Guideline (S2k) on Acute Therapy and Management of Anaphylaxis: 2021 Update

guidelines

Allergo J Int (2021) 30:1–25 https://doi.org/10.1007/s40629-020-00158-y

Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update

S2k-Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Medical Association of German Allergologists (AeDA), the Society of Pediatric Allergology and Environmental Medicine (GPA), the German Academy of Allergology and Environmental Medicine (DAAU), the German Professional Association of Pediatricians (BVKJ), the Society for Neonatology and Pediatric Intensive Care (GNPI), the German Society of Dermatology (DDG), the Austrian Society for Allergology and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Anaesthesiology and Intensive Care Medicine (DGAI), the German Society of Pharmacology (DGP), the German Respiratory Society (DGP), the patient organization German Allergy and Asthma Association (DAAB), the German Working Group of Anaphylaxis Training and Education (AGATE)

Johannes Ring · Kirsten Beyer · Tilo Biedermann · Andreas Bircher · Matthias Fischer · Thomas Fuchs · Axel Heller · Florian Hoffmann · Isidor Huttegger · Thilo Jakob · Ludger Klimek · Matthias V. Kopp · Claudia Kugler · Lars Lange · Oliver Pfaar · Ernst Rietschel · Franziska Rueff · Sabine Schnadt · Roland Seifert · Britta Stöcker · Regina Treudler · Christian Vogelberg · Thomas Werfel · Margitta Worm · Helmut Sitter · Knut Brockow

Published online: 28 January 2021 © The Author(s) 2021

Keywords Anaphylaxis · Food allergy · Drug LT Leukotriene allergy · Adrenalin · Emergency management · NSAID Non-steroidal anti-inﬂammatory drugs Pharmacotherapy · Group education · Auto-injector · PAF Platelet-activating factor COVID-19 · Vaccination s.c. Subcutaneous

Abbreviations Background ACE Angiotensin converting enzyme AGATE German Working Group of Anaphylaxis Train- Anaphylaxis is an acute systemic reaction involving ing and Education symptoms of an immediate-type allergic reaction that CD Cluster of differentiation can comprise the whole organism and potentially be DAAB Patient organization German Allergy and fatal [1–3]. Asthma Association Although anaphylaxis is a highly acute process in EIA Exercise-induced anaphylaxis terms of its symptoms, there is a chronic immunolog- FDEIA Food-dependent exercise-induced anaphy- ical imbalance underlying this condition that leads to laxis immediate reactions as soon as contact with the elic- FiO2 Inspired oxygen fraction itor occurs. This chronic condition may have severe ICD International Statistical Classification of Dis- effects of both a psychological and an organizational eases and Related Health Problems nature on the everyday life of affected individuals. IgE Immunoglobulin E The definition of anaphylaxis is not internationally i.m. Intramuscular standardized. Also, a number of different classifica- i.v. Intravenous tion systems are in use. The most commonly used

K Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update 1 guidelines

classification in German-speaking countries is used not provide evidence-based information on whether in this guideline. specific treatments have been effective. Anaphylactic reactions are among the most severe, It is well known that patients, e.g., after successfully potentially life-threatening, and dramatic events in al- treated anaphylaxis due to an insect sting, are not op- lergology. Acute treatment is carried out according timally followed-up [9–11]. These problems in basic to international guidelines and recommendations in management underline the need for further research, textbooks. This guideline is an update of earlier ver- as well as the importance of the guideline presented sions from 1994, 2007, and 2014 [4–8] and takes in- here. ternational guidelines [3, 7] into consideration (see This guideline is intended for all physicians, as well Addendum). as other individuals active in health care, involved in Anaphylactic reactions may spontaneously cease the acute treatment, diagnostics, and management of at any stage of symptoms, but may also progress patients with anaphylaxis. in severity despite adequate treatment. This unpre- dictability makes it difficult to evaluate the efficacy of Epidemiology of anaphylaxis therapeutic procedures. Single-case observations do In recent years, a number of studies on the world- wide prevalence of anaphylactic reactions have been Prof.Dr.Dr.J.Ring( ) · T. Biedermann · C. Kugler · published [12–21]. Due to the varying definitions, as K. Brockow Department Dermatology and Allergology Biederstein, well as the fact that anaphylaxis with fatal outcome is Technical University Munich, Biedersteiner Straße 29, 80802 Munich, Germany O. Pfaar [email protected] Section of Rhinology and Allergy, Department of K. Beyer Otorhinolaryngology, Head and Neck Surgery, University Department of Pediatrics, Division of Pulmonology, Hospital Marburg, Philipps-University Marburg, Marburg, Immunology and Critical Care Medicine, Germany Charité—University Hospital Berlin, Berlin, Germany E. Rietschel A. Bircher Department of Pediatrics, University Hospital Cologne, Department of Dermatology, University Hospital of Basel, Cologne, Germany Basel, Switzerland F.Rueff M. Fischer Department of Dermatology and Allergology, Hospital of the Clinic for Anaesthesiology, Intensive Care Medicine, Ludwig Maximilians University, Munich, Germany Emergency Medicine and Pain Therapy, ALB FILS Hospitals Göppingen, Göppingen, Germany S. Schnadt German Allergy and Asthma Association, T. Fuchs Mönchengladbach, Germany Department of Dermatology, University Hospital Göttingen, Göttingen, Germany R. Seifert Institute of Pharmacology, Hannover Medical School, A. Heller Hannover, Germany Department of Anesthesiology and Operative Intensive Care Medicine, Medical Faculty, University of Augsburg, B. Stöcker Augsburg, Germany Medical practice for pediatrics and youth medicine, Poppelsdorfer Allee, Bonn, Germany F.Hoffmann Dr. von Hauner Children’s Hospital, Ludwig Maximilians R. Treudler University, Munich, Germany Department of Dermatology, Venereology, and Allergology, Leipzig Interdisciplinary Allergy Center, University Hospital I. Huttegger Leipzig, Leipzig, Germany Department of Pediatrics, University Hospital Salzburg, Salzburg, Austria C. Vogelberg Department of Pediatric Pneumology and Allergology, T. Jakob University Hospital Carl Gustav Carus, Technical University Department of Dermatology and Allergology, University of Dresden, Dresden, Germany Medical Center Gießen (UKGM), Justus-Liebig-University Gießen, Gießen, Germany T. Werfel Immunodermatology and Experimental Allergology Unit, L. Klimek Department of Dermatology, Allergology, and Venereology, Center of Rhinology and Allergology, Wiesbaden, Germany Medical University Hannover, Hannover, Germany M. V. Kopp M. Worm Pediatric Respiratory Medicine, Department of Pediatrics, Department of Dermatology, Venereology, and Allergology, Inselspital, Bern University Hospital, University of Bern, Charité—University Hospital Berlin, Berlin, Germany Bern, Switzerland H. Sitter L. Lange Institute for Surgical Research, Philipps-University Marburg, St. Marien-Hospital Bonn, Bonn, Germany Marburg, Germany

2 Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update K guidelines

Table 1 Common elicitors of severe anaphylactic reac- Pathophysiology tions in children and adults (data from the anaphylaxis registry March 2017, n= 8046 [28, 29]) Anaphylaxis is usually caused by an immunologi- Elicitors Children Adults cal reaction—most frequently an immunoglobulin E (in %) (in %) (IgE)-mediated allergy. IgE activates mast cells and Foods 60 16 basophils via cross-linking of high-affinity IgE re- Insect venoms 22 52 ceptors, leading to increased expression of surface Drugs 7 22 markers (CD63, CD203c), as indirectly measurable Others 5 3 on basophils. The symptoms of anaphylactic reac- Unknown 7 6 tions are mediated by a variety of substances released from mast cells and basophil granulocytes such as histamine, prostaglandins, leukotrienes (LTB 4, LTC 4, not always diagnosed, one needs to assume a certain and LTD 4), tryptase, platelet-activating factor (PAF), number of unreported cases. heparin, proteases, serotonin, and cytokines [30–34]. A limitation with regard to data on the epidemiol- The relative importance of these mediators in humans ogy of anaphylaxis arises due to the variable coding cannot easily be estimated for methodological reasons of anaphylaxis according to ICD-10. There are several and is a matter of discussion. There is consensus that ICD-10 codes that can include anaphylaxis. The new histamine is involved in anaphylactic reactions [30]. ICD-11 will be introduced in 2022, possibly with a new Thus, the intravenous application of histamine can classification of anaphylaxis [22–24]. There is a par- elicit anaphylactic symptoms in healthy individu- ticular need for classification regarding whether re- als [35, 36]. Furthermore, there is discussion as to peated cutaneous reactions in manifest type I allergy whether, in addition to IgE in rare cases (e.g., dex- can already be regarded as anaphylaxis, whether, by tran 4,5), other antibody classes can also elicit similar definition, involvement of at least two organ systems symptoms to, or aggravate, an IgE-mediated reaction; is required, or whether involvement of only the res- the complement split products, C3a, C4a, and C5a piratory and/or cardiovascular system can represent (anaphylatoxins), are the most important mediators a severe reaction and thus be classified as anaphy- in this context and, in addition to basophils, also laxis. There is currently no national or international neutrophils and macrophages play a role as rele- consensus on this question. Published data regard- vant effector cells that can be activated via immune ing epidemiology need to be evaluated taking these complex receptors (CD16, CD32, or CD64) [37, 38]. aspects into consideration [25, 26]. Furthermore, there are anaphylactic reactions in Retrospective studies show that up to 1–2% of pa- which no immunological sensitization can be de- tients in an emergency unit at a primary care hospi- tected. These reactions are referred to as “pseudo- tal (maximal care) present due to anaphylactic reac- allergic reactions” [37] or “non-immunological ana- tions [18]. The number of anaphylaxis-related fatal- phylaxis” [1]. The mechanisms of this non-aller- ities is estimated to be between one and three cases gic anaphylaxis include: IgE-independent release per year per million population [19]. Recent studies of vasoactive mediators, possibly via MAS-related from the US, UK, and Australia show incidence rates G protein-coupled receptor [39]; direct activation of anaphylaxis of between 7–50/100,000 per year and of the complement system; interactions with the show an increased incidence of anaphylaxis in recent kallikrein–kinin system; interactions with arachidonic decades. In particular food-induced anaphylaxis in acid metabolism; as well as psychoneurogenic reflex children and drug-induced anaphylaxis in adults have mechanisms. The state of knowledge of the patho- increased, although the mortality rate has remained physiology of these reactions is undoubtedly less well unchanged [19–21]. established than for allergic anaphylaxis. Data from the anaphylaxis registry of German- Anaphylaxis can be particularly severe in patients speaking countries, as well as data from other coun- with increased basal serum tryptase levels and/or tries around the world, show that foods are the most mastocytosis [40–44]; however, normal tryptase levels common elicitors of anaphylaxis in childhood [26]. In- have often been measured, especially in children with sect venoms and drugs are the most frequent elicitors food-induced anaphylaxis [45]. Previous use of beta- in adults (Table 1); however, there are international adrenoceptor antagonists and angiotensin converting differences with regard to this ranking. In childhood, enzyme (ACE) inhibitors can intensify the severity of boys are more often affected by anaphylaxis than are anaphylactic symptoms [27, 28, 44, 46]. girls, possibly due to the more frequent occurrence In the case of beta-adrenoceptor antagonists, of food allergies in boys; these differences between a blockade of the cardiostimulatory and mast cell- sexes disappear after puberty [27]. stabilizing effects of adrenalin play a role, while ACE inhibitors reduce bradykinin metabolism, resulting in increased vasodilatation. The use of cyclooxygenase inhibitors (non-steroidal anti-inflammatory drugs, NSAID) can also cause increased production

