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Increased Use of Adrenaline in the Management of Childhood Anaphylaxis Over the Last Decade
Original Article
Increased Use of Adrenaline in the Management of Childhood Anaphylaxis Over the Last Decade Kristina Rueter, MD, FRACP, PEMa,b,c, Brennan Ta, BScc, Natasha Bear, BSc, MStatd, Michaela Lucas, MD, FRACP, FRCPAb,e,f,g, Meredith L. Borland, MD, FACEMa,c,h, and Susan L. Prescott, PhD, MD, FRACPa,b Perth and Crawley, Western Australia, Australia
What is already known about this topic? Emergency department physicians play a key role in identifying and addressing anaphylaxis. However, there is evidence that adrenaline has been significantly underused in this lifethreatening condition and other management and follow-up procedures have been suboptimal. What does this article add to your knowledge? This is the first study to find evidence that identification and management of anaphylaxis in a pediatric emergency department (PED) significantly improved over a 10-year period after an intensified training program for medical staff and improved interdisciplinary cooperation. How does this study impact current management guidelines? The use of well-developed training programs for the recognition, management, and follow-up of anaphylaxis in the PED environment is urgently required. PEDs and allergy/ immunology departments need to cooperate to optimize anaphylaxis education and management.
BACKGROUND: We recently determined that allergy training programs have improved physician recognition and diagnosis of pediatric anaphylaxis in the last decade. a
School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia b Department of Paediatric Immunology, Princess Margaret Hospital for Children, Perth, Western Australia, Australia c Department of Paediatric Emergency Medicine, Princess Margaret Hospital for Children, Perth, Western Australia, Australia d Department of Clinical Research and Education, Child and Adolescent Health Services, Perth, Western Australia, Australia e School of Medicine and Pharmacology and School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia f Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia g Department of Immunology, Pathwest and Sir Charles Gairdner Hospital, Perth, Western Australia, Australia h School of Primary, Aboriginal and Rural Healthcare, University of Western Australia, Crawley, Western Australia, Australia This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of interest: S. L. Prescott is on regional scientific advisory boards of the Nestlé Nutrition Institute and Danone; has received consultancy fees from Bayer Pharmaceuticals; has received lecture fees and payment for developing educational presentations from the Nestlé Nutrition Institute, Danone, Bayer, and ALK Abello; receives royalties from a book; and has received travel expenses and speaker fees from these companies and from ALK Abello. The rest of the authors declare that they have no relevant conflicts of interest. Received for publication April 2, 2017; revised November 13, 2017; accepted for publication November 15, 2017. Available online -Corresponding author: Kristina Rueter, MD, FRACP, PEM, Princess Margaret Hospital for Children, Roberts Rd, Perth 6008, Western Australia, Australia. E-mail: [email protected]. 2213-2198 Ó 2018 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology https://doi.org/10.1016/j.jaip.2017.11.038
OBJECTIVE: To investigate for changes in management, in particular the appropriate use of adrenaline for the treatment of anaphylaxis in a tertiary pediatric emergency department (PED). METHODS: We conducted a retrospective case note study including children aged 0 to 16 years coded and verified for anaphylaxis comparing cases in years 2003/2004 with 2012. This included standardized information on clinical presentation, demographic characteristics, vital signs, mode of transport, and management of anaphylaxis including the use of adrenaline and/or adjunct therapy. Follow-up management plans were also recorded. RESULTS: In 2003/2004, a total of 92 cases were coded and verified for anaphylaxis from 83,832 PED presentations compared with 159 cases from 71,822 PED presentations in 2012. A significantly higher proportion of cases were appropriately managed with adrenaline in 2012 compared with 2003/2004, when intensive training programs had not yet been introduced (P [ .03). Vital signs were more frequently documented in 2012 (P < .001) than in 2003/2004, and there was significantly less administration of other medications (corticosteroids, bronchodilators, and antihistamines) (P < .05). Also, changes in discharge management occurred with an improved dispensing/ prescription of adrenaline autoinjectors and more frequent followup arrangement with specialist allergy services (P < .001). CONCLUSIONS: There was a significant improvement in the management of anaphylaxis over this 10-year period. This change was observed after the introduction of intensified physician training programs in which anaphylaxis management was a key component highlighting the importance of cooperation between pediatric emergency and allergy services. Ó 2018 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2017;-:---) Key words: Childhood; Anaphylaxis; Food allergy; Physician training; Anaphylaxis management; Adrenaline 1
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Abbreviations used GP- general practitioner ICD-10- International Classification of Diseases, Tenth Revision PED- pediatric emergency department
INTRODUCTION Anaphylaxis is a severe and potentially fatal systemic allergic reaction involving 2 or more organ systems within minutes to a few hours after contact with allergy-causing substances.1 The dramatic increase in anaphylaxis has occurred in parallel to the worldwide increase in allergic diseases in general, particularly in the pediatric population.2-5 Prompt treatment with adrenaline, the only first-line intervention for anaphylaxis, is recommended for all age groups to prevent potentially fatal progression. However, there is evidence that adrenaline has been significantly underused.6-8 Although other drugs are often given in anaphylaxis including H1 antihistamines, corticosteroids, and inhaled b2-sympathomimetics,9,10 there is limited evidence for the effectiveness of these in the acute treatment of anaphylaxis.11 There is also concern that other management and follow-up procedures are suboptimal or incomplete.12,13 Current practice guidelines recommend that patients are observed in a clinical setting for at least 4 hours after an episode of anaphylaxis or treatment with adrenaline and that adrenaline autoinjectors should be prescribed before discharge.14 Patients and/or carers should also be provided with appropriate instruction and training in the use of the device.14 It is also recommended that all patients who experienced anaphylaxis are referred to specialist allergy services to assist with identifying the offending trigger, appropriate allergy testing, and additional support and education.15 Given that the rates of this potentially fatal condition are rising,4 and contributing significantly to morbidity and health care costs, appropriate management is of critical importance and has been identified as a major issue.6,7,16,17 To our knowledge, no studies have investigated whether this has been addressed with improved medical education. We recently determined that allergy training programs had improved physician recognition and diagnosis of pediatric anaphylaxis in the last decade.5 The aim of the present study was to determine whether the management of anaphylaxis in children had also improved over this 10-year period after the introduction of intensified training programs and new anaphylaxis guidelines, relating in particular to the use of adrenaline. This study also provided an opportunity to examine changes in the characteristics of presenting cases (features of anaphylaxis, suspected triggers, and rate of biphasic anaphylaxis) over the time period. METHODS Emergency department anaphylaxis data We compared data from the years 2003/2004, when the International Classification of Diseases, Tenth Revision (ICD-10), codes were introduced in the Perth metropolitan area, with data from 2012, after intensified training programs, new anaphylaxis guidelines, and enhanced cooperation between pediatric emergency specialists and allergists/immunologists were introduced in our tertiary pediatric emergency department (PED). We focused on comparing the mode of arrival to the hospital, documentation of vital signs,
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adrenaline administration, use of adjunct therapy, adrenaline prescription, and arrangement of follow-up with an allergist/clinical immunologist. Information about ethnicity was obtained along with other personal details by clerking the patient before the medical assessment in the emergency department (ED). Ethnicity was reported by the patient’s parent or guardian. The methodology for the identification of anaphylaxis has been previously reported.5 We conducted a detailed retrospective chart examination of all cases coded as anaphylaxis (aged 0-16 years) presenting to the main tertiary PED in Perth, Western Australia. We compared data from January 1, 2003, to December 31, 2004 (period 1), when ICD-10 codes were introduced, with data from January 1, 2012, to December 31, 2012 (period 2), after intensified training programs and new anaphylaxis guidelines were introduced. Because the number of cases was small in 2003, we included an additional year (2004) to provide an adequate sample size for the preintervention phase. ICD codes were automatically assigned to patients on the basis of the diagnoses entered onto the ED information system by the treating physician. Charts with ICD-10 codes including anaphylactic shock after sting (T63.9), anaphylaxis (T78.2), food anaphylaxis (T78.0), anaphylaxis, unknown cause (T78.2), anaphylaxis, adverse drug reaction (T78.2), anaphylaxis not due to serum, not shock (T78.2), anaphylactic shock due to immunization (T80.5), anaphylactic shock due to serum (T80.5), and anaphylaxis due to drug (T88.6) were reviewed. We used criteria from the 2006 Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium for the definition and management of anaphylaxis.14 A biphasic reaction was defined as an initial anaphylactic reaction with a period of resolution of 1 hour or longer, during which there were no new symptoms or treatment administered, followed by a second-phase anaphylactic reaction within the next 72 hours, not caused by antigen reexposure.18,19 In our chart review, we also examined potential biphasic reactions, defined as representations to the hospital with anaphylaxis within 72 hours of initial presentation. All cases (aged 0-16 years) coded as anaphylaxis were independently reviewed by 2 allergists/clinical immunologists to verify the diagnosis. Information was collected on standardized forms. Demographic characteristics, identification of anaphylaxis, mode of transport, asthma history, clinical symptoms, medications administered, disposition, prescriptions of adrenaline autoinjectors, and arrangement to be followed up by an allergist were recorded for cases coded as anaphylaxis comparing period 1 with period 2.
