The relation of oral bisphosphonates to bone marrow lesion volume among women with osteoarthritis.

OBJECTIVE: Bone marrow lesions (BMLs) contribute to pain and progression of knee OA. Bisphosphonates may be a potential disease-modifier through amelioration of BMLs. We sought to determine the effect of oral bisphosphonates on BML volume over 12 months. DESIGN: Women in the Osteoarthritis Initiative who newly initiated an oral bisphosphonate were propensity-score matched to non-initiators. BML volume was assessed using sagittal turbo spin echo fat-suppressed intermediate-weighted MR images at the index date and 12 months later. A validated semi-automated process was used to segment subchondral OA-related BMLs to determine total volume of BMLs based on number of voxels within the outlined area of interest. Mean change in BML volume over 12 months among bisphosphonate initiators was compared with non-initiators using multiple linear regression. RESULTS: 145 bisphosphonate initiators were identified, who were well-matched to their comparators. The difference in mean change in total BML volume between the two groups, regardless of presence of baseline BMLs, was not significant (P = 0.4, 95% CI -156.6 to +354.2). The proportion of participants with decreased, increased, or unchanged BML volumes over the 12 months were similar in both groups. Among those with baseline BMLs, bisphosphonate initiators had a greater proportion with a decrease in BML volume compared with stable or increased BML volume than non-initiators (P = 0.03). CONCLUSIONS: In this 'real-world' setting of women starting bisphosphonates, we found no clear evidence of benefit on BML volume over a 12-month period, though a trend towards a decrease in BML volume was noted.

A role for G protein-coupled receptor 137b in bone remodeling in mouse and zebrafish.

G protein-coupled receptor 137b (GPR137b) is an orphan seven-pass transmembrane receptor of unknown function. In mouse, Gpr137b is highly expressed in osteoclasts in vivo and is upregulated during in vitro differentiation. To elucidate the role that GPR137b plays in osteoclasts, we tested the effect of GPR137b deficiency on osteoclast maturation and resorbing activity. We used CRISPR/Cas9 gene editing in mouse-derived ER-Hoxb8 immortalized myeloid progenitors to generate GPR137b-deficient osteoclast precursors. Decreasing Gpr137b in these precursors led to increased osteoclast differentiation and bone resorption activity. To explore the role of GPR137b during skeletal development, we generated zebrafish deficient for the ortholog gpr137ba. Gpr137ba-deficient zebrafish are viable and fertile and do not display overt morphological defects as adults. However, analysis of osteoclast function in gpr137ba-/- mutants demonstrated increased bone resorption. Micro-computed tomography evaluation of vertebral bone mass and morphology demonstrated that gpr137ba-deficiency altered the angle of the neural arch, a skeletal site with high osteoclast activity. Vital staining of gpr137ba-/- fish with calcein and alizarin red indicated that bone formation in the mutants is also increased, suggesting high bone turnover. These results identify GPR137b as a conserved negative regulator of osteoclast activity essential for normal resorption and patterning of the skeleton. Further, these data suggest that coordination of osteoclast and osteoblast activity is a conserved process among vertebrates and may have similar regulation.

Effects of Teriparatide on Joint Erosions in Rheumatoid Arthritis: A Randomized Controlled Trial.

OBJECTIVE: Articular erosions correlate with disability in rheumatoid arthritis (RA). Biologic agents reduce erosion progression in RA, but erosion healing occurs infrequently. This study was undertaken to assess the effects of the anabolic agent teriparatide on joint erosion volume in RA patients treated with a tumor necrosis factor inhibitor (TNFi). METHODS: We conducted a randomized controlled trial in 24 patients with erosive RA, osteopenia, and disease activity controlled by TNFi treatment for at least 3 months. Half were randomized to receive teriparatide for 1 year and the others constituted a wait-list control group. Subjects and primary rheumatologists were not blinded with regard to treatment assignment, but all outcomes were assessed in a blinded manner. The primary outcome measure was change in erosion volume determined by computed tomography at 6 anatomic sites. Significance within each hand and anatomic site was based on a 2-tailed test, with P values less than 0.05 considered significant. RESULTS: Baseline characteristics of the treatment groups were well balanced. After 52 weeks, the median change in erosion volume in the teriparatide group was -0.4 mm3 (interquartile range [IQR] -34.5, 29.6) and did not differ significantly from that in controls (median change +9.1 mm3 [IQR -29.6, 26.4]) (P = 0.28). No significant difference in change in erosion volume was noted at the radius, ulna, or metacarpophalangeal joints. Bone mineral density improved at the femoral neck and lumbar spine in the teriparatide group. CONCLUSION: Our findings indicate that teriparatide treatment for 1 year does not significantly reduce erosion volume in the hands or wrists of patients with established RA with disease activity controlled by TNFi treatment.

