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Update on perioperative hypersensitivity reactions: joint document of the Brazilian Society of Anesthesiology (SBA) and Brazilian Association of Allergy and Immunology (ASBAI) – Part I: post-crisis guidelines and treatment This document was published in Arquivos de Asma, Alergia e Imunologia DOI: 10.5935/2526-5393.20190051 with the consent of authors and editors.

Maria Anita Costa Spindola Dirceu Solé Marcelo Vivolo Aun Liana Maria Tôrres de Araújo Azi Luiz Antonio Guerra Bernd Daniela Bianchi Garcia Albertina Varandas Capelo Débora de Oliveira Cumino Alex Eustáquio Lacerda Luciana Cavalcanti Lima Edelton Flávio Morato Rogean Rodrigues Nunes Norma de Paula Motta Rubini Jane da Silva Maria Angela Tardelli Alexandra Sayuri Watanabe Erick Freitas Curi Flavio Sano About the authors

Abstract

Experts from the Brazilian Association of Allergy and Immunology (ASBAI) and the Brazilian Society of Anesthesiology (SBA) interested in the issue of perioperative anaphylaxis, and aiming to strengthen the collaboration between the two societies, combined efforts to study the topic and to prepare a joint document to guide specialists in both areas. The purpose of the present series of two articles was to report the most recent evidence based on the collaborative assessment between both societies. This first article will consider the updated definitions, treatment and guidelines after a perioperative crisis. The following article will discuss the major etiologic agents, how to proceed with the investigation, and the appropriate tests.

KEYWORDS
Allergy and immunology; Hypersensitivity; Anaphylaxis; Perioperative period

Resumo

Especialistas da Associação Brasileira de Alergia e Imunologia (ASBAI) e da Sociedade Brasileira de Anestesiologia (SBA) interessados no tema anafilaxia perioperatória reuniram-se com o objetivo de intensificar a colaboração entre as duas sociedades no estudo desse tema e elaborar um documento conjunto que possa guiar os especialistas de ambas as áreas. O objetivo desta série de dois artigos foi mostrar as evidências mais recentes alicerçadas na visão colaborativa entre as sociedades. Este primeiro artigo versará sobre as definições mais atuais, formas de tratamento e as orientações após a crise no perioperatório. No próximo artigo serão discutidos os principais agentes causais e a condução da investigação com testes apropriados.

PALAVRAS-CHAVE
Alergia e imunologia; Hipersensibilidade; Anafilaxia; Período perioperatório

Introduction

Perioperative hypersensitivity reactions are of great concern to anesthesiologists. Daily, every time a procedure is performed under anesthesia several agents that are administered sequentially can trigger allergic reactions of lesser or greater severity. It is difficult to estimate the incidence of these events due to the heterogeneity of the studies and the variety of medications used worldwide. The incidence of perioperative hypersensitivity reactions is thought to vary between 1:353 and 1:18,600 procedures.11 Kemps HI, Cook TM, Thomas M, et al. UK anaesthetists’ perspectives and experiences of severe perioperative anaphylaxis: NAP6 baseline survey. Br J Anaesth. 2017;119:132-9.,22 Mertes PM, Volcheck GW, Garvey LH, et al. Epidemiology of perioperative anaphylaxis. Presse Med. 2016;45:758-67.

Mortality is higher than in anaphylaxis from other causes and oscillates from 3% to 9%.33 Mertes PM, Lambert M, Guéabt-Rodriguez RM, et al. Perioperative anaphylaxis. Immunol Allergy Clin N Am. 2009;29:429-51. In Brazil, a cross-sectional study carried out by answering a questionnaire (although without further investigation) indicated the incidence of anaphylaxis as greater than 7:10,000 anesthesias, which is higher than the previously described figure in the literature.44 Garro LS, Aun MV, Soares IS, et al. Specific questionnaire detects a high incidence of intra-operative hypersensitivity reactions. Clinics. 2018;113:1202-12. The greatest risk factor for perioperative hypersensitivity reaction is an earlier reaction, without adequate investigation.55 Dewachter P, Kopac P, Laguna JJ, et al. Anaesthetic management of patients with pre-existing allergic conditions: a narrative review. Br J Anaesth. 2019;123:e50-e64.,66 Volcheck GW, Hepner DL. Identification and management of perioperative anaphylaxis. J Allergy Clin Immunol Pract. 2019;7:2134-42. The collaboration among anesthesiologists, allergists and immunologists is fundamental to carry out the investigation.

Few countries have organized an approach to diagnose, treat and investigate suspected perioperative allergic reactions, with published joint guideline documents that can guide both specialties.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,88 Benahmed S, Picot MC, Dumas F, et al. Accuracy of a pharmacovigilance algorithm in diagnosing drug hypersensitivity reactions. Arch Intern Med. 2005;:1500-5.

Method

A search was performed in the PubMed database, in English, French, Spanish and Italian, for the past 20 years, with the combination of the terms “perioperative”, “anaphylaxis”, “management”, “treatment”, “protocols”, “anesthesia”, “allergy” and “hypersensitivity”. The articles were selected according to their current and clinical relevance.

Nomenclature

Medical nomenclature changes over time, depending upon the acquisition of new scientific knowledge.88 Benahmed S, Picot MC, Dumas F, et al. Accuracy of a pharmacovigilance algorithm in diagnosing drug hypersensitivity reactions. Arch Intern Med. 2005;:1500-5. The question of using accurate nomenclature for research and planning of global health actions is highly important, especially for drug hypersensitivity reactions, an ever-growing global health problem.

As a consequence, the World Health Organization (WHO), in its International Classification of WHO Disease ICD-11, will already bring advances such as the pioneering subsection of drug hypersensitivity.99 Tanno LK, Torres MJ, Castells M, et al. What can we learn in drug allergy management from World Health Organization's international classifications?. Allergy. 2018;73:987-92. This concern may translate into a better registry even for fatal cases.1010 Tanno LK, Simons FE, Annesi-Maesano I, et al. Fatal anaphylaxis registries data support changes in the WHO anaphylaxis mortality coding rules. Orphanet J Rare Dis. 2017;12:8.

The nomenclature used in the present article complies with the revised allergy nomenclature.1111 Johansson SGO, Bieber T, Dahl R, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004;113:832-6. Obsolete terms (such as, anaphylactoid) should be discontinued as they are not in accordance with the classification and new concepts of mechanisms.1212 Ebo DG, Clarke RC, Mertes PM, et al. Molecular mechanisms and pathophysiology of perioperative hypersensitivity and anaphylaxis: a narrative review. Br J Anaesth. 2019;123:e38-e49. Thus, concepts used in this article obey the definitions proposed by Johansson et al., 20041111 Johansson SGO, Bieber T, Dahl R, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004;113:832-6.:

Hypersensitivity: Reproducible signs or symptoms, initiated by exposure to a defined stimulus, in doses tolerated by normal individuals.

Allergy: Hypersensitivity reaction triggered by a specific immune mechanism.

Anaphylaxis: Severe, systemic or generalized, life-threatening hypersensitivity reaction.

The term allergy should only be used when there is a proven IgE- or IgG-mediated mechanism, or concrete evidence of complement-related immune complex. Although it may seem paradoxical, the expression non-allergic anaphylaxis can be used in cases where these mechanisms cannot be proven.1111 Johansson SGO, Bieber T, Dahl R, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004;113:832-6.

Adults

Clinical aspects and classification of severity

The miscellany of clinical presentations of perioperative hypersensitivity is the result of different pathophysiological, immunological or non-immunological mechanisms involved combined with the comorbidities and diseases determining the surgery. The variability of these combinations challenges the anesthesiologist in care of the patient.

It is very difficult to specify the effects of each exact mediator because of the ethical concerns preventing anaphylaxis induction in humans, and the multiplicity of mediators of anaphylaxis that are simultaneously released.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,1212 Ebo DG, Clarke RC, Mertes PM, et al. Molecular mechanisms and pathophysiology of perioperative hypersensitivity and anaphylaxis: a narrative review. Br J Anaesth. 2019;123:e38-e49.

However, signs and symptoms of anaphylaxis can be expected as a result of some of the currently known effects of the major mediators of anaphylaxis. There is evidence that histamine, leukotrienes and Platelet Activating Factor (PAF) are involved in vasodilation, capillary leakage, and bronchospasm.1212 Ebo DG, Clarke RC, Mertes PM, et al. Molecular mechanisms and pathophysiology of perioperative hypersensitivity and anaphylaxis: a narrative review. Br J Anaesth. 2019;123:e38-e49.

Hypersensitivity reaction presumptive diagnosis is based on the development of clinical manifestations primarily affecting the cardiovascular, respiratory, and integumentary systems. The particular presentation will depend on the combination of the pharmacological action resulting from the various substances used in sequence, mediators released, and the previous clinical condition of the patient.

The clinical scale described in 1977 in the investigation on colloids1313 Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet. 1977;1:466-9. was adapted by the Société Française d’Anesthesie et Réanimation (SFAR) and remains a valuable guide for reaction severity classification based on the intensity of signs and symptoms (Table 1).1414. Reducing the risk of the anaphylaxis during anaesthesia. Short text. Ann Fr Anesth Reanim. 2011;30:212-22.1616 Hopkins PM, Cooke PJ, Clarke RC, et al. Consensus clinical scoring for suspected perioperative immediate hypersensitivity reactions. Br J Anaesth. 2019;123:e29-37.

