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1965

Exercise, carbon dioxide and cystic fibrosis: a pilotstudyMichael Brook MayorYale University

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BON DIOXIDE AND S A PILOT STUDY

ROO K M A YOR

■ § s

Digitized by the Internet Archive in 2017 with funding from

The National Endowment for the Humanities and the Arcadia Fund

https://archive.org/details/exercisecarbondiOOmayo

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EXERCISE, CARBON DIOXIDE

AND CYSTIC FIBROSIS >

A PILOT STUDY

Michael Brook Mayor, BEE.

Yale University, 1959

A thesis submitted to the faculty

of the Yale University School of

Medicine in partial fulfillment

of the requirement for the degree

of Doctor of Medicine.

Department of Pediatrics

Yale University School of Medicine

May 10, 1965

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ACKNOWLEDGE

My deepest gratitude goes to Dr. Vivian Tappan, without whom this

project would never have been initiated.

I want to extend heartfelt thanks to Dr. Guy Rivard and Katherine

Anlyan for the skill and time invested in the pulmonary function measure¬

ments, and to Dorothy Nixon for her advise and counsel over techniques

and equipment. I am indebted, also, to Dr. Norman S» Talner for the

use of his laboratory and equipment.

The final form of this paper owes a great deal to Joyce Heeley,

Elizabeth Kennard, and Barbara Dinner stein.

This Study was conducted in part under a Public Health Service

Summer Fellowship, PHS 1 SOL FR 05358-01.

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TABLE OF CONTENTS

page

Introduction .1

Materials & Methods .. .. 6

Results . ...... 9

Discussion . 12

Summary & Conclusion.22

Bibliography

Illustrations

follows page

1. Gas Sampling Assembly...7

2. Gas Sampling Assembly.7

3. Gas Collecting Bottle.7

4. Scholander Gas Analyzer . 8

5. Summing Point .. 15

6. Schenatic Diagram .. 15

7. Schenatic Diagram: Respiratory Center.15

8. CO2 1/2 time vs. age. 22

9. CO,_ 1/2 time vs. Classification.22

10. RV/TLC vs. COz 1/2 time. 22

11. RV vs. CO^ time. 22

12. VC vs. CO2 1/2 time .. 22

13. FRC vs. CO^ 1/2 time. 22

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INTRODUCTION

- 1

Cystic fibrosis is apparently an inborn error of metabolism with wide-

spread clinical and pathological effects. Its most intimate secrets, of

specific cause and detailed mechanism, are still fast. The flux in concept

of this disease had lead to a lack of definition and uniformity. The bio«

chemical changes in the exocrine glandular system are still speculative

and controversial.

Effects to clarify the genetic characteristics of the disease have lead

to the conclusion that it is probably recessive, and may or may not con¬

form to Mendelian genetic principles. Orzalesi et al, 1963, found no

significant abnormalities in sweat electrolytes, anamesis or pulmonary

function in the parents of children with cystic fibrosis.'*'

The cardio-pulmonary complications of the disease often become the

dominant determinants of its course as those with the disorder grow

2 beyond infancy. Therefore, as the disease progresses, the pulmonary

manifestations assume a critical position in the therapeutic control of

the disease.

The currently available laboratory tests of pulmonary function have not

provided unequivocal indicators of cardio-pulmonary status or of changes

3 4 5 in status 3 3 . In normals, the spirometric measurement of vital

capacity may have a range of values of as much as + 34% . Polgar &

Chernick (op. cit.) found that variations in the longitudinal study of

pulmonary functionwere generally independent of symptoms and therapy

in chronic obstructive lung disease. Cook et al (op. cit.) found the ratio

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of RV/TLC in patients with cystic fibrosis to have the best statistical

correlation with their clinical rating system. Mitchell et a], 1964,

analysed factors influencing prognosis in chronic obstructive broncho-

pulmonary disease . They found the RV/TLC of only "slight influence"

in predicting or correlating with mortality and disability.

In addition, significant changes occur in the performance of any

given individual on spirometric testing as a result of learning effect.

