Anaesthesia, surgery, and life-threatening allergic reactions: protocol and methods of the 6th National Audit Project (NAP6) of the Royal College of Anaesthetists.

BACKGROUND: Anaphylaxis during anaesthesia is a serious complication for patients and anaesthetists. METHODS: The Sixth National Audit Project (NAP6) of the Royal College of Anaesthetists examined the incidence, predisposing factors, management, and impact of life-threatening perioperative anaphylaxis in the UK. NAP6 included: a national survey of anaesthetists' experiences and perceptions; a national survey of allergy clinics; a registry collecting detailed reports of all Grade 3-5 perioperative anaphylaxis cases for 1 yr; and a national survey of anaesthetic workload and perioperative allergen exposure. NHS and independent sector (IS) hospitals were approached to participate. Cases were reviewed by a multi-disciplinary expert panel (anaesthetists, intensivists, allergists, immunologists, patient representatives, and stakeholders) using a structured process designed to minimise bias. Clinical management and investigation were compared with published guidelines. This paper describes detailed study methods and reports on project engagement by NHS and IS hospitals. The methodology includes a new classification of perioperative anaphylaxis and a new structured method for classifying suspected anaphylactic events including the degree of certainty with which a causal trigger agent can be attributed. RESULTS: NHS engagement was complete (100% of hospitals). Independent sector engagement was limited (13% of approached hospitals). We received >500 reports of Grade 3-5 perioperative anaphylaxis, with 266 suitable for analysis. We identified 199 definite or probable culprit agents in 192 cases. CONCLUSIONS: The methods of NAP6 were robust in identifying causative agents of anaphylaxis, and support the accompanying analytical papers.

Anaesthesia, surgery, and life-threatening allergic reactions: epidemiology and clinical features of perioperative anaphylaxis in the 6th National Audit Project (NAP6).

BACKGROUND: Anaphylaxis during anaesthesia is a serious complication for patients and anaesthetists. METHODS: The 6th National Audit Project (NAP6) on perioperative anaphylaxis collected and reviewed 266 reports of Grades 3-5 anaphylaxis over 1 yr from all NHS hospitals in the UK. RESULTS: The estimated incidence was ≈1:10 000 anaesthetics. Case exclusion because of reporting delays or incomplete data means true incidence might be ≈70% higher. The distribution of 199 identified culprit agents included antibiotics (94), neuromuscular blocking agents (65), chlorhexidine (18), and Patent Blue dye (9). Teicoplanin comprised 12% of antibiotic exposures, but caused 38% of antibiotic-induced anaphylaxis. Eighteen patients reacted to an antibiotic test dose. Succinylcholine-induced anaphylaxis, mainly presenting with bronchospasm, was two-fold more likely than other neuromuscular blocking agents. Atracurium-induced anaphylaxis mainly presented with hypotension. Non-depolarising neuromuscular blocking agents had similar incidences to each other. There were no reports of local anaesthetic or latex-induced anaphylaxis. The commonest presenting features were hypotension (46%), bronchospasm (18%), tachycardia (9.8%), oxygen desaturation (4.7%), bradycardia (3%), and reduced/absent capnography trace (2.3%). All patients were hypotensive during the episode. Onset was rapid for neuromuscular blocking agents and antibiotics, but delayed with chlorhexidine and Patent Blue dye. There were 10 deaths and 40 cardiac arrests. Pulseless electrical activity was the usual type of cardiac arrest, often with bradycardia. Poor outcomes were associated with increased ASA, obesity, beta blocker, and angiotensin-converting enzyme inhibitor medication. Seventy per cent of cases were reported to the hospital incident reporting system, and only 24% to Medicines and Healthcare products Regulatory Agency via the Yellow Card Scheme. CONCLUSIONS: The overall incidence of perioperative anaphylaxis was estimated to be 1 in 10 000 anaesthetics.

Cross-sectional study of perioperative drug and allergen exposure in UK practice in 2016: the 6th National Audit Project (NAP6) Allergen Survey.

BACKGROUND: Details of the current UK drug and allergen exposure were needed for interpretation of reports of perioperative anaphylaxis to the 6th National Audit Project (NAP6). METHODS: We performed a cross-sectional survey of 356 NHS hospitals determining anaesthetic drug usage in October 2016. All cases cared for by an anaesthetist were included. RESULTS: Responses were received from 342 (96%) hospitals. Within-hospital return rates were 96%. We collected 15 942 forms, equating to an annual caseload of 3.1 million, including 2.4 million general anaesthetics. Propofol was used in 74% of all cases and 90% of general anaesthetics. Maintenance included a volatile agent in 95% and propofol in 8.7%. Neuromuscular blocking agents were used in 47% of general anaesthetics. Analgesics were used in 88% of cases: opioids, 82%; paracetamol, 56%; and non-steroidal anti-inflammatory drugs, 28%. Antibiotics were administered in 57% of cases, including 2.5 million annual perioperative administrations; gentamicin, co-amoxiclav, and cefuroxime were most commonly used. Local anaesthetics were used in 74% cases and 70% of general anaesthetics. Anti-emetics were used in 73% of cases: during general anaesthesia, ondansetron in 78% and dexamethasone in 60%. Blood products were used in ≈3% of cases, gelatin <2%, starch very rarely, and tranexamic acid in ≈6%. Chlorhexidine and povidone-iodine exposures were 74% and 40% of cases, and 21% reported a latex-free environment. Exposures to bone cement, blue dyes, and radiographic contrast dye were each reported in 2-3% of cases. CONCLUSIONS: This survey provides insights into allergen exposures in perioperative care, which is important as denominator data for the NAP6 registry.

Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6).

BACKGROUND: Anaphylaxis during anaesthesia is a serious complication for patients and anaesthetists. There is little published information on management and outcomes of perioperative anaphylaxis in the UK. METHODS: The 6th National Audit Project of the Royal College of Anaesthetists (NAP6) collected and reviewed 266 reports of Grade 3-5 anaphylaxis from all UK NHS hospitals over 1 yr. Quality of management was assessed against published guidelines. RESULTS: Appropriately senior anaesthetists resuscitated all patients. Immediate management was 'good' in 46% and 'poor' in 15%. Recognition and treatment of anaphylaxis were prompt in 97% and 83% of cases, respectively. Epinephrine was administered i.v. in 76%, i.m. in 14%, both in 6%, and not at all in 11% of cases. A catecholamine infusion was administered in half of cases. Cardiac arrests (40 cases; 15%) were promptly treated but cardiac compressions were omitted in half of patients with unrecordable BP. The surgical procedure was abandoned in most cases, including 10% where surgery was urgent. Of 54% admitted to critical care, 70% were level 3, with most requiring catecholamine infusions. Ten (3.8%) patents (mostly elderly with cardiovascular disease) died from anaphylaxis. Corticosteroids and antihistamines were generally administered early. We found no clear evidence of harm or benefit from chlorphenamine. Two patients received vasopressin and one glucagon. Fluid administration was inadequate in 19% of cases. Treatment included sugammadex in 19 cases, including one when rocuronium had not been administered. Adverse sequelae (psychological, cognitive, or physical) were reported in one-third of cases. CONCLUSIONS: Management of perioperative anaphylaxis could be improved, especially with respect to administration of epinephrine, cardiac compressions, and i.v. fluid. Sequelae were common.

An observational national study of anaesthetic workload and seniority across the working week and weekend in the UK in 2016: the 6th National Audit Project (NAP6) Activity Survey.

BACKGROUND: UK national anaesthetic activity was studied in 2013 but weekend working was not examined. Understanding changes since 2013 in workload and manpower distribution, including weekends, would be of value in workforce planning. METHODS: We performed an observational survey of NHS hospitals' anaesthetic practice in October 2016 as part of the 6th National Audit Project of the Royal College of Anaesthetists (NAP6). All cases cared for by an anaesthetist during the study period were included. Patient characteristics and details of anaesthetic conduct were collected by local anaesthetists. RESULTS: Responses were received from 342/356 (96%) hospitals. In total, 15 942 cases were reported, equating to an annual anaesthetic workload of ≈3.13 million cases. Approximately 95% (9888/10 452) of elective and 72% (3184/4392) of emergency work was performed on weekdays and 89% (14 145/15 942) of activity was led by senior (consultant or career grade) anaesthetists and 1.1% (180/15942) by those with <2 yr anaesthetic experience. During weekends case urgency increased, the proportion of healthy patients reduced and case mix changed. Cases led by senior anaesthetists fell to 80% (947/1177) on Saturday and 66% (342/791) on Sunday. Senior involvement in obstetric anaesthetic activity was 69% (628/911) during the week and 45% (182/402) at weekends, compared with 93% (791/847) in emergency orthopaedic procedures during the week and 89% (285/321) at weekends. Since 2013, the proportion of obese patients, elective weekend working, and depth of anaesthesia monitoring has increased [12% (1464/12 213) vs 2.8%], but neuromuscular monitoring has not [37% (2032/5532) vs 38% of paralysed cases]. CONCLUSIONS: Senior clinicians deliver most UK anaesthesia care, including at weekends. Our findings are important for any planned workforce reorganisation to rationalise 7-day working.