Table 1
Classification of severity and clinical signs of anaphylaxis.1414. Reducing the risk of the anaphylaxis during anaesthesia. Short text. Ann Fr Anesth Reanim. 2011;30:212-22.

15 Mertes PM, Malinovsky JM, Jouffroy L. Working Group of the SFAR and SFA, Aberer W, Tereehorst I, et al. Reducing the risk of anaphylaxis during anesthesia: 2011 update guidelines for clinical practice. J Investig Allergol Clin Immunol. 2011;21:442-53.
-1616 Hopkins PM, Cooke PJ, Clarke RC, et al. Consensus clinical scoring for suspected perioperative immediate hypersensitivity reactions. Br J Anaesth. 2019;123:e29-37.

In the perioperative period, cardiovascular and respiratory signs can progress rapidly.1717, et al. The diagnosis and management of anaphylaxis: an updated practical parameter. J Allergy Clin immunol. 2005;115(Suppl. 2):S483-523. Cardiovascular collapse may be the only manifestation and the initial event can be a cardiorespiratory arrest.1818 Dewachter P, Mouton-Faivre C, Emala CW. Anaphylaxis and anesthesia: controversies and new insights. Anesthesiology. 2009;111:1141-50. Absence of cutaneous signs, such as generalized erythema and urticaria, does not rule out the diagnosis33 Mertes PM, Lambert M, Guéabt-Rodriguez RM, et al. Perioperative anaphylaxis. Immunol Allergy Clin N Am. 2009;29:429-51. and may appear only when vascular perfusion is reestablished.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64. Hypersensitivity reaction should be suspected in the presence of hypotension or tachycardia as isolated and unexpected signs not responding to usual treatment. Patients with a pre-existing cardiac condition or using beta-blockers are more likely to develop severe hypotension or shock.1515 Mertes PM, Malinovsky JM, Jouffroy L. Working Group of the SFAR and SFA, Aberer W, Tereehorst I, et al. Reducing the risk of anaphylaxis during anesthesia: 2011 update guidelines for clinical practice. J Investig Allergol Clin Immunol. 2011;21:442-53. Bradycardia can also occur.1919 Brown SGA. Cardiovascular aspects of anaphylaxis: implications for treatment and diagnosis. Curr Opin Allerg Clin Immunol. 2005;5:359-64. Its onset may be related to rapid vascular leakage, subsequent hypovolemia and Bezold-Jarish reflex.2020 Clarke R, Sadleir P, Van Niekerk AW, et al. Quantification of volume loss and haemodynamic changes of Gelofusine-induced anaphylaxis during cardiopulmonar by-pass. Anaesth Intensive Care. 2011;39:492-5.

Associated with immediate hypersensitivity reactions, acute coronary events, known as allergic angina, or Kounis syndrome, may result from the release of mediators by cardiac mast cells.2121 Kounis NG. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigma?. Int J Cardiol. 2006;110:7-14.,2222 Franco Hernandez JA, García Hernandez A, Lahoz Rodríguez D. Kounis syndrome secondary to an allergic reaction to metamizole. Rev Esp Anestesiol Reanim. 2012;59:217-9.

Although bronchospasm is more common in patients with underlying airway hyperreactivity, such as asthma, chronic obstructive pulmonary disease or obesity,77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64. in a series of patients with a history of asthma and intraoperative anaphylaxis, based on the logistic regression results, we can suggest that bronchospasm during anesthesia should also be attributed to anaphylaxis, and not exclusively to the history of asthma of the patient. Additionally, it was found that it was not bronchospasm incidence that was increased, but the severity of the reactions.2323 Gouel-Chéron A, Neukirch C, Aubier B, et al. Anaphylactic bronchospasm during general anesthesia is not related to asthma. Allergy. 2015;70:453-6.

At hypersensitivity onset, it is very difficult to predict the speed of progression of reaction or its severity.2424 Simmons FE, Ardusso LR, Bilò MB, et al. World Allergy Organization anaphylaxis guidelines: summary. J Allergy Clin Immunol. 2011;127:587-93. Thus, early presumptive diagnosis must be considered in the presence of hypotension and bronchospasm unresponsive to usual measures or subsequent unexpected cardiac arrest without a clinical or surgical rationale.2525 Kroigaard M, Garvey LH, Gillberg L, et al. Scandinavian Clinical Practice Guidelines on the diagnosis, management and follow-up of anaphylaxis during anaesthesia. Acta Anesthesiol Scand. 2007;51:655-70.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8. Next step is to start performing the differential diagnosis.

We can say IgE-mediated reactions are associated with greater severity, but it is impossible to define whether a reaction was IgE-mediated only based on initial severity.2424 Simmons FE, Ardusso LR, Bilò MB, et al. World Allergy Organization anaphylaxis guidelines: summary. J Allergy Clin Immunol. 2011;127:587-93.

Grade III and IV multisystemic reactions meet the criteria for anaphylaxis, life-threatening and are most likely mediated by IgE.1515 Mertes PM, Malinovsky JM, Jouffroy L. Working Group of the SFAR and SFA, Aberer W, Tereehorst I, et al. Reducing the risk of anaphylaxis during anesthesia: 2011 update guidelines for clinical practice. J Investig Allergol Clin Immunol. 2011;21:442-53.,2727 Dewachter P, Mouton-Faivre C, Hepner DL. Perioperative Anaphylaxis: what should be known?. Curr Allergy Asthma Rep. 2015;15:21.

Differential diagnosis

Some clinical signs and symptoms of the hypersensitivity reaction may mirror patient response to anesthesia or surgery, such as inadequate level of anesthesia, hypovolemia and hemorrhage resulting from vascular injury, which may not be swiftly identified.

Differential diagnosis with conditions unrelated to hypersensitivity may be hindered by factors listed on Table 2.2828 Spindola MAC, da Silva J. Anafilaxia e anestesia. In: In: Nunes RR, Bagatini A, Duarte LTD (org), Sociedade Brasileira de Anestesiologia. PROANESTESIA Programa de Atualização em Anestesiologia: Ciclo 1. Porto Alegre: Artmed Panamericana; 2018. p. 9-49 (Sistema de Educação Continuada à Distância, vol. 3).

Table 2
Diagnosis of perioperative anaphylaxis.2828 Spindola MAC, da Silva J. Anafilaxia e anestesia. In: In: Nunes RR, Bagatini A, Duarte LTD (org), Sociedade Brasileira de Anestesiologia. PROANESTESIA Programa de Atualização em Anestesiologia: Ciclo 1. Porto Alegre: Artmed Panamericana; 2018. p. 9-49 (Sistema de Educação Continuada à Distância, vol. 3).

Among several conditions that can be confused with hypersensitivity, some are listed on Table 3. In addition, the temporal relationship may provide some clues (Table 4).

Table 3
Differential diagnosis of intraoperative hypersensitivity. Adapted from 1515 Mertes PM, Malinovsky JM, Jouffroy L. Working Group of the SFAR and SFA, Aberer W, Tereehorst I, et al. Reducing the risk of anaphylaxis during anesthesia: 2011 update guidelines for clinical practice. J Investig Allergol Clin Immunol. 2011;21:442-53.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.,2727 Dewachter P, Mouton-Faivre C, Hepner DL. Perioperative Anaphylaxis: what should be known?. Curr Allergy Asthma Rep. 2015;15:21.
Table 4
Possible triggers of hypersensitivity reaction in the intraoperative period, according to anesthesia timeline. Adapted from 2929 Ewan PW, Dugué P, Mirakian R, et al. BSACI guidelines for the investigation of suspected anaphylaxis during general anesthesia. Clin Exp Allergy. 2009;40:15-31.,3030 Laguna JJ, Archilla J, Doña I, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Immunol. 2018;28:216-32.,3131 Volcheck GW, Mertes PM. Local and general anesthetics immediate hypersensitivity reactions. Immunol Allergy Clin N Am. 2014;34:525-46..

Immediate treatment (during anesthesia)

The foundations of the treatment of immediate reaction hypersensitivity are: early recognition; epinephrine in adequate doses; and correct replacement of intravascular volume.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.

As mentioned above, the diagnosis is presumptive and based on clinical signs. Regardless of the mechanism, whether it is IgE dependent or not, at the onset of anaphylaxis, it is hard to predict the progression rate and the severity of the condition. Fatality can occur in minutes,77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,2424 Simmons FE, Ardusso LR, Bilò MB, et al. World Allergy Organization anaphylaxis guidelines: summary. J Allergy Clin Immunol. 2011;127:587-93. thus one should not wait for multisystemic impairment to start treatment (Table 5).3232 Kemp SF, Lockey RF, Simmons FE, et al. Epinephrine: the drug of choice for anaphylaxis: a statement of the World Allergy Organization. Allergy. 2008;63:1061-70.

