Elsevier Editorial System(tm) for Annals of Allergy, Asthma & Immunology Manuscript Draft Manuscript Number: Title: Epinephrine auto-injector needle lengths Can both subcutaneous and periosteal/intraosseous injection be avoided? Article Type: Original Article Keywords: anaphylaxis; food allergy; epinephrine; epinephrine autoinjector; allergy; skin to bone distance; skin to muscle distance; intramuscular; subcutaneous; epimysium; periosteal; intraosseous Corresponding Author: Professor Sten Dreborg, MD, PhD Corresponding Author's Institution: Women's and Children's Health First Author: Sten Dreborg, MD, PhD Order of Authors: Sten Dreborg, MD, PhD; Laura Kim, MD; Gina Tsai, MD, PhD; Harold Kim, MD, PhD Abstract: Background: Administration of epinephrine should be intramuscularly in the anterolateral aspect of the thigh. The length of the epinephrine autoinjector, EAI, needle should assure intramuscular injection. Objective: To discuss suitable needle lengths of EAIs based on ultrasound measurements related to weight. Methods: The skin to muscle distance (STMD) and skin to bone distance (STBD) was measured by ultrasound on the mid third anterolateral area of the right thigh, applying either high pressure (max)(8 lb.)(HPEAI) or low pressure (min)(LPEAI) on an ultra-sound probe. Three hundred two children and adolescents and 99 adults were included. The STMDmax and STMDmin as well as the STBDmax and STBDmin were estimated. Results: Using HPEAIs, the risk of periosteal/intraosseous penetration was 32% in children weighing less than 15 kg. The risk of subcutaneous injection was 12% in adolescents and 33% in adults. With LPEAIs, there was no risk of periosteal/intraosseous injection and the risk of subcutaneous injections in adolescents and adults was less, 2 and 10%, respectively. A new EAI aimed for injection in small children would have no risk of periosteal/intraosseous injection but 71% chance of subcutaneous deposit of epinephrine. Conclusion: Common HPEAIs have a high risk of periosteal/intraosseous penetration in children and subcutaneous injections in overweight and obese adults. The LPEAIs have some risk of subcutaneous injection in adults. HPEAIs 0.1 mg epinephrine and shorter needle has no risk of periosteal/intraosseous injection but a high risk of subcutaneous deposit. For use in adult, over-weight/obese patients, HPEAIs and LPEAIs should have longer needles. Future studies should focus on the triggering pressures and the variations in needle length. Suggested Reviewers:
Opposed Reviewers:
Cover Letter
Uppsala 2017-11-18
Annals of Allergy, Asthma and Clinical Immunology Editor In Chief Professor Gailen D. Marshall, Jr Institutionen för kvinnors och barns hälsa Department of Women’s and Children’s Health Akademiska sjukhuset SE-751 85 Uppsala Besöksadress/Visiting address: Ing/Entr 95/96 (Obst/Gyn, Pediatrics) Drottninggatan 4, 4th floor (IMCH) Telefon/Phone: 018-611 00 00 (växel) +46 18 611 00 00 (switchboard) Telefax/Fax: +46 (0)18 55 97 75 (Obst/Gyn) +46 (0)18 611 55 83 (Pediatrics) +46 (0)18 50 80 13 (IMCH) www.kbh.uu.se E-post/E-mail:
[email protected] [email protected] Organisationsnummer/VAT 202100-293201
Regarding manuscript Epinephrine auto-injector needle lengths Can both subcutaneous and periosteal/intraosseous injection be avoided?
This manuscript is a new submission. In the autumn of 2017, we submitted a paper not considering the number of figures and tables accepted by the journal. Therefore, we had to totally revise the paper. The manuscript has been read and approved by all the authors. Contributors’ Statements: Sten Dreborg: Dr Dreborg carried out the original analyses, drafted the original manuscript, revised the manuscript, and approved the final manuscript as submitted. Laura Kim and Gina Tsai conceptualized and designed the study, reviewed and revised the manuscript, and approved the final manuscript as submitted. Harold Kim: Dr Kim conceptualized and designed the study, reviewed and revised the manuscript and approved the final manuscript as submitted. The authors certify that they have (collectively) personally written at least 90 percent of the manuscript. The manuscript has not been published previously in print/ electronic format or in another language. The manuscript is based on original data previously published in three separate papers. The manuscript is not under consideration by any other publisher or by electronic media. Best regards
Sten Dreborg
Sten Dreborg Affiliated Professor Child and Adolescent Allergology University of Uppsala, Sweden
[email protected] +46-733423341
*Title Page
Epinephrine auto-injector needle lengths Can both subcutaneous and periosteal/intraosseous injection be avoided? Sten Dreborg1MD, PhD, Laura Kim2MD, Gina Tsai3MD, Harold Kim3,4MD, PhD Short title: EAI needle length 1) Child and Adolescent Allergology, Women’s and Children’s Health, University of Uppsala, Sweden 2) Faculty of Medicine, University British Columbia, Canada 3) Department of Medicine, Western University, Canada. 4) Department of Medicine, McMaster University, Canada Corresponding author Sten Dreborg Women’s and Children’s Health, Uppsala University SE-751 85 Uppsala, Sweden +46-733423341;
