopausal.37'38 The largest population study, in Bologna, estimated a prevalence rate of 2.7% among men aged 30 to 60 years.39 Lavie,'7 in a survey of 1502 Israeli men, identified OSA in about 1% of those who completed the questionnaire. Franceschi and associates40 gave a questionnaire to 1051 consecutive patients admitted to a general hospital in Italy because of non-sleep-related illness; OSA was found in 14 (1.3%). From these data the prevalence rate of OSA appears to be at least 1% among men. However, the true rate may be lower, since all these studies were susceptible to selection bias and included mild cases.
Diagnosis OSA should be suspected whenever hypersomnia and snoring coexist. Also, patients may complain of nocturnal restlessness, frequent urination or enuresis and choking.'-6 Daytime symptoms include morning headache and the neuropsychologic CAN MED ASSOC J 1991; 144 (6)
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changes described previously. 1-6 Since the patient may be unaware of many of these symptoms the evidence given by third parties is important in the evaluation of suspected cases. Findings that may be present on physical examination include obesity, systemic hypertension, plethora associated with polycythemia and evidence of pulmonary hypertension and cor pulmonale;'-6 however, none of these need necessarily be seen. Evidence of predisposing conditions such as hypothyroidism, acromegaly, and maxillofacial and oronasopharyngeal abnormalities should be sought.1-6 The diagnosis of OSA is confirmed and the degree of severity established by means of overnight observation in a sleep laboratory.
Treatment Treatment criteria have not yet been clearly established. The decision to treat is currently based on an overall assessment of severity; this takes into account the Al, the extent of hypersomnia, other neuropsychologic sequelae, nocturnal arterial oxygen desaturation and sleep disruption, and the presence of cardiac dysrhythmias, pulmonary hypertension or abnormal daytime blood gas values.3'6 Treatment starts with the identification of aggravating factors and an attempt to eliminate them. The use of alcohol, sedatives and antihistamines should be avoided at night.3 4' Similarly, if obesity is present and can be corrected the OSA may be substantially alleviated or even resolved.42'43 Unfortunately, weight loss measures do not appear to be any more successful in this group than in obese people in general. There have been reports of various treatments of OSA, many of which have met with only limited success. These include the use of tongue-retaining devices,44 nasopharyngeal tubes,45 electrical stimulation of upper airway muscles46 and devices to influence body position during sleep in people with positional (supine) apnea. Most of these methods are too disruptive. The administration of oxygen is not effective in most cases of OSA.6,47 The tricyclic antidepressant protriptyline appears to have some selective dilating action on the upper airway muscles and may be useful in some mild cases of OSA.4849 This drug also suppresses rapid-eye-movement (REM) sleep and so may be effective in treating respiratory disorders associated with REM sleep.48 Treatment with respiratory stimulants such as medroxyprogesterone50 and acetazolamide5' has met with only limited success. When specific otorhinolaryngologic abnormalities such as nasopharyngeal tumours and tonsillar hypertrophy are present surgical correction frequently, although not invariably, alleviates or resolves the disorder.52 However, people with such abnormalities 692
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account for a very small proportion of those with OSA.' 352 Various procedures to reconstruct the maxillomandibular and hyoid bones have been proposed for OSA, but these are complex and extensive, are performed only in specialized centres and currently have limited applicability.53 A surgical procedure that has received considerable attention is uvulopalatopharyngoplasty (UPPP); it entails removal of part of the soft palate and adjacent oropharyngeal tissue. This technique, however, has been found to yield mean response rates of only 40% to 50%, response usually being defined as a significant reduction in the Al rather than cure.54-56 OSA may recur or worsen after the initial response to treatment.56 In one study the death rate among patients treated with UPPP was the same as that among untreated patients.32 Although success rates may ultimately increase with modification of surgical technique or improved patient selection through verification of the site of upper airway obstruction preoperatively57'58 such approaches have not yet been widely evaluated or proven to be effective. Therefore, it is the position of many sleep disorder centres that UPPP cannot currently be recommended as a standard first-line therapy for OSA. Until recently tracheostomy was the traditional definitive therapy for OSA. This procedure bypasses the site of airway obstruction and thus eliminates obstructive apneic episodes. However, although effective it is associated with major psychosocial, medical and economic implications that make it unacceptable in many cases.59 60 Nasal CPAP is now accepted as the standard treatment of OSA.6'1-1 A continuous flow of air is delivered from a blower unit to a tightly-fitting nasal mask held in place by head straps. Nasal CPAP acts as a "pneumatic splint," preventing collapse of the upper airway in all phases of respiration.6',7'72 The device is used for the entire sleep