The same can be said of the values obtained by different technicians

testing the same individual, even with correction for the learning effect.

Pulmonary function testing, though a product and a tool of the science,

must constantly be interpreted with due regard for the art of the tester

and the degree of cooperation of the subject.

The purpose of this inquiry, then, is to design and evaluate a test of

cardio-pulmonary function which might provide a more sensitive measure

than current methods.

Considerable effort has been spent in an attempt to define the basic

pathophysiology of cystic fibrosis. The alterations of exocrine glandular

secretions are widespread, whatever their site of secretion in the bodies

of these patients. Certain complications of the disease can reasonably

be explained on the basis of the marked increase in the viscosity of these

secretions. These include: pancreatic enzymatic insufficiency secondary

to obstruction of the pancreatic ductules; focal biliary cirrhosis secondar

to intrahepatic biliary obstruction; recurrent pulmonary small-airway

obstruction and peri-bronchiolar inflammatory reaction, leading to

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atelectasis and recurrent pulmonary infection. In the older age group,

the cardio-pulmonary problems usually far outweigh the digestive dif¬

ficulties.

The airway obstruction, inflammation and recurrent infection may

produce pulmonary hypertension and cor pulmonale and widespread des-

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truction of lung tissue . The consensus of those studying pulmonary

function in cystic fibrosis is that there is no change in the total lung

capacity. There is a volumetric and dynamic picture consistent with

widespread airway obstruction, greater in expiration than inspiration.

A prominent early characteristic of pulmonary involvement is

9 atelectasis, which involves the right lung almost exclusively . The

net result is a loss of the normal distribution and mixing of inspired

air^. However, there is often no consequent change in the blood gas

values for CO^ and O^.

From the preceding, it comes apparent that cystic fibrosis is marked

by frequent exacerbations in the pulmonary arena, characterized early

by acute diffuse small airway obstruction, peri-bronchiolar inflammation,

bronchiolar thickening, early fibrosis and recurrent infection. Pro¬

gression and chronicity bring further fibrosis, emphysema, and inter¬

mittent hypoxemia with pulmonary hypertension. Hypercapnea and res¬

piratory acidosis, with and without compensation or complications, and

right heart failure may mark the disease.

All of the above pathological consequences could be prevented if

effective means could be found to bring the physical properties of the

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viscid secretions back to normal. Many forms of therapy directed

toward this end have been deviseds on the basis of the in vitro charac«

teristics of these secretions. Their therapeutic efficiency can finally

be judged only by in vivo demonstration of effectiveness. The need for

techniques that can dependably measure changes produced by the disease

and changes produced by therapy is obvious.

Procedures for the evaluation of cardio-pulmonary function have pro¬

liferated as a result. Many of these are very precise; yet all have

their limitations. Measurement of carbon dioxide or oxygen in exhaled

air or arterial blood can be very accurately performed. Frequently,

the values in the resting state are entirely within normal limits in the

face of significant disease. The discomfort and complications attendant

on arterial puncture pose additional problems. An oxygen equilibration

3 index, devised by Demuth et al , 1962, produced too many false positives.

The complicated interplay of cardiac and pulmonary and other factors,

compensatory change in one area balancing destructive change in another,

makes the interpretation of values obtained at rest difficult and at times

misleading.

With due regard for the dangers of over-simplification, two broad

categories emerge:

1. Parameters measurably effected by disease, which are, also,

significantly influenced by factors unrelated to disease; ie., those re¬

quiring maximum patient cooperation in their measurement.

2. Parameters subject to tight homeostatic control. Compensatory

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mechanisms, cardio-pulmonary, biochemical etc., keep these parameter s

within the normal range at rest. This is particularly true of carbon

dioxide values; arterial, venous, and alveolar.

These conditions prompted a search for a test of cardio-pulmonary

function which would accurately reflect the dynamic capacities of the

system.

