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Effects of gravity and exercise on the pulmonary diffusing capacity in children with cystic fibrosis
March, 1969 T h e J o u r n a l o[ P E D I A T R I C S
393
Effects of gravity and exerciseon the pulmonary diffusing capacity in children Mth cystic fibrosis Eighteen children with cystic fibrosis underwent studies o[ the diffusing capacity of carbon monoxide [ollowing exercise and in sitting and head-down positions. These children, in contrast to normal subjects, were unable to increase the diffusion rate following the 'head-down position or exercise. These findings were even present in 8 of the 18 children who had normal lung volumes, normal mechanics o[ breathing, and normal gas mixing.
Patricla S. Zelkowitz, M.D., and Samuel T. Giammona, M.D., with the technical assistance of Grace Silva and Alfred Jalowayski MIAMI~ FLA.
T i=~E total pulmonary diffusing capacity of the lung for oxygen (or the test gas carbon monoxide) is a result of the diffusing capacity of the pulmonary membrane and the rate of the uptake of the gas by chemical combination by the blood in the pulmonary capillaries. The normal total lung diffusing capacity at rest varies with age, sex, and size. Increases in the total lung diffusing capacity From the Department o[ Pediatrics, University o[ Miami School of Medicine. Supported by a grant [rom the American Medical Association, Education and Research Foundation, Committee [or Research on Tobacco and Health, and by a grant from the American Heart Association and the Suncoast Heart Association. Facilities provided by the Papanieolaou Cancer Institute. Reprints: Samuel T. Giammona, M.D., Department of Pediatr;cs, University o[ Miami, School o[ Medicine. P.O. Box 875, Biscayne Annex, Miami, Florida 33152.
reflect the availability of additional alveolar membrane surfaces for diffusion or increase of the instantaneous pulmonary capillary blood volume. The puhnonary diffusing capacity, as measured by single-breath carbon monoxide absorption, is greater in the supine than in the upright position in normal children at rest/ reflecting the large reserve of diffusing capacity available to the normal child. Exercise produces even greater increases in the pulmonary diffusing capacity than those found by postural changes? Several investigators have reported that resting diffusing measurements in children with cystic fibrosis are normal.2, 3 The effects of gravity and exercise on diffusing capacity in these children have not been documented. This study was undertaken to determine if changes in diffusing Vol. 74, No. 3, pp. 393-398
3 94
Zelkowitz and Giamraona
The Journal o[ Pediatrics March 1969
capacity (DL) of patients with cystic fibrosis (C.F.) occurred with different body positions and after exercise. In addition, lung volumes and ventilatory tests were obtained.
METHODS Subjects. Eighteen children with C.F. (8 boys, 10 girls), ranging in age from 5 to 13 years, formed the study group. Eight normal children (6 boys, 2 girls) were studied simultaneously to insure the validity of techniques in our laboratory during the study period. Thirteen of the children with C.F. had either normal or minimally abnormal chest roentgenograms. T h e remaining 5 children had moderately advanced disease. Their average age was 8.4 +_ 1.8 years, and their mean body surface area (BSA) was 0.92 + 0.09 sq.M. The normal children were 8.6 _+ 2.1 years of age and had a mean BSA of 1.12 _+0.2 sq.M. (Table I ) . Measurements
of
diffusing
capacity
(DL). The single-breath carbon monoxide diffusing capacity was measured by the method of Krogh, 6 as modified by Forster and associates 4 and Ogilvie and associates? The principle of this method is that uptake of carbon monoxide is measured by noting the change in alveolar Peo when the breath is held at a constant known volume for measured periods of time. Duplicate D L determinations were performed with each child in a sitting and a 15 degree head-down position, as well as immediately following exercise to exhaustion. The head-down position was maintained for 10 minutes prior
Table I Children with C. F.
Normal children
18 8 10
8 6 2
Age (years)
8.4 +- 1.8"
8.6 + 2.1
Body surface area (BSA) (sq. M.)
0.92 -+ .09
-1.12 -+ 0.2
Predicted BSA
1.05
1.07
Number Males Females
*Standard deviation.
