Route of drug administration in out-of-hospital cardiac arrest: A protocol for a randomised controlled trial (PARAMEDIC-3).

Aims: The PARAMEDIC-3 trial evaluates the clinical and cost-effectiveness of an intraosseous first strategy, compared with an intravenous first strategy, for drug administration in adults who have sustained an out-of-hospital cardiac arrest. Methods: PARAMEDIC-3 is a pragmatic, allocation concealed, open-label, multi-centre, superiority randomised controlled trial. It will recruit 15,000 patients across English and Welsh ambulance services. Adults who have sustained an out-of-hospital cardiac arrest are individually randomised to an intraosseous access first strategy or intravenous access first strategy in a 1:1 ratio through an opaque, sealed envelope system. The randomised allocation determines the route used for the first two attempts at vascular access. Participants are initially enrolled under a deferred consent model.The primary clinical-effectiveness outcome is survival at 30-days. Secondary outcomes include return of spontaneous circulation, neurological functional outcome, and health-related quality of life. Participants are followed-up to six-months following cardiac arrest. The primary health economic outcome is incremental cost per quality-adjusted life year gained. Conclusion: The PARAMEDIC-3 trial will provide key information on the clinical and cost-effectiveness of drug route in out-of-hospital cardiac arrest.Trial registration: ISRCTN14223494, registered 16/08/2021, prospectively registered.

CPR Quality Officer role to improve CPR quality: A multi-centred international simulation randomised control trial.

Background: An out-of-hospital cardiac arrest requires early recognition, prompt and quality clinical interventions, and coordination between different clinicians to improve outcomes. Clinical team leaders and clinical teams have high levels of cognitive burden. We aimed to investigate the effect of a dedicated Cardio-Pulmonary Resuscitation (CPR) Quality Officer role on team performance. Methods: This multi-centre randomised control trial used simulation in universities from the UK, Poland, and Norway. Student Paramedics participated in out-of-hospital cardiac arrest scenarios before randomisation to either traditional roles or assigning one member as the CPR Quality Officer. The quality of CPR was measured using QCPR® and Advanced Life Support (ALS) elements were evaluated. Results: In total, 36 teams (108 individuals) participated. CPR quality from the first attempt (72.45%, 95% confidence interval [CI] 64.94 to 79.97) significantly increased after addition of the CPR Quality role (81.14%, 95% CI 74.20 to 88.07, p = 0.045). Improvement was not seen in the control group. The time to first defibrillation had no significant difference in the intervention group between the first attempt (53.77, 95% CI 36.57-70.98) and the second attempt (48.68, 95% CI 31.31-66.05, p = 0.84). The time to manage an obstructive airway in the intervention group showed significant difference (p = 0.006) in the first attempt (168.95, 95% CI 110.54-227.37) compared with the second attempt (136.95, 95% CI 87.03-186.88, p = 0.1). Conclusion: A dedicated CPR Quality Officer in simulated scenarios improved the quality of CPR compressions without a negative impact on time to first defibrillation, managing the airway, or adherence to local ALS protocols.

Automated external defibrillator location and socioeconomic deprivation in Great Britain.

OBJECTIVE: The early use of automated external defibrillators (AEDs) improves outcomes in out-of-hospital cardiac arrest (OHCA). We investigated AED access across Great Britain (GB) according to socioeconomic deprivation. METHODS: Cross-sectional observational study using AED location data from The Circuit: the national defibrillator network led by the British Heart Foundation in partnership with the Association of Ambulance Chief Executives, Resuscitation Council UK and St John Ambulance. We calculated street network distances between all 1 677 466 postcodes in GB and the nearest AED and used a multilevel linear mixed regression model to investigate associations between the distances from each postcode to the nearest AED and Index of Multiple Deprivation, stratified by country and according to 24 hours 7 days a week (24/7) access. RESULTS: 78 425 AED locations were included. Across GB, the median distance from the centre of a postcode to an AED was 726 m (England: 739 m, Scotland: 743 m, Wales: 512 m). For 24/7 access AEDs, the median distances were further (991 m, 994 m, 570 m). In Wales, the average distance to the nearest AED and 24/7 AED was shorter for the most deprived communities. In England, the average distance to the nearest AED was also shorter in the most deprived areas. There was no association between deprivation and average distance to the nearest AED in Scotland. However, the distance to the nearest 24/7 AED was greater with increased deprivation in England and Scotland. On average, a 24/7 AED was in England and Scotland, respectively, 99.2 m and 317.1 m further away in the most deprived than least deprived communities. CONCLUSION: In England and Scotland, there are differences in distances to the nearest 24/7 accessible AED between the most and least deprived communities. Equitable access to 'out-of-hours' accessible AEDs may improve outcomes for people with OHCA.

