Sleep Apnea in Acromegaly Ronald R. Grunstein, MB, BS; Kian Y. Ho, MD; and Colin E. Sullivan, MB, BS, PhD
• Objective: To provide information on the nature, prevalence, and severity of sleep apnea in patients with acromegaly. • Design: Consecutive case series. • Setting: Tertiary referral hospital. • Patients: Fifty-three patients with acromegaly were consecutively referred: 33 patients were referred because of clinical suspicion of sleep apnea and 20 patients were referred without suspected apnea. • Measurements: Sleep studies as well as growth hormone and insulin-like growth factor 1 (IGF-1) measurements were done. • Main Results: Thirty-one patients (93%; 95% CI, 85% to 100%) referred because of suspicion of sleep apnea had sleep apnea compared with 12 patients (60%; CI, 37% to 83%) referred without suspected sleep apnea. Patients with sleep apnea did not have biochemical evidence of increased disease activity (random growth hormone, 12.7 ± 4.4 |xg/L; mean growth hormone at 24-hour sampling, 10.8 ± 8.4 |xg/L; IGF-1, 90.0 ± 7.5 nmol/L) compared with patients without sleep apnea (random growth hormone, 14.2 ± 4.9 H,g/L, P> 0.2; mean growth hormone, 12.4 ± 3.5 |ig/L, P> 0.2; IGF-1, 90.0 ± 10.0 nmol/L, P> 0.2). Central sleep apnea was the predominant type of apnea in 33% (CI, 18% to 47%) of patients and was associated with higher random growth hormone and IGF-1 levels than was obstructive apnea (random growth hormone, 23.4 ± 3.9 compared with 8.8 ± 3.1 jjig/L, P< 0.001; IGF-1, 126 ± 17.5 compared with 72.5 ± 7.5 nmol/L, P 0.2 except where noted. f P < 0.001. XP = 0.11. § P = 0.06.
Transcutaneous carbon dioxide tension was measured continuously using a capnometer (Hewlett-Packard 47210A), and ribcage and abdominal wall motion were recorded using a respiratory inductive plethysmograph (Respitrace, Ambulatory Monitoring, Ardesley, New York). Diaphragm electromyography was done using two gold-plated cup electrodes placed in the right subcostal region, one at the mid-clavicular line and the other, 2.0 cm lateral to it. The interelectrode impedance level was kept below 3.0 kilohms. Sleep was monitored using two channels of electroencephalogram (C4/A, and C3/A 2 ), two channels of electro-oculogram, and one channel of submental electromyogram. To facilitate analysis, sleep stages 1 and 2 were combined, as were stages 3 and 4. Sleep stages were expressed as a percentage of total sleep time. All variables were recorded continuously on a 16-channel polygraph (Model 78; Grass Instruments, Quincy, Massachusetts). Apnea was defined as cessation of airflow for 10 seconds or longer. Hypopnea was defined as a 50% or greater decrease in thoraco-abdominal activity without cessation of airflow associated with at least a 4% decrease in oxygen saturation. All variables were used to determine the frequency and nature of apneic and hypopneic episodes. The number of episodes per hour of sleep was calculated and expressed as a respiratory disturbance index. For convenience, all such respiratory events were considered to be episodes of apnea. Apnea was classified as either central (absence of airflow associated with cessation of breathing as shown by inductive plethysmography and diaphragm electromyography) or obstructive (absence of airflow despite recorded breathing efforts and diaphragm electromyographic phasic activity). Episodes of "mixed apnea" (absence of airflow associated with cessation of breathing effort in the first part of the event, followed by a period of chest-wall movement and phasic electromyographic activity) were separated into central and obstructive components, and the time of each component was measured. The duration of all obstructive and central events was measured and expressed as a percentage of total sleep time—either central apnea time or obstructive apnea time. Patients were classified as having predominantly central sleep apnea if they had a respiratory disturbance index of 5 or greater and had a longer duration of central apnea than obstructive apnea. Similar criteria were used to classify predominantly obstructive apnea. The mean duration of apnea was also calculated. Oxygen saturation data were expressed as the mean minimum oxygen saturation (mean of the nadir oxygen saturation values reached during each apnea) and the lowest oxygen saturation level reached during the sleep study. 528
Respiratory F u n c t i o n Forced expiratory volume in 1 second (FEV,) and forced vital capacity (FVC) were measured with the subject in the sitting position using a spirometer (Vitalograph Ltd., Buckingham, England). Values were reported as a percentage of those predicted from height and age. Arterial blood gases were sampled with the patient in the supine position from the radial artery after infiltration with 1% lignocaine while the patient was awake (Corning Blood Gas Analyzer, Medfield, Massachusetts).
Endocrine Measurements The extent of pituitary hyperfunction was assessed using measurements of growth hormone and IGF-1 levels. In 30 patients, growth hormone level was measured from a single randomly obtained or fasting sample. In 23 patients (20 patients from group 2 and 3 patients from group 1), growth hormone secretion was studied from measurements obtained at 20-minute intervals during a 24-hour period. We used these data to determine whether the mean growth hormone output or pulsatile pattern of secretion was related to the extent of respiratory impairment during sleep. Respiratory sleep and 24hour hormone sampling studies were done on separate nights less than 1 week apart to avoid possible effects of the blood sampling procedure on the quality of the sleep study. Patients having blood sampling were hospitalized at the Clinical Investigation Unit at St Vincent's Hospital. After the patient fasted overnight at 0800 hours an intravenous cannula was inserted, and blood samples were obtained every 20 minutes beginning at 0900 hours. Patients were encouraged to walk freely during the day and were allowed to sleep after 2200 hours without sleep monitoring. Hospital meals were served at 0930, 1300, and 1800 hours. Sleep studies were done at the Sleep Disorders Center within 1 week of the 24-hour growth hormone studies. Seventy-three samples taken from each patient's 24hour study were measured using one assay. The mean 24-hour growth hormone concentration was obtained by averaging these 73 measurements. In these 20 studies, fasting growth hormone (the first sample of the 24-hour study) correlated significantly with mean 24-hour growth hormone levels (r = 0.78, P = 0.001). Thus, a single growth hormone measurement was found to be a reasonable estimate of mean 24-hour growth hormone concentration (29). The pulsatile characteristics of growth hormone secretion were analyzed using CLUSTER, a computer-assisted pulse detection algorithm (11) that allowed quantitation of pulse frequency, amplitude (incremental increase over preceding nadir), and the coefficient of variation of growth hormone around the 24-hour mean (cv24h).
