Anaphylaxis Refractory to intramuscular adrenaline during in‐hospital food challenges: A case series and proposed management

Anaphylaxis is a severe, systemic hypersensitivity reaction that can be potentially life‐threatening. Anaphylaxis during oral food challenge is not uncommon and can usually be effectively managed with intramuscular adrenaline as first line treatment. Although very rare, fatal anaphylaxis during in‐hospital food challenge has been reported.


| INTRODUC TI ON
Anaphylaxis is 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 breathing and/or the circulation and may occur without typical skin features or circulatory shock being present". 1 Based on 10 European studies, the incidence of anaphylaxis is around 1.5-7.9 per 10 000 person years, with a prevalence of 0.3%. 2 Hospitalizations due to anaphylaxis have increased over the past two decades, but fatal anaphylaxis is very uncommon and the rate of fatal food anaphylaxis has not increased over the same time period. 3 Oral food challenges (OFC) are a key tool to confirm the diagnosis or resolution of food allergy. 4 Anaphylaxis during OFC is not uncommon, and rates vary by patient age, food tested and geographical region. Anaphylaxis is not predictable. 5 A retrospective, multicentre survey of 1635 children and adolescents undergoing a hospital-based peanut food OFC demonstrated an 11% anaphylaxis rate in this group, 6 which is in line with previously reported rates of adrenaline use in 9%-11% of OFC. 7,8 Fatal anaphylaxis due to food is rare, 9 and until recently, no cases of fatal anaphylaxis had been reported during hospital-based OFC. However, two recent deaths have been reported in the context of OFC conducted in specialist centres: a 3-year-old boy following a baked milk OFC in the USA, 10 and an 11-year-old boy who died after a peanut OFC. 11 The risk of severe anaphylaxis during OFC conducted under medical supervision must therefore be recognized. In this paper, we present four cases of severe anaphylaxis during hospital-based OFC that were refractory to initial treatment and discuss the management approach to these cases.

| ME THODS
This paper is based on four paediatric cases of severe anaphylaxis during hospital-based food challenge that were refractory to initial treatment, between 2018 and 2019 in the South-East of England.
Informed consent was obtained from the families for this report.
Data on the indications for challenge, challenge procedure, nature of the reaction, treatment given and response to therapy were collected from the chart of each patient.

| Case 1
A 17-year-old Caucasian male with isolated peanut allergy and index reaction at age 1 year (hives and facial angioedema after eating peanut butter). He had since avoided peanut, with no further reactions. He had been prescribed fluticasone/salmeterol inhaler for asthma but was non-compliant although this did not cause him significant symptoms and baseline spirometry was within normal range. Allergy testing at most recent follow-up was consistent with PR10 sensitization and declining levels of IgE against seed storage proteins, suggesting that true peanut allergy may have resolved and been replaced by pollen food allergy syndrome (see Table 1). An OFC was therefore undertaken to clarify his diagnosis prior to transitioning to adult services, given his decision not to carry adrenaline auto-injector on the basis that he could not remember experiencing a reaction.

| Case 2
A 15-year-old teenage male of Afro Caribbean origin, with multiple allergies to cow's milk, egg, peanut, cashew, pistachio and shrimp.
He was prescribed a regular budesonide/formoterol inhaler, and his asthma was well-controlled with minimal breakthrough symptoms. He had experienced previous anaphylaxis at age 10 years to an unknown trigger (possibly nut/egg contamination) which was treated with IM adrenaline. During his most recent clinic review, he reported he was eating significant quantities of rice cakes containing milk. Based on this history and clinical testing (Table 1), was booked to undergo a baked milk OFC to assess tolerance to baked milk.
He completed the full challenge protocol (1.37 g milk protein baked into a muffin). Thirty minutes later, he experienced chest tightness and self-administered his salbutamol inhaler prior to informing the supervising nurse. He immediately received 500 mcg IM adrenaline via needle and syringe, oral cetirizine and prednisolone, nebulized salbutamol and high flow oxygen. Despite this, he continued to experience significant dyspnoea and was treated with a further two 500 mcg doses of IM adrenaline (also via needle and syringe) with no improvement. He was given an intravenous adrenaline bolus of 10 micrograms of adrenaline (equivalent to 0.17 mcg/ kg) over five minutes with immediate benefit. No further adrenaline was required, and he was discharged the following day.

