ALL THE BETA-2 BRONCHODILATORS ARE ABLE TO PROVOKE SUDDEN DEATH IN ASTHMATICS
Dr. Victor N. Solopov
«Asthma Service», Medical Services Ltd., Moscow
Albuterol. Fenoterol. Formoterol. Epinephrine. Sudden death from asthma
The different types of bronchial response to Albuterol (Alb), Fenoterol (Fen), Formoterol (Frm) and epinephrine (Epi) resulted after their consecutive inhalation and interaction in patients’ airways were discovered in blind study in 850 subjects. 590 females and 260 males aged 16-45 years were examined. The examination program consisted of the pulmonary function (PF) investigation, pharmacological testing using Alb, Fen, Frm and Epi. 286 patients were testing with Alb, 280 patients — with Fen and 284 patients — with Frm.
The PF investigation and pharmacological testing were carried out according to the following scheme:1) initial evaluation of the PF; 2) inhalation of beta-2-agonist: 400 mcg of Alb, or 400 mcg of Fen, or 24 mcg of Frm; 3) repeated evaluation of the PF 20 min later; 4) inhalation of 0.1% solution of epinephrine hydrochloride (0.5 ml) by means of nebulizer generating particles with size less than 5.0 mcm; 5) repeated evaluation of the PF 10 min later. Distribution of the patients into groups for investigation and the choice of beta-2-agonist for every person were carried out with blind method by two non-contacting investigators. It was found that interaction of all these beta-2-agonists with Epi causes in some cases a severe bronchoconstriction and it seems to be the proven cause of asthmatics’ sudden death.
In some retrospective investigations it was reported that high doses of fenoterol inhalations may be responsible for sudden death epidemic in asthmatics , . Later these reports were cited in the workshop report «Global Strategy for Asthma Management and Prevention» . This is in agreement with our earlier data that the cause of sudden death is probably connected with asthmatics’ epinephrine interaction with inhaled beta-2-agonists (in particular, with fenoterol) . And this interaction causes a severe bronchoconstriction which can lead to a fatal asthmatic attack. With this in mind we decided to study the results of interaction of different beta-2-agonists and epinephrine in patients’ airways.
PATIENTS AND METHODS
We examined 850 severe asthmatic patients with daily persisting symptoms aged 16-45 years and analyzed their clinical records. There were 590 women (mean age±SEM 36.9±0.89 years) and 260 men (mean age ± SEM 37.1 ± 0.93 years). Allergological investigation (skin of RAST tests) was positive in 350 patients. 97 patients had intolerance to aspirin and other non-steroid antiinflammatory drugs (NSAID); 748 patients were given inhaled steroid therapy equivalent on average to 800-1500 mcg of beclomethasone dipropionate and 102 subjects — peroral (5-20 mg/day of prednisolone).
The examination program consisted of the pulmonary function (PF) investigation and pharmacological testing using Alb, Fen, Frm and Epi. Investigation of the PF was carried out with the patients having an empty stomach. Twelve hours prior to the PF investigation, sympathomimetics were not administrated. 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 beta-2-agonist (400 mcg of Alb, or 400 mcg of Fen, or 24 mcg of Frm); 3) repeated evaluation of the PF 20 min later; 4) inhalation of 0.1% solution of epinephrine hydrochloride (0.5 ml) by means of nebulizer generating particles with size less than 5.0 mcm; 5) repeated evaluation of the PF 10 min later. 286 patients were testing with Alb, 280 patients — with Fen and 284 patients — with Frm. The distribution of the patients into groups for investigation and the choice of beta-2-agonist for every person were carried out with blind method by two non-contacting investigators.
The idea of using such sequence of pharmacological testing consisted in observing the result of epinephrine interaction with its synthetic analogues in asthmatics’ airways.
Evaluation of the PF indices was carried out by means of computer spirometer and the results were expressed as a percent of predicted values . 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 . The changes exceeding 10% of predicted values were accepted as reliable.
Statistical analysis of the obtained results was performed by applying the methods of variation statistic. Taking into account the normal distribution of signs Student’s unpaired and paired t-tests were used. .
Initially all the investigated patients were divided into 4 groups: a, b, c and d, depending not on the type of the beta-2-agonist but on the response to epinephrine (table 1).
Table 1. All the patients’ investigation results depending on the response to epinephrine inhaled after beta-2-agonist
|Patients’ subgroups||FEV1, %||D FEV1beta-2 %||D FEV1epi, %|
|b) (n=387)||61.2±0.96||22.1±0.65 **||-0.8±0.24 NS|
|c) (n=151)||59.7±1.03||14.1±0.87 **||19.6±0.78 **|
|d) (n=138)||60.0±1.19||15.7±0.93 **||-23.5±1.08 **|
FEV1 – forced expiratory volume per the 1st sec;DFEV1 beta-2 – response to beta-2-agonist; DFEV1epi – response to epinephrine; ** – Student’s test (p<0.01): groups b), c) and d) vs. group a), NS – non significant.
