OBSTRUCTIVE DISEASE OF THE AIRWAYS IN CYSTIC FIBROSIS

(1)

(Received April 22; revision accepted for publication June 27, 1967.)

Supported in part by Research Grants (5 ROl HE 0801503) from the National Institutes of Flealth, Public Health Service, with additional support from the Health Research Council contract No. U1613 and the New York Heart Association.

R.B.M. is recipient of Career Development Award No. 1-K 3-HE 31,667, National Institutes of

Health, Public Health Service; 0.R.L. is recipient of Career Scientist Award, Contract 1-259, New York City Health Research Council; R.H.I., Jr., is Postdoctoral Research Fellow, National Institutes of Health, Public Health Service.

Presented, in part, at the April 1967 meeting of the Society for Pediatric Research, Atlantic City, New Jersey.

ADDRESS: (A.PF.) Cardiovascular Institute, Michael Reese Medical Center, 29th Street and Ellis Avenue, Chicago, Illinois 60616.

PEDIATRICS, Vol. 41, No. 3, March 1968 560

OBSTRUCTIVE

DISEASE

OF THE

AIRWAYS

IN CYSTIC

FIBROSIS

Robert B. Mellins, M.D., 0. Robert Levine, M.D., Roland H. Ingram, Jr., M.D.,

and Alfred P. Fishman, M.D.

Departments of Pediatrics and Medicine, Columbia University, College of Physicians and Surgeons, and The Cardiorespiratory Laboratory of The Presbyterian Hospital, New York, New York

ABSTRAc’F. A study of the interrelationships of

instantaneous air flow, lung volume, and transpul-monary pressure over the range of the vital capac-ity has demonstrated striking differences in the de-terminants of maximum expiratory flow in cystic

fibrosis and asthma. At high lung volumes,

max-imum expiratory flow rates in asthma are limited by the mechanical characteristics of the lungs and airways, whereas in cystic fibrosis and in the nor-mal they are dependent on effort. At lower lung

volumes, maximum expiratory flow rates are

rela-tively more reduced in cystic fibrosis than in

asthma and pressures in excess of those required to produce maximum flow actually depress flow. Also, forced expiration is associated with a transient

re-versa! in the slope of the single breath nitrogen curve in cystic fibrosis and not in asthma.

From these studies it is concluded that: (1) air-way obstruction is less uniform and involves larger airways in cystic fibrosis than in asthma, and (2) increased expiratory pressure is associated with col-lapse of some of the larger airways over most of the range of the vital capacity in cystic fibrosis.

A major clinical implication of these studies is that the effectiveness of cough is impaired by large airway collapse in cystic fibrosis. Pediatrics,

41:560, 1968, CYSTIC FIBROSIS, ASTHMA,

OBSTRUC-TIVE DISEASES OF AIRWAYS, PULMONARY FUNCTION

TESTS, MECHANICS OF BREATHING, BRONCHIAL OB-STRUCTION.

P

REVIOUS STUDIES in this laboratoryl and

elsewhereZ have demonstrated that

pulmonary disability in cystic fibrosis

devel-ops from bronchial obstruction with little or

no involvement of the parenchyma by

em-physema. Also, in a separate study based on

the technique of Fry and Hyatt3 for

analyz-ing the mechanics of breathing, we found

characteristic alterations in the relationship

of air flow, transpulmonary pressure,#{176} and

lung volume in the presence of bronchial

obstruction resulting from asthma. The

most characteristic feature of the asthmatic

#{176}Transpulmonary pressure is the difference in pressure between the pleural space and the mouth.

attack was the occurrence of maximum

rates of air flow at low transpulmonary

pressures, even when the lungs were

over-distended; little improvement in the rates

of air flow was accomplished by increasing

pressure. Thus, in asthma, maximum rates

of expiratory air flow over the entire range

of the vital capacity seem to be limited by

the dimensions of the airways and not by

the driving pressure. In the present study

the technique of Fry and Hyatt has been

applied to the study of patients with cystic

fibrosis in the attempt to determine the sites

and mechanisms of obstruction, using

nor-mal subjects and patients with asthma for

(2)

ARTICLES

SUBJECTS

The physical characteristics and

physio-logical data of the 31 children in the

pres-ent study are given in Table I. The

chil-dren may be divided into three groups: the

first consists of 8 normal children, the

sec-ond of 10 children with asthma, and the

third of 13 children with cystic fibrosis. The

three groups are comparable with respect

to range of age and size. The patients with

acute asthma and cystic fibrosis had: (1)

reduced vital capacity,

(

2

)

increased

resid-ual volume

(

when compared to the

nor-mai, the residual volume represented an

in-creased fraction of the total lung capacity),

(3) reduced peak expiratory flow rate, (4)

increased inspiratory and expiratory air

flow resistance (reflected also by a reduced

maximum breathing capacity), and (5)

re-duced dynamic compliance. Between acute

attacks in the asthmatic patients, these ab-normalities reverted toward normal.