A number of factors led to the study of the profile of CO^ output from

the lungs in response to exercise. One of the primary functions of the

cardio-pulmonary circuit is to maintain physiologic levels of carbon

dioxide in the circulating blood. The gradient for oxygen is from with¬

out inward; that for carbon dioxide the reverse, since almost all of

it arises from endogenous metabolic processes. The amount of CO^ to

be disposed of by the lungs can be increased by increasing the rate of some

of these metabolic processes. The increased muscular activity of exer¬

cise is one of the most physiological means for achieving such an increase.

This study was based on the assumption that elimination of CO^ by

the lungs, if followed from rest, through moderate exercise, to equili¬

brium following exercise, might show a time course significantly dif¬

ferent from the normal in patients with lung damage due to cystic fibrosis.

The advantages, in addition to those enumerated above, were: an ex¬

perimental protocol involving little patient discomfort, abundant material

in exhaled gas for analysis, and accurate and proven methods for measure¬

ment of gaseous CO^.

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MATERIALS AND METHODS

The experimental protocol described below was designed entirely by

the author, with the exception of the Scholander gas analysis of CO^

and

The patients participating in this study were drawn from the popu-

lation of cystic fibrosis patients under care of Dr. Vivian Tappan and

the Chest Metabolic Clinic of the Yale-New Haven Community Hospital.

They were fourteen in number, seven males from 5 —11/ 1Z to 16-5/12

years of age and seven females from 6-0/12 to 23-1/12 years of age.

Of the control group two were siblings of patients in the test, one

a 15-7/12 year old female, (B.L.), the other a 10-1/12 year old male

(D,Mt). The other four were volunteers drawn from among the pre¬

operative admissions to the Yale-New Haven Ear , Nose, and Throat

service for elective tonsil-adenoidectomies. Except for the hypertrophi

lymphoid tissue bringing them to operation they were entirely well. All

of the subjects tested had been going to school or working and came to

testing directly from their usual activities.

Each subject rested in the laboratory for at least fifteen minutes be¬

fore the first minute volume of exhaled air was collected.

The equipment used in the performance of this study was as follows:

Lanooy hyperbolic bicycle ergometer, 0-200/400 Watts

One-way 1J1 valve, 1" ID

British cloth-covered corrugated tubing, 7", 1" ID

Rubber mouth-piece & sponge-rubber nose clamp

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Aluminum "T" shape stop-cock, 3-way tap, 3/4" ID

Neoprene latex meteorological balloons, 30 L capacity

Precision Wet Test gas meter. Precision Sci. Co., 3L/rev.

Gas collecting tubes, glass, 125 ml

Gas sampling assembly, see fig. 1_

Scholander gas analyser

Each subject was an hour or more post prandial. Each was instructed

carefully in the techniques to be employed in the test. For each minute

volume collected in the meteorological balloon, the nose clip was placed,

the mouthpiece adjusted airtight, and the patient allowed fifteen to thirty

seconds to wash out the efferent limb of the system. The three way tap

on the stopcock was then turned to conduct the exhaled air into a

previously wrung-out balloon. After the lapse of exactly one minute,

the stopcock was returned to its initial position and the neck of the

balloon was clamped with a rubber shielded Kelly clamp.

Within ten minutes of its collection, three litres of sample were fed

through the wet test meter via the special connector (fig. 2) filling the con¬

nector with sample. The rubber section was clamped and disconnected

from the meter. The vaccine bottle stopper was driven down over the

nercury-filled sampling needle (fig. 3) and 150 ml of sample gas was

admitted to the glass collecting bottle as the mercury was drained from

it. The collecting bottle stopcocks were closed, the lower first and then

the upper, to ensure that no pressure gradient existed with room air.

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Fig 2: Sampling Assembly; note vacuum bottle stopper

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Fig. 3: Glass Collecting Bottle with Sampling Needle

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The connector was lifted off the needle* returned to the wet test meter,

and the remaining gas volume was measured. This procedure was

used for all of the six gas samples taken from each subject.

Precautions were taken to prevent loss of sample volume and contam«

ination with room air, including periodic tests of the integrity of the

balloons.

Minute volume samples were taken from the subjects as follows:

1: at rest, after ten to fifteen minutes sitting quietly in the

laboratory.