Quantitative measurement of medial femoral knee cartilage volume - analysis of the OA Biomarkers Consortium FNIH Study cohort.

OBJECTIVE: Large studies of knee osteoarthritis (KOA) require well-characterized efficient methods to assess progression. We previously developed the local-area cartilage segmentation (LACS) software method, to measure cartilage volume on magnetic resonance imaging (MRI) scans. The present study further validates this method in a larger patient cohort and assesses predictive validity in a case-control study. METHOD: The OA Biomarkers Consortium FNIH Project, a case-control study of KOA progression nested within the Osteoarthritis Initiative (OAI), includes 600 subjects in four subgroups based on radiographic and pain progression. Our software tool measured change in medial femoral cartilage volume in a central weight-bearing region. Different sized regions of cartilage were assessed to explore their sensitivity to change. The readings were performed on MRI scans at the baseline and 24-month visits. We used standardized response means (SRMs) for responsiveness and logistic regression for predictive validity. RESULTS: Cartilage volume change was associated strongly with radiographic progression (odds ratios (OR) = 4.66; 95% confidence intervals (CI) = 2.85-7.62). OR were significant but of lesser magnitude for the combined radiographic and pain progression outcome (OR = 1.70; 95% CI = 1.40-2.07). For the full 600 subjects, theSRM was -0.51 for the largest segmented area. Smaller areas of cartilage segmentation were also able to predict the case-control status. The average reader time for the largest area was less than 20 min per scan. Smaller areas could be assessed with less reader time. CONCLUSION: We demonstrated that the LACS method is fast, responsive, and associated with radiographic and pain progression, and is appropriate for existing and future large studies of KOA.

Printed three-dimensional airway model assists planning of single-lung ventilation in a small child.

BACKGROUND: Single-lung ventilation in infants and small children is challenging because suitable sizes of double-lumen cuffed tracheal tubes are not available. A 6-yr-old child required pulmonary saline washout for primary alveolar proteinosis, and therefore needed sequential single-lung ventilation in order to achieve safe oxygenation. Before undertaking this potentially hazardous procedure, we practised bronchial intubation on an anatomical model of her airway constructed from computed tomography (CT) data. METHODS: We created a full-scale, anatomically accurate, transparent plastic model of the trachea and main bronchi on a three-dimensional printer using data from a CT scan. We then performed several different airway approaches to identify those likely to be most suitable, ex vivo, before the clinical procedure was carried out on the patient. RESULTS: The model helped us to choose the type and size of bronchial tubes and to practise their insertion beforehand. Subsequently, during anaesthesia, the chosen technique was successful. CONCLUSIONS: Three-dimensional printing of a model of the airway of a small child aided planning of bronchial intubation and single-lung ventilation. Three-dimensional printing of airway structures may have wider application in anaesthesia practice.

Current UK dental sedation practice and the 'National Institute for Health and Care Excellence' (NICE) guideline 112: sedation in children and young people.

