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Epinephrine, auto-injectors, and anaphylaxis
Accepted Manuscript Title: Epinephrine, auto-injectors and anaphylaxis: challenges of dose, depth and device Author: Julie Brown PII: DOI: Reference:
S1081-1206(18)30334-X https://doi.org/10.1016/j.anai.2018.05.001 ANAI 2544
To appear in:
Annals of Allergy, Asthma & Immunology
Received date: Revised date: Accepted date:
29-3-2018 2-5-2018 3-5-2018
Please cite this article as: Julie Brown, Epinephrine, auto-injectors and anaphylaxis: challenges of dose, depth and device, Annals of Allergy, Asthma & Immunology (2018), https://doi.org/10.1016/j.anai.2018.05.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Epinephrine, Auto-injectors and Anaphylaxis: Challenges of Dose, Depth and Device Julie Brown, MDCM, MPH Seattle Children’s Hospital and University of Washington 1 2 3 4 5 6 7 8 9 10
Julie C. Brown, MDCM, MPH, corresponding author Associate Professor, Pediatric Emergency Medicine Seattle Children's Hospital P.O. Box 5371 MB.7.528, 4800 Sandpoint Way NE, Seattle, WA 98105 206-987-4016 OFFICE 206-696-8268 CELL 206-729-3070 FAX [email protected] Conflict of Interest: none Funding source: none Clinical Trial registration: N/A Keywords: epinephrine, auto-injector, EpiPen, Auvi-Q, anaphylaxis, needle, depth, weight, obesity, intramuscular, subcutaneous, bone Abbreviations: EAI – epinephrine auto-injector, ED – emergency department, EMS – emergency medical services FDA – Food and Drug Administration, AAP – American Academy of Pediatrics Word Count: 3993 Figures: 5 Tables: none
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Acknowledgements: Thank you to Kristen Follmer and Thomas Agosti for their assistance with graphs and to Rebecca Watson for kindly sharing images. 1
Key Messages:
Epinephrine is the only first-line medication for the treatment of anaphylaxis, and must be readily available in the community with doses and exposed needle lengths that are optimized to best meet the needs of patients of all sizes and weights.
Optimal dosing is based on common practice, but is not well studied. There are no pharmacokinetic or pharmacodynamic data involving patients in anaphylaxis.
The recently marketed 0.1 mg EAI will be the first approved device for patients weighing 7.5-15 kg, which allows for dosing closer to the recommended 0.01 mg/kg. It will also have a shorter needle that may be more appropriate for this weight range.
The 0.15 mg epinephrine auto-injector (EAI) gives increasing less than the recommended 0.01 mg/kg dose as the patient approaches 30 kg. Data are lacking to determine if this is clinically important, but switching at 20 or 25 kg may be better than switching at 30 kg.
A higher dose EAI might better meet the needs of larger patients, but data are lacking. 2 Page 2 of 36
An EAI with a longer needle might better meet the needs of obese patients, but data are lacking.
Pre-hospital and hospital providers should review their anaphylaxis preparedness, and consider using anaphylaxis kits or pre-filled syringes when EAIs are not used.
1 2
Abstract: Objectives: 1. To review epinephrine dosing, site and route of administration, focusing on
3
special populations (patients weighing less that 15 kg, and obese patients). 2. To discuss storage and
4
delivery of epinephrine in pre-hospital and hospital settings.
5
Data Sources: Review of published literature.
6
Study Selection: Relevancy.
7
Results: The recommended 0.01 mg/kg (max 0.3-0.5 mg) epinephrine dose in anaphylaxis is based on
8
limited pharmacokinetic data in healthy volunteers. There are no pharmacokinetic or
9
pharmacodynamics studies involving patients in anaphylaxis. When epinephrine auto-injectors (EAIs) are
10
used in infants, the dose increasingly exceeds the recommended dose as weight decreases, although the
11
clinical significance is unclear. Limited data indicate that the intramuscular route and lateral thigh site
12
are superior. Ultrasound studies suggest that 0.15 EAI needles may be too long for many patients under
13
15 kg and 0.3 mg EAI needles may be too short for obese patients over 30 kg. A newly available 0.1 mg
14
EAI has a lower dose and shorter needle better suited to patients 7.5-15 kg. In some medical settings,
15
vials and syringes may provide a safe, efficient alternative with substantial cost savings over EAIs.
16
Conclusion: EAIs should be available in the community with doses and needle depths that meet the
17
needs of all patients. More research on epinephrine pharmacodynamics are needed in children and 3 Page 3 of 36
1
adults in anaphylaxis, in order to better delineate what optimal doses should be. Optimizing epinephrine
2
dose and delivery has the potential to improve anaphylaxis outcomes and prevent adverse events.
3 4
Introduction:
5
Epinephrine is a life-saving medication for the treatment of anaphylaxis.1-3
6
Epinephrine auto-injectors (EAIs) allow for reliable delivery of epinephrine during
7
allergic reactions the community setting, and must be able to deliver an effective dose
8
to an appropriate intramuscular depth, for patients of all ages, weights and sizes.4 This
9
review discusses epinephrine dosing and pharmacokinetics, the use of EAIs for patients
10
across a range of weights and skin-to-muscle and skin-to-bone distances, and issues
11
around epinephrine storage and preparation for anaphylaxis emergencies in health care
12
settings.
13 14
Epinephrine dose and route:
15
The standard Food and Drug Administration (FDA) approved dose and route for
16
epinephrine is 0.01 mg/kg intramuscularly for children 30 kg or less, with a maximum of
17
0.3 mg in children and teenagers, and 0.5 mg in adults.5 These dose recommendations
18
are extrapolated from other uses of epinephrine and are supported by scant evidence.
19
There are no pharmacodynamic studies evaluating dose-response or comparing
20
efficacy or safety with different doses of epinephrine, even in healthy subjects.6 This
4 Page 4 of 36
1
dosing strategy is, however, supported by over 40 years of clinical practice and appears
2
to work well and with an excellent safety record.7, 8
3
The pharmacokinetics of intramuscular epinephrine have only been studied in a
4
few small studies involving healthy volunteers, mostly adults.9-14 In all of these studies,
5
there is a clear peak in plasma epinephrine within minutes of intramuscular
6
administration in the lateral thigh, tapering off over 1-2 hours. In a study of 13 healthy
7
men, the increases in plasma epinephrine concentrations were much greater when
8
epinephrine was given intramuscularly in the thigh versus either subcutaneously or
9
intramuscularly in the deltoid.13 In 17 healthy children, intramuscular administration in
10
the thigh resulted in a greater increase in plasma epinephrine level versus
11
subcutaneous administration in the deltoid.11, 15 There are, however, no pharmacokinetic
12
studies involving patients in anaphylaxis, where drug pharmacokinetics might be
13
substantially different due to extravascular fluid losses and other physiologic changes.
14
There are also no true pharmacodynamic studies. In the only study approaching a dose-
15
response study, EpiPen and EpiPen Jr devices were used in 12 healthy children
16
between 15 and 30 kg, according to which device had been prescribed for them.12 Side
17
effects were more frequent and more severe in children receiving epinephrine 0.01-
18
0.014 mg/kg than in those receiving epinephrine 0.008- 0.009 mg/kg. However, the
19
study is limited by small sample size and the weight differences between those
20
receiving the two devices.
21 22 23
Epinephrine concentration
5 Page 5 of 36
1
The concentration of epinephrine typically used in anaphylaxis is 1 mg/mL,
2
formerly referred to as 1:1,000. The nomenclature was changed to improve safety
3
drawing up the dose correctly.16, 17 Ultimately, any concentration can be used that
4
delivers the dose of 0.01 mg/kg to the patient, but the 1 mg/mL concentration allows for
5
a reasonable volume for intramuscular injection. In a dire setting where only 0.1 mg/mL
6
epinephrine were available, this concentration could be used, but a large volume would
7
need to be injected. For example, in an adult patient, a 0.3 mg dose would require a 3
8
mL injection.
9 10 11
Epinephrine site of administration: Most small-dose intramuscular medications, including intramuscular
12
vaccinations, are typically given in the deltoid muscle to patients older than 2 years. 18
13
The Center for Disease Control (CDC) recommends injecting in the vastus lateralis
14
muscle for infants 12 months and younger, and for infants 1-2 years until the deltoid
15
muscle mass is adequate.18 After age 2, the deltoid muscle is preferred, although the
16
vastus lateralis may still be used. However, epinephrine use in anaphylaxis is an
17
exception, as guidelines universally recommend administration in the lateral thigh for all
18
ages.1-3 This is based on the significantly and dramatically higher mean maximum
19
plasma epinephrine concentration observed with intramuscular injection in the vastus
20
lateralis muscle versus deltoid muscle observed in Simons’ study of 13 adult men.13 It is
21
rare that such a small study would guide such widespread practice, but the results are
22
compelling, and there are no other studies which compare pharmacokinetic or
6 Page 6 of 36
1
pharmacodynamics responses with intramuscular dosing at different sites, or in other
2
populations, such as patients in anaphylaxis.
