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3.  Reply from the authors 
BJA: British Journal of Anaesthesia  2014;112(6):1121-1123.
doi:10.1093/bja/aeu173
PMCID: PMC4020385  PMID: 24829427
4.  Increased μ-opioid receptor expression in metastatic lung cancer 
BJA: British Journal of Anaesthesia  2014;113(Suppl 1):i103-i108.
Background
We and others have previously demonstrated that the μ-opioid receptor (MOR) is overexpressed in several human malignancies. There is a seven-fold increase in MOR in cell lines of human lung cancer. In animal models, overexpression of MOR promotes tumour growth and metastasis. We, therefore, examined whether MOR expression is increased in metastatic lung cancer.
Methods
In this study, we examined the association between MOR expression and metastasis in archived biopsy samples from patients with lung cancer. Paraffin-embedded patient material was stained using MOR antibody and scored qualitatively by two independent pathologists using a four-point scale.
Results
In human lung cancer and normal adjacent lung samples obtained from 34 lung cancer patients, MOR expression was increased significantly in cancer samples from patients with lung cancer compared with adjacent control tissue (P=0.0242). When the samples from patients with metastatic lung cancer were separated from the cohort of the total number of patients with lung cancer, we observed an approximately two-fold increase in MOR expression (P=0.0013).
Conclusions
The association between the expression of MOR and the progression of the tumour is consistent with the hypothesis of a direct effect of MOR on cancer progression.
doi:10.1093/bja/aeu165
PMCID: PMC4111280  PMID: 24920011
lung cancer; metastasis; methylnaltrexone; MOR; μ-opioid receptor
5.  Morphine stimulates cancer progression and mast cell activation and impairs survival in transgenic mice with breast cancer 
BJA: British Journal of Anaesthesia  2014;113(Suppl 1):i4-i13.
Background
Morphine stimulates angiogenesis and cancer progression in mice. We investigated whether morphine influences tumour onset, development, and animal model survival, and whether µ-opioid receptor (MOR), lymphangiogenesis, mast cell activation, and substance P (SP) are associated with the tumour-promoting effects of morphine.
Methods
Transgenic mice with a rat C3(1) simian virus 40 large tumour antigen fusion gene which demonstrate the developmental spectrum of human infiltrating ductal breast carcinoma were used. Mice were treated at different ages with clinically relevant doses of morphine or phosphate-buffered saline to determine the effect on tumour development and progression, and on mouse survival. Tumours were analysed for MOR, angiogenesis, lymphangiogenesis, SP, and mast cell activation by immunofluorescent- or laser scanning confocal-microscopy. Cytokine and SP levels were determined by enzyme-linked immunosorbent assay.
Results
Morphine did not influence tumour development when given before the onset of tumour appearance, but significantly promoted progression of established tumours, and reduced survival. MOR-immunoreactivity (ir) was observed in larger but not in smaller tumours. Morphine treatment resulted in increased tumour angiogenesis, peri-tumoural lymphangiogenesis, mast cell activation, and higher levels of cytokines and SP in tumours. SP-ir co-localized with mast cells and elsewhere in the tumours.
Conclusions
Morphine does not affect the onset of tumour development, but it promotes growth of existing tumours, and reduces overall survival in mice. MOR may be associated with morphine-induced cancer progression, resulting in shorter survival. Mast cell activation by morphine may contribute to increased cytokine and SP levels, leading to cancer progression and refractory pain.
doi:10.1093/bja/aeu090
PMCID: PMC4111281  PMID: 24861561
analgesics, opioid, morphine; angiogenesis, lymphangiogenesis; cancer; mast cells; μ-opioid receptor
6.  Association between neuraxial analgesia, cancer progression, and mortality after radical prostatectomy: a large, retrospective matched cohort study 
BJA: British Journal of Anaesthesia  2013;113(Suppl 1):i95-i102.