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Table 2 Severity scale for the classifcation of anaphy- tially. There may be primary cardiovascular reactions lactic reactions (modifed from [6, 47]). The classifcation without preceding cutaneous or pulmonary symp- is made according to the most severe symptoms observed toms. In 5–20% of affected individuals, a protracted (no symptom is mandatory) or biphasic clinical course may develop following Grade Skin and Abdomen Respiratory Cardiovascular general tract successful treatment, with renewed symptoms after subjective 6–24h [48–50]. In addition to acute symptoms imme- symptoms diately after allergen contact and a biphasic course, I Itch – – – there are also initially delayed anaphylactic reactions, Flush whereby the symptoms only occur some hours after Urticaria exposure. These particular kinetics have been well Angioedema documented, for example, for the allergen galactose- II Itch Nausea Rhinorrhea Tachycardia alpha-1,3-galactose in mammal meat allergy (“red Flush Cramps Hoarseness (increase by meat”) and are most likely due to a delayed release or ≥ 20/min) systemic availability of the allergens or their binding Urticaria Vomitus Dyspnea Hypotension sites [51–53]. However, also in peanut allergy, the Angioedema (decrease by 20mmHg systolic median time from consumption to symptom onset is pressure) 55min [54]. Arrhythmia At the start of an anaphylactic reaction, symptoms III Itch Vomiting Laryngeal Shock may be observed as “prodromal symptoms” with edema mild itch or a burning sensation on the palms and Flush Defecation Bronchospasm soles or in the anogenital area, metallic taste, anxiety, headache, and disorientation. Young children are un- Urticaria Cyanosis able to adequately report these symptoms; they often Angioedema exhibit agitation and withdrawal behavior as initial IV Itch Vomiting Respiratory Cardiac arrest symptoms prior to objective signs. arrest Flush Defecation Itch, erythema (flush), urticaria, and angioedema Urticaria (Quincke’s edema) develop on the skin and mucous Angioedema membranes, also on skin areas that have not come into direct contact with the elicitor (systemic reaction). The skin is the organ most often affected in of leukotrienes, as well as facilitated absorption of anaphylaxis. orally ingested allergens, thereby leading to increased In the upper airways, patients often report a burn- anaphylactic symptoms. ing, prickling, or itching sensation on the tongue or palate as initial signs. Swelling of the uvula and tongue Clinical symptoms can be observed in the oropharynx. Clinical signs include hoarseness or muffled speech, difficulty in swal- Anaphylactic reactions manifest mainly on the skin, as lowing, with salivation or inspiratory stridor. Laryn- well as in the respiratory tract, gastrointestinal tract, geal edema can potentially rapidly lead to obstruction and cardiovascular system. The working group dis- of the upper airways and life-threatening hypoxia. cussed whether the guideline should use a classifi- In the lungs, bronchoconstriction and dyspnea cation of severity grades, since current treatment is may develop, especially in patients with bronchial performed according to the symptoms of anaphylaxis. asthma. Clinical signs include wheezing, prolonged The majority favored a severity classification. There expiration, and tachypnea. Bronchial obstruction is are various classifications of anaphylaxis severity in the main symptom in life-threatening reactions, espe- theliterature[7, 8, 10, 29], each classification having cially in children and adolescents. Here, the severity advantages and disadvantages. The group decided on of asthma correlates directly with the severity of ana- a modification of the currently most frequently used phylaxis. Varying degrees of vasoconstriction may classification in Germany, which was also used in the develop in some cases, with an extreme increase in previous guideline [5, 6]. According to the intensity of pulmonary vascular resistance occurring, sometimes clinical symptoms, anaphylaxis can be classified into leading to respiratory arrest and need for resuscita- severity grades I–IV (Table 2). tion. Pulmonary edema may occur as a result of the The symptoms of anaphylactic reactions are mostly impaired permeability [55–57]. of acute onset and can progress rapidly. Within min- Gastrointestinal symptoms include partly cramp- utes, symptoms can intensify and lead to shock and like abdominal pain, nausea, vomiting, and diarrhea. death. However, the reaction can also cease sponta- Furthermore, one may see increased intestinal mo- neously at any stage and resolve. With a reaction of tor activity involving meteorism, urge to defecate, and grade I severity, the further development and dynam- even involuntary defecation. Other abdominal symp- ics of the reaction cannot be predicted. The symptoms can include urge to urinate or micturition, as toms may vary and occur simultaneously or sequen- well uterine cramps. In children, mild oral symp-

4 Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update K guidelines

toms or perioral redness with vomiting may be the only symptoms of food-induced anaphylaxis. Risk factors for anaphylactic reactions As a result of vasodilatation and impaired permeability, there is a loss of fluid into the tissues, lead- Augmentation Concomitant ing to hemoconcentration and intravascular hypov- Other factors factors diseases olemia, followed by arterial hypotension and tachycardia. Direct cardiac symptoms such as arrhythmia or bradycardia may occur. • Physical exertion • Bronchial asthma • Certain allergens Symptoms of the central nervous system include • Infections • Cardiovascular disease (type and amount) restlessness, withdrawal behavior, headache, cerebral • Mental stress • Mastocytosis • Age • Drugs* • Thyroid disease • Male sex spasms, impaired consciousness, or loss of conscious- • Alcohol • Degree of sensitizatiion ness. A change in behavior is often observed in chil- • Level of sIgE dren, manifesting as anxiety or sometimes also ag- gressiveness. Older children, adolescents, and adults may experience a “sense of impending doom.” *Beta-blockers and ACE inhibitors may increase the severity of anaphylaxis If an anaphylactic reaction occurs during general Fig. 1 Risk factors for anaphylactic reactions anesthesia, the patient is unable to report early symptoms such as itch or nausea. If observed, erythema, urticaria, or cardiovascular reactions (tachycardia or anaphylaxis-inducing drugs. This phenomenon is re- hypotension), as well as changes in bronchoconstric- ferred to as augmentation or summation anaphylaxis. tion affecting ventilation (increased airway resistance, A more common form is food-dependent exercise-in- decreased expiratory flow), are particularly significant duced anaphylaxis (FDEIA), which is most frequently [58]. elicited by wheat or subspecies such as spelt, green Causal factors of lethal anaphylaxis include airway spelt, or emmer [65, 66]. obstruction and/or cardiovascular failure, either as a direct effect on the heart or as a sequela of impaired Risk factors of severe anaphylaxis microcirculation with shock; disseminated intravascular coagulation or adrenaline overdose have been Certain endogenous or exogenous factors can in- observed in rare cases [59, 60]. crease the risk of severe anaphylaxis. Risk factors of this kind (Fig. 1), which are independent of the Allergens and elicitors elicitor, include advanced age, severe cardiovascular disease, (inadequately treated) bronchial asthma, The most common elicitors of severe anaphylactic re- use of certain drugs that promote mast cell activa- actions include drugs, insect venoms, and foods. The tion or leukotriene secretion (such as NSAID), and ranking of these elicitors is determined by various mastocytosis [28, 41, 67]. factors, such as mode of detection, age group, and Evidence for an increased risk of severe anaphy- geographic region. In German-speaking countries, laxis under medication with beta-adrenoceptor antag- elicitors of anaphylactic reactions have been regis- onists (beta-blockers) is based on a number of case tered since 2006 in an “Anaphylaxis Registry,” where reports and case series [68–70], as well as two case allergy centers in Germany, Austria, and Switzerland, control studies on anaphylaxis frequency and severity as well as other European countries, report cases after administration of radiographic contrast media of severe allergic reactions. In children, foods are [71, 72]. Recent data from the European anaphylaxis the most common elicitors of severe anaphylactic registry confirm that the use of beta-adrenoceptor an- reactions, whereas insect venoms and drugs are com- tagonists is associated with an increased risk for severe mon elicitors in adults [25]. The anaphylaxis registry anaphylaxis (odds ratio [OR] 1.86) [28]. also makes it possible to promptly identify very rare Considering elicitor-dependent subgroups of ana- elicitors of anaphylaxis—most recently in foods, e.g., phylaxis, there are reports of food-induced anaphy- spices or new exotic fruits [28]. laxis showing that allergic bronchial asthma is a ma- Contact with the elicitor of anaphylaxis classically jor risk factor [73]. Finally, the elicitor itself may be occurs via oral or parenteral (hematogenous) expo- a risk factor—it is known that primary sensitization sure. In rare cases, anaphylaxis can also be elicited to peanut or fish, both highly potent allergens, repre- via airborne contact or, even more rarely, via skin sents a risk factor per se for severe reactions [74]. contact (contact anaphylaxis) in highly sensitized individuals [61–63]. Anaphylactic symptoms may also Diagnosis and important differential diagnoses occur depending on a combination of various factors, e.g., allergen exposure together with physical exer- Since the clinical symptoms of anaphylaxis are not cise, known as exercise-induced anaphylaxis (EIA) [64, always characteristic, diagnosis may be challenging. 65], alcohol, mental or emotional stress, infection, or Therefore, it is important to differentiate other acute simultaneous exposure to other allergens, or use of reactions from symptoms of anaphylaxis, such as

