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Interrelationship of airflow limitation and ventilation inhomogeneity in obstructive lung disease Ross, Jocelyn Susan 1989

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INTERRELATIONSHIP OF AIRFLOW LIMITATION VENTILATION INHOMOGENEITY IN OBSTRUCTIVE LUNG DISEASE AND by JOCELYN SUSAN ROSS BSR, The U n i v e r s i t y o f B r i t i s h Columbia, 1980 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENT FOR THE DEGREE OF MASTER OF SCIENCE i n THE FACULTY OF GRADUATE STUDIES [INTERDISCIPLINARY STUDIES] Departments o f P h y s i o l o g y and M e d i c i n e We a c c e p t t h i s t h e s i s as c o n f o r m i n g t o t h e r e q u i r e d s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA A p r i l 198 9 © J o c e l y n Susan Ross, 1989 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of P h y s i o l o g y and M e d i c i n e ( R e s p i r a t o r y M e d i c i n e ) The University of British Columbia Vancouver, Canada Date A p r i l 20, 1989  DE-6 (2/88) ABSTRACT The purpose of t h i s study was to investigate the i n t e r r e l a t i o n s h i p between airflow l i m i t a t i o n and v e n t i l a t i o n inhomogeneity i n individuals with asthma and c y s t i c f i b r o s i s . Tests of forced expiration [the forced expiratory volume i n one second (FEV^) and the forced expiratory flow during 25-75% of the v i t a l capacity (FEF25-75%^ ^ a n c * t^ i e s i n < ? l e - b r e a t n nitrogen test [slope of Phase III (SB^/I^) ] were conducted i n fourteen control subjects [mean age 24 years], fourteen i n d i v i d u a l s with asthma [mean age 23 years] and seven individuals with c y s t i c f i b r o s i s [mean age 20 years]. The tests were conducted according to the standards and procedures of the American Thoracic Society and the National Heart and Lung I n s t i t u t e . A questionnaire assessing a c t i v i t y l e v e l and subjective rating of symptoms was also administered. A l l subjects were tested on two occasions within a seven month period, from July to February. The subjects were able to complete a l l of the test procedures without d i f f i c u l t y . The control group had the highest mean values of 102% and 95% predicted for FEV.^  and F E F 2 5 - 7 5 % respectively. The asthmatic group f e l l between the control and c y s t i c f i b r o s i s groups with mean FEV^ and F E F 2 5 - 7 5 % values of 80% and 59% predicted respectively. In the c y s t i c f i b r o s i s group, the mean FEV^ was 44% predicted and the mean F E F 2 5 - 7 5 % w a s 2 4 * predicted. The SBN2/L% mean values followed a s i m i l a r trend with the lowest percent predicted values i n the control group [115%] followed by the asthmatic group [153%] and i i t h e c y s t i c f i b r o s i s group w i t h t h e h i g h e s t mean [937%]. In t h e c y s t i c f i b r o s i s group, t h e S B ^ / I ^ was d i s p r o p o r t i o n a t e l y i m p a i r e d i n comparison t o t h e s e v e r i t y o f a i r f l o w l i m i t a t i o n . Over a l l groups, t h e c o e f f i c i e n t s o f v a r i a t i o n f o r t h e S B ^ / L ^ ave r a g e d l e s s t h a n 10%. W i t h i n a g i v e n t e s t s e s s i o n , t h e t e s t s o f a i r f l o w l i m i t a t i o n and v e n t i l a t i o n i nhomogeneity were c o r r e l a t e d , however, t h e change i n t h e s e t e s t v a l u e s between t h e two t e s t s e s s i o n s d i d not c o r r e l a t e . The d i f f e r e n c e i n mean t e s t v a l u e s between t h e a s t h m a t i c and c y s t i c f i b r o s i s groups c o u l d be e x p l a i n e d on t h e b a s i s o f t h e u n d e r l y i n g mechanisms o f a i r w a y o b s t r u c t i o n i n t h e s e d i s e a s e s . The m o d e r a t e l y i m p a i r e d t e s t performance i n t h e a s t h m a t i c group may r e f l e c t t h e v a r i a b l e b r o n c h o c o n s t r i c t i o n and a i r w a y i n f l a m m a t i o n i n t h i s d i s e a s e , whereas t h e s e v e r e l y i m p a i r e d t e s t p erformance i n t h e c y s t i c f i b r o s i s group i s l i k e l y due t o t h e g r e a t e r degree and s e v e r i t y o f o b s t r u c t i o n from mucus p l u g g i n g and b r o n c h i e c t a s i s . I n a l l groups, t h e l a c k o f c o r r e l a t i o n o f t h e change i n t e s t v a l u e s i n i n d i v i d u a l s between t e s t s e s s i o n s r e f l e c t s t h e d i f f e r e n t p a t h o p h y s i o l o g i c phenomenon t h a t i n f l u e n c e s each t e s t , and a l s o t h e d i f f e r e n t t i m e c o u r s e s o f r e c o v e r y o f a i r f l o w r a t e s and v e n t i l a t i o n homogeneity towards b a s e l i n e l e v e l s . Thus, on d i f f e r e n t o c c a s i o n s , v e n t i l a t i o n inhomogeneity can be more s e v e r e t h a n e x p e c t e d from assessment o f a i r f l o w l i m i t a t i o n . I n a d d i t i o n , w i t h i n a t e s t s e s s i o n i n t h e c y s t i c f i b r o s i s group, t h e SBNg/I^ was more s e v e r e l y i m p a i r e d t h a n e x p e c t e d on t h e b a s i s o f s p i r o m e t r y . S i n c e more s e v e r e v e n t i l a t i o n i n h o mogeneity may e x i s t i n c y s t i c f i b r o s i s and asthma compared t o a i r f l o w l i m i t a t i o n , i t may w e l l be t h a t t h e i n c l u s i o n o f t h e S B ^ t e s t [which t h i s s t u d y has shown t o have a s a t i s f a c t o r y c o e f f i c i e n t o f v a r i a t i o n ] might be u s e f u l i n t h e management o f t h e s e c h r o n i c d i s e a s e s . F u r t h e r r e s e a r c h i s n e c e s s a r y t o d e t e r m i n e whether t h e S B ^ / L ^ can p r e d i c t t h e r a t e o f d e c l i n e i n s p i r o m e t r y i n t h e s e i n d i v i d u a l s . i v TABLE OF CONTENTS A b s t r a c t i i L i s t Of Tables..- v i i i L i s t o f Figures i x Acknowledgements x i I n t r o d u c t i o n 1 Purpose 1 Purpose o f t h e S i n g l e B r e a t h N i t r o g e n T e s t 1 Components o f t h e SBN 2 Test 3 L i m i t a t i o n s o f t h e C l o s i n g Volume Measurement 9 Development o f t h e Slo p e o f Phase I I I Measurement 10 P h y s i o l o g i c I m p l i c a t i o n s o f t h e Slo p e o f Phase I I I 12 Measurement o f E x p i r a t o r y Flow Rate 21 R a t i o n a l e f o r t h e S e l e c t e d T e s t s i n A s t h m a t i c S u b j e c t s 24 R a t i o n a l e f o r t h e S e l e c t e d T e s t s i n C y s t i c F i b r o s i s S u b j e c t s 29 S p e c i f i c Purposes o f t h i s Study 32 Methods 33 R e s e a r c h D e s i g n 33 S u b j e c t s 34 P r o c e d u r e s 35 G e n e r a l P r o c e d u r e s 35 V S p e c i f i c P r o c e d u r e s 36 1. C a l i b r a t i o n o f t h e S p i r o m e t e r 36 2. C a l i b r a t i o n o f t h e N i t r o g e n A n a l y z e r 38 3. Performance o f t h e S p i r o m e t r y T e s t s 40 4. Performance o f t h e SBN 2 T e s t s 41 5. C o m p l e t i o n o f t h e Q u e s t i o n n a i r e 43 Data A n a l y s i s 44 R e s u l t s 47 S u b j e c t C h a r a c t e r i s t i c s 47 C h a r a c t e r i s t i c s o f Group Performance 47 S p i r o m e t r y 47 S p i r o m e t r y and SBN 2 T r a c i n g s 52 R e p r o d u c i b i l i t y o f t h e Test R e s u l t s 56 I n t e r r e l a t i o n s h i p Amongst V a r i a b l e s W i t h i n a S e s s i o n . . . . 56 I n t e r r e l a t i o n s h i p o f t h e Change i n V a r i a b l e s Between Two S e s s i o n s 66 D i s c u s s i o n 76 D i f f e r e n t i a t i n g t h e Performance o f t h e C y s t i c F i b r o s i s and A s t h m a t i c Groups 76 S p i r o m e t r y and SBN 2 Test R e s u l t s 7 6 D i f f e r e n c e s i n t h e SBN 2 T r a c i n g s 77 I n t e r r e l a t i o n s h i p Between A i r f l o w L i m i t a t i o n and V e n t i l a t i o n Inhomogeneity 80 R e l a t i o n s h i p Between Normal and Abnormal Test R e s u l t s 80 v i R e l a t i o n s h i p o f Test R e s u l t s W i t h i n a S e s s i o n 82 1. S p i r o m e t r y and t h e SBN 2/L% 82 2. E f f e c t o f B r o n c h o d i l a t i o n on S p i r o m e t r y and t h e SBN 2/L% 83 3. S u b j e c t i v e and O b j e c t i v e F i n d i n g s 84 R e l a t i o n s h i p o f t h e Change i n Te s t R e s u l t s Between S e s s i o n s 85 1. S p i r o m e t r y and t h e SBN 2/L%.. 85 2. S u b j e c t i v e and O b j e c t i v e F i n d i n g s 86 I m p l i c a t i o n s o f t h e Study 88 C o n c l u s i o n s 90 R e f e r e n c e s 92 App e n d i c e s 100 A V e n t i l a t i o n and A i r f l o w O b s t r u c t i o n Study: Q u e s t i o n n a i r e 100 B I n t e r r e l a t i o n s h i p o f V e n t i l a t i o n Inhomogeneity and A i r f l o w L i m i t a t i o n i n an A s t h m a t i c S u b j e c t P r e and P o s t B r o n c h o d i l a t i o n 102 v i i LIST OF TABLES I . S u b j e c t C h a r a c t e r i s t i c s : D e s c r i p t i v e S t a t i s t i c s 48 I I . D e s c r i p t i v e S t a t i s t i c s f o r t h e Dependent V a r i a b l e s f o r t h e C o n t r o l Group i n Both Test S e s s i o n s 49 I I I . D e s c r i p t i v e S t a t i s t i c s f o r t h e Dependent V a r i a b l e s f o r t h e A s t h m a t i c Group i n B o t h T e s t S e s s i o n s 50 IV. D e s c r i p t i v e S t a t i s t i c s f o r t h e Dependent V a r i a b l e s f o r t h e C y s t i c F i b r o s i s Group i n B o t h Test S e s s i o n s 51 V. R e p r o d u c i b i l i t y o f V a r i a b l e s Over t h e Two S e s s i o n s f o r t h e C o n t r o l Group: Spearman Rank Order C o r r e l a t i o n s 57 V I . R e p r o d u c i b i l i t y o f t h e SBN 2/L%: C o e f f i c i e n t s o f V a r i a t i o n W i t h i n S u b j e c t s f o r Each Group 58 V I I . I n t e r r e l a t i o n s h i p Among V a r i a b l e s f o r Each Group W i t h i n One S e s s i o n : Spearman Rank C o r r e l a t i o n s 59 V I I I . I n t e r r e l a t i o n s h i p o f V a r i a b l e s When C a t e g o r i z e d as Normal o r Abnormal: Frequency Data f o r Each Group f o r One S e s s i o n 67 IX. I n t e r r e l a t i o n s h i p o f t h e Change i n V a r i a b l e s Between Two S e s s i o n s : Spearman Rank Order C o r r e l a t i o n s f o r t h e Three Groups 68 v i i i LIST OF FIGURES 1. X-Y R e c o r d i n g o f t h e S i n g l e - B r e a t h N i t r o g e n Test 5 2. Equipment Set up f o r t h e S p i r o m e t r y T e s t s 37 3. Equipment Set up f o r t h e S i n g l e - B r e a t h N i t r o g e n Test....39 4. X-Y R e c o r d i n g o f t h e S i n g l e - B r e a t h N i t r o g e n T e s t from a C o n t r o l S u b j e c t 53 5. X-Y R e c o r d i n g o f t h e S i n g l e - B r e a t h N i t r o g e n Test from a Severe A s t h m a t i c S u b j e c t 54 6. X-Y R e c o r d i n g o f t h e S i n g l e - B r e a t h N i t r o g e n Test from a C y s t i c F i b r o s i s S u b j e c t 55 7. R e l a t i o n s h i p Between % P r e d i c t e d FEV^ and t h e % P r e d i c t e d SBN 2/L% f o r t h e C o n t r o l Group 60 8. R e l a t i o n s h i p Between % P r e d i c t e d F E F ^ ^ c - o , and t h e % P r e d i c t e d SBN 2/L% f o r t h e C o n t r o l Group 61 9. R e l a t i o n s h i p Between % P r e d i c t e d FEV"1 and t h e % P r e d i c t e d SBN 2/L% f o r t h e A s t h m a t i c Group 62 10. R e l a t i o n s h i p Between % P r e d i c t e d F E F 2 5 - 7 5 % a n c i t h e % P r e d i c t e d SBN 2/L% f o r t h e A s t h m a t i c Group 63 11. R e l a t i o n s h i p Between % P r e d i c t e d FEV^ and t h e % P r e d i c t e d SBN 2/L% f o r t h e C y s t i c F i b r o s i s Group 64 12. R e l a t i o n s h i p Between % P r e d i c t e d F E F 2 5 - 7 5 % and t h e % P r e d i c t e d SBN 2/L% f o r t h e C y s t i c F i b r o s i s Group 65 i x 13. R e l a t i o n s h i p Between t h e Change i n % P r e d i c t e d FEV^ and t h e Change i n % P r e d i c t e d SBN 2L% f o r t h e C o n t r o l Group 69 14. R e l a t i o n s h i p Between t h e Change i n % P r e d i c t e d F E F 2 5 - 7 5 % a n c i t h e Change ^ n % P r e d i c t e d SBN 2/L% f o r t h e C o n t r o l Group 70 15. R e l a t i o n s h i p Between t h e Change i n % P r e d i c t e d FEV 1 and t h e Change i n % P r e d i c t e d SBN 2L% f o r t h e A s t h m a t i c Group 71 16. R e l a t i o n s h i p Between t h e Change i n % P r e d i c t e d F E F 2 5 - 7 5 % and t h e Change i n % P r e d i c t e d SBN 2/L% f o r t h e A s t h m a t i c Group 72 17. R e l a t i o n s h i p Between t h e Change i n % P r e d i c t e d FEV^ and t h e Change i n % P r e d i c t e d SBN 2L% f o r t h e C y s t i c F i b r o s i s Group 73 18. R e l a t i o n s h i p Between t h e Change i n % P r e d i c t e d F E F 2 5 - 7 5 % and t h e Change i n % P r e d i c t e d SBN 9/L% f o r t h e C y s t i c F i b r o s i s Group 74 X ACKNOWLEDGEMENTS I would l i k e to acknowledge the invaluable support and guidance of my committee, Drs DV Bates, E Dean and RT Abboud. Their i n s p i r a t i o n has led me to an even higher summit than my experience on Everest previously had. In the process of working with them, I have been exposed to a multitude of other treks that are possible both on and o f f Everest. I would also l i k e to acknowledge the assistance of Dr B Nakielna and a l l of the subjects who pa r t i c i p a t e d i n the study. And l a s t but not least, I would l i k e to recognize those special people who formed the support team that helped to make the summit b i d successful. x i INTRODUCTION PURPOSE The purpose of t h i s study was to investigate the i n t e r r e l a t i o n s h i p between airflow l i m i t a t i o n and v e n t i l a t i o n inhomogeneity i n two examples of obstructive lung disease. In healthy subjects and subjects with asthma or c y s t i c f i b r o s i s [CF], the slope of Phase III of the single-breath nitrogen test and tests of forced expiratory volume and forced expiratory flow were measured i n the same session to assess v e n t i l a t i o n inhomogeneity and airflow l i m i t a t i o n respectively. In addition, the tests were repeated on a second occasion to examine the rel a t i o n s h i p of the change i n these variables between two test sessions. PURPOSE OF THE SINGLE BREATH NITROGEN TEST The single breath nitrogen [SB^] test was introduced by Fowler [1949] as a useful test for detecting abnormalities i n intrapulmonary gas mixing and the d i s t r i b u t i o n of v e n t i l a t i o n . The s e n s i t i v i t y and r e l a t i v e s i m p l i c i t y of t h i s t e s t permitted i t s extensive application both c l i n i c a l l y and epidemiologically since that time [Buist, 1975]. In 1968, Anthonisen et a l and Woolcock et a l demonstrated that conventional lung function tests such as: lung volumes, 1 f o r c e d e x p i r a t o r y volume i n one second [FEV^], maximal e x p i r a t o r y f l o w r a t e , a i r w a y r e s i s t a n c e and measures o f e l a s t i c r e c o i l , were t o o i n s e n s i t i v e t o d e t e c t t h e e a r l y s t a g e s o f s m a l l a i r w a y d i s e a s e . A l t h o u g h o t h e r more s e n s i t i v e t e s t s [ r a d i o a c t i v e gas t e c h n i c s and f r e q u e n c y dependence o f co m p l i a n c e ] were a b l e t o d e t e c t p e r i p h e r a l a i r w a y o b s t r u c t i o n , t h e d i f f i c u l t y i n c o n d u c t i n g t h e s e t e s t s r e n d e r e d them u n s u i t a b l e f o r r o u t i n e o r wide s c a l e s t u d i e s [McCarthy e t a l , 1972]. F u r t h e r , McCarthy e t a l [1972] and B u i s t e t a l [1973] c o n c l u d e d t h a t t h e s i n g l e b r e a t h t e s t was s i m p l e t o p e r f o r m and c o n s i d e r a b l y more s e n s i t i v e i n d e t e c t i n g e a r l y p e r i p h e r a l a i r w a y d i s e a s e t h a n c o n v e n t i o n a l l u n g f u n c t i o n t e s t s . These c o n c l u s i o n s were based on t h e i r r e s p e c t i v e i n v e s t i g a t i o n s o f b o t h smokers and nonsmokers . i n a group o f 112 s u b j e c t s from t h e g e n e r a l p o p u l a t i o n [ u s i n g an Argon b o l u s t e c h n i c ] , and 1,073 s u b j e c t s a t an emphysema s c r e e n i n g c e n t e r [ u s i n g t h e SBN 2 method]. The work o f C o s i o e t a l [1978] made a s i g n i f i c a n t c o n t r i b u t i o n t o t h e body o f l i t e r a t u r e s u p p o r t i n g t h e SBN 2 t e s t . They p e r f o r m e d r o u t i n e s p i r o m e t r y and t h e SBN 2 t e s t on 36 p a t i e n t s p r i o r t o thoracotomy f o r l o c a l i z e d pulmonary l e s i o n s . F o l l o w i n g t h i s t h e y q u a n t i f i e d t h e amount o f a i r w a y d i s e a s e i n t h e e x c i s e d specimens and d e s i g n a t e d t h o s e h a v i n g t h e g r e a t e s t p r o p o r t i o n o f normal a i r w a y s as Group 1 and t h o s e h a v i n g t h e g r e a t e s t p r o p o r t i o n o f d i s e a s e d a i r w a y s as Group 4. They t h e n compared t h e s e groups t o t h e p r e o p e r a t i v e pulmonary f u n c t i o n t e s t [PFT] r e s u l t s . Only t h e SBN„ t e s t was 2 s t a t i s t i c a l l y d i f f e r e n t between Groups 1 and 2, w h i c h i n d i c a t e d t h a t t h i s t e s t was more s e n s i t i v e i n d e t e c t i n g e a r l y a i r w a y disease-when p a t h o l o g i c a l changes were s t i l l p o t e n t i a l l y r e v e r s i b l e . B a i l e e t a l [1982] extended t h i s work i n t h e i r i n v e s t i g a t i o n o f t h e e f f e c t o f a c u t e p e r i p h e r a l a i r w a y i n f l a m m a t i o n on t e s t s o f s m a l l a i r w a y f u n c t i o n . The i n f l a m m a t i o n was i n d u c e d i n a dog model by n e b u l i z a t i o n o f 0.25% HC1 t o t h e s m a l l a i r w a y s p r e f e r e n t i a l l y . The s l o p e o f Phase I I I o f t h e SBN 2 t e s t i n c r e a s e d s i g n i f i c a n t l y and dynamic l u n g c o m p l i a n c e d e c r e a s e d s i g n i f i c a n t l y i m m e d i a t e l y a f t e r n e b u l i z a t i o n , and t h e s e changes p e r s i s t e d t h r o u g h o u t t h e e x p e r i m e n t . These i n v e s t i g a t o r s c o n c l u d e d t h a t m i n i m a l a c u t e i n f l a m m a t i o n o f t h e p e r i p h e r a l a i r w a y s r e s u l t s i n p h y s i o l o g i c a b n o r m a l i t i e s t h a t can be d e t e c t e d w i t h t h e s e t e s t s o f s m a l l a i r w a y f u n c t i o n . COMPONENTS OF THE SBN 2 TEST The SBN 2 t e s t i s performed w i t h t h e s u b j e c t w e a r i n g a n o s e c l i p and c o n n e c t e d t o a mouthpiece, w h i l e u s u a l l y i n a s i t t i n g p o s i t i o n . The s u b j e c t t a k e s two deep i n s p i r a t i o n s o f ambient a i r t h e n e x h a l e s t o r e s i d u a l volume [RV] p r i o r t o t a k i n g a v i t a l c a p a c i t y [VC] b r e a t h o f 100% oxygen. As t h e s u b j e c t e x h a l e s t h i s b r e a t h a t a r e g u l a t e d f l o w r a t e , t h e n i t r o g e n [N 2] c o n c e n t r a t i o n i n t h e e x p i r a t e i s c o n t i n u o u s l y m o n i t o r e d a t t h e mouth and p l o t t e d a g a i n s t l u n g volume. The p l o t o f l u n g volume on t h e a b s c i s s a and N 9 c o n c e n t r a t i o n on t h e 3 o r d i n a t e p roduces a c h a r a c t e r i s t i c 4-phase graph shown i n F i g u r e 1. Each phase o f t h e SBN 2 p l o t i s r e p r e s e n t a t i v e of. t h e e x t e n t o f v e n t i l a t i o n o f a s p e c i f i c l u n g r e g i o n , and t h u s o f t h e c o n c e n t r a t i o n o f N 2 c o n t a i n e d w i t h i n . Phase I appears as a h o r i z o n t a l l i n e as t h e a n a t o m i c a l dead space c o n t a i n i n g 100% oxygen i s emptied, w i t h a z e r o c o n c e n t r a t i o n o f N 2 . A sha r p upward d e f l e c t i o n o f t h e l i n e o c c u r s a t t h e onset o f Phase I I w h i c h r e p r e s e n t s t h e e x h a l a t i o n o f t h e i n t e r f a c e gas between dead space and a l v e o l a r a i r . S i n c e t h e r e i s d i f f u s i o n a c r o s s t h i s i n t e r f a c e , t h e l i n e has a s l o p e r a t h e r t h a n a s t e p - l i k e p a t t e r n [ S c h a c h t e r , 1986]. T h i s s l o p e i s f o l l o w e d by t h e s h a l l o w e r s l o p e o f Phase I I I w h i c h r e p r e s e n t s a l v e o l a r e mptying. The s l o p e o f Phase I I I i s d e t e r m i n e d by t h e homogeneity o f a l v e o l a r v e n t i l a t i o n and t h u s may v a r y from a r e l a t i v e p l a t e a u i n normals t o a prominent s l o p e i n s u b j e c t s w i t h pulmonary d i s e a s e [ S c h a c h t e r , 1986]. Phase IV o c c u r s as a n o t h e r upward d e f l e c t i o n from t h e s l o p e o f Phase I I I and i n t h e normal s e a t e d s u b j e c t o c c u r s because a i r w a y c l o s u r e p r e v e n t s f u r t h e r emptying from dependent r e g i o n s , and t h e e x p i r e d gas comes i n c r e a s i n g l y from upper l u n g zones. The volume above r e s i d u a l volume a t which t h e onset o f Phase IV o c c u r s i s termed t h e c l o s i n g volume [CV] o r t h e c l o s i n g c a p a c i t y when r e f e r r i n g t o t h e a b s o l u t e l u n g volume. The SBN 2 t e s t has t h e r e f o r e been used as a t e s t o f dependent a i r w a y c l o s u r e and as an i n d e x o f s m a l l a i r w a y s 4 F i g . 