Table 5
Management according to severity.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,1515 Mertes PM, Malinovsky JM, Jouffroy L. Working Group of the SFAR and SFA, Aberer W, Tereehorst I, et al. Reducing the risk of anaphylaxis during anesthesia: 2011 update guidelines for clinical practice. J Investig Allergol Clin Immunol. 2011;21:442-53.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.

Epinephrine

Epinephrine is the only medication that reduces hospitalization and death in the event of an anaphylactic reaction. One of epinephrine beta-adrenergic’ effects, suppression of the release of mediators by mast cells and basophils, is thought to explain its precise indication.3232 Kemp SF, Lockey RF, Simmons FE, et al. Epinephrine: the drug of choice for anaphylaxis: a statement of the World Allergy Organization. Allergy. 2008;63:1061-70. As for the use of epinephrine in patients with cardiovascular disease, it is necessary to remember that the heart is a target organ in anaphylaxis. Mast cells are present in the myocardium and in the intima of coronary arteries. Releasing histamine, leukotrienes and prostaglandins can cause coronary spasm leading to myocardial infarction, arrhythmias or both,3333 Simmons FE. Anaphylaxis: recent advances in assessment and treatment. J Allergy Clin Immunol. 2009;124:625-36. even if epinephrine has not been administered.3434 Mueller UR. Cardiovascular disease and anaphylaxis. Curr Opin Allergy. 2007;:337-41. Thus, there is no absolute contraindication to the use of epinephrine in anaphylaxis in any scenario.3535 Lieberman P, Nicklas RA, Randolph C, et al. Anaphylaxis – a practice parameter update 2015. Ann Allergy Asthma Immunol. 2015;115:341-84.

Cardiorespiratory arrest occurs within 5 minutes in cases of iatrogenic anaphylaxis,3636 Pumphrey RS. Lessons for management from a study of fatal reactions. Clin Exp Allergy. 2000;30:1114-50. therefore, one should not wait for the condition to worsen before starting treatment. Even though anesthesiologists are specialists familiar with the daily use of intravenous (IV) epinephrine and in infusion, the use of intramuscular (IM) epinephrine is recommended by consensus on perioperative anaphylaxis while waiting for the preparation of dilution, monitoring, or if venous access has been lost.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.

It is important to remember that starting treatment with IM epinephrine joins speed and safety with a lower risk of overdose,3737 Campbell RL, Bellolio F, Knutson BD, et al. Higher risk of cardiovascular complications and overdose after administration of intravenous bolus epinephrine compared with intramuscular epinephrine. J Allergy Clin Immunol Pract. 2014;3:76-80. and these are important factors for outcome, since in a large series on anaphylaxis casualties, only 23% of deaths were in patients who received epinephrine before cardiac arrest.3838 Xu YS, Kastner M, Harada L, et al. Anaphylaxis-related deaths in Ontario: a retrospective review of cases from 1986 to 2011. Allergy Asthma Clin Immunol. 2014;10:38. and excessive dose or very fast IV administration can cause arrythmias. 3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88.The site for epinephrine injection is the thigh, in the middle third of the vastus lateralis muscle.2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.

Regardless of the route used, the dose of epinephrine must be expressed in micrograms, and not in a ratio (1:1000), a factor identified as a source of error of medication administration.3232 Kemp SF, Lockey RF, Simmons FE, et al. Epinephrine: the drug of choice for anaphylaxis: a statement of the World Allergy Organization. Allergy. 2008;63:1061-70.,4040 Kanwar M, Irvin CB, Frank JJ, et al. Confusion about epinephrine dosing leading to iatrogenic overdose: a life-threatening problem with a potential solution. Ann Emerg Med. 2010;55:341-4. The treatment of perioperative immediate hypersensitivity reactions is summarized in Tables 6 and 7.

Table 6
Immediate treatment of anaphylaxis. Adapted from 77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.,3030 Laguna JJ, Archilla J, Doña I, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Immunol. 2018;28:216-32.,3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88..
Table 7
Epinephrine dilution methods.2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.

There are several methods for correctly diluting epinephrine and they should be taught during the training practices for perioperative anaphylaxis.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64. The only presentation available in Brazil for epinephrine contains 1,000 µg.mL−1.

Several publications, from different countries77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,2525 Kroigaard M, Garvey LH, Gillberg L, et al. Scandinavian Clinical Practice Guidelines on the diagnosis, management and follow-up of anaphylaxis during anaesthesia. Acta Anesthesiol Scand. 2007;51:655-70.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.,3030 Laguna JJ, Archilla J, Doña I, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Immunol. 2018;28:216-32.,4040 Kanwar M, Irvin CB, Frank JJ, et al. Confusion about epinephrine dosing leading to iatrogenic overdose: a life-threatening problem with a potential solution. Ann Emerg Med. 2010;55:341-4. recommend an “anaphylaxis kit” containing leaflets/cards with, among others:

Simple treatment algorithms;

Differential diagnosis;

Tables with dosing, routes and dilution of epinephrine and other vasopressors;

Instructions for obtaining blood samples (type of sampling tube, instructions on how and where to send the sample);

Form for recording the medications administered and measures taken.

Some guidelines on this consensus have been developed along the lines of these recommendations above, and some of them should be emphasized:

  1. In grade I SFAR there is no immediate indication for epinephrine. One must remain alert, because in the suspicion of worsening, prompt treatment should be instituted.2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.

  2. The following are worsening signs in adults2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.:

    Systolic Blood Pressure (SBP) < 60 mmHg.2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8. It is recommended to start cardiac compressions with SBP < 50 mmHg;

    Life-threatening tachy or bradyarrhythmias;

    Oxygen saturation < 90%;

    Great difficulty to ventilate the lungs;

    Inspiratory pressure > 40 cm H2O;

    Low EtCO2. It is considered an estimate of low cardiac output and has been used as a predictor of anaphylaxis severity.4141 Gouel-Cheron A, de Chaisemartin L, Jonsson F, et al. Low end-tidal CO2 as a marker of a real-time severity marker of intra-anaesthetic acute hypersensitivity reactions. Br J Anaesth. 2017;119:908-17. It is suggested to start cardiac massage immediately77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.;

    Airway edema. If suspected, consider early tracheal intubation.2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.

  3. Intravenous volume administration. Aggressive volume replacement is an essential step to ensure adequate blood flow to vital organs.2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8. In severe anaphylaxis, poor distribution and hypovolemia lead to decrease in venous return and circulatory failure.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64. We recommend 20 mL.kg−1, repeating if necessary.2020 Clarke R, Sadleir P, Van Niekerk AW, et al. Quantification of volume loss and haemodynamic changes of Gelofusine-induced anaphylaxis during cardiopulmonar by-pass. Anaesth Intensive Care. 2011;39:492-5.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8. The recommendation is fast infusion of 500 mL of crystalloid for Grade II reactions and 1,000 mL for Grade III, which should be repeated in case of inadequate response, as described by several authors.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,1515 Mertes PM, Malinovsky JM, Jouffroy L. Working Group of the SFAR and SFA, Aberer W, Tereehorst I, et al. Reducing the risk of anaphylaxis during anesthesia: 2011 update guidelines for clinical practice. J Investig Allergol Clin Immunol. 2011;21:442-53.,2525 Kroigaard M, Garvey LH, Gillberg L, et al. Scandinavian Clinical Practice Guidelines on the diagnosis, management and follow-up of anaphylaxis during anaesthesia. Acta Anesthesiol Scand. 2007;51:655-70.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.,3030 Laguna JJ, Archilla J, Doña I, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Immunol. 2018;28:216-32.,3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88.

  4. For Grade IV, follow the current resuscitation protocol.

  5. It is important to observe positioning of patient, who should be placed in a supine position as soon as possible when resuscitation maneuvers are required,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8. with elevation of the lower limbs.1515 Mertes PM, Malinovsky JM, Jouffroy L. Working Group of the SFAR and SFA, Aberer W, Tereehorst I, et al. Reducing the risk of anaphylaxis during anesthesia: 2011 update guidelines for clinical practice. J Investig Allergol Clin Immunol. 2011;21:442-53.

Refractory anaphylaxis

There is no refractory anaphylaxis definition, but after 10 minutes of treatment with adequate doses of epinephrine and volume, reassessment and probable adjunct strategies are required.4242 Garvey LH, Belhage B, Kroigaard M, et al. Treatment with epinephrine (adrenaline) in suspected anaphylaxis during anesthesia in Denmark. Anesthesiology. 2011;115:111-6.,4343 Gouel-Cheron A, Harpan A, Mertes PM, et al. Management of anaphylactic shock in the operating room. Presse Med. 2016;45:774-83.

Besides the inclusion of other therapeutic management measures, reviewing the differential diagnosis and checking if the possible antigen has been discontinued are essential.2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.,3030 Laguna JJ, Archilla J, Doña I, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Immunol. 2018;28:216-32. In some cases described agents, such as gelatin and chlorhexidine-impregnated central venous catheter, have not been removed, and in others, a second dose of the antigen has still been administered.3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88.