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Table 3 Important differential diagnoses of anaphylaxis decrease in blood pressure (manifesting as, e.g., Cardiovascular diseases Vasovagal syncope collapse, tachycardia, incontinence) Cardiogenic shock 2. Sudden onset of symptoms in two or more organ Cardiac arrhythmia systems: skin (e.g., acute urticaria, angioedema, Hypertensive crisis flush, mucosal edema), gastrointestinal tract (e.g., Pulmonary embolism abdominal cramps, vomiting), respiratory tract Myocardial infarction (e.g., dyspnea, wheezing, cough, stridor), or car- Hemorrhagic shock diovascular system (e.g., decreased blood pressure, Aortic dissection collapse, incontinence) after contact with a likely Tension pneumothorax allergen or anaphylactic trigger Endocrinological diseases Carcinoid syndrome 3. Drop in blood pressure after contact with an aller- Pheochromocytoma gen known to the patient or another anaphylaxis Thyreotoxic crisis trigger Hypoglycemia Neuropsychiatric diseases Hyperventilation syndrome Pharmacology of the most important drugs in Anxiety/panic attacks the treatment of anaphylaxis Dissociative disorders and conversion (e.g., globus hystericus) The following substances have proven to be effective Psychosis in the pharmacological treatment of anaphylaxis. Artefacts (Muenchhausen syndrome) Somatoform disorders (e.g., psychogenic Vasoactive substances dyspnea, vocal cord dysfunction) Epilepsy Adrenaline (epinephrine) Coma, e.g., metabolic, traumatic The most important drug in the acute treatment of Airway diseases Acute severe asthma (without involvement anaphylaxis is adrenaline (epinephrine) [75, 76]. By of other organs) activating alpha- and beta-receptors, adrenaline func- Acute stenosing laryngotracheitis (croup tionally antagonizes all relevant pathomechanisms of episode) anaphylaxis via vasoconstriction, reduction of vas- Tracheal/bronchial obstruction (e.g., foreign cular permeability, bronchodilatation, reduction of body) edema, and positive inotropy of the heart. When Skin diseases Urticarial diseases and hereditary/acquired angioneurotic angioedema administered intravenously or intramuscularly, it has Note: In physical urticaria, intensive contact with the elicitor may also give the fastest onset of action of all anaphylaxis drugs. rise to anaphylaxis In patients not requiring resuscitation, immediate Pharmacological/toxic reac- Ethanol intramuscular administration of adrenaline at a dose tions Histamine intoxication, e.g., in fish poison- of 0.15–0.6mg to the outside of the upper thigh is the ing (scombroid) pharmacological treatment of first choice. The risk of Opiates (morphine) severe cardiac side effects is considerably lower com- Hoigné’s syndrome pared to intravenous administration. In the absence of an effect, and depending on adverse events, the injection can be repeated every 5–10min subject to other manifestations of isolated urticaria, bronchial clinical symptoms. obstruction, vomiting, nausea, diarrhea, agitation, The subcutaneous injection of adrenaline is no loss of consciousness, cardiac arrhythmia, and/or longer recommended due to its insufficient absorp- cardiac arrest. Relevant differential diagnoses are tion and resulting delayed action. listed in Table 3. After appropriate acute treatment, If symptoms fail to stabilize and circulatory or it is helpful to determine mediators in blood, in par- respiratory decompensation is imminent, adrenaline ticular serum tryptase—ideally 1–3h after the onset should be given intravenously [77]. To this end, a di- of anaphylaxis and, if possible, as compared to basal lution of 1mg adrenaline in 100ml NaCl 0.9%, i.e., serum tryptase. Tryptase can also be determined a solution of 10µg/ml titrated with single boluses of retrospectively—even post mortem—but is not nec- 1µg/kg body weight (BW), is used under continuous essarily elevated [41, 45, 67]. monitoring of circulatory parameters depending on The following symptoms are considered to be char- effects and side effects. acteristic criteria for anaphylaxis [8]: Electrocardiogram (ECG), pulse, and blood pres- 1. Sudden onset of skin symptoms (e.g., acute ur- sure monitoring is required (see below for adrenaline ticaria, angioedema, flush, mucosal edema) to- dosing in cardiac and circulatory arrest). In patients gether with sudden respiratory symptoms (e.g., receiving beta-adrenoceptor antagonist therapy and dyspnea, wheezing, cough, stridor) or a sudden failing to respond to several doses of adrenaline or other vasoactive substances (see below), administration of glucagon is recommended since this has a pos-

6 Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update K guidelines

itive inotropic effect and leads to the up-regulation of Noradrenaline Since noradrenaline is a highly po- beta-adrenoreceptors on the cell surface [78]. How- tent alpha- and somewhat less potent beta-1 adreno- ever, glucagon only has an effect on cardiac symp- ceptor agonist and has a lower stimulatory potency at toms. the beta2-adrenoceptor compared to adrenaline, its In addition to its intramuscular administration, bronchodilatory effect is lower at therapeutic doses. adrenaline can also be given by inhalation in the Therefore, its principal effect is an increase in periph- case of laryngeal edema and is also effective in bron- eral resistance and systolic blood pressure. Its effect chospasm. Here, the administration of adrenaline, on the lungs is comparatively small. Noradrenaline undiluted (e.g., 3–5ml at a concentration of 1mg/ml) is used particularly when volume replacement and via a nebulizer using a breathing mask/mouthpiece adrenaline have an insufficient effect [76, 84]. Due together with oxygen is recommended. The inhaled to its marked vasoconstrictive effects, it should be administration of adrenaline does not replace par- used only as a continuous intravenous infusion under enteral administration and should only be used in an strict blood pressure and pulse monitoring. Dosage is additive capacity [58]. 0.02–0.15µg/kg per minute. If bronchial obstruction is the major symptom, the additional administration of inhaled beta-adrenocep- Vasopressin The use of vasopressin in the treatment toragonistsiseffective,e.g., salbutamol, at an initial of severe hypotension has been described by anes- dose of two puffs—if ineffective, between four and thetists [85]. eight puffs, and/or subcutaneous terbutaline. In the There are individual reports on the successful use case of young children, the efficacy of inhaling a dosed of vasopressin in volume- and catecholamine-refrac- aerosol can be increased by using a “spacer,” together tory shock. This is not an evidence-based treatment; with a mask if required. it is optional in extremely severe situations of per- In the past, ephedrine was recommended instead sistent shock when treatment with volume and other of adrenaline for hypotension during pregnancy. catecholamines has failed. An effect on mortality or However, the evidence for ephedrine is even more duration of intensive care hospitalization could not be scant than for adrenaline; therefore, in line with the shown for children. Dosage is 0.01–0.03 international recommendations of other authors, the authors rec- units (IU)/min. ommend the administration of adrenaline also in anaphylaxis during pregnancy [79]. Oxygen Even when administered appropriately, adrenaline is not always effective and therapeutic failure or side In manifest cardiovascular or pulmonary reactions, effects may be observed. The increase in cardiac the administration of oxygen via a breathing mask is output results in increased oxygen consumption and recommended, in particular a non-rebreather mask. cardiac muscle necrosis. Adrenaline can also have The administration of high-flow oxygen (100%) is rec- arrhythmogenic effects; therefore, in patients with ommended. A laryngeal mask or tube may be helpful. pre-existing coronary disease, intravenous adrenaline Only on rare occasions is tracheal intubation by an ex- may cause angina pectoris or myocardial infarction. perienced physician (usually an emergency physician Although there is no absolute contraindication for or anesthetist) necessary. The reader is referred here adrenaline in severe life-threatening anaphylaxis, the to the S1 guidelines for prehospital airway manage- indication should be carefully considered in patients ment, which provide an algorithm explaining both the with cardiovascular disease. In the case of asystolic indication for and the performance of invasive pre- cardiac arrest or pulseless electrical activity on ECG, hospital airway management (Fig. 2;[58]). 1mg i.v. adrenaline is given every 3–5min in adults or 0.01mg/kg in children [80, 81]. Volume replacement

Other vasoactive substances A major pathophysiologic aspect of anaphylaxis is the Dopamine, noradrenaline, and vasopressin are used resulting relative hypovolemia induced by vasodilata- in the emergency setting by emergency physicians, tion and capillary leakage [86]. As such, it is clear as well as under intensive care conditions using car- that volume therapy can only be used in addition to diopulmonary motoring. the crucial mast cell-stabilizing and vasoconstrictor effect of adrenaline therapy [87–89]. This can only be Dopamine Dopamine, which acts on alpha- and achieved with a large-lumen intravenous catheter. If it beta-adrenoceptors and has a short half-life [82, 83], is not possible to perform an intravenous injection, in- is no longer used in German emergency and intensive traosseous access needs to be obtained. Anaphylactic care medicine since it can elicit undesired tachycar- shock in adults requires rapid administration of a high dia and is markedly less effective in stabilizing blood amount of volume: 1–3l of balanced electrolyte solu- pressure than adrenaline or noradrenaline, which can tion depending on response. In children, 20ml/kg BW be well titrated with syringe drivers. are initially administered by hand as rapidly as possible. After re-evaluation, repeated boluses of 20ml/kg

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Respiratory failure

Algorithm Bolus? Bolus event Are No invasive measures Yes needed? Is anesthesia needed? Yes O2 administration Open airways if needed Airway devices if needed No Preoxygenation Selection of Non-invasive ventilation anesthesia method if needed

Prospect In stridor/spasticity: No Yes nebulized salbutamol/adrenaline of successful intubation?

