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Year of Publication
1.  Demystifying propensity scores 
doi:10.1093/bja/aet290
PMCID: PMC3854550  PMID: 24318697
2.  Clinical decision-making augmented by simulation training: neural correlates demonstrated by functional imaging: a pilot study 
BJA: British Journal of Anaesthesia  2013;112(1):124-132.
Background
Investigation of the neuroanatomical basis of clinical decision-making, and whether this differs when students are trained via online training or simulation training, could provide valuable insight into the means by which simulation training might be beneficial.
Methods
The aim of this pilot prospective parallel group cohort study was to investigate the neural correlates of clinical decision-making, and to determine if simulation as opposed to online training influences these neural correlates. Twelve third-year medical students were randomized into two groups and received simulation-based or online-based training on anaphylaxis. This was followed by functional magnetic resonance imaging scanning to detect brain activation patterns while answering multiple choice questions (MCQs) related to anaphylaxis, and unrelated non-clinical (control) questions. Performance in the MCQs, salivary cortisol levels, heart rate, and arterial pressure were also measured.
Results
Comparing neural responses to clinical and non-clinical questions (in all participants), significant areas of activation were seen in the ventral anterior cingulate cortex and medial prefrontal cortex. These areas were activated in the online group when answering action-based questions related to their training, but not in the simulation group. The simulation group tended to react more quickly and accurately to clinical MCQs than the online group, but statistical significance was not reached.
Conclusions
The activation areas seen could indicate increased stress when answering clinical questions compared with general non-clinical questions, and in the online group when answering action-based clinical questions. These findings suggest simulation training attenuates neural responses related to stress when making clinical decisions.
doi:10.1093/bja/aet326
PMCID: PMC3854551  PMID: 24065729
computer simulation; magnetic resonance imaging, functional; stress, psychological
3.  Morphine stimulates platelet-derived growth factor receptor-β signalling in mesangial cells in vitro and transgenic sickle mouse kidney in vivo 
BJA: British Journal of Anaesthesia  2013;111(6):1004-1012.
Background
Pain and renal dysfunction occur in sickle cell disease. Morphine used to treat pain also co-activates platelet-derived growth factor receptor-β (PDGFR-β), which can adversely affect renal disease. We examined the influence of morphine in mesangial cells in vitro and in mouse kidneys in vivo.
Methods
Mouse mesangial cells treated with 1 μM morphine in vitro or kidneys of transgenic homozygous or hemizygous sickle or control mice (n=3 for each), treated with morphine (0.75, 1.4, 2.14, 2.8, 3.6, and 4.3 mg kg−1 day−1 in two divided doses during the first, second, third, fourth, fifth, and sixth weeks, respectively), were used. Western blotting, bromylated deoxy uridine incorporation-based cell proliferation assay, reverse transcriptase-polymerase chain reaction, immunofluorescent microscopy, and blood/urine chemistry were used to analyse signalling, cell proliferation, opioid receptor (OP) expression, and renal function.
Results
Morphine stimulated phosphorylation of PDGFR-β and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) to the same extent as induced by platelet-derived growth factor-BB (PDGF-BB) and promoted a two-fold increase in mesangial cell proliferation. The PDGFR-β inhibitor, AG1296, OP antagonists, and silencing of μ- and κ-OP abrogated morphine-induced MAPK/ERK phosphorylation and proliferation by ∼100%. Morphine treatment of transgenic mice resulted in phosphorylation of PDGFR-β, MAPK/ERK, and signal transducer and activator of transcription 3 (Stat3) in the kidneys. Morphine inhibited micturition and blood urea nitrogen (BUN) clearance and increased BUN and urinary protein in sickle mice.
Conclusion
Morphine stimulates mitogenic signalling leading to mesangial cell proliferation and promotes renal dysfunction in sickle mice.
doi:10.1093/bja/aet221
PMCID: PMC3828056  PMID: 23820675
morphine; nephropathy; pain; platelet-derived growth factor; sickle cell disease
4.  Regional anaesthesia to prevent chronic pain after surgery: a Cochrane systematic review and meta-analysis† 
BJA: British Journal of Anaesthesia  2013;111(5):711-720.
Background
Regional anaesthesia may reduce the risk of persistent (chronic) pain after surgery, a frequent and debilitating condition. We compared regional anaesthesia vs conventional analgesia for the prevention of persistent postoperative pain (PPP).
Methods
We searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and CINAHL from their inception to May 2012, limiting the results to randomized, controlled, clinical trials (RCTs), supplemented by a hand search in conference proceedings. We included RCTs comparing regional vs conventional analgesia with a pain outcome at 6 or 12 months. The two authors independently assessed methodological quality and extracted data. We report odds ratios (ORs) with 95% confidence intervals (CIs) as our summary statistic based on random-effects models. We grouped studies according to surgical interventions.