AIM: Describe current dental sedation practice for under 19-year-olds in the UK and compare it with the recommendations of NICE guidance 112. METHOD: Members of the Society for the Advancement of Anaesthesia in Dentistry and members of the Dental Sedation Teachers Group were invited to participate in an online survey. RESULTS: Two hundred and sixty-six dentists and doctors completed the survey. Eighty-two percent were operator and sedationist (operator-sedationist). Ninety-five percent provided written information and 94% obtained written consent. Eighty-four percent kept a written or electronic sedation record. Eighty-six percent complied with life support training expectations. Eighty-six percent had immediate access to resuscitation equipment. Sixty-seven percent of sedationists reported that treatment could not be completed under sedation for <10% of cases during the previous year. When sedation was unsuccessful, 61% said they would schedule general anaesthesia and 54.5% would schedule advanced sedation care. Forty-nine percent believed that a dentist was an appropriate person to provide advanced sedation for 12-18 years. Only 24% thought a dentist should provide advanced sedation for children<12 years, with 75% preferring an anaesthetist. The appropriate setting for advanced sedation was thought to be primary care by 33% and secondary care by 68%. CONCLUSIONS: We found good agreement between the current practice of sedation and the recommendations of the NICE guidance 112.

The 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: protocol, methods and analysis of data.

Accidental awareness during general anaesthesia with recall is a potentially distressing complication of general anaesthesia that can lead to psychological harm. The 5th National Audit Project was designed to investigate the reported incidence, predisposing factors, causality and impact of accidental awareness. A nationwide network of local co-ordinators across all UK and Irish public hospitals reported all new patient reports of accidental awareness to a central database, using a system of monthly anonymised reporting over a calendar year. The database collected the details of the reported event, anaesthetic and surgical technique, and any sequelae. These reports were categorised into main types by a multidisciplinary panel, using a formalised process of analysis. The main categories of accidental awareness were: certain or probable; possible; during sedation; on or from the intensive care unit; could not be determined; unlikely; drug errors; and statement only. The degree of evidence to support the categorisation was also defined for each report. Patient experience and sequelae were categorised using current tools or modifications of such. The 5th National Audit Project methodology may be used to assess new reports of accidental awareness during general anaesthesia in a standardised manner, especially for the development of an ongoing database of case reporting. This paper is a shortened version describing the protocols, methods and data analysis from 5th National Audit Project - the full report can be found at http://www.nationalauditprojects.org.uk/NAP5_home#pt.

The 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: summary of main findings and risk factors.

We present the main findings of the 5th National Audit Project on accidental awareness during general anaesthesia. Incidences were estimated using reports of accidental awareness as the numerator, and a parallel national anaesthetic activity survey to provide denominator data. The incidence of certain/probable and possible accidental awareness cases was ~1:19 600 anaesthetics (95% CI 1:16 700-23 450). However, there was considerable variation across subtypes of techniques or subspecialties. The incidence with neuromuscular blockade was ~1:8200 (1:7030-9700), and without it was ~1:135 900 (1:78 600-299 000). The cases of accidental awareness during general anaesthesia reported to 5th National Audit Project were overwhelmingly cases of unintended awareness during neuromuscular blockade. The incidence of accidental awareness during caesarean section was ~1:670 (1:380-1300). Two thirds (82, 66%) of cases of accidental awareness experiences arose in the dynamic phases of anaesthesia, namely induction of and emergence from anaesthesia. During induction of anaesthesia, contributory factors included: use of thiopental; rapid sequence induction; obesity; difficult airway management; neuromuscular blockade; and interruptions of anaesthetic delivery during movement from anaesthetic room to theatre. During emergence from anaesthesia, residual paralysis was perceived by patients as accidental awareness, and commonly related to a failure to ensure full return of motor capacity. One third (43, 33%) of accidental awareness events arose during the maintenance phase of anaesthesia, most due to problems at induction or towards the end of anaesthesia. Factors increasing the risk of accidental awareness included: female sex; age (younger adults, but not children); obesity; anaesthetist seniority (junior trainees); previous awareness; out-of-hours operating; emergencies; type of surgery (obstetric, cardiac, thoracic); and use of neuromuscular blockade. The following factors were not risk factors for accidental awareness: ASA physical status; race; and use or omission of nitrous oxide. We recommend that an anaesthetic checklist, to be an integral part of the World Health Organization Safer Surgery checklist, is introduced as an aid to preventing accidental awareness. This paper is a shortened version describing the main findings from 5th National Audit Project - the full report can be found at http://www.nationalauditprojects.org.uk/NAP5_home#pt.

The 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: patient experiences, human factors, sedation, consent and medicolegal issues.