Anaphylaxis education From February 2010, the Australian Society for Clinical Immunology and Allergy anaphylaxis guidelines20,21 were incorporated into electronic PED guidelines with online access to management and training information. Printed copies of anaphylaxis action plans were maintained in a separate and easily accessible location. In each term (of 10 weeks), 36 junior doctors rotated through our PED. All major decisions made by the junior staff were discussed with the senior staff. Number of staff, composition of staff (percentage of general practitioner [GP] trainees, ED trainees, and pediatric trainees in the group of junior doctors), and level of training were consistent during both time periods. Senior staff remained the same and consisted of a mixture of pediatricians, pediatric ED physicians, and ED physicians. The training was performed by a consultant pediatric allergist and emergency physician who was also available for any questions and concerns regarding allergic
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FIGURE 1. Case selection flow diagram.
reactions/anaphylaxis while working clinically in both PED and pediatric immunology settings. Specific emphasis was placed on the management of anaphylaxis in a PED setting. In 2012, both senior and junior staff had better and direct access to consistent educational programs compared with that in 2003/ 2004. These programs included a compulsory educational face-toface session for junior staff at the beginning of their term incorporating adrenaline autoinjector demonstrations with trainer devices, and videos demonstrating the correct use of devices (although these had previously been available to patients, parents, and families, medical staff were not specifically schooled in their use until 2010). Attendance was taken for each session and, upon a review of our records, we determined that 5% of junior staff failed to attend the session because of illness or personal circumstances. Senior staff attended the session once a year. Clinical staff were also provided with guidelines for discharge including referral to allergy services, initial allergen avoidance recommendations, provision of anaphylaxis information packs to families, and provision of an adrenaline autoinjector, directly dispensed by the PED to ensure immediate access to a device in the event of a biphasic reaction or immediate reexposure after discharge. The families were also provided with a prescription to purchase a second adrenaline autoinjector after discharge and information on biphasic anaphylaxis. The study was approved by the Ethics and Research Governance (GEKO, approval number 8660) at Princess Margaret Hospital for Children in Perth, Western Australia.
Statistical analysis All analyses were performed using Stata 14 (StataCorp, College Station, Tex). Outcomes were reported as means and SDs for continuous data and analyzed using independent t tests. Categorical data were represented as frequencies and proportions. Difference in proportions was assessed using chi-square test or the Fisher exact test (when expected cell count was less than 5). For the management of anaphylaxis odds ratios, 95% CIs were produced using logistic regression. The year 2012 was the reference category. Alpha was set at P < .05.
RESULTS A total of 83,832 cases presented to our PED between January 1, 2003, and December 31, 2004 (period 1), and 71,822 cases presented between January 1, 2012, and December 31, 2012 (period 2). This yielded 136 cases coded with anaphylaxis from period 1 and 177 cases from period 2. After review we confirmed anaphylaxis in 92 cases in period 1 and 159 cases in period 2 (Figure 1). Population characteristics The general characteristics of these populations are presented in Table I. Males were overrepresented in both time periods. We noted a significant increase in the proportion of Africans and Asians affected by anaphylaxis in the study population. The diagnosis of anaphylaxis was more accurate in 2012 (90% verified as correctly coded on the basis of symptoms) compared with
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TABLE I. Demographic characteristics and suspected triggers of children presenting to the PED with anaphylaxis in 2003/2004 and 2012 Characteristic
Anaphylaxis diagnoses Coded for anaphylaxis, n Verified cases, n Proportion correctly identified Sex, n (%) Male Female Age (y), mean SD Ethnicity, n (%) European Aboriginal Asian African First anaphylaxis Trigger, n (%) Food Drug Insect Other Food trigger Peanut Tree nut Egg Cow milk Fish and seafood Other History of asthma, n (%) On current treatment for asthma, n (%)
2003/2004
2012
TABLE II. Clinical features of anaphylaxis and documentation of vital signs in children presenting to the PED in 2003/2004 and 2012
P value Symptoms
136 92 67.6%
177 159 89.8%
69 (75) 23 (25) 6.6 4.2
111 (69.8) 48 (30.2) 5.8 4.4
.379
114 1 20 9 63
.058 .999 .004 .028 .345
.182
83 0 2 0 42
(97.6) (0) (2.3) (0) (47.7)
46 3 26 3
(59.0) 114 (84.4) <.001 (3.8) 4 (3.0) .709 (33.3) 13 (9.6) <.001 (3.8%) 4 (3.0) .709
14 9 10 6 1 6 28 6
(30.4) (19.6) (21.7) (13.0) (2.2) (13.0) (35.4) (10.3)
33 36 17 5 5 18 44 7
(79.2) (0.7) (13.9) (6.2) (41.4)
<.001
(29.0) (31.6) (14.9) (4.4) (4.4) (15.8) (31.0) (5.3)
.852 .126 .297 .050 .674 .660 .498 .205
Respiratory Wheeze Shortness of breath Tongue swelling Persistent cough Hoarse voice Stridor Throat tightness Cardiovascular Pale, floppy, cyanotic or loss of consciousness Skin Angioedema/urticaria Gastrointestinal Vomiting Abdominal pain Miscellaneous Itchy eyes/nose Throat tingling Grouped Displayed at least 1 respiratory symptom Vital signs Respiratory rate/min SaO2 in % Blood pressure (mm Hg) Heart rate/min
2003/2004 2012 (N [ 92), n (%) (N [ 159), n (%) P value
45 15 9 23
(49) (16) (10) (25)
44 43 25 43
(28) (27) (16) (27)
.001 .052 .2 .7
20 (22) 13 (14)
34 (21) 15 (9)
.9 .3
12 (13)
19 (12)
.8
82 (89)
124 (78)
28 (30) 3 (3)
33 (21) 14 (9)
.1 .1
9 (10) 11 (12)
14 (9) 13 (8)
.8 .3
88 (96)
146 (92)
.3
76 75 52 78
144 152 129 154
(83) (82) (57) (85)
(91) (96) (81) (97)
.027
.065 <.001 <.001 <.001
P < .05 was considered statistically significant.
68% of cases in 2003/2004 as previously reported5 (Figure 1), and vital signs (blood pressure, heart rate, and SaO2) were recorded more frequently in 2012 (P < .001) (Table II). Overall, the predominant suspected allergen trigger was food, with a significant increase observed between 2003/2004 and 2012 (Table I). A similar proportion of children presented with their first episode of anaphylaxis over both time periods. In twothirds of the children with previous adverse reactions, the suspected offending allergen was the same. The presenting features of anaphylaxis were generally similar, with respiratory signs being the more frequent defining symptom of anaphylaxis than cardiovascular compromise (Table I). Wheeze was reported more frequently in 2003/2004 than in 2012 (P ¼ .001) and angioedema more frequently in 2012 (P ¼ .027), but other features were similar. The potential rate of biphasic anaphylaxis captured via chart review was 2.8% (7 out of 251) and was also similar between 2003/2004 and 2012. There was no significant difference in the mode of transport to hospital (Table III). In 2012, there was a tendency for patients with anaphylaxis to stay longer, on average, in the PED than in 2003/2004. This result, however, did not reach significance (median [interquartile range]2003/ 2004 vs 2012: 216.0 minutes [128.0-654.5] vs 252.0 minutes [189-588]; P ¼ .177). Patient disposition was significantly more likely to be admission to the PED observation ward in 2012 (P < .001).
