Emergency Management of Anaphylaxis in Chinese Primary Care Units: Systematic Analysis of 77 Cases

Background Anaphylaxis is a potentially fatal medical emergency and prompt, appropriate administration of epinephrine is critical. However, the actual clinical practices of emergency management of anaphylaxis in Chinese primary care remain unclear. Objective To evaluate the actual emergency management of anaphylaxis in Chinese primary care units compared to current guidelines. Methods Systematic analysis of published case reports of anaphylaxis initially treated in Chinese primary care units from January 2014 through December 2018. Results A total of 77 cases were included in this analysis. The patients came from 22 provinces of China. Mean age was 42 years, and 49 (64.5%) were male. All the patients developed severe anaphylactic reactions, with mortality rate of 5.2%. Only 21 (27.3%) patients received epinephrine as rst-line intervention. The rst dose of epinephrine ranged from 0.0625 mg to 0.5 mg in children and 0.1 mg to1.0 mg in adults. The percentage of adult patients who received initial epinephrine dose of 1.0 mg (73.7%) was signicantly higher than that of 0.5 mg (19.3%; p < 0.001). The percentage of patients who received subcutaneous (SC), intramuscular (IM), or intravenous (IV) bolus injection was 44.3%, 36.1%, and 19.7%, respectively. Among patients who received epinephrine, 80.3% received an overdose. All the 5 patients who developed serious adverse effects associated with epinephrine had received an overdose, and 4 of these had received route of IV bolus injection. Conclusion and Clinical Relevance The actual emergency management of anaphylaxis in Chinese primary care is not consistent with current guidelines. Under-use, overdose and inappropriate route of epinephrine administration are the major problems. Targeted training is therefore strongly suggested for Chinese general practitioners.


Introduction
Anaphylaxis is a life-threatening medical emergency and prompt appropriate emergency management is critical. International guidelines published by the World Allergy Organization (WAO), the European Academy of Allergy and Clinical Immunology (EAACI), the American Academy of Allergy, Asthma and Immunology (AAAAI), and the American College of Allergy, Asthma and Immunology (ACAAI) concur with the recommendations of intramuscular (IM) injection of epinephrine in the mid-outer thigh as rst-line treatment for anaphylaxis, whereas inhaled ß2-adrenergic agonists, H1-and H2-antihistamines, and glucocorticoids are regarded as second or third-line medications [1][2][3] .
General practitioners play an important role in the management of anaphylaxis. However, prevalent clinical practices with respect to emergency treatment of anaphylaxis in Chinese primary care units are not well identi ed. Limited studies found under-use and/or inappropriate use of epinephrine during treatment of anaphylaxis in China [4][5][6] , but all these studies were investigated in large hospitals in Beijing before the year of 2014; in addition, these reports did not provide speci c information about the critical initial treatment of anaphylaxis.
Accordingly, we evaluated the actual emergency treatment of anaphylaxis initially treated in Chinese primary care units by analyzing published cases during period of 2014 to 2018. The objective was to identify the gaps between current clinical practices of initial treatment of anaphylaxis in Chinese primary care units and current guidelines, so as to provide further suggestions for improvement of anaphylaxis management in primary care in China.

Search strategy
According to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines, we searched online literature through several international and Chinese databases including PubMed, ScienceDirect, Web of Science, Wanfang database (http:// med.wanfangdata.com.cn), China National Knowledge Internet database (http://www.cnki.net), and VIP database (http://www. cqvip.com).

Selection criteria
Case reports pertaining to anaphylaxis that quali ed the following criteria were included: (a) with de nite diagnosis of anaphylaxis based on the anaphylaxis guidelines [1][2][3]7] ; (b) initially treated in Chinese primary care units; (c) availability of complete records of the trigger, symptoms and signs, initial treatment, speci c dosage and route of epinephrine if used, and outcome; (d) published between January 1, 2014 to December 31, 2018; (e) published in Chinese or English. The exclusion criteria were as the following: (a) duplicate publication; (b) with insu cient data for diagnosis and/or speci c emergency medical therapy for anaphylaxis; (c) cardiac arrest occurred before the rst administration of epinephrine.

