H. Kemp

Reliability of Conditioned Pain Modulation: a Systematic Review

Abstract A systematic literature review was undertaken to determine if conditioned pain modulation (CPM) is reliable. Longitudinal, English language observational studies of the repeatability of a CPM test paradigm in adult humans were included. Two independent reviewers assessed the risk of bias in 6 domains; study participation; study attrition; prognostic factor measurement; outcome measurement; confounding and analysis using the Quality in Prognosis Studies (QUIPS) critical assessment tool. Intraclass correlation coefficients (ICCs) less than 0.4 were considered to be poor; 0.4 and 0.59 to be fair; 0.6 and 0.75 good and greater than 0.75 excellent. Ten studies were included in the final review. Meta-analysis was not appropriate because of differences between studies. The intersession reliability of the CPM effect was investigated in 8 studies and reported as good (ICC = 0.6-0.75) in 3 studies and excellent (ICC > 0.75) in subgroups in 2 of those 3. The assessment of risk of bias demonstrated that reporting is not comprehensive for the description of sample demographics, recruitment strategy, and study attrition. The absence of blinding, a lack of control for confounding factors, and lack of standardisation in statistical analysis are common. Conditioned pain modulation is a reliable measure; however, the degree of reliability is heavily dependent on stimulation parameters and study methodology and this warrants consideration for investigators. The validation of CPM as a robust prognostic factor in experimental and clinical pain studies may be facilitated by improvements in the reporting of CPM reliability studies.

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: 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.

Use of Corneal Confocal Microscopy to Evaluate Small Nerve Fibers in Patients With Human Immunodeficiency Virus

Importance Objective quantification of small fiber neuropathy in patients with human immunodeficiency virus (HIV)–associated sensory neuropathy (HIV-SN) is difficult but needed for diagnosis and monitoring. In vivo corneal confocal microscopy (IVCCM) can quantify small fiber damage. Objective To establish whether IVCCM can identify an abnormality in corneal nerve fibers and Langerhans cells in patients with and without HIV-SN. Design, Setting, and Participants This prospective, cross-sectional cohort study was conducted between July 24, 2015, and September 17, 2015. Twenty patients who were HIV positive were recruited from adult outpatient clinics at Chelsea and Westminster Hospital NHS Foundation Trust in England. These patients underwent IVCCM at Moorfields Eye Hospital NHS Foundation Trust in London, England, and the IVCCM images were analyzed at Weill Cornell Medicine–Qatar in Ar-Rayyan, Qatar. Patients were given a structured clinical examination and completed validated symptom questionnaires and the Clinical HIV-Associated Neuropathy Tool. Results from patients with HIV were compared with the results of the age- and sex-matched healthy control participants (n = 20). All participants were classified into 3 groups: controls, patients with HIV but without SN, and patients with HIV-SN. Main Outcomes and Measures Comparison of corneal nerve fiber density, corneal nerve branch density, corneal nerve fiber length, corneal nerve fiber tortuosity, and corneal Langerhans cell density between healthy controls and patients with HIV with and without SN. Results All 40 participants were male, and most (≥70%) self-identified as white. Of the 20 patients with HIV, 14 (70%) had HIV-SN. This group was older (mean [SD] age, 57.7 [7.75] years) than the group without HIV-SN (mean [SD] age, 42.3 [7.26] years) and the controls (mean [SD] age, 53.8 [10.5] years). Corneal nerve fiber density was reduced in patients with HIV compared with the controls (26.7/mm2 vs 38.6/mm2; median difference, −10.37; 95.09% CI, −14.27 to −6.25; P < .001) and in patients with HIV-SN compared with those without (25.8/mm2 vs 30.7/mm2; median difference, −4.53; 95.92% CI, −8.85 to −0.26; P = .03). Corneal nerve branch density and corneal nerve fiber length were reduced in patients with HIV, but no differences were identified between those with neuropathy and without neuropathy (corneal nerve branch density: 95.83/mm2 for the controls vs 72.37/mm2 for patients with HIV; median difference, −24.53; 95.32% CI, −50.62 to −3.13; P = .01; and corneal nerve fiber length: 28.4 mm/mm2 for the controls vs 21.9 mm/mm2 for patients with HIV; median difference, −5.24; 95.09% CI, −8.83 to −1.38; P = .001). Tortuosity coefficient was increased in patients with HIV compared with controls (16.44 vs 13.95; median difference, 2.34; 95.09% CI, 0.31 to 4.65; P = .03) and in those with HIV-SN compared with those without (17.84 vs 14.18; median difference, 4.32; 95.92% CI, 0.68-9.23; P = .01). No differences were identified in corneal Langerhans cell density (19.84 cells/mm2 for the controls vs 41.43 cells/mm2 for patients with HIV; median difference, 9.38; 95% CI, −12.51 to 26.34; P = .53). Conclusions and Relevance In vivo corneal confocal microscopy could be used in the assessment of HIV-SN, but larger studies are required to confirm this finding.

