Sex, pain, and the microbiome: The relationship between baseline gut microbiota composition, gender and somatic pain in healthy individuals.

BACKGROUND AND AIM: Relative to men, women present with pain conditions more commonly. Although consistent differences exist between men and women in terms of physiological pain sensitivity, the underlying mechanisms are incompletely understood and yet could inform the development of effective sex specific treatments for pain. The gut microbiota can modulate nervous system functioning, including pain signaling pathways. We hypothesized that the gut microbiota and critical components of the gut-brain axis might influence electrical pain thresholds. Further, we hypothesized that sex, menstrual cycle, and hormonal contraceptive use might account for inter-sex differences in pain perception. METHODS: Healthy, non-obese males (N = 15) and females (N = 16), (nine of whom were using hormonal contraceptives), were recruited. Male subjects were invited to undergo testing once, whereas females were invited three times across the menstrual cycle, based on self-reported early follicular (EF), late follicular (LF), or mid-luteal (ML) phase. On test days, electrical stimulation on the right ankle was performed; salivary cortisol levels were measured in the morning; levels of lipopolysaccharide-binding protein (LBP), soluble CD14 (sCD14), pro-inflammatory cytokines were assessed in plasma, and microbiota composition and short-chain fatty acids (SCFAs) levels were determined in fecal samples. RESULTS: We observed that the pain tolerance threshold/pain sensation threshold (PTT/PST) ratio was significantly lesser in women than men, but not PST or PTT alone. Further, hormonal contraceptive use was associated with increased LBP levels (LF & ML phase), whilst sCD14 levels or inflammatory cytokines were not affected. Interestingly, in women, hormonal contraceptive use was associated with an increase in the relative abundance of Erysipelatoclostridium, and the relative abundances of certain bacterial genera correlated positively with pain sensation thresholds (Prevotella and Megasphera) during the LF phase and cortisol awakening response (Anaerofustis) during the ML phase. In comparison with men, women displayed overall stronger associations between i) SCFAs data, ii) cortisol data, iii) inflammatory cytokines and PTT and PST. DISCUSSION AND CONCLUSION: Our findings support the hypothesis that the gut microbiota may be one of the factors determining the physiological inter-sex differences in pain perception. Further research is needed to investigate the molecular mechanisms by which specific sex hormones and gut microbes modulate pain signaling pathways, but this study highlights the possibilities for innovative individual targeted therapies for pain management.

European Section/Board of Anaesthesiology/European Society of Anaesthesiology consensus statement on competency-based education and training in anaesthesiology.

: The change from time-based to competency-based medical education has been driven by society's requirement for greater accountability of medical practitioners and those who train them. The European Society of Anaesthesiology and European Section/Board of Anaesthesiology (Anaesthesiology Section of the European Union Medical Specialists) endorse the general principles of competency-based medical education and training (CBMET) outlined by the international competency-based medical education collaborators. A CBMET curriculum is built on unambiguously defined learning objectives, each of which offers a measurable outcome, amenable to assessment using valid and reliable tools. The European training requirements laid out by the European Board of Anaesthesiology define four 'Generic Competences', namely expert clinician, professional leader, academic scholar and inspired humanitarian. A CBMET programme should clearly document core competencies, defined end-points, proficiency standards, practical descriptions of teaching and assessment practices and an assessment plan. The assessment plan should balance the need to provide regular, multidimensional formative feedback to the trainee with the need to inform high stakes decisions. A trainee who has not achieved a proficiency standard should be provided with an individualised training plan to address specific competencies or deficits. Programme formats will inevitably differ given the constraints of scale and resource that apply in different settings. The resources necessary to develop and maintain a CBMET programme in anaesthesiology include human capital, access to clinical learning opportunities, information technology and physical infrastructure dedicated to training and education. Simulation facilities and faculty development require specific attention. Reflective practice is an important programme element that supports wellbeing, resilience and achievement of professional goals. CBMET programmes should enable establishment of a culture of lifelong learning for the anaesthesiology community.

Postoperative analgesic effect, of preoperatively administered dexamethasone, after operative fixation of fractured neck of femur: randomised, double blinded controlled study.