Assays Growth hormone was measured using a double-antibody radioimmunoassay with the First International Reference Preparation 66/217, which has a 2 IU/mg standard potency. The inter- and intra-coefficients of variation were 12.5% and 4.1%, respectively, at 2.6 /xg/L. Insulin-like growth factor I (IGF-I or somatomedin C) was measured by radioimmunoassay after acid ethanol extraction using two different radioimmunoassays. Samples from group 1 were measured at the endocrine laboratory, Royal Prince Alfred Hospital, using the method of Baxter and colleagues (12) and had a normal reference range of 11 to 37 nmol/L for patients who are 40 years of age. The inter- and intra-coefficients of variation for this method were 8.7% and 11.8%, respectively. Samples from group 2 were measured at the Garvan Institute of Medical Research using a commercial kit (INCSTAR, Immuno Nuclear Corporation, Stillwater, Minnesota) with an established normal range of 10 to 35 nmol/L. The inter- and intra-coefficients of variation for this method were 11.0% and 8.2%, respectively. Nine samples were measured using both assays and yielded a correlation coefficient of r = 0.89 (P < 0.001). The agreement between the assays was excellent.
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Statistical Analysis
Effect of Treatment
Values are expressed as means ± SE. Patient groups were compared using unpaired /-tests and chi-square analysis where appropriate. Multiple linear regression was used to assess the relation of age and sleep apnea to hypertension. Confidence intervals (CIs) of 95% were used.
Mean random growth hormone and IGF-1 levels did not differ between patients previously treated for acromegaly and those untreated for the disorder (growth hormone level, 13.5 ± 3.9 /xg/L compared with 31.0 ± 9.5 mlU/L; IGF-1, 87.8 ± 10.0 nmol/L compared with 98.7 ± 12.2 nmol/L; P = 0.6). Of the 33 previously treated patients, 26 had sleep apnea compared with 17 of 20 in the untreated group. Biochemical activity of disease and presence and severity of sleep apnea were unrelated to treatment status.
Results Of the 53 patients studied, 51 (96%; CI, 96% to 100%) snored heavily during sleep, whereas 43 (81%; CI, 70% to 92%) had sleep apnea as defined by a respiratory disturbance index of 5 or greater, fulfilling standard diagnostic criteria for sleep apnea (6) (Table 1). Figure 1 shows the histogram of sleep apnea severity for both selected (group 1) and unselected (group 2) patients expressed as a percentage of group totals. Thirty-one patients (93%; CI, 85% to 100%) from group 1 had sleep apnea compared with 12 patients (60%; CI, 37% to 83%) from group 2.
Anthropometric and Respiratory Data Thirty-six (68%) patients were men and 17 (32%) were women. There were no differences in age, obesity, IGF-1 levels, mean 24-hour growth hormone levels, or respiratory function between men and women. Women under 50 years of age experienced less sleep apnea (respiratory disturbance index, 2 ± 2) than did older women (respiratory disturbance index, 32 ± 8; P < 0.01). Men tended to have sleep apnea more frequently than did women (P = 0.06, chi-square test). Patients with sleep apnea were older than those without the disorder (Table 1).
Growth Hormone Secretion and IGF-1 All 20 patients who had not received treatment for their acromegaly had increased IGF-1 levels. Of the 33 patients previously treated for acromegaly, 28 had elevated IGF-1 levels. Thus, 48 of 53 had biochemical evidence of active disease. Mean growth hormone and IGF-1 levels did not differ between patients with and those without sleep apnea (Tables 1 and 2). In the 20 previously untreated patients, IGF-1 levels of those with (15 patients) and those without (5 patients) sleep apnea were similar (92.7 ± 10.8 nmol/L compared with 122.0 ± 33.6 nmol/L; P > 0.2). No relation existed between the severity of sleep apnea (as measured by either respiratory disturbance index or mean minimum oxygen saturation) and IGF-1 level. Moreover, 4 of the 5 patients who had normal IGF-1 concentrations were found to have sleep apnea. Of the 23 patients with detailed growth hormone secretory profiles, 16 had sleep apnea (2, predominantly central and 14, predominantly obstructive) (Table 2). In the subgroup having more extensive growth hormone measurements, no differences in mean growth-hormone level and growthhormone pulsatility were found between patients with and those without sleep apnea.
Selected and Nonselected Groups Patients in group 1 had selection bias for sleep apnea (respiratory disturbance index, 37 ± 4 compared with 17 ± 5, P = 0.001). Eleven of the 33 group-1 patients and 9 of the 20 group-2 (unselected) patients had received no treatment for acromegaly. The two groups did not differ in the prevalence of central apnea (group 1,11 patients; group 2, 3 patients) compared with obstructive apnea (group 1, 20 patients; group 2, 9 patients) (chisquare test, P > 0.2). The two groups did not differ in degree of active acromegaly (IGF-1 levels for group 1, 87.3 ± 8.8 nmol/L compared with group-2 levels, 97.4 ± 12.1 nmol/L; P> 0.2). Group-1 patients were slightly older (55 ± 2 years compared with 47 ± 3 years, P = 0.03) but were similar in degree of obesity (body mass index, 29.6 ± 0.9 compared with 29.5 ± 1.3). Hypertension Of the 43 patients who had sleep apnea, 22 had hypertension. All 10 patients who did not have sleep apnea were normotensive (chi-square test, P = 0.003). Patients who were hypertensive had higher respiratory disturbance indices (43 ± 6) and a greater degree of sleep hypoxemia (minimum oxygen saturation, 73 ± 3%) than did those who were normotensive (18 ± 3 and
Figure 1. Frequency distribution of sleep-disordered breathing in patients with acromegaly. Measured by respiratory disturbance index in events per hour in group 1 (33 patients; • ) and group 2 (20 patients; ^ ) .
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529
Table 2. Growth Hormone Profiles for 23 Patients with Acromegaly Not Referred for Suspected Sleep Apnea* Variable Men/women, nln IGF-1, nmollL Mean growth hormone, \xglL Cv24h, % Amp, fig/L
Apnea in = 16) MIA 98.8 ± 15.8 10.8 ± 8.4 30.6 ± 7.5 4.6 ± 1.2
No Apnea (#i = 7) 86.0 12.4 34.2 9.6
2/5 ±11.0 ± 3.5 ± 8.6 ± 2.7t
* Values are expressed as mean ± SE where appropriate. IGF-1 = insulin-like growth factor type 1. Cv24h = coefficient of variation over the 24-hour growth hormone mean value. Amp = incremental growth hormone increase above the preceding nadir. t P = 0.11. For all other results, P > 0.2.
85 ± 1%, respectively; P < 0.007). Mean 24-hour growth hormone and IGF-1 levels and body mass index did not differ between patients with hypertension and those without hypertension. Hypertensive patients were older (60 ± 2 compared with 45 ± 2 years, P < 0.009). The data were then analyzed to determine whether the degree of sleep apnea (respiratory disturbance index) was an independent predictor of hypertension after adjusting for age using multiple linear regression. After this analysis, both respiratory disturbance index (partial regression coefficient, 0.62 units per event per hour; 95% CI, 0.11 to 1.13; P = 0.01) and age (1.2% per year; CI, 0.3% to 2.1%; P = 0.005) were found to be independent predictors of hypertension. Type of Apnea Fourteen patients had predominantly central apnea (33%; CI, 18% to 47%), and 29 patients had predominantly obstructive apnea (67%; CI, 53% to 82%). Several factors were associated with central sleep apnea (Table 3). Patients with central sleep apnea had higher IGF-1 levels and mean random growth hormone levels, indicating that the degree of hypersecretion was strongly associated with central sleep apnea. In addition, patients with central sleep apnea had lower waking arterial carbon dioxide levels than did those with obstructive sleep apnea. The two groups did not differ in age, weight, sleep apnea severity, sleep architecture, medications, or incidence of hypertension. Discussion Our study of 53 patients has shown that snoring and sleep apnea are extremely common in patients with acromegaly. Our data also show that sleep apnea in acromegaly is predominantly of the central type in 30% of patients. Although the degree of growth hormone hypersecretion was related to the presence of a central pattern of apnea, it was unrelated to the occurrence of the apnea. Finally, hypertension in acromegaly was strongly associated with sleep apnea. Although previous studies have reported an association between sleep apnea and acromegaly (5-10), an accurate estimate of the prevalence, nature, and severity of sleep apnea in acromegaly has not been possible because of the small patient samples studied, the lack of information on patient selection, and limitations in the 530
extent and intensity of sleep monitoring. We have done detailed overnight polysomnography in large groups of selected and unselected patients. The prevalence of acromegaly has been estimated to be between 38 (13) and 60 (14) cases per million. Because the population base of our sleep disorders center is 5 million persons, we estimated that 200 to 300 persons with acromegaly live in our referral area. Our patient group, therefore, included more than 20% of those persons. Our total patient group was not randomly selected, and a clear referral bias toward patients with symptoms of sleep apnea existed. In our subset of consecutive referrals from another institution (group 2), however, 60% of patients had sleep apnea. Assuming that there were 300 patients with acromegaly in our referral base and that we found at least 42 with sleep apnea, then the lowest estimated prevalence of sleep apnea in acromegaly is 17%. Thus, an estimate of the minimum prevalence must be well above the prevalence of sleep apnea in the general population, which has been estimated to be between 1% and 5% (1). In addition, almost all of our patients had heavy snoring, compared with 19% of persons in the general adult population (15). The data show a strong association between sleep apnea and acromegaly. Sleep apnea was associated in our patient group with increasing age and tended to be more common in men and in women over 50 years of age. This trend parallels findings from the general population (1). One difference between our patient group and the general population was that obesity was not a predisposing factor in sleep apnea in our patient group. Increases in body mass index in patients with acromegaly may, however, be due to increased muscle mass rather than to the increased body fat typically seen in obesity (16). Previous studies that examined the relation between sleep apnea and biochemical activity of acromegaly have suggested that patients with active disease (meaTable 3. Characteristics of Patients with Acromegaly According to Prominent Apnea Type* Variable Men/women, nln Age, y Body mass index, kglm2 Random growth hormone, fJLgIL IGF-1, nmollL Respiratory disturbance index, events/hour MMOS, % Min o2, % Total sleep time, min Stages 1 and 2, % total sleep time Stages 3 and 4, % total sleep time Stage REM, % total sleep time po 2 , mm Hg pco 2 , mm Hg
Central (n = 14)
Obstructive (n = 29)
mi
22/7 57 ± 2 29 ± 1 8.8 ± 3.It 72.5 ± 7.5$
50 30 23.4 126
±4 ±1 ± 3.9 ± 17.5
33 ± 89 ± 81 ± 328 ± 79.7 ± 4.9 ± 15.4 ± 84 ± 39 ±
6 1 3 24 2.7 1.5 2.1 2 1
37 ± 88 ± 75 ± 325 ± 77.6 ± 4.0 ± 18.4 ± 80 ± 42 ±
5 1 2 14 1.7 1.2 1.3 3 1§
* Values are expressed as mean ± SE where appropriate. IGF-1 = insulin-like growth factor type 1. MMOS = mean minimum oxygen saturation. Min o2 = lowest oxygen saturation during sleep study; REM = rapid eye movement. P > 0.2 except where noted. t P= 0.001. $P= 0.01. § P = 0.03.
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sured by growth hormone levels) are more likely to have (7) or exclusively (9) have sleep apnea. These studies have been limited by the lack of either full sleep monitoring or detailed growth hormone and IGF-1 measurements, or both. In contrast to these earlier studies, we found no relation between the presence of sleep apnea and the degree of growth hormone hypersecretion in either treated or untreated patients. Although most treated patients still had biochemically active disease, 4 of 5 treated patients with normal IGF-1 levels (considered to be in biochemical remission and disease free) had sleep apnea. There is no a priori reason to expect a simple correlation between disease activity and sleep apnea. The pathophysiologic changes that cause sleep apnea are diverse, and these changes are unlikely to correlate at any one time with growth-hormone hypersecretion. The diverse pathophysiology of sleep apnea in acromegaly was emphasized by the unexpectedly high rate of central sleep apnea seen in this patient group, suggesting the involvement of abnormal central respiratory control. Central apnea is associated with a wide range of disorders, and many potential mechanisms have been described (18-21). The cause of apnea in acromegaly is unclear. Somatostatin is involved in both the control of breathing (22) and in the inhibitory control of growth hormone secretion. Because acromegaly results from unrestrained release of growth hormone, it is possible that in a subgroup of patients, acromegaly and sleep apnea may share a common pathophysiologic mechanism with defects occurring in central somatostatin pathways. Another possible mechanism relates to elevated levels of growth hormone or IGF-1; such elevations may affect central respiratory control and thus induce central apnea. This theory is supported by the correlation between growth hormone hypersecretion and the prevalence of central apnea. Cardiac failure can also induce central apnea (21) and is a feature of endstage acromegaly. Cardiac failure was considered a possible cause of apnea in only 2 of our patients because none of the other 12 patients with central apnea had evidence of cardiac disease. Whatever the mechanism, it is clear that the association between apnea and acromegaly is not simply the result of narrowing of an airway caused by macroglossia and soft-tissue swelling. The main cardiovascular abnormality in acromegaly is systemic hypertension. There seems to be more than a chance association between these factors because hypertension occurs more frequently in patients with acromegaly than in the general population (23) and because the blood pressure level is sometimes reduced by successful trans-sphenoidal surgery. One possible mechanism of hypertension in acromegaly is the retention of sodium and water (24). Our results indicate that sleep apnea may be another important cause of hypertension. This theory is supported by the observation that hypertension occurs in over 50% of patients with sleep apnea who do not have acromegaly, possibly caused by increased sympathetic activity induced by repetitive asphyxia (25, 26). Sleep apnea is also associated with increased cardiovascular disease (25) and mortality (27). In view of these findings, sleep apnea may be a factor in the increased incidence of cardiorespiratory deaths
noted previously in acromegaly (14, 28), and its diagnosis and treatment should be considered in the overall assessment of this disorder. Acknowledgments: The authors thank Ms. Belinda Brooks, Ms. Madeline Kinloch, and Ms. Deirdre Stewart as well as the staff of the Sleep Disorders Centre at Royal Prince Alfred Hospital for their assistance; Dr. Michael Berthon-Jones for statistical and database advice; and the many physicians who referred the patients in this study. Grant Support: by the National Health and Medical Research Council of Australia and the New South Wales Department of Health. Requests for Reprints: R. Grunstein, MB, BS, Sleep Disor ers Centre, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney, New South Wales, 2050 Australia. Current Author Addresses: Dr. Grunstein: Sleep Disorders Centre, Royal Prince Alfred Hospital, Missenden Road. Camperdown, Sydney, New South Wales, 2050 Australia. Dr. Ho: Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, Sydney, New South Wales, 2010 Australia. Dr. Sullivan: David Read Laboratory, Department of Medicine, University of Sydney, New South Wales, 2006 Australia.