3 4 5
Epinephrine depth of administration: When epinephrine is drawn up into a syringe, the depth can be controlled by the
6
length of the injection needle and the depth to which it is injected. The Center for
7
Disease Control (CDC) recommends using a 1-inch needle for vastus lateralis muscle
8
injections in children 1 month and older.18 In adults, the CDC advises considering a 1.5
9
inch needle for deltoid injections in patients over 70 kg, and recommends this length for
10
men ≥118 kg and women ≥91 kg, but does not give similar specific guidance on needle
11
length by weight for vastus lateralis muscle injections in these patients. No other
12
specific guidance is available, including in anaphylaxis guidelines and practice
13
parameters.1-3
14 15 16
Epinephrine Repeat Dosing: Most guidelines recommend that epinephrine doses can be repeated in
17
anaphylaxis every 5 to 15 minutes, and sooner if determined to be indicated by a
18
clinician.1 The timing of repeat dosing of epinephrine is likely based on pharmacokinetic
19
studies, which typically show a peak in plasma level within 5 minutes in healthy
20
volunteers, although this has not been correlated with time to symptom resolution in
21
patients in anaphylaxis. If repeated intramuscular injections are needed, the patient
7 Page 7 of 36
1
should be placed on an epinephrine drip. Intravenous bolus epinephrine is associated
2
with an increased risk of serious adverse events, including pulmonary edema and
3
arrhythmias, and should be avoided.2
4 5 6
Epinephrine auto-injectors (EAIs): In the United States, 0.15 mg and 0.3 mg epinephrine auto-injectors (EIAs) have
7
been available since 1980. This year, a 0.1 mg dose EAI will be available for the first
8
time, from one American manufacturer.19 These limited dosing options result in making
9
compromises relative to the 0.01 mg/kg ideal dosing recommendation. The 0.15 device
10
is approved for patients 15-30 kg, and the 0.3 mg device for patients 30 kg or more. The
11
0.1 mg Auvi-Q device is approved for patients weighing 7.5-15 kg.
12
The exposed needle lengths of the three 0.15 mg EIAs marketed in the United
13
States are similar, and approximately 12-13 mm.20, 21 Estimates of exposed needle
14
lengths of the three 0.3 mg EIAs marketed in the United States vary by information
15
source but are similar, approximately 15.2 mm.20-22 The 0.1 mg Auvi-Q device has an
16
exposed needle length of 7.4mm. 23
17 18 19
EAI Dosing for Patients Weighing Less than 15 kg: Allergic reactions are common in patients weighing less than 15 kg, and
20
prescribing epinephrine for this group of patients has been challenging for allergists,
21
primary care, and emergency providers alike. In a 2002 study in Manitoba, over 2% of 8 Page 8 of 36
1
all children between 6 months and 3 years received epinephrine prescriptions.24 Given
2
normal age and weight distributions, these would be primarily children less than 15 kg. 25
3
In our urban pediatric emergency department (ED) with 38,000 annual visits, over 30%
4
of 1,178 visits for anaphylaxis between 2010 and 2017 were for patients less than 15
5
kg. The mean age of these patients was 2.5 years, range 116 days to 5.1 years.
6
Until recently, and wherever a 0.1 mg EAI is unavailable (which currently
7
includes all countries other than the United States), providers are faced with three
8
imperfect prescribing solutions for children weighing less than 15 kg. The first option is
9
to provide the family with an ampule or vial and syringe, and instructions on drawing up
10
a correct dose. A study of parents of children with food allergies showed that
11
immediately after training in an allergy clinic, and with a visual instruction card at their
12
disposal, some parents still took as long as four minutes to draw up a dose of
13
epinephrine from an ampule into a syringe, and made as high as 40-fold dosing errors,
14
even without the stress of a child in anaphylaxis.26 This approach is consequently not
15
generally recommended. The second approach is to provide the family with a pre-filled
16
syringe with the correct dose already drawn up. There is evidence that epinephrine is
17
stable and sterile in syringes for up to 3 months.27-29 However, training in correct use of
18
a needle and syringe is still required, and a safe means for carrying the syringe is
19
crucial, to ensure the plunger isn’t accidentally depressed. This is not easily
20
accomplished. There may soon be products on the market that provide a better pre-
21
filled syringe solution, with specially designed syringes and carrying containers. 30 The
22
third and most often preferred option, is to use the 0.15 mg device for infants of all
23
weights. The American Academy of Allergy Asthma and Immunology “Ask the Expert” 9 Page 9 of 36
1
web pages supports this approach.31 This is also described as recommended by the
2
Canadian Paediatric Society32 and specifically recommended European Academy of
3
Allergy and Clinical Immunology.33 The Canadian Society of Allergy and Immunology
4
recommends that given the lack of a suitable alternative, the 0.15 mg epinephrine auto-
5
injector be prescribed for infants and children weighing less than 15 kg. 34 The 2017
6
American Academy of Pediatrics clinical report acknowledged the challenge of treating
7
small children who require an epinephrine prescription and suggested that physicians
8
discuss the options and their risks and benefits with families.4
9
Using a 0.15 mg EAI off-label for children <15 kg results in doses in excess of
10
0.01 mg/kg. This problem becomes more and more pronounced the less the infant
11
weighs, with a 5 kg infant receiving 3 times the FDA recommended dose (Figure 1).
12
These higher doses have never been demonstrated to post a risk to healthy infants, and
13
clinical experience suggests that infants handle doses higher than 0.01 mg/kg quite
14
well.35 However, even appropriately administered therapeutic doses have in rare cases
15
caused serious adverse events in adults,8, 36 so until better pharmacodynamic and
16
epidemiologic information is available for children, it seems prudent to provide dosing as
17
close to FDA approved guidelines whenever possible.
18
The introduction of a 0.1 mg EAI allows for EAI dosing for infants and toddlers
19
that better approximates the ideal dose. When the 0.1 mg/kg dose is used for patients
20
weighing the minimum approved weight of 7.5 kg, the dose is 0.0133 mg/kg, which is
21
133% of the ideal 0.01 mg/kg dose. When it is used off-label for patients weighing as
22
low as 5 kg, patients will receive twice rather than three times the ideal dose (Figure 2).
10 Page 10 of 36
1 2 3
EAI Dosing for Patients Between 15 and 30 kg: Prescribing within FDA approved dosing recommendations for patients 15-30 kg
4
ensures that the patient never exceeds the recommended 0.01 mg/kg dose. However, a
5
patient using a 0.15 mg dose auto-injector will fall increasingly below 0.01 mg/kg as
6
their weight increases (Figure 1). A child who weighs 29 kg receives only 0.0052 mg/kg
7
of epinephrine, approximately half the ideal dose. For this reason, some providers
8
switch to the 0.3 mg formulation at 25 kg or even lower weights, preferring to exceed
9
this recommended dose rather than risk under-dosing their patients. A 2017 American
10
Academy of Pediatrics (AAP) clinical report states that it is appropriate to switch to the
11
0.3 mg auto-injector once a child reaches 25 kg.4 This matches earlier
12
recommendations by the AAP.15 Similarly, the Canadian Paediatric Society cites 25 kg
13
as the recommended weight for switching,32 and the European Academy of Allergy and
14
Clinical Immunology recommends switching at 25 kg.33
15 16 17
EAI Dosing for Patients Weighing > 40 kg By 40 kg, a patient using a 0.3 mg EAI receives only 77% of an 0.01 mg/kg ideal
18
dose, with decreasing percentage relative to ideal dose with increasing weight (Figure
19
2). There are no data to guide if one standard adult dose is sufficient, or if weight-based
20
dosing should continue beyond 30 kg.
21
11 Page 11 of 36
1 2
Epinephrine Depth of Delivery and Patients Weighing Less than 15 kg: When epinephrine is delivered via an EAI, the depth of medication delivery is
3
determined based on tissue compression, needle length, and propulsive forces.
4
However, compression and needle length alone determine the skin-to-bone distance:
5
after the amount of tissue compression required for EAI activation, the needle tip must
6
end before bone to allow for appropriate intramuscular delivery, and prevent needle-
7
bending and potential injuries. In small patients, the EAI needle length plus tissue
8
compression could be sufficient to place the needle tip into bone. In a study of 100
9
children less than 15 kg with food allergies, with exposed needle length defined as 12.7
10
mm, an ultrasound probe was used to provide an estimated 2-8 pounds of pressure and
11
the skin-to-bone distance was measured.37 In 29% of the children studied, and 60% of
12
children who were less than 10 kg, the skin-to-bone distance after compression
13
exceeded 12.7 mm. A 0.15 mg EAI therefore risks injection into bone in these subjects.
14
In a similar study of 51 children less than 15 kg with food allergies, needle length was
15
again defined as 12.7 mm, and a 10-lb compression was provided by an Auvi-Q-shaped
16
probe to simulate what is typically required for device activation.21 In 43.1% of subjects,
17
the device would be expected to strike bone. Pen-shaped 0.15 mg EAI devices, which
18
have similar needle lengths and activation forces acting on an even more localized
19
area,20 would be expected to have similar results. While these studies raise theoretical
20
concerns about the effectiveness and safety of current 0.15 mg EAI device use in
21
children weighing under 15 kg, there are no reports in the literature of adverse events
22
attributed to needle depth in patients less than 15 kg, despite frequent off-label use.
23
Perhaps users take steps to mitigate the potential for injection into bone, such as 12 Page 12 of 36
1
bunching the thigh muscle during injection, to increase the skin-to-bone distance (Figure
2
3).
3
None of the patients in the above studies would risk injection into bone with the
4
7.4 mm exposed needle length that is in a 0.1 mg Auvi-Q device, after accounting for
5
tissue compression. Estimating from a graph, in about 16% of patients, the skin-to-
6
muscle distance would exceed this needle length, after compression, by 0.1-1.8 mm.21
7
However, drug delivery to muscle also depends on propulsion, which was not
8
considered in these studies. The high pressure EAIs marketed in the United States fire
9
epinephrine with significant propulsive force which delivers the medication well beyond
10
the needle tip.22, 38 Propulsive forces would probably be sufficient to deliver epinephrine
11
the small additional distance to muscle in these patients.