2: during the last minute of a six minute period of moderate exercise

the work load being judged according to the capacities of each

subj ect.

3: during the minute immediately following cessation of exercise.

4, 5, & 6: during the one minute intevals beginning 3, 7, and 19

minutes respectively following the cessation of exercise.

The six samples thus obtained were analysed from their gas collecting

bottles on the same day. Using the transfer pipette and the Scholander

gas analyser apparatus’^, (fig- 4), the percent concentration of COg

and C>2 of each sample was measured, and the minute volume of COg cal¬

culated.

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RESULTS

- 9

The protocol described above provided six values of CO^ output in

ml/min. for each subject. These values were processed to determine

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the time in minutes required for the V to fall to halfway between

° • the steady state V of exercise and the average resting V

y co2 co2

This time determination was made graphically on semilogarithmic

ruled paper. V was plotted logarithmically on the ordinate, and coZ

the midpoint in time of the minute during which the C02 was collected

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served as the abscissa coordinate. Three values of V were en» coz

teredo One, collected during minute 5 to minute 6 of exercise, is

the steady state value referred to above. The second is from the

minute volume collected immediately following exercise. The third

is from the minute volume collected next in sequence. This was usually

obtained starting three minutes after cessation of exercise. A best**

fitting straight line was drawn with these three values, plotted on semi-

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logarithmic ruled paper. The resting V is the average of the minute coz

volume collected before exercise and that collected 19 minutes after

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exercise. The V used to determine the 1/2 time was the average of

C°2 • •

the steady state exercise V and the resting V , and the 1/2 time co2 co2

was read as the time at which the best«fitting straight line defined

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above crossed the 1/2 time V co2

It was noted that the raw real CC>2 1/2 time tended to increase with

age, necessitating some correction. In order to make the results of

testing individuals of different ages comparable, the real CO^ 1/2 times

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determined for the normal subjects were plotted versus age to the

nearest month. A regression line was estimated and laid on the plot.

Only after this was completed were the points representing the patients

studied also plotted, as shown in fig. 8.

The regression line so determined was used to determine the pre¬

dicted CO2 1/2 time. For all the cystic fibrosis patients, the real

1/2 time, experimentally determined, and the predicted 1/2 time for

a patient of that age, taken from the regression line, were compared

yielding the % predicted 1/2 time for each patient.

A more refined analysis of the effects of exercise would have to

establish a more rigid relationship between age and exercise load. A

plot of 1/2 time versus exercise load was tried and did not appear to

offer significant advantages.

One of the patients studied (M. L.) could not be exercised except at

the lightest of exercise loads available (10 Kw). Her CO^ response curve

was so flat that her 1/2 time could not be determined with accuracy and

she was omitted from the study. All of the other patients and all of the

normal volunteers are included in the results.

In order to test the validity of the CO^ 1/2 time as an objective

measurement, it was compared with several other available methods

of evaluation.

The first of these is shown in fig. 9. A medically qualified observer

(V.T.) with intimate and long-term aquaintance with each of the patients

sorted each of the thirteen into one of three classes. These classes

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formulated on the basis of overall capacities for physical activity. In

class I were all those patients with no discernable difference from the

normal population in their reaction to physical activity. Class II con¬

tained those known to have minimal limitation} or slight dyspnea on

strenuous activity. In class III were those with moderate to severe

limitation, dyspneic on restricted activity. Fig. 9 shows a plot of the %

predicted l/Z time for each of the four groups: six controls, six

patients in class I, four in class II, and three in class III. The patient

omitted (M.L.) fell in class III. The small numbers ajoining each

point correspond to the kilowatt exercise load each individual sustained.

Comparisons were, also, made between the % predicted l/Z time

and several pulmonary function parameters. These were: RV/TLC

(fig. 10), RV (fig. 11), VC (fig. 1Z), and FRC (fig. 13). All were ex¬

pressed in terms of % of predicted value for those between age 5 and

4Z age 17, using the data of Helliesen et al . The two individuals over

17 years of age (C„ McM, a patient, and B.D., a control) were plotted

relative to the normal values for the adult cardiopulmonary laboratory

at this center.

