Expectoration Disturbances and Bronchial Obstruction

Expectoration Disturbances and Bronchial Obstruction

V.N. Solopov, I.V. Lunichkina
Medical Center «PuImonologist», Moscow, USSR

Key Words. Asthma, Chronic obstructive pulmonary diseases, Cough efficacy, Expectorants, Ambroxol, Bromhexine, S-Carboxymethylcysteine, Acetylcysteine, Sodium bicarbonate.

Abstract. Two methods for the efficacy evaluation of the respiratory tract clearance by cough, measuring the time of expectoration (Texp) of sputum mixed with hem-containing indicators after their inhalation were use in patients with bronchial obstruction. In the first method, the patients studied inhaled their own hemoglobin (Hb) and in the second one they inhaled a finely pulverized powder of hem-containing substances which were obtained from donor erythrocyte mass. 195 subjects were examined: 44 with intrinsic bronchial asthma (BA), 7 with obstructive bronchitis (OB) and 22 with purulent obstructive bronchitis (FOB). Patients expectorating not less than 30 ml/day of sputum were selected. The control group consisted of 18 patients with non-obstructive bronchitis (NOB) and 40 healthy volunteers, nonsmokers. The sputum for analysis after the inhalation of the indicator in healthy persons was collected during coughing stimulated by inhaling a hypertonic solution (15% NaCl+1% NaHCO3. It was found that Texp depends on the form of illness (means ± SEM): (1) with Hb technique, BA: 41.5 ± 3.4 h; OB: 59.3 ± 5.7 h and POB: 128.8 ± 15.3 h and (2) with the powdered indicator technique BA: 53.4 ± 7.6 h; OB: 68.8 ± 6.6 h and POB: 101.1 ± 11.8 h. Control group: in patients with NOB, Texp measure with the Hb technique was 31.4 ± 4.3 h and with the powdered indicator 30.0 ± 10.3 h. In healthy volunteers, the presence of hem-containing substances in sputum after 36 h was not found. Correlation analysis of our data revealed the presence of a direct relationship between the pulmonary function impairment and the value of Texp only in the group of patients suffering from OB.
A comparison of the efficacy of peroral and inhalation expectorants as shown by their influence on initial, values of Texp was carried out. Expectoration efficacy amounted to (mean ± SEM): (1) peroral drugs: ambroxol 41 2 ± 5 1% bromhexine 37.9 ± 8.6%, S-carboxymethylcysteine 30.4 ± 7.6%, and (2) inhalation drugs: n-acetylcysteine 55.3 ± 5.3%, 2% solution of sodium bicarbonate 58.4 ± 3.8% and sodium bicarbonate in a dry aerosol form 52.5 ± 9.7% The choice of the drug and the route of administration (peroral or inhalation) are determined to the degree of expectoration disturbances: first degree (Texp 36-48 h) can be compensated by peroral drugs, second degree (Texpexp 72 h and more) are decompensated an require the use of active bronchial toilet methods, such as bronchoscopy, or an increased number of daily drug inhalations. 54-66 h) by inhalation drugs, and third degree (T