METHODS

The method used to study the dynamic

behavior of the lung was based on that of

Fry and Hyatt3 and has been described in

detail previously.4 In brief, it involves the

continuous recording of air flow, lung

vol-ume, and transpulmonary pressure during

tidal breathing and during vital capacity

maneuvers performed with increasing

ex-piratory effort. Simultaneous flow-volume

and flow-pressure curves were recorded by

means of an oscilloscopic recording

appara-tus. Each tracing was interrupted at 0.04

second intervals in order to compare

cone-sponding values of pressure, flow, and

vol-ume with respect to time. Although the

rec-ords include the entire respiratory cycle,

only expiration was studied in detail.

The rate of air flow was measured with a

Silverman-type pneumotachograph

con-nected to an appropriate pressure

trans-ducer. The screen was electrically heated

and periodically flushed with compressed

air to keep it dry. For subjects with high

flow rates a large pneumotachograph was

used with a screen 83 mm in diameter. It

produced linear responses up to a flow rate

of 10 1 per second. For subjects with low

flow rates, a smaller pneumotachograph

was used with a screen 44 mm in diameter.

It produced linear responses up to a flow

rate of 3 1 per second. The time lag

follow-ing a sudden burst of air through the

pneu-motachographs was less than 0.004 second.

Changes in respired volume were

deter-mined by electrical integration of the flow

signal. Esophageal pressure was measured

with a balloon catheter system conforming

to the specification of Milic-Emili5 and was

used as a measure of pleural pressure.

The slope for dynamic compliance was

obtained from the pressure-volume loop by

electrical subtraction from the pressure

sig-nal of a voltage proportional to air flow.

The slope for inspiratory and expiratory air

flow resistance was obtained from the

pres-sure-flow loop by electrical subtraction

from the pressure signal of a voltage

pro-portional to volume.6

The functional residual volume was

de-termined by the nitrogen washout method.

The alveolar nitrogen concentration was

determined at the end of 7 minutes and

was used as a measure of the evenness of

distribution of inspired air. Since the error

in underestimating the functional residual

volume in the presence of severe airway

ob-struction has been shown to be less than

10% when a 15 minute washout period is

used,8’#{176} the test period was extended to 15

minutes in those patients with evidence of

very poor distribution as trbitrarily defined

by 7-minute alveolar nitrogen

concentra-tions above 7%. The concentration of

nitro-gen at the mouth was analyzed

contin-uously by a rapid nitrogen analyzer of the

Lilly-Hervey type. The nitrogen analyzer

was calibrated using gas mixtures, the

com-position of which was established by the

micro-Scholander technique. The time lag

following the sudden burst of gas across the

sampling needle of the analyzer was less

than 0.04 second.

The distribution of ventilation was also

assessed from a continuous record of

ex-pired nitrogen during a forced vital

(3)

562 CYSTIC FIBROSIS

TABLE I

SUMMARY OF PhYsIcAL CHARACTERISTICS AND PHYSIOLOGICAL DATA*

Data Normal

Asthma

(11t

Fibrosis Acute Attack

8 Minutes

After

Bronchodilator

Asymptomatic

Number of Subjects 8 10 10 6 13

Age(yr) H 1.5 1.5 13 1.3

(8-15) (11.5-14) (11.5-14) (H-14) (8-18)

v.C. 100 48 69 1O2

% predictedt (86-113) (31-79) (40-91) (78-H7) (35-71)

T.L.C. 99 94 lii 93

%

predictedt (88-110) (63-1’2) (90-130) (55-116)

RV(FLCXIOO 4 44 31 56

% (1-7) (9-59) (24-39) (3’2-73)

7minute 0.8 4.1 1.0 6.7

Alv.N2% (0.4-1.1) (1.6-6.7) (0.4-1.7) (.9-13.2)

M.B.C. 73 24 45 89 59

1/minute/M2 (5-9O) (10-50) (5-79) (77-IH) (17-101)

R1 4.3 0.0 7.8 3.1 8.5

cm 1120/l/second (1.4-6.4) (6.8-37.0) (2.5-10.9) (1.9-4.7) (3.3-19.9)

RE 5.9 27.7 11.1 5. 11.1

cm 1120/1/second (.8-9.O) (7A-54.0) (3.8-0.7) (3.2-10.6) (6.O-27.0)

C/FRC .063 .02O .039 .066

mi/cm 1120/ml (.051-071) (.013-.08) (.018.063) (.040-085) (.011-039)

PEFR 5.5 1.4 5.6

1/second (4.1-6.8) (0.5-1.6) (0.6-4.8) (3.-6.9) (1.5-5.0)

MEF?S/MEFI .9 3J2 3.1 7.3

(1.9-.S) (.3-S.7) (1.8-4.3) (.3-3.7) (3.5-11.0)

PPI -5 -6 -p24 -‘21 -fl

cm 1120 (- 18 to -3) (-1 to -30) (- 15to -3) (- 18 to -30) (- 18 to -3)

* Mean and range; range is in parentheses.

t Calculated on the basis of the predicted values, according to height, of Cook and Hamann 20

FRC during the acute attack calculated by subtracting the inspiratory capacity during the acute attack from T.L.C. obtained after the inhalation of a bronchodilator.

