SummaryBackgroundPrevious preclinical research has shown that extracorporeal devices can be used to enhance the delivery and distribution of systemically administered anticancer drugs, resulting in increased intratumoural concentrations. We aimed to assess the safety and feasibility of targeted release and enhanced delivery of doxorubicin to solid tumours from thermosensitive liposomes triggered by mild hyperthermia, induced non-invasively by focused ultrasound.MethodsWe did an open-label, single-centre, phase 1 trial in a single UK hospital. Adult patients (aged ≥18 years) with unresectable and non-ablatable primary or secondary liver tumours of any histological subtype were considered for the study. Patients received a single intravenous infusion (50 mg/m2) of lyso-thermosensitive liposomal doxorubicin (LTLD), followed by extracorporeal focused ultrasound exposure of a single target liver tumour. The trial had two parts: in part I, patients had a real-time thermometry device implanted intratumourally, whereas patients in part II proceeded without thermometry and we used a patient-specific model to predict optimal exposure parameters. We assessed tumour biopsies obtained before and after focused ultrasound exposure for doxorubicin concentration and distribution. The primary endpoint was at least a doubling of total intratumoural doxorubicin concentration in at least half of the patients treated, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02181075, and is now closed to recruitment.FindingsBetween March 13, 2015, and March 27, 2017, ten patients were enrolled in the study (six patients in part I and four in part II), and received a dose of LTLD followed by focused ultrasound exposure. The treatment resulted in an average increase of 3·7 times in intratumoural biopsy doxorubicin concentrations, from an estimate of 2·34 μg/g (SD 0·93) immediately after drug infusion to 8·56 μg/g (5·69) after focused ultrasound. Increases of two to ten times were observed in seven (70%) of ten patients, satisfying the primary endpoint. Serious adverse events registered were expected grade 4 transient neutropenia in five patients and prolonged hospital stay due to unexpected grade 1 confusion in one patient. Grade 3–4 adverse events recorded were neutropenia (grade 3 in one patient and grade 4 in five patients), and grade 3 anaemia in one patient. No treatment-related deaths occurred.InterpretationThe combined treatment of LTLD and non-invasive focused ultrasound hyperthermia in this study seemed to be clinically feasible, safe, and able to enhance intratumoural drug delivery, providing targeted chemo-ablative response in human liver tumours that were refractory to standard chemotherapy.FundingOxford Biomedical Research Centre, National Institute for Health Research.

SummaryThe distribution of medico-legal claims in English anaesthetic practice is unreported. We studied National Health Service Litigation Authority claims related to anaesthesia since 1995. All claims were reviewed by three clinicians and variously categorised, including by type of incident, claimed outcome and cost. Anaesthesia-related claims account for 2.5% of all claims and 2.4% of the value of all claims. Of 841 relevant claims 366 (44%) were related to regional anaesthesia, 245 (29%) obstetric anaesthesia, 164 (20%) inadequate anaesthesia, 95 (11%) dental damage, 71 (8%) airway (excluding dental damage), 63 (7%) drug related (excluding allergy), 31 (4%) drug allergy related, 31 (4%) positioning, 29 (3%) respiratory, 26 (3%) consent, 21 (2%) central venous cannulation and 18 (2%) peripheral venous cannulation. Defining which cases are, from a medico-legal viewpoint, 'high risk' is uncertain, but the clinical categories with the largest number of claims were regional anaesthesia, obstetric anaesthesia, inadequate anaesthesia, dental damage and airway, those with the highest overall cost were regional anaesthesia, obstetric anaesthesia, and airway and those with the highest mean cost per closed claim were respiratory, central venous cannulation and drug error excluding allergy. The data currently available have limitations but offer useful information. A closed claims analysis similar to that in the USA would improve the clinical usefulness of analysis.

Summary Claims notified to the NHS Litigation Authority in England between 1995 and 2007 and filed under anaesthesia were analysed to explore patterns of injury and cost related to airway or respiratory events. Of 841 interpretable claims the final dataset contained 96 claims of dental damage, 67 airway‐related claims and 24 respiratory claims. Claims of dental damage contributed a numerically important (11%), but financially modest (0.5%) proportion of claims. These claims predominantly described injury during tracheal intubation or extubation; a minority associated with electroconvulsive therapy led to substantial cost per claim. The total cost of (non‐dental) airway claims was £4.9 million (84% closed, median cost £30 000) and that of respiratory claims was £3.3 million (81% closed, median £27 000). Airway and respiratory claims account for 12% of anaesthesia‐related claims, 53% of deaths, 27% of cost and ten of the 50 most expensive claims in the dataset. Airway claims most frequently described events at induction of anaesthesia, involved airway management with a tracheal tube and typically led to hypoxia and patient death or brain injury. Airway trauma accounted for one third of airway claims and these included deaths from mediastinal injury at intubation. Pulmonary aspiration and tube misplacement, including oesophageal intubation, led to several claims. Among respiratory claims, ventilation problems, combined with hypoxia, were an important source of claims. Although limited clinical details hamper analysis, the data suggest that most airway and respiratory‐related claims arise from sentinel events. The absence of clinical detail and denominators limit opportunities to learn from such events; much more could be learnt from a closed claim or sentinel event analysis scheme.