[email protected]. Key words: anaphylaxis; food allergy; epinephrine; epinephrine auto-injector; allergy; skin to bone distance; skin to muscle distance; intramuscular; subcutaneous; epimysium; periosteal; intraosseous Clinical Trial registry: The original studies were registered. Funding: None. Conflicts of interests: The authors have no conflicts of interest. Financial disclosure statement: Noting to disclose. Title: Short title: Manuscript word count: Figures: Tables: References:
Words: 4+8 Words: 3 3,409 5 3 35
Supplementary material 3 pages Abbreviations EAI HPEAI LPEAI STMD STBD STMDmin STMDmax STBDmin STBDmax
Epinephrine Auto-injector High pressure EAI Low pressure EAI Skin to muscle distance Skin to bone distance Skin to muscle distance, low pressure Skin to muscle distance, high pressure Skin to bone distance, low pressure Skin to bone distance, high pressure
*Manuscript Click here to download Manuscript: Annals Manuscript_EO.docx
Click here to view linked References
1
1 2 3
Introduction
4
treatment for anaphylaxis 1,2. Outside of the hospital setting, epinephrine auto-injectors (EAIs)
5
are the standard method of administering epinephrine. In Europe and North America, the high
6
pressure EAIs (HPEAI) Epipen®/EpipenJr®3 are currently the most commonly prescribed
7
EAIs. Other HPEAIs have been marketed, including Auvi-Q®/Allerject®4,5 and Jext®. To
8
avoid the risk of periosteal/intraosseous injection, Auvi-Q® 0.1 mg with a shorter needle than
9
the other HPEAIs (7.5 mm vs 15 mm) has recently been introduced. All these EAIs require
10
high pressure to release the needle and the injection of epinephrine. Recently, a low pressure
11
EAI (LPEAI), Emerade®, has been introduced
12
pressure. The LPEAIs have longer needles than the HPEAIs and one higher dose (0.5
13
mg)(Table 1).
Currently, the prompt administration of intramuscular epinephrine is the recommended
6,7
. For proper injection, it requires low
14 8-12
15
The dose of epinephrine recommended for treatment of anaphylaxis is 0.01 mg/kg
.
16
However, due to the life-threatening nature of anaphylaxis, there have been no randomized
17
controlled trials to evidentially support this dosage; the recommended doses have been
18
determined empirically. Based on this assumed effective dose of epinephrine in anaphylaxis,
19
0.1 mg should be administered to children weighing about 10 kg, 0.15 mg epinephrine should
20
be administered to younger children, 0.30 mg to adolescents and 0.5 mg to adults. The
21
recommended doses vary between countries and academic societies. Proposed dosage
22
recommendations are shown in Table 2 a-d. Actually, the proposed dose 0.01 mg/kg would
23
result in doses of 0.1 mg to children weighing 10 kg, 0.15 mg to children weighing 15 kg, 0.3
24
mg to adolescents weighing 30 kg and 0.5 mg to those weighing 50 kg. However, 0.3 mg has
25
even been prescribed to adults since HPEAIs containing more than 0.3 mg have not been
26
marketed in many jurisdictions. HPEAIs are available with doses 0.15 and 0.30 mg. LPEAIs
2 27
are available at these same doses, as well as 0.5 mg. Recently, Auvi-Q® 0.1 mg has been
28
introduced for children less than 15 kg.
29
There is a risk for injecting Epinephrine into the subcutaneous tissue instead of the muscular
30
department. Many papers have studied the needle length of EAIs trying to reveal the risk for
31
subcutaneous injection. Different methods to assess for subcutaneous versus intramuscular
32
injections have been used: Computed tomography, 13 injection in pigs 14-16, ballistic gel 17 and
33
ultrasound of human mid anterolateral aspect of the right thigh 17-23.
34 35
Recent data demonstrate that a significant number of patients may receive Epinephrine
36
subcutaneously with the currently available EAIs
37
significant number of children with confirmed food allergy weighing less than 15 kg
38
be at risk of receiving the injection into the periosteum or bone 19,20.
17-19,24
. It has also been shown that a 19
may
39 40
The recently introduced Auvi-Q® 0.1 mg HPEAI is intended for use in small children. The
41
needle length, 7.5 mm, is as much as half as long as that of other HPEAIs. It was constructed
42
to avoid periosteal/intraosseous injection of epinephrine.
43 44
Based on data on the distance from skin to muscle and skin to bone, obtained by ultrasound of
45
the middle anterolateral aspect of the right thigh, published by Kim et al 18-20, the possibility
46
of subcutaneous as well as periosteal/intraosseous injection of epinephrine, will be discussed
47
in relation to weight.
48 49 50
3 51 52
Methods
53 54 55
Patients
56
reported
57
at the Western University in London, Ontario, Canada and all patients, parents or legal
58
guardians provided written, informed consent before participating in this study.
Patients assessed at a referral only allergy clinic were consecutively included. As already 18-20
, the study was approved by the Lawson Health Research Institute Ethics Board
59 60
Consecutive patients with diagnosed food allergy based on an appropriate history and positive
61
skin prick tests were included. All patients required a prescription for an EAI.