1. X-Y recording of the s l n g l e r b r e a t h nitrogen t e s t . Percent nitrogen 1s displayed on the y- a x i s and exhaled volume i s on the x-axis. Phase I represents dead space gas. Phase II represents a n i x t u r e of dead space and a l v e o l a r gas. Phase III represents true a l v e o l a r gas, and Phase IV represents the c l o s i n g volume. 5 d i s e a s e [McCarthy e t a l , 1972]. C o i n c i d e n t w i t h t h e i n c r e a s i n g use o f t h e c l o s i n g volume t e s t , s e v e r a l a t t e m p t s were made t o c l a r i f y t h e s p e c i f i c u n d e r l y i n g mechanism r e s p o n s i b l e f o r t h e o c c u r r e n c e o f Phase IV. The p h y s i o l o g i c mechanism c o u l d t h e o r e t i c a l l y be e x p l a i n e d by any o f t h e f o l l o w i n g : 1. a i r w a y c l o s u r e , 2. d e c r e a s e d a l v e o l a r c o m p l i a n c e , 3. a l v e o l a r c o l l a p s e o r , 4. e x p i r a t o r y f l o w l i m i t a t i o n [ Engel e t a l , 1975]. I n 1967 D o l l f u s s e t a l c o n c o m i t a n t l y measured t h e xenon [Xe] c o n c e n t r a t i o n i n s e q u e n t i a l l u n g r e g i o n s u s i n g s c i n t i l l a t i o n c o u n t e r s a r r a n g e d v e r t i c a l l y on t h e p o s t e r i o r t h o r a x and one a l s o l o c a t e d a t t h e mouth. A b o l u s o f Xe was i n t r o d u c e d a t t h e mouth d u r i n g i n s p i r a t i o n s s t a r t i n g from d i f f e r e n t l u n g volumes r a n g i n g from RV t o 90% VC. Throughout t h e range o f i n s p i r a t i o n s s t a r t i n g from 26-95% VC, t h e s e a u t h o r s c o n c l u d e d t h a t r e g i o n a l v e n t i l a t i o n i nhomogeneity e x i s t e d and c o u l d be e x p l a i n e d by t h e e f f e c t o f g r a v i t y . T h i s r e s u l t e d i n a l i n e a r i n c r e a s e i n Xe c o n c e n t r a t i o n from apex t o base. A t low l u n g volumes [between r e s i d u a l volume and 25% VC], r e g i o n a l v e n t i l a t i o n inhomogeneity was a t t r i b u t e d t o t h e o c c u r r e n c e o f a i r w a y c l o s u r e , r e s u l t i n g i n s e q u e n t i a l emptying and r e v e r s a l o f t h e normal Xe g r a d i e n t . The o c c u r r e n c e o f a i r w a y c l o s u r e was f u r t h e r s u p p o r t e d by t h e measures o f e x p i r e d Xe c o n c e n t r a t i o n a t t h e mouth. The Xe c o n c e n t r a t i o n showed l i t t l e change u n t i l between 20-15% VC a t w h i c h p o i n t t h e r e was an a b r u p t change which t h e a u t h o r s a t t r i b u t e d t o t h e p r o g r e s s i v e base t o apex a i r w a y c l o s u r e . H y a t t and R o d a r t e [1975] a t t r i b u t e d t h e onset o f Phase IV o f t h e SBN 0 t e s t t o 6 dynamic a i r w a y c o m p r e s s i o n r a t h e r t h a n a i r w a y c l o s u r e . They s u g g e s t e d t h a t t h e sudden r i s e i n N 2 c o n c e n t r a t i o n t o w a r d t h e end o f t h e VC o c c u r r e d a t a t i m e when t h e l u n g r e a c h e d f l o w l i m i t a t i o n . T h i s would cause t h e dependent l u n g r e g i o n s t o empty e a r l y and r e a c h f l o w l i m i t a t i o n ; a i r w a y c l o s u r e need not be p o s t u l a t e d . They o b s e r v e d t h a t t h e volume a t w h i c h Phase IV o c c u r r e d c o u l d be changed by v a r y i n g t h e e x p i r a t o r y f l o w r a t e ; t h e y c o n s i d e r e d t h a t t h i s o b s e r v a t i o n s t r e n g t h e n e d t h e i r t h e o r y o f e x p i r a t o r y f l o w l i m i t a t i o n . The most d e f i n i t i v e e x p e r i m e n t s t o c l a r i f y t h e c l o s i n g volume mechanism were c o n d u c t e d by E n g e l e t a l i n 1975. T h e i r normal s u b j e c t s were p a r t i a l l y e q u i l i b r a t e d w i t h N 20, t h e n h e l d t h e i r b r e a t h w h i l e a b o l u s o f Xe was d e l i v e r e d a t t h e mouth o r i n j e c t e d i n t r a v e n o u s l y . As t h e N 20 was a b s orbed i n t o t h e c i r c u l a t i o n i t s e t up a p r e s s u r e g r a d i e n t between t h e mouth and a l v e o l i , p r o d u c i n g gas f l o w . The Xe c a r r i e d i n by t h i s gas f l o w was d i s t r i b u t e d p r o p o r t i o n a l l y t o t h e N 20 a b s o r p t i o n i n t o t h e c i r c u l a t i o n [assuming p a t e n t a i r w a y s ] , and t h u s i n p r o p o r t i o n t o t h e r e g i o n a l b l o o d f l o w . S i n c e t h e r e i s g r e a t e r p e r f u s i o n o f b a s a l zones, t h e Xe c o n c e n t r a t i o n would have a base t o apex v e r t i c a l g r a d i e n t . The a u t h o r s compared t h e d i s t r i b u t i o n o f Xe as i t was c a r r i e d i n by t h e N 20 w i t h t h e i n t r a v e n o u s [IV] b o l u s , a t l u n g volumes b o t h above and below CV. A t FRC t h e N 20 b o l u s d i s t r i b u t i o n c l o s e l y matched t h a t o f t h e IV b o l u s . However, c l o s e t o RV t h e r e was a g r e a t e r amount o f t h e N 20 b o l u s d i s t r i b u t e d t o t h e apex t h a n t h e base w h i l e t h e IV b o l u s d i s t r i b u t i o n remained unchanged. The a u t h o r s 7 c o n c l u d e d t h a t t h i s must i n d i c a t e t h a t a i r w a y c l o s u r e i n t h e dependent a i r w a y s was o c c u r r i n g , s i n c e t h e p r e s s u r e g r a d i e n t s e t up by N 20 a b s o r p t i o n i n t o t h e c i r c u l a t i o n would f a i l t o produce a f l o w o f Xe i n t o t h e a l v e o l i o n l y i f a i r w a y s l e a d i n g t o them became c o m p l e t e l y o b s t r u c t e d . N a r r o w i n g o f dependent a i r w a y s as p r o p o s e d by H y a t t and Rod a r t e [1975] c o u l d not e x p l a i n t h e i r r e s u l t s . I n a d d i t i o n , t h e o t h e r p r o p o s e d t h e o r i e s t o e x p l a i n t h e CV were not s u p p o r t e d by t h e r e s u l t s o f E n g e l e t a l [1975]. These a u t h o r s o b s e r v e d t h a t t h e N 20 b o l u s d i s t r i b u t i o n o f Xe a t RV was s i m i l a r t o t h a t w h i c h o c c u r r e d when a b o l u s o f Xe was i n h a l e d from RV-even though t h e f l o w r a t e [0.2-0.5 L/s] was t e n f o l d g r e a t e r t h a n t h a t d u r i n g N 20 a b s o r p t i o n . I f t h e d i s t r i b u t i o n o f t h e N 20 b o l u s was d e t e r m i n e d by r e g i o n a l r e s i s t a n c e , t h e n i t would be f l o w s e n s i t i v e and would not have d i s p l a y e d a s i m i l a r d i s t r i b u t i o n when t h e two f l o w r a t e s were so d i f f e r e n t . These a u t h o r s a l s o r u l e d out a l v e o l a r c o l l a p s e i n t h e dependent l u n g r e g i o n s based on t h e i r f i n d i n g t h a t t h e IV b o l u s d i d not change i t s d i s t r i b u t i o n a t RV as t h e N 20 b o l u s had, i n d i c a t i n g t h e p r e s e n c e o f a i r f i l l e d p e r f u s e d dependent a l v e o l i w h i c h d i d not exchange gas w i t h t h e t r a c h e a . They c o n s i d e r e d t h a t t h e s i m i l a r i t y o f d i s t r i b u t i o n o f t h e N 20 b o l u s n e a r RV, t o t h a t o f a Xe b o l u s i n h a l e d from RV, c o n s t i t u t e d s u b s t a n t i a l e v i d e n c e t h a t a i r w a y c l o s u r e c o m p l e t e l y a c c o u n t e d f o r t h e d i s t r i b u t i o n o f v e n t i l a t i o n a t t h a t l u n g volume. They f u r t h e r c o n c l u d e d t h a t a p o t e n t i a l d e c r e a s e i n c o m p l i a n c e a t low l u n g volumes would not i n f l u e n c e t h e d i s t r i b u t i o n o f 8 v e n t i l a t i o n . LIMITATIONS OF THE CLOSING VOLUME MEASUREMENT D e s p i t e t h e v a l u a b l e a p p l i c a t i o n s o f t h e CV measurement, i t was found t o be l i m i t e d i n cases o f a i r f l o w o b s t r u c t i o n as shown by Abboud and Morton [1975]. These i n v e s t i g a t o r s o b s e r v e d a low i n c i d e n c e o f abnormal CV measures i n s u b j e c t s w i t h m i l d a i r f l o w o b s t r u c t i o n . Marcq and M i n e t t e [1980] o b s e r v e d a d e c r e a s e o r absence o f CV i n s u b j e c t s w i t h a i r f l o w o b s t r u c t i o n and c o n c l u d e d from t h e i r r e s u l t s t h a t phase IV was p r e d o m i n a n t l y d e t e r m i n e d by i n t r a r e g i o n a l gas g r a d i e n t s i n t h e s e s u b j e c t s . T h i s c o n c l u s i o n was f u r t h e r e x p l a i n e d by Andersen and Rasmussen [1981] who s t a t e d t h a t t h e range o f a i r w a y o p e n i n g p r e s s u r e s i n a i r w a y d i s e a s e widens, so t h a t open and c l o s e d a i r w a y s now o c c u r w i t h i n r e g i o n s as w e l l as between r e g i o n s . The consequence o f t h i s i s t h a t t h e d i s t a n c e between r e g i o n s w i t h d i f f e r e n t N 2 c o n c e n t r a t i o n s d e c r e a s e s , so t h a t e q u a l i z a t i o n o f t h e normal i n t e r r e g i o n a l g r a d i e n t may o c c u r e i t h e r by m o l e c u l a r d i f f u s i o n o r c a r d i o g e n i c m i x i n g . I n a d d i t i o n , t h e development o f enhanced c o l l a t e r a l v e n t i l a t i o n c o n t r i b u t e s t o t h e r e d u c t i o n o f t h e N 2 g r a d i e n t between open and c l o s e d l u n g u n i t s so t h a t t h e normal i n t e r r e g i o n a l g r a d i e n t w i l l be u n d e r e s t i m a t e d and may appear normal o r d i s a p p e a r c o m p l e t e l y . The net r e s u l t would be a c o n t i n u o u s r i s i n g s l o p e o f Phase I I I w i t h a normal o r absent Phase IV. T h e r e f o r e A ndersen and Rasmussen [1981] c o n c l u d e d t h a t a l t h o u g h t h e 9 measurement o f CV i s s u f f i c i e n t l y s e n s i t i v e t o r e v e a l t h e s t r u c t u r a l a b n o r m a l i t i e s i n p e r i p h e r a l a i r w a y s d u r i n g t h e e a r l y s t a g e s o f a i r f l o w l i m i t a t i o n , t h i s s e n s i t i v i t y d e c r e a s e s as g e n e r a l i z e d a i r f l o w o b s t r u c t i o n i n c r e a s e s . They s u g g e s t e d t h a t CV measurements would o n l y be u s e f u l i n asymptomatic s u b j e c t s o r p a t i e n t s w i t h near normal s p i r o m e t r y . DEVELOPMENT OF THE SLOPE OF PHASE I I I MEASUREMENT W h i l e t h e i n c i d e n c e o f i n v a l i d measures o f CV i n s u b j e c t s w i t h a i r w a y o b s t r u c t i o n was b e i n g i n v e s t i g a t e d , t h e a b i l i t y o f t h e s l o p e o f Phase I I I o f t h e SBN 2 t e s t t o d e t e c t v e n t i l a t i o n i n h o m o g e n e i t y i n t h e s e s u b j e c t s was g i v e n f u r t h e r a t t e n t i o n . Andersen and Rasmussen [1981] r e p o r t e d t h a t i n s u b j e c t s w i t h a i r f l o w o b s t r u c t i o n , t h e s l o p e o f Phase I I I [SBN 2/L%] r e v e a l e d abnormal t e s t v a l u e s i n t h e p r e s e n c e o f normal CV v a l u e s . They c o n c l u d e d t h a t t h e p r o g r e s s i o n and r e m i s s i o n o f p e r i p h e r a l a i r w a y d y s f u n c t i o n i s more l i k e l y t o be r e v e a l e d by t h e SBN 2/L% [which c o n t i n u e s t o i n c r e a s e w i t h t h e development o f a i r w a y o b s t r u c t i o n ] t h a n s p i r o m e t r y . Oxhoj. e t a l [1977] a l s o c o n c l u d e d t h a t t h e SBN 2/L% was more s e n s i t i v e t h a n f l o w r e c o r d i n g s and r o u t i n e s p i r o m e t r y i n t h e i r i n v e s t i g a t i o n o f l u n g d i s e a s e i n m i d d l e aged smokers. They o b t a i n e d abnormal SBN 2/L% v a l u e s i n 40-60% o f t h e smokers w h i l e CV and FEV 1 measures were a p p r o x i m a t e l y e q u a l l y s e n s i t i v e , w i t h abnormal v a l u e s i n 10-30% o f t h e smokers. These a u t h o r s c o n c l u d e d t h a t t h e SBN„/L% was t h e most v a l i d s i n g l e measurement f o r d e t e c t i o n 10 o f s m a l l a i r w a y a b n o r m a l i t y r e l a t e d t o smoking i n t h e 50 and 60 y e a r aged s u b j e c t s t h e y s t u d i e d . M o r p h o l o g i c s t u d i e s c o n ducted by C o s i o e t a l [1980] and P e t t y e t a l [1980] found minor m o r p h o l o g i c and f u n c t i o n a l a b n o r m a l i t i e s i n t h e s m a l l a i r w a y s or a l v e o l i o f s u b j e c t s who had d e m o n s t r a t e d normal s p i r o m e t r y and a s t e e p SBNg/l^. They s u g g e s t e d t h a t t h e s e a b n o r m a l i t i e s may p r e cede o v e r t a i r f l o w l i m i t a t i o n i n t h e c o u r s e o f development o f c h r o n i c a i r w a y d i s e a s e . Berend e t a l [1984] a l s o a s s o c i a t e d an i n c r e a s e d SBN2/L% w i t h f u n c t i o n a l derangements such as changes i n e l a s t i c i t y i n non-emphysematous l u n g s . The SBN2/L% has a l s o been i n v e s t i g a t e d i n l o n g i t u d i n a l s t u d i e s as a p r e d i c t o r o f t h e r a t e o f d e c l i n e i n FEV^. O l o f s s o n e t a l [1986] randomly s e l e c t e d two groups by t h e i r b i r t h d a t e , c o n d u c t e d PFT i n i t i a l l y and t h e n a g a i n a f t e r a seven y e a r i n t e r v a l . These i n v e s t i g a t o r s found t h a t t h e s t e e p e r t h e SBN2/L% was on i n i t i a l assessment, t h e f a s t e r was t h e r a t e o f d e c l i n e i n FEV^ d u r i n g t h e f o l l o w - u p . T h i s r e l a t i o n s h i p p e r s i s t e d even when o n l y t h e s u b j e c t s w i t h a normal FEV^ on i n i t i a l assessment were a n a l y z e d . T h e i r f i n d i n g s a g r e e d w i t h t h e e a r l i e r work o f Beaty e t a l [1984] and B u i s t e t a l [1984]. However, i n m i d d l e - a g e d smokers, S t a n e s c u e t a l [1987] r e c e n t l y c o n c l u d e d t h a t t h e S B ^ / I ^ d i d not a c c u r a t e l y p r e d i c t t h e d e c l i n e i n FEV^. A l l o f t h e s e s t u d i e s were l i m i t e d by t h e two d a t a p o i n t s - t h e i n i t i a l and f i n a l measures, and a h i g h v a r i a b i l i t y o f FEV- r a t e o f d e c l i n e between s u b j e c t s . Thus, 11 B u i s t e t a l [1988] s t u d i e d 734 s u b j e c t s [smokers and nonsmokers] s e l e c t e d randomly from county employees and an emphysema s c r e e n i n g c e n t e r o v er a n i n e t o e l e v e n y e a r p e r i o d ; d u r i n g w h i c h t h e SBN 2 t e s t and s p i r o m e t r y were a s s e s s e d t h r e e t o f i v e t i m e s . They found t h a t o n l y t h e CC/TLC measure o f t h e SBN 2 t e s t was s i g n i f i c a n t l y r e l a t e d t o t h e r a t e o f d e c l i n e o f FEV^ when a d j u s t m e n t s were made f o r smoking, age, sex and h e i g h t . However, t h e CC/TLC was not a b l e t o c o n s i s t e n t l y i d e n t i f y t h e smoker who w i l l p r o g r e s s t o an abnormal FEV^, w h i c h t h e i n v e s t i g a t o r s p a r t i a l l y e x p l a i n e d on t h e b a s i s t h a t many smokers do not p r o g r e s s t o d e v e l o p c h r o n i c a i r f l o w l i m i t a t i o n and t h u s may never produce an abnormal FEV^. B u i s t e t a l t h u s c o n c l u d e d t h a t t h e SBN 2 t e s t was l i m i t e d i n i t s a b i l i t y t o p r e d i c t t h e smoker o r nonsmoker who would d e v e l o p c h r o n i c a i r f l o w l i m i t a t i o n . PHYSIOLOGIC IMPLICATIONS OF THE SLOPE OF PHASE I I I The l i t e r a t u r e has t h u s c l e a r l y d e m o n s t r a t e d t h e s i g n i f i c a n t r o l e o f t h e SBN 2/L% i n d e t e c t i n g v e n t i l a t i o n i n h o m o g e n e i t y - o f t e n when t e s t s o f a i r f l o w l i m i t a t i o n were no r m a l . The p h y s i o l o g i c mechanisms u n d e r l y i n g t h e SBN 2/L% and t h u s t h e v e n t i l a t i o n inhomogeneity, have been t h e t o p i c o f c o n s i d e r a b l e i n v e s t i g a t i o n and have l e d t o t h e development o f s e v e r a l t h e o r i e s . 12 B u i s t and Ross [1973] d e s c r i b e d t h e o c c u r r e n c e o f r e g i o n a l [ p a r a l l e l ] i nhomogeneity and s t r a t i f i e d [ s e r i e s ] inhomogeneity as t h e most l i k e l y e x p l a n a t i o n f o r t h e SBN 2/L%. R e g i o n a l i n h o mogeneity was a t t r i b u t e d t o d i f f e r e n c e s i n t i m e c o n s t a n t s between d i f f e r e n t l u n g r e g i o n s as d i s c u s s e d by O t i s e t a l [1956], and t o g r a v i t y - d e t e r m i n e d d i f f e r e n c e s i n volume change o f a l v e o l i i n d i f f e r e n t l u n g zones [ A n t h o n i s e n e t a l , 1970]. S t r a t i f i e d i nhomogeneity was a t t r i b u t e d t o i n c o m p l e t e d i f f u s i o n m i x i n g i n t h e most d i s t a l a l v e o l i [Krogh and L i n d h a r d , 1917; E n g e l e t a l , 1973]. B u i s t and Ross [1973] c o n c l u d e d t h a t a p o s i t i v e S B ^ / I ^ was a r e s u l t o f s e q u e n t i a l emptying o f dependent r e g i o n s w i t h low a N 2 c o n c e n t r a t i o n f o l l o w e d by non-dependent r e g i o n s w i t h a h i g h e r N 2 c o n c e n t r a t i o n . In a d d i t i o n , a r e a s w i t h a h i g h r e g i o n a l volume and t h u s a h i g h N 2 c o n c e n t r a t i o n and i n c o m p l e t e d i f f u s i o n m i x i n g , would c o n t r i b u t e l a t e i n t h e e x p i r a t i o n . They f u r t h e r s u g g e s t e d t h a t any d i s e a s e w h i c h r e s u l t e d i n a i r w a y o b s t r u c t i o n would a c c e n t u a t e e i t h e r r e g i o n a l or s t r a t i f i e d i nhomogeneity, o r b o t h , t h u s i n c r e a s i n g t h e p o s i t i v e s l o p e o f Phase I I I . E n g e l e t a l [1974] i n v e s t i g a t e d t h e i n t r i n s i c m e c h a n i c a l d e t e r m i n a n t s o f v e n t i l a t i o n . They used an o p e n - c h e s t e d dog p r e p a r a t i o n t o e l i m i n a t e t h e i n f l u e n c e o f g r a v i t y on v e n t i l a t i o n , and compared t h e s e r e s u l t s w i t h an i n t a c t p r e p a r a t i o n . W i t h c a t h e t e r s , t h e y measured t h e N 2 c o n c e n t r a t i o n a t v a r i o u s l o c a t i o n s . They o b s e r v e d an upward SBN 2/L% i n b o t h p r e p a r a t i o n s , and r e l a t e d t h i s t o i n t r i n s i c m e c h a n i c a l p r o p e r t i e s i n t h e open-chested model. T h i s was 13 c o n s i s t e n t w i t h p r e v i o u s work where s i g n i f i c a n t d i f f e r e n c e s i n e l a s t i c p r o p e r t i e s between t h e upper and l o w e r l o b e s o f t h e dog were documented [ F a r i d y e t a l , 1967] . The p o s i t i v e S B ^ / I ^ was o b t a i n e d i r r e s p e c t i v e o f t h e s a m p l i n g s i t e , w h i c h i n d i c a t e d a f i x e d e mptying p a t t e r n i n a l l l u n g u n i t s such t h a t w e l l v e n t i l a t e d u n i t s e m p t i e d p r i o r t o p o o r l y v e n t i l a t e d u n i t s . The a u t h o r s found no s i g n i f i c a n t d i f f e r e n c e i n t h e S B ^ / I ^ when measured i n t h e t r a c h e a and b r o n c h i . They t h u s s u g g e s t e d t h a t t h e SBN2/L% i s d e t e r m i n e d w i t h i n l u n g u n i t s s m a l l e r t h a n t h o s e w i t h 3 mm a i r w a y s l e a d i n g t o them. T h i s was c o n f i r m e d by t h e i r f i n d i n g o f r e l a t i v e l y l a r g e v a r i a t i o n s i n v e n t i l a t i o n / u n i t volume w i t h i n s m a l l u n i t s , i e s i g n i f i c a n t v e n t i l a t i o n i n h o m o g e n e i t y . These a u t h o r s were t h u s a b l e t o p a r t i t i o n t h e SBN2/L% measured i n t h e t r a c h e a o f a s u p i n e i n t a c t dog i n t o t h r e e components: 52% due t o t h e l a r g e v a r i a t i o n i n v e n t i l a t i o n / u n i t volume w i t h i n t e r m i n a l u n i t s , 34% due t o t h e e f f e c t s o f g r a v i t y and 14% due t o t h e d i f f e r e n t e l a s t i c p r o p e r t i e s between upper and lower zones. E n g e l e t a l [1974] a l s o c o n s i d e r e d t h e i m p l i c a t i o n s o f t h e r e l a t i v e p r o p o r t i o n s o f t h e SBN 2/L% components t h a t t h e y had d e t e r m i n e d . They s u g g e s t e d t h a t d u r i n g t h e Xe b o l u s t e c h n i c , t h e l a r g e v e r t i c a l Xe g r a d i e n t w h i c h i s e s t a b l i s h e d by g r a v i t y may mask t h e c o n t r i b u t i o n o f t h e o t h e r components, and t h u s may account f o r some o f t h e v a r i a t i o n i n t h e o r i e s o f t h e p h y s i o l o g i c b a s i s f o r t h e s l o p e o f Phase I I I . T h i s concept o f masking had been demonstrated by A n t h o n i s e n e t a l [1970] who s t u d i e d s u b j e c t s a f t e r t h e y i n h a l e d a Xe b o l u s a t t h e onset o f 14 a 100% VC i n s p i r a t i o n from RV. These investigators were able to reverse the Xe slope of Phase III by t i l t i n g the subject head down on i n s p i r a t i o n and upright on expiration. With t h i s technic the Xe was d i s t r i b u t e d to the non-dependent base when inverted and then following return to upright, expired f i r s t from the dependent base. Thus the early expirate would have a high Xe concentration which would decrease over the course of expiration as the apex increased i t s contribution to the expirate. However, when the SBN2 test was performed with t h i s invert-upright technic, the SBN2/L% was not changed. The authors concluded that t h i s indicated the presence of a non-gravity dependent intraregional inhomogeneity which was too great to be masked by the induced interregional N 2 gradient between apex and base. They further concluded that d i f f u s e lung disease would have a major influence on the SBN2/L% by increasing the intraregional inhomogeneity. Marcq and Minette [1980] added to the work of these investigators when they studied the e f f e c t of gravity reversal on Phase III and IV measured with the SBN2 test and bolus technics. These investigators concluded that the slope of Phase III of the bolus t e s t was primarily related to interregional inhomogeneities and that of the SBN2 test primarily related to non-gravity determined intraregional inhomogeneities. Macklem [1979] explained v e n t i l a t i o n inhomogeneity on the basis of the influence of enlarged airspaces, c h a r a c t e r i s t i c of emphysema. He theorized that the d i f f u s i o n pathways would be too long for complete mixing to occur so that intraregional 15 s e q u e n t i a l emptying, t h u s v e n t i l a t i o n i nhomogeneity, would r e s u l t . The p r e s s u r e - v o l u m e b e h a v i o r and t h u s t h e v e n t i l a t i o n / u n i t volume o f some a i r s p a c e s would a l s o be a l t e r e d , c o n t r i b u t i n g f u r t h e r t o s e q u e n t i a l emptying. I n a d d i t i o n , Macklem s u g g e s t e d t h a t a i r w a y d i s e a s e c o u l d c o n t r i b u t e t o v e n t i l a t i o n inhomogeneity on t h e b a s i s o f d i f f e r i n g t i m e c o n s t a n t s between p a r a l l e l u n i t s . S i n c e t h e e x p i r a t o r y f l o w r a t e f o r t h e SBN 2 t e s t i s l e s s t h a n 0.5 L/s t h i s f a c t o r would u n l i k e l y have an i n f l u e n c e . However, as f l o w i s i n c r e a s e d , t h e degree o f s e q u e n t i a l emptying and t h u s v e n t i l a t i o n inhomogeneity would i n c r e a s e due t o t h e i n f l u e n c e o f u n i t s w i t h l o n g t i m e c o n s t a n t s . Macklem t h u s s u g g e s t e d t h a t one can d i f f e r e n t i a t e between volume and f l o w dependent s e q u e n t i a l emptying by o b s e r v i n g t h e e f f e c t o f i n c r e a s i n g e x p i r a t o r y f l o w r a t e on e x p i r e d N 2 c o n c e n t r a t i o n . I f volume dependent s e q u e n t i a l emptying p r e d o m i n a t e s , due t o e i t h e r i n c o m p l e t e d i f f u s i o n m i x i n g or changes i n v e n t i l a t i o n / u n i t volume, i t would not be i n f l u e n c e d by e x p i r a t o r y f l o w . T h e r e f o r e , f l o w dependence o f t h e N 2 c o n c e n t r a t i o n would suggest t h a t t h e s e q u e n t i a l emptying which was p r e s e n t , p r i m a r i l y depended on d i f f e r e n c e s i n t i m e c o n s t a n t s . P a i v a and E n g e l [1981] examined t h e i n f l u e n c e o f anatomic asymmetry on t h e i n t e r a c t i o n o f c o n v e c t i o n and gas-phase d i f f u s i o n w i t h i n t h e l u n g a c i n u s and used t h e i r f i n d i n g s t o e x p l a i n t h e SBN 2/L%. They s t u d i e d a model c o n s i s t i n g o f two trumpet shaped u n i t s j o i n e d a t a b r a n c h p o i n t and whose r e l a t i v e l e n g t h s and volumes c o u l d be v a r i e d . When t h e two 16 u n i t s were s y m m e t r i c a l , t h e u n i t gas c o n c e n t r a t i o n s were c o n s t a n t a t end i n s p i r a t i o n and e x p i r a t i o n so t h a t t h e SBN 2/L% was h o r i z o n t a l . However, when t h e two u n i t s were a s y m m e t r i c a l , t h e oxygen c o n c e n t r a t i o n a t end i n s p i r a t i o n was g r e a t e r i n t h e s h o r t e r u n i t due t o more r a p i d d i f f u s i o n d e s p i t e t h e e q u i v a l e n t c o n d u c t i v e f l o w p e r u n i t volume t o t h e two u n i t s . The gas between t h e two u n i t s d i d not e q u i l i b r a t e due t o t h e i n t e r d e p e n d e n c e o f gas t r a n s p o r t a l o n g p a r a l l e l p a t h s . On e x p i r a t i o n t h e oxygen c o n c e n t r a t i o n f e l l i n t h e s h o r t u n i t and caused a p r o g r e s s i v e d e c r e a s e i n e x p i r e d oxygen as e x p i r a t i o n p r o c e e d e d . Some o f t h e e x p i r e d N 2 from t h e l a r g e r u n i t d i f f u s e d back i n t o t h e s h o r t e r u n i t from t h e b r a n c h - p o i n t which r e s u l t e d i n a lower e x p i r e d N 2 . Then i n l a t e e x p i r a t i o n as t h e N 2 c o n c e n t r a t i o n i n t h e s h o r t e r u n i t i n c r e a s e d , t h e r e was l e s s r e t r o g r a d e d i f f u s i o n and t h u s an i n c r e a s e i n e x p i r e d N 2 ~ c r e a t i n g t h e r i s i n g SBN 2/L%. These a u t h o r s t h u s c o n c l u d e d t h a t n e i t h e r s t r a t i f i c a t i o n o r s e q u e n t i a l emptying o f p a r a l l e l u n i t s i s n e c e s s a r y t o produce a r i s i n g SBN 2/L%; and f u r t h e r t h a t i n t r a - a c i n a r a i r w a y asymmetry c o u l d account f o r p a r t o f t h e SBN 2/L%. I n a d d i t i o n , t h e y r e p o r t e d t h a t a s y m m e t r i c a l pathways w h i c h had a p r o x i m a l l y l o c a t e d b r a n c h - p o i n t , c o n t r i b u t e d s i g n i f i c a n t l y t o t h e SBN 2/L% and t h u s t h e more p e r i p h e r a l t h e asymmetry [ i e d i s t a l t o 2 0 t h g e n e r a t i o n ] t h e l e s s o f an e f f e c t i t would have on t h e SBN 2/L%. Co r m i e r and B e l a n g e r [1981a] i n v e s t i g a t e d t h e i n f l u e n c e o f gas exchange on t h e s l o p e o f Phase I I I . They de m o n s t r a t e d t h a t t h e s l o p e o f Phase I I I was g r e a t e r d u r i n g t h e SBN 9 t e s t t h a n 1 7 t h e r e v e r s e d SBN 2 t e s t w h i c h used 100% oxygen as t h e r e s i d e n t gas. They e x p l a i n e d t h e i r f i n d i n g s on t h e b a s i s o f gas exchange o c c u r r i n g d u r i n g t h e slow VC e x p i r a t i o n r e q u i r e d f o r t h e SBN 2 t e s t . The N 2 c o n c e n t r a t i o n i n c r e a s e d w i t h e x p i r a t o r y t i m e so t h a t t h e SBN 2/L% would be s t e e p e r i n t h e SBN 2 t e s t and f l a t t e r i n t h e r e v e r s e d SBN 2 t e s t w hich has a n e g a t i v e s l o p e . These i n v e s t i g a t o r s a l s o d emonstrated t h a t compared w i t h r e s t , e x e r c i s e r e s u l t e d i n a s t e e p e r SBN 2/L% d u r i n g t h e SBN 2 t e s t and a g r e a t e r f l a t t e n i n g o f t h e SBN 2/L% d u r i n g t h e r e v e r s e SBN 2 t e s t [Cormier and B e l a n g e r , 1981b]. They e x p l a i n e d t h e s e f i n d i n g s on t h e b a s i s o f t h e i n c r e a s e d oxygen uptake d u r i n g e x e r c i s e w h i c h would i n c r e a s e t h e N 2 c o n c e n t r a t i o n . I n a d d i t i o n , C o r m i e r and B e l a n g e r [1983] were a b l e t o q u a n t i f y t h e c o n t r i b u t i o n o f gas exchange t o t h e SBN 2/L% and found t h i s t o be 10.2% i n normal s u b j e c t s a t r e s t . P e t t y e t a l [1980] a t t e m p t e d t o d i f f e r e n t i a t e between t h e l o s s o f e l a s t i c r e c o i l and s m a l l a i r w a y p a t h o l o g y as d e t e r m i n a n t s o f an abnormal SBN 2/L% and c l o s i n g c a p a c i t y [CC]. They c o n d u c t e d SBN 2 t e s t s on whole l u n g specimens w i t h l e s s t h a n 10% o f t h e parenchyma i n v o l v e d i n a c u t e o r c h r o n i c d i s e a s e , and t h e n s t u d i e d t h e morphology o f t h e s e specimens. They c o u l d not f i n d a d i f f e r e n c e i n e l a s t i c r e c o i l between a group o f l u n g s w i t h a normal CC and a n o t h e r group w i t h an abnormal CC. However t h e y found t h a t o c c l u s i o n o f t h e a i r w a y s by c e l l s and mucus, mural i n f l a m m a t i o n and i n c r e a s e d a i r w a y smooth muscle t h i c k n e s s a l l c o r r e l a t e d w i t h an i n c r e a s e d SBN„/L%. They c o n c l u d e d t h a t t h e abnormal CC and SBN 9/L% were 18 a s s o c i a t e d w i t h p a t h o l o g i c changes i n s m a l l a i r w a y s and not w i t h changes i n e l a s t i c r e c o i l . B erend e t a l [1984] f u r t h e r i n v e s t i g a t e d t h e r e l a t i v e i m p o r t a n c e o f t h e inhomogeneity of e l a s t i c p r o p e r t i e s o f l u n g u n i t s and t h e p r e s e n c e o f s m a l l a i r w a y l e s i o n s i n d e t e r m i n i n g t h e magnitude o f SBN 2/L%. They p e r f o r m e d SBN 2 t e s t s and d e t e r m i n e d p r e s s u r e - v o l u m e c u r v e s on 11 emphysematous f r e e and 17 emphysematous e x c i s e d human l u n g s and on two groups o f 23 smokers and 24 nonsmokers. T h e i r r e s u l t s showed t h a t i n emphysematous f r e e l u n g s , t h e SBN 2/L% was b e t t e r c o r r e l a t e d w i t h e l a s t i c p r o p e r t i e s o f t h e l u n g s as compared t o b r o n c h i o l a r i n f l a m m a t i o n . They s u g g e s t e d t h a t i n c r e a s i n g i n h o mogeneity o f l u n g e l a s t i c p r o p e r t i e s r e s u l t e d i n t h e i n c r e a s e d s l o p e o f Phase I I I . I n t h e emphysematous l u n g s however, t h e y were u n a b l e t o demonstrate any s i g n i f i c a n t c o r r e l a t i o n s , w h i c h t h e y a t t r i b u t e d t o t h e i n t e r p l a y between a i r w a y o b s t r u c t i o n and i n f l a m m a t i o n , a i r w a y and parenchymal d e s t r u c t i o n and i n h o m o g e n e i t y o f e l a s t i c p r o p e r t i e s . The group o f smokers d e m o n s t r a t e d a s i g n i f i c a n t r e l a t i o n s h i p between SBN 2/L% and l u n g e l a s t i c p r o p e r t i e s , w h i c h was not p r e s e n t i n t h e nonsmokers. However, t h e a u t h o r s r e p o r t e d t h a t t h e degree o f p e r i p h e r a l a i r w a y i n f l a m m a t i o n was unknown i n t h e s e s u b j e c t s and may have i n f l u e n c e d t h e i r r e s u l t s . The c h a r a c t e r i s t i c s o f v e n t i l a t i o n i n h o mogeneity were f u r t h e r s t u d i e d i n t h e i n v e s t i g a t i o n o f c a r d i a c o s c i l l a t i o n s and t h e e f f e c t o f b r e a t h - h o l d i n g . C a r d i a c o s c i l l a t i o n s a r e 19 seen as o s c i l l a t i o n s i n t h e N 2 c o n c e n t r a t i o n d u r i n g Phase I I I o f t h e SBN 2 t e s t . They a r e c o n s i d e r e d t o be t h e r e s u l t o f p r e s s u r e waves c r e a t e d by t h e h e a r t which a c t downstream o f b i f u r c a t i o n s t o d i s p l a c e t h e gas from p o o r l y v e n t i l a t e d a r e a s i n t o t h e common stream o f e x p i r e d a i r [Langer e t a l , 1960]. E n g e l e t a l [1974] c o n c l u d e d t h a t t h i s c a r d i a c a c t i o n p r o v i d e d a dynamic component t o gas m i x i n g on i n s p i r a t i o n , e x p i r a t i o n and d u r i n g b r e a t h h o l d i n g . Verhamme e t a l [1982] demonstrated a d e c r e a s e i n a m p l i t u d e o f t h e s e o s c i l l a t i o n s i n r e l a t i o n t o i n c r e a s i n g s e v e r i t y o f a i r w a y o b s t r u c t i o n . They e x p l a i n e d t h i s f i n d i n g on t h e b a s i s o f l o n g t i m e c o n s t a n t s i n t h e a r e a s o f s e v e r e a i r w a y o b s t r u c t i o n , which would dampen t h e e f f e c t o f t h e c a r d i a c a c t i o n . B r e a t h - h o l d i n g had a s i m i l a r e f f e c t i n damping t h e s e o s c i l l a t i o n s i n p e r i p h e r a l a i r w a y s [Engel e t a l , 1974]. The b r e a t h - h o l d e n a b l e d e q u a l i z a t i o n o f i n t r a r e g i o n a l N 2 g r a d i e n t s by m o l e c u l a r d i f f u s i o n and c a r d i o g e n i c m i x i n g , so t h a t t h e c a r d i a c o s c i l l a t i o n s were d e c r e a s e d i n a m p l i t u d e . These i n v e s t i g a t o r s a l s o r e p o r t e d a f l a t t e n i n g o f t h e SBN 2/L% f o l l o w i n g b r e a t h - h o l d i n g . They c o u l d not demonstrate any d i f f e r e n c e i n t h e i n t e r r e g i o n a l N 2 c o n c e n t r a t i o n a f t e r b r e a t h h o l d i n g , w h i c h t h e y a t t r i b u t e d t o t h e l o n g b r o n c h i a l p a t h f o r d i f f u s i o n between l o b e s . They t h u s c o n c l u d e d t h a t t h e i n t r a r e g i o n a l gas m i x i n g p roceeds more r a p i d l y and i s r e s p o n s i b l e f o r t h e f l a t t e n i n g o f t h e SBN 2/L% f o l l o w i n g b r e a t h -h o l d i n g . The d i s c u s s i o n o f r e g i o n a l and s t r a t i f i e d v e n t i l a t i o n i n h o m o g e n e i t y can b e s t be c o n c l u d e d by c o n s i d e r i n g t h e 20 s u g g e s t i o n o f E n g e l and Macklem [1977] t h a t t h e s e two c a t e g o r i e s may not be d i s t i n c t e n t i t i e s . F o r example, c o l l a t e r a l v e n t i l a t i o n o f an o b s t r u c t e d u n i t i n p a r a l l e l w i t h a n o t h e r u n i t would r e s u l t i n s e r i a l i n h o m o g e n e i ty. Thus, many f a c t o r s must be c o n s i d e r e d b e f o r e t h e v e n t i l a t i o n d i s t r i b u t i o n and t h e r e s u l t a n t S B ^ / L ^ can be i n t e r p r e t e d . MEASUREMENT OF EXPIRATORY FLOW RATE T h i s s t u d y compared measurement o f t h e SBNg/I^ t o two r o u t i n e t e s t s o f a i r f l o w l i m i t a t i o n - t h e f o r c e d e x p i r a t o r y volume i n one second [FEV^] and t h e f o r c e d e x p i r a t o r y f l o w d u r i n g 25-75% o f t h e VC [ F E F o c _ c . ] . The FEV^ i s t h e maximum volume t h a t can be e x p i r e d from a f u l l i n s p i r a t i o n i n one second. At h i g h l