References 1. Sullivan CE, Issa FG. Obstructive sleep apnea. Clin Chest Med. 1985;6:633-50. 2. Chappel WF, Booth JA. A case of acromegaly with laryngeal symptoms and pharyngeal symptoms. J Laryng Otol. 1896;10:142-50. 3. Roxburgh F, Collis AJ. Notes on a case of acromegaly. Br Med J. 1896;ii:63-5. 4. Marie P. Sur deux cas d'acromegalic: hypertrophic singuliere, non congenitalie, des extremites superieures, inferieures et cephalique. Rev Med. 1886;6:297-333. 5. Laroche C, Festal G, Poenaru S, Caquet R, Lemaigre D, Auperin A. Une observation de respiratoin periodique chez une acromegalic Ann Med Interne (Paris). 1976;127:381-5. 6. Guilleminault C, van den Hoed J, Mitler MM. Clinical overview of the sleep apnea syndromes. In: Guilleminault C, Dement WC; eds. Sleep Apnea Syndromes. New York: Alan R. Liss; 1978:1-12. 7. Perks WH, Horrocks PM, Cooper RA, Bradbury S, Allen A, Baldock N. Sleep apnea in acromegaly. Br Med J. 1980;280:894-7. 8. Mezon BJ, West P, MaClean JP, Kryger M. Sleep apnea in acromegaly. Am J Med. 1980;69:615-8. 9. Hart TB, Radow SK, Blackard WG, Tucker HS, Cooper KR. Sleep apnea in active acromegaly. Arch Intern Med. 1985;145:865-6. 10. Pekkarinen T, Partinen M, Pelkonen R, Iivanainen M. Sleep apnea and daytime sleepiness in acromegaly: relationship to endocrinological factors. Clin Endocrinol. 1987;27:649-54. 11. Veldhuis JD, Johnson ML. Cluster analysis: a simple, versatile, and robust algorithm for endocrine pulse detection. Am J Physiol. 1986; 250:E486-93. 12. Baxter RC, Brown AS, Turtle JR. Radioimmunoassay for somatomedin C: comparison with radioreceptor assay in patients with growth-hormone disorders, hypothyroidism, and renal failure. Clin Chem. 1982;28:488-95. 13. Alexander L, Appleton D, Hall R, Ross WM, Wilkinson R. Epidemiology of acromegaly in the Newcastle region. Clin Endocrinol (Oxf). 1980;12:71-9. 14. Bengtsson BA, Eden S, Ernest I, Oden A, Sjogren B. Epidemiology and long-term survival in acromegaly. Acta Med Scand. 1988;223: 327-35. 15. Lugaresi E, Cirignotta F, Coccagna G, Piana C. Some epidemiological data on snoring and circulatory disturbances. Sleep. 1980;3: 221-4. 16. Bengtsson BA, Brummer RJ, Eden S, Bosaeus I. Body composition in acromegaly. Clin Endocrinol (Oxf). 1989;30:121-30. 17. Phillipson EA, Remmers JE. Indications and standards for cardiopulmonary sleep studies. Am Rev Respir Dis. 1989;139:559-68. 18. Sullivan CE, Issa FG, Berthon-Jones M. Pathophysiology of sleep apnea. In: Saunders NA, Sullivan CE; eds. Sleep and Breathing. New York: Marcel Dekker; 1984:299-363. 19. Bradley TD, McNicholas WT, Rutherford R, Popkin J, Zamel N, Phillipson EA. Clinical and physiologic heterogeneity of the central sleep apnea syndrome. Am Rev Respir Dis. 1986;134:217-21. 20. Issa FG, Sullivan CE. Reversal of central sleep apnea using nasal CPAP. Chest. 1986;90:165-71. 21. White D. Central sleep apnea. In: Kryger MH, Roth T, Dement WC. Principles and Practice of Sleep Medicine. Philadelphia: W.B. Saunders; 1989:513-24. 22. Kalia M, Fuxe K, Agnati LF, Hokfelt T, Harfstrand A. Somatostatin
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Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19735/ by a University of California San Diego User on 01/08/2017
531
23.
24.
25.
26.
produces apnea and is localized in medullary respiratory nuclei: a possible role in apneic syndromes. Brain Res. 1984;296:339-44. Daughaday WH. Clinical developments over the past 100 years of acromegaly. In: Robbins RJ, Melmed S; eds. Acromegaly: A Century of Scientific and Clinical Progress. New York: Plenum Press; 1987:129-57. Karlberg BE, Ottosson AM. Acromegaly and hypertension: role of the renin-angiotensin-aldosterone system. Acta Endocrinol (Copenh). 1982;100:581-7. Shepard JW. Cardiorespiratory changes in sleep apnea. In: Kryger MH, Roth T, Dement WC. Principles and Practice of Sleep Medicine. Philadelphia: W.B. Saunders; 1989:537-51. Hedner J, Ejnell H, Sellgren J, Hedner T, Wallin G. Is high and
532
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of Internal
Medicine
fluctuating muscle nerve sympathetic activity in the sleep apnoea syndrome of pathogenetic importance for the development of hypertension? J Hypertens. 1988;6:S529-31. 27. He J, Kryger MH, Zorick FJ, Conway W, Roth T. Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients. Chest. 1988;94:9-14. 28. Wright AD, Hill DM, Lowy C, Fraser TR. Mortality in acromegaly. Q J Med. 1970;39:1-16. 29. Ho KY, Weissberger AJ, Marbach P, Lazarus L. Therapeutic efficacy of the somatostatin analog SMS 201-995 (Octreotide) in acromegaly: effects of dose and frequency and long-term safety. Ann Intern Med. 1990;112:173-81.
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• Objective: To provide information on the nature, prevalence, and severity of sleep apnea in patients with acromegaly. • Design: Consecutive case series. • Setting: Tertiary referral hospital. • Patients: Fifty-three patients with acromegaly were consecutively referred: 33 patients were referred because of clinical suspicion of sleep apnea and 20 patients were referred without suspected apnea. • Measurements: Sleep studies as well as growth hormone and insulin-like growth factor 1 (IGF-1) measurements were done. • Main Results: Thirty-one patients (93%; 95% CI, 85% to 100%) referred because of suspicion of sleep apnea had sleep apnea compared with 12 patients (60%; CI, 37% to 83%) referred without suspected sleep apnea. Patients with sleep apnea did not have biochemical evidence of increased disease activity (random growth hormone, 12.7 ± 4.4 |xg/L; mean growth hormone at 24-hour sampling, 10.8 ± 8.4 |xg/L; IGF-1, 90.0 ± 7.5 nmol/L) compared with patients without sleep apnea (random growth hormone, 14.2 ± 4.9 H,g/L, P> 0.2; mean growth hormone, 12.4 ± 3.5 |ig/L, P> 0.2; IGF-1, 90.0 ± 10.0 nmol/L, P> 0.2). Central sleep apnea was the predominant type of apnea in 33% (CI, 18% to 47%) of patients and was associated with higher random growth hormone and IGF-1 levels than was obstructive apnea (random growth hormone, 23.4 ± 3.9 compared with 8.8 ± 3.1 jjig/L, P< 0.001; IGF-1, 126 ± 17.5 compared with 72.5 ± 7.5 nmol/L, P 0.2 except where noted. f P < 0.001. XP = 0.11. § P = 0.06.
Transcutaneous carbon dioxide tension was measured continuously using a capnometer (Hewlett-Packard 47210A), and ribcage and abdominal wall motion were recorded using a respiratory inductive plethysmograph (Respitrace, Ambulatory Monitoring, Ardesley, New York). Diaphragm electromyography was done using two gold-plated cup electrodes placed in the right subcostal region, one at the mid-clavicular line and the other, 2.0 cm lateral to it. The interelectrode impedance level was kept below 3.0 kilohms. Sleep was monitored using two channels of electroencephalogram (C4/A, and C3/A 2 ), two channels of electro-oculogram, and one channel of submental electromyogram. To facilitate analysis, sleep stages 1 and 2 were combined, as were stages 3 and 4. Sleep stages were expressed as a percentage of total sleep time. All variables were recorded continuously on a 16-channel polygraph (Model 78; Grass Instruments, Quincy, Massachusetts). Apnea was defined as cessation of airflow for 10 seconds or longer. Hypopnea was defined as a 50% or greater decrease in thoraco-abdominal activity without cessation of airflow associated with at least a 4% decrease in oxygen saturation. All variables were used to determine the frequency and nature of apneic and hypopneic episodes. The number of episodes per hour of sleep was calculated and expressed as a respiratory disturbance index. For convenience, all such respiratory events were considered to be episodes of apnea. Apnea was classified as either central (absence of airflow associated with cessation of breathing as shown by inductive plethysmography and diaphragm electromyography) or obstructive (absence of airflow despite recorded breathing efforts and diaphragm electromyographic phasic activity). Episodes of "mixed apnea" (absence of airflow associated with cessation of breathing effort in the first part of the event, followed by a period of chest-wall movement and phasic electromyographic activity) were separated into central and obstructive components, and the time of each component was measured. The duration of all obstructive and central events was measured and expressed as a percentage of total sleep time—either central apnea time or obstructive apnea time. Patients were classified as having predominantly central sleep apnea if they had a respiratory disturbance index of 5 or greater and had a longer duration of central apnea than obstructive apnea. Similar criteria were used to classify predominantly obstructive apnea. The mean duration of apnea was also calculated. Oxygen saturation data were expressed as the mean minimum oxygen saturation (mean of the nadir oxygen saturation values reached during each apnea) and the lowest oxygen saturation level reached during the sleep study. 528
Respiratory F u n c t i o n Forced expiratory volume in 1 second (FEV,) and forced vital capacity (FVC) were measured with the subject in the sitting position using a spirometer (Vitalograph Ltd., Buckingham, England). Values were reported as a percentage of those predicted from height and age. Arterial blood gases were sampled with the patient in the supine position from the radial artery after infiltration with 1% lignocaine while the patient was awake (Corning Blood Gas Analyzer, Medfield, Massachusetts).
Endocrine Measurements The extent of pituitary hyperfunction was assessed using measurements of growth hormone and IGF-1 levels. In 30 patients, growth hormone level was measured from a single randomly obtained or fasting sample. In 23 patients (20 patients from group 2 and 3 patients from group 1), growth hormone secretion was studied from measurements obtained at 20-minute intervals during a 24-hour period. We used these data to determine whether the mean growth hormone output or pulsatile pattern of secretion was related to the extent of respiratory impairment during sleep. Respiratory sleep and 24hour hormone sampling studies were done on separate nights less than 1 week apart to avoid possible effects of the blood sampling procedure on the quality of the sleep study. Patients having blood sampling were hospitalized at the Clinical Investigation Unit at St Vincent's Hospital. After the patient fasted overnight at 0800 hours an intravenous cannula was inserted, and blood samples were obtained every 20 minutes beginning at 0900 hours. Patients were encouraged to walk freely during the day and were allowed to sleep after 2200 hours without sleep monitoring. Hospital meals were served at 0930, 1300, and 1800 hours. Sleep studies were done at the Sleep Disorders Center within 1 week of the 24-hour growth hormone studies. Seventy-three samples taken from each patient's 24hour study were measured using one assay. The mean 24-hour growth hormone concentration was obtained by averaging these 73 measurements. In these 20 studies, fasting growth hormone (the first sample of the 24-hour study) correlated significantly with mean 24-hour growth hormone levels (r = 0.78, P = 0.001). Thus, a single growth hormone measurement was found to be a reasonable estimate of mean 24-hour growth hormone concentration (29). The pulsatile characteristics of growth hormone secretion were analyzed using CLUSTER, a computer-assisted pulse detection algorithm (11) that allowed quantitation of pulse frequency, amplitude (incremental increase over preceding nadir), and the coefficient of variation of growth hormone around the 24-hour mean (cv24h).