62 63
Three groups of children and adolescents participated, i.e. Group 1: Children less than 12
64
years of age weighing less than 15 kg (n=100) 19; Group 2: Children less than 12 years of age
65
weighing 15-30 kg (n=102), Group 3: Adolescents, 12 – 18 yrs of age weighing > 30 kg
66
(n=100)20. In total, 302 children and adolescents were included, 125 girls and 177 boys.
67
Furthermore, 99 adults (range 18-72 yrs.), 69 of whom were females, were included in the
68
study18. Data on the patients included has been published previously18-20. Further patient
69
characteristics are given in eTable 1 and 2. The subjects were assessed from July 2012 to June
70
2014.
71 72
Ultrasound estimation of the distance skin to muscle (STMD) and skin to bone (STBD)
73
An ultrasound of the mid anterolateral aspect of the mid anterolateral right thigh, i.e. the
74
recommended location for injecting an EAI, was completed on all of the subjects applying
75
high pressure and low pressure using a Sonosite Titan® ultrasound machine. The pressure was
76
applied to simulate the pressure required to trigger the EAI. The estimated pressure to mimic
77
the pressure applied to high-pressure epinephrine autoinjectors, HPEAI, about 8 pounds was
4 78
used. To mimic the pressure applied to the low-pressure epinephrine autoinjector, LPEAI, low
79
pressure was applied.
80
Four ultrasound measurements were collected on each patient: skin-to-muscle depth with low
81
pressure (STMDmin), skin-to-muscle depth with high pressure (STMDmax), skin-to-bone depth
82
with low pressure (STBDmin) and skin-to-bone depth with high pressure (STBDmax). Figure 1
83
shows the principle of measurement. The STMD was measured from the skin surface to the
84
inner aspect of the fascia of the vastus lateralis muscle and the bone depth was measured at
85
the outer aspect of the periosteum of the femur as illustrated in Figure 1. The ultrasound
86
measurements were performed by one investigator.
87 88
Analysis
89
Data from all included children and adults were analyzed together and in weight groups.
90 91
Song et al. 14 reported on the potential effect of propulsion of the injection bolus spreading to
92
94 % beyond the tip of the needle in pig subcutaneous tissue. However, Diacono et al.
93
found the fascia to be an impermeable barrier to fluids injected by EAIs. Furthermore, the
94
entire needle orifice must pass completely into the muscle for proper administration of an
95
intramuscular injection. The injection must pass the epimysium. If part of the orifice was
96
within the epimysium during the injection, epinephrine would spread within the loose
97
epimysium tissue16.
16
98 99
The needle lengths used in this study are those provided by the EAI manufacturers3-7. Since
100
the difference in mean needle length of several HPEAIs 0.15 mg epinephrine is with fractions
101
of a mm, we regarded all these HPEAIs 0.15 mg having a needle length of 13 mm and the 0.3
102
mg HPEAIs having a needle length of 15 mm. The LPEAI has the declared needle length 16
5 103
mm for the 0.15 mg dose and 23 mm for the EAIs with 0.3 and 0.5 mg doses. Furthermore,
104
the new Auvi-Q® 0.1 mg has a needle length of 7.5 mm (Table 1).
105 106
The length of the needle’s eye of EpiPen®/EpiPenJr® was estimated to be 2 mm and that of
107
LPEAI was reported by the manufacturer to be 1.7 mm25. Since specifications allow some
108
variation, we considered all needle orifices to be 2 mm. Therefore, considering the findings by
109
Diacono et al.16 we used the needle length minus 2 mm for estimation of the STMD threshold.
110
For estimation of the STBD, the full length of the needles were used, Table 1.
111 112
The ultrasounds of the mid anterolateral thigh with high and low pressure were measured to
113
identify whether children and adults with prescribed EAIs would be at risk of subcutaneous or
114
periosteal/ intraosseous delivery of epinephrine.
115 116
We present different dosages, i.e. a) the recommended dose based on weight accepting 0.01
117
mg/kg8; b) the dose used by the manufacturers based on weight,; c) the dosing recommended
118
by the EAACI guidelines; d) the recent Swedish recommendations 10, Table 2 a-d. Results are
119
presented in relation to weight limits for children less than 15 kg, 15-30 kg, adolescents >30
120
kg and adults.
121 122
Outcome variables
123
We used two primary outcome variables: the proportion of children with 1) STBD less than
124
the total needle length and 2) STMD more than the needle length minus 2 mm, Table 1.
125 126
Statistics
6 127
We estimated the proportion (number and percentage) of subjects who would likely receive
128
epinephrine intramuscularly and subcutaneously, respectively, using high and low pressure
129
EAIs. Since the technique of measuring distance by ultrasound is not precise and differences
130
in estimated distances are small the number of patients at risk of subcutaneous or
131
periosteal/intraosseous injection are graded semi-quantitatively in classes, as illustrated in
132
Table 3.
