Anaesthetic allergy: Anaphylaxis management guideline & references

This information was prepared by ASCIA in conjunction with ANZAAG, the Australian & New Zealand Anaesthetic Allergy Group.

Suspected perioperative allergic reactions are rare but can be life-threatening. The diagnosis is difficult to make in the perioperative setting, but prompt recognition and correct treatment is necessary to ensure a good outcome. A group of 26 international experts in perioperative allergy (anaesthesiologists, allergists, and immunologists) contributed to a modified Delphi consensus process, which covered areas such as differential diagnosis, management during and after anaphylaxis, allergy investigations, and plans for a subsequent anaesthetic. They were asked to rank the appropriateness of statements related to the immediate management of suspected perioperative allergic reactions. Statements were selected to represent areas where there is a lack of consensus in existing guidelines, such as dosing of epinephrine and fluids, the management of impending cardiac arrest, and reactions refractory to standard treatment. The results of the modified Delphi consensus process have been included in the recommendations on the management of suspected perioperative allergic reactions. This paper provides anaesthetists with an overview of relevant knowledge on the immediate and postoperative management of suspected perioperative allergic reactions based on current literature and expert opinion. In addition, it provides practical advice and recommendations in areas where consensus has been lacking in existing guidelines.

The fundamentals of cardiac resuscitation include the immediate provision of high-quality cardiopulmonary resuscitation combined with rapid defibrillation (as appropriate). These mainstays of therapy set the groundwork for other possible interventions such as medications, advanced airways, extracorporeal cardiopulmonary resuscitation, and post-cardiac arrest care, including targeted temperature management, cardiorespiratory support, and percutaneous coronary intervention. Since 2015, an increased number of studies have been published evaluating some of these interventions, requiring a reassessment of their use and impact on survival from cardiac arrest. This 2019 focused update to the American Heart Association advanced cardiovascular life support guidelines summarizes the most recent published evidence for and recommendations on the use of advanced airways, vasopressors, and extracorporeal cardiopulmonary resuscitation during cardiac arrest. It includes revised recommendations for all 3 areas, including the choice of advanced airway devices and strategies during cardiac arrest (eg, bag-mask ventilation, supraglottic airway, or endotracheal intubation), the training and retraining required, the administration of standard-dose epinephrine, and the decisions involved in the application of extracorporeal cardiopulmonary resuscitation and its potential impact on cardiac arrest survival.

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.

This second joint document, written by experts from the Brazilian Association of Allergy and Immunology (ASBAI) and Brazilian Society of Anesthesiology (SBA) concerned with perioperative anaphylaxis, aims to review the pathophysiological reaction mechanisms, triggering agents (in adults and children), and the approach for diagnosis during and after an episode of anaphylaxis. As anaphylaxis assessment is extensive, the identification of medications, antiseptics and other substances used at each setting, the comprehensive data documentation, and the use of standardized nomenclature are key points for obtaining more consistent epidemiological information on perioperative anaphylaxis.

Perioperative anaphylaxis is a severe adverse event during anesthesia that requires prompt diagnosis and treatment by physicians, including anesthesiologists. Muscle relaxants and antibiotics are the most common drugs that cause perioperative anaphylaxis in Japan, as in many countries. In addition, sugammadex appears to be a primary causative agent. Obtaining previous anesthesia records is necessary in a patient with a history of allergic reactions during anesthesia, whenever possible, to avoid recurrence of anaphylaxis. Although medical staff are likely to notice abnormal vital signs because of complete monitoring during anesthesia, surgical drapes make it difficult to notice the appearance of skin symptoms. Even if there are no skin symptoms, anaphylaxis should be suspected, especially when hypotension resistant to inotropes and vasopressors persists. For improving the diagnostic accuracy of anaphylaxis, it is helpful to collect blood samples to measure histamine/tryptase concentrations immediately after the events and at baseline. The first-line treatment for anaphylaxis is adrenaline. In the perioperative setting, adrenaline should be administered through the intravenous route, which has a faster effect onset and is secured in most cases. Adrenaline can cause serious complications including severe arrhythmias if the appropriate dose is not selected according to the severity of symptoms. The anesthesiologist should identify the causative agent after adverse events. The gold standard for identifying the causative agent is the skin test, but in vitro tests including specific IgE antibody measurements and basophil activation tests are also beneficial. The Working Group of the Japanese Society of Anesthesiologists has developed this practical guide to help appropriate prevention, early diagnosis and treatment, and postoperative diagnosis of anaphylaxis during anesthesia.Grade of recommendations and levels of evidence Anaphylaxis is a relatively rare condition with few controlled trials, and thus a so-called evidence-based scrutiny is difficult. Therefore, rather than showing evidence levels and indicating the level of recommendation, this practical guideline only describes the results of research available to date. The JSA will continue to investigate anaphylaxis during anesthesia, and the results may lead to an amendment of this practical guideline.

This report has been prepared by an EAACI task force representing the five EAACI Sections and the EAACI Executive Committee composed of specialists that reflect the broad opinion on allergy expressed by various clinical and basic specialties dealing with allergy. The aim of this report is to propose a revised nomenclature for allergic and related reactions that can be used independently of target organ or patient age group. The nomenclature is based on the present knowledge of the mechanisms which initiate and mediate allergic reactions. However, the intention has not been to revise the nomenclature of nonallergic hypersensitivity.

Perioperative hypersensitivity reactions (POH) constitute a clinical and diagnostic challenge, a consequence of heterogeneous clinical presentations, and multiple underlying pathomechanisms. POH do not necessarily involve an allergen-specific immune response with cross-linking of specific immunoglobulin E (sIgE) antibodies on mast cells and basophils. POH can also result from alternative specific and non-specific effector cell activation/degranulation such as complement-derived anaphylatoxins and off-target occupancy of mast cell, basophil, or both surface receptors. Moreover, POH and anaphylaxis can occur independent from mast cell and basophil degranulation. The manifestations of POH primarily affect the cardiovascular, respiratory, and integumentary systems. POH present within the context of surgical or procedural pathology and the effects of surgical and anaesthetic techniques on pre-existing physiological reserve. The majority of cases of appropriately-treated intraoperative anaphylaxis can be considered a compensated cardiovascular anaphylaxis. With increasing severity of anaphylaxis, maldistribution and hypovolaemia lead to reduced venous return and circulatory failure. Treatment with a combination of epinephrine and i.v. fluid is critical for successful resuscitation, although the excessive use of epinephrine without adequate volume expansion may be deleterious. Neural control of the airways is important in the pathophysiology of bronchospasm. Anticholinergic drug premedication is beneficial in patients with hyperreactive airways. Pulmonary oedema can result from a combination of pulmonary capillary hypertension, incompetence of the alveolocapillary membrane, or both. Angioedema can be distinguished mechanistically into histaminergic and non-histaminergic (e.g. bradykinin-mediated). An understanding of the molecular mechanisms and pathophysiology of POH are essential for the immediate management and subsequent investigation of these cases.

Cognitive aids are prompts designed to help users complete a task or series of tasks. They may take the form of posters, flowcharts, checklists, or even mnemonics. It has been suggested that the use of cognitive aids improves performance and patient outcomes during anesthetic emergencies; however, a systematic assessment of the evidence is lacking. The aim of this literature review was to determine (1) whether cognitive aids improve performance of individuals and teams and (2) whether recommendations can be made for future cognitive aid design, testing, and implementation. Medical, nursing, and psychology databases were searched using broad criteria to find cognitive aids that have been reported in the literature for use in anesthetic emergencies. The reference lists of the articles selected for review were also screened to identify additional studies. Selected articles that described the evaluation of cognitive aids used in anesthetic emergencies were reviewed to determine how the content of the aid was derived, how the design was evaluated, and the success of the aid in improving technical and team performance. The search yielded 22 cognitive aids developed to support clinicians during anesthetic emergencies that had been evaluated in 23 studies. Ten studies using simulation suggested that technical performance improves with the use of cognitive aids in some anesthetic emergencies such as malignant hyperthermia, cardiopulmonary resuscitation, and airway management. However, in 3 of the simulator-based evaluations, participants had either no improvement or took longer to diagnose and treat and made more incorrect diagnoses. Four studies investigated the effect of the aids on teamwork with differing conclusions. One study suggested improved participants' coordination patterns and one found aids improved their decision-making scores, but 2 other studies indicated that there was no improvement and even provided evidence of reduced levels of team communication when teams used a cognitive aid in simulated conditions. The designs of cognitive aids were rarely considered. Education may compensate for a poorly designed aid, but only by ingraining correct actions for situations in which the aid provides little or no guidance. Cognitive aids should continue to be developed from established clinical guidelines where guidelines exist. They would also benefit from more extensive simulation-based usability testing before use. Further evidence is required to explore the effects of cognitive aids in anesthetic emergencies, how they affect team function, and their design considerations.

