Dr. Victor N. Solopov
«Asthma Service», Medical Services Ltd., Moscow

KEY WORDS

Asthma evolution. Fenoterol. Epinephrine. Sudden death from asthma

ABSTRACT

The different types of bronchial response to fenoterol (Fen) and epinephrine (Epi) resulted after their consecutive inhalation and interaction in patients' airways depending on the evolution in asthma were studied in 396 subjects. 278 females and 118 males aged 16-69 years were examined. The examination program consisted of the pulmonary function (PF) investigation, pharmacological testing using Fen, Epi, as well as evaluation of the illness duration (Till) and the reversibility of bronchial obstruction (RBO).
The PF investigation and pharmacological testing were carried out according to the following scheme: 1) initial evaluation of the PF; 2) inhalation of 0.4 mg of Fen; 3) repeated evaluation of the PF 20 min later; 4) 2 min inhalation of 0.1% solution of epinephrine hydrochloride by means of ultrasonic nebulizer with productivity 0.5 ml/min and particle size less than 5.0 mm; 5) repeated evaluation of the PF 10 min later. RBO index was calculated as follows:

where:

Till was determined as a length of the period from the appearance of the first asthmatic symptoms: persistent cough, dyspnea, wheezing and breathlessness up to moment of the patient's investigation and was confirmed more precisely by the clinical records data.
It was found that interaction of Fen and Epi seems to be a naturally determined process manifesting by the appearance of consecutive «waves» of epinephrine-induced bronchodilation and bronchoconstriction. Epinephrine-induced bronchoconstriction against the background fenoterol inhalation appears in spite of a long term steroid treatment. The severity of alpha-induced bronchoconstriction depends on the evolution in asthma and it seems to be one of the causes of asthmatics sudden death.

INTRODUCTION

As it is known, the main pathogenetic syndrome determining all the clinical symptoms of bronchial asthma (cough, dyspnea, wheezing and breathlessness) is the airflow obstruction. And so far as chronic airflow obstruction is to be prevented, physicians require a knowledge of the evolution in asthma, especially in relation to new medication strategies. In spite of the fact that subjective state of patients does not always correlate with the manifestation of bronchial obstruction [1], its progression determines finally the prognosis of the disease since it results in irreversible obstruction [2], which resists the majority of antiasthmatic drugs. As a result an increase of asthmatic mortality was noted [3], as well as of cases of sudden death of patients [4], whose subjective and objective status was rather reliable.
What is the veritable cause of fatal cases in one asthmatic population and of «longevity» in another and why does, despite a wide use of refined antiasthmatic drugs, the disease take an irrepressible course and what is the actual cause of this phenomenon? Probably, the cause seems to be in the fact, that every stage of evolution of the disease has its own peculiarities based on the different response to the bronchodilating drugs presented by beta-2-agonists and their interaction in patients’ organism with their own epinephrine. With this in mind we decided to study the results of fenoterol and epinephrine interaction in patients’ airways.

PATIENTS AND METHODS

We examined 396 asthmatic patients aged 16-69 years and analyzed their clinical records. There were 278 women (mean age±SEM 43.2±0.67 years) and 118 men (mean age±SEM 41.1±1.22 years). Past allergic history was found in 42 patients: they were hypersensitive to house dust and animal hair. However, desensitization therapy was not effective and attempts to eliminate the causative allergen failed. 52 patients had intolerance to aspirin and other non-steroid antiinflammatory drugs (NSAID); 24 patients were cigarette smokers and 74 — ex-smokers. The smoking duration was from 1 to 30 years. 109 patients were given a steroid therapy: 70 subjects — peroral (5-20 mg/day of prednisolone) and 39 subjects — inhaled steroids (300-400 mcg twice a day of beclomethasone dipropionate).
The examination program consisted of the pulmonary function (PF) investigation, pharmacological testing using fenoterol (Fen), epinephrine (Epi), as well as evaluation of the illness duration (Till) and the reversibility of bronchial obstruction (RBO).
Investigation of the PF was carried out 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. The scheme of the pharmacological testing differed from the generally accepted in clinical practice. The main difference was in the sequence of the testing: 1) initial evaluation of the PF; 2) inhalation of 0.4 mg of fenoterol; 3) repeated evaluation of the PF 20 min later; 4) 2 min inhalation of 0.1% solution of epinephrine hydrochloride by means of ultrasonic nebulizer with productivity 0.5 ml/min and particle size less than 5.0 mm; 5) repeated evaluation of the PF 10 min later. The idea of using such sequence of pharmacological testing consisted in selective evaluation antiedematous effect of epinephrine after selective bronchospasmolytic action of fenoterol, and observing the result of epinephrine interaction with its synthetic analogue fenoterol in asthmatics’ airways. In 51 patients initial pharmacological testing was carried out twice: the first time — on usual scheme (with Fen and Epi) and the second time — with selective alpha-stimulator naphazoline nitrate (Naph) instead of epinephrine.
Evaluation of the PF indices was carried out by means of different computer spirometers (made by «Cosmed» and «Vitalograph» companies) but the results were expressed as a percent of identical predicted values [5]. All the changes of the PF indices during the pharmacological testing: «+» — increasing or «-» — decreasing were also calculated as a percent of predicted values since it permits to estimate more objectively a reversibility of airflow obstruction [6].
The changes exceeding 10% of predicted values were accepted as reliable. The reversibility of bronchial obstruction was calculated as follows:

where:

The illness duration (Till) was determined as a length of the period from the appearance of the first asthmatic symptoms: persistent cough, dyspnea, wheezing and breathlessness up to moment of the patient's investigation and was confirmed more precisely by the clinical records data.
Statistical analysis of the obtained results was performed by applying the methods of variation statistic and correlation analysis. In cases of normal distribution of signs Student's unpaired and paired t-tests were used and linear correlation was calculated. In cases of abnormal distribution of signs non-parametric methods were used: Wilkoxon's unpaired criterion as well as Spearman's correlation were calculated [7].

RESULTS

The initial analysis of the obtained results was carried out according only to the values of the FEV₁.

The initial PF evaluation in the studied population revealed, that the FEV₁ index in 116 subject exceeded 80% of predicted values. It should be noted that 53 of them were in clinical remission, 30 — completed before the investigation the course of steroid treatment and 33 patients received peroral or inhaled steroids. The remaining 280 patients with FEV₁=80% and lower were in exacerbation phase in spite of the fact that 76 of them were given long term peroral and inhaled steroid therapy. At first all the patients were divided into 4 groups according to the PF state: a) FEV₁>80%; b) FEV₁=61-80%; c) FEV₁=41-60% and d) FEV₁=40% and lower. The results of pharmacological testing and reversibility of bronchial obstruction in these groups are presented in table 1.

Table 1 . The results of pharmacological testing and reversibility of bronchial obstruction
depending on the initial values of FEV₁ in the studied population (means±SEM)

* — Student's test (* — p<0.05, ** — p<0.01), *W — Wilkoxon's test (p<0.05): group b) vs. group a), group d) vs. group c);
RBO — reversibility of bronchial obstruction; Till — duration of illness.

As it is seen from this table on the one hand the worsening of the disease is revealed by the decreasing of FEV₁ and on the other hand the increasing of Till is accompanied with increasing of bronchial response to fenoterol. At the same time the reversibility of airflow obstruction is on decrease. As to response to epinephrine the absolutely evident fact is that it does not exceed 10% of predicted values in all the groups constituted in this manner.

For further analysis all the patients were divided into groups depending not only on the values of FEV₁ but also on the response to epinephrine (table 2).

Table 2. Patients' investigation results depending on the initial FEV₁ values and response to epinephrine
in the studied population (means±SEM)

Till — duration of illness;* — Student's test (* — p<0.05, ** — p<0.01), *W — Wilkoxon's test (p<0.05): the 2nd, the 3d and the 4th groups vs. the 1st group,
the 5th, the 6th and the 7th group vs. the 4th group; NS — non significant.