Results
We identified 23 RCTs. We pooled data from 250 participants in three trials after thoracotomy with outcomes at 6 months. Data favoured epidural anaesthesia for the prevention of PPP with an OR of 0.33 (95% CI 0.20–0.56). We pooled two studies investigating paravertebral block for breast cancer surgery; pooled data of 89 participants with outcomes ∼6 months favoured paravertebral block with an OR of 0.37 (95% CI 0.14–0.94). Adverse effects were reported sparsely.
Conclusions
Epidural anaesthesia and paravertebral block, respectively, may prevent PPP after thoracotomy and breast cancer surgery in about one out of every four to five patients treated. Small numbers, performance bias, attrition, and incomplete outcome data especially at 12 months weaken our conclusions.
doi:10.1093/bja/aet213
PMCID: PMC3793661  PMID: 23811426
chronic pain; meta-analysis; prevention; regional anaesthesia; systematic review
5.  Evaluation of two delirium screening tools for detecting post-operative delirium in the elderly 
BJA: British Journal of Anaesthesia  2013;111(4):612-618.
Background
Postoperative delirium in the elderly is common and associated with poor outcomes, but often goes unrecognized. Delirium screening tools, validated in postoperative settings are lacking. This study compares two screening tools [Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and Nursing Delirium Symptom Checklist (NuDESC)] with a DSM-IV-based diagnosis of delirium, conducted by neuropsychiatric examination in postoperative settings.
Methods
Consecutive English-speaking patients, ≥70 yr, undergoing surgery with general anaesthesia and capable of providing informed consent, were recruited. Diagnostic test characteristics were compared for each screening tool vs neuropsychiatric examination, both in the Post-Anaesthesia Care Unit (PACU), and daily during inpatient hospitalization, adjusting for repeated measures.
Results
Neuropsychiatric examination identified delirium in 45% of 91 patients evaluated in the PACU and in 32% of 166 subsequent delirium assessments on the ward in the 58 admitted patients. The sensitivity [95% confidence interval (CI)] of delirium detection of the CAM-ICU in the PACU, and in all repeated assessments was 28% (16–45%) and 28% (17–42%), respectively; for the NuDESC (scoring threshold ≥2), 32% (19–48%) and 29% (19–42%), respectively, and the NuDESC (threshold ≥1), 80% (65–91%) and 72% (60–82%), respectively. Specificity was >90% for both the CAM-ICU and the NuDESC (threshold ≥2); specificity for the NuDESC (threshold ≥1), in the PACU was 69% (54–80%) and 80% (73–85%) for all assessments.
Conclusions
While highly specific, neither CAM-ICU nor NuDESC (threshold ≥2) are adequately sensitive to identify delirium post-operatively; NuDESC (threshold ≥1) increases sensitivity, but reduces specificity.
doi:10.1093/bja/aet167
PMCID: PMC3770063  PMID: 23657522
aged; delirium; neuropsychological tests; perioperative period; sensitivity and specificity
6.  Preoperative risk factors in 10 418 patients with prior myocardial infarction and 5241 patients with prior unstable angina undergoing elective coronary artery bypass graft surgery 
BJA: British Journal of Anaesthesia  2013;111(3):417-423.
Background
The EuroSCORE associates coronary artery bypass graft (CABG) surgery with higher perioperative risk in the first 3 months after a myocardial infarction (MI). The optimal scheduling of CABG surgery after unstable angina (UA) is unknown. We investigated the preoperative predictors of adverse outcomes in patients undergoing CABG with prior MI or UA and investigated the importance of time interval between the cardiac event and CABG.
Methods
The Hospital Episode Statistics database (April 2006–March 2010) was analysed for elective admissions for CABG. Independent preoperative patient factors influencing length of stay, readmission rates, and mortality, were identified by logistic regression and presented as adjusted odds ratios (ORs).
Results
A total of 10 418 patients with prior MI (mortality 1.8%) and 5241 patients with prior UA (mortality 2.2%) were included in the respective cohorts. Multiple risk factors were identified in each population including liver disease and renal failure. The time interval from cardiac event (MI or UA) to elective CABG surgery did not influence perioperative outcomes when analysed as a continuous measure or using the arbitrary 3-month threshold [MI, OR 1.1 (0.78–1.57) and UA, OR 0.65 (0.39–1.09)].