Adjudication
The physician adjudicators (H.L. and C.J.) independently reviewed each case to validate the diagnosis of anaphylaxis and evaluate the dose and route of epinephrine administration and associated incidence of adverse effects. Disagreements, if any, were resolved by consensus.
The diagnosis of anaphylaxis was validated using the international guidelines [1][2][3]7] . Overdose of epinephrine for anaphylaxis was de ned as a dose that exceeded the dose recommended by anaphylaxis guidelines, i.e., 0.01 mg/kg of 1:1000 solution with a maximal dose of 0.5 mg in adults or 0.3 mg in children for IM and SC routes, or 0.001 mg/kg of 1:10000 solution or 1:100000 solution with a maximal dose of 0.1 mg for slow IV injection [1,3,7,8] .
Cardiovascular adverse effects were de ned according to Campbell et al [8] . Hypertension was de ned as systolic blood pressure ≥ 180 mm Hg and/or diastolic blood pressure ≥ 120 mm Hg. Cardiac ischemia was determined based on both elevated troponin T level and symptoms of cardiac ischeamia. Angina pectoris was de ned as chest pressure, tightness or pain without elevation of troponin T level. Stroke was de ned as onset of new neurologic de cit. The criteria for evaluation of adverse effects associated with epinephrine were: (1) cases for whom both the administered dose of epinephrine and the route of administration was reported; (2) the onset of cardiovascular complications developed after epinephrine administration; and (3) without concurrent use of epinephrine-like agents (e.g., ephedrine, norepinephrine, hydroxylamine, or dopamine).

Statistical analysis
Statistical analyses were performed with SPSS version 20.0 (SPSS Chicago, IL). Normality of distribution of continuous variables was assessed using single-sample Kolmogorov-Smirnov test. Comparisons between continuous variables were performed by the independent sample t test or nonparametric rank test (Mann-Whitney U-test); Comparisons between categorical variables were performed by the Chisquared test or the Fisher's exact test. Statistical signi cance was set as P < .05 and all tests were 2sided.

Emergency management of anaphylaxis
Supplemental oxygen (49.4%) was the most commonly administered initial treatment (Table 3). 74.7% of the patients received oxygen therapy via nasal catheter; 12.7% were administered via face mask. Only 27.3% of the patients received epinephrine as rst-line intervention. Glucocorticoids were most commonly administered drugs during the course of anaphylaxis. Out of 77 patients, 73 (94.8%) were administered glucocorticoids, of which dexamethasone accounted for 97.3%; whereas 64 (83.1%) received epinephrine during the course of anaphylaxis.

Dose and route of epinephrine administration
The dose of epinephrine ranged from 0.0625 mg to 0.5 mg among children (age <18 years) and 0.1 mg to1.0 mg among adults (age ≥65 years) ( Table 4) [9][10][11][12] . Among 4 children with available data on dose and route of epinephrine administration, 3 received an overdose of epinephrine, and only 1 received epinephrine intramuscularly. Among 57 adult patients with available data on epinephrine dose and route, 46 (80.7%) received an overdose of epinephrine, of them 42 (73.7%) received an initial dose of 1.0 mg; only 11 adult patients (19.3%; p<0.001) received a recommended initial dose of 0.5 mg. The number of adult patients who received epinephrine by the route of SC, IM, and IV bolus injection was 25 (43.9%), 21 (36.8%), and 11 (19.3%), respectively.

Adverse effects of epinephrine
Among the 64 patients who received epinephrine, 5 developed serious adverse effects associated with epinephrine (Table 5), including 2 cases of hypertension, 1 case of ventricular arrhythmias, 1 case of myocardial ischeamia, and 1 case of pulmonary edema. All of them had received an overdose of epinephrine; and 4 of them had received epinephrine by IV bolus injection.