Introduction: Prompt treatment is necessary to assure patient survival during crisis. Obstetric cardiac arrest (OCA) and malignant hyperthermia (MH) are rarely occurring crises. Cognitive aids (CAs) consolidate management and assist treatment decisions. We investigated a novel method to encourage resident physician CA use during simulated crises.

Methods: Resident physicians were examined during 31 simulated crises of OCA and MH. CAs reviewed in a prior lecture were placed on resuscitation carts. The confederate emergency management team consisted of two anesthesiologists, two critical care nurses, and a medical student who was assigned to act as the CA "Reader." If the subject failed to manage the crisis, the Reader would prompt the subject to use the CA. If the subject still failed to manage the crisis, the Reader would read the aid aloud to the subject. Steps were scored if completed; physiologic variables were recorded. Subject performance was examined before and after Reader introduction.

Results: OCA: No subjects performed all critical steps before introduction of the Reader. Twenty-two percent of Anesthesiology (AN) and 31% of Obstetrics (OB) trainees used the CA. MH: All subjects (AN) correctly diagnosed MH and administered the first dantrolene dose at 7.3 ± 2.5 minutes (PETCO2 72 ± 8 mm Hg, temperature 41.5 °C ± 1.3 °C) but skipped critical treatment steps. Thirty-three percent of subjects used the CA. After Reader introduction, all critical actions for both OCA and MH were completed.

Conclusions: Reader introduction resulted in execution of all critical actions. During the debriefing of the simulated scenarios, subjects acknowledged the benefit of the Reader.

Simulation-based education is often highlighted as a method to prepare health personnel to handle clinical emergencies through repeated training and the design of supports. As one of the most common clinical emergencies in anaesthesia, anaphylaxis is often included in simulation scenarios at both graduate and postgraduate levels. Case reviews of anaphylaxis management continue to identify deficiencies in clinical responses. We evaluated the evidence to support the use of simulation to address these deficiencies. We undertook a comprehensive review of the MEDLINE and Embase databases with MESH terms 'Anaphylaxis', 'Anaesthesia', 'Simulation training', and variations of these terms. Articles were also searched from reference lists in the identified papers. A total of 39 articles on perioperative anaphylaxis simulation were identified, with most focusing on the clinical skills of individuals. However, anaphylaxis scenarios are also being used in assessment of teams and in the evaluation of broader system performance. Many countries mandate simulation training and competency assessment at graduate and postgraduate levels: despite this, none of the articles linked simulation training or assessment with improved patient management or outcomes. We found evidence that in situ simulation and use of cognitive aids lead to improved teamwork and task performace. Quantitative and qualitative evidence for simulation-based perioperative training is limited. Future studies should investigate whether simulation training in perioperative anaphylaxis, particularly in situ simulation, translates into improved patient management and outcomes.

The incidence of immune-mediated anaphylaxis during anesthesia ranges from 1 in 10,000 to 1 in 20,000. Neuromuscular blocking agents represent the most frequently involved substances, followed by latex and antibiotics, but every drug or substance used may be involved. Diagnosis relies on tryptase measurements at the time of the reaction and skin tests and specific IgE or basophil activation assays.

Background: The aim of this study was to ascertain whether anaesthetic induction-related anaphylactic bronchospasm could be distinguished from other types of bronchospasm by clinical features and response to treatment. Such features could then be used to identify a group of patients in whom skin testing is indicated.

Methods: We retrospectively studied data from 183 patients referred to an anaesthetic allergy clinic because of bronchospasm during induction. For the analysis, the patients were divided into two groups depending on whether there was evidence suggesting immunological anaphylaxis.

Results: When the patients in whom intradermal tests were positive were compared with those in whom intradermal tests were negative, the skin test-positive patients had significantly more severe reactions, and they were more commonly associated with other clinical signs. Mast cell tryptase (MCT) was an excellent discriminator between reactions likely to be allergic and those unlikely to be allergic.

Conclusions: Anaphylactic bronchospasm related to induction of anaesthesia is more likely to be severe than bronchospasm due to non-immune causes. An allergic cause is more likely if there are associated features of anaphylaxis (skin changes, hypotension, angioedema) or elevated MCT. Patients with any of these features should undergo immuno-allergolical investigation

Perioperative hypersensitivity reactions (POH) constitute a clinical and diagnostic challenge, a consequence of heterogeneous clinical presentations, and multiple underlying pathomechanisms. POH do not necessarily involve an allergen-specific immune response with cross-linking of specific immunoglobulin E (sIgE) antibodies on mast cells and basophils. POH can also result from alternative specific and non-specific effector cell activation/degranulation such as complement-derived anaphylatoxins and off-target occupancy of mast cell, basophil, or both surface receptors. Moreover, POH and anaphylaxis can occur independent from mast cell and basophil degranulation. The manifestations of POH primarily affect the cardiovascular, respiratory, and integumentary systems. POH present within the context of surgical or procedural pathology and the effects of surgical and anaesthetic techniques on pre-existing physiological reserve. The majority of cases of appropriately-treated intraoperative anaphylaxis can be considered a compensated cardiovascular anaphylaxis. With increasing severity of anaphylaxis, maldistribution and hypovolaemia lead to reduced venous return and circulatory failure. Treatment with a combination of epinephrine and i.v. fluid is critical for successful resuscitation, although the excessive use of epinephrine without adequate volume expansion may be deleterious. Neural control of the airways is important in the pathophysiology of bronchospasm. Anticholinergic drug premedication is beneficial in patients with hyperreactive airways. Pulmonary oedema can result from a combination of pulmonary capillary hypertension, incompetence of the alveolocapillary membrane, or both. Angioedema can be distinguished mechanistically into histaminergic and non-histaminergic (e.g. bradykinin-mediated). An understanding of the molecular mechanisms and pathophysiology of POH are essential for the immediate management and subsequent investigation of these cases.

These guidelines represent the updated consensus of experts in the field of immediate hypersensitivity reactions occurring during anesthesia. They provide a series of valid, widely accepted, effective, and easily teachable guidelines that are the fruit of current knowledge, research, and experience. The guidelines are based on the findings of international scientific research and have been implemented in France under the auspices of the French Society for Anaesthesia and Intensive Care (Société Française d'Anesthésie et de Réanimation [SFAR]) and the French Society of Allergology (Société Française d'Allergologie [SFA]). The members of the European Network for Drug Allergy approved the guidelines. This paper presents the most relevant clinical implications of the guidelines.

Background: Intraoperative anaphylaxis is a rare but serious occurrence, often triggered by neuromuscular-blocking drugs (NMBDs). Previous reports suggest that the rates of anaphylaxis may be greater for rocuronium than for other NMBDs, but imprecise surrogate metrics for new patient exposures to NMBDs complicate interpretation.

Methods: This was a retrospective, observational cohort study of intraoperative anaphylaxis to NMBDs at two hospitals between 2006 and 2012. Expert anesthetic and immunologist collaborators investigated all referred cases of intraoperative anaphylaxis where NMBDs were administered and identified those where a NMBD was considered responsible. New patient exposures for each NMBD were extracted from electronic anesthetic records compiled during the same period. Anaphylaxis rates were calculated for each NMBD using diagnosed anaphylaxis cases as the numerator and the number of new patient exposures as the denominator.