BACKGROUND: Fractured neck of femur is a common cause of hospital admission in the elderly and usually requires operative fixation. In a variety of clinical settings, preoperative glucocorticoid administration has improved analgesia and decreased opioid consumption. Our objective was to define the postoperative analgesic efficacy of single dose of dexamethasone administered preoperatively in patients undergoing operative fixation of fractured neck of femur. METHODS: Institutional ethical approval was granted and written informed consent was obtained from each patient. Patients awaiting for surgery at Cork University Hospital were recruited between July 2009 and August 2012. Participating patients, scheduled for surgery were randomly allocated to one of two groups (Dexamethasone or Placebo). Patients in the dexamethasone group received a single dose of intravenous dexamethasone 0.1 mg kg -1 immediately preoperatively. Patients in the placebo group received the same volume of normal saline. Patients underwent operative fixation of fractured neck of femur using standardised spinal anaesthesia and surgical techniques. The primary outcome was pain scores at rest 6 h after the surgery. RESULTS: Thirty seven patients were recruited and data from thirty patients were analysed. The groups were similar in terms of patient characteristics. Pain scores at rest 6 h after the surgery (the principal outcome) were lesser in the dexamethasone group compared with the placebo group [0.8(1.3) vs. 3.9(2.9), mean(SD) p = 0.0004]. Cumulative morphine consumption 24 h after the surgery was also lesser in the dexamethasone group [7.7(8.3) vs. 15.1(9.4), mean(SD) mg, p = 0.04]. CONCLUSIONS: A single dose of intravenous dexamethasone 0.1 mg kg -1 administered before operative fixation of fractured neck of femur improve significantly the early postoperative analgesia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01550146 , date of registration: 07/03/2012.

Determination of the minimum initial intrathecal dose of isobaric 0.5% bupivacaine for the surgical repair of a proximal femoral fracture: A prospective, observational trial.

BACKGROUND: Femoral neck fractures usually require operative fixation. Spinal anaesthesia is the preferred technique for many anaesthetists, although single-shot spinal anaesthesia may have severe haemodynamic side-effects. OBJECTIVE: To determine the initial minimum intrathecal dose of 0.5% isobaric bupivacaine required in order to achieve surgical anaesthesia within 15 min. DESIGN: Prospective controlled trial using the Dixon and Massey up-and-down method. SETTING: Patients awaiting surgery for proximal femoral fractures at Cork University Hospital were recruited between September 2012 and December 2012. PATIENTS: With institutional ethics approval and having obtained written informed consent from each, American Society of Anesthesiologists' physical status I to III patients aged more than 60 years were recruited. Twenty-three patients were recruited to the study, of which 22 were managed as per protocol. One patient was excluded because of the inability to insert an intrathecal catheter. INTERVENTION: A 22-guage spinal catheter was inserted between the L3 and L5 vertebral levels. An initial dose of 1 ml 0.5% isobaric bupivacaine was arbitrarily chosen as a starting point. The dose in subsequent patients was determined by the outcome of the preceding spinal block and adjusted by 0.1 ml until data on six independent pairs of patients with successful block/failed block were acquired. MAIN OUTCOME MEASURES: The minimum effective local anaesthetic dose of intrathecal 0.5% isobaric bupivacaine to achieve surgical anaesthesia was defined as the primary outcome. RESULTS: The minimum effective local anaesthetic dose of 0.5% bupivacaine was 0.24 ml (95% confidence interval 0.18 to 0.68). CONCLUSION: Our findings may influence clinicians' initial dose selection for spinal anaesthesia when a spinal catheter is used. The dose may be less than previously thought. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01680120.

The effect of simulation-based training on initial performance of ultrasound-guided axillary brachial plexus blockade in a clinical setting - a pilot study.