Unsuccessful EGA (≤ two attempts) Video-assisted ETI Children: laryngeal mask (≤ two attempts) Mask ventilation Mask ventilation Not in children Children: pharyngeal tube

Cricothyrotomy

Successful Successful Successful Successful

Respiratory monitoring Ventilatory monitoring Pulse oximetry, capnography if needed Pulse oximetry and capnography

Fig. 2 Algorithm for prehospital airway management (from [58]). EGA epiglottic airway, ETI endotracheal intubation are administered until hemodynamic stabilization is profile and a wide therapeutic window. One can as- achieved. sume an effect on allergic reactions. Therefore, anti- Gelatin and dextran solutions—despite their posi- histamines should be given in all anaphylactic reactive hemodynamic effects—should not be used in ana- tions in order to antagonize the effect of histamine phylaxis due to their histamine-releasing potency and as early on as at the initial stage, once vital functions their own risk of inducing anaphylaxis (e.g., in the case have been stabilized. Under no circumstances should of dextran without pretreatment with low molecular immediate life-saving measures such as intramuscu- hapten-dextran) [7]. lar administration of adrenaline, volume replacement, According to the most recent evaluation by the Eu- or oxygen administration be delayed by the use of an- ropean Medicines Agency (EMA), hydroxyethyl starch tihistamines! (HES) preparations are contraindicated in the criti- In terms of intravenous administration in the cally ill [90–92]. Due to the lack of relevant literature, acute treatment of anaphylaxis, only the first-genera- the guideline group is somewhat reluctant to make tion histamine H1-receptor antagonists dimetindene recommendations. (0.1mg/kg BW) and clemastine (0.05mg/kg BW), with their well-known sedative side effects, are available. Antihistamines (histamine H1-receptor antagonists) At higher doses, antihistamines may show antimuscarinic effects ranging from tachycardia, mouth dry- The central role of histamine as a mediator of aller- ness, intestinal atony, urinary retention, increased gic reactions and the effect of histamine H1-receptor intraocular pressure to glaucoma attack and paradox- antagonists in acute urticaria or rhinoconjunctivitis ical states of arousal [94]. Therefore, these symptoms are undisputed; however, their effects on circulation need to be borne in mind. and bronchoconstriction have not been demonstrated Second-generation histamine H1-antagonists are [93]. Antihistamines have a slower onset of action not approved as yet for the treatment of anaphylaxis compared to adrenaline, but have a good benefit–risk and are not available for intravenous injection; nev-

8 Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update K guidelines

ertheless, the newer, more selective histamine H1- General aspects and treatment measures antagonists are often recommended as an oral treatment, having shown rapid onset of action in placebo- When and how should allergen contact be stopped? controlled skin test studies [93].Inthecaseoforalan- tihistamine administration, the maximum approved In the case of anaphylaxis, one should first establish dose is primarily recommended. However, the expert whether it is possible to stop further allergen expo- group agrees that higher doses (up to a maximum sure. In particular situations (e.g., infusions), this can of four times the approved single dose) can be given be readily achieved and should be done immediately. in individual cases, as recommended in the treat- The use of a tourniquet on an extremity and/or sub- ment of chronic urticaria [95]. Further studies with cutaneous injection of adrenaline around a local aller- newer H1-receptor antagonists for the treatment of gen depot (e.g., wasp sting or injection site of allergen- anaphylaxis are urgently required. In particular, in- specific immunotherapy) is no longer recommended, travenous preparations of modern non-sedating H1- since the therapeutic benefit is questionable and there antihistamines would be desirable. is a risk of distracting from more important measures. Thereislittleevidenceforaneffectofhistamine H2-receptor antagonists in the treatment of acute anaphylactic reactions. One study reports a reduction in cutaneous symptoms after the additional administration of ranitidine compared with the use Table 4 Emergency equipment for the treatment of ana- of a histamine H1-receptor antagonists alone in the phylactic reactions in the medical offce treatment of allergic reactions [96]. There is somewhat Stethoscope more evidence for the prevention of hypersensitivity Blood pressure monitor reactions by the addition of histamine H2-receptor Pulse oximeter, possibly also blood glucose meter antagonists, although the effect was not evaluated Tourniquet, venous catheters (in different sizes), syringes, infusion set, separately from other drugs [97, 98]. There are case adhesive tape for catheter fixation reports in the literature on anaphylactic reactions Oxygen and nebulizer set with oxygen mask (different sizes) caused by ranitidine [99]. The combined use of Bag valve mask (different sizes) histamine H1- and H2-receptor antagonists can be Suction device attempted [100]. Guedel tube where appropriate Volume for infusion (e.g., balanced electrolyte solution) Glucocorticoids Drugs for injection: adrenaline, glucocorticoid, histamine H1-receptor antagonist Glucocorticoids plays a secondary role in the acute Short-acting beta2-adrenoceptor agonist, e.g., salbutamol for inhalation phase of anaphylaxis due to their comparatively slow (preferably as an inhalation solution for administration via a nebulizer set with mask, if necessary in metered dose with, e.g., inhalation aid/spacer/ onset of action [101]. mask, autohaler) There are no systematic clinical studies for this Automated external defibrillator indication. However, glucocorticoids are effective in the treatment of asthma. A non-specific membrane- stabilizing effect within 10–30min of administra- Table 5 Five-second round for rapid evaluation of vital tion of very high doses of glucocorticoids (in adults, parameters (from A. Bohn, Bundesverband Ärztliche Leiter 500–1000mg independent of the potency of the sub- Rettungsdienst Deutschland (ÄLRD) (www.aelrd.de)) Five-second Examination of vital signs (spontaneous movement) stance) has been postulated in review articles [4, 101, round 102]. In the absence of intravenous access, gluco- A—Airway Muffled speech, swollen tongue corticoids may also be given orally in syrup form B—Breathing Evaluation of breathing (dyspnea, stridor, wheezing; or rectally in suppository form, especially in small optional: auscultation, pulse oximetry) children (e.g., prednisolone suppositories or rectal C—Circulation Evaluation of recap time (preferably forehead or ster- enemas) at a dose of 2mg/kg. num) In the case of slow response and unclear evidence, Pulse (strength, frequency, regularity) and blood pressure treatment with glucocorticoids should only be per- D—Disability Consciousness, blood glucose measurement formed once vital functions have been stabilized E—Exposure Inspection of easily visible areas of skin areas and and immediate life-saving measures have been per- mucous membranes, question patient regarding other formed, such as oxygen administration, intramuscular symptoms (e.g., nausea, vomiting, headache, feeling of adrenaline use, or volume substitution! chest pressure, impaired vision, pruritus) Secondary AMPLE approach survey Known Allergies, possible elicitors of acute reaction, risk factors (asthma, other pre-existing diseases) Medication Patient history Last meal Events

K Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update 9 guidelines

Table 6 Alarm limit values for vital signsa 1. Anaphylaxis with cardiovascular and/or respiratory Alarm limit values depend- Under 1–5 Years 6–14 Years >14 Years failure(gradeIVanaphylaxis) ing on age 1 year 2. Anaphylaxis with a predominantly cardiovascular Heart rate (/min) >160 >130 >120 >110 reaction (grade II/III anaphylaxis) Blood pressure (systolic, <50 <60 <60 <70 3. Anaphylaxis with predominant upper airways ob- mmHg) struction (grade II/III anaphylaxis) Respiratory rate (/min) >40 >35 >30 >25 4. Anaphylaxis with predominant lower airways ob- Oxygen saturation (%) <92 <92 <92 <92 struction (grade II/III anaphylaxis) aThese values may vary due to high individual variability and can be re- 5. Anaphylaxis with predominant gastrointestinal in- garded as guide values. Evidence-based data from clinical studies are not volvement (grade II anaphylaxis) available 6. Anaphylaxis with systemically mediated generalized skin manifestation and subjective symptoms Should one call for help? (grade I anaphylaxis).

If possible, further help should be called for in order How should the patient be positioned? to achieve the conditions for adequate medical care. All practice-based physicians should keep emergency Immediately after examination, symptom-oriented equipment available for the treatment of anaphylac- positioning of the patient needs to be carried out. tic reactions (Table 4). The team should be regularly A flat position and avoidance of abrupt changes in trained, with the option of designating tasks. In the position (sitting up, standing up) or further physical case of severe anaphylactic reactions, the emergency exertion (running) are a fundamental strategy. Posi- services/paramedics should be alerted (in Germany, tioning can vary according to the situation. Sitting/ call 112). standing up and physical exercise (running) should be avoided due to abrupt volume shift (“venous col- How should symptoms and complaints be recorded? lapse”) or aggravation of anaphylaxis (co-factors). In the case of impaired consciousness but intact circu- First of all, a short history should be taken and a basic lation, especially in preclinical situations, stable side- physical examination carried out. This comprises the positioning is recommended. To improve the hemo- following steps summarized in a “five-second round” dynamic situation, Trendelenburg positioning (legs (Table 5)(www.aelrd.de). up) can be performed. In situations where respiratory Alarm values for vital parameters are listed in Ta- distress is the leading symptom (dyspnea), a half- ble 6. These examinations need to be repeated over sitting position may be better. When treating chil- the course of treatment at regular intervals. dren, care must be taken not to exert any force during Young children can be examined while held by positioning that may increase the child’s anxiety. a parent. The initial aim is to calm the child and the parents in order to create an adequate examination How should anaphylaxis with cardiovascular arrest and treatment environment. When small children are be treated? restless, it may be difficult or impossible to examine the oral cavity and perform lung auscultation. Caus- Cardiopulmonary resuscitation with chest compres- ing irritation with a tongue depressor may increase sions and mouth-to-mouth breathing at a ratio of 30:2 airway obstruction and should be avoided. In this (compressions:breaths) in adults should be initiated. case, and in addition to general signs of dyspnea, In children, resuscitation is initiated in line with the such as retraction of the thorax or the nasal wings, current European Resuscitation Council (ERC) guide- attention should be paid to other clinical signs of up- lines, i.e., after five initial breaths, two breaths are per respiratory tract obstruction, such as inspiratory given after every 15 chest compressions. An auto- stridor or salivation, as well as lower airway obstruc- mated defibrillator should be used and early defibril- tion with a prolonged expiratory phase and expiratory lation performed in the case of ventricular fibrillation. stridor or wheezing. An intravenous or intraosseous catheter is required for further drug treatment. Adrenaline (intravenous or in- How should severity be assessed? traosseous) at a dose of 1 mg in adults or 0.01 mg/kg is the drug of first choice and is repeated in at 3- to Based on this examination, the degree of severity of 5-min intervals until stabilization of spontaneous cir- anaphylaxis should be evaluated and the most life- culation has been achieved [80, 81]. For sufficient threatening leading symptom identified. The most oxygenation in emergency care, bag-valve-mask ven- life-threatening symptom needs to be treated first. tilation with 100% oxygen is sufficient. If optimization This leads to the six most common scenarios ([103]; measures (positioning of the head, Guedel tube, two- Fig. 3): person technique) are unsuccessful in the case of dif- ficulties with mask ventilation, supraglottic airway devices are used. Laryngeal masks and laryngeal tubes

10 Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update K guidelines

Fig. 3 Acute treatment of the most common anaphy- Anaphylaxis lactic patterns. Inh inhaled

Stop allergen contact Call for help

Basic physical examination – severity scoring (I–IV)

Define severity and leading major symptoms

Grade IV Grade II or III Grade II or III Grade II or III Grade II or III Grade I

Hypotension, Dysphonia, Dyspnoea, Nausea, Pruritus, flush, Cardiac/circulatory shock, uvula swelling, bronchial abdominal colic, urticaria, arrest unconciousness inspiratory stridor obstruction vomiting angioedema

Symptom-oriented positioning

Cardiopulmonary Adrenaline i.m. Resuscitation oxygen inh.

Automatic defibrillator

i.v. / i. ossary catheter i.v. catheter

β2-sympatho- Adrenaline Adrenaline mimetic i.v. / i. ossary inh. inh.

