Exploiting in silico modelling to enhance translation of liver cell therapies from bench to bedside.

Cell therapies are emerging as promising treatments for a range of liver diseases but translational bottlenecks still remain including: securing and assessing the safe and effective delivery of cells to the disease site; ensuring successful cell engraftment and function; and preventing immunogenic responses. Here we highlight three therapies, each utilising a different cell type, at different stages in their clinical translation journey: transplantation of multipotent mesenchymal stromal/signalling cells, hepatocytes and macrophages. To overcome bottlenecks impeding clinical progression, we advocate for wider use of mechanistic in silico modelling approaches. We discuss how in silico approaches, alongside complementary experimental approaches, can enhance our understanding of the mechanisms underlying successful cell delivery and engraftment. Furthermore, such combined theoretical-experimental approaches can be exploited to develop novel therapies, address safety and efficacy challenges, bridge the gap between in vitro and in vivo model systems, and compensate for the inherent differences between animal model systems and humans. We also highlight how in silico model development can result in fewer and more targeted in vivo experiments, thereby reducing preclinical costs and experimental animal numbers and potentially accelerating translation to the clinic. The development of biologically-accurate in silico models that capture the mechanisms underpinning the behaviour of these complex systems must be reinforced by quantitative methods to assess cell survival post-transplant, and we argue that non-invasive in vivo imaging strategies should be routinely integrated into transplant studies.

Expert consensus on training and accreditation for extracorporeal cardiopulmonary resuscitation an international, multidisciplinary modified Delphi Study.

BACKGROUND: A multidisciplinary group of stakeholders were used to identify: (1) the core competencies of a training program required to perform in-hospital ECPR initiation (2) additional competencies required to perform pre-hospital ECPR initiation and; (3) the optimal training method and maintenance protocol for delivering an ECPR program. METHODS: A modified Delphi process was undertaken utilising two web based survey rounds and one virtual meeting. Experts rated the importance of different aspects of ECPR training, competency and governance on a 9-point Likert scale. A diverse, representative group was targeted. Consensus was achieved when greater than 70% respondents rated a domain as critical (> or = 7 on the 9 point Likert scale). RESULTS: 35 international ECPR experts from 9 countries formed the expert panel, with a median number of 14 years of ECMO practice (interquartile range 11-38). Participant response rates were 97% (survey round one), 63% (virtual meeting) and 100% (survey round two). After the second round of the survey, 47 consensus statements were formed outlining a core set of competencies required for ECPR provision. We identified key elements required to safely train and perform ECPR including skill pre-requisites, surrogate skill identification, the importance of competency-based assessment over volume of practice and competency requirements for successful ECPR practice and skill maintenance. CONCLUSIONS: We present a series of core competencies, training requirements and ongoing governance protocols to guide safe ECPR implementation. These findings can be used to develop training syllabus and guide minimum standards for competency as the growth of ECPR practitioners continues.

Developing key performance indicators for adult critical care transfer services: Scoping review and Delphi technique.

In 2021 NHS England commissioned regional Adult Critical Care Transfer Services. These services will replace a historically predominant ad hoc approach to adult critical care transfers nationally. It is anticipated that these new formal services will provide a system of robust regional & national governance previously acknowledged to be deficient. As part of this process, it is important that an agreed set of transfer service quality indicators are developed to drive equitable improvement in patient care. We used a Delphi technique to develop a set of key performance indicators through consensus for a recently established London critical care transfer service. We believe this may be the first-time key performance indicators have been developed for adult critical care transfer services using a consensus method. We hope services will consider tracking similar measures to enable benchmarking and drive improvements in patient care.

Early quantitative infrared pupillometry for prediction of neurological outcome in patients admitted to intensive care after out-of-hospital cardiac arrest.

BACKGROUND: Quantitative pupillometry is recommended for neuroprognostication after out-of-hospital cardiac arrest 72 h or more after ICU admission, but the feasibility and utility of earlier assessment is unknown. METHODS: This was a study of the utility of an early quantitative pupillometry index in predicting neurological outcome in patients with reduced consciousness after out-of-hospital cardiac arrest. Quantitative infrared pupillometry index was measured at 0, 6, 24, 48, and 72 h from admission. Acceptable predictive utility was defined as a positive predictive value of >95% and false positive rate of zero, with a narrow 95% confidence interval (95% CI). RESULTS: At least one quantitative pupillometry index measurement was available from within the first 6 h for all 77 patients who met inclusion criteria. A quantitative pupillometry index ≤2.4 at baseline and ≤2.3 within the first 6 h met the criteria for utility. The positive predictive value of the baseline cut-off (≤2.4) for poor neurological outcome was 1.00 (95% CI, 0.54-1.00) with an estimated false positive rate of 0% (95% CI, 0-9%). The positive predictive value of the 6 h cut-off (≤2.3) for poor neurological outcome was 1.00 (95% CI, 0.59-1.00) with an estimated false positive rate of 0% (95% CI, 0-8%). Sensitivities of these cut-offs for ruling out poor neurological outcomes at 0 and 6 h were 19% and 22%, respectively. Of seven patients with a quantitative pupillometry index ≤2.3 within 6 h of ICU admission, none survived. Analyses that used quantitative pupillometry index measurements from 24 to 72 h, but excluded baseline and 6 h values, were not predictive by the utility criteria. CONCLUSIONS: Quantitative pupillometry within 6 h of ICU admission after out-of-hospital cardiac arrest may identify patients with a very low chance of neurologically intact survival. Further studies of early quantitative pupillometry in this population are warranted.