(4)

FLOW-VOLUME FLOW-PRESSURE

FLOW

Lit/sec

FLOW

Lit/sec

3

LUNG VOLUME

Lit

0-4O 0 +40

PRESSURE

cm H20 ARTICLES

100% oxygen from the tidal end-expiratory

position. The rate of air flow, the volume of

air expired, and the transpulmonary

pres-sure were recorded simultaneously with the

concentration of nitrogen in expired air.

PROCEDURE

The nasopharynx was anesthetized with

lidocaine (Xylocaine) and the bailoon

catheter was introduced into the esophagus.

Its position in the mid-esophagus was

ad-justed to avoid artefacts arising from the

upper esophagus.1#{176} The patient was trained

to produce an expiratory flow-volume curve

of maximum area (left portion of Fig. 1) as

previously reported. In brief, the nose was

clamped and the patient breathed quietly

through the pneumotachograph; on

corn-mand he inspired to peak inspiration and

then exhaled forcefully down to a residual

volume. During the procedure,

simulta-neous flow-volume and flow-pressure curves

were recorded. This procedure was

re-peated several times with different degrees

of expiratory effort until an expiratory

flow-volume curve was recorded which

repre-sented the maximum achievable flow at

each volume throughout the vital capacity.

Each patient was then given 2.25% racemic

epinephrinef by aerosol and the procedure

was repeated. Those curves which

repre-sent the maximum expiratory flow at each

lung volume are designated maximum

ex-f Vaponefrin; courtesy of U.S. Vitamin and Pharmaceutical Corporation, 800 Second Avenue, New York, New York.

NORMAL, WM.

Fic. 1. Simultaneous flow-volume (left) and flow-pressure (right) curves of

W.M. (a healthy, 12-year-old boy) recorded during a maximum flow vital

capacity maneuver. The volume of air in the lung is plotted on the abscissa. Air flow is plotted on the ordinate with inspiration below and expiration above the abscissa. Beginning at the end of a quiet expiration, a and s re-spectively, these curves were recorded during a normal tidal breath (small loops) and during a forced expiration from peak lung inflation, b and t re-.spectively, to full expiration, e and p respectively. Peak expiratory flow

rates are reached at c and u. Expiration then continues along segments

c-d-e and u-v-p. Each point on the expiratory portion of the flow-volume

curve represents the maximum flow achievable at that lung volume. The

(5)

FLOW-VOLUME FLOW-PRESSURE

2 2

FLOW

Lit/sec o

FLOW

Lit/sec o 2

CYSTIC FIBROSIS, BR.

FLOW

O Lit/sec

FLOW

O Lit/sec 2

LUNG VOLUME

Lit

0-40 0 +40

PRESSURE

cm H20

564

ASTHMA,

PC.

EXP

7INSP

3 2 I

FIG. 2. Simultaneous flow-volume and flow-pressure curves of P.C., a 13-ear-old boy with acute asthma (top), and B.R., a 10-year-old girl with cys-tic fibrosis (bottom). As in Figure 1, each point on the expiratory portion of

the flow-volume curve represents the maximum flow achievable at that lung volume. In the asthmatic patient, maximum expiratory flow rates are re-duced over the entire range of the vital capacity and are achieved with relatively low transpulmonary pressures, even at high lung volumes. In

cystic fibrosis, maximum flow rates are greater in the top portion of the

vital capacity and less in the lower portion.

piratory flow-volume (MEFV) and

maxi-mum expiratory flow-pressure (MEFP)

curves.

RESULTS

The left half of Figure 1 illustrates the

normal MEFV curve of W.M., a healthy,

12-year-old boy. After reaching peak flow

(c) in early expiration, flow descends along

segment c-d-e as lung volume decreases.

The right half of Figure 1 shows the normal

M EFP curve simultaneously inscribed.