Results: Twenty-one patients were diagnosed with anaphylaxis to an NMBD. The incidence of anaphylaxis was 1 in 22,451 new patient exposures for atracurium, 1 in 2,080 for succinylcholine, and 1 in 2,499 for rocuronium (P < 0.001).

Conclusions: In Auckland, the rate of anaphylaxis to succinylcholine and rocuronium is approximately 10-fold higher than to atracurium. Previous estimates of NMBD anaphylaxis rates are potentially confounded by inaccurate proxies of new patient exposures. This is the first study to report anaphylaxis rates using a hard denominator of new patient exposures obtained directly from anesthetic records.

Background: The mortality from perioperative anaphylaxis has recently been quoted in a range between 3 and 9%. However, it was our impression in Western Australia that we had had no deaths from perioperative anaphylaxis for over a decade. As we have comprehensive processes in place to investigate both perioperative anaphylaxis and anaesthesia-related deaths, we undertook this study to determine our actual perioperative anaphylaxis mortality rate.

Methods: We obtained the number of deaths related to perioperative anaphylaxis for the decade 2000-2009 from the database of the West Australian Anaesthetic Mortality Committee; in Western Australia it is a legal requirement to report all deaths that occur within 48 h of an anaesthetic, and all deaths due to a complication of an anaesthetic. We obtained the number of cases of perioperative anaphylaxis for the same period from the database of the West Australian Anaesthetic Drug Reaction Clinic.

Results: From 2000 to 2009, there were 45 anaesthesia-related deaths in Western Australia, but none of these involved anaphylaxis. Over this period, there were 264 cases classified by the West Australian Anaesthetic Drug Reaction Clinic as anaphylaxis. The 95% confidence interval for the observed 0/264 mortality rate is 0-1.4%. There were about three million anaesthetics administered in Western Australia over the decade, giving a perioperative anaphylaxis rate of ~1:11,000.

Conclusions: Our incidence of perioperative anaphylaxis was within expectations, but our mortality rate was lower than recently quoted figures. It is likely that the current true perioperative anaphylaxis mortality rate is within the range 0-1.4%.

Neuromuscular blocking drugs (NMBDs) are the most common cause of intraoperative anaphylaxis in Western Australia. Differences in the rates of anaphylaxis between individual agents have been surmised in the past, but not proven, and are an important consideration if agents are otherwise equivalent.We estimated a rate of anaphylaxis to NMBDs by analysing cases of NMBD anaphylaxis referred to the only specialized diagnostic centre in Western Australia over a 10 yr period. Exposure was approximated by analysing a 5 yr period of NMBD ampoule sales data. Agents were also ranked according to the prevalence of cross-reactivity in patients with previous NMBD anaphylaxis.Rocuronium was responsible for 56% of cases of NMBD anaphylaxis, succinylcholine 21%, and vecuronium 11%. There was no difference in the severity of reactions for different NMBDs. Rocuronium had a higher rate of IgE-mediated anaphylaxis compared with vecuronium (8.0 vs 2.8 per 100,000 exposures; P=0.0013). The prevalence of cross-reactivity after NMBD anaphylaxis suggested that succinylcholine also has a high risk of triggering anaphylaxis. Cisatracurium had the lowest prevalence of cross-reactivity in patients with known anaphylaxis to rocuronium or vecuronium.Rocuronium has a higher rate of IgE-mediated anaphylaxis compared with vecuronium, a result that is statistically significant and clinically important. Cisatracurium had the lowest rate of cross-reactivity in patients who had previously suffered anaphylaxis to rocuronium or vecuronium.

We audited patients with anaphylaxis to muscle relaxants during anaesthesia referred to the Department of Anaesthesia at the Royal Adelaide Hospital between the start of 2000 and the end of 2009. Of the 220 patients tested during this period, 43 had a positive intradermal test to the muscle relaxant given during their anaesthetic. The majority of these were to rocuronium and suxamethonium. Where rocuronium was the index agent, 65% of patients cross-reacted with another relaxant and 29% of patients with suxamethonium as their index agent demonstrated cross-reaction with another relaxant.

The procedures, results and outcomes of investigation of 50 patients with clinical episodes of anaesthesia-associated anaphylaxis were retrospectively reviewed. Assessment was performed by measurement of serum tryptase and specific IgE and a combination of skin prick and intradermal skin testing. Testing was performed both for agents received during the anaesthetic and for agents the patient may encounter in future procedures. Twenty of 50 patients underwent a subsequent procedure after assessment. Sensitisation to neuromuscular blocking agents was identified in 18 patients (36%). Sensitisation to propofol (14 patients; 28%) and latex (four patients; 8%) was also frequently identified. No precise cause was identified in 11 cases (22%). Reactivity to more than one agent was identified in 14 patients (28%). Serum tryptase was measured within six hours of the episode in only 28 of the 50 cases. All the patients with elevated serum tryptase had clinically severe reactions. One patient initially found to be sensitised to propofol had another reaction during a second procedure, prompting further assessment where chlorhexidine reactivity was identified. Subsequent surgery in that patient and in 19 other patients where agents implicated in the testing were avoided, proceeded without incident. The results reaffirm that neuromuscular blocking agents are the most common cause of anaphylaxis during anaesthesia. The importance of serum tryptase measurement at the time of the acute episode needs to be emphasised. Investigation should include screening for chlorhexidine and latex in all patients, as exposure to both these agents is common and may be overlooked.

Background: Chlorhexidine (CHL) has antiseptic and disinfectant properties used to prevent hospital-acquired infections. CHL-induced anaphylaxis is poorly reported in surgical literature despite government warnings and growing recognition. The aim of this review is to increase awareness of CHL-induced anaphylaxis in the surgical population.

Methods: Literature review of Embase, Medline, PubMed and the Cochrane library using 'anaphylaxis (and) chlorhexidine' search terms.

Results: Thirty-six articles were published on surgical patients suffering anaphylaxis to CHL. Within these, seven patients had two proven separate anaphylactic reactions and one had three separate proven anaphylactic reactions. The most commonly affected speciality was urology. The majority occurred during elective procedures. A history of atopy was surprisingly uncommon as was bronchospasm. Six patients required active chest compressions and 39.71% of patients had their surgical procedure abandoned. Unplanned intensive care admissions occurred in 27.94%.

Discussion: In order to reduce abandoned procedures, unplanned intensive care unit admissions, morbidity and mortality associated with CHL-induced anaphylaxis we recommend the following: rationalization of CHL-containing products, greater vigilance regarding subtle symptoms of CHL allergy, appropriate investigation of these symptoms and a greater awareness of CHL-containing products. Lastly, we outline the appropriate investigations and highlight the need for meticulous documentation in those who are CHL allergic.

Anaphylaxis is a clinical emergency, and all healthcare professionals should be familiar with its recognition and acute and ongoing management. These guidelines have been prepared by the European Academy of Allergy and Clinical Immunology (EAACI) Taskforce on Anaphylaxis. They aim to provide evidence-based recommendations for the recognition, risk factor assessment, and the management of patients who are at risk of, are experiencing, or have experienced anaphylaxis. While the primary audience is allergists, these guidelines are also relevant to all other healthcare professionals. The development of these guidelines has been underpinned by two systematic reviews of the literature, both on the epidemiology and on clinical management of anaphylaxis. Anaphylaxis is a potentially life-threatening condition whose clinical diagnosis is based on recognition of a constellation of presenting features. First-line treatment for anaphylaxis is intramuscular adrenaline. Useful second-line interventions may include removing the trigger where possible, calling for help, correct positioning of the patient, high-flow oxygen, intravenous fluids, inhaled short-acting bronchodilators, and nebulized adrenaline. Discharge arrangements should involve an assessment of the risk of further reactions, a management plan with an anaphylaxis emergency action plan, and, where appropriate, prescribing an adrenaline auto-injector. If an adrenaline auto-injector is prescribed, education on when and how to use the device should be provided. Specialist follow-up is essential to investigate possible triggers, to perform a comprehensive risk assessment, and to prevent future episodes by developing personalized risk reduction strategies including, where possible, commencing allergen immunotherapy. Training for the patient and all caregivers is essential. There are still many gaps in the evidence base for anaphylaxis.