period every night. In most cases therapy must be continued indefinitely if the discontinuation of alcohol or sedative use at night or the treatment of predisposing factors such as obesity and specific otorhinolaryngologic abnormalities is not successful. The benefit of either tracheostomy or nasal CPAP is supported by evidence from uncontrolled case series in which the presence of abnormal function was assessed before and after the start of therapy.5961' 70-72 The evidence is so strong that randomized controlled studies will likely never be carried out. Therapy with tracheostomy or nasal CPAP eliminates apneic episodes completely in most cases, and in the absence of underlying lung disease oxygen saturation and sleep quality and pattern return to normal throughout the night.'4'59-70 The alleviation of symptoms is often dramatic, occurring within the first few days after the start of therapy. In the largest
reported series of patients who underwent tracheostomy and were followed up over a long period 94% of 50 patients reported complete disappearance of daytime somnolence.59 Those with symptoms of impaired concentration, morning headaches and confusion, personality change, nocturnal enuresis, abnormal movements during sleep and impotence experienced complete resolution of these symptoms after tracheostomy.59 Nasal CPAP has been reported to be equally effective in completely relieving these neuropsychologic complications.61-70 Through the use of psychometric indices improvement has been objectively documented.73-75 In a study involving eight OSA patients hemodynamic studies showed sustained decreases in nocturnal pulmonary hypertension after tracheostomy, the mean pulmonary artery pressure falling from 49 (SD 8) to 22 (SD 4) mm Hg.'4 Signs of right ventricular failure in OSA patients resolved in all those who complied with long-term nasal CPAP therapy.62'63,70 Tracheostomy and nasal CPAP have been found to alleviate systemic hypertensionl4'59'62'65 and to resolve arrhythmias due to OSA.26'28 The results of the two controlled studies described previously3",32 strongly support the effectiveness of therapy in lowering the death rate. In the first study there was an increased 8-year cumulative death rate among 246 untreated OSA patients, as compared with no deaths among 58 patients treated with nasal CPAP or tracheostomy. In the second study the age-adjusted 5-year rate of death from cardiovascular causes was 5.4 per 100 patients in the untreated group of 127 patients with mild OSA, as compared with no deaths in the group of 71 patients with more severe OSA treated with tracheostomy. Serious adverse consequences of nasal CPAP appear to be exceedingly rare. There have been reports of cases in which nocturnal hypoxemia was worse after the start of nasal CPAP.3'76,77 However, such complications are very unusual and are detected during the first application, which should always be monitored, preferably in a sleep laboratory. Although some patients refuse nasal CPAP because of discomfort or inconvenience, most appear to accept it as long-term treatment. Formal evaluation of compliance over 1 to 3 years in several studies has indicated that about 75% of patients who begin home nasal CPAP use continue to use it.64,78-81 Patients who discontinue it likely had less prolonged nocturnal desaturation8' and less severe daytime hypersomnolence80 before therapy. The main problems encountered during treatment are nasal and pharyngeal dryness, for which humidification may be added to the circuit, and eye or facial discomfort, which is often alleviated through mask refitting.64'80'8' Technical modifications of conventional nasal CPAP apparatus are being examined for improved comfort
and compliance; these include various mask modifications and the independent adjustment of inspiratory and expiratory positive airway pressures.82 In general, spousal acceptance of nasal CPAP therapy is very good.80'8'
Summary Although the true incidence of OSA is unknown the condition is clearly common. It usually presents as hypersomnolence in a patient who snores, although other neuropsychologic or cardiovascular abnormalities may prompt the patient to seek medical attention. OSA is associated with significant complications and probably an increased risk of death. However, it can be effectively treated by relatively simple, safe and inexpensive means in the form of nasal CPAP. Therefore, recognition of OSA by health professionals is extremely important.
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39. Cirignotta F, D'Alessandro R, Partinen OM et al: Prevalence of sleep apnoeas and heavy snorers disease. Sleep Res 1988; 17: 162 40. Franceschi M, Smirne S, Zamproni P et al: Excessive daytime sleepiness in a non-selected in-patient population. Sleep Res 1980; 9: 196 41. Scrima L, Broudy M, Nay K et al: Increased severity of obstructive sleep apnea after bedtime alcohol ingestion: diagnostic potential and proposed mechanism of action. Sleep 1982; 5: 318-328 42. Aubert-Tulkens G, Culee C, Rodenstein DO: Cure of sleep apnea syndrome after long-term nasal continuous positive airway pressure therapy and weight loss. Sleep 1989; 12: 216222 43. Suratt PM, McTier R, Findley LJ et al: Changes in breathing and the pharynx after weight loss in obstructive sleep apnea. Chest 1987; 92: 631-637 44. Cartwright RD, Samelson CF: The effects of nonsurgical treatment for obstructive sleep apnea: the tongue-retaining device. JAMA 1982; 248: 705-709 45. Nahmias JS, Karetzky MS: Treatment of the obstructive sleep apnea