To the Editor,
Anaphylaxis is a life‐threatening clinical emergency, and prompt intramuscular (IM)
injection of epinephrine is critical.1, 2, 3 Current practices pertaining to the initial
treatment of anaphylaxis in China remain unclear. In this study, we assessed the actual
initial treatment and the use of epinephrine for anaphylaxis in China by systematic
analysis of published case reports between 2014 and 2018.
1
An online literature search was performed in PubMed, Web of Science, ScienceDirect,
China National Knowledge Internet database (http://www.cnki.net), Wanfang database
(http://med.wanfangdata.com.cn), and VIP database (http://www.cqvip.com). The following
key words were used: “anaphylaxis,” “anaphylactic reactions,” “anaphylactic reaction,”
“anaphylactic shock,” “reactions, anaphylactic,” “reaction, anaphylactic,” “shock,
anaphylactic,” “kounis,” “kounis syndrome,” and “china”. The inclusion criteria were
as follows: (a) diagnosis of anaphylaxis1; (b) availability of records about the anaphylaxis;
(c) published from January 1, 2014, to December 31, 2018; (d) published in English
or Chinese. Exclusion criteria were as follows: (a) cases with incomplete data; (b)
duplicate publication; (c) cases in which cardiac arrest occurred prior to the administration
of epinephrine. Overdose of epinephrine was defined as administration of a dose that
exceeded the dose recommended by the guidelines. 2, 3, 4
2
A total of 7579 articles were retrieved on database search, and a total of 819 patients
from 748 case reports were included in this review (Figure S1). These patients were
distributed across 30/31 (96.8%) provinces in mainland China except Tibet (Figure
S2). Patient characteristics are summarized in Table S1. The median age was 46.1 years,
and 53.0% patients were male. More than 2/3rd of the episodes of anaphylaxis occurred
among inpatients. All the patients except one (99.9%) presented severe anaphylactic
reactions (cardiovascular and/or respiratory compromise). The mortality rate was 5.6%.
3
Removal of the likely trigger (57.3%) and supplemental oxygen (42.1%) were the 2 most
commonly administered initial treatment followed by glucocorticoids (19.8%) and intravenous
(IV) fluid support (14.9%; Table 1). Only 14.2% patients were appropriately treated
with epinephrine as the first‐line intervention. The percentage of patients treated
with glucocorticoids was significantly higher than the percentage of those treated
with epinephrine as the first‐line treatment (19.8% vs. 14.2%; P < .001), as the first‐line
medication (44.3% vs. 38.5%, P = .016), or during the course of anaphylaxis (94.7%
vs. 70.8%, P < .001).
Table 1
Treatment of patients with anaphylaxis
Patients with available data, n
Value
First‐line treatment, n (%)
Removal of the trigger
819
469 (57.3)
Oxygen
819
345 (42.1)
Glucocorticoid
819
162(19.8)*
Fluid
819
122 (14.9)
Epinephrine
819
116 (14.2)
Vasopressor
819
34 (4.2)
H1‐antihistamine
819
25 (3.1)
Atropine
819
5 (0.6)
Calcium gluconate
819
4 (0.5)
Aminophylline
819
2 (0.2)
TCM
819
2 (0.2)
Beta‐2‐agonist
819
1 (0.1)
NSAIDs
819
1 (0.1)
First‐line medication, n (%)
Glucocorticoid
819
363 (44.3)**
Epinephrine
819
315 (38.5)
Vasopressor
819
62 (7.6)
H1‐antihistamine
819
51 (6.2)
Calcium gluconate
819
7 (0.9)
Atropine
819
5 (0.6)
Aminophylline
819
4 (0.5)
Respiratory stimulant
819
4 (0.5)
TCM
819
3 (0.4)
Beta‐2‐agonist
819
2 (0.2)