Secure airways

Oxygen inh.

Forced Volume substitution i.v. / i. ossary

Dimetindene i.v.

Glucocorticosteroid i.v.

Basic physical examination

Define leading symptom and assess indication for further therapy

Additional therapy Therapy escalation Therapy escalation Therapy escalation Therapy escalation No escalation

Persistant Persistant Persistant Other Persistant Similar subsiding shock, bronchial nausea, abdominal leading symptom laryngeal edema symptoms unconciousness obstruction colic, vomiting

Adrenaline Adrenaline i.m. / i.v., Consider Consider Choose appropriate i.v. / i. ossary β2-sympatho- antiemetics/ coniotomy leading symptom of (or i.m.) mimetics s.c. / i.v. spasmolytics i.v. Initial therapy level and complete specific measures Consider other Consider securing not yet applied catecholamines the airway i.v. / i. ossary (under anesthesia)

Surveillance

Prescribe emergency set, instruct in adrenaline autoinjector use, refer Discharge to allergist for further diagnosis and treatment

K Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update 11 guidelines

Table 7 Pharmacotherapy for children, adolescents, and adults under intensive care conditions Substance Indication Route of administration Dose <15kg BW 15–30kg >30–60kg BW >60kg BW in BW adults Adrenaline Cardiac arrest/ i.v./i.o. 10µg/kg 0.1ml/kg BW 0.1ml/kg BW 0.1ml/kg BW 1mg 1:10,000a resuscitation (1mg/10ml) Adrenaline Respiratory Intramuscular 10µg/kg 0.05–0.1ml 0.15–0.3ml 0.3–0.6ml 0.3–0.6mg 1:1000b symptoms Shock (1mg/ml) Adrenaline In severe shock Titrating i.v./i.o. 1µg/kg 0.01ml/kg BW 0.01ml/kg BM 0.01ml/kg BW 0.1–0.6mg 1:10,000a (if i.m. not possi- (1mg/10ml) ble) Adrenaline – Continuous infusion – 0.05–1.0µg/kg/ 0.05–1.0µg/kg/ 0.05–1.0µg/kg/ 0.05–1.0µg/kg/ min min min min Adrenaline 1:1000 – Inhaled via nebulizer – 3mlb 4mlb 5mlb 5mlb (1mg/ml) Dimetindene – Intravenous 0.1mg/kg 1mlc 2–3mlc 4mlc 8mlc or 1ml/10kg BW Prednisolone – Intravenous 2mg/ml 25mg 50mg 100mg 250–1000mg Salbutamol – Inhaled – 4–8 Puffs MDI 4–8 Puffs MDI 4–8 Puffs MDI 2–4 Puffs Terbutaline per spacer per spacer per spacer MDI per spacer Reproterold – Continuous infusion – 0.1µg/kg/min 0.1µg/kg/min 0.1µg/kg/min 0.1µg/kg/min Volume – Infusion (balanced elec- 10–20ml/ 10–20ml/kg 10–20ml/kg 10–20ml/kg 500–1000ml trolyte solution, Ringer’s kg acetate solution) Oxygen – Nasal cannula – 2–12l/min 2–12l/min 2–12l/min 2–12l/min Non-rebreather mask MDI metered-dose inhaler, Amp ampoule, BW body weight aFor intravenous/intraosseous administration, 1ml of 1:1000 solution (= 1mg adrenaline in 1ml of commercial solution) with 9ml NaCl 0.9% (final concentration 1:10,000= 0.1mg/ml) or prefilled adrenaline syringe (1mg/10ml) are used bFor intramuscular administration and inhalation, the undiluted commercially available solution is used (adrenaline 1:1000, 1mg/ml) cOf a basic concentration for 1mg/ml (1ml contains 1mg dimetindene maleate) dReproterol can also be given as a bolus can be used in all age groups. Alternatively, a pharyn- 0.3mg, or 0.5mg are practical single doses for ad- geal tube can be used in small children; here, ventila- ministration. In the case of insufficient response, tion is induced via a nasal tube (tube length= tip of the the intramuscular injection can be repeated after nose–ear tragus) while holding the mouth and other 5–10min. nostril closed. Endotracheal intubation represents the Oxygen administration is recommended with the final method of airway management. This can also aim of increasing the inspired oxygen fraction (FiO2) be performed as a first step in the case of sufficient to >0.5. This is possible with a non-rebreather oxygen expertise. It has been shown for all age groups that mask. Nasal tubes do not increase FiO2 sufficiently. endotracheal intubation should only be performed by In all cases of impaired consciousness, vomiting experienced individuals [58, 104]. should be expected at any time. This needs to be For successful resuscitation, it is important to considered when positioning the patient. The mouth compensate for the underlying volume deficiency should be opened using the Esmarch (jaw thrust) ma- by means of forced volume replacement, according neuver and inspected for vomited material or foreign to the pathophysiology of anaphylaxis. Immediate bodies (e.g., dental prostheses). An operational suc- transfer to and treatment on an intensive care unit tion unit is helpful. are recommended (Table 7). An intravenous catheter is necessary for further treatment (Table 7). If this is not possible, an in- How should anaphylaxis with a cardiovascular traosseous catheter is indicated. The central aim of reaction as the leading symptom be treated? treatment is to compensate for the relative volume loss. Forced volume replacement with a crystalloid As an immediate measure, intramuscular (body solution (balanced electrolyte solution) is required in weight-adjusted) injection of adrenaline is recom- the form of a volume bolus over 5min. In adults, mended, especially when there is no intravenous 500–1000ml are administered, while in children the catheter (Fig. 3;Table7). In this situation, the volume bolus is initially 20ml/kg. A flow rate of this adrenaline auto-injectors used for layperson admin- magnitude requires a large-lumen indwelling venous istration may be advantageous for their rapid usabil- catheter (≥18 gauge) or several catheters. ity. Standardized doses of auto-injectors of 0.15mg,

12 Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update K guidelines

Table 8 Pharmacotherapy for children, adolescents, and adults under non-intensive conditions (e.g., outpatient setting) Substance Administration <7.5kg BW 7.5–25 (–30)d kg BW 30–60kg BW >60kg BW Adrenaline Intramuscular 50–600μg Adrenaline Auto-injector i.m. Not approved 150µg 300µg 1–2× 300µg or 500µg Adrenaline Inhalation nebulizer 2–5mlb Adrenaline Intravenousa Titrating bolus doses 1μg/kg BW Dimetindene Intravenous 1mlc 1ml/10kg BWc 1Amp= 4mlc 1–2 Amp= 4–8 mlc (max. 4ml) (1ml/10kg BW) Prednisolone Intravenous 50mg 100mg 250mg 500–1000mg Salbutamol Inhaled 2 Puffs via spacer 2 Puffs via spacer 2–4 Puffs via spacer 2–4 Puffs via spacer Terbutaline Volume Bolus (NaCl 0.9%) 20ml/kg BW 20ml/kg BW 10–20ml/kg BW 10–20ml/kg BW Oxygen Inhaled 2–10l/min 5–12l/min 5–12l/min 5–12l/min AMP ampoule, BW body weight aFor intravenous administration, a 1-mg/ml adrenaline solution is diluted in 100ml NaCl 0.9% (ﬁnal concentration, 10mg/ml) bFor inhalation, the original concentration of the commercial solution is used (1mg/ml) cAn original concentration of 1mg/ml (1ml contains 1mg dimetindene maleate) dVarious weight-dependent approvals for different auto-injectors

In persistent or life-threatening shock, fractionated for the treatment of bronchial obstruction (Tables 7 intravenous/intraosseous or intramuscular adminis- and 8). It is important to note that patients with ana- tration of adrenaline or as a continuous drip is indi- phylaxis often have little experience with inhalation cated. Antiallergic drugs like histamine H1-receptor therapy and can more easily use spacers for metered antagonists (note: antimuscarinic side-effects of se- dose inhalers or procedures with continuous aerosol dating anthistamines!) or glucocorticoids should be administration (such as masks for pressure/oxygen used after stabilization of vital functions and adminis- connection and electric nebulizers). This also holds tration of i.m. adrenaline (Table 7). Continuous blood true for young children and children without experi- pressure and pulse monitoring is indicated in these ence with inhalation therapy. Compact battery-driven situations. With adequate expertise, other sympath- nebulizers are now available and can also be used in omimetic drugs such as noradrenaline may be used emergency preclinical situations. If therapy needs or a continuous infusion initiated with pumps under to be escalated, repeated i.m. adrenaline is given. continuous monitoring. If resuscitation is imminent, intravenous administration of adrenaline can be considered. A further How should anaphylaxis with upper airway treatment modality is the application of an injectable obstruction as the leading symptom be treated? beta2-adrenoceptor agonist (e.g., terbutaline s.c. or reproterole i.v.) (Table 7). Clinically detectable swelling in the area of the upper In acute severe asthma with muscular exhaustion airways is characteristic for this situation. This may and failure of non-invasive ventilation, emergency be identifiable as swelling of the tongue or uvula, dys- anesthesia with invasive ventilation may be necessary phonia, or inspiratory stridor. These situations can [65]. Here, the current guidelines and recommenda- become life-threatening if the laryngeal entrance is tions on anesthesia with esketamine and midazolam obstructed. As an immediate measure, intramuscu- should be followed [104]. lar injection of adrenaline and oxygen administration are recommended (Fig. 3). Additional inhalation of How should anaphylaxis with predominantly adrenaline is also indicated in such situations (Ta- abdominal symptoms be treated? bles 7 and 8). If the treatment response is insufficient, airway management according to the algorithm Anaphylaxis with predominantly abdominal symp- in the S1 guideline for prehospital airway manage- toms is treated in the same way as anaphylaxis with ment should be performed (Fig. 2;[58]). generalized skin symptoms (Fig. 3). Only if there is insufficient response to systemically administered How should anaphylaxis with bronchial obstruction antiallergic drugs will gastrointestinal symptoms be as the leading symptom be treated? treated separately. Nausea, vomiting, or abdominal cramps may be the relevant symptoms. Antiemet- This symptom is one of the most common in ana- ics such as metoclopramide, antihistamines (e.g., phylaxis. In all potentially life-threatening situations, dimenhydrinate) or serotonin-[5-HT3] antagonists adrenaline should be given intramuscularly. Topi- (e.g., ondansetron) can be used for treatment. For cal bronchodilator therapy is of central importance abdominal cramps, intravenous administration of ([105]; Fig. 3). Various short-acting beta-adrenoceptor a muscarinic receptor antagonist (butylscopolamine) agonists (e.g., salbutamol, terbutaline) are approved may be considered.

K Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update 13 guidelines

How should anaphylaxis with predominantly skin What are the special considerations for planned symptoms be treated? provocation testing in anaphylaxis?

Placing an intravenous catheter is the first measure Whenever a procedure that carries a risk of anaphy- taken. A crystalloid solution drip (e.g., balanced elec- laxis is planned (allergy provocation test, allergen- trolyte solution) is recommended to keep this open. specific immunotherapy with hymenoptera venom), Antiallergic drugs such as dimetindene or glucocorti- careful preparation is essential, including: coids are applied at usual doses (Fig. 3;Table8). Monitoring sheet with emergency medication and emergency plan. Special aspects of hospital treatment Emergency drugs prepared in weight-adjusted doses near to the patient. Which emergency drugs should be stored in the Rapid medical care if allergic symptoms occur. emergency department or on the ward? Intravenous catheters for rapid administration of intravenous drugs and volume. In emergency departments and on wards where The indication to administer medication is estab- provocation tests or allergy procedures with in- lished according to the flow diagram (Fig. 3). creased risk for anaphylaxis are performed, up to two adrenaline auto-injectors each in the doses 300μgor It is advisable that affected patients or, in the case of 500μg should be kept available. If the treatment of young children, their parents learn to use the auto-in- children is expected, a further two 150-µg adrenaline jector themselves under close instruction from med- auto-injectors must be kept available. Adrenaline ical personnel in order to train for administration at inhalation using a nebulizer should be available. In home. If possible, training should be with the same addition, injectable histamine H1-receptor antago- type of auto-injector as the one that will be used by nists and glucocorticoids, as well as salbutamol for the patient. This approach enables patients to gain inhalation with appropriate devices (spacer or moist confidence in administering an auto-injector and re- inhalation), should be on hand. duce the fear associated with its use.

How should patients with acute anaphylaxis be How should anaphylaxis be treated on the intensive treated in the emergency department? care unit?

Individuals presenting to the emergency department One advantage of high care (on an intensive care unit) with suspected anaphylaxis need to be treated im- with continuous monitoring is that shock states can mediately. In order to make the diagnosis of “ana- be detected and treated earlier. If the intensive care phylaxis,” the clinical criteria need to be applied personnel become aware of anaphylaxis, whether due (see above). In addition to an immediate evaluation to hypotension, tachycardia, a warning signal from of clinical signs and symptoms (Fig. 3), continuous the monitor, or low oxygen saturation, the principal monitoring of circulation, including measurement of procedure does not differ from other settings. Com- pulse, blood pressure, and peripheral oxygen via pulse monelicitorsofanaphylaxisonanintensivecareunit oximetry, must be established. Patients with severe include drugs and blood products; therefore, the very anaphylactic reactions (e.g., requiring an adrenaline first measure to take is to discontinue administra- auto-injector) should be hospitalized and supervised tion of the potential allergen or elicitor. The priority- for 24h due to the risk of a biphasic (bimodal) reac- oriented ABCDE (airway, breathing, circulation, dis- tion. ability, and exposure) approach (Table 5) described above is then initiated. Depending on the ongoing How should anaphylaxis be treated on the ward? mode of intravenous catecholamine treatment, syringe pumps may need to be adapted. Adrenaline Elicitors of anaphylaxis on the ward are often drugs should be given due to its mast-cell stabilizing action, used there for treatment. Reactions to parenterally which is unique among catecholamines. One needs administered substances occur rapidly after use. In to bear in mind that, under continuous vasopressor the case of substances for enteral administration, treatment, the normal intramuscular administration delayed symptoms are also possible. The first mea- of 0.3–0.5mg adrenaline may have reduced efficacy sure to be taken is to discontinue allergen exposure due to peripheral hypoperfusion. Therefore, intra- and—depending on the grade of severity—alert the venous administration in intensive care is performed emergency team. in 50μg bolus doses in adults and 1μg/kg bolus doses in children [81] until the patient is stabilized, preferably via a central venous catheter; alternatively, peripheral administration is also possible.

14 Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update K guidelines

What needs to be considered in discharge – Is there prolonged expiration with reduced expira- management after an anaphylactic reaction? tory flow or a decrease in pulse oximetry oxygen saturation? Following successful treatment of anaphylaxis, pa- – Is there decreased lung compliance? tients, and/or their relatives where appropriate, should be informed about the condition and undergo The differential diagnosis in the context of viscerosur- adequate allergy diagnostics (Table 8). If anaphylaxis gical procedures needs to differentiate eventeration occurred intraoperatively, an anesthesia document syndrome, which may manifest clinically as prostacy- needs to be issued and the patients must be informed clin-mediated flushing, tachycardia, and hypotension. about the reaction. It is absolutely essential to docu- If the working diagnosis severe anaphylaxis or ment reactions, together with symptoms, co-factors, anaphylactic shock is confirmed, treatment with and possible elicitors. An emergency first-aid kit is adrenaline is immediately initiated. In adults with prescribed (see below). severe shock but maintained circulation, titrated Patients with food allergies should receive an in- adrenaline in 0.1- to 0.3-mg bolus doses is adminis- dividually tailored therapeutic elimination diet under tered until systolic blood pressure rises to 100mmHg. the guidance of a nutritionist with allergy expertise (in At the same time, volume therapy is initiated with Germany, the addresses of certified specialists can be 1–3l of balanced electrolyte solution. Histamine H1- obtained from the German Allergy and Asthma Asso- receptor antagonists and optionally H2-antagonists ciation [Deutscher Allergie- und Asthmabund, DAAB] and glucocorticoids, as described above, are then and the working group on dietetics in allergology [Ar- administered intravenously. Extended hemodynamic beitskreis Diätetik in der Allergologie]). Following reac- monitoring should be considered. If these measures tions to insect stings, the possibility of allergen-spe- are able to stabilize the patient, one needs to decide cific immunotherapy should be discussed. whether and to what extent the surgical procedure If the elicitor of anaphylaxis with extracutaneous can be performed or continued. Further intensive symptoms cannot be reliably avoided (e.g., insect monitoring is recommended depending on severity. stings, foods) or there is an increased anaphylaxis risk, patients should be advised to carry an emer- What are the special aspects of treatment in the gency first-aid kit with them at all times, together medical office? with a written document, e.g., anaphylaxis passport (see section below on patient management and self- Which elicitors of anaphylaxis are common in the medication). The patient should receive instructions medical office? regarding emergency management and the use of emergency medication. If the elicitor is a drug used Possible elicitors in the medical office include aller- in the hospital setting, an allergy passport should be gen solutions used in allergen-specific immunother- provided with detailed documentation of the reaction apy (hyposensitization), as well as natural rubber la- in order to allow allergy diagnostics. In the case of tex, local anesthetics, and drugs used in the medical recurrent reactions, an attempt at long-term pharma- office (e.g., antibiotics, cyclooxygenase inhibitors, ra- cological treatment can be considered, such as long- diographic contrast media, vaccines, and intravenous term administration of antihistamines or an anti-IgE iron). Furthermore, patients with severe allergic reac- antibody such as omalizumab [106, 107]. tions to hymenoptera venoms or foods may present For questions regarding everyday management, to the nearest medical office. particularly in food-induced anaphylaxis, patients should be referred to a patient organization for sup- How should a medical office prepare for emergency port (e.g., in Germany, the DAAB). treatment?

How should perioperative anaphylaxis be managed? All medical ofﬁces should keep emergency equipment available for the treatment of anaphylaxis. Since ana- During analgosedation or general anesthesia, the pa- phylactic reactions are not a regular occurrence in tient is not able to communicate early symptoms such most medical ofﬁces, regular training in anaphylaxis as itch or nausea; therefore, continuous supervision recognition, as well as pharmacological and non- and observation of respiratory and cardiovascular pharmacological treatment, needs to be performed function is important. If unexpected hypotension or (especially with regard to distribution of tasks, posi- tachycardia occur in the perioperative setting, other tioning, calling for help, oxygen, recording respiratory possible symptoms of anaphylaxis need to be imme- and cardiovascular function). Regular training of diately sought: team procedures during anaphylaxis improves medi- – Is erythema, swelling, or urticaria developing, pos- cal care in the emergency situation. A written, easily sibly beginning on the arm receiving the infusion? accessible emergency plan with a description of the necessarydrugsanddosagesishighlyrecommended. Patients should be treated in a room separated from

K Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update 15 guidelines

other patients yet easily accessible to several care- the sternum or fingertip can provide information on givers. In the pediatric setting, the weight-adjusted cardiovascular function. dosages for emergency therapy in children with aller- Caution should be taken with the intravenous ad- gen-specific immunotherapy can already be noted on ministration of adrenaline; this should be reserved the documentation sheet. for physicians with expertise and requires continuous It is helpful to define the following specifications in blood pressure and pulse monitoring (exception: re- preparation for an emergency situation: suscitation situation with an i.v. catheter already in Where is the emergency equipment stored? place). What is the exact procedure in an emergency? In the case of anaphylaxis with medium to se- Who is responsible for what? (inform the physician, vere involvement of the respiratory or cardiovascular take care of the patient, call for help, etc.) system, the emergency medical and rescue services In which room will the patient be treated? should be promptly alerted following discontinuation of allergen exposure (in Germany, call 112). What emergency equipment should a medical office keep available? How is discharge managed in the medical office?