Assays Growth hormone was measured using a double-antibody radioimmunoassay with the First International Reference Preparation 66/217, which has a 2 IU/mg standard potency. The inter- and intra-coefficients of variation were 12.5% and 4.1%, respectively, at 2.6 /xg/L. Insulin-like growth factor I (IGF-I or somatomedin C) was measured by radioimmunoassay after acid ethanol extraction using two different radioimmunoassays. Samples from group 1 were measured at the endocrine laboratory, Royal Prince Alfred Hospital, using the method of Baxter and colleagues (12) and had a normal reference range of 11 to 37 nmol/L for patients who are 40 years of age. The inter- and intra-coefficients of variation for this method were 8.7% and 11.8%, respectively. Samples from group 2 were measured at the Garvan Institute of Medical Research using a commercial kit (INCSTAR, Immuno Nuclear Corporation, Stillwater, Minnesota) with an established normal range of 10 to 35 nmol/L. The inter- and intra-coefficients of variation for this method were 11.0% and 8.2%, respectively. Nine samples were measured using both assays and yielded a correlation coefficient of r = 0.89 (P < 0.001). The agreement between the assays was excellent.
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Statistical Analysis
Effect of Treatment
Values are expressed as means ± SE. Patient groups were compared using unpaired /-tests and chi-square analysis where appropriate. Multiple linear regression was used to assess the relation of age and sleep apnea to hypertension. Confidence intervals (CIs) of 95% were used.
Mean random growth hormone and IGF-1 levels did not differ between patients previously treated for acromegaly and those untreated for the disorder (growth hormone level, 13.5 ± 3.9 /xg/L compared with 31.0 ± 9.5 mlU/L; IGF-1, 87.8 ± 10.0 nmol/L compared with 98.7 ± 12.2 nmol/L; P = 0.6). Of the 33 previously treated patients, 26 had sleep apnea compared with 17 of 20 in the untreated group. Biochemical activity of disease and presence and severity of sleep apnea were unrelated to treatment status.
Results Of the 53 patients studied, 51 (96%; CI, 96% to 100%) snored heavily during sleep, whereas 43 (81%; CI, 70% to 92%) had sleep apnea as defined by a respiratory disturbance index of 5 or greater, fulfilling standard diagnostic criteria for sleep apnea (6) (Table 1). Figure 1 shows the histogram of sleep apnea severity for both selected (group 1) and unselected (group 2) patients expressed as a percentage of group totals. Thirty-one patients (93%; CI, 85% to 100%) from group 1 had sleep apnea compared with 12 patients (60%; CI, 37% to 83%) from group 2.
Anthropometric and Respiratory Data Thirty-six (68%) patients were men and 17 (32%) were women. There were no differences in age, obesity, IGF-1 levels, mean 24-hour growth hormone levels, or respiratory function between men and women. Women under 50 years of age experienced less sleep apnea (respiratory disturbance index, 2 ± 2) than did older women (respiratory disturbance index, 32 ± 8; P < 0.01). Men tended to have sleep apnea more frequently than did women (P = 0.06, chi-square test). Patients with sleep apnea were older than those without the disorder (Table 1).
Growth Hormone Secretion and IGF-1 All 20 patients who had not received treatment for their acromegaly had increased IGF-1 levels. Of the 33 patients previously treated for acromegaly, 28 had elevated IGF-1 levels. Thus, 48 of 53 had biochemical evidence of active disease. Mean growth hormone and IGF-1 levels did not differ between patients with and those without sleep apnea (Tables 1 and 2). In the 20 previously untreated patients, IGF-1 levels of those with (15 patients) and those without (5 patients) sleep apnea were similar (92.7 ± 10.8 nmol/L compared with 122.0 ± 33.6 nmol/L; P > 0.2). No relation existed between the severity of sleep apnea (as measured by either respiratory disturbance index or mean minimum oxygen saturation) and IGF-1 level. Moreover, 4 of the 5 patients who had normal IGF-1 concentrations were found to have sleep apnea. Of the 23 patients with detailed growth hormone secretory profiles, 16 had sleep apnea (2, predominantly central and 14, predominantly obstructive) (Table 2). In the subgroup having more extensive growth hormone measurements, no differences in mean growth-hormone level and growthhormone pulsatility were found between patients with and those without sleep apnea.
Selected and Nonselected Groups Patients in group 1 had selection bias for sleep apnea (respiratory disturbance index, 37 ± 4 compared with 17 ± 5, P = 0.001). Eleven of the 33 group-1 patients and 9 of the 20 group-2 (unselected) patients had received no treatment for acromegaly. The two groups did not differ in the prevalence of central apnea (group 1,11 patients; group 2, 3 patients) compared with obstructive apnea (group 1, 20 patients; group 2, 9 patients) (chisquare test, P > 0.2). The two groups did not differ in degree of active acromegaly (IGF-1 levels for group 1, 87.3 ± 8.8 nmol/L compared with group-2 levels, 97.4 ± 12.1 nmol/L; P> 0.2). Group-1 patients were slightly older (55 ± 2 years compared with 47 ± 3 years, P = 0.03) but were similar in degree of obesity (body mass index, 29.6 ± 0.9 compared with 29.5 ± 1.3). Hypertension Of the 43 patients who had sleep apnea, 22 had hypertension. All 10 patients who did not have sleep apnea were normotensive (chi-square test, P = 0.003). Patients who were hypertensive had higher respiratory disturbance indices (43 ± 6) and a greater degree of sleep hypoxemia (minimum oxygen saturation, 73 ± 3%) than did those who were normotensive (18 ± 3 and
Figure 1. Frequency distribution of sleep-disordered breathing in patients with acromegaly. Measured by respiratory disturbance index in events per hour in group 1 (33 patients; • ) and group 2 (20 patients; ^ ) .
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529
Table 2. Growth Hormone Profiles for 23 Patients with Acromegaly Not Referred for Suspected Sleep Apnea* Variable Men/women, nln IGF-1, nmollL Mean growth hormone, \xglL Cv24h, % Amp, fig/L
Apnea in = 16) MIA 98.8 ± 15.8 10.8 ± 8.4 30.6 ± 7.5 4.6 ± 1.2
No Apnea (#i = 7) 86.0 12.4 34.2 9.6
2/5 ±11.0 ± 3.5 ± 8.6 ± 2.7t
* Values are expressed as mean ± SE where appropriate. IGF-1 = insulin-like growth factor type 1. Cv24h = coefficient of variation over the 24-hour growth hormone mean value. Amp = incremental growth hormone increase above the preceding nadir. t P = 0.11. For all other results, P > 0.2.
