Autonomic reflexes in sleep apnoea syndrome
Research Paper
Clinical Autonomic Research 1, 125-130 (1991)
TEN patients with obstructive sleep apnoea syndrome cured by uvulopalatopharyngoplasty were compared to nine patients considered as surgical failures, using cardiovascular reflex tests--Valsalva manoeuvre, respiratory sinus arrhythmia, isometric handgrip and head-up tilt. T w o patients had signs of moderate vagal dysfunction, but no case of definite autonomic nervous dysfunction was diagnosed. The overall results i n d i c a t e d sympathetic overreactivity, positively correlated to oxygen desaturation indices and remaining after successful treatment. Four patients did not exhibit bradycardia during sleep apnoea. Two of them had decreased respiratory sinus arrhythmia when awake, but two had normal values. This implies a difference in vagal responsiveness between the awake and sleeping states, or that other factors besides vagus function influence the bradycardia response to apnoea. The group mean values were all within normal limits. There was no significant difference between the two groups in any test. A u t o n o m i c nervous dysfunction therefore does not seem to contribute to surgical failure, nor to occur with increased incidence a m o n g patients with primary obstructive sleep apnoea syndrome.
Autonomic nervous system function in patients w i t h primary obstructive sleep apnoea syndrome Eva Svanborg 1,cA, MD PhD, Britt Carlsson-Nordlander z, MD PhD, H&kan Larsson 2, MD PhD, Charlotte Sachs z, M D PhD and Lennart Kaijser 4, M D Professor of Medicine
Departments of 1Clinical Neurophysiology and 20to-Rhino-Laryngology, S6der Hospital, Box 38 100, S-100 64, Stockholm; 3Department of Neurology, Karolinska Hospital, Stockholm; and 4Department of Clinical Physiology, Huddinge Hospital, Stockholm, Sweden. CACorresponding Author
Key words: Autonomic nervous function, Cardiovascular reflex tests, Obstructive sleep apnoeas, Sleep apnoea syndrome
Introduction Obstructive sleep apnoea syndrome (OSAS) is a condition whose aetiology is unknown (primary) or may be related to contributing factors. These include structural defects in the upper airway, obesity, alcoholism and neuromuscular diseases. In the two latter cases, the primary disease causes apnoea through decreased tone in the upper airway muscles. Sleep-related hypotonia of the upper airway dilator muscles has also previously been shown to be a key element in the obstruction of the hypopharynx in apnoea. 1'2 Multiple system atrophy with autonomic failure is another possible cause of decreased upper airway muscle function, since it may cause denervation of these muscles. 3 There are several case reports of autonomic failure patients also suffering from upper airway obstruction and sleep apnoeas, 4-6 but it is not known whether the reverse may be true, i.e. if there is an increased incidence of autonomic dysfunction among patients with primary OSAS. Autonomic dysfunction in itself may not produce dramatic symptoms and could therefore remain occult in patients presenting with OSAS. A lesser degree of denervation might cause clinical symptoms during sleep only, when the muscle tone is normally reduced. In a previous study 7 we noticed that some of our patients, notably those with severe OSAS, did not exhibit the typical bradycardia response to apnoea. 8'9 Since a diminished or lacking respiratory © Rapid Communications of Oxford Ltd.
sinus arrhythmia points to autonomic dysfunction, the question was raised whether these patients were afflicted with both disorders. Since the aetiology of O S A S is often multifactorial, it is not surprising that surgical treatment, based on the assumption that structural defects are the main cause of obstruction, fails in many patients. The most frequently performed type of surgery is uvulo-palato-pharyngoplasty (UPPP). This treatment has a success rate of 60% in follow-up studies 6 months after surgery, despite careful preoperative evaluation of the anatomy of the upper airways. 1° We speculated whether some of these 'UPPP-failures' could have a primary neurogenic lesion in the upper airways as a result of an occult autonomic dysfunction. To test this hypothesis one group of 'UPPPfailures' and one sex-, age- and weight-matched group of 'UPPP-successes' underwent a comprehensive battery of cardiovascular reflex tests to assess both sympathetic and parasympathetic function. In a previous study ~1 the same tests were applied to some patients with untreated OSAS, with great interindividual variations in results. The purpose of this study was to determine whether autonomic dysfunction could contribute to surgical failure, i.e. if it would occur more frequently in 'UPPP-failures', but also whether there was any consistency in the type of changes revealed, and lastly if occurrence of autonomic dysfunction could be related to the degree of respiratory disturbance. Clinical Autonomic Research. vol 1 • 1991
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E. Svanborget al. Methods
and
Patients
A utonomic cardiovascular reflex tests: All patients were subjected to a standardized test battery which was performed in one 3 h session. The patients were awake and in the supine position. Initial blood pressure and pulse values were recorded after 10 min rest. Blood pressure was measured by the indirect cuff method. Automatic inflation was made, to a level above systolic pressure followed by automatic deflation at constant rate. The Korotkow sounds were registered by microphone. Both sounds and pressures were recorded on an ink-jet writer (Siemens Elema Mingograph). The heart rate was calculated from the R - R intervals in the electrocardiogram (ECG). Detailed testing procedures have previously been published by Kaijser and Sachs .2 together with normal values from healthy control subjects in different age groups. The patients in the present study were tested in the same laboratory. Contralateral isometric handgrip : 13"14 Isometric handgrip was performed for 2 min at one-third of maximal voluntary contraction force. The heart rate was calculated before, during, and 2 min after the handgrip. Blood pressure was measured at 1 min intervals as described above by the indirect cuff method. Forearm blood flow was measured in the resting contralateral arm by venous occlusion plethysmography. The maximal increase in each of the variables were noted. Respiratory sinus arrhythmia ( R S A ) :is The patient breathed through a mouthpiece connected to a pneumotachograph at a tidal volume of 2 1. RSA was defined as the mean difference between the highest and lowest heart rate during a respiratory cycle as calculated from ten consecutive cycles. Valsalva ratio: t6'.7 The patient was instructed to maintain an expiratory pressure of 40 mmHg for 20 s by blowing through a mouthpiece. The Valsalva ratio was defined as a ratio between the highest heart rate during the Valsalva manoeuvre and the lowest heart rate during 20 s immediately afterwards. Head-up tilt: 18 The patient was placed in a head-up tilt position maintained for 8 min. Blood pressure was measured at rest and during the last minute of tilt. Sleep apnoea recordings." All patients underwent preoperative whole-night polysomnographic recordings of electroencephalogram (EEG), electrooculogram (EOG), chin electromyogram (EMG), airflow through nostrils and mouth (3-channel thermistor Nihon Kohden ZE-732A), respiration movements (Siemens Sensor 230, a piezoelectric movement sensor), and ECG on a Grass model 126
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8-10D. The polysomnograms were analysed according to standard techniques. 19'2° The ECG was checked meticulously for heart rate changes in association with apnoeas. A response was considered positive if there was a change of more than nine beats/min at the end of apnoea compared to the beginning, calculated from the difference in R - R intervals. Simultaneous with the polysomnographic recording arterial oxygen saturation (SaO2) (Biox III, earprobe), respiration- and body movements were recorded on a Graphtec servocorder at paper speed 1 cm/min. Respiration- and body movements were recorded by means of a static charge sensitive bed (SCSB) (BioMatt, Biorec Inc, Finland). This is a sensitive kinaesthetic transducer permitting recording of all kinds of body movements from a mattress on which the patient is lying. 21 Recording with slow paper speed clearly demonstrates the respiration patterns, in particular the diamond-shaped periodic respiration movements typical of upper-airway obstruction. 7 From this recording an oxygen desaturation index (ODI), i.e. the average number of desaturations of 4% or more per sleeping hour, was calculated. The percentage periodic respiration movements during total sleeping time was also noted. Renewed SCSB-oximetry recordings were made 6 months post-operatively.
Patients: Nineteen male patients with OSAS were studied. The diagnosis was based on clinical symptoms and the result of a polysomnographic recording. The patients were all heavy snorers and reported daytime symptoms in the form of increased sleepiness, morning headaches, concentration difficulties etc. Thyroid-stimulating hormone levels were within normal limits in all cases. None of them had any obvious predisposing factor, such as massive obesity, endocrine disease or anatomical malformation. None had a neurological deficit. Four patients had a diagnosis of essential hypertension, for which two were on antihypertensive medication with the beta-blocker, Metoprolol. Another patient was on the calcium channel blocker, Verapamil, and the angiotensin converting enzyme inhibitor, Enalaprilmaleat. The fourth patient was not on antihypertensive drugs at the time of the cardiovascular reflex testing. A patient was considered successfully treated if the ODI was reduced by at least two-thirds and the percentage periodic respiration movement time decreased by at least 50% in a recording performed 6 months after surgery. Ten patients filled these criteria for 'UPPP-success' while nine were considered 'UPPP-failures'. Individual data are listed in Table 1. The cardiovascular reflex test session was performed 8-15 months after surgery. All patients were given a questionnaire concern-
A utonotaic reflexes in sleep apnoea syndrome Table 1. Individual data concerning age, body mass index (BMI), preoperative apnoea index (AI), pre- and postoperative oxygen desaturation index (ODI) and percentages of pre- and postoperative periodic respiration during sleep. Patients nos 1-9 belong to the ' UPPP-failure' group, nos 10-19 to the "UPPP-success" group. Group mean values are presented at the foot of the table. Upper normal limit values: BMI 29 (40 or more: medically at risk because of obesity), AI 4, ODI 5, periodic respiration 43%
Patient no.
Age
BMI
Preoperative AI
1 2 3 4 5 6 7 8 9
55 54 53 62 40 60 50 46 50
27.4 25.6 31.1 29.8 20.4 36.2 36.4 24.8 31.9
9 26 66 48 14 16 63 20 24
10 11 12 13 14 15 16 17 18 19
65 44 43 50 43 51 62 43 67 47
32.5 31.2 23.7 24.0 24.5 29.5 29.5 29.7 19.6 29.7
Mean 1-9 10-19
52 52
29.3 27.4
Preoperative ODI
Postoperative ODI
Preoperative % periodic respiration
Postoperative % periodic respiration
23 38 52 57 5 60 82 9 57
14 9 34 38 9 36 28 5 54
49 61 86 99 57 99 90 30 84
54 47 58 87 51 99 60 26 58
29 43 35 12 54 15 51 57 40 66
14 75 35 11 33 44 67 65 18 49
2 24 4 1 2 5 8 7 0 1
56 95 60 90 70 92 90 98 60 73
11 30 14 17 25 10 0 24 10 11
31.8 40.2
42.6 41.1
25.2 5.4
72,8 78.4
60 15
,
ing subjective symptoms indicating autonomic dysfunction such as vertigo, fainting, impotence, urinary or bowel difficulties, and decreased sweating. Results
The mean test results for both groups are shown in Table 2. They were all within normal limits and there was no statistically significant difference in any of these tests between the two groups (MannWhitney U-test). Individual data for 'UPPP-success' patients and 'UPPP-failure' patients are given in Table 3. Minor deviations were seen in individual cases. Patient no. 7 had signs of a moderate vagal dysfunction in a decreased RSA and heart rate change in the isometric handgrip test. Patient no.
9 had decreased responses to the isometric handgrip test, but otherwise no indications of sympathetic dysfunction (normal orthostatic responses). He was on calcium-blocking anti-hypertensive medication (Verapamil). Patient no. 11 had decreased sympathetically mediated responses in the isometric handgrip and head-up tilt tests, and was on the beta-blocker, Metoprolol. Patient no. 1 had a slightly decreased RSA and patients nos 5, 12, 14 and 19 exhibited slight decreases in one of the responses to the isometric handgrip test, but all other test results were normal. Patient no. 17 had a normal RSA but abnormality in the Valsalva ratio and during isometric exercise. Patient no. 18 had very divergent test results with values outside both + and - 2SD. This might be explained by a malfunction in the central control
Table 2. Mean values (1SD between parentheses) for "UPPP-failure' and 'UPPP-success' patient groups. Reference values from normal control subjects of different ages from Kaijser and Sachs 12 Valsalva ratio
RSA
Isometric handgrip Bloodflow HR increase % change
UPPP-failures UPPP-successes Normals 40-60 years Normals > 60 years
1.8 (0.6) 1.6 (0.5) 1.9(0.3) 1.7 (0.4)
10 (10) 13 (7) 20 (7) 9 (4)
69 (52) 39 (43) 90(80) 64 (49)
11 (7) 8 (5) 23 (9) 13 (11)
Head-up tilt
Systolic BP change
Diastolic BP change
HR change
Systolic BP change
Diastolic BP change
19 (11) 19 (12) 44(14) 26 (18)
16 (9) 19 (6) 33(17) 14 (10)
11 (7) 17 (12) 13 (8) 11 (8)
8(11) 9 (17) - 2 (8) 9 (20)
5 (6) 5 (18) 6 (8) 3 (13)
Clinical Autonomic Research. vol 1 • 1991
127
E. Svanborget al. Table 3.
Individual cardiovascular reflex test results
Patient no.
Valsalva ratio
1 2 3 4~'b 5 6 7 8 9 10 ~ 11 b 12 13 14 15 16 ~ 17 18 a 19
RSA
Isometric handgrip Blood flow increase %
HR change
BPs change
Head-up tilt BP D change
1.8 1.4 1.8 1.2 3.1 ( + ) 2.4 1.3 1.4 1.6
5.0 ( - ) 10.0 13.0 1.5 6.0 6.0 2.9 ( - ) 12.4 35.0
114 115 122 23 41 23 36 139 8(-)
24 7 10 12 14 15 -2 (-) 15 4(-)
20 35 25 24 8(-) 8 (-) 19 30 4(--)
35 15 20 20 12 16 4 5 16
2.0 1.2 1.4 2.6 1.7 1,4 1.3 1.2 2.6 2.0
2.1 10.3 25,4 20.2 5.7 7.2 8.3 11.0 39.0 ( + ) 15.3
28 3 (-) 17 47 23 21 13 139 107 49
12 5 4 (-) 14 10 8 4 3(-) 0 (-) 16
48 30 20 20 6(-) 41 16 10(-) 10 10(--)
20 20 24 16 12 12 28 18 -4 20
(-) (+)
(-) (+)
HR change 22 18 0 14 10 10 10 8 3 11 0 25 27 38(+) 18 15 11 2 5
BPs change 20 ( + ) 5 -4 19 8 0 8 20 ( + ) -8 -7 -22 -4 12 16 17 12 2 29 36
Resting BPs
Resting BPD
Resting HR
115 120 155 152 112 151 138 130 176
61 90 92 92 64 106 92 90 100
66 80 78 56 82 92 67 73 80
132 110 120 136 108 122 148 120 143 154
88 82 76 102 80 98 92 85 88 102
55 7O 58 53 54 68 80 73 58 60
BPD change 7 5 -8 10 4 11 8 10 0
22 (-)-33(-) 16 28 ( + ) ( + ) 12 ( + ) 16 0 -3 -13 (+) 6
a Indicates age above 60 years, b Indicates beta-blocking antihypertensive medication. ( - ) value below 2SD compared with reference values. ( + ) value above 2SD compared with reference values. HR, heart rate; BPs, systolic blood pressure; BPD, diastolic blood pressure.