133 134 135 136 137 138 139 140
No patients would have a subcutaneous or periosteal/intraosseous injection, green color 1– 3 percent of patients would have a subcutaneous or periosteal/intraosseous injection, white color 4 – 14 percent of patients would have a subcutaneous or periosteal/intraosseous injection, orange color ≥15 percent of patients would have a subcutaneous or periosteal/intraosseous injection, red color
141 142
7 143 144
Results
145 146 147
Patient sample
148
elsewhere18-20. In this study, we have pooled the total population of the three published studies
149
to examine if the needle lengths of the currently available of EAIs would place patients at risk
150
of subcutaneous injections or periosteal/intraosseous injections. The age and weight
151
distribution of children is given in eTable 1. A total 302 children and adolescents, 2 months to
152
18 years, 125/302 (41%) girls and 99 adults, 69 women (70%), 18 – 72 years of age, were
153
included. Patient characteristics are presented in eTable 1 and 2. Since children, adolescents
154
and adults from all weight groups were included, the age varied from 0.2 years to 72 years
155
and the weight from 5 kg to 149 kg
Basic data and statistics of the samples investigated has been published separately
156 157
The majority of patients (73%) had one or more allergic disease in addition to food allergy.
158
Many children (38%) were sensitized to cow’s milk, hen’s egg, soy and wheat, peanut (61%)
159
and tree-nuts (25%). Furthermore, 34 % had pollen-induced allergic rhinitis and/or
160
sensitization to fruits and (41%) were sensitized to indoor allergens, mainly house dust mite,
161
cat and dog. Adults, on the other and were sensitized mainly to indoor allergens 79% and
162
pollens 77%, eTable 2.
163 164
The mean compression with the application of high pressure was 14.1 mm (range 3.7 – 31.0
165
mm). The compression was mainly of the muscle. Using all data the mean compression of the
166
muscle was 90.2%, of the total compression. Thus, increased pressure on the EAI induces
167
only slight reduction of the STMDmax, mainly influencing the STBDmax.
168
8 169 170 171
Epinephrine autoinjector needle length in relation to weight
172
analyses and in Table 2a-d. Since the needle length of the EAIs varies with the dose of
173
epinephrine, differences in dose related to weight influences the risk for subcutaneous and
174
periosteal/intraosseous injection. The chance of subcutaneous or periosteal/intraosseous
175
injections using HPEAI, and LPEAI, are presented in Figures 2 - 5, and Table 3.
Different doses are recommended by authorities and academic societies, are discussed under
176 177 178
Skin to bone distance, STBD
179
limits, i.e. 15, 30 and 60 kg, (Table 1) are illustrated in Figure 2 for HPEAI data and in Figure
180
3 for LPEAI data.
The full needle length of the EAI was used in the calculations. The different proposed weight
181 182
Using our ultrasound based distance from skin to bone; HPEAIs with a needle length of 13
183
mm would possibly cause a periosteal/intraosseous injection in 32% children weighing less
184
than 15 kg and in 10% of those weighing 15-30 kg. A few adolescents weighing more than 30
185
kg, and no adult patient had a STBDmax less than 15 mm, i.e. would possibly get a
186
periosteal/intraosseous injection using a HPEAI. The new HPEAI 0.1 mg has no risk of
187
hitting the bone when used in children less than 30 kg.
188 189
If using a LPEAI, no children, adolescents, or adults would have a periosteal/intraosseous
190
injection, Table 3.
191 192 193 194
Skin to muscle distance, STMD
195
minus 2 mm (needle orifice), Table 1.
The distance from the skin to muscle was measured and compared to the length of the needles
9 196
Using a HPEAI in children weighing less than 30 kg, there was no risk of subcutaneous
197
injection. However, adolescents weighing >30 kg, 12%, and adults, 33%, would probably get
198
a subcutaneous injection, Table 3.
199 200
One% of children weighing 30 kg and 10 % of adults were at
201
risk for subcutaneous injection if using a LPEAI.
202 203
10 204 205
Discussion
206
In recent years the possibility of subcutaneous or periosteal/intraosseous injection of
207
epinephrine using EAIs has been widely discussed. There are several studies on the subject
208
using computed tomography13, injection into ballistic gel17, pig subcutaneous tissue14-16 or by
209
using ultrasound in humans18-23. This study, is the most extensive one investigating the
210
relationships between the distances from skin to muscle, STMD, and from the skin surface to
211
the bone, STBD, as estimated by ultrasound within the mid anterolateral aspect of the right
212
thigh, the recommended area for intramuscular injection of epinephrine using EAIs 18-20.
213 214
We studied 401 patients, 0.2 to 72 years of age, at risk of anaphylaxis due to food allergy with
215
data originating from three reports performed with the same design and equipment18-20.
216
Patients referred to the clinic were consecutively included. Thus, the sample represents truly
217
food allergic children and adults from Ontario, Canada.
218 219
In this paper, we have analyzed all patients together correlating STMD and STBD with
220
weight.
221 222
Even though this is the most extensive study on STMD and STBD, we still have relatively
223
few numbers of patients per age group. Therefore, we have graded the possible risk of
224
subcutaneous and periosteal/intraosseous injection semi-quantitatively using classes as
225
identified in the data presented in our results. Table 3 summarized the risks of subcutaneous
226
and bony injections based on the different age and weight classes.
