522 Paez

and others:

Canad. Med. Ass. J.

Sept. 3,1966, vol. 95

Direct Tracheal Instillation

The Effects of Direct Instillations of a Therapeutic Mixture

Into the Tracheobronchial Tree
PEDRO N. PAEZ, M.D.,* MANUEL MANSANGKAY, M.D.f and
BRIAN J. SPROULE, M.D., F.R.C.P.[C],:j: Edmonton, Alta.
Twenty-two patients with chronic productive bronchitis
or bronchiectasis were treated by direct instillations of
normal saline and N-acetylcysteine into the trachea
through a percutaneous catheter following a period of
conventional routine therapy.
The instillation, using either normal saline or varying
concentrations of N-acetylcysteine did not produce
significant change in alveolar gas exchange as reflected
by measurement of arterial PaCO* and the alveolar
arterial gradient for oxygen during and after the intro
duction of the medication into the bronchial tree.
Studies were carried out after patients had been stabilized breathing pure oxygen on an BPPB machine for
30 minutes.

Evaluation of the treatment by means of pulmonary

function tests demonstrated significant improvement in
overall function following therapy.
The results indicate that the technique of tracheo
bronchial lavage is physiologically benign and that
overall improvement in pulmonary function can be
obtained by this means in cases of the type described
in this study.

adequate treatment of lung disease involves

r|1HE
a simultaneous attack on a number of patho-

and specific therapeutic

physiologic abnormalities,
one
facet of the

directed at
or another
disturbance are difficult to evaluate because of the
mutually interdependent nature of the alterations,
in addition to an immense natural variation in dayto-day lung function.1'2
One aspect of chronic lung disease which is re
versible is the obstruction caused by secretions. The
mucus may be stagnant, thick and dry because of
primary defects in its quality (as in cystic fibrosis)
or because of secondary modifications related to
poor drainage, bronchospasm and ineffective cough.
In any event this material might be expected to
become more mobile if large quantities of fluid
could be deposited into the tracheobronchial tree.
To achieve this purpose, the insertion of a plastic
indwelling catheter into the trachea has been advocated.35 However, studies by Simenstad, Galway
and MacLean6 and Halmagyi, Colebatch and
Starzecki7 have indicated a drop in the compliance
of the lung and an increased right-to-left shunt as
a result of instillations of large quantities of normal
saline into the bronchial tree, and Lillehei8 has
reported that acute inflammatory changes of the
mucosa result from such instillation therapy.
The administration of N-acetylcysteine (Mucobeen re
myst), a specific mucolytic agent, has associated
ported by a number of authors to be
measures

?Instructor in Medicine, University of Alberta Hospital, Ed

monton, Alberta.
University of Alberta Hospital, Edmonton.
fResearch Fellow,
JAssociate Professor of Medicine, University of Alberta,
Edmonton.
Address reprint requests to: Dr. Pedro N. Paez, Fitness Re
search Unit, University of Alberta, Edmonton, Alberta.

traite* 22 malades souffrant de bronchite chro

ou de bronchectasie, au
moyen d'instillations directes dans la trache de serum
salin normal et de N-actylcyst&ne par voie d'un
catheter percutane, apres un traitement classique.
L'instillation, a base de serum salin normal ou de
diverses concentrations de N-acetylcyst^ine, n'a pas
entraine' de changement notable dans Fchange de gaz
alveolaire, comme l'indique la mesure du PaCOa arteriel
et de la differentielle de pression d'oxygene entre
l'alveole et le sang arteriel pendant et apres l'introduction du medicament dans l'arbre bronchique. L'etude
a ete enterprise apres qu'on eut stabilise les malades
en les faisant respirer de Foxygene pur dans une
machine IPPB pendant 30 minutes.
L'evaluation du traitement au moyen des epreuves
de la fonction pulmonaire a permis de montrer une
amelioration notable de la fonction globale apres
On

nique a secretions abondantes

traitement.