of the autonomic nervous system rather than by peripheral lesions. The responses during head-up tilt deviated from the normal range in seven patients. In five cases this consisted of elevation of the systolic blood pressure outside + 2 S D of the values from age-matched normal controls. This was seen in two cases belonging to the 'UPPP-failure' group and in three cases belonging to the 'UPPP-success' group. In Fig. 1 the distribution of the orthostatic systolic
~5 E Z
-30
-20
- 10 O 10 20 Systolic blood pressure (mmHg)
30
40
FIG. 1. Distribution of systolic blood pressurechangesto head-uptilt in all 19 patientswith obstructivesleepapnoeasyndrome.The lines indicate mean (thick line) and + 2SD (thinner lines on either side) of the normal control values. Patients nos 1-9 ('UPPP-failures') are indicated by light grey, patientsnos 10-19 (' UPPP-successes') are indicatedby darkgrey. 128
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blood pressure change in all 19 patients is shown. Most of these individuals reacted with increases in systolic pressure to this test. Patients nos 1, 7, 16 and 18 did not exhibit any bradycardia response even to apnoeas longer than 30 s seen during polysomnographic recordings. Patients nos 1 and 7 also had decreased RSA when awake, indicating vagal dysfunction. Patients nos 16 and 18 were both more than 60 years old, an age at which decreases in RSA are common. However, they both had RSA values well above the lower limit even for younger subjects. Linear regression analysis was made on pre- and postoperative ODI:s and preoperative apnoea indices (AI) versus the results of the different cardiovascular reflex tests. There were statistically significant positive correlations between pre- and postoperative O D I and the percentage blood flow increase in the contralateral arm during isometric handgrip (p < 0.01, R = 0.62 with regards to preoperative ODI; ? < 0.05, R = 0.46 with regards to postoperative ODI). This was also true between preoperative ODI and orthostatic systolic blood pressure change (p < 0.05, R = 0.49). There was no statistically significant correlation between any of the other variables. Only one patient (no. 18) had subjective symptoms (vertigo, impotence, decreased sweating) to such an extent that autonomic dysfunction could be suspected on clinical grounds, but his test results were suggestive of central malfunction. Ten more
A utanomic reflexes in sleep apnaea syndrome
patients responded positively to at least one item in the questionnaire, most frequently impotence, but in none were there objective evidence, on testing, of an autonomic lesion to explain their symptoms. Discussion
The lack of correlation between subjective symptoms and objective findings in the cardiovascular reflex tests could be explained by the fact that the symptoms the patients reported (dizziness, urinating difficulties, impotence, etc) are not specific for autonomic lesions and may have a multifactorial origin. Furthermore our investigations were designed to assess cardiovascular aspects of autonomic function. Two patients only had signs of moderate vagal dysfunction in their cardiovascular reflex tests, and they did not report any corresponding subjective symptoms. In the remaining patients the abnormal results may have been due to their medication or there was only one single deviating response. In the latter cases both the parasympathetic and the sympathetic systems were obviously intact, since all other test results were above lower normal limits. Hanly et al. 22 concluded on the basis of data from seven patients that the heart rate response to forced respiratory manoeuvres including Valsalva during wakefulness could be used to predict the response to obstructive apnoea. The results of the present study indicate that this is not always true, since two patients who lacked the typical bradycardia response even to long sleep apnoeas had a normal or, in one case, even increased Valsalva ratio and RSA. One tentative explanation might be a difference in vagal responsiveness between the sleeping and awake states in these cases. Vagal dysfunction is obviously not the only cause of absence of the bradycardia response to apnoea. In agreement with previous studies 11'~3 it is however evident that deviations in some autonomically controlled functions are not uncommon among OSAS-patients. In the present study a frequent finding was an exaggerated increase in systolic blood pressure during postural change. Although this may not be clinically :'significant, it does suggest an increased sympathetic drive in these patients. The lack of an inverse relationship between changes in blood pressure and heart rate was further evidence of an abnormality in our patients, as during head-up tilt there is normally an increase in heart rate when the blood pressure decreases. In the 'UPPP-failure' group, in particular, there was an increase in heart rate parallel with the increase in blood pressure. In our patients there were other signs of sympathetic hyperreactivity which increased in
parallel with the severity of OSAS, as expressed by the oxygen desaturation index (ODI). Thus, the average number of hypoxic episodes per sleeping hour both pre- and postoperatively were significantly correlated to the percentage of blood flow increase in the isometric handgrip test, which is a sympathetically mediated response. Increased sympathetic activity could also be the cause of the significant positive correlation between preoperative ODI:s and increases in systolic blood pressure during head-up tilt test. In contrast to this, Pressman and Fry 24 found evidence of decreasing sympathetic and increasing parasympathetic activity in parallel with higher AI:s when studying the direct pupil light reflex. The pupillary reflex probably indicates only local and not generalized autonomic nervous activity. It is noteworthy that the results of the present study imply an increase in sympathetic activity also among patients who were successfully treated, when there were few respiratory abnormalities to increase sympathetic activity, such as hypoxia. The relationship between OSAS and arterial hypertension has been increasingly emphasized. The prevalence of OSAS in patients with a primary diagnosis of essential hypertension has been estimated to be 26-47.8%. 2227 Hypertension is also common among OSAS-patients, 28 although large epidemiological studies have not been performed. The common denominator in both conditions could be increased sympathetic nervous system activity. Clark et al. 29 have found increased levels of urine and plasma catecholamines in patients with OSAS. Hedner et al. 3° recorded a high muscle sympathetic nerve activity in wakefulness in OSAS-patients, increasing further during sleep apnoeas followed by decrease when breathing was resumed. Increased muscle sympathetic nerve responses to vascular reflex tests have been demonstrated in patients with borderline hypertension. 31'32 In OSAS, it is probable that nocturnal apnoea is the primary cause of arterial hypertension, as hypoxia-induced stimulation of peripheral chemoreceptors is known to cause peripheral vasoconstriction and increase blood pressure. 33 Jennum et al. 34 have also found that blood pressure was reduced during effective treatment of OSAS-patients, and that this reduction was significantly related both to decreases in apnoea indices and plasma adrenaline. On the other hand, Hedner et al. 3s found no correlation between the severity of OSAS expressed in terms of ODI and the hypertension in their patients. A proven explanation for the long-term haemodynamic changes in OSAS-patients is thus lacking, but in patients with essential hypertension it has been suggested that the chemoreceptor reflex is exaggerated and that this is of pathophysiological importance. 3c"38 Constant nocturnal hypoxia, as Clinical Autonomic Research. vol 1 • 1991
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al.
seen in OSAS, may permanently change the sensitivity of the chemoreceptors. Somers et aL 39 have demonstrated that patients with borderline hypertension have exaggerated sympathetic muscle nerve responses to hypoxic chemoreceptor stimulation, and that this increased activity rose considerably during apnoea. This may be of importance for the increased mortality-rate in OSAS. 4° In the majority of these patients there is a cardiac or cerebrovascular cause of death which often occurs suddenly at night. 41'42 High sympathetic nervous system activity may trigger ventricular fibrillation 43 and cause or contribute to sudden death. In conclusion, this study indicates that decreased autonomic nervous system function is not a major contributing factor to failure of UPPP surgery, as abnormal results were not more common among patients who had an insignificant postoperative improvement compared to those who were successfully treated. Neither do OSAS-patients appear to have an increased incidence of autonomic dysfunction, The most constant finding was a tendency to sympathetic overreactivity, which was positively correlated to the degree of respiratory disturbance. References 1. Guilleminault C, Hill MW, Blair Simmons F, Dement WC. Obstructive sleep apnea: electromyographic and fiber-optic studies. Exp Neural 1978; 62: 48-67. 2. Remmers JE, de Groot WJ, Sauerland EK, Anch AM. Pathogenesis of airway occlusion during sleep. J Appl Physiol 1978i 44: 931-938. 3. Guindi GM, Bannister R, Gibson WPR, Payne JK. Laryngeal EMG in multiple system atrophy with autonomic failure. J Neural Neuros#rg Psych 1981; 44: 49-53. 4. GuilleminaultC, Briskin JG, GreenfieldMS, SilvestriR. The impact of autonomic nervous system dysfunction on breathing during sleep. Sleep 1981; 4: 265-278. 5. Kavey NB, Wbyte J, Blitzer A, Gidro-Frank S. Sleel~related obstruction presenting as snoring or sleep apnea. Laryngoscope 1989; 99: 851--854. 6. Munschauer FE, Lob L, Bannister R, Newsom Davis J. Abnormal respiration and sudden death during sleep in multiple system atrophy with autonomic failure. Neurology 1990; 40: 677-679. 7. Svanborg E, Larsson H, Carlsson-Nordlander B, Pirskanen R. A limited diagnostic investigation for obstructive sleep apnea syndrome~oximetry and static charge sensitive bed. Chest 1990; 98: 1341-1345. 8. Guilleminault C, Conally S, Winkle R, Melvin K, Tilkian A. Cyclical variation of the heart rate in sleep apnoea syndrome. Lancet 1984; i: 126-131. 9. Zwillich C, Devlin T, White D, Douglas N, Wall J, Martin R. Bradycardia during sleep apnea: characteristics and mechanism. J Clin Invest 1982; 69: 1286-1292. I0. Larsson H, Carlsson-Nordlander B, Svanborg E. Long-time follow up of UPPP for obstructive sleep apnea syndrome: results of sleep apnea recordings and subjective evaluation 6 months and 2 years after surgery. Acta Otolaryngol (Stockb) 1991; !11: 582-590. 11. Sachs C, Kaijser L. Autonomic regulation of cardiopulmonary functions in sleep apnea syndrome and narcolepsy. Sleep 1982; 8: 227-238. 12. Kaijser L, Sachs C. Autonomic cardiovascular reflexes in old age. Clin Physiol I985; 5: 34%357. 13. Freyschuss U. Cardiovascularadjustment to somatomotor activation. Acta Phjsid Stand 1970; 342 (suppl). 14. Eklund B, Kaljser L. Effect of regional alfa- and beta blockade on blood flow in the resting forearm during contralateral isometric handgrip. J Phy*iol 1976; 262: 39-50.