227 228
The general epinephrine dosage recommendation of 0.01 mg/kg body weight has not been
229
adequately studied but is generally used in health care for the treatment of anaphylaxis 26,27.
11 230
However, these recommendations are not fully employed by EAI manufacturers and academic
231
societies (Table 2). Most recommendations suggest 0.3 mg to all patients weighing more than
232
20, 25 or 30 kg, including heavy adults. The proposed, empiric dose, 0.01 mg/kg up to 0.5
233
mg, would result in doses of 0.15 mg to children weighing 15 kg (7.5 – 30 kg), 0.3 mg to
234
adolescents weighing 30 kg (15 – 60 kg) and 0.5 mg to those weighing >60 kg (25 – >100
235
kg). The limits given within brackets are proposed doses for weight groups.
236 237
The high pressure for ultrasound technique applied in our study was about 8 lb.,
238
corresponding to about 35 Newton. Schwirtz 28 investigated the pressure needed to release
239
needles of Epipen® and Jext® EAIs. The range of force needed for activation of Epipen and
240
Jext varied between 36 and 57 N (Extracted from non-precise figure). According to the
241
manufacturer, the Auvi-Q® EAI needs 10 lb. for activation, i.e. about 45 N. Thus, the
242
approximate pressure applied in our study is within the range needed for activation of
243
HPEAIs.
244 245
The true distance from skin to muscle and bone, respectively, during the delivery of an EAI
246
will vary with the pressure applied to release the EAI. In our study, we have identified that
247
EAIs applied with high pressure (8 lb., with the proper footprint to the skin compress mainly
248
the muscle (>90% of compression). Therefore, there was some reduction of the STMD and
249
more pronounced reduction of the STBD when comparing high and low pressure distances.
250 251
We did not have exact data from all manufacturers on the pressure that is required to trigger
252
their respective EAIs. We recommend that manufacturers of all EAIs should declare the
253
pressure needed to release the EAI needle and document the STBD/STMD in appropriate
254
samples of patients of similar numbers as that used in this study.
12 255 256
We conclude that subcutaneous injection using a HPEAI is most common in adults and
257
children/adolescents weighing more than 30 kg. Ten% and 33% are at risk of a subcutaneous
258
injection when using LPEAIs and HPEAIs, respectively. In this study, we found
259
subcutaneous injection uncommon in children.
260 261
It has been argued that injection in living or dead mammalian tissue or the use of computer
262
tomography13 would mimic the in vivo clinical situation better than measuring the STMD and
263
STBD by ultrasound17-23. In vivo mammalian studies cannot be performed in humans due to
264
ethical issues. But these studies have been completed in pigs14 and other animals that have
265
skin and fascia that are different from that of humans. Therefore, future studies of EAIs
266
should be based on ultrasound assessments to confirm intramuscular injections. We would
267
suggest that measurements of serum epinephrine levels be completed with new EAIs as
268
well26,27. H
269
According to our data, periosteal/intraosseous injection is most common in children weighing
270
less than 15 kg using HPEAIs (32%), whereas, no children are at risk of getting a
271
periosteal/intraosseous injection if using an LPEAI device. If the injections hits the bone, the
272
device may not deliver epinephrine due to plugging with cortical bone. As well, if the
273
injection is delivered into the periosteal space, there is a risk of rapid absorption of the
274
concentrated form of epinephrine. This could be lead to serious side effects including cardiac
275
arrhythmias and death.
276 277
Auvi-Q® 0.1 mg was introduced to reduce the risk of periosteal/intraosseous injection. As
278
noted above, this is a major drawback of other HPEAIs aimed for use in children. Our data
279
confirm that the new Auvi-Q® 0.1 mg product does not have a risk of hitting the bone.
13 280
However, there is a risk of subcutaneous injection increased from 0 to 71% when using our
281
method of estimating the likely injection of the full dose of epinephrine into the intramuscular
282
compartment.
283 284
Recently, Greenberger et al.29 discussed contemporary issues regarding EAIs. They discussed
285
several points of interest that are addressed in our study. Greenberger et al.29 claim
286
penetrating the fascia may not be a problem, provided the force of the injection is strong
287
enough29. To achieve such a potent force, we believe the devices must be modified. The
288
HPEAIs use one spring for penetration of the skin and for injection of epinephrine, whereas
289
the LPEAI uses two separate springs that makes it easier to increase the pressure on the
290
injection fluid without increased injection force. Furthermore, our data show the needle length
291
and the pressure on the skin, i.e. the degree of compression of the tissues, is essential for
292
reducing the number of adults receiving a subcutaneous injection. Moreover, Greenberger et
293
al.29 propose the LPEAI with a longer needle may increase the risk for periosteal/intraosseous
294
injection. However, our data reveal the risk of periosteal/intraosseous injection was reduced
295
by using the LPEAI. This is achieved by requiring less pressure to trigger the device leading
296
to less compression of the muscle. Finally, the Greenberger paper29 brings up the possibility
297
of needle-free injection device. That subject has recently been reviewed by Ravi et al.30. This
298
type of device may be useful. However, the depth of an injection would rely on the force
299
applied on the injection fluid30. Therefore, further documentation on the possibility to apply a
300
pressure suitable for penetration of the muscle in both overweight and thin patients is required
301
before this technique can be endorsed.