Conclusions
Our hypothesis generating data suggest that the increased risk currently allocated in the EuroSCORE for an interval of 3 months between MI and CABG should be critically re-evaluated. Furthermore, prior MI should not be discounted as a risk factor if it is more than 3 months old.
doi:10.1093/bja/aet107
PMCID: PMC3743515  PMID: 23592695
cardiac anaesthesia; cardiovascular anaesthesia; heart, ischaemia
7.  Oral choline supplementation for postoperative pain 
BJA: British Journal of Anaesthesia  2013;111(2):249-255.
Background
Activation of nicotinic receptors with nicotine has been shown to reduce post-surgical pain in clinical and preclinical studies. Choline is a selective agonist at α7-type nicotinic receptors that does not have addictive or sympathetic activating properties. It is anti-nociceptive in animal studies. We conducted a double-blind randomized trial of oral choline supplementation with lecithin to aid in the treatment of pain after gynaecological surgery.
Methods
Sixty women having open gynaecological surgery were randomly assigned to receive 20 g of lecithin before surgery or placebo. Plasma choline concentration and tumour necrosis factor (TNF) were measured. Pain report was the primary outcome measure.
Results
We achieved a small but statistically significant increase in choline after surgery with oral supplementation. Plasma TNF was not decreased and pain report was not different between groups at rest or with movement. There were no adverse effects of treatment.
Conclusions
Oral supplementation with lecithin during the perioperative period resulted in very slow absorption and thus only a small increase in plasma choline was achieved. This concentration was inadequate to reduce TNF as has been shown in other studies. The absence of an anti-inflammatory effect was likely related to our failure to demonstrate efficacy in pain reduction.
doi:10.1093/bja/aet031
PMCID: PMC3841409  PMID: 23568851
analgesia; anti-inflammatory agents; nutritional requirements; pain; pain measurement
8.  Anticipation of the difficult airway: preoperative airway assessment, an educational and quality improvement tool 
BJA: British Journal of Anaesthesia  2013;111(2):276-285.
Background
Assessment of the potentially difficult airway (DA) is a critical aspect of resident education. We investigated the impact of a new assessment form on airway prediction and management by anaesthesia residents. We hypothesized that residents would demonstrate improvement in evaluation of DAs over the study duration.
Methods
After IRB approval, anaesthesia residents were randomized into two groups: control (existing form) and experimental (new form). Data were collected prospectively from August 2008 to May 2010 on all non-obstetric adult patients undergoing non-emergent surgery.
Results
Eight thousand three hundred and sixty-four independent preoperative assessments were collected and 8075 were analysed. The experimental group had the higher completion rate than the control group (94.3% vs 84.3%, P=0.001). DA prediction was higher for the control group (71.2%) compared with the experimental group (69.1%; P=0.032). A significant improvement in prediction rates was found over time for the experimental group (likelihood estimate=0.00068, P=0.031).
Conclusions
The use of a comprehensive airway assessment did not improve resident ability to predict a DA in an academic, tertiary-based hospital, anaesthesiology residency training programme.
doi:10.1093/bja/aet029
PMCID: PMC3711391  PMID: 23471752
airway; education, medical students
9.  Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar 
BJA: British Journal of Anaesthesia  2013;111(2):143-151.
Although previously considered entirely reversible, general anaesthesia is now being viewed as a potentially significant risk to cognitive performance at both extremes of age. A large body of preclinical as well as some retrospective clinical evidence suggest that exposure to general anaesthesia could be detrimental to cognitive development in young subjects, and might also contribute to accelerated cognitive decline in the elderly. A group of experts in anaesthetic neuropharmacology and neurotoxicity convened in Salzburg, Austria for the BJA Salzburg Seminar on Anaesthetic Neurotoxicity and Neuroplasticity. This focused workshop was sponsored by the British Journal of Anaesthesia to review and critically assess currently available evidence from animal and human studies, and to consider the direction of future research. It was concluded that mounting evidence from preclinical studies reveals general anaesthetics to be powerful modulators of neuronal development and function, which could contribute to detrimental behavioural outcomes. However, definitive clinical data remain elusive. Since general anaesthesia often cannot be avoided regardless of patient age, it is important to understand the complex mechanisms and effects involved in anaesthesia-induced neurotoxicity, and to develop strategies for avoiding or limiting potential brain injury through evidence-based approaches.
doi:10.1093/bja/aet177
PMCID: PMC3711392  PMID: 23722106
anaesthesia, general; anaesthetics; cognitive disorder; neurotoxicity syndromes; postoperative complications
10.  Is number sense impaired in chronic pain patients? 
BJA: British Journal of Anaesthesia  2014;113(6):1024-1031.
Background
Recent advances in imaging have improved our understanding of the role of the brain in painful conditions. Discoveries of morphological changes have been made in patients with chronic pain, with little known about the functional consequences when they occur in areas associated with ‘number-sense’; thus, it can be hypothesized that chronic pain impairs this sense.