The 5th National Audit Project of the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland into accidental awareness during general anaesthesia yielded data related to psychological aspects from the patient, and the anaesthetist, perspectives; patients' experiences ranged from isolated auditory or tactile sensations to complete awareness. A striking finding was that 75% of experiences were for < 5 min, yet 51% of patients (95% CI 43-60%) experienced distress and 41% (95% CI 33-50%) suffered longer-term adverse effect. Distress and longer-term harm occurred across the full range of experiences but were particularly likely when the patient experienced paralysis (with or without pain). The patient's interpretation of what is happening at the time of the awareness seemed central to later impact; explanation and reassurance during suspected accidental awareness during general anaesthesia or at the time of report seemed beneficial. Quality of care before the event was judged good in 26%, poor in 39% and mixed in 31%. Three quarters of cases of accidental awareness during general anaesthesia (75%) were judged preventable. In 12% of cases of accidental awareness during general anaesthesia, care was judged good and the episode not preventable. The contributory and human factors in the genesis of the majority of cases of accidental awareness during general anaesthesia included medication, patient and education/training. The findings have implications for national guidance, institutional organisation and individual practice. The incidence of 'accidental awareness' during sedation (~1:15 000) was similar to that during general anaesthesia (~1:19 000). The project raises significant issues about information giving and consent for both sedation and anaesthesia. We propose a novel approach to describing sedation from the patient's perspective which could be used in communication and consent. Eight (6%) of the patients had resorted to legal action (12, 11%, to formal complaint) at the time of reporting. The 5th National Audit Project methodology provides a standardised template that might usefully inform the investigation of claims or serious incidents related to accidental awareness during general anaesthesia.

5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: protocol, methods, and analysis of data.

BACKGROUND: Accidental awareness during general anaesthesia (AAGA) with recall is a potentially distressing complication of general anaesthesia that can lead to psychological harm. The 5th National Audit Project (NAP5) was designed to investigate the reported incidence, predisposing factors, causality, and impact of accidental awareness. METHODS: A nationwide network of local co-ordinators across all the UK and Irish public hospitals reported all new patient reports of accidental awareness to a central database, using a system of monthly anonymized reporting over a calendar year. The database collected the details of the reported event, anaesthetic and surgical technique, and any sequelae. These reports were categorized into main types by a multidisciplinary panel, using a formalized process of analysis. RESULTS: The main categories of accidental awareness were: certain or probable; possible; during sedation; on or from the intensive care unit; could not be determined; unlikely; drug errors; and statement only. The degree of evidence to support the categorization was also defined for each report. Patient experience and sequelae were categorized using current tools or modifications of such. CONCLUSIONS: The NAP5 methodology may be used to assess new reports of AAGA in a standardized manner, especially for the development of an ongoing database of case reporting. This paper is a shortened version describing the protocols, methods, and data analysis from NAP5--the full report can be found at http://www.nationalauditprojects.org.uk/NAP5_home.

5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: patient experiences, human factors, sedation, consent, and medicolegal issues.

The 5th National Audit Project (NAP5) of the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland into accidental awareness during general anaesthesia (AAGA) yielded data related to psychological aspects from the patient, and the anaesthetist, perspectives; patients' experiences ranged from isolated auditory or tactile sensations to complete awareness. A striking finding was that 75% of experiences were for <5 min, yet 51% of patients [95% confidence interval (CI) 43-60%] experienced distress and 41% (95% CI 33-50%) suffered longer term adverse effect. Distress and longer term harm occurred across the full range of experiences but were particularly likely when the patient experienced paralysis (with or without pain). The patient's interpretation of what is happening at the time of the awareness seemed central to later impact; explanation and reassurance during suspected AAGA or at the time of report seemed beneficial. Quality of care before the event was judged good in 26%, poor in 39%, and mixed in 31%. Three-quarters of cases of AAGA (75%) were judged preventable. In 12%, AAGA care was judged good and the episode not preventable. The contributory and human factors in the genesis of the majority of cases of AAGA included medication, patient, and education/training. The findings have implications for national guidance, institutional organization, and individual practice. The incidence of 'accidental awareness' during sedation (~1:15,000) was similar to that during general anaesthesia (~1:19,000). The project raises significant issues about information giving and consent for both sedation and anaesthesia. We propose a novel approach to describing sedation from the patient's perspective which could be used in communication and consent. Eight (6%) of the patients had resorted to legal action (12, 11%, to formal complaint) at the time of reporting. NAP5 methodology provides a standardized template that might usefully inform the investigation of claims or serious incidents related to AAGA.