302 303
Future investigations of the influence of needle length of EAIs using ultrasound should apply
304
a precise pressure31. The pressure should be defined according to the specification limits
14 305
approved by authorities, i.e. assuring precise correct pressure on the device. Furthermore, the
306
variation in needle length according to the manufacturers authority approved variation should
307
be taken into account. Thus, we recommend manufacturers to document the ability of both the
308
shortest and the longest needles that may pass the quality control to deliver epinephrine in the
309
muscle and not risk penetrating the periosteum/bone.
310 311
Other complications to the use of EAIs should be considered. Brown has recently published a
312
case series of lacerations and embedded needles after use of epinephrine auto-injectors in
313
children
314
hitting the bone. There have also been several case reports of fatal gas gangrene after injection
315
of epinephrine into the subcutaneous or intramuscular space33,34. Furthermore, there has been
316
cases reported to authorities of deep, longstanding pain after the use of autoinjectors that may
317
have been caused by needles injuring the periosteum or bone.
32
. It is possible that broken and embedded needles may occur due to the needle
318 319
We have no data on the variation in needle length or in the pressure needed for activation of
320
different EAIs.
321 322
In summary, the currently most commonly used high and low pressure EAIs may not deliver
323
epinephrine intramuscularly in a significant number of patients. There is a risk of
324
subcutaneous injection in patients with high weight, most pronounced in adults when using
325
HPEAIs, and to a lesser extent when using LPEAIs in adults. The new Auvi-Q® 0.1 mg EAI
326
has a high risk of subcutaneous injection when used in small children using our method of
327
predicting subcutaneous injection. The risk of periosteal/intraosseous penetration is highest in
328
young children using HPEAIs. There was no risk for periosteal/intraosseous injection in
329
adults in our study or when using LPEAIs or the new Auvi-Q® 0.1 mg EAI in small children.
15 330 331
We suggest that new and marketed EAIs should document the possible risk of subcutaneous
332
as well as periosteum/intraosseal injection. We propose to use ultrasound probes of the same
333
footprint as the respective EAI, analyze the influence of the variation of needle length as well
334
as the variation in pressure specified in the product monograph. Clinicians should be aware
335
that currently available EAIs are not appropriate for all of their patients.
336
*References
References 1. Muraro A, Werfel T, Hoffmann-Sommergruber K, et al. EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy 2014;69:1008-25. 2. Simons FE, Ardusso LR, Bilo MB, et al. International consensus on (ICON) anaphylaxis. The World Allergy Organization journal 2014;7:9. 3. EpiPen®/EpiPen® Jr. Prescribing Information. Day Pharma; 2014. 4. Allerject® 0.15 mg/ Allerject® 0.30 mg Prescribing Information. Laval, Quebec, Canada: Sanofi-Aventis; 2013. 5. US. S AuviQ prescribing information. Bridgewater. NJ: SanofiAventis US; 2012. 6. Product resume Emerade. MEDECA Pharma AB; 2017. 7. Emerade®: The New Adrenaline Auto-injector for Emergency Treatment of Anaphylaxis. In: iMed Systems Ltd. London. 8. Simons FE, Gu X, Silver NA, Simons KJ. EpiPen Jr versus EpiPen in young children weighing 15 to 30 kg at risk for anaphylaxis. J Allergy Clin Immunol 2002;109:1715. 9. Emergency medical treatment of anaphylactic reactions. Resuscitation 1999;41:92-9. 10. Gottberg L, Editor. Anafylaxi. Rekommendationer för omhändertagande och behandling, 2015 [Anaphylaxis. Recommendations for care and treatment 2015]. Svenska Föreningen för Allergologi, SFFA (Swedish Association for Allergology). 2 ed. Stockholm: 2015. 11. Muraro A, Roberts G, Worm M, et al. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy 2014;69:1026-45. 12. Sicherer SH, Sampson HA. Food allergy: Epidemiology, pathogenesis, diagnosis, and treatment. J Allergy Clin Immunol 2014;133:291-307; quiz 8. 13. Song TT, Nelson MR, Chang JH, Engler RJ, Chowdhury BA. Adequacy of the epinephrine autoinjector needle length in delivering epinephrine to the intramuscular tissues. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 2005;94:539-42. 14. Song TT, Merrill NL, Cole JW. Delivery depth of epinephrine by auto-injector into the subcutaneous tissue of pig. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 2013;111:143-5. 15. Song TT. Epinephrine autoinjectors: Compression and propulsion do have a role in delivery depth. The journal of allergy and clinical immunology In practice 2015;3:827-8. 16. Diacono D, Pumphrey RS, Sharma V, Arkwright PD. The deep fascia of the thigh forms an impenetrable barrier to fluid injected subcutaneously by autoinjectors. The journal of allergy and clinical immunology In practice 2015;3:297-9. 17. Stecher D, Bulloch B, Sales J, Schaefer C, Keahey L. Epinephrine autoinjectors: is needle length adequate for delivery of epinephrine intramuscularly? Pediatrics 2009;124:65-70. 18. Tsai G, Kim L, Nevis IF, et al. Auto-injector needle length may be inadequate to deliver epinephrine intramuscularly in women with confirmed food allergy. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 2014;10:39. 19. Kim L, Nevis IF, Tsai G, et al. Children under 15 kg with food allergy may be at risk of having epinephrine auto-injectors administered into bone. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 2014;10:40.