u n g volumes [ i e a t t h e o nset o f t h e t e s t ] t h e FE'V^ i s f l o w and t h u s e f f o r t dependent. T h i s d i s a d v a n t a g e was f e l t t o be outweighed by t h e h i g h r e p r o d u c i b i l i t y t h a t t h e FEV^ t e s t e x h i b i t s , w h i c h e n a b l e s i n t e r p r e t a t i o n o f r e l a t i v e l y s m a l l changes i n a i r w a y r e s i s t a n c e [ A n t h o n i s e n , 1986]. The c o e f f i c i e n t o f v a r i a t i o n has been d e t e r m i n e d as 3% i n normals and 8.1% i n t h o s e w i t h o b s t r u c t i v e d i s e a s e [Pennock e t a l , 1981]. The FEV 1 i s o f t e n r e p o r t e d as a r a t i o t o t h e f o r c e d v i t a l c a p a c i t y [FVC] t o i n d i c a t e t h e p o r t i o n o f t h e FVC t h a t i s e x p i r e d i n one second. The e x p r e s s i o n o f t h i s r a t i o p e r m i t s some d i f f e r e n t i a t i o n between o b s t r u c t i v e and r e s t r i c t i v e d i s e a s e p a t t e r n s where b o t h FVC and 21 FEV^ are decreased. Normal values for the FEV^ are weighted by sex, age and height and are considered to be within 1.65 x SEE of the predicted value [Crapo et a l , 1981]. Leuallen and Fowler [1955] introduced the FEF 2^_ 7^^ as a test for airway obstruction that was more sensi t i v e than the FEV^. This flow rate i s calculated as the slope of the l i n e drawn between the points at which 25% and 75% of the v i t a l capacity has been delivered. The representative volume i s thus the middle h a l f of the FVC and the time to d e l i v e r t h i s volume i s the l a t e r , effort-independent part of the FVC maneuver. Normal values are determined si m i l a r to the FEV^ as described by Crapo et a l [1981] . In obstructive disease, the F F j F25-75% f a l l s to a lower percent of predicted normal than the FEV^ [Anthonisen, 1986]. However, t h i s increased s e n s i t i v i t y i s o f f s e t by the fact that the FEF^^_^^^ has a greater c o e f f i c i e n t of v a r i a t i o n , being 8% i n normals and 14% i n those with obstructive disease [Pennock et a l , 1981]. Neither of these pulmonary function tests are sensitive to early peripheral airways disease. Macklem and Mead [1967] i n t h e i r c l a s s i c study, used an intraluminal catheter to measure airway pressure i n open-chested l i v i n g dogs and i n excised lungs. They were able to separate airflow resistance into peripheral resistance [ie that from the catheter to the a l v e o l i ] and central resistance [ie that from the catheter to the trachea]. Their results showed that between 80-100% VC almost a l l of the airflow resistance was central i n o r i g i n and 22 between 10-80% VC p e r i p h e r a l r e s i s t a n c e i n c r e a s e d t o a maximum o f o n l y 15%. These i n v e s t i g a t o r s commented t h a t s i n c e t h e p e r i p h e r a l a i r w a y s c o n t r i b u t e d such a minor component o f t h e t o t a l r e s i s t a n c e , [because o f t h e i r v e r y l a r g e c r o s s - s e c t i o n a l a r e a ] , t h e r e c o u l d be c o n s i d e r a b l e d i s e a s e p r e s e n t r e s u l t i n g i n a c o n s i d e r a b l e i n c r e a s e i n p e r i p h e r a l r e s i s t a n c e , but l e a d i n g t o a v e r y s m a l l e f f e c t on t o t a l a i r w a y r e s i s t a n c e . I t i s t h e t o t a l a i r w a y r e s i s t a n c e t h a t p r i m a r i l y d e t e r m i n e s t h e FEV^ and F E F 2 5 - 7 5 % and t h e r e f o r e t h e y have l i m i t e d s e n s i t i v i t y t o e a r l y p e r i p h e r a l a i r w a y s d i s e a s e . However, c h a r a c t e r i s t i c s o t h e r t h a n r e s i s t a n c e may be more r e a d i l y d e t e c t a b l e i n t h e s e p e r i p h e r a l a i r w a y s . A l v e o l i d i s t a l t o o b s t r u c t e d s m a l l a i r w a y s would have i n c r e a s e d t i m e c o n s t a n t s , and t h u s d i s p l a y v e n t i l a t i o n i n h o m o g e n e i t y . Thus t h e SBN2/L% would be e x p e c t e d t o d e t e c t s m a l l a i r w a y s d i s e a s e t h r o u g h i t s assessment o f v e n t i l a t i o n homogeneity, b e f o r e t h e FEV^ and F E F 2 5 - 7 5 % s n o w abnormal v a l u e s . As n o t e d e a r l i e r , t h i s has been shown t o o c c u r . But what has not so f a r been s t u d i e d i s t h e v a r i a t i o n i n b o t h v e n t i l a t o r y i n d i c e s and t h e SBN2/L% i n t h e same i n d i v i d u a l s as t h e i r c o n d i t i o n v a r i e s e i t h e r s p o n t a n e o u s l y o r as a consequence o f t r e a t m e n t . Thus t h e p r e s e n t s t u d y was d e s i g n e d t o compare and c o n t r a s t changes i n t h e FEV^ and FEF2^_ 7^^/ t o v a r i a t i o n s i n t h e SBN2/L% i n p a t i e n t s w i t h o b s t r u c t i v e a i r w a y s d i s e a s e -s p e c i f i c a l l y asthma or c y s t i c f i b r o s i s [both d i s e a s e s i n w h i c h v a r i a t i o n s commonly o c c u r ] . The i n f o r m a t i o n o b t a i n e d may g i v e 23 i n s i g h t i n t o t h e o c c u r r e n c e and magnitude o f a i r f l o w l i m i t a t i o n and v e n t i l a t i o n inhomogeneity i n s m a l l a i r w a y s d i s e a s e , and p e r m i t t h e i n t e r r e l a t i o n s h i p between t h e s e two t y p e s o f measurement t o be examined. RATIONALE FOR THE SELECTED TESTS IN ASTHMATIC SUBJECTS Asthma i s d i f f i c u l t t o d e f i n e and can b e s t be d e s c r i b e d as ' n o n - s p e c i f i c a i r w a y r e a c t i v i t y ' [ B a t e s , 1989]. I n d i v i d u a l s may p r e s e n t w i t h v a r i a b l e degrees o f b r o n c h i a l o b s t r u c t i o n and wheezing d a t i n g from c h i l d h o o d o r e a r l y a d u l t h o o d , a i r w a y h y p e r r e a c t i v i t y , and h y p e r i n f l a t i o n w i t h o u t d e s t r u c t i v e changes. A i r w a y h y p e r r e a c t i v i t y i s t h e predominant f e a t u r e o f asthma, and i s o f t e n not c l e a r l y r e l a t e d t o an a l l e r g i c mechanism [B a t e s , 1989]. H y p e r r e a c t i v i t y may a l s o p r e s e n t as a consequence o f an i n f l a m m a t o r y r e a c t i o n i n t h e a i r w a y s [Holtzman e t a l , 1983] i n d u c e d by a s p e c i f i c a n t i g e n [ I s h i z a k a and I s h i z a k a , 1970], upper r e s p i r a t o r y t r a c t i n f e c t i o n s [Empey e t a l , 1976] o r n o n - s p e c i f i c i r r i t a n t s such as ozone [Golden e t a l , 1978]. I n m i l d asthma [ c h a r a c t e r i z e d by r e v e r s i b l e a i r f l o w l i m i t a t i o n ] smooth muscle c o n t r a c t i o n p r e d o m i n a t e s , whereas a i r w a y i n f l a m m a t i o n and mucous p l u g g i n g a r e a l s o p r e v a l e n t i n more s e v e r e s t a t e s [ B a t e s , 1989]. T h i s l e a d s t o t h i c k e n i n g o f t h e basement membrane and h y p e r p l a s i a o f t h e b r o n c h i a l smooth muscle c e l l s . D e s t r u c t i v e changes i n t h e a l v e o l i and t h e s u r r o u n d i n g c a p i l l a r y beds seen i n emphysema a r e not p r e s e n t i n asthma. 24 Asthma o f t e n p r e s e n t s as a co u r s e o f e x a c e r b a t i o n s and r e m i s s i o n s and as d e f i n e d by Bat e s [ 1 9 8 9 ] , a s t h m a t i c s may p r e s e n t i n f i v e s t a g e s from complete r e m i s s i o n t o s t a t u s a s t h m a t i c u s . T h i s a u t h o r summarized t h e pulmonary f u n c t i o n changes common t o each o f t h e s e s t a g e s and t h e y a r e p r e s e n t e d as f o l l o w s . D u r i n g complete r e m i s s i o n t h e i n d i v i d u a l has c o m p l e t e l y normal pulmonary f u n c t i o n . The o c c u r r e n c e o f t h i s phase i s l i k e l y l e s s o f t e n t h a n i s assumed on t h e b a s i s o f r e s o l u t i o n o f t h e p a t i e n t ' s symptoms a l o n e . S e v e r a l s t u d i e s have d e m o n s t r a t e d i m p a i r e d PFTs d u r i n g t h e asymptomatic phase whi c h B a t e s [ 1 9 8 9 ] r e f e r s t o as th e s t a t e o f p a r t i a l r e m i s s i o n [ B a t e s , 1 9 5 2 ; B e a l e e t a l , 1 9 5 2 ; Cade and P a i n , 1 9 7 3 ; McCarthy and S i g u r d s o n , 1 9 8 0 ] . T h i s s t a g e o f p a r t i a l r e m i s s i o n may be c h a r a c t e r i z e d by i n t r a and i n t e r r e g i o n a l v e n t i l a t i o n i n h o m o g e n e i t y , f r e q u e n c y dependence o f co m p l i a n c e , v e n t i l a t i o n -p e r f u s i o n [V/Q] mismatch, an i n c r e a s e i n f u n c t i o n a l r e s i d u a l c a p a c i t y , r e s i d u a l volume and t o t a l l u n g c a p a c i t y , and a de c r e a s e i n VC and i n s p i r a t o r y c a p a c i t y . The PFT a b n o r m a l i t i e s i n t h e s t a g e s o f moderate and s e v e r e bronchospasm r e f l e c t t h e prominence o f a i r w a y o b s t r u c t i o n . T h e r e f o r e , i n a d d i t i o n t o w o r s e n i n g o f t h e PFTs from t h e p r e v i o u s s t a g e t h e r e i s a de c r e a s e i n FEV^, F E F 2 5 _ 7 5 o . / peak f l o w r a t e and maximal b r e a t h i n g c a p a c i t y . The u n d e r l y i n g p a t h o l o g y and a l t e r e d mechanics t h a t a r e r e s p o n s i b l e f o r t h e PFT changes i n asthma have been i n v e s t i g a t e d a t t h e d i f f e r e n t s t a g e s o f d i s e a s e . Loke e t a l 2 5 [1981] i n v e s t i g a t e d t h e s i t e o f a i r w a y o b s t r u c t i o n i n asymptomatic a s t h m a t i c c h i l d r e n . They found t h a t t h e s i t e o f a i r w a y o b s t r u c t i o n c o u l d be c e n t r a l , p e r i p h e r a l o r b o t h . T h u r l b e c k [1984] s u g g e s t e d t h a t a l t e r e d f u n c t i o n i n c h r o n i c a i r f l o w o b s t r u c t i o n s h o u l d be c o n s i d e r e d as i n v o l v i n g a b n o r m a l i t i e s i n t h e v a r i o u s components o f t h e l u n g , t h e c e n t r a l and p e r i p h e r a l a i r w a y s and t h e parenchyma. He c o n c l u d e d t h a t t h e c o - e x i s t e n c e o f v a r i o u s causes o f f l o w - l i m i t a t i o n would r e n d e r t h e use o f one t e s t t o d e t e c t a i r f l o w l i m i t a t i o n i n a p p r o p r i a t e . The r e v e r s i b i l i t y o f PFT changes w i t h d i s e a s e r e m i s s i o n or t r e a t m e n t has been a f o c u s o f s t u d y i n attempt t o e l u c i d a t e t h e u n d e r l y i n g p a t h o l o g i c mechanisms i n asthma. Engstrom [1964] s t u d i e d a s t h m a t i c c h i l d r e n from an a c u t e a t t a c k t o symptom f r e e s t a t u s . He found t h a t a l t h o u g h a i r w a y o b s t r u c t i o n [ d e t e r m i n e d by c a l c u l a t i o n o f pulmonary f l o w r e s i s t a n c e ] would r e v e r s e r a p i d l y i n 1-2 days, v e n t i l a t o r y impairment [measured by s t a t i c l u n g volumes and f o r c e d e x p i r a t o r y volumes] d i d not r e v e r s e as r a p i d l y o r c o m p l e t e l y . B oth VC and FEV^ c o n t i n u e d t o i n c r e a s e a f t e r complete n o r m a l i z a t i o n o f a i r w a y r e s i s t a n c e . F u r t h e r , he f o u n d t h a t h y p e r i n f l a t i o n would remain even a f t e r r e s o l u t i o n o f o b s t r u c t i o n . On t h e b a s i s o f t h e s e o b s e r v a t i o n s he s u g g e s t e d t h a t some minor p e r i p h e r a l o b s t r u c t i o n s remained and t h a t t h e normal b a l a n c e o f o p p o s i n g f o r c e s between t h e t h o r a x and l u n g s was d i s t u r b e d - p o s s i b l y due t o parenchymal changes. G o l d e t a l [1967] i n v e s t i g a t e d e l a s t i c r e c o i l i n asthma more t h o r o u g h l y t o d e t e r m i n e whether p e r s i s t e n t h y p e r i n f l a t i o n was due t o changes 26 i n l u n g e l a s t i c r e c o i l . They demonstrated t h a t p r o l o n g e d a i r w a y o b s t r u c t i o n i s a s s o c i a t e d w i t h a d e c r e a s e i n e l a s t i c r e c o i l and l e a d s t o h y p e r i n f l a t i o n . T h i s would account f o r t h e p e r s i s t e n t h y p e r i n f l a t i o n d e s p i t e r e s o l u t i o n o f a i r w a y o b s t r u c t i o n . These i n v e s t i g a t o r s c o u l d not d e f i n e t h e cause o f t h e d e c r e a s e i n r e c o i l but i n d i c a t e d t h a t i t d e v e l o p s s l o w l y and p e r s i s t e d f o r 1-2 wk a f t e r r e l i e f o f o b s t r u c t i o n . However, p r o l o n g e d r e l i e f o f o b s t r u c t i o n r e s u l t e d i n a normal e l a s t i c r e c o i l w h i c h e l i m i n a t e s emphysematous d e s t r u c t i v e changes as a c a u s a t i v e f a c t o r . These i n v e s t i g a t o r s s u p p o r t e d t h e c o n c l u s i o n s o f F r y and H y a t t [1960] t h a t d e c r e a s e d f l o w r a t e s i n c h r o n i c asthma a r e p r o b a b l y r e l a t e d t o abnormal e l a s t i c r e c o i l , b r o n c h o c o n s t r i c t i o n and a i r w a y i n f l a m m a t i o n . F u r t h e r i n v e s t i g a t i o n i n t o t h e s t a t i c e l a s t i c p r o p e r t i e s o f a s t h m a t i c l u n g s was c o n d u c t e d by Woolcock and Read [1968] who o b s e r v e d a d e c r e a s e i n e l a s t i c r e c o i l t h a t p e r s i s t e d i n t o r e m i s s i o n i n some p a t i e n t s . They c o n c l u d e d t h a t t h e mechanism r e s p o n s i b l e was complex and not c l e a r l y r e l a t e d t o a i r w a y o b s t r u c t i o n . However, M a r t i n e t a l [1980] s t a t e d t h a t changes i n l u n g e l a s t i c r e c o i l c o u l d not c o m p l e t e l y account f o r h y p e r i n f l a t i o n , s i n c e i t i s p o s s i b l e t o r e a c h an e n d - e x p i r a t o r y l u n g volume t h a t i s above t h e r e s t i n g volume o f t h e c h e s t w a l l . These i n v e s t i g a t o r s examined t h e mechanism o f h y p e r i n f l a t i o n i n a s t h m a t i c s by o b s e r v i n g l u n g and c h e s t w a l l mechanics f o l l o w i n g i n d u c t i o n o f p r o g r e s s i v e b r o n c h o c o n s t r i c t i o n . They o b s e r v e d p e r s i s t e n t a c t i v i t y o f t h e i n s p i r a t o r y muscles [ i n t e r c o s t a l s and a c c e s s o r i e s ] t h r o u g h o u t e x p i r a t i o n , and r e c r u i t m e n t o f t h e a b d o m i n a l s . The i n s p i r a t o r y muscle a c t i v i t y i n c r e a s e d w i t h 27 p r o g r e s s i v e b r o n c h o c o n s t r i c t i o n and a c t e d t o l i m i t t h e development o f p o s i t i v e p l e u r a l p r e s s u r e s - t h u s e x p i r a t o r y f l o w l i m i t a t i o n , and t o promote h y p e r i n f l a t i o n . These i n v e s t i g a t o r s s u g g e s t e d t h a t t h e abdominal muscle a c t i v i t y was c o o r d i n a t e d w i t h t h e i n s p i r a t o r y muscles t o o p t i m i z e d i a p h r a g m a t i c f u n c t i o n , by i n c r e a s i n g t h e abdominal p r e s s u r e and t h u s r e s t o r i n g t h e d i a p h r a g m a t i c l e n g t h . They t h u s c o n c l u d e d t h a t s u s t a i n e d i n s p i r a t o r y muscle a c t i v i t y d u r i n g e x p i r a t i o n i s a major d e t e r m i n a n t o f h y p e r i n f l a t i o n . The p e r s i s t e n c e o f abnormal pulmonary f u n c t i o n d u r i n g t h e asymptomatic s t a g e i n d i c a t e s a need f o r c l o s e m o n i t o r i n g o f t h e s e p a t i e n t s a t a l l phases o f t h e i r d i s e a s e p r o c e s s . B e a l e e t a l [1952] i n d i c a t e d t h a t t h e o c c u r r e n c e o f marked PFT changes i n t h e symptom-free a s t h m a t i c was s i g n i f i c a n t i n t h a t t h e u n d e r l y i n g p a t h o l o g y r e s p o n s i b l e f o r t h e s e changes c o u l d l e a d t o hypoxemia and more i r r e v e r s i b l e a i r w a y o b s t r u c t i o n i f not r e c o g n i z e d and managed e f f e c t i v e l y . Z a p l e t a l e t a l [1971] i n d i c a t e d t h a t a i r w a y o b s t r u c t i o n was one o f t h e main f e a t u r e s o f asthma and c y s t i c f i b r o s i s , and t h a t i t s a c c u r a t e assessment i s i m p o r t a n t f o r c l i n i c a l d i a g n o s i s and management. However, Woolcock and Read [1965] o b s e r v e d v a r i a b i l i t y i n t h e e x t e n t o f FEV^ changes d u r i n g r e c o v e r y from an a c u t e e p i s o d e o f asthma due t o t h e i n f l u e n c e o f c o i n c i d e n t changes i n l u n g volumes on a i r w a y c a l i b e r , w h i c h may l i m i t t h e u s e f u l n e s s o f t h i s t e s t i n m o n i t o r i n g a i r w a y o b s t r u c t i o n . 28 RATIONALE FOR THE SELECTED TESTS IN CYSTIC FIBROSIS SUBJECTS C y s t i c f i b r o s i s , l i k e asthma, i s a d i s e a s e i n w h i c h a i r f l o w o b s t r u c t i o n i s a major cause o f symptoms. I t i s a h e r e d i t a r y c o n d i t i o n w h i c h a f f e c t s t h e f u n c t i o n o f e x o c r i n e g l a n d s and i n v o l v e s t h e membrane t r a n s p o r t o f sodium, c h l o r i d e and o t h e r i o n s . I t i s u s u a l l y d i a g n o s e d i n i n f a n c y o r e a r l y c h i l d h o o d . D i a g n o s i s i s based on a h i g h s a l t c o n t e n t i n sweat, t h e p r e s e n c e o f v i s c i d b r o n c h i a l mucus and r a d i o l o g i c a l changes, and d e f i c i e n c y i n p a n c r e a t i c enzymes. The mucus p l u g s i n t h e l u n g a r e t e n a c i o u s and e f f e c t i v e l y o b s t r u c t t h e a i r w a y s l e a d i n g t o a i r f l o w o b s t r u c t i o n , inhomogeneous v e n t i l a t i o n [and t h u s V/Q mismatch and hypoxemia], and i n c r e a s e d work o f b r e a t h i n g t o overcome t h e i n c r e a s e d a i r w a y r e s i s t a n c e . The sequence o f a i r w a y o b s t r u c t i o n l e a d i n g t o a i r t r a p p i n g and l o s s o f e l a s t i c r e c o i l has been demonstrated by F e a t h e r b y e t a l [1970] w i t h f u r t h e r c o n f i r m a t i o n o f t h e l o s s o f l u n g r e c o i l by M a n s e l l e t a l [1974]. T h i s l o s s o f l u n g r e c o i l may o c c u r w i t h o u t t h e development o f m o r p h o l o g i c emphysema [B a t e s , 1989] . Pulmonary i n f e c t i o n i s a c l a s s i c f e a t u r e o f CF s i n c e t h e v i s c i d mucus p l u g s become p u r u l e n t and o f t e n d e v e l o p s t a p h y l o c o c c a l and pseudomonal i n f e c t i o n s [ S c a n l i n , 1988]. T h i s o f t e n l e a d s t o t h e development o f b r o n c h i e c t a s i s and pneumonia. C y s t i c f i b r o s i s i s a t e r m i n a l d i s e a s e as t h e s e p a t i e n t s succumb t o c o r pulmonale secondary t o t h e c h r o n i c hypoxemia and pulmonary h y p e r t e n s i o n [ B e i e r e t a l , 1966]. 