to and during the collection of all samples. Exercise was performed on a bicycle ergometer and varied with the tolerance of each child. A Rudolph five-way valve (W. E. Collins, Co., Boston, Mass.) was used during the procedure with the child inspiring from a bag in box system and expiring first into the spirometer and finally into a collecting bag to obtain alveolar samples. The inspired gas contained 0.5 per cent carbon monoxide and 1 per cent neon in room air. The spirometer tracings were used to record the time of breath holding, the inspired volume, and the volume expired into the collecting spirometer prior to collection of the alveolar samples. To insure adequate washout of the dead space, a volume of 500 ml. or half of the vital capacity, whichever was less, was required to be cleared. T h e time of breath holding did not vary more than 20 per cent from 10 seconds. The children were encouraged to inspire and expire maximally during each determination. Alveolar samples were analyzed with gas chromatography (Microtek M T 220), which utilized a thermal conductivity detector with helium as the carrier gas. The following equation was used for all calculations6: DL (ml./min. x mm.Hg) -~ 60 Fco initial VA (STPD) x - x logN B.P.-47 Fco terminal Time of breath holding The VA refers to total alveolar volume and is determined by the dilution of neon that occurs during breath holding. The FGo initial and terminal refer to the concentration of carbon monoxide in the alveolar sample at the onset of the test and after 10 seconds of breath holding, during which time diffusion occurs. Any duplicate DL determination that did not check within 3 ml. per min. • ram. H g was discarded and repeated. Lung volumes and ventilatory tests. T h e vital capacity ( V C ) , expiratory reserve volume ( E R V ) , and inspiratory capacity (IC) were measured by conventional techniques on a 9 L. Collins spirometer. The functional residual capacity (FRC) was determined by the nitrogen washout method as described
Volume 74 Number 3
Pulmonary diffusing capacity
by D a r l i n g a n d associates. 7 D u r i n g this washout, t h e e n d tidal n i t r o g e n c o n c e n t r a t i o n after b r e a t h i n g o x y g e n for 2 m i n u t e s was accurately recorded. Total lung capacity ( T L C ) was c a l c u l a t e d as t h e s u m of t h e F R C a n d I C . T h e residual v o l u m e ( R V ) was c a l c u l a t e d as t h e d i f f e r e n c e b e t w e e n t h e FRC and ERV. The maximum breathing capacity (MBC), maximum mid-expiratory flow rate (MMEFR), a n d t h e o n e a n d t h r e e second t i m e d v i t a l capacities ( F E V 1 , F E V ~ ) w e r e
Table II
Children I Normal with C. F. children Mean sitting DL (ml./min. ram. Fig)
14.4 -+ 3.7
22.1 -+ 4.8
Per cent of predicted
93 -+ 24%
115 -+ 21%
D L head down
15.0 + 4.3
24.3 -+ 4.7
Per cent increase over sitting D L DL after exercise
4% 14.9 + 5.0
Per cent increase over sitting DL
3%
10% 28.0 + 3.4 27%
395
p e r f o r m e d on t h e Collins s p i r o m e t e r w i t h t h e 1,920 r a m . p e r m i n u t e speed. Normal predicted pulmonary function values w e r e c a l c u l a t e d o n the basis of t h e n o r m a l d a t a of G i a m m o n a a n d D a l y ? T h e d a t a w e r e s u b j e c t e d to a statistical analysis by u s i n g t h e S t u d e n t ' s t test a n d the p a i r e d c o m p a r i s o n t test used f o r t h e h e a d - d o w n position a n d the exercise studies, s
RESULTS T h e m e a n sitting D L of the 18 c h i l d r e n w i t h C . F . was t 4 . 0 _+ 3.7 ml. p e r m i n u t e x ram. H g ( T a b l e I I ) . T h i s represents a m e a n of 93 + 24 p e r c e n t of t h e i r p r e d i c t e d values. T h e r a n g e w a s f i ' o m 9.0 to 24.6 ml. p e r minute x mm. Hg (Table III). In a headd o w n p o s i t i o n t h e m e a n D L was 15.0 + 4.3. A f t e r exercise t h e m e a n D L was 14.9 + 5.0 in the 11 c h i l d r e n in w h o m this d e t e r m i n a tion was possible; t h e o t h e r 7 c h i l d r e n e i t h e r refused to c o o p e r a t e o r w e r e u n a b l e to h o l d t h e i r b r e a t h f o l l o w i n g exercise. T h e s e values of 1 5 . 0 a n d 14.8 r e p r e s e n t a 4 a n d 3 p e r c e n t increase o v e r t h e sitting values a n d are not statistically different. T h e n o r m a l c h i l d r e n h a d a m e a n sitting
'Fable III
Patient
Sitting. DL
1. M.AI "14.4 2. D.B.t 14.3 3. P.B. ~ 10.5 4. A.C.* 13.9 5. D.C. ~ 15.4 6. J.C-t 9.0 7. S.D.~ 15.5 8. P.D. * i4-3 9. B.G.-~ tl,2 I0. J.H. 24.6 11. P.J. 15.3 12. D.J.t 13.6 13. W.J. ~ 11.9 14. A.K. ~ 14.0 15. S.O. ~ 12.3 16. C.S. ~ 11.4 17. A.W. I4.8 18. C.H. 12.8 Mean -+ S.D. 14.4 -+ 3.7 *Normal standard pulmonary function. "~2minute nitrogen over 2 per cent.