20. Dreborg S, Wen X, Kim L, et al. Do epinephrine auto-injectors have an unsuitable needle length in children and adolescents at risk for anaphylaxis from food allergy? Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 2016;12:11. 21. Johnstone J, Hobbins S, Parekh D, O'Hickey S. Excess subcutaneous tissue may preclude intramuscular delivery when using adrenaline autoinjectors in patients with anaphylaxis. Allergy 2015;70:703-6. 22. Bhalla MC, Gable BD, Frey JA, Reichenbach MR, Wilber ST. Predictors of epinephrine autoinjector needle length inadequacy. The American journal of emergency medicine 2013;31:1671-6. 23. Kim H, Dinakar C, McInnis P, et al. Inadequacy of current pediatric epinephrine autoinjector needle length for use in infants and toddlers. Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 2017;118:719-25 e1. 24. Song TT. Predictors of epinephrine autoinjector needle length inadequacy. The American journal of emergency medicine 2014;32:473-4. 25. Emerade® epinephrine autoinjector, orifice and needle specification. personal communication ed: Medeca Pharma; 2015. 26. Simons FE, Roberts JR, Gu X, Simons KJ. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol 1998;101:33-7. 27. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol 2001;108:871-3. 28. Schwirtz A, Seeger H. Comparison of the robustness and functionality of three adrenaline auto-injectors. Journal of asthma and allergy 2012;5:39-49. 29. Greenberger PA, Wallace DV, Lieberman PL, Gregory SM. Contemporary issues in anaphylaxis and the evolution of epinephrine autoinjectors: What will the future bring? Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 2017;119:333-8. 30. Ravi AD, Sadhna D, Nagpaal D, Chawla L. Needle free injection technology: A complete insight. Int J Pharma Investig 2015;5:192-9. 31. Andersen HH, Lundgaard AC, Petersen AS, et al. The Lancet Weight Determines Wheal Diameter in Response to Skin Prick Testing with Histamine. PloS one 2016;11:e0156211. 32. Brown JC, Tuuri RE, Akhter S, et al. Lacerations and Embedded Needles Caused by Epinephrine Autoinjector Use in Children. Annals of emergency medicine 2016;67:307-15 e8. 33. Van Hook R, Vandevelde AG. Letter: Gas gangrene after intramuscular injection of epinephrine: report of fatal case. Annals of internal medicine 1975;83:669-70. 34. Stuart Hannah RC, Heddle R, Smith W. Fatal gas gangrene related to selfinjection treatment of anaphylaxis. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 2011;106:538. 35. Lieberman P, Nicklas RA, Randolph C, et al. Anaphylaxis--a practice parameter update 2015. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 2015;115:341-84.
Table
Table 1 Auto-injectors commonly used in Europe and/or North America in 2017. The mean needle lengths of the HPEAIs Epipen®/EpipenJr® and Jext® differ less than one mm. Therefore, we use 13 mm (STMD) and 15 mm (STBD) for both HPEAIs. Auvi-Q® 0.1 mg that has been introduced recently has a substantially shorter needle.
Needle length, mm
Epinephrine autoinjector (EAI)
Penetrating needle length mm
Distance from the skin surface to within the muscle (- 2 mm)17
13
11
15
13
7.5 16 23 23
5.5 14 21 21
Epipen Jr® 0.15 mg* Jext® 0.15 mg* Epipen® 0.3 mg* Jext® 0.3 mg* Auvi-Q® 0.1 mg* Emerade® 0.15 mg ** Emerade® 0.3 mg ** Emerade® 0.5 mg **
Pressure
Thrusted or Pressed hard
Slight pressure
* These devices are high-pressure epinephrine autoinjectors, HPEAIs ** This device is a low-pressure epinephrine autoinjector, LPEAI
Table 2 Dose of epinephrine as recommended by different authorities and academic societies. a. Dosing of intramuscular epinephrine according to the 0.01 mg/kg rule 8-12. Dose by EAI 0.5 mg
Dose/kg
kg 50
0.01
0.3 mg
30
0.01
0.15 mg
15
0.01
b. According to EAACI guidelines 11. Weight 7.5 - 25 kg
Dose 0.15 mg
mg/kg 0.02 - 0.006
25 – 30 kg*
0.3 mg
0.012 – 0.01
* No dose recommended for adolescents weighing more than 30 kg. c. According to AAAAI practice parameter 2015 35.
0.01
15 - 30 kg
0.3 mg
0.01 – 0.005
d. According to the Swedish Anaphylaxis document 10. Weight 10* - 20 kg
Dose 0.15 mg
mg/kg >0.015 - 0.008
20 – 60 kg
0.3 mg
0.016 – 0.005
> 60** kg
0.5 mg
0.008 – < 0.008
* Even lower. ** Tentative.