Introduction

The present article is based on published and unpublished investigations carried out by the authors in the last 4 years. It deals with the concept of expectoration disturbances in patients with bronchial obstruction and ways for correcting them.
Impairment of mucus secretion is of great importance in the pathogenesis of bronchial obstruction in patients suffering from chronic obstructive pulmonary diseases. hypersecretion, its stasis and accumulation in the respiratory tract aggravates bronchial obstruction and worsens the illness [1]. That is why the correction of the inadequate bronchial drainage is of paramount importance in the therapy of chronic ob structive pulmonary disease
Despite the wide use of expectorants and mucolytics with various mechanisms of activity [2, 3] therapists often come across situations when the expectoration therapy is of low efficacy The cause seems to be the lack of clinical approach which could enable one to select the optimal therapy depending on the degree of expectoration disturbances.
According to the present knowledge, the process of respiratory tract clearance of the accumulated secretions is achieved by mucociliary [4] and cough [5] mechanisms and depends also on other factors, such as rheological properties of bronchial mucus, state of bronchial permeability and quantity of accumulated secretions
Investigations of the last years in this field [4, 6] have been devoted mainly to the mucociliary transport efficacy evaluation by means of different techniques measuring tracheal mucus velocity or lung mucociliary clearance Utilizing the radioaerosol technique by monitoring the patient during lung mucociliary clearance recording all coughs and by measuring sputum quantity and counting its radioactivity, it is possible to estimate the cough efficacy from the amount of radioaerosol expectorated with the sputum over a short observation period [4] This approach results in a measure of the contribution of mucociliary or cough clearance, but not of the efficacy, duration and completeness of respiratory tract clearance of accumulated secretions, because it demands especially a prolonged period of time Another approach for the cough clearance efficacy estimation involves the measurement of the total expectoration time (Texp) of the bronchial secretions stained or mixed with an indicator after its inhalation and can be used for a long-term investigation. In this context, we considered it reasonable to mix the respiratory tract contents of the patients with a hem-containing substance and to evaluate the cough clearing efficacy by measuring the time of its expulsion with the sputum.
The principal tasks of research were the following:
(1) determination of the efficacy of the respiratory tract clearance by cough on the basis of the Texp value in patients with bronchial obstruction suffering from bronchial asthma (BA) and chronic bronchitis (CB);
(2) determination of the comparability of different techniques of Texp evaluation with the use of some hem-containing substances and
(3) comparison of the efficacy of the available peroral and inhalation expectorants with the aim of their differential administration depending on the degree of the expectoration disturbances.

Patients and Methods

195 subjects (136 males and 68 females aged 23-ft7 years) were examined There were 137 patients with bronchial obstruction 44 of them (mean age ± SEM 46.8 ± 1.95 years) were affected by intrinsic BA 71 patients (mean age ± SEM 51.6± 7.6 years) by obstructive bronchitis (OB) and 22 patients (mean age ± SEM 46.5 ± 3.7 years) by purulent-obstructive bronchitis (POB).
The control group consisted of 58 subjects without bronchial obstruction: 18 patients (mean age ±SEM 375±27 years) with non-obstructive bronchitis (NOB) and 40 healthy nonsmoking volunteers (mean age ± SEM 31.5 ± 6.3 years) who had no respiratory tract diseases and record of occupational health hazards Patients expectorating not less than 30 ml/day of sputum were selected 42 CB and 34 BA patients expectorated 30-50 ml/day of sputum, 56 CB and 10 BA patients expectorated 60-90 ml/day of sputum, 13 CB patients expectorated 100-200 ml/day of sputum.
The examination program consisted of a pulmonary function (PF) investigation, the determination of Texp, sputum adhesion (during the peroral expectorant testing) and evaluation of the efficacy of the prescribed expectorants.
Investigation of the PF was carried out in the morning with the patients having an empty stomach Eight hours prior to the PF investigation, sympathomimetics were not given, and 12 h before the investigation theophylline preparations were withdrawn.
Texp was determined by means of two techniques. In the first technique, the patients studied inhaled their own hemoglobin (Hb) isolated from erythrocytes of venous blood, the quantity being 1.0 g per 20 0 ml of physiological solution To obtain a uniform distribution of Hb, a penetration even to small bronchi and mixing with the entire mass of bronchial secretions, the inhalation was continued up to 50 mm and was carried out by means of highly productive (4 ml/mm) ultrasonic nebulizer, generating particles less than 5.0 mm To prevent the bronchoconstriction of the small bronchi and central aerosol deposition, especially in asthmatic patients, the patients inhaled two doses of fenoterol before the investigation After inhalation, to remove Hb remnants from mouth and pharynx the patients were told to rinse the oral cavity and to drink 300 ml of water.
The staining intensity of the expectorated sputum collected every 6 h was evaluated by means of the amidopyrine reaction an excess (double volume) of the reagent, consisting of equal quantities of 3% hydrogen peroxide, 30% acetic acid and 5% alcohol amidopyrine solution was added to 2-3 ml of the tested sputum The bluish-violet staining of sputum was evaluated in comparison with a standard five-grade color scale The sputum testing was carried out every 6 h until three negative results were obtained To exclude erroneously positive results, the patients’ sputa were tested for occult blood (Hb) prior to investigation In case of a positive result, the investigation was not carried out.
The second technique is a simplified modification of the first and was used for drug testing A finely pulverized powder of hem containing substances (with particle sizes not more than 5.0 mm) obtained from the donor erythrocyte mass, was used for inhalation into the respiratory tract of patients. A turboinhaler «spinhaler» was used for the endobronchial introduction of the powdered indicator (200 mg/investigation) [7]. Identification of hem-containing substances in the expectorated sputum was also carried out by means of the amidopyrine reaction.
To determine the time during which the removal of an inhaled indicator from the respiratory tract of healthy subjects is achieved, we tested the sputum collected during coughing stimulated by inhaling 15.0 ml of a hypertonic solution (15% NaCI+1% NaHCO3) at varying time intervals: 10 persons after 18 h, 10 persons after 24 h, 10 persons after 30 h and 10 persons after 36 h.
The adhesive properties of the sputum were evaluated by measuring the force of its adhesion to the glass at the moment of tear-off. The patients’ morning sputa collected in dry clean glass flasks were used for investigation. The procedure was as follows: about 0.5 g of sputum was placed on a dry clean glass slide, and then it was covered with a contact glass plate connected with a tearing-off device. The tear-off strength of the contact plate was measured by means of a tensometric force measuring device. Adhesion values were calculated as follows:

A = F/S

where S = the contact space (m2), F = the tear-off force (N) and A = adhesion (N/ m2). Each measurement was carried out three times, and the average value was calculated [8].
Assessment of the efficacy of prescribed expectorants was carried out according to the following scheme: (1) initial evaluation of Texp and sputum adhesion; (2) administration of the expectorant; (3) repeated determination of Texp
To evaluate objectively the efficacy of expectorants, we calculated the coefficient «expectoration efficiency» showing the decrease in Texp following administration of preparations as a percentage of initial values [9]. against the background of administered expectorants within the first 3-4 days of treatment, and (4) daily determination of sputum adhesion against the background of treatment with peroral expectorants.

initial Texp – repeated Texp
Expectoration efficiency = ———————————————— x 100%.
initial Texp

For a comparative investigation, we chose three present-day peroral expectorants (ambroxol. bromhexine, S-carboxyme-thylcysteine) and two inhalation drugs (n-acetylcysteine and sodium bicarbonate).
The course of treatment with expectorants lasted 10-15 days. The following preparation doses were used: (1) peroral drugs: ambroxol (90 mg/day). bromhexine (96 mg/day) and S-carboxyme-thylcysteine (1.5 g/day), and (2) inhalation drugs: acetylcysteine (800 mg/day; 400 mg per 15.0 ml of physiological solution, two times a day) and 2% solution of sodium bicarbonate (15.0 ml, two times a day). Inhalation of acetylcysteine and sodium bicarbonate solution were carried out by means of an ultrasonic nebulizer until nebulization of the entire volume of solutions were complete. Inhalation of sodium bicarbonate as an aerosol of a finely pulverized powder was carried out with a turboinhaler («spinhaler») [10]. The daily dose amounted to 1.5 g (0.5 g, three times).
Peroral expectorants were prescribed to patients with BA and those with CB, but inhalation expectorant therapy only to patients with CB. The group for comparison during expectorant testing comprised 29 patients (12 with BA and 17 with CB) who did not receive any expectorants but were examined according to the same program in parallel with the patient groups.

Table 1. Values of Texp and PF indices in 15 patients with BA and 15 CB patients

Texp, h BA (n = 15) CB (n = 15) p
41.5 ± 3.4 85.2 ± 10.2 < 0.01
PF indices, % ofpredicted values [11]
VC 54.2 ± 4.2 75.0 ± 6.9 < 0.05
FEV1 46.6 ± 3.6 64.8 ± 5.7 < 0.05
Vmax25% 32.9 ± 3.7 54.2 ± 6.2 < 0.05
Vmax50% 26.8 ± 5.8 47.3 ± 8.9 > 0.05
Vmax75% 13.2 ± 2.8 37.9 ± 8.9 < 0.05
Means ± SEM. Vmax25%, Vmax50%, Vmax 75% = Maximum expiratory flow at 25, 50 and 75%, respectively, of forced vital capacity.