The views, opinions and decision-making of UK-based paramedics on the use of pre-hospital 12-lead electrocardiograms in acute stroke patients: a qualitative interview study.

Introduction: A qualitative exploration into the views, opinions and decision-making of paramedics involved in undertaking pre-hospital 12-lead electrocardiograms (PHECGs) for stroke patients was undertaken, in order to gain a deeper understanding of the clinical and occupational context that the paramedics work within, the acceptability of the paramedics in using PHECGs for stroke patients and the consequences and influences of their decision-making. Methods: Data were collected via semi-structured interviews and analysed using the framework method, with the underpinning theoretical framework of cognitive continuum theory. A purposive sample of 14 paramedics was recruited and interviewed. Results: Five themes were generated from the analysis of the interviews: (1) 'time is brain': minimising delays and rapid transport to definitive care; (2) barriers and facilitators to undertaking PHECGs for stroke patients; (3) recognising and gaining cues; (4) maintaining patient dignity, self-protection and fully informed consent; and (5) education, experience and engagement with evidence. Conclusion: The study showed mixed views on the usefulness of PHECGs, but all participants agreed that PHECGs should not cause additional delays. Paramedic decision-making on recording PHECGs relies on intuitive and quasi-rational cognitive modes, and requires a number of clinical, logistical and ethical considerations. The findings suggest careful consideration is needed of the benefits and potential drawbacks of incorporating PHECGs into pre-hospital stroke care.

Association of Real-Time Feedback and Cardiopulmonary-Resuscitation Quality Delivered by Ambulance Personnel for Out-of-Hospital Cardiac Arrest.

Background High-quality cardiopulmonary resuscitation (CPR) is associated with improved survival from out-of-hospital cardiac arrest and includes chest compression depth, chest compression rate, and chest compression fraction within international guideline recommendations. Previous studies have demonstrated divergent results of real-time feedback on CPR performance and patient outcomes. This study investigated the association between emergency medical service CPR quality and real-time CPR feedback for out-of-hospital cardiac arrest. Methods and Results This study collected out-of-hospital cardiac arrest data within the Capital Region of Denmark and compared CPR quality delivered by ambulance personnel. Data were collected in 2 consecutive phases from October 2018 to February 2020. Median chest compression depth was 6.0 cm (no feedback) and 5.9 cm (real-time feedback) (P=0.852). Corresponding proportion of guideline-compliant chest compressions for depth was 16.6% and 28.7%, respectively (P<0.001). Median chest compression rate per minute was 111 and 109 (P<0.001), respectively. Corresponding guideline adherence proportion for compression rate was 65.4% compared with 80.4% (P<0.001), respectively. Chest compression fraction was 78.9% compared with 81.9% (P<0.001), respectively. The combination of guideline-compliant chest compression depth and chest compression rate simultaneously was 8.5% (no feedback) versus 18.8% (feedback) (P<0.001). Improvements were not significant for return of spontaneous circulation (odds ratio [OR], 1.08 [95% CI, 0.84-1.39]), sustained return of spontaneous circulation (OR, 1.00 [95% CI, 0.77-1.31]), or survival to hospital discharge (OR, 0.91 [95% CI, 0.64-1.30]). Conclusions Real-time feedback was associated with improved guideline compliance for chest compression depth, rate, and fraction but not return of spontaneous circulation, sustained return of spontaneous circulation, or survival to hospital discharge. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04152252.