One should be aware of the risk factors for fatal reactions. A significant finding was the association of increased age, physical status according to the American Society of Anesthesiology (ASA), morbid obesity, coronary artery disease, and use of beta-blockers or angiotensin-converting enzyme inhibitors.3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88. Another study also found that age over 50 years and the presence of cardiovascular disease were factors of greater risk for fatal drug anaphylaxis.4343 Gouel-Cheron A, Harpan A, Mertes PM, et al. Management of anaphylactic shock in the operating room. Presse Med. 2016;45:774-83.,4444 Turner P, Jerschow E, Umasunthar T, et al. Fatal anaphylaxis: mortality rate and risk factors. J Allergy Clin Immunol Pract. 2017;5:1169-78. Both groups of patients need higher levels of vigilance.

Table 8 shows other options for treatment in the case of refractory anaphylaxis.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.,3030 Laguna JJ, Archilla J, Doña I, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Immunol. 2018;28:216-32.,4747 Platt PR, Clarke RC, Jonson GH, et al. Efficacy of sugammadex in rocuronium-induced or antibiotic-induced anaphylaxis. A case-control study. Anaesthesia. 2015;70:1264-7.

Table 8
Refractory anaphylaxis management.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.,4646 Clarke RC, Sadleir PH, Platt PR. The role of sugammadex in the development and modification of an allergic response to rocuronium: evidence from a cutaneous model. Anaesthesia. 2012;67:266-73.,4747 Platt PR, Clarke RC, Jonson GH, et al. Efficacy of sugammadex in rocuronium-induced or antibiotic-induced anaphylaxis. A case-control study. Anaesthesia. 2015;70:1264-7.

In cases of Refractory Anaphylaxis, other measures are indicated, in addition to drug therapy (Table 9):

Table 9
Suggested management for suspected anaphylaxis and perioperative allergy in children.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.
  1. Establish an arterial line, both to support monitoring and to enable blood sampling.33 Mertes PM, Lambert M, Guéabt-Rodriguez RM, et al. Perioperative anaphylaxis. Immunol Allergy Clin N Am. 2009;29:429-51.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.

  2. Whenever possible, perform transthoracic or transesophageal ultrasound to obtain accurate ventricular function assessment.2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.

  3. When available in the surgical environment, cardiopulmonary bypass can be used as part of the resuscitation process.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.,3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88.,4545 Weiss GM, Fandrick AD, Sidebotham D. Successful rescue of an adult with refractory anaphylactic shock and abdominal compartment syndrome with venoarterial extracorporeal membrane oxygenation and bedside laparotomy. Semin Cardiothor Vasc Anesthesia. 2015;19:66-70.

  4. Sugammadex, previously presented as an astonishing option for treatment of anaphylaxis, not only to rocuronium, has no evidence so far to justify its use in the treatment of anaphylaxis.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88.,4646 Clarke RC, Sadleir PH, Platt PR. The role of sugammadex in the development and modification of an allergic response to rocuronium: evidence from a cutaneous model. Anaesthesia. 2012;67:266-73.,4747 Platt PR, Clarke RC, Jonson GH, et al. Efficacy of sugammadex in rocuronium-induced or antibiotic-induced anaphylaxis. A case-control study. Anaesthesia. 2015;70:1264-7.

Specificities in pregnant women

Anaphylaxis is uncommon during pregnancy and shows a rate of approximately 3 for every 100,000 births in studies in the United States and the United Kingdom.4848 Hepner DL, Castells M, Mouton-Faivre C, et al. Anaphylaxis in the clinical setting of obstetric anesthesia: a literature review. Anesth Analg. 2013;117:1357-67. The main agents involved are beta-lactam antibiotics, latex and neuromuscular blockers.3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88. It is important to underline that, in the obstetric scenario several other causes can cause profound hypotension and hinder the diagnosis. Early recognition and prompt initiation of treatment are critical.4949 McCall SJ, Bunch KJ, Brocklehurst P, et al. The incidence characteristics, managements and outcomes of anaphylaxis in pregnancy: a population-based descriptive study. BJOG. 2018;125:965-71.

Main measures involve:

Manual left displacement of the uterus, to achieve aorta-cava decompression, is the fundamental measure. It must be maintained while cardiac massage is applied.5050 Lavonas EJ, Drennan IR, Gabrielli A, et al. Part 10: special circumstances of resuscitation 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;132(Suppl. 2):S501-18.

Although phenylephrine is the recommended vasopressor for use in hypotension related to regional block,5151 Kinsella SM, Carvalho B, Dyer RA, et al. International consensus statement on the management of hypotension with vasopressor during cesarean section under spinal anesthesia. Anaesthesia. 2018;73:71-92. in anaphylaxis, epinephrine is the recommended drug, in doses according to the severity scale.1414. Reducing the risk of the anaphylaxis during anaesthesia. Short text. Ann Fr Anesth Reanim. 2011;30:212-22.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.,3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88.,4848 Hepner DL, Castells M, Mouton-Faivre C, et al. Anaphylaxis in the clinical setting of obstetric anesthesia: a literature review. Anesth Analg. 2013;117:1357-67.

The impact on uteroplacental circulation will be short due to the short half-life of epinephrine,5252 Hood D, Dewan D, James F. Maternal and fetal effects of epinephrine in gravid ewes. Anesthesiology. 1986;:64-610. and fetal survival is maximized by maternal resuscitation.4848 Hepner DL, Castells M, Mouton-Faivre C, et al. Anaphylaxis in the clinical setting of obstetric anesthesia: a literature review. Anesth Analg. 2013;117:1357-67.

Quickly start replacement with crystalloids; large volumes may be required.4848 Hepner DL, Castells M, Mouton-Faivre C, et al. Anaphylaxis in the clinical setting of obstetric anesthesia: a literature review. Anesth Analg. 2013;117:1357-67.

Establish an airway and ventilate the lungs with 100% FiO2 to compensate for the increase in consumption.4848 Hepner DL, Castells M, Mouton-Faivre C, et al. Anaphylaxis in the clinical setting of obstetric anesthesia: a literature review. Anesth Analg. 2013;117:1357-67. Pay attention to airway particularities of the pregnant patient.5353 Mushambi MC, Jaladi S. Airway management and training in obstetric anaesthesia. Curr Opin Anaesthesiol. 2016;29:261-7.

Emergency cesarean section should be considered after 5 minutes of circulatory failure, despite efforts to resuscitate.1414. Reducing the risk of the anaphylaxis during anaesthesia. Short text. Ann Fr Anesth Reanim. 2011;30:212-22.

Post-mortem cesarean section should be indicated after 4 minutes of maternal cardiorespiratory arrest.4848 Hepner DL, Castells M, Mouton-Faivre C, et al. Anaphylaxis in the clinical setting of obstetric anesthesia: a literature review. Anesth Analg. 2013;117:1357-67.,5454 Simmons FER, Schatz M. Anaphylaxis during pregnancy. J Allergy Clin Immunol. 2012;130:597-605.,5555 Lipman S, Cohen S, Einav S, et al. The Society of Obstetric Anesthesia and Perinatology Consensus Statement on the management of cardiac arrest in pregnancy. Anesth Analg. 2014;118:1003-16.

Specificities in children

The challenges for diagnosing perioperative anaphylaxis in children are similar to those in adults. Symptom onset can be delayed if the antigen is in a coated catheter or if the route of exposure is cutaneous, as reduced peripheral perfusion can make cutaneous manifestations absent, and surgical drapes can hinder physical examination and access to the airway.5656 Stepanovic B, Sommerfield D, Lucas M, et al. An update on allergy and anaphylaxis in pediatric anesthesia. Paediatr Anaesth. 2019;29:892-900.

A recent retrospective study on perioperative anaphylaxis in children gathered 29 cases, which occurred during 10 years in the United Kingdom, France and the United States. Cardiovascular collapse was the first sign in 59% of cases, followed by tachycardia and bronchospasm. In 55% of cases there was involvement in multiple systems and in four cases, cardiorespiratory arrest.5757 Khaleva E, Franz A, Garvey LH, et al. Perioperative anaphylaxis in children: etiology, time sequence, and patterns of clinical reactivity. Pediatr Allergy Immunol. 2020;31:85-94. In the pediatric cohort of the NAP6 of the Royal College of Anaesthetists,5858 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: epidemiology and clinical features of perioperative anaphylaxis in the 6th National Audit Project. Br J Anaesth. 2018;121:159-71. a study carried out to characterize the incidence, risk factors, treatment, clinical results and investigation of perioperative anaphylaxis, 11 cases of anaphylaxis were reported in children under 16 years. In these patients, bronchospasm and/or high airway pressure were the initial signs identified in 64% of cases.3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88. These findings contrast with the study by Khaleva et al.,5757 Khaleva E, Franz A, Garvey LH, et al. Perioperative anaphylaxis in children: etiology, time sequence, and patterns of clinical reactivity. Pediatr Allergy Immunol. 2020;31:85-94. in which the authors underline the fact that their findings (in a population with a mean age of 11 years) were analogous to those in adult patients in the NAP6 study regarding hypotension as the most frequent sign. The lowest blood pressure value recorded was <50 mmHg.5757 Khaleva E, Franz A, Garvey LH, et al. Perioperative anaphylaxis in children: etiology, time sequence, and patterns of clinical reactivity. Pediatr Allergy Immunol. 2020;31:85-94.,5959 Thomas M, Harper N, Cook T. Paediatric anaesthesia. Anaesthesia, surgery and life-threatening allergic reactions: from the Report and findings of the 6th National Audit Project, Royal College of Anaesthetists. 2018;:216-21. No cardiorespiratory arrest or death occurred in the pediatric cohort of NAP6.5959 Thomas M, Harper N, Cook T. Paediatric anaesthesia. Anaesthesia, surgery and life-threatening allergic reactions: from the Report and findings of the 6th National Audit Project, Royal College of Anaesthetists. 2018;:216-21. Contrary to what was proposed for adults,3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88. no blood pressure value was established below which cardiorespiratory resuscitation should be started before the occurrence of cardiac arrest.5959 Thomas M, Harper N, Cook T. Paediatric anaesthesia. Anaesthesia, surgery and life-threatening allergic reactions: from the Report and findings of the 6th National Audit Project, Royal College of Anaesthetists. 2018;:216-21.