Anaphylaxis is a serious, rapid-onset, allergic reaction that may cause death. Severe anaphylaxis is characterised by life-threatening upper airway obstruction, bronchospasm and/or hypotension. Anaphylaxis in children is most often caused by food. Bronchospasm is a common symptom, and there is usually a background of atopy and asthma. Venom- and drug-induced anaphylaxis are more common in adults, in whom hypotension is more likely to occur. Diagnosis can be difficult, with skin features being absent in up to 20% of people. Anaphylaxis must be considered as a differential diagnosis for any acute-onset respiratory distress, bronchospasm, hypotension or cardiac arrest. The cornerstones of initial management are putting the patient in the supine position, administering intramuscular adrenaline into the lateral thigh, resuscitation with intravenous fluid, support of the airway and ventilation, and giving supplementary oxygen. If the response to initial management is inadequate, intravenous infusion of adrenaline should be commenced. Use of vasopressors should be considered if hypotension persists. The patient should be observed for at least 4 hours after symptom resolution and referred to an allergist to assist with diagnosis, allergen avoidance measures, risk assessment, preparation of an action plan and education on the use of self-injectable adrenaline. Provision of a MedicAlert bracelet should also be arranged.

Background: The unpredictability of anaphylactic reactions and the need for immediate, often improvised treatment will make controlled trials impracticable; other means must therefore be used to determine optimal management.

Objectives: This study aimed to investigate the circumstances leading to fatal anaphylaxis.

Methods: A register was established including all fatal anaphylactic reactions in the UK since 1992 that could be traced from the certified cause of death. Data obtained from other sources suggested that deaths certified as due to anaphylaxis underestimate the true incidence. Details of the previous medical history, the reaction and necropsy were sought for all cases.

Results: Approximately half the 20 fatal reactions recorded each year in the UK were iatrogenic, and a quarter each due to food or insect venom. All fatal reactions thought to have been due to food caused difficulty breathing that in 86% led to respiratory arrest; shock was more common in iatrogenic and venom reactions. The median time to respiratory or cardiac arrest was 30 min for foods, 15 min for venom and 5 min for iatrogenic reactions. Twenty-eight per cent of fatal cases were resuscitated but died 3 h-30 days later, mostly from hypoxic brain damage. Adrenaline (epinephrine) was used in treatment of 62% of fatal reactions but before arrest in only 14%.

Conclusions: Immediate recognition of anaphylaxis, early use of adrenaline, inhaled beta agonists and other measures are crucial for successful treatment. Nevertheless, a few reactions will be fatal whatever treatment is given; optimal management of anaphylaxis is therefore avoidance of the cause whenever this is possible. Predictable cross-reactivity between the cause of the fatal reaction and that of previous reactions had been overlooked. Adrenaline overdose caused at least three deaths and must be avoided. Kit for self-treatment had proved unhelpful for a variety of reasons; its success depends on selection of appropriate medication, ease of use and good training.

A patient undergoing anaesthesia for coronary artery bypass surgery developed what was subsequently confirmed to be an anaphylactic reaction to succinylated gelatin (Gelofusine). By virtue of being on cardiopulmonary bypass, rapid detection, quantification and treatment of volume loss (by vasodilatation and extravasation) was possible. The patient required 51 ml/kg of resuscitative fluids in the 15 minutes after onset of anaphylaxis, or 73% of her calculated preoperative blood volume. Alpha-adrenoceptor agonists and vasopressin were required to manage ongoing vasoplegia. This case emphasises the importance of volume resuscitation and vasopressors in the treatment of anaphylaxis.

Objectives: To assess a protocol for treatment of sting anaphylaxis.

Design: Prospective assessment of treatment with oxygen, intravenous infusion of adrenaline (epinephrine), and volume resuscitation with normal saline.

Setting: Sub-study of a venom immunotherapy trial.

Participants: 21 otherwise healthy adults with systemic allergic reactions to diagnostic sting challenge.

Main outcome measures: Response to treatment, total adrenaline dose and infusion duration, recurrence of symptoms after stopping the infusion, and additional volume resuscitation.

Results: 19 participants required intervention according to the protocol. All received adrenaline, and five received volume resuscitation. In nine cases, physical signs of anaphylaxis recurred after initial attempts at stopping adrenaline but resolved after recommencing the infusion. The median total dose and infusion duration were 590 micro g and 115 minutes respectively, but were significantly higher for eight patients who had hypotensive reactions (762 micro g and 169 minutes respectively). Hypotension was always accompanied by a relative bradycardia, which was severe and treated with atropine in two patients. Widespread T wave inversion occurred, before starting treatment with adrenaline, in one person with an otherwise mild reaction. All patients fully recovered and were fit for same day discharge, apart from the person with ECG changes who was observed overnight and discharged the following day.

Conclusions: Carefully titrated intravenous adrenaline combined with volume resuscitation is an effective strategy for treating sting anaphylaxis, however severe bradycardia may benefit from additional treatment with atropine. Cardiac effects of anaphylaxis, perhaps including neurocardiogenic mechanisms, may be an important factor in some lethal reactions.

Observations in 205 patients with cardiovascular manifestations of anaphylactic shock confirmed the belief that adrenaline is the drug of first choice in management and that colloid solutions are preferable to crystalloid solutions in volume replacement. Arrhythmias and elevated filling pressures are more common in patients with cardiac disease but the sympathetic response appears to override the cardiac effects of histamine in healthy patients.

The World Allergy Organization (WAO) Guidelines for the assessment and management of anaphylaxis are a widely disseminated and used resource for information about anaphylaxis. They focus on patients at risk, triggers, clinical diagnosis, treatment in health care settings, self-treatment in the community, and prevention of recurrences. Their unique strengths include a global perspective informed by prior research on the global availability of essentials for anaphylaxis assessment and management and a global agenda for anaphylaxis research. Additionally, detailed colored illustrations are linked to key concepts in the text [Simons et al.: J Allergy Clin Immunol 2011;127:593.e1-e22]. The recommendations in the original WAO Anaphylaxis Guidelines for management of anaphylaxis in health care settings and community settings were based on evidence published in peer-reviewed, indexed medical journals to the end of 2010. These recommendations remain unchanged and clinically relevant. An update of the evidence base was published in 2012 [Simons et al.: Curr Opin Allergy Clin Immunol 2012;12:389-399]. In 2012 and early 2013, major advances were reported in the following areas: further characterization of patient phenotypes; development of in vitro tests (for some allergens) that help distinguish clinical risk of anaphylaxis from asymptomatic sensitization; epinephrine (adrenaline) research, including studies of a new epinephrine auto-injector for use in community settings, and randomized controlled trials of immunotherapy to prevent food-induced anaphylaxis. Despite these advances, the need for additional prospective studies, including randomized controlled trials of interventions in anaphylaxis is increasingly apparent. This 2013 Update highlights publications from 2012 and 2013 that further contribute to the evidence base for the recommendations made in the original WAO Anaphylaxis Guidelines. Ideally, it should be used in conjunction with these Guidelines and with the 2012 Guidelines Update.

Anaphylaxis is an acute and potentially lethal multi-system allergic reaction. Most consensus guidelines for the past 30 years have held that epinephrine is the drug of choice and the first drug that should be administered in acute anaphylaxis. Some state that properly administered epinephrine has no absolute contraindication in this clinical setting. A committee of anaphylaxis experts assembled by the World Allergy Organization has examined the evidence from the medical literature concerning the appropriate use of epinephrine for anaphylaxis. The Committee strongly believes that epinephrine is currently underutilized and often dosed suboptimally to treat anaphylaxis, is under-prescribed for potential future self-administration, that most of the reasons proposed to withhold its clinical use are flawed, and that the therapeutic benefits of epinephrine exceed the risk when given in appropriate i.m. doses.

Adrenaline (epinephrine) is the recommended first line treatment for patients with anaphylaxis. This review discusses the safety and efficacy of adrenaline in the treatment of anaphylaxis in the light of currently available evidence. A pragmatic approach to use of adrenaline auto-injectors is suggested.

Background: Epinephrine is the drug of choice for the management of anaphylaxis, and fatal anaphylaxis is associated with delayed epinephrine administration. Data on adverse cardiovascular (CV) complications and epinephrine overdose are limited.

Objective: To compare rates of CV adverse events and epinephrine overdoses associated with anaphylaxis management between various routes of epinephrine administration among patients with anaphylaxis in the emergency department.

Methods: This was an observational cohort study from April 2008 to July 2012. Patients in the emergency department who met diagnostic criteria for anaphylaxis were included. We collected demographics; route of epinephrine administration; trigger; overdose; and adverse CV events, including arrhythmia, cardiac ischemia, stroke, angina, and hypertension.

Results: The study cohort included 573 patients, of whom, 301 (57.6%) received at least 1 dose of epinephrine. A total of 362 doses of epinephrine were administered to 301 patients: 67.7% intramuscular (IM) autoinjector, 19.6% IM injection, 8.3% subcutaneous injection, 3.3% intravenous (IV) bolus, and 1.1% IV continuous infusion. There were 8 CV adverse events and 4 overdoses with 8 different patients. All the overdoses occurred when epinephrine was administered IV bolus. Adverse CV events were associated with 3 of 30 doses of IV bolus epinephrine compared with 4 of 316 doses of IM epinephrine (10% vs 1.3%; odds ratio 8.7 [95% CI, 1.8-40.7], P = .006). Similarly, overdose occurred with 4 of 30 doses of IV bolus epinephrine compared with 0 of 316 doses of IM epinephrine (13.3% vs 0%; odds ratio 61.3 [95% CI, 7.5 to infinity], P < .001).

Conclusion: The risk of overdose and adverse CV events is significantly higher with IV bolus epinephrine administration. Analysis of the data supports the safety of IM epinephrine and a need for extreme caution and further education about IV bolus epinephrine in anaphylaxis.

This case describes a 29-year-old woman who presented with an acute severe anaphylactic reaction to penicillin. In addition to other medications administered in the emergency department, she received 0.1 mg intravenously of 1:10 000 epinephrine, after which she immediately developed severe chest pain. Her ECG showed ST elevations consistent with an anterior myocardial infarction, and her serum troponin level was elevated. A CT angiogram showed no signs of coronary artery disease or abnormal anatomy. This case is an example of vasospasm-induced myocardial injury and illustrates a potential danger of intravenous epinephrine use. The authors were able to identify only 2 other case reports where therapeutic doses of epinephrine have been reported to cause this phenomenon.

Purpose of review: Anaphylaxis is frightening and patients commonly fear their next reaction will be fatal. This review looks at the characteristics of fatal reactions to find if a fatal recurrence is predictable.

Recent findings: Most publications on fatal anaphylaxis are case reports that do not help predict risks. Most epidemiological studies focus on non-fatal reactions. The UK fatal anaphylaxis register demonstrates that over two-thirds of those dying from sting reactions and over four-fifths dying from drug anaphylaxis had no previous indication of their allergy, whereas those dying from food allergy had usually had previous reactions but these were typically not severe. Recent reports of anaphylaxis epidemiology based on diagnostic coding or attendance for treatment may be biased by differences in health service resource utilization according to the cause and course of the reaction.

Summary: Most fatal anaphylactic reactions are unpredictable. The appropriate management after recovery from a severe reaction may be protective against a fatal recurrence. An accurate identification of the cause and effective avoidance is a crucial part of this management, together with effective treatment of asthma for those with food allergy, immunotherapy for sting allergy, the avoidance of drugs that potentiate anaphylaxis, and effective training in self-treatment.

Background: Literature on the use of epinephrine in the treatment of anaphylaxis during anesthesia is very limited. The objective of this study was to investigate how often epinephrine is used in the treatment of suspected anaphylaxis during anesthesia in Denmark and whether timing of treatment is important.

Methods: A retrospective study of 270 patients investigated at the Danish Anaesthesia Allergy Centre after referral due to suspected anaphylaxis during anesthesia was performed. Reactions had been graded by severity: C1, mild reactions; C2, moderate reactions; C3, anaphylactic shock with circulatory instability; C4, cardiac arrest. Use of epinephrine, dosage, route of administration, and time between onset of circulatory instability and epinephrine administration were noted.

Results: A total of 122 (45.2%) of referred patients had C3 or C4 reactions; of those, 101 (82.8%) received epinephrine. Route of administration was intravenous in 95 (94%) patients. Median time from onset of reported hypotension to treatment with epinephrine was 10 min (range, 1-70 min). Defining epinephrine treatment less than or equal to 10 min after onset of hypotension as early, and more than 10 min as late, infusion was needed in 12 of 60 patients (20%) treated early versus 12 of 35 patients (34%) treated late (odds ratio, 2.09) (95% confidence interval, 0.81-5.35).

Conclusion: Anaphylaxis may be difficult to diagnose during anesthesia, and treatment with epinephrine can be delayed as a consequence. Anaphylaxis should be considered and treated in patients with circulatory instability during anesthesia of no apparent cause who do not respond to the usual treatments.

We report a prospective, randomized, blinded, placebo-controlled, 6-way crossover study of intramuscular versus subcutaneous injection of epinephrine in young men. Peak plasma epinephrine concentrations were significantly higher (P < .01) after epinephrine was injected intramuscularly into the thigh than after epinephrine was injected intramuscularly or subcutaneously into the upper arm. We recommend intramuscular injection of epinephrine into the thigh as the preferred route and site of injection of this life-saving medication in the initial treatment of anaphylaxis.

Background: Prompt injection of epinephrine is the cornerstone of systemic anaphylaxis treatment. The rate of epinephrine absorption has not been reported previously in allergic children.

Objective: Our objective was to study the clinical pharmacology of epinephrine in this population.

Methods: We performed a prospective, randomized, blinded, parallel-group study in 17 children with a history of anaphylaxis to food, Hymenoptera venom, or other substances. We injected 0.01 ml/kg epinephrine solution (maximum 0.3 ml [0.3 mg]) subcutaneously, or 0.3 mg epinephrine intramuscularly from an autoinjector. Plasma epinephrine concentrations, heart rate, blood pressure, and adverse effects were monitored.

Results: In nine children who received epinephrine subcutaneously, the mean maximum plasma epinephrine concentration (+/- SEM) was 1802 +/- 214 pg/ml, achieved at a mean time of 34 +/- 14 minutes (range, 5 to 120 minutes). Only two of the nine children achieved maximum plasma concentrations by 5 minutes. In eight children who received epinephrine intramuscularly, the mean maximum plasma concentration was 2136 +/- 351 pg/ml, achieved at a mean time of 8 +/- 2 minutes, which was significantly faster than the mean time at which maximum plasma concentrations were achieved after subcutaneous epinephrine injection (p < 0.05). Six of the eight children achieved maximum plasma concentrations by 5 minutes. The terminal elimination half-life was 43 +/- 15 minutes. No serious adverse effects were noted in any child.

Conclusions: In children, recommendations for subcutaneous epinephrine injection are based on anecdotal experience, and should be reevaluated in view of our finding of delayed epinephrine absorption when this route is used. This delay might have important clinical implications during an episode of systemic anaphylaxis. The intramuscular route of injection is preferable.

Anaphylaxis remains one of the most feared intraoperative emergencies for the anaesthetist. It is often sudden onset and dramatic yet, when treated appropriately, the vast majority of patients make a complete recovery.

As the doctor responsible for the patient's survival and recovery from such a perioperative incident, anaesthetists must have a good understanding of the nature of the crisis and its effective treatment. The experience gained from investigating patients with anaphylaxis in an anaesthetic allergy clinic suggests that diagnosis, treatment and follow-up are not always optimal. It is difficult to be always ready for a crisis that is rare, but we identify areas where improvements can be made.