5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: summary of main findings and risk factors.

We present the main findings of the 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia (AAGA). Incidences were estimated using reports of accidental awareness as the numerator, and a parallel national anaesthetic activity survey to provide denominator data. The incidence of certain/probable and possible accidental awareness cases was ~1:19,600 anaesthetics (95% confidence interval 1:16,700-23,450). However, there was considerable variation across subtypes of techniques or subspecialities. The incidence with neuromuscular block (NMB) was ~1:8200 (1:7030-9700), and without, it was ~1:135,900 (1:78,600-299,000). The cases of AAGA reported to NAP5 were overwhelmingly cases of unintended awareness during NMB. The incidence of accidental awareness during Caesarean section was ~1:670 (1:380-1300). Two-thirds (82, 66%) of cases of accidental awareness experiences arose in the dynamic phases of anaesthesia, namely induction of and emergence from anaesthesia. During induction of anaesthesia, contributory factors included: use of thiopental, rapid sequence induction, obesity, difficult airway management, NMB, and interruptions of anaesthetic delivery during movement from anaesthetic room to theatre. During emergence from anaesthesia, residual paralysis was perceived by patients as accidental awareness, and commonly related to a failure to ensure full return of motor capacity. One-third (43, 33%) of accidental awareness events arose during the maintenance phase of anaesthesia, mostly due to problems at induction or towards the end of anaesthesia. Factors increasing the risk of accidental awareness included: female sex, age (younger adults, but not children), obesity, anaesthetist seniority (junior trainees), previous awareness, out-of-hours operating, emergencies, type of surgery (obstetric, cardiac, thoracic), and use of NMB. The following factors were not risk factors for accidental awareness: ASA physical status, race, and use or omission of nitrous oxide. We recommend that an anaesthetic checklist, to be an integral part of the World Health Organization Safer Surgery checklist, is introduced as an aid to preventing accidental awareness. This paper is a shortened version describing the main findings from NAP5--the full report can be found at http://www.nationalauditprojects.org.uk/NAP5_home.

The state of UK anaesthesia: a survey of National Health Service activity in 2013.

BACKGROUND: Details of current UK anaesthetic practice are unknown and were needed for interpretation of reports of accidental awareness during general anaesthesia (GA) within the 5th National Audit Project. METHODS: We surveyed NHS anaesthetic activity to determine numbers of patients managed by anaesthetists and details of 'who, when, what, and where': activity included GA, local anaesthesia, sedation, or patients managed awake. Anaesthetists in NHS hospitals collected data on all patients for 2 days. Scaling enabled estimation of annual activity. RESULTS: Hospital response rate was 100% with 20,400 returns. The median return rate within departments was 98% (inter-quartile range 0.95-1). Annual numbers (% of total) of general anaesthetics, sedation, and awake cases were 2,766,600 (76.9%), 308,800 (8.6%), and 523,100 (14.5%), respectively. A consultant or career grade anaesthetist was present in more than 87% of cases. Emergency cases accounted for 23.1% of workload, 75% of which were undertaken out of hours. Specialties with the largest workload were orthopaedics/trauma (22.1%), general surgery (16.1%), and gynaecology (9.6%): 6.2% of cases were non-surgical. The survey data describe: who anaesthetized patients according to time of day, urgency, and ASA grade; when anaesthesia took place by day and by weekday; the distribution of patient types, techniques, and monitoring; where patients were anaesthetized. Nine patients out of 15 460 receiving GA died intraoperatively. CONCLUSIONS: Anaesthesia in the UK is currently predominantly a consultant-delivered service. The low mortality rate supports the safety of UK anaesthetic care. The survey data should be valuable for planning and monitoring anaesthesia services.

Age-related changes in EEG power spectra in infants during sevoflurane wash-out.