The United Kingdom Eating Disorders Genetics Initiative.

OBJECTIVE: The United Kingdom Eating Disorders Genetics Initiative (EDGI UK), part of the National Institute for Health and Care Research (NIHR) Mental Health BioResource, aims to deepen our understanding of the environmental and genetic etiology of eating disorders. EDGI UK launched in February 2020 and is partnered with the UK eating disorders charity, Beat. Multiple EDGI branches exist worldwide. This article serves the dual function of providing an in-depth description of our study protocol and of describing our initial sample including demographics, diagnoses, and physical and psychiatric comorbidities. METHOD: EDGI UK recruits via media and clinical services. Anyone living in England, at least 16 years old, with a lifetime probable or clinical eating disorder is eligible to sign up online: edgiuk.org. Participants complete online questionnaires, donate a saliva sample for genetic analysis, and consent to medical record linkage and recontact for future studies. RESULTS: As of September 2022, EDGI UK recruited 7435 survey participants: 98% female, 93.1% white, 97.8% cisgender, 65.9% heterosexual, and 52.1% have a university degree. Over half (57.8%) of these participants have returned their saliva DNA kit. The most common diagnoses are anorexia nervosa (48.3%), purging disorder (37.8%), bulimia nervosa (37.5%), binge-eating disorder (15.8%), and atypical anorexia nervosa (7.8%). CONCLUSION: EDGI UK is the largest UK eating disorders study and efforts to increase its diversity are underway. It offers a unique opportunity to accelerate eating disorder research. Researchers and participants with lived experience can collaborate on projects with unparalleled sample size. PUBLIC SIGNIFICANCE STATEMENT: Eating disorders are debilitating and costly for society but are under-researched due to underfunding. EDGI UK is one of the largest eating disorder studies worldwide with ongoing recruitment. The collected data constitute a resource for secondary analysis. We will combine data from all international EDGI branches and the NIHR BioResource to facilitate research that improves our understanding of eating disorders and their comorbidities.

Phase 2 randomised placebo-controlled trial of spironolactone and dexamethasone versus dexamethasone in COVID-19 hospitalised patients in Delhi.

BACKGROUND: In this phase 2 randomised placebo-controlled clinical trial in patients with COVID-19, we hypothesised that blocking mineralocorticoid receptors using a combination of dexamethasone to suppress cortisol secretion and spironolactone is safe and may reduce illness severity. METHODS: Hospitalised patients with confirmed COVID-19 were randomly allocated to low dose oral spironolactone (50 mg day 1, then 25 mg once daily for 21 days) or standard of care in a 2:1 ratio. Both groups received dexamethasone 6 mg daily for 10 days. Group allocation was blinded to the patient and research team. Primary outcomes were time to recovery, defined as the number of days until patients achieved WHO Ordinal Scale (OS) category ≤ 3, and the effect of spironolactone on aldosterone, D-dimer, angiotensin II and Von Willebrand Factor (VWF). RESULTS: One hundred twenty patients with PCR confirmed COVID were recruited in Delhi from 01 February to 30 April 2021. 74 were randomly assigned to spironolactone and dexamethasone (SpiroDex), and 46 to dexamethasone alone (Dex). There was no significant difference in the time to recovery between SpiroDex and Dex groups (SpiroDex median 4.5 days, Dex median 5.5 days, p = 0.055). SpiroDex patients had significantly lower D-dimer levels on days 4 and 7 (day 7 mean D-dimer: SpiroDex 1.15 µg/mL, Dex 3.15 µg/mL, p = 0.0004) and aldosterone at day 7 (SpiroDex 6.8 ng/dL, Dex 14.52 ng/dL, p = 0.0075). There was no difference in VWF or angiotensin II levels between groups. For secondary outcomes, SpiroDex patients had a significantly greater number of oxygen free days and reached oxygen freedom sooner than the Dex group. Cough scores were no different during the acute illness, however the SpiroDex group had lower scores at day 28. There was no difference in corticosteroid levels between groups. There was no increase in adverse events in patients receiving SpiroDex. CONCLUSION: Low dose oral spironolactone in addition to dexamethasone was safe and reduced D-dimer and aldosterone. Time to recovery was not significantly reduced. Phase 3 randomised controlled trials with spironolactone and dexamethasone should be considered. TRIAL REGISTRATION: The trial was registered on the Clinical Trials Registry of India TRI: CTRI/2021/03/031721, reference: REF/2021/03/041472. Registered on 04/03/2021.