The broken lines on figs. 9 through 13 represent the 100% levels

for the ordinate and ascissa where appropriate, to facilitate interpretation.

The units used to indicate work load are written Kw . These units

are unique to the Lanooy ergometer. They are not equivalent to

kilowatts.

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12 -

DISCUSSION

In discussing the findings of this exercise study it may be useful to

set them against the backdrop of some of the general and specific in¬

formation available about ventilation, CC>2 output, intake and

exertion.

Foremost among the functions of the cardio-pulmonary unit are the

maintenance of physiologic levels of oxygen, carbon dioxide and hydrogen

ion concentration. In a normal young male oxygen intake is about 250 ml,

CC>2 output is approximately 200 ml for a respiratory quotient of 0.8.

In the face of severe stress, his intake may increase up to 22 times,

and his CO^ output as much as fifty times these levels. Functional

reserve of this magnitude makes it possible to maintain normal resting

values of Pq and Pqq^ i-n the arterial blood in spite of severe lung

damage due to disease. For this reason, many authors have studied

patients under some form of stress, hoping to delineate the extent of

damage more accurately.

Consideration of these studies may be facilitated by review of some of

the factors involved.

Acute hypoxia stimulates respiration only via the carotid and aortic

chemoreceptors. Hypoxia without hypercapnia will not stimulate respir¬

ation until the F^ drops to less than 14%, corresponding to an arterial

°2

Pq of less than 60 mm Hg. This is less true with chronic hypoxia.

Hypercapnia stimulates respiration both via the chemoreceptors

and acting directly on the respiratory center. Any rise in the F

TO,

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- 13

produces a nearly linear rise in ventilation.

The inter-relationships of the 02 and C02 levels on the stimulation

of respiration are recognized but not clearly defined. Lowering the

Pq^ of the blood enchances the response to any given an<5 increases

12 the sensitivity of the respiratory center to CO^ . The respiratory

center is also sensitive to H+ concentration. The effect of CO^ may

depend on the subsequent formation of carbonic acid with the release of

+ H .

Additional studies have compared the P„„ sensitivity of adults and

13 14 infants , the capacity of man to store CO^ on an acute basis , and the

15 change in pH of the blood when the whole body is titrated with C02

The results of these inquiries have leant support to current concepts

of ventilatory chemistry,, have served to clarify and extend them, and

have provided some quantitative tools for their application. Their short¬

coming has been their failure to provide clear and precise exposition of

basic functional interrelationships.

Studies performed on man at rest have been more successful in this

regard than studies on man exercising. One difficulty has been in identifying

the specific mechanisms leading to the linear increase in ventilatory

volume at increasing levels of external work. This increase is linear

over a limited range; ie. , not exceeding 70% of the maximum six minute

work level of which the particular subject is capable^. Measurement

of arterial lactic acid, Pq^, ^CO an<^ c-*-ear^y eliminate these

parameters from any measure of control in exercise. Within 30% of

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i X. . ; J3 I _ ’ • . slxixi&v

j i . Io o rd - . cio« i >

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-14-

this maximum work level, rises in lactic acid and H concentration

17 contribute to but do not supplant the basic stimulus to hyperpnea „

The ventilatory responses so easily demonstrable when exogenous

18 CO;? is used are not cut of the same cloth as the ventilatory responses

to exercise,, Much work in this field has been directed toward isolating

a servomechanistic loop seeking a homeostatic set point. This wo rk

has been given added impetus by the demonstrated constancy of the

arterial P , and by the fact that manipulation of the P„„ , P,~ , C02 UUZ u2

and pH give rise to activity that tends to restore these values toward

normal. Perhaps Occam's razor has been applied here to aggressively.

It seems realistic to accept two modes of operation for the respiratory

center. One seems devoted to regulating the parameters to which de¬

tectors in the system are sensitive. The other is seemingly a higher

order of function predicated on the unique capacities made available

by the collective organized function of aggregations of nerve cells.