Summary This study examines the incidence and site of tracheal tube impingement during nasotracheal fibreoptic intubation, and the efficacy of anticlockwise tube rotation to overcome the problem. Forty‐three patients underwent fibreoptic‐assisted nasotracheal intubation using a preformed nasal tube, and a second fibrescope was used to observe any obstruction to passage of the tracheal tube. Impingement occurred in 10 cases, with the most common site being the right arytenoid cartilage. Rotation resulted in successful intubation in all 10 cases, but proximal rotation did not always result in an equal degree of rotation at the tube tip. We conclude that the site of impingement for nasotracheal intubation with preformed nasal tubes is located at the posterior structures of the laryngeal inlet and that anticlockwise rotation is a simple and effective solution.

SummaryWe analysed 366 claims related to regional anaesthesia and analgesia from the 841 anaesthesia . Non-obstetric claims were more likely to relate to severe outcomes than obstetric ones. The maximum values of claims were higher for claims related to neuraxial blocks and eye blocks than for peripheral nerve blocks. Despite many limitations, including lack of clinical detail for each case, the dataset provides a useful overview of the extent, patterns and cost associated with the claims.

To demonstrate the feasibility and safety of using focused ultrasound planning models to determine the treatment parameters needed to deliver volumetric mild hyperthermia for targeted drug delivery without real-time thermometry. Materials and Methods: This study was part of the Targeted Doxorubicin, or TARDOX, phase I prospective trial of focused ultrasound-mediated, hyperthermia-triggered drug delivery to solid liver tumors (ClinicalTrials.gov identifier NCT02181075). Ten participants (age range, 49-68 years; average age, 60 years; four women) were treated from March 2015 to March 2017 by using a clinically approved focused ultrasound system to release doxorubicin from lyso-thermosensitive liposomes. Ultrasonic heating of target tumors (treated volume: 11-73 cm 3 [mean 6 standard deviation, 50 cm 3 6 26]) was monitored in six participants by using a minimally invasive temperature sensor; four participants were treated without real-time thermometry. For all participants, CT images were used with a patient-specific hyperthermia model to define focused ultrasound treatment plans. Feasibility was assessed by comparing model-prescribed focused ultrasound powers to those implemented for treatment. Safety was assessed by evaluating MR images and biopsy specimens for evidence of thermal ablation and monitoring adverse events. Results: The mean difference between predicted and implemented treatment powers was 20.1 W 6 17.7 (n = 10). No evidence of focused ultrasound-related adverse effects, including thermal ablation, was found. Conclusion: In this 10-participant study, the authors confirmed the feasibility of using focused ultrasound-mediated hyperthermia planning models to define treatment parameters that safely enabled targeted, noninvasive drug delivery to liver tumors while monitored with B-mode guidance and without real-time thermometry. Pubished under a CC BY 4.0 license.

SummaryInadequate anaesthesia may cause distress to the patient and lead to medical litigation. All claims made to the NHS Litigation Authority 1995-2007 were obtained and the data was examined independently by all authors and classified. In a dataset of 1067 claims there were 161 cases of inadequate anaesthesia and data were suitable for analysis in 159: intra-operative awareness (79), brief awake paralysis (20) and inadequate regional anaesthesia (60). The total cost of closed claims was £3.2m. Cost was incurred in 100% of claims of brief awake paralysis, 87% of claims of awareness and 80% of claims of inadequate regional blockade. Mean cost of closed claims was £32 680 for anaesthetic awareness, £29 345 for inadequate regional blockade and £24 364 for brief awake paralysis. Inadequate anaesthesia accounts for 19% of anaesthesia-related claims in the NHS in England. Strategies that reduce anaesthetic awareness, drug errors and inadequate regional blockade are known and their improved implementation is likely to reduce such claims.

SummaryWe compared the incidence and site of impingement of a flexometallic tracheal tube with those of the re‐usable intubating laryngeal mask (ILMA) tube in 60 anaesthetised patients undergoing nasotracheal fibreoptic intubation for oral surgery. A two‐scope technique was used, observing the site of impingement with one scope whilst intubating with the other. The tubes were 6.0‐mm in females and 6.5‐mm in males. Impingement occurred with 10 (33%) flexometallic and 2 (7%) ILMA tubes (p < 0.032). In all but one case, the impingement was posterior to the right arytenoid cartilage. When impingement was observed, a single disempaction with a 90° anticlockwise rotational manoeuvre overcame impingement in every case except one, allowing successful intubation. We conclude that the incidence of impingement of the tracheal tube, and therefore of potential laryngeal trauma from nasotracheal fibreoptic intubation, is significantly greater with the flexometallic tube than with the ILMA tube.