130
Clinical Autonomic Research. vol 1 • 1991
15. Melcher A. Respiratory sinus arrhythmia in man. Atta Physiol Stand 1976; 435 (suppl). 16. Levin AB. A simple test of cardiac function based upon heart rate changes induced by Valsalva manoeuvre. A m J Cardio/1966; 18: 90-99. 17. Wheeler T, Watkins PJ. Cardiac denervation in diabetes. Br MedJ 1973; iv: 584-586. 18. Thulesius O. Patophyaldiogical classification and diagnosis of orthostatic hypotension. Cardiology 1976; 61 (suppl 1): 180. 19. Rechtschaffen A, Kales A. A Manual of Slandardized Terminology, Techniques, and Scoring System for Sleep Stages of Human Subjects. Los Angeles: Brain Information Service/Brain Research Institute, UCLA, 1968. 20. Keenan Bomstein S. Respiratory monitoring during sleep: polysomnography. In: Guilleminault C, ed. Skeping and Waking Disorders. Indications and Techniques. Menlo Park: Addison Wesley, 1982; 183-212. 21. Alihanka J, Vaahtoranta K, Saarikivi I. A new method for long-term monitoring of ballistocardiography, heart rate and respiration. A m J Physiol 1981; 240: 384-392. 22. Hanly PJ, George CF, Millar TW, Kryger MH. Heart rate response to breath&did, Valsalva and Mueller maneuvers in obstructive sleep apnea. Chest 1989; 95: 735-739. 23. Guilleminauh C, Tilkian A, Lehrman K, Fomo L, Dement WC. Sleep apnoea syndrome: states of sleep and autonomic dysfunction. J Neurol Neurosurg Psjcb 1977; 40: 718-725. 24. Pressman MR, Fry JM. Relationship of autonomic nervous system activity to daytime sleepiness and prior sleep. Sleep 1989; 12: 239-245. 25. Fletcher EC, DeBehnke RD, Lovoi MS, Gorin AB. Undiagnosed sleep apnea in patients with essential hypertension. Ann Intern Med 1985; 103: 19(~195. 26. Kales A, Cadieux R, Shaw L, Vela-Bueno A, Bixler E, Schneck D, Locke T, Soldatos C. Sleep apnoea in a hypertensive population. Lancet 1984; ii: 1003-1008. 27. WilliamsAJ, Houston D, Finberg S, Lam C, Kinney JL, Santiago S. Sleep apnea syndrome and essential hypertension. A m J Cordial 1985; 55: 1019-1022. 28. Kales A, Cadieux RJ, Bixler EO, Sdidatos CR, Vela-Bueno A, Misoul CA, Locke TW. Severe obstructive sleep apnea: I Onset, clinical course, and characteristics. J Chron Dis 1985; 38: 419-¢25. 29. Clark RW, Boudoulas H, Schaal SF, Schmidt HS. Adrenergic hyperactivity and cardiac abnormality in primary disorders of sleep. Neurology 1980; 30: 113--119. 30. Fledner J, Ejnell H, Sellgren J, Hedner T, Wallin G. Is high and fluctuating muscle nerve sympathetic activity in the sleep apnoea syndrome of pathogenetie importance for the development of hypertension? J Hypertens 1988; 6: 529-531. 31. Miyajima E, Yamada Y, Matsukawa T, Tochikubo O, Ishii M, Kaneko Y. Neurogenoc abnormalities in young borderline hypertensives. Clin Exp H3pertens 1988; AI0 (suppl 1): 209-223. 32. Rea RF, Hamdan M. Baroreflex control of muscle sympathetic nerve activity in borderline hypertension. Circulation 1990; 82: 856-862. 33. Heistad DD, Abboud FM. Circulatory adjustments to hypoxia. Circulation 1980; 61: 463469. 34. Jennum P, Wildschiodtz G, Juel Christensen N, Schwartz T. Blood pressure, catecholamines, and pancreatic polypeptide in obstructive sleep apnea with and without nasal continuous positive airway pressure (nCPAP) treatment. A m J Hypertens 1989; 2: 847-852. 35. Hedner J, Ejnell H, Caidahl K. Left ventricular hypertrophy independent of hypertension in patients with obstructive sleep apnea. J Hjpertens 1990; 8: 941-946. 36. PrzybylskiJ. Do arterial chemoreceptors play a role in the pathogenesis of hypertension? Med H:potheses 1981; 7: 127-131. 37. Trzebski A, Tafd M, Zoltowski M, Przybylski j. Increased sensitivity of the arterial chemoreceptor drive in young men with mild hypertension. Cardiovase Res 1982; 16: 165-172. 38. Fukuda Y, Sato A, Trzebski A. Carotid chemoreceptor discharge responses to hypoxia and hypercapnia in normotensive and spontaneously hypertensive rats. J Auton Nerv Syst 1987; 19: 1-11. 39. Somers VK, Mark AL, Abboud FM. Potentiation of sympathetic nerve responses to hypoxia in borderline hypertensive subjects. Hypertension 1988; 11: 608-612. 40. He J, Kryger MH, Zorick FJ, Conway W, Roth T. Mortality and apnoea index in obstructive sleep apnoea. Cheer1988; 94: 9-14. 41. Partinen M, Jamieson A, Guilleminadit C. Long-term outcome for obstructive sleep apnea syndrome patients. Chest 1988; 94: 1200-1204. 42. Koskenvuo M, Kaprio J, Telakivi T, Partinen M, HeikkiliiK, Soma S. Snoring as a risk factor for ischemic heart disease and stroke in man. Br MedJ 1987; 294: 16-19. 43. Lown B, Verrier RL, Rabinowitz SH. Neural and psychologic mechanisms and the problem of sudden cardiac death. A m J Cardiol 1977; 39: 890~902.
A C K N O W L E D G E M E N T S . The authors thank Dr H. G. H~rdemark for his help with the statistical analysis, and Professors Gunnar Wallin and Mikael Elam, Department of Clinical Neurophysiology, Sahlgrenska Hospital, Gothenburg, for valuable advice. This work has been supported by grants from the Karolinska Institute and the Swedish Society of Medicine.
Received 4 February 1991 ; accepted with revision 28 March 1991.