NSAIDs
819
1 (0.1)
Fluid
819
1 (0.1)
No medication
819
1 (0.1)
Treatment during the course of anaphylaxis, n (%)
Epinephrine
819
580 (70.8)
Oxygen
819
648 (79.1)
Nasal catheter
648
484 (74.7)
Face mask
648
82 (12.7)
Endotracheal intubation
648
77 (11.9)
Noninvasive ventilator
648
3 (0.5)
Tracheotomy
648
2 (0.3)
Fluid support
819
583 (71.2)
Normal saline
583
229 (39.3)
Glucose solution
583
83 (14.2)
Balanced solution
583
71 (12.2)
Colloid solution
583
64 (11.0)
Glucose saline
583
17 (2.9)
TCM solution
583
1 (0.2)
50% Glucose solution
583
1 (0.2)
Unspecified
583
117 (20.1)
Inhaled beta‐2 agonists
819
10 (1.2)
H1‐antihistamines
819
343 (41.9)
H2‐antihistamines
819
12 (1.5)
Glucocorticoids
819
776 (94.7)*
Dexamethasone
776
683 (88.0)
Methylprednisolone
776
72 (9.3)
Hydrocortisone
776
20 (2.6)
Unspecified
776
1 (0.1)
Vasopressors
819
382 (46.6)
Note
Data presented as frequency (%) unless indicated otherwise. Removal of the trigger
(57.3%), oxygen (42.1%), glucocorticoid (19.8%), and IV fluid support (14.9%) were
the top 4 most commonly administered first‐line interventions. Only 14.2% patients
were treated with epinephrine as the initial treatment. In the analysis of first‐line
medications, 315 patients (38.5%) were administered epinephrine; glucocorticoids (44.3%)
were the most commonly used drugs. Compared to the percentage of patients treated
with epinephrine that of patients treated with corticosteroids were significantly
higher as the first‐line treatment (χ
2 = 298.029, P < .001), as the first‐line medication (χ
2 = 5.798, P = .016), or during the course of anaphylaxis (χ
2 = 164.557, P < .001), respectively. TCM, traditional Chinese medicine and NSAIDs,
nonsteroid anti‐inflammatory drugs.
*
P < .01.
**
P < .05 vs percentage of patients treated with epinephrine.
John Wiley & Sons, Ltd
4
Out of the 580 patients who received epinephrine (Table 2), the initial dosage of
epinephrine showed wide variability from 0.03 to 3 mg in children and form 0.01 to
20 mg in adults.5, 6, 7, 8
Table 2
Initial dosage and route of administration of epinephrine
Administration of epinephrine in patients with available data
Group
(n)
Dosage (mg)
Route (n)
Overdose (n)
IM
SC
IV injection
IV infusion
Intra‐tracheal
unspecified
Total (n)
Children
(54)
>0.5
1
2
4
0
0
0
7
7
0.5
2
7
4
0
0
0
13
13
0.4
0
0
0
1
0
0
1
1
0.3
4
5
5
0
0
0
14
12
<0.3
0
5
6
1
0
2
14
9
Unspecified
0
2
2
0
0
1
5
NA
Total
7
21
21
2
0
3
54
42
Adults
(526)
>1.0
1
1
13
0
0
1
16
16
1.0
50
115
135
1
1
0
302a
302
0.7
0
0
1
0
0
0
1
1
0.5
24
52
37
0
0
3
116
37
<0.5
6
9
27
3
0
3
48
29
Unspecified
0
2
15
3
0
23
43
NA
Total
81
179
228b, c
7
1
30
526
385
Total
88
200
249
9
1
33
580
427
Note
Data presented as frequency (n) unless indicated otherwise. In children, the top 2
common doses of epinephrine were 0.3 mg (28.6%) and 0.5 mg (26.5%), and the top 2
common routes of epinephrine were IV bolus injection and SC injection (both 41.2%).
In children, the percentage of epinephrine overdose by IM injection, SC injection,
IV bolus injection, and IV infusion was 71.4%, 73.7%, 100.0%, and 100%, respectively.
In adults, the percentage of patients who received a dose of 1.0 mg (62.5%) was significantly
higher than that of 0.5 mg (24.0%; χ
2 = 129.391, P < .001).The number of patients who received IM, SC, IV bolus injection
and IV infusion was 81 (16.3%), 179 (36.1%), 228 (46.0%), and 7 (1.4%), respectively.