BACKGROUND: In preparing novice anesthesiologists to perform their first ultrasound-guided axillary brachial plexus blockade, we hypothesized that virtual reality simulation-based training offers an additional learning benefit over standard training. We carried out pilot testing of this hypothesis using a prospective, single blind, randomized controlled trial. METHODS: We planned to recruit 20 anesthesiologists who had no experience of performing ultrasound-guided regional anesthesia. Initial standardized training, reflecting current best available practice was provided to all participating trainees. Trainees were randomized into one of two groups; (i) to undertake additional simulation-based training or (ii) no further training. On completion of their assigned training, trainees attempted their first ultrasound-guided axillary brachial plexus blockade. Two experts, blinded to the trainees' group allocation, assessed the performance of trainees using validated tools. RESULTS: This study was discontinued following a planned interim analysis, having recruited 10 trainees. This occurred because it became clear that the functionality of the available simulator was insufficient to meet our training requirements. There were no statistically significant difference in clinical performance, as assessed using the sum of a Global Rating Score and a checklist score, between simulation-based training [mean 32.9 (standard deviation 11.1)] and control trainees [31.5 (4.2)] (p = 0.885). CONCLUSIONS: We have described a methodology for assessing the effectiveness of a simulator, during its development, by means of a randomized controlled trial. We believe that the learning acquired will be useful if performing future trials on learning efficacy associated with simulation based training in procedural skills. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01965314. Registered October 17th 2013.

The gut microbiota in persistent post-operative pain following breast cancer surgery.

Persistent post-surgical pain (PPSP) is defined as pain which continues after a surgical operation in a significant form for at least three months (and is not related to pre-existing painful conditions). PPSP is a common, under-recognised, and important clinical problem which affects millions of patients worldwide. Preventative measures which are currently available include the selection of a minimally invasive surgical technique and an aggressive multimodal perioperative analgesic regimen. More recently, a role for the gut microbiota in pain modulation has become increasingly apparent. This study aims to investigate any relationship between the gut microbiota and PPSP. A prospective observational study of 68 female adult patients undergoing surgery for management of breast cancer was carried out. Stool samples from 45 of these patients were obtained to analyse the composition of the gut microbiota. Measures of pain and state-trait anxiety were also taken to investigate further dimensions in any relationship between the gut microbiota and PPSP. At 12 weeks postoperatively, 21 patients (51.2%) did not have any pain and 20 patients (48.8%) reported feeling pain that persisted at that time. Analysis of the gut microbiota revealed significantly lower alpha diversity (using three measures) in those patients reporting severe pain at the 60 min post-operative and the 12 weeks post-operative timepoints. A cluster of taxa represented by Bifidobacterium longum, and Faecalibacterium prausnitzii was closely associated with those individuals reporting no pain at 12 weeks postoperatively, while Megamonas hypermegale, Bacteroides pectinophilus, Ruminococcus bromii, and Roseburia hominis clustered relatively closely in the group of patients fulfilling the criteria for persistent post-operative pain. We report for the first time specific associations between the gut microbiota composition and the presence or absence of PPSP. This may provide further insights into mechanisms behind the role of the gut microbiota in the development of PPSP and could inform future treatment strategies.

Nerve growth factor-mediated regulation of pain signalling and proposed new intervention strategies in clinical pain management.

Nerve growth factor (NGF) is the founding member of the neurotrophins family of proteins. It was discovered more than half a century ago through its ability to promote sensory and sympathetic neuronal survival and axonal growth during the development of the peripheral nervous system, and is the paradigmatic target-derived neurotrophic factor on which the neurotrophic hypothesis is based. Since that time, NGF has also been shown to play a key role in the generation of acute and chronic pain and in hyperalgesia in diverse pain states. NGF is expressed at high levels in damaged or inflamed tissues and facilitates pain transmission by nociceptive neurons through a variety of mechanisms. Genetic mutations in NGF or its tyrosine kinase receptor TrkA, lead to a congenital insensitivity or a decreased ability of humans to perceive pain. The hereditary sensory autonomic neuropathies (HSANs) encompass a spectrum of neuropathies that affect one's ability to perceive sensation. HSAN type IV and HSAN type V are caused by mutations in TrkA and NGF respectively. This review will focus firstly on the biology of NGF and its role in pain modulation. We will review neuropathies and clinical presentations that result from the disruption of NGF signalling in HSAN type IV and HSAN type V and review current advances in developing anti-NGF therapy for the clinical management of pain.

Postoperative pain and the gut microbiome.