From the point of peak inflation (t) at -24

cm H20, flow rises sharply in expiration

reaching peak flow with a pressure of +55

cm H20 at point u4 None of the normal

children we have studied has been able to

exceed these pressures without first closing

the glottis or mouthpiece. Within the range

of pressures generated at high lung

vol-umes the relation of pressure to flow has

been direct and positive in all normal

chil-dren. As expiration proceeds, maximum flow

rates lower in the vital capacity (d-e) are

achieved with progressively lower pressures

(v-p). Thus, in the normal child, maximum

flow in the top portion of the vital capacity

is pressure dependent, i.e., depends on

ef-fort, and is limited by the velocity of mus-cle contraction; but, lower in the vital

ca-pacity, maximal flow is limited by the

(6)

FLOW-VOLUME FLOW-PRESSURE .-u

EXPt

_________

FLOW

INSP

1

0 Lit/sec

2

0

2

0

B. R.

2

I FLOW

0 Lit/ sec

Lit

The upper portion of Figure 2 shows the

MEFV and MEFP curves of P.C., a

13-year-old boy, during an acute attack of

asthma. As indicated previously, such

curves are characteristic of the acute attack.

Although this patient is of comparable size

and total lung capacity to the normal

sub-ject, W.M., the vital capacity (b-e) is

smaller and maximum flow rates are

re-duced over the entire range of the vital

ca-pacity. Peak flow (c) is achieved ‘vith a

pressure of +8 cm water. Pressures

exceed-ing this value at the same lung volume did

not increase peak flow. Thus in contrast to

the normal, in asthma the mechanical

prop-erties of the lungs limit flow even at high

lung volumes.

The lower portion of Figure 2 shows the

MEFV and MEFP curves of B.R., a

10-year-old girl with cystic fibrosis. Similar

curves were obtained from each patient

with cystic fibrosis. This patient is of

com-parable size and total lung capacity to the

normal and asthmatic subjects previously

discussed. Although maximum flow rates

are below those of the normal, when

com-pared to the asthmatic subject, the depres-sion of flow is relatively less in the top por-tion of the vital capacity and relatively

4o

LUNG VOLUME PRESSURE

cm/H20

FIG. 3. The upper portion shows the maximum expiratory flow-volume and

flow-pressure curves of P.C., the same asthmatic patient shown in Figure 2, following the inhalation of a bronchodilator. The vital capacity (b-c) is in-creased, primarily as the result of an increase in the expiratory reserve vol-ume, (a-c) and higher maximum flow rates are achieved throughout. Maxi-mum flow rates near the top of the vital capacity (c) are now achieved with higher pressures (u). The lower portion shows the maximum expiratory

flow-volume and flow-pressure curves of BR., the same patient with cystic

fibrosis shown in Figure 2, following the inhalation of a bronchodilator.

When compared with the curves in the lower portion of Figure 2, very

(7)

flows

(

c

)

are seen at higher pressures

(

u)

than in asthma. Maximum flow rates high

in the vital capacity, though less than

nor-mal, increase directly with pressure. Thus,

in contrast to the asthmatic subject and

similar to the normal, velocity of muscle

contraction rather than the mechanical

prop-erties of the lung limits flow high in the

vital capacity. Lower in the vital capacity

flow is limited in all three groups by the

mechanical properties of the lung. Also of

note is the observation that flow during the

expiratory phase of tidal breathing is usually

close to maximal levels in cystic fibrosis.

The difference in the degree to which

maximum flow is affected by lung volume

in asthma and in cystic fibrosis is revealed

by an analysis of the ratios of maximum

ex-piratory flow at 75% of the vital capacity to

that at 25% of the vital capacity

(

MEF75/

MEF25

)

in Table I. When compared to the

normal, this ratio is slightly elevated in acute

asthma and markedly elevated in cystic

fibrosis.

Inhalation of the bronchodilator,

race-mic epinephrine, was without effect on the

MEFV and MEFP curves of the normal.

The upper portion of Figure 3 shows the

MEFV and MEFP curves of P.C., the same

asthmatic patient shown in Figure 2,

fol-lowing the inhalation of the bronchodilator.

The vital capacity (b-e) is enlarged

primar-ily as the result of an increase in the

expir-atory reserve volume (a-e) and maximum

flow rates are higher throughout. Peak flow

(c) is higher and is reached at a higher

pressure, i.e., +29 cm water pressure (u).

Although maximum flow rates at the top of

the vital capacity are now higher,

examina-tion of several sets of flow-volume and

flow-pressure curves indicate that, in

con-trast to the normal, they are still achieved

with pressures well below maximum effort.

Thus, flow is still limited by the mechanical

properties of the lungs. The lower portion

of Figure 3 shows the MEFV and MEFP

curves of B.R., the same patient with cystic

fibrosis shown in Figure 2, following the

in-halation of the bronchodilator. There is a

small increase in the vital capacity and

peak flow. In general, however, there is

lit-tie change in maximum flow rates, or the

pressures at which they are achieved, and

by inference in the mechanical properties

of the lung. This was also the case for the

other patients with cystic fibrosis.