Computational Fluorescence Suppression in Shifted Excitation Raman Spectroscopy.

Fiber-based Raman spectroscopy in the context of in vivo biomedical application suffers from the presence of background fluorescence from the surrounding tissue that might mask the crucial but inherently weak Raman signatures. One method that has shown potential for suppressing the background to reveal the Raman spectra is shifted excitation Raman spectroscopy (SER). SER collects multiple emission spectra by shifting the excitation by small amounts and uses these spectra to computationally suppress the fluorescence background based on the principle that Raman spectrum shifts with excitation while fluorescence spectrum does not. We introduce a method that utilizes the spectral characteristics of the Raman and fluorescence spectra to estimate them more effectively, and compare this approach against existing methods on real world datasets.

Specific in situ immuno-imaging of pulmonary-resident memory lymphocytes in human lungs.

Introduction: Pulmonary-resident memory T cells (TRM) and B cells (BRM) orchestrate protective immunity to reinfection with respiratory pathogens. Developing methods for the in situ detection of these populations would benefit both research and clinical settings. Methods: To address this need, we developed a novel in situ immunolabelling approach combined with clinic-ready fibre-based optical endomicroscopy (OEM) to detect canonical markers of lymphocyte tissue residency in situ in human lungs undergoing ex vivo lung ventilation (EVLV). Results: Initially, cells from human lung digests (confirmed to contain TRM/BRM populations using flow cytometry) were stained with CD69 and CD103/CD20 fluorescent antibodies and imaged in vitro using KronoScan, demonstrating it's ability to detect antibody labelled cells. We next instilled these pre-labelled cells into human lungs undergoing EVLV and confirmed they could still be visualised using both fluorescence intensity and lifetime imaging against background lung architecture. Finally, we instilled fluorescent CD69 and CD103/CD20 antibodies directly into the lung and were able to detect TRM/BRM following in situ labelling within seconds of direct intra-alveolar delivery of microdoses of fluorescently labelled antibodies. Discussion: In situ, no wash, immunolabelling with intra-alveolar OEM imaging is a novel methodology with the potential to expand the experimental utility of EVLV and pre-clinical models.

Screening patients for unintentional carbon monoxide exposure in the Emergency Department: a cross-sectional multi-centre study.

BACKGROUND: Low-level exposure to carbon monoxide (CO) is a significant health concern but is difficult to diagnose. This main study aim was to establish the prevalence of low-level CO poisoning in Emergency Department (ED) patients. METHODS: A prospective cross-sectional study of patients with symptoms of CO exposure was conducted in four UK EDs between December 2018 and March 2020. Data on symptoms, a CO screening tool and carboxyhaemoglobin were collected. An investigation of participants' homes was undertaken to identify sources of CO exposure. RESULTS: Based on an ED assessment of 4175 participants, the prevalence of suspected CO exposure was 0.62% (95% CI; 0.41-0.91%). CO testing in homes confirmed 1 case of CO presence and 21 probable cases. Normal levels of carboxyhaemoglobin were found in 19 cases of probable exposure and in the confirmed case. CONCLUSION: This study provides evidence that ED patients with symptoms suggestive of CO poisoning but no history of CO exposure are at risk from CO poisoning. The findings suggest components of the CO screening tool may be an indicator of CO exposure over and above elevated COHb. Clinicians should have a high index of suspicion for CO exposure so that this important diagnosis is not missed.