For the classification of severity of reactions, the modified Ring and Messner scale (used for adults)1414. Reducing the risk of the anaphylaxis during anaesthesia. Short text. Ann Fr Anesth Reanim. 2011;30:212-22.,1515 Mertes PM, Malinovsky JM, Jouffroy L. Working Group of the SFAR and SFA, Aberer W, Tereehorst I, et al. Reducing the risk of anaphylaxis during anesthesia: 2011 update guidelines for clinical practice. J Investig Allergol Clin Immunol. 2011;21:442-53. has been used (Table 1).5757 Khaleva E, Franz A, Garvey LH, et al. Perioperative anaphylaxis in children: etiology, time sequence, and patterns of clinical reactivity. Pediatr Allergy Immunol. 2020;31:85-94.,6060 Michavila Gomez AV, Belver Gonzalez MT, Alvarez NC, et al. Perioperative anaphylactic reactions: review and procedure protocol in paediatrics. Allergol Immunopathol (Madr). 2015;43:203-14. For the pediatric cases reported in a French study,6161 Mertes PM, Alla F, Trechot P, et al. Anaphylaxis during anesthesia in France: an 8-year national survey. J Allergy Clin Immunol. 2011;128:366-73. the most severe manifestations, with cardiovascular symptoms and bronchospasm, occurred in the reactions mediated by IgE (Grade III), while the non-mediated by IgE were classified as Grade I, in the large majority. In the same study performed between 1997 and 2004,6161 Mertes PM, Alla F, Trechot P, et al. Anaphylaxis during anesthesia in France: an 8-year national survey. J Allergy Clin Immunol. 2011;128:366-73. latex ranked first amongst the agents involved. In two recently published studies, neuromuscular blockers occupy the top positions.5757 Khaleva E, Franz A, Garvey LH, et al. Perioperative anaphylaxis in children: etiology, time sequence, and patterns of clinical reactivity. Pediatr Allergy Immunol. 2020;31:85-94.,5959 Thomas M, Harper N, Cook T. Paediatric anaesthesia. Anaesthesia, surgery and life-threatening allergic reactions: from the Report and findings of the 6th National Audit Project, Royal College of Anaesthetists. 2018;:216-21.

Immediate treatment (during anesthesia)

The management of suspected perioperative allergic reactions involves three major steps: well-timed diagnosis, correct epinephrine dose and adequate intravascular volume replacement (Table 9). The perioperative allergy guidelines are consistent on the following recommendation: Grade 1 reactions do not require treatment with epinephrine.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.

In all allergic reactions, the systematic approach (ABCD) is recommended: call for help; monitor, maintain a patent airway and perform early intubation when there is risk of glottis edema; check breathing, administer 100% oxygen and start controlled mechanical ventilation in the presence of respiratory failure; drug circulation support: do not delay epinephrine administration at the beginning, using IM route until venous access is secured and while the epinephrine solution is being diluted for IV administration. Perform the following important measures: stop surgery, remove possible triggers, reduce inhaled anesthetic concentration and raise lower limbs in case of arterial hypotension.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.

Programs implementing knowledge and training for correct epinephrine dose administration during management of pediatric anaphylaxis should be encouraged.6262 Kerton M, Jones A, Gough C, et al. Paediatric anaphylaxis management: training staff to draw up the correct dose of epinephrine. Br J Anaesth. 2018;120:881-2.

As in adults, the management of pediatric perioperative anaphylaxis is guided by the clinical presentation. Crystalloid fluid therapy (20 mL.kg−1), repeated as necessary, is recommended, if possible, warmed. The current recommendations are presented in Table 5.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.

Epinephrine is the first line drug for treatment of anaphylaxis. Once anaphylaxis is diagnosed epinephrine can be lifesaving when administered as soon as possible. In addition to its vasoconstrictor effect, it prevents or reduces airway edema (laryngeal edema), hypotension and shock. It is an important bronchodilator and has inotropic and chronotropic effects.6363 Sicherer SH, Simons ES. Epinephrine for first-aid management of anaphylaxis. Pediatrics. 2017;139:e20164006.

Children respond uniformly to epinephrine.6464 Muraro A, Roberts G, Clark A, et al. The management of anaphylaxis in childhood: position paper of the European academy of allergology and clinical immunology. Allergy. 2007;62:857-71. When administered IM, in the lateral part of the thigh, it can reduce hospitalization time, as well as morbidity and mortality, as the route enables rapid administration and does not require an existing access. In addition, the peak of action after administered intramuscularly is faster than after the subcutaneous route and it is not associated with serious adverse effects in children and is considered tenfold safer than when administered intravenously.3737 Campbell RL, Bellolio F, Knutson BD, et al. Higher risk of cardiovascular complications and overdose after administration of intravenous bolus epinephrine compared with intramuscular epinephrine. J Allergy Clin Immunol Pract. 2014;3:76-80. As in treatment for adults, several drugs such as, norepinephrine, vasopressin and glucagon are recommended for treatment of children presenting anaphylaxis refractory to epinephrine.2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.

When indicated, hydroxyethyl starch is the preferred colloid solution, as it is less likely to trigger allergic reactions. As recommended by NAP65959 Thomas M, Harper N, Cook T. Paediatric anaesthesia. Anaesthesia, surgery and life-threatening allergic reactions: from the Report and findings of the 6th National Audit Project, Royal College of Anaesthetists. 2018;:216-21. there is no evidence to administer gelatin-containing solutions.

Bronchospasm due to anaphylactic reaction should be treated with epinephrine following the criteria mentioned above (intramuscular initially and intravenous only after preparation of correct epinephrine dilution).

Secondary treatments for anaphylaxis have not been established in children. Although their role in anaphylaxis remains unclear, corticosteroids are beneficial in the management of other allergic diseases.6565 Liu MC, Proud D, Lichtenstein LM, et al. Effects of prednisone on the cellular responses and release of cytokines and mediators after segmental allergen challenge of asthmatic subjects. J Allergy Clin Immunol. 2001;108:e29-38. Corticosteroids can be useful in cases showing prolonged reaction (dexamethasone 0.1–0.4 mg.kg−1, maximum 12 mg and hydrocortisone 2 to 4 mg.kg−1, maximum 200 mg).77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.

There is no clear evidence that H1 or H2 blockers (diphenhydramine or ranitidine) alter anaphylactic outcomes in children. The use of IV or IM of these drugs is not recommended. Consider using them orally for symptomatic treatment of angioedema, urticaria and itching in children who are not sedated and able to ingest the drug.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.

The decision to continue or interrupt the surgery will be determined by the urgency of the surgery, anaphylaxis reaction grade, response to treatment and the symptoms of underlying comorbidities.2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.

Post-crisis management

Administer corticosteroids and antihistamines;

Collect samples for tryptase analysis;

Consider continuing or interrupting the procedure;

Transfer the patient to the recommended unit;

At hospital discharge, provide written guidance;

Refer to an allergy service.

Post-crisis drugs do not replace first-line drugs, such as epinephrine, but can be used in mild reactions (Grade I).3030 Laguna JJ, Archilla J, Doña I, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Immunol. 2018;28:216-32.

After patient stabilization, corticosteroid can be administered as part of secondary therapy2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.,3030 Laguna JJ, Archilla J, Doña I, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Immunol. 2018;28:216-32. after adequate resuscitation.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64. Its major indication in anaphylaxis used to be for preventing late phase or biphasic reactions. However, because of corticosteroid potential adverse effects and the lack of compelling evidence of its role in reducing or preventing biphasic reaction, after recently performing a systematic review of 31 studies the authors have not recommended routine use of corticosteroid in anaphylaxis, although the existing anaphylaxis guidelines still recommend it.6666 Alqurashi W, Ellis AK. Do corticosteroids prevent biphasic anaphylaxis?. J Allergy Clin Immunol. 2017;5:1194-205.

Antihistamines can be used, as no harm has been demonstrated with their use, although they do not modify the outcome.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88.

Sample collection for tryptase analysis

Tryptase is a serine protease, produced primarily by mast cells and, to a lesser extent, by basophils and myeloid progenitors. It exists in four isoforms, but only the alpha and beta types (the main) contribute to the total serum value of tryptase.6767 Vitte J. Human mast cell tryptase in biology and medicine. Mol Immunol. 2015;63:18-24.