Management of anaphylaxis with adrenaline Appropriate treatment of anaphylaxis with adrenaline before and after arrival at PED occurred in significantly more cases with confirmed anaphylaxis in 2012 than in 2003/2004 (P ¼ .03) (Table IV). In all cases, adrenaline was given intramuscularly. Focusing on cases in which adrenaline was not administered, there was a significantly higher proportion of patients to whom adrenaline was not given despite being clinically indicated and available in 2003/2004 (P ¼ .009). To further investigate this, we analyzed different subgroups (Table IV). Failure of adrenaline administration by paramedics, GPs, primary care takers, or schools before patients arrived at hospital was not significantly different over time. However, after arrival at the hospital the odds of being mismanaged were 88% lower in 2012 compared with 2003/2004 (P < .001). Differences in anaphylaxis management over time were also reflected in the reduced use of adjunctive medications. There were less first-generation (sedating) and more second-generation (nonsedating) antihistamines being prescribed in 2012 (P < .001). Corticosteroids (P < .001) and b2-agonists (P ¼ .029) were administered significantly less in 2012 (Table IV). Number and allocation of hospital beds did not change between 2003/2004 and 2012. However, there were significantly more children with anaphylaxis admitted to the PED observation
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TABLE III. Mode of arrival, length of stay, disposition, dispensing/prescription of adrenaline autoinjector, and arrangement of follow-up by an allergist/immunologist for children presenting with anaphylaxis to a PED in 2003/2004 and 2012 2003/2004
Mode of arrival, n (%) Ambulance Private vehicle Aircraft Other Median PED length of stay (min), median (IQR) Disposition, n (%) Home Ward PED observation ward Intensive care unit Dispensing/prescription of adrenaline autoinjector, n (%) Follow-up by allergy service, n (%) Already linked or new referral
43 48 0 1 216 26 27 37 2 50
2012
P value
(46.7) (52.2) (0) (1.1) (128-654.5)
66 93 0 0 252
(41.5) (58.5) (0) (0) (189-588)
(28.3) (29.4) (40.2) (2.2) (53.4)
21 3 134 1 129
(13.2) (1.9) (84.3) (0.6) (81.1)
<.001
158 (99.4)
<.001
81 (88.0)
.249
.177
<.001
TABLE IV. Administration of adrenaline and adjunct therapy in children with anaphylaxis presenting to the PED in 2003/2004 and 2012 Anaphylaxis management
Adrenaline indicated/given Suboptimal* Adrenaline not given Mismanagement† Mismanaged by PED doctors Paramedics GP Family School/day care H1 antihistamine Antihistamine type First-generation Second-generation H1 antihistamine and adrenaline Both not given Adrenaline only Antihistamine only Adrenaline and antihistamine Corticosteroids b2-agonist
2003/2004, n (%)
2012, n (%)
OR (95% CI) (2003/2004 reference category)
P value
N 11 44 37 N
¼ 92 (12) (47.8) (40.2) ¼ 45
N ¼ 159 45 (28.3) 75 (47.2) 39 (24.5) N ¼ 39
2.91 (1.42-5.96) 0.97 (0.58-1.63) 0.48 (0.28-0.84)
.030 .920 .009
16 14 2 13 0 76
(35.6) (31.1) (4.4) (28.9) (0) (82.6)
4 13 0 22 0 116
0.12 (0.04-0.36) 0.50 (0.23-1.09) NA 0.98 (0.47-2.02) NA 0.57 (0.30-1.07)
<.001 .083 .133 .948 NA .082
NA NA
<.001 <.001
(10.6) (33.3) (0) (56.4) (0) (73.0)
43 (82.7) 9 (17.3)
25 (22.9) 85 (77.1)
5 11 28 48 53 25
13 30 47 69 46 25
(5.4) (12.0) (30.4) (52.2) (57.6) (27.2)
(8.2) (18.9) (29.6) (43.4) (28.9) (15.7)
1.55 1.70 0.96 0.70 0.30 0.50
(0.53-4.49) (0.81-3.61) (0.55-1.68) (0.42-1.18) (0.17-0.51) (0.27-0.93)
.420 .157 .884 .180 <.001 .029
GP, General practitioner; NA, not applicable; OR, odds ratio. P < .05 was considered statistically significant. Out of 37 cases, 8 were mismanaged in 2 groups (hospital and paramedics [n ¼ 2], hospital and family [n ¼ 3], and paramedic and family [n ¼ 3]) in 2003/2004. In 2012, we could not identify any cases that were mismanaged in 2 areas. *Cases would have required adrenaline but did not receive any either because of a first presentation with an allergic reaction/anaphylaxis (primary caretaker cannot be expected to have the knowledge and equipment regarding anaphylaxis management) or because symptoms self-resolved before adrenaline was available. †Adrenaline was indicated and available but not given.
ward for a more than 4-hour observation period in 2012 than were admitted to the inpatient ward overnight (Table III). The proportion of children discharged with an adrenaline autoinjector significantly increased in 2012 (children with anaphylaxis to drugs were excluded from analysis, because avoidance is the primary management without indication for prescription of an adrenaline autoinjector), as did the proportion of children provided with arrangements for follow-up by allergy services (Table III).
DISCUSSION We found evidence that the management of anaphylaxis in a PED environment significantly improved after the introduction of structured physician training programs and greater collaboration between pediatric emergency specialists and allergists/immunologists. Although education and implementation of management guidelines for physicians treating patients with anaphylaxis has been identified globally as a shortfall,6,7,22-24 to
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our knowledge there are no studies investigating the impact of training programs on anaphylaxis management in children. Our goal was to address this important knowledge gap in the PED environment, because emergency physicians work on the front line for anaphylaxis management, and rates of anaphylaxis and allergies are dramatically rising.4,25,26 In our own PED cohort, a 2.2-fold increase in verified anaphylaxis cases within 10 years was particularly observed among infants.5 This age shift is significant because anaphylaxis can be underrecognized in this age group27,28 because of a broad range of subtle and sometimes unspecific symptoms,28 underscoring the need for education and increased awareness.29 Up to 70% of patients presenting to the ED with anaphylaxis can be misdiagnosed or miscoded.5,15,30,31 We have previously shown that physician training programs can improve the correct identification and coding of anaphylaxis5 and here we have demonstrated that this is also associated with improved pharmacological and general management of anaphylaxis. Vital signs were more frequently documented in 2012 compared with 2003/ 2004, indicating an increased awareness of the observational tools required for assessing and observing anaphylaxis. Globally, the prevalence of food allergy seems to be higher per se in Australian children.32,33 We noted a significant increase in anaphylaxis in the African and Asian population (Table I), which was also observed in a British study.34 This may be due to a general increase in the African and Asian population in Perth, but the increase in the Asian population also mirrors other studies’ suggestion that this population may be more predisposed to allergy in a Western environment.35 It would be of interest to investigate whether this also may apply to the African population. In both time periods, respiratory symptoms were a far more frequent sign of anaphylaxis than cardiovascular compromise, which is consistent with other pediatric studies.12,36 Adrenaline is advocated as a first-line treatment for anaphylaxis, yet underuse of adrenaline has been described in numerous studies,13,23,37-39 with higher use noted in more specialized centers.31,40 This range may reflect not only patient selection but also differences in the knowledge and experience of junior medical staff, teaching facilities, accessibility of specialist services, and availability, awareness, and reinforcement of guidelines. We suggest that the changes in anaphylaxis management at our center were related to intensified teaching programs including online accessible PED anaphylaxis guidelines, implementation of compulsory PED training and teaching sessions for medical staff, and improved cooperation between pediatric emergency specialists and allergists/immunologists. Management by GPs, paramedics, primary care givers, and school/day-care facilities remained similar within the 2 time periods (Table IV). This may reflect national primary care guidelines for schools/day-care facilities in Australia since 200320,21; however, our study was not designed to investigate this in detail. On the basis of pharmacokinetic studies,41,42 current guidelines advise to give adrenaline intramuscularly into the lateral thigh. Compared with other studies,43,44 in our study, all physicians followed this advice over both time periods. Instead of receiving first-line adrenaline treatment, patients are often treated with second-line therapies.9,10 There is no strong evidence to show that antihistamines,45 corticosteroids,46 or bronchodilators are effective in anaphylaxis management. They should therefore
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not be “routinely” administered in acute anaphylaxis and most importantly should not be considered a substitute for adrenaline. Our teaching incorporated this key point and our analysis revealed that significantly less second-line therapies were administered in 2012. According to current guidelines, it is advised that children are observed for at least 4 hours in the hospital setting after the onset of anaphylaxis or adrenaline administration.15 Follow-up arrangement with an allergist is highly recommended because anaphylaxis has a high risk of recurrence and the cause of the anaphylaxis may be unclear at the time of discharge from the ED.47 PED physicians play a pivotal role in this long-term transition. We have reinforced this in our PED teaching program. The arrangement of follow-up in our PED over both time periods was much higher than that seen in other studies (28%45% only),12,13 and a significant improvement was also observed in 2012, supporting the role of improved training programs and teaching facilities. After discharge from the ED, patients are at risk of being exposed to the same allergen, triggering further anaphylaxis or cross-reactions. There is also a risk of biphasic anaphylaxis. Therefore, these patients should be discharged from the ED with 2 adrenaline autoinjectors, or provided with the necessary prescription. The rate of adrenaline autoinjector dispensing/prescription in our PED was higher than that in other studies,31,38,47 with a significant improvement in 2012. Again, this is most likely a reflection of a successful physician training program. Biphasic anaphylaxis is a well-known complication of anaphylaxis. In our cohort of 251 cases of verified anaphylaxis, we identified 7 cases of biphasic anaphylaxis (2.8%). Rates in most other studies12,31,48-50 have been even lower. In contrast, a recently published Canadian PED-based study found a much higher rate (14.7%).51 Differences in rates may be explained by the different patient groups investigated, incomplete documentation, different awareness, or a different study design. It also needs to be taken into consideration that some patients may have developed biphasic anaphylaxis after discharge but did not return to the ED for representation and documentation. Hence, there is the likelihood that some cases of biphasic anaphylaxis were missed. However, considering that our ED is the only dedicated tertiary pediatric ED in the state of Western Australia, patients who lived around the metropolitan area would most likely have represented to our ED if they sought medical advice for a second bout of anaphylactic symptoms. Consistent with Katz et al,50 none of our patients exhibited a more severe reaction in the second half of the biphasic phase. On the basis of this and the comparatively low rate of biphasic anaphylaxis in numerous studies, we would not support a routinely prolonged (>4 hours) observation period in hospital after anaphylaxis or routine dispensing/prescription of more than 2 adrenaline autoinjectors. Instead, patients and their families would benefit from increased knowledge and awareness about biphasic anaphylaxis, which can be achieved by providing detailed information before discharge. Ideally, a prospective study admitting all patients with anaphylaxis for at least 72 hours, or following them in the community for an equivalent period, would be necessary to gain more insight into the frequency and presentation of biphasic anaphylaxis. However, this presents logistic challenges and may not be cost-effective. Because our hospital has the only tertiary PED in our state, a strength of our study is that a high proportion of anaphylactic cases present to our hospital. As a result, ED physicians see a
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high proportion of acute cases of anaphylaxis and play a key role in correctly identifying and addressing this life-threatening condition. A comparison of 2 significant time periods (before and after an intensified PED training program and improved cooperation between pediatric allergists/immunologists and pediatric emergency specialists) is therefore of particular value. It could be argued that other circumstantial factors influenced the results. However, neither medical education at the university nor curricula for basic/advanced trainees changed within this period of time, and nor did the composition of medical staff rotating through our PED. Furthermore, the medical service and hospital structure in Western Australia and the location, architecture, and facilities of our tertiary PED did not undergo significant changes within this 10-year period either. Although this is the first study on anaphylaxis management, the benefits of training programs and improved interdisciplinary cooperation aiming to improve clinical care in other medical areas have been supported by the literature.52-54 A limitation of this study is its retrospective nature. We cannot exclude the fact that some results may be influenced by incomplete documentation or a lack of awareness of health professionals. Because of poor documentation regarding the time of onset of first anaphylaxis signs, we were also unable to investigate for delayed administration of adrenaline, which is known to be associated with increased morbidity and mortality.55 We focused on cases coded for and verified as anaphylaxis. We cannot ignore that coding errors (cases of anaphylaxis accidentally coded for various allergic reactions) could have influenced our results. Another limitation of this study is that the educational intervention was implemented at a group level and not at an individual level. As a result, the effects of the educational program on individual caregivers could not be established. Future well-designed prospective studies looking at the impact of training programs on the management of anaphylaxis should address these issues.
CONCLUSIONS Rates of anaphylaxis are on the rise, particularly in children. Immediate recognition of the condition and prompt treatment with adrenaline is crucial given the risk of death, the considerable morbidity, and the significant burden for the health care system. This is the first study to suggest that identification, management, and arrangement of follow-up for anaphylaxis in a PED significantly improved over a 10-year period after the introduction of an intensified training program for medical staff and improved cooperation between pediatric emergency specialists and allergists/immunologists. Our study provides a platform for larger prospective well-designed future studies looking at the impact of well-developed training programs where PEDs and allergy/ immunology departments cooperate to optimize identification, management, and follow-up of anaphylaxis. REFERENCES 1. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117:391-7. 2. Turner PJ, Gowland MH, Sharma V, Ierodiakonou D, Harper N, Garcez T, et al. Increase in anaphylaxis-related hospitalizations but no increase in fatalities: an analysis of United Kingdom national anaphylaxis data, 1992-2012. J Allergy Clin Immunol 2015;135:956-963.e1.
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3. Nocerino R, Leone L, Cosenza L, Berni Canani R. Increasing rate of hospitalizations for food-induced anaphylaxis in Italian children: an analysis of the Italian Ministry of Health database. J Allergy Clin Immunol 2015;135:833-835.e3. 4. Mullins RJ, Dear KB, Tang ML. Time trends in Australian hospital anaphylaxis admissions in 1998-1999 to 2011-2012. J Allergy Clin Immunol 2015;136: 367-75. 5. Rueter K, Ta B, Bear N, Lucas M, Prescott S. Physician training programs significantly improve diagnosis in cases coded as anaphylaxis over time: a major factor compounding time-trend data? J Allergy Clin Immunol Pract 2017;5: 858-60. 6. Beyer K, Eckermann O, Hompes S, Grabenhenrich L, Worm M. Anaphylaxis in an emergency setting—elicitors, therapy and incidence of severe allergic reactions. Allergy 2012;67:1451-6. 7. Worm M, Eckermann O, Dolle S, Aberer W, Beyer K, Hawranek T, et al. Triggers and treatment of anaphylaxis: an analysis of 4,000 cases from Germany, Austria and Switzerland. Dtsch Arztebl Int 2014;111:367-75. 8. Fromer L. Prevention of anaphylaxis: the role of the epinephrine auto-injector. Am J Med 2016;129:1244-50. 9. Gaeta TJ, Clark S, Pelletier AJ, Camargo CA. National study of US emergency department visits for acute allergic reactions, 1993 to 2004. Ann Allergy Asthma Immunol 2007;98:360-5. 10. Fleming JT, Clark S, Camargo CA Jr, Rudders SA. Early treatment of foodinduced anaphylaxis with epinephrine is associated with a lower risk of hospitalization. J Allergy Clin Immunol Pract 2015;3:57-62. 11. Sheikh A, Hippisley-Cox J, Newton J, Fenty J. Trends in national incidence, lifetime prevalence and adrenaline prescribing for anaphylaxis in England. J R Soc Med 2008;101:139-43. 12. Braganza SC, Acworth JP, McKinnon DR, Peake JE, Brown AF. Paediatric emergency department anaphylaxis: different patterns from adults. Arch Dis Childhood 2006;91:159-63. 13. Melville N, Beattie T. Paediatric allergic reactions in the emergency department: a review. Emerg Med J 2008;25:655-8. 14. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Ann Emerg Med 2006;47:373-80. 15. Campbell RL, Li JT, Nicklas RA, Sadosty AT, Members of the Joint Task Force; Practice Parameter Workgroup. Emergency department diagnosis and treatment of anaphylaxis: a practice parameter. Ann Allergy Asthma Immunol 2014;113:599-608. 16. Mullins RJ, Loh RK. Childhood food allergy and anaphylaxis: an educational priority. Med J Aust 2015;202:7. 17. Storey P, Fitzharris P. Adrenaline in anaphylaxis: overtreatment in theory, undertreatment in reality. Postgraduate Med J 2015;91:1-2. 18. Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol 2005;95:217-26. 19. Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics 2000;106:762-6. 20. Baumgart K, Brown S, Gold M, Kemp A, Loblay R, Loh R, et al. ASCIA guidelines for prevention of food anaphylactic reactions in schools, preschools and child-care centres. J Paediatr Child Health 2004;40:669-71. 21. Vale S, Smith J, Said M, Mullins RJ, Loh R. ASCIA guidelines for prevention of anaphylaxis in schools, pre-schools and childcare: 2015 update. J Paediatr Child Health 2015;51:949-54. 22. Adeli M, Hendaus MA, Abdurrahim LI, Alhammadi AH. The importance of educating postgraduate pediatric physicians about food allergy. Adv Med Educ Pract 2016;7:597-602. 23. Ninchoji T, Iwatani S, Nishiyama M, Kamiyoshi N, Taniguchi-Ikeda M, Morisada N, et al. Current situation of treatment for anaphylaxis in a Japanese pediatric emergency center [published online ahead of print April 13, 2016]. Pediatr Emerg Care. https://doi.org/10.1097/PEC.0000000000000691. 24. Fineman SM, Bowman SH, Campbell RL, Dowling P, O’Rourke D, Russell WS, et al. Addressing barriers to emergency anaphylaxis care: from emergency medical services to emergency department to outpatient follow-up. Ann Allergy Asthma Immunol 2015;115:301-5. 25. Motosue MS, Bellolio MF, Van Houten HK, Shah ND, Campbell RL. Increasing emergency department visits for anaphylaxis, 2005-2014. J Allergy Clin Immunol Pract 2017;5:171-175.e3. 26. Dyer AA, Lau CH, Smith TL, Smith BM, Gupta RS. Pediatric emergency department visits and hospitalizations due to food-induced anaphylaxis in Illinois. Ann Allergy Asthma Immunol 2015;115:56-62. 27. Simons FE, Sampson HA. Anaphylaxis epidemic: Fact or fiction? J Allergy Clin Immunol 2008;122:1166-8.