syndrome using a nasopharyngeal tube. Chest 1988; 94: 1142-1147 46. Miki H, Hida W, Chonan T et al: Effects of submental electrical stimulation during sleep on upper airway patency in patients with obstructive sleep apnea. Am Rev Respir Dis 1989; 140: 1285-1289 47. Smith PL, Haponik EF, Bleecker ER: The effects of oxygen in patients with sleep apnea. Am Rev Respir Dis 1984; 130: 958963 48. Smith PL, Haponik EF, Allen RP et al: The effects of protriptyline in sleep-disordered breathing. Am Rev Respir Dis 1983; 127: 8-13 49. Bonora M, St. John WM, Bledsoe TA: Differential elevation by protriptyline and depression by diazepam of upper airway respiratory motor activity. Am Rev Respir Dis 1985; 131: 41 45 50. Strohl KP, Hensley MJ, Saunders NA et al: Progesterone administration and progressive sleep apneas. JAMA 1981; 245: 1230-1232 51. Tojima H, Kunitomo F, Kimura H et al: Effects of acetazolamide in patients with the sleep apnoea syndrome. Thorax 1988; 43: 113-119 52. Aubert-Tulkens G, Hamoir M, van den Eeckhaut J et al: Failure of tonsil and nose surgery in adults with long-standing severe sleep apnea syndrome. Arch Intern Med 1989; 149: 2118-2121 53. Guilleminault C, Quera-Salva MA, Powell NB et al: Maxillomandibular surgery for obstructive sleep apnoea. Eur Respir J 1989; 2: 604-612 54. Cohn MA, Hernandez S, Foster AC et al: Uvulopalatopharyngoplasty in obstructive sleep apnea: clinical evaluation in 92 consecutive patients [abstr]. Chest 1983; 84: 336 55. Fujita S, Conway W, Zorick F et al: Evaluation of the effectiveness of uvulopalatopharyngoplasty. Sleep Res 1983; 12: 248 56. Schoen LS, Weisenberger S, Anand VK et al: Long-term effectiveness of uvulopalatopharyngoplasty. Sleep Res 1985; 14:212 57. Shepard JW, Thawley SE: Evaluation of the upper airway by computerized tomography in patients undergoing uvulopalatopharyngoplasty for obstructive sleep apnea. Am Rev Respir Dis 1989; 140: 711-716 58. Sher AE, Thorpy MJ, Shprintzen RJ et al: Predictive value of Muller maneuver in selection of patients for uvulopalatopharyngoplasty. Laryngoscope 1985; 95: 1483-1487 59. Guilleminault C, Simmons FB, Motta J et al: Obstructive sleep apnea syndrome and tracheostomy: long-term follow-up experience. Arch Intern Med 1981; 141: 985-988 60. Conway WA, Victor LD, Magitligan J et al: Adverse effects of tracheostomy for sleep apnea. JAMA 1981; 246: 347-350
61. Sullivan CE, Issa FG, Berthon-Jones M et al: Reversal of obstructive sleep apnoea by continuous positive airway pressure applied through the nares. Lancet 1981; 1: 862-865 62. Sullivan CE, Berthon-Jones M, Issa FG: Remission of severe obesity-hypoventilation syndrome after short-term treatment during sleep with nasal continuous positive airway pressure. Am Rev Respir Dis 1983; 128: 177-181 63. Sullivan CE, Issa FG, Berthon-Jones M et al: Home treatment of obstructive sleep apnoea with continuous positive airway pressure applied through a nose-mask. Bull Eur Physiopathol Respir 1984; 20: 49-54 64. Issa FG, Costas LV, Berthon-Jones M et al: Nasal CPAP treatment for obstructive sleep apnea: long-term experience with 117 patients [abstrJ. Am Rev Respir Dis 1985; 131: A108 65. Rapoport DM, Sorkin B, Gamy SM et al: Reversal of the "pickwickian syndrome" by long-term use of nocturnal nasalairway pressure. N Engl J Med 1982; 307: 931-933 66. Sanders MH, Moore SE, Eveslage J: CPAP via nasal mask: a treatment for occlusive sleep apnea. Chest 1983; 83: 144-145 67. Sanders MH: Nasal CPAP effect on patterns of sleep apnea. Chest 1984; 86: 839-844 68. Guilleminault C, Nino-Murcia G, Heldt G et al: Alternative treatment to tracheostomy in obstructive sleep apnea syndrome: nasal continuous positive airway pressure in young children. Pediatrics 1986; 78: 797-802 69. McEvoy RD, Thornton AT: Treatment of obstructive sleep apnea syndrome with nasal continuous positive airway pressure. Sleep 1984; 7: 313-325 70. Frith RW, Cant BR: Severe obstructive sleep apnoea treated with long term nasal continuous positive airway pressure. Thorax 1985; 40: 45-50 71. Strohl KP, Redline S: Nasal CPAP therapy, upper airway muscle activation, and obstructive sleep apnea. Am Rev Respir Dis 1986; 134: 555-558 72. Rapoport DM, Garay SM, Roldring RM: Nasal CPAP in obstructive sleep apnea: mechanisms of action. Bull Eur Physiopathol Respir 1983; 19: 616-620 73. Derderian SS, Bridenbaugh RH, Rajagopal KR: Neuropsychologic symptoms in obstructive sleep apnea improve after treatment with nasal continuous positive airway pressure. Chest 1988; 94: 1023-1028 74. Rajagopal KR, Bennett LL, Dullard TA et al: Overnight nasal CPAP improves hypersomnolence in sleep apnea. Chest 1986; 90: 172-176 75. Millman RP, Fogel BS, McNamara ME et al: Depression as a manifestation of obstructive sleep apnea: reversal with nasal continuous positive airway pressure. J Clin Psychiatry 1989; 50: 348-351 76. Krieger J, Weitzenblum E, Monassier JP et al: Dangerous hypoxemia during continuous positive airway pressure treatment of obstructive sleep apnoea. Lancet 1983; 2: 1429-1430 77. Andersen APD, Alving J, Lildholdt T et al: Obstructive sleep apnea initiated by a lax epiglottis: a contraindication for continuous positive airway pressure. Chest 1987; 91: 621-623 78. Sanders MH, Gruendl CA, Rogers RM: Patient compliance with nasal CPAP therapy for sleep apnea. Chest 1986; 90: 330-333 79. Krieger J, Kurtz D: Objective measurement of compliance with nasal CPAP treatment for obstructive sleep apnoea syndrome. Eur Respir J 1988; 1: 436-438 80. Waldhorn RE, Herrick TW, Nguyen MC et al: Long-term compliance with nasal continuous positive airway pressure therapy of obstructive sleep apnea. Chest 1990; 97: 33-38 81. Nino-Murcia G, McCann CC, Bliwise DL et al: Compliance and side effects in sleep apnea patients treated with nasal continuous positive airway pressure. West J Med 1989; 150: 165-169 82. Sanders MH, Kern N: Obstructive sleep apnea treated by independently adjusted inspiratory and expiratory positive airway pressures via nasal mask: physiologic and clinical implications. Chest 1990; 98: 317-324
