Melatonin treatment has consistent but transient beneficial effects on sleep measures and pain in patients with severe chronic pain: the DREAM-CP randomised controlled trial.

BACKGROUND: Sleep disturbance is a major issue for patients with chronic pain. Melatonin has been shown to improve symptoms of fibromyalgia, but its efficacy in other chronic non-malignant pain conditions is not fully known. Hence, we determined the effect of melatonin in patients with severe noncancer chronic pain. METHODS: This was a randomised double-blinded crossover trial of modified-release melatonin as Circadin™ compared with placebo. Sixty male and female subjects with chronic severe pain were randomised to receive either 2 mg of Circadin™ or placebo before sleep for 6 weeks, followed by a >4 week washout, then crossing over to the other treatment. Sleep disturbance, quality, and latency were measured using three different validated sleep assessment tools. The primary outcome measure was self-reported sleep disturbance after 6 weeks of treatment. Adverse events were also recorded. RESULTS: Sleep disturbance after 6 weeks was not significantly altered by melatonin treatment, but differences between melatonin and placebo treatment periods after 3 weeks were seen: sleep disturbance (P=0.014), latency (P=0.04), overall sleep quality (P=0.004), and effect of pain on sleep (P=0.032). Pain intensity scores improved during both treatment periods (both P<0.001). There were no differences in adverse events between treatment periods. CONCLUSIONS: Circadin™ treatment did not improve sleep disturbance in patients with severe chronic pain compared with placebo at 6 weeks, but there were consistent improvements in aspects of sleep in the shorter term. Given its favourable safety profile, it could be beneficial for some patients with chronic pain. CLINICAL TRIAL REGISTRATION: ISRCTN12861060.

Supraneural versus Infraneural Approach to transforaMinal Epidural StEroid injection for unilateral lumbosacral radicular pain (SIAMESE): a study protocol for a randomised non-inferiority trial.

Background: Lumbosacral radicular pain is commonly treated by transforaminal steroid epidural injection. There are two methods: the supraneural and the infraneural approaches. The supraneural approach can result in rare but catastrophic consequences from injury to the radiculomedullary artery. The infraneural technique avoids the artery; both approaches show efficacy and are used locally. Methods: This is a protocol for a randomised, single-blinded, non-inferiority trial of infraneural vs supraneural transforaminal epidural injection for lumbosacral radicular pain at a tertiary referral pain management clinic. Adult patients (n=92) with moderate-to-severe lumbosacral radicular pain of >3 months duration, scheduled for transforaminal epidural steroid injection, will be randomised to epidural by either the infraneural or supraneural approach. Only the treating physicians will know which route is used. The primary outcome measure is the differential impact on pain intensity score at 3 months. Secondary outcome measures will include disability and function scores, sleep and activity measures, and adverse events. Participants will be followed up for 12 months. Conclusions: This study will determine whether the techniques are comparable and, if so, will enable recommendations for the use of an approach without risk of artery damage and catastrophic injury. Clinical trial registration: ISRCTN 36195887.

Breast-Q sensory outcomes of non-neurotized, autologous, unilateral breast reconstruction with a minimum of 3-year follow-up.

INTRODUCTION: Sensory reinnervation of autologous breast tissue after free flap reconstruction is highly variable. There is no long-term follow-up data exploring spontaneous reinnervation and how this affects patients' quality of life nor the nerve-related symptoms they experience. To address this issue, we invited patients with a minimum of 3 years after non-neurotized, free flap breast reconstruction to complete patient-reported outcome measures exploring sensation, quality of life and breast-related symptoms. METHODS: We performed a retrospective cohort study of patients undergoing unilateral Muscle-Sparing Transverse Rectus Abdominus Muscle (MS-TRAM) or deep inferior epigastric artery perforator (DIEP) flap breast reconstruction between 01-01-2015 and 31-12-2019 in the Department of Plastic and Reconstructive Surgery at Manchester University NHS Foundation Trust. We invited participants to complete the recently developed Breast-Q© Breast Sensation Module. RESULTS: All patients had undergone unilateral immediate (n = 85) or delayed (n = 82) breast reconstruction after mastectomy using either a free DIEP (n = 150) or TRAM (n = 17) flap reconstruction a minimum of 3 years prior. The median age at operation was 48. Sensation after reconstruction was significantly reduced in the reconstructed breast compared with the contralateral breast (P < 0.0001) with a reduction in reported quality of life (immediate (68.0 [54.0, 89.0]) and delayed (68.0 [62.0, 83.8])). The sensation was significantly better in immediate vs delayed procedures (P = 0.024). Sensory scores after reconstruction increased with age (P = 0.036). DISCUSSION: Breast sensation after non-neurotized reconstruction with autologous tissue is significantly reduced at long-term follow-up with a reduction in quality of life. A minimum outcome set for quantification of breast sensation is required and future research into the cost-benefit of neurotized, autologous breast reconstruction is needed.

Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents III: The 2023 Geneva revision.

The set of guidelines for good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents was developed following an international consensus conference in Copenhagen in 1996 (Viby-Mogensen et al., Acta Anaesthesiol Scand 1996, 40, 59-74); the guidelines were later revised and updated following the second consensus conference in Stockholm in 2005 (Fuchs-Buder et al., Acta Anaesthesiol Scand 2007, 51, 789-808). In view of new devices and further development of monitoring technologies that emerged since then, (e.g., electromyography, three-dimensional acceleromyography, kinemyography) as well as novel compounds (e.g., sugammadex) a review and update of these recommendations became necessary. The intent of these revised guidelines is to continue to help clinical researchers to conduct high-quality work and advance the field by enhancing the standards, consistency, and comparability of clinical studies. There is growing awareness of the importance of consensus-based reporting standards in clinical trials and observational studies. Such global initiatives are necessary in order to minimize heterogeneous and inadequate data reporting and to improve clarity and comparability between different studies and study cohorts. Variations in definitions of endpoints or outcome variables can introduce confusion and difficulties in interpretation of data, but more importantly, it may preclude building of an adequate body of evidence to achieve reliable conclusions and recommendations. Clinical research in neuromuscular pharmacology and physiology is no exception.

The incidence and management of peripheral nerve injury in England (2005-2020).

Peripheral nerve injury (PNI) is a significant health problem that confers lifelong impact on those injured. Current interventions are purely surgical; however, outcomes remain poor. There is a lack of high-quality epidemiological data that is needed to identify populations involved, current healthcare demands, and ensure resources are distributed to the greatest effect, to reduce the injury burden. METHODS: Anonymized hospital episode statistical (HES) data on admitted patient care was obtained from NHS Digital for all National Health Service (NHS) patients sustaining PNI of all body regions between 2005 and 2020. Total numbers of finished consultant episodes (FCEs) or FCEs/100,000 population were used to demonstrate changes in demographic variables, anatomical locations of injury, mechanisms of injury, speciality, and main operation. RESULTS: There was a mean national incidence of 11.2 (95% CI 10.9, 11.6) events per 100,000 population per year. Males were at least twice as likely (p < 0.0001) to sustain a PNI. Upper limb nerves at or distal to the wrist were most commonly injured. Knife injuries increased (p < 0.0001), whereas glass injuries decreased (p < 0.0001). Plastic surgeons increasingly managed PNI (p = 0.002) as opposed to orthopaedic surgeons (p = 0.006) or neurosurgeons (p = 0.001). There was an increase in neurosynthesis (p = 0.022) and graft procedures (p < 0.0001) during the study period. DISCUSSION: PNI is a significant national healthcare problem predominantly affecting distal, upper limb nerves of men of working age. Injury prevention strategies, improved targeted funding and rehabilitation pathways are needed to reduce the injury burden and improve patient care.

Generic versus reference listed ropivacaine for peripheral nerve blockade: A randomised, triple-blinded, crossover, equivalence study in volunteers.