Methods
First, an audit of the use of numbers in gold-standard pain assessment tools in patients with acute and chronic pain was undertaken. Secondly, experiments were conducted with patients with acute and chronic pain and healthy controls. Participants marked positions of numbers on lines (number marking), before naming numbers on pre-marked lines (number naming). Finally, subjects bisected lines flanked with ‘2’ and ‘9’. Deviations from expected responses were determined for each experiment.
Results
Four hundred and ninety-four patients were audited; numeric scores in the ‘moderate’ and ‘severe’ pain categories were significantly higher in chronic compared with acute pain patients. In experiments (n=150), more than one-third of chronic pain patients compared with 1/10th of controls showed greater deviations from the expected in number marking and naming indicating impaired number sense. Line bisection experiments suggest prefrontal and parietal cortical dysfunction as cause of this impairment.
Conclusions
Audit data suggest patients with chronic pain interpret numbers differently from acute pain sufferers. Support is gained by experiments indicating impaired number sense in one-third of chronic pain patients. These results cast doubts on the appropriateness of the use of visual analogue and numeric rating scales in chronic pain in clinics and research.
doi:10.1093/bja/aeu255
PMCID: PMC4235572  PMID: 25082664
acute pain; chronic pain; hemi-spatial neglect; mild cognitive impairment
11.  Theoretical modelling of fibrinogen supplementation with therapeutic plasma, cryoprecipitate, or fibrinogen concentrate 
BJA: British Journal of Anaesthesia  2014;113(4):585-595.
Background
We aimed to create a theoretical tool to model the effect of three haemostatic agents containing fibrinogen (therapeutic plasma, cryoprecipitate, and fibrinogen concentrate) on the patient's plasma fibrinogen level.
Methods
A mathematical model was developed step-wise. The relationship between the amount of haemostatic agent and plasma fibrinogen level was plotted for each agent. A fibrinogen concentration simulator (FCSamount) was developed, where the amount of haemostatic agent was calculated from patient characteristics, agent characteristics, and target plasma fibrinogen level. Refinements were introduced so that (i) FCSamount would account for in vivo fibrinogen recovery, (ii) circulatory volume would not increase ad infinitum with increasing amounts, and (iii) red blood cells would be included in the simulation if haematocrit decreased below a certain level. A second FCS (FCSlevel) was created to calculate fibrinogen levels resulting from specified amounts of haemostatic agents.
Results
Fibrinogen concentration in haemostatic agents has a critical impact on their ability to increase patients' fibrinogen levels. If the target plasma fibrinogen level approaches the concentration of the fibrinogen source, the required amounts increase exponentially; it is impossible to achieve a target above the concentration of the fibrinogen source.
Conclusions
We successfully developed two theoretical tools answering the questions: ‘How much therapeutic plasma, cryoprecipitate, or fibrinogen concentrate would be needed to achieve a specified target fibrinogen level?’ and ‘What would be the resultant fibrinogen level for a specified amount of haemostatic agent?’ The current tools are not intended for clinical application, but they are potentially useful for educational purposes.
doi:10.1093/bja/aeu086
PMCID: PMC4166889  PMID: 25064078
computer simulation; cryoprecipitate; drug dosage calculations; fibrinogen; plasma
12.  Survival after postoperative morbidity: a longitudinal observational cohort study† 
BJA: British Journal of Anaesthesia  2014;113(6):977-984.
Background
Previous studies have suggested that there may be long-term harm associated with postoperative complications. Uncertainty exists however, because of the need for risk adjustment and inconsistent definitions of postoperative morbidity.
Methods
We did a longitudinal observational cohort study of patients undergoing major surgery. Case-mix adjustment was applied and morbidity was recorded using a validated outcome measure. Cox proportional hazards modelling using time-dependent covariates was used to measure the independent relationship between prolonged postoperative morbidity and longer term survival.
Results
Data were analysed for 1362 patients. The median length of stay was 9 days and the median follow-up time was 6.5 yr. Independent of perioperative risk, postoperative neurological morbidity (prevalence 2.9%) was associated with a relative hazard for long-term mortality of 2.00 [P=0.001; 95% confidence interval (CI) 1.32–3.04]. Prolonged postoperative morbidity (prevalence 15.6%) conferred a relative hazard for death in the first 12 months after surgery of 3.51 (P<0.001; 95% CI 2.28–5.42) and for the next 2 yr of 2.44 (P<0.001; 95% CI 1.62–3.65), returning to baseline thereafter.