In order to show the relationship

be-tween pressure and flow at fixed expired

volumes, the data from several sets of

flow-volume and flow-pressure curves has been

replotted as families of isovolume

pressure-flow curves11 in Figures 4 and 5. In the

nor-mal, except for the top curve which

repre-sents flow rates at 90% of the total lung

ca-pacity, each of these demonstrates

flow-max-ima, i.e., points on the pressure-flow curve

indicated by the arrow beyond which

in-creased pressure results in decreased flow.11

These occur at progressively lower

pres-sures with decreasing lung volume. The

upper portion of Figure 5 shows the

isovol-ume pressure-flow curves for asthmatic

subject S.B. Flow is seen to reach a plateau

at relatively low pressures. Flow remains

constant over a wide range of pressures and

does not appear to decrease until pressures

exceed +40 cm water. These curves

con-trast with those shown for patient E.H.

with cystic fibrosis (lower panel). As in the

normal subject, flow-maxima are not seen at

high lung volumes (95% of the total lung

capacity). At lower lung volumes, flow

de-creases rapidly beyond the flow-maxima.

Single breath nitrogen curves recorded

during the performance of a forced vital

ca-pacity are shown in Figures 6 and 7. The

record of the transpulmonary pressure

dem-onstrates that the degree of effort used

dur-ing the performance of this maneuver was

comparable to that in Figures 1 and 2. In

the normal subject (Figure 6) the nitrogen

curve rises rapidly as the dead space

oxy-gen is cleared and then reaches a plateau as

alveolar gas is expired. In asthma (upper

portion of Figure 7), the portion of the

curve representing alveolar gas shows a

prolonged rising slope in contrast to the

normal plateau. The shape of this portion

of the curve is not altered significantly,

(8)

% TLC

S-90

X-80 0-70 1-60

to-40

=

+20 +30 +40 5O

-10 0 +10

PRESSURE

cm/H20

567

FLOW

Lit/sec

4

3

2

0

FIG. 4. Isovolume pressure-flow curves for the normal subject, W.M.,

re-corded from above downwards at 90, 80, 70, 60, and 40% of the total lung

capacity (TLC). Flow-maxima indicated by the arrows are seen in each curve except the top one.

cystic fibrosis, the alveolar portion of the

nitrogen curve is particularly sensitive to

the degree of effort used. With moderate

effort there is usually an initial plateau

sim-ilar to that of the normal, followed by a

ris-ing slope. W7ith more forceful expiration

(lower Portion of Figure 7) there is a dip

or transient reversal of the slope in the

ini-tial plateau followed by a progressive rise

in the nitrogen curve. A marked change in

slope of the nitrogen curve during

expira-tion of alveolar gas was seen in all of the

patients with cystic fibrosis; a dip or

rever-sal of slope was seen in 10 of the 13

pa-tients.

COMMENT

The present work relating air flow,

vol-ume, and pressure over the range of the

vital capacity has demonstrated striking

differences in the determinants of maximum

flow in asthma and cystic fibrosis. In the

normal child, flow rates at the top of the

vital capacity depend chiefly on effort since

the lungs and airways are not flow limiting

at high lung volumes. Flow-maxima, and

therefore flow limitation by the lungs and

airways, are seen only at lung volumes

below 90% of the total lung capacity (Fig.

4). In the top portion of the vital capacity,

maximum rates of air flow are reached with

lower expiratory pressures in acute asthma

than in cystic fibrosis. Furthermore,

flow-maxima are not seen at the top of the vital

capacity with any of the expiratory

pres-sures of which tile patients with cystic

fibrosis are capable. Thus, maximum flow

(9)

2

CYSTIC FIBROSIS, E.H.

PRESSURE

cm/ H20

+ 50 568

FLOW

Lit/sec

0

2

FLOW

Lit/sec

0#{149}

ASTHMA,

S.B.

FIG. 5. Isovolume pressure-flow curves in SB. with asthma (top) and Eli.

with cystic fibrosis (bottom). From above downwards these curves are

re-corded for each patient at 95, 90, 85, 80, and 75% of the total lung capacity

(TLC). In asthma, once maximum flow rates are achieved, flow remains

con-stant until transpulmonary pressures are above +40 cm water. In cystic fibrosis, flow-maxima indicated by the arrows are seen in each curve except the top one, and flow decreases markedly as pressures exceed those required

to produce maximum flow.

effort in cystic fibrosis, whereas they are

limited by the mechanical properties of the

lungs and airways in asthma. In the

mid-portion of the vital capacity, maximum flow

rates are markedly curtailed in both

condi-tions and are produced with only small

pressures. However, while flow rates

re-main constant as pressure exceeds that

nec-essary to produce maximum flow in acute

asthma (upper portion, Fig. 5), they are

actually decreased by excessive expiratory

pressures in cystic fibrosis (lower portion,

Fig.5).