Results

The first evaluation of Texp carried out in patients with BA and CB (by means of the Hb technique) showed that the values of this index vary within a wide range and depend on the form, stage and seriousness of the illness (tables 1, 2).
As can be seen from table 1, in spite of the statistically significant more pronounced impairment of PF in patients with BA, their Texp is half of that in patients with CB. In the juxtaposed study of patient and control groups, by means of the Hb and hem-containing indicator inhalation methods, it was found on the one hand a difference in the Texp value depending on the form of illness, and, on the other hand, a comparability of results in identical groups (table 2) [7]. The latter suggests that Texp is an objective index of the bronchial clearing efficacy.
In the group of healthy subjects, the determination of hem-containing indicators in sputum expectorated after coughing stimulated by inhaling a hypertonic solution showed that after 36 h all qualitative reactions had been negative (table 3). As it is evident, the indicator evacuation time in healthy persons does not exceed the time interval from 30 to 36 h.

Table 2. Comparative evaluation of two investigation methods:
PF values and Texp in the studied populations

Groups PF index: FEV1, % of
predicted values
Texp, h P
autologic Hb powdered
indicator
Control
NOB
97.1±2.95
(n=18)
31.4±4.3
(n=13)
30.0±10.3
(n=5)
>0.05
PatientBA 51.9±5.1
(n=36)
NS
41.5±3.4
(n=15)
NS
53.4±7.6
(n=16)
>0.05
OB 47.7±2.1
(n=58)
59.3±5.7*
(n=32)
68.8±6.6**
(n=26)
>0.05
POB 50.5±6.1
(n=16)
128.0±15.3*
(n=9)
101.1±11.8**
(n=7)
>0.05
Means ± SEM. * p< 0.01 compared to NOB (Hb technique); ** p< 0.01 compared to NOB (powered indicator technique).

Table 3. Results of the determination of indicator expulsion in healthy persons

Qualitative reaction Investigation time
18h 24h 30h 36h
Positive 2 3 3
Negative 8 7 7 10

Table 4. Coefficient of paired correlation for Texp (h) with PF indices (% of predicted values) in patients studied

Groups PF indices
VC FEV1 FEF 25-75% FEF 75-85%
Control
NOB 0.010
>0.05
0.120
>0.05
0.175
>0.05
0.009
>0.05
Patients
BA -0.126
>0.05
-0.272
>0.05
-0.188
>0.05
-0.121
>0.05
OB -0.317
<0.05
-0.374
<0.01
-0.374
<0.01
-0.373
<0.01
POB -0.484
>0.05
-0.188
>0.05
-0.151
>0.05
-0.585
>0.05
FEF 25-75% = Forced expiratory flow between 25 and 75% of vital capacity;
FEF 75-85% = forced expiratory flow between 75 and 85% of vital capacity

To determine any interrelationship between the expectoration and ventilation disturbances, we carried out the correlation analysis which revealed the presence of a direct relationship between the PF impairment and the value of Texp only in the group of patients with OB (table 4).
The influence of the expectorants on Texp values is presented in table 5. As can be seen from this table, Texp values decreased in patients who were being treated with expectorants compared with the group who were not given any expectorants. The results of the PF investigation showed that already during the first 3 days of expectorant therapy, FEV1) (expressed as percent of predicted values) significantly (p < 0.01, n = 89) increased from 52.4 ± 2.46 to 61.6 ± 1.66% (means ±SEM). Compared to the group who was not given expectorants, FEV, was unaltered: the initial value was 56.1 ± 5.7% and after 3 days of therapy with broncholytics and antibiotics 51.4 ± 5.3%.
The results of the sputum adhesiveness measurement in the course of peroral treatment demonstrated a positive influence of ambroxol and bromhexine on this rheological characteristic of bronchial secretions after 1-5 days on treatment (table 6). No influence of S-carboxymethylcysteine on sputum adhesion was found.
The efficacy of peroral and inhalation expectorants and Texp dynamics against the background of expectoration therapy depending on the initial values are presented in tables 7-10. As can be seen from table 7, all the peroral expectorants did not differ with respect to expectoration efficiency. Inhalation expectorants were also comparable as to expectoration efficacy (table 9).
After a 3-month course of treatment with expectorants, 12 patients (8 with OB and 4 with POB) achieving no stable remission were examined once again (table 11); they had the same expectoration disorders as in the exacerbation phase during the first investigation.

