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Respiratory control in familial dysautonomia
T h e ] o u r n a l of P E D I A T R I C S
509
Respiratory control in familial dysautonomia The response to increased carbon dioxide (4 per cent) and reduced oxygen (12 per cent) inhalations in subjects with dysautonomia has been compared to that in normal individuals. In both instances, the patient with dysautonomia revealed a reduced ability to cope with these stresses, with potentially serious consequences. These observations are significant in the pathophysiology of familial dysautonomia and suggest approaches to therapy.
Juan Filler, M.D., Alfred A. Smith, M.D., Samuel Stone, M.D., and Joseph Daneis, M.D.* NEW
YORK~
FAMILIAL
N. Y.
DYSAUTONOMIA
iS
an
inherited disease commonly manifest at birth but difficult to diagnose at that time. At a later age, a well-defined clinical picture makes recognition relatively simple? There is evidence of a diffuse neurological defect; symptoms referable to the autonomic nervous system are prominent; among them are alacrima, postural hypotension, and dysphagia. Studies of the physiologic responses to methacholine 2 and to norepinephrin& indicate a parasympathetic insufficiency and an exaggerated response to both agents which contribute to the autonomic instability of these subjects.
From the Departments o/Pediatrics and Psychiatry, New York University Medical Center. Supported by Grant No. H.E. 3436 from the National Heart Institute of the National Institutes of Health, United States Public Health Service, and by grants from the Dysautonomia Association and the National Foundation. *Career Investigator of the National Institute of Child Health and Human Development, National Institutes o] Health. Address, Department of Pediatrics, New York University Medical Center, 550 First Ave., New York, N . Y. 10016.
Less prominent in the symptomatology is the sensory defect. The patients are relatively insensitive to pain, and frequently the corneal and patellar reflexes are absent? Evidence that the sensory defect is peripheral, at least in part, has recently been provided. The intradermal injection of histamine fails to elicit the axon flare which depends, neurologically, only on an intact peripheral sensory nerve. 4 The defective taste discrimination previously described a appears to result from an absence of fungiform papillae and taste buds on the tongue? Both signs are consistently found in dysautonomia, and may serve as reliable diagnostic tests even at birth. In the present study, the possibility of a sensory defect in respiratory control has been explored. The sensitivity of the respiratory center has been investigated by correlating the concentration of inspired carbon dioxide and its partial pressure in arterial blood with the amount of pulmonary ventilation. The response of the peripheral chemoreceptor mechanism (glomus aorticum and glomus caroticum) to hypoxia was tested by acutely lowering the concentration
5 I 0
Filler et aL
T a b l e I.
March 1965
T h e v e n t i l a t o r y r e s p o n s e to CO2 i n t h e d y s a u t o n o m i c a n d n o r m a l s u b j e c t
Dysautonomia patients
Pa~ie,,t
v~ (ml.)
go 2 (L./min./1V[. 2)
Vco2 (L./min./M.2)
[ 2 ~ COs
[ 3 ~ COt
r 4 ~ C0~ I 5 ~ C0~
18 16 14 18 20 28
18 16 14 20 22 30
18 18 14 20 25 30
20 18 16 22 25 29
20 20 18 23 26 30
20
Average
19
23.3
21.5
21.7
26~5
25.3
M.W, B.L. K. S. D.B. K. E. D.G.
200 307 150 240 230 264
320 330 207 340 264 320
360 348 225 400 273 444
406 466 330 450 306 530
506 490 320 500 417 600
585
231.8
297
341.6
414.6
472
555
24 32
570 510
M.W. B.L. K.S. D.B. K.E. D.G.
3.60 4.90 2.50 4.64 4:60 7.4Q
5.74 5.30 2.90 6.80 5.80 9.60
6.50 6.30 3.20 7.90 6.80 13.30
8.i3 8.40 5.20 10.00 7.60 15.35
10.12 9.80 6.40 11.50 10.84 18.00
11.70
Average
4.61
6.02
7.33
9.11
11.11
13.86
13.60 16.30
M.W. B.L. K. S. D. B. K. E. D. G.
180 114 300 186 178 226
192 138 338 112 144 200
194 145 358 152 127 176
233 130 410
262 112 560
154 169
160 192
Average
197
t82
192
219
257
232
M.W. B. L. K.S. D. B. K.E. D.G.
154 109 328 146 153 152
167 114 300 106 121 200
171 112 292 113 100 204
192 136 340
190 I3I 400
205
106 162
124 178
Average
t 74
168
165
187
205
255 235 205
151 126 161
.87 .82 .88 .95 .84 1.00
.88 .77 .81 .74 .79 1.16
.81 .95 .83
.73 ,86 .71
D. G.
.85 ,96 1.09 .79 .82 .67
.69 .96
,79 .93
Average
.86
.89
.86
.85
.80
M.W.
R
1% C0~
IV[.W. B.L. K.S. D. B. K.E. D.G.
Average
gE (L./min./M3)
] Room air
B, L, K. S. D, B. K.E.
.80 .64 .62 .69
Respiratory frequency (f), tidal volume (Vw), minute ventilation (V~), oxygen uptake (Voz), carbon dioxide output (Vo%),
Volume
Patient B. C. R.P. C. W. D, G. S. V.
Average B, C, K.P. C.W. D.G. S. V. Average
66
[
Number 3
Room air
Respiratory control in [arailial dysautonomia
I
1% CO~
Normal subjects I 2% CO, I
3% CO t
I
4% co~
I
511
5% co~
24 13 16 18 20
24 16 18 24 22
22 16 22 28 28
38 20 26 32 32
44 24 32 36 36
42
18.2
20.8
23.2
29.6
34.4
41
40
150 280 278 180 170
180 305 340 268 206
268 455 330 250 260
260 460 400 368 260
330 600 430 372 340
490
211.6
260
312.6
349.6
414.4
420
350
B.C. R.P. C. W, D. G, S.V.