BACKGROUND: Generic drug preparations do not require the same degree of scrutiny as the originally licensed preparation before they can be approved for clinical use. The permitted tolerance limits for bioequivalent preparations might be associated with clinically relevant differences for drugs with a narrow therapeutic index, such as local anaesthetics. OBJECTIVE: We compared pharmacokinetic and pharmacodynamic characteristics of generic and reference listed or original preparations of ropivacaine. DESIGN: The current healthy volunteer study used a randomised, triple-blinded, cross-over equivalence design. SETTING: Tertiary university hospital, Medical University of Vienna. SUBJECTS: Healthy male volunteers (N=18) aged 18 to 60 years. INTERVENTIONS: A series of three ultrasound-guided ulnar nerve blocks separated by at least 6 days were carried out on each volunteer. Reference listed ropivacaine (NaropinTM) was used for two blocks and a generic preparation of ropivacaine was used for the other block. Sensory block onset and duration were evaluated using loss of pinprick sensation. MAIN OUTCOME MEASURES: Duration of sensory block was the primary outcome. Secondary outcomes included time-to-onset of sensory block, ropivacaine pharmacokinetics from venous blood samples and pH of the preparations. Equivalence was evaluated using the ratios of means and 90% confidence intervals (CIs) of log transformed data. RESULTS: Equivalence was demonstrated for the primary outcome measure, the duration of sensory block [original : generic ratio 1.01 (90% CI 0.87 to 1.16); P < 0.007] and all pharmacokinetic variables. Equivalence could not be concluded for time-to-onset of sensory block [reference : generic ratio 0.80 (90% CI 0.63 to 1.03); P = 0.27], although reproducibility of this variable using our experimental model was lower than for other variables. The generic preparation was significantly more alkaline [difference 0.06 pH units (95% CI 0.04 to 0.07); P < 0.0001]. CONCLUSION: Our finding of equivalence for sensory block duration and key pharmacokinetic variables between a generic and original preparation of ropivacaine is reassuring. The significant, but small, difference in pH is not clinically important. TRIAL REGISTRATION: EudraCT 2019-003148-61, German Clinical Trials Register (DRKS 00017750).

Melatonin Is a Feasible, Safe, and Acceptable Intervention in Doctors and Nurses Working Nightshifts: The MIDNIGHT Trial.

Nightshift working is associated with sleep deprivation, fatigue and attention/concentration deficits which, in healthcare workers, may impact on patient safety. Clinical staff in the UK routinely work several 12 h nightshifts in a row at about 1-3 month intervals. We investigated the feasibility and acceptability of a crossover trial of melatonin administration in clinical staff working nightshifts with an exploration of effects on sleep measures and attention/concentration tasks. This was a pilot, double-blinded, randomized, placebo-controlled crossover feasibility trial in doctors and nurses working 3 consecutive nightshifts at a tertiary referral hospital in the UK. Twenty five male and female subjects were randomized to receive either 6mg Circadin™ slow release melatonin or placebo before sleep after each consecutive nightshift, followed by a washout period, before crossing over to the other experimental arm. We used actigraphy for objective assessment of sleep parameters. The trial design was feasible and acceptable to participants with negligible side effects, but elevated melatonin levels were prolonged during the active arm (P=0.016). Double digit addition testing, a concentration/attention task, improved with melatonin treatment (P<0.0001). Lapses of vigilance or judgement while doctors or nurses are working nightshifts could impact on patient safety and melatonin may be a useful intervention. This study supports the conclusion that a larger definitive trial of this design is both feasible and safe. Clinical Trial Registration: identifier ISRCTN15529655. https://www.isrctn.com/.

A national survey of anaesthetists' preferences for their own end of life care.

OBJECTIVES: To describe individual views, wishes, and preferences for end of life care and to report UK anaesthetists' personal perspectives. METHODS: The 'bigconversations' questionnaire was developed by modifying an existing framework for end of life discussions. An online cross-sectional survey of UK anaesthetists was then conducted using the questionnaire in January 2019. RESULTS: The bigconversations questionnaire was validated as measuring the important aspects of end of life care by an expert panel and was found to have moderate test-retest reliability. Responses were received from 760/1913 (40%) of those invited to take part. Overall, 698/760 (92%) of respondents wished to be well informed about their condition and prognosis and 518/760 (68%) wanted to be heavily involved in decision-making about their health. Meanwhile, 639/760 (84%) of respondents would choose to forego treatment aimed at prolonging life should that life be of poor quality. The desire to spend time with family was a theme which arose from the qualitative analysis. CONCLUSION: This study provides the first systematic description of UK doctors', specifically anaesthetists', personal preferences for end of life care. Broad trends were identified: to be well informed; to avoid high-intensity medical treatments if terminally unwell; to spend remaining time with family and friends; and to be symptom-free and well cared for. However, a substantial minority expressed different, indeed opposite, opinions. This variation highlights that good quality end of life care must be driven by discussion of an individual's values, wishes, and preferences.

Mortality and morbidity in oesophageal atresia.