| Case 4
A 15-year-old white Caucasian female with multiple nut allergies (peanut, hazelnut, macadamia) and prior anaphylaxis to peanut requiring 2 doses of IM adrenaline at age 13 years. She had well-controlled asthma (beclomethasone twice daily

| D ISCUSS I ON
National and international guidelines recommend the administration of intramuscular adrenaline for initial management of anaphylaxis. [12][13][14] Despite this, adrenaline remains significantly underused, both in the community, 15 but also in hospital 16 and even in simulated scenarios errors frequently occur. 17 There are, unsurprisingly,

F I G U R E 1 Proposed adrenaline infusion guideline 29
no randomized controlled on the use of adrenaline for anaphylaxis, and recommendations are based on observational data, consensus opinion and pharmacological effect. 14,18,19 Adrenaline should be administered intramuscularly to the anterolateral thigh, using 1:1000 adrenaline at a dose of 0.01 mL/kg (maximum dose 500 mcg or 0.5 mL of 1:1000). Alternatively, fixed doses based on age and weight can be used for greater ease. 12,13 . Intramuscular adrenaline works best if used promptly, before anaphylaxis has had time to progress 20 and it has an excellent safety profile. 12,13,21 Transient effects after IM adrenaline administration include pallor, tremor, dizziness, palpitations and headache; these indicate that a therapeutic dose has been given. 14 Around 10% of patients who use IM adrenaline for food-induced anaphylaxis continue to experience anaphylaxis requiring at least one further dose to alleviate symptoms. 15,22 All of our patients experienced life-threatening anaphylaxis, with prominent lower respiratory tract involvement (bronchoconstriction). All four were teenagers, an age group known to be at higher risk of fatal reactions. 23,24 They also had asthma, a common feature in fatal food-induced anaphylaxis, affecting up to 75% of cases. 23,24 Of note, they demonstrated worsening of symptoms despite multiple doses of IM adrenaline, thus it is possible that these patients might have suffered a fatal outcome had their reactions occurred out of hospital. 25 Intramuscular adrenaline administration alone is not a guarantee of anaphylaxis reversal: in fact, one third of fatalities due to food-anaphylaxis in the UK receive timely adrenaline and yet still die. [26][27][28] Given the available data from venom-induced anaphylaxis, 29 it is likely that this reflects a need for more intensive adrenaline administration-beyond that achievable with adrenaline auto-injectors-together with intravenous fluids. A further concern is the limited impact of intramuscular adrenaline on cardiovascular function during anaphylaxis, in contrast to the significant beneficial effects on respiratory symptoms. 30 Therefore, patients requiring more than two doses of IM adrenaline are likely to require an adrenaline infusion. 12,13 Intravenous adrenaline is not without risks, and guidelines suggest its use be limited to "those experienced in the use and titration of vasopressors in their normal clinical practice (e.g. anaesthetists, emergency physicians, intensive care doctors)." 12 However, the protocol suggested by Brown et al 29   An additional key element in the management of severe anaphylaxis is avoiding an upright posture, which has been associated with fatal events (thought to be due to postural hypotension in the context of an anaphylaxis-induced decrease in venous return, causing sudden circulatory collapse 14,32 ). A recumbent or semi-recumbent posture with legs elevated is preferable. 14,26 It is crucial that in severe reactions, healthcare staff avoid the temptation to move patients to a stabilization/ high dependency area prior to stabilization.
This may entail the setting up of an adrenaline infusion in a clinical area where staff are unfamiliar with its use: this must be addressed in any local protocol, and risk mitigated through staff training and support from critical care areas.
In summary, we report four cases of refractory anaphylaxis successfully treated with low-dose intravenous adrenaline through a peripheral canula. While IM adrenaline remains the mainstay of first aid management of anaphylaxis, we encourage physicians who routinely perform procedures such as OFC to consider a framework for managing refractory reactions; this should include consideration of a peripheral intravenous adrenaline infusion (according to Figure 1 & Table 2) as a rescue option while specialist critical care support is obtained.  Apply high flow oxygen. Do not move the patient but leave in semi-recumbent position. 3. Administer 2nd dose of IM adrenaline at 10 mcg/kg maximum 500 mcg using needle and syringe, into anterolateral thigh (use opposite side to initial IM adrenaline) 4. Apply ECG/HR/BP monitoring IV adrenaline infusion (see Figure 1): • Secure 2 x wide-bore intravenous cannula, for example antecubital fossa. • Prepare IV adrenaline infusion and initiate as per Figure 1 • Give IV fluids vis second cannula (adrenaline may be ineffective in the absence of adequate fluid resuscitation) • Seek urgent intensive care or anaesthetic support