The present approach to the diagnosis, management and follow-up of anaphylaxis during anaesthesia varies in the Scandinavian countries. The main purpose of these Scandinavian Clinical Practice Guidelines is to increase the awareness about anaphylaxis during anaesthesia amongst anaesthesiologists. It is hoped that increased focus on the subject will lead to prompt diagnosis, rapid and correct treatment, and standardised management of patients with anaphylactic reactions during anaesthesia across Scandinavia. The recommendations are based on the best available evidence in the literature, which, owing to the rare and unforeseeable nature of anaphylaxis, mainly includes case series and expert opinion (grade of evidence IV and V). These guidelines include an overview of the epidemiology of anaphylactic reactions during anaesthesia. A treatment algorithm is suggested, with emphasis on the incremental titration of adrenaline (epinephrine) and fluid therapy as first-line treatment. Recommendations for primary and secondary follow-up are given, bearing in mind that there are variations in geography and resources in the different countries. A list of National Centres from which anaesthesiologists can seek advice concerning follow-up procedures is provided. In addition, an algorithm is included with advice on how to manage patients with previous suspected anaphylaxis during anaesthesia. Lastly, Appendix 2 provides an overview of the incidence, mechanisms and possibilities for follow-up for some common drug groups.

We aimed to establish the frequency and nature of drug administration error in anaesthesia (a significant subset of error in medicine) at two hospitals. Anaesthetists were asked to return a study form anonymouslyfor every anaesthetic, indicating whether or not a drug administration error or pre-error (defined as any incident with potential to become an error) had occurred. Further details were sought if the response was affirmative. From 10,806 anaesthetics, 7794 study forms were returned, representing response rates of 80% from Hospital A and 57% from Hospital B (72% overall). The frequency (95% confidence intervals) of drug administration error; of any type, per anaesthetic was 0.0075 (0.006 to 0.009), of i.v. bolus errors was 0.005 (0.0035 to 0.006) and of pre-errors was 0.004 (0.003 to 0.005), with no significant difference between hospitals. Overall, one drug administration error was reported for every 133 anaesthetics. The two largest individual categories of error involved incorrect doses (20%) and substitutions (20%) with i.v. boluses of drug. Of the i.v. bolus substitutions, 69% occurred between different pharmacological classes. One patient was aware while under muscle relaxation, and two required prolonged ventilation. In addition, 47 transient physiological effects were reported, of which five required intervention. We conclude that drug administration error during anaesthesia is considerably more frequent than previously reported.

Erratum in
Circulation. 2011 Feb 15;123(6):e239
Circulation. 2011 Oct 11;124(15):e405

Objective: Epinephrine (Epi) is the treatment of choice for reversing cardiovascular collapse in anaphylactic shock (AS). In this condition, most treatment guidelines have been anecdotally derived and no randomized clinical trials have been conducted. In the present study, we examined the time course of haemodynamic recovery in a canine model of AS when Epi was administered at the initiation of allergen challenge before fully developed shock had occurred.

Methods: Randomized, controlled, crossover studies were performed approximately 3-5 weeks apart in ragweed-sensitized dogs while the animals were ventilated and anaesthetized. Epi was administered by bolus intravenous (i.v.), subcutaneous (s.c.), intramuscular (i.m.) routes and by continuous i.v. infusion (CI). The findings obtained in the Epi treatment (T) studies were compared with those found in a no treatment (NT) study. In the bolus studies, Epi was administered at 0.01 mg/kg, while in the CI study, the dose of Epi was titrated to maintain mean arterial pressure (MAP) at 70% of preshock levels. MAP, cardiac output (CO), stroke volume (SV), and pulmonary wedge pressure (Pwp) were determined over a 3 h period.

Results: In the CI study, haemodynamics (CO, MAP, and SV) were significantly higher than those measured in the NT study and the bolus studies over approximately the first hour of the study. In the CI study, the amount of Epi infused was significantly less than in the bolus studies.

Conclusion: When administered at the initiation of allergen challenge, bolus treatment of Epi by i.m., i.v., or s.c. routes caused limited haemodynamic improvement in AS. In contrast, constant infusion of Epi at a lower total dose produced significant haemodynamic improvement. Within the limits of this anaesthetized canine model, the results suggest that CI should be the preferred route in the treatment of AS when this treatment option is available.

The availability of sugammadex as a selective encapsulating agent for rocuronium has led to speculation that it may be useful in mitigating rocuronium-induced anaphylaxis. Off-label use of sugammadex for this indication has already been documented in case reports although there are theoretical objections to the likelihood of an allergen-binding agent's being able to attenuate the immunological cascade of anaphylaxis. Using a cutaneous model of anaphylaxis in rocuronium-sensitised patients, we were unable to demonstrate that sugammadex was effective in attenuating the type-1 hypersensitivity reaction after it has been triggered by rocuronium, but we were able to demonstrate that these patients are anergic to sugammadex-bound rocuronium. These findings demonstrate that a cyclodextrin can bind an allergen and exclude it from interacting with the immune system, and may potentially lead to novel applications in other allergic diseases. However, there is no evidence that sugammadex should be used for the treatment of rocuronium-induced anaphylaxis, and clinical management should follow established protocols.

We investigated the effect of rocuronium- and sugammadex-induced mast cell increase and degranulation in rat portal triads. Forty-two rats, in six groups, received either rocuronium 1 mg.kg(-1); sugammadex 15 mg.kg(-1); sugammadex 100 mg.kg(-1); rocuronium 1 mg.kg(-1) and 5 min later, sugammadex 15 mg.kg(-1); rocuronium 1 mg.kg(-1) and 5 min later, sugammadex 100 mg.kg(-1); or isotonic saline. Total mast cell numbers were significantly higher with rocuronium only, than in all other groups (p<0.003), although in all active groups, the number was greater than the control. Total mast cell number was significantly higher with rocuronium and low-dose sugammadex compared with low-dose sugammadex only. The number of tryptase-positive mast cells with rocuronium only was significantly higher than in all other groups (p<0.003). Tryptase-positive mast cell numbers in both groups receiving both rocuronium and sugammadex were significantly higher compared with both groups receiving sugammadex only. Rocuronium increased mast cell numbers, and degranulation was mitigated by sugammadex. These results suggest that sugammadex may be beneficial in treatment of rocuronium-induced anaphylaxis.

We report 13 cases of presumed rocuronium-induced anaphylaxis in which sugammadex was administered with the intention of reversing the immunological reaction. Of these 13 cases, eight (62%) were later confirmed to be type-1 hypersensitivity reactions to rocuronium, three (23%) were triggered by an antibiotic and two (15%) were non-immunologically mediated. Response to treatment was scored by the treating anaesthetist, and compared with haemodynamic and inotrope measurements from the resuscitation and anaesthetic records. Haemodynamic improvement was seen in only six (46%) cases, three of which were associated with a non-rocuronium trigger. Of the three cases in which the treating anaesthetist thought that sugammadex had been beneficial, one was not caused by rocuronium, one had no improvement in blood pressure and one required 8.5 times as much adrenaline in boluses after, compared with the period before, sugammadex administration. These data suggest that sugammadex does not modify the clinical course of a suspected hypersensitivity reaction.

The Resuscitation Council UK has updated its Guideline for healthcare providers on the Emergency treatment of anaphylaxis. As part of this process, an evidence review was undertaken by the Guideline Working Group, using an internationally-accepted approach for adoption, adaptation, and de novo guideline development based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence to decision (EtD) framework, referred to as GRADE-ADOLOPMENT. A number of significant changes have been made, which will be reflected in the updated Guideline. These include: emphasis on repeating intramuscular adrenaline doses after 5 min if symptoms of anaphylaxis do not resolve; corticosteroids (e.g. hydrocortisone) no longer being routinely recommended for the emergency treatment of anaphylaxis; interventions for reactions which are refractory to initial treatment with adrenaline; a recommendation against the use of antihistamines for the acute management of anaphylaxis; and guidance relating to the duration of observation following anaphylaxis, and timing of discharge.