II ressort des resultats que le lavage tracheo-bronchique est une methode benigne au point de vue
physiologique et que l'amelioration globale de la fonc
tion pulmonaire peut etre obtenue par cette methode
dans le cas de pathologies du type qui est decrit ici.

with clinical improvement when used by various

lung disease.3,9 Therefore
important to measure the acute
alterations in gas exchange produced by instilla
tions of N-acetylcysteine and normal saline through
an indwelling catheter into the tracheobronchial
means to treat chronic
we felt that it was

tree.

As a corollary study, pulmonary function meas

ured after a week of repeated instillation therapy
was compared to values recorded before treatment.

Material

Twenty-two patients with chronic lung disease

(Table I) complicated by viscous secretions were
selected for this study and admitted to the Univer
sity of Alberta Hospital where an intensive program
of conventional therapy was carried out. For a
minimum of one week, nebulization of a mixture
of one part cyclopentamine and isopropyledinethrine (Aerolone) and four parts of a mucolytic
aerosol solution (Tergemist) was given by glass
nebulizer for 10 minutes every two hours during
the day, in addition to four 15-minute periods of
positive pressure breathing assistance using a Bird
Mark 7 Respirator. A heated main-stream nebulizer
filled with benzalkonium chloride 2 c.c, propylene
glycol 200 c.c, aqua dist. ad 4000 c.c was attached

to the output hose of the respirator, and one part

Aerolone:four parts Tergemist nebulized in the
side-stream nebulizer. Postural drainage and chest
physiotherapy were administered twice daily to all
patients and antibiotics given in full therapeutic
doses as indicated by the reports of sputum sensi-

Canad. Med. Ass. J.

Paez

Sept. 3, 1966, vol. 95

and others:

DmEcr Tracheal Instillation 523

TABLE I..Twenty-two Patients with Chronic Lung

Disease in the Present Study
Sex
Patient No. Age
Diagnosis

Asthma, bronchiectasis
Bronchiectasis
Chronic bronchitis, emphysema
Acute bronchitis, asthma
Asthma, bronchiectasis
Bronchiectasis, asthma
Bronchiectasis
Chronic bronchitis, emphysema
Asthma, emphysema
Bronchiectasis
Chronic bronchitis, fibrosis
Chronic bronchitis, emphysema
Chronic bronchitis, fibrosis
Asthma, chronic bronchitis
Bronchiectasis, emphysema
Bronchiectasis
Bronchiectasis (cylindrical)
Bronchiectasis
Bronchiectasis
Bronchiectasis
Bronchiectasis
Bronchiectasis

(cylindrical)

tivities. The patients were treated in this way until

maximal improvement was considered to have been
achieved. This was defined as a time when the
vital capacity and forced expiratory volume in one
second measured by a McKesson Vitalor on con
secutive days had a variation of less than 5%. It
was then considered that the patient was incapable
of further improvement. This criterion of stability
was based on previous studies from this laboratory
which indicated a variation within the same subject
of 2.5% on repeated spirometric measurement.10

Methods

The following baseline parameters of lung func

tion, measured after five minutes of bronchodilator
inhalation, were recorded: vital capacity, total lung
capacity, forced expiratory volume in one-half and
in one second, maximal voluntary ventilation, diffus
ing capacity and mixing index. The subdivisions of
lung volume were recorded on a Godart Pulmotest,
diffusing capacity was measured by an end-tidal
technique,11 and mixing efficiency estimated from
the helium dilution curve.12
A local anesthetic was then introduced into the
skin of the patient at the level of the first space
between the cricoid cartilage and the first tracheal
ring. An 18-gauge thin-walled needle was intro
duced into the tracheal lumen through which a
vinyl tube (internal diameter 0.5 mm. and external
diameter 1.0 mm.) was passed (Fig. 1). The
catheter was manipulated into an appropriate posi
tion and the needle was then withdrawn, leaving
the tube in situ. The tip of the tube was left close
to the most affected area or in the trachea itself if
the lesion was considered to involve both lungs

diffusely.
A therapeutic mixture composed of 7 ml. of
normal saline, 3 ml. of N-acetylcysteine (3%) and
three drops of isoproteronol was instilled through
the tube every hour during the day and every three

