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.

Specialist perioperative allergy clinic services in the UK 2016: Results from the Royal College of Anaesthetists Sixth National Audit Project.

BACKGROUND: Guidelines for investigation of perioperative drug allergy exist, but the quality of services is unknown. Specialist perioperative anaphylaxis services were surveyed through the Royal College of Anaesthetists 6th National Audit Project. OBJECTIVES: We compare self-declared UK practice in specialist perioperative allergy services with national recommendations. METHODS: A SurveyMonkey™ questionnaire was distributed to providers of allergy services in the UK. Responses were assessed for adherence to the best practice recommendations of the British Society for Allergy and Clinical Immunology (BSACI), the Association of Anaesthetists of Great Britain and Ireland and the National Institute for Health and Care Excellence (NICE) Guidance on Drug Allergy-CG183. RESULTS: Over 1200 patients were evaluated in 44 centres annually. Variation in workload, waiting times, access, staffing and diagnostic approach was noted. Paediatric centres had the longest routine waiting times (most wait >13 weeks) in contrast to adult centres (most wait <12 weeks). Service leads are allergists/immunologists (91%) or anaesthetists (7%). Potentially important differences were seen in: testing repertoire [10/44 (23%) lacked BSACI compliant neuromuscular blocking agent (NMBA) panels and 17/44 (39%) lacked a NAP6-defined extended panel; many failed to screen all cases for chlorhexidine 19/44 (43%) or latex 21/44 (48%)], staffing [only 26/44 (59%) had specialist nurses and 18/44 (41%) an anaesthetist] and provision of information [18/44 (41%) gave immediate information in clinic and 5/44 (11%) sign-posted support groups]. Most centres were able to provide diagnostic challenges to antibiotics [40/44 (91%]) and local anaesthetics [41/44 (93%)]. CONCLUSIONS AND CLINICAL RELEVANCE: Diagnostic testing is not harmonized, with marked variability in the NMBA panels used to identify safe alternatives. Chlorhexidine and latex are not part of routine testing in many centres. Poor access to services and patient information provision require attention. Harmonization of diagnostic approach is desirable, particularly with regard to a minimum NMBA panel for identification of safe alternatives.

Anaesthesia-associated hypersensitivity reactions: seven years' data from a British bi-specialty clinic.

Our bi-specialty clinic was established to systematically investigate patients with suspected peri-operative hypersensitivity reactions. Four hundred and ten patients were studied; 316 following an intra-operative reaction ('postoperative' group) and 94 with a previous history of reaction, referred before undergoing anaesthesia ('pre-operative' group). In the postoperative group, 173 (54.7%) were diagnosed with IgE-mediated reactions: 65 (37.6%) to neuromuscular blocking drugs; 54 (31.2%) antibiotics; 15 (8.7%) chlorhexidine and 12 (6.9%) patent blue dye. Reactions were severe in 114 patients (65.9%). All reactions to patent blue dye were severe. We identified IgE sensitisation in 22 (13.2%) cases with isolated mucocutaneous reactions. Only 173 (54.7%) patients had serum tryptase samples taken. Referrers' suspected causal agent was confirmed in only 37.2% of patients. Of 94 patients reviewed 'pre-operatively', 29 (30.8%) were diagnosed with IgE-mediated hypersensitivity reactions, reinforcing the importance of investigating this group of patients. Knowledge of the range of causative agents identified in our study should guide the investigation of suspected peri-operative hypersensitivity reactions.

Leisure time physical activity before and during mid-pregnancy and offspring adiposity in mid-childhood.