In excess of 300 million surgical procedures are undertaken worldwide each year. Despite recognition of the prevalence of postoperative pain, and improvements in pain management techniques, poorly controlled postoperative pain remains a major unresolved challenge globally. An estimated 71% and 51% of patients experience moderate to severe pain after surgery in in-patient and outpatient settings, respectively. Inadequately controlled pain after surgery is associated with significant perioperative morbidity including myocardial infarction and pulmonary complications. As many as 20-56% of patients develop chronic pain after commonly performed procedures such as hernia repair, hysterectomy, and thoracotomy. Traditional analgesics and interventions are often ineffective or partially effective in the treatment of postoperative pain, resulting in a chronic pain condition with related socio-economic impacts and reduced quality of life for the patient. Such chronic pain which occurs after surgery is referred to as Persistent Post-Surgical Pain (PPSP). The complex ecosystem that is the gastrointestinal microbiota (including bacteria, fungi, viruses, phage) plays essential roles in the maintenance of the healthy state of the host. A disruption to the balance of this microbiome has been implicated not only in gastrointestinal disease but also neurological disorders including chronic pain. The influence of the gut microbiome is well documented in the context of visceral pain from the gastrointestinal tract while a greater understanding is emerging of the impact on inflammatory pain and neuropathic pain (both of which can occur during the perioperative period). The gut microbiome is an essential source for driving immune maturation and maintaining appropriate immune response. Given that inflammatory processes have been implicated in postoperative pain, aberrant microbiome profiles may play a role in the development of this type of pain. Furthermore, the microorganisms in our gut produce metabolites, neurotransmitters, and neuromodulators which interact with their receptors to regulate peripheral and central sensitisation associated with chronic pain. Microbiota-derived mediators can also regulate neuroinflammation, which is associated with activation of microglia as well as infiltration by immune cells, known to modulate the development and maintenance of central sensitisation. Moreover, risk factors for developing postoperative pain include anxiety, depression, and increased stress response. These central nervous system-related disorders have been associated with an altered gut microbiome and microbiome targeted intervention studies indicate improvements. Females are more likely to suffer from postoperative pain. As gonadal hormones are associated with a differential microbiome and pre-clinical studies show that male microbiome confers protection from inflammatory pain, it is possible that the composition of the microbiome and its by-products contribute to the increased risk for the development of postoperative pain. Very little evidence exists relating the microbiome to somatic pain. Here we discuss the potential role of the gut microbiome in the aetiology and pathophysiology of postoperative pain in the context of other somatic pain syndromes and what is known about microbe-neuron interactions. Investigations are needed to determine the specific role of the gut microbiome in this type of pain which may help inform the development of preventative interventions as well as management strategies to improve patient outcome.

Perioperative pregabalin improves pain and functional outcomes 3 months after lumbar discectomy.

BACKGROUND: Patient outcome after lumbar discectomy for radicular low back pain is variable and the benefit is inconsistent. Many patients continue to experience pain 3 months after surgery. Pregabalin, a membrane stabilizer, may decrease perioperative central sensitization and subsequent persistent pain. METHODS: Forty patients undergoing lumbar discectomy were randomly allocated to receive either pregabalin (300 mg at 90 minutes preoperatively and 150 mg at 12 and 24 hours postoperatively) or placebo at corresponding times in a double-blinded manner. Our primary outcome was the change in the present pain intensity (PPI) (visual analog scale [VAS], 0-100 mm [PPI-VAS, McGill Pain Questionnaire]) from preoperatively to 3 months postoperatively. RESULTS: The decrease in PPI-VAS score at 3 months was greater in patients who received pregabalin (37.6 +/- 19.6 mm) (mean +/- sd) than those who received placebo (25.3 +/- 21.9 mm) (P = 0.08). The Roland Morris disability score at 3 months was less in patients who received pregabalin (2.7 +/- 2.4) than in those who received placebo (5.6 +/- 4.8) (P = 0.032). Pregabalin administration was associated with greater pain tolerance thresholds in both lower limbs compared with placebo at 24 hours postoperatively. CONCLUSION: Perioperative pregabalin administration is associated with less pain intensity and improved functional outcomes 3 months after lumbar discectomy.

Determinants of outcome for patients undergoing lumbar discectomy: a pilot study.