Quality indicators for post-resuscitation care after out-of-hospital cardiac arrest: a joint statement from the Association for Acute Cardiovascular Care of the European Society of Cardiology, the European Resuscitation Council, the European Society of Intensive Care Medicine, and the European Society for Emergency Medicine.

AIMS: Quality of care (QoC) is a fundamental tenet of modern healthcare and has become an important assessment tool for healthcare authorities, stakeholders and the public. However, QoC is difficult to measure and quantify because it is a multifactorial and multidimensional concept. Comparison of clinical institutions can be challenging when QoC is estimated solely based on clinical outcomes. Thus, measuring quality through quality indicators (QIs) can provide a foundation for quality assessment and has become widely used in this context. QIs for the evaluation of QoC in acute myocardial infarction are now well-established, but no such indicators exist for the process from resuscitation of cardiac arrest and post-resuscitation care in Europe. METHODS AND RESULTS: The Association of Acute Cardiovascular Care of the European Society Cardiology, the European Resuscitation Council, European Society of Intensive Care Medicine and the European Society for Emergency Medicine, have reflected on the measurement of QoC in cardiac arrest. A set of QIs have been proposed, with the scope to unify and evolve QoC for the management of cardiac arrest across Europe. CONCLUSION: We present here the list of QIs (6 primary QIs and 12 secondary Qis), with descriptions of the methodology used, scientific justification and motives for the choice for each measure with the aim that this set of QIs will enable assessment of the quality of postout-of-hospital cardiac arrest management across Europe.

Management of comatose survivors of out-of-hospital cardiac arrest in Europe: current treatment practice and adherence to guidelines. A joint survey by the Association for Acute CardioVascular Care (ACVC) of the ESC, the European Resuscitation Council (ERC), the European Society for Emergency Medicine (EUSEM), and the European Society of Intensive Care Medicine (ESICM).

AIMS: International guidelines give recommendations for the management of comatose out-of-hospital cardiac arrest (OHCA) survivors. We aimed to investigate adherence to guidelines and disparities in the treatment of OHCA in hospitals in Europe. METHODS AND RESULTS: A web-based, multi-institutional, multinational survey in Europe was conducted using an electronic platform with a predefined questionnaire developed by experts in post-resuscitation care. The survey was disseminated to all members of the societies via email, social media, websites, and newsletters in June 2021. Of 252 answers received, 237 responses from different units were included and 166 (70%) were from cardiac arrest centres. First-line vasopressor used was noradrenaline in 195 (83%) and the first-line inotrope was dobutamine in 148 (64%) of the responses. Echocardiography is available 24/7 in 204 (87%) institutions. Targeted temperature management was used in 160 (75%) institutions for adult comatose survivors of OHCA with an initial shockable rhythm. Invasive or external cooling methods with feedback were used in 72 cardiac arrest centres (44%) and 17 (24%) non-cardiac arrest centres (P < 0.0003). A target temperature between 32 and 34°C was preferred by 46 centres (21%); a target between 34 and 36°C by 103 centres (52%); and <37.5°C by 35 (16%). Multimodal neuroprognostication was poorly implemented and a follow-up at 3 months after discharge was done in 71 (30%) institutions. CONCLUSION: Post-resuscitation care is not well established and varies among centres in European hospitals. Cardiac arrest centres have a higher coherence with guidelines compared with respondents from non-cardiac arrest centres. The overall inconsistency in approaches and deviation from recommendations could be a focus for improvement.

Tri-mode optical biopsy probe with fluorescence endomicroscopy, Raman spectroscopy, and time-resolved fluorescence spectroscopy.

We present an endoscopic probe that combines three distinct optical fibre technologies including: A high-resolution imaging fibre for optical endomicroscopy, a multimode fibre for time-resolved fluorescence spectroscopy, and a hollow-core fibre with multimode signal collection cores for Raman spectroscopy. The three fibers are all enclosed within a 1.2 mm diameter clinical grade catheter with a 1.4 mm end cap. To demonstrate the probe's flexibility we provide data acquired with it in loops of radii down to 2 cm. We then use the probe in an anatomically accurate model of adult human airways, showing that it can be navigated to any part of the distal lung using a commercial bronchoscope. Finally, we present data acquired from fresh ex vivo human lung tissue. Our experiments show that this minimally invasive probe can deliver real-time optical biopsies from within the distal lung - simultaneously acquiring co-located high-resolution endomicroscopy and biochemical spectra.