The incidence of life-threatening anaphylactic reactions related to anesthesia is approximately 1 in 6000 anesthetics administered, and is associated with mortality as high as 5%. In such cases the use of extracorporeal membrane oxygenation (ECMO) in the setting of refractory shock following anaphylaxis may be life saving. Abdominal compartment syndrome (ACS) itself and in this case complicating ECMO support, is a potentially devastating complication of high-volume resuscitation. Decompressive laparotomy is the treatment of choice for ACS. We present a patient treated with venoarterial ECMO for refractory shock following anaphylaxis who developed ACS that was successfully treated with urgent decompressive laparotomy performed in the intensive care unit. This case report highlights the role of abdominal compartment syndrome as a rare but potentially fatal cause of low circuit flow in ECMO-supported patients and proposes a stepwise approach to decision making in this setting. Urgent decompressive laparotomy is potentially lifesaving in this circumstance, and should be urgently considered once other causes of low ECMO flow have been excluded.

In recent years, extracorporeal membrane oxygenation has become increasingly common in the treatment of in-hospital cardiac arrest in non-cardiac surgery patients. This includes cardiac arrest secondary to perioperative anaphylactic shock refractory to standard advanced life support protocols, which is a rare but catastrophic event associated with significant mortality. Neuromuscular blocking drugs are most commonly implicated in perioperative anaphylaxis, with rocuronium playing a major role. In this article, we report two cases of young and otherwise fit and well patients who experienced a perioperative arrest secondary to rocuronium anaphylaxis before elective surgery; both patients did not respond to conventional advanced life support, but survived neurologically intact after institution of urgent veno-arterial extracorporeal membrane oxygenation.

Background: Severe anaphylaxis can be associated with cardiovascular collapse that is difficult to manage and does not respond to treatment with epinephrine. Because anaphylaxis is uncommon, unpredictable and may be fatal, a prospective, randomized, controlled trial in humans on the best management is difficult and guidelines are based on theory and anecdotes only.

Methods and results: We report six cases in which the use of vasopressin was successful in the treatment of anaphylactic shock.

Conclusions: Standard treatment of anaphylactic shock, including discontinuation of the causative agent, administration of epinephrine, and infusion of IV fluids, did not stabilize cardiocirculatory function, and adding arginine vasopressors resulted in prompt hemodynamic stabilization.

Purpose: To report the use of vasopressin to treat a patient who, after failing to respond to volume expansion and epinephrine administration, experienced an anaphylactic reaction to rocuronium.

Clinical features: A 17-yr-old female was scheduled to undergo transnasal, transsphenoidal resection of a pituitary tumour. Shortly after induction of general anesthesia, for which rocuronium 50 mg iv was administered to facilitate tracheal intubation, the patient developed severe hypotension and diffuse erythema. This severe,allergic response was refractory to the administration of intravenous fluids, epinephrine, and phenylephrine. However, arginine vasopressin, administered intravenously as a bolus of two units, followed by an infusion of 2 U.hr(-1), rapidly corrected the hemodynamic instability. Her recovery from this episode was uneventful, but surgery was cancelled. Skin testing, performed six weeks later, was positive for rocuronium and negative for cisatracurium and latex, as well as all other medications administered. Eight weeks later, the surgical procedure was performed, uneventfully, using cisatracurium as the muscle relaxant.

Conclusions: Vasopressin may be effective in the resuscitation of anesthetized patients, with hemodynamic instability associated with anaphylaxis resistant to epinephrine and alpha-agonists.

Background: Epinephrine and more recently arginine vasopressin (AVP) alone or in combination have been proposed in patients with anaphylactic shock, but few experimental data exist. The authors investigated the effects of epinephrine only, AVP only, or epinephrine followed by AVP in a model of anaphylactic shock.

Methods: Ovalbumin-sensitized Brown Norway rats were anesthetized, intubated, and shock induced with ovalbumin. Rats (n = 6/group) were randomly allocated to receive 5 min after shock onset: (1) saline (no-treatment group); (2) two boluses of epinephrine followed by continuous infusion (epinephrine group); (3) AVP bolus followed by continuous infusion (AVP group); (4) epinephrine bolus followed by AVP continuous infusion (epinephrine + AVP group). Mean arterial pressure (MAP) and skeletal muscle oxygen pressure (PtiO2) were measured. Continuous infusion rates were titrated to reach MAP values of 60 mmHg. Survival was analyzed.

Results: Without treatment, MAP and PtiO2 decreased rapidly with 0% survival. In the epinephrine group, MAP and PtiO2 recovered after an initial decrease, with 84% survival. In the AVP group, MAP was partially restored and subsequently decreased; PtiO2 values decreased to values similar to those in the no-treatment group; survival was 0%. In the epinephrine + AVP group, MAP and PtiO2 values increased more slowly as compared with the epinephrine group; survival was 100%.

Conclusions: In this model of anaphylactic shock, early treatment with epinephrine followed by continuous epinephrine or vasopressin infusion resulted in an excellent survival rate, whereas vasopressin only resulted in a 100% death rate. These experimental results suggest that epinephrine must still be considered as the first-line drug to treat anaphylactic shock.

Anaphylaxis is an uncommon but serious complication of anaesthesia. Most current guidelines for the management of anaphylaxis list only epinephrine as a vasopressor to use in the event of cardiovascular collapse. We present two cases of anaphylaxis under anaesthesia where return of spontaneous circulation was refractory to epinephrine, but occurred following the administration of the alpha-agonist metaraminol. Potential advantages and disadvantages of using epinephrine in this setting, the role of alpha-agonists and some potential mechanisms accounting for their role in successful management are reviewed

Severe anaphylactic shock is a life-threatening situation that needs immediate treatment of progressive hemodynamic failure. We report two cases of severe anaphylactic shock treated with arginine-vasopressin (AVP): In a 42-year-old male patient anaphylactic shock was caused by the sting of a hornet. At the scene, he was found unconscious, cyanotic, with a heart rate of 130/min without measurable blood pressure. The patient was intubated and ventilated with 100% oxygen, intravenous epinephrine (1 mg over 2 min) had no effect on blood pressure. After injection of 10 IU vasopressin, followed by infusion of 40 IU vasopressin, hemodynamics could be stabilized at once. In the second case, a 47-year-old male patient was stung by a wasp. At the scene he was unconscious, blood pressure was not measurable, heart rate was 140/min. The patient was treated with 40 IU vasopressin followed by rapid infusion of 500 ml NaCl 0.9%. After injection of vasopressin, blood pressure raised to 80/50 mm Hg and heart rate decreased to 90/min. Both patients needed ventilator therapy for several days and recovered fully.

A short cut review was carried out to establish whether a glucagon infusion is of benefit in patients with refractory anaphylaxis. 62 papers were found using the reported search, of which two presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of these best papers are tabulated. A clinical bottom line is stated.

This 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations for advanced life support includes updates on multiple advanced life support topics addressed with 3 different types of reviews. Topics were prioritized on the basis of both recent interest within the resuscitation community and the amount of new evidence available since any previous review. Systematic reviews addressed higher-priority topics, and included double-sequential defibrillation, intravenous versus intraosseous route for drug administration during cardiac arrest, point-of-care echocardiography for intra-arrest prognostication, cardiac arrest caused by pulmonary embolism, postresuscitation oxygenation and ventilation, prophylactic antibiotics after resuscitation, postresuscitation seizure prophylaxis and treatment, and neuroprognostication. New or updated treatment recommendations on these topics are presented. Scoping reviews were conducted for anticipatory charging and monitoring of physiological parameters during cardiopulmonary resuscitation. Topics for which systematic reviews and new Consensuses on Science With Treatment Recommendations were completed since 2015 are also summarized here. All remaining topics reviewed were addressed with evidence updates to identify any new evidence and to help determine which topics should be the highest priority for systematic reviews in the next 1 to 2 years.

Aim: To report our 10 year experience with noradrenaline use in children with septic shock focusing on doses, routes of administration and complications.

Methods: Retrospective single-centre review of children with septic shock who received noradrenaline between 2000 and 2010.