Research Paper
Clinical Autonomic Research 1, 125-130 (1991)
TEN patients with obstructive sleep apnoea syndrome cured by uvulopalatopharyngoplasty were compared to nine patients considered as surgical failures, using cardiovascular reflex tests--Valsalva manoeuvre, respiratory sinus arrhythmia, isometric handgrip and head-up tilt. T w o patients had signs of moderate vagal dysfunction, but no case of definite autonomic nervous dysfunction was diagnosed. The overall results i n d i c a t e d sympathetic overreactivity, positively correlated to oxygen desaturation indices and remaining after successful treatment. Four patients did not exhibit bradycardia during sleep apnoea. Two of them had decreased respiratory sinus arrhythmia when awake, but two had normal values. This implies a difference in vagal responsiveness between the awake and sleeping states, or that other factors besides vagus function influence the bradycardia response to apnoea. The group mean values were all within normal limits. There was no significant difference between the two groups in any test. A u t o n o m i c nervous dysfunction therefore does not seem to contribute to surgical failure, nor to occur with increased incidence a m o n g patients with primary obstructive sleep apnoea syndrome.
Autonomic nervous system function in patients w i t h primary obstructive sleep apnoea syndrome Eva Svanborg 1,cA, MD PhD, Britt Carlsson-Nordlander z, MD PhD, H&kan Larsson 2, MD PhD, Charlotte Sachs z, M D PhD and Lennart Kaijser 4, M D Professor of Medicine
Departments of 1Clinical Neurophysiology and 20to-Rhino-Laryngology, S6der Hospital, Box 38 100, S-100 64, Stockholm; 3Department of Neurology, Karolinska Hospital, Stockholm; and 4Department of Clinical Physiology, Huddinge Hospital, Stockholm, Sweden. CACorresponding Author
Key words: Autonomic nervous function, Cardiovascular reflex tests, Obstructive sleep apnoeas, Sleep apnoea syndrome
Introduction Obstructive sleep apnoea syndrome (OSAS) is a condition whose aetiology is unknown (primary) or may be related to contributing factors. These include structural defects in the upper airway, obesity, alcoholism and neuromuscular diseases. In the two latter cases, the primary disease causes apnoea through decreased tone in the upper airway muscles. Sleep-related hypotonia of the upper airway dilator muscles has also previously been shown to be a key element in the obstruction of the hypopharynx in apnoea. 1'2 Multiple system atrophy with autonomic failure is another possible cause of decreased upper airway muscle function, since it may cause denervation of these muscles. 3 There are several case reports of autonomic failure patients also suffering from upper airway obstruction and sleep apnoeas, 4-6 but it is not known whether the reverse may be true, i.e. if there is an increased incidence of autonomic dysfunction among patients with primary OSAS. Autonomic dysfunction in itself may not produce dramatic symptoms and could therefore remain occult in patients presenting with OSAS. A lesser degree of denervation might cause clinical symptoms during sleep only, when the muscle tone is normally reduced. In a previous study 7 we noticed that some of our patients, notably those with severe OSAS, did not exhibit the typical bradycardia response to apnoea. 8'9 Since a diminished or lacking respiratory © Rapid Communications of Oxford Ltd.
sinus arrhythmia points to autonomic dysfunction, the question was raised whether these patients were afflicted with both disorders. Since the aetiology of O S A S is often multifactorial, it is not surprising that surgical treatment, based on the assumption that structural defects are the main cause of obstruction, fails in many patients. The most frequently performed type of surgery is uvulo-palato-pharyngoplasty (UPPP). This treatment has a success rate of 60% in follow-up studies 6 months after surgery, despite careful preoperative evaluation of the anatomy of the upper airways. 1° We speculated whether some of these 'UPPP-failures' could have a primary neurogenic lesion in the upper airways as a result of an occult autonomic dysfunction. To test this hypothesis one group of 'UPPPfailures' and one sex-, age- and weight-matched group of 'UPPP-successes' underwent a comprehensive battery of cardiovascular reflex tests to assess both sympathetic and parasympathetic function. In a previous study ~1 the same tests were applied to some patients with untreated OSAS, with great interindividual variations in results. The purpose of this study was to determine whether autonomic dysfunction could contribute to surgical failure, i.e. if it would occur more frequently in 'UPPP-failures', but also whether there was any consistency in the type of changes revealed, and lastly if occurrence of autonomic dysfunction could be related to the degree of respiratory disturbance. Clinical Autonomic Research. vol 1 • 1991
125
E. Svanborget al. Methods
and
Patients
A utonomic cardiovascular reflex tests: All patients were subjected to a standardized test battery which was performed in one 3 h session. The patients were awake and in the supine position. Initial blood pressure and pulse values were recorded after 10 min rest. Blood pressure was measured by the indirect cuff method. Automatic inflation was made, to a level above systolic pressure followed by automatic deflation at constant rate. The Korotkow sounds were registered by microphone. Both sounds and pressures were recorded on an ink-jet writer (Siemens Elema Mingograph). The heart rate was calculated from the R - R intervals in the electrocardiogram (ECG). Detailed testing procedures have previously been published by Kaijser and Sachs .2 together with normal values from healthy control subjects in different age groups. The patients in the present study were tested in the same laboratory. Contralateral isometric handgrip : 13"14 Isometric handgrip was performed for 2 min at one-third of maximal voluntary contraction force. The heart rate was calculated before, during, and 2 min after the handgrip. Blood pressure was measured at 1 min intervals as described above by the indirect cuff method. Forearm blood flow was measured in the resting contralateral arm by venous occlusion plethysmography. The maximal increase in each of the variables were noted. Respiratory sinus arrhythmia ( R S A ) :is The patient breathed through a mouthpiece connected to a pneumotachograph at a tidal volume of 2 1. RSA was defined as the mean difference between the highest and lowest heart rate during a respiratory cycle as calculated from ten consecutive cycles. Valsalva ratio: t6'.7 The patient was instructed to maintain an expiratory pressure of 40 mmHg for 20 s by blowing through a mouthpiece. The Valsalva ratio was defined as a ratio between the highest heart rate during the Valsalva manoeuvre and the lowest heart rate during 20 s immediately afterwards. Head-up tilt: 18 The patient was placed in a head-up tilt position maintained for 8 min. Blood pressure was measured at rest and during the last minute of tilt. Sleep apnoea recordings." All patients underwent preoperative whole-night polysomnographic recordings of electroencephalogram (EEG), electrooculogram (EOG), chin electromyogram (EMG), airflow through nostrils and mouth (3-channel thermistor Nihon Kohden ZE-732A), respiration movements (Siemens Sensor 230, a piezoelectric movement sensor), and ECG on a Grass model 126
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8-10D. The polysomnograms were analysed according to standard techniques. 19'2° The ECG was checked meticulously for heart rate changes in association with apnoeas. A response was considered positive if there was a change of more than nine beats/min at the end of apnoea compared to the beginning, calculated from the difference in R - R intervals. Simultaneous with the polysomnographic recording arterial oxygen saturation (SaO2) (Biox III, earprobe), respiration- and body movements were recorded on a Graphtec servocorder at paper speed 1 cm/min. Respiration- and body movements were recorded by means of a static charge sensitive bed (SCSB) (BioMatt, Biorec Inc, Finland). This is a sensitive kinaesthetic transducer permitting recording of all kinds of body movements from a mattress on which the patient is lying. 21 Recording with slow paper speed clearly demonstrates the respiration patterns, in particular the diamond-shaped periodic respiration movements typical of upper-airway obstruction. 7 From this recording an oxygen desaturation index (ODI), i.e. the average number of desaturations of 4% or more per sleeping hour, was calculated. The percentage periodic respiration movements during total sleeping time was also noted. Renewed SCSB-oximetry recordings were made 6 months post-operatively.