An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis: A Phase Ib/IIa Randomized Controlled Clinical Trial (DEFINE).

Rationale: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. Objectives: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. Methods: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. Measurements and Main Results: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 + SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2-7; P = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. Conclusions: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registered with ClinicalTrials.gov (NCT04473053) and EudraCT (2020-002230-32).

The pre-hospital 12-lead electrocardiogram is associated with longer delay and worse outcomes in patients presenting to emergency medical services with acute stroke: a linked cohort study.

Objectives: To investigate the association between pre-hospital 12-lead electrocardiogram (PHECG) use in patients presenting to emergency medical services (EMS) with acute stroke, and clinical outcomes and system delays. Methods: Multi-centre linked cohort study. Patients with verified acute stroke admitted to hospital via EMS were identified through routinely collected hospital data and linked to EMS clinical records via EMS unique identifiers. Ordinal and logistic regression analyses were undertaken to analyse the relationship between having a PHECG and modified Rankin Scale (mRS); hospital mortality; pre-hospital time intervals; door-to-scan and door-to-needle times; and rates of thrombolysis. Results: Of 1161 eligible patients admitted between 29 December 2013 and 30 January 2017, PHECG was performed in 558 (48%). PHECG was associated with an increase in mRS (adjusted odds ratio [aOR] 1.30, 95% confidence interval [CI] 1.01-1.66, p = 0.04) and hospital mortality (aOR 1.83, 95% CI 1.26-2.67, p = 0.002). There was no association between PHECG and administration of thrombolytic treatment (aOR 1.06, 95% CI 0.75-1.52, p = 0.73). Patients who had PHECG recorded spent longer under the care of EMS (median 49 vs 43 minutes, p = 0.006). No difference in times to receiving brain scan (median 28 with PHECG vs 29 minutes no PHECG, p = 0.32) or thrombolysis (median 46 vs 48 minutes, p = 0.37) were observed. Conclusion: The PHECG was associated with worse outcomes and longer delays in patients with acute ischaemic stroke.

Protocol for a scoping review on the development of policy, guidelines and protocols within emergency medical services.

Introduction: Emergency medical services (EMS) use a combination of policy, clinical practice guidelines and protocols to set out their expectations for service delivery and to inform patient care. While these are integral to how EMS now operate, relatively little is known about how they are developed, or the processes involved. Therefore, the aim of this scoping review is to understand what is known in the literature about the development of policy, guidelines and protocols within EMS. Methods: This scoping review will follow the Arksey and O'Malley (2005) methodological framework for scoping reviews. A search strategy has been developed using index term definitions, building from authors' knowledge of the field. The following electronic databases will be searched from 2002 to 2021 for all types of publication: CINAHL, Medline, Academic Search Complete and PsycINFO, EMBASE, Nursing and Allied Health, the Cochrane library, NICE Evidence, Scopus, OpenGrey, EThOS, Google Scholar, Google search and key EMS journal websites. The results will be downloaded using EndNoteX9 reference management software and duplicates will be removed. Titles and abstracts of the results will be independently screened for their relevance to the research question, and the full text of each selected publication will be assessed against pre-determined inclusion and exclusion criteria to determine its eligibility. The reference list and forward citations will be searched for articles meeting the eligibility criteria. A second researcher will independently assess a 10% sample of results to allow for validation of this assessment. Data will be extracted and charted on the characteristics of the publications and the knowledge they contribute on the development of policy, guidelines or protocols. Accompanying narratives will be presented to identify themes and gaps in the available evidence. A critical appraisal will be undertaken of the included publications, where empirical research is presented.

Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics.

BACKGROUND: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate. METHODS: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis. FINDINGS: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 - 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43-18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55-95% CI 0.31-0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. INTERPRETATION: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events. FUNDING: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).