Results: We identified 144 children with septic shock treated with noradrenaline, in 22% as the first-line drug. The median volume resuscitation before vasoactive agent administration was 50 mL/kg interquartile range [IQR: 30-70]. Mean doses of noradrenaline ranged from 0.5 ± 0.4 μg/kg per min (starting dose) to 2.5 ± 2.2 μg/kg per min (maximum dose). Noradrenaline was administered via peripheral venous access or intra-osseous route in 19% of cases for a median duration of 3 h [IQR: 2-4] without any adverse effects. The use of noradrenaline increased over the study period. Mortality rate was 45% with a significant decrease over the study period. Adverse effects included arrhythmia in two children and hypertension in eight children. None of these arrhythmias required treatment and hypertension resolved with the noradrenaline dose reduction.

Conclusion: Higher doses of noradrenaline than those suggested in the literature may be necessary to reverse hypotension and hypoperfusion. The use of noradrenaline through peripheral venous access or intra-osseous route was safe, without any adverse effects.

Objectives: To assess the feasibility of a large, randomized controlled trial of combination epinephrine-arginine vasopressin for in-pediatric intensive care unit cardiopulmonary arrest refractory to initial epinephrine dosing.

Design: Prospective, pilot, matched controlled clinical trial using exception from informed consent.

Setting: Pediatric intensive care unit in a university-affiliated tertiary care children's hospital.

Patients: All patients <18 yrs of age admitted to the pediatric intensive care unit with cardiopulmonary arrest requiring chest compressions and epinephrine (0.01 mg/kg) were eligible.

Interventions: Patients who remained in cardiopulmonary arrest despite an initial dose of epinephrine received arginine vasopressin (0.8 U/kg) rescue as the second vasopressor, followed by additional epinephrine if needed.

Measurements and main results: Outcome variables included return of spontaneous circulation (≥20 min), survival at 24 hrs, survival to hospital discharge, and neurologic status at discharge. Favorable neurologic status was defined as Pediatric Cerebral Performance Categories 1, 2, and 3, or no change from admission. Data were compared to a retrospective, matched cohort of patients who experienced cardiopulmonary arrest requiring ≥ two doses of vasopressor, and did not receive arginine vasopressin (n = 20). Of 2,654 patients admitted to the pediatric intensive care unit, 29 (1.1%) had refractory cardiopulmonary arrest: five patients were excluded, 14 missed for inclusion, and ten were enrolled. There was increased 24-hr survival (80% vs. 30%, odds ratio 9.33, 95% confidence interval 1.51-57.65) in arginine vasopressin patients. There was no significant difference in return of spontaneous circulation, survival to hospital discharge, or favorable neurologic status at discharge.

Conclusions: These pilot data provide support for a larger randomized controlled trial of arginine vasopressin therapy during cardiopulmonary resuscitation for in-hospital pediatric cardiac arrest.

Introduction: The incidence of anaphylactic reactions during anesthesia is between 1:5000 and 1:25000 and it is one of the few causes of mortality directly related to general anesthesia. The most important requirements in the treatment of this clinical condition are early diagnosis and maintenance of vital organ perfusion. Epinephrine administration is generally considered as the first line treatment of anaphylactic reactions. However, recently, new pharmacological approaches have been described in the treatment of different forms of vasoplegic shock.

Case presentation: We describe the case of a child who was undergoing surgery for ventricular septal defect, with an anaphylactic reaction to heparin that was refractory to epinephrine infusion and was effectively treated by low dose vasopressin infusion.

Conclusion: In case of anaphylactic shock, continuous infusion of low-dose vasopressin might be considered after inadequate response to epinephrine, fluid resuscitation and corticosteroid administration.

Background: This project was devised to estimate the incidence of major complications of airway management during anaesthesia in the UK and to study these events.

Methods: Reports of major airway management complications during anaesthesia (death, brain damage, emergency surgical airway, unanticipated intensive care unit admission) were collected from all National Health Service hospitals for 1 yr. An expert panel assessed inclusion criteria, outcome, and airway management. A matched concurrent census estimated a denominator of 2.9 million general anaesthetics annually.

Results: Of 184 reports meeting inclusion criteria, 133 related to general anaesthesia: 46 events per million general anaesthetics [95% confidence interval (CI) 38-54] or one per 22,000 (95% CI 1 per 26-18,000). Anaesthesia events led to 16 deaths and three episodes of persistent brain damage: a mortality rate of 5.6 per million general anaesthetics (95% CI 2.8-8.3): one per 180,000 (95% CI 1 per 352-120,000). These estimates assume that all such cases were captured. Rates of death and brain damage for different airway devices (facemask, supraglottic airway, tracheal tube) varied little. Airway management was considered good in 19% of assessable anaesthesia cases. Elements of care were judged poor in three-quarters: in only three deaths was airway management considered exclusively good.

Conclusions: Although these data suggest the incidence of death and brain damage from airway management during general anaesthesia is low, statistical analysis of the distribution of reports suggests as few as 25% of relevant incidents may have been reported. It therefore provides an indication of the lower limit for incidence of such complications. The review of airway management indicates that in a majority of cases, there is 'room for improvement'.

Biphasic anaphylactic reactions have been found to develop in as many as 20% of anaphylactic reactions. The biphasic reaction can be less severe, equally severe, or more severe than the initial reaction, ranging in degree from mild symptoms to fatal reactions. In this review, retrospective and prospective studies as well as case studies and case series are discussed in an attempt to gain insight on the incidence of biphasic reactions, the potential clinical characteristics suggestive of a uniphasic reaction developing into a biphasic reaction, and the recommendations for observation periods after an anaphylactic reaction.

Background: Anaphylaxis is an acute systemic allergic reaction, which can be life-threatening. H(1)-antihistamines are commonly used as an adjuvant therapy in the treatment of anaphylaxis. We sought to assess the benefits and harm of H(1)-antihistamines in the treatment of anaphylaxis.

Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library); MEDLINE (1966 to June 2006); EMBASE (1966 to June 2006); CINAHL (1982 to June 2006) and ISI Web of Science (1945 to July 2006). We also contacted pharmaceutical companies and international experts in anaphylaxis in an attempt to locate unpublished material. Randomized and quasi-randomized-controlled trials comparing H(1)-antihistamines with placebo or no intervention were eligible for inclusion. Two authors independently assessed articles for inclusion.

Results: We found no studies that satisfied the inclusion criteria.

Conclusions: Based on this review, we are unable to make any recommendations for clinical practice. Randomized-controlled trials are needed, although these are likely to prove challenging to design and execute.

Serum (or plasma) levels of total and mature tryptase measurements are recommended in the diagnostic evaluation of systemic anaphylaxis and systemic mastocytosis, but their interpretation must be considered in the context of a complete workup of each patient. Total tryptase levels generally reflect the increased burden of mast cells in patients with all forms of systemic mastocytosis (indolent systemic mastocytosis, smoldering systemic mastocytosis, systemic mastocytosis associated with a hematologic clonal non-mast cell disorder, aggressive systemic mastocytosis, and mast cell leukemia) and the decreased burden of mast cells associated with cytoreductive therapies in these disorders. Causes of an elevated total tryptase level other than systemic mastocytosis must be considered, however, and include systemic anaphylaxis, acute myelocytic leukemia, various myelodysplastic syndromes, hypereosinophilic syndrome associated with the FLP1L1-PDGFRA mutation, end-stage renal failure, and treatment of onchocerciasis. Mature (beta) tryptase levels generally reflect the magnitude of mast cell activation and are elevated during most cases of systemic anaphylaxis, particularly with parenteral exposure to the inciting agent.

Anaphylaxis during pregnancy is rare but life threatening to both mother and fetus. The anaesthetist may be unexpectedly faced with an obstructing airway, severe bronchospasm and cardiac arrest requiring perimortem caesarean delivery to relieve aortocaval compression. We present a case of anaphylaxis-induced hyperfibrinolysis, an infrequently discussed complication that could exacerbate postpartum haemorrhage and hamper resuscitative efforts.