BACKGROUND: Effects of maternal leisure time physical activity (LTPA) on paediatric obesity are unknown. The objective of this study was to examine associations of maternal LTPA with offspring overall and central adiposity in mid-childhood. METHODS: We analysed data from 802 mother-child dyads from Project Viva, a prospective pre-birth cohort study. Women reported average weekly LTPA before and during mid-pregnancy. At age 7-10 years, we measured fat, truncal fat and lean mass with dual-energy X-ray absorptiometry. Using multivariable linear regression, we examined associations of maternal LTPA with offspring adiposity, adjusting for child age and sex, maternal race/ethnicity, education, age, pre-pregnancy body mass index, marital status and smoking status. RESULTS: Mean (standard deviation) of LTPA before and during mid-pregnancy were 9.5 (8.1) and 7.1 (7.0) h week(-1) . At mean age 7.8 (0.8) years, childhood fat, truncal fat and lean mass indices were 4.3 (1.8), 1.4 (0.8) and 12.9 (1.4) kg m(-2) . We did not find that higher maternal LTPA was associated with lower child adiposity outcomes. For example, compared with 0-3 h week(-1) of LTPA during mid-pregnancy, children of mothers with +8 h week(-1) had fat mass index 0.07 kg m(-2) (95% confidence interval: -0.22, 0.36). In analyses of within-person LTPA change from before to mid-pregnancy, compared with +2 h week(-1) decrease in LTPA, increased LTPA (2 ± h week(-1) ) was associated with a 0.09 kg m(-2) fat mass index (-0.25, 0.43). CONCLUSIONS: Contrary to our hypothesis, higher LTPA before and during mid-pregnancy, and the change between them, were not associated with lower adiposity in mid-childhood.

Ophthalmic patients on antithrombotic drugs: a review and guide to perioperative management.

The changing profile of patients undergoing ophthalmic surgery, with an increase in prevalence of antiplatelet and anticoagulant drug use, predisposes to bleeding complications. This mandates an awareness of these agents, allowing optimal patient management. We review traditional and newer agents in the context of cataract, vitreoretinal, glaucoma and oculoplastic surgery. Recommendations are given for continuation, cessation and re-commencement of these agents in order to minimise the risk of bleeding and thrombotic/thromboembolic complications.

Impact of a walking intervention during pregnancy on post-partum weight retention and infant anthropometric outcomes.

Few studies have investigated the impact of lifestyle interventions during pregnancy on post-partum weight retention and infant growth. Thirty seven previously non-exercising, overweight or obese pregnant women were randomly assigned to a walking intervention or non-intervention control. For the follow-up study, weight of the mother and weight, length and body composition of the infant were collected at 1 month post-partum (n=37) and 6 months post-partum (n=33). Analysis of variance and linear regression were conducted to determine the differences and association in maternal post-partum weight retention and child outcomes. At 6 months post-partum, weight retention of obese women in the intervention group (Int-OB) was -0.10±8.11 kg; while, obese women in the control group (Con-OB) was 6.35±7.47 kg. A significantly higher percentage of Con-OB women retained more than 5 kg at 6 months post-partum (P=0.046). Even though statistically non-significant between the groups, the growth trend observed among offspring of obese women in the control group was consistently higher than the offspring of obese women in the intervention group from birth to 6-months. Third trimester gestational weight gain rate significantly predicted 6-m weight-for-length z-score after controlling for birth weight, treatment group and pre-pregnancy body mass index (r 2=0.31, ß=1.75, P=0.03). The reduced post-partum weight retention observed among the obese women in the intervention group may be explained in part by the lifestyle modification during pregnancy.

MTSS1, a novel target of DNA methyltransferase 3B, functions as a tumor suppressor in hepatocellular carcinoma.

DNA methyltransferase 3B (DNMT3B) mediates gene silencing via epigenetic mechanisms during hepatocellular carcinoma (HCC) progression. We aimed to identify novel targets of DNMT3B and their potential regulatory mechanisms in HCC. Metastasis suppressor 1 (MTSS1) was one of the DNMT3B targets and selected for further study. DNMT3B overexpression was detected in 81.25% of clinical HCC specimens and was negatively associated with MTSS1 in HCC cells and clinical samples. The underlying mechanism by which DNMT3B silences MTSS1 was studied using a combination of methylation-specific polymerase chain reaction (PCR) and bisulfite genome sequencing, chromatin immunoprecipitation-PCR and luciferase reporter assays. We found that the MTSS1 promoter region was sparsely methylated, and the methylation inhibitors failed to abolish DNMT3B-mediated MTSS1 silencing. DNMT3B protein bound directly to the 5'-flanking region (-865/-645) of the MTSS1 gene to inhibit its transcription. The functional role of MTSS1 was investigated using in vitro and in vivo tumorigenicity assays. As a result, MTSS1 exerted tumor suppressor effects and arrested cells in the G2/M phase, but not the G1/S phase of the cell cycle when it was depleted or overexpressed in HCC cells. Taken together, MTSS1, a novel target of DNMT3B, is repressed by DNMT3B via a DNA methylation-independent mechanism. MTSS1 was further characterized as a novel tumor suppressor gene in HCC. These findings highlight how DNMT3B regulates MTSS1, and such data may be useful for the development of new treatment options for HCC.