85 ± 1%, respectively; P < 0.007). Mean 24-hour growth hormone and IGF-1 levels and body mass index did not differ between patients with hypertension and those without hypertension. Hypertensive patients were older (60 ± 2 compared with 45 ± 2 years, P < 0.009). The data were then analyzed to determine whether the degree of sleep apnea (respiratory disturbance index) was an independent predictor of hypertension after adjusting for age using multiple linear regression. After this analysis, both respiratory disturbance index (partial regression coefficient, 0.62 units per event per hour; 95% CI, 0.11 to 1.13; P = 0.01) and age (1.2% per year; CI, 0.3% to 2.1%; P = 0.005) were found to be independent predictors of hypertension. Type of Apnea Fourteen patients had predominantly central apnea (33%; CI, 18% to 47%), and 29 patients had predominantly obstructive apnea (67%; CI, 53% to 82%). Several factors were associated with central sleep apnea (Table 3). Patients with central sleep apnea had higher IGF-1 levels and mean random growth hormone levels, indicating that the degree of hypersecretion was strongly associated with central sleep apnea. In addition, patients with central sleep apnea had lower waking arterial carbon dioxide levels than did those with obstructive sleep apnea. The two groups did not differ in age, weight, sleep apnea severity, sleep architecture, medications, or incidence of hypertension. Discussion Our study of 53 patients has shown that snoring and sleep apnea are extremely common in patients with acromegaly. Our data also show that sleep apnea in acromegaly is predominantly of the central type in 30% of patients. Although the degree of growth hormone hypersecretion was related to the presence of a central pattern of apnea, it was unrelated to the occurrence of the apnea. Finally, hypertension in acromegaly was strongly associated with sleep apnea. Although previous studies have reported an association between sleep apnea and acromegaly (5-10), an accurate estimate of the prevalence, nature, and severity of sleep apnea in acromegaly has not been possible because of the small patient samples studied, the lack of information on patient selection, and limitations in the 530
extent and intensity of sleep monitoring. We have done detailed overnight polysomnography in large groups of selected and unselected patients. The prevalence of acromegaly has been estimated to be between 38 (13) and 60 (14) cases per million. Because the population base of our sleep disorders center is 5 million persons, we estimated that 200 to 300 persons with acromegaly live in our referral area. Our patient group, therefore, included more than 20% of those persons. Our total patient group was not randomly selected, and a clear referral bias toward patients with symptoms of sleep apnea existed. In our subset of consecutive referrals from another institution (group 2), however, 60% of patients had sleep apnea. Assuming that there were 300 patients with acromegaly in our referral base and that we found at least 42 with sleep apnea, then the lowest estimated prevalence of sleep apnea in acromegaly is 17%. Thus, an estimate of the minimum prevalence must be well above the prevalence of sleep apnea in the general population, which has been estimated to be between 1% and 5% (1). In addition, almost all of our patients had heavy snoring, compared with 19% of persons in the general adult population (15). The data show a strong association between sleep apnea and acromegaly. Sleep apnea was associated in our patient group with increasing age and tended to be more common in men and in women over 50 years of age. This trend parallels findings from the general population (1). One difference between our patient group and the general population was that obesity was not a predisposing factor in sleep apnea in our patient group. Increases in body mass index in patients with acromegaly may, however, be due to increased muscle mass rather than to the increased body fat typically seen in obesity (16). Previous studies that examined the relation between sleep apnea and biochemical activity of acromegaly have suggested that patients with active disease (meaTable 3. Characteristics of Patients with Acromegaly According to Prominent Apnea Type* Variable Men/women, nln Age, y Body mass index, kglm2 Random growth hormone, fJLgIL IGF-1, nmollL Respiratory disturbance index, events/hour MMOS, % Min o2, % Total sleep time, min Stages 1 and 2, % total sleep time Stages 3 and 4, % total sleep time Stage REM, % total sleep time po 2 , mm Hg pco 2 , mm Hg
Central (n = 14)
Obstructive (n = 29)
mi
22/7 57 ± 2 29 ± 1 8.8 ± 3.It 72.5 ± 7.5$
50 30 23.4 126
±4 ±1 ± 3.9 ± 17.5
33 ± 89 ± 81 ± 328 ± 79.7 ± 4.9 ± 15.4 ± 84 ± 39 ±
6 1 3 24 2.7 1.5 2.1 2 1
37 ± 88 ± 75 ± 325 ± 77.6 ± 4.0 ± 18.4 ± 80 ± 42 ±
5 1 2 14 1.7 1.2 1.3 3 1§
* Values are expressed as mean ± SE where appropriate. IGF-1 = insulin-like growth factor type 1. MMOS = mean minimum oxygen saturation. Min o2 = lowest oxygen saturation during sleep study; REM = rapid eye movement. P > 0.2 except where noted. t P= 0.001. $P= 0.01. § P = 0.03.
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sured by growth hormone levels) are more likely to have (7) or exclusively (9) have sleep apnea. These studies have been limited by the lack of either full sleep monitoring or detailed growth hormone and IGF-1 measurements, or both. In contrast to these earlier studies, we found no relation between the presence of sleep apnea and the degree of growth hormone hypersecretion in either treated or untreated patients. Although most treated patients still had biochemically active disease, 4 of 5 treated patients with normal IGF-1 levels (considered to be in biochemical remission and disease free) had sleep apnea. There is no a priori reason to expect a simple correlation between disease activity and sleep apnea. The pathophysiologic changes that cause sleep apnea are diverse, and these changes are unlikely to correlate at any one time with growth-hormone hypersecretion. The diverse pathophysiology of sleep apnea in acromegaly was emphasized by the unexpectedly high rate of central sleep apnea seen in this patient group, suggesting the involvement of abnormal central respiratory control. Central apnea is associated with a wide range of disorders, and many potential mechanisms have been described (18-21). The cause of apnea in acromegaly is unclear. Somatostatin is involved in both the control of breathing (22) and in the inhibitory control of growth hormone secretion. Because acromegaly results from unrestrained release of growth hormone, it is possible that in a subgroup of patients, acromegaly and sleep apnea may share a common pathophysiologic mechanism with defects occurring in central somatostatin pathways. Another possible mechanism relates to elevated levels of growth hormone or IGF-1; such elevations may affect central respiratory control and thus induce central apnea. This theory is supported by the correlation between growth hormone hypersecretion and the prevalence of central apnea. Cardiac failure can also induce central apnea (21) and is a feature of endstage acromegaly. Cardiac failure was considered a possible cause of apnea in only 2 of our patients because none of the other 12 patients with central apnea had evidence of cardiac disease. Whatever the mechanism, it is clear that the association between apnea and acromegaly is not simply the result of narrowing of an airway caused by macroglossia and soft-tissue swelling. The main cardiovascular abnormality in acromegaly is systemic hypertension. There seems to be more than a chance association between these factors because hypertension occurs more frequently in patients with acromegaly than in the general population (23) and because the blood pressure level is sometimes reduced by successful trans-sphenoidal surgery. One possible mechanism of hypertension in acromegaly is the retention of sodium and water (24). Our results indicate that sleep apnea may be another important cause of hypertension. This theory is supported by the observation that hypertension occurs in over 50% of patients with sleep apnea who do not have acromegaly, possibly caused by increased sympathetic activity induced by repetitive asphyxia (25, 26). Sleep apnea is also associated with increased cardiovascular disease (25) and mortality (27). In view of these findings, sleep apnea may be a factor in the increased incidence of cardiorespiratory deaths
noted previously in acromegaly (14, 28), and its diagnosis and treatment should be considered in the overall assessment of this disorder. Acknowledgments: The authors thank Ms. Belinda Brooks, Ms. Madeline Kinloch, and Ms. Deirdre Stewart as well as the staff of the Sleep Disorders Centre at Royal Prince Alfred Hospital for their assistance; Dr. Michael Berthon-Jones for statistical and database advice; and the many physicians who referred the patients in this study. Grant Support: by the National Health and Medical Research Council of Australia and the New South Wales Department of Health. Requests for Reprints: R. Grunstein, MB, BS, Sleep Disor ers Centre, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney, New South Wales, 2050 Australia. Current Author Addresses: Dr. Grunstein: Sleep Disorders Centre, Royal Prince Alfred Hospital, Missenden Road. Camperdown, Sydney, New South Wales, 2050 Australia. Dr. Ho: Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, Sydney, New South Wales, 2010 Australia. Dr. Sullivan: David Read Laboratory, Department of Medicine, University of Sydney, New South Wales, 2006 Australia.
