Drug-Induced Anaphylactic Shock

1 Национальный научный центр фармаконадзора, Россия, 127051, г. Москва, Малая Сухаревская площадь, д. 2, корп. 2 2 Первый Московский государственный медицинский университет им. И. М. Сеченова Минздрава России, Россия, 119991, г. Москва, ул. Трубецкая, д. 8, стр. 2 3 Медицинская академия им. С. И. Георгиевского Крымский федеральный университет им. В. И. Вернадского, Россия, 295051, Симферополь, бульвар Ленина, д. 5/7


Introduction
Anaphylactic shock (AS) is one of the most dangerous complications of drug therapy [1,2].According to WHO, it is rather difficult to establish anaphylactic shock prevalence because of differences in AS diagnosing and coding between countries worldwide, and impossibility of undertaking prospective cohort studies to investigate it.The average overall prevalence of AS is 80-120 cases per million person-years, and the total mortality reaches 1% (the mortality rate of 1-5.5 per million population per year) [2].It is worth noting that these indicators tend to grow continuously due to an increasing number of potential allergens [3].
Purpose of the work was to identify factors associated with a high AS risk based on 2010-2018 records made in the Republic of Crimea.

Materials and Methods
The objects of the study of anaphylaxis cases were reports on adverse reactions (AR) to medicinal remedies (MR), which were recorded in the regional database of spontaneous reports -ARCAD (Adverse Reactions in Crimea, Autonomic Database), for the period of 2010-2018.112 anaphylactic shock cases occurred dur-
The incidence of AS associated with different groups of MR was studied with regard to the codes of Anatomical Therapeutic Chemical (ATC) Classification System of the World Health Organization [10], data from instructions of the State Register of Medicinal Remedies of the Russian Federation and Ukraine (for cases recorded before the Republic of Crimea became the part of the Russian Federation).
The severity of adverse reactions recorded in patients was established according to the definition contained in clause 51 of article 4 of Federal Law «On Circulation of Medicinal Remedies» dated 12 April 2010, No. 61 [11].
The frequency of events (fractions, % of the total number) was calculated with the aid of MS Excel 2016.