3.60 3.67 4.46 3.26 3.37
4.33 4.90 6.12 6.42 4.53
5.90 7.30 7.25 7.00 7,34
9,93 9.20 10.38 11.75 8.30
14.51 14.50 13.78 13.40 12,20
20.67
Average
3.67
5.26
6.96
9.80
13.68
17.50
B.C. R.P. C.W. D. G. S.V. Average B. C, R. P. C.W. D. G. S.V. Average
14.20
137 144 177 176 140
154 156 129 202 140
144 182 189 178 143
167 178 183 185 138
165 179 166 218 187
233
154.8
156.2
167.2
166.5
183
260
126 132 152 153 133
133 130 133 167 106
124 145 154 160 100
158 128 157 168 120
144 151 137 180 162
196
139.2
133.8
136.6
146.2
287
250
154.8
223
B.C. R. P. C.W. D.G. S.V.
.90 .92 .86 .87 .95
,86 .82 1.03 ,83 .75
.86 .80 .81 .90 .70
.94 ,72 .86 .91 .87
.87 .85 .82 .92 .86
.86
Average
.90
.86
.81
.864
.864
.865
and respiratory quotient (R).
.87
5 12
Filler eta[.
March 1965
T a b l e II. T h e response to r o o m aii, 4 per cent CO2, and 12 per cent 02 in d y s a u t o n o m i c and n o r m a l subject
Dysautonomia patients ~ Normal subjects Patient t Room air I 4 % CO~ I. 12% O~ Patient I R~~ i ~oo-CO~ .1 12% 03 f
V~
(L,/min./M3)
M.W. K.S. K.E. D.G. J.S. R.H.
18 14 20 28 20 22
20 18 26 30 21 24
10 10 15 12 10 18
Average
20
23
12.5
M.W. K.S. K.E. D.G. J.S. R.H. Average
S,oo (% )
P~eo2 (man. Hg)
4.73
10.12 6.40 10.84 18.00 9.95 12.70 11.33
6.84 4.24 9.34 7.90 7.55 9.80 7.61
M.W. K.S. K.E. D.G. J.S. R.H.
98.5 88 95 95.5 93 89
97.5 89 95 89.5 90 96
37 51 56 68.5 41 62
Average
93.1
92.8
52.6
48 38 42 36 38 36
54 46 44 43 47 44
46 39 41 37 40 40
39.7
46.3
40.5
M.W. K.S. K.E. D.G. J.S. R.H. Average
pH
3.60 2.50 4.60 7.40 4.56 5.72
J.G. E.D. E.T. G.F. J.P. Average J.G. E.D. E.T. G.F. J.P. Average J.G. E.D. E.T. G.F. J.P. Average J.G. E.D. E.T. G.F. J.P.
M.W. K.S. K.E. D.G. J.s. R.H.
7.37 7.36 7.34 7.50 7.45 7.41
7.33 7.32 7.33 7.44 7.41 7.35
7.38 7.34 7.36 7.48 7.41 7.39
Average
7.40
7.36
7.39
Average J.G. E.D. E.T. G.F. J.P. Average
20 12 24 15 20
26 16 28 26 28
18 12 28 14 19
18.2
24.8
12.8
3.54 3.80 3.76 3.90 5.20 4.04
8.36 9.10 9.10 12.65 15.50 10.94
4.83 5.00 4,80 6.90 5.80 5.47
98 97 91 96 96
97 93 93 98 95
80 76 75 84 74
95.6
95.2
77.8
40 38 38 36 35
44 39 40 38 41
34 32 37 30 32
37.4
40.4
33
7.41 7.41 7.43 7.39 7.43
7.38 7.40 7.42 7.38 7.40
7.46 7.46 7.41 7.45 7.44
7.41
7.40
7.44
Respiratory frequency (f), minute ventilation (VN), oxygensaturation (Sao2), partial pressure of CO2 (Paco2), and pI-I.
of inspired oxygen a n d measuring the a m o u n t of ventilation and the arterial oxygen saturation. MATERIAL
AND METHODS
T h e response to inhalation of CO2 was measured in 6 patients with dysautonomia, aged 9 to 25 years, and in 5 n o r m a l subjects, as controls. E a c h subject breathed in succession: room air, 1, 2, 3, and 4 p e r cent
CO2 in aii, with a d e q u a t e rest periods between runs. T h r e e patients with dysautonomia were also tested with 5 per cent CO2, The CO,, mixtures were administered through an anesthesia bag connected to the inspiratory side of a two-way valve with a dead space of 35 ml. A f t er 12 to 15 minutes of inhalation of the inspired mixture, w h e n a "steady state" was achieved, the expired air was collected an d measured in a Tissot
Volume 66 Number 3
Respiratory control in [arniliaI dysautonomia
5 13
pired air were analyzed in a Scholander microanalyzer and expressed as milliliters per minute per square meter. The 02 and CO2 content and 02 capacity of the arterial blood were determined in a manometric Van Slyke apparatus and the 02 saturation expressed as the percentage of total hemoglobin in the form of oxyhemoglobin. The pH was measured with an Astrup electrode and the pCO2 determined indirectly from the Singer and Hastings nomogram, and expressed in millimeters of mercury.
spirometer from which samples were taken for 02 and CO2 analysis. The response to hypercapnia and hypoxia was tested in 6 patients with dysautonomia and in 5 normal individuals while breathing the following mixtures in sequence, with rest periods between each test: room air, 4 per cent CO2 in air, and 12 per cent 02 in nitrogen. Following each breathing period of at least 10 minutes (except in those few instances where the condition of the patient made interruption necessary), samples of blood were taken from the brachial artery through an indwelling Cournand needle while the minute ventilation was measured simultaneously in a Tissot spirometer. Samples for analysis were taken from the spirometer to measure respiratory gas exchange. The 02 and CO2 concentrations in the ex-
RESULTS The respective values for respiratory frequency (f), tidal Volume (VT), minute ventilation (VE), oxygen uptake (Voz), carbon dioxide output (Vco2), and respiratory quotient (R) during breathing of room
4.6
4.0 o. . . . . . . . c~--
-o
-z~
Normals M.W. B.L.