References 1. Sullivan CE, Issa FG. Obstructive sleep apnea. Clin Chest Med. 1985;6:633-50. 2. Chappel WF, Booth JA. A case of acromegaly with laryngeal symptoms and pharyngeal symptoms. J Laryng Otol. 1896;10:142-50. 3. Roxburgh F, Collis AJ. Notes on a case of acromegaly. Br Med J. 1896;ii:63-5. 4. Marie P. Sur deux cas d'acromegalic: hypertrophic singuliere, non congenitalie, des extremites superieures, inferieures et cephalique. Rev Med. 1886;6:297-333. 5. Laroche C, Festal G, Poenaru S, Caquet R, Lemaigre D, Auperin A. Une observation de respiratoin periodique chez une acromegalic Ann Med Interne (Paris). 1976;127:381-5. 6. Guilleminault C, van den Hoed J, Mitler MM. Clinical overview of the sleep apnea syndromes. In: Guilleminault C, Dement WC; eds. Sleep Apnea Syndromes. New York: Alan R. Liss; 1978:1-12. 7. Perks WH, Horrocks PM, Cooper RA, Bradbury S, Allen A, Baldock N. Sleep apnea in acromegaly. Br Med J. 1980;280:894-7. 8. Mezon BJ, West P, MaClean JP, Kryger M. Sleep apnea in acromegaly. Am J Med. 1980;69:615-8. 9. Hart TB, Radow SK, Blackard WG, Tucker HS, Cooper KR. Sleep apnea in active acromegaly. Arch Intern Med. 1985;145:865-6. 10. Pekkarinen T, Partinen M, Pelkonen R, Iivanainen M. Sleep apnea and daytime sleepiness in acromegaly: relationship to endocrinological factors. Clin Endocrinol. 1987;27:649-54. 11. Veldhuis JD, Johnson ML. Cluster analysis: a simple, versatile, and robust algorithm for endocrine pulse detection. Am J Physiol. 1986; 250:E486-93. 12. Baxter RC, Brown AS, Turtle JR. Radioimmunoassay for somatomedin C: comparison with radioreceptor assay in patients with growth-hormone disorders, hypothyroidism, and renal failure. Clin Chem. 1982;28:488-95. 13. Alexander L, Appleton D, Hall R, Ross WM, Wilkinson R. Epidemiology of acromegaly in the Newcastle region. Clin Endocrinol (Oxf). 1980;12:71-9. 14. Bengtsson BA, Eden S, Ernest I, Oden A, Sjogren B. Epidemiology and long-term survival in acromegaly. Acta Med Scand. 1988;223: 327-35. 15. Lugaresi E, Cirignotta F, Coccagna G, Piana C. Some epidemiological data on snoring and circulatory disturbances. Sleep. 1980;3: 221-4. 16. Bengtsson BA, Brummer RJ, Eden S, Bosaeus I. Body composition in acromegaly. Clin Endocrinol (Oxf). 1989;30:121-30. 17. Phillipson EA, Remmers JE. Indications and standards for cardiopulmonary sleep studies. Am Rev Respir Dis. 1989;139:559-68. 18. Sullivan CE, Issa FG, Berthon-Jones M. Pathophysiology of sleep apnea. In: Saunders NA, Sullivan CE; eds. Sleep and Breathing. New York: Marcel Dekker; 1984:299-363. 19. Bradley TD, McNicholas WT, Rutherford R, Popkin J, Zamel N, Phillipson EA. Clinical and physiologic heterogeneity of the central sleep apnea syndrome. Am Rev Respir Dis. 1986;134:217-21. 20. Issa FG, Sullivan CE. Reversal of central sleep apnea using nasal CPAP. Chest. 1986;90:165-71. 21. White D. Central sleep apnea. In: Kryger MH, Roth T, Dement WC. Principles and Practice of Sleep Medicine. Philadelphia: W.B. Saunders; 1989:513-24. 22. Kalia M, Fuxe K, Agnati LF, Hokfelt T, Harfstrand A. Somatostatin
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Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19735/ by a University of California San Diego User on 01/08/2017
531
23.
24.
25.
26.
produces apnea and is localized in medullary respiratory nuclei: a possible role in apneic syndromes. Brain Res. 1984;296:339-44. Daughaday WH. Clinical developments over the past 100 years of acromegaly. In: Robbins RJ, Melmed S; eds. Acromegaly: A Century of Scientific and Clinical Progress. New York: Plenum Press; 1987:129-57. Karlberg BE, Ottosson AM. Acromegaly and hypertension: role of the renin-angiotensin-aldosterone system. Acta Endocrinol (Copenh). 1982;100:581-7. Shepard JW. Cardiorespiratory changes in sleep apnea. In: Kryger MH, Roth T, Dement WC. Principles and Practice of Sleep Medicine. Philadelphia: W.B. Saunders; 1989:537-51. Hedner J, Ejnell H, Sellgren J, Hedner T, Wallin G. Is high and
532
1 October 1991 • Annals
of Internal
Medicine
fluctuating muscle nerve sympathetic activity in the sleep apnoea syndrome of pathogenetic importance for the development of hypertension? J Hypertens. 1988;6:S529-31. 27. He J, Kryger MH, Zorick FJ, Conway W, Roth T. Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients. Chest. 1988;94:9-14. 28. Wright AD, Hill DM, Lowy C, Fraser TR. Mortality in acromegaly. Q J Med. 1970;39:1-16. 29. Ho KY, Weissberger AJ, Marbach P, Lazarus L. Therapeutic efficacy of the somatostatin analog SMS 201-995 (Octreotide) in acromegaly: effects of dose and frequency and long-term safety. Ann Intern Med. 1990;112:173-81.
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