Conclusions
Prolonged morbidity after surgery is associated with a risk of premature death for a longer duration than perhaps is commonly thought; however, this risk falls with time. We suggest that prolonged postoperative morbidity measured in this way may be a valid indicator of the quality of surgical healthcare. Our findings reinforce the importance of research and quality improvement initiatives aimed at reducing the duration and severity of postoperative complications.
doi:10.1093/bja/aeu224
PMCID: PMC4235571  PMID: 25012586
complications; complications, morbidity; complications, neurological; surgery, non-cardiac
13.  Sex differences in pain: a brief review of clinical and experimental findings 
Summary
Recent years have witnessed substantially increased research regarding sex differences in pain. The expansive body of literature in this area clearly suggests that men and women differ in their responses to pain, with increased pain sensitivity and risk for clinical pain commonly being observed among women. Also, differences in responsivity to pharmacological and non-pharmacological pain interventions have been observed; however, these effects are not always consistent and appear dependent on treatment type and characteristics of both the pain and the provider. Although the specific aetiological basis underlying these sex differences is unknown, it seems inevitable that multiple biological and psychosocial processes are contributing factors. For instance, emerging evidence suggests that genotype and endogenous opioid functioning play a causal role in these disparities, and considerable literature implicates sex hormones as factors influencing pain sensitivity. However, the specific modulatory effect of sex hormones on pain among men and women requires further exploration. Psychosocial processes such as pain coping and early-life exposure to stress may also explain sex differences in pain, in addition to stereotypical gender roles that may contribute to differences in pain expression. Therefore, this review will provide a brief overview of the extant literature examining sex-related differences in clinical and experimental pain, and highlights several biopsychosocial mechanisms implicated in these male–female differences. The future directions of this field of research are discussed with an emphasis aimed towards further elucidation of mechanisms which may inform future efforts to develop sex-specific treatments.
doi:10.1093/bja/aet127
PMCID: PMC3690315  PMID: 23794645
gender differences; opioid analgesics; pain; pain perception; sex differences
14.  Psychosocial interventions for managing pain in older adults: outcomes and clinical implications† 
Summary
Interest in the use of psychosocial interventions to help older adults manage pain is growing. In this article, we review this approach. The first section reviews the conceptual background for psychosocial interventions with a special emphasis on the biopsychosocial model of pain. The second section highlights three psychosocial interventions used with older adults: cognitive behavioural therapy, emotional disclosure, and mind–body interventions (specifically mindfulness-based stress reduction and yoga). The final section of the paper highlights important future directions for work in this area.
doi:10.1093/bja/aet129
PMCID: PMC3690316  PMID: 23794650
age; chronic pain
15.  Assessment of patients with chronic pain 
Summary
Chronic pain is a public health concern affecting 20–30% of the population of Western countries. Although there have been many scientific advances in the understanding of the neurophysiology of pain, precisely assessing and diagnosing a patient's chronic pain problem is not straightforward or well-defined. How chronic pain is conceptualized influences how pain is evaluated and the factors considered when making a chronic pain diagnosis. There is no one-to-one relationship between the amount or type of organic pathology and pain intensity, but instead, the chronic pain experience is shaped by a myriad of biomedical, psychosocial (e.g. patients' beliefs, expectations, and mood), and behavioural factors (e.g. context, responses by significant others). Assessing each of these three domains through a comprehensive evaluation of the person with chronic pain is essential for treatment decisions and to facilitate optimal outcomes. This evaluation should include a thorough patient history and medical evaluation and a brief screening interview where the patient's behaviour can be observed. Further assessment to address questions identified during the initial evaluation will guide decisions as to what additional assessments, if any, may be appropriate. Standardized self-reported instruments to evaluate the patient's pain intensity, functional abilities, beliefs and expectations, and emotional distress are available, and can be administered by the physician, or a referral for in depth evaluation can be made to assist in treatment planning.
doi:10.1093/bja/aet124
PMCID: PMC3841375  PMID: 23794641
assessment; chronic pain; measurement; multidimensional
16.  Managing malaria in the intensive care unit 
BJA: British Journal of Anaesthesia  2014;113(6):910-921.
The number of people travelling to malaria-endemic countries continues to increase, and malaria remains the commonest cause of serious imported infection in non-endemic areas. Severe malaria, mostly caused by Plasmodium falciparum, often requires intensive care unit (ICU) admission and can be complicated by cerebral malaria, respiratory distress, acute kidney injury, bleeding complications, and co-infection. The mortality from imported malaria remains significant. This article reviews the manifestations, complications and principles of management of severe malaria as relevant to critical care clinicians, incorporating recent studies of anti-malarial and adjunctive treatment. Effective management of severe malaria includes prompt diagnosis and early institution of effective anti-malarial therapy, recognition of complications, and appropriate supportive management in an ICU. All cases should be discussed with a specialist unit and transfer of the patient considered.
doi:10.1093/bja/aeu157
PMCID: PMC4235570  PMID: 24946778
ARDS; ICU; imported infections; malaria
17.  Impact of anaesthetics and surgery on neurodevelopment: an update 
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i53-i72.
