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Three Part Question

Should [children with allergies] carry [more than one adrenaline autoinjector] in case of [anaphylactic reaction]?

Clinical Scenario

You treat a 7 year old girl in paediatric A&E for anaphylactic shock after eating peanuts to which she is allergic. Her mother had used her Epipen before the ambulance arrived, however the symptoms did not improve. The child subsequently received more adrenaline, steroids and antihistamine in the department. You wonder if the child should have two Epipens with them which can be used in an emergency?

Search Strategy

Medline 1946 to June Week 1 2013
EMBASE 1980 to 2013 Week 26

“((exp hypersensitivity/) OR (exp anaphylaxis/) OR (anaphyla$.mp) OR (allerg$.mp) OR (acute ADJ allergic ADJ reaction)) AND ((exp epinephrine/) OR (exp self, administration/) OR (exp injections, intramuscular/) OR (adrenalin$.mp) OR (autoinjector.mp) OR (auto-injector.mp) OR (epipen.mp) OR (auvi-q.mp) OR (JEXT.mp) OR (IM.mp) OR (intramuscular$.mp)) AND (exp drug administration schedule/) OR (‘epinephrine/ad [Administration& Dosage]) OR (multiple.mp) OR (repeat.mp) OR (double.mp) OR (two ADJ doses.mp) OR (2 ADJ doses.mp)
Limits – Humans, English Language, Children 0-18 years

Search Outcome

861 papers in total, of which 9 were relevant

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Rudders, SA et al 2010 USA	315 eligible paediatric admissions for allergy and anaphylaxis based on ICD9 codes collected over a 5-year period.	Large scale, multicentre medical chart review	M adrenaline is received in anaphylactic reactions before arrival in PED.	31% of patients received one dose of IM adrenaline before PED arrival 3% of patients received two or more doses of IM adrenaline before PED arrival	No mention of the AAI dose used – possible if a lower dose was used (0.15mg) then heavier children (those >10years) may have been under dosed.
			IM adrenaline is received in anaphylactic reactions.	44% of anaphylactic reactions received adrenaline, 12% received more than one dose.
			Older children are more likely to received more than one dose of adrenaline	Patients greater than 10 years old (p=0.01) and those treated at an outside hospital before transfer to the tertiary centre (p=0.002) were more likely to receive one dose Patients who owned an AAI were not statistically more likely to receive more than one dose.
Jarvinen, KM et al 2009 USA	436 positive paediatric oral food challenges performed in a tertiary allergy centre identified using online database search.	Retrospective electronic case note review	IM adrenaline is used for serious reactions	50 children were treated with adrenaline 3 (0.06%) children received 2 doses of adrenaline	Small sample size No analysis of the one dose and two dose groups
			Older children were more likely to receive adrenaline than younger children	Adrenaline group were significantly older than those not treated p<0.001.
Jarvinen, KM et al. 2008 USA	413 questionnaires given to parents of consecutive children (up to the age of 18) presenting for an initial or follow up appointment to hospital based allergy clinic over a 6-month period.	Self reported questionnaire cross sectional study.	A small number of children require two doses of IM adrenaline	211 parents reported a history of anaphylaxis, only 20% parents used an AAI. In total 95 reactions had been treated with adrenaline, 81% received a single dose, 19% received multiple dose.	Self report questionnaire – recall bias
			Past medical history of asthma is associated with increased doses of adrenaline	Children in the multiple dose group had asthma than those in the one dose group, p=0.005.
			Children with more severe symptoms are more likely to receive multiple doses	Symptoms of throat closure were associated with multiple doses of adrenaline
			Requirement for multiple doses is not associated with a delay in the first dose of adrenaline.	Children in the multiple dose groups received their first dose of adrenaline sooner than the single dose group.
			After multiple doses of adrenaline, hospital admission is required.	Children who had received multiple doses were observed in the hospital longer than those who received only one dose, p=0.003
Manivannan, V. 2009 USA	All patients presenting to two ED and all other health care providers in Minnesota.	Population based retrospective cohort study	IM adrenaline is used for serious reactions.	208 cases of anaphylaxis were identified 104 anaphylactic cases received adrenaline – of which 27 (13%) received more than one dose. The 2nd dose of adrenaline was provided by a healthcare professional in 100% of cases	Retrospective study – may have missed cases.
			Those receiving two doses were significantly younger than the one dose group	The two dose group were significantly younger than the one dose group, p=0.06.
			Those receiving two doses require hospital admission	Number of hospital admissions was significantly greater in the two dose group (48.1% vs 15.6% of one dose group), p=0.001.
			More respiratory and cardiovascular symptoms were seen in two dose group	Those in the two dose group were more likely to have wheezing symptoms (p=0.003), cyanosis (p=0.001) or hypotension (p=0.03)
Huang, F et al 2012 USA	213 paediatric patients who had presented to the PED of tertiary centre anaphylaxis using ICD9.	Retrospective, single centre electronic case note review	IM adrenaline is given for serious reactions	13 (6%) children received more than one dose of adrenaline
			Hospitalisation more likely for the two-dose group.	9 of 13 in the multiple dose groups were hospitalised compared with 18 of 156 in the single dose group, p<0.001. Children with two doses are more likely to be admitted to intensive case, p<0.0001 However if the two doses were given before arrival in PED patients were less likely to be admitted than those who had both or one of the doses administered by PED staff, p<0.05.
Rudder, SA et al. USA 2010	All patients presenting to 3 major ED’s with stinging insect hypersensitivity – from ICD9 codes over a 6-year period.	Large multicentre retrospective medical record study.	More than one dose of IM adrenaline is used in some allergic reactions.	152 patients met the ICD9 criteria, 26% of which had symptoms of anaphylaxis. 16% of patients received 2 doses of adrenaline – all before arrival at ED.	No analysis of the outcomes for the one dose and two dose groups.
Arkwright PD. 2009 UK	All children presenting to a specialist paediatric allergy outpatient clinic who had an AAI prescribed.	Single centre, retrospective case note study	Ownership of AAI devices	298 children were included, 282 had more than one device	Only food allergic children. Not clear if the devices were held in the same location or for different locations (e.g. home and school)
			Use of multiple doses	% of children had received multiple doses of adrenaline . 18 parents had used the device, however no parents had used 2 devices for the same reaction.
Kelso, JM. 2006 USA	All Children attending allergy clinic for allergy injections over a 5 year period (n=9592)	Single centre, retrospective case notes study.	More than one dose of IM adrenaline is used in some allergic reactions	64 (0.67%) children required adrenaline, 54 received one dose, 8 (13%) received two doses and 2 (3%) children received 3 doses for their symptoms.	SC injections used from 2000-2002 and then a mixture of SC and IM from 2003-2004 – known not to be the more effective result for adrenaline.
			No difference between the one and greater than one dose groups	No significant difference between one and greater than one dose groups.