Table 3 STMD and STBD in relation to weight. Numbers/percent of patients at risk of subcutaneous or periosteal/intraosseous injection graded in classes. See text.
n STMD Children 30 kg Adults, > 18 years STBD Children 30 kg Adults, > 18 years
103 99 100 99
103 99 100 99
Auvi-Q® HPEAI 5.5 mm n 71 53
7.5 mm n 0 0
Epipen®/EpipenJr®/Jext® HPEAI HPEAI 11 mm 13 mm n n 0 0 12 33 13 mm 15 mm n n 33 10 3
0
Emerade® LPEAI 14 mm n 1 0
16 mm n 0 0
LPEAI 21 mm n
2 10 23 mm n
0
0
Figure Legend
1
Legends to figures Figure 1 Schematic drawing showing an EAI penetrating the skin, subcutaneous tissue, fascia lata, endomysium and the muscle1.
Figure 2 STBDmax against weight. The two horizontal solid lines indicate the length of the needles of HPEAIs. The broken line indicates the needle length of the new EAI for small children, Auvi-Q® 0.1 mg. The solid vertical lines indicate 15, 30, and 60 kg2. The red areas indicate STBDmax data with a risk of periosteal/intraosseous injection. As indicated by the area with black horizontal lines, there is no risk of periosteal/intraosseous injection using the short-needled new HPEAI, Auvi-Q® 0.1 mg
Figure 3 STBDmin against weight. The two horizontal solid lines indicate the length of the needles of LPEAIs. The solid vertical lines indicate 15, 30, and 60 kg2.
Figure 4 STMDmax against weight. The two horizontal solid lines indicate the length of the needles of HPEAIs minus 2 mm. The short broken line indicates the needle length of the new HPEAI for small children, Auvi-Q® 0.1 mg. The solid vertical lines indicate 15, 30, and 60 kg2. The red area to the right indicates STMDmax data with a risk of subcutaneous injection. The red area to the left indicates STMDmax data with a risk of subcutaneous injection using the new short-needled HPEAI Auvi-Q® 0.1 mg
Figure 5 STMDmin against weight. The two horizontal solid lines indicate the length of the needles of LPEAIs minus 2 mm. The solid vertical lines indicate 15, 30, and 60 kg2. The red area indicates STMDmin with a risk of subcutaneous injection.
Figure
EAI
Figure 1
STMD
STBD Fascia lata Endomysium
? mm Needle orifice 2 mm
Quadriceps
Periosteum Femur
Figure 2 60 BMI < 25 kg/m2 BMI 25 - 29.9 kg/m2 BMI > 30 kg/m2
50
STBDmax mm
40
30
20
10
0 4
6
8
20
Weight kg
40
60
80
Figure 3
70
60
STBD min mm
50
40
30
20
10 4
6 5
8 7
30
10 9
20
Weight (kg)
50 40
70 60
80
90 100
Figure 4 30 BMI < 25 kg/m2 25 - 29.9 kg/m2 > 30 kg/m2
STMDmax mm
20
10
0 4
6
8
20
40
Weight
60
80
Figure 5 60
50
STMDmin
40
30
20
10
0 4
6 5
8 7
30
10 9
20
Weight (kg)
50 40
70 60
80
90 100
E-Supplement
E-Supplement
Epinephrine auto-injector needle lengths Can both subcutaneous and periosteal/intraosseous injection be avoided?
Supplementary material eTable 1 – 2:
2
eTable 1
Summary data on 302 children and adolescents needing EAI for emergency treatment in the community.
Percentile
Children 0 – 18 yrs, n 302 Age, years Sex, girls: n = 125, 41% Height, cm Weight, kg BMI Adults, >18 yrs Age, years Sex, females: n = 68 Height, cm Weight, kg BMI kg/m2, 60% > 25; 25% >30
Median
Mean
max
min
5
95
6
6.9
18
0.7
1.0
16.0
114.3 20.6 16.8
120.5 29.0 17,8
190.5 88.9 33.0
52.1 5.0 6.0*
73.7 9.1 11.5
177.8 72.6 27.0
35.0
37.2
72
18
25.0
47.8
167.6 72.6 26.0
168,3 76.0 26.8
195.6 149.2 50.2
142.2 45.4 17.9
162.6 63.5 22.3
175.3 83.9 30.0
* A three year old boy, weight 5 kg, height 91.4 cm
eTable 2
Basic data on 302 children/adolescents and 99 adults needing EAI for emergency treatment in the community. Since the number of adults was close to 100, percentages are not given.
Sensitization by SPT/allergy Milk, egg, soy, wheat Lentils, beans, peas Shrimp, fish, shell-fish Peanut Tree-nut Pollen, fruits, vegetables In-door allergens Allergic diseases Rhinitis Asthma Eczema Urticaria Any Medication EAI and or β2 agonist Asthma without EAI/ β2-agonist EAI EAI + β2 agonist + Inhaled steroids
Children & Adolescents n 302 n %
n
%
116 18 23 186 77 104 123
38 6 8 61 25 34 41
10 9 32 29 33 76 78
10 9 32 29 33 77 79
122 113 107 30 220
40 37 35 10 73
73 52 10 6 86
74 53 10 6 88
155 9
51.2 3
52 13 46 5
53 13 46 5
Adults n 99