Discussion
To our knowledge, this is the rst study that assessed the actual emergency management of anaphylaxis in Chinese primary care by analyzing treatment details in reported cases. To evaluate the appropriateness of clinical practice in Chinese primary care against the guidelines, we analyzed the use of epinephrine as rst-line intervention, as rst-line medication, and during the whole course of anaphylaxis.
Epinephrine is life-saving for anaphylaxis because of its alpha-1adrenergic effects on preventing and relieving anaphylactic shock as well as airway obstruction. Failure to use it promptly may lead to fatality, hypoxic ischemic encephalopathy, or biphasic anaphylaxis [13,14] . International guidelines concur with recommendation of epinephrine as rst-line drug for treatment of patients with con rmed or suspected anaphylaxis [15] . However, as shown in our data, there are considerable under-use of epinephrine as rstline treatment in anaphylaxis in Chinese primary care. Moreover, compared to epinephrine, glucocorticoids seem to be more frequently used in Chinese anaphylactic cases. This may imply a general lack of awareness of the appropriate emergency treatment in anaphylaxis among Chinese primary care providers.
According to internationals guidelines, as the rst-line medication choice in anaphylaxis, epinephrine should be injected intramuscularly in the mid-outer thigh at a dose of 0.01 mg/kg of a 1:1000 (1 mg/mL) solution, up to a maximum of 0.5 mg in adults and 0.3 mg in children [1][2][3] . However, the rst dose of epinephrine showed in this analysis ranged from 0.0625 mg to 1.0 mg, and 80.3% patients had received an overdose of epinephrine. In China, epinephrine is only available in the form of 1 mg: 1 mL (1:1000) ampules, while other concentrations or epinephrine auto-injectors are not available. Another possible reason may be the lack of clarity about appropriate dosage and route of epinephrine administration for different indications, e.g., a rst IV bolus dosage of 1 mg (1:10000) is recommended for cardiac arrest [16][17][18] .
Two pharmacokinetic studies conducted in children and adults demonstrated that, compared to SC injection in the arm, IM injection of epinephrine into the mid-outer thigh is more effective and is therefore recommend by guidelines as the preferred route of epinephrine administration in anaphylaxis [19,20] . The SC or inhalational routes for epinephrine are not recommended owing to the lower e cacy. However, most of the patients in this study were treated with epinephrine via SC injection (44.3%), and 19.7% of the patients received IV bolus injection. Data pertaining to the site of injection was available only for 2 patients, and neither of them received epinephrine in accordance with the recommended site of injection.
In patients with adequate circulation, IV injection of epinephrine may cause serious, life-threatening adverse effects. Slow IV infusion, but not IV bolus injection, is considered only when anaphylaxis is refractory to IM injection of regular doses or anaphylactic shock is imminent or has developed. Currently, there is no established dosage for IV infusion of epinephrine in anaphylaxis [3] . A prospective study demonstrated the e cacy of a 1:100000 solution of epinephrine administered intravenously by infusion pump at the initial rate of 2-10 mg/min and titrated according to the clinical response or side effects [21,22] . It is suggested that IV epinephrine for anaphylaxis should be administered under the guidance of those experienced in the use of vasopressors (anesthetists, emergency physicians, etc.) and under close hemodynamic monitoring [23] . In the present study, 4 of the 5 patients who developed life-threatening adverse effects received epinephrine by IV bolus injection, indicating which is a potentially harmful route of epinephrine administration in anaphylaxis.
Our study indicates that the actual emergency treatment of anaphylaxis in Chinese primary care does not comply with current guidelines. Consistent with the previous study including more inpatients [24] , under-use, overdose, and inappropriate administration route of epinephrine were identi ed as the major problems. Notably, none of these problems was noticed or discussed in these publications. This may imply a general lack of awareness about the appropriate dose and route of epinephrine for anaphylaxis in many Chinese primary care providers. Our ndings call for more efforts to change this situation. In 2017, Chinese expert consensus of penicillin skin test developed by the Expert Committee on Clinical Application of Antibiotics and Evaluation of Bacterial Resistance of the National Health and Family Planning Commission recommended IM or SC injection of epinephrine for treatment of anaphylactic shock [25] . Meanwhile, the guidelines for clinical drug use in the Pharmacopoeia of the People's Republic of China (2015 Edition) also recommend SC or IM route of epinephrine administration for treatment of anaphylaxis in adults. Therefore, we strongly underline the need to update the Chinese guidelines for treatment of anaphylaxis in accordance with the international guidelines. In addition, a targeted nationwide educational program about the international anaphylaxis management guidelines should be implemented to facilitate optimal patient care. Moreover, as recommended, written emergency protocol for diagnosis and management of anaphylaxis may be posted in primary care facilities and rehearsed regularly just like cardio-pulmonary resuscitation (CPR).

Limitations
Although reported cases may not be entirely representative of the actual clinical practices, systematic analysis of published case reports was the only feasible way for us to determine emergency treatment details in these patients nationwide. To minimize the risk of bias, we have established rigorous inclusion/exclusion criteria and performed a thorough literature search to include more cases of anaphylaxis initially treated in Chinese primary care units. Moreover, we searched Chinese literature to increase the yield of cases and to improve the representativeness of our ndings.

Conclusion
There are some critical gaps between actual emergency management of anaphylaxis in Chinese primary care and international anaphylaxis guidelines. Under-use, overdose and inappropriate route of epinephrine administration are the major problems identi ed in this analysis. Targeted training in this respect is strongly suggested for Chinese primary care providers.
Con ict of Interest Disclosures: There are no con icts of interest to declare.
Availability of data and materials: Yes, they are available.
Acknowledgements: The authors thank Prof. Haijun Wang and Prof. Ling Zhang for their guidance on methodology and approval of this manuscript.  The patients were widely distributed across 22 provinces/autonomous regions /municipalities in mainland China. Shandong, Jiangsu, Henan, Anhui and Hubei were the top 5 provinces where the most number of patients with anaphylaxis (12,9,7,5, and 5, respectively) were included in this study.