Download The Impact of Autonomic Nervous System Dysfunction on Breathing

Sleep 4(3):263-278
1981 Raven Press, New York
©
The Impact of Autonomic Nervous System
Dysfunction on Breathing During Sleep
*Christian Guilleminault, tJonathan G, Briskin, :j:Michael S. Greenfield,
and *Rosalia Silvestri
*Sleep Disorders Clinic, tDivision of Cardiology, and 't-Division of F;ndocrinology and
Metabolism, Stanford University School of Medicine, Stanford, California
Summary: Ten patients with autonomic nervous system dysfunction (familial
dysautonomia, juvenile diabetes, or Shy-Drager syndrome) were studied to
assess the impact of their impairment on breathing during sleep. Several types
of breathing dysfunction during sleep were identified independent of the patients' primary complaints. Obstructive sleep apnea syndrome was the most
common; central sleep apnea and disturbances of the respiratory oscillator also
were seen. Esophageal reflux was found to be the cause of some sleep-related
problems. The observed respiratory irregularities were not associated with the
usual cardia\.: response; a .. decoupling" of heart rate from the respiratory cycle
was noted during sleep in these patients. Key Words: Breathing during
sleep-Autonomic nervous system dysfunction-Juvenile diabetes-Familial
dysautonomia-Shy-Drager syndrome-Sleep apnea-Esophageal reflux.
In mammals, sleep and sleep states have a substantial impact on the functioning
of the autonomic nervous system. Baust and Bohnert (1969) showed that, in the cat,
an increase in parasympathetic tone occurs; this peaks during rapid eye movement
(REM) sleep and is associated with a decrease in sympathetic activity. Considering the major involvement of the autonomic nervous system in the control of
breathing, we thought it interesting to evaluate the impact of autonomic dysfunction in humans on breathing during sleep.
Patients with Shy-Drager syndrome have been shown to present obstructive
sleep apnea (Castaigne et aI., 1977; Guilleminault et aI., 1977; Chokroverty et aI.,
1978). However, in our own studies, the population previously reported was elderly. We have since had the opportunity to study young subjects presenting
juvenile diabetes or familial dysautonomia during wakefulness and sleep, and to
evaluate their breathing patterns during sleep. This report presents an analysis of
Accepted for publication May 1981.
Address correspondence and reprint requests to Dr. Guilleminault at Sleep Disorders Center TD114,
Stanford University School of Medicine, Stanford, California 94305.
These results were presented orally at the American Academy of Neurology meeting, held in April
of 1981.
263
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C. GUILLEMINAULT ET AL.
the different abnormal, sleep-related breathing patterns noted in each of three
patient groups. Subjects ranged in age from adolescence to the early sixties.
METHODS
Patient Population
A total of 10 patients, subdivided into 3 groups, was studied. Four patients had
received a diagnosis of Shy-Drager syndrome (mean age = 60.1 years). Four
patients were diagnosed with juvenile diabetes and autonomic neuropathy (mean
age = 25 years). Two adolescent girls presented with familial dysautonomia (mean
age = 13.5 years). These patients were selected specifically because of abnormal
breathing patterns monitored objectively during sleep, independently of their
clinical symptoms. Table I summarizes some of their clinical data.
The four Shy-Drager patients presented neurological symptoms (essentially
extrapyramidal symptoms), cardiovascular problems with orthostatic hypotension and, in two patients, repetitive syncope during the daytime. All presented
sexual problems; three were completely impotent and one had significant difficulty with erection and ejaculation. Three of the four complained of disabling
daytime somnolence. All patients were receiving medications on a chronic basis to
control extrapyramidal symptoms and orthostatic hypotension. Chronically prescribed dopaminergic medication was not discontinued during the sleep-related
investigations.
The 4 diabetic patients all had been receiving subcutaneous insulin injections for
at least 7 years on a daily basis. At the time of the study, all were considered as
presenting controlled diabetes. None of them was receiving any other medication.