K.S. 9 . . . . . 9 D.B. o ........ ra K . E . 9 -----
5.4
2,/ ,,,- ,A
i~x***m D.E.
~P
VE R
f-.,.
2.8
,,
: 1
.'ff
2.2 /
.-" ..-
/ d. ........,,
1.6
/.
1.0
0
i
.. .~ ,../1
A if
f
/
i"
I ~'-~
I
i
i
I
I
I
2
3
4
5
6
FI coz Fig. 1. The ventilatory response to increasing concentrations of inspired CO2, Thick line represents average values in 5 control subjects; each symbol represents an individual patient with dysautonomia. Fxoo2, fractional
V~
concentration of inspired CO2. -R-; minute ventilation at various over resting ventilation.
Fleo~
5 14
March 1965
Filler et al.
air, 1.2, 2.5, 3.7, 4.5, and 5.1 per cent CO2 in air are expressed in Table I for the patients with familial dysautonomia and for control subjects. In Table I I a r e also indicated the values for minute ventilation, oxygen saturation (Sao2), partial pressure of CO2 (Pac%), and p H of the arterial blood obtained in patients and in control subjects while breathing, respectively, room air, 4 per cent CO2 in air, and 12 per cent 02 in nitrogen. The significant features are presented graphically in the figures. In Fig. 1 are plotted the ventilatory responses in each patient to increasing concentrations of CO2 in the inspired air, expressed as the ratio of minute ventilation while breathing different CO2 mixtures over the resting ventilation while breathing room air. The average values in all 5 normal subjects under the same conditions are plotted as a thick line. In control subjects the average increase in VE over the resting ventilation while breathing 1.2, 2.5, 3.7, 4.5, and 5.1 per cent CO2 was, respectively, 136.6 per cent, 180.8, 254.5, 319.7, and 454.5 per
E) Norrnals o M.W. 9 K.S. El K . E . I I D.G. xJ.S. AR.H.
T ME R
2
.L
0
' ,,,,,-~ 35
cent, while in patients with dysautonomia under the same conditions, the average percentage increases were: 127, 154.6, 192.2, 245.5, and 292.4 per cent, respectively. In Fig. 2 the slope of the line indicates the increase in millimeters of mercury of Pae% necessary to double the minute ventilation; in normal subjects an increase of 1.7 mm. Hg was enough to double the V~, whereas in dysautonomic patients it required an increase of 4 to 6 mm. Hg to achieve the same effect. In Fig. 3 are plotted the average changes in minute ventilation, oxygen saturation, partial pressure of CO2, and p H of the arterial blood in normal subjects (solid line) and in dysautonomic patients (broken line) while breathing consecutively room air, 4 per cent CO2 in air, and 12 per cent oxygen. In the control group, the effects of inspiring 4 per cent CO2 were similar to those described previously in the literature, i.e., a threefold increase in minute ventilation, slight increase in Pae% and no change in Sa% or pH. T h e dysautonomic patients, under the same conditions, showed less increase in VE, higher elevation in Paeo2 accompanied by a significant drop in p H ; the Sao2 remained practically unaltered. The administration of 12 per cent 02 in normal subjects produced the expected changes in the arterial blood: moderate drop in Sao2, an increase in minute ventilation of 135 per cent over the resting value, causing a drop in Paco2 and elevation of pH. In the dysautonomic patient the same hypoxic stimulus decreased markedly the arterial 02 saturation in spite of a higher increase in VE (160 per cent); the Paco2 and p H remained unchanged. DISCUSSION
30
40
45
I 50
r 55
I 60
Pac0z (ram Hg) Fig. 2. The relation between arteriaI pCO2 (Paco~) and the increase in minute ventilation. The average of the results in 5 control subjects is presented as one line; the dysautonomic responses are presented individually. The greater slope in dysautonomia indicates that a greater change in Pacoe is necessary to produce a corresponding increase in minute ventilation.
Haldane and Priestley G presented evidence in 1905 that the respiratory center is sensitive to CO2 concentration in the blood. A progressive increase in the fractional concentration of inspired CO2 induces a progressive increase in minute ventilation, thus preventing the excessive accumulation of CO2 in the arterial blood. Gray suggested in his "multiple factor" theory that carbon
Volume 66 Number 3
Respiratory control in familial dysautonomia
I00
SQo2
80
(%)
60
5O
Po c% 40 (mm Hg) 30 15 O
•/E
Io
(llmlmz) 0
I 4%
I
COz
ROOM AIR
I
t2% 02
Fig. 3. Average values for arterial oxygen saturation (Sao.), partial pressure of arterial CO2 (Paco~) and minute ventilation (17~) in 5 control subjects (solid line) and in 6 dysautonomic patients (broken line) while breathing, respectively, room air, 4 per cent CO~ in air, and 12 per cent 02.