This table shows that these groups comprised the patients with different response to all the pharmacological agents: groups a) and b) were presented by subjects with the lack of reaction to epinephrine. They differed one from the other only by the response to the beta-2-agonists: in the group b) it exceeded and in the group a) it did not exceeded 10% of predicted values. The patients of groups c) and d) had the absolutely contrary response to epinephrine: in the first case it was positive and in the second case – negative.
Thus in 151 patients the result of interaction of beta-2-bronchodilator with epinephrine was positive and in 138 patients – expressively negative. In the “positive group” lung function index (FEV1) increased by 19.6±0.78% (as a percent of predicted values). But in the “negative group” it decreased by 23.5±1.08% (as a percent of predicted values). The clinical manifestations of this interaction in patients was quite different. The subjects of the “positive group” felt an additional relief in their breathe. In patients of the “negative group” this interaction caused intensive cough with expiratory dyspnea and widespread rhonchi were heard through out the chest. Then in 48 subjects of this group epinephrine inhalation and performing repeated spirometric measurement resulted in severe breathlessness which was abolished only by the intensive care management. In other patients of this group this inhalation test stimulated cough and in some time all the subjects felt dyspnea. So it is proved that interaction of synthetic bronchodilators and epinephrine in asthmatics’ organism can manifest not only as an bronchodilation but as a severe bronchoconstriction.
Table 2. The value of induced bronchoconstriction in Alb, Fen and Frm groups
|The value of Epi-induced
Then we compare the value of induced bronchoconstriction depending on the type of preinhaled beta-2-agonist (table2). One can see that in spite of the selected drug type the value of the bronchoconstriction after “beta-2-agonist – epinephrine” interaction is the same.
Firstly, the obtained data (tables 1 and 2) show that bronchial obstruction in asthmatics can manifest 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 severe bronchoconstriction to epinephrine inhaled after beta-2-agonists. Secondly, one can see that the bronchoconstrictive action of epinephrine after preliminary inhalation of beta-2-agonists does not depend essentially on the type of the bronchodilator used: the value of Epi-induced bronchoconstriction on average is identical in all three groups.
Thus the result of “beta-2-agonist – epinephrine” interaction in asthmatics’ airways was dangerous in 138 subjects (16% of the investigated population) despite the beta-2-bronchodilator type. One can see on average more high frequency of bronchoconstriction in “Albuterol” and “Formoterol” groups, but it needs more wide investigations.
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 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 .
And one of the most probable causes of sudden death is bronchoconstriction associated with an interaction of bronchodilator drugs with endogenous catecholamines released in the asthmatics’ blood stream. One can see that all the asthmatics differ one from the another by the results of “beta-2-agonist – epinephrine interaction”. And a severe bronchoconstriction to beta-2-agonists acted together with epinephrine in asthmatics’ organism may cause a fatal asthmatic attack and their sudden death.
Summarizing the above discussion of the investigation we may rightfully state that airflow obstruction in asthmatics is characterized not only by quantitative (a decrease of the PF indices) but qualitative changes in the respiratory tract (bronchial response) to different farmacological agents. All the asthmatics differ one from the another by the response to beta-2-agonists and epinephrine which may cause a severe bronchoconstriction leading to a fatal asthmatic attack and sudden death. And the main cause of sudden death in asthmatics is truelly connected with the use of different beta-2-agonists.
So we conclude that all the publications concerning mutual relations of bronchodilating drugs and asthmatics’ sudden death are not fantastic. And the main cause of sudden death in asthmatics is connected with “beta-2-agonist – epinephrine interaction”.
The author would like to express his gratitude to company «VITALOGRAPH Ltd.» for the help in supplying «VITALOGRAPH COMPACT» spirometer, used in carrying out this investigation.
1. Crane J, Pearce N, Flatt A, Burgess C, Jackson R, Kwong T, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-83: case-control study. Lancet 1989; 1: 917-922.
2. Spitzer WO, Suissa S, Ernst P, Horwitz RI, Habbick B, Cockcroft D, et al. The use of beta-agonists and the risk of death and near death from asthma. N Engl J Med 1992; 326: 501-506.
3. Global Strategy for Asthma Management and Prevention. National Institutes of Health, National Heart, Lung and Blood Institute. Revised 2002. Updated from NHLBI/WHO Workshop Report: Global Strategy for Asthma Management and Preven-tion Issued January, 1995. NIH Publication No 02-3659.
4. Solopov VN. Evolution in asthma: epinephrine healer versus epinephrine killer. Moscow, 1992 (rus). English version is available in Internet on https://www.solopov.ru/eng/main.htm .
5. Morris JF, Koski A, Breese JD: Normal values and Evaluation of Forced End-Expiratory Flow. Amer Rev Resp Dis 1975; 111: 755-762.
6. Brown RD, Grattan G: Reversibility of airflow obstruction. Lancet 1988; 1: 586-587.
7. Glantz SA. Primer of biostatistics. NY, McGraw-Hill Inc., 1994.
8. Picado C, Montserrat JM, Pablo J, Augusti-Vival A: Predisposing factor to death after recovery from a life-threatening asthmatic attack. J Asthma 1989; 26: 231-236.
Dr. Victor N. Solopov
28 Lenskaya str.
129327, PO BOX 23