BACKGROUND: Several classification systems exist to predict mortality in oesophageal atresia, the most widely quoted of these being over 20 years old. No classification system exists to predict morbidity. We sought to test whether these classification systems remain relevant and to determine whether they can be useful to predict morbidity. In addition, we aimed to identify independent risk factors for predicting mortality and morbidity. METHODS: Neonates presenting with oesophageal atresia over a 20-year period (1990-2010) were retrospectively reviewed. Discriminative statistical analysis compared the performance of current classification systems. Stepwise logistic regression analysis of the influence of perioperative risk factors on mortality and duration of ventilatory support and intensive care unit stay were performed. RESULTS: All classification systems predicted mortality in this series of 248 neonates. Birth weight, cardiac anomalies and pre-operative pneumonia were independent risk factors for predicting mortality in oesophageal atresia. The Waterston classification is the most useful classification for predicting post-operative morbidity in terms of length of hospital stay and time spent ventilated. CONCLUSION: Despite advances in the neonatal care of the very low birth weight infant and those with congenital cardiac disease, these conditions remain relevant in predicting mortality and morbidity in oesophageal atresia.

Comparing cardiac output monitors and defining agreement: A systematic review and meta-analysis.

BACKGROUND: Measuring cardiac output is common in critical care and perioperative medicine. Different monitoring systems are often judged against others in comparative studies. There is no agreed standard or definition on which to base the conclusions of such studies. OBJECTIVES: To review comparative studies of cardiac output monitors using an agreement:tolerability index (ATI) as a measure of monitor precision. To compare the ATI of a monitor with the conclusions of authors regarding agreement and clinical utility. DESIGN: Systematic review of comparative studies of cardiac output monitoring systems. The precision of each monitor was standardised against an ATI using a tolerability interval based on the normal range for cardiac index. The conclusions of each study were described as positive, neutral or negative, depending on whether authors reported the monitor to be acceptably precise and/or clinically useful. Comparison was made between the precision of a monitor and the likelihood of it being favoured by authors. DATA SOURCES: PubMed was searched up to March 2012. ELIGIBILITY CRITERIA: Studies published in English that compared two or more methods for measuring cardiac output in adult humans. RESULTS: A total of 213 papers documenting 409 separate comparisons of two methods of measuring cardiac output were included. ATIs for the different comparisons varied from 0.07 to 6.84 (where an ATI < 1 indicates acceptable agreement, 1-2 marginal and >2 unacceptable agreement). Thirty-one percent of authors defined their own terms for acceptable agreement. ATI was only moderately correlated with the conclusions of the authors (Spearman rho = 0.47, P < 0.0001). CONCLUSIONS: Authors should define what constitutes acceptable agreement a priori when reporting comparative studies of cardiac output monitors. The ATI and the tolerability interval may be a useful basis for helping define acceptable precision.

Effect of sex and pregnancy on the potency of intrathecal bupivacaine: determination of ED50 for motor block with the up-down sequential allocation method.

BACKGROUND AND OBJECTIVE: The up-down sequential allocation model has been adapted to estimate the relative potency ratios for analgesia and motor block of the most commonly used epidural and intrathecal local anaesthetics. The aim of this study was to establish the median effective doses (ED50) for motor block with intrathecal bupivacaine and to estimate the ED50 ratios of these in male, female and pregnant patients. METHODS: In this prospective, double-blind, parallel group, up-down sequential allocation study, we enrolled 30 male patients, 30 female, non-pregnant patients and 30 pregnant patients undergoing elective surgery under combined spinal-epidural anesthesia. The first two groups consisted of male or female patients undergoing elective lower limb surgery and the third group consisted of pregnant women at term (>36 and <41 weeks) with singleton pregnancies undergoing elective caesarean delivery. Patients received intrathecal isobaric bupivacaine 0.5% as part of the spinal-epidural anaesthesia technique. The initial dose was 4 mg and the testing interval was 1 mg with subsequent doses being determined by the outcome in the previous patient in the same group. The end point for efficacy was the occurrence of motor block in the lower limbs within 5 min. RESULTS: There were significant (P < 0.0001) differences in ED50 estimates for motor block with intrathecal bupivacaine: 6.9 mg for men [95% confidence interval (CI), 5.2-8.6), 5.2 mg for women (95% CI, 4.5-5.8) and 3.4 mg for pregnant women (95% CI, 2.9-4.0). CONCLUSION: We have demonstrated a hierarchy of potencies for motor block with intrathecal bupivacaine for men, women and pregnant women suggesting possible relevant differences owing to the effects of both sex and pregnancy.

Up-down determination of the 90% effective dose of phenylephrine for the treatment of spinal anesthesia-induced hypotension in parturients undergoing cesarean delivery.