Patients: Nineteen male patients with OSAS were studied. The diagnosis was based on clinical symptoms and the result of a polysomnographic recording. The patients were all heavy snorers and reported daytime symptoms in the form of increased sleepiness, morning headaches, concentration difficulties etc. Thyroid-stimulating hormone levels were within normal limits in all cases. None of them had any obvious predisposing factor, such as massive obesity, endocrine disease or anatomical malformation. None had a neurological deficit. Four patients had a diagnosis of essential hypertension, for which two were on antihypertensive medication with the beta-blocker, Metoprolol. Another patient was on the calcium channel blocker, Verapamil, and the angiotensin converting enzyme inhibitor, Enalaprilmaleat. The fourth patient was not on antihypertensive drugs at the time of the cardiovascular reflex testing. A patient was considered successfully treated if the ODI was reduced by at least two-thirds and the percentage periodic respiration movement time decreased by at least 50% in a recording performed 6 months after surgery. Ten patients filled these criteria for 'UPPP-success' while nine were considered 'UPPP-failures'. Individual data are listed in Table 1. The cardiovascular reflex test session was performed 8-15 months after surgery. All patients were given a questionnaire concern-
A utonotaic reflexes in sleep apnoea syndrome Table 1. Individual data concerning age, body mass index (BMI), preoperative apnoea index (AI), pre- and postoperative oxygen desaturation index (ODI) and percentages of pre- and postoperative periodic respiration during sleep. Patients nos 1-9 belong to the ' UPPP-failure' group, nos 10-19 to the "UPPP-success" group. Group mean values are presented at the foot of the table. Upper normal limit values: BMI 29 (40 or more: medically at risk because of obesity), AI 4, ODI 5, periodic respiration 43%
Patient no.
Age
BMI
Preoperative AI
1 2 3 4 5 6 7 8 9
55 54 53 62 40 60 50 46 50
27.4 25.6 31.1 29.8 20.4 36.2 36.4 24.8 31.9
9 26 66 48 14 16 63 20 24
10 11 12 13 14 15 16 17 18 19
65 44 43 50 43 51 62 43 67 47
32.5 31.2 23.7 24.0 24.5 29.5 29.5 29.7 19.6 29.7
Mean 1-9 10-19
52 52
29.3 27.4
Preoperative ODI
Postoperative ODI
Preoperative % periodic respiration
Postoperative % periodic respiration
23 38 52 57 5 60 82 9 57
14 9 34 38 9 36 28 5 54
49 61 86 99 57 99 90 30 84
54 47 58 87 51 99 60 26 58
29 43 35 12 54 15 51 57 40 66
14 75 35 11 33 44 67 65 18 49
2 24 4 1 2 5 8 7 0 1
56 95 60 90 70 92 90 98 60 73
11 30 14 17 25 10 0 24 10 11
31.8 40.2
42.6 41.1
25.2 5.4
72,8 78.4
60 15
,
ing subjective symptoms indicating autonomic dysfunction such as vertigo, fainting, impotence, urinary or bowel difficulties, and decreased sweating. Results
The mean test results for both groups are shown in Table 2. They were all within normal limits and there was no statistically significant difference in any of these tests between the two groups (MannWhitney U-test). Individual data for 'UPPP-success' patients and 'UPPP-failure' patients are given in Table 3. Minor deviations were seen in individual cases. Patient no. 7 had signs of a moderate vagal dysfunction in a decreased RSA and heart rate change in the isometric handgrip test. Patient no.
9 had decreased responses to the isometric handgrip test, but otherwise no indications of sympathetic dysfunction (normal orthostatic responses). He was on calcium-blocking anti-hypertensive medication (Verapamil). Patient no. 11 had decreased sympathetically mediated responses in the isometric handgrip and head-up tilt tests, and was on the beta-blocker, Metoprolol. Patient no. 1 had a slightly decreased RSA and patients nos 5, 12, 14 and 19 exhibited slight decreases in one of the responses to the isometric handgrip test, but all other test results were normal. Patient no. 17 had a normal RSA but abnormality in the Valsalva ratio and during isometric exercise. Patient no. 18 had very divergent test results with values outside both + and - 2SD. This might be explained by a malfunction in the central control
Table 2. Mean values (1SD between parentheses) for "UPPP-failure' and 'UPPP-success' patient groups. Reference values from normal control subjects of different ages from Kaijser and Sachs 12 Valsalva ratio
RSA
Isometric handgrip Bloodflow HR increase % change
UPPP-failures UPPP-successes Normals 40-60 years Normals > 60 years
1.8 (0.6) 1.6 (0.5) 1.9(0.3) 1.7 (0.4)
10 (10) 13 (7) 20 (7) 9 (4)
69 (52) 39 (43) 90(80) 64 (49)
11 (7) 8 (5) 23 (9) 13 (11)
Head-up tilt
Systolic BP change
Diastolic BP change
HR change
Systolic BP change
Diastolic BP change
19 (11) 19 (12) 44(14) 26 (18)
16 (9) 19 (6) 33(17) 14 (10)
11 (7) 17 (12) 13 (8) 11 (8)
8(11) 9 (17) - 2 (8) 9 (20)
5 (6) 5 (18) 6 (8) 3 (13)
Clinical Autonomic Research. vol 1 • 1991
127
E. Svanborget al. Table 3.
Individual cardiovascular reflex test results
Patient no.
Valsalva ratio
1 2 3 4~'b 5 6 7 8 9 10 ~ 11 b 12 13 14 15 16 ~ 17 18 a 19
RSA
Isometric handgrip Blood flow increase %
HR change
BPs change
Head-up tilt BP D change
1.8 1.4 1.8 1.2 3.1 ( + ) 2.4 1.3 1.4 1.6
5.0 ( - ) 10.0 13.0 1.5 6.0 6.0 2.9 ( - ) 12.4 35.0
114 115 122 23 41 23 36 139 8(-)
24 7 10 12 14 15 -2 (-) 15 4(-)
20 35 25 24 8(-) 8 (-) 19 30 4(--)
35 15 20 20 12 16 4 5 16
2.0 1.2 1.4 2.6 1.7 1,4 1.3 1.2 2.6 2.0
2.1 10.3 25,4 20.2 5.7 7.2 8.3 11.0 39.0 ( + ) 15.3
28 3 (-) 17 47 23 21 13 139 107 49
12 5 4 (-) 14 10 8 4 3(-) 0 (-) 16
48 30 20 20 6(-) 41 16 10(-) 10 10(--)
20 20 24 16 12 12 28 18 -4 20
(-) (+)
(-) (+)
HR change 22 18 0 14 10 10 10 8 3 11 0 25 27 38(+) 18 15 11 2 5
BPs change 20 ( + ) 5 -4 19 8 0 8 20 ( + ) -8 -7 -22 -4 12 16 17 12 2 29 36
Resting BPs
Resting BPD
Resting HR
115 120 155 152 112 151 138 130 176
61 90 92 92 64 106 92 90 100
66 80 78 56 82 92 67 73 80
132 110 120 136 108 122 148 120 143 154
88 82 76 102 80 98 92 85 88 102
55 7O 58 53 54 68 80 73 58 60
BPD change 7 5 -8 10 4 11 8 10 0
22 (-)-33(-) 16 28 ( + ) ( + ) 12 ( + ) 16 0 -3 -13 (+) 6
a Indicates age above 60 years, b Indicates beta-blocking antihypertensive medication. ( - ) value below 2SD compared with reference values. ( + ) value above 2SD compared with reference values. HR, heart rate; BPs, systolic blood pressure; BPD, diastolic blood pressure.