Conferences continuedfrom page 685 June 13-15, 1991: College of Family Physicians of Canada (Ontario and Manitoba chapters) Spring Seminar Minaki Lodge, Kenora, Ont. Ontario Chapter, College of Family Physicians of Canada,
4000 Leslie St., Willowdale, ON M2K 2R9; (416) 493-7641, fax (416) 493-9630 June 14-15, 1991: Suicide, Sleep and School Problems in Children and Adolescents Health Sciences Centre, University of Calgary University of Calgary Health Sciences Centre, 3330 Hospital Dr. NW, Calgary, AB T2N 4N 1; (403) 220-7240 June 16-18, 1991: Canadian College of Health Service Executives Annual Conference Toronto Canadian College of Health Service Executives, 201-17 York St., Ottawa, ON KIN 5S7; (613) 235-7218, fax (613) 235-5451 June 21, 1991: Multiple Organ and Retrieval Exchange
(MORE) Program of Ontario Annual Meeting Royal York Hotel, Toronto Cheryl Rosell, executive director, 503-984 Bay St., Toronto, ON M5S 2A5; (416) 921-1130 or 1-800-263-2833 June 24-26, 1991: 8th International Congress on Group Medicine Helsinki L.R. International Ltd., Makelankatu 2 B, 00500 Helsinki,
Finland; telephone 358-0-773-1177, fax 358-0-7731187
July 14-18, 1991: International Conference on Nutrition and Immunology (sponsors include the World Health Organization Collaborating Centre for Research and Training in Nutritional Immunology and the Memorial University of Newfoundland) Hotel Newfoundland, St. John's Dr. Ranjit K. Chandra, Dr. Charles A. Janeway Child Health Centre, St. John's, NF Al A I R8; (709) 778-4519, fax (709) 778-4191 July 14-20, 1991: 1st World Congress on Wilderness Medicine (7th Annual Meeting of the Wilderness Medical Society and I st in a series of quadrennial international events) Chateau Whistler Resort, Whistler, BC Abstract deadline is Apr. 1, 1991. Dr. Douglas A. Gentile, Vanderbilt University, 243 Medical Center South, Nashville, TN 37212, (615) 343-4836, fax (615) 343-6873; or Dian M. Simpkins, Wilderness Medical Society, PO Box 397, Point Reyes Station, CA 94956, (415) 663-9107
continued on page 726 CAN MED ASSOC J 1991; 144 (6)
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Clinical features and treatment of obstructive sleep apnea R. John Kimoff, MD, FRCPC; Manuel G. Cosio, MD; Maurice McGregor, MD, FRCP Objective: To review the clinical features and treatment of obstructive sleep apnea
(OSA).
Data source and selection: All articles on OSA published in French and English between 1970 and 1990 and indexed in Index Medicus were reviewed. Studies addressing the epidemiologic features and clinical aspects of OSA were selected, and special emphasis was given to articles reporting the effects of treatment on morbidity and mortality rates. Main results: OSA is characterized by episodes of upper airway obstruction during sleep that result in repetitive hypoxemia and sleep disruption. OSA leads to various neuropsychologic and cardiovascular complications, including daytime hypersomnolence, cognitive impairment, systemic and pulmonary hypertension and cardiac arrhythmias. There is suggestive evidence that the death rate among affected people is increased. The true incidence of OSA is unknown, but estimates have varied from 1% upwards among men. The current treatment with the greatest overall effectiveness and acceptability is nasal continuous positive airway pressure. Conclusion: This common, readily treatable disorder is associated with serious complications and therefore must be widely recognized by health professionals.
Objectif: Examiner les caracteristiques cliniques et le traitement de l'apnee obstructive du sommeil (AOS). Source des donnees et selection: Tous les articles sur I'AOS publies en francais et en anglais entre 1970 et 1990 et figurant dans l'Index Medicus ont ete examines. Les etudes sur les caracteristiques epidemiologiques et les aspects cliniques de l'AOS ont ete selectionnees, avec insistance speciale sur les articles precisant les effets du traitement sur les taux de morbidite et de mortalite. Principaux resultats: L'AOS se caracterise par des episodes d'occlusion des voies respiratoires superieures pendant le sommeil, occlusion resultant en hypoxemie repetitive et troubles du sommeil. L'AOS conduit a diverses complications neuropsychologiques et cardiovasculaires, notamment l'hypersomnolence diume, les handicaps cognitifs, l'hypertension systemique et pulmonaire et l'arythmie. Les preuves laissent penser que les taux de deces ont augmente chez les personnes touchees. L'incidence reelle de 1'AOS est inconnue, mais les estimations varient de 1 % et plus chez les hommes. Le traitement actuel le plus efficace et le plus acceptable globalement est la pression nasale continue positive sur les voies aeriennes superieures. Conclusion: Ce problbme courant et de traitement facile est associe A des complications graves et doit donc etre largement reconnu par les specialistes de la sante. From the Department ofMedicine, McGill University, and the Desmond N. Stoker Pulmonary and Sleep Laboratory, Royal Victoria
Hospital, Montreal, Que.