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.

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.

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

The Royal College of Anaesthetists 6th National Audit Project examined Grade 3‐5 perioperative anaphylaxis for 1 year in the UK.

Pain Assessment in INTensive care (PAINT): an observational study of physician-documented pain assessment in 45 intensive care units in the United Kingdom.

Pain is a common and distressing symptom experienced by intensive care patients. Assessing pain in this environment is challenging, and published guidelines have been inconsistently implemented. The Pain Assessment in INTensive care (PAINT) study aimed to evaluate the frequency and type of physician pain assessments with respect to published guidelines. This observational service evaluation considered all pain and analgesia‐related entries in patients’ records over a 24‐h period, in 45 adult intensive care units (ICUs) in London and the South‐East of England. Data were collected from 750 patients, reflecting the practice of 362 physicians. Nearly two‐thirds of patients (n = 475, 64.5%, 95%CI 60.9–67.8%) received no physician‐documented pain assessment during the 24‐h study period. Just under one‐third (n = 215, 28.6%, 95%CI 25.5–32.0%) received no nursing‐documented pain assessment, and over one‐fifth (n = 159, 21.2%, 95%CI 19.2–23.4)% received neither a doctor nor a nursing pain assessment. Two of the 45 ICUs used validated behavioural pain assessment tools. The likelihood of receiving a physician pain assessment was affected by the following factors: the number of nursing assessments performed; whether the patient was admitted as a surgical patient; the presence of tracheal tube or tracheostomy; and the length of stay in ICU. Physician‐documented pain assessments in the majority of participating ICUs were infrequent and did not utilise recommended behavioural pain assessment tools. Further research to identify factors influencing physician pain assessment behaviour in ICU, such as human factors or cultural attitudes, is urgently needed.

Sensory Profiling in Animal Models of Neuropathic Pain: A Call for Back-Translation

This Topical Review considers the misalignment between outcome measures traditionally reported in animal models of neuropathic pain* and those employed for estimating pain intensity and the impact/burden of pain in clinical trials. In particular, we propose that traditional methods of assessing rodent sensory thresholds could have predictive utility for the sensory profiling approaches being explored for patient stratification in clinical trials. To initiate this process we propose a “research agenda” to develop and validate a protocol and normative values for sensory profiling in rodents which reflects the best established clinical methods. This could then be used to establish definitive sensory profiles of new and existing rodent neuropathic pain models. In general, animal modelling of neuropathic pain has two main goals: Firstly, to identify pain mechanisms and thus potential targets for drug development. However, it is difficult to identify clear examples of the success of this approach in delivering new drugs for neuropathic pain, with the exception of high concentration topical capsaicin[20]. Secondly, animal models are used in an attempt to predict the clinical efficacy of a novel therapeutic and thus justify the initiation of clinical trials. We concentrate on the latter aspect and ask whether the drug response associated with specific sensory profiles in animal models might predict the most appropriate patients to examine in exploratory clinical trials?