One of these aggregations, the respiratory center, seems to be so

organized that it responds to muscular activity, among other things,

and its response is such that significant change in the variables dependent

on ventilation are prevented. Some of the tools of the discipline of

electronic servomechanisms might be applied here with some profit. The

diagram showin in fig. 7 is such an application. Before elaborating on

this diagram some of the limitations imposed on formulating it must be

pointed out and emphasized.

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- 15

This diagram must not be interpreted as a direct translation of

the function of the respiratory center into electronic circuitry. Only

the vocabulary and symbols are to be applied, not the electronics.

Any quantitative behavior implied is intended only as a gross approx¬

imation.

This diagram is recognizably only a very crude approximation of the

components and functioning of the human respiratory system. It is

intended as a rough sketch of a very complex pattern that is at present

only dimly perceived. It is hoped that this approach will lend clearer

insights and raise clearly defined questions. Perhaps further work can

then be applied to elaborating and refining this representation to make

it even more useful.

Certain basic definitions are necessary before the diagram itself

can be discussed.

Figure 5 shows a summing point represented as an open circle. The

solid lines with directional arrows represent neural pathways. A, B,

C ....... are inputs to the summing point which act upon it, as indicated

by the associated algebraic sign, so as to produce the actuating signal

E (s) = A + B - C ............ As was pointed out above, this "sum"

should be seen as indicative of direction of effect, not as a precise,

algebraic result.

Fig. 6^ presents functional neuronal groups to visualize their response

to certain of the influences impinging on them. Increasing or decreasing

E (s) will produce an increase or decrease, respectively, in C (s), the

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controlled variable. Nothing more than that is implied. The dotted

lines with directional arrows indicate non«neural, humoral pathways.

M, N, P o . represent measurable humoral parameters, and

their site of action on the "transducer neurons" of the nervous system

is indicated by the dark bars, and the algebraic signs beneath each

indicates the direction of effect on C (s) produced by increasing M, N,

P, etc.

Having thus defined the basic vocabulary, the respiratory center

can be diagrammed with its important functional relationships, as in

Fig. 7. Only those pathways particularly pertinent to respiration

and physical work have been made explicit. Additional factors, known

and unknown, are acknowledged but not elaborated.

Using this diagram, it becomes easy to point out that the motor nerve

activity C (s) which drives the muscles of respiration to produce a given

Q

ventilation, V, is the result of a multitude of controlling factors. The

interplay of these factors is well described by the diagram to support

the contention that it is unnecessary to insist that a humoral factor be

the principle regulator of respiration in exertion.

However, it has been very difficult to accept that the oxygen and carbon

dioxide levels in the milieu interne might have no controlling influence on

respiration during exercise. Since the cardinal function of respiration is

to acquire oxygen and dispose of carbon dioxide, it would be very rash

to propose some completely unrelated mechanism to regulate respiration

without first searching for some role for carbon dioxide and/or oxygen.

Obviously, it is important to search for humoral factors which may

. .

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- 17 -

effect changes in respiration, and which may act at any point of influence.

Thus, it has been demonstrated that raising the hydrogen ion con¬

centration or the P„„ will increase the output of the respiratory center co2

19 by direct effect . It has been shown that the aortic and carotid chemo-

20 receptors are sensitive to pH, P__ , and P . The feedback loop co2 <J2

o

from V is closed via these sensors.

However, it may now be timely to formulate and investigate more

fully the alternative pathways for stimulation of respiration.

The many investigations already reported would seem to point to a

capacity built in to the system, whose characteristics enable an anti¬

cipatory adjustment of ventilation to prevent any change in oxygen

or carbon dioxide levels in the circulating blood. Such an extraordinary

wisdom cannot be asserted for the body without careful and difficult

investigation. It does seem timely to propose it, and to employ the cd n~ t.

cepts and vocabulary of electronic technology more extensively in in¬

vestigating it.