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28. Simons FE, Sampson HA. Anaphylaxis: unique aspects of clinical diagnosis and management in infants (birth to age 2 years). J Allergy Clin Immunol 2015;135: 1125-31. 29. Fromer L, Sclar D, Cohen L, Robinson L. Economic burden of anaphylaxis in the USA. Allergy Asthma Proc 2012;33:374. 30. Harduar-Morano L, Simon MR, Watkins S, Blackmore C. Algorithm for the diagnosis of anaphylaxis and its validation using population-based data on emergency department visits for anaphylaxis in Florida. J Allergy Clin Immunol 2010;126:98-104.e4. 31. Huang F, Chawla K, Jarvinen KM, Nowak-Wegrzyn A. Anaphylaxis in a New York City pediatric emergency department: triggers, treatments, and outcomes. J Allergy Clin Immunol 2012;129:162-168.e1-68.e3. 32. Prescott SL, Pawankar R, Allen KJ, Campbell DE, Sinn JKh, Fiocchi A, et al. A global survey of changing patterns of food allergy burden in children. World Allergy Organ 2013;6:21. 33. Allen KJ, Koplin JJ. Why does Australia appear to have the highest rates of food allergy? Pediatr Clin North Am 2015;62:1441-51. 34. Buka RJ, Crossman RJ, Melchior CL, Huissoon AP, Hackett S, Dorrian S, et al. Anaphylaxis and ethnicity: higher incidence in British South Asians. Allergy 2015;70:1580-7. 35. Yocum MW, Butterfield JH, Klein JS, Volcheck GW, Schroeder DR, Silverstein MD. Epidemiology of anaphylaxis in Olmsted County: a populationbased study. J Allergy Clin Immunol 1999;104:452-6. 36. Campbell RL, Hagan JB, Manivannan V, Decker WW, Kanthala AR, Bellolio MF, et al. Evaluation of National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network criteria for the diagnosis of anaphylaxis in emergency department patients. J Allergy Clin Immunol 2012; 129:748-52. 37. Mehl A, Wahn U, Niggemann B. Anaphylactic reactions in children—a questionnaire-based survey in Germany. Allergy 2005;60:1440-5. 38. Campbell RL, Luke A, Weaver AL, St Sauver JL, Bergstralh EJ, Li JT, et al. Prescriptions for self-injectable epinephrine and follow-up referral in emergency department patients presenting with anaphylaxis. Ann Allergy Asthma Immunol 2008;101:631-6. 39. Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM, Bernstein DI, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010;126:477-480.e1-480.e42. 40. Nogic C, Belousoff J, Krieser D. The diagnosis and management of children presenting with anaphylaxis to a metropolitan emergency department: a 2-year retrospective case series. J Paediatr Child Health 2016;52:487-92.
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41. Simons FE, Roberts JR, Gu X, Simons KJ. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol 1998;101:33-7. 42. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol 2001;108:871-3. 43. Plumb B, Bright P, Gompels MM, Unsworth DJ. Correct recognition and management of anaphylaxis: not much change over a decade. Postgrad Med J 2015;91:3-7. 44. Rudders SA, Arias SA, Camargo CA Jr. Trends in hospitalizations for foodinduced anaphylaxis in US children, 2000-2009. J Allergy Clin Immunol 2014;134:960-962.e3. 45. Sheikh A, Ten Broek V, Brown SG, Simons FE. H1-antihistamines for the treatment of anaphylaxis: Cochrane systematic review. Allergy 2007;62:830-7. 46. Choo KJ, Simons E, Sheikh A. Glucocorticoids for the treatment of anaphylaxis: Cochrane systematic review. Allergy 2010;65:1205-11. 47. Dhami S, Panesar SS, Roberts G, Muraro A, Worm M, Bilò MB, et al. Management of anaphylaxis: a systematic review. Allergy 2014;69:168-75. 48. Grunau BE, Li J, Yi TW, Stenstrom R, Grafstein E, Wiens MO, et al. Incidence of clinically important biphasic reactions in emergency department patients with allergic reactions or anaphylaxis. Ann Emerg Med 2014;63:736-744.e2. 49. Rohacek M, Edenhofer H, Bircher A, Bingisser R. Biphasic anaphylactic reactions: occurrence and mortality. Allergy 2014;69:791-7. 50. Katz Y, Nowak-Wegrzyn A, Spergel JM. Prevalence of biphasic response in anaphylaxis due to purposeful administration of allergenic food. Ann Allergy Asthma Immunol 2015;115:526-7. 51. Lee S, Sadosty AT, Campbell RL. Update on biphasic anaphylaxis. Curr Opin Allergy Clin Immunol 2016;16:346-51. 52. Stratil J, Rieger MA, Voelter-Mahlknecht S. Optimizing cooperation between general practitioners, occupational health and rehabilitation physicians in Germany: a qualitative study. Int Arch Occup Environ Health 2017;90: 809-21. 53. Shapiro MJ, Morey JC, Small SD, Langford V, Kaylor CJ, Jagminas L, et al. Simulation based teamwork training for emergency department staff: Does it improve clinical team performance when added to an existing didactic teamwork curriculum? Qual Saf Health Care 2004;13:417-21. 54. Luckstead-Gosdin A, Vinson L, Greenwell C, Tweed J. Caring for kids: bridging gaps in pediatric emergency care through community education and outreach. Crit Care Nurs Clin North Am 2017;29:143-55. 55. Gonzalez-Perez A, Aponte Z, Vidaurre CF, Rodriguez LA. Anaphylaxis epidemiology in patients with and patients without asthma: a United Kingdom database review. J Allergy Clin Immunol 2010;125:1098-1104.e1.
Increased Use of Adrenaline in the Management of Childhood Anaphylaxis Over the Last Decade Kristina Rueter, MD, FRACP, PEMa,b,c, Brennan Ta, BScc, Natasha Bear, BSc, MStatd, Michaela Lucas, MD, FRACP, FRCPAb,e,f,g, Meredith L. Borland, MD, FACEMa,c,h, and Susan L. Prescott, PhD, MD, FRACPa,b Perth and Crawley, Western Australia, Australia
What is already known about this topic? Emergency department physicians play a key role in identifying and addressing anaphylaxis. However, there is evidence that adrenaline has been significantly underused in this lifethreatening condition and other management and follow-up procedures have been suboptimal. What does this article add to your knowledge? This is the first study to find evidence that identification and management of anaphylaxis in a pediatric emergency department (PED) significantly improved over a 10-year period after an intensified training program for medical staff and improved interdisciplinary cooperation. How does this study impact current management guidelines? The use of well-developed training programs for the recognition, management, and follow-up of anaphylaxis in the PED environment is urgently required. PEDs and allergy/ immunology departments need to cooperate to optimize anaphylaxis education and management.