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.

BACKGROUND: The Royal College of Anaesthetists 6th National Audit Project examined Grade 3-5 perioperative anaphylaxis for 1 year in the UK. OBJECTIVE: To describe the causes and investigation of anaphylaxis in the NAP6 cohort, in relation to published guidance and previous baseline survey results. METHODS: We used a secure registry to gather details of Grade 3-5 perioperative anaphylaxis. Anonymous reports were aggregated for analysis and reviewed in detail. Panel consensus diagnosis, reaction grade, review of investigations and clinic assessment are reported and compared to the prior NAP6 baseline clinic survey. RESULTS: A total of 266 cases met inclusion criteria between November 2015 and 2016, detailing reactions and investigations. One hundred and ninety-two of 266 (72%) had anaphylaxis with a trigger identified, of which 140/192 (75%) met NAP6 criteria for IgE-mediated allergic anaphylaxis, 13% lacking evidence of positive IgE tests were labelled "non-allergic anaphylaxis". 3% were non-IgE-mediated anaphylaxis. Adherence to guidance was similar to the baseline survey for waiting time for clinic assessment. However, lack of testing for chlorhexidine and latex, non-harmonized testing practices and poor coverage of all possible culprits was confirmed. Challenge testing may be underused and many have unacceptably delayed assessments, even in urgent cases. Communication or information provision for patients was insufficient, especially for avoidance advice and communication of test results. Insufficient detail regarding skin test methods was available to draw conclusions regarding techniques. CONCLUSION AND CLINICAL RELEVANCE: Current clinical assessment in the UK is effective but harmonization of approach to testing, access to services and MHRA reporting is needed. Expert anaesthetist involvement should increase to optimize diagnostic yield and advice for future anaesthesia. Dynamic tryptase evaluation improves detection of tryptase release where peak tryptase is <14 µg/L and should be adopted. Standardized clinic reports containing appropriate details of tests, conclusions, avoidance, cross-reactivity and suitable alternatives are required to ensure effective, safe future management options.

UK anaesthetists' perspectives and experiences of severe perioperative anaphylaxis: NAP6 baseline survey.

BACKGROUND: There is limited information on UK anaesthetists' perspectives and experiences of perioperative anaphylaxis. This baseline survey of the Sixth National Audit Project (NAP6) aimed to identify relevant departmental preparedness and practices, and individual experiences, perceptions and drug-avoidance patterns. METHODS: All anaesthetists in 356 UK NHS hospitals were invited to complete an electronic survey. RESULTS: 11 104 anaesthetists (77% crude response rate) from 341 (96%) hospitals responded. Most had immediate access to guidelines for anaphylaxis treatment (87%) and established referral pathways for investigation (82%), but a minority reported access to designated treatment packs (37%) or an anaphylaxis lead (35%). Anaesthetists reported 1734 cases of suspected perioperative anaphylaxis in 2014-5 of which 81% were referred for specialist investigation and 14% reported to the Medicines and Healthcare Products Regulatory Agency (MHRA). In their career, 76% of respondents had seen a case of perioperative anaphylaxis (1:7.25 years of practice) and 4% reported a death (1:311 years of practice), equivalent to 2.3% of events being fatal. Agents most frequently perceived to cause anaphylaxis were antibiotics, particularly penicillins, and neuromuscular blocking agents, notably rocuronium. Suxamethonium and penicillins were avoided by a higher proportion of respondents than events attributed to these drugs whereas the converse was true for atracurium and teicoplanin. CONCLUSIONS: This is the largest ever survey of anaesthetists' practices and experiences relating to perioperative anaphylaxis. It identifies gaps in preparedness and referral for further investigation and to the UK MHRA. It provides important data about drugs implicated in such events and anaesthetists' attitudes to anaphylaxis.

Teicoplanin allergy - an emerging problem in the anaesthetic allergy clinic.