Co-enrolment to UK Critical Care Studies - A 2019 update.

In 2013, a group of clinicians on behalf of the National Institute for Health Research, collaborated with ICU Steps to produce guidance about people being enrolled in more than one critical care trial. This is referred to as "co-enrolment" and can be where a person takes part in one study at the same time as another study (or one after the other in a short time-frame). For instance, being part of a study looking at sepsis drugs and a mechanical ventilation weaning study. The drivers for developing this guidance were a lack of any existing guidance, nationally and internationally, at that time, and a desire to ensure high quality research is conducted. The emphasis was on making trials as safe as possible for patients and ensuring robust trial outcomes. Critical care was seen to lead in this, with our exemplar guidance used across all health research. We wish to revisit this guidance now that there is more experience of coenrolment in critical care trials. There is also more awareness of different consent models, such as deferred consent (taking consent when a person is awake and able to give consent) and consultee consent (asking families or independent professionals to consent). Consenting to coenrolment is an important ethical consideration for the revision of this guidance.

RAND appropriateness panel to determine the applicability of UK guidelines on the management of acute respiratory distress syndrome (ARDS) and other strategies in the context of the COVID-19 pandemic.

BACKGROUND: COVID-19 has become the most common cause of acute respiratory distress syndrome (ARDS) worldwide. Features of the pathophysiology and clinical presentation partially distinguish it from 'classical' ARDS. A Research and Development (RAND) analysis gauged the opinion of an expert panel about the management of ARDS with and without COVID-19 as the precipitating cause, using recent UK guidelines as a template. METHODS: An 11-person panel comprising intensive care practitioners rated the appropriateness of ARDS management options at different times during hospital admission, in the presence or absence of, or varying severity of SARS-CoV-2 infection on a scale of 1-9 (where 1-3 is inappropriate, 4-6 is uncertain and 7-9 is appropriate). A summary of the anonymised results was discussed at an online meeting moderated by an expert in RAND methodology. The modified online survey comprising 76 questions, subdivided into investigations (16), non-invasive respiratory support (18), basic intensive care unit management of ARDS (20), management of refractory hypoxaemia (8), pharmacotherapy (7) and anticoagulation (7), was completed again. RESULTS: Disagreement between experts was significant only when addressing the appropriateness of diagnostic bronchoscopy in patients with confirmed or suspected COVID-19. Adherence to existing published guidelines for the management of ARDS for relevant evidence-based interventions was recommended. Responses of the experts to the final survey suggested that the supportive management of ARDS should be the same, regardless of a COVID-19 diagnosis. For patients with ARDS with COVID-19, the panel recommended routine treatment with corticosteroids and a lower threshold for full anticoagulation based on a high index of suspicion for venous thromboembolic disease. CONCLUSION: The expert panel found no reason to deviate from the evidence-based supportive strategies for managing ARDS outlined in recent guidelines.

Extracorporeal membrane oxygenation (ECMO): Radiographic appearances, complications and imaging artefacts for radiologists.

Extracorporeal membrane oxygenation (ECMO) is a form of cardiopulmonary support primarily used in cardiothoracic and intensive care unit (ICU) settings. The purpose of this review is to familiarise radiologists with the imaging features of ECMO devices, their associated complications and appropriate imaging protocols for contrast-enhanced CT imaging of ECMO patients. This paper will provide a brief introduction to ECMO and the imaging modalities utilised in ECMO patients, followed by a description of the types of ECMO available and cannula positioning. Indications and contraindications for ECMO will be outlined followed by a description of the complications associated with ECMO, which radiologists should recognise. Finally, the imaging protocol and interpretation of contrast-enhanced CT imaging in ECMO patients will be discussed. In the current clinical climate with millions of COVID-19 cases around the world and tens of thousands of critically ill patients, many requiring cardiopulmonary support in intensive care units, the use of ECMO in adults has increased, and thus so has the volume of imaging. Radiologists need to be familiar with the types of ECMO available, the correct positioning of the catheters depending on the type of ECMO being utilised, and the associated complications and imaging artefacts.

Extracorporeal Cardiopulmonary Resuscitation in Adults. Interim Guideline Consensus Statement From the Extracorporeal Life Support Organization.

DISCLAIMER: Veno-arterial extracorporeal membrane oxygenation (ECMO) is increasingly being deployed for selected patients in cardiac arrest who do not attain a native circulation with conventional CPR (ECPR). This ELSO guideline is intended to be a practical guide to implementing ECPR and the early management following establishment of ECMO support. Where a paucity of high-quality evidence exists, a consensus has been reached amongst the authors to provide guidance to the clinician. This guideline will be updated as further evidence in this field becomes available.

Clinician Perceptions of the Impact of a Shock Team Approach in the Management of Cardiogenic Shock: A Qualitative Study.

INTRODUCTION: Designated cross-specialty shock teams have been proposed as a mechanism to manage the complexity of decision-making and facilitate collaborative, patient-centred care-planning in cardiogenic shock. Observational data support the notion that shock protocols and teams may improve survival, but there is an absence of data interrogating how clinicians engage with and value the shock team paradigm. This study sought to explore clinician perceptions of the value of the shock call system on decision making and the management of CGS. MATERIALS & METHODS: A descriptive qualitative approach was used. