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Published in final edited form as:

J Allergy Clin Immunol Pract. 2023 July ; 11(7): 2043–2048. doi:10.1016/j.jaip.2023.04.037.

Refractory Anaphylaxis: A New Entity for Severe Anaphylaxis

Guillaume Pouessel, MDa,b, Antoine Deschildre, MDb, Timothy E. Dribin, MDc, Ignacio
J. Ansotegui, MD, PhDd, Victoria Cardona, MD, PhDe, R. Sharon Chinthrajah, MD, PhDf,
Motohiro Ebisawa, MD, PhDg, Antonella Muraro, MD, PhDh, Graham Roberts, DMi, Hugh A.
Sampson, MDj, Susan Waserman, MD, FRCPCk, Robert A. Wood, MDl, Margitta Worm, MDm,
Paul J. Turner, FRCPCH, PhDn
aDepartment of Pediatrics, Children’s Hospital, Roubaix, France
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bPediatric Pulmonology and Allergy Department, Hospital Jeanne de Flandre, CHU Lille, Lille,
France
cDivision of Emergency Medicine, Cincinnati Children’s Hospital Medical Center, Department of
Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
dDepartment of Allergy and Immunology, Hospital Quironsalud Bizkaia, Bilbao, Spain
eAllergySection, Department of Internal Medicine, Hospital Vall d’Hebron, and ARADyAL
research network, Barcelona, Spain
fSean N. Parker Center for Allergy and Asthma Research at Stanford University, Division of
Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, Stanford,
Calif
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gNational Hospital Organization Sagamihara National Hospital, Sagamihara, Japan

hFood Allergy Centre Padua University Hospital, Padua, Italy
iDepartment of Medicine, University of Southampton, Southampton, UK, NIHR Southampton
Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust,
Southampton, David Hide Asthma and Allergy Centre, St. Mary’s Hospital, Isle of Wight, UK
jIcahn School of Medicine at Mount Sinai, New York, NY
kDivisionof Clinical Immunology and Allergy, Department of Medicine, McMaster University,
Hamilton, Ont, Canada
lDivision
of Pediatric Allergy, Immunology, and Rheumatology, Department of Pediatrics, Johns
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Hopkins University School of Medicine, Baltimore, Md

mDivision
of Allergy and Immunology, Department of Dermatology, Venerology and Allergology,
Charité—Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany
nNational Heart & Lung Institute, Imperial College London, London, UK

Abstract

Corresponding author: Guillaume Pouessel, MD, Department of Paediatrics, CH Roubaix, Boulevard Lacordaire, F-59056 Roubaix,
France. [email protected]. 2213-2198.
 Pouessel et al. Page 2

Anaphylaxis reactions lie on a spectrum of severity, ranging from relatively mild lower respiratory
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involvement (depending on the definition of anaphylaxis used) to more severe reactions that
are refractory to initial treatment with epinephrine and may rarely cause death. A variety of
grading scales exist to characterize severe reactions, but there is a lack of consensus about the
optimal approach to define severity. More recently, a new entity called refractory anaphylaxis
(RA) has emerged in the literature, characterized by the persistence of anaphylaxis despite initial
epinephrine treatment. However, slightly different definitions have been proposed to date. In this
Rostrum, we review these definitions as well as data relating to epidemiology, elicitors, risk
factors, and management of RA. We propose a need to align the different definitions for RA, to
improve epidemiological surveillance, advance our understanding of the pathophysiology of RA,
and optimize management strategies to reduce morbidity and mortality.

Keywords
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Food allergy; Anaphylaxis; Epinephrine; Auto-injector; Emergency management; Intensive care;

Refractory

Anaphylaxis is described by the World Allergy Organization as “a serious systemic

hypersensitivity reaction that is usually rapid in onset and may cause death. Severe
anaphylaxis is characterized by potentially life-threatening compromise in airway, breathing,
and/or the circulation, and may occur without typical skin features or circulatory shock
being present.”1 It is the most severe clinical presentation of acute systemic allergic
reactions, but evidence suggests that the majority of less severe anaphylaxis reactions
resolve spontaneously without treatment.2–4 Significant underuse of epinephrine to treat
anaphylaxis in medical settings and the community is well documented.2 Large case
series, including the European Anaphylaxis Registry (Network for Online Registration of
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Anaphylaxis [NORA]), report that only less than 20% of anaphylaxis reactions are treated
with epinephrine.3,4 Despite this, fatal anaphylaxis remains a very rare event with a fatality
rate ranging from 0.5 to 1 death/million person-years.5,6 Consistent with these data, a recent
systematic review and meta-analysis found that around 90% of anaphylaxis events respond
to a single dose of epinephrine.6

However, 2% to 3% of anaphylaxis reactions do not respond to 2 epinephrine doses,6

and these reactions are unpredictable. Our current inability to identify those at greatest
risk of more severe reactions remains one of the biggest evidence gaps in allergy.7,8 One
contributory factor is the wide variation in how best to define severity, with different
definitions used in the literature and even inconsistency in applying the same severity
grading system by different authors.9,10 Work in this area is often focused on fatal
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anaphylaxis, perhaps because there is no question over severity with respect to these tragic
events. However, it is difficult to identify predictors of fatal reactions because fatalities
are very rare and details often lacking in terms of the circumstances leading up to the
fatal event.5,11,12 Near-fatal anaphylaxis should be an easier entity in terms of identifying
potential risk factors because it is more common and easier to investigate (owing to the
ability to capture accurate data about the reaction onset [triggers, risk factors], treatment, and
progression). However, there is a paucity of data on near-fatal anaphylaxis. Among 3,510

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anaphylaxis cases documented in the Allergy-Vigilance Network (2002–2022), there were

45 near-fatal events and 25 fatalities.13 In the United Kingdom, intensive care unit (ICU)
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admissions for food anaphylaxis are almost 10 times higher than fatal food anaphylaxis.14
However, ICU admission is not synonymous with near-fatal anaphylaxis. In the United
States, Motosue et al15 reported an ICU admission rate of 5.3% among 38,695 patients of all
ages seen in emergency departments for food anaphylaxis (2005–2014); 2,057 (5.3%) were
admitted to the ICU, but only 174 (0.45%) were classified as having a near-fatal episode.
Ramsey et al16 described 1,989 children admitted between 2010 and 2015 to 131 ICUs in
North America with anaphylaxis, of whom 1,631 had a primary diagnosis of anaphylaxis;
only 5% had hypotension and 19% required intubation, which in the context of a median
admission duration of 19 hours, implies that the majority were admitted for observation
rather than critical care management. Similarly, the discord between ICU admission and
reaction severity was documented in a case series of 166 children admitted to an ICU in
France (2003–2013),17 where a quarter of cases were only categorized as grade 2 reactions
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(according to Ring and Messmer classification, ie, nonsevere anaphylaxis), and only 52 of
134 (39%, data missing for 32 cases) were treated with 3 or more doses of adrenaline.18

Whereas any epinephrine is not a good indicator of severity,2 there is increasing recognition
that a sub-optimal response to epinephrine when given appropriately at onset of anaphylaxis
can be a useful indicator of severity.19–22 Arguably, this circumvents the issues over what
symptoms constitute a severe reaction and how these might be assigned a severity grade
(and with which grading system), because nonsevere reactions would not be resistant to
epinephrine treatment. These events are often referred to in the literature as refractory
anaphylaxis (RA), although there are subtle differences between the proposed definitions
(Table I). Definitions used by the Resuscitation Council UK (RCUK), World Allergy
Organization Consensus on Definition of Food Allergy Severity (DEFASE), and for an
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analysis of data held by NORA all propose a suboptimal response to at least 2 doses of
intramuscular (IM) epinephrine as indicative of RA.20–22 Another definition proposed by
a 21-member panel of experts in the United States using Delphi methodology proposed
a definition of anaphylaxis “that must be treated with three or more appropriate doses
of epinephrine (or initiation of an intravenous [IV] epinephrine infusion) in addition to
symptom directed medical management, such as an IV fluid bolus for hypotension or
supplemental oxygen for hypoxia or shock,”19 although subsequent clarification with the
lead author (T. Dribin, personal communication) noted that mention of additional therapy
was to “ensur [e] that patients receive appropriate resuscitative efforts before reactions
are classified as refractory” rather than imply a requisite for assigning a label of RA.
The Consortium for Food Allergy Research (CoFAR) recently proposed that RA might be
considered by a need for more than 3 doses of IM epinephrine,23 that is, 1 more than the
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other definitions proposed.

A key distinction, perhaps, is the purpose of the RA definition. The purpose of the
RCUK definition21 was to guide awareness of a more severe anaphylaxis event (suboptimal
response to 2 epinephrine doses, to which at least 98% of anaphylaxis events would usually
respond) and, thus, act as a trigger for treatment escalation and calling for additional
specialist help—rather than to be used for retrospective analyses.

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EPIDEMIOLOGY OF RA
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We undertook a review of studies reporting 3 or more individuals treated with 3 or more

doses of epinephrine (Table II).18,20,24–32 RA (by this definition) occurs in around 2%
of anaphylaxis reactions. In a systematic review of 151 individuals with anaphylaxis who
received 3 or more epinephrine doses, at meta-analysis, this was equivalent to a rate of 2.2%
(95% CI 51.1%–4.1%) of anaphylaxis events.6 This is higher than the 0.37% rate reported
by NORA, although this database also includes non-anaphylaxis reactions (depending on
the definition used).20 RA may be less frequent in children.20 Medications were the most
common elicitor in both adults and children, with most reactions occurring in the hospital
and mainly in the perioperative setting. Antibiotics and radiocontrast media were the most
common drugs involved in both NORA and a French cohort of 52 children admitted to the
ICU.18,20 Food allergens (particularly peanut, cows’ milk, and tree nuts) were the second
most common triggers.17,18,20 Notably, among 52 children admitted to a French ICU for RA
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(14 food-related), 6 occurred during diagnostic oral food challenges.18

MANAGEMENT OF RA
Data from the U.K. Fatal Anaphylaxis Registry indicate that one-third of deaths from food
anaphylaxis (in the community setting) occur despite timely administration of epinephrine.33
Evidence from case series34,35 and animal models36,37 of severe anaphylaxis suggest that
refractory reactions may be due to a combination of38:

• Delayed or insufficient delivery of epinephrine, including hypovolemia that

adversely affects systemic distribution

• Ongoing release of inflammatory mediators

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• Rarely, tachyphylaxis to further epinephrine administration.

On this basis, the RCUK Anaphylaxis working group developed an approach to identify
reactions that need more intensive management and seek appropriate help early—hence,
the rationale to define RA as a suboptimal response to 2 rather than 3 doses of
epinephrine. The RCUK algorithm for RA (Figure 1) specifically includes strategies to
ensure effective airway management and tissue oxygenation and optimize systemic delivery
of epinephrine.39 The cornerstone of this is to initiate a low-dose, IV epinephrine infusion
while simultaneously giving sufficient fluid resuscitation (which can amount to 3–5 L in
adults) to counteract the massive fluid shifts that occur in anaphylaxis and support delivery
of epinephrine at a tissue level.21 This recommendation is based on evidence from case
reports of severe human anaphylaxis34,35 and animal models40 that suggest that low-dose
IV epinephrine infusions may be more efficient in the treatment of anaphylaxis than the
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use of other routes of administration and/or IV bolus therapy. In terms of second-line

vasopressors, there is insufficient evidence to recommend any particular vasopressor (ie,
norepinephrine, vasopressin, or meta-raminol) at this time.41 A reasonable approach is to
start additional vasopressors, preferably via a central line, in patients who continue to be
hypotensive despite maximal epinephrine and fluid resuscitation. Metaraminol is commonly
used in many countries in perioperative settings, but it is unlikely to be effective in reactions
refractory to IV epinephrine, given their shared pharmacological effects. Glucagon is

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recommended as adjunct therapy in patients with RA on concomitant betablockers.39 These

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gaps in evidence might be better addressed if a consensus on defining RA and systematic

data collection of such cases could be implemented.

RISK PREDICTION
It is challenging for clinicians to identify allergic patients at risk of more severe reactions,
and in many cases, the proposed risk factors (such as any asthma) are so common that
they lack any real clinical utility.7 This results in food-allergic individuals often managed
as being at equal risk of severe and even fatal reactions—causing unnecessary anxiety,
excessive dietary restriction, and reduced health-related quality of life.7

Because RA is more common than near-fatal and fatal anaphylaxis, using this outcome may
better define specific risk factors for severity—although for this to happen constructively,
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there needs to be consensus on how to define RA. Existing data confirm that the most
common cause of RA is medication (Table II). An analysis of data from the EAR reported
a variety of potential risk factors (including asthma and malignant disease) at univariate
analysis, but unfortunately, the low number of cases identified (n = 42) precluded a suitably
powered multivariate analysis to be undertaken to control for confounding factors (eg, the
triggering allergen).20 No risk factors were identified in a cohort of 52 children with RA
in France, although hypotonia at presentation (related to the reaction) was noted to be
associated with a higher risk of RA.18

CONCLUSIONS
Anaphylaxis is a highly dynamic, potentially life-threatening emergency condition that
requires early recognition. Most reactions respond to first-line treatment with IM
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epinephrine; reactions that do not require urgent treatment escalation. A global consensus
on how best to define RA may reduce morbidity and mortality by improving the recognition
of RA, particularly by those with less experience in managing anaphylaxis. In addition, an
aligned definition of RA applied across multiple cohorts may help identify predictors of
more severe reactions as well as inform optimal second-line management of more severe
anaphylaxis events.

Acknowledgments
Conflicts of interest: G. Pouessel has provided consultation and speaker services for Aimmune Therapeutics/Nestlé,
Bausch and Lomb, Stallergenes, Novartis, ALK-Abello, and Bioprojet; serves as a medical consultant/advisor
for Bioprojet, CTRS, and AI Therapeutics/Nestlé, outside the submitted work. A. Deschildre reports personal
fees from Novartis, ALK, GlaxoSmithKline (GSK), Sanofi, Regeneron, AstraZeneca, Aimmune Therapeutics,
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Nestlé, Stallergenes Greer, and DBV Technologies; grants from Fondation du Souffle, and Conseil Régional
Hauts-de-France Research Program 2014 to 2018, outside the submitted work. I. J. Ansotegui reports personal fees
from Abbott, Bayer, Bial, Faes Farma, Menarini, Merck, Sharpe, and Dohme (MSD), Roxall, Sanofi, Organon,
and UCB, outside the submitted work. R. Sharon Chinthrajah reports grants from the National Institute for Allergy
and Infectious Diseases (NIAID), Consortium for Food Allergy Research (CoFAR), Regeneron, Stanford Maternal
and Child Health Research Institute (MCHRI), and FARE; Advisory Board Member at Alladapt Therapeutics,
Novartis, Genentech, Allergenis, Intrommune Therapeutics, and IgGenix, outside the submitted work. M. Ebisawa
reports personal fees from Novartis, ALK, Viatris, Sanofi, and ARS-Pharmaceuticals outside the submitted work.
A. Muraro reports personal fees from Aimmune Therapeutics, DVB Technologies, Viatris, Novartis, Menarini,
and Sanofi Regeneron, outside the submitted work. G. Roberts reports being employed by the University
of Southampton plus honorary contracts at University Hospital Southampton National Health Service (NHS)

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 Pouessel et al. Page 6

Foundation Trust and the Isle of Wight Trust; holds the position of president of British Society of Allergy and
Clinical Immunology; and authorship of the European Academy of Allergy and Clinical Immunology food allergy
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and anaphylaxis guidelines. H. A. Sampson reports consulting fees from N-Fold, LLC, DBV Technologies, Abbvie,
and Siolta Therapeutics; grants to his institution from the NIAID and Allergenis; and royalties from Elsevier,
outside the submitted work. S. Waserman has received personal fees and grants from Aimmune Therapeutics;
personal fees and nonfinancial support as President of the Canadian Allergy, Asthma, and Immunology Foundation;
has served as an advisory board member for Aralez, Mylan, Pediapharm, and Pfizer, Canada; and has served
as an advisory board member for Food Allergy Canada, outside of the submitted work. R. A. Wood receives
research support from the National Institutes of Health, Food Allergy Research and Education, Aimmune, DBV
Technologies, Genentech, Novartis, Sanofi, Regeneron, and Siolta; and receives royalty fees from UpToDate,
outside the submitted work. M. Worm reports consultation and speaker fees for ALK Abello, Viatris, Sanofi,
Regeneron, Aimmune Therapeutics, DBV Technologies, Abbvie, Eli Lilly, GSK, and CSL Behring, outside the
submitted work. P. J. Turner reports grants from the U.K. Food Standards Agency, JM Charitable Foundation,
NIHR/Imperial Biomedical Research Centre and End Allergies Together; personal fees from the U.K. Food
Standards Agency, DBV Technologies, Aimmune Therapeutics, Allergenis, and ILSI Europe, outside the submitted
work. The rest of the authors declare that they have no relevant conflicts of interest.

Abbreviations used
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EAR European Anaphylaxis Registry

ICU Intensive care unit

IM Intramuscular

IV Intravenous

RA Refractory anaphylaxis

RCUK Resuscitation Council United Kingdom

REFERENCES
1. Cardona V, Ansotegui IJ, Ebisawa M, El-Gamal Y, Fernandez Rivas M, Fineman S, et al.
Author Manuscript

World Allergy Organization anaphylaxis guidance 2020. World Allergy Organ J 2020;13:100472.
[PubMed: 33204386]
2. Dribin TE, Waserman S, Turner PJ. Who needs epinephrine? Anaphylaxis, autoinjectors, and
parachutes. J Allergy Clin Immunol Pract 2023;11:1036–46. [PubMed: 36796511]
3. Worm M, Moneret-Vautrin A, Scherer K, Lang R, Fernandez-Rivas M, Cardona V, et al. First
European data from the network of severe allergic reactions (NORA). Allergy 2014;69:1397–404.
[PubMed: 24989080]
4. Noimark L, Wales J, Du Toit G, Pastacaldi C, Haddad D, Gardner J, et al. The use of adrenaline
autoinjectors by children and teenagers. Clin Exp Allergy 2012;42:284–92. [PubMed: 22181034]
5. Umasunthar T, Leonardi-Bee J, Hodes M, Turner PJ, Gore C, Habibi P, et al. Incidence of fatal food
anaphylaxis in people with food allergy: a systematic review and meta-analysis. Clin Exp Allergy
2013;43:1333–41. [PubMed: 24118190]
6. Patel N, Chong KW, Yip AYG, Ierodiakonou D, Bartra J, Boyle RJ, et al. Use of multiple
epinephrine doses in anaphylaxis: a systematic review and meta-analysis. J Allergy Clin Immunol
Author Manuscript

2021;148:1307–15. [PubMed: 33862009]

7. Turner PJ, Arasi S, Ballmer-Weber B, Baseggio Conrado A, Deschildre A, Gerdts J, et al. Global
Allergy, Asthma European Network (GA2LEN) Food Allergy Guideline Group. Risk factors for
severe reactions in food allergy: rapid evidence review with meta-analysis. Allergy 2022;77:2634–
52. [PubMed: 35441718]
8. Dribin TE, Schnadower D, Wang J, Camargo CA Jr, Michelson KA, Shaker M, et al. Anaphylaxis
knowledge gaps and future research priorities: a consensus report. J Allergy Clin Immunol
2022;149:999–1009. [PubMed: 34390722]

J Allergy Clin Immunol Pract. Author manuscript; available in PMC 2023 December 13.
 Pouessel et al. Page 7

9. Stafford A, Bartra J, Aston A, Mills ENC, Fernandez-Rivas M, Turner PJ. Improving severity
scoring of food-induced allergic reactions: a global “best-worst scaling” exercise. J Allergy Clin
Author Manuscript

Immunol Pract 2021;9:4075–4086.e5. [PubMed: 34293502]

10. Stafford A, Turner PJ. Grading the severity of anaphylaxis. Curr Opin Allergy Clin Immunol
2023;23:218–25. [PubMed: 36924389]
11. Perez-Codesido S, Rosado-Ingelmo A, Privitera-Torres M, Pérez Fernández E, Nieto-Nieto A,
Gonzalez-Moreno A, et al. Incidence of fatal anaphylaxis: a systematic review of observational
studies. J Investig Allergol Clin Immunol 2022;32:245–60.
12. Turner PJ, Campbell DE. Epidemiology of severe anaphylaxis: can we use population-based
data to understand anaphylaxis? Curr Opin Allergy Clin Immunol 2016;16:441–50. [PubMed:
27490124]
13. Pouessel G, Alonzo S, Divaret-Chauveau A, Dumond P, Bradatan E, Liabeuf V, et al. Fatal and
near-fatal anaphylaxis: the Allergy-Vigilance Network data (2002e2020). Allergy 2023;78:1628–
38. [PubMed: 36645170]
14. Vyas D, Ierodiakonou D, Harrison DA, Russell T, Turner PJ, Boyle RJ. Increase in intensive
care unit admissions for anaphylaxis in the United Kingdom 2008e2012. J Allergy Clin Immunol
Author Manuscript

2016;137:AB57.
15. Motosue MS, Bellolio MF, Van Houten HK, Shah ND, Campbell RL. Risk factors for severe
anaphylaxis in the United States. Ann Allergy Asthma Immunol 2017;119:356–361.e2. [PubMed:
28958375]
16. Ramsey NB, Guffey D, Anagnostou K, Coleman NE, Davis CM. Epidemiology of anaphylaxis in
critically ill children in the United States and Canada. J Allergy Clin Immunol Pract 2019;7:2241–
9. [PubMed: 31051271]
17. Pouessel G, Chagnon F, Trochu C, Labreuche J, Lejeune S, Recher M, et al. French Group for
Pediatric Intensive Care and Emergencies (GFRUP). Anaphylaxis admissions to pediatric intensive
care units in France. Allergy 2018;73:1902–5. [PubMed: 29787624]
18. Pouessel G, Trochu C, Chagnon F, Diesnis R, Leteurtre S, Deschildre A, et al. .Severe and
refractory anaphylaxis in paediatric intensive care unit. Allergy. Published online March 17, 2023.
10.1111/all.15712
19. Dribin TE, Sampson HA, Camargo CA Jr, Brousseau DC, Spergel JM, Neuman MI, et al.
Persistent, refractory, and biphasic anaphylaxis: a multidisciplinary Delphi study. J Allergy Clin
Author Manuscript

Immunol 2020;146:1089–96. [PubMed: 32853640]

20. Francuzik W, Dölle-Bierke S, Knop M, Scherer Hofmeier K, Cichocka-Jarosz E, García BE,
et al. Refractory anaphylaxis: data From the European Anaphylaxis Registry. Front Immunol
2019;10:2482. [PubMed: 31749797]
21. Sargant N, Dodd A, Hughes A, Whyte AF, Soar J, Turner PJ. Refractory anaphylaxis: treatment
algorithm. Allergy 2021;76:1595–7. [PubMed: 33594699]
22. Arasi S, Nurmatov U, Dunn-Galvin A, Roberts G, Turner PJ, Shinder SB, et al. WAO consensus
on DEfinition of Food Allergy SEverity (DEFASE). World Allergy Organ J 2023;16:100753.
[PubMed: 36910595]
23. Chinthrajah RS, Jones SM, Kim EH, Sicherer SH, Shreffler W, Lanser BJ, et al. Updating the
CoFAR Grading Scale for systemic allergic reactions in food allergy. J Allergy Clin Immunol
2022;149:2166–21670.e1. [PubMed: 35026206]
24. Schummer C, Wirsing M, Schummer W. The pivotal role of vasopressin in refractory anaphylactic
shock. Anesth Analg 2008;107:620–4. [PubMed: 18633042]
Author Manuscript

25. 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;122:133–8.
[PubMed: 18547626]
26. Brown SG, Stone SF, Fatovich DM, Burrows SA, Holdgate A, Celenza A, et al. Anaphylaxis:
clinical patterns, mediator release, and severity. J Allergy Clin Immunol 2013;132:1141–1149.e5.
[PubMed: 23915715]
27. Campbell RL, Bashore CJ, Lee S, Bellamkonda VR, Li JT, Hagan JB, et al. Predictors of repeat
epinephrine administration for emergency department patients with anaphylaxis. J Allergy Clin
Immunol Pract 2015;3:576–84. [PubMed: 26032476]

J Allergy Clin Immunol Pract. Author manuscript; available in PMC 2023 December 13.
 Pouessel et al. Page 8

28. Tsuang A, Menon NR, Bahri N, Geyman LS, Nowak-Węgrzyn A. Risk factors for multiple
epinephrine doses in food-triggered anaphylaxis in children. Ann Allergy Asthma Immunol
Author Manuscript

2018;121:469–73. [PubMed: 29940309]

29. Anvari S, Blackman AC, Anagnostou A. Insights from 275 cases of childhood anaphylaxis in the
United States. J Allergy Clin Immunol Pract 2019;7:1696–1699.e2. [PubMed: 30580049]
30. Gabrielli S, Clarke A, Morris J, Eisman H, Gravel J, Enarson P, et al. Evaluation of prehospital
management in a Canadian emergency department anaphylaxis cohort. J Allergy Clin Immunol
Pract 2019;7:2232–2238.e3. [PubMed: 31035000]
31. Liu X, Lee S, Lohse CM, Hardy CT, Campbell RL. Biphasic reactions in emergency department
anaphylaxis patients: a prospective cohort study. J Allergy Clin Immunol Pract 2020;8:1230–8.
[PubMed: 31704438]
32. Alviani C,Burrell S,Macleod A,Edees S,Roberts G,Turner PJ,et al. .Anaphylaxis refractory
to intramuscular adrenaline during in-hospital food challenges: a case series and proposed
management. Clin Exp Allergy 2020;50:1400–5. [PubMed: 32997857]
33. Pumphrey R, Sturm G. Risk factors for fatal anaphylaxis. In: Moneret-Vautrin DA, editor.
Advances in Anaphylaxis Management. London: Future Medicine; 2014. p. 32–48.
Author Manuscript

34. Brown SG, Blackman KE, Stenlake V, Heddle RJ. Insect sting anaphylaxis; prospective evaluation
of treatment with intravenous adrenaline and volume resuscitation. Emerg Med J 2004;21:149–54.
[PubMed: 14988337]
35. Smith PL, Kagey-Sobotka A, Bleecker ER, Traystman R, Kaplan AP, Gralnick H, et al.
Physiologic manifestations of human anaphylaxis. J Clin Invest 1980;66:1072–80. [PubMed:
6776143]
36. Bautista E, Simons FE, Simons KJ, Becker AB, Duke K, Tillett M, et al. Epinephrine fails to
hasten hemodynamic recovery in fully developed canine anaphylactic shock. Int Arch Allergy
Immunol 2002;128:151–64. [PubMed: 12065916]
37. Dewachter P, Raëth-Fries I, Jouan-Hureaux V, Menu P, Vigneron C, Longrois D, et al.
A comparison of epinephrine only, arginine vasopressin only, and epinephrine followed by
arginine vasopressin on the survival rate in a rat model of anaphylactic shock. Anesthesiology
2007;106:977–83. [PubMed: 17457129]
38. Brown SG. The pathophysiology of shock in anaphylaxis. Immunol Allergy Clin North Am
2007;27:165–75. [PubMed: 17493496]
Author Manuscript

39. Anaphylaxis Working Group of Resuscitation Council UK. Emergency

Treatment of Anaphylaxis: Guidelines for Healthcare Providers. May
2021. Accessed April 15, 2023. https://www.resus.org.uk/sites/default/files/2021-05/
Emergency%20Treatment%20of%20Anaphylaxis%20May%202021_0.pdf
40. Mink SN, Simons FE, Simons KJ, Becker AB, Duke K. Constant infusion of epinephrine, but
not bolus treatment, improves haemodynamic recovery in anaphylactic shock in dogs. Clin Exp
Allergy 2004;34:1776–83. [PubMed: 15544604]
41. Dodd A, Hughes A, Sargant N, Whyte AF, Soar J, Turner PJ. Evidence update for the treatment of
anaphylaxis. Resuscitation 2021;163:86–96. [PubMed: 33895231]
Author Manuscript

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FIGURE 1.
RCUK algorithm for RA. IO, intraosseus. Reprinted with permission.39
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TABLE I.