Table 5. Texp dynamics in patients treated with expectorants (means ± SEM)

Treatment Preparations Texp, h P
initial against the
treatment
background
Peroral
expectorants
Ambroxol (n=21)
Bromhexine (n=18)
S-Carboxymethilcystein(n=16)
45.3±4.9
59.1±5.7
60.8±8.6
26.7±3.8
36.4±5.6
39.8±5.9
<0.01
<0.01
<0.05
Inhalation
expectorants
n-Acetylcysteine(n=7)
2% solution of sodium bicarbonate (n=14)
dry aerosol of sodium bicarbonate (n=13)
86.6±11.5
96.9±12.0
73.9±5.7
36.9±5.3
36.0±2.6
37.4±8.8
<0.05
<0.01
<0.01
Without any expectorants (n=17) 62.1±8.6 53.5±9.7 <0.05

Table 6. Influence of peroral expectorants on sputum adhesion (means±SEM)

Treatment Sputum adhesion, x10(4) N/m(2)
initial
values
1-5 days
of treatment
6-9 days
of treatment
10-15 days
of treatment
Ambroxol (n=21) 0.35±0.04 0.28±0.06 0.30±0.09 0.30±0.06
Bromhexine (n=18) 0.35±0.05 0.28±0.07 0.29±0.07 0.29±0.06
Carboxymethilcystein(n=16) 0.33±0.08 0.35±0.09 0.54±0.15 0.35±0.1
Without expectorants (n=12) 0.36±0.05 0.49±0.1 0.37±0.16 0.30±0.1

Table 7. Expectoration efficiency of peroral expectorants  means± SEM)

Preparations Expectoration efficiency, %
1 Ambroxol 41.2±5.1*
2 Bromhexine 37.9±8.6**
3 Carboxymethilcystein 30.4±7.6
* p > 0.05, vs. The 2nd group; ** * p > 0.05, vs. The 3rd group

Table 8. Texp dynamics against the background of peroral expectorant
therapy depending on the initial values  (means± SEM)

Texp group Texp, h p
initial against the treatment
background
Up to 48 h (n=19) 36.4±2.9 24.4±4.8 <0.05
54-66 h (n=21) 61.3±1.9 48.0±6.3 <0.05
72 h and more (n=15) 105.4±8.1 49.1±6.7 <0.01

Table 9. Expectoration efficiency of inhalation expectorants (means± SEM)

Preparation Expectoration efficiency, %
1 n-Acetylcysteine 55.3±5.3*
2 2% solution of sodium bicarbonate 58.4±3.8**
3 dry aerosol of sodium bicarbonate 52.5±9.7
* p > 0.05, vs. The 2nd group; ** * p > 0.05, vs. The 3rd group

Table 10. Texp dynamics against the background of inhalation expectorants
therapy depending on the initial values (means± SEM)

Texp group Texp, h p
initial against the treatment
background
Up to 48 h (n=4) 43.5±2.9 12.0±4.2 <0.01
54-66 h (n=10) 60.0±2.4 28.8±4.6 <0.001
72 h and more (n=20) 107.1±5.7 45.6±4.9 <0.001

Table 11. Texp values in the exacerbation phase and 3 months
later in patients achieving no stable remission (means± SEM)

Patients Texp, h P
exacerbation phase 3 months later
OB (n=8) 69.0±12.1 58.5±12.5 >0.05
POB (n=4) 151.0±18.1 144.0±12.1 >0.05

Table 12. Classification of expectoration disturbances

Texp Degree of disturbances Stage
6-30 h 0
36-48 h 1 Compensated
54-66 h 2 Compensated
72 h and more 3 Decompensated