of the autonomic nervous system rather than by peripheral lesions. The responses during head-up tilt deviated from the normal range in seven patients. In five cases this consisted of elevation of the systolic blood pressure outside + 2 S D of the values from age-matched normal controls. This was seen in two cases belonging to the 'UPPP-failure' group and in three cases belonging to the 'UPPP-success' group. In Fig. 1 the distribution of the orthostatic systolic
~5 E Z
-30
-20
- 10 O 10 20 Systolic blood pressure (mmHg)
30
40
FIG. 1. Distribution of systolic blood pressurechangesto head-uptilt in all 19 patientswith obstructivesleepapnoeasyndrome.The lines indicate mean (thick line) and + 2SD (thinner lines on either side) of the normal control values. Patients nos 1-9 ('UPPP-failures') are indicated by light grey, patientsnos 10-19 (' UPPP-successes') are indicatedby darkgrey. 128
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blood pressure change in all 19 patients is shown. Most of these individuals reacted with increases in systolic pressure to this test. Patients nos 1, 7, 16 and 18 did not exhibit any bradycardia response even to apnoeas longer than 30 s seen during polysomnographic recordings. Patients nos 1 and 7 also had decreased RSA when awake, indicating vagal dysfunction. Patients nos 16 and 18 were both more than 60 years old, an age at which decreases in RSA are common. However, they both had RSA values well above the lower limit even for younger subjects. Linear regression analysis was made on pre- and postoperative ODI:s and preoperative apnoea indices (AI) versus the results of the different cardiovascular reflex tests. There were statistically significant positive correlations between pre- and postoperative O D I and the percentage blood flow increase in the contralateral arm during isometric handgrip (p < 0.01, R = 0.62 with regards to preoperative ODI; ? < 0.05, R = 0.46 with regards to postoperative ODI). This was also true between preoperative ODI and orthostatic systolic blood pressure change (p < 0.05, R = 0.49). There was no statistically significant correlation between any of the other variables. Only one patient (no. 18) had subjective symptoms (vertigo, impotence, decreased sweating) to such an extent that autonomic dysfunction could be suspected on clinical grounds, but his test results were suggestive of central malfunction. Ten more
A utanomic reflexes in sleep apnaea syndrome
patients responded positively to at least one item in the questionnaire, most frequently impotence, but in none were there objective evidence, on testing, of an autonomic lesion to explain their symptoms. Discussion
The lack of correlation between subjective symptoms and objective findings in the cardiovascular reflex tests could be explained by the fact that the symptoms the patients reported (dizziness, urinating difficulties, impotence, etc) are not specific for autonomic lesions and may have a multifactorial origin. Furthermore our investigations were designed to assess cardiovascular aspects of autonomic function. Two patients only had signs of moderate vagal dysfunction in their cardiovascular reflex tests, and they did not report any corresponding subjective symptoms. In the remaining patients the abnormal results may have been due to their medication or there was only one single deviating response. In the latter cases both the parasympathetic and the sympathetic systems were obviously intact, since all other test results were above lower normal limits. Hanly et al. 22 concluded on the basis of data from seven patients that the heart rate response to forced respiratory manoeuvres including Valsalva during wakefulness could be used to predict the response to obstructive apnoea. The results of the present study indicate that this is not always true, since two patients who lacked the typical bradycardia response even to long sleep apnoeas had a normal or, in one case, even increased Valsalva ratio and RSA. One tentative explanation might be a difference in vagal responsiveness between the sleeping and awake states in these cases. Vagal dysfunction is obviously not the only cause of absence of the bradycardia response to apnoea. In agreement with previous studies 11'~3 it is however evident that deviations in some autonomically controlled functions are not uncommon among OSAS-patients. In the present study a frequent finding was an exaggerated increase in systolic blood pressure during postural change. Although this may not be clinically :'significant, it does suggest an increased sympathetic drive in these patients. The lack of an inverse relationship between changes in blood pressure and heart rate was further evidence of an abnormality in our patients, as during head-up tilt there is normally an increase in heart rate when the blood pressure decreases. In the 'UPPP-failure' group, in particular, there was an increase in heart rate parallel with the increase in blood pressure. In our patients there were other signs of sympathetic hyperreactivity which increased in
parallel with the severity of OSAS, as expressed by the oxygen desaturation index (ODI). Thus, the average number of hypoxic episodes per sleeping hour both pre- and postoperatively were significantly correlated to the percentage of blood flow increase in the isometric handgrip test, which is a sympathetically mediated response. Increased sympathetic activity could also be the cause of the significant positive correlation between preoperative ODI:s and increases in systolic blood pressure during head-up tilt test. In contrast to this, Pressman and Fry 24 found evidence of decreasing sympathetic and increasing parasympathetic activity in parallel with higher AI:s when studying the direct pupil light reflex. The pupillary reflex probably indicates only local and not generalized autonomic nervous activity. It is noteworthy that the results of the present study imply an increase in sympathetic activity also among patients who were successfully treated, when there were few respiratory abnormalities to increase sympathetic activity, such as hypoxia. The relationship between OSAS and arterial hypertension has been increasingly emphasized. The prevalence of OSAS in patients with a primary diagnosis of essential hypertension has been estimated to be 26-47.8%. 2227 Hypertension is also common among OSAS-patients, 28 although large epidemiological studies have not been performed. The common denominator in both conditions could be increased sympathetic nervous system activity. Clark et al. 29 have found increased levels of urine and plasma catecholamines in patients with OSAS. Hedner et al. 3° recorded a high muscle sympathetic nerve activity in wakefulness in OSAS-patients, increasing further during sleep apnoeas followed by decrease when breathing was resumed. Increased muscle sympathetic nerve responses to vascular reflex tests have been demonstrated in patients with borderline hypertension. 31'32 In OSAS, it is probable that nocturnal apnoea is the primary cause of arterial hypertension, as hypoxia-induced stimulation of peripheral chemoreceptors is known to cause peripheral vasoconstriction and increase blood pressure. 33 Jennum et al. 34 have also found that blood pressure was reduced during effective treatment of OSAS-patients, and that this reduction was significantly related both to decreases in apnoea indices and plasma adrenaline. On the other hand, Hedner et al. 3s found no correlation between the severity of OSAS expressed in terms of ODI and the hypertension in their patients. A proven explanation for the long-term haemodynamic changes in OSAS-patients is thus lacking, but in patients with essential hypertension it has been suggested that the chemoreceptor reflex is exaggerated and that this is of pathophysiological importance. 3c"38 Constant nocturnal hypoxia, as Clinical Autonomic Research. vol 1 • 1991
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al.
seen in OSAS, may permanently change the sensitivity of the chemoreceptors. Somers et aL 39 have demonstrated that patients with borderline hypertension have exaggerated sympathetic muscle nerve responses to hypoxic chemoreceptor stimulation, and that this increased activity rose considerably during apnoea. This may be of importance for the increased mortality-rate in OSAS. 4° In the majority of these patients there is a cardiac or cerebrovascular cause of death which often occurs suddenly at night. 41'42 High sympathetic nervous system activity may trigger ventricular fibrillation 43 and cause or contribute to sudden death. In conclusion, this study indicates that decreased autonomic nervous system function is not a major contributing factor to failure of UPPP surgery, as abnormal results were not more common among patients who had an insignificant postoperative improvement compared to those who were successfully treated. Neither do OSAS-patients appear to have an increased incidence of autonomic dysfunction, The most constant finding was a tendency to sympathetic overreactivity, which was positively correlated to the degree of respiratory disturbance. References 1. Guilleminault C, Hill MW, Blair Simmons F, Dement WC. Obstructive sleep apnea: electromyographic and fiber-optic studies. Exp Neural 1978; 62: 48-67. 2. Remmers JE, de Groot WJ, Sauerland EK, Anch AM. Pathogenesis of airway occlusion during sleep. J Appl Physiol 1978i 44: 931-938. 3. Guindi GM, Bannister R, Gibson WPR, Payne JK. Laryngeal EMG in multiple system atrophy with autonomic failure. J Neural Neuros#rg Psych 1981; 44: 49-53. 4. GuilleminaultC, Briskin JG, GreenfieldMS, SilvestriR. The impact of autonomic nervous system dysfunction on breathing during sleep. Sleep 1981; 4: 265-278. 5. Kavey NB, Wbyte J, Blitzer A, Gidro-Frank S. Sleel~related obstruction presenting as snoring or sleep apnea. Laryngoscope 1989; 99: 851--854. 6. Munschauer FE, Lob L, Bannister R, Newsom Davis J. Abnormal respiration and sudden death during sleep in multiple system atrophy with autonomic failure. Neurology 1990; 40: 677-679. 7. Svanborg E, Larsson H, Carlsson-Nordlander B, Pirskanen R. A limited diagnostic investigation for obstructive sleep apnea syndrome~oximetry and static charge sensitive bed. Chest 1990; 98: 1341-1345. 8. Guilleminault C, Conally S, Winkle R, Melvin K, Tilkian A. Cyclical variation of the heart rate in sleep apnoea syndrome. Lancet 1984; i: 126-131. 9. Zwillich C, Devlin T, White D, Douglas N, Wall J, Martin R. Bradycardia during sleep apnea: characteristics and mechanism. J Clin Invest 1982; 69: 1286-1292. I0. Larsson H, Carlsson-Nordlander B, Svanborg E. Long-time follow up of UPPP for obstructive sleep apnea syndrome: results of sleep apnea recordings and subjective evaluation 6 months and 2 years after surgery. Acta Otolaryngol (Stockb) 1991; !11: 582-590. 11. Sachs C, Kaijser L. Autonomic regulation of cardiopulmonary functions in sleep apnea syndrome and narcolepsy. Sleep 1982; 8: 227-238. 12. Kaijser L, Sachs C. Autonomic cardiovascular reflexes in old age. Clin Physiol I985; 5: 34%357. 13. Freyschuss U. Cardiovascularadjustment to somatomotor activation. Acta Phjsid Stand 1970; 342 (suppl). 14. Eklund B, Kaljser L. Effect of regional alfa- and beta blockade on blood flow in the resting forearm during contralateral isometric handgrip. J Phy*iol 1976; 262: 39-50.