The elements shown in Table 4 are recommended as Since the possibilities for patient monitoring are lim- emergency equipment in a medical office. A pulse ited in the medical office, transfer to a hospital for oximeter should be available, whereas ECG and blood monitoring is recommended in the case of severe or pressure monitors are not standard equipment in all not reliably classifiable anaphylaxis. Otherwise, dis- medical offices. charge management is the same as from hospital, as listed above (Table 9). What is the procedure in an emergency? Special aspects in childhood Acute treatment is performed as described above (treatment in the hospital) with no essential differ- With regard to the dosing of certain drugs used in ences. the treatment of anaphylaxis, the special dosages for Adrenaline is also administered in the medical of- children need to be taken into account. fice by physicians not experienced in emergency treatment, preferably intramuscularly. Administration can be repeated if circulation is not stabilized. If there is no monitor, heart rate and blood pressure can be measured, while the capillary refill time on the skin of

Table 9 Important aspects of discharge management of anaphylaxis patients Table 10 Indications for the prescription of an adrenaline Identification of the Allergy history auto-injector elicitor If necessary, referral to allergy diagnostics (specific Patients with systemic allergic reactions and bronchial asthma (even with IgE and/or skin test) no history of anaphylaxis) Recommendations In food allergy: individually tailored therapeutic Progressive severity of symptoms of the systemic allergic reaction for the prevention of elimination diet (patient organizations, e.g., DAAB, History of prior anaphylactic reactions to elicitors that cannot be reliably renewed reactions “dietetics in allergy” working group, German Society avoided for Nutritional Medicine) Systemic allergy with extracutaneous symptoms to potent allergens such as In insect venom allergy: consider indication for peanuts, tree nuts, milk, sesame allergen-specific immunotherapy Strong sensitization with increased risk of anaphylaxis—prior to allergy In drug allergy: avoidance and allergy passport provocation testing recommended Patients that react to minute amounts of allergen Recommendations Written plan for pharmacological self-management for pharmacological (anaphylaxis passport) Adults with mastocytosis (also without known anaphylaxis) self-management Prescription of emergency drugs in body weight-adjusted doses Table 11 Indications for the prescription of an additional Training in administration (second) adrenaline auto-injector Recommendations Information on support from patient organizations History of extremely severe anaphylaxis for everyday man- for problems in childcare facilities, school, shopping, agement travelling Obesity >100kg BW Information regarding non-labeled allergens in foods Uncontrolled bronchial asthma Nearest emergency medical care is poorly accessible Information on and referral to specialized allergy- Especially high risk for severe anaphylaxis (e.g., adults with mastocytosis trained nutritionists after anaphylaxis) DAAB German Allergy and Asthma Association (Deutscher Allergie- und Organizational: second auto-injector for childcare facility, school, or depend- Asthmabund) ing on the family situation

16 Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update K guidelines

Patient management and self-medication Table 12 Contents of an emergency frst-aid kit for patients with anaphylaxis Target groups for the prescription of an emergency Adrenaline Auto-injector for intramuscular, body weight-adjusted ad- first-aid kit, including an adrenaline auto-injector ministration >7.5 to 25kg BW or 150μga >15–30kg BW: Indications for the prescription of an emergency first- >25 to 50kg BW or 300μga aid kit, including an adrenaline auto-injector, are >30–50kg BW: listed in Tables 10 and 11. >50kg BW: 300–500–600μg We recommend that all patients with: Histamine Depending on patient age and preference, orally as fluid 1. A history of anaphylaxis H1-receptor or (lozenge) tablet. The dose of the non-sedating antihis- antagonist tamine may be increased up to four times a single dose. 2. Systemic allergic reactions with extracutaneous For dimetindene drops, weight-adjusted dose, as with the symptoms and high future risk of anaphylaxis (e.g., intravenous formulation, can also be recommended as an due to well-known potent allergens such as peanut, oral dose (see Table 8) tree nuts, milk, sesame) or at high risk for life-threat- Glucocorticoid According to patient age and preference, oral (liquid or ening reactions (e.g., bronchial asthma) tablet) or rectal with 50–100mg prednisolone equivalent 3. Highly sensitized persons without previous anaphy- BW body weight In known bronchial asthma or previous reaction with bronchospasm: addi- lactic reactions but high-grade suspicion of an in- tionally a beta2-adrenoceptor agonist creased anaphylaxis risk—prior to allergy provoca- If severe obstruction of the upper airways is expected (laryngeal edema), tion testing additionally an inhaled adrenaline preparation with spray head for pharma- ceutical vials (needs to be specially requested from the pharmacist) be provided with an emergency first-aid kit if the elic- Note: An emergency first-aid kit should include an anaphylaxis passport with written instructions on how to use the contents itor cannot be reliably avoided, as in the case of, e.g., aApproval differs for each auto-injector preparation insect venom or food anaphylaxis. The precise indications are given in more detail in Table 10.Itis normally possible to avoid an elicitor in the case of tients, 2S albumin-specific IgE is so high that one can drug-induced anaphylaxis following adequate allergy assume with 90–95% probability that these patients diagnostics, education, and the issuing of an allergy will suffer an anaphylactic reaction even though they passport. have never have eaten this food allergen before [109, 111]. Oral food challenges are often not performed in Can an emergency first-aid kit also be prescribed in these patients, or only at a later point in time (e.g., at patients with high-grade suspicion for anaphylaxis the time of school entrance). These patients can be di- prior to allergy testing? agnosed with “high-grade suspicion” of, e.g., peanut or tree nut allergy without ever having experienced Children with atopic eczema (atopic dermatitis, a clinical reaction. These patients should also receive eczema) are often sensitized to common food al- an adrenaline auto-injector, as well as therapeutic nu- lergens, especially after early onset severe eczema trition counselling in order to consistently avoid the [108, 109]. In the case of clinically relevant sensitiza- highly suspected foods and, where necessary, replace tions, these patients often experience an anaphylactic nutrients lacking in their avoidance diet. reaction after first oral exposure. In order to evaluate the clinical relevance of this, an oral food challenge What should the emergency first-aid kit contain? is performed, often in the inpatient setting [110]. Since there is often an interval of several weeks or In German-speaking countries, physicians often pre- months between the time of indication and the per- scribe several drugs for patients to be put together in formance of oral challenge tests, patients can be given an emergency first-aid kit, which should be carried an adrenaline auto-injector in the interim. Instruc- at all times together with the anaphylaxis passport. tion for use with the help of an auto-injector trainer The authors recommend an adrenaline auto-injector, (“dummy”) is essential. When considering the ratio- a histamine H1-receptor antagonist, a glucocorticoid, nale for this approach, one needs to consider the time and, in patients with bronchial asthma or a prior re- interval until oral challenge testing, the likelihood of action with bronchospasm, an inhaled bronchodilator a clinically relevant food allergy, and the probable (beta2-adrenoceptor agonist) (Table 12). severity of a reaction depending on concomitant dis- When selecting the histamine H1-receptor antag- eases such as asthma, as well as the likelihood of onist, swallowing ability and individual preference accidental exposure. in terms of form of administration should be taken In peanut or tree nut allergy, the risk of a systemic into consideration (drops for small children, tablets reaction increases with the concentration of allergen- or lozenges for older children and adults). If there specific IgE antibodies against storage proteins [109, is a history of difficulty in swallowing (e.g., laryngeal 111]. The best predictor of clinical relevance is specific edema), administration in liquid form is preferred. IgE against the 2S albumins (Ara h 2 in peanut, Cor The same criteria apply to glucocorticoids (1–2mg/kg a 14 in hazelnut, and Ana o 3 in cashew). In some pa- BW), whereby rectal administration is also possible.

K Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update 17 guidelines

The expert group recommends the treatment of ana- When is an adrenaline auto-injector no longer phylaxis with antihistamines in increased doses (up indicated? to four times the approved single dose). The new second-generation selective histamine H1-receptor An expert group of the European Academy of Allergy antagonists are not approved for the treatment of and Clinical Immunology (EAACI) has intensively ad- anaphylaxis; however, they can be recommended dressed the topic of the need for patients with insect alongside sedating antihistamines for oral emergency venom allergy to carry emergency self-medication treatment, since they have shown a rapid onset of ac- at all times [114] and has formulated recommenda- tion in placebo-controlled skin test studies and fewer tions on the prescription of adrenaline auto-injectors, side effects, such as sedation. For asthma patients, which have been included in the current guidelines inhaled beta2-adrenoceptor agonists are additionally for the treatment of insect venom allergy [46]. Accord- prescribed. Alternatively, in the case of a prior history ing to these recommendations, the prescription of an of laryngeal edema, an adrenaline preparation for adrenaline auto-injector is no longer necessary when inhalation may be prescribed. the risk of a renewed systemic reaction is approxi- There are various commercially available adrenaline mately comparable to that of the normal population. auto-injectors that differ in dose, handling, injection This can be assumed after successful immunotherapy mechanism, and needle length. Special instruction is and a well-tolerated sting reaction—either after a field necessary, the preparations cannot be easily substi- sting or after a sting challenge. tuted, and repeat prescriptions need to be organized After completion of allergen-specific immunother- [112]. The “aut idem” box needs to be ticked on the apy, adrenaline auto-injector prescription is no longer prescription. necessary in patients with only cutaneous/mucosal symptoms (grade I) or in patients that have reacted When should two adrenaline auto-injectors be with more than cutaneous symptoms (grade II), but prescribed? have no additional risk factors for non-response to venom immunotherapy [114]. Risk factors include Table 11 shows a list of indications in which two severe insect sting reaction (grade III or IV), bee adrenaline auto-injectors should be prescribed. venom allergy, high risk of exposure (e.g., bee-keeper), The dosing of adrenaline for self-management in a systemic response under immunotherapy, mast cell anaphylaxis is a less controlled initial measure and disease, elevated basal serum tryptase, and treat- does not need to be the same as adrenaline admin- ment with ACE inhibitors. Whether the auto-injector istration under medical supervision and appropriate can be dispensed with once the maintenance dose of monitoring. Due to a lack of data, dose recommen- venom immunotherapy has been reached is discussed dations for self-management are given for children controversially. Between 70 and 80% of experts felt in approximate relation to body weight, but are not that patients with only cutaneous/mucosal symptoms calculated directly from body weight in adults [113]. (grade I) would not need an auto-injector once the There is scant evidence on the optimal adrenaline maintenance dose had been reached. Table 10 lists dose or number of adrenaline auto-injectors required indications for the prescription of adrenaline auto- for self-management. There are cases in which physi- injectors. cians or patients feel it necessary to prescribe a second adrenaline auto-injector. Co-existing bronchial What should training with the emergency first-aid kit asthma is a well-known risk factor for use of a sec- include? ond adrenaline injector. The authors recommend prescribing a second adrenaline auto-injector for the in- Most anaphylactic emergencies occur in the course of dications listed in Table 11. everyday life, often at home. Therefore, training on It is important to ensure that patients are pre- emergency self-management should cover all mea- scribed a second auto-injector, or replacement auto- sures that patients need to consider or take them- injector, that uses the same technique as their previ- selves in the case of a (renewed) emergency situation. ous device. Patients should carry their emergency first The patient should be instructed on how to: aid kit for immediate first aid with them at all times. 1. Recognize anaphylactic reactions From an organizational perspective, it makes sense 2. Administer symptom-related self-medication in individual cases to prescribe two adrenaline auto- 3. Store drugs correctly injectors for different locations (e.g., school, childcare 4. Make an emergency call for help (in Germany and facility, workplace, and in the case of separated par- Austria, call 112, in Switzerland, 144; report anaphy- ents). However, this can lead to confusion and lack of laxis/anaphylactic shock, follow telephone instruc- protection compared to patients that have their auto- tions given by the rescue center) injector on them at all times. Therefore, the group recommends the prescription of a single auto-injector Potential elicitors (foods, insects, drugs) should be to be carried at all times. preserved if possible.