One of them had an advanced diabetic retinopathy, two had symptoms of diabetic
nephropathy, two were impotent, one had difficulty with ejaculation but not
erection, one had obvious orthostatic hypotension with clinical symptoms (the
other three had a drop of systolic pressure of 15 mmlHg and of diastolic pressure of
10 mm/Hg upon standing up after lying relaxed on a bed for 15 minutes; however,
they were without clinical complaints). None of them complained of daytime
sleepiness, but one of them reported intermittent "heartburn" during sleep and
consulted for a frightening episode of "choking during sleep."
The two adolescent girls with familial dysautonomia presented a relative insensitivity to pain; moderate postural hypotension without clinical complaint was
noted at examination. Both complained of cold hands and feet, had poor motor
coordination, and presented hypoactive deep tendon reflexes on all four limbs.
One displayed important emotional lability and was receiving psychiatric care
(psychotherapy); she also presented repetitive cyclical vomiting and frequent
pneumonia. The other one had unexplained bursts of rectal temperature increases
and had a history of moderate breath-holding spells when near 18 months of age,
which resolved spontaneously when she was about 2Y2 years of age. Both
presented substantial body growth retardation, but had developed some secondary sexual characteristics [Tanner Stages 2 and 3 (Tanner, 1962)]. All medications
had been interrupted for a minimum of one week prior to the sleep studies in
both cases.
Sleep. Vol. 4. No.3. 1981
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TABLE 1. Clinical data on 10 patients with autonomic nervous system dysfunction
Case # and
primary problem
Shy-Drager syndrome
Case #1
Case #2
Case #3
Case #4
Juvenile diabetes
Case #1
Case #2
Case #3
Case #4
Familial dysautonomia
Case #1
Case #2
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Abnormal cardiac
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tested
Age
Sex
EDS"
Snoring
Impotence
Vomiting or
heartburn
59
61
59
61
M
M
M
M
+++"
+++
+++
+++
+++
+++
+++
+++
+++
+++
+
0
0
0
0
0
0
0
0
+++
+++
+++
+
18
21
30
40
M
M
M
M
0
0
0
0
0
+
++
+++
+
+
+
0
0
0
0
+
+
+
++
+++
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+
+++
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F
0
0
0
0
Not known
Not known
0
0
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+
0
0
13
14
0
" EDS, Excessive Daytime Somnolence.
" Symbols: +, mild; ++, moderate; +++, severe.
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C. GUILLEMINAULT ET AL.
None of the patients was overweight, nor did they present otolaryngologic or
facial structural abnormaiilies.
Daytime Testing
Pulmonary function tests were obtained for all Shy-Drager and familial
dysautonomia patients and for 2 of the 4 juvenile diabetics. Hypoxic and hypercapnic response curves were performed in 3 of the 4 Shy-Drager patients, one
(nonvomiting) adolescent familial dysautonomia case, and 2 juvenile diabetics
(Read, 1967; Rebuck and Cambell, 1974).
Night-Time Testing
Each subject was monitored polygraphically for at least 2 nights; some subjects
were monitored for up to 6 nights over a period of time (the mean number of
monitored nights was 3). In each case, the variables recorded depended on the
patient's group and original findings; however, all subjects underwent a standard
monitoring procedure on the first night.
Testing Before Lights Out
Each subject was submitted to the following standardized series of tests, which
was repeated twice. (1) Investigation of respiratory influence on heart rate [the
"Bennet Test" (Bennet et aI., 1978)]. The patient was requested to lie relaxed on a
couch for 10 min, and then to perform maximal deep-breathing maneuvers for one
min. (2) Investigation of Valsalva maneuver on heart rate. (3) Investigation of a
cold stress on heart rate (Khurana et aI., 1980).