Fig. 1..Catheter for endobronchial instillation.

hours during the night. The bronchodilator was

added to obviate the bronchospastic reaction which
has been demonstrated to occur in association with
administration of N-acetylcysteine.13 Instillations
were carried out with the patient prone, lying on
the right side, supine, and lying on the left side in
turn, and the previously established regimen of
nebulization and postural drainage was continued
during this course of treatment.
Abnormalities in gas exchange brought about by
the instillation procedures were investigated by
measuring arterial blood gases in 12 of the 22
patients, during and immediately after the treat
ments. In these particular patients the instillations
were carried out after a 30-minute period during
which pure oxygen had been administered by a
positive pressure breathing machine working at a
pressure of 20 cm. H20 and at a constant rate.
Abnormalities of blood gases under these circum
stances represent the effects of right-to-left intraof dif
pulmonary shunting, since abnormalities
fusion and in the relationship of ventilation to per
fusion are overcome.14 The effect of instillations of
normal saline was compared to that of various
concentrations of N-acetylcysteine, including the

therapeutic mixture previously described, by

analyzing arterial blood samples drawn during
instillation, and 15 minutes after each procedure.
Blood samples were analyzed in duplicate on an
Astrup apparatus for pH, Pco2 and Po2 and
checked within 2.5% for Pco2 and 5% for Po2.
Results are reported as alveolar arterial oxygen
figure reflects the venous
gradients since this
when
admixture
arterial
hyperoxia is present.15
After seven days the catheter was withdrawn and
pulmonary function following maximal bronchodilatation was measured for comparison with the
values recorded before instillation therapy.

lml. of bronchodilator/100 ml.

Therapeutic mixture seven parts normal saline, three parts N-acetylcysteine,
PaC02 arterial carbon-dioxide tension (mm. Hg).
P02 (A-a) alveolar arterial oxygen tension difference (mm. Hg).
Conc. % concentration % of N-acetylcysteine.
=

The results were analysed by using the t test of

significance (critical value of t at the .05 level) that
divides the mean of the differences by the standard
error

of the differences.

Results
Instillation of normal saline, N-acetylcysteine in
various concentrations, or the therapeutic mixture
(seven parts normal saline, three parts N-acetyl
cysteine, 1 ml. bronchodilator/100 c.c.) had little
effect on blood gas exchange under these circum
stances. Instillation of the most concentrated solu
tion of N-acetylcysteine (18%) did produce some
modest increase in right-to-left shunting but the
effect was already decreasing when the measure
ment was repeated 15 minutes after the procedure
(Table II). The assisted ventilation used in this
experiment may have masked ventilation-perfusion
abnormalities which would have been present
under circumstances in which ventilation was not
assisted. However, under these particular circum
stances

there was little evidence of increased right-

shunting.
Pulmonary function before and after a week of
therapy is shown in Tables IIIA and B. The vital
capacity, maximal voluntary ventilation, the halfsecond and one-second forced expiratory volumes,
diffusing capacity and mixing index all increased
following the procedure. The total lung capacity
was not changed. Although the increase in pulmo
nary function was not large, the improvement was
noted in virtually all the patients and therefore
the changes were statistically significant (Table
IV). The changes were in excess of the intraindividual variation of a repeated test in the same
subject.
to-left

Subjectively the majority of the patients stated

that there was a reduction in a "tight" feeling of the
chest and that this was associated with easier
evacuation of sputum.
Complications