Impact of availability of catheter laboratory facilities on management and outcomes of acute myocardial infarction presenting with out of hospital cardiac arrest.

OBJECTIVES: We aimed to identify whether the availability of catheter laboratory affects clinical outcomes of out-of-hospital cardiac arrest (OHCA) complicating myocardial infarction (AMI). METHODS: Patients admitted with a diagnosis of AMI and OHCA from the Myocardial Ischaemia National Audit Project (MINAP) between 2010 to 2017 were stratified into three groups based on initial hospital's catheter laboratory status: hospitals without a catheter laboratory (No-catheter lab hospitals), hospitals with diagnostic catheter laboratory (Diagnostic hospitals), and hospitals with PCI facilities (PCI hospitals). We used multivariable logistic regression to evaluate factors associated with clinical outcomes. RESULTS: We included 12,303 patients of which 9,798 were admitted to PCI hospitals, 1,595 to no-catheter lab hospitals, and 910 to diagnostic hospitals. Patients admitted to PCI hospitals were more frequently reviewed by a cardiologist (96%, p < 0.001) than no-catheter lab hospitals (80%) and diagnostic hospitals (74%), and more likely to receive coronary angiography (PCI hospitals (87%), diagnostic hospitals (31%), no-catheter lab hospitals (54%), p < 0.001). They also were more likely to undergo PCI (PCI hospitals (42%), diagnostic hospitals (17%), no-catheter lab hospitals (17%), p < 0.001). After adjustment, there was no significant difference in the in-hospital mortality (OR 0.76, 95% CI 0.55-1.06) or re-infarction (OR 1.28, 95% CI 0.72-2.26) in patients admitted to PCI hospitals nor in patients admitted to diagnostic hospitals (mortality (OR 1.28, 95% CI 0.72-2.26), re-infarction (OR 1.38, 95% CI 0.68-2.82)). CONCLUSION: There is variation in coronary angiography use between hospitals without a catheter laboratory and PCI centres, which was not associated with better in-hospital survival.

British Cardiovascular Intervention Society Consensus Position Statement on Out-of-hospital Cardiac Arrest 2: Post-discharge Rehabilitation.

Out-of-hospital cardiac arrest (OHCA) is a major public health issue that poses significant challenges both in immediate management and long-term follow-up. Survivors of OHCA often experience a combination of complex medical, physical and psychological needs that have a significant impact on quality of life. Guidelines suggest a multi-dimensional follow-up to address both physical and non-physical domains for survivors. However, it is likely that there is substantial unwarranted variation in provision of services throughout the UK. Currently, there is no nationally agreed model for the follow-up of OHCA survivors and there is an urgent need for a set of standards and guidelines in order to ensure equal access for all. Accordingly, the British Cardiovascular Interventional Society established a multi-disciplinary working group to develop a position statement that summarises the most up-to-date evidence and provides guidance on essential and desirable services for a dedicated follow-up pathway for survivors of OHCA.

British Cardiovascular Interventional Society Consensus Position Statement on Out-of-Hospital Cardiac Arrest 1: Pathway of Care.

Out-of-hospital cardiac arrest (OHCA) affects 80,000 patients per year in the UK; despite improvements in care, survival to discharge remains lower than 10%. NHS England and several societies recommend all resuscitated OHCA patients be directly transferred to a cardiac arrest centre (CAC). However, evidence is limited that all patients benefit from transfer to a CAC, and there are significant organisational, logistic and financial implications associated with such change in policies. Furthermore, there is significant variability in interventional cardiovascular practices for OHCA. Accordingly, the British Cardiovascular Interventional Society established a multidisciplinary group to address variability in practice and provide recommendations for the development of cardiac networks. In this position statement, we recommend: the formal establishment of dedicated CACs; a pathway of conveyance to CACs; and interventional practice to standardise our approach. Further research is needed to understand the role of CACs and which interventions benefit patients with OHCA to support wide-scale changes in networks of care across the UK.