Background
Systemic opioids are immunosuppressive, which could promote tumour recurrence. We, therefore, test the hypothesis that supplementing general anaesthesia with neuraxial analgesia improves long-term oncological outcomes in patients having radical prostatectomy for adenocarcinoma.
Methods
Patients who had general anaesthesia with neuraxial analgesia (n=1642) were matched 1:1 based on age, surgical year, pathological stage, Gleason scores, and presence of lymph node disease with those who had general anaesthesia only. Medical records were reviewed. Outcomes of interest were systemic cancer progression, recurrence, prostate cancer mortality, and all-cause mortality. Data were analysed using stratified proportional hazards regression, the Kaplan–Meier method, and log-rank tests. The median follow-up was 9 yr.
Results
After adjusting for comorbidities, positive surgical margins, and adjuvant hormonal and radiation therapies within 90 postoperative days, general anaesthesia only was associated with increased risk for systemic progression [hazard ratio (HR)=2.81, 95% confidence interval (CI) 1.31–6.05; P=0.008] and higher overall mortality (HR=1.32, 95% CI 1.00–1.74; P=0.047). Although not statistically significant, similar findings were observed for the outcome of prostate cancer deaths (adjusted HR=2.2, 95% CI 0.88–5.60; P=0.091).
Conclusions
This large retrospective analysis suggests a possible beneficial effect of regional anaesthetic techniques on oncological outcomes after prostate surgery for cancer; however, these findings need to be confirmed (or refuted) in randomized trials.
doi:10.1093/bja/aet467
PMCID: PMC4164176  PMID: 24346021
anaesthesia, general; analgesia, epidural, spinal; cancer progression; neoplasm metastasis; prostatectomy; prostatic neoplasms
7.  Intrajugular balloon catheter reduces air embolism in vitro and in vivo 
BJA: British Journal of Anaesthesia  2015;114(6):973-978.
Background
Neurosurgical procedures requiring a sitting position may put the patient at risk of a potentially life-threatening air embolism. Transient manual jugular venous compression limits further air entry in this situation. This study presents an alternative technique aimed at reducing the risk of air embolism.
Methods
In an in vitro model, an intrajugular balloon catheter was inserted to demonstrate that this device prevents air embolism. In an in vivo study, this device was bilaterally placed into jugular vessels in pigs. Using an ultrasound technique, blood flow was monitored and jugular venous pressure was recorded before and during cuff inflation. Air was applied proximally to the inflated cuffs to test the hypothesis that this novel device blocks air passage.
Results
In vitro, the intrajugular balloon catheter reliably prevented further air entry (n=10). Additionally, accumulated air could be aspirated from an orifice of the catheter (n=10). In vivo, inflation of the catheter balloon completely obstructed venous blood flow (n=8). Bilateral inflation of the cuff significantly increased the proximal jugular venous pressure from 9.8 (2.4) mm Hg to 14.5 (2.5) mm Hg (n=8, P<0.05). Under conditions mimicking an air embolism, air passage across the inflated cuffs was prevented and 78 (20%) (n=6) of the air dose could be aspirated by the proximal orifice of the catheter.
Conclusions
These findings may serve as a starting point for the development of intrajugular balloon catheters designed to reduce the risk of air embolism in patients undergoing neurosurgery in a sitting position.
doi:10.1093/bja/aev040
PMCID: PMC4436929  PMID: 25835025
anesthesia; catheterization; embolism, air; jugular veins; models, animal; neurosurgical procedures; patient positioning; posture
9.  Demystifying propensity scores 
doi:10.1093/bja/aet290
PMCID: PMC3854550  PMID: 24318697
10.  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
11.  Systemic oxygen extraction during exercise at high altitude 
BJA: British Journal of Anaesthesia  2014;114(4):677-682.
Background
Classic teaching suggests that diminished availability of oxygen leads to increased tissue oxygen extraction yet evidence to support this notion in the context of hypoxaemia, as opposed to anaemia or cardiac failure, is limited.