BACKGROUND: We recently determined that allergy training programs have improved physician recognition and diagnosis of pediatric anaphylaxis in the last decade. a
School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia b Department of Paediatric Immunology, Princess Margaret Hospital for Children, Perth, Western Australia, Australia c Department of Paediatric Emergency Medicine, Princess Margaret Hospital for Children, Perth, Western Australia, Australia d Department of Clinical Research and Education, Child and Adolescent Health Services, Perth, Western Australia, Australia e School of Medicine and Pharmacology and School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia f Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia g Department of Immunology, Pathwest and Sir Charles Gairdner Hospital, Perth, Western Australia, Australia h School of Primary, Aboriginal and Rural Healthcare, University of Western Australia, Crawley, Western Australia, Australia This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of interest: S. L. Prescott is on regional scientific advisory boards of the Nestlé Nutrition Institute and Danone; has received consultancy fees from Bayer Pharmaceuticals; has received lecture fees and payment for developing educational presentations from the Nestlé Nutrition Institute, Danone, Bayer, and ALK Abello; receives royalties from a book; and has received travel expenses and speaker fees from these companies and from ALK Abello. The rest of the authors declare that they have no relevant conflicts of interest. Received for publication April 2, 2017; revised November 13, 2017; accepted for publication November 15, 2017. Available online -Corresponding author: Kristina Rueter, MD, FRACP, PEM, Princess Margaret Hospital for Children, Roberts Rd, Perth 6008, Western Australia, Australia. E-mail: [email protected]. 2213-2198 Ó 2018 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology https://doi.org/10.1016/j.jaip.2017.11.038
OBJECTIVE: To investigate for changes in management, in particular the appropriate use of adrenaline for the treatment of anaphylaxis in a tertiary pediatric emergency department (PED). METHODS: We conducted a retrospective case note study including children aged 0 to 16 years coded and verified for anaphylaxis comparing cases in years 2003/2004 with 2012. This included standardized information on clinical presentation, demographic characteristics, vital signs, mode of transport, and management of anaphylaxis including the use of adrenaline and/or adjunct therapy. Follow-up management plans were also recorded. RESULTS: In 2003/2004, a total of 92 cases were coded and verified for anaphylaxis from 83,832 PED presentations compared with 159 cases from 71,822 PED presentations in 2012. A significantly higher proportion of cases were appropriately managed with adrenaline in 2012 compared with 2003/2004, when intensive training programs had not yet been introduced (P [ .03). Vital signs were more frequently documented in 2012 (P < .001) than in 2003/2004, and there was significantly less administration of other medications (corticosteroids, bronchodilators, and antihistamines) (P < .05). Also, changes in discharge management occurred with an improved dispensing/ prescription of adrenaline autoinjectors and more frequent followup arrangement with specialist allergy services (P < .001). CONCLUSIONS: There was a significant improvement in the management of anaphylaxis over this 10-year period. This change was observed after the introduction of intensified physician training programs in which anaphylaxis management was a key component highlighting the importance of cooperation between pediatric emergency and allergy services. Ó 2018 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2017;-:---) Key words: Childhood; Anaphylaxis; Food allergy; Physician training; Anaphylaxis management; Adrenaline 1
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Abbreviations used GP- general practitioner ICD-10- International Classification of Diseases, Tenth Revision PED- pediatric emergency department
INTRODUCTION Anaphylaxis is a severe and potentially fatal systemic allergic reaction involving 2 or more organ systems within minutes to a few hours after contact with allergy-causing substances.1 The dramatic increase in anaphylaxis has occurred in parallel to the worldwide increase in allergic diseases in general, particularly in the pediatric population.2-5 Prompt treatment with adrenaline, the only first-line intervention for anaphylaxis, is recommended for all age groups to prevent potentially fatal progression. However, there is evidence that adrenaline has been significantly underused.6-8 Although other drugs are often given in anaphylaxis including H1 antihistamines, corticosteroids, and inhaled b2-sympathomimetics,9,10 there is limited evidence for the effectiveness of these in the acute treatment of anaphylaxis.11 There is also concern that other management and follow-up procedures are suboptimal or incomplete.12,13 Current practice guidelines recommend that patients are observed in a clinical setting for at least 4 hours after an episode of anaphylaxis or treatment with adrenaline and that adrenaline autoinjectors should be prescribed before discharge.14 Patients and/or carers should also be provided with appropriate instruction and training in the use of the device.14 It is also recommended that all patients who experienced anaphylaxis are referred to specialist allergy services to assist with identifying the offending trigger, appropriate allergy testing, and additional support and education.15 Given that the rates of this potentially fatal condition are rising,4 and contributing significantly to morbidity and health care costs, appropriate management is of critical importance and has been identified as a major issue.6,7,16,17 To our knowledge, no studies have investigated whether this has been addressed with improved medical education. We recently determined that allergy training programs had improved physician recognition and diagnosis of pediatric anaphylaxis in the last decade.5 The aim of the present study was to determine whether the management of anaphylaxis in children had also improved over this 10-year period after the introduction of intensified training programs and new anaphylaxis guidelines, relating in particular to the use of adrenaline. This study also provided an opportunity to examine changes in the characteristics of presenting cases (features of anaphylaxis, suspected triggers, and rate of biphasic anaphylaxis) over the time period. METHODS Emergency department anaphylaxis data We compared data from the years 2003/2004, when the International Classification of Diseases, Tenth Revision (ICD-10), codes were introduced in the Perth metropolitan area, with data from 2012, after intensified training programs, new anaphylaxis guidelines, and enhanced cooperation between pediatric emergency specialists and allergists/immunologists were introduced in our tertiary pediatric emergency department (PED). We focused on comparing the mode of arrival to the hospital, documentation of vital signs,
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adrenaline administration, use of adjunct therapy, adrenaline prescription, and arrangement of follow-up with an allergist/clinical immunologist. Information about ethnicity was obtained along with other personal details by clerking the patient before the medical assessment in the emergency department (ED). Ethnicity was reported by the patient’s parent or guardian. The methodology for the identification of anaphylaxis has been previously reported.5 We conducted a detailed retrospective chart examination of all cases coded as anaphylaxis (aged 0-16 years) presenting to the main tertiary PED in Perth, Western Australia. We compared data from January 1, 2003, to December 31, 2004 (period 1), when ICD-10 codes were introduced, with data from January 1, 2012, to December 31, 2012 (period 2), after intensified training programs and new anaphylaxis guidelines were introduced. Because the number of cases was small in 2003, we included an additional year (2004) to provide an adequate sample size for the preintervention phase. ICD codes were automatically assigned to patients on the basis of the diagnoses entered onto the ED information system by the treating physician. Charts with ICD-10 codes including anaphylactic shock after sting (T63.9), anaphylaxis (T78.2), food anaphylaxis (T78.0), anaphylaxis, unknown cause (T78.2), anaphylaxis, adverse drug reaction (T78.2), anaphylaxis not due to serum, not shock (T78.2), anaphylactic shock due to immunization (T80.5), anaphylactic shock due to serum (T80.5), and anaphylaxis due to drug (T88.6) were reviewed. We used criteria from the 2006 Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium for the definition and management of anaphylaxis.14 A biphasic reaction was defined as an initial anaphylactic reaction with a period of resolution of 1 hour or longer, during which there were no new symptoms or treatment administered, followed by a second-phase anaphylactic reaction within the next 72 hours, not caused by antigen reexposure.18,19 In our chart review, we also examined potential biphasic reactions, defined as representations to the hospital with anaphylaxis within 72 hours of initial presentation. All cases (aged 0-16 years) coded as anaphylaxis were independently reviewed by 2 allergists/clinical immunologists to verify the diagnosis. Information was collected on standardized forms. Demographic characteristics, identification of anaphylaxis, mode of transport, asthma history, clinical symptoms, medications administered, disposition, prescriptions of adrenaline autoinjectors, and arrangement to be followed up by an allergist were recorded for cases coded as anaphylaxis comparing period 1 with period 2.
Anaphylaxis education From February 2010, the Australian Society for Clinical Immunology and Allergy anaphylaxis guidelines20,21 were incorporated into electronic PED guidelines with online access to management and training information. Printed copies of anaphylaxis action plans were maintained in a separate and easily accessible location. In each term (of 10 weeks), 36 junior doctors rotated through our PED. All major decisions made by the junior staff were discussed with the senior staff. Number of staff, composition of staff (percentage of general practitioner [GP] trainees, ED trainees, and pediatric trainees in the group of junior doctors), and level of training were consistent during both time periods. Senior staff remained the same and consisted of a mixture of pediatricians, pediatric ED physicians, and ED physicians. The training was performed by a consultant pediatric allergist and emergency physician who was also available for any questions and concerns regarding allergic
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FIGURE 1. Case selection flow diagram.
reactions/anaphylaxis while working clinically in both PED and pediatric immunology settings. Specific emphasis was placed on the management of anaphylaxis in a PED setting. In 2012, both senior and junior staff had better and direct access to consistent educational programs compared with that in 2003/ 2004. These programs included a compulsory educational face-toface session for junior staff at the beginning of their term incorporating adrenaline autoinjector demonstrations with trainer devices, and videos demonstrating the correct use of devices (although these had previously been available to patients, parents, and families, medical staff were not specifically schooled in their use until 2010). Attendance was taken for each session and, upon a review of our records, we determined that 5% of junior staff failed to attend the session because of illness or personal circumstances. Senior staff attended the session once a year. Clinical staff were also provided with guidelines for discharge including referral to allergy services, initial allergen avoidance recommendations, provision of anaphylaxis information packs to families, and provision of an adrenaline autoinjector, directly dispensed by the PED to ensure immediate access to a device in the event of a biphasic reaction or immediate reexposure after discharge. The families were also provided with a prescription to purchase a second adrenaline autoinjector after discharge and information on biphasic anaphylaxis. The study was approved by the Ethics and Research Governance (GEKO, approval number 8660) at Princess Margaret Hospital for Children in Perth, Western Australia.
Statistical analysis All analyses were performed using Stata 14 (StataCorp, College Station, Tex). Outcomes were reported as means and SDs for continuous data and analyzed using independent t tests. Categorical data were represented as frequencies and proportions. Difference in proportions was assessed using chi-square test or the Fisher exact test (when expected cell count was less than 5). For the management of anaphylaxis odds ratios, 95% CIs were produced using logistic regression. The year 2012 was the reference category. Alpha was set at P < .05.