Predicted DL
Per cent predicted
15.7 15.7 14.9 12,9 15.7 13.2 17.4 15.1 17.8 19.t 13.2 18.3 13.6 16.0 14.1 15.1 17.0 12.8 15.4 -+ 1.9
92 91 70 108 98 68 8995 63 129 116 74 88 88 87 75 87 164 93 + 24
I Head-down DL I 19.4 15.1 -13.6 15.0 8.1 15.2 t4.6 11.4 26.1 13.4 13.7
12.2 16.0 11.1 II.9 16.7
22.2 15.0 + 4.3
A[terexercise DL -13.8 12.6 12.6 ---I6.8 -
-
27.9 --11.2 15.8 12.0 10.4 11.5 18.8 14.9 + 5.0
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Z e l k o w i t z and G i a m m o n a
Table IV. DL
The Journal of Pediatrics March 1969
( m l . / m i n . x ram. H g ) of n o r m a l children
Subject
Sitting D L
Predicted D L
Per cent of predicted
Head-down D L
After exercise D L
19 20 21 22 23 24 ,25 26 Mean + S.D.
32.2 20.8 18.9 16.5 25.3 22.3 21.5 19.5 22.1 + 4.8
24.1 22.9 20.4 14.9 23.9 21.8 15.5 13.6 19.6 + 4.3
134 91 93 111 106 102 139 143 115 + 21
30.6 28.2 24.3 15.4 26.2 26.7 22.3 21.1 24.3 + 4.7
31.3 30.6 26.0 -28.6 31.5 25.5 22.5 28.0 +- 3.4
T a b l e V. Diffusion studies in 8 children with cystic fibrosis w i t h n o r m a l standard pulmonary function
Patient
3. 4. 5. 8. 13. 15. 16. 14.
P.B. A.C. D.C. P.D. W.J. S.O. C.S. A.K.
Age
Vital capacity
Maximum voluntary ventilation
8 5 9 6 7 8 8 10
96%* 124 110 110 115 120 119 10,5
97%* 100 104 96 110 131 105 95
RV/ TLC
25%t 29 27 36 33 32 31 26
2 minute nitrogen
1.0t 0.4 1.5 0.2 0.3 1.5 0.5 0,5
DL sitting
DL head-down
10.5 13.9 15.4 16.1 11.9 12.3 11.4 14.0
13.6 15.0 14.6 12.2 11.I 11.9 16.0
-
-
DL exercise
Per cent change of D L exercise versus sitting
12.6 12.6
+20 -10
16.6 11.2 12.0 10.4 15.8
+3 -6 -2 -9 +13
*Per cent predicted. "~Actual per cent.
T a b l e V I . S t a n d a r d p u l m o n a r y function studies 8 children with cystic fibrosis
Normal children
104 +- 17%t
107 -+ 14%
Maximum voluntary ventilationt
91 + 21%
92 +- 16%
Per cent nitrogen after 2 minutes 02 breathing:~
1.7 -+ 1.3%
0.7 -+ 0.4%
Vital capacity**
*Per cent of predicted. "~Standard deviation. :~Actual per cent.
D L of 22.1 _+ 4.8 ml. p e r m i n u t e x ram. Hg, which represents 115 p e r cent of their predicted value. I n the h e a d - d o w n position the m e a n D L was 24.3 + 4.7, which represents a 10 p e r cent increase over sitting; the difference is statistically significant (p < 0.01).