Complications arising from placing a catheter in

the tracheobronchial tree and leaving it there for a
week appeared to be minimal. A brief episode of
coughing was frequently observed immediately
after introduction of the catheter, but this quickly
subsided. If cough persisted, minor changes in the
position of the tip of the catheter usually caused
this symptom to disappear. By the end of the sevenday treatment period, an inflammatory skin re
action was usually observed at the point where the
catheter pierced the skin. The fistula always closed
immediately after the catheter was withdrawn and
a leak was never detected even with a forceful
Valsalva maneuver.
The instillation procedure itself was symptomatically well tolerated. In two patients vomiting
was induced with the initial treatment and was
associated with the expectoration of large volumes
of sputum. The nightly three-hourly treatments
interfered with sleep, causing minor complaints
from most patients.
Discussion

Although we are well aware of the difficulty inevaluating therapy in this sort of disease

herent in

process, there

was

reasonable evidence that the

improvement obtained with a vigorous program of

conventional therapy had reached a plateau in these
patients. Therefore we attribute the improvement

subsequently obtained to

the instillation.

Canad. Med. Ass. J.

Sept. 3, 1966, vol. 95

Paez

and others:

Direct Tracheal Instillation 525

TABLE IIIA..Results of Pulmonary Function Before and After Treatment

Suggestions that the direct instillation of material

produced significant
intrapulmonary shunting and a decrease in com
pliance are not substantiated by our results. The
into the tracheobronchial tree

differences between the results of our studies and

those of Halmagyi, Colebatch and Starzecki,7 which
were done on sheep, may have been due to a
species variation or may have been related to the

TABLE IV..Summary of the Statistical Analysis

of the

Parameters Measured

526

PAEZ AND OTHERS:

DIRECT TRACHEAL INSTILLATION

Larger dose of solution per unit time employed by

Halmagyi.
On theoretical grounds the surface tension of the
lung could be affected by mechanical rinsing out of
"surfactant material" by lavage with large quantities
of fluid. However, the slight increase in vital
capacity and flow rates documented here indicates
that the mechanical properties of the lung were not
adversely affected by this procedure and, in addition, the minute volume produced by a constant
pressure setting of the positive pressure machine
was unchanged during or immediately following
the instillation, suggesting that dynamic lung compliance is not acutely altered. It would also appear
that the procedure is benign in respect of the acute
alterations in ventilation-perfusion relationships
which were reflected by our blood gas values.
We are not in a position to assess the moderately
long-term inflammatory changes in bronchial walls
which have been described by Lillehei8 in associalion with the instillation of normal saline. Such
alterations seem to be unlikely in this particular
group of patients in view of the improvement in
most of the parameters of lung function following
therapy.
The action of N-acetylcysteine, independent of
the techniques of tracheobronchial instillation, cannot be determined by this study. Its action in vitro
depends upon the concentration of the sulfhydryl
radical in contact with mucus, and it is likely that
the amount deposited per unit time on the
bronchial mucosa is critical in liquefying secretions.
Since nebulization has a limited capacity to deposit
medication because of the small particle size required to reach the smallest dimensions of the
bronchial tree, it appeared logical to us to deliver
the agent by direct deposition.

Canad.3, Med.
1966, Ass.
voL. J.
95
SUMMARY

Twenty-two patients with chronic productive

bronchitis or bronchiectasis were treated by direct
instillations of normal saline and N-acetylcysteine into
the trachea through an indwelling vinyl catheter.
The instillation itself, using either normal saline or
different concentrations of N-acetylcysteine, did not
produce significant changes in alveolar gas exchange,
as reflected by measurement of arterial Pco2 and the
alveolar arterial gradient for oxygen during or immediately after the introduction of the medication into
the bronchial tree.
Evaluation of the treatment by means of pulmonary
function tests demonstrated slight significant improvement in overall function following therapy.
The results indicate that the technique of tracheobronchial lavage is physiologically benign and that
overall improvement in pulmonary function can be
obtained by this means in cases of the type described
in this study.
REFERENCES

1. LEVINE, E. R.: Dis. Chest, 31: 155, 1957.

2. GOLDBERG, I. AND CHERNIACK, R. M.: Amer. Rev. Resp.

Dis., 91: 13, 1965.