Results and Discussion
The cases of severe allergic reactions in the form of AS amounted to 1.74% of the total number of AR cases for the respective period (6428 reports).
The first stage of the study was aimed at establishing the main pharmacological groups of drugs, which were associated with development of severe allergic reactions in the form of anaphylaxis.It was noted that leader in AS incidence in the Republic of Crimea during 2010-2018 was the group of antimicrobial drugs for systemic administration (ATC code -J01) -38 cases.A rarer cause of AS were drugs from the group of local anesthetics (ATC code -N01B) -14 cases, analgesics-antipyretics (ATC code -N02B) -10 cases, X-ray contrast iodinecontaining substances (ATC code -V08A) -8 cases, and non-steroidal anti-inflammatory drugs (ATC code -M01A) -5 cases (fig.).The remaining 37 cases of AS were associated with MR from various pharmacological groups.
A detailed analysis of AS cases during application of antimicrobial drugs for systemic use has shown that the most frequent cause of such complications was the use of antibacterial drugs of the group of cephalosporins (30 cases, 78.9% of the total number of AS cases related to group J01).The prevalence of AS cases during the use of cephalosporins is presented in table 1.
In three cases, development of AS associated with the use of drugs from the group of fluoroquinolones, and two AS cases were observed during treatment of patients with amino glycoside antibiotics (Amikacin) and drugs from the group of penicillins.In one case the AR of emergency type was due to the use of a drug combination containing antibiotic azalide/ azithromycin.Among local anesthetics, the AS incidence was the highest for lidocaine (6 cases) and combined drugs on the basis of articaine (6 cases).One case Оставшиеся 37 случаев развития АШ были ассоциированы с применением ЛС из различных фармакологических групп.
Среди местных анестетиков лидерами по частоте развития АШ стали лидокаин (6 случаев) и комбинированные препараты на осно-of such AR was observed when novocaine and bupivacaine were used.It should be noted that the AS develops during use of drugs belonging to this group very rarely.Besides, several studies point out the importance of differential diagnosis between an AS response and more commonly occurring vasovagal events including low-dose local anesthetics and featuring similar symptoms (breathing disorders, faintness, arterial blood pressure changes, convulsions) [12,13].
AS were also observed in patients during the use of antipyretic analgesics.In 5 cases, the clinical symptoms of AS developed during parenteral administration of analgin.In 3 cases, the AS was associated with the use of drugs containing paracetamol or paracetamol alone.
Most frequently, patients experienced AS because of parenteral administration of a MR, which can be explained by high bioavailability typical for intravenous and intramuscular routes of administration (table 2).
The next part of the study included analysis of case histories of allergic patients with clinical presentation of AS.Timely and correctly recorded case histories of patients with allergies containing information on prescription of drugs allows defining the probability of allergic responses to their administration.Analysis of the nature of patients' sensibilization has shown that in most cases the case history of allergies was informative to predict allergic reactions (84 cases, 75%); in 15 cases (13.4%) there was sensibilization to drugs, in 4 cases (3.6%) -to domestic allergens, in 2 cases (1.8%) -to food-based allergens, and in 3 cases (2.7%) a combined sensibilization (to food, domestic and pollen allergens) was observed.In 4 cases (3.5%), the history of allergies was unknown.
Изучение категории НР выявило 8 смертельных исходов вследствие развития АШ на фоне введения ЛС; в 4 случаях смерть была вызвана парентеральным введением препаратов группы β-лактамных антибиотиков: 3 слу-in 15 cases -within the first 5 minutes after administration, in 17 cases -within 30 minutes after administration.These data confirm a high rate of anaphylaxis development that requires a physician to be trained in emergency medical care.In 3 cases, development of clinical symptoms was observed within the first 45-60 minutes after administration of a suspected drug.In 9 cases, AS symptoms were first observed later than 1 hour after MR administration.In 49 cases of adverse reactions, information about the rate of their development was missing.
A significant factor for evaluation of a causeeffect relation between intake of a suspected drug and occurring AR is the number of drugs prescribed concurrently.Analysis of reports has shown that development of AS symptoms was observed in most cases (63 cases, 56.2%) during drug administration as a monotherapy.Distribution of the remaining cases is shown in table 3.
Study of the AR category revealed 8 lethal outcomes due to AS to MR; in 4 cases death was caused by parenteral administration of drugs from the group of β-lactam antibiotics, Ceftriaxon (3 cases) and amoxicillin/clavulanate (1 case).In 97 cases, AS was life-threatening and required emergency pharmacological therapy and immediate discontinuation of drug administration.In 3 cases, information reports mentioned the need in patient's hospitalization, and in 1 case AS led to temporary disability.In 3 cases, AR category was not mentioned.
AS is an emergency condition requiring immediate parenteral administration of a MR to correct cardiovascular and respiratory disturbances and save the patient's life.The main drugs considered as the emergency medical care standards for AS include solutions of adrenaline hydrochloride, glucocorticosteroids (prednisolone, dexamethasone, hydrocortisone), dimedrol and aminophylline [15,16].
Analysis of the treatment options demonstrated that to reverse the AS, non-selective adrenergic agonists, glucocorticosteroids and antiallergic drugs employed most frequently.The distribution of respective groups of drugs by the frequency of their use for AR correction is given in table 5. Adrenalin hydrochloride solution was administered to patients in 69.6% of cases, which is rational according to emergency medical care standards in reversing AS.The frequency of use of glucocorticosteroids for AR correction amounted to 94 cases (83.9%), the most often drug of choice being dexamethasone.Antihistamines were used much rarer to reverse AS.
The total number of prescriptions of drugs from this group was equal to 42, i. e. 37.5% of the total number of cases of medical correction of AS.
Our findings were corroborated by a number of international studies described high prevalence of drug-induced AS cases.Studies on fatal anaphylaxis in USA in 1999-2010 discovered 2458 such cases, wherein in 58.8% of cases AS was caused by drugs [8].In Latin America, the AS development most commonly associated with the use of NSAID drugs (57.8%) and antibiotics (19.5%) [17].AS incidence rate in Kazan city, Russia, which was studied using the data on medical aid available for 1995 and 1999 years, was found equal to 3.5% and 4.4 % of all acute allergic reactions, respectively.MR were the cause of AS in 50% and 62% of cases, respectively.The retrospective analysis of medical charts of pediatric population for the period of 2009-2013 years, which was carried out in South Korea, identified 991 anaphylaxis cases.The cases of drug-induced anaphylaxis were most often recorded for the use of antibiotics (34.9%) and non-steroid antiinflammatory drugs (17.9%) [18].
Analysis of published data and our findings highlight the pharmacological groups mostly contributing to AS to include antimicrobial drugs for systemic use and NSAID [19].In our study, AS has been rather frequently (14 and 8 cases, respectively) associated with administration of local anesthetics and X-ray contrast compounds, which requires further investigation of the incidence and features of development of severe allergic and pseudoallergic reactions during their use.

Conclusion
Summarizing the analysis of information reports recorded in the Republic of Crimea in 2010-2018, the attention should be paid to high incidence and speed of development of AS adverse reactions.Among all pharmacological groups, the 'leaders' in AS prevalence included β-lactam antibiotics, local anesthetics and anti-pyretic analgesics.Considering high AS development rate, the facts of commonly ignored information on drugs and allergies as a part of a case history, and the AS improper therapies, the urgent need in conducting additional education events for physicians specializing in different fields and distribution of information materials (posters, algorithms) aimed at eliminating medical aid errors should be warranted.