dioxide has a double and additive effect on the respiratory center, i.e., as a specific stimulus and by increasing the acidity of the blood. ~ Patients with dysautonomia appear to have a decreased sensitivity of the respiratory center to CO2. W h e n the concentration is increased in the inspired air, the ventilation ratio does not increase as much as in normal subjects (Fig. 1) and, consequently, the amount of ventilation is insufficient to prevent the development of respiratory acido-
5 15
sis. T h e reduced ventilatory response results from the relatively small increase in respiratory frequency, the increase in tidal volume being comparable to that in the normal subject. T h e sensitivity of the respiratory center can also be evaluated by comparing the increase in the ventilatory response with 4 per cent CO2 with the partial pressure of CO2 in the arterial blood. I n F i g . 2, it is evident that it requires a considerably larger increase in Paeo2 to double the minute ventilation in the dysautonomic patient than in the normal person. It is unlikely that mechanical defects in the lungs or chest are the cause of these observations because roentgenograms of the chest were negative and the lung volumes were normal in those patients tested. T h e response to hypoxia is believed to be initiated peripherally in the glomus aorticum and glomus caroticum. T h e normal subject on breathing 12 per cent O~_ responded with a slight increase in minute ventilation, inadequate to prevent a moderate fall in arterial 02 saturation, but enough to decrease the Paeo2 and increase the pH. T h e subject displayed no discomfort during the ten-minute test period. T h e response of the dysautonomic patient to 12 per cent 02 was dramatically different. I n three instances the test had to be terminated within a few minutes because of severe cyanosis in one patient, syncope in the second, and grand mal convulsions in the third. Measurements of the oxygen saturations at this time revealed that they had dropped to seriously low levels. Administration of oxygen quickly relieved the symptoms. It is evident that the defensive mechanism to acute hypoxia is inadequate in the dysautonomic patients; however, the reason for this is not clear. T h e increase in minute ventilation was equal to or greater than that in the normal person; despite this, the blood was not as effectively ventilated, as indicated by the sharp drop in 02 saturation and unchanged Paeo2 and pH. Theoretically three explanations can be offered to explain these findings: (1) a decrease in diffusibility of
5 16
March 1965
Filler et al.
gases across the alveolocapillary membrane, but such abrupt changes within the membrane seem improbable; (2) the opening of new shunts in the lungs; and (3) the selective distribution of the blood to the least ventilated parts of the lungs. This last would be analogous to the development of a greatly increased physiologic dead space during the hypoxic stimulus. This approach to the study of respiratory physiology/in dysautonomia was suggested by the evidence of sensory defects elsewhere. It appears that the sensory defect may be considerably more fundamental to the symptomatology in dysautonomia than previously appreciated. If the sensory defect proves to be as generalized as now seems likely, it may account for some of the manifestations generally attributed to the neuromuscular or autonomic systems. For example, awkwardness may result from inadequate proprioceptive appreciation of motion, as well as from a neuromuscular disturbance. Also, lack of homeostasis in the cardiovascular system could result from deficiency in the baroceptor mechanisms as well as in the autonomic system. This is not to imply that the entire defect in dysautonomia is sensory, because there is cogent evidence to the contrary. These observations on respiratory physiology also have clinical significance in the care of the patient with dysautonomia. It is evidently important to protect him from abrupt changes in oxygen or carbon dioxide levels. A visit to high altitudes would seem unwise. However, airplane travel in modern pressurized cabins probably constitutes no risk. Underwater swimming could be hazardous. One patient with dysautonomia has drowned, and another had to be rescued following a demonstration of his endurance in remaining submerged! T h e risk to the patient of respiratory disease is well known. It would appear desirable to monitor the blood for oxygen saturation and Paco2 in any severe respiratory disease, and consider the vigorous administration of oxygen with mechanical respirators when indicated.
SUMMARY
T h e sensitivity of the respiratory center to progressively higher concentrations of carbon dioxide in air has been tested in 6 dysautonomic and 5 normal subjects. T h e increase in minute ventilation was not as great in the dysautonomic patient as in the normal person. As a consequence of this diminished sensitivity of the respiratory center, breathing 4 per cent CO2 in air induced a respiratory acidosis. T h e response to acute hypoxia, presumed to be through the peripheral chemoreceptors, was also tested in 6 dysautonomic patients and in 5 normal subjects. I n the normal subject the inhalation of 12 per cent 02 caused a moderate drop in arterial 02 saturation, a slight increase in minute ventilation, and respiratory alkalosis. There were no obvious systemic symptoms. This contrasted with the dramatic response in the dysautonomic individuals in w h o m syncope, convulsions, and severe cyanosis were induced. This was accompanied by a sharp drop in 02 saturation and no change in Paeo2 or pH. There is no clear explanation for these findings.
REFERENCES
1. Riley, C. M.: Familial dysautonomia, Advances in Pediat. 9: 157, 1957. 2. Smith, A. A., and Dancis, J.: Sensory defect in familial dysautonomia, presented at the meeting of the American Pediatric Society, Seattle, Wash., June 16-18, 1964. 3. Smith, A. A., and Dancis, J.: Exaggerated response to norepinephrine in familial dysautonomia, New England J. Med. 270: 704, 1964. 4. Smith, A. A., and Dancis, J.: Response to intradermal histamine in familial dysautonomia--a diagnostic test, J. PEDIAT. 63: 889, 1963. 5. Smith, A. A., and Dancls, J.: Taste discrimination in familial dysautonomia, Pediatrics 33: 441, 1964. 6. Haldane, J. S., and Priestley, J. G.: The regulation of the lung-ventilation, J. Physiol. 32: 225, 1905. 7. Gray, J. S.: Pulmonary ventilation and its physiological regulation, Springfield, Ill., 1950, Charles C Thomas, Publisher.