29 M e l l i n s e t a l [1968] compared t h e c h a r a c t e r i s t i c s o f a i r w a y o b s t r u c t i o n i n CF and asthma. They o b s e r v e d t h a t CF p a t i e n t s d e m o n s t r a t e d e f f o r t dependent f l o w a t h i g h l u n g volumes whereas a s t h m a t i c s a r e l i m i t e d by t h e m e c h a n i c a l p r o p e r t i e s o f t h e i r l u n g s t h r o u g h o u t e x p i r a t i o n . They s u g g e s t e d t h a t a t h i g h l u n g volumes some a i r w a y s f u n c t i o n n o r m a l l y i n CF and t h a t t h e s m a l l e r volume o f n o r m a l l y f u n c t i o n i n g l u n g would account f o r t h e peak f l o w s b e i n g l e s s t h a n n o r m a l . However, M a n s e l l e t a l [1974] s u g g e s t e d volume d i s p l a c e m e n t from b r o n c h i e c t a t i c a i r w a y s as a more l i k e l y e x p l a n a t i o n f o r t h e e f f o r t dependent f l o w i n CF. M a n s e l l e t a l [1974] d e m o n s t r a t e d d e c r e a s e d e l a s t i c r e c o i l i n CF and a t h i g h l u n g volumes t h e y o b s e r v e d t h e paradox o f a d e c r e a s e d e l a s t i c r e c o i l a s s o c i a t e d w i t h a d e c r e a s e i n c o m p l i a n c e . A t low t o moderate l u n g volumes, c o m p l i a n c e was r e l a t i v e l y normal and t h u s t h i s phenomenon c o u l d not be a t t r i b u t e d t o p r o g r e s s i v e gas t r a p p i n g d u r i n g e x p i r a t i o n . They c o n c l u d e d t h a t t h e d e c r e a s e d c o m p l i a n c e o b s e r v e d a t h i g h l u n g volumes was c o m p a t i b l e w i t h a d e f i c i e n c y i n l u n g u n i t s w h i c h had p r e v i o u s l y been r e p o r t e d by E s t e r l y and Oppenheimer [1968] . T h e r e f o r e , a l t h o u g h a i r w a y o b s t r u c t i o n i s a prominent f e a t u r e o f CF and asthma, t h e c h a r a c t e r i s t i c s o f t h e o b s t r u c t i o n are d i f f e r e n t i n t h e s e two d i s e a s e s . Sobonya and T a u s s i g [1986] s t u d i e d t h e l u n g morphology post-mortem and compared i t t o c o n t r o l s who had d i e d from causes o t h e r t h a n CF. They d e s c r i b e d a c o u r s e o f mucopurulent p l u g g i n g w i t h enlargement o f b r o n c h i a l g l a n d s l e a d i n g t o a c u t e 30 and c h r o n i c a i r w a y i n f l a m m a t i o n . Over t i m e t h i s d e v e l o p e d i n t o b r o n c h i e c t a s i s , but d i d not l e a d t o s i g n i f i c a n t a l v e o l a r d e s t r u c t i o n o r emphysema. They o b s e r v e d v a r y i n g t y p e s o f p a t h o l o g y i n t h e d i f f e r e n t age g roups. Those who d i e d a t an e a r l y age had a predominance o f b r o n c h i e c t a s i s and s m a l l a i r w a y d i l a t i o n w i t h mucus p l u g g i n g . The o l d e r p a t i e n t s had s m a l l a i r w a y s t e n o s e s w i t h l e s s d i l a t i o n , and no s i g n o f w o r s e n i n g b r o n c h i e c t a s i s w i t h i n c r e a s i n g age. A l t h o u g h t h e r e was m i l d a l v e o l a r enlargement i n most c a s e s , t h e i n t e r n a l s u r f a c e a r e a was shown t o be w e l l p r e s e r v e d . However, t h r e e p a t i e n t s i n t h e i r 20s had m o r p h o l o g i c e v i d e n c e o f m i l d emphysema, de m o n s t r a t e d by s m a l l l e s i o n s around s m a l l b r o n c h i and b r o n c h i o l e s . Thus s m a l l a i r w a y d i s e a s e was predominant w i t h e i t h e r d i l a t i o n , s t e n o s i s o r b o t h . Mucus g l a n d enlargement was not a u n i v e r s a l f i n d i n g d e s p i t e markedly i n c r e a s e d mucus i n t h e l u n g s . The s m a l l amount o f pneumonia p r e s e n t was g i v e n l e s s s i g n i f i c a n c e t h a n t h e mucus p l u g s and a i r w a y i n f l a m m a t o r y changes. T h e r e f o r e , a i r w a y o b s t r u c t i o n i s t h e prominent pulmonary m a n i f e s t a t i o n o f CF and as B e i e r e t a l [1966] emphasized, w o r s e n i n g a i r w a y o b s t r u c t i o n i s s i g n i f i c a n t l y a s s o c i a t e d w i t h c h r o n i c hypoxemia and t h e development o f c o r p u l m o n a l e - t h u s end-stage d i s e a s e . 31 SPECIFIC PURPOSES OF THIS STUDY The purposes of t h i s study can thus be summarized: 1. To investigate the i n t e r r e l a t i o n s h i p between airflow l i m i t a t i o n and v e n t i l a t i o n inhomogeneity as they are measured by the FEV- and FEF 0 [- tests and the J 1 25-75% SBN2/L% respectively, i n asthmatic and c y s t i c f i b r o s i s subjects. 2. To determine whether either of these tests correlates with the individual's subjective report of symptoms and exercise capacity. 3. To determine whether the slope of Phase III of the single breath N 2 test i s l i k e l y to be a useful addition to routine spirometry i n following the course of these two diseases. 32 METHODS RESEARCH DESIGN Three groups o f s u b j e c t s p a r t i c i p a t e d i n t h e s t u d y ; s p e c i f i c a l l y two p a t i e n t groups-one c o n s i s t i n g o f a s t h m a t i c p a t i e n t s and t h e o t h e r c o n s i s t i n g o f c y s t i c f i b r o s i s p a t i e n t s , and a c o n t r o l group o f h e a l t h y s u b j e c t s . A w i t h i n s u b j e c t e x p e r i m e n t a l d e s i g n was used t o examine t h e i n t e r r e l a t i o n s h i p s o f t h e f o l l o w i n g f o u r dependent v a r i a b l e s : FEV^, F E F 2 5 - 7 5 % ' S B ^ / I ^ and s u b j e c t i v e r a t i n g o f symptoms. A l l s u b j e c t s were t e s t e d on two o c c a s i o n s w i t h i n a seven month p e r i o d , from J u l y t o F e b r u a r y . On each o f t h e s e o c c a s i o n s , t h r e e a c c e p t a b l e measures o f t h e pulmonary f u n c t i o n v a r i a b l e s FEV^ and F F j F 2 5 - 7 5 % were o b t a i n e d and t h e ' b e s t ' measures from each s e s s i o n were used as t h e two r e p e a t e d t r i a l s f o r s t a t i s t i c a l a n a l y s i s . Three a c c e p t a b l e t r a c i n g s o f t h e SBN 2 t e s t were o b t a i n e d a t each s e s s i o n and an average S B ^ / I ^ v a l u e was d e t e r m i n e d from t h e t h r e e measured v a l u e s . A q u e s t i o n n a i r e a s s e s s i n g s u b j e c t i v e r a t i n g o f symptoms and e x e r c i s e c a p a c i t y was c o m p l e t e d by each s u b j e c t d u r i n g each v i s i t . The q u e s t i o n n a i r e s were s c o r e d i n a s t a n d a r d i z e d manner f o r d a t a a n a l y s i s . 33 SUBJECTS S u b j e c t s ranged from 18 t o 2 6 y e a r s o f age. The l o w e r l i m i t o f t h i s age c r i t e r i o n was chosen t o ensure t h a t t h e s u b j e c t s would be a b l e t o p e r f o r m t h e r e q u i r e d pulmonary f u n c t i o n t e s t s a c c u r a t e l y and r e p r o d u c i b l y , and t o c o n t r o l f o r d e v e l o p m e n t a l changes i n t h e l u n g s . The upper l i m i t was d e t e r m i n e d t o e l i m i n a t e t h e i n c l u s i o n o f c y s t i c f i b r o s i s s u b j e c t s w i t h end-stage d i s e a s e and p o t e n t i a l emphysematous changes as o b s e r v e d by Sobonya and T a u s s i g [1986]. S u b j e c t s i n t h e p a t i e n t groups were r e c r u i t e d from t h e p o p u l a t i o n s o f a s t h m a t i c and c y s t i c f i b r o s i s s u b j e c t s i n t h e Lower M a i n l a n d . The c o n t r o l group was f r e e o f r e s p i r a t o r y d i s e a s e and r e c r u i t e d from t h e g e n e r a l p o p u l a t i o n . S u b j e c t s i n b o t h t h e e x p e r i m e n t a l and c o n t r o l groups were non-smokers, f r e e o f h e a r t f a i l u r e , and d i d not p r e s e n t w i t h o t h e r m e d i c a l p a t h o l o g y u n r e l a t e d t o t h e i r d i s e a s e p r o c e s s . No attempt was made t o c o n t r o l f o r t h e s t a g e o r a c u t e n e s s o f d i s e a s e p r o c e s s - o t h e r t h a n t o ensure t h a t t h e i r symptoms d i d not l i m i t t h e i r a b i l i t y t o p e r f o r m t h e t e s t s . A minimum endurance c a p a c i t y was r e q u i r e d so t h a t s u b j e c t s c o u l d t r a v e l t o t h e l a b o r a t o r y and p e r f o r m t h e SBN 2 t e s t s and s p i r o m e t r y w i t h o u t e x c e s s i v e s h o r t n e s s o f b r e a t h . I n d i v i d u a l m e d i c a t i o n s were r e c o r d e d but not a l t e r e d f o r t h e p urposes o f t h e s t u d y . D u r i n g t h e f i r s t t e s t i n g s e s s i o n , s u b j e c t s were a s s e s s e d i n terms o f t h e i r a b i l i t y t o p e r f o r m t h e t e s t s a c c u r a t e l y and 34 r e p r o d u c i b l y a f t e r an a p p r o p r i a t e l e a r n i n g p e r i o d . P r i o r t o t h e s t u d y i t was d e c i d e d t h a t i f a s u b j e c t was u n a b l e t o a c h i e v e t h i s performance l e v e l o r became e x c e s s i v e l y s h o r t o f b r e a t h d u r i n g t h e p r o c e d u r e s , t h a t i n d i v i d u a l would be e x c l u d e d from t h e s t u d y . I f t h e s u b j e c t was u n a b l e t o meet t h e s e c o n d i t i o n s a t t h e second t e s t s e s s i o n , t e s t i n g was d e l a y e d u n t i l t h e y c o u l d r e a c h t h i s performance l e v e l . PROCEDURES G e n e r a l P r o c e d u r e s ; The s u b j e c t s were r e q u e s t e d not t o p a r t i c i p a t e i n any e x e r c i s e o r heavy p h y s i c a l a c t i v i t y on t h e day o f a t e s t s e s s i o n , t o m i n i m i z e t h e i n f l u e n c e o f f a t i g u e and t h e i n c i d e n c e o f e x e r c i s e i n d u c e d bronchospasm. They were r e q u e s t e d t o a v o i d e a t i n g a heavy meal w i t h i n two hours o f t h e t e s t and t o wear c o m f o r t a b l e n o n - r e s t r i c t i v e c l o t h i n g . The s u b j e c t s f o l l o w e d t h e i r u s u a l m e d i c a t i o n regimen but were asked t o w i t h h o l d t h e use o f t h e i r b r o n c h o d i l a t o r i n h a l e r s i x hours p r i o r t o t e s t i n g . The s u b j e c t s a r r i v e d a t t h e l a b o r a t o r y 15 minutes p r i o r t o t h e commencement o f t e s t i n g p r o c e d u r e s t o a l l o w f o r f a m i l i a r i z a t i o n w i t h t h e environment and t e s t e r , and t o e s t a b l i s h a r e s t i n g s t a t e . D u r i n g t h i s t i m e a b r i e f h i s t o r y o r update from t h e f i r s t s e s s i o n was t a k e n and t h e i r h e i g h t and w e i g h t were d e t e r m i n e d . A l l t e s t i n g p r o c e d u r e s were e x p l a i n e d 35 t o t h e s u b j e c t s p r i o r t o t h e i r [or t h e i r p a r e n t ' s ] w r i t t e n c o n s e n t t o t h e s t u d y . The o r d e r o f t e s t i n g [ i e s p i r o m e t r y and SBN2 t e s t ] was randomized amongst a l l s u b j e c t s and upon r e -assessment, each i n d i v i d u a l p e r f o r m e d t h e o p p o s i t e sequence t o t h e o r i g i n a l s e s s i o n . S u b j e c t s were r e q u i r e d t o p e r f o r m a minimum o f t h r e e a c c e p t a b l e t e s t s o f b o t h t h e FEV^ t F E F 2 5 - 7 5 % ^ and S B ^ / I ^ . Each t e s t s e s s i o n was completed w i t h i n 90 mi n u t e s , i n c l u d i n g t h r e e t o f i v e minute r e s t p e r i o d s between t r i a l s and t e n minutes between t e s t s . I n t h e r e s t p e r i o d between t e s t s , t h e s u b j e c t s completed a q u e s t i o n n a i r e r e g a r d i n g t h e p r e s e n c e and s e v e r i t y o f t h e i r symptoms, and t h e i r e x e r c i s e t o l e r a n c e . As recommended i n t h e American T h o r a c i c S o c i e t y [ATS] g u i d e l i n e s [1987], a l l t e s t i n g was c a r r i e d out by t h e same e x p e r i e n c e d i n d i v i d u a l t o c o n t r o l f o r p o t e n t i a l t e s t e r v a r i a b i l i t y . A l l p r o c e d u r e s and i n t e r a c t i o n s w i t h t h e s u b j e c t s were c a r r i e d out i n a s t a n d a r d i z e d manner. S p e c i f i c P r o c e d u r e s : 1. C a l i b r a t i o n o f t h e S p i r o m e t e r . An Ohio 842® d r y - r o l l i n g - s e a l s p i r o m e t e r c o n n e c t e d t o a (3) H e w l e t t P a c k a r d 7046A X-Y r e c o r d e r was used t o p e r f o r m t h e s p i r o m e t r i c t e s t s [ F i g . 2 ] . The s p i r o m e t e r was c a l i b r a t e d p r i o r t o each p e r i o d o f t e s t i n g . The s p i r o m e t e r m a i n t a i n e d i t s c a l i b r a t i o n between s u b j e c t s and was t h u s r e c a l i b r a t e d o n l y i f 36 » F i g . 2. Equipment set up f o r the spirometry t e s t s . A l l equipment was arranged on a t a b l e . The spirometer i s on the l e f t with the nitrogen analyzer ontop and the remainder of the single-breath nitrogen equipment [out of the p i c t u r e ] located to the l e f t . The x-y recorder i s to the r i g h t of the spirometer. 37 i t was shut o f f between t e s t i n g s e s s i o n s . C a l i b r a t i o n was p e r f o r m e d f o l l o w i n g 15 minutes o f warm-up, u s i n g a t h r e e l i t e r c a l i b r a t i o n s y r i n g e . Three v e r i f i c a t i o n l i n e s were o b t a i n e d f o r each c h a n n e l o f t h e x-y r e c o r d e r t h a t would r e c o r d volume. F o l l o w i n g t h i s p r o c e d u r e , t h e BTPS c o r r e c t i o n s w i t c h on t h e s p i r o m e t e r was s e t a c c o r d i n g t o t h e ambient t e m p e r a t u r e w h i c h ranged from 20-28 degrees C e l s i u s . 2. C a l i b r a t i o n o f t h e N i t r o g e n A n a l y z e r . A 505 N i t r a l y z e r N i t r o g e n Gas Meter® and Sargent-Welch D i r e c T o r r 8805® vacuum pump were used t o p e r f o r m t h e SBN 2 t e s t s [ F i g . 3 ] . The a n a l y z e r was c a l i b r a t e d p r i o r t o each p e r i o d o f t e s t i n g and r e c a l i b r a t e d o n l y i f i t was shut o f f between t e s t i n g s e s s i o n s . C a l i b r a t i o n was p e r f o r m e d f o l l o w i n g 30 m i n utes o f warm-up. The s a m p l i n g n e e d l e v a l v e was opened t o a c h i e v e a maximal d e f l e c t i o n on t h e a n a l y z e r . The a n a l y z e r was t h e n a d j u s t e d t o r e a d 79.6% N 2, r e f l e c t i n g room a i r . F o l l o w i n g t h i s , t h e n e e d l e v a l v e was s l i g h t l y c l o s e d u n t i l t h e a n a l y z e r dropped by 3% N 2 a c c o r d i n g t o t h e o p e r a t i n g i n s t r u c t i o n s . The a n a l y z e r was f i n a l l y a d j u s t e d t o a g a i n d i s p l a y 79.6% N 2 . The x-y r e c o r d e r was t h e n c a l i b r a t e d w i t h t h e a n a l y z e r and t h r e e v e r i f i c a t i o n l i n e s were o b t a i n e d . A l i n e a r i t y check o f t h e n i t r o g e n a n a l y z e r was p e r f o r m e d a t t h e onset and end o f t h e s t u d y , and a t monthly i n t e r v a l s d u r i n g t h e s t u d y . A d e f l e c t i o n on t h e r e c o r d e r was o b t a i n e d f o r each o f t h e s i x d i f f e r e n t c o n c e n t r a t i o n s o f N 9 [ r a n g i n g 38 F i g . 3. Equipment set up f o r the s i n g l e - b r e a t h nitrogen t e s t . A l l equipment was arranged on a t a b l e . The mouthpiece assembly i s on the l e f t with the e x p i r a t o r y flow gauge to i t s l e f t and the nitrogen sensor at the base of the rubber mouthpiece. The •outhpiece assembly i s connected to the oxygen bag and the sealed volume box which contains the bag. The volume box i s connected to the spirometer located to i t s r i g h t . The vacuum pump [under the t a b l e ] and x-y recorder [to the r i g h t of the spirometer] are out of the p i c t u r e . The nitrogen meter i s ontop of the spirometer. 3 9 from 0.2% t o 79.6%] t h a t were a n a l y z e d . To d e t e r m i n e l i n e a r i t y , t h e N 2 c o n c e n t r a t i o n was p l o t t e d on t h e a b s c i s s a a g a i n s t t h e r e c o r d e r d e f l e c t i o n i n c e n t i m e t e r s on t h e o r d i n a t e . 3. Performance o f t h e S p i r o m e t r y T e s t s . The s p i r o m e t r y t e s t s were co n d u c t e d a c c o r d i n g t o t h e ATS g u i d e l i n e s [1987]. The s u b j e c t was s e a t e d u p r i g h t i n a c h a i r and m o n i t o r e d t o p r e v e n t a l t e r a t i o n s i n p o s t u r e . F o l l o w i n g d e t a i l e d e x p l a n a t i o n o f t h e t e s t , t h e s u b j e c t p e r f o r m e d r e p e a t e d maximal f o r c e d e x p i r a t i o n maneuvers u n t i l t h r e e a c c e p t a b l e t r a c i n g s were o b t a i n e d . The s u b j e c t r e s t e d t h r e e m i n u t es between t r i a l s t o e n a b l e maximal pe r f o r m a n c e . The t e s t e r coached t h e s u b j e c t i n a s t a n d a r d manner t o ensure o p t i m a l and c o n s i s t e n t e f f o r t . A c c e p t a b l e t r a c i n g s f o r t h e FEV^ were s e l e c t e d a c c o r d i n g t o ATS [1987] c r i t e r i a . The r e s u l t s were a n a l y z e d w i t h t h e back e x t r a p o l a t i o n method w h e r e i n z e r o t i m e was d e t e r m i n e d by e x t r a p o l a t i n g t h e s t e e p e s t p o r t i o n o f t h e e x p i r a t o r y t r a c i n g back t o where i t i n t e r s e c t e d t h e t i m e a x i s . From t h i s p o i n t t h e one second p o i n t on t h e t i m e a x i s was d e t e r m i n e d and i t s v e r t i c a l i n t e r c e p t w i t h t h e c u r v e r e p r e s e n t e d t h e f o r c e d e x p i r a t o r y volume i n one second. The g r e a t e s t volume a c h i e v e d was t h e n compared t o age, sex and h e i g h t matched p r e d i c t e d v a l u e s . The s p i r o m e t r i c r e f e r e n c e v a l u e s and normal l i m i t s [1.65 x s t a n d a r d e r r o r o f t h e e s t i m a t e (SEE)] r e p o r t e d by Crapo e t a l [1981] were used. 40 The F E F 2 5 - 7 5 % w a s o b t a i n e d from t h e s i n g l e ' b e s t - t e s t ' c u r v e as p e r t h e ATS [1987] g u i d e l i n e s . T h i s c u r v e i s r e p r e s e n t e d by t h a t w i t h t h e l a r g e s t sum o f FVC and FEV 1. The F F j F 2 5 - 7 5 % w a s d e t e r m i n e d from t h e s l o p e o f t h e l i n e drawn t h r o u g h t h e two p o i n t s where 25% and 75% o f t h e VC had been e x p i r e d . T h i s v a l u e was t h e n compared t o t h e s p i r o m e t r i c r e f e r e n c e v a l u e s and normal l i m i t s [1.65 x SEE] r e p o r t e d by Crapo e t a l [1981]. 