W.O. Fenn has speculated on this mode of operation for the respiratory

center in the face of exercise, calling it a 5behavioristic approach1 to

21 its function . None of this speculation should be construed as minimizing

the importance of the chemosensitive mechanisms in homeostasis. In

the face of exercise in the intact animal and man these simpler chemical

22 23 24 25 drives seem not to play a dominant role in regulating respiration 5 3 *

A few other details pertinent to humans in exercise are relevant here.

Cronin Macintosh, 1962, found that muscular efficiency was measurably

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- 18

greater under conditions of induced hypoxia . This may be related to the

increased contractility of actinomyosin in an acid medium. Pulmonary

blood volume drops in normal subjects by a mean of 6% during supine

exercise for three minutes at 112. 5 Kg«M/min . Pulmonary diffusing

capacity increases when normals are subjected to moderate to severe

degrees of exercise; at mild exercise levels the diffusing capacity may

not change. In the face of chronic lung disease, the rise is less, and

Z 8 in most individuals, there was seen to be no change or a fall . Both

ventilation and perfusion are greater in the more dependent areas of

the lungs, with a higher ventilation to perfusion ratio in the upper lung

fields. These findings were not significantly changed in normals by

29 exercise . Oxygen consumption, pulse rate and work load are closely

related. The pulse rate may be misleading in those in poor physical

30 training

Working capacity, defined by pulse rate limits of 170/minute, has been

studied. This has been shown to increase linearly with age and to be

32, 33 consistently greater in males than females . Whereas, studies of

i i • 34 the pulse rates m recovery from exercise have not been rewarding ,

several other measurements of exercise in heart disease have been

35, 36 fruitful

The development of exercise tests in the evaluation of pulmonary

disease has been more limited. Jones et al, 1963, measured the change

in FEV produced by exercise and Gandevia, 1963, observed the response

37 38 of minute ventilation in the last minute of a four minute exercise test ’

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- 19

Of more specific interest in terms of the present study are the reports

39 40 41 of Berg, 1947, Erikson, 1957, and Refsum, 1964 ’ 5 . These

investigations were concerned with the response to acute exercise,

with measurement of oxygen and carbon dioxide curves during the re¬

covery phase. These studies used short exercise regimens of one minute

under a moderate to large work load. Results showed a small but

definite difference in the different groups under consideration. The

overlap with the normal population in all these measurements was consid¬

erable. Only 2/3 of Refsum1s group of cases fell outside the normal

range.

The objectives of this particular study are limited. First it provides

a preliminary evaluation of the efficacy of this type of exercise stress

test in the study of cardio-pulmonary disease. Second, it can serve,

as a pilot study, as a nucleus around which improved a refined exercise

tests may develop.

In the face of the paucity of experimental regimens available for the

conduct of a test of this kind, it is the purpose of this inquiry to provide

a first, gross evaluation of the usefulness of such a test in children with

cystic fibrosis . It is hoped that such an effort will help to determine

whether or not attempts to polish and refine and perfect such tests might

be fruitful in the investigation and treatment of pulmonary disease.

Formal statistical analysis was not brought to bear on the data of

the present study, because of the small sample size, because of the

inherent coarseness in this context of minute volume measurements.

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~ 20

and because of the large scatter resulting. Carefully designed and

executed visual displays of data, described above, are adequate for this

purpose.

In all of figures 8 through 13, though a very broad correlation between

the presence of pulmonary disease and an elevation in the CO^ half time

can be visualized, it is also apparent that the degree of overlap be¬

tween the diseased and the normal population is considerable. The low¬

est 1/2 time was shown by one of the patients (G.A.). He was, also,

the youngest individual tested at 5-11/12 years, but his exercise level,

20 Kw, was equal to the work done by the oldest patient in the group

(C. McM.), 23-1/12 years old.

For this reason only the very broadest of generalizations can be

made regarding the results of this study.

From figures 8 and 9j it is apparent that none of the normals showed

half times over 150% of predicted. Among the patients, six of the thir¬

teen plotted fall above 150% of predicted half time. In addition the minimal

half time of each of the patient groups is greater the more marked the

involvement by disease, though less significance can be attached to such

an observation. It is of interest to note that none of the class III 1/2 times

fell below 100%.