12 13 14
Epinephrine Depth of Delivery in Children and Adults Weighing 15 kg or more: There are two ultrasound studies considering depth of medication delivery in
15
children 15 kg or more. In a study of 100 children weighing 15-30 kg (group 1) and >30
16
kg (group 2), an ultrasound probe was used to “simulate the pressure required to trigger
17
a high pressure EAI” and the skin-to-bone distance was measured.22 The exposed
18
needle length was defined as 12.7 mm for group 1 and 15.2 mm for group 2. In group 1,
19
11% of the children were at risk of injection into bone using an 0.15 mg EIA, and 1%
20
would be expected to inject subcutaneously. In group 2, 3% of the children were at risk
21
of injection into bone using an 0.3 mg EIA, and 9% would be expected to inject
22
subcutaneously. In another study of 93 children ages 1-16 with food allergies, the 13 Page 13 of 36
1
exposed needle length was defined as 12.7 mm for children <30 kg and 15.9 mm for
2
children >30kg. Overall, 20% of these children (approximately 13% of healthy weight
3
children and 47% of obese children), had a skin-to-muscle greater than the needle
4
length at the mid-thigh, but this did not account for tissue compression.39 Neither of
5
these two studies considered propulsion, which might allow for increased delivery to
6
muscle for those subjects where the needle tip would end subcutaneously.
7
The chance of subcutaneous injection is likely to increase in adulthood. In North
8
America 38% of adults are obese: 7.7% of men and 9.9% of women are morbidly
9
obese.40 Based on a study of 50 men and 50 women with CT thigh images, 2% of the
10
men and 28% of the women had a skin-to-muscle distance that exceeded 14.3 mm (the
11
defined exposed needle length of EpiPen in this study), after accounting for 8-lb tissue
12
compression.41 In a similar study of 50 men and 50 women with food allergies who were
13
prescribed an EAI, ultrasound was used to measure skin-to-muscle distance with
14
compression.42 With 8 pounds of compression, 28% of women and none of the men
15
had a distance greater than 15.2 mm (the defined exposed needle length of EpiPen in
16
this study). Finally, in a study of 60 males and 60 females visiting an
17
ED, with compression “mimicking the pressure provided with proper auto-injection”,
18
28% of women and none of the men had a distance greater than 15.9 mm (the exposed
19
needle length of the longest available auto-injector at the time of this study).43
20
The results of these ultrasound studies, however, do not necessary indicate that
21
drug delivery will not be intramuscular in these patients, because the propulsive forces
22
of EAIs provide additional benefit in helping the medication reach the intramuscular
23
space beyond the needle tip. Propulsion is clearly capable of delivering medications to 14 Page 14 of 36
1
the intramuscular space, as evidenced by needle free intramuscular injection devices
2
that rely on propulsive forces alone.44 Although in vitro studies in pork tissue suggest
3
that fascia may act as a barrier to the movement of drugs from the subcutaneous tissue
4
into muscle,45 in vivo studies demonstrate extensive movement of molecules similar in
5
size to epinephrine through fascia.46
6
Clinical information on the use of epinephrine in obese patients is limited. In
7
studies of patients with fatal anaphylaxis, auto-injectors were felt to be of insufficient
8
depth to reach muscle in at least some cases, but the role this may have played in the
9
lethal outcome is unclear.47 In a study of 321 patients presenting to the ED for food
10
allergy or stinging insect allergic reactions, the 69 obese patients were no more likely to
11
receive 2 or more doses of epinephrine than their normal weight or under-weight
12
peers.48 However, the majority of these subjects were children, where the skin-to-bone
13
distances may have been smaller despite obesity. Results were reported to be similar
14
when the 60 adults were evaluated separately, but the number of obese adults in this
15
subset may not have been sufficient to answer this question well.
16 17 18
Storage of Epinephrine in Health Care Environments: In health care environments, epinephrine can be stored in auto-injectors, in vials
19
or ampules and drawn up when needed, or in pre-filled syringes. Each approach has
20
advantages and disadvantages. Storage in auto-injectors provides potentially the fastest
21
option in the hands of competent users, and prevents erroneous intravenous
22
epinephrine use in an anaphylactic emergencies.49 However, this approach is 15 Page 15 of 36
1
expensive and limits dosing options. In addition, even when used by medical providers,
2
there have been many reported injuries, primarily involving upside-down use of EpiPen
3
devices resulting in thumb injections and failed patient drug administration.50 In a review
4
of 105 unintentional injections from EAIs reported to the Food and Drug Administration
5
Adverse Event Reporting System, more than one third of the individuals injected were
6
health care professionals. Finally, after a change in packaging resulted in EpiPens
7
being sold to hospitals in pairs along with similar looking trainers, reports emerged of
8
hospitals mistaking trainers for devices, and providers attempting to use a trainer when
9
a real device was needed.51
10
A second approach is to stock vials or ampules and draw up the appropriate
11
weight-based dose when needed.49 In a simulation study in our ED evaluating nurse
12
administration of epinephrine to a simulated anaphylaxis patient, we observed
13
difficulties in gathering supplies efficiently, and drawing up medication using ampules
14
and filter straws. This prompted us to switch to using epinephrine kits that are easier
15
and faster to use. These kits contain an epinephrine vial, a vial-access needle, a 1-inch
16
25-gauge needle, alcohol swabs, gauze and a bandage (Figure 4). The switch to a vial
17
eliminates the need for a filter straw which was difficult to use with a 1 mL syringe. The
18
kits are regularly prepared and distributed by our inpatient pharmacy and stocked in
19
medication dispensing areas and crash carts throughout the hospital. An important
20
safety adjunct to this effort is the use of a weight-based code sheet, which readily
21
identifies the correct concentration, dose and volume of medication that should be given
22
to the patient.
16 Page 16 of 36
1
A variation of the vial and syringe approach, which is gaining traction in pre-
2
hospital care around the country, is to use a kit that limits dosing to two EAI doses, 0.15
3
and 0.3 mg. This simplifies training of emergency medical service providers and aims to
4
improve speed of administration and minimize errors. The Check-and-Inject™ kit
5
developed by the King County Emergency Medical Services (EMS) system, was
6
implemented along with extensive training of all EMS providers in recognition and
7
treatment of anaphylaxis, including quarterly hands-on training drawing up medications
8
with verification and certification of competency (Figure 5).44 This program has saved an
9
estimated $334,000 annually in medication costs for the county’s EMS system, while
10 11
maintaining access to epinephrine on all EMS vehicles in the county. A third approach, rarely used, is to stock pre-filled syringes in medical areas.
12
There are currently no epinephrine prefilled syringes that have been FDA-approved for
13
clinical use.52 In most pediatric environments, this would require a range of dosing
14
options and complex pharmacy procedures to be effective. However, this process has
15
been reported in some environments, such as neonatal intensive care. 53 This might also
16
be a practical approach prior to administration of high-risk chemotherapeutics, or the
17
administration of contrast dyes in patients known to be at risk. While there are United
18
States Pharmacopeia standards for compounded medications allowing only 1-3 days of
19
storage after compounding,54 there is no guidance specific to non-compounded
20
medications intended for intramuscular use. While medications stored in syringes can
21
cause infections when delivered intravenously,55 the risk with intramuscular injection is
22
likely very low, although a Clostridial infection following an EpiPen injection in a thigh
23
has been reported.56 17 Page 17 of 36
1 2
Discussion:
3 4
Despite lacking pharmacokinetic data and limited EAI dose and needle length
5
options, epinephrine has nevertheless demonstrated a long track record of safe and
6
effective treatment for anaphylaxis. No long-term serious adverse advents have been
7
reported with the correct-dose intramuscular use of epinephrine in children. Adverse
8
events in adults are rare.60 Most reported adverse events either involve significant
9
overdosing or intravenous bolus dosing.36, 61 Despite this, and despite being the only
10
medication that plays a significant role in management of anaphylaxis, 1-3 epinephrine is
11
frequently under-utilized in community, pre-hospital and emergency settings.57-60 Many
12
more anaphylaxis deaths are associated with delayed use of epinephrine, or incorrect
13
actions while in anaphylaxis, such as being propped up while unconscious or rapidly
14
raised to a standing position.59
15
The arrival of a new lower-dose shorter-need EAI on the market will allow for
16
better tailoring of an EAI to match young childrens’ needs. Pediatric patients deserve
17
this equal attention to their health and safety. Perhaps it will also encourage
18
conversations between providers and parents about the early epinephrine use in
19
anaphylaxis in general, thereby decreasing parental reluctance to use an EAI when their
20
child needs it, regardless of device. It could similarly ignite interest by EMS or
21
emergency providers, perhaps leading to increased awareness and familiarity with all of
22
the epinephrine auto-injector options available in the community.
23 18 Page 18 of 36
1
Conclusion:
2 3
Epinephrine is a critical medication for the treatment of anaphylaxis. EAIs should
4
be available in the community with doses and exposed needle lengths that are
5
optimized to best meet the needs of patients of all sizes and weights. More research on
6
epinephrine pharmacodynamics is needed, ideally involving both children and adults in
7
anaphylaxis, in order to better delineate what optimal doses should be. Optimizing the
8
dose of epinephrine and ensuring its delivery to the optimal body location has the
9
potential to improve anaphylaxis outcomes and prevent adverse events. Better
10
information would allow the large and growing allergy community to be better and more
11
safely served in the community and health care settings. The ideal means for storing
12
and delivering epinephrine in pre-hospital and hospital environments warrants further
13
study to determine how to best balance efficiency, patient safety, provider safety, and
14
health care costs.
15 16 17 18 19
Editorial Addendum : The product “Auvi-Q 0.1mg” listed in this manuscript as in development was
20
approved for commercial use in the USA on May 1, 2018.
21
19 Page 19 of 36
1
20 Page 20 of 36
1
References:
2
1. Campbell RL, Li JT, Nicklas RA, Sadosty AT. Emergency department diagnosis and
3
treatment of anaphylaxis: a practice parameter. Ann Allergy Asthma Immunol.
4
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2. Lieberman P, Nicklas R, Oppenheimer J, Kemp S, Lang D. The Diagnosis and
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4. Sicherer SH, Simons FER, SECTION ON ALLERGY AND IMMUNOLOGY.
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5. Epinephrine Injection USP, 1 mg/mL (1:1,000), Prescribing Information. Available at:
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6. Lieberman P. The 10-second rule and other myths about epinephrine and
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autoinjectors Ann Allergy Asthma Immunol. 2011;107:198.