There are at least two possible

explana-tions for the differences in tile degree to

which maximum flow is altered at high and

low lung volumes in cystic fibrosis and in

asthma.

1. The retractive force of the lung may

be increased to a greater extent at high

lung volumes in cystic fibrosis resulting in

an increased dilating force on the airways.

The observation (Table I) that pressures at

peak inspiration in the patients with cystic

fibrosis are in the same range as in asthma

argues against this possibility.

2. Non-uniformity of airway obstruction

(10)

80

NITROGEN 40

0

+40

0

-40

PRESSURE

om/H,O

FLOW

Lit/sec

569

The observation that in cystic fibrosis flow

always increases with pressure high in the

vital capacity suggests that at high lung

volumes some airways are capable of

func-tioning normally and, by inference, that the

areas of lung parenchyma surrounding

these airways are relatively normal. That

the level of peak flow is lower than normal

in cystic fibrosis may be attributed to a

smaller volume of normally functioning

lung and to weakness of those muscles

re-sponsible for maximal expiratory effort. The

marked decrease in flow in the lower

por-tion of tile vital capacity may then be

at-tributed to the emptying of poorly

venti-lated areas through obstructed airways, the

lumens of which become progressively

smaller with decreasing lung volume.

Sup-port for this possibility is given by the

ob-servation that the slope of the alveolar

por-tion of the single breath nitrogen curve is

relatively flat initially and relatively steep

in its terminal portion.

The initial plateau in the alveolar portion

of the single breath nitrogen curve in cystic

fibrosis indicates that lung units receiving a

relatively large share of the inspired

oxy-gen, i.e., well ventilated areas, empty early

in expiration. Evidence suggesting that,

even in this portion of the vital capacity,

there is a small contribution to expiration

from poorly ventilated regions is provided

by the transient reversal in slope seen with

more forceful expiration (lower portion,

Fig. 7). As the rate of application of the

driving pressure increases, there is a

rela-tive decrease in the contribution of gas

from obstructed areas, i.e., those airways

with high time constants,12 which is

indi-cated by momentary decrease in the

con-centration of expired nitrogen. The failure

to detect a change or reversal in slope of

the nitrogen curve during forceful effort in

asthma suggests that: (1) there is more

uniform involvement of airways in asthma

than in cystic fibrosis, and (2) such

non-uni-formity as exists in asthma occurs between

smaller lung units than in cystic fibrosis,

presumably as the result of obstruction of

smaller airways.

Significance of Decreasing Flow with Increasing Pressure in Cystic Fibrosis

It has been demonstrated that the

magni-tude of decrease in flow from maximal

lev-els as pressure increases is in part an

arte-fact related to the fact that, because of gas

compression at high intrathoracic pressure,

lung volume and hence airway size are

smaller than would be calculated from

2 VOLUME

Lit

0

(11)

looso,

NR0GEN

FLOW

PRESSURE cm 110

VOLUME LI?

&

100 S CYSTIC FiBROSIS, J. D.

MIROGEN

C

FIG. 7. Single breath nitrogen curves (FEN,) for P.C., with asthma (top), and J.l)., with cystic fibrosis (bottom). As inFigure 6, these were recorded during a forced

vital capacity maneuver and transpulmonary pressure (P), expiratory air flow rate

(F), and lung volume (V) are included. In contrast to the steady rise in the alveolar

portion of the FE,,. curve in asthma, there is a transient dip in the curve of the

patient with cystic fibrosis.

measurements of volume at the mouth.13

The fact that the total lung capacities are

comparable in cystic fibrosis and asthma

and that the expiratory pressures are the

same or higher in asthma suggests that the

difference in the shapes of the isovolume

pressure-flow curves in these two conditions

cannot be attributed simply to gas

compres-sion. In studies in which flow and pressure

are measured at fixed lung volumes

deter-mined plethysmographically,14 there is

nev-ertheless a decrease in flow from maximal

levels as pressure increases in some

sub-jects. In order to explain this decrease in

flow with increasing pressure as well as to

analyze the mechanism limiting flow during

expiration in the normal, Mead, et al.14

have found it useful to develop the concept

of the equal pressure point (EPP), i.e., the

point along the airways where the pressure

at the inner wall equals pleural pressure.

The pressure drop from the alveoli to this

point is equal to the static recoil pressure of

the lung, while the pressure drop from this

point to the outside is equal to pleural

pres-sure. Any compression of airways must occur

downstream, or proximally, from the EPP.