Summary
Accumulating preclinical and clinical evidence suggests the possibility of neurotoxicity from neonatal exposure to general anaesthetics. Here, we review the weight of the evidence from both human and animal studies and discuss the putative mechanisms of injury and options for protective strategies. Our review identified 55 rodent studies, seven primate studies, and nine clinical studies of interest. While the preclinical data consistently demonstrate robust apoptosis in the nervous system after anaesthetic exposure, only a few studies have performed cognitive follow-up. Nonetheless, the emerging evidence that the primate brain is vulnerable to anaesthetic-induced apoptosis is of concern. The impact of surgery on anaesthetic-induced brain injury has not been adequately addressed yet. The clinical data, comprising largely retrospective cohort database analyses, are inconclusive, in part due to confounding variables inherent in these observational epidemiological approaches. This places even greater emphasis on prospective approaches to this problem, such as the ongoing GAS trial and PANDA study.
doi:10.1093/bja/aet054
PMCID: PMC3667344  PMID: 23542078
brain, anaesthesia, molecular effects; nerve, damage (postoperative); nerve, neurotransmitters; nerve, regeneration
18.  Isoflurane and sevoflurane increase interleukin-6 levels through the nuclear factor-kappa B pathway in neuroglioma cells 
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i82-i91.
Background
Isoflurane can increase pro-inflammatory cytokine interleukin (IL)-6 levels. However, the up-stream mechanism remains unknown. Nuclear factor-kappa B (NF-κB) promotes the generation of pro-inflammatory cytokines. We examined the effects of isoflurane and sevoflurane on the NF-κB signalling pathway and its association with IL-6 levels in cultured cells.
Methods
H4 human neuroglioma cells (H4 cells), and mouse primary neurones and microglia were treated with 2% isoflurane or 4.1% sevoflurane for 6 h, for analysis of IL-6 and NF-κB. Pyrrolidine dithiocarbamate (an NF-κB inhibitor) or 2-deoxy-d-glucose (2-DG) (an inhibitor of glucose glycolysis) was applied 1 h before anaesthetic treatment.
Results
Isoflurane or sevoflurane treatment increased the levels of IL-6 [isoflurane: 410% (54); sevoflurane: 290% (24)], the nuclear levels of NF-κB [isoflurane: 170% (36); sevoflurane: 320% (30)], and the transcription activity of NF-κB in H4 cells. Moreover, isoflurane enhanced the transcription activity of NF-κB in mouse microglia, but not primary neurones. Finally, pyrrolidine dithiocarbamate and 2-DG attenuated isoflurane-induced increases in IL-6 and NF-κB, and the transcription activity of NF-κB.
Conclusions
These studies in H4 cells suggest that the NF-κB signalling pathway could contribute to isoflurane or sevoflurane-induced neuroinflammation. This could lead to the targeted intervention of anaesthetic-induced neuroinflammation.
doi:10.1093/bja/aet115
PMCID: PMC3667345  PMID: 23604542
anaesthetic; interleukin-6; NF-κB
19.  Isoflurane affects the cytoskeleton but not survival, proliferation, or synaptogenic properties of rat astrocytes in vitro 
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i19-i28.
Background
More than half of the cells in the brain are glia and yet the impact of general anaesthetics on these cells is largely unexamined. We hypothesized that astroglia, which are strongly implicated in neuronal well-being and synapse formation and function, are vulnerable to adverse effects of isoflurane.
Methods
Cultured rat astrocytes were treated with 1.4% isoflurane in air or air alone for 4 h. Viability, proliferation, and cytoskeleton were assessed by colorimetric assay, immunocytochemistry, or a migration assay at the end of treatment or 2 days later. Also, primary rat cortical neurones were treated for 4 days with conditioned medium from control [astrocyte-conditioned media (ACM)], or isoflurane-exposed astrocytes (Iso-ACM) and synaptic puncta were assessed by synapsin 1 and PSD-95 immunostaining.
Results
By several measures, isoflurane did not kill astrocytes. Nor, based on incorporation of a thymidine analogue, did it inhibit proliferation. Isoflurane had no effect on F-actin but reduced expression of α-tubulin and glial fibrillary acidic protein both during exposure (P<0.05 and P<0.001, respectively) and 2 days later (P<0.01), but did not impair astrocyte motility. ACM increased formation of PSD-95 but not synapsin 1 positive puncta in neuronal cultures, and Iso-ACM was equally effective.