Methods
At 75 m above sea level, and after 7–8 days of acclimatization to 4559 m, systemic oxygen extraction [C(a−v)O2] was calculated in five participants at rest and at peak exercise. Absolute [C(a−v)O2] was calculated by subtracting central venous oxygen content (CcvO2) from arterial oxygen content (CaO2) in blood sampled from central venous and peripheral arterial catheters, respectively. Oxygen uptake (V˙O2) was determined from expired gas analysis during exercise.
Results
Ascent to altitude resulted in significant hypoxaemia; median (range) SpO2 87.1 (82.5–90.7)% and PaO2 6.6 (5.7–6.8) kPa. While absolute C(a−v)O2 was reduced at maximum exercise at 4559 m [83.9 (67.5–120.9) ml litre−1 vs 99.6 (88.0–151.3) ml litre−1 at 75 m, P=0.043], there was no change in oxygen extraction ratio (OER) [C(a−v)O2/CaO2] between the two altitudes [0.52 (0.48–0.71) at 4559 m and 0.53 (0.49–0.73) at 75 m, P=0.500]. Comparison of C(a−v)O2 at peak V˙O2 at 4559 m and the equivalent V˙O2 at sea level for each participant also revealed no significant difference [83.9 (67.5–120.9) ml litre1 vs 81.2 (73.0–120.7) ml litre−1, respectively, P=0.225].
Conclusion
In acclimatized individuals at 4559 m, there was a decline in maximum absolute C(a−v)O2 during exercise but no alteration in OER calculated using central venous oxygen measurements. This suggests that oxygen extraction may have become limited after exposure to 7–8 days of hypoxaemia.
doi:10.1093/bja/aeu404
PMCID: PMC4364061  PMID: 25501722
altitude; blood gas analysis; exercise; hypoxia; oxygen; physiology
12.  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
13.  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
14.  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
15.  Macrophage–sensory neuronal interaction in HIV-1 gp120-induced neurotoxicity‡ 
BJA: British Journal of Anaesthesia  2014;114(3):499-508.
Background
Human immunodeficiency virus (HIV)-associated sensory neuropathy (SN) is the most frequent neurological complication of HIV disease. Among the probable mechanisms underlying HIV-SN are neurotoxicity induced by the HIV glycoprotein gp120 and antiretroviral therapies (ART). Since HIV-SN prevalence remains high in patients who have not been exposed to toxic ART drugs, here we focused on gp120-mediated mechanisms underlying HIV-SN.
Methods
We hypothesized that a direct gp120–sensory neurone interaction is not the cause of neurite degeneration; rather, an indirect interaction of gp120 with sensory neurones involving macrophages underlies axonal degeneration. Rat dorsal root ganglion (DRG) cultures were used to assess gp120 neurotoxicity. Rat bone marrow-derived macrophage (BMDM) cultures and qPCR array were used to assess gp120-associated gene expression changes.
Results
gp120 induced significant, but latent onset, neurite degeneration until 24 h after application. gp120–neurone interaction occurred within 1 h of application in <10% of DRG neurones, despite neurite degeneration having a global effect. Application of culture media from gp120-exposed BMDMs induced a significant reduction in DRG neurite outgrowth. Furthermore, gp120 significantly increased the expression of 25 cytokine-related genes in primary BMDMs, some of which have been implicated in other painful polyneuropathies. The C–C chemokine receptor type 5 (CCR5) antagonist, maraviroc, concentration-dependently inhibited gp120-induced tumour necrosis factor-α gene expression, indicating that these effects occurred via gp120 activation of CCR5.
Conclusions
Our findings highlight macrophages in the pathogenesis of HIV-SN and upstream modulation of macrophage response as a promising therapeutic strategy.
doi:10.1093/bja/aeu311
PMCID: PMC4332570  PMID: 25227937
cytokines; HIV envelope protein; macrophages; maraviroc; peripheral nervous system diseases; peripheral neuropathies
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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