Based on a report prepared at the request of the Conseil d'evaluation des technologies de la sante du Quebec. Dr.
Kimoff was supported by a research fellowship of the Canadian Lung Association.
Dr.
Kimoff is assistant professor, Dr. Cosio professor and Dr. McGregor professor emeritus, Department ofMedicine, McGill University.
Reprint requests to: Dr. Manuel G. Cosio, Rm. L4.09, Royal Victoria Hospital, 687 Pine Ave. W, Montreal, PQ H3A JAI -
For prescribing information see page 81 0
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In recent years there has been increasing awareness of the prevalence and significance of respiratory disorders during sleep. One of these, obstructive sleep apnea (OSA), was only recently recognized but has already been found to occur frequently in the population. Because it is associated with significant complications that are treatable this disorder must be widely recognized. We therefore decided to review articles published in French and English between 1970 and 1990 that were indexed in Index Medicus. Studies addressing the epidemiologic features and clinical aspects of OSA were selected, and special emphasis was given to articles reporting the effects of treatment on morbidity and mortality rates.
Etiologic features OSA is due to temporary obstruction of the oropharynx or hypopharynx during sleep. It is characterized by loud snoring that is repeatedly interrupted by episodes of complete upper airway obstruction and resolves with temporary arousal. A commonly used definition is a condition in which 10 or more episodes of obstruction, each lasting more than 10 seconds, are detected per hour of sleep.1 The OSA syndrome refers to the constellation of neuropsychologic and cardiovascular complications resulting from the recurrent episodes of hypoxemia or the repetitive interruption of sleep or both. The cause of OSA is poorly defined but appears to be multifactorial; upper airway tract malformation, oropharyngeal muscle dysfunction and abnormal respiratory drive each play a greater or lesser part. Obesity and alcohol consumption are well recognized as aggravating factors.
Complications Neuropsychologic Neuropsychologic disturbance is marked by excessive daytime sleepiness or hypersomnolence. It is the result of major disruption of normal sleep patterns because of repetitive arousal from sleep. Patients experience episodes of falling asleep while seated quietly and even while performing purposeful activities. These episodes can occur during work or social functions and can lead to embarrassment, domestic discord, decreased work productivity, loss of employment and an increased incidence of accidents. I6 Hypersomnolence is the single most important presenting symptom and frequently identifies which patients will require, and accept, specific therapy. It is not, however, a symptom physicians have learned to elicit in their training. Hypersomnolence is not 690
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tiredness, fatigue or lassitude but, rather, clearcut sleepiness. It develops over a long period and is first experienced by a person as sleep onset when his or her attention is not demanded (e.g., when watching television, listening to a dull speaker at a meeting, reading quietly or waiting at a traffic light). Eventually more alerting situations are affected, such as long-distance driving or quiet conversation. The recording of specific historical details from the subject and his or her spouse is crucial to the diagnosis, particularly since patients sometimes do not realize the severity of their sleepiness. This is perhaps because they find it socially unacceptable or have slipped into it so gradually. Impairment of intellectual performance such as decreased concentration and memory loss is reported by most patients.'-3 Such personality changes as irritability and moodiness are seen in about 50% of subjects,'3 and more severe psychiatric disturbances such as major depression and psychosis have been reported.' In one study' 42% of patients reported decreased libido and impotence, and 30% experienced nocturnal enuresis. Cognitive impairment can be objectively detected in patients who become hypoxemic during sleep. Measurement of attention concentration, complex problem-solving and shortterm recall has been found to give scores in the impaired range.7'8 OSA in children can present as inattention at school and unexplained cor pulmonale. Physicians should pay attention to mothers' complaints of children snoring between colds. Automobile accidents have been reported to occur 2.0 to 2.6 times more frequently among patients with OSA than among others.9"'0 In the latter series one-third of OSA patients had been involved in an automobile accident within the preceding 5 years. Of 150 patients found to have OSA in a sleep laboratory 54% had had automobile accidents, 45% had had problems at work, and 14% were unable to work.' CMA guidelines recognize that untreated patients who drive are a threat to themselves and others."