RESULTS A total of 83,832 cases presented to our PED between January 1, 2003, and December 31, 2004 (period 1), and 71,822 cases presented between January 1, 2012, and December 31, 2012 (period 2). This yielded 136 cases coded with anaphylaxis from period 1 and 177 cases from period 2. After review we confirmed anaphylaxis in 92 cases in period 1 and 159 cases in period 2 (Figure 1). Population characteristics The general characteristics of these populations are presented in Table I. Males were overrepresented in both time periods. We noted a significant increase in the proportion of Africans and Asians affected by anaphylaxis in the study population. The diagnosis of anaphylaxis was more accurate in 2012 (90% verified as correctly coded on the basis of symptoms) compared with
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TABLE I. Demographic characteristics and suspected triggers of children presenting to the PED with anaphylaxis in 2003/2004 and 2012 Characteristic
Anaphylaxis diagnoses Coded for anaphylaxis, n Verified cases, n Proportion correctly identified Sex, n (%) Male Female Age (y), mean SD Ethnicity, n (%) European Aboriginal Asian African First anaphylaxis Trigger, n (%) Food Drug Insect Other Food trigger Peanut Tree nut Egg Cow milk Fish and seafood Other History of asthma, n (%) On current treatment for asthma, n (%)
2003/2004
2012
TABLE II. Clinical features of anaphylaxis and documentation of vital signs in children presenting to the PED in 2003/2004 and 2012
P value Symptoms
136 92 67.6%
177 159 89.8%
69 (75) 23 (25) 6.6 4.2
111 (69.8) 48 (30.2) 5.8 4.4
.379
114 1 20 9 63
.058 .999 .004 .028 .345
.182
83 0 2 0 42
(97.6) (0) (2.3) (0) (47.7)
46 3 26 3
(59.0) 114 (84.4) <.001 (3.8) 4 (3.0) .709 (33.3) 13 (9.6) <.001 (3.8%) 4 (3.0) .709
14 9 10 6 1 6 28 6
(30.4) (19.6) (21.7) (13.0) (2.2) (13.0) (35.4) (10.3)
33 36 17 5 5 18 44 7
(79.2) (0.7) (13.9) (6.2) (41.4)
<.001
(29.0) (31.6) (14.9) (4.4) (4.4) (15.8) (31.0) (5.3)
.852 .126 .297 .050 .674 .660 .498 .205
Respiratory Wheeze Shortness of breath Tongue swelling Persistent cough Hoarse voice Stridor Throat tightness Cardiovascular Pale, floppy, cyanotic or loss of consciousness Skin Angioedema/urticaria Gastrointestinal Vomiting Abdominal pain Miscellaneous Itchy eyes/nose Throat tingling Grouped Displayed at least 1 respiratory symptom Vital signs Respiratory rate/min SaO2 in % Blood pressure (mm Hg) Heart rate/min
2003/2004 2012 (N [ 92), n (%) (N [ 159), n (%) P value
45 15 9 23
(49) (16) (10) (25)
44 43 25 43
(28) (27) (16) (27)
.001 .052 .2 .7
20 (22) 13 (14)
34 (21) 15 (9)
.9 .3
12 (13)
19 (12)
.8
82 (89)
124 (78)
28 (30) 3 (3)
33 (21) 14 (9)
.1 .1
9 (10) 11 (12)
14 (9) 13 (8)
.8 .3
88 (96)
146 (92)
.3
76 75 52 78
144 152 129 154
(83) (82) (57) (85)
(91) (96) (81) (97)
.027
.065 <.001 <.001 <.001
P < .05 was considered statistically significant.
68% of cases in 2003/2004 as previously reported5 (Figure 1), and vital signs (blood pressure, heart rate, and SaO2) were recorded more frequently in 2012 (P < .001) (Table II). Overall, the predominant suspected allergen trigger was food, with a significant increase observed between 2003/2004 and 2012 (Table I). A similar proportion of children presented with their first episode of anaphylaxis over both time periods. In twothirds of the children with previous adverse reactions, the suspected offending allergen was the same. The presenting features of anaphylaxis were generally similar, with respiratory signs being the more frequent defining symptom of anaphylaxis than cardiovascular compromise (Table I). Wheeze was reported more frequently in 2003/2004 than in 2012 (P ¼ .001) and angioedema more frequently in 2012 (P ¼ .027), but other features were similar. The potential rate of biphasic anaphylaxis captured via chart review was 2.8% (7 out of 251) and was also similar between 2003/2004 and 2012. There was no significant difference in the mode of transport to hospital (Table III). In 2012, there was a tendency for patients with anaphylaxis to stay longer, on average, in the PED than in 2003/2004. This result, however, did not reach significance (median [interquartile range]2003/ 2004 vs 2012: 216.0 minutes [128.0-654.5] vs 252.0 minutes [189-588]; P ¼ .177). Patient disposition was significantly more likely to be admission to the PED observation ward in 2012 (P < .001).
Management of anaphylaxis with adrenaline Appropriate treatment of anaphylaxis with adrenaline before and after arrival at PED occurred in significantly more cases with confirmed anaphylaxis in 2012 than in 2003/2004 (P ¼ .03) (Table IV). In all cases, adrenaline was given intramuscularly. Focusing on cases in which adrenaline was not administered, there was a significantly higher proportion of patients to whom adrenaline was not given despite being clinically indicated and available in 2003/2004 (P ¼ .009). To further investigate this, we analyzed different subgroups (Table IV). Failure of adrenaline administration by paramedics, GPs, primary care takers, or schools before patients arrived at hospital was not significantly different over time. However, after arrival at the hospital the odds of being mismanaged were 88% lower in 2012 compared with 2003/2004 (P < .001). Differences in anaphylaxis management over time were also reflected in the reduced use of adjunctive medications. There were less first-generation (sedating) and more second-generation (nonsedating) antihistamines being prescribed in 2012 (P < .001). Corticosteroids (P < .001) and b2-agonists (P ¼ .029) were administered significantly less in 2012 (Table IV). Number and allocation of hospital beds did not change between 2003/2004 and 2012. However, there were significantly more children with anaphylaxis admitted to the PED observation
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5
TABLE III. Mode of arrival, length of stay, disposition, dispensing/prescription of adrenaline autoinjector, and arrangement of follow-up by an allergist/immunologist for children presenting with anaphylaxis to a PED in 2003/2004 and 2012 2003/2004
Mode of arrival, n (%) Ambulance Private vehicle Aircraft Other Median PED length of stay (min), median (IQR) Disposition, n (%) Home Ward PED observation ward Intensive care unit Dispensing/prescription of adrenaline autoinjector, n (%) Follow-up by allergy service, n (%) Already linked or new referral
43 48 0 1 216 26 27 37 2 50
2012
P value
(46.7) (52.2) (0) (1.1) (128-654.5)
66 93 0 0 252
(41.5) (58.5) (0) (0) (189-588)
(28.3) (29.4) (40.2) (2.2) (53.4)
21 3 134 1 129
(13.2) (1.9) (84.3) (0.6) (81.1)
<.001
158 (99.4)
<.001
81 (88.0)
.249
.177
<.001
TABLE IV. Administration of adrenaline and adjunct therapy in children with anaphylaxis presenting to the PED in 2003/2004 and 2012 Anaphylaxis management
Adrenaline indicated/given Suboptimal* Adrenaline not given Mismanagement† Mismanaged by PED doctors Paramedics GP Family School/day care H1 antihistamine Antihistamine type First-generation Second-generation H1 antihistamine and adrenaline Both not given Adrenaline only Antihistamine only Adrenaline and antihistamine Corticosteroids b2-agonist
2003/2004, n (%)
2012, n (%)
OR (95% CI) (2003/2004 reference category)
P value
N 11 44 37 N
¼ 92 (12) (47.8) (40.2) ¼ 45
N ¼ 159 45 (28.3) 75 (47.2) 39 (24.5) N ¼ 39
2.91 (1.42-5.96) 0.97 (0.58-1.63) 0.48 (0.28-0.84)
.030 .920 .009
16 14 2 13 0 76
(35.6) (31.1) (4.4) (28.9) (0) (82.6)
4 13 0 22 0 116
0.12 (0.04-0.36) 0.50 (0.23-1.09) NA 0.98 (0.47-2.02) NA 0.57 (0.30-1.07)
<.001 .083 .133 .948 NA .082
NA NA
<.001 <.001
(10.6) (33.3) (0) (56.4) (0) (73.0)
43 (82.7) 9 (17.3)
25 (22.9) 85 (77.1)
5 11 28 48 53 25
13 30 47 69 46 25
(5.4) (12.0) (30.4) (52.2) (57.6) (27.2)
(8.2) (18.9) (29.6) (43.4) (28.9) (15.7)
1.55 1.70 0.96 0.70 0.30 0.50
(0.53-4.49) (0.81-3.61) (0.55-1.68) (0.42-1.18) (0.17-0.51) (0.27-0.93)
.420 .157 .884 .180 <.001 .029
GP, General practitioner; NA, not applicable; OR, odds ratio. P < .05 was considered statistically significant. Out of 37 cases, 8 were mismanaged in 2 groups (hospital and paramedics [n ¼ 2], hospital and family [n ¼ 3], and paramedic and family [n ¼ 3]) in 2003/2004. In 2012, we could not identify any cases that were mismanaged in 2 areas. *Cases would have required adrenaline but did not receive any either because of a first presentation with an allergic reaction/anaphylaxis (primary caretaker cannot be expected to have the knowledge and equipment regarding anaphylaxis management) or because symptoms self-resolved before adrenaline was available. †Adrenaline was indicated and available but not given.
ward for a more than 4-hour observation period in 2012 than were admitted to the inpatient ward overnight (Table III). The proportion of children discharged with an adrenaline autoinjector significantly increased in 2012 (children with anaphylaxis to drugs were excluded from analysis, because avoidance is the primary management without indication for prescription of an adrenaline autoinjector), as did the proportion of children provided with arrangements for follow-up by allergy services (Table III).