Current definitions of RA

Source Definition of RA
Pouessel et al.

21-member Expert Panel “Anaphylaxis that must be treated with three or more appropriate doses of epinephrine (or initiation of an intravenous epinephrine infusion) in addition to symptom
(US)19 directed medical management, such as an intravenous fluid bolus for hypotension or supplemental oxygen for hypoxia or shock.”
European Anaphylaxis “Anaphylaxis which, despite treatment with at least two doses of minimum 300mcg adrenaline [epinephrine], does not achieve normalization of symptoms.”*
Registry (NORA)20 *ie, persistence of significant hypoxia, hypotension, confusion, collapse and loss of consciousness, or incontinence.

Resuscitation Council UK21 “Anaphylaxis requiring ongoing treatment* despite two (appropriate) doses of intramuscular adrenaline [epinephrine].”
*ie, further epinephrine is indicated, due to suboptimal improvement in respiratory and/or cardiovascular symptoms.
Consortium for Food Allergy Lower respiratory symptoms (eg, throat tightness with stridor, wheezing, chest tightness, dyspnea, or cough) associated with a requirement for supplemental oxygen and
Research (CoFAR)23 refractoriness to short-acting bronchodilator treatment (including IM epinephrine)*
OR Respiratory compromise requiring mechanical support
OR Reduced blood pressure with associated symptoms of end-organ dysfunction (eg, hypotonia (collapse) and syncope)
*Examples of refractoriness could include continuous albuterol nebulizer or epinephrine IV infusion or > 3 IM epinephrine injections.

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TABLE II.

Main findings of studies reporting RA (treated with 3+ epinephrine doses)*

Study Location n Elicitors Age % Male Main findings

Pouessel et al.

Schummer et al, 200824 Germany 6 Perioperative drugs 6 of 6 6 adults 66 Vasopressin (with fluid supprot) successful in managing RA.

Järvinen et al, 200825 United States 6 Foods 6 of 6 6 children - PMHx of asthma in 6/6.
Mean age: 6 y Peanut is a common cause of RA
Brown et al, 201326 Australia, EDs 45 Oral drugs 16 of 45 1 child, 51 Oral medicines are a common cause of RA. Medication (both oral and
Foods 12 of 45 44 adults injected) is associated with severe reactions (OR ~4). Asthma or COPD
Insect sting 10 of 45 Mean age: 44 y associated with hypoxemia (OR 3). Heart disease, diabetes, hypertension,
and associated medication are not risk factors after correcting for
confounding by age.
Campbell et al, 201527 United States, EDs 9 - - - The overall rate of ≥ 3 epinephrine doses was 1.5%.

Tsuang et al, 201828 United States 5 Foods 5 of 5 5 children - -

Anvari et al, 201929 United States 5 - 5 children - The overall rate of ≥ 3 epinephrine doses was 1.8%.

Gabrielli et al, 201930 Canada, EDs 48 - - - The overall rate of ≥ 3 epinephrine doses was 1.4%.

Francuzik et al, 201920 Europe, registry 42 Drugs 21 of 42 Mean age: 41 y 21/42 Drugs are the main triggers for RA, with most events occurring in
Foods 9 of 42 perioperative settings. Age was not a risk factor for RA.
Insect sting 8 of 42
Liu et al, 202031 United States, EDs 16 - - - The overall rate of ≥ 3 epinephrine doses was 3.7%.

Alviani et al, 202032 United Kingdom 4 Diagnostic OFC for f ood allergy 4 4 children 50 Low-dose IV epinephrine is well- tolerated and effective.
of 4
Pouessel et al, 202318 France, PICU 52 Drugs 28 of 52 52 children 50 Most reactions occur in hospital (71%), mainly perioperatively (40%).
admission Foods 14 of 52 Mean age: 8.9 y Rescue treatment with IV epinephrine infusion and fluid therapy is
suboptimal.

COPD, Chronic obstructive pulmonary disease; EDs, emergency departments; OR, odds ratio; PICU, Pediatric Intensive Care Units; PMHx, past medical history.
*
Only studies reporting ≥ 3 cases are included.

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