Cardiovascular Hemodynamic and cardiac abnormalities are felt to be due to the repeated episodes of hypoxemia and hypercapnia and to fluctuations in intrathoracic pressure and autonomic tone during the periods of obstructed breathing; they are associated with various neurohumoral changes, including a persistently elevated catecholamine level.'2-16 Systemic and pulmonary artery pressures increase progressively to varying degrees depending on the duration of apnea and the degree of oxygen desaturation.'2-'4 In severely affected people systemic pressures may remain
M-
elevated day and night. Systemic hypertension has been reported in 50% to 60% of OSA patients."' 71'8 Conversely, sleep studies involving unselected patients with essential hypertension revealed that 20% to 30% of them had OSA.'9-2' Sustained pulmonary hypertension, often associated with clinical evidence of right ventricular failure, has been observed in about 20% of OSA patients.22-24 In such patients it has usually been associated with obstructive airways disease or morbid obesity.22-24 However, Fletcher and associates,25 in a study involving patients with chronic obstructive pulmonary disease, OSA and pulmonary hypertension, found that treatment of OSA substantially lowered the pulmonary artery pressures and improved right ventricular function. Thus, OSA, as well as pulmonary impairment, contributes significantly to the genesis of sustained pulmonary hypertension in such cases. Cardiac arrhythmias have been reported to be a significant complication of OSA in several series.18,26-28 Gf 400 OSA patients examined during sleep with a Holter monitor 11% had sinus arrest, 8% had second-degree heart block, and 20% had various other arrhythmias.26 The arrhythmias occurred predominantly during apneic episodes.26 In a study by Miller27 and in a recent report from our laboratory28 the main finding of concern was prolonged sinus pauses during apneic episodes in 9% and 8% of patients respectively. These three studies showed that the prevalence rate of ventricular arrhythmias was not significantly higher among patients with apnea than among control subjects. However, Shepard and collaborators,'8 in a study involving people with more severe apnea, found a significant increase in ventricular ectopy when the oxygen saturation fell below 60%.18
Death rate The death rate may be higher among people with OSA than among others because of the cardiovascular abnormalities described previously. Several early studies reported high death rates in small groups of patients with pickwickian syndrome who had severe OSA.2930 Two recent retrospective case series strongly suggested an increased death rate among men with OSA.3'32 A causal relation is suggested by the observation that 55% of deaths in one series occurred during sleep.33 Even though women are less commonly affected by OSA than men they may be at greater risk of death.34 He and colleagues3' retrospectively assessed the deaths in a group of 246 untreated men with OSA. Patients with an apnea index (Al [number of apneic episodes per hour]) greater than 20 had a probability of an 8-year cumulative survival of 0.63 (standard
deviation [SD] 0.17). The probability of 8-year survival in patients with an AI below 20 was 0.96 (SD 0.02). None of 58 patients who received tracheostomy or nasal continuous positive airway pressure (CPAP) died. The Stanford Sleep Group assessed the deaths among 198 OSA patients;32 71 had "more severe" apnea (mean AI 69 [SD 23]) and underwent tracheostomy, and 127 had "less severe" apnea (mean AI 43 [SD 30.5]) and were instructed only to lose weight. Over 5 years the age-adjusted mean cardiovascular death rate was 5.9 per 100 patients (95% confidence interval 2.1 to 11.6) in the conservatively treated group. There were no deaths in the tracheostomy group. In a third retrospective study, involving 91 patients with OSA and 35 control subjects followed for approximately 2.5 years, there were nine and four deaths respectively; this difference was not statistically significant.35 Similarly, Thorpy and coworkers36 found no difference in the 5-year and 10-year survival rates between OSA patients who underwent tracheostomy and untreated control subjects. However, the AI was not recorded in the former study and was only 5 in the latter. Thus, some or possibly all of these patients were much less severely affected than those in the previous studies.3",32
Prevalence rate The prevalence of OSA is unknown. The condition affects older children and adults, predominantly middle-aged men. Over 60% of patients are obese.",2 Women account for 12% to 35% of OSA patients, and most are postmenopausal.37'38 The largest population study, in Bologna, estimated a prevalence rate of 2.7% among men aged 30 to 60 years.39 Lavie,'7 in a survey of 1502 Israeli men, identified OSA in about 1% of those who completed the questionnaire. Franceschi and associates40 gave a questionnaire to 1051 consecutive patients admitted to a general hospital in Italy because of non-sleep-related illness; OSA was found in 14 (1.3%). From these data the prevalence rate of OSA appears to be at least 1% among men. However, the true rate may be lower, since all these studies were susceptible to selection bias and included mild cases.
Diagnosis OSA should be suspected whenever hypersomnia and snoring coexist. Also, patients may complain of nocturnal restlessness, frequent urination or enuresis and choking.'-6 Daytime symptoms include morning headache and the neuropsychologic CAN MED ASSOC J 1991; 144 (6)
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1--
changes described previously. 1-6 Since the patient may be unaware of many of these symptoms the evidence given by third parties is important in the evaluation of suspected cases. Findings that may be present on physical examination include obesity, systemic hypertension, plethora associated with polycythemia and evidence of pulmonary hypertension and cor pulmonale;'-6 however, none of these need necessarily be seen. Evidence of predisposing conditions such as hypothyroidism, acromegaly, and maxillofacial and oronasopharyngeal abnormalities should be sought.1-6 The diagnosis of OSA is confirmed and the degree of severity established by means of overnight observation in a sleep laboratory.