BACKGROUND AND OBJECTIVE: One-third of patients who undergo lumbar discectomy continue to suffer from persistent pain postoperatively. Greater preoperative warmth thresholds and greater preoperative cerebrospinal fluid concentrations of stable serum nitric oxide metabolites are associated with a worse outcome. The principal objective of this study was to examine the relationship between patient outcome (defined using the Modified Stauffer-Coventry evaluating criteria) and preoperative pain perception threshold to an electrical stimulus. METHODS: A prospective observational pilot study of patients (n = 39) was performed. Quantitative sensory testing, visual analogue scales for anxiety and pain, the Hospital Anxiety and Depression (HADS) Scale and the McGill Pain Questionnaire were completed, and serum nitric oxide metabolites were measured perioperatively. Excised disc tissue was examined histologically, and immunohistochemistry for phospholipase A2 was performed. RESULTS: Ten patients (26%) had an unsatisfactory outcome. Those with a satisfactory outcome had greater preoperative pain perception thresholds over the affected dermatome, which decreased by 2 months postoperatively. These patients also demonstrated a decrease in nitric oxide metabolites from preoperatively to 18 h postoperatively. Greater preoperative HADS scores, and greater pain intensity 4 h and 24 h postoperatively were associated with an unsatisfactory outcome. CONCLUSION: Patients with a satisfactory outcome demonstrate a decrease in pain perception thresholds and plasma concentration of stable nitric oxide metabolites during the perioperative period. Patients with an unsatisfactory outcome following lumbar discectomy experience greater preoperative anxiety and greater pain during the early postoperative period. These findings justify a larger prospective observational study.

When pain after surgery doesn't go away...

Chronic post-surgical pain is a common, under-recognized and important clinical problem which affects millions of patients worldwide. It results from a series of neuroplastic changes associated most commonly with peripheral nerve injury at the time of surgery. Predisposing factors include the type of surgery, pre-operative and acute post-operative pain intensity, and probably psychological (e.g. pain-catastrophizing) and genetic factors [e.g. GCH1 (GTP cyclohydrolase 1) haplotype]. Preventive measures which are currently available include selection of a minimally invasive surgical technique and an aggressive multimodal perioperative analgesic regimen. Very promising therapeutic agents which target the sensitization process are currently in development.

An ergonomic task analysis of spinal anaesthesia.

BACKGROUND AND OBJECTIVE: Ergonomics is the study of physical interaction between humans and their working environment. The objective of this study was to characterize the performance of spinal anaesthesia in an acute hospital setting, applying ergonomic task analysis. METHODS: A data capture sheet was developed using a series of multidisciplinary expert discussions and piloted on: five procedures. The final version of this sheet was applied to 24 further procedures. Data were acquired using direct observations, video recordings and application of a questionnaire. The domains of interest were patient, operator and environmental factors related to ergonomic performance. RESULTS: At least one important deficit in ergonomic performance was identified during each of the 24 procedures. None of the 24 assistants who helped to position the patients had specific training for this purpose. Eleven out of 24 operators exhibited marked (>/=60 degrees ) thoracolumbar flexion for at least a part of the procedure. Seven out of 24 operators positioned the instrument tray to their nondominant side prior to commencing the procedure. All studied patients were exposed during at least a part of the procedure at a relatively low temperature [17.5 +/- 1 degrees C (16-20.7) (mean +/- SD (range)]. CONCLUSION: In the setting described, spinal anaesthesia is usually performed in a manner which is clearly suboptimal in terms of ergonomics. This underrecognized problem needs to be addressed through education and training.

Deliberate practice using validated metrics improves skill acquisition in performance of ultrasound-guided peripheral nerve block in a simulated setting.