INTRODUCTION: Hypotension frequently complicates spinal anesthesia for cesarean delivery, and vasopressors are the mainstay for treatment. The most effective dose of phenylephrine for the treatment of spinal anesthesia-induced hypotension has not been estimated. METHODS: Healthy nonlaboring women undergoing a cesarean delivery were recruited. All women received spinal anesthesia using hyperbaric bupivacaine 12 mg with fentanyl and morphine. Each subject received an i.v. crystalloid fluid bolus before and at the time of initiation of spinal anesthesia (preload and coload). An up-down sequential allocation method using the biased-coin design was used to estimate the 90% effective dose (ED(90)) of phenylephrine. The assigned phenylephrine dose was based on the response of the preceding subject. If the systolic blood pressure (SBP) decreased > 20% of baseline (i.e., SBP 20%) or to an SBP < 90 mm Hg, the assigned dose of phenylephrine was administered. If the SBP returned to within 20% of baseline or > or = 90 mm Hg within 1 min, this was considered a success, otherwise it was a failure. The initial dose of phenylephrine was 100 microg. The ED(90) with 95% confidence intervals (CIs) was calculated using the maximum likelihood estimation and Firth logistic regression. RESULTS: Sixty-nine subjects were screened to participate, of whom 66 subjects consented. Forty-five of the enrolled subjects experienced spinal anesthesia-induced hypotension and received a blinded dose of phenylephrine. Those subjects who developed hypotension received doses of phenylephrine between 80 and 180 microg. No subjects experienced hypertension. Determined with the maximum likelihood estimation method, the ED(90) of phenylephrine was 147 microg (95% CI, 98-222 microg). With Firth regression, the probability of a successful response at 150 microg is 90.5% (95% CI, 66.0%-99.0%). CONCLUSION: In this study, we estimated that the ED(90) of phenylephrine required to treat spinal anesthesia-induced hypotension in cesarean delivery is approximately 150 microg.

Genetic variability of the mu-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women.

Labor initiates one of the most intensely painful episodes in a woman's life. Opioids are used to provide analgesia with substantial interindividual variability in efficacy. mu-Opioid receptor (muOR, OPRM1) genetic variants may explain differences in response to opioid analgesia. We hypothesized that OPRM1 304A/G polymorphism influences the median effective dose (ED(50)) of intrathecal fentanyl via combined spinal-epidural for labor analgesia. Nulliparous women were prospectively recruited around 35 weeks gestation (n=224), and genotyped for 304A/G polymorphism. Those requesting neuraxial labor analgesia were enrolled in one of the two double-blinded trials: up-down sequential allocation (SA, n=50) and a separate confirmatory random-dose allocation trial (RA, n=97). Effective analgesia from intrathecal fentanyl was defined by >or=60 min analgesia with verbal rating score

Motor blocking minimum local anesthetic concentrations of bupivacaine, levobupivacaine, and ropivacaine in labor.

BACKGROUND AND OBJECTIVES: Adequate comparison of blocking capabilities of local anesthetics should be done with some knowledge of their relative potencies. The objective of this clinical trial was to simultaneously determine the motor blocking minimum local anesthetic concentrations (MMLAC) and the relative potency ratios for racemic bupivacaine, levobupivacaine, and ropivacaine during labor. METHODS: We studied parturients with singleton term pregnancies in vertex presentation. Each patient received a 20 mL epidural bolus of bupivacaine, levobupivacaine, or ropivacaine determined by the MMLAC model. Baseline and 30 min after injection, measurements of pain and muscle strength were performed, with assessment of motor strength in the legs at 30 min being the primary outcome measure. RESULTS: There were no differences in demographic, hemodynamic, or obstetric characteristics between the patients receiving the three local anesthetics. The estimated MMLAC with the 95% confidence intervals (CI) were: Bupivacaine: 0.26% wt/vol (0.22-0.30); Levobupivacaine: 0.30% wt/vol (0.25-0.36); Ropivacaine: 0.34% wt/vol (0.29-0.38). ANOVA of MMLAC estimates was significant (F = 3.32, P = .046), and when ranked by analgesic potencies, a significant linear trend (P = .014) to increasing motor blocking potencies from ropivacaine to levobupivacaine to bupivacaine was also found. CONCLUSIONS: This study confirms a motor blocking hierarchy for the three pipecoloxylidines.