Treatment Treatment criteria have not yet been clearly established. The decision to treat is currently based on an overall assessment of severity; this takes into account the Al, the extent of hypersomnia, other neuropsychologic sequelae, nocturnal arterial oxygen desaturation and sleep disruption, and the presence of cardiac dysrhythmias, pulmonary hypertension or abnormal daytime blood gas values.3'6 Treatment starts with the identification of aggravating factors and an attempt to eliminate them. The use of alcohol, sedatives and antihistamines should be avoided at night.3 4' Similarly, if obesity is present and can be corrected the OSA may be substantially alleviated or even resolved.42'43 Unfortunately, weight loss measures do not appear to be any more successful in this group than in obese people in general. There have been reports of various treatments of OSA, many of which have met with only limited success. These include the use of tongue-retaining devices,44 nasopharyngeal tubes,45 electrical stimulation of upper airway muscles46 and devices to influence body position during sleep in people with positional (supine) apnea. Most of these methods are too disruptive. The administration of oxygen is not effective in most cases of OSA.6,47 The tricyclic antidepressant protriptyline appears to have some selective dilating action on the upper airway muscles and may be useful in some mild cases of OSA.4849 This drug also suppresses rapid-eye-movement (REM) sleep and so may be effective in treating respiratory disorders associated with REM sleep.48 Treatment with respiratory stimulants such as medroxyprogesterone50 and acetazolamide5' has met with only limited success. When specific otorhinolaryngologic abnormalities such as nasopharyngeal tumours and tonsillar hypertrophy are present surgical correction frequently, although not invariably, alleviates or resolves the disorder.52 However, people with such abnormalities 692
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account for a very small proportion of those with OSA.' 352 Various procedures to reconstruct the maxillomandibular and hyoid bones have been proposed for OSA, but these are complex and extensive, are performed only in specialized centres and currently have limited applicability.53 A surgical procedure that has received considerable attention is uvulopalatopharyngoplasty (UPPP); it entails removal of part of the soft palate and adjacent oropharyngeal tissue. This technique, however, has been found to yield mean response rates of only 40% to 50%, response usually being defined as a significant reduction in the Al rather than cure.54-56 OSA may recur or worsen after the initial response to treatment.56 In one study the death rate among patients treated with UPPP was the same as that among untreated patients.32 Although success rates may ultimately increase with modification of surgical technique or improved patient selection through verification of the site of upper airway obstruction preoperatively57'58 such approaches have not yet been widely evaluated or proven to be effective. Therefore, it is the position of many sleep disorder centres that UPPP cannot currently be recommended as a standard first-line therapy for OSA. Until recently tracheostomy was the traditional definitive therapy for OSA. This procedure bypasses the site of airway obstruction and thus eliminates obstructive apneic episodes. However, although effective it is associated with major psychosocial, medical and economic implications that make it unacceptable in many cases.59 60 Nasal CPAP is now accepted as the standard treatment of OSA.6'1-1 A continuous flow of air is delivered from a blower unit to a tightly-fitting nasal mask held in place by head straps. Nasal CPAP acts as a "pneumatic splint," preventing collapse of the upper airway in all phases of respiration.6',7'72 The device is used for the entire sleep period every night. In most cases therapy must be continued indefinitely if the discontinuation of alcohol or sedative use at night or the treatment of predisposing factors such as obesity and specific otorhinolaryngologic abnormalities is not successful. The benefit of either tracheostomy or nasal CPAP is supported by evidence from uncontrolled case series in which the presence of abnormal function was assessed before and after the start of therapy.5961' 70-72 The evidence is so strong that randomized controlled studies will likely never be carried out. Therapy with tracheostomy or nasal CPAP eliminates apneic episodes completely in most cases, and in the absence of underlying lung disease oxygen saturation and sleep quality and pattern return to normal throughout the night.'4'59-70 The alleviation of symptoms is often dramatic, occurring within the first few days after the start of therapy. In the largest
reported series of patients who underwent tracheostomy and were followed up over a long period 94% of 50 patients reported complete disappearance of daytime somnolence.59 Those with symptoms of impaired concentration, morning headaches and confusion, personality change, nocturnal enuresis, abnormal movements during sleep and impotence experienced complete resolution of these symptoms after tracheostomy.59 Nasal CPAP has been reported to be equally effective in completely relieving these neuropsychologic complications.61-70 Through the use of psychometric indices improvement has been objectively documented.73-75 In a study involving eight OSA patients hemodynamic studies showed sustained decreases in nocturnal pulmonary hypertension after tracheostomy, the mean pulmonary artery pressure falling from 49 (SD 8) to 22 (SD 4) mm Hg.'4 Signs of right ventricular failure in OSA patients resolved in all those who complied with long-term nasal CPAP therapy.62'63,70 Tracheostomy and nasal CPAP have been found to alleviate systemic hypertensionl4'59'62'65 and to resolve arrhythmias due to OSA.26'28 The results of the two controlled studies described previously3",32 strongly support the effectiveness of therapy in lowering the death rate. In the first study there was an increased 8-year cumulative death rate among 246 untreated OSA patients, as compared with no deaths among 58 patients treated with nasal CPAP or tracheostomy. In the second study the age-adjusted 5-year rate of death from cardiovascular causes was 5.4 per 100 patients in the untreated group of 127 patients with mild OSA, as compared with no deaths in the group of 71 patients with more severe OSA treated with tracheostomy. Serious adverse consequences of nasal CPAP appear to be exceedingly rare. There have been reports of cases in which nocturnal hypoxemia was worse after the start of nasal CPAP.3'76,77 However, such complications are very unusual and are detected during the first application, which should always be monitored, preferably in a sleep laboratory. Although some patients refuse nasal CPAP because of discomfort or inconvenience, most appear to accept it as long-term treatment. Formal evaluation of compliance over 1 to 3 years in several studies has indicated that about 75% of patients who begin home nasal CPAP use continue to use it.64,78-81 Patients who discontinue it likely had less prolonged nocturnal desaturation8' and less severe daytime hypersomnolence80 before therapy. The main problems encountered during treatment are nasal and pharyngeal dryness, for which humidification may be added to the circuit, and eye or facial discomfort, which is often alleviated through mask refitting.64'80'8' Technical modifications of conventional nasal CPAP apparatus are being examined for improved comfort
and compliance; these include various mask modifications and the independent adjustment of inspiratory and expiratory positive airway pressures.82 In general, spousal acceptance of nasal CPAP therapy is very good.80'8'
Summary Although the true incidence of OSA is unknown the condition is clearly common. It usually presents as hypersomnolence in a patient who snores, although other neuropsychologic or cardiovascular abnormalities may prompt the patient to seek medical attention. OSA is associated with significant complications and probably an increased risk of death. However, it can be effectively treated by relatively simple, safe and inexpensive means in the form of nasal CPAP. Therefore, recognition of OSA by health professionals is extremely important.