4. Performance o f t h e SBN 2 T e s t s . The SBN 2 t e s t s were conducted a c c o r d i n g t o t h e p r o c e d u r e s o u t l i n e d by M a r t i n and Macklem [1973], u s i n g t h e method o f B u i s t and Ross [1973]. T h i s method d i f f e r e d from t h e s t a n d a r d i z e d t e s t d e s c r i b e d by K j e l l m e r e t a l [1959] i n t h a t t h e s u b j e c t i n s p i r e d a VC b r e a t h o f oxygen from RV i n s t e a d o f FRC, and t h e s l o p e o f Phase I I I was c a l c u l a t e d from t h e b e s t f i t l i n e t h r o u g h t h e l a s t t w o - t h i r d s o f t h e c u r v e , r a t h e r t h a n from t h e i n c r e a s e i n N 2 between 750-1250 ml e x p i r e d volume. The t e s t v a l u e s i n t h i s s t u d y were t h e n compared w i t h t h e r e f e r e n c e v a l u e s o f B u i s t and Ross [1973]. The s u b j e c t was s e a t e d on an a d j u s t a b l e s t o o l so t h a t t h e mouth was a l i g n e d w i t h t h e mouthpiece. The s u b j e c t s a t u p r i g h t and was m o n i t o r e d t o p r e v e n t a l t e r a t i o n s i n p o s t u r e . F o l l o w i n g d e t a i l e d e x p l a n a t i o n o f t h e p r o c e d u r e t h e s u b j e c t was c o n n e c t e d t o t h e system v i a a mouthpiece and n o s e c l i p , and p e r f o r m e d a p e r i o d o f t i d a l b r e a t h i n g . The s u b j e c t t h e n p e r f o r m e d two slow 41 VC maneuvers b e f o r e i n h a l i n g a slow VC b r e a t h o f oxygen. An i n t e r n a l r e s i s t o r on t h e e x p i r a t o r y p o r t o f t h e b r e a t h i n g v a l v e was used t o a s s i s t t h e s u b j e c t i n m a i n t a i n i n g a f l o w r a t e o f 0.3-0.4 L/s d u r i n g t h e f i n a l VC e x p i r a t i o n , as done p r e v i o u s l y by Abboud and Morton [1975]. DeGroodt e t a l [1983] have r e p o r t e d t h a t t h e e f f e c t o f i n s p i r a t o r y f l o w r a t e on t h e SBN 2/L% i s c o n t r o v e r s i a l and t h a t t h e r e i s more agreement on t h e e f f e c t o f e x p i r a t o r y f l o w r a t e on t h e SBN 2/L%. W i t h i n c r e a s i n g e x p i r a t o r y f l o w r a t e , t h e SBN 2/L% f l a t t e n s and a i r w a y c l o s u r e o c c u r s sooner. A t h i g h e r f l o w r a t e s t h e r e may a l s o be i n f l u e n c e from dynamic a i r f l o w l i m i t a t i o n . Thus t h e s t a n d a r d f l o w r a t e o f 0.3-0.4 L/s was adopted i n t h e p r e s e n t s t u d y . Andersen and Rasmussen [1981] and DeGroodt e t a l [1983] have a l s o r e p o r t e d t h a t t h e SBN2/L% was not a f f e c t e d by an i n t e r n a l r e s i s t o r and recommended i t s use. The s u b j e c t r e p e a t e d t h e s e s i n g l e b r e a t h n i t r o g e n t e s t s u n t i l t h r e e a c c e p t a b l e t r a c i n g s were o b t a i n e d . The s u b j e c t r e s t e d f i v e m inutes between t r i a l s t o r e s t o r e t h e normal n i t r o g e n g r a d i e n t . The examiner coached t h e s u b j e c t s i n a s t a n d a r d manner t o ensure VC b r e a t h s and adherence t o slow f l o w r a t e s . The a c c e p t a n c e c r i t e r i a f o r t h e SBN 2 t r a c i n g s s e t by M a r t i n and Macklem [1973] i n c l u d e d : t h e mean e x p i r a t o r y f l o w [ a f t e r t h e f i r s t 500 ml i s e x p i r e d ] must be l e s s t h a n o r e q u a l t o 0.5 L / s ; d i f f e r e n c e s i n VC between t e s t s must not exceed 10%; t h e d i f f e r e n c e between i n s p i r e d and e x p i r e d VC must be 42 l e s s t h a n 5%; and t h e r e must not be a s t e p change i n t h e N 2 c o n c e n t r a t i o n w i t h c o n t i n u i n g c a r d i o g e n i c o s c i l l a t i o n s . Once t h e s e c r i t e r i a were met, i n t r a - s e s s i o n r e p r o d u c i b i l i t y was measured and t h e SBN 2/L% was c a l c u l a t e d . The SBN 2/L% was d e t e r m i n e d by t h e ' b e s t - f i t ' l i n e drawn t h r o u g h t h e t r a c i n g between 70% o f t h e e x p i r e d VC and t h e onset o f Phase IV. T h i s method was b ased on t h e work o f B u i s t e t a l [197 9] t o a v o i d t h e p o t e n t i a l o v e r s h o o t i n f l o w a t t h e onset o f e x p i r a t i o n . F u r t h e r m o r e , Dunning and A l l a m [1976] r e p o r t e d t h a t p a t i e n t s w i t h s e v e r e a i r w a y o b s t r u c t i o n may e x h i b i t a normal SBN 2/L% e a r l y i n t h e e x p i r a t i o n , which t h e n appears markedly abnormal l a t e r i n t h e e x p i r a t i o n . The mean o f t h r e e a c c e p t a b l e s l o p e s was t h e n c a l c u l a t e d . 5. C o m p l e t i o n o f t h e Q u e s t i o n n a i r e . A q u e s t i o n n a i r e was d e v e l o p e d t o a s s e s s t h e s u b j e c t s ' symptoms and p h y s i c a l endurance. The q u e s t i o n n a i r e [Appendix A] i n c l u d e d c a t e g o r i e s p e r t a i n i n g t o cough, s l e e p p a t t e r n s , and c u r r e n t a c t i v i t y l e v e l . The M e d i c a l R e s e a r c h C o u n c i l [1960] s t a n d a r d i z e d q u e s t i o n n a i r e on r e s p i r a t o r y symptoms was used t o r a t e dyspnea, and a s t a n d a r d i z e d m e t a b o l i c e q u i v a l e n t t a b l e [Ford, 1986] was used t o r a t e endurance. The s u b j e c t was o r i e n t a t e d t o t h e q u e s t i o n n a i r e and t h e n completed t h e q u e s t i o n n a i r e w i t h o u t a s s i s t a n c e between t e s t s , a t each t e s t s e s s i o n . The q u e s t i o n n a i r e s were s c o r e d b ased on a c o d i n g system w i t h t h e t o t a l p o s s i b l e s c o r e r a n g i n g from 0 [no symptoms and s a t i s f a c t o r y endurance] t o 29 [ s e v e r e symptoms and 43 l i m i t e d e n d u r a n c e ] . The t o t a l s c o r e on t h e q u e s t i o n n a i r e t h a t t h e s u b j e c t a c h i e v e d a t each t e s t s e s s i o n was i n c l u d e d i n t h e d a t a a n a l y s i s . DATA ANALYSIS C a l c u l a t i o n s f o r t h e s p i r o m e t r y and SBN 2 t e s t s from a l l t h e t r a c i n g s and t a b u l a t i o n o f t h e q u e s t i o n n a i r e s were p e r f o r m e d d u r i n g t h e same p e r i o d . The t r a c i n g s were coded and a r r a n g e d i n a random o r d e r , and t h e n a n a l y z e d by an i n v e s t i g a t o r b l i n d t o t h e c o d i n g system. The d a t a were a n a l y z e d i n s i x s t a g e s u s i n g n o n p a r a m e t r i c methods. F i r s t , d e s c r i p t i v e s t a t i s t i c s were c a l c u l a t e d f o r age, h e i g h t and w e i g ht o f t h e s u b j e c t s i n each group. D e s c r i p t i v e s t a t i s t i c s were a l s o c a l c u l a t e d f o r t h e f o u r p r i m a r y v a r i a b l e s o f i n t e r e s t namely, FEV^, F E F 2 5 - 7 5 % ' SBN 2/L% and s c o r e s on t h e q u e s t i o n n a i r e , f o r each group. F o r t h e c a l c u l a t i o n o f t h e d e s c r i p t i v e s t a t i s t i c s , FEV^, F E F 2 5 - 7 5 % a n c * SBN 2/L% were e x p r e s s e d as a p e r c e n t a g e o f t h e p r e d i c t e d v a l u e f o r each v a r i a b l e f o r each s u b j e c t . F o r s t a t i s t i c a l a n a l y s i s , t h e d a t a f o r FEV^, FEF,,^^,-^ and SBN 2/L% were f u r t h e r e x p r e s s e d as a p e r c e n t a g e o f t h e 95th p e r c e n t c o n f i d e n c e i n t e r v a l [one t a i l ] , i e 1.65 x SEE, f o r each v a r i a b l e . T h i s was done t o c o n t r o l f o r d i f f e r e n c e s i n c o e f f i c i e n t s o f v a r i a t i o n between t h e s p i r o m e t r i c and SBN 9 44 t e s t s . I n t h e case o f t h e FEV.^ and F E F 2 5 _ 7 5 % , t h i s p r o d u c t was s u b t r a c t e d from t h e p r e d i c t e d mean f o r each s u b j e c t i n o r d e r t o d e t e r m i n e t h e l o w e s t a c c e p t a b l e normal l i m i t . I n t h e case o f th e SB^/L 5*;, t h i s p r o d u c t was added t o t h e p r e d i c t e d mean f o r each s u b j e c t i n o r d e r t o det e r m i n e t h e h i g h e s t a c c e p t a b l e normal l i m i t . A l l s t a t i s t i c a l t e s t s were p e r f o r m e d on d a t a e x p r e s s e d as d e s c r i b e d above, t h u s t h e r e s u l t s and d i s c u s s i o n s i m i l a r l y p r e s e n t and d i s c u s s t h e d a t a i n t h i s form. A s i g n i f i c a n c e l e v e l o f p l e s s t h a n 0.05 was s e l e c t e d f o r a l l s t a t i s t i c a l t e s t s . Second, W i l c o x o n matched p a i r s t e s t s were used t o de t e r m i n e whether any d i f f e r e n c e s e x i s t e d between t h e two t e s t s e s s i o n s f o r each o f t h e f o u r p r i m a r y v a r i a b l e s f o r each group. T h i r d , t o e s t a b l i s h t h e r e p r o d u c i b i l i t y o f t h e d a t a , c o e f f i c i e n t s o f v a r i a t i o n [CV] were c a l c u l a t e d u s i n g t h e t h r e e r e p e a t e d measures o f t h e S B ^ / I ^ f o r each s u b j e c t w i t h i n each group. F u r t h e r , Spearman rank c o r r e l a t i o n c o e f f i c i e n t s [R] were c a l c u l a t e d w i t h i n each v a r i a b l e between s e s s i o n s f o r t h e c o n t r o l group. Four, t h e i n t e r r e l a t i o n s h i p s o f t h e v a r i a b l e s w i t h each o t h e r were examined u s i n g Spearman rank c o r r e l a t i o n c o e f f i c i e n t s . 45 F i v e , f r e q u e n c y t a b l e s were c o n s t r u c t e d w i t h i n each group t o examine t h e r e l a t i o n s h i p o f normal o r abnormal v a l u e s i n one v a r i a b l e w i t h t h e o c c u r r e n c e o f normal o r abnormal v a l u e s i n a n o t h e r v a r i a b l e w i t h i n one s e s s i o n . These f r e q u e n c y t a b l e s , however, c o u l d not be s t a t i s t i c a l l y a n a l y z e d because o f t h e l i m i t e d c e l l s i z e s . And s i x , t o d e t e r m i n e t h e r e l a t i o n s h i p o f change o b s e r v e d w i t h i n one v a r i a b l e compared w i t h t h e change i n a n o t h e r v a r i a b l e between t h e two t e s t s e s s i o n s , change s c o r e s were c a l c u l a t e d by s u b t r a c t i n g t h e v a l u e f o r each v a r i a b l e i n s e s s i o n two from t h a t i n s e s s i o n one. Spearman rank c o r r e l a t i o n c o e f f i c i e n t s were t h e n c a l c u l a t e d u s i n g t h e s e change s c o r e s . 4 6 RESULTS SUBJECT CHARACTERISTICS The c h a r a c t e r i s t i c s o f t h e c o n t r o l and e x p e r i m e n t a l groups i n c l u d i n g gender, age, h e i g h t and weight a r e summarized i n Ta b l e I . T h i r t y - f i v e s u b j e c t s i n t o t a l were i n c l u d e d i n t h e s t u d y ; 14 i n t h e c o n t r o l group, 14 i n t h e a s t h m a t i c group and 7 i n t h e CF group. The average weight was lo w e r i n t h e CF group, o t h e r w i s e t h e age and h e i g h t c h a r a c t e r i s t i c s were s i m i l a r amongst t h e groups. CHARACTERISTICS OF GROUP PERFORMANCE S p i r o m e t r y : A l l s u b j e c t s who s a t i s f i e d t h e c r i t e r i a f o r i n c l u s i o n i n t h e s t u d y were a b l e t o complete b o t h t e s t s e s s i o n s . The i n t e r v a l between t e s t s e s s i o n s ranged from one t o f o u r months. Three a c c e p t a b l e FEV^ t F E F 2 5 - 7 5 % ^ a n d S B N 2 t r a c : > - n c J s were o b t a i n e d w i t h o u t d i f f i c u l t y i n each s e s s i o n . The d e s c r i p t i v e s t a t i s t i c s f o r t h e q u e s t i o n n a i r e , FEV^, F F j F 2 5 - 7 5 % a n d SBN 2/L% f o r each o f t h e two s e s s i o n s a r e summarized f o r each group i n T a b l e s I I - I V . The d e s c r i p t i v e s t a t i s t i c s were based on t h e p e r c e n t o f t h e p r e d i c t e d v a l u e s a c h i e v e d by each s u b j e c t . The c o n t r o l group had t h e h i g h e s t mean v a l u e s f o r FEV- and 47 TABLE I SUBJECT CHARACTERISTICS: DESCRIPTIVE STATISTICS [Mean ± SD] CONTROL ASTHMATIC CYSTIC FIBROSIS GROUP GROUP GROUP N=14 N=14 N=7 Female: 14 11 6 Male: 0 3 1 AGE [ y e a r s ] Female: 23.6 ± 1.91 23.3 ± 2.69 21.2 ± 1.83 Male: - 22.0 ± 2.00 19.0 HEIGHT [cm] Female: 166.8 ± 3.88 162.7 ± 5.43 164.3 + 3.96 Male: - 179.0 ± 1.00 178.0 WEIGHT [kg] Female: 57.2 ± 2.98 58.8 ± 8.61 52.0 + 7.68 Male: - 72.0 ± 4.73 79.5 48 TABLE I I DESCRIPTIVE STATISTICS FOR THE DEPENDENT VARIABLES FOR THE CONTROL GROUP [N=14] IN BOTH TEST SESSIONS SESSION 1 SESSION 2 VARIABLE QUESTIONNAIRE*: Mean +SD 1.2 ± 1.48 1 . 2 + 1 . 1 9 Median 0.5 1.0 Range 0 . 0 - 4 . 0 0 . 0 - 3 . 0 FEV 1**: Mean ± SD 1 0 2 . 0 ± 1 1 . 7 2 9 7 . 6 ± 7 . 2 1 Median 1 0 2 . 6 9 6 . 2 Range 8 8 . 1 - 1 2 6 . 8 8 6 . 3 - 1 1 3 . 4 FEF **• r £ i C 2 5 - 7 5 % ' Mean + SD 95.2 + 21.65 92.3 ± 21.69 Median 100.6 90.9 Range 65.3 - 142.6 61.2 - 135.6 SBN 2/L%***: Mean + SD 114.5 ± 27.34 116.0 ± 28.08 Median 112.6 100.8 Range 62.2 - 186.4 89.5 - 176.6 Q u e s t i o n n a i r e s c o r e s range from 0 - 2 9 : z e r o = m i n i m a l symptoms and s a t i s f a c t o r y endurance, 29 = s e v e r e symptoms and l i m i t e d endurance. Data e x p r e s s e d as p e r c e n t o f p r e d i c t e d [Crapo e t a l , 1981] Data e x p r e s s e d as p e r c e n t o f p r e d i c t e d [ B u i s t and Ross, 1973] 4 9 TABLE III DESCRIPTIVE STATISTICS FOR THE DEPENDENT VARIABLES FOR THE ASTHMATIC GROUP [N=14] IN BOTH TEST SESSIONS SESSION 1 SESSION 2 VARIABLE QUESTIONNAIRE*: Mean + SD 7.1+4.44 5 . 9 ± 3 . 8 3 Median 7.5 5.5 Range 1.0-18.0 0.0-12.0 FEV 1**: Mean + SD 80.0 ± 18.46 83.2 ± 21.98 Median 85.7 84.7 Range 56.0 - 108.9 44.4 - 114.8 F E F * * • £ E , C25-75% ' Mean ± SD 59.0 ± 29.48 65.2 ± 34.02 Median 69.7 70.4 Range 21.8-97.0 14.0 - 115.9 SBN2/L%***: Mean + SD 152.8 ± 124.43 132.1 ± 94.19 Median 109.6 109.8 Range 66.0 - 514.2 39.8 - 405.5 Questionnaire scores range from 0 - 2 9 : zero = minimal symptoms and sa t i s f a c t o r y endurance, 29 = severe symptoms and l i m i t e d endurance. Data expressed as percent of predicted [Crapo et a l , 1981] Data expressed as percent of predicted [Buist and Ross, 1973] 50 TABLE IV DESCRIPTIVE STATISTICS FOR THE DEPENDENT VARIABLES FOR THE CYSTIC FIBROSIS GROUP [N=7] IN BOTH TEST SESSIONS SESSION 1 SESSION 2 VARIABLE QUESTIONNAIRE*: Mean + SD 10.7 ± 6.52 11.4 ± 6.58 Median 9.0 12.0 Range 5.0-24.0 0.0-22.0 FEV 1**: Mean + SD 44.2 ± 20.14 48.1 ± 11.03 Median 4 6.1 44.8 Range 18.5-70.8 32.1-66.2 FEF * *• E25-75% • Mean + SD 23.6 ± 15.06 22.9 ± 6.27 Median 25.5 21.0 Range 7.2-47.4 14.5-33.8 SBN2/L%***: Mean + SD 936.6 + 393.44 788.2 + 256.29 Median 94 8.8 693.5 Range 452.4 - 1427.3 505.7 - 1090.9 Questionnaire scores range from 0 - 29: zero = minimal symptoms and sa t i s f a c t o r y endurance, 29 = severe symptoms and l i m i t e d endurance. Data expressed as percent of predicted [Crapo et a l , 1981] Data expressed as percent of predicted [Buist and Ross, 1973] 51 F F j F25-75%* F o r e x a m P l e i n session one, the FEV^ and F E F25-75% were 102.0 and 95.2% predicted respectively. The asthmatic group f e l l between the control and CF groups with FEV^ and F E F25-75% v a l u e s o f 80.0 and 59.0% predicted respectively. In the CF group the FEV"1 was 44.2% predicted and the F E F 2 5 _ 7 5 0 5 was 23.6% predicted. The SBN2/L% values followed a s i m i l a r trend with the lowest percent predicted mean i n the control group [114.5%], followed by the asthmatic group [152.8%] and the CF group with the highest mean [936.6%]. In session two the same trends were observed for both the spirometry and SB^/I^ mean values. Spirometry and SBN9 Tracings: The spirometry tracings d i f f e r e d markedly i n t h e i r appearance amongst groups, being smallest i n magnitude and more gently sloped i n the severe asthmatic subjects and a l l CF subjects. The SB^ tracings of the severe asthmatics and a l l CF subjects also had a c h a r a c t e r i s t i c appearance which d i f f e r e d s i g n i f i c a n t l y from the control group as well as each other. A representative S B ^ tra c i n g from the control group i s displayed i n Figure 4. Phase IV was less evident amongst the younger subjects i n t h i s group. The SB^ tracings of the mild asthmatics approximated those of the control subjects. The S B N 2 tracings of the severe asthmatics displayed a concavity during Phase III [Figure 5], while the CF subjects displayed a steep and continuous slope [Figure 6]. In these subjects, the 52 F i g . 4. X-Y recording of the single-breath nitrogen t e s t from a c o n t r o l subject. Percent nitrogen i s displayed on the y-axis and exhaled volume i s on the x-axis. 53 F i g . 5. X-Y recording of the single-breath nitrogen t e s t from a severe asthmatic subject. Percent nitrogen i s displayed on the y-axis and exhaled volume i s on the x-axis. 54 F i g . 6. X-Y recording of the single-breath nitrogen t e s t from a c y s t i c f i b r o s i s subject. Percent nitrogen 1s displayed on the y-axis and exhaled volume i s on the x-axis. 55 cardiac o s c i l l a t i o n s were absent and Phase IV was t y p i c a l l y i ndistinguishable. REPRODUCIBILITY OF THE TEST RESULTS Within the control group, spirometry and SBN2/L% values and questionnaire scores [expressed as a %predicted lower/upper l i m i t ] between session one and two were highly correlated [Table V]. Table VI shows the c o e f f i c i e n t s of v a r i a t i o n [CV] for each te s t session within each group for the SBN2/L%. Over a l l groups, the CV for the SBN2/L% averaged less than 10%. INTERRELATIONSHIP AMONGST VARIABLES WITHIN A SESSION Using the Wilcoxon matched pairs test, no s i g n i f i c a n t differences were observed for any variable [expressed as a %predicted lower/upper l i m i t ] within groups, between session one and session two [p> 0.05]. Therefore, analysis of the i n t e r r e l a t i o n s h i p between variables was conducted using one single session. The Spearman rank correlations for a l l three groups between FEV^, F E F25-75%' S B N 2 / L % a n c i t n e questionnaire scores appear i n Table VII. The correlations for FEV^ vs SBN2/L% and F E F 2 5 _ 7 5 % vs SBN2/L% appear i n Figures 7-12. At the p< 0.05 l e v e l , FEV^ correlated p o s i t i v e l y with FEF 2^_ 7^ D, and both 56 TABLE V REPRODUCIBILITY OF VARIABLES OVER THE TWO SESSIONS FOR THE CONTROL GROUP [N=14]: SPEARMAN RANK ORDER CORRELATIONS [R] VARIABLE SPEARMAN R p LEVEL Questionnaire FEV^ ^ F E F25-75% SBN2/L% 0.59 0.75 0.88 0.65 0.03 0.01 <0.01 0.02 57 TABLE VI REPRODUCIBILITY OF THE SBN9/L%: COEFFICIENTS OF VARIATION [SD/MEAN %] WITHIN SUBJECTS FOR EACH GROUP SESSION 1 SESSION 2 GROUP CONTROL [N=14] Mean + SD 7.5+5.14 5.9+3.47 Median 6.0 6.0 Range 2 - 1 7 0 - 1 2 ASTHMATIC [N=14] Mean +SD 9.8+4.84 8.4+3.97 Median 9.5 7.5 Range 3 - 1 9 2 - 1 6 CYSTIC FIBROSIS [N=7] Mean +SD 3.6+2.64 7 . 9 ± 2 . 5 0 Median 3.0 8.0 Range 1 - 8 4 - 1 0 58 TABLE V I I INTERRELATIONSHIP AMONG VARIABLES FOR EACH GROUP WITHIN ONE SESSION: SPEARMAN RANK CORRELATIONS [R] SPEARMAN R CONTROL GROUP [N=14] ASTHMATIC GROUP [N=14] CYSTIC FIBROSIS GROUP [N=7] COMPARISON Questionnaire vs FEV^^ F E F 2 5 - 7 5 % -0.39 -0.12 0.17 0.14 •0.07 0.20 •0.41 •0.20 0.63 FEV vs FEF„ „ 0.58* SBN^7L%°* -0.54* 0.82** •0.63* 0.96* •0.93* F E F 2 5 _ 7 5 % vs SBN2/L% -0.63* -0.54* -0.86* * p<0.05 ** p<0.01 59 %PRED FEV1 vs %PRED SBN2/L% CONTROL GROUP • 4 134.4S8 • o • 8BM2/L* (tpredlcted upper H a l t ! F i g . 