3. WEBB, W. R.: J. Thorac. Cardiov. .Surg., 44: 330, 1962.
4. RADIGAN, L. R. AND KING, R. D.: ASurgery, 4: 184, 1960.
5. ARONOVITCH, M.: Dis. Chest, 39: 251, 1961.

6. SIMENSTAD, J. D., GALWAY, C. F. AND MACLEAN, L. D.:

Surg. Gynec. Obstet., 115: 721, 1962.

7. HALMAGYI, D. F., COLEBATCH, H. J. AND STARZECKI, B.

Thorax, 17: 244, 1962.

8. LILLEHEI, J. P.: Clin. Res., 11: 302, 1963

(abstract).

9. IMPERATO, P. J., PALANCA, L. M. AND FERNANDEZ, J. P.:

Amer. Rev. Resp. Dis., 90: 111, 1964.

10. LYNNE-DAVIES, P.: The relationship of routine pulmonary

function studies to pulmonary mechanics in obstructive airway disease, Master's thesis, University of

Alberta, May 1965.

11. BATES, D. V., BoucoT, N. G. AND DORMER, A. E.: J.
Physiol. (London), 129: 237, 1955.
12. BATES, D. V. AND CHRIsTIE, R. V.: Cliii. Sci., 9: 17, 1950.

13. BERNSTEIN, I. L. AND AUSDENMOORE, R. W.: Dis. Chest,

46: 469, 1964.

14. MILLER, W. F., SPROULE, B. J. AND CUSHING, I. B.: Amer.

Rev. Tuberc., 79: 315, 1959.

15. DEJOURS, P.: Respiration, Oxford University Press, New
York, 1966, p. 122.

PAGES OUT OF THE PAST: FROM THE JOURNAL OF FIFTY YEARS AGO

SHOCK OR HEMORRHAGE AS THE CAUSE

OF DEATH
If we only knew what shock was, essentially, we might
decide the question. But in all probability the truth is on
both sides and on neither. I imagine that, even where
bleeding is excessive, shock enters in; and that one completes what the other begins. If shock consists in a disturbance of the rhythm of the circulation, characterized by
the displacement of a critical quantity of blood from the
arterial to the venous side, then h.emorrhage from the
arterial side would be apt to aggravate the condition. On
the other hand, to transfuse blood, introducing it on the
venous side, does not get at the root of the trouble, which I
conceive to be a serious upset of the rhythm of the circulation, due to interference with the physiological nervous
equilibrium of the vaso-motor system, probably affecting the
veno-pressor factor more than that of arterial tone. I have
given blood (17 oz.) to one abdominal case with serious
lesions of the gut, and severe internal kemorrhage, and it
did no good, either immediate or remote. The man died in

a few hours from shock. I have given salt solution to others,

and while it brought back the pulse at the wrist (they were
all pulseless or nearly so), this effect was very transitory,
and they have died within a short time. In fact, in two
cases, I got the impression that the intravenous saline had
actually hastened death. Its effect is purely one of volume;
the fluid soon escapes into the urine or the tissues; and the
fundamental disorder is not remedied. While this has been
the case with the wounds of the abdomen, I must say that
several patients suffering from severe wounds of the extremities, in shock, pulseless, or nearly so, have been
apparently saved by a timely infusion of saline. The nature,
or the degree of shock, in one and the other instance, is
probably different. I might add that latterly I have employed instead of normal saline a gelatine solution (25 g.
to the 1.) as recommended by Hogan of San Francisco
(J. A. M. A., July 1915), the idea being that such a solution,
colloidal in nature as it is, will stay in the vessels much
longer than saline. This I have found to be true enough;
the pulse and blood pressure are restored, though remaining
low, for from five to eight hours instead of one or two.E. A. Archibald, Canad. Med. Ass. 1., 6: 783, 1916.