STUDY OBJECTIVES: The aim of this study was to compare the effects of deliberate vs. self-guided practices (both using validated metrics) on the acquisition of needling skills by novice learners. DESIGN: Randomized Controlled Study. SETTING: Simulation lab, Department of Anesthesia, St.Vincent's Hospital, Dublin. SUBJECTS: Eighteen medical students. INTERVENTIONS: Students were assigned to either (i) deliberate practice (n = 10) or (ii) self-guided practice (n = 8) groups. After completion of a 'learning phase', subjects attempted to perform a predefined task, which entailed advancing a needle towards a target on a phantom gel under ultrasound guidance. Subsequently, all subjects practiced this task using predefined metrics. Only subjects in the deliberate practice group had an expert anesthesiologist during practice. Immediately after completing 'practice phase', all subjects attempted to perform the same task, and, on the following day, made two further attempts in succession. Two trained consultant anesthesiologists assessed a video of each performance independently using the pre-defined metrics. MEASUREMENTS: Number of procedural steps completed and number of errors made. MAIN RESULTS: Compared with novices who self-guided their practice using metrics, those who undertook expert-supervised deliberate practice using metrics completed more steps (performance metrics) immediately after practice (median [range], 14.5 [12-15] vs. 3 [1-10], p < 0.0001) and 24 h later (15 [12-15] vs. 4.5 [1-11], p < 0.0001 and 15 [11-15] vs. 4 [2-14], p < 0.0001). They also made fewer errors immediately after practice (median [range], 0 [0-0] vs. 5 [3-8], p < 0.0001) and 24 h later, (0 [0-3] vs. 6.5 [3-8], p < 0.0001 and 0 [0-3] vs. 4 [2-7], p < 0.0001). CONCLUSION: Combining deliberate practice with metrics improved acquisition of needling skills.

An evaluation of operating room throughput in a stand-alone soft-tissue trauma operating theatre.

BACKGROUND: Operating room time is a limited, expensive commodity in acute hospitals. Strategies aimed at reduction of non-operative time improve operating room throughput and capacity. We conducted a prospective study to evaluate and augment operating room throughput and capacity using context-specific work practice changes. METHODS: Following institutional and ethical approval, an interdisciplinary group designed and introduced a series of work practice changes specific to a stand-alone soft tissue trauma theatre, comprising modifications to patient processing, staff behaviours and additional anaesthesiologist hours. Time intervals relating to each patient were measured during a 16 week period before and after implementing work practice changes. The primary outcome measure was non-operative time, with daily caseload and cancellations amongst secondary outcome measures. RESULTS: 251 procedures were included over 58 working days (8 to 17 Monday to Friday). Non-operative time [55.6 (31.1) vs 52.3 (9.8) minutes, p = 0.48], daily caseload [4 [1-9] vs 4 [2-7], p = 0.56], and the number of daily cancellations [3 [0-11] vs 5 [0-8], p = 0.38], did not differ between baseline and study phases. Regional anaesthesia for upper limb surgery increased during the study phase [26/59 (44.0%) vs 10/63 (15.9%), p = 0.014] with resultant decrease in mean duration of recovery room stay [20.7 (17.7) vs 30 (20.5) minutes, p = 0.0001] and increased recovery room bypass [26/116 (22.4%) vs 6/135 (4.4%), p = 0.0002]. Avoidable delays accounted for 124.8 (72.2) minutes of theatre time lost each day. CONCLUSION: In conclusion, additional attending anaesthesiologist hours combined with work practice changes did not impact on measures of theatre throughput and capacity. The study identified important variables that contribute to avoidable delays, and points the way for future research.

Development of performance and error metrics for ultrasound-guided axillary brachial plexus block.

PURPOSE: Change in the landscape of medical education coupled with a paradigm shift toward outcome-based training mandates the trainee to demonstrate specific predefined performance benchmarks in order to progress through training. A valid and reliable assessment tool is a prerequisite for this process. The objective of this study was to characterize ultrasound-guided axillary brachial plexus block to develop performance and error metrics and to verify face and content validity using a modified Delphi method. METHODS: A metric group (MG) was established, which comprised three expert regional anesthesiologists, an experimental psychologist and a trained facilitator. The MG deconstructed ultrasound-guided axillary brachial plexus block to identify and define performance and error metrics. Experts reviewed five video recordings of the procedure performed by anesthesiologists with different levels of expertise to aid task deconstruction. Subsequently, the MG subjected the metrics to "stress testing", a process to ascertain the extent to which the performance and error metrics could be scored objectively, either occurring or not occurring with a high degree of reliability. Ten experienced regional anesthesiologists used a modified Delphi method to reach consensus on the metrics. RESULTS: Fifty-four performance metrics, organized in six procedural phases and characterizing ultrasound-guided axillary brachial plexus block and 32 error metrics (nine categorized as critical) were identified and defined. Based on the Delphi panel consensus, one performance metric was modified, six deleted and three added. CONCLUSION: In this study, we characterized ultrasound-guided axillary brachial plexus block to develop performance and error metrics as a prerequisite for outcome-based training and assessment. Delphi consensus verified face and content validity.