Conclusions
Isoflurane decreased expression of microtubule and intermediate filament proteins in astrocytes in vitro, but did not affect their viability, proliferation, motility, and ability to support synapses.
doi:10.1093/bja/aet169
PMCID: PMC3667346  PMID: 23722058
astrocytes; isoflurane
20.  Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain 
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i29-i38.
Background
Exposure of the fetal or neonatal non-human primate (NHP) brain to isoflurane or ketamine for 5 h causes widespread apoptotic degeneration of neurones, and exposure to isoflurane also causes apoptotic degeneration of oligodendrocytes (OLs). The present study explored the apoptogenic potential of propofol in the fetal and neonatal NHP brain.
Method
Fetal rhesus macaques at gestational age 120 days were exposed in utero, or postnatal day 6 rhesus neonates were exposed directly for 5 h to propofol anaesthesia (n=4 fetuses; and n=4 neonates) or to no anaesthesia (n=4 fetuses; n=5 neonates), and the brains were systematically evaluated 3 h later for evidence of apoptotic degeneration of neurones or glia.
Results
Exposure of fetal or neonatal NHP brain to propofol caused a significant increase in apoptosis of neurones, and of OLs at a stage when OLs were just beginning to myelinate axons. Apoptotic degeneration affected similar brain regions but to a lesser extent than we previously described after isoflurane. The number of OLs affected by propofol was approximately equal to the number of neurones affected at both developmental ages. In the fetus, neuroapoptosis affected particularly subcortical and caudal regions, while in the neonate injury involved neocortical regions in a distinct laminar pattern and caudal brain regions were less affected.
Conclusions
Propofol anaesthesia for 5 h caused death of neurones and OLs in both the fetal and neonatal NHP brain. OLs become vulnerable to the apoptogenic action of propofol when they are beginning to achieve myelination competence.
doi:10.1093/bja/aet173
PMCID: PMC3667347  PMID: 23722059
anaesthetics i.v., propofol; developing brain; neurones; non-human primates; oligodendroglia; toxicity
21.  Distinct long-term neurocognitive outcomes after equipotent sevoflurane or isoflurane anaesthesia in immature rats 
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i39-i46.
Background
Many anaesthetics when given to young animals cause cell death and learning deficits that persist until much later in life. Recent attempts to compare the relative safety or toxicity between different agents have not adequately controlled for the relative dose of anaesthetic given, thereby making direct comparisons difficult.
Methods
Isoflurane or sevoflurane were given at 1 minimum alveolar concentration (MAC) for 4 h to postnatal day 7 (P7) rat pups. Beginning at P75 these animals underwent fear conditioning and at P83 Morris water maze testing to assess working memory, short-term memory and early long-term memory using delays of 1 min, 1 h, and 4 h.
Results
No difference between groups was seen in fear conditioning experiments. Morris water maze learning was equivalent between groups, and no difference was seen in working memory. Sevoflurane-treated animals had a deficit in early long-term memory, and isoflurane-treated animals had a deficit in both short-term and early long-term memory.
Conclusions
Both isoflurane and sevoflurane delivered at 1 MAC for 4 h to immature rats caused a deficit in long-term memory. Isoflurane also caused a deficit in short-term memory. Isoflurane might be more detrimental than sevoflurane in very young animals.
doi:10.1093/bja/aet103
PMCID: PMC3695640  PMID: 23592692
animals; isoflurane toxicity; memory drug effects; newborn; sevoflurane toxicity
22.  Potentiation of GABAA receptor activity by volatile anaesthetics is reduced by α5GABAA receptor-preferring inverse agonists 
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i73-i81.
Background
Animal studies have shown that memory deficits in the early post-anaesthetic period can be prevented by pre-treatment with an inverse agonist that preferentially inhibits α5 subunit-containing γ-aminobutyric acid type A (α5GABAA) receptors. The goal of this in vitro study was to determine whether inverse agonists that inhibit α5GABAA receptors reduce anaesthetic potentiation of GABAA receptor activity.
Methods
Cultures of hippocampal neurones were prepared from Swiss white mice, wild-type mice (genetic background C57BL/6J and Sv129Ev) and α5GABAA receptor null mutant (Gabra5−/−) mice. Whole-cell voltage clamp techniques were used to study the effects of the α5GABAA receptor-preferring inverse agonists L-655,708 and MRK-016 on anaesthetic potentiation of GABA-evoked currents.