Since the driving pressure of tile upstream

or distal segment is fixed at any given lung

volume, flow through this segment can only

increase by the movement of the EPP,

dis-tally shortening the upstream segment and

decreasing its resistance. Once maximum

flow has been reached, this implies that the

EPP has stopped moving upstream. When

pressures in excess of those necessary to

pro-duce maximum flow are associated with a

fixed flow rate, this implies that there has

ASThMA, PC.

+40

L

PRESSUREcm IlO

FLOW

III

Lc F

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571

Fic. 8. Single frames from cineradiographic studies of the aivays of a patient with cystic fibrosis fol-lowing the instillation of propyliodone (Dionosil oily). Tile frame on the left, taken during inspiration, shows the lumina of tile bronchiectatic airways to be widely patent. Tile frame on the right, taken dur-ing forced expiration, demonstrates collapse of the proximal portions of the bronchiectatic aivays.

Simi-lar findings were noted during cough.

also been an increase in the resistance of the downstream segment which is proportional to the increase in pressure. That this occurs

in asthma is suggested by the plateau seen

in the isovolume pressure-flow curves.

Mead and co-workers have concluded that

a decrease in maximum flow as pressures

exceed those required to produce maximum

flow represents the movement downstream

(toward the mouth) of the EPP, increasing

tile resistance of

tue

upstream segment. If

we consider the lungs of the patient with

cystic fibrosis as a unit, a similar inference

may he drawn from the shape of the

isovol-time pressure-flow curves suggesting that

larger airways may collapse to an unusual

degree with high expiratory pressures in

this disease causing the EPP to move

down-stream, or proximally, with a concomitant

decrease in flow. On the other hand, if we

consider tile lungs to be composed of

seg-ments with grossly different time constants,

tile maximal expiratory flow rate will

de-pend not only on lung volume hut also on

time. Nonetheless, we would still be forced

to conclude from the shape of the

isovol-ume pressure-flow curves that: (1) high in

the vital capacity the EPP continues to

move upstream (away from the mouth) in

some airways over the range of pressures

generated by these patients, and

(

2

)

lower

in the vital capacity some of the larger

air-ways collapse with movement of the EPP

downstream (toward the mouth) once

pressures exceed those required for

maxi-mal flow.

Clinical Implications

The results of the present studies provide

physiological evidence in support of the

pathological demonstrations that asthma is

a diffuse process affecting small airways15”6

whereas cystic fibrosis is a patchy disease of

large airways, in which there is irregular

and saccular dilatation of the segmental

bronchi, with little evidence of excessive

al-veolar dilatation or disruption of respiratory

passages distal to the terminal bronchioles.1,l

The relatively greater increase in

maxi-mum flow rates as the volume of air in the

lungs increased in the patients with cystic

fibrosis suggests that they should be able to

improve ventilation to a greater extent than

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CYSTIC FIBROSIS

of the end-expiratory position. This

predic-lion is supported by the surprisingly high

maximum breathing capacities frequently

seen in the presence of extensive

pulmo-nary disease. Also, the measurement of

air-flow resistance is apt to be more variable in

patients with cystic fibrosis than with acute

asthma, depending upon the lung volume

at which it is measured.

Finally, the results of the present studies

suggest that cough is apt to be ineffective

in cystic fibrosis as the result of large

air-way collapse. Airways which are upstream

from the collapsed airways would be

ex-pected to retain secretions during a cough

or forced expiration. Confirmation of this is

provided by cineradiographic studies of the

airways of a patient with cystic fibrosis

(

Fig. 8

).

During forced expiration there is

collapse of the proximal segment of

bron-chiectatic airways with retention of contrast

media distal to the collapse. A similar

mechanism has been demonstrated to occur

in some patients with bronchiectasisl7 and

with bronchitis and emphysema.18

Hereto-fore, the increased viscosity and impaction19

of bronchial secretions have been held to be

mainly responsible for the ineffectiveness of

the cough mechanism in cystic fibrosis. The

existence of a second mechanism, i.e.,

col-lapse of the large airways during cough,

sug-gests the desirability of postural drainage

as a therapeutic measure for mobilizing

bronchial secretions since it does not involve

an increase in expiratory pressures and the

associated threat of bronchial collapse.

SUMMARY

A study of the interrelationships of

in-stantaneous air flow, lung volume, and

trans-pulmonary pressure over the range of the

vital capacity has demonstrated striking

differences in the determinants of maximum

expiratory flow in cystic fibrosis and

asthma. At high lung volumes, maximum

expiratory flow rates in asthma are limited

by the mechanical characteristics of the

lungs and airways, whereas in cystic fibrosis

and in the normal they are dependent on

effort. At lower lung volumes, maximum

ex-piratory flow rates are relatively more

re-duced in cystic fibrosis than in asthma and

pressures in excess of those required to

pro-duce maximum flow actually depress flow.

Also, forced expiration is associated with a

transient reversal in the slope of the single

breath nitrogen curve in cystic fibrosis and

not in asthma.