BACKGROUND: Anaphylaxis to teicoplanin appears to be extremely rare, with only one confirmed case report worldwide. Two anaesthetic allergy clinics in the UK have received a number of suspected cases referred for investigation, and we present here the first case series of teicoplanin allergy. METHODS: We investigated 20 cases of suspected teicoplanin allergy, identified from the two clinics over a period of two years. We devised a set of five criteria to categorize the certainty of their diagnosis. These included: (1) reaction within 15 min of administration of teicoplanin, (2) ≥2 features of anaphylaxis present, (3) positive skin testing or challenge testing, (4) raised serum mast cell tryptase (MCT), (5) alternative diagnosis excluded. Based on these criteria we defined the likelihood of IgE-mediated allergy to teicoplanin as: definite-met all criteria; probable-met criteria 1.2 and 5, plus 3 or 4; uncertain-met criteria 1.2 and 5; excluded- any others. RESULTS: We identified 7 'definite', 7 'probable' and 2 'uncertain' cases of teicoplanin allergy. Four cases were excluded. CONCLUSIONS: IgE-mediated anaphylaxis to teicoplanin appears to be more common than previously thought. This is true even if only definitive cases are considered. Investigation of teicoplanin allergy is hampered by the lack of standardized skin test concentrations. In some cases, there was a severe clinical reaction, but without any skin test evidence of histamine release. The mechanism of reaction in these cases is not known and requires further study.

Efficacy, safety and pharmacokinetics of sugammadex 4 mg kg-1 for reversal of deep neuromuscular blockade in patients with severe renal impairment.

BACKGROUND: This study evaluated efficacy and safety of sugammadex 4 mg kg(-1) for deep neuromuscular blockade (NMB) reversal in patients with severe renal impairment (creatinine clearance [CLCR] <30 ml min(-1)) vs those with normal renal function (CLCR ≥80 ml min(-1)). METHODS: Sugammadex 4 mg kg(-1) was administered at 1-2 post-tetanic counts for reversal of rocuronium NMB. Primary efficacy variable was time from sugammadex to recovery to train-of-four (T4/T1) ratio 0.9. Equivalence between groups was demonstrated if two-sided 95% CI for difference in recovery times was within -1 to +1 min interval. Pharmacokinetics of rocuronium and overall safety were assessed. RESULTS: The intent-to-treat group comprised 67 patients (renal n=35; control n=32). Median (95% CI) time from sugammadex to recovery to T4/T1 ratio 0.9 was 3.1 (2.4-4.6) and 1.9 (1.6-2.8) min for renal patients vs controls. Estimated median (95% CI) difference between groups was 1.3 (0.6-2.4) min; thus equivalence bounds were not met. One control patient experienced acceleromyography-determined NMB recurrence, possibly as a result of premature sugammadex (4 mg kg(-1)) administration, with no clinical evidence of NMB recurrence observed. Rocuronium, encapsulated by Sugammadex, was detectable in plasma at day 7 in 6 patients. Bioanalytical data for sugammadex were collected but could not be used for pharmacokinetics. CONCLUSIONS: Sugammadex 4 mg kg(-1) provided rapid reversal of deep rocuronium-induced NMB in renal and control patients. However, considering the prolonged sugammadex-rocuronium complex exposure in patients with severe renal impairment, current safety experience is insufficient to support recommended use of sugammadex in this population. CLINICAL TRIAL REGISTRATION: NCT00702715.

National pholcodine consumption and prevalence of IgE-sensitization: a multicentre study.

BACKGROUND: The aim of this study was to test, on a multinational level, the pholcodine (PHO) hypothesis, i.e. that the consumption of PHO-containing cough mixtures could cause higher prevalence of IgE antibodies to PHO, morphine (MOR) and suxamethonium (SUX). As a consequence the risk of anaphylaxis to neuromuscular blocking agents (NMBA) will be increased. METHODS: National PHO consumptions were derived from the United Nations International Narcotics Control Board (INCB) database. IgE and IgE antibodies to PHO, MOR, SUX and P-aminophenyl-phosphoryl choline (PAPPC) were measured in sera from atopic individuals, defined by a positive Phadiatop test (>0.35 kU(A)/l), collected in nine countries representing high and low PHO-consuming nations. RESULTS: There was a significant positive association between PHO consumption and prevalences of IgE-sensitization to PHO and MOR, but not to SUX and PAPPC, as calculated both by exposure group comparisons and linear regression analysis. The Netherlands and the USA, did not have PHO-containing drugs on the markets, although the former had a considerable PHO consumption. Both countries had high figures of IgE-sensitization. CONCLUSION: This international prevalence study lends additional support to the PHO hypothesis and, consequently, that continued use of drugs containing this substance should be seriously questioned. The results also indicate that other, yet unknown, substances may lead to IgE-sensitization towards NMBAs.