Following exercise, the m e a n D L was 28.0 + 3.4, which is 27 p e r cent greater t h a n the sitting, resting value (p = 0.01) (Tables II, IV). Results of routine splrometry a n d nitrogen washout studies showed t h a t of the 18 child r e n with C.F. studied, 8 h a d n o r m a l stand a r d p u l m o n a r y functions ( T a b l e V ) . These 8 children h a d n o r m a l lung volumes, n o r m a l timed vital capacity, n o r m a l m a x i m u m m i d expiratory flow rate, a n d gas mixing. Five children h a d 2 m i n u t e nitrogens over 2 p e r cent a n d o t h e r evidence of m o d e r a t e l y adv a n c e d disease ( T a b l e I I I , Patients 2, 6, 7, 9, 12). T h e r e m a i n i n g 5 children h a d mini m a l changes d u e to C.F. T h e m e a n vital capacity of the 18 children with C.F. was 104 _+ 17 p e r cent of predicted. T h e i r m a x i m u m v o l u n t a r y ventilation was 91 + 21 p e r cent a n d the 2 m i n u t e nitrogen was 1.7 • 1.3 p e r cent ( T a b l e V I ) . T h e n o r m a l chil-
Volume 74 Number 3
dren had a V C of 107 _+ I4 per cent, M V V of 92 + 16 per cent, and a 2 minute nitrogen of 0.7 + 0.4 per cent. Only the 2 minute nitrogen varied significantly between the normal children and those with C.F. (0.02
< p > 0.01). DISCUSSION
Nmnerous studies have shown that the pulmonary diffusing capacity of normal children and adults will increase significantly following exercise or a change from t h e upright to a supine position. 1, 9, 10 This increase occurs because of the large additional alveolar surface available for diffusion and because of the ability to increase the pulmonary capillary blood volume. Although several reports have shown children with C.F. to have normal resting pulmonary diffusion capacity, 2, 3 there has been no documentation of their ability to increase the total lung diffusing capacity under stressing conditions such as exercise. In the present study, the children with C.F., when placed in a head-down position, had a 4 per cent increase of D L ; the normal subjects had a 10 per cent increase. With exercise, the children with C.F. had a 3 per cent increase, in contrast to a 27 per cent increase of the normal children (Table I I ) . Of the 8 children with normal standard pulmonary function tests, only 2 (Patients 3, 14) had a significant increase of D L with exercise. The diffusing capacity for C O is dependent upon the instantaneous volume of capillary blood available for gas exchange, the rate of combination of C O with intracellular hemoglobin, and the physical characteristics of the pulmonary membrane. The mechanism by which exercise increases diffusing capacity is unknown. An increase in the pulmonary capillary blood volmne by the use of pressure suit inflation or tourniquets is responsible for an increase in DL, and this in p a r t occurs during exercise. Changes in cardiac output and pulmonary vascular pressures, however, are without significant effect? ~ The data of these 8 children suggest that some unknown alteration of the pulmonary capillary bed has occurred very
Pulmonary diffusing capacity
397
early in the course of their disease; the child with C.F. appears to be using all available pulmonary capillary membrane surface for diffusion at rest. Of these 18 patients, 3 have been hospitalized within the past year because of progressive pulmonary involvement (Patients 6, 9, 12). Even the resting D L of these 3 patients is now significantly reduced. This alteration of diffusing capacity may be due to many reasons, including uneven ventilation as demonstrated by their poor gas mixing, indicated by the N2 washout curve. T h e inability of the child with C.F. to increase diffusion rate with exercise or gravity in the face of normal lung volumes, normal gas mixing, and normal mechanics of breathing represents a profound loss of adaptability. This loss may be responsible for the poor exercise tolerance, dyspnea, and cyanosis observed during physical activity. Further studies are needed to ascertain if these findings are due to a loss of membrane surface area or if the change occurs in the pulmonary capillary bed. SUMMARY
Eighteen children with cystic fibrosis and 8 normal children had diffusion D L measurements in sitting and head-down positions after exercise. The children with cystic fibrosis were unable to increase their DL with gravity or exercise, while the normal children had expected normal responses. This alteration was present even in the face of normal routine pulmonary function studies. REFERENCES
1. Giammona, S. T., and Daly, W. J.: Pulmonary diffusing capacity in normal children, ages 4 to 13, Am. J. Dis. Child. I10: 144, 1965. 2. Strang, L. B.: Measurements of pulmonary diffusing capacity in children, Arch. Dis. Childhood 35: 232, 1960. 3. Beier, F. R., Renzetti, A. D., Mitchell, M., and Watanabe, S.: Pulmonary pathophysiology in cystic fibrosis, Am. Rev. Resp. Dis. 9: 430, 1966. 4. Forster, R. E., et al.: The absorption of carbon monoxide by the lung's during breathholding, J. Clin. Invest. 33: 1135, 1954. 5. Ogilvie, C. M., et al.: Standardized breathholding technique for the clinical measure-
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Zelkowitz and Giamrnona
ment of diffusing capacity of the lung for carbon monoxide, J. Clin. Invest. 36: 1, 1957. 6. Krogh, M.: Diffusion of gases through the lungs of man, J. Physiol. t9: 271, 1915. 7. Darling, R. C., Cournand, A., and Richards, D. W., Jr.: Studies on the intrapulmonary mixture of gases. III. An open circuit method for measuring residual air, J. Clin. Invest. 19: 601, 1940. 8. Snedecor, G. W.: Statistical methods, ed. 5, Ames, Iowa, 1956, Iowa State College Press.
The Journal of Pediatrics March 1969
9. Lewis, B. M., et al.: Effects of body position, ganglionic blockade and norepinephrine on the pulmonary capillary bed, J. Clin. Invest. 39: 1345, 1960. 10. Ross, J. C., Frayser, R., and ttickam, Ji B.: A study of the mechanism by which exercise increases the pulmonary diffusing capacity for carbon monoxide, J. Clin. Invest. 38: 916, 1959.