DISCUSSION We found evidence that the management of anaphylaxis in a PED environment significantly improved after the introduction of structured physician training programs and greater collaboration between pediatric emergency specialists and allergists/immunologists. Although education and implementation of management guidelines for physicians treating patients with anaphylaxis has been identified globally as a shortfall,6,7,22-24 to
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our knowledge there are no studies investigating the impact of training programs on anaphylaxis management in children. Our goal was to address this important knowledge gap in the PED environment, because emergency physicians work on the front line for anaphylaxis management, and rates of anaphylaxis and allergies are dramatically rising.4,25,26 In our own PED cohort, a 2.2-fold increase in verified anaphylaxis cases within 10 years was particularly observed among infants.5 This age shift is significant because anaphylaxis can be underrecognized in this age group27,28 because of a broad range of subtle and sometimes unspecific symptoms,28 underscoring the need for education and increased awareness.29 Up to 70% of patients presenting to the ED with anaphylaxis can be misdiagnosed or miscoded.5,15,30,31 We have previously shown that physician training programs can improve the correct identification and coding of anaphylaxis5 and here we have demonstrated that this is also associated with improved pharmacological and general management of anaphylaxis. Vital signs were more frequently documented in 2012 compared with 2003/ 2004, indicating an increased awareness of the observational tools required for assessing and observing anaphylaxis. Globally, the prevalence of food allergy seems to be higher per se in Australian children.32,33 We noted a significant increase in anaphylaxis in the African and Asian population (Table I), which was also observed in a British study.34 This may be due to a general increase in the African and Asian population in Perth, but the increase in the Asian population also mirrors other studies’ suggestion that this population may be more predisposed to allergy in a Western environment.35 It would be of interest to investigate whether this also may apply to the African population. In both time periods, respiratory symptoms were a far more frequent sign of anaphylaxis than cardiovascular compromise, which is consistent with other pediatric studies.12,36 Adrenaline is advocated as a first-line treatment for anaphylaxis, yet underuse of adrenaline has been described in numerous studies,13,23,37-39 with higher use noted in more specialized centers.31,40 This range may reflect not only patient selection but also differences in the knowledge and experience of junior medical staff, teaching facilities, accessibility of specialist services, and availability, awareness, and reinforcement of guidelines. We suggest that the changes in anaphylaxis management at our center were related to intensified teaching programs including online accessible PED anaphylaxis guidelines, implementation of compulsory PED training and teaching sessions for medical staff, and improved cooperation between pediatric emergency specialists and allergists/immunologists. Management by GPs, paramedics, primary care givers, and school/day-care facilities remained similar within the 2 time periods (Table IV). This may reflect national primary care guidelines for schools/day-care facilities in Australia since 200320,21; however, our study was not designed to investigate this in detail. On the basis of pharmacokinetic studies,41,42 current guidelines advise to give adrenaline intramuscularly into the lateral thigh. Compared with other studies,43,44 in our study, all physicians followed this advice over both time periods. Instead of receiving first-line adrenaline treatment, patients are often treated with second-line therapies.9,10 There is no strong evidence to show that antihistamines,45 corticosteroids,46 or bronchodilators are effective in anaphylaxis management. They should therefore
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not be “routinely” administered in acute anaphylaxis and most importantly should not be considered a substitute for adrenaline. Our teaching incorporated this key point and our analysis revealed that significantly less second-line therapies were administered in 2012. According to current guidelines, it is advised that children are observed for at least 4 hours in the hospital setting after the onset of anaphylaxis or adrenaline administration.15 Follow-up arrangement with an allergist is highly recommended because anaphylaxis has a high risk of recurrence and the cause of the anaphylaxis may be unclear at the time of discharge from the ED.47 PED physicians play a pivotal role in this long-term transition. We have reinforced this in our PED teaching program. The arrangement of follow-up in our PED over both time periods was much higher than that seen in other studies (28%45% only),12,13 and a significant improvement was also observed in 2012, supporting the role of improved training programs and teaching facilities. After discharge from the ED, patients are at risk of being exposed to the same allergen, triggering further anaphylaxis or cross-reactions. There is also a risk of biphasic anaphylaxis. Therefore, these patients should be discharged from the ED with 2 adrenaline autoinjectors, or provided with the necessary prescription. The rate of adrenaline autoinjector dispensing/prescription in our PED was higher than that in other studies,31,38,47 with a significant improvement in 2012. Again, this is most likely a reflection of a successful physician training program. Biphasic anaphylaxis is a well-known complication of anaphylaxis. In our cohort of 251 cases of verified anaphylaxis, we identified 7 cases of biphasic anaphylaxis (2.8%). Rates in most other studies12,31,48-50 have been even lower. In contrast, a recently published Canadian PED-based study found a much higher rate (14.7%).51 Differences in rates may be explained by the different patient groups investigated, incomplete documentation, different awareness, or a different study design. It also needs to be taken into consideration that some patients may have developed biphasic anaphylaxis after discharge but did not return to the ED for representation and documentation. Hence, there is the likelihood that some cases of biphasic anaphylaxis were missed. However, considering that our ED is the only dedicated tertiary pediatric ED in the state of Western Australia, patients who lived around the metropolitan area would most likely have represented to our ED if they sought medical advice for a second bout of anaphylactic symptoms. Consistent with Katz et al,50 none of our patients exhibited a more severe reaction in the second half of the biphasic phase. On the basis of this and the comparatively low rate of biphasic anaphylaxis in numerous studies, we would not support a routinely prolonged (>4 hours) observation period in hospital after anaphylaxis or routine dispensing/prescription of more than 2 adrenaline autoinjectors. Instead, patients and their families would benefit from increased knowledge and awareness about biphasic anaphylaxis, which can be achieved by providing detailed information before discharge. Ideally, a prospective study admitting all patients with anaphylaxis for at least 72 hours, or following them in the community for an equivalent period, would be necessary to gain more insight into the frequency and presentation of biphasic anaphylaxis. However, this presents logistic challenges and may not be cost-effective. Because our hospital has the only tertiary PED in our state, a strength of our study is that a high proportion of anaphylactic cases present to our hospital. As a result, ED physicians see a
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high proportion of acute cases of anaphylaxis and play a key role in correctly identifying and addressing this life-threatening condition. A comparison of 2 significant time periods (before and after an intensified PED training program and improved cooperation between pediatric allergists/immunologists and pediatric emergency specialists) is therefore of particular value. It could be argued that other circumstantial factors influenced the results. However, neither medical education at the university nor curricula for basic/advanced trainees changed within this period of time, and nor did the composition of medical staff rotating through our PED. Furthermore, the medical service and hospital structure in Western Australia and the location, architecture, and facilities of our tertiary PED did not undergo significant changes within this 10-year period either. Although this is the first study on anaphylaxis management, the benefits of training programs and improved interdisciplinary cooperation aiming to improve clinical care in other medical areas have been supported by the literature.52-54 A limitation of this study is its retrospective nature. We cannot exclude the fact that some results may be influenced by incomplete documentation or a lack of awareness of health professionals. Because of poor documentation regarding the time of onset of first anaphylaxis signs, we were also unable to investigate for delayed administration of adrenaline, which is known to be associated with increased morbidity and mortality.55 We focused on cases coded for and verified as anaphylaxis. We cannot ignore that coding errors (cases of anaphylaxis accidentally coded for various allergic reactions) could have influenced our results. Another limitation of this study is that the educational intervention was implemented at a group level and not at an individual level. As a result, the effects of the educational program on individual caregivers could not be established. Future well-designed prospective studies looking at the impact of training programs on the management of anaphylaxis should address these issues.
CONCLUSIONS Rates of anaphylaxis are on the rise, particularly in children. Immediate recognition of the condition and prompt treatment with adrenaline is crucial given the risk of death, the considerable morbidity, and the significant burden for the health care system. This is the first study to suggest that identification, management, and arrangement of follow-up for anaphylaxis in a PED significantly improved over a 10-year period after the introduction of an intensified training program for medical staff and improved cooperation between pediatric emergency specialists and allergists/immunologists. Our study provides a platform for larger prospective well-designed future studies looking at the impact of well-developed training programs where PEDs and allergy/ immunology departments cooperate to optimize identification, management, and follow-up of anaphylaxis. REFERENCES 1. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117:391-7. 2. Turner PJ, Gowland MH, Sharma V, Ierodiakonou D, Harper N, Garcez T, et al. Increase in anaphylaxis-related hospitalizations but no increase in fatalities: an analysis of United Kingdom national anaphylaxis data, 1992-2012. J Allergy Clin Immunol 2015;135:956-963.e1.
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