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7. Lieberman P. Epinephrine Dosing. Available at: http://www.aaaai.org/ask-the-
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8. Wood JP, Traub SJ, Lipinski C. Safety of epinephrine for anaphylaxis in the
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emergency setting. World J Emerg Med. 2013;4:245-251.
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9. Edwards ES. Bioavailability of Auvi-Q and EpiPen: Focus on Pharmacokinetics. Clin
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Pediatr (Phila). 2013;52:890.
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10. Edwards ES, Gunn R, Simons ER, et al. Bioavailability of epinephrine from Auvi-Q
8
compared with EpiPen. Ann Allergy Asthma Immunol. 2013;111:132-137.
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11. Simons FE, Roberts JR, Gu X, Simons KJ. Epinephrine absorption in children with a
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history of anaphylaxis. J Allergy Clin Immunol. 1998;101:33-37.
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12. Simons FE, Gu X, Silver NA, Simons KJ. EpiPen Jr versus EpiPen in young children
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weighing 15 to 30 kg at risk for anaphylaxis. J Allergy Clin Immunol. 2002;109:171-175.
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13. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular
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versus subcutaneous injection. J Allergy Clin Immunol. 2001;108:871-873.
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14. Rackley R, Lawrence T, Li H, Liu S, Elder M. Auvi-Q® Versus EpiPen® Auto-
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Partial Area Under the Curve. Palm Beach, FL: Eastern Allergy Conference; 2013
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15. Sicherer SH, Simons FE, Section on Allergy and Immunology, American Academy
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Pediatrics. 2007;119:638-646.
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16. Institute for Safe Medication Practices. Farewell to ratio expressions on single entity
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17. Wheeler DW, Carter JJ, Murray LJ, et al. The effect of drug concentration
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18. Center for Disease Control and Prevention. Epidemiology and Prevention of
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https://www.cdc.gov/vaccines/pubs/pinkbook/vac-admin.html#route. Accessed Mar 12,
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19. kaleo. U.S. FDA Grants Priority Review for an Epinephrine Auto-Injector in
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Development by Kaleo Specifically for Infants and Small Children. Available at:
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21. Kim H, Dinakar C, McInnis P, et al. Inadequacy of current pediatric epinephrine
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autoinjector needle length for use in infants and toddlers. Ann Allergy Asthma Immunol.
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22. Dreborg S, Wen X, Kim L, et al. Do epinephrine auto-injectors have an unsuitable
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needle length in children and adolescents at risk for anaphylaxis from food allergy?
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23. kaleo. Multidisciplinary Review NDA 201-739, S-008 and S-009 -- Auvi-Q
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24. Simons FE, Peterson S, Black CD. Epinephrine dispensing patterns for an out-of-
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hospital population: a novel approach to studying the epidemiology of anaphylaxis. J
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Allergy Clin Immunol. 2002;110:647-651.
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25. Centers for Disease Control and Prevention. Data Table of Weight-for-age Charts.
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26. Simons FE, Chan ES, Gu X, Simons KJ. Epinephrine for the out-of-hospital (first-
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aid) treatment of anaphylaxis in infants: is the ampule/syringe/needle method practical?
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J Allergy Clin Immunol. 2001;108:1040-1044.
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27. Kerddonfak S, Manuyakorn W, Kamchaisatian W, Sasisakulporn C,
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Teawsomboonkit W, Benjaponpitak S. The stability and sterility of epinephrine prefilled
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syringe. Asian Pac J Allergy Immunol. 2010;28:53-57.
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28. Rawas-Qalaji M, Simons FE, Collins D, Simons KJ. Long-term stability of
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epinephrine dispensed in unsealed syringes for the first-aid treatment of anaphylaxis.
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Ann Allergy Asthma Immunol. 2009;102:500-503.
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29. Zenoni D, Priori G, Bellan C, Invernizzi RW. Stability of diluted epinephrine in
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prefilled syringes for use in neonatology. European Journal of Hospital Pharmacy.
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2012;19:378-380.
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30. AllergyStop. Available at: http://www.allergystopnow.com/. Accessed 06/01, 2016.
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31. Lieberman P. Use of an automatic epinephrine injector (Junior) versus epinephrine
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drawn from a syringe in a 9 month-old weighing 18.5 pounds. Available at:
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http://www.aaaai.org/ask-the-expert/use-of-automatic-epinephrine-injector. Accessed
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03/06, 2018.
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32. Cheng A. Emergency treatment of anaphylaxis in infants and children. Paediatr
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Child Health. 2011;16:35-40.
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33. Muraro A, Roberts G, Worm M, et al. Anaphylaxis: guidelines from the European
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Academy of Allergy and Clinical Immunology. Allergy. 2014;69:1026-1045.
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34. Halbrich M, Mack DP, Carr S, Watson W, Kim H. CSACI position statement:
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epinephrine auto-injectors and children < 15 kg. Allergy Asthma Clin Immunol.
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2015;11:20.
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35. Lieberman P. Proper dose of epinephrine in an infant weighing less than 15 kg:
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Which is best, automatic epinephrine injection or syringe with vial? Available at:
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https://www.aaaai.org/ask-the-expert/dose-epinephrine-infant. Accessed Mar 22, 2018.
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36. Campbell RL, Bellolio MF, Knutson BD, et al. Epinephrine in anaphylaxis: higher risk
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of cardiovascular complications and overdose after administration of intravenous bolus
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epinephrine compared with intramuscular epinephrine. J Allergy Clin Immunol Pract.
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2015;3:76-80.
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37. Kim L, Nevis IF, Tsai G, et al. Children under 15 kg with food allergy may be at risk
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of having epinephrine auto-injectors administered into bone. Allergy Asthma Clin
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Immunol. 2014;10:40-1492-10-40. eCollection 2014.
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38. Schwirtz A, Seeger H. Comparison of robustness and functionality of three
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adrenaline auto-injectors. J Asthma Allergy. 2012;5:39-49.
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39. Bewick DC, Wright NB, Pumphrey RS, Arkwright PD. Anatomic and anthropometric
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determinants of intramuscular versus subcutaneous administration in children with
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epinephrine autoinjectors. J Allergy Clin Immunol Pract. 2014;1:692-694.
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40. Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in Obesity
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Among Adults in the United States, 2005 to 2014. JAMA. 2016;315:2284-2291.
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41. Song TT, Nelson MR, Chang JH, Engler RJ, Chowdhury BA. Adequacy of the
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epinephrine autoinjector needle length in delivering epinephrine to the intramuscular
3
tissues. Ann Allergy Asthma Immunol. 2005;94:539-42.
4
42. Tsai G, Kim L, Nevis IF, et al. Auto-injector needle length may be inadequate to
5
deliver epinephrine intramuscularly in women with confirmed food allergy. Allergy
6
Asthma Clin Immunol. 2014;10:39.
7
43. Bhalla MC, Gable BD, Frey JA, Reichenbach MR, Wilber ST. Predictors of
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epinephrine autoinjector needle length inadequacy. Am J Emerg Med. 2013;31:12-
9
1671-6.
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44. Gutierrez MJ, Stout RR, Williamson D, et al. A spring-powered device for
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subcutaneous, intramuscular & intradermal injections using an auto-disable syringe.
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Drug Delivery Technology. 2009;9:18-23.
13
45. Diacono D, Pumphrey RS, Sharma V, Arkwright PD. The deep fascia of the thigh
14
forms an impenetrable barrier to fluid injected subcutaneously by autoinjectors. J Allergy
15
Clin Immunol Pract. 2015;3:2-297-9.
16
46. Edwards ES. Development of a Novel Approach to Assess Qualitative and
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Quantitative Dynamics Associated with the Subcutaneous or Intramuscular
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Administration of Pharmaceuticals and Associated Parenteral Delivery Systems. [PhD].
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Richmond, Virginia: Virginia Commonwealth University; 2011.
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47. Pumphrey RS, Gowland MH. Further fatal allergic reactions to food in the United
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Kingdom, 1999-2006. J Allergy Clin Immunol. 2007;119:1018-1019.
3
48. Rudders SA, Geyer BC, Banerji A, Phipatanakul W, Clark S, Camargo CAJ. Obesity
4
is not a risk factor for repeat epinephrine use in the treatment of anaphylaxis. J Allergy
5
Clin Immunol. 2012;130:1216-8.
6
49. Institute for Safe Medication Practices. EPINEPHrine for anaphylaxis: Autoinjector
7
or 1 mg vial or ampul? ISMP Nurse AdviseERR. 2016;14(1):1-4.
8
50. Simons FE, Edwards ES, Read EJ,Jr, Clark S, Liebelt EL. Voluntarily reported
9
unintentional injections from epinephrine auto-injectors. J Allergy Clin Immunol.
10
2010;125:419-423.e4.
11
51. Institute for Safe Medication Practices. Confusion Between EpiPen Training Device
12
and Active Pen. ISMP Medication Safety Alert! Nurse Advise-ERR. 2012;10(8):1-2.
13
52. Thompson C. No Syringe Is Approved as a Standalone Storage Container, FDA
14
Says. Available at:
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http://www.ashp.org/menu/News/PharmacyNews/NewsArticle.aspx?id=4260. Accessed
16
August 23, 2016.
17
53. Zenoni D, Priori G, Bellan C, Invernizzi RW. Stability of diluted epinephrine in
18
prefilled syringes for use in neonatology. Euro J Hosp Pharm Sci Pra. 2012;19:378-380.
19
54. American Society of Health System Pharmacists. ASHP guidelines on compounding
20
sterile preparations. Am J Health Syst Pharm. 2014;71:145-166. 28 Page 28 of 36
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55. Webb G. FDA's Lax Investigation Leads to Shipment of Contaminated Syringes.
2
Available at: http://charlottesville.legalexaminer.com/miscellaneous/fdas-lax-
3
investigation-leads-to-shipment-of-contaminated-syringes/. Accessed September 23,
4
2016.