509
Respiratory control in familial dysautonomia The response to increased carbon dioxide (4 per cent) and reduced oxygen (12 per cent) inhalations in subjects with dysautonomia has been compared to that in normal individuals. In both instances, the patient with dysautonomia revealed a reduced ability to cope with these stresses, with potentially serious consequences. These observations are significant in the pathophysiology of familial dysautonomia and suggest approaches to therapy.
Juan Filler, M.D., Alfred A. Smith, M.D., Samuel Stone, M.D., and Joseph Daneis, M.D.* NEW
YORK~
FAMILIAL
N. Y.
DYSAUTONOMIA
iS
an
inherited disease commonly manifest at birth but difficult to diagnose at that time. At a later age, a well-defined clinical picture makes recognition relatively simple? There is evidence of a diffuse neurological defect; symptoms referable to the autonomic nervous system are prominent; among them are alacrima, postural hypotension, and dysphagia. Studies of the physiologic responses to methacholine 2 and to norepinephrin& indicate a parasympathetic insufficiency and an exaggerated response to both agents which contribute to the autonomic instability of these subjects.
From the Departments o/Pediatrics and Psychiatry, New York University Medical Center. Supported by Grant No. H.E. 3436 from the National Heart Institute of the National Institutes of Health, United States Public Health Service, and by grants from the Dysautonomia Association and the National Foundation. *Career Investigator of the National Institute of Child Health and Human Development, National Institutes o] Health. Address, Department of Pediatrics, New York University Medical Center, 550 First Ave., New York, N . Y. 10016.
Less prominent in the symptomatology is the sensory defect. The patients are relatively insensitive to pain, and frequently the corneal and patellar reflexes are absent? Evidence that the sensory defect is peripheral, at least in part, has recently been provided. The intradermal injection of histamine fails to elicit the axon flare which depends, neurologically, only on an intact peripheral sensory nerve. 4 The defective taste discrimination previously described a appears to result from an absence of fungiform papillae and taste buds on the tongue? Both signs are consistently found in dysautonomia, and may serve as reliable diagnostic tests even at birth. In the present study, the possibility of a sensory defect in respiratory control has been explored. The sensitivity of the respiratory center has been investigated by correlating the concentration of inspired carbon dioxide and its partial pressure in arterial blood with the amount of pulmonary ventilation. The response of the peripheral chemoreceptor mechanism (glomus aorticum and glomus caroticum) to hypoxia was tested by acutely lowering the concentration
5 I 0
Filler et aL
T a b l e I.
March 1965
T h e v e n t i l a t o r y r e s p o n s e to CO2 i n t h e d y s a u t o n o m i c a n d n o r m a l s u b j e c t
Dysautonomia patients
Pa~ie,,t
v~ (ml.)
go 2 (L./min./1V[. 2)
Vco2 (L./min./M.2)
[ 2 ~ COs
[ 3 ~ COt
r 4 ~ C0~ I 5 ~ C0~
18 16 14 18 20 28
18 16 14 20 22 30
18 18 14 20 25 30
20 18 16 22 25 29
20 20 18 23 26 30
20
Average
19
23.3
21.5
21.7
26~5
25.3
M.W, B.L. K. S. D.B. K. E. D.G.
200 307 150 240 230 264
320 330 207 340 264 320
360 348 225 400 273 444
406 466 330 450 306 530
506 490 320 500 417 600
585
231.8
297
341.6
414.6
472
555
24 32
570 510
M.W. B.L. K.S. D.B. K.E. D.G.
3.60 4.90 2.50 4.64 4:60 7.4Q
5.74 5.30 2.90 6.80 5.80 9.60
6.50 6.30 3.20 7.90 6.80 13.30
8.i3 8.40 5.20 10.00 7.60 15.35
10.12 9.80 6.40 11.50 10.84 18.00
11.70
Average
4.61
6.02
7.33
9.11
11.11
13.86
13.60 16.30
M.W. B.L. K. S. D. B. K. E. D. G.
180 114 300 186 178 226
192 138 338 112 144 200
194 145 358 152 127 176
233 130 410
262 112 560
154 169
160 192
Average
197
t82
192
219
257
232
M.W. B. L. K.S. D. B. K.E. D.G.
154 109 328 146 153 152
167 114 300 106 121 200
171 112 292 113 100 204
192 136 340
190 I3I 400
205
106 162
124 178
Average
t 74
168
165
187
205
255 235 205
151 126 161
.87 .82 .88 .95 .84 1.00
.88 .77 .81 .74 .79 1.16
.81 .95 .83
.73 ,86 .71
D. G.
.85 ,96 1.09 .79 .82 .67
.69 .96
,79 .93
Average
.86
.89
.86
.85
.80
M.W.
R
1% C0~
IV[.W. B.L. K.S. D. B. K.E. D.G.
Average
gE (L./min./M3)
] Room air
B, L, K. S. D, B. K.E.
.80 .64 .62 .69
Respiratory frequency (f), tidal volume (Vw), minute ventilation (V~), oxygen uptake (Voz), carbon dioxide output (Vo%),
Volume
Patient B. C. R.P. C. W. D, G. S. V.
Average B, C, K.P. C.W. D.G. S. V. Average
66
[
Number 3
Room air
Respiratory control in [arailial dysautonomia
I
1% CO~
Normal subjects I 2% CO, I
3% CO t
I
4% co~
I
511
5% co~
24 13 16 18 20
24 16 18 24 22
22 16 22 28 28
38 20 26 32 32
44 24 32 36 36
42
18.2
20.8
23.2
29.6
34.4
41
40
150 280 278 180 170
180 305 340 268 206
268 455 330 250 260
260 460 400 368 260
330 600 430 372 340
490
211.6
260
312.6
349.6
414.4
420
350
B.C. R.P. C. W, D. G, S.V.