7. Relationship between the ^predicted FEV1 [mean - 1.65xSEE] and the Xpredicted SBN2/LX [mean + 1.65xSEE] f o r the control group. 60 %PRED FEF25-75% vs %PRED SBN2/L% CONTROL GROUP 4 • 202.975 * © • 8BM2/L* (tpxedlcted upper H a l t ] F i g . 8. Relationship between the ^predicted FEF25-75X [mean - 1.65xSEE] and the ^predicted SBN2/LX [mean + 1.65xSEE] f o r the control group. 61 %PRED FEV1 vs %PRED SBN2/L% ASTHMATIC GROUP •+ •+ 38.953 166.200 293.447 8BM2/L* (^predicted upper H a l t ] F i g . 9. Relatio n s h i p between the Xpredicted FEV1 [mean - 1.65xSEE] and the Xpredicted SBN2/LX [mean + 1.65xSEE] f o r the asthmatic group. 62 %PRED FEF25-75% vs %PRED SBN2/L% ASTHMATIC GROUP 144.780 • 117.218 89.656 62.093 O • 34.531 • 38.953 o • one case • - 2 cases R—0.54 o 166.200 8BM2/L* I\pr©dieted upper H a l t ) 293.447 F i g . 10. Relationship between the Xpredicted FEF25-75X [mean - 1.65xSEE] and the Xpredicted SBN2/LX [mean + 1.65xSEE] f o r the asthmatic group. 63 %PRED FEV1 vs %PRED SBN2/L% CYSTIC FIBROSIS GROUP 85.240 • 69.(47 R - - 0 . 9 3 > O c u u o, + 54.053 r4 > H h. 36.460 22.866 • 261.634 530.300 798.966 8BH2/L* (^predicted upper H a i t i F i g . 11.. Relat i o n s h i p between the Xpredicted FEV1 [mean - 1.65xSEE] and the Xpredicted SBN2/LX [mean + 1.65xSEEJ f o r the c y s t i c f i b r o s i s group. 64 %PRED FEF25-75% vs %PRED SBN2/L% CYSTIC FIBROSIS GROUP 8BN2/IA (%pxedlcted upp«r l i m i t ] F i g . 12. Relationship between the Xpredicted FEF25-75X [mean - 1.65xSEE] and the Xpredicted SBN2/LX [mean + 1.65xSEE] f o r the c y s t i c f i b r o s i s group. 65 correlated negatively with the SBN2/L%. The questionnaire did not correlate with any of the variables. The same pattern of correlations was observed i n the asthmatic and CF groups. The association between FEV-, F E F 0 c - C C L and the SBN0/L% i s 1' 25-75% 2 further presented i n a summary of frequency tables [Table VIII] r e l a t i n g normal and abnormal values for a l l three groups. In the control group, tests were normal for a l l subjects except one who had an abnormal FEF~ C _.-0 with a normal SBN~/L%. In zo—ID15 z the asthmatic group seven subjects had a normal FEV^ and SBN2/L%, while four subjects had an abnormal FEV^ with a normal SBN2/L%, and three subjects had both an abnormal FEV-j^  and SBN2/L%. The F E F25-75% v a l u e s followed a s i m i l a r r e l a t i o n s h i p with the SBN2/L% i n t h i s group. In the CF group a l l of these values were abnormal. INTERRELATIONSHIP OF THE CHANGE IN VARIABLES BETWEEN TWO SESSIONS The i n t e r r e l a t i o n s h i p of the change i n the variables [expressed as a %predicted lower/upper l i m i t ] from test session one to session two i s presented i n Table IX for the three groups. The correlations for FEV-j^  vs SBN2/L% and F E F 2 5 _ 7 5 0 j vs SBN2/L% appear i n Figures 13-18. In a l l three groups, the change i n FEV^ was p o s i t i v e l y correlated [Spearman rank order correlation] with the change i n F F j F25-75% ^P< 0-05]. The change i n SBN„/L% did not correlate with the change i n the 66 TABLE VIII INTERRELATIONSHIP OF VARIABLES WHEN CATEGORIZED AS NORMAL OR ABNORMAL: FREQUENCY DATA FOR EACH GROUP FOR ONE SESSION CONTROL ASTHMATIC CYSTIC FIBROSIS GROUP GROUP GROUP [N=14] [N=14] [N=7] CATEGORY Normal F E V^ normal SBN„/L%** 14 7 0 abnormal SBN2/L% 0 0 0 Abnormal FEV-j^  normal SBN?/L% 0 4 0 abnormal SBN2/L% 0 3 7 Normal F E F 2 5 _ 7 5 % * * * normal SBN„/L% 13 7 0 abnormal SBN2/L% 0 0 0 Abnormal F E F 2 ^ _ 7 5 ^ normal SBN?/L% 1 4 0 abnormal SBN2/L% 0 3 7 * Normal FEV- > %predicted minus 1.65 x SEE [Crapo et a l , 1981] ** Normal SBN?/L% < %predicted plus 1.65 x SEE [Buist and Ross, 1973T *** Normal F E F 9 R _ > %predicted minus 1.65 x SEE [Crapo et a l , 1981] / 3 * 67 TABLE IX INTERRELATIONSHIP OF THE CHANGE IN VARIABLES BETWEEN TWO SESSIONS: SPEARMAN RANK ORDER CORRELATIONS [R] FOR THE THREE GROUPS SPEARMAN R CONTROL GROUP [N=14] ASTHMATIC GROUP [N=14] CYSTIC FIBROSIS GROUP [N=7] COMPARISON OF CHANGE AMONGST VARIABLES Questionnaire vs FEV. FEF SBN^L? 5* 0.17 •0.01 •0.11 0.11 •0.02 0.20 •0.78* •0.80* 0.55 FEV vs FEF 9 1 SBKphi^ 0.78** •0.48 0.94** •0.12 0.89* •0.75 [*] F E F25-75% V S S B N 2 / L % -0.44 -0.17 -0.64 [*] approaching p<0.05 * p<0.05 ** p<0.01 68 CHANGE FEV1 vs CHANGE SBN2/L% CONTROL GROUP 20.(35 • • 14.016 1—0.48 7.401 .784 OO -5.832 • -19.008 • -1.500 16.608 CHANGS IM 8BM2/L% [tprodictod npp«z H a i t i F i g . 13. Relati o n s h i p between the change i n ^predicted FEV1 [mean • 1.65xSEE] and the change i n Xpredicted SBN2/LX [mean + 1.65xSEE] f o r the c o n t r o l group. 69 CHANGE FEF25-75% vs CHANGE SBN2/L% CONTROL GROUP • — — — - — 27.771 • > e 16.362 K—0.44 • M 0 m t» i M M l o o o 4.952 -6.457 -17.666 4 4 4 --19.608 4 - 4 4 -1.500 16.608 CHANGE IN SBM2/IA (%pr•dieted upper H a i t i F i g . 14. Relat i o n s h i p between the change i n Xpredicted FEF25-75X mean - 1.65xSEE] and the change i n Xpredicted SBN2/LX mean + 1.65xSEEJ f o r the co n t r o l group. 70 CHANGE FEV1 vs CHANGE SBN2/L% ASTHMATIC GROUP 29.754 • 12.£04 -4.546 -21.697 F — 0 . 1 2 -38.847 • -18.353 21.750 61.853 CHAM OB IM 8BM2/L% [tpzedicted opp«z H a l t ] F i g . 15. Relati o n s h i p between the change i n Xpredicted FEV1 [mean - 1.65xSEE] and the change i n Xpredicted SBN2/LX [mean + 1.65xSEEJ f o r the asthmatic group. CHANGE FEF25-75% vs CHANGE SBN2/L% ASTHMATIC GROUP 45.338 • 20.647 -4.045 -28.737 -53.428 • o o o R—0.17 -18.353 21.750 61.653 CHAMOB IM 8BM2/L% Itpradictad upper H a i t i F i g . 16. Rel a t i o n s h i p between the change 1n Xpredicted FEF25-75X Emean - 1.65xSEE] and the change 1n Xpredicted SBN2/LX mean + 1.65xSEE] f o r the asthmatic group. CHANGE FEV1 vs CHANGE SBN2/L% CYSTIC FIBROSIS GROUP • — 9.435 * o .993 • R—0.75 -7.448 15.890 24.331 • -28.557 79.S00 187.557 CHANGS IH 8BM2/L% [tpredlcted upper H a l t ) F i g . 17. Relati o n s h i p between the change 1n Xpredicted FEV1 mean - 1.65xSEE] and the change i n {predicted SBN2/LX mean + 1.65xSEEJ f o r the c y s t i c f i b r o s i s group. 73 X V CHANGE FEF25-75% vs CHANGE SBN2/L% CYSTIC FIBROSIS GROUP 4-19.894 4 > O 10.723 4 0 0.64 M Oi 0 m r~ i m n (h to hi 1.552 -7.619 -16.790 4 4 4 --28.557 4 - 4 4 79.500 187.557 CHANGS IM 8BM2/L* («pr«dlct*d upper H a i t i F i g . 18. Relat i o n s h i p between the change In Xpredicted FEF25-75X [mean - 1.65xSEE] and the change In Xpredicted SBN2/LX [mean + 1.65xSEE] f o r the c y s t i c f i b r o s i s group. 74 other variables i n any group, although the c o r r e l a t i o n between SBN2/L% and FEV^ was approaching significance i n the CF group [p=0.06]. In the CF group, the change i n questionnaire scores correlated negatively with the change i n FEV^ and F E F25-75% [p< 0.05]. A low score on the questionnaire r e f l e c t e d minimal symptoms and a s a t i s f a c t o r y endurance capacity. 75 DISCUSSION This study investigated the i n t e r r e l a t i o n s h i p between airflow l i m i t a t i o n and v e n t i l a t i o n inhomogeneity as measured by spirometry and the SB^/I^ respectively, i n subjects with asthma and c y s t i c f i b r o s i s . The results of t h i s study quantified the airflow l i m i t a t i o n and v e n t i l a t i o n inhomogeneity i n each of these groups, and determined the i n t e r r e l a t i o n s h i p between them. Based on these findings and t h e i r implications, conclusions can be made about the role of the SB^/I^ i n the assessment and management of individuals with asthma and c y s t i c f i b r o s i s over the course of disease. DIFFERENTIATING THE PERFORMANCE OF THE CYSTIC FIBROSIS AND ASTHMATIC GROUPS Spirometry and SBN^ Test Results: In the descriptive s t a t i s t i c s shown i n Tables II-IV, the mean tes t scores of the asthmatic group f e l l between those of the control and CF groups, which were highly normal and abnormal respectively. These findings are consistent with the presentation of asthma and CF, wherein asthma presents with variable degrees of airway obstruction over time, and i s not r e l e n t l e s s l y progressive i n i t s course [Bates, 1989; McFadden, 1988]. Cystic f i b r o s i s however, i s characterized by a gradual 7 6 and persistent decrease i n pulmonary function, with more rapid declines during exacerbations [Scanlin, 1 9 8 8 ] . Amongst the asthmatic and CF groups, there were only a few subjects who exemplified moderate disease severity. This bimodal d i s t r i b u t i o n i s also r e f l e c t e d i n the frequency data of Table VIII where only eight subjects f e l l i n a category r e f l e c t i n g mild to moderate disease-when one test score was normal and the other was abnormal. In the CF group, the mean SBN2/L% [936.6% predicted] was s i g n i f i c a n t l y more impaired than the mean FEV^ [44.2% predicted] or mean F E F 2 5 - 7 5 % [23.6% predicted]. This indicates that i n the CF group, more severe v e n t i l a t i o n inhomogeneity was present than would be expected from the degree of airflow l i m i t a t i o n detected by spirometry. Thus, these re s u l t s suggest that i n c l u s i o n of the SBN2/L% i s necessary to accurately determine the degree of v e n t i l a t i o n inhomogeneity i n in d i v i d u a l s with c y s t i c f i b r o s i s . Differences i n the SBN2 Tracings: The v a r i a t i o n i n test results amongst groups i s also r e f l e c t e d i n the actual SBN2 tracings i l l u s t r a t e d i n Figures 4 - 6 . In the asthmatic group, the tracings of the mild asthmatics were q u a l i t a t i v e l y s i m i l a r to the controls, again exemplifying the variable degree of airway obstruction i n asthma. The tracings of the severe asthmatics however, had a concave SBN0/L%. Tomioka et a l [1988] described a s i m i l a r 77 concavity during Phase IV of the SBN2 test i n t h e i r examination of the re l a t i o n s h i p between airway closure and c o l l a t e r a l v e n t i l a t i o n . They used a dog and pig model since these animals have a well developed and poorly developed c o l l a t e r a l v e n t i l a t i o n respectively. They observed the greatest concavity in the dog model and attributed t h i s finding to v e n t i l a t i o n of closed units through c o l l a t e r a l channels which would decrease the concentration of the tracer gas i n the expirate. Woolcock and Macklem [1971] have previously reported that resistance through c o l l a t e r a l channels i s greater than that through small airways, thus l i m i t i n g c o l l a t e r a l v e n t i l a t i o n . However, with the onset of airway closure there would be greater p o t e n t i a l for c o l l a t e r a l v e n t i l a t i o n [Tomioka et a l , 1988]. Andersen and Rasmussen [1981] have reported that the development of enhanced c o l l a t e r a l v e n t i l a t i o n i n disease may contribute to the reduction of the N 2 gradient between open and closed lung units . Therefore, i t i s possible that c o l l a t e r a l v e n t i l a t i o n d i s t a l to obstructed airways may be responsible for the curvature seen during Phase III i n the severe asthmatics of the present study. Furthermore, Phase IV was d i f f i c u l t to di s t i n g u i s h i n these tracings, as predicted by Andersen and Rasmussen [1981] on the basis of a decreased i n t e r r e g i o n a l N 2 gradient secondary to s i g n i f i c a n t intraregional inhomogeneity. The SBN2/L% concavity was not seen i n the tracings of the CF group, which displayed a steep and continuous slope without a c l e a r l y distinguishable Phase IV. This may be explained by the differences i n underlying pathology between these two 78 diseases. Although small airway obstruction i s prevalent i n both CF and asthma, the underlying mechanisms d i f f e r . Airway obstruction i n asthma results predominantly from bronchoconstriction and airway inflammation of variable location and severity [Gold et a l , 1967; Bates, 1989]. The persistent airway obstruction i n CF i s characterized primarily by mucus plugging and the development of bronchiectasis [Scanlin, 1988]. These differences were exhibited i n the findings of Mansell et a l [1974] who observed e f f o r t dependence of flow at high lung volumes i n individuals with CF, but not i n asthmatics. They attributed t h e i r findings to volume displacement from bronchiectatic airways i n CF i n d i v i d u a l s . Thus, the steep and continuous SB^/I^ seen i n the CF subjects i n the present study may r e f l e c t a more s i g n i f i c a n t and permanent pathology than i n the asthmatic subjects. Furthermore, the small v i t a l capacity observed i n the CF subjects r e l a t i v e to the asthmatics, may also contribute to a greater degree of v e n t i l a t i o n inhomogeneity. If c o l l a t e r a l v e n t i l a t i o n was a factor i n producing the concave SBN2/L% in the asthmatic group, i t i s possible that c o l l a t e r a l v e n t i l a t i o n was not as prominent i n the CF group, or that i t s e f f e c t was masked by the s i g n i f i c a n t intraregional inhomogeneity. Since adjacent alveolar units may be subtended by a common bronchiole that i s bronchiectatic or obstructed by tenacious mucus plugs, v e n t i l a t i o n would be impaired to a l l of these units and c o l l a t e r a l v e n t i l a t i o n amongst them would be i n e f f e c t i v e . 79 In the SBN2 tracings of both the severe asthmatic and CF subjects, the cardiac o s c i l l a t i o n s were absent. Since a breath-hold d i d not occur during the procedure, the damping of the o s c i l l a t i o n s can not be explained by equalization of the in t r a r e g i o n a l N 2 gradients previously reported by Engel et a l [1974]. Thus i t i s more l i k e l y that these re s u l t s can be explained on the basis of increased time constants i n the areas of severe airway obstruction, which would dampen the pressure waves generated by the cardiac action, as suggested by Verhamme et a l [1982]. Increased time constants are c h a r a c t e r i s t i c of asthma and CF primarily due to the increased airway resistance, although a decrease i n e l a s t i c r e c o i l may also contribute i n the l a t e r stages of disease [Gold et a l , 1967; Featherby et a l , 1970]. INTERRELATIONSHIP BETWEEN AIRFLOW LIMITATION AND VENTILATION INHOMOGENEITY Relationship between Normal and Abnormal Test Results: In the spirometry and SBN2 tests, the asthmatic subjects displayed normal or abnormal results, while the CF subjects had consistently abnormal results, as shown i n Table VIII. This may r e f l e c t the differences i n disease severity between the groups. In the asthmatic group there was a predominance of subjects who were i n complete remission and a few subjects who were severe, while the CF group had a predominance of subjects 80 with severe disease and two moderately severe subjects. Another factor which may account for the differences between groups i s the v a r i a b i l i t y of airway obstruction i n asthma; which may present as central or peripheral airway obstruction, or both [Loke et a l , 1981]. The prevalence of central airway obstruction i n asthma has gained recent attention i n the investig a t i o n of laryngeal and g l o t t a l c o n s t r i c t i o n during bronchoconstriction [Collett et a l , 1983; C o l l e t t et a l , 1986]. These investigators observed g l o t t a l and laryngeal c o n s t r i c t i o n during histamine induced bronchospasm, with a resultant decrease i n flow rates to 35% of t h e i r i n i t i a l value. The ef f e c t of central and peripheral obstruction on spirometry and the SB^/I^ was investigated by Simonsson and Malmberg [1964] . They studied subjects with central airway obstruction due to a tumor or tracheal stenosis, and subjects with the same pathology i n addition to chronic obstructive pulmonary disease [COPD]. They observed that both groups had airflow obstruction, but only the COPD group with peripheral airway obstruction had an abnormal SB^/I^. Antic and Macklem [1976] reported that the airway obstruction i n asthmatics i s predominantly central i n the absence of factors such as smoking, chronic bronchitis and recurrent respiratory t r a c t i n f e c t i o n s . These factors were not present i n the majority of the asthmatic subjects i n the present study, suggesting a predominance of central airway obstruction which may explain why i n some cases the SB^/I^ was normal when the FEV^ was abnormal, contrary to results previously reported i n the l i t e r a t u r e [Beale et a l , 1952; Cade and Pain, 1973]. The 81 SBN2/L% i s sensi t i v e to peripheral airway disease c h a r a c t e r i s t i c of smokers, i n whom i t often detects abnormality i n pulmonary function when spirometry i s normal [McCarthy et a l , 1976; Hogg et a l , 1985; Bates, 1989]. Relationship of Test Results Within a Session: 1. Spirometry and the SBN2/L%. The d i s t r i b u t i o n of v e n t i l a t i o n i s one of the determinants of ve n t i l a t i o n - p e r f u s i o n [V/Q] matching [West, 1985], and the V/Q mismatch seen i n asthma has been largely attributed to uneven peripheral airways obstruction [Roca et a l , 1988; West, 1982]. Thus, the res u l t s of the present study of airflow l i m i t a t i o n and v e n t i l a t i o n inhomogeneity are consistent with the work of Roca et a l [1988]. These investigators studied the re l a t i o n s h i p between spirometry and V/Q inequality i n ten acute asthmatics who were refractory to bronchodilator therapy. They studied these subjects from admission to discharge, and again 3-4 weeks post-discharge. They observed simultaneous improvement i n spirometry and V/Q matching i n only one subject. Overall, spirometry returned to baseline at discharge, but recovery i n V/Q was not complete u n t i l 3-4 weeks later-the point at which the spirometry and V/Q matching correlated. In the present study, any subject who was h o s p i t a l i z e d during the study, was tested a minimum of three weeks post discharge. Consistent with the findings of Roca et a l [1988], the spirometry and SBN9/L% correlated within each group 82 [Figures 7-12, Table VII]. The lack of c o r r e l a t i o n between spirometry and V/Q matching i n the study of Roca et a l [1988] was explained on the basis of airflow rates being l a r g e l y determined by large airway properties, and gas exchange being more rel a t e d to peripheral airway obstruction from edema or mucus plugging [Rodriguez-Roisin et a l , 1984; Rubinfeld et a l , 1978; Wagner et a l , 1978]. This hypothesis can also be extended to the present study wherein the SBN2/L% of the CF group was highly abnormal compared to the asthmatic group, r e f l e c t i n g the more permanent airway changes i n c y s t i c f i b r o s i s . 