Accuracy of ten isoflurane vaporisers in current clinical use.

There is a lack of independent data regarding the accuracy of isoflurane vaporisers in current clinical use. We studied the accuracy of 10 isoflurane vaporisers (six Penlon Sigma Delta, four Datex-Ohmeda Isotec 5) taken from our operating theatres and anaesthetic rooms. Isoflurane output was measured at a range of fresh gas flow rates using both 100% oxygen and a 1:2 oxygen:nitrous oxide mixture as carrier gas. Within a clinical range of fresh gas flow rates (1-6 l.min(-1)) the worst relative output deviation of each vaporiser was at least ±20%, with under-delivery of isoflurane being commoner than over-delivery. Relative output deviation ranged from -62% to +21%, which could lead to a risk of awareness or overdose. Despite the existence of an in-house calibration schedule, the vaporisers we found in current clinical use under- or occasionally over-delivered isoflurane to a dangerous and unpredictable extent.

Fibrinolysis during anaphylaxis, and its spontaneous resolution, as demonstrated by thromboelastography.

A large and ever-growing number of agents used in anaesthesia can precipitate acute anaphylactic reactions after their administration. Anaphylaxis is a sudden onset (or rapidly progressive), severe systemic allergic reaction, affecting multiple organ systems. The number of people who suffer severe systemic allergic reactions is increasing. The incidence is about 1-3 reactions per 10 000 population per annum, although anaphylaxis is not always recognized; therefore, certain UK studies may underestimate the incidence. In this case report, we present an episode of acute fibrinolysis associated with life-threatening anaphylaxis, demonstrated by thromboelastography (TEG) and resolving spontaneously. This is despite an added fibrinolytic insult in the form of cardiopulmonary bypass. There is a paucity of literature detailing fibrinolysis occurring during anaphylaxis, most likely due to the limited availability of TEG in the acute setting and the primary clinical focus of delivering life-saving interventions.

Magnitude and time course of impaired primary haemostasis after stopping chronic low and medium dose aspirin in healthy volunteers.

Aspirin ingestion within the previous 7-10 days is often considered a relative contraindication to performing invasive procedures. However, aspirin is an important component of many patients' treatment and withholding therapy for this time may be dangerous. To measure both the magnitude of the impairment in primary haemostasis induced by aspirin and how much recovery of platelet function occurs within 48 h of stopping aspirin, we studied serial changes in bleeding time (BT) in a randomized, double-blind, placebo-controlled study. Fifty-two healthy volunteers had BT performed before and at 2, 9, 24 and 48 h after a 7-day course of either aspirin 75 mg, 300 mg or placebo. The main outcome recorded was BT at each time. Nearly 25% of subjects had extended BT to more than 10 min, but no BT were greater than 10 min, 48 h after stopping aspirin. There was a small but statistically significant (P < 0.01) difference between the 48-h and baseline BT in both aspirin groups (49 and 64 s in the 75 mg and 300 mg groups, respectively). There was no difference in the magnitude or time course of effect between low and medium dose aspirin (P = 0.392 and P = 0.797, respectively). We conclude that despite considerable inter-individual variability in the magnitude of aspirin effect on primary haemostasis, the time course of effect was consistent. In healthy volunteers, the defect in primary haemostasis had largely disappeared 48 h after the last dose.

Demand on primary health care after day surgery.

We have audited the frequency and nature of demands made on general practitioners, and the rate of surgical and anaesthetic complications within the first 7 days after day surgery. Semi-structured questionnaires were posted to the general practitioners of patients who attended the hospital's day care ward for a surgical procedure over a 6 month period. In all, 1798 questionnaires were sent, of which 1533 (85.3%) were returned. A total of 247 (16.7%) patients consulted their general practitioners after day surgery, the principal reason being pain (113 patients). Patients who underwent incisional intermediate surgery had the highest rate (31.5%) of general practitioner consultations. This audit has quantified the workload which day surgery places upon general practitioners. It also demonstrates the importance of categorising the various procedures performed on a day case basis when examining patient outcome. Patients who underwent non-incisional minor surgery consulted their general practitioner less often than those who underwent incisional minor surgery, who in turn consulted their practitioner less often than those who underwent incisional intermediate surgery. It seems likely that an increase in workload for general practitioners is inevitable if more complex procedures are performed on a day case basis.