5
56. EpiPen, Prescribing Information. Available at:
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https://www.epipen.com/en/prescribing-information/. Accessed August 5, 2016.
7
57. Capps JA, Sharma V, Arkwright PD. Prevalence, outcome and pre-hospital
8
management of anaphylaxis by first aiders and paramedical ambulance staff in
9
Manchester, UK. Resuscitation. 2010;81:653-657.
10
58. Tiyyagura GK, Arnold L, Cone DC, Langhan M. Pediatric anaphylaxis management
11
in the prehospital setting. Prehosp Emerg Care. 2014;18:46-51.
12
59. Pumphrey R. Anaphylaxis: can we tell who is at risk of a fatal reaction? Curr Opin
13
Allergy Clin Immunol. 2004;4:285-290.
14
60. Fineman SM, Bowman SH, Campbell RL, et al. Addressing barriers to emergency
15
anaphylaxis care: from emergency medical services to emergency department to
16
outpatient follow-up. Ann Allergy Asthma Immunol. 2015;115:301-305.
17
61. McLean-Tooke AP, Bethune CA, Fay AC, Spickett GP. Adrenaline in the treatment
18
of anaphylaxis: what is the evidence? BMJ. 2003;327:1332-1335.
19
29 Page 29 of 36
1 2
Figure 1: Epinephrine dose percent above and below a 0.01 mg/kg ideal, by weight at which the switch between 0.15 mg and 0.3 mg devices is made (20 kg, 25 kg or 30 kg).
3 4
Figure 2: Epinephrine dosing compared to a 0.01 mg/kg ideal, using a 4 epinephrine auto-injector (EAI) strategy versus a 2 EAI strategy.
5 6 7
Figure 3: Administration of an epinephrine auto-injector to a well-restrained infant, demonstrating how a single holder can bunch the thigh muscle during administration to increase the skin-to-bone depth.
8 9 10
Figure 4: Epinephrine 1 mg/mL vial and supply kit for anaphylaxis, prepared by the inpatient pharmacy and stocked wherever 1 mg/mL epinephrine is needed throughout the hospital.
11 12
Figure 5: Emergency Epinephrine Check-and-Inject™ Kit for Emergency Medical Service Providers.
13 14
30 Page 30 of 36
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Figure1_SwitchWeightVsIdealDose.JPG
3
31 Page 31 of 36
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Figure3_4DoseVs2DoseStrategy.JPG
3
32 Page 32 of 36
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33 Page 33 of 36
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Figure4_Restrained&BunchedThigh.jpg
2
34 Page 34 of 36
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Figure5_EpiKit.jpg
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35 Page 35 of 36
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Figure6_check&inject2image.JPG
36 Page 36 of 36
S1081-1206(18)30334-X https://doi.org/10.1016/j.anai.2018.05.001 ANAI 2544
To appear in:
Annals of Allergy, Asthma & Immunology
Received date: Revised date: Accepted date:
29-3-2018 2-5-2018 3-5-2018
Please cite this article as: Julie Brown, Epinephrine, auto-injectors and anaphylaxis: challenges of dose, depth and device, Annals of Allergy, Asthma & Immunology (2018), https://doi.org/10.1016/j.anai.2018.05.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Epinephrine, Auto-injectors and Anaphylaxis: Challenges of Dose, Depth and Device Julie Brown, MDCM, MPH Seattle Children’s Hospital and University of Washington 1 2 3 4 5 6 7 8 9 10
Julie C. Brown, MDCM, MPH, corresponding author Associate Professor, Pediatric Emergency Medicine Seattle Children's Hospital P.O. Box 5371 MB.7.528, 4800 Sandpoint Way NE, Seattle, WA 98105 206-987-4016 OFFICE 206-696-8268 CELL 206-729-3070 FAX [email protected] Conflict of Interest: none Funding source: none Clinical Trial registration: N/A Keywords: epinephrine, auto-injector, EpiPen, Auvi-Q, anaphylaxis, needle, depth, weight, obesity, intramuscular, subcutaneous, bone Abbreviations: EAI – epinephrine auto-injector, ED – emergency department, EMS – emergency medical services FDA – Food and Drug Administration, AAP – American Academy of Pediatrics Word Count: 3993 Figures: 5 Tables: none
11 12
1 Page 1 of 36
Acknowledgements: Thank you to Kristen Follmer and Thomas Agosti for their assistance with graphs and to Rebecca Watson for kindly sharing images. 1
Key Messages:
Epinephrine is the only first-line medication for the treatment of anaphylaxis, and must be readily available in the community with doses and exposed needle lengths that are optimized to best meet the needs of patients of all sizes and weights.
Optimal dosing is based on common practice, but is not well studied. There are no pharmacokinetic or pharmacodynamic data involving patients in anaphylaxis.
The recently marketed 0.1 mg EAI will be the first approved device for patients weighing 7.5-15 kg, which allows for dosing closer to the recommended 0.01 mg/kg. It will also have a shorter needle that may be more appropriate for this weight range.
The 0.15 mg epinephrine auto-injector (EAI) gives increasing less than the recommended 0.01 mg/kg dose as the patient approaches 30 kg. Data are lacking to determine if this is clinically important, but switching at 20 or 25 kg may be better than switching at 30 kg.
A higher dose EAI might better meet the needs of larger patients, but data are lacking. 2 Page 2 of 36
An EAI with a longer needle might better meet the needs of obese patients, but data are lacking.
Pre-hospital and hospital providers should review their anaphylaxis preparedness, and consider using anaphylaxis kits or pre-filled syringes when EAIs are not used.
1 2
Abstract: Objectives: 1. To review epinephrine dosing, site and route of administration, focusing on
3
special populations (patients weighing less that 15 kg, and obese patients). 2. To discuss storage and
4
delivery of epinephrine in pre-hospital and hospital settings.
5
Data Sources: Review of published literature.
6
Study Selection: Relevancy.
7
Results: The recommended 0.01 mg/kg (max 0.3-0.5 mg) epinephrine dose in anaphylaxis is based on
8
limited pharmacokinetic data in healthy volunteers. There are no pharmacokinetic or
9
pharmacodynamics studies involving patients in anaphylaxis. When epinephrine auto-injectors (EAIs) are
10
used in infants, the dose increasingly exceeds the recommended dose as weight decreases, although the
11
clinical significance is unclear. Limited data indicate that the intramuscular route and lateral thigh site
12
are superior. Ultrasound studies suggest that 0.15 EAI needles may be too long for many patients under
13
15 kg and 0.3 mg EAI needles may be too short for obese patients over 30 kg. A newly available 0.1 mg
14
EAI has a lower dose and shorter needle better suited to patients 7.5-15 kg. In some medical settings,
15
vials and syringes may provide a safe, efficient alternative with substantial cost savings over EAIs.
16
Conclusion: EAIs should be available in the community with doses and needle depths that meet the
17
needs of all patients. More research on epinephrine pharmacodynamics are needed in children and 3 Page 3 of 36
1
adults in anaphylaxis, in order to better delineate what optimal doses should be. Optimizing epinephrine
2
dose and delivery has the potential to improve anaphylaxis outcomes and prevent adverse events.
3 4
Introduction:
5
Epinephrine is a life-saving medication for the treatment of anaphylaxis.1-3
6
Epinephrine auto-injectors (EAIs) allow for reliable delivery of epinephrine during
7
allergic reactions the community setting, and must be able to deliver an effective dose
8
to an appropriate intramuscular depth, for patients of all ages, weights and sizes.4 This
9
review discusses epinephrine dosing and pharmacokinetics, the use of EAIs for patients
10
across a range of weights and skin-to-muscle and skin-to-bone distances, and issues
11
around epinephrine storage and preparation for anaphylaxis emergencies in health care
12
settings.
13 14
Epinephrine dose and route:
15
The standard Food and Drug Administration (FDA) approved dose and route for
16
epinephrine is 0.01 mg/kg intramuscularly for children 30 kg or less, with a maximum of
17
0.3 mg in children and teenagers, and 0.5 mg in adults.5 These dose recommendations
18
are extrapolated from other uses of epinephrine and are supported by scant evidence.
19
There are no pharmacodynamic studies evaluating dose-response or comparing
20
efficacy or safety with different doses of epinephrine, even in healthy subjects.6 This
4 Page 4 of 36
1
dosing strategy is, however, supported by over 40 years of clinical practice and appears
2
to work well and with an excellent safety record.7, 8
3
The pharmacokinetics of intramuscular epinephrine have only been studied in a
4
few small studies involving healthy volunteers, mostly adults.9-14 In all of these studies,
5
there is a clear peak in plasma epinephrine within minutes of intramuscular
6
administration in the lateral thigh, tapering off over 1-2 hours. In a study of 13 healthy
7
men, the increases in plasma epinephrine concentrations were much greater when
8
epinephrine was given intramuscularly in the thigh versus either subcutaneously or
9
intramuscularly in the deltoid.13 In 17 healthy children, intramuscular administration in
10
the thigh resulted in a greater increase in plasma epinephrine level versus
11
subcutaneous administration in the deltoid.11, 15 There are, however, no pharmacokinetic
12
studies involving patients in anaphylaxis, where drug pharmacokinetics might be
13
substantially different due to extravascular fluid losses and other physiologic changes.
14
There are also no true pharmacodynamic studies. In the only study approaching a dose-
15
response study, EpiPen and EpiPen Jr devices were used in 12 healthy children
16
between 15 and 30 kg, according to which device had been prescribed for them.12 Side
17
effects were more frequent and more severe in children receiving epinephrine 0.01-
18
0.014 mg/kg than in those receiving epinephrine 0.008- 0.009 mg/kg. However, the
19
study is limited by small sample size and the weight differences between those
20
receiving the two devices.