130
Clinical Autonomic Research. vol 1 • 1991
15. Melcher A. Respiratory sinus arrhythmia in man. Atta Physiol Stand 1976; 435 (suppl). 16. Levin AB. A simple test of cardiac function based upon heart rate changes induced by Valsalva manoeuvre. A m J Cardio/1966; 18: 90-99. 17. Wheeler T, Watkins PJ. Cardiac denervation in diabetes. Br MedJ 1973; iv: 584-586. 18. Thulesius O. Patophyaldiogical classification and diagnosis of orthostatic hypotension. Cardiology 1976; 61 (suppl 1): 180. 19. Rechtschaffen A, Kales A. A Manual of Slandardized Terminology, Techniques, and Scoring System for Sleep Stages of Human Subjects. Los Angeles: Brain Information Service/Brain Research Institute, UCLA, 1968. 20. Keenan Bomstein S. Respiratory monitoring during sleep: polysomnography. In: Guilleminault C, ed. Skeping and Waking Disorders. Indications and Techniques. Menlo Park: Addison Wesley, 1982; 183-212. 21. Alihanka J, Vaahtoranta K, Saarikivi I. A new method for long-term monitoring of ballistocardiography, heart rate and respiration. A m J Physiol 1981; 240: 384-392. 22. Hanly PJ, George CF, Millar TW, Kryger MH. Heart rate response to breath&did, Valsalva and Mueller maneuvers in obstructive sleep apnea. Chest 1989; 95: 735-739. 23. Guilleminauh C, Tilkian A, Lehrman K, Fomo L, Dement WC. Sleep apnoea syndrome: states of sleep and autonomic dysfunction. J Neurol Neurosurg Psjcb 1977; 40: 718-725. 24. Pressman MR, Fry JM. Relationship of autonomic nervous system activity to daytime sleepiness and prior sleep. Sleep 1989; 12: 239-245. 25. Fletcher EC, DeBehnke RD, Lovoi MS, Gorin AB. Undiagnosed sleep apnea in patients with essential hypertension. Ann Intern Med 1985; 103: 19(~195. 26. Kales A, Cadieux R, Shaw L, Vela-Bueno A, Bixler E, Schneck D, Locke T, Soldatos C. Sleep apnoea in a hypertensive population. Lancet 1984; ii: 1003-1008. 27. WilliamsAJ, Houston D, Finberg S, Lam C, Kinney JL, Santiago S. Sleep apnea syndrome and essential hypertension. A m J Cordial 1985; 55: 1019-1022. 28. Kales A, Cadieux RJ, Bixler EO, Sdidatos CR, Vela-Bueno A, Misoul CA, Locke TW. Severe obstructive sleep apnea: I Onset, clinical course, and characteristics. J Chron Dis 1985; 38: 419-¢25. 29. Clark RW, Boudoulas H, Schaal SF, Schmidt HS. Adrenergic hyperactivity and cardiac abnormality in primary disorders of sleep. Neurology 1980; 30: 113--119. 30. Fledner J, Ejnell H, Sellgren J, Hedner T, Wallin G. Is high and fluctuating muscle nerve sympathetic activity in the sleep apnoea syndrome of pathogenetie importance for the development of hypertension? J Hypertens 1988; 6: 529-531. 31. Miyajima E, Yamada Y, Matsukawa T, Tochikubo O, Ishii M, Kaneko Y. Neurogenoc abnormalities in young borderline hypertensives. Clin Exp H3pertens 1988; AI0 (suppl 1): 209-223. 32. Rea RF, Hamdan M. Baroreflex control of muscle sympathetic nerve activity in borderline hypertension. Circulation 1990; 82: 856-862. 33. Heistad DD, Abboud FM. Circulatory adjustments to hypoxia. Circulation 1980; 61: 463469. 34. Jennum P, Wildschiodtz G, Juel Christensen N, Schwartz T. Blood pressure, catecholamines, and pancreatic polypeptide in obstructive sleep apnea with and without nasal continuous positive airway pressure (nCPAP) treatment. A m J Hypertens 1989; 2: 847-852. 35. Hedner J, Ejnell H, Caidahl K. Left ventricular hypertrophy independent of hypertension in patients with obstructive sleep apnea. J Hjpertens 1990; 8: 941-946. 36. PrzybylskiJ. Do arterial chemoreceptors play a role in the pathogenesis of hypertension? Med H:potheses 1981; 7: 127-131. 37. Trzebski A, Tafd M, Zoltowski M, Przybylski j. Increased sensitivity of the arterial chemoreceptor drive in young men with mild hypertension. Cardiovase Res 1982; 16: 165-172. 38. Fukuda Y, Sato A, Trzebski A. Carotid chemoreceptor discharge responses to hypoxia and hypercapnia in normotensive and spontaneously hypertensive rats. J Auton Nerv Syst 1987; 19: 1-11. 39. Somers VK, Mark AL, Abboud FM. Potentiation of sympathetic nerve responses to hypoxia in borderline hypertensive subjects. Hypertension 1988; 11: 608-612. 40. He J, Kryger MH, Zorick FJ, Conway W, Roth T. Mortality and apnoea index in obstructive sleep apnoea. Cheer1988; 94: 9-14. 41. Partinen M, Jamieson A, Guilleminadit C. Long-term outcome for obstructive sleep apnea syndrome patients. Chest 1988; 94: 1200-1204. 42. Koskenvuo M, Kaprio J, Telakivi T, Partinen M, HeikkiliiK, Soma S. Snoring as a risk factor for ischemic heart disease and stroke in man. Br MedJ 1987; 294: 16-19. 43. Lown B, Verrier RL, Rabinowitz SH. Neural and psychologic mechanisms and the problem of sudden cardiac death. A m J Cardiol 1977; 39: 890~902.
A C K N O W L E D G E M E N T S . The authors thank Dr H. G. H~rdemark for his help with the statistical analysis, and Professors Gunnar Wallin and Mikael Elam, Department of Clinical Neurophysiology, Sahlgrenska Hospital, Gothenburg, for valuable advice. This work has been supported by grants from the Karolinska Institute and the Swedish Society of Medicine.
Received 4 February 1991 ; accepted with revision 28 March 1991.