References 1. Guilleminault C, Hoed J, Mitler MM: Clinical overview of the sleep apnea syndromes. In Guilleminault C, Dement WC (eds): Sleep Apnea Syndromes, Liss, New York, 1978: 1-12 2. Block AJ, Cohn MA, Conway WA et al: Indications and standards for cardiopulmonary sleep studies. Sleep 1985; 8: 371-379 3. Sullivan CE, Issa FG: Obstructive sleep apnea. Clin Chest Med 1985; 6: 633-651 4. Strohl KP, Saunders NA, Sullivan CE: Sleep apnea syndromes. In Saunders NA, Sullivan CE (eds): Sleep and Breathing (Lung Biology in Health and Disease ser, vol 21), Dekker, New York, 1984: 365-402 5. Association of Sleep Disorders Centers and the Association for the Psychophysiological Study of Sleep: Diagnostic classification of sleep and arousal disorders (1st ed). Sleep 1979; 2: 1-154 6. Weil JV, Cherniack NS, Dempsey JA et al: Respiratory disorders of sleep: pathophysiology, clinical implications, and therapeutic approaches. Am Rev Respir Dis 1987; 136: 755761 7. Findley LJ, Barth JT, Powers DC et al: Cognitive impairment in patients with obstructive sleep apnea and associated hypoxemia. Chest 1986; 90: 686-690 8. Kales A, Caldwell AB, Cadieux RJ et al: Severe obstructive sleep apnea: 2. Associated psychopathology and psychosocial consequences. J Chronic Dis 1985; 5: 427-434 9. George CF, Nickerson PW, Hanly PJ et al: Sleep apnoea patients have more automobile accidents [C]. Lancet 1987; 2: 447 10. Findley IU, Bonnie RJ: Sleep apnea and auto crashes: What is the doctor to do? Chest 1988; 94: 225-226 11. Physicians' Guide to Driver Examination, 4th ed, Can Med Assoc, Ottawa, 1987 12. Parrish JM, Shepard JW: Cardiovascular effects of sleep disorders. Chest 1990; 97: 1220-1226 13. Tilkian AG, Guilleminault C, Schroeder JS et al: Hemodynamics in sleep-induced apnea: studies during wakefulness and sleep. Ann Intern Med 1976; 85: 714-719 14. Motta J, Guilleminault C, Schroeder JS et al: Tracheostomy and hemodynamic changes in sleep-induced apnea. Ann Intern Med 1978; 89: 454-458 15. Clark RW, Boudoulas H, Schaal SF et al: Adrenergic hyperacCAN MED ASSOC J 1991; 144 (6)
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Conferences continuedfrom page 685 June 13-15, 1991: College of Family Physicians of Canada (Ontario and Manitoba chapters) Spring Seminar Minaki Lodge, Kenora, Ont. Ontario Chapter, College of Family Physicians of Canada,
4000 Leslie St., Willowdale, ON M2K 2R9; (416) 493-7641, fax (416) 493-9630 June 14-15, 1991: Suicide, Sleep and School Problems in Children and Adolescents Health Sciences Centre, University of Calgary University of Calgary Health Sciences Centre, 3330 Hospital Dr. NW, Calgary, AB T2N 4N 1; (403) 220-7240 June 16-18, 1991: Canadian College of Health Service Executives Annual Conference Toronto Canadian College of Health Service Executives, 201-17 York St., Ottawa, ON KIN 5S7; (613) 235-7218, fax (613) 235-5451 June 21, 1991: Multiple Organ and Retrieval Exchange
(MORE) Program of Ontario Annual Meeting Royal York Hotel, Toronto Cheryl Rosell, executive director, 503-984 Bay St., Toronto, ON M5S 2A5; (416) 921-1130 or 1-800-263-2833 June 24-26, 1991: 8th International Congress on Group Medicine Helsinki L.R. International Ltd., Makelankatu 2 B, 00500 Helsinki,
Finland; telephone 358-0-773-1177, fax 358-0-7731187
July 14-18, 1991: International Conference on Nutrition and Immunology (sponsors include the World Health Organization Collaborating Centre for Research and Training in Nutritional Immunology and the Memorial University of Newfoundland) Hotel Newfoundland, St. John's Dr. Ranjit K. Chandra, Dr. Charles A. Janeway Child Health Centre, St. John's, NF Al A I R8; (709) 778-4519, fax (709) 778-4191 July 14-20, 1991: 1st World Congress on Wilderness Medicine (7th Annual Meeting of the Wilderness Medical Society and I st in a series of quadrennial international events) Chateau Whistler Resort, Whistler, BC Abstract deadline is Apr. 1, 1991. Dr. Douglas A. Gentile, Vanderbilt University, 243 Medical Center South, Nashville, TN 37212, (615) 343-4836, fax (615) 343-6873; or Dian M. Simpkins, Wilderness Medical Society, PO Box 397, Point Reyes Station, CA 94956, (415) 663-9107
continued on page 726 CAN MED ASSOC J 1991; 144 (6)
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