From these studies it is concluded that:

(

1

)

airway obstruction is less uniform and

involves larger airways in cystic fibrosis

than in asthma, and

(

2

)

increased

expira-tory pressure is associated with collapse of

some of the larger airways over most of the

range of the vital capacity in cystic fibrosis.

A major clinical implication of these

studies is that the effectiveness of cough is

impaired by large airway collapse in cystic

fibrosis.

REFERENCES

1. Goldring, R. Nt., Fishman. A. P., Turino,

C. M., Cohen, H. I., Denning. C. R., and

Andersen, D. H. : Pulmonary hypertension and cor pulmonale in cystic fibrosis of the

pancreas. J. Pediat., 65:501, 1964.

2. Bowden, D. H., Fischer, V. W’., an(l Wyatt,

J. P. : Cor pulmonale in cvsti fibrosis. Amer. J. Med., 38:226, 1965.

3. Fry, D. L., and Hyatt, R. E. : Pulmonary

me-chanics: A unified analysis of the relation-ship between pressure, volume and gas flow in the lungs of normal and diseased human subjects. Amer. J. Med., 29:672, 1960. 4. Mellins, R. B., Lord, C., and Fishman, A. P.:

Dynamk behavior of the lung in acute

asthma. Med. Thorac., 24:85, 1967.

5. Milic-Emili, J., Mead, J., Turner, j. M., and

Glauser, E. M.: Improved technique for

estimating pleural pressure from esophageal balloons. J. Appl. Phvsiol., 19:207, 1964. 6. Mead, J., and Whittenberger, j. L.: Physical

properties of human lungs measured (luring spontaneous respiration. J. AppI. Phvsiol., 5:779, 1953.

7. Darling, B. C., Cournand, A.. and Ricilards,

D. W., Jr.: Studies on the intrapulmonary mixture of gases. III. Tile open circuit method for measuring residual air. J. Clin.

Invest., 19:609, 1940.

8. Emanuel, C., Briscoe, \V. A., and Cournand, A.: A method for tile determination of the volume of air in the lungs: measurements in chronic pulmonary empllvsema. J. Ciin.

Invest., 40:329, 1961.

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A.: Reliabiiity of estimation of functional residual capacity in the emphysematous

pa-tient. Amer. Rev. Resp. Dis., 87:820, 1963.

10. Milic-Emili, J., Mead, J., and Turner, J. M.:

Topography of esophageal pressure as a

function of posture in man. J. Appl.

Physioi., 19:212, 1964.

11. Hyatt, B. E., Schilder, D. P., and Fry, D. L.:

Relation between maximum expiratory flow

and degree of lung inflation. J. Appl.

Physiol., 13:331, 1958.

12. Otis, A. B., McKerrov, C. B., Bartlett, R. A., Mead, J., Mcllrov, M. B., Selverstone, N. J.,

and Radford, E. P., Jr.: Mechanical factors in distribution of pulmonary ventilation. J.

AppI. Phvsiol., 8:427, 1956.

13. Ingram, R. H., Jr., and Schilder, D. P.: Effect of gas compression on pulmonary pressure,

flow and volume relationship. J. Appl.

Physiol., 21:1821, 1966.

14. Mead, J., Turner, J. M., Mackiem, P. T., and Little, J. B.: Significance of the relationship

between lung recoil and maximum

expira-tory flow. J. Appl. Physiol., 22:95, 1967.

15. Dunniil, M. S.: The pathology of asthma with

special reference to changes in the bron-chial mucosa. J. Clin. Path., 13:27, 1960.

16. Lowell, F. C.: Bronchial asthma. Amer. J.

Med., 20:778, 1956.

17. Fraser, R. C., Macklem, P. T., and Brown,

W. C.: Airway dynamics in bronchiectasis:

a combined cinefluoroscopic and

manomet-nc study. Amer. J. Roentgen., 93:821, 1965.

18. Macklem, P. T., Fraser, B. C., and Brown,

W. C.: Bronchial pressure measurements

in emphysema and bronchitis. J. Ciin.

Invest., 44:897, 1965.

19. Waring, W. W., Brunt, C. H., and Human, B. C.: Mucoid impaction of the bronchi in cystic fibrosis. PEDIATRICS, 39:166, 1967.

20. Cook, C. D., and Hamann, J. F.: Relation of

lung volumes to height in healthy persons

between the ages of 5 and 38 years. J. Pediat.,

59:710, 1961.

Acknowledgment

The authors are grateful to Dr. Carolyn R.

Den-ning for referring her patients for study and to Dr.

David H. Baker and Dr. Walter E. Berdon for

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1968;41;560

Pediatrics

Robert B. Mellins, O. Robert Levine, Roland H. Ingram, Jr. and Alfred P. Fishman