For maneuvers 2 and 3, patients were seated comfortably on a bed (with the
upper part of the bed at a set angle of 75°). During the cold stress test, 2 plastic
bags filled with ice were applied to the patient's cheeks, chin, and forehead for
1 min.
During each test, which included baseline recordings pre- and postmanipulation, heart rate (electrocardiogram lead II) and respiration (monitored by means of
thoracic and abdominal strain gauges) were recorded on a Grass Model 7 Polygraph with paper speed at 10 mm/sec for the first run and 25 mm/sec for the second.
(See Fig. 1 for example). Heart rate also was monitored on a 24-hour Holter
ambulatory electrocardiogram in 6 out of 10 subjects.
Nocturnal Monitoring
The following variables were monitored systematically: electroencephalogram
(EEG), using C3 iA2 -C4 iA 1 of the 10-20 international placement system; electrooculogram (EOG); chin electromyogram (EMG); electrocardiogram (ECG) lead
II; respiration (respiratory effort monitored by thoracic and abdominal strain
gauges; airflow monitored by thermistors placed in front of each nostril and the
mouth with results integrated to give a one-signal output); and continuous oxygen
saturation (Hewlett-Packard ear oxymeter).
Several other variables were monitored simultaneously, depending on the re-
Sleep, Vol. 4, No.3, 1981
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FIG. L Example of recording during cold stress test while awake in a juvenile diabetic patient (case #2). ECG
Note the absence of heart rate change during the test.
=
lead II (speed 10 mmlsec).
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C. GUILLEMINAULT ET AL.
cording night and the patient's group. Endoesophageal pH was monitored for one
night in the familial dysautonomia patients and in 2 of the 4 diabetics. Nocturnal
penile tumescence (NPT) was monitored in all diabetics and two Shy-Drager
patients during 3 successive nights; during these recordings, blood pressure was
monitored using an external Doppler system blood pressure recorder every 10 to 15
min. Two Shy-Drager patients and one diabetic patient who presented clinical
evidence of severe cardiovascular problems underwent more complex
hemodynamic study during wakefulness and sleep. A right heart and femoral
artery catheterization was performed, by placing a Swan-Ganz thermodilution
catheter and a femoral arterial catheter. Pulmonary and femoral arterial pressures
were recorded continuously during wakefulness to evaluate autonomic reflexes;
interventions were used to test baroreceptors and afferent nerve pathways (tilt
table, Valsalva maneuver, amyl nitrite, and carotid massage), central integrative
centers (Valsalva maneuver and mental arithmetic), sympathetic outflow (Valsalva maneuver and cold pressor test), organic responsiveness (norepinephrine and
angiotensin infusion), and presence of functioning nerve endings (metaraminol).
During sleep, pressures and blood gases were obtained.
All monitored variables were recorded on a Grass Polygraph at a paper speed of
10 mm/sec. Hemodynamic variables were monitored simultaneously on a
Hewlett-Packard recorder, and NPT was monitored on an independent recorder.
Analysis of Data and Control Values
Sleep and wakefulness were scored in 30-sec epochs following the Rechtschaffen and Kales (1968) criteria. Apnea and hypopnea were scored following standard
international criteria (Tassinari et al., 1972) and each apnea was further scored as
central, obstructive, or mixed. Esophageal reflux was scored when esophageal pH
dropped to under 4. (Calibration of the pH probe was performed before and after
recording, and evaluation of proper gastric acidity was performed prior to
monitoring. )
We use the term respiratory abnormality in this report to cover any abnormality
of breathing during sleep lasting for less than 10 sec (usually only one or two
breaths) and consisting of the following: absence of one breath as marked by
absence of normally expected inspiration; reduction of inspiration time (ti), defined as the time spent from the polygraphically recorded "trough" seen at the
end of expiration to the "peak" seen at the end of inspiration; reduction, by at
least 50%, of the amplitude of movements monitored by strain gauges and airflow
monitored by thermistors.