393
Effects of gravity and exerciseon the pulmonary diffusing capacity in children Mth cystic fibrosis Eighteen children with cystic fibrosis underwent studies o[ the diffusing capacity of carbon monoxide [ollowing exercise and in sitting and head-down positions. These children, in contrast to normal subjects, were unable to increase the diffusion rate following the 'head-down position or exercise. These findings were even present in 8 of the 18 children who had normal lung volumes, normal mechanics o[ breathing, and normal gas mixing.
Patricla S. Zelkowitz, M.D., and Samuel T. Giammona, M.D., with the technical assistance of Grace Silva and Alfred Jalowayski MIAMI~ FLA.
T i=~E total pulmonary diffusing capacity of the lung for oxygen (or the test gas carbon monoxide) is a result of the diffusing capacity of the pulmonary membrane and the rate of the uptake of the gas by chemical combination by the blood in the pulmonary capillaries. The normal total lung diffusing capacity at rest varies with age, sex, and size. Increases in the total lung diffusing capacity From the Department o[ Pediatrics, University o[ Miami School of Medicine. Supported by a grant [rom the American Medical Association, Education and Research Foundation, Committee [or Research on Tobacco and Health, and by a grant from the American Heart Association and the Suncoast Heart Association. Facilities provided by the Papanieolaou Cancer Institute. Reprints: Samuel T. Giammona, M.D., Department of Pediatr;cs, University o[ Miami, School o[ Medicine. P.O. Box 875, Biscayne Annex, Miami, Florida 33152.
reflect the availability of additional alveolar membrane surfaces for diffusion or increase of the instantaneous pulmonary capillary blood volume. The puhnonary diffusing capacity, as measured by single-breath carbon monoxide absorption, is greater in the supine than in the upright position in normal children at rest/ reflecting the large reserve of diffusing capacity available to the normal child. Exercise produces even greater increases in the pulmonary diffusing capacity than those found by postural changes? Several investigators have reported that resting diffusing measurements in children with cystic fibrosis are normal.2, 3 The effects of gravity and exercise on diffusing capacity in these children have not been documented. This study was undertaken to determine if changes in diffusing Vol. 74, No. 3, pp. 393-398
3 94
Zelkowitz and Giamraona
The Journal o[ Pediatrics March 1969
capacity (DL) of patients with cystic fibrosis (C.F.) occurred with different body positions and after exercise. In addition, lung volumes and ventilatory tests were obtained.
METHODS Subjects. Eighteen children with C.F. (8 boys, 10 girls), ranging in age from 5 to 13 years, formed the study group. Eight normal children (6 boys, 2 girls) were studied simultaneously to insure the validity of techniques in our laboratory during the study period. Thirteen of the children with C.F. had either normal or minimally abnormal chest roentgenograms. T h e remaining 5 children had moderately advanced disease. Their average age was 8.4 +_ 1.8 years, and their mean body surface area (BSA) was 0.92 + 0.09 sq.M. The normal children were 8.6 _+ 2.1 years of age and had a mean BSA of 1.12 _+0.2 sq.M. (Table I ) . Measurements
of
diffusing
capacity
(DL). The single-breath carbon monoxide diffusing capacity was measured by the method of Krogh, 6 as modified by Forster and associates 4 and Ogilvie and associates? The principle of this method is that uptake of carbon monoxide is measured by noting the change in alveolar Peo when the breath is held at a constant known volume for measured periods of time. Duplicate D L determinations were performed with each child in a sitting and a 15 degree head-down position, as well as immediately following exercise to exhaustion. The head-down position was maintained for 10 minutes prior
Table I Children with C. F.
Normal children
18 8 10
8 6 2
Age (years)
8.4 +- 1.8"
8.6 + 2.1
Body surface area (BSA) (sq. M.)
0.92 -+ .09
-1.12 -+ 0.2
Predicted BSA
1.05
1.07
Number Males Females
*Standard deviation.