Recent data from the NAP6 study show that the collection of samples for tryptase analysis as soon as possible – notably in the first 15 minutes after the reaction, just after stabilizing the patient – is associated with higher peak levels.6868 Egner W, Cook TM, Garcez T, et al. Specialist perioperative allergy clinic services in the UK 2018: Results from the Royal College of Anaesthetists Sixth National Audit Project (NAP6) investigation of perioperative anaphylaxis. Clin Exp Allergy. 2018;48:846-61. The most recent recommendation restated the importance of withdrawing the first sample within 1 hour after reaction onset. It is also recommended to collect a second sample 2–4 hours post-reaction. If it is not possible to obtain the two samples, a single sample should be obtained within 1–4 hours.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64. The baseline sample for comparison should be collected 24 hours after the reaction or, later, at the time of the skin tests.

An algorithm has recently been validated and it has been used for the interpretation of the results. It has international acceptance and also is the most effective tool. After the reaction, using the algorithm formula, the levels of tryptase must be higher than [(1.2 × baseline tryptase) + 2] µg.L−1, thus it enables us to distinguish an anaphylactic from and non- anaphylactic event, perioperatively.6969 Vitte J, Amadei L, Gouitaa M, et al. Paired acute-baseline serum tryptase levels in perioperative anaphylaxis: an observational study. Allergy. 2019;74:1157-65.,7070 Baretto RL, Beck S, Heslegrave J, et al. Validation of international consensus equation for acute serum total tryptase in mast cell activation: a perioperative perspective. Allergy. 2017;72:20314.

Post-mortem samples can be used due to the high stability of tryptase.7171 Laroche D, Gomis P, Gallimidi E, et al. Diagnostic value of histamine and tryptase concentrations in severe anaphylaxis with shock or cardiac arrest during anesthesia. Anesthesiology. 2014;121:272-9.

Decision to continue the procedure

During an anaphylaxis episode, it can be difficult to predict the rate of progression, the severity and duration of the reaction, as well as its recurrence after its control.2424 Simmons FE, Ardusso LR, Bilò MB, et al. World Allergy Organization anaphylaxis guidelines: summary. J Allergy Clin Immunol. 2011;127:587-93. However, when this reaction occurs at the beginning or during surgery, once the patient condition is stable after treatment, the critical dilemma is to choose to continue, abbreviate or stop the proposed procedure

The decision has to be individualized, based on the following factors7272 Garvey LH. Practical aspects of perioperative anaphylaxis. Trends Anaesth Crit Care. 2013;3:320-6.:

Physical status (ASA) of the patient;

Urgency of the procedure (cancer vs. cosmetic surgery);

Severity of the reaction;

Speed of the response to treatment.

It is also important to consider whether:

The stage of the surgery permits the interruption, or procedure conclusion will be less physiologically deleterious to the patient;

The surgical position allows resuscitation maneuvers;

The hypersensitivity reaction may exacerbate complications of the procedure (for example, occurrence of bowel wall edema in procedures involving intestinal anastomosis)7373 Sadleir PHM, Clarke RC, PLatt PR. Consequences of proceeding surgery after resuscitation from intra-operative anaphylaxis. Anaesthesia. 2018;73:32-9. or if, in the case of surgery with anticipated major bleeding, blood loss may be increased by the activation of other pathways due to anaphylaxis.7474 Guilarte M, Sala-Cunill A, Luengo O, et al. The mast cell, contact, and coagulation system connection in anaphylaxis. Front Immunol. 2017;8:846.

For those patients whose hypersensitivity reaction was difficult to control, requiring high doses of epinephrine and/or prolonged vasopressors infusion, the interruption of the surgery seems clear.

References on the issue are scarce. Anaphylaxis protocols in general do not discuss this matter. In one of the NAP6 publications,3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88. and in the most recent international consensus dealing with the management of suspected perioperative allergic reactions,77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64. the authors raise the study by Sadleir et al.7373 Sadleir PHM, Clarke RC, PLatt PR. Consequences of proceeding surgery after resuscitation from intra-operative anaphylaxis. Anaesthesia. 2018;73:32-9. Despite being an observational study and analyzing patients submitted to only three surgery specialties (vascular, ORL and neurosurgery), the authors classified as severity indexes the epinephrine dosing necessary for the resolution of the condition, ICU admission for mechanical ventilation and ICU length of stay, in addition to sequelae related to hypersensitivity, or unexpected sequelae from the same procedure without the hypersensitivity reaction.

This study by Sadleir et al.7373 Sadleir PHM, Clarke RC, PLatt PR. Consequences of proceeding surgery after resuscitation from intra-operative anaphylaxis. Anaesthesia. 2018;73:32-9. reported that:

In low-risk SFAR I and II immediate hypersensitivity reactions, after reaction resolution the surgery was completed;

In Grade III, no significant differences were found regarding the sequelae related to hypersensitivity between the group in which the surgery was completed (after the reaction had resolved) and the group in which surgery was interrupted;

In Grade IV patients, the procedure was completed only when patients were undergoing emergency surgery. This guidance is endorsed by other authors.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88.

There are also risks when postponing the surgery, as the patient is not exempt from a new reaction7373 Sadleir PHM, Clarke RC, PLatt PR. Consequences of proceeding surgery after resuscitation from intra-operative anaphylaxis. Anaesthesia. 2018;73:32-9. and the delay in performing a new surgery (the patient will be evaluated after 4–6 weeks of the event) can be harmful for oncological surgeries, for example.7373 Sadleir PHM, Clarke RC, PLatt PR. Consequences of proceeding surgery after resuscitation from intra-operative anaphylaxis. Anaesthesia. 2018;73:32-9.,7575 Garvey LH. Perioperative hypersensitivity reactions: diagnosis, treatment and evaluation. Curr Treat Options Allergy. 2016;3:113-28.

No matter what decision is to be made, it should be widely discussed between the surgical and anesthetic teams, assessing the risks and benefits for the patient.7575 Garvey LH. Perioperative hypersensitivity reactions: diagnosis, treatment and evaluation. Curr Treat Options Allergy. 2016;3:113-28.

For genuinely urgent cases, which require surgery before the investigation is carried out, a comprehensive discussion between the anesthetic and surgical teams must be carried out again, balancing the risk-benefit and assessing a series of detailed guidelines aiming to minimize the risk (See Appendix).

Patient medical chart

Norm 2174/2017 enacted by the Brazilian Federal Council of Medicine,7676 Conselho Federal de Medicina. Resolução 2.174, de 14 de dezembro de 2017. Dispões sobre a prática do ato anestésico e revoga a Resolução CFM 1.806/2006. Diário Oficial da União. Publicado em 27/02/2018. Edição 39. Seção 1. Páginas 75-84. which provides for the practice of the anesthetic act, aims to improve the safety of the anesthetic procedure and warrant patient safety. It states, in its first article, item III, the minimum documentation of anesthetic procedures, concerning prescription, clinical progress notes, and pre, intra and post-anesthetic treatment. In its Annexes II and III, the norm details the data to be recorded, including data on allergies to drugs and latex, to the numerical recording of vital sign values, the solutions and drugs administered, in addition to the brief description of complications and adverse events associated or not with anesthesia, and their respective management. These records also extend to the post-anesthetic recovery period.7676 Conselho Federal de Medicina. Resolução 2.174, de 14 de dezembro de 2017. Dispões sobre a prática do ato anestésico e revoga a Resolução CFM 1.806/2006. Diário Oficial da União. Publicado em 27/02/2018. Edição 39. Seção 1. Páginas 75-84. As this norm is mandatory for anesthesia practice, it is crucial for the allergy specialist, who will be the patient's referral specialist, to be familiar with it and may request further details when assessing the patient.

Proper registration in the patient medical chart, not limited to the anesthesia record, is the first measure for further evaluation. The main data worth registering are:

Time interval between the last administered drugs and the onset of symptoms;

A comprehensive report of the signs of the reaction;

Treatment required to stabilize the reaction;

Time required for recovery;

Patient co-morbidities not reported in the anesthesia record.

Concerning the particular materials used in the various surgical specialties and which are not described in the anesthesia record, they must be listed in the surgery report, medical supplies expense sheet, for further analysis of an adverse event. Anesthetists from each surgical specialty can help being aware and registering substances such as antibiotics present in bone cement in the anesthesia record,7777 Christiansen IS, Pederson P, Kroigaard M, et al. Anaphylaxis to intravenous gentamicin with suspected sensitization through gentamicina-loaded bone cement. J Allergy Clin Immunol Pract. 2016;4:1258. or even antibiotics for intracameral use.7878 Moissiev E, Levinger E. Anaphylactic reaction following intracameral cefuroxime injection during cataract surgery. J Cataract Refract Surg. 2013;39:1432-4. Accurate recording of the administration of these substances, via different routes, is often neglected. However, these data are crucial when investigating a hypersensitivity reaction. The form suggested by Laguna et al.3030 Laguna JJ, Archilla J, Doña I, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Immunol. 2018;28:216-32. is an approach to gathering data related to the reaction and consistently conveying it to the allergist. The form would be one of components of the “anaphylaxis kit” previously proposed.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.,3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88.