3.60 3.67 4.46 3.26 3.37
4.33 4.90 6.12 6.42 4.53
5.90 7.30 7.25 7.00 7,34
9,93 9.20 10.38 11.75 8.30
14.51 14.50 13.78 13.40 12,20
20.67
Average
3.67
5.26
6.96
9.80
13.68
17.50
B.C. R.P. C.W. D. G. S.V. Average B. C, R. P. C.W. D. G. S.V. Average
14.20
137 144 177 176 140
154 156 129 202 140
144 182 189 178 143
167 178 183 185 138
165 179 166 218 187
233
154.8
156.2
167.2
166.5
183
260
126 132 152 153 133
133 130 133 167 106
124 145 154 160 100
158 128 157 168 120
144 151 137 180 162
196
139.2
133.8
136.6
146.2
287
250
154.8
223
B.C. R. P. C.W. D.G. S.V.
.90 .92 .86 .87 .95
,86 .82 1.03 ,83 .75
.86 .80 .81 .90 .70
.94 ,72 .86 .91 .87
.87 .85 .82 .92 .86
.86
Average
.90
.86
.81
.864
.864
.865
and respiratory quotient (R).
.87
5 12
Filler eta[.
March 1965
T a b l e II. T h e response to r o o m aii, 4 per cent CO2, and 12 per cent 02 in d y s a u t o n o m i c and n o r m a l subject
Dysautonomia patients ~ Normal subjects Patient t Room air I 4 % CO~ I. 12% O~ Patient I R~~ i ~oo-CO~ .1 12% 03 f
V~
(L,/min./M3)
M.W. K.S. K.E. D.G. J.S. R.H.
18 14 20 28 20 22
20 18 26 30 21 24
10 10 15 12 10 18
Average
20
23
12.5
M.W. K.S. K.E. D.G. J.S. R.H. Average
S,oo (% )
P~eo2 (man. Hg)
4.73
10.12 6.40 10.84 18.00 9.95 12.70 11.33
6.84 4.24 9.34 7.90 7.55 9.80 7.61
M.W. K.S. K.E. D.G. J.S. R.H.
98.5 88 95 95.5 93 89
97.5 89 95 89.5 90 96
37 51 56 68.5 41 62
Average
93.1
92.8
52.6
48 38 42 36 38 36
54 46 44 43 47 44
46 39 41 37 40 40
39.7
46.3
40.5
M.W. K.S. K.E. D.G. J.S. R.H. Average
pH
3.60 2.50 4.60 7.40 4.56 5.72
J.G. E.D. E.T. G.F. J.P. Average J.G. E.D. E.T. G.F. J.P. Average J.G. E.D. E.T. G.F. J.P. Average J.G. E.D. E.T. G.F. J.P.
M.W. K.S. K.E. D.G. J.s. R.H.
7.37 7.36 7.34 7.50 7.45 7.41
7.33 7.32 7.33 7.44 7.41 7.35
7.38 7.34 7.36 7.48 7.41 7.39
Average
7.40
7.36
7.39
Average J.G. E.D. E.T. G.F. J.P. Average
20 12 24 15 20
26 16 28 26 28
18 12 28 14 19
18.2
24.8
12.8
3.54 3.80 3.76 3.90 5.20 4.04
8.36 9.10 9.10 12.65 15.50 10.94
4.83 5.00 4,80 6.90 5.80 5.47
98 97 91 96 96
97 93 93 98 95
80 76 75 84 74
95.6
95.2
77.8
40 38 38 36 35
44 39 40 38 41
34 32 37 30 32
37.4
40.4
33
7.41 7.41 7.43 7.39 7.43
7.38 7.40 7.42 7.38 7.40
7.46 7.46 7.41 7.45 7.44
7.41
7.40
7.44
Respiratory frequency (f), minute ventilation (VN), oxygensaturation (Sao2), partial pressure of CO2 (Paco2), and pI-I.
of inspired oxygen a n d measuring the a m o u n t of ventilation and the arterial oxygen saturation. MATERIAL
AND METHODS
T h e response to inhalation of CO2 was measured in 6 patients with dysautonomia, aged 9 to 25 years, and in 5 n o r m a l subjects, as controls. E a c h subject breathed in succession: room air, 1, 2, 3, and 4 p e r cent
CO2 in aii, with a d e q u a t e rest periods between runs. T h r e e patients with dysautonomia were also tested with 5 per cent CO2, The CO,, mixtures were administered through an anesthesia bag connected to the inspiratory side of a two-way valve with a dead space of 35 ml. A f t er 12 to 15 minutes of inhalation of the inspired mixture, w h e n a "steady state" was achieved, the expired air was collected an d measured in a Tissot
Volume 66 Number 3
Respiratory control in [arniliaI dysautonomia
5 13
pired air were analyzed in a Scholander microanalyzer and expressed as milliliters per minute per square meter. The 02 and CO2 content and 02 capacity of the arterial blood were determined in a manometric Van Slyke apparatus and the 02 saturation expressed as the percentage of total hemoglobin in the form of oxyhemoglobin. The pH was measured with an Astrup electrode and the pCO2 determined indirectly from the Singer and Hastings nomogram, and expressed in millimeters of mercury.
spirometer from which samples were taken for 02 and CO2 analysis. The response to hypercapnia and hypoxia was tested in 6 patients with dysautonomia and in 5 normal individuals while breathing the following mixtures in sequence, with rest periods between each test: room air, 4 per cent CO2 in air, and 12 per cent 02 in nitrogen. Following each breathing period of at least 10 minutes (except in those few instances where the condition of the patient made interruption necessary), samples of blood were taken from the brachial artery through an indwelling Cournand needle while the minute ventilation was measured simultaneously in a Tissot spirometer. Samples for analysis were taken from the spirometer to measure respiratory gas exchange. The 02 and CO2 concentrations in the ex-
RESULTS The respective values for respiratory frequency (f), tidal Volume (VT), minute ventilation (VE), oxygen uptake (Voz), carbon dioxide output (Vco2), and respiratory quotient (R) during breathing of room
4.6
4.0 o. . . . . . . . c~--
-o
-z~
Normals M.W. B.L.