Discussion

Since the average Texp value in patients with NOB is comparable with the indicator evacuation time in healthy volunteers, one may conclude that severe expectoration disturbances take place in all patients with bronchial obstruction and are not observed in NOB group. The presence of a direct relationship between the PF impairment and the value of Texp in the OB group is explained probably by the leading role of the expectoration disturbances in bronchial obstruction in these patients. Concerning patients with BA, the lack of correlation between Texp and PF indices is determined by the fact that the leading role in bronchial obstruction belongs to bronchospasm and inflammatory edema of mucosa, but not to expectoration disturbances. It is quite probable that more considerable expectoration disturbances in patients with FOB are determined to a large extend by the purulent nature of inflammation in the respiratory tract causing high sputum viscosity and its greater adhesion to the bronchial wall.
Various manifestation of expectoration disturbances in patients of investigated groups and the variability of the Texp index within each group necessitate the use of a differential approach to treatment taking into account the efficiency of the prescribed expectorants. This study has demonstrated that the efficacy of different peroral medicines in the correction of mucologic disturbances does not exceed on the average 30-40% (table 7). This might be explained by the fact that an indirect influence on the sputum rheological properties can improve its transport up to a certain limit. Since the mechanism of action of the peroral expectorants is different [2, 3, 12], it is possible that its curative effect may be increased by combining them, for example, ambroxol + carboxymethylcysteine or by the use of analogue combinations.
At the same time, full compensation of the expectoration disturbances with peroral expectorants was achieved at initial values of Texp before 48 h. In patients with Texp exceeding 48 h (54 h and more), no full compensation of bronchial clearance was observed (table 8).
Further improvement over and above that attained through the use of peroral drugs can be achieved by the use of active bronchial toilet methods or by stimulating the cough mechanism. The findings proved the high efficacy of the aerosol therapy in the bronchial drainage restoration. However, the efficacy of the inhalation expectorants based on stimulated cough clearance and optimization of the sputum rheological properties is also limited: it does not exceed 50-60% (table 9). At the same time, it is evident that in patients with Texp exceeding 66 h (72 h and more), no compensation of bronchial clearance was achieved (table 10); therefore correction of the bronchial drainage must be differentiated depending not only on the nature of rheological properties of bronchial contents but also on the degree of manifestation of expectoration disturbances and therapeutic potentialities of the preparation used.
In accordance with the data of presented in this study, a classification of expectoration disturbances can be suggested and is given in table 12.
Expectoration disturbances of the first degree can be compensated by the administration of present-day peroral preparations and those of the second degree by inhalation therapy. Thus the possibility of complete correction of impairments of the first and second degrees by the present-day expectorants permitted us to consider them as compensated. Severe expectoration disturbances of the third degree are not corrected by expectorants being administrated on common schemes and must be considered as decompensated. What are the possible ways of correcting disturbances of the third degree? The empirical approach of clinicians determines the treatment methods for these patients (presented mainly by subjects with POB). As a rule, it provides bronchoscopies and endobronchial instillations. However, these treatment methods do not ensure any sufficient and lasting effect; the number of treatment procedures being limited. According to our investigations, effective restoration and maintenance of the optimal bronchial clearance in this situation probably can be achieved firstly by the use solely of inhalation expectorant therapy and secondly by increasing the number of daily inhalations of the expectorants depending on the Texp values. For example:

(1) initial Texp value is 72 h;

(2) optimal Texp value must be not more than 36 h (100%);

(3) Texp initial /Texp optimal is 72/36 x 100 = 200%;

(4) average expectoration efficiency of inhalation drugs (two inhalations per day) is 55.4%, and

(5) the number of necessary inhalations per day is:

200%-100% / 55.4% x 2 = 3.61 or 3-4 inhalations per day.

The results of examinations of the patients with OB and POB 3 months after a course of treatment with expectorants (table 11) show that expectoration disturbances which had not been corrected with treatment are one of the causes not permitting to achieve a stable remission. Concerning the pronounced expectoration disturbances especially in patients with OB and POB caused by changes in the bronchial mucosa (the ciliary epithelium atrophy and hyperplasia of goblet cells), they require a prolonged systematic corrective therapy directed at the daily evacuation of the bronchial secretions. In spite of the fact that expectoration impairment is only one of a number of mechanisms of obstruction formation, its effective correction can provide a substantial improvement of PF and of the prognosis of the disease.

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Received: June 8, 1989 Accepted after revision: July 15, 1991

Dr. V.N. Solopov
28 Lenscaya str., Moscow, 129327, PO BOX 23
“IP LIV”

asthma@rambler.ru

Expectoration disturbances and bronchial obstruction.
Published in «Respiration» (Sep-Dec 1991), 58/5-6, p. 287-293

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