Comment(s)

Eight of the above studies found patients requiring more than one dose of adrenaline during anaphylaxis, ranging from 0.08% 68to 35% 67 of all anaphylactic cases. Two studies found those who received multiple doses were significantly older than the one-dose groups, p=0.0161 and p<0.00168. The strength of the AAI used in these paper is not clear, for those between the weights of 15-30kg 58 (more likely in older children), the junior 0.15mg AAI may be insufficient so multiple doses may be required to appropriately control symptoms. Manivannen et al contradicted the previous studies, they found that those in the multiple dose group were significantly younger than those in one dose group, p=0.06. Of note, this paper included both adult and paediatric patients hence the wider age range which may have affected the results. Manivannen believes ED doctors may be confident to administer multiple doses to younger patients, however may be more wary with older patients with increased cardiovascular risk factors. Age was not the only significant difference found between the groups, Jarvinen found asthmatic children were more likely to receive multiple doses of adrenaline, p=0.005. It could be that atopic children will suffer with more severe symptoms and this severity requires more adrenaline to control. It has been previously noted that delay in administration of adrenaline can lead to death, both Jarvinen studies noted the time between initial onset of symptoms and first dose of adrenaline was significantly shorter in the multiple dose group, suggesting that a large time lag does not lead to multiple doses. It is thought the severity of the symptoms is worse, therefore the AAI is used more readily and due to the severity of the symptoms more adrenaline is used in hospital. Across all 7 of the studies only 6% of 2nd adrenaline doses were provided by parents or patients, it is unclear if this is because patients/parents tend to carry only one device or if they were unwilling to use a second device even if one was available. Rates of hospital admission are much higher after multiple doses of adrenaline, although this is attributed to the severity of the anaphylactic symptoms rather than a consequence of greater amounts of adrenaline. From the studies available it appears there is a small subset of anaphylactic patients who will require multiple doses of adrenaline, however currently paramedics or emergency departments often provide this dose. Some authors have called for patients to be instructed to carry two AAI devices with them at all times, however it is well known that many patients/parents do not even carry one device with them and expecting them to carry two may be unreasonable. Along with the extra cost of prescribing and the ready availability of emergency medical care across the majority of the UK, the need for each patient to carry two devices is low.

Clinical Bottom Line

Although some patients will require multiple doses of adrenaline, healthcare professionals in emergency departments can provide this. Expecting patients to carry two AAI’s at all times is unreasonable and unnecessary.

References

1. Rudders SA, Banerji A, Corel B, Clark S, Camargo CA. Multicenter Study of Repeat Epinephrine Treatments for Food-Related Anaphylaxis Pediatrics 2010;125(4):e711-e8.
2. Järvinen KM, Amalanayagam S, Shreffler WG, Noone S, Sicherer SH, Sampson HA, et al. Epinephrine treatment is infrequent and biphasic reactions are rare in food-induced reactions during oral food challenges in children. Journal of Allergy and Clinical Immunology 2009;124(6):1267-72.
3. Järvinen KM, Sicherer SH, Sampson HA, Nowak-Wegrzyn A. Use of multiple doses of epinephrine in food-induced anaphylaxis in children J Allergy Clin Immunol 2008;122(1):133-8.
4. Manivannan V, Campbell RL, Bellolio MF, Stead LG, Li JT, Decker WW. Factors associated with repeated use of epinephrine for the treatment of anaphylaxis Ann Allergy Asthma Immunol 2009;103(5):395-40
5. Huang F, Chawla K, Järvinen KM, Nowak-Węgrzyn A. Anaphylaxis in a New York City pediatric emergency department: triggers, treatments, and outcomes J Allergy Clin Immunol. 2012;129(1):162-8.e1-3.
6. Rudders SA, Banerji A, Katzman DP, Clark S, Camargo Jr CA. Multiple epinephrine doses for stinging insect hypersensitivity reactions treated in the emergency department. Annals of Allergy, Asthma & Immunology. 2010;105(1):85-93.
7. Arkwright PD. Automatic epinephrine device use in children with food allergies Journal of Allergy and Clinical Immunology 2009;123(1):267-8.
8. Kelso JM. A second dose of epinephrine for anaphylaxis: how often needed and how to carry. J Allergy Clin Immunol 2006;117(2):464-5.