4 Cook et al studied 64 patients with cystic fibrosis, age 6 to 25 years .

70% showed an increase, outside of the normal range, of the ratio RV/TLC.

Only 46% showed an elevated RV. 34% showed a fall in VC, and 21% an

increase in FRC.

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- 21 -

In the group of patients studied here, only 46% had elevated RV/TLC.

46%, also, had a % predicted half time of over 150%, but only 33% had

both an elevated RV/TLC and an elevated 1/2 time.

In figures 10 through 13, both ordinate and abscissa are plotted

linear~linear in percentage deviation from the predicted value concerned.

If there were no significant relationship between the disease and the values

of the ordinate and abscissa coordinates, the points as plotted should

group themselves at random. They would show radical symmetry around

the intersection of the ordinate and abscissa 100% lines. If the disease

effected only the ordinate quantity, the plot would show an axis of symmetry

around the 100% line arising from the abscissa. If both the ordinate and

abscissa values were significantly effected by the disease, the points

plotted should tend to segregate in one of the quadrants formed by the

100% lines.

In all of these figures, the disease seems to have tended to raise the

1/2 time above that predicted for that age. In fig. 10, the disease tends

to elevate the RV/TLC, and the points tend to fall in the upper-right

quadrant.

In fig. 11, the disease tends to raise the RV, and the points tend to

fall in the upper-right quadrant.

In fig. 12, the vital capacity is decreased in most, and the points

tend to fall in the lower-right quadrant.

In fig. 13, the functional residual capacity is decreased in most, and

the points tend to fall in the lower-right quadrant.

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~ 22

SUMMARY k CONCLUSION

It should be emphasized again in closings that the skew seen here

may well be produced by factors other than the pathologic pulmonary

forces in cystic fibrosis. The size of the normal group is insufficient

to ensure that they are in fact completely reliable to represent the

normal population with any exactness. The results shown above are

not inconsistent with the initial hypothesis that pulmonary disease,

and cystic fibrosis in particular, will prolong the time required for the

elimination of excess CO^ resulting from exercise.

The test in its present form is inadequate to provide a definitive

and clinically useful laboratory test of pulmonary function. However,

it does provide additional evidence that there may be some promise in

further development and refinement of the study of the diseased lung

under stress.

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.

OVERALL SUMMARY

Twenty subjects, fourteen patients with cystic fibrosis and six normal

individuals, were moderately exercised on a bicycle ergometer.

Collections of minute volumes of expired air before, during and follow¬

ing exercise were made.

The times required for the carbon dioxide output to fall half way to

the level at rest were calculated.

These times, for cystic fibrosis patients, were compared with the

times for normals and with selected objective tests of pulmonary function.

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APPENDIX

Tabulated Data

Patient Age Height^ 2

Work load CO y time"" 2

rv/tic

Gr « A . 5 11/12 110 20 0.20 .31

L.L. 6 0/l2 128 10 0.78 .42

■ if R.M. 6 8/l2 118 10 0.70 • 25

M.M. 7 4/12 116 25 1.38 .24

E.S. 8 5/12 123 10 1.82 .51

-n N.C. 8 7/12 129 15 1.12 .28

S.M. 9 0/l2 130 40 1.00 .22

M.Ii. 9 l/l2 127 10 3o50 .44

1.1. 10 0/12 121 10 1»73 o35

D.D. 1310/12 138 50 1.71 - »37

D.R. 14 4/12 161 50 lo 51 .26

«j • D o 15 7/12 149 50 0.94 .31

H J.McN « 16 5/l2 161 40 1.50 »49

C.McM. 23 l/l2 163 20 1.95 .30

Normal Age Height’*' 2

Work load C0^ y time^ 2

rv/tlc

D.R. 6 6/12 107 15 0.73 J • .A, • 8 7/12 121 20 0.39 D.M. 10 l/l2 144 50 1.13 A. Gr. 13 0/l2 158 30 1.27 B.L. 15 7/12 153 40 0.88

B «D. 22 7/12 162 50 1.50

1: centimeters 2 s Kw» see text 3s minutes

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