18 Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update K guidelines

Anaphylaxis emergency plan

Name, first name: Signs of beginning reaction Skin: • Wheals, redness • swelling of lips and face • Itch (palms, soles, genital area) or Gastrointestinal: Date of birth: • Nausea, vomitus, cramps, diarrhea • Prickling in the mouth and throat Others: Known elicitors of anaphylaxis • Runny nose / Anxiety / Vertigo

First aid Asthma? 1. Stay with patient/child ! yes (yes, increased risk for severe reaction) emergency call 112 2. Antihistamine and cortisone Issued by

name and amount

name and amount date, signature 3. Adrenalin autoinjector prepared and watch Patient for signs of anaphylaxis In case of emergency please notify: Name, Tel. No.

Signs of severe reaction Where is the emergency set for immediate help stored? Airway: • Sudden hoarseness, cough wheezing, dyspnea ! Empowerment of parents to apply drugs Cardiovascular: • Blood pressure loss, loss of conscience Handling of adrenalin autoinjector Concomitant or subsequent occurrence of symptoms in different organs: Skin / Gastrointestinal / Airways / cardiovascular Each reaction after (eg wasp sting, cow’s milk, …)

First Aid 1. Adrenalin autoinjector into the lateral part of upper thigh muscle

name of adrenalin autoinjector 2. Positioning with dyspnea: sitting with cardiovascular symptoms: flat with unconsciousness: stable side positioning 3. With dyspnea additional airway spray place for sticker of respective preparation name 4. Call paramedic or emergency physician (112) societies involved 5. Notify contact of patient 6. Additional application of antihistamine and glucocorticoid (see above)

In case of doubt: Apply adrenalin autoinjector!

Fig. 4 Anaphylaxis emergency plan

K Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update 19 guidelines

Self-medication is given according to symptoms handling adrenaline auto-injectors, as well as allergen and the degree of certainty that allergen contact has avoidance strategies, behavior in high-risk situations occurred: the correct stage-appropriate administra- in everyday life, and possibilities of risk manage- tion of a number of drugs for acute medication is ment. It is often necessary to individualize training to an essential part of patient information, since the address well-known individual problems and expec- highest degree of uncertainty is found in this regard tations. The authors recommend anaphylaxis group among patients and their families. If it is certain that training whenever available. At present, anaphylaxis contact with an anaphylaxis elicitor has taken place training programs are generally not reimbursed by (insect sting without successful allergen-specific im- insurances and hence not available in all regions of munotherapy, eating allergy-eliciting food, use of an Germany. allergy-eliciting drug), the anaphylaxis emergency plan needs to be followed (Fig. 4). The emergency Where can one find further aids for the everyday plan and anaphylaxis passport are important aids management of anaphylaxis? that the allergy sufferer should have on them at all times. In addition to standardized written anaphylaxis emer- All patients with a history of anaphylaxis or their gency plans and the anaphylaxis passport, other in- relatives/guardians should receive individual instruc- formation materials (such as brochures, shopping tion, including a practical demonstration of how to guides, restaurant maps with information on specific handle the emergency kit, at the time of prescribing. food allergies for the kitchen, documents for air travel, This training includes: information about the etc.) can be made available by patient organizations elicitors of anaphylaxis, their avoidance, referral to (in Germany, e.g., the DAAB). These organizations a nutritionist with allergy experience for advice on also provide support in everyday management (Ta- a therapeutic elimination diet in the case of food- ble 9). induced anaphylaxis, the symptoms of anaphylaxis, Adrenaline auto-injection trainers and training ma- as well theoretical and practical knowledge (including terial are also available from the manufacturers of a demonstration) on how to administer emergency adrenaline auto-injectors, as well as from the DAAB. drugs in the event of a renewed anaphylactic episode. Further aids (bags for the emergency kit, as well as These instructions should be repeated with each new stickers or clothing with warning messages) can be prescription of an adrenaline auto-injector. The pa- ordered via patient organizations or the internet. SOS tient, as well as those in their social environment, emergency bracelets or capsules are not yet popular especially care-takers of children, also need to be in- in German-speaking countries and often go unnoticed structed in the use of self-medication. Standardized in emergency situations. anaphylaxis emergency plans are available to this end It seems important to involve not only affected pa- (Fig. 4), as are anaphylaxis documents and recom- tients and their social environment (e.g., parents), but mendations for emergency management in childcare also physicians active in the field of allergy and ana- facilities and schools. A summary of self-management phylaxis management, as well as other occupational instructions is also given in the anaphylaxis passport, groups such as paramedics, emergency services, hos- which, in addition to triggers, includes drug dosage pital emergency departments, organizers of first aid and mode of administration depending on the clinical courses, and patient organizations [116]. symptoms. Overall, the acute management of anaphylaxis patients in Germany can be positively evaluated; Who should receive anaphylaxis group education? however, there are still considerable problems in long-term management, e.g., in children in daycare Anaphylaxis group education is recommended for all centers and schools, as well as shortcomings in the patients at high risk for renewed anaphylaxis. In addi- prompt administration of adrenaline, further diag- tion to the mandatory individual instruction with the nostics, training, and education [28, 75]. emergency first-aid kit, the German working group on It is important to make the medical profession anaphylaxis training and education (Arbeitsgemein- aware of this potentially life-threatening problem and schaft Anaphylaxie Training und Edukation,AGATE) familiarize them with the possibility of intramuscu- has developed an outpatient educational program. lar adrenaline administration, including the use of The program (consisting of individual educational adrenaline auto-injectors for self-medication. units, 2× 3h), uses a target-oriented and self-con- tained concept comprising written, standardized, and Anaphylaxis after COVID-19 vaccination interdisciplinary components for patients with anaphylaxis and carers of children and adolescents (e.g., Recently vaccination programs against COVID-19 parents), including a manual, documentation for par- have been started in several countries. Rare cases ticipants, and sample time schedules [113, 115]. The of severe allergic reactions have been reported from educational program focuses on practical aspects United Kingdom and USA; this has led to unset- of self-management, including role-playing, e.g., on tledness and fear among patients and vaccinating

20 Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update K guidelines

physicians. The guideline group and allergological Foundation (Deutscher Allergie- und Asthma Bund, societies therefore developed position statements DAAB) have cooperated. [117, 118] stressing the fact that some patients with Consensus conferences were held in Wiesbaden in deﬁned allergic conditions may be at increased risk September 2017, in Mainz in March 2018, in Kas- for anaphylaxis after COVID-19 vaccination, espe- sel in June 2018, in Mainz in March 2019, and in cially patients with severe allergic reactions to drugs Hannover in September 2019. The recommendations or vaccines as well as known hypersensitivities to elaborated during the conferences are based on a lit- ingredients of the respective vaccines. In unclear erature search evaluating clinical studies, case series, cases allergy diagnostics should be performed prior individual case reports, experimental investigations, to COVID-19 vaccination; also patients should be ob- as well as participants’ experiences and theoretical served over 30 minutes after vaccine injection. Physi- considerations. Case series were assigned the highest cians and health personel involved in vaccination level of relevance, whereas theoretical considerations centers should be aware of possible risks of anaphy- were only included when neither single case reports laxis and the necessary acute treatment modalities nor case series or experimental investigations were [117, 118]. available for evaluation. The number of scientiﬁcally reliable studies on anaphylaxis is overall so limited Addendum that management remains empirical in many aspects and is often based on pathophysiological considera- Production of the text tions.

Following a decision of the board of the German So- Development stage S2k ciety for Allergy and Immunology (DGAKI) in 2017, the “anaphylaxis” working group was asked to up- AWMF Guidelines register number 061-025 date the text of the present guidelines together with other scientific societies and experts from other areas. Completed 2021 In addition to allergology, these experts come from anesthesiology and intensive medicine, dermatology, Next revision 2025 pediatrics, internal medicine, pulmonology, otolaryn- gology, psychosomatics, pharmacology, emergency ICD-10 numbers T 78, T 80, J 45, L 23 medicine, and theoretical surgery. Funding Open Access funding enabled and organized by Allergy societies in Austria and Switzerland, as well Projekt DEAL. as representatives of patient organizations, have also participated. Conflict of interest Conflict of interest statements—in addi- In addition to members of the DGAKI, represen- tion to the guideline report—can be found in tabular form and accessed on the AWMF website for the S2k guideline on tatives of the Society of practicing allergists (Ärzte- “acute therapy and management of anaphylaxis: 2020 update” verband Deutscher Allergologen,AeDA),Societyfor (www.awmf.org/leitlinien/detail/ll/061-025.html). pediatric allergology and environmental medicine (Gesellschaft für pädiatrische Allergologie und Umwelt- Open Access This article is licensed under a Creative Com- medizin, GPA), College of children and adolescents mons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in physicians in Germany (Berufsverband der Kinder- any medium or format, as long as you give appropriate credit und Jugendärzte Deutschlands,BVKJ),Societyfor to the original author(s) and the source, provide a link to neonatology and pediatric intensive medicine (Gesell- the Creative Commons licence, and indicate if changes were schaft für Neonatologie und pädiatrische Intensivmedi- made. The images or other third party material in this article zin, GNDPI), German Academy for Allergology and are included in the article’sCreative Commons licence, unless Environmental medicine (Deutsche Akademie für Al- indicated otherwise in a credit line to the material. If material lergologe und Umweltmedizin, DAAU), Austrian Soci- is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or ety for Allergology and Immunology (Österreichis- exceeds the permitted use, you will need to obtain permis- che Gesellschaft für Allergologie und Immunologie, sion directly from the copyright holder. To view a copy of this ÖGAI), Swiss Society for Allergology and Immunol- licence, visit http://creativecommons.org/licenses/by/4.0/. ogy (Schweizerische Gesellschaft für Allergologie und Immunologie,SGAI),GermanSocietyforAnesthesi- ology and Intensive Medicine (Deutsche Gesellschaft References für Anästhesiologie und Intensivmedizin,DGAI),Ger- man Society for Pharmacology (Deutsche Gesellschaft 1. Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, für Pharmakologie, DGP), Working group anaphylaxis Lockey RF,et al. Revised nomenclature for allergy for global training and education (Arbeitsgemeinschaft Anaphy- use: Report of the Nomenclature Review Committee of the World Allergy Organization. J Allergy Clin Immunol. laxie Training und Edukation,AGATE)aswellasthe 2004;113:832–6. patient organization German Allergy and Asthma 2.RingJ,editor.Anaphylaxis.Basel:Karger;2010.

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