to and during the collection of all samples. Exercise was performed on a bicycle ergometer and varied with the tolerance of each child. A Rudolph five-way valve (W. E. Collins, Co., Boston, Mass.) was used during the procedure with the child inspiring from a bag in box system and expiring first into the spirometer and finally into a collecting bag to obtain alveolar samples. The inspired gas contained 0.5 per cent carbon monoxide and 1 per cent neon in room air. The spirometer tracings were used to record the time of breath holding, the inspired volume, and the volume expired into the collecting spirometer prior to collection of the alveolar samples. To insure adequate washout of the dead space, a volume of 500 ml. or half of the vital capacity, whichever was less, was required to be cleared. T h e time of breath holding did not vary more than 20 per cent from 10 seconds. The children were encouraged to inspire and expire maximally during each determination. Alveolar samples were analyzed with gas chromatography (Microtek M T 220), which utilized a thermal conductivity detector with helium as the carrier gas. The following equation was used for all calculations6: DL (ml./min. x mm.Hg) -~ 60 Fco initial VA (STPD) x - x logN B.P.-47 Fco terminal Time of breath holding The VA refers to total alveolar volume and is determined by the dilution of neon that occurs during breath holding. The FGo initial and terminal refer to the concentration of carbon monoxide in the alveolar sample at the onset of the test and after 10 seconds of breath holding, during which time diffusion occurs. Any duplicate DL determination that did not check within 3 ml. per min. • ram. H g was discarded and repeated. Lung volumes and ventilatory tests. T h e vital capacity ( V C ) , expiratory reserve volume ( E R V ) , and inspiratory capacity (IC) were measured by conventional techniques on a 9 L. Collins spirometer. The functional residual capacity (FRC) was determined by the nitrogen washout method as described
Volume 74 Number 3
Pulmonary diffusing capacity
by D a r l i n g a n d associates. 7 D u r i n g this washout, t h e e n d tidal n i t r o g e n c o n c e n t r a t i o n after b r e a t h i n g o x y g e n for 2 m i n u t e s was accurately recorded. Total lung capacity ( T L C ) was c a l c u l a t e d as t h e s u m of t h e F R C a n d I C . T h e residual v o l u m e ( R V ) was c a l c u l a t e d as t h e d i f f e r e n c e b e t w e e n t h e FRC and ERV. The maximum breathing capacity (MBC), maximum mid-expiratory flow rate (MMEFR), a n d t h e o n e a n d t h r e e second t i m e d v i t a l capacities ( F E V 1 , F E V ~ ) w e r e
Table II
Children I Normal with C. F. children Mean sitting DL (ml./min. ram. Fig)
14.4 -+ 3.7
22.1 -+ 4.8
Per cent of predicted
93 -+ 24%
115 -+ 21%
D L head down
15.0 + 4.3
24.3 -+ 4.7
Per cent increase over sitting D L DL after exercise
4% 14.9 + 5.0
Per cent increase over sitting DL
3%
10% 28.0 + 3.4 27%
395
p e r f o r m e d on t h e Collins s p i r o m e t e r w i t h t h e 1,920 r a m . p e r m i n u t e speed. Normal predicted pulmonary function values w e r e c a l c u l a t e d o n the basis of t h e n o r m a l d a t a of G i a m m o n a a n d D a l y ? T h e d a t a w e r e s u b j e c t e d to a statistical analysis by u s i n g t h e S t u d e n t ' s t test a n d the p a i r e d c o m p a r i s o n t test used f o r t h e h e a d - d o w n position a n d the exercise studies, s
RESULTS T h e m e a n sitting D L of the 18 c h i l d r e n w i t h C . F . was t 4 . 0 _+ 3.7 ml. p e r m i n u t e x ram. H g ( T a b l e I I ) . T h i s represents a m e a n of 93 + 24 p e r c e n t of t h e i r p r e d i c t e d values. T h e r a n g e w a s f i ' o m 9.0 to 24.6 ml. p e r minute x mm. Hg (Table III). In a headd o w n p o s i t i o n t h e m e a n D L was 15.0 + 4.3. A f t e r exercise t h e m e a n D L was 14.9 + 5.0 in the 11 c h i l d r e n in w h o m this d e t e r m i n a tion was possible; t h e o t h e r 7 c h i l d r e n e i t h e r refused to c o o p e r a t e o r w e r e u n a b l e to h o l d t h e i r b r e a t h f o l l o w i n g exercise. T h e s e values of 1 5 . 0 a n d 14.8 r e p r e s e n t a 4 a n d 3 p e r c e n t increase o v e r t h e sitting values a n d are not statistically different. T h e n o r m a l c h i l d r e n h a d a m e a n sitting
'Fable III
Patient
Sitting. DL
1. M.AI "14.4 2. D.B.t 14.3 3. P.B. ~ 10.5 4. A.C.* 13.9 5. D.C. ~ 15.4 6. J.C-t 9.0 7. S.D.~ 15.5 8. P.D. * i4-3 9. B.G.-~ tl,2 I0. J.H. 24.6 11. P.J. 15.3 12. D.J.t 13.6 13. W.J. ~ 11.9 14. A.K. ~ 14.0 15. S.O. ~ 12.3 16. C.S. ~ 11.4 17. A.W. I4.8 18. C.H. 12.8 Mean -+ S.D. 14.4 -+ 3.7 *Normal standard pulmonary function. "~2minute nitrogen over 2 per cent.