Results
L-655,708 (50 nM) reduced sevoflurane potentiation of GABA-evoked current in wild-type neurones but not Gabra5−/− neurones, and produced a rightward shift in the sevoflurane concentration–response plot [sevoflurane EC50: 1.9 (0.1) mM; sevoflurane+L-655,708 EC50: 2.4 (0.2) mM, P<0.05]. Similarly, L-655,708 (50 nM) reduced isoflurane potentiation of GABA-evoked current [isoflurane: 4.0 (0.6) pA pF−1; isoflurane+L-655,708: 3.1 (0.5) pA pF−1, P<0.01]. MRK-016 also reduced sevoflurane and isoflurane enhancement of GABA-evoked current [sevoflurane: 1.5 (0.1) pA pF−1; sevoflurane+MRK-016 (10 nM): 1.2 (0.1) pA pF−1, P<0.05; isoflurane: 3.5 (0.3) pA pF−1; isoflurane+MRK-016 (1 nM): 2.9 (0.2) pA pF−1, P<0.05].
Conclusions
L-655,708 and MRK-016 reduced the potentiation by inhaled anaesthetics of GABAA receptor activated by a low concentration of GABA. Future studies are required to determine whether this effect contributes to the memory preserving properties of inverse agonists after anaesthesia.
doi:10.1093/bja/aet038
PMCID: PMC3732063  PMID: 23535829
anaesthetics volatile, sevoflurane, isoflurane; brain, GABA; electrophysiology
23.  Mitochondrial protectant pramipexole prevents sex-specific long-term cognitive impairment from early anaesthesia exposure in rats  
BJA: British Journal of Anaesthesia  2013;110(Suppl 1):i47-i52.
Background
Exposure to general anaesthesia during critical stages of brain development results in long-lasting cognitive impairment. Co-administration of protective agents could minimize the detrimental effects of anaesthesia. Co-administration of R(+)pramipexole (PPX), a synthetic aminobenzothiazol derivative that restores mitochondrial integrity, prevents anaesthesia-induced mitochondrial and neuronal damage and prevents early development of cognitive impairment. Here, we determine the protective effects of PPX into late adulthood in male and female rats.
Methods
Postnatal day 7 rats of both sexes were exposed to mock anaesthesia or combined midazolam, nitrous oxide, and isoflurane anaesthesia for 6 h with or without PPX. Cognitive abilities were assessed between 5 and 7 months of age using Morris water maze spatial navigation tasks.
Results
Examination of spatial reference memory revealed that female, but not male, neonatal rats exposed to anaesthesia showed slowing of acquisition rates, which was significantly improved with PPX treatment. Examination of memory retention revealed that both male and female anaesthesia-treated rats have impaired memory retention performance compared with sham controls. Co-treatment with PPX resulted in improvement in memory retention in both sexes.
Conclusion
PPX provides long-lasting protection against cognitive impairment known to occur when very young animals are exposed to anaesthesia during the peak of brain development. Anaesthesia-induced cognitive impairment appears to be sex-specific with females being more vulnerable than males, suggesting that they could benefit more from early prevention.
doi:10.1093/bja/aet073
PMCID: PMC3732064  PMID: 23616588
anaesthetics volatile, isoflurane; anaesthetics gases, nitrous oxide; memory; neonates; oxygen, toxicity; recovery, cognitive
24.  Reply from the authors 
BJA: British Journal of Anaesthesia  2014;112(6):1121-1123.
doi:10.1093/bja/aeu173
PMCID: PMC4020385  PMID: 24829427
25.  Failure mode and effects analysis of the universal anaesthesia machine in two tertiary care hospitals in Sierra Leone 
BJA: British Journal of Anaesthesia  2014;113(3):410-415.
Background
Anaesthesia care in developed countries involves sophisticated technology and experienced providers. However, advanced machines may be inoperable or fail frequently when placed into the austere medical environment of a developing country. Failure mode and effects analysis (FMEA) is a method for engaging local staff in identifying real or potential breakdowns in processes or work systems and to develop strategies to mitigate risks.
Methods
Nurse anaesthetists from the two tertiary care hospitals in Freetown, Sierra Leone, participated in three sessions moderated by a human factors specialist and an anaesthesiologist. Sessions were audio recorded, and group discussion graphically mapped by the session facilitator for analysis and commentary. These sessions sought to identify potential barriers to implementing an anaesthesia machine designed for austere medical environments—the universal anaesthesia machine (UAM)—and also engaging local nurse anaesthetists in identifying potential solutions to these barriers.
Results
Participating Sierra Leonean clinicians identified five main categories of failure modes (resource availability, environmental issues, staff knowledge and attitudes, and workload and staffing issues) and four categories of mitigation strategies (resource management plans, engaging and educating stakeholders, peer support for new machine use, and collectively advocating for needed resources).
Conclusions
We identified factors that may limit the impact of a UAM and devised likely effective strategies for mitigating those risks.
doi:10.1093/bja/aeu096
PMCID: PMC4136424  PMID: 24833727
austere anaesthesia; failure mode and effects analysis, FMEA; quality improvement; Sierra Leone

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