Respiratory irregularities are seen in stage 1 non-REM (NREM) and in REM sleep
in normal subjects; therefore, we did not score them when they occurred during these
sleep states. On the other hand, in normal control adolescents and young adults
monitored in our laboratory, respiratory irregularities are uncommon in stages 2,
3, and 4 NREM sleep. We used data already published by Carskadon et al.
(1978), obtained on normal controls aged 9 to 14, as control values for the dysautonomia patients. (Normally, the fewest longer-than-five-sec pauses per min
of sleep are seen during stages 2, 3, and 4 NREM sleep, averaging less than
Sleep, Vol. 4, No.3, 1981
BREATHING AND AUTONOMIC NERVOUS SYSTEM DYSFUNCTION 269
half the number seen during REM sleep. The number of short abnormal respiratory events seen in control girls during sleep was 0.017 per min of stage 3-4
NREM sleep [Carskadon et aI., 1978].)
RESULTS
The results presented here focus on abnormalities of breathing seen during
sleep.
Daytime Testing
The "Bennet Test," cold stress test, and Valsalva maneuver were abnormal in
all Shy-Drager patients and in 3 of 4 of the diabetics. In case #2 of the familial
dysautonomia group, no response was seen to the "Bennet Test" and Valsalva
maneuver, but mild response to the cold stress test was noted. The last 2 patients
(l diabetic, 1 familial dysautonomia) responded to all 3 tests.
The hemodynamic tests confirmed the existence of severe cardiovascular dysfunction secondary to autonomic nervous system disturbances in the 2 ShyDrager patients and 1 of the juvenile diabetics investigated (Briskin et aI, 1978).
Figure 2 presents a tracing obtained on case #3 of the diabetic group.
Nocturnal (Sleep) Monitoring
All patients presented some type of breathing abnormality during sleep, as per
the above-given definitions. However, several different types of abnormality were
seen.
Type J-Obstructive Sleep Apnea Syndrome
Six of the 10 patients presented predominantly obstructive sleep apnea syndromes as shown in Table 2. It is interesting to note that there was no correlation
between hypoxic and hypercapnic responses while patients were awake, and the
presence or degree of sleep apnea syndrome. As can be seen in Figs. 3 and 4, a
similar absence of heart rate response to obstruction during sleep was noted in the
59-year-old Shy-Drager patient and the 30-year-old juvenile diabetic. In Fig. 3, use
of an endoesophageal pressure balloon allowed better appreciation of the 2 components of the apneic events recorded; there is a short diaphragmatic inhibition
and then, after this initial component, a progressive increase in diaphragmatic
effort against an obstructed airway. In both examples shown, termination of the
apnea is associated with an "arousal," defined as a "lightening" of sleep with a
change in sleep stage, but not necessarily a return to alpha EEG activity. The
arousal response also is indicated by the appearance of fast or slow eye movements, as is seen in Fig. 4.
In all patients with predominantly obstructive sleep apnea and autonomic dysfunction, a clear dissociation between heart rate and respiratory response was
noted. The duration of each apneic event varied within the same sleep state, when
intermittent apneas were monitored, as can be seen in Fig. 4. Patterns of sudden
bursts of periodically repetitive obstructive apnea could be noted (as shown in
Sleep, Vol. 4, No.3, 1981
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No change in heart rate was noted during any of the daytime tests, and no change in nocturnal penile tumescence was
monitored. The subject presented a severe autonomic nervous system dysfunction.
1\
BREATHING AND AUTONOMIC NERVOUS SYSTEM DYSFUNCTION 271
TABLE 2. Obstructive sleep apnea syndrome
Case # and
primary problem
Shy-Drager syndrome
Case #1
Case #2
Case #3
Case #4
Juvenile diabetes
Case #2
Case #3
Sleep state
in which lowest
O2 values
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Apnea/hypopnea
index"
Lowest O2
saturation
during
sleepb (%)
62
58
59
12
25
32
26
68
REM
REM
REM
REM
9
81
11
77
REM sleep
Stage 2
NREM sleep
sleep
sleep
sleep
sleep
[Total number of apneas/Total sleep time (min)] x 60.