Predicted DL
Per cent predicted
15.7 15.7 14.9 12,9 15.7 13.2 17.4 15.1 17.8 19.t 13.2 18.3 13.6 16.0 14.1 15.1 17.0 12.8 15.4 -+ 1.9
92 91 70 108 98 68 8995 63 129 116 74 88 88 87 75 87 164 93 + 24
I Head-down DL I 19.4 15.1 -13.6 15.0 8.1 15.2 t4.6 11.4 26.1 13.4 13.7
12.2 16.0 11.1 II.9 16.7
22.2 15.0 + 4.3
A[terexercise DL -13.8 12.6 12.6 ---I6.8 -
-
27.9 --11.2 15.8 12.0 10.4 11.5 18.8 14.9 + 5.0
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Z e l k o w i t z and G i a m m o n a
Table IV. DL
The Journal of Pediatrics March 1969
( m l . / m i n . x ram. H g ) of n o r m a l children
Subject
Sitting D L
Predicted D L
Per cent of predicted
Head-down D L
After exercise D L
19 20 21 22 23 24 ,25 26 Mean + S.D.
32.2 20.8 18.9 16.5 25.3 22.3 21.5 19.5 22.1 + 4.8
24.1 22.9 20.4 14.9 23.9 21.8 15.5 13.6 19.6 + 4.3
134 91 93 111 106 102 139 143 115 + 21
30.6 28.2 24.3 15.4 26.2 26.7 22.3 21.1 24.3 + 4.7
31.3 30.6 26.0 -28.6 31.5 25.5 22.5 28.0 +- 3.4
T a b l e V. Diffusion studies in 8 children with cystic fibrosis w i t h n o r m a l standard pulmonary function
Patient
3. 4. 5. 8. 13. 15. 16. 14.
P.B. A.C. D.C. P.D. W.J. S.O. C.S. A.K.
Age
Vital capacity
Maximum voluntary ventilation
8 5 9 6 7 8 8 10
96%* 124 110 110 115 120 119 10,5
97%* 100 104 96 110 131 105 95
RV/ TLC
25%t 29 27 36 33 32 31 26
2 minute nitrogen
1.0t 0.4 1.5 0.2 0.3 1.5 0.5 0,5
DL sitting
DL head-down
10.5 13.9 15.4 16.1 11.9 12.3 11.4 14.0
13.6 15.0 14.6 12.2 11.I 11.9 16.0
-
-
DL exercise
Per cent change of D L exercise versus sitting
12.6 12.6
+20 -10
16.6 11.2 12.0 10.4 15.8
+3 -6 -2 -9 +13
*Per cent predicted. "~Actual per cent.
T a b l e V I . S t a n d a r d p u l m o n a r y function studies 8 children with cystic fibrosis
Normal children
104 +- 17%t
107 -+ 14%
Maximum voluntary ventilationt
91 + 21%
92 +- 16%
Per cent nitrogen after 2 minutes 02 breathing:~
1.7 -+ 1.3%
0.7 -+ 0.4%
Vital capacity**
*Per cent of predicted. "~Standard deviation. :~Actual per cent.
D L of 22.1 _+ 4.8 ml. p e r m i n u t e x ram. Hg, which represents 115 p e r cent of their predicted value. I n the h e a d - d o w n position the m e a n D L was 24.3 + 4.7, which represents a 10 p e r cent increase over sitting; the difference is statistically significant (p < 0.01).
