ALL THE BETA-2 BRONCHODILATORS ARE ABLE TO PROVOKE SUDDEN DEATH IN ASTHMATICS<\/p>\n
Dr. Victor N. Solopov
\n\u00abAsthma Service\u00bb, Medical Services Ltd., Moscow<\/p>\n
KEY WORDS<\/p>\n
Albuterol. Fenoterol. Formoterol. Epinephrine. Sudden death from asthma<\/p>\n
ABSTRACT<\/p>\n
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 \u2014 with Fen and 284 patients \u2014 with Frm.
\nThe 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.<\/p>\n
INTRODUCTION<\/p>\n
In some retrospective investigations it was reported that high doses of fenoterol inhalations may be responsible for sudden death epidemic in asthmatics [1], [2]. Later these reports were cited in the workshop report \u00abGlobal Strategy for Asthma Management and Prevention\u00bb [3]. This is in agreement with our earlier data that the cause of sudden death is probably connected with asthmatics\u2019 epinephrine interaction with inhaled beta-2-agonists (in particular, with fenoterol) [4]. 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\u2019 airways.<\/p>\n
PATIENTS AND METHODS<\/p>\n
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\u00b1SEM 36.9\u00b10.89 years) and 260 men (mean age \u00b1 SEM 37.1 \u00b1 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 \u2014 peroral (5-20 mg\/day of prednisolone).
\nThe 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 \u2014 with Fen and 284 patients \u2014 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.
\nThe idea of using such sequence of pharmacological testing consisted in observing the result of epinephrine interaction with its synthetic analogues in asthmatics\u2019 airways.
\nEvaluation of the PF indices was carried out by means of computer spirometer and the results were expressed as a percent of predicted values [5]. All the changes of the PF indices during the pharmacological testing: \u00ab+\u00bb \u2014 increasing or \u00ab-\u00bb \u2014 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.
\nStatistical 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. [7].<\/p>\n
RESULTS<\/p>\n
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).<\/p>\n
Table 1. All the patients’ investigation results depending on the response to epinephrine inhaled after beta-2-agonist
\n(means\u00b1SEM)<\/p>\n
| Patients\u2019 subgroups<\/td>\n | FEV1, %<\/td>\n | D FEV1beta-2 %<\/td>\n | D FEV1epi, %<\/td>\n<\/tr>\n | ||||||||
| a) (n=174)<\/td>\n | 59.9\u00b11.11<\/td>\n | 7.53\u00b10.36<\/td>\n | 0.9\u00b10.18**<\/td>\n<\/tr>\n | ||||||||
| b) (n=387)<\/td>\n | 61.2\u00b10.96<\/td>\n | 22.1\u00b10.65 **<\/td>\n | -0.8\u00b10.24 NS<\/td>\n<\/tr>\n | ||||||||
| c) (n=151)<\/td>\n | 59.7\u00b11.03<\/td>\n | 14.1\u00b10.87 **<\/td>\n | 19.6\u00b10.78 **<\/td>\n<\/tr>\n | ||||||||
| d) (n=138)<\/td>\n | 60.0\u00b11.19<\/td>\n | 15.7\u00b10.93 **<\/td>\n | -23.5\u00b11.08 **<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/div>\n 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.<\/p>\n 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. Table 2. The value of induced bronchoconstriction in Alb, Fen and Frm groups \n
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