2. E f f e c t of Bronchodilation on Spirometry and the SB^/I^. Roca et a l [1988] also suggested that persistent V/Q mismatch as a consequence of peripheral airway changes may explain why the subjects i n t h e i r study were unresponsive to bronchodilator treatment. Deychakiwsky et a l [1985] bronchodilated asthmatic subjects with antigen-induced bronchoconstriction, and observed v e n t i l a t i o n inhomogeneity which did not always return to baseline when the spirometry returned to normal. Similar r e s u l t s were achieved i n our laboratory when spirometry and the S B ^ test were conducted on an asthmatic subject pre and post bronchodilation [unpublished findings-see Appendix B]. Following bronchodilation, the subject had a 34% increase i n FEV^, 45% increase i n F E F25-75% and an 11% increase i n SB^/I^. Based on s i m i l a r findings, Siegler et a l [1976] concluded that the e f f e c t of a 83 bronchodilator on the SB^/I^ i s d i f f i c u l t to predict for a given patient. They suggested that the bronchodilator may act to increase the interregional N 2 gradient by increasing the gradient i n regional volume, or decrease the i n t r a r e g i o n a l inhomogeneity by narrowing the range of c r i t i c a l opening pressures. 3 . Subjective and Objective Findings. Although the pulmonary function tests correlated within each group, there was no c o r r e l a t i o n between them and the questionnaire scores [Table VII]. The questionnaire assessed the presence and severity of symptoms, the a c t i v i t y l e v e l and endurance capacity. Thus, a subject who maintained a high a c t i v i t y l e v e l regardless of symptoms, would score lower on the questionnaire than expected. This may have been a factor i n both the asthmatic and CF groups who tended to report a greater a c t i v i t y l e v e l than would be anticipated from t h e i r test r e s u l t s . Boyle et a l [1976] have previously observed that adults with CF were more active than might be expected by t h e i r disease severity. In addition, denial of symptoms and overestimation of exercise tolerance may have been prevalent i n the CF group i n the present study. One CF subject for example, denied any shortness of breath and reported p a r t i c i p a t i o n i n a 20 minute exercise program 3 times a week, although she was unable to slowly walk a short distance to the laboratory without obvious shortness of breath. In the asthmatic group, the lack of c o r r e l a t i o n could also be explained by a diminished 84 perception of changes i n pulmonary function. Rubinfeld and Pain [1977] observed s i g n i f i c a n t changes i n airflow and residual volume before symptoms were reported by t h e i r subjects. However, Burki et a l [1978] reported that asthmatics were more perceptive of inspiratory loads than normals. In addition to these known influences on an i n d i v i d u a l ' s subjective report, the questionnaire may not have been s u f f i c i e n t l y sensitive to accurately r e f l e c t the abnormalities i n pulmonary function. Relationship of the Change i n Test Results Between Sessions: 1. Spirometry and the SBN^yi^. Although the change i n FEV^ correlated with the change i n F E F 2 5 - 7 5 % ^ n e a c ^ 9 J r o u P f there was no c o r r e l a t i o n between the change i n spirometry and SB^/L^, as shown i n Figures 13-18 and Table IX. However, i n the CF group t h i s c o r r e l a t i o n was approaching significance, which may be a r e f l e c t i o n of the greater severity and permanence of the pathology i n t h i s group. These findings are consistent with the work of Deychakiwsky et a l [1985] who observed a c o r r e l a t i o n between spirometry and v e n t i l a t i o n inhomogeneity that was not maintained a f t e r a change i n status when bronchospasm was induced. In addition, the r e s u l t s of the present study are consistent with the conclusions of Roca et a l [1988]. These investigators had concluded from t h e i r observations of a lack of c o r r e l a t i o n between airflow l i m i t a t i o n and gas exchange i n acute asthmatics 85 u n t i l 3-4 weeks post discharge, that spirometry and V/Q inequality indicate d i f f e r e n t pathophysiologic phenomena. They further concluded that impairment of V/Q matching can not be i n f e r r e d from spirometric results during acute severe asthma, and that both should be assessed during acute and asymptomatic disease states. As previously discussed, the r e s u l t s of the present study also demonstrated a c o r r e l a t i o n between spirometry and the SB^/I^ within a single session at a subacute disease state. However, the lack of c o r r e l a t i o n of change i n spirometry and SB^/L^ between two sessions suggests that these two tests do not change i n a s i m i l a r manner over time. This i s consistent with the d i f f e r e n t time courses for recovery of airflow rates and V/Q matching reported by Roca et a l [1988] during an acute disease state. It i s p l a u s i b l e that a subject could have an exacerbation of disease following a t e s t i n g session, and that the recovery of airflow and v e n t i l a t i o n homogeneity would be at d i f f e r e n t stages upon reassessment at the next t e s t i n g session. The subjects i n the present study were seen over a one to four month i n t e r v a l , and often reported a change i n status during that time i n t e r v a l . Therefore, the r e s u l t s of the present study extend the observations and conclusions of Roca et a l [1988] over a longer period of time, and during a less acute disease state. 2. Subjective and Objective Findings. The change i n questionnaire scores and t e s t r e s u l t s between sessions did not correlate except for the change i n 86 spirometry scores i n the CF group [Table IX]. The lack of co r r e l a t i o n may be explained as per the previous discussion of the findings within one test session. In the CF group, the co r r e l a t i o n between the change i n questionnaire scores and spirometry r e s u l t s may be explained by the substantial work of breathing i n these individuals who had the greatest severity of disease. Both the increased resistance to airflow and increased e l a s t i c work due to hyperinflation contribute s i g n i f i c a n t l y to the work of breathing [Collett et a l , 1988]. Thus, an improvement or deterioration i n t h e i r airflow obstruction would l i k e l y be recognized as a change from the previous t e s t . In addition, the observation that the change i n SBN2/L% was not s i m i l a r l y correlated with the change i n questionnaire score could be explained by the observations of Roca et a l [1988]. These investigators observed that l i m i t a t i o n s i n maximal expiratory flow were related to symptoms of dyspnea and wheezing, while V/Q mismatch was a more s i l e n t manifestation of pathology that was less related to symptoms. Therefore, even though the CF individuals appeared to have underestimated t h e i r symptoms and exercise l i m i t a t i o n , the questionnaire was able to detect the change i n these subjective findings. 87 IMPLICATIONS OF THE STUDY The r e s u l t s of the present study support the i n c l u s i o n of the SBN2/L% i n pulmonary function t e s t i n g as suggested by others [Andersen and Rasmussen, 1981; Beale et a l , 1952; Buist et a l , 1984; Olofsson et a l , 1986; Oxhoj et a l , 1977]. Determination of the SB^/I^ provides assessment of the 'quiet zone' of the lung defined by Mead [1970], where s i g n i f i c a n t pathology can develop before i t i s often detected by tests of airflow l i m i t a t i o n . More s p e c i f i c a l l y , i n individuals with asthma or c y s t i c f i b r o s i s , the v e n t i l a t i o n inhomogeneity can be more severe than expected from assessment of airflow l i m i t a t i o n . Thus, t h i s suggests that the incl u s i o n of the SB^ t e s t i n the management of these chronic diseases would be b e n e f i c i a l . Deychakiwsky et a l [1985] and Roca et a l [1988] largely a t t r i b u t e d the impaired gas exchange seen i n these diseases to V/Q mismatch, which emphasizes the necessity of monitoring the v e n t i l a t i o n inhomogeneity i n these i n d i v i d u a l s . Further research i s needed to confirm and extend the r e s u l t s of t h i s study. To delineate the i n t e r r e l a t i o n s h i p between airflow l i m i t a t i o n and v e n t i l a t i o n inhomogeneity further, i t would be b e n e f i c i a l to perform the procedures i n t h i s study every three months, over a two year period. During t h i s greater time i n t e r v a l , the airflow l i m i t a t i o n and v e n t i l a t i o n inhomogeneity could be characterized during more 88 subtle and frequent changes i n disease state. In addition, such a longitudinal study could determine whether the SB^/I^ can predict the rate of decline i n spirometry i n these in d i v i d u a l s , which would be of great prognostic value. 89 CONCLUSIONS The conclusions from t h i s study are: 1. The slope of Phase III of the single-breath nitrogen te s t was r e l a t i v e l y easy to perform and well tolerated by the subjects. Repeated measures within subjects were more reproducible than previously reported i n the l i t e r a t u r e . S p e c i f i c a l l y , the c o e f f i c i e n t s of v a r i a t i o n over a l l groups for the SB^/L 5^ averaged less than 10%. Thus, t h i s non-invasive procedure was a simple and r e l i a b l e test of v e n t i l a t i o n inhomogeneity i n individuals with asthma or c y s t i c f i b r o s i s . 2. In t h i s study, the indices of airflow l i m i t a t i o n and v e n t i l a t i o n inhomogeneity i n the asthmatic group showed a range of values from normal to abnormal; but were consistently abnormal i n the c y s t i c f i b r o s i s group. This could be explained by differences i n the underlying mechanisms of airway obstruction i n these diseases; asthma being characterized by variable bronchoconstriction and airway inflammation, and c y s t i c f i b r o s i s causing a more severe obstruction and inhomogeneity as a re s u l t of mucus plugging and bronchiectasis. 90 In the c y s t i c f i b r o s i s group, the severity of v e n t i l a t i o n inhomogeneity was greater than would be expected by the severity of airflow l i m i t a t i o n during the same test session. This suggests that inc l u s i o n of the SBN2/L% i s necessary to determine the degree of v e n t i l a t i o n inhomogeneity in these i n d i v i d u a l s . At a given test session, tests of forced expiration were correlated with the slope of Phase III i n a l l groups [R values for the SBN2/L% vs FEV 1 and F E F25-75% correlations respectively were - 0 . 5 4 and - 0 . 6 3 i n the control group, - 0 . 6 3 and - 0 . 5 4 i n the asthmatic group, and - 0 . 9 3 and - 0 . 8 6 i n the c y s t i c f i b r o s i s group]. However, between two d i f f e r e n t test sessions, the changes in the two tests [spirometry and SBN2/L%] were not i n t e r - c o r r e l a t e d . This may r e f l e c t the d i f f e r e n t pathophysiologic phenomenon that influence each test, tests of forced expiration being predominantly influenced by large airway properties and the single-breath nitrogen test being more influenced by peripheral airway properties. In addition, these res u l t s r e f l e c t the d i f f e r e n t time courses of recovery of airflow rates and v e n t i l a t i o n homogeneity towards baseline l e v e l s . Since more severe v e n t i l a t i o n inhomogeneity may exist i n asthma and c y s t i c f i b r o s i s compared to airflow l i m i t a t i o n , i t may well be that the i n c l u s i o n of the SBN2 test might be useful i n the management of these chronic diseases. 91 The interpretation of pulmonary function tests i s l i m i t e d by the degree of v a r i a b i l i t y associated with the p a r t i c u l a r t e s t s ; the c o e f f i c i e n t s of v a r i a t i o n being greater for the slope of Phase III than those for spirometry. Despite the greater v a r i a b i l i t y inherent i n the measurement of the SB^/I^, t h i s study has indicated a role for i t s i n c l u s i o n with routine spirometry i n the management of indiv i d u a l s with asthma and c y s t i c f i b r o s i s . 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Was the amount: less than usual the same as usual greater than usual 3. In the last 24 hours, how would you best describe your shortness of breath: Not troubled with breathlessness except with strenuous exercise. Troubled by shortness of breath when hurrying on the level or walking up a sl i g h t h i l l . Walk slower than people of the same age on the level because of breathlessness or have to stop for breath when walking at own pace on the l e v e l . Stop for breath after walking about 100 yards or after a few minutes on the l e v e l . Too breathless to leave the house or breathless when dressing or undressing. 4. Over the l a s t 3 days, how many hours of continuous sleep did you usually get in a night: 7 hours or more 6 hours 5 hours 4 hours or less 1 101 Over the last 3 days, when you slept at night, did you use: 1 pillow or less 2 or more pillows Over the la s t 3 days, when you got up i n the morning, did you feel rested t i r e d Over the last 24 hours, how far could you walk on the le v e l at a comfortable pace and in good weather: 1 block or less 2 blocks 3 blocks 4 blocks 5 or more blocks In this past week, did you participate i n exercise that involved: no s p e c i f i c exercise recreational a c t i v i t i e s a regular program once a week for at least 10-20 minutes a regular program 2 times a week for at least 10-20 minutes a regular program 3 times a week for at least 10-20 minutes Ci r c l e the category which best describes the maximal l e v e l of a c t i v i t y that you could perform on average over the la s t 3 days: self-care reading or watching TV desk work driving a car walking at 1 mph cooking car repair walking at 2 mph bicycling at 5 mph bowling golfing with motorcart general housework pushing l i g h t powermower walking at 3 mph bicycling at 6 mph golfing with handcart badminton [doubles] heavy housework or repairs raking leaves or grass golf [carrying clubs] dancing slow swimming tennis [doubles] digging i n the garden walking at 4 mph bicycling at 10 mph hiking or skating mowing lawn with hand mower walking or jogging at 5 mph bicycling at 11 mph li g h t downhill skiing tennis [singles] 1 0 2 APPENDIX B INTERRELATIONSHIP OF VENTILATION INHOMOGENEITY AND AIRFLOW LIMITATION IN AN ASTHMATIC SUBJECT PRE AND POST BRONCHODILATION Introduction: Asthmatics are commonly prescribed bronchodilators to decrease t h e i r airflow l i m i t a t i o n i n the management of t h e i r disease. The e f f e c t of bronchodilators on airflow obstruction has been well documented [Paterson et a l , 1979]. Since an abnormal FEV 1 t F E F25_75%^ a n d SBN2/L% are determined by d i f f e r e n t pathophysiologic processes, i t i s of inte r e s t to follow the e f f e c t of bronchodilation on these tests and the pathophysiology that influences them. Thus, these tests were conducted i n an asthmatic subject pre and post bronchodilation. Methods; 1. Subject C h a r a c t e r i s t i c s . The subject was a 22 year old male, 178 cm i n height and 77.3 kg i n weight. He was diagnosed as a c h i l d and experienced frequent respiratory infections throughout his childhood, but was able to attend school on a regular basis and keep up with his peers. At the time of the study, he was working f u l l time as a carpenter and p a r t i c i p a t e d i n recreational a c t i v i t i e s . On 103 the questionnaire, he reported that he was not troubled with breathlessness except with strenuous exercise and that he was capable of the maximum a c t i v i t y l e v e l on the questionnaire [6-7 METS]. He used a Ventolin® inhaler, 2 puffs bid, on a regular basis. He reported that although his inhaler gave him r e l i e f , i t was l i m i t e d i n degree and duration. 2. Procedure. During one test session t h i s subject repeated the complete tes t protocol as outlined i n the methods [with the exception of the questionnaire] following the use of his bronchodilator. He used two puffs of his Ventolin® inhaler and then rested for 15 minutes. Following t h i s , he repeated the test sequence i n the same order as he had i n i t i a l l y . Results: The subject completed both of the test protocols without any d i f f i c u l t y . Throughout the test session he exhibited a prominent wheeze at rest which was accentuated during the t e s t s . Although t h i s wheeze was less pronounced post-bronchodilation, i t was s t i l l c l e a r l y evident. The subjects test results pre and post bronchodilation, and the percent change, are summarized i n the Table. The FEV^ improved by 34.2% and the F E F 2 5 _ 7 ^ improved by 44.8%, while the SBN«/L% appeared to worsen by 10.9%. 104 TABLE SPIROMETRY AND SBN9/L% RESULTS* PRE AND POST BRONCHODILATION IN AN ASTHMATIC SUBJECT FEV 1 Pre-bronchodilator** 56.7 Post-bronchodilator 76.1 % change 34.2 44.8 10.9 * Values expressed as % predicted. ** Bronchodilation was performed with a Ventolin - 7 Salbutamol inhaler [2 p u f f s ] . FEF 25-75% SBN2/L% 30.8 147.3 44.6 163.4 105 Discussion: Previous work i n asthmatics has shown that the FEV^ consistently increases and SBN2/L% consistently decreases following bronchodilation [Olofsson et a l , 1985]. However, the VC had increased by almost as much as the FEV^ i n these subjects. Deychakiwsky et a l [1985] had observed a poor c o r r e l a t i o n between changes i n airflow l i m i t a t i o n and v e n t i l a t i o n d i s t r i b u t i o n following bronchoconstriction. Thus, Sackner et a l [1977] concluded that the FEV1 i s a more sensit i v e indicator of change following bronchodilation than the SBN2/L%. This conclusion may account for the res u l t s seen i n t h i s subject wherein the SBN2/L% increased somewhat i n comparison to the increase i n FEV^ and FEF 2^_ 7^^. The findings i n the present study may also be explained by the r e l a t i v e contributions of central and peripheral airway obstruction. It i s possible that the bronchodilator acted to r e l i e v e a s i g n i f i c a n t portion of the central airway obstruction and less of the peripheral obstruction. In addition, the r e l i e f of the peripheral obstruction may have been non-uniform, which would contribute to v e n t i l a t i o n inhomogeneity. These explanations can only be hypothesized however, since the discussion i s based on the r e s u l t s of only one subject. Thus, the re l a t i o n s h i p between indices of airflow l i m i t a t i o n and v e n t i l a t i o n inhomogeneity requires further study. 106 

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