The table 2 shows that the first three groups included subjects with FEV₁ value exceeded 80% and different response to epinephrine: the first group consisted of patients with a proven positive response (increase of FEF_25-75 exceeded 10% of predicted values).
The second group according to this criterion included the patients with negative response to epinephrine and the third one demonstrated the lack of the response to this pharmacological agent. A reliable positive response to fenoterol (taking into account the changes of FEF_25-75) was commonly recorded in all these three groups. A difference between the changes in FEV₁ index in these groups was not taken into account because in two of them it did not exceed 10% of predicted values. The 4th, 5th, 6th and 7th groups comprised subjects with the FEV₁ values 80% and less of predicted ones. The bronchial response to epinephrine in these patients was also different: the 4th and the 5th groups were presented by subjects with the lack of reaction to epinephrine. They differed one from the other only by the response to fenoterol (taking into account FEV₁ as well as FEF_25-75 indices): in the 5th group it exceeded and in the 4th group it did not exceeded 10% of predicted values. The patients of the 6th and the 7th groups had the absolutely contrary response to epinephrine: in the first case it was positive (increase of the FEV₁ and FEF_25-75 indices) and in the second case — negative (decrease of all the PF indices).
The clinical manifestations of epinephrine inhalation in patients of the 6th and 7th groups was quite different. The subjects of the 6th group felt an additional relief in their breathe after the epinephrine inhalation in comparison with fenoterol one. In patients of the 7th group epinephrine inhalation caused intensive cough with expiratory dyspnea and widespread rhonchi were heard through — out the chest. Then in 20 subjects of this group epinephrine inhalation and performing repeated spirometric measurement resulted in severe breathlessness which was abolished only by intravenous injection of 240 mg aminophylline and 90 mg prednisolone. In other patients of this group epinephrine inhalation stimulated cough and in some time all the subjects felt dyspnea. As to the response to fenoterol it was markedly positive in all the groups of patients except the 4th one. Mean duration of illness (Till) was the lowest in the first group and the highest in the last group.
The obtained results demonstrate the fact that asthmatics differ not only according to the PF indices values but also according to responses to fenoterol and epinephrine which can be absolutely contradictory. Of interest is the fact that judging from individual peculiarities, habits and steroid treatment all the groups were relatively homogenous (table 3).

Table 3. Individual peculiarities of the patients under study

To define more precisely the mechanism of bronchodilation or bronchoconstriction resulted by the epinephrine inhalation 30 patients of the 6th and 21 patients of the 7th groups were repeatedly tested using a selective antiedematous alfa-stimulator naphazoline nitrate (Naph) instead of epinephrine following the same scheme. The changes of FEV₁ to Naph inhalation were 15.8±1.68 and -18.6±2.59 correspondingly (means±SEM). This result is completely analogous to the epinephrine action.
To prove the independence of bronchial response to epinephrine from that to fenoterol in performing sequential testing, 21 subjects with absence of reliable response to fenoterol were selected from the 1st and the 6th as well as from the 2nd and 7th groups (table 4).

Table 4. Investigation results in patients with the lack of a reliable response to fenoterol
(means±SEM)

Epi+ — a positive response to epinephrine in group of patients; Epi- — a negative response to epinephrine in group of patients;

** — Student's test (p<0.01), *W — Wilkoxon's test (p<0.05): the group Epi- vs. the group Epi+; NS — non significant.

The data of the table 4 show that despite the fact that in all these patients the bronchodilating effect of fenoterol was not registered, the inhalation of epinephrine induced bronchodilation in one part of patients and bronchoconstriction in the other. It is quite obvious that the mean value of illness duration is almost twice higher in the second case that in the first. The obtained results suggest that a bronchial response to epinephrine (after the preliminary inhalation of fenoterol) can be manifested as an additional bronchodilation or bronchoconstriction of different grade.
Thus the obtained data show that evolution in bronchial obstruction in asthmatics manifests not only by a decrease of the PF indices but also by a change in bronchial response to pharmacological agents, as well as by an appearance of bronchoconstriction to epinephrine.