K.S. 9 . . . . . 9 D.B. o ........ ra K . E . 9 -----
5.4
2,/ ,,,- ,A
i~x***m D.E.
~P
VE R
f-.,.
2.8
,,
: 1
.'ff
2.2 /
.-" ..-
/ d. ........,,
1.6
/.
1.0
0
i
.. .~ ,../1
A if
f
/
i"
I ~'-~
I
i
i
I
I
I
2
3
4
5
6
FI coz Fig. 1. The ventilatory response to increasing concentrations of inspired CO2, Thick line represents average values in 5 control subjects; each symbol represents an individual patient with dysautonomia. Fxoo2, fractional
V~
concentration of inspired CO2. -R-; minute ventilation at various over resting ventilation.
Fleo~
5 14
March 1965
Filler et al.
air, 1.2, 2.5, 3.7, 4.5, and 5.1 per cent CO2 in air are expressed in Table I for the patients with familial dysautonomia and for control subjects. In Table I I a r e also indicated the values for minute ventilation, oxygen saturation (Sao2), partial pressure of CO2 (Pac%), and p H of the arterial blood obtained in patients and in control subjects while breathing, respectively, room air, 4 per cent CO2 in air, and 12 per cent 02 in nitrogen. The significant features are presented graphically in the figures. In Fig. 1 are plotted the ventilatory responses in each patient to increasing concentrations of CO2 in the inspired air, expressed as the ratio of minute ventilation while breathing different CO2 mixtures over the resting ventilation while breathing room air. The average values in all 5 normal subjects under the same conditions are plotted as a thick line. In control subjects the average increase in VE over the resting ventilation while breathing 1.2, 2.5, 3.7, 4.5, and 5.1 per cent CO2 was, respectively, 136.6 per cent, 180.8, 254.5, 319.7, and 454.5 per
E) Norrnals o M.W. 9 K.S. El K . E . I I D.G. xJ.S. AR.H.
T ME R
2
.L
0
' ,,,,,-~ 35
cent, while in patients with dysautonomia under the same conditions, the average percentage increases were: 127, 154.6, 192.2, 245.5, and 292.4 per cent, respectively. In Fig. 2 the slope of the line indicates the increase in millimeters of mercury of Pae% necessary to double the minute ventilation; in normal subjects an increase of 1.7 mm. Hg was enough to double the V~, whereas in dysautonomic patients it required an increase of 4 to 6 mm. Hg to achieve the same effect. In Fig. 3 are plotted the average changes in minute ventilation, oxygen saturation, partial pressure of CO2, and p H of the arterial blood in normal subjects (solid line) and in dysautonomic patients (broken line) while breathing consecutively room air, 4 per cent CO2 in air, and 12 per cent oxygen. In the control group, the effects of inspiring 4 per cent CO2 were similar to those described previously in the literature, i.e., a threefold increase in minute ventilation, slight increase in Pae% and no change in Sa% or pH. T h e dysautonomic patients, under the same conditions, showed less increase in VE, higher elevation in Paeo2 accompanied by a significant drop in p H ; the Sao2 remained practically unaltered. The administration of 12 per cent 02 in normal subjects produced the expected changes in the arterial blood: moderate drop in Sao2, an increase in minute ventilation of 135 per cent over the resting value, causing a drop in Paco2 and elevation of pH. In the dysautonomic patient the same hypoxic stimulus decreased markedly the arterial 02 saturation in spite of a higher increase in VE (160 per cent); the Paco2 and p H remained unchanged. DISCUSSION
30
40
45
I 50
r 55
I 60
Pac0z (ram Hg) Fig. 2. The relation between arteriaI pCO2 (Paco~) and the increase in minute ventilation. The average of the results in 5 control subjects is presented as one line; the dysautonomic responses are presented individually. The greater slope in dysautonomia indicates that a greater change in Pacoe is necessary to produce a corresponding increase in minute ventilation.
Haldane and Priestley G presented evidence in 1905 that the respiratory center is sensitive to CO2 concentration in the blood. A progressive increase in the fractional concentration of inspired CO2 induces a progressive increase in minute ventilation, thus preventing the excessive accumulation of CO2 in the arterial blood. Gray suggested in his "multiple factor" theory that carbon
Volume 66 Number 3
Respiratory control in familial dysautonomia
I00
SQo2
80
(%)
60
5O
Po c% 40 (mm Hg) 30 15 O
•/E
Io
(llmlmz) 0
I 4%
I
COz
ROOM AIR
I
t2% 02
Fig. 3. Average values for arterial oxygen saturation (Sao.), partial pressure of arterial CO2 (Paco~) and minute ventilation (17~) in 5 control subjects (solid line) and in 6 dysautonomic patients (broken line) while breathing, respectively, room air, 4 per cent CO~ in air, and 12 per cent 02.