Post-treatment measures

After treatment and recording the measures taken on the medical chart, the next actions are:

  1. Check the collection of biological samples for tests: As described before, investigation during the acute phase comprises collecting blood (in a dry tube) for tryptase test. Currently this is the only test to be requested during the crisis. Up to two samples can be withdrawn, within the first four hours from reaction onset.1818 Dewachter P, Mouton-Faivre C, Emala CW. Anaphylaxis and anesthesia: controversies and new insights. Anesthesiology. 2009;111:1141-50.,7979 Egner W, Sargur RR, Shrimpton A, et al. A 17-year experience in perioperative anaphylaxis 1998–2015: harmonizing optimal detection of mast cell mediator release. Clin Exp Allergy. 2016;46:1465-73.,8080 Beck SC, Wilding T, Buka RJ, et al. Biomarkers in human anaphylaxis: a critical appraisal of current evidence and perspectives. Front Immunol. 2019;10:1-11. On average, 4 mL are collected for adults, and 0.5 mL is sufficient for children. Ideally, samples should be centrifuged and frozen at −20 °C, before being sent to the reference laboratory.8181 Soar J, Pumphrey R, Cant A, et al. Emergency treatment of anaphylactic reactions – guidelines for healthcare providers. Resuscitation. 2008;77:157-69. Other tests (histamine, methylhistamine in urine) are not used in practice due to difficulties in sample collection and low sensitivity.3030 Laguna JJ, Archilla J, Doña I, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Immunol. 2018;28:216-32.

  2. Determine the unit the patient will be transferred to: Patients who had mild (Grade I) or moderate (Grade II) reactions that quickly resolve after treatment still require 6-hours observation at least.2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.,8282 Muraro A, Roberts G, Worm M, et al. Anaphylaxis: Guidelines from the European Academy of Allergy and Clinical Immunology. Allergy. 2014;69:1026-45. Intensive Care Unit admission will be required in Grade IV patients and in the majority of Grade III patients, particularly those with prolonged resuscitation or requiring maintenance of vasopressor hemodynamic support.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,88 Benahmed S, Picot MC, Dumas F, et al. Accuracy of a pharmacovigilance algorithm in diagnosing drug hypersensitivity reactions. Arch Intern Med. 2005;:1500-5.,3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88.,8383 Demoly P, Adkinson NF, Brockow K, et al. International consensus on drug allergy. Allergy. 2014;69:420-37. Table 10 summarizes the follow-up after a reaction.

    Table 10
    Follow-up after the anaphylactic reaction.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,3030 Laguna JJ, Archilla J, Doña I, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Immunol. 2018;28:216-32.,3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88.,8282 Muraro A, Roberts G, Worm M, et al. Anaphylaxis: Guidelines from the European Academy of Allergy and Clinical Immunology. Allergy. 2014;69:1026-45.,8383 Demoly P, Adkinson NF, Brockow K, et al. International consensus on drug allergy. Allergy. 2014;69:420-37.
  3. Provide written information to be handed to the patient and/or family: To avoid the recurrence of the adverse event, it is crucial to notify the patient when recovered, and the family members and/or guardians.8484 Scolaro RJ, Crilly HM, Maycock EJ, et al. The Australian and New Zealand anaesthetic allergy group perioperative anaphylaxis investigation guidelines. Anaesth Intensive Care. 2017;45:543-55. Harper et al.3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88. found pitfalls in the communication with patients, as in 14% of the cases no information was given and in 27% the information was conveyed only orally. This situation has been commonly observed regarding patients referred to the Drug Reaction Assessment Center of the Federal University of Santa Catarina (NARTAD), where some of the authors of the present article carry out their activities.2828 Spindola MAC, da Silva J. Anafilaxia e anestesia. In: In: Nunes RR, Bagatini A, Duarte LTD (org), Sociedade Brasileira de Anestesiologia. PROANESTESIA Programa de Atualização em Anestesiologia: Ciclo 1. Porto Alegre: Artmed Panamericana; 2018. p. 9-49 (Sistema de Educação Continuada à Distância, vol. 3). The written report to be provided by the anesthetist who assisted the patient must describe the clinical presentation, drug therapies administered and their outcome and a list of substances to be avoided until further allergist assessment.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.,3030 Laguna JJ, Archilla J, Doña I, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Immunol. 2018;28:216-32.,3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88.,8383 Demoly P, Adkinson NF, Brockow K, et al. International consensus on drug allergy. Allergy. 2014;69:420-37. The investigation of the reaction occurring in a complex scenario such as the perioperative period, will require more than only the knowledge about negative and positive values for the tests, which may affect the safety of the ensuing recommendations.8585 Demoly P, Adkinson NF, Brockow K, et al. International consensus on drug allergy. Allergy. 2014;69:420-37. Table 11 shows the management at the time of patient discharge.

    Table 11
    Procedures to be follow at hospital discharge of patient.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,1515 Mertes PM, Malinovsky JM, Jouffroy L. Working Group of the SFAR and SFA, Aberer W, Tereehorst I, et al. Reducing the risk of anaphylaxis during anesthesia: 2011 update guidelines for clinical practice. J Investig Allergol Clin Immunol. 2011;21:442-53.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8.,3030 Laguna JJ, Archilla J, Doña I, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Immunol. 2018;28:216-32.,3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88.

  4. Refer to an allergy service for evaluation after reaction: The assessment in specialized clinics is recommended, with the collaboration between anesthetists and allergists.77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.,1515 Mertes PM, Malinovsky JM, Jouffroy L. Working Group of the SFAR and SFA, Aberer W, Tereehorst I, et al. Reducing the risk of anaphylaxis during anesthesia: 2011 update guidelines for clinical practice. J Investig Allergol Clin Immunol. 2011;21:442-53.,2525 Kroigaard M, Garvey LH, Gillberg L, et al. Scandinavian Clinical Practice Guidelines on the diagnosis, management and follow-up of anaphylaxis during anaesthesia. Acta Anesthesiol Scand. 2007;51:655-70.,2626 Kolawole H, Marshall SD, Crilly H, et al. Australian and New Zealand Anaesthetic Allergy Group/Australian and New Zealand College of Anaesthetists Perioperative Anaphylaxis Management Guidelines. Anaesth Intensive Care. 2017;45:151-8. The evaluation by the allergist cannot be replaced by pharmacovigilance algorithms, since the latter are based mainly on history, and are not specific to hypersensitivity reactions.8585 Demoly P, Adkinson NF, Brockow K, et al. International consensus on drug allergy. Allergy. 2014;69:420-37. The presumption of involvement of a particular drug is not a reliable way to exclude agents. Many patients are unduly exposed to risk by ruling out the wrong agent and, at the same time, being deprived of useful drugs. A study found that in 73% of the cases there was no correspondence between the substance blamed for the reaction and the agent actually involved.8686 Kroigaard M, Garvey LH, Menné T, et al. Allergic reactions in anaesthesia: are suspected causes confirmed on subsequent testing?. Br J Anaesth. 2005;95:486-71.

As patients will be tested, the information about the drugs used during the reaction must be clear (name of the substance, trade name), thus preventing a patient who received a certain neuromuscular blocker (atracurium) from having skin tests performed with another drug (vecuronium, for example).5959 Thomas M, Harper N, Cook T. Paediatric anaesthesia. Anaesthesia, surgery and life-threatening allergic reactions: from the Report and findings of the 6th National Audit Project, Royal College of Anaesthetists. 2018;:216-21.

A standard printed form for communication may be employed.3030 Laguna JJ, Archilla J, Doña I, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Immunol. 2018;28:216-32.

Establishing an interaction between allergist and anesthesiologist for a joint investigation is crucial.

The resolution of an anaphylaxis reaction finishes only when the investigation is completed and safe alternatives to perform a future procedure are provided.8787 Guyer AC, Saff RR, Conroy M, et al. Comprehensive allergy evaluation is useful in the subsequent care of patients with drug hypersensitivity reactions during anesthesia. J Allergy Clin Immunol Pract. 2015;3:94-100.,8888 Chiriac AM, Tacquarad C, Fadhel NB, et al. Safety of subsequent general anesthesia in patients allergic to neuromuscular blocking agents: value of allergy skin tests. Br J Anaesth. 2018;120:1437-40.

In Brazil, the appointment of specialists in Perioperative Anaphylaxis by each Regional Office of both SBA and ASBAI societies is an objective to be pursued.

Appendix

In the ideal scenario, every patient after a hypersensitivity reaction would be properly investigated, with a multidisciplinary approach as suggested by NAP6, including discussing strategies for a future anesthesia.8989 Harper N, Cook T. Anaesthesia, surgery and life-threatening allergic reactions - Summary of main findings. Br J Anaesth. 2018;121:183-91. This assessment should be performed 4–6 weeks after the event, under the penalty of a false negative result, however, situations other than the ideal may occur:

  1. a) Urgent reoperation in a patient who experienced anaphylaxis and with data from the anesthesia record;

  2. b) Urgent surgery in a patient with a history of perioperative hypersensitivity reaction not investigated and for which there is no documentation;

  3. c) Patient who suffered a suspected reaction to previous perioperative hypersensitivity, of which there is no available documentation.