Following exercise, the m e a n D L was 28.0 + 3.4, which is 27 p e r cent greater t h a n the sitting, resting value (p = 0.01) (Tables II, IV). Results of routine splrometry a n d nitrogen washout studies showed t h a t of the 18 child r e n with C.F. studied, 8 h a d n o r m a l stand a r d p u l m o n a r y functions ( T a b l e V ) . These 8 children h a d n o r m a l lung volumes, n o r m a l timed vital capacity, n o r m a l m a x i m u m m i d expiratory flow rate, a n d gas mixing. Five children h a d 2 m i n u t e nitrogens over 2 p e r cent a n d o t h e r evidence of m o d e r a t e l y adv a n c e d disease ( T a b l e I I I , Patients 2, 6, 7, 9, 12). T h e r e m a i n i n g 5 children h a d mini m a l changes d u e to C.F. T h e m e a n vital capacity of the 18 children with C.F. was 104 _+ 17 p e r cent of predicted. T h e i r m a x i m u m v o l u n t a r y ventilation was 91 + 21 p e r cent a n d the 2 m i n u t e nitrogen was 1.7 • 1.3 p e r cent ( T a b l e V I ) . T h e n o r m a l chil-
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dren had a V C of 107 _+ I4 per cent, M V V of 92 + 16 per cent, and a 2 minute nitrogen of 0.7 + 0.4 per cent. Only the 2 minute nitrogen varied significantly between the normal children and those with C.F. (0.02
< p > 0.01). DISCUSSION
Nmnerous studies have shown that the pulmonary diffusing capacity of normal children and adults will increase significantly following exercise or a change from t h e upright to a supine position. 1, 9, 10 This increase occurs because of the large additional alveolar surface available for diffusion and because of the ability to increase the pulmonary capillary blood volume. Although several reports have shown children with C.F. to have normal resting pulmonary diffusion capacity, 2, 3 there has been no documentation of their ability to increase the total lung diffusing capacity under stressing conditions such as exercise. In the present study, the children with C.F., when placed in a head-down position, had a 4 per cent increase of D L ; the normal subjects had a 10 per cent increase. With exercise, the children with C.F. had a 3 per cent increase, in contrast to a 27 per cent increase of the normal children (Table I I ) . Of the 8 children with normal standard pulmonary function tests, only 2 (Patients 3, 14) had a significant increase of D L with exercise. The diffusing capacity for C O is dependent upon the instantaneous volume of capillary blood available for gas exchange, the rate of combination of C O with intracellular hemoglobin, and the physical characteristics of the pulmonary membrane. The mechanism by which exercise increases diffusing capacity is unknown. An increase in the pulmonary capillary blood volmne by the use of pressure suit inflation or tourniquets is responsible for an increase in DL, and this in p a r t occurs during exercise. Changes in cardiac output and pulmonary vascular pressures, however, are without significant effect? ~ The data of these 8 children suggest that some unknown alteration of the pulmonary capillary bed has occurred very
Pulmonary diffusing capacity
397
early in the course of their disease; the child with C.F. appears to be using all available pulmonary capillary membrane surface for diffusion at rest. Of these 18 patients, 3 have been hospitalized within the past year because of progressive pulmonary involvement (Patients 6, 9, 12). Even the resting D L of these 3 patients is now significantly reduced. This alteration of diffusing capacity may be due to many reasons, including uneven ventilation as demonstrated by their poor gas mixing, indicated by the N2 washout curve. T h e inability of the child with C.F. to increase diffusion rate with exercise or gravity in the face of normal lung volumes, normal gas mixing, and normal mechanics of breathing represents a profound loss of adaptability. This loss may be responsible for the poor exercise tolerance, dyspnea, and cyanosis observed during physical activity. Further studies are needed to ascertain if these findings are due to a loss of membrane surface area or if the change occurs in the pulmonary capillary bed. SUMMARY
Eighteen children with cystic fibrosis and 8 normal children had diffusion D L measurements in sitting and head-down positions after exercise. The children with cystic fibrosis were unable to increase their DL with gravity or exercise, while the normal children had expected normal responses. This alteration was present even in the face of normal routine pulmonary function studies. REFERENCES
1. Giammona, S. T., and Daly, W. J.: Pulmonary diffusing capacity in normal children, ages 4 to 13, Am. J. Dis. Child. I10: 144, 1965. 2. Strang, L. B.: Measurements of pulmonary diffusing capacity in children, Arch. Dis. Childhood 35: 232, 1960. 3. Beier, F. R., Renzetti, A. D., Mitchell, M., and Watanabe, S.: Pulmonary pathophysiology in cystic fibrosis, Am. Rev. Resp. Dis. 9: 430, 1966. 4. Forster, R. E., et al.: The absorption of carbon monoxide by the lung's during breathholding, J. Clin. Invest. 33: 1135, 1954. 5. Ogilvie, C. M., et al.: Standardized breathholding technique for the clinical measure-
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Zelkowitz and Giamrnona
ment of diffusing capacity of the lung for carbon monoxide, J. Clin. Invest. 36: 1, 1957. 6. Krogh, M.: Diffusion of gases through the lungs of man, J. Physiol. t9: 271, 1915. 7. Darling, R. C., Cournand, A., and Richards, D. W., Jr.: Studies on the intrapulmonary mixture of gases. III. An open circuit method for measuring residual air, J. Clin. Invest. 19: 601, 1940. 8. Snedecor, G. W.: Statistical methods, ed. 5, Ames, Iowa, 1956, Iowa State College Press.
The Journal of Pediatrics March 1969
9. Lewis, B. M., et al.: Effects of body position, ganglionic blockade and norepinephrine on the pulmonary capillary bed, J. Clin. Invest. 39: 1345, 1960. 10. Ross, J. C., Frayser, R., and ttickam, Ji B.: A study of the mechanism by which exercise increases the pulmonary diffusing capacity for carbon monoxide, J. Clin. Invest. 38: 916, 1959.