The effect of anaesthetic agents on induction, recovery and patient preferences in adult day case surgery: a 7-day follow-up randomized controlled trial.

BACKGROUND AND OBJECTIVE: To compare induction, pre- and post-discharge recovery characteristics and patient preferences between four anaesthetic regimens in adult day-surgery. METHODS: Randomized controlled trial. In all, 1158 adults assigned to: propofol induction and maintenance, propofol induction with isoflurane/N2O, or sevoflurane/N2O maintenance, or sevoflurane/N2O alone. We prospectively recorded induction and pre-discharge recovery characteristics, collected 7-day post-discharge recovery characteristics using patient diaries and patient preferences by telephone follow-up. RESULTS: Recruitment rate was 73%--of the 425 refusals, 226 were not willing to risk a volatile induction. During induction, excitatory movements and breath holding were more common with sevoflurane only (P < 0.01). Injection pain and hiccup were more common with propofol induction (P < 0.01). In the recovery room and the postoperative ward, both nausea and vomiting were more common with sevoflurane only (P < 0.01). This difference disappeared within 48 h. There was no difference between groups in the mental state on awakening, recovery time, time to discharge or overnight admissions; then was also no difference in pain between the four groups for each of the seven postoperative days (P < 0.01), nor any differences in concentration or forgetfulness. Patients took 6.5 days (95% CI: 6.0-7.0, n = 693) to resume normal activities. Patients who received sevoflurane only were more likely to recall an unpleasant induction and least likely to want the same induction method again (P < 0.01). CONCLUSION: Differences in outcome between the four regimens are transient; sevoflurane is not an ideal sole agent for adult day case anaesthesia and, in this setting, patients base their preferences for future anaesthetics on the method of induction.

Clinical and economic choices in anaesthesia for day surgery: a prospective randomised controlled trial.

We compared the cost-effectiveness of general anaesthetic agents in adult and paediatric day surgery populations. We randomly assigned 1063 adult and 322 paediatric elective patients to one of four (adult) or two (paediatric) anaesthesia groups. Total costs were calculated from individual patient resource use to 7 days post discharge. Incremental cost-effectiveness ratios were expressed as cost per episode of postoperative nausea and vomiting (PONV) avoided. In adults, variable secondary care costs were higher for propofol induction and propofol maintenance (propofol/propofol; p < 0.01) than other groups and lower in propofol induction and isoflurane maintenance (propofol/isoflurane; p < 0.01). In both studies, predischarge PONV was higher if sevoflurane/sevoflurane (p < 0.01) was used compared with use of propofol for induction. In both studies, there was no difference in postdischarge outcomes at Day 7. Sevoflurane/sevoflurane was more costly with higher PONV rates in both studies. In adults, the cost per extra episode of PONV avoided was pound 296 (propofol/propofol vs. propofol/ sevoflurane) and pound 333 (propofol/sevoflurane vs. propofol/isoflurane).

The effect of neuromuscular blockade on oxygen supply, consumption, and total chest compliance in patients with high oxygen requirements undergoing mechanical ventilation.

We investigated the effects of neuromuscular blockade with atracurium on oxygen consumption, oxygen delivery and total chest compliance in 20 sedated intensive care patients who required mechanical ventilation with an inspired oxygen fraction of at least 0.6. The reverse Fick method was used to measure oxygen consumption. Total chest compliance was measured from the ventilator pneumotachograph and pressure transducer. Measurements were made before neuromuscular blockade, at a standard level of neuromuscular blockade, and after demonstrated recovery of neuromuscular function. There was no statistical difference in any of the parameters measured. However there were large changes in oxygen consumption (range -35% to +17%) and total chest compliance (range -19.7% to +9.7%) in individuals. We conclude that in the setting of critical oxygenation, neuromuscular blockade cannot be assumed to reduce oxygen requirements or improve total lung compliance. If, however, neuromuscular blockade is selected as an adjunct to therapy, we recommend that the indices of oxygenation are calculated.