Among the 476 patients with record of both the epinephrine dose and the route, 385
(80.9%) patients received an overdose of epinephrine. The percentage of overdose was
significantly more likely with IV bolus injection (99.5%) as compared to that with
IM injection (63.0%; χ
2 = 89.064, P < .001) or SC injection (65.5%; χ
2 = 85.639, P < .001). IM, Intramuscular; SC, Subcutaneous; IV, intravenous; NA, not
available.
a
P < .01 vs 0.5 mg.
b
P < .01 vs IM injection.
c
P < .01 vs SC injection.
John Wiley & Sons, Ltd
Among children, the two most commonly administered initial doses of epinephrine were
0.3 mg (28.6%) and 0.5 mg (26.5%), and the two most common routes of administration
were IV bolus injection (41.2%) and subcutaneous (SC) injection (41.2%). Only seven
children (13.7%) received epinephrine by IM route. Most (89.4%) of children were administered
an initial overdose of epinephrine. The percentage of children who received epinephrine
overdose by IV bolus injection, SC injection, and IM injection was 100.0%, 73.7%,
and 71.4%, respectively.
Among adult patients, the percentage of patients who received an initial dose of 1.0 mg
(62.5%) was significantly higher than the percentage of those who received 0.5 mg
(24.0%; P < .001). The percentage of patients who received epinephrine via IM injection
(16.3%) was significantly lower than those who received IV bolus (46.0%, P < .001)
or SC injection (36.1%, P < .001). Out of the 476 patients for whom the records of
the epinephrine dose and the route of administration were available, 385 (80.9%) patients
received an initial overdose of epinephrine. The percentage of overdose was more common
with IV bolus injection (99.5%) as compared to IM injection (63.0%; P < .001) or SC
injection (65.5%; P < .001).
5
Out of 580 patients who received epinephrine, 54 (9.3%) developed serious adverse
effects associated with epinephrine (Table S2), including ventricular arrhythmias
(59.3%), hypertension (20.4%), pulmonary edema (13.0%), myocardial ischemia (5.6%),
and stroke (1.9%). Among the 52 patients with complete records of both the dose and
route of administration of epinephrine, 50 (96.2%) patients had received an overdose
and 45 (86.5%) were administered epinephrine by IV bolus injection.
6
To the best of our knowledge, this is the first study that evaluated the actual initial
treatment of anaphylaxis in China based on a literature review. Due to the space limitation,
only four of the 748 studies included in this review were referenced. Our results
indicated considerable underuse of epinephrine as the initial treatment of anaphylaxis.
In contrast, glucocorticoids were inappropriately used as the first‐line drug in place
of epinephrine. Moreover, 81.6% patients had received an overdose of epinephrine,
and 45.5% patients received IV bolus injection, both of which were proved to be significantly
associated with serious adverse effects of epinephrine. Our findings suggest that
the actual initial treatment of anaphylaxis in China does not comply with the international
anaphylaxis guidelines. Of note, none of these problems was discussed or mentioned
in these reports. This implies a general lack of awareness about the gaps in the initial
treatment of anaphylaxis among many Chinese healthcare professionals.9 Our findings
call for concerted efforts to remedify the current situation and to promote the safety
of Chinese patients with anaphylaxis.
7
The study has a selection bias because the cases come from published reports. However,
a large enough sample size helped negate this limitation to a certain extent. We established
rigorous inclusion/exclusion criteria to minimize the risk of bias, and a thorough
literature search was performed to include more cases of anaphylaxis. Moreover, Inclusion
of Chinese literature helped increase the yield of cases and improved the representativeness
of our findings.
8
Our study highlights some critical gaps in the initial treatment of anaphylaxis in
China when compared against the international guidelines. Underuse, overdose, and
inappropriate route of administration of epinephrine, as well as overuse of glucocorticoids,
are the major problems. The epinephrine overdose and administration of IV bolus injection
significantly increase the risk of serious adverse effects of epinephrine. Targeted
training on the initial treatment of anaphylaxis is strongly suggested for healthcare
providers in China.
CONFLICT OF INTEREST
There are no conflicts of interest to declare.
Supporting information
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