DISCUSSION

The first analysis of the investigation results (table 1) demonstrates a curious fact: the airflow obstruction evolution in asthmatics is manifested on the one hand, by a decrease of the FEV₁ index and on the other hand — by an increase of bronchial response to fenoterol, which is connected, probably, with an increase of bronchial smooth muscle contraction. In a total of the patients there was no observed an essential response to epinephrine (exceeding 10% of predicted values), although a tendency to an increase of bronchoconstriction to this agent was obvious. At the same time it was found that despite an increase of a bronchial response to fenoterol in parallel to evolution in asthma the reversibility of airflow obstruction decreased. If in the first 8-9 years of asthma history bronchodilators, in particular fenoterol, can restore the airflow conductance on average by 82-100%, in the following years it is possible only by 55-68%. An increase of bronchoconstriction to epinephrine does not explain such decreasing the reversibility of bronchial obstruction (RBO), because in a total its value does not exceed on average 3%.
Some what a different situation was observed when the patients were distributed not only by the values of the FEV₁ index but also by the bronchial response to epinephrine (table 2). It was found that the bronchial response to epinephrine in subjects was quite different: one could see bronchodilation, bronchoconstriction or the lack of reliable response as a duration of illness changed. A logic question then raised: what is the mechanism of epinephrine bronchodilation or bronchoconstriction against the background of previous fenoterol inhalation? Is it resulted by the additional beta or alpha-adrenoreceptor stimulating action of epinephrine? The results of repeated testing of 51 patients of the 6th and 7th groups with antiedematous alpha-adrenostimulator naphazoline nitrate (Naph) allowed to assert that these effects of epinephrine were resulted due to its alpha-adrenoreceptor stimulating action. This statement is once again confirmed by the data from table 4: in absence of a proven bronchial response to selective beta-2-agonist fenoterol the inhaled epinephrine induced in the first case a bronchodilation and in the second — bronchoconstriction which obviously resulted by the stimulation of alpha-adrenoreceptors.
Thus summing up one may conclude that evolution of airflow obstruction in asthmatics is manifested through a change of the bronchial response to epinephrine (table 2). In the debut of asthma one can observe a positive response to epinephrine determined by the decreasing the bronchial mucosa edema (the 1st group). Concerning the key role of inflammation in asthma development [8] one may designate it as the first «wave» of inflammation. Then the positive response to epinephrine is replaced to its negative one (the 2nd group). At the same time in the both groups one can see a positive response to fenoterol. But a reliable response to epinephrine (exceeding 10% of predicted values) is revealed only by the change of the FEF_25-75 as the FEV₁ index is actually normal.
A further progression of bronchial obstruction in asthmatics is closely connected with an appearance of a steady smooth muscle spasm (the 3rd group). At this stage the ratio between the bronchodilation and bronchoconstriction to epinephrine is probably 1:1 that is deduced from the lack of proven response to this agent. The further evolution of airflow obstruction in asthmatics (on average 10 years later of its debut) has apparently two pathways: the first is based on irreversible obstruction progression (the 4th group) and the second — on the bronchial smooth muscle spasm enhancement (the 5th group). In both cases an essential decrease of all the PF indices (FEV₁ and FEF_25-75) is observed. One can see the lack of bronchial response to epinephrine in these groups but the difference in fenoterol action. In the 4th group the lack of reliable response to fenoterol is connected probably with bronchial obturation with mucus plugs as a result of severe expectoration disorders [9, 10]. On the contrary in the 5th group the value of bronchial response to fenoterol is the highest.
The next stage of evolution in airflow obstruction of asthmatics is connected with the appearance of the second inflammation «wave» also accompanied with a positive response to epinephrine (the 6th group in table 2). Probably as a result of a new inflammation «wave» in the subjects of the 6th group one can see a decrease of response to fenoterol in comparison with the patients of the 5th group . The further progression of inflammation results in the appearance of alpha-induced bronchoconstriction in the 7th group of patients (table 2). And this situation is characterized by the prevalence of epinephrine bronchoconstrictive action over the bronchodilative effect of fenoterol. At this stage the situation apparently starts to be getting out of the management control. Under consideration of these findings it is understandable showing up some cases of so called «unstable» or «emotional» («nervous-psychic» — in the Russian literature) asthma: a release of great amounts of endogenous epinephrine (or norepinephrine) due to stress or emotional unstability associated with an excessive use of beta-sympathomimetics provokes the development of alpha-induced bronchoconstriction and its clinical manifestations (cough, dyspnea, wheezing and breathlessness). Just among the emotionally unstable asthmatics frequent cases of sudden death are observed despite an active corticosteroid treatment [11]. And one of the most probable causes of sudden death is alpha-induced bronchoconstriction associated with a release in the blood stream of a great amount of endogenous catecholamines.
Thus a certain sequence of the pathophysiological events in evolution of airflow obstruction in asthmatics has been revealed (fig. 1): against the background of PF impairment as far as of increasing of illness duration (Till), one can see the appearance of two positive and two negatives «waves» representing the bronchial response to epinephrine.