BACKGROUND: Few electroencephalography (EEG) data are available in anaesthetized infants. This study aimed to identify EEG characteristics that might warn of awakening (AW) from sevoflurane anaesthesia in infants. METHODS: Twenty intubated infants [aged 39-77 weeks post-menstrual age (PMA)] were studied after surgery during sevoflurane wash-out. EEG was recorded at the end of surgery and throughout emergence. Changes in EEG time and frequency domains were described. RESULTS: At the end of surgery, mean end-tidal sevoflurane concentration was 2.3% (range 1.5-3.5) before wash-out and reduced to 0.3% (0.1-0.6) when AW began. On AW, movement artifacts made signals difficult to interpret. Before awakening, most power was within frequencies ≤4 Hz, but trends over time were variable. Summated power in frequencies between 20 and 70 Hz was almost always <5 µV(2). During anaesthesia, there were two common power spectra: infants >52 weeks PMA had obvious summated power in the frequency range 5-20 Hz (P5-20 Hz) (mean 308, median 320, range 110-542 µV(2)), which decreased before awakening began [mean decrease 252 µV(2) (95% CI 153-351)], whereas younger infants had low P5-20 Hz throughout. P5-20 Hz during anaesthesia increased with age; power in this frequency band of ~100 µV(2) separated infants younger and older than 52 weeks PMA. CONCLUSIONS: During sevoflurane wash-out, decreasing P5-20 Hz might warn of impending AW in infants >3 months old, but not in younger infants.

Procedural sedation and analgesia in children by non-anesthesiologists in an emergency department.

Procedural sedation and analgesia (PSA) is a standard of care for the management of acute procedural pain and anxiety in the emergency department (ED). However, there is evidence that PSA practice is still ineffective and potentially unsafe in many pediatric settings. PSA has to be regarded as a separate medical act that should be provided only by well-trained and credentialized professionals, within a context of transparency, registration and ongoing quality control. Only by maintaining strict criteria regarding professional competences, safety precautions, monitoring, recovery and rescue facilities an optimal patient safety can be guaranteed. Besides, ED professionals have a duty to deliver effective PSA, not only from a procedural point of view (i.e. guaranteeing predictable procedural success and timing) but also from a patient's perspective (i.e. achieving optimal procedural comfort). An effective PSA program on a pediatric ED means that a professional is easily available at all times who is trained in the safe use of highly controllable drugs that match the sedation need and guarantee an optimal level of comfort without the need for forced immobilization or restraint. A high-quality PSA service includes the adequate use of local or topical anesthesia, the systematic application of non-pharmacologic techniques, the availability of effective PSA drugs and the possibility of rescue anesthesia in case PSA is unsuccessful or is expected to be ineffective or unsafe in a given patient. PSA for children, including deep sedation, should be formally incorporated in the training program for emergency physicians.

Risk of cardiac catheterization under anaesthesia in children with pulmonary hypertension.

BACKGROUND: Children with primary pulmonary hypertension (PHT) are a high-risk group who require assessment by cardiac catheterization under anaesthesia. Complications, including death, have occurred during anaesthesia in these patients, but the true risk has not been quantified. METHODS: The clinical records of children with PHT undergoing general anaesthesia for pulmonary vascular resistance studies were reviewed retrospectively. Data collected included pre-catheter measures of severity of disease, details of clinical management, and complications occurring within 24 h of the start of anaesthesia. RESULTS: During the past 5 yr, 75 consecutive patients were catheterized and usable records were available in 70. The age range was 0.1-18 yr (mean 7.1). Four children required external cardiac massage [6% (95% confident limits 1-11%)] and one of these died. Of the four, two had an arrhythmia related to the mechanical effects of catheterization, one was hypotensive during anaesthesia and the other had fatal cardiac failure in recovery. All four had severe PHT as judged by echocardiographic estimation of tricuspid regurgitant jet velocity>4 m s-1. CONCLUSIONS: Resuscitation or death occurred in 6% of cases. Any associated risk factors could not be determined because the number of complications was too small. Risks may be highest in children with severe idiopathic PHT and symptoms of chest pain, syncope, or dizziness.