21 22 23
Epinephrine concentration
5 Page 5 of 36
1
The concentration of epinephrine typically used in anaphylaxis is 1 mg/mL,
2
formerly referred to as 1:1,000. The nomenclature was changed to improve safety
3
drawing up the dose correctly.16, 17 Ultimately, any concentration can be used that
4
delivers the dose of 0.01 mg/kg to the patient, but the 1 mg/mL concentration allows for
5
a reasonable volume for intramuscular injection. In a dire setting where only 0.1 mg/mL
6
epinephrine were available, this concentration could be used, but a large volume would
7
need to be injected. For example, in an adult patient, a 0.3 mg dose would require a 3
8
mL injection.
9 10 11
Epinephrine site of administration: Most small-dose intramuscular medications, including intramuscular
12
vaccinations, are typically given in the deltoid muscle to patients older than 2 years. 18
13
The Center for Disease Control (CDC) recommends injecting in the vastus lateralis
14
muscle for infants 12 months and younger, and for infants 1-2 years until the deltoid
15
muscle mass is adequate.18 After age 2, the deltoid muscle is preferred, although the
16
vastus lateralis may still be used. However, epinephrine use in anaphylaxis is an
17
exception, as guidelines universally recommend administration in the lateral thigh for all
18
ages.1-3 This is based on the significantly and dramatically higher mean maximum
19
plasma epinephrine concentration observed with intramuscular injection in the vastus
20
lateralis muscle versus deltoid muscle observed in Simons’ study of 13 adult men.13 It is
21
rare that such a small study would guide such widespread practice, but the results are
22
compelling, and there are no other studies which compare pharmacokinetic or
6 Page 6 of 36
1
pharmacodynamics responses with intramuscular dosing at different sites, or in other
2
populations, such as patients in anaphylaxis.
3 4 5
Epinephrine depth of administration: When epinephrine is drawn up into a syringe, the depth can be controlled by the
6
length of the injection needle and the depth to which it is injected. The Center for
7
Disease Control (CDC) recommends using a 1-inch needle for vastus lateralis muscle
8
injections in children 1 month and older.18 In adults, the CDC advises considering a 1.5
9
inch needle for deltoid injections in patients over 70 kg, and recommends this length for
10
men ≥118 kg and women ≥91 kg, but does not give similar specific guidance on needle
11
length by weight for vastus lateralis muscle injections in these patients. No other
12
specific guidance is available, including in anaphylaxis guidelines and practice
13
parameters.1-3
14 15 16
Epinephrine Repeat Dosing: Most guidelines recommend that epinephrine doses can be repeated in
17
anaphylaxis every 5 to 15 minutes, and sooner if determined to be indicated by a
18
clinician.1 The timing of repeat dosing of epinephrine is likely based on pharmacokinetic
19
studies, which typically show a peak in plasma level within 5 minutes in healthy
20
volunteers, although this has not been correlated with time to symptom resolution in
21
patients in anaphylaxis. If repeated intramuscular injections are needed, the patient
7 Page 7 of 36
1
should be placed on an epinephrine drip. Intravenous bolus epinephrine is associated
2
with an increased risk of serious adverse events, including pulmonary edema and
3
arrhythmias, and should be avoided.2
4 5 6
Epinephrine auto-injectors (EAIs): In the United States, 0.15 mg and 0.3 mg epinephrine auto-injectors (EIAs) have
7
been available since 1980. This year, a 0.1 mg dose EAI will be available for the first
8
time, from one American manufacturer.19 These limited dosing options result in making
9
compromises relative to the 0.01 mg/kg ideal dosing recommendation. The 0.15 device
10
is approved for patients 15-30 kg, and the 0.3 mg device for patients 30 kg or more. The
11
0.1 mg Auvi-Q device is approved for patients weighing 7.5-15 kg.
12
The exposed needle lengths of the three 0.15 mg EIAs marketed in the United
13
States are similar, and approximately 12-13 mm.20, 21 Estimates of exposed needle
14
lengths of the three 0.3 mg EIAs marketed in the United States vary by information
15
source but are similar, approximately 15.2 mm.20-22 The 0.1 mg Auvi-Q device has an
16
exposed needle length of 7.4mm. 23
17 18 19
EAI Dosing for Patients Weighing Less than 15 kg: Allergic reactions are common in patients weighing less than 15 kg, and
20
prescribing epinephrine for this group of patients has been challenging for allergists,
21
primary care, and emergency providers alike. In a 2002 study in Manitoba, over 2% of 8 Page 8 of 36
1
all children between 6 months and 3 years received epinephrine prescriptions.24 Given
2
normal age and weight distributions, these would be primarily children less than 15 kg. 25
3
In our urban pediatric emergency department (ED) with 38,000 annual visits, over 30%
4
of 1,178 visits for anaphylaxis between 2010 and 2017 were for patients less than 15
5
kg. The mean age of these patients was 2.5 years, range 116 days to 5.1 years.
6
Until recently, and wherever a 0.1 mg EAI is unavailable (which currently
7
includes all countries other than the United States), providers are faced with three
8
imperfect prescribing solutions for children weighing less than 15 kg. The first option is
9
to provide the family with an ampule or vial and syringe, and instructions on drawing up
10
a correct dose. A study of parents of children with food allergies showed that
11
immediately after training in an allergy clinic, and with a visual instruction card at their
12
disposal, some parents still took as long as four minutes to draw up a dose of
13
epinephrine from an ampule into a syringe, and made as high as 40-fold dosing errors,
14
even without the stress of a child in anaphylaxis.26 This approach is consequently not
15
generally recommended. The second approach is to provide the family with a pre-filled
16
syringe with the correct dose already drawn up. There is evidence that epinephrine is
17
stable and sterile in syringes for up to 3 months.27-29 However, training in correct use of
18
a needle and syringe is still required, and a safe means for carrying the syringe is
19
crucial, to ensure the plunger isn’t accidentally depressed. This is not easily
20
accomplished. There may soon be products on the market that provide a better pre-
21
filled syringe solution, with specially designed syringes and carrying containers. 30 The
22
third and most often preferred option, is to use the 0.15 mg device for infants of all
23
weights. The American Academy of Allergy Asthma and Immunology “Ask the Expert” 9 Page 9 of 36
1
web pages supports this approach.31 This is also described as recommended by the
2
Canadian Paediatric Society32 and specifically recommended European Academy of
3
Allergy and Clinical Immunology.33 The Canadian Society of Allergy and Immunology
4
recommends that given the lack of a suitable alternative, the 0.15 mg epinephrine auto-
5
injector be prescribed for infants and children weighing less than 15 kg. 34 The 2017
6
American Academy of Pediatrics clinical report acknowledged the challenge of treating
7
small children who require an epinephrine prescription and suggested that physicians
8
discuss the options and their risks and benefits with families.4
9
Using a 0.15 mg EAI off-label for children <15 kg results in doses in excess of
10
0.01 mg/kg. This problem becomes more and more pronounced the less the infant
11
weighs, with a 5 kg infant receiving 3 times the FDA recommended dose (Figure 1).
12
These higher doses have never been demonstrated to post a risk to healthy infants, and
13
clinical experience suggests that infants handle doses higher than 0.01 mg/kg quite
14
well.35 However, even appropriately administered therapeutic doses have in rare cases
15
caused serious adverse events in adults,8, 36 so until better pharmacodynamic and
16
epidemiologic information is available for children, it seems prudent to provide dosing as
17
close to FDA approved guidelines whenever possible.
18
The introduction of a 0.1 mg EAI allows for EAI dosing for infants and toddlers
19
that better approximates the ideal dose. When the 0.1 mg/kg dose is used for patients
20
weighing the minimum approved weight of 7.5 kg, the dose is 0.0133 mg/kg, which is
21
133% of the ideal 0.01 mg/kg dose. When it is used off-label for patients weighing as
22
low as 5 kg, patients will receive twice rather than three times the ideal dose (Figure 2).
10 Page 10 of 36
1 2 3
EAI Dosing for Patients Between 15 and 30 kg: Prescribing within FDA approved dosing recommendations for patients 15-30 kg
4
ensures that the patient never exceeds the recommended 0.01 mg/kg dose. However, a
5
patient using a 0.15 mg dose auto-injector will fall increasingly below 0.01 mg/kg as
6
their weight increases (Figure 1). A child who weighs 29 kg receives only 0.0052 mg/kg
7
of epinephrine, approximately half the ideal dose. For this reason, some providers
8
switch to the 0.3 mg formulation at 25 kg or even lower weights, preferring to exceed
9
this recommended dose rather than risk under-dosing their patients. A 2017 American
10
Academy of Pediatrics (AAP) clinical report states that it is appropriate to switch to the
11
0.3 mg auto-injector once a child reaches 25 kg.4 This matches earlier
12
recommendations by the AAP.15 Similarly, the Canadian Paediatric Society cites 25 kg
13
as the recommended weight for switching,32 and the European Academy of Allergy and
14
Clinical Immunology recommends switching at 25 kg.33
15 16 17
EAI Dosing for Patients Weighing > 40 kg By 40 kg, a patient using a 0.3 mg EAI receives only 77% of an 0.01 mg/kg ideal
18
dose, with decreasing percentage relative to ideal dose with increasing weight (Figure
19
2). There are no data to guide if one standard adult dose is sufficient, or if weight-based
20
dosing should continue beyond 30 kg.
21
11 Page 11 of 36
1 2
Epinephrine Depth of Delivery and Patients Weighing Less than 15 kg: When epinephrine is delivered via an EAI, the depth of medication delivery is
3
determined based on tissue compression, needle length, and propulsive forces.