Fig. 1. Evolution of airflow obstruction in asthmatics

Of note is the fact that bronchoconstrictive effect of epinephrine exceeds its bronchodilating action. Our data concerning the duration of illness from table 2 confirm once again that evolution in asthma is manifested in the debut by the «wave» of alpha-induced bronchodilation and in the final — by the «wave» of alpha-induced bronchoconstriction. The statement that the absolutely contrary response to epinephrine is determined by the evolution in asthma but not the individual features of patients is confirmed by a relatively homogenous personnel of the investigated groups (table 3).
Thus the first inflammation «wave» results in the development of different types of airflow obstruction: with bronchospasm (the 5th group) or irreversible obstruction (the 4th group). The onset of a new — the second inflammation «wave» and further progression of bronchial obstruction results in a pronounced alpha-induced bronchoconstriction and non-controlled situation (the 7th group). If one assumes that evolution in asthma gives the example of a naturally determined phenomenon, its further development may be presented in two ways (fig. 1 — dotted line): an aggravation of irreversible obstruction (the lack of a reliable response to fenoterol) or an enhancement of bronchospasm (the presence of a reliable response to this agent). In the latter case the administration of beta-2-agonists proves to be efficient but in the former case it does not. The result of the former case may be catastrophic. As to the patients with a bronchospasm prevalence in the airflow obstruction survived the second inflammation «wave», the further evolution in their asthma is probably determined by the appearance of the third «wave» of inflammation and recurrence of the above-described pathophysiological events.
A reasoning about the evolution in asthma as a naturally determined «wave live» phenomenon does not imply, for example, that at one or another stage of this process one can observe sole alpha-induced bronchodilation or bronchoconstriction. But probably every stage of the evolution in airflow obstruction in asthmatics is characterized by the frequency prevalence of the determined response to the beta- and alpha-adrenostimulation.
As to the pharmacological testing performing solely with selective beta-2-sympathomimetics its possibilities do not permit in a similar at the first sight population to reveal all the peculiarities of the development and further evolution of airflow obstruction in asthmatics. And this thesis is obviously illustrated by the data from table 2: in the subjects of the 5th, 6th and 7th groups having on average the identical PF indices a positive response to fenoterol does not reflect the real situation. And only the further alpha-adrenoreceptor stimulating effects of epinephrine permit to evaluate the asthma severity and prognosis.

Pharmacological testing according to the suggested scheme facilitates to distinguish several types of the airflow obstruction irrespective of its expression (table 2):
a) BRONCHOSPASTIC type (the 3rd and 5th groups). A prevailed mechanism of the airflow obstruction in this case is the bronchial smooth muscle spasm.
b) INFLAMMATORY-EDEMATOUS type (the 1st and 6th groups). This type of airflow obstruction is characterized by the combination of bronchial smooth muscle spasm and mucosa edema.
c) ALPHA-BRONCHOCONSTRICTIVE type (the 2nd and 7th groups) is characterized by the presence of the bronchial smooth muscle spasm and a perverted response to epinephrine;
d) IRREVERSIBLE type of the airflow obstruction probably is connected with severe expectoration disturbances.
Determination of the different types of bronchial obstruction gives the possibility to carry out more precise treatment changing in case of necessity steroid therapy. And the main criteria of management efficacy are the following: an increase of the PF indices up to the maximal normal values, a decrease of the severity of bronchospasm (as judged by response to fenoterol) accompanied with an increase of the bronchial obstruction reversibility, as well as disappearance of alpha-induced bronchoconstriction (as judged by response to epinephrine or selective alpha-stimulators).

CONCLUSION

Summarizing the above discussion of the investigation we may rightfully state that the evolution of airflow obstruction in asthmatics characterized not only by quantitative (a decrease of the PF indices), but also qualitative (a different response to epinephrine) changes in the respiratory tract. The evolution in asthma proves to be a naturally determined process despite the fact that an objective situation not always corresponds to its subjective estimation of the patient or his physician. And natural laws of asthma evolution determine the occurrence of favourable or unfavourable periods in the patients' life, a risk of sudden death and prognosis of the disease.

ACKNOWLEDGMENTS

The author would like to express his gratitude to companies «VITALOGRAPH Ltd.» and «COSMED» for their help in supplying spirometers, used in carrying out this investigation.

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Dr. Victor N. Solopov
2/9-316 Chicherine str.
129327, Moscow, Russia
Tel. (095) 189-5988
www.asthma.ru
E-mail: asthma@consultant.ru