Accuracy of equipment was limited to values above approximately 35%
(Hewlett-Packard ear oximeter).
a
b
Fig. 4), or abrupt isolated obstructive apnea might appear. In cases where a low
apnea index was monitored, very few apneic episodes were recorded in stage 3-4
NREM sleep.
Type 2-Central Sleep Apnea Syndrome
The juvenile diabetic case #4 presented bursts of central sleep apneic events,
seen predominantly during stages 1 and 2 NREM sleep and REM sleep. His apnea
index was 6 and his longest apneic event was 52 sec, recorded during REM sleep
with an associated oxygen saturation of 84%.
Type 3-Respiratory Irregularities During Sleep Associated with Abnormal
Drops in Esophageal pH
The familial dysautonomia case # 1 and juvenile diabetic case # 1 presented clinical symptoms pointing to esophageal reflux, with the mention of. sleep-related
"heart burn." The familial dysautonomia patient presented frequent cyclical
vomiting, and the juvenile diabetic reported intermittent (2-4 months apart)
episodes of abrupt awakenings during the night with a feeling of choking and
inability to breath after awakening, associated with a panicked feeling of near
death due to complete airway obstruction. The latter patient's symptoms had
appeared 18 months prior to recording. Monitoring during sleep, when we performed it, did not demonstrate any vomiting or laryngospasm in either of the 2
cases. However, we did note repetitive long drops in endoesophageal pH to between 3.8 and 1.9. The mean duration of the pH drop episodes was 21 min (range
1-105 min). They were seen during all stages of sleep, including stage 3-4 NREM
sleep, as is seen in Fig. 5. The episodes frequently were associated with respiratory irregularities such as short hypopnea, skipped breaths, pauses, or abrupt
termination of inspiration with resulting reduction in inspiration time. These respiratory irregularities seen during lowered pH were associated frequently with sleep
Sleep, Vol. 4, No.3, 1981
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end oesophageal pressure during the obstructive sleep apnea and the complete absence of heart rate response to the obstructive event. EEG alpha arousal
can be noted clearly at the end of each apneic event. Note also the diaphragmatic inhibition at the beginning of the apnea.
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apnea of varying duration during stage 2 NREM sleep. Note the dissociation of heart rate and respiration, as seen also in Fig. 3 (Shy-Drager patient). No
clear alpha EEG arousal can be noted at the end of the apnea; however. eye movements are seen indicating an arousal response.
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BREATHING AND AUTONOMIC NERVOUS SYSTEM DYSFUNCTION 275
stage changes, and sometimes led eventually to EEG alpha arousal. Compared to
normative data published by DeMeester et al. (1980), these results are indicative
of a pathological esophageal reflux being responsible for the respiratory irregularities.
Type 4-Respiratory Irregularities During Sleep Without Drops in
Esophageal pH
This type of breathing abnormality was seen in one patient only (familial
dysautonomia, case #2). It has not been described previously. When respiratory
irregularities were tabulated in stage 2 and stage 3-4 (slow wave) sleep, we noted
0.25 respiratory irregularities per min during stage 2 (irrespective of type) and 0.20
during stage 3-4 (compared with 0.022 and 0.017, respectively, for normal controls; Carskadon et al., 1978).
Figure 6 shows examples of the respiratory irregularities; we have presented
those seen during stage 3-4 (slow wave) sleep, as this is the sleep stage known to
be associated with the most regular respiratory pattern. These respiratory irregularities were not associated with any changes in esophageal pH or heart rate.
Although sleep state changes were noted in association with the respiratory irregularities at times, no systematic pattern emerged. No complete alpha EEG
arousal was noted at the end of any of these irregularities in respiratory rhythm.