4
However, compression and needle length alone determine the skin-to-bone distance:
5
after the amount of tissue compression required for EAI activation, the needle tip must
6
end before bone to allow for appropriate intramuscular delivery, and prevent needle-
7
bending and potential injuries. In small patients, the EAI needle length plus tissue
8
compression could be sufficient to place the needle tip into bone. In a study of 100
9
children less than 15 kg with food allergies, with exposed needle length defined as 12.7
10
mm, an ultrasound probe was used to provide an estimated 2-8 pounds of pressure and
11
the skin-to-bone distance was measured.37 In 29% of the children studied, and 60% of
12
children who were less than 10 kg, the skin-to-bone distance after compression
13
exceeded 12.7 mm. A 0.15 mg EAI therefore risks injection into bone in these subjects.
14
In a similar study of 51 children less than 15 kg with food allergies, needle length was
15
again defined as 12.7 mm, and a 10-lb compression was provided by an Auvi-Q-shaped
16
probe to simulate what is typically required for device activation.21 In 43.1% of subjects,
17
the device would be expected to strike bone. Pen-shaped 0.15 mg EAI devices, which
18
have similar needle lengths and activation forces acting on an even more localized
19
area,20 would be expected to have similar results. While these studies raise theoretical
20
concerns about the effectiveness and safety of current 0.15 mg EAI device use in
21
children weighing under 15 kg, there are no reports in the literature of adverse events
22
attributed to needle depth in patients less than 15 kg, despite frequent off-label use.
23
Perhaps users take steps to mitigate the potential for injection into bone, such as 12 Page 12 of 36
1
bunching the thigh muscle during injection, to increase the skin-to-bone distance (Figure
2
3).
3
None of the patients in the above studies would risk injection into bone with the
4
7.4 mm exposed needle length that is in a 0.1 mg Auvi-Q device, after accounting for
5
tissue compression. Estimating from a graph, in about 16% of patients, the skin-to-
6
muscle distance would exceed this needle length, after compression, by 0.1-1.8 mm.21
7
However, drug delivery to muscle also depends on propulsion, which was not
8
considered in these studies. The high pressure EAIs marketed in the United States fire
9
epinephrine with significant propulsive force which delivers the medication well beyond
10
the needle tip.22, 38 Propulsive forces would probably be sufficient to deliver epinephrine
11
the small additional distance to muscle in these patients.
12 13 14
Epinephrine Depth of Delivery in Children and Adults Weighing 15 kg or more: There are two ultrasound studies considering depth of medication delivery in
15
children 15 kg or more. In a study of 100 children weighing 15-30 kg (group 1) and >30
16
kg (group 2), an ultrasound probe was used to “simulate the pressure required to trigger
17
a high pressure EAI” and the skin-to-bone distance was measured.22 The exposed
18
needle length was defined as 12.7 mm for group 1 and 15.2 mm for group 2. In group 1,
19
11% of the children were at risk of injection into bone using an 0.15 mg EIA, and 1%
20
would be expected to inject subcutaneously. In group 2, 3% of the children were at risk
21
of injection into bone using an 0.3 mg EIA, and 9% would be expected to inject
22
subcutaneously. In another study of 93 children ages 1-16 with food allergies, the 13 Page 13 of 36
1
exposed needle length was defined as 12.7 mm for children <30 kg and 15.9 mm for
2
children >30kg. Overall, 20% of these children (approximately 13% of healthy weight
3
children and 47% of obese children), had a skin-to-muscle greater than the needle
4
length at the mid-thigh, but this did not account for tissue compression.39 Neither of
5
these two studies considered propulsion, which might allow for increased delivery to
6
muscle for those subjects where the needle tip would end subcutaneously.
7
The chance of subcutaneous injection is likely to increase in adulthood. In North
8
America 38% of adults are obese: 7.7% of men and 9.9% of women are morbidly
9
obese.40 Based on a study of 50 men and 50 women with CT thigh images, 2% of the
10
men and 28% of the women had a skin-to-muscle distance that exceeded 14.3 mm (the
11
defined exposed needle length of EpiPen in this study), after accounting for 8-lb tissue
12
compression.41 In a similar study of 50 men and 50 women with food allergies who were
13
prescribed an EAI, ultrasound was used to measure skin-to-muscle distance with
14
compression.42 With 8 pounds of compression, 28% of women and none of the men
15
had a distance greater than 15.2 mm (the defined exposed needle length of EpiPen in
16
this study). Finally, in a study of 60 males and 60 females visiting an
17
ED, with compression “mimicking the pressure provided with proper auto-injection”,
18
28% of women and none of the men had a distance greater than 15.9 mm (the exposed
19
needle length of the longest available auto-injector at the time of this study).43
20
The results of these ultrasound studies, however, do not necessary indicate that
21
drug delivery will not be intramuscular in these patients, because the propulsive forces
22
of EAIs provide additional benefit in helping the medication reach the intramuscular
23
space beyond the needle tip. Propulsion is clearly capable of delivering medications to 14 Page 14 of 36
1
the intramuscular space, as evidenced by needle free intramuscular injection devices
2
that rely on propulsive forces alone.44 Although in vitro studies in pork tissue suggest
3
that fascia may act as a barrier to the movement of drugs from the subcutaneous tissue
4
into muscle,45 in vivo studies demonstrate extensive movement of molecules similar in
5
size to epinephrine through fascia.46
6
Clinical information on the use of epinephrine in obese patients is limited. In
7
studies of patients with fatal anaphylaxis, auto-injectors were felt to be of insufficient
8
depth to reach muscle in at least some cases, but the role this may have played in the
9
lethal outcome is unclear.47 In a study of 321 patients presenting to the ED for food
10
allergy or stinging insect allergic reactions, the 69 obese patients were no more likely to
11
receive 2 or more doses of epinephrine than their normal weight or under-weight
12
peers.48 However, the majority of these subjects were children, where the skin-to-bone
13
distances may have been smaller despite obesity. Results were reported to be similar
14
when the 60 adults were evaluated separately, but the number of obese adults in this
15
subset may not have been sufficient to answer this question well.
16 17 18
Storage of Epinephrine in Health Care Environments: In health care environments, epinephrine can be stored in auto-injectors, in vials
19
or ampules and drawn up when needed, or in pre-filled syringes. Each approach has
20
advantages and disadvantages. Storage in auto-injectors provides potentially the fastest
21
option in the hands of competent users, and prevents erroneous intravenous
22
epinephrine use in an anaphylactic emergencies.49 However, this approach is 15 Page 15 of 36
1
expensive and limits dosing options. In addition, even when used by medical providers,
2
there have been many reported injuries, primarily involving upside-down use of EpiPen
3
devices resulting in thumb injections and failed patient drug administration.50 In a review
4
of 105 unintentional injections from EAIs reported to the Food and Drug Administration
5
Adverse Event Reporting System, more than one third of the individuals injected were
6
health care professionals. Finally, after a change in packaging resulted in EpiPens
7
being sold to hospitals in pairs along with similar looking trainers, reports emerged of
8
hospitals mistaking trainers for devices, and providers attempting to use a trainer when
9
a real device was needed.51
10
A second approach is to stock vials or ampules and draw up the appropriate
11
weight-based dose when needed.49 In a simulation study in our ED evaluating nurse
12
administration of epinephrine to a simulated anaphylaxis patient, we observed
13
difficulties in gathering supplies efficiently, and drawing up medication using ampules
14
and filter straws. This prompted us to switch to using epinephrine kits that are easier
15
and faster to use. These kits contain an epinephrine vial, a vial-access needle, a 1-inch
16
25-gauge needle, alcohol swabs, gauze and a bandage (Figure 4). The switch to a vial
17
eliminates the need for a filter straw which was difficult to use with a 1 mL syringe. The
18
kits are regularly prepared and distributed by our inpatient pharmacy and stocked in
19
medication dispensing areas and crash carts throughout the hospital. An important
20
safety adjunct to this effort is the use of a weight-based code sheet, which readily
21
identifies the correct concentration, dose and volume of medication that should be given
22
to the patient.
16 Page 16 of 36
1
A variation of the vial and syringe approach, which is gaining traction in pre-
2
hospital care around the country, is to use a kit that limits dosing to two EAI doses, 0.15
3
and 0.3 mg. This simplifies training of emergency medical service providers and aims to
4
improve speed of administration and minimize errors. The Check-and-Inject™ kit
5
developed by the King County Emergency Medical Services (EMS) system, was
6
implemented along with extensive training of all EMS providers in recognition and
7
treatment of anaphylaxis, including quarterly hands-on training drawing up medications
8
with verification and certification of competency (Figure 5).44 This program has saved an
9
estimated $334,000 annually in medication costs for the county’s EMS system, while
10 11
maintaining access to epinephrine on all EMS vehicles in the county. A third approach, rarely used, is to stock pre-filled syringes in medical areas.
12
There are currently no epinephrine prefilled syringes that have been FDA-approved for
13
clinical use.52 In most pediatric environments, this would require a range of dosing
14
options and complex pharmacy procedures to be effective. However, this process has
15
been reported in some environments, such as neonatal intensive care. 53 This might also
16
be a practical approach prior to administration of high-risk chemotherapeutics, or the
17
administration of contrast dyes in patients known to be at risk. While there are United
18
States Pharmacopeia standards for compounded medications allowing only 1-3 days of
19
storage after compounding,54 there is no guidance specific to non-compounded
20
medications intended for intramuscular use. While medications stored in syringes can
21
cause infections when delivered intravenously,55 the risk with intramuscular injection is
22
likely very low, although a Clostridial infection following an EpiPen injection in a thigh
23
has been reported.56 17 Page 17 of 36
1 2
Discussion:
3 4
Despite lacking pharmacokinetic data and limited EAI dose and needle length
5
options, epinephrine has nevertheless demonstrated a long track record of safe and
6
effective treatment for anaphylaxis. No long-term serious adverse advents have been
7
reported with the correct-dose intramuscular use of epinephrine in children. Adverse
8
events in adults are rare.60 Most reported adverse events either involve significant
9
overdosing or intravenous bolus dosing.36, 61 Despite this, and despite being the only
10
medication that plays a significant role in management of anaphylaxis, 1-3 epinephrine is
11
frequently under-utilized in community, pre-hospital and emergency settings.57-60 Many
12
more anaphylaxis deaths are associated with delayed use of epinephrine, or incorrect
13
actions while in anaphylaxis, such as being propped up while unconscious or rapidly
14
raised to a standing position.59
15
The arrival of a new lower-dose shorter-need EAI on the market will allow for
16
better tailoring of an EAI to match young childrens’ needs. Pediatric patients deserve
17
this equal attention to their health and safety. Perhaps it will also encourage
18
conversations between providers and parents about the early epinephrine use in
19
anaphylaxis in general, thereby decreasing parental reluctance to use an EAI when their
20
child needs it, regardless of device. It could similarly ignite interest by EMS or
21
emergency providers, perhaps leading to increased awareness and familiarity with all of
22
the epinephrine auto-injector options available in the community.