dioxide has a double and additive effect on the respiratory center, i.e., as a specific stimulus and by increasing the acidity of the blood. ~ Patients with dysautonomia appear to have a decreased sensitivity of the respiratory center to CO2. W h e n the concentration is increased in the inspired air, the ventilation ratio does not increase as much as in normal subjects (Fig. 1) and, consequently, the amount of ventilation is insufficient to prevent the development of respiratory acido-
5 15
sis. T h e reduced ventilatory response results from the relatively small increase in respiratory frequency, the increase in tidal volume being comparable to that in the normal subject. T h e sensitivity of the respiratory center can also be evaluated by comparing the increase in the ventilatory response with 4 per cent CO2 with the partial pressure of CO2 in the arterial blood. I n F i g . 2, it is evident that it requires a considerably larger increase in Paeo2 to double the minute ventilation in the dysautonomic patient than in the normal person. It is unlikely that mechanical defects in the lungs or chest are the cause of these observations because roentgenograms of the chest were negative and the lung volumes were normal in those patients tested. T h e response to hypoxia is believed to be initiated peripherally in the glomus aorticum and glomus caroticum. T h e normal subject on breathing 12 per cent O~_ responded with a slight increase in minute ventilation, inadequate to prevent a moderate fall in arterial 02 saturation, but enough to decrease the Paeo2 and increase the pH. T h e subject displayed no discomfort during the ten-minute test period. T h e response of the dysautonomic patient to 12 per cent 02 was dramatically different. I n three instances the test had to be terminated within a few minutes because of severe cyanosis in one patient, syncope in the second, and grand mal convulsions in the third. Measurements of the oxygen saturations at this time revealed that they had dropped to seriously low levels. Administration of oxygen quickly relieved the symptoms. It is evident that the defensive mechanism to acute hypoxia is inadequate in the dysautonomic patients; however, the reason for this is not clear. T h e increase in minute ventilation was equal to or greater than that in the normal person; despite this, the blood was not as effectively ventilated, as indicated by the sharp drop in 02 saturation and unchanged Paeo2 and pH. Theoretically three explanations can be offered to explain these findings: (1) a decrease in diffusibility of
5 16
March 1965
Filler et al.
gases across the alveolocapillary membrane, but such abrupt changes within the membrane seem improbable; (2) the opening of new shunts in the lungs; and (3) the selective distribution of the blood to the least ventilated parts of the lungs. This last would be analogous to the development of a greatly increased physiologic dead space during the hypoxic stimulus. This approach to the study of respiratory physiology/in dysautonomia was suggested by the evidence of sensory defects elsewhere. It appears that the sensory defect may be considerably more fundamental to the symptomatology in dysautonomia than previously appreciated. If the sensory defect proves to be as generalized as now seems likely, it may account for some of the manifestations generally attributed to the neuromuscular or autonomic systems. For example, awkwardness may result from inadequate proprioceptive appreciation of motion, as well as from a neuromuscular disturbance. Also, lack of homeostasis in the cardiovascular system could result from deficiency in the baroceptor mechanisms as well as in the autonomic system. This is not to imply that the entire defect in dysautonomia is sensory, because there is cogent evidence to the contrary. These observations on respiratory physiology also have clinical significance in the care of the patient with dysautonomia. It is evidently important to protect him from abrupt changes in oxygen or carbon dioxide levels. A visit to high altitudes would seem unwise. However, airplane travel in modern pressurized cabins probably constitutes no risk. Underwater swimming could be hazardous. One patient with dysautonomia has drowned, and another had to be rescued following a demonstration of his endurance in remaining submerged! T h e risk to the patient of respiratory disease is well known. It would appear desirable to monitor the blood for oxygen saturation and Paco2 in any severe respiratory disease, and consider the vigorous administration of oxygen with mechanical respirators when indicated.
SUMMARY
T h e sensitivity of the respiratory center to progressively higher concentrations of carbon dioxide in air has been tested in 6 dysautonomic and 5 normal subjects. T h e increase in minute ventilation was not as great in the dysautonomic patient as in the normal person. As a consequence of this diminished sensitivity of the respiratory center, breathing 4 per cent CO2 in air induced a respiratory acidosis. T h e response to acute hypoxia, presumed to be through the peripheral chemoreceptors, was also tested in 6 dysautonomic patients and in 5 normal subjects. I n the normal subject the inhalation of 12 per cent 02 caused a moderate drop in arterial 02 saturation, a slight increase in minute ventilation, and respiratory alkalosis. There were no obvious systemic symptoms. This contrasted with the dramatic response in the dysautonomic individuals in w h o m syncope, convulsions, and severe cyanosis were induced. This was accompanied by a sharp drop in 02 saturation and no change in Paeo2 or pH. There is no clear explanation for these findings.
REFERENCES
1. Riley, C. M.: Familial dysautonomia, Advances in Pediat. 9: 157, 1957. 2. Smith, A. A., and Dancis, J.: Sensory defect in familial dysautonomia, presented at the meeting of the American Pediatric Society, Seattle, Wash., June 16-18, 1964. 3. Smith, A. A., and Dancis, J.: Exaggerated response to norepinephrine in familial dysautonomia, New England J. Med. 270: 704, 1964. 4. Smith, A. A., and Dancis, J.: Response to intradermal histamine in familial dysautonomia--a diagnostic test, J. PEDIAT. 63: 889, 1963. 5. Smith, A. A., and Dancls, J.: Taste discrimination in familial dysautonomia, Pediatrics 33: 441, 1964. 6. Haldane, J. S., and Priestley, J. G.: The regulation of the lung-ventilation, J. Physiol. 32: 225, 1905. 7. Gray, J. S.: Pulmonary ventilation and its physiological regulation, Springfield, Ill., 1950, Charles C Thomas, Publisher.