DISCUSSION
The autonomic nervous system is known to link peripheral receptors and central commands involved in the control of breathing. It is not surprising that patients who present impairment of the autonomic nervous system are found to have
abnormal breathing patterns during sleep. Shy-Drager patients already have been
singled out several times in the recent past for their abnormal respiration during
sleep (Castaigne et al., 1977; Guilleminault et al., 1977; Chokroverty et al., 1978;
Lehrman et al., 1978). Juvenile diabetics with autonomic neuropathy and patients
with familial dysautonomia have received much less attention. However, our
study demonstrates that breathing problems during sleep could endanger the lives
of many patients with autonomic neuropathies, independent of the patients' ages
and the causes of the autonomic lesions.
Our studies also demonstrate that several factors may be responsible for abnormal breathing patterns noted during sleep. Multivariable monitoring must be
performed, including not only respiratory but also cardiac and esophageal indices,
when a patient with autonomic nervous system dysfunction is investigated. The
same respiratory irregularity may be secondary to different insults to the autonomic nervous system.
It is interesting to note that there does not seem to be any correlation between
waking hypercarbic and hypoxic response and obstructive sleep apnea syndrome
in patients with autonomic dysfunction; the same already has been reported for
patients without autonomic lesions. In our patient popUlation, heart rate and
respiration are "decoupled" during both wakefulness and sleep. One of our
juvenile diabetics (case #3) presented a nearly complete cardiac denervation, with
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FIG. 6. Examples of respiratory irregularities seen in a 14-year-old girl with familial dysautonomia. Note the absence of esophageal reflux and heart rate
changes. These irregularities reoccurred throughout the night, and were seen often during stage 3-4 NREM (slow wave) sleep.
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BREATHING AND AUTONOMIC NERVOUS SYSTEM DYSFUNCTION 277
very abnormal cardiovascular responses; there was, however, a complete dissociation between his hemodynamic findings and the moderate obstructive sleep
apnea syndrome that he presented. Although he did present sleep stage changes at
the termination of apneic events, few of these were alpha EEG arousal. The
relationship between hemodynamic changes and the EEG alpha arousal needs to
be investigated further, and the role of baroreceptor stimulation in the arousal
response in obstructive sleep apnea must be evaluated.
One of the interesting findings of this study was obtained on the familial
dysautonomia case #2 patient. This adolescent girl had normal hypercarbic responses while awake, and did not present any major respiratory or clinical problems when awake or asleep. However, she did present continuous respiratory
irregularities with frequent interruption of inspiration, or absence of initiation of
inspiration and lack of one breath, while in stage 3-4 NREM (slow wave) sleep,
the state known to be associated with the most regular respiratory pattern, particularly in the young. During slow wave sleep (stage 3-4 NREM sleep), chemical
control of ventilation supposedly is at its best. Can a subject with respiratory
irregularities as seen in this young woman eventually develop a more pronounced
respiratory problem, as seen in the subject with a very moderate central sleep
apnea syndrome [borderline abnormal, with an apnea index of 6 where 5 is considered normal (Guilleminault et aI., 1978)]? What are the reasons for the continuous
abortion of inspiration and the irregular breathing with decrease of diaphragmatic
output (hypopnea) or absence of continuous function of the respiratory oscillator?
Further studies of these borderline cases may give us more insight into the multifaceted components of the control of breathing during sleep.
Note: Since writing and orally presenting this paper, we have read the article of
Rees et al. (1981) reporting a study of diabetic patients with autonomic
neuropathy. They also noted the presence of central and obstructive sleep-related
apneas in their patient population.
ACKNOWLEDGMENTS
This work was supported by a grant from the KROC Foundation, by Public
Health Service Research Grant R.R. 80 from the General Clinical Research Centers, and by INSERM to CG.
We thank S. Bornstein, S. Coburn, and D. Zeiger for their technical help.
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