As general rules in situations of genuine urgency without investigation, one should:

Avoid agents administered or to which the patient was exposed up to 60 minutes before the event77 Garvey LH, Dewachter P, Hepner DL, et al. Management of suspected immediate perioperative allergic reactions: an international overview and consensus recommendations. Br J Anaesth. 2019;123:e50-e64.;

Avoid substances administered by all other routes, intramuscular, subcutaneous, spinal, epidural and other sites within 2 hours after the onset of the condition,9090 Garvey LH, Ebo DG, Mertes PM, et al. An EAACI position paper on the investigation of perioperative immediate hypersensitivity reactions. Allergy. 2019;74:1872-84. which should also be possible agents and be excluded;

Exclude latex (environment and medical devices). In Brazil, there is Collegiate Board Resolution RDC 37/2015 concerning medical devices and data about latex content and risk of allergy in medical supplies.9292 Silva Jr JB. Resolução RDC n° 37, de 26 de agosto de 2015. Ministério da Saúde/Agência Nacional de Vigilância Sanitária/Diretoria Colegiada. Dispõe sobre a padronização de frases de declaração de conteúdo de látex de borracha natural em rótulos de dispositivos médicos. Diário Oficial da União. Edição 164, Seção 1, Página 46. List all materials and equipment beforehand and check, removing from the room, those with latex. Maintain the precautions also in the postoperative period (post-anesthetic recovery room, inpatient and intensive care unit)9191 Cabañes N, Igea JM, de la Hoz B, et al. Latex allergy: position paper. J Investig Allergol Clin Immunol. 2012;22:313-30.;

Perform the surgery as the first one on the morning list3030 Laguna JJ, Archilla J, Doña I, et al. Practical guidelines for perioperative hypersensitivity reactions. J Investig Allergol Immunol. 2018;28:216-32.,9191 Cabañes N, Igea JM, de la Hoz B, et al. Latex allergy: position paper. J Investig Allergol Clin Immunol. 2012;22:313-30.;

All antibiotics belonging to the same class of that administered in the suspected event3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88. should be excluded. Get advice from Hospital Infection Committee. Chosen agent should be administered in the operating room before anesthetic induction, with the patient awake and monitored to facilitate identifying the agent involved.9393 Marinho S. Perioperative anaphylaxis – time for a NAP6!. Clin Exp Allergy. 2018;48:1252-4. Cardiovascular resuscitation will also be easier without anesthesia drug effects upon the cardiovascular function1515 Mertes PM, Malinovsky JM, Jouffroy L. Working Group of the SFAR and SFA, Aberer W, Tereehorst I, et al. Reducing the risk of anaphylaxis during anesthesia: 2011 update guidelines for clinical practice. J Investig Allergol Clin Immunol. 2011;21:442-53.;

Regarding general anesthesia induction agents, if propofol has been used and general anesthesia is necessary, the agents indicated are halogenated, thiopental, etomidate (non-lipid formulation) and ketamine.3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88.

Tracheal intubation: if required to exclude neuromuscular blockers, remifentanil, magnesium sulfate and topical anesthesia will be valuable. Replace remifentanil with alfentanil if that was used previously.3939 Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121:172-88. Also consider dexmedetomidine for awake intubation,8989 Harper N, Cook T. Anaesthesia, surgery and life-threatening allergic reactions - Summary of main findings. Br J Anaesth. 2018;121:183-91.,9494 Cabrini L, Baiardo Redealli M, Ball L, et al. Awake fiberoptic intubation protocols in the operating room for anticipated difficult airway: a systematic review and meta-analysis of randomized controlled trials. Anesth Analg. 2019;128:971-80. including cases of allergy to local anesthetics9595 Madhere M, Vangura D, Saidov A. Dexmedetomidine as sole agent for awake fiberoptic intubation in a patient with local anesthetic allergy. J Anaesth. 2011;25:592-4.;

If neuromuscular blockers have been administered during the event, they should be excluded due to high rate of cross-reactivity, unless its administration is absolutely mandatory. Remember that cross-reactivity is more frequent among amino steroid blockers than among benzylisoquinoline derivatives9696 Mertes PM, De Blay F, Dong S. Risque allergique en anesthésie. Presse Med. 2013;42:269-79. and that pancuronium (which has an inflexible structure) appears to be less likely to have cross-reactivity with other amino-steroids. For patients who suffered anaphylaxis with rocuronium and vecuronium, cisatracurium was found to be the agent that had the lowest rate of cross-reactivity to them9797 Sadleir PHM, Clarke RC, Bunning DL, et al. Anaphylaxis to neuromuscular blocking drugs: incidence and cross-reactivity in Western Australia from 2002 to 2011. Br J Anaesth. 2013;110:981-7.;

If chlorhexidine has been used previously, check for its presence in gel for urethral use, coated catheters for central venous puncture, ophthalmic solutions and antiseptic wipes9898 Opstrup MS, Poulsen LK, Malling HJ, et al. Dynamics of specific IgE in chlorhexidine allergic patients with and without accidental re-exposure. Clin Exp Allergy. 2016;46:1090-8.;

Remember that some colloid solutions for volume replacement (IV) may contain alpha-gal9999 Mullins RJ. The relationship between red meat allergy and sensitization to gelatin and galactose-alpha-1,3-galactose. J Allergy Clin Immunol. 2012;125:1334-42. and are not allowed to be used in patients with alpha-gal syndrome55 Dewachter P, Kopac P, Laguna JJ, et al. Anaesthetic management of patients with pre-existing allergic conditions: a narrative review. Br J Anaesth. 2019;123:e50-e64.;

Check for the use of radiological contrasts and dyes for lymphangiography;

Be aware of histamine-releasing drugs, such as phenanthrene morphine and codeine. These are different from phenylpiperidine derivatives, as they are not associated with histamine release.100100 Ebo DG, Fischer MM, Hagendorens MM, et al. Anaphylaxis during anaesthesia: diagnostic approach. Allergy. 2007;62:471-87. Atracurium also releases histamine by direct action3131 Volcheck GW, Mertes PM. Local and general anesthetics immediate hypersensitivity reactions. Immunol Allergy Clin N Am. 2014;34:525-46.;

Remember that local anesthetics can cause an allergic reaction, that is, IgE-mediated. Reactions to local anesthetics correspond to less than 1% of reactions attributed to anesthetics101101 Bhole MV, Manson AL, Seneviratne SL, et al. IgE-mediate allergy to local anaesthetic: separating fact from perception: a UK perspective. Br J Anaesth. 2012;108:903-11.;

Ethylene oxide is a gas used to sterilize most medical supplies. Although reactions are rare in the perioperative setting, there appears to be an increased risk of sensitization in patients with myelomeningocele and ventriculoperitoneal shunts,9090 Garvey LH, Ebo DG, Mertes PM, et al. An EAACI position paper on the investigation of perioperative immediate hypersensitivity reactions. Allergy. 2019;74:1872-84. and there are also reports in patients undergoing hemodialysis.102102 Akhavan BJ, Osborn UA, Mathew R. Anaphylactic reaction to ethylene oxide in a hemodialysis patient. SAGE Open Med Case Rep. 2019;7, 2050313X19838744. The diagnostic test is to search for specific IgE,103103 Opstrup MS, Mosbech H, Garvey LH. Allergic sensitization to ethyelene oxide in patients with suspected allergic reactions during surgery and anesthesia. J Investig Allergol Clin Immunol. 2010;20:69-70. but the test is not available in Brazil. It is very hard to prevent using ethylene oxide. The replacement of medical supplies and the use of material that can be steam sterilized, and the adoption of measures to minimize ethylene oxide exposure have been recommended, whenever possible.104104 Garvey LH. Old, new and hidden causes of perioperative hypersensitivity. Curr Pharm Des. 2016;22:6814-24.,105105 Bache S, Petersen JT, Garvey LH. Anaphylaxis to ethylene oxide – a rare and overlooked phenomenon?. Acta Anaesthesiol Scand. 2011;55:1279-82. Pretreatment with omalizumab has been described.106106 Listyo A, Hofmaeier KS, Bandschapp O, et al. Severe anaphylactic shock due to ethylene oxide in a patient with myelomeningocele: successful exposure prevention and pretreatment with omalizumab. Anesth Analg Case Rep. 2014;2:3-6.

  • This document was published in Arquivos de Asma, Alergia e Imunologia DOI: 10.5935/2526-5393.20190051 with the consent of authors and editors.

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Publication Dates

  • Publication in this collection
    18 Dec 2020
  • Date of issue
    Sep-Oct 2020

History

  • Received
    2 Dec 2019
  • Accepted
    20 June 2020
Sociedade Brasileira de Anestesiologia R. Professor Alfredo Gomes, 36, 22251-080 Botafogo RJ Brasil, Tel: +55 21 2537-8100, Fax: +55 21 2537-8188 - Campinas - SP - Brazil
E-mail: bjan@sbahq.org