23 18 Page 18 of 36
1
Conclusion:
2 3
Epinephrine is a critical medication for the treatment of anaphylaxis. EAIs should
4
be available in the community with doses and exposed needle lengths that are
5
optimized to best meet the needs of patients of all sizes and weights. More research on
6
epinephrine pharmacodynamics is needed, ideally involving both children and adults in
7
anaphylaxis, in order to better delineate what optimal doses should be. Optimizing the
8
dose of epinephrine and ensuring its delivery to the optimal body location has the
9
potential to improve anaphylaxis outcomes and prevent adverse events. Better
10
information would allow the large and growing allergy community to be better and more
11
safely served in the community and health care settings. The ideal means for storing
12
and delivering epinephrine in pre-hospital and hospital environments warrants further
13
study to determine how to best balance efficiency, patient safety, provider safety, and
14
health care costs.
15 16 17 18 19
Editorial Addendum : The product “Auvi-Q 0.1mg” listed in this manuscript as in development was
20
approved for commercial use in the USA on May 1, 2018.
21
19 Page 19 of 36
1
20 Page 20 of 36
1
References:
2
1. Campbell RL, Li JT, Nicklas RA, Sadosty AT. Emergency department diagnosis and
3
treatment of anaphylaxis: a practice parameter. Ann Allergy Asthma Immunol.
4
2014;113:599-608.
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2. Lieberman P, Nicklas R, Oppenheimer J, Kemp S, Lang D. The Diagnosis and
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Management of Anaphylaxis Practice Parameter: 2010 Update. J Allergy Clin Immunol.
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2010;126:477-477-480.
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3. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, et al.
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Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma and
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Immunology Epidemiology of Anaphylaxis Working Group. Ann Allergy Asthma
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Immunol. 2006;97:596-602.
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4. Sicherer SH, Simons FER, SECTION ON ALLERGY AND IMMUNOLOGY.
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Epinephrine for First-aid Management of Anaphylaxis. Pediatrics.
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2017;139:10.1542/peds.2016-4006. Epub 2017 Feb 13.
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5. Epinephrine Injection USP, 1 mg/mL (1:1,000), Prescribing Information. Available at:
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http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/205029s004lbl.pdf.
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6. Lieberman P. The 10-second rule and other myths about epinephrine and
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7. Lieberman P. Epinephrine Dosing. Available at: http://www.aaaai.org/ask-the-
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8. Wood JP, Traub SJ, Lipinski C. Safety of epinephrine for anaphylaxis in the
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emergency setting. World J Emerg Med. 2013;4:245-251.
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9. Edwards ES. Bioavailability of Auvi-Q and EpiPen: Focus on Pharmacokinetics. Clin
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Pediatr (Phila). 2013;52:890.
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10. Edwards ES, Gunn R, Simons ER, et al. Bioavailability of epinephrine from Auvi-Q
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compared with EpiPen. Ann Allergy Asthma Immunol. 2013;111:132-137.
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11. Simons FE, Roberts JR, Gu X, Simons KJ. Epinephrine absorption in children with a
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history of anaphylaxis. J Allergy Clin Immunol. 1998;101:33-37.
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12. Simons FE, Gu X, Silver NA, Simons KJ. EpiPen Jr versus EpiPen in young children
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weighing 15 to 30 kg at risk for anaphylaxis. J Allergy Clin Immunol. 2002;109:171-175.
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13. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular
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versus subcutaneous injection. J Allergy Clin Immunol. 2001;108:871-873.
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14. Rackley R, Lawrence T, Li H, Liu S, Elder M. Auvi-Q® Versus EpiPen® Auto-
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15. Sicherer SH, Simons FE, Section on Allergy and Immunology, American Academy
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16. Institute for Safe Medication Practices. Farewell to ratio expressions on single entity
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17. Wheeler DW, Carter JJ, Murray LJ, et al. The effect of drug concentration
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19. kaleo. U.S. FDA Grants Priority Review for an Epinephrine Auto-Injector in
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21. Kim H, Dinakar C, McInnis P, et al. Inadequacy of current pediatric epinephrine
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autoinjector needle length for use in infants and toddlers. Ann Allergy Asthma Immunol.
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2017;118:719-725.e1.
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22. Dreborg S, Wen X, Kim L, et al. Do epinephrine auto-injectors have an unsuitable
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needle length in children and adolescents at risk for anaphylaxis from food allergy?
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Allergy Asthma Clin Immunol. 2016;12:11-016-0110-8. eCollection 2016.
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24. Simons FE, Peterson S, Black CD. Epinephrine dispensing patterns for an out-of-
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hospital population: a novel approach to studying the epidemiology of anaphylaxis. J
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Allergy Clin Immunol. 2002;110:647-651.
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25. Centers for Disease Control and Prevention. Data Table of Weight-for-age Charts.
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5, 2016.
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26. Simons FE, Chan ES, Gu X, Simons KJ. Epinephrine for the out-of-hospital (first-
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aid) treatment of anaphylaxis in infants: is the ampule/syringe/needle method practical?
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J Allergy Clin Immunol. 2001;108:1040-1044.
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27. Kerddonfak S, Manuyakorn W, Kamchaisatian W, Sasisakulporn C,
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Teawsomboonkit W, Benjaponpitak S. The stability and sterility of epinephrine prefilled
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syringe. Asian Pac J Allergy Immunol. 2010;28:53-57.
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28. Rawas-Qalaji M, Simons FE, Collins D, Simons KJ. Long-term stability of
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epinephrine dispensed in unsealed syringes for the first-aid treatment of anaphylaxis.
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Ann Allergy Asthma Immunol. 2009;102:500-503.
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29. Zenoni D, Priori G, Bellan C, Invernizzi RW. Stability of diluted epinephrine in
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prefilled syringes for use in neonatology. European Journal of Hospital Pharmacy.
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2012;19:378-380.
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30. AllergyStop. Available at: http://www.allergystopnow.com/. Accessed 06/01, 2016.
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31. Lieberman P. Use of an automatic epinephrine injector (Junior) versus epinephrine
12
drawn from a syringe in a 9 month-old weighing 18.5 pounds. Available at:
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http://www.aaaai.org/ask-the-expert/use-of-automatic-epinephrine-injector. Accessed
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03/06, 2018.
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32. Cheng A. Emergency treatment of anaphylaxis in infants and children. Paediatr
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Child Health. 2011;16:35-40.
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33. Muraro A, Roberts G, Worm M, et al. Anaphylaxis: guidelines from the European
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34. Halbrich M, Mack DP, Carr S, Watson W, Kim H. CSACI position statement:
2
epinephrine auto-injectors and children < 15 kg. Allergy Asthma Clin Immunol.
3
2015;11:20.
4
35. Lieberman P. Proper dose of epinephrine in an infant weighing less than 15 kg:
5
Which is best, automatic epinephrine injection or syringe with vial? Available at:
6
https://www.aaaai.org/ask-the-expert/dose-epinephrine-infant. Accessed Mar 22, 2018.
7
36. Campbell RL, Bellolio MF, Knutson BD, et al. Epinephrine in anaphylaxis: higher risk
8
of cardiovascular complications and overdose after administration of intravenous bolus
9
epinephrine compared with intramuscular epinephrine. J Allergy Clin Immunol Pract.
10
2015;3:76-80.
11
37. Kim L, Nevis IF, Tsai G, et al. Children under 15 kg with food allergy may be at risk
12
of having epinephrine auto-injectors administered into bone. Allergy Asthma Clin
13
Immunol. 2014;10:40-1492-10-40. eCollection 2014.
14
38. Schwirtz A, Seeger H. Comparison of robustness and functionality of three
15
adrenaline auto-injectors. J Asthma Allergy. 2012;5:39-49.
16
39. Bewick DC, Wright NB, Pumphrey RS, Arkwright PD. Anatomic and anthropometric
17
determinants of intramuscular versus subcutaneous administration in children with
18
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45. Diacono D, Pumphrey RS, Sharma V, Arkwright PD. The deep fascia of the thigh
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Figure 1: Epinephrine dose percent above and below a 0.01 mg/kg ideal, by weight at which the switch between 0.15 mg and 0.3 mg devices is made (20 kg, 25 kg or 30 kg).
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Figure 2: Epinephrine dosing compared to a 0.01 mg/kg ideal, using a 4 epinephrine auto-injector (EAI) strategy versus a 2 EAI strategy.
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Figure 3: Administration of an epinephrine auto-injector to a well-restrained infant, demonstrating how a single holder can bunch the thigh muscle during administration to increase the skin-to-bone depth.
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Figure 4: Epinephrine 1 mg/mL vial and supply kit for anaphylaxis, prepared by the inpatient pharmacy and stocked wherever 1 mg/mL epinephrine is needed throughout the hospital.
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Figure 5: Emergency Epinephrine Check-and-Inject™ Kit for Emergency Medical Service Providers.
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Figure1_SwitchWeightVsIdealDose.JPG
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Figure3_4DoseVs2DoseStrategy.JPG
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Figure4_Restrained&BunchedThigh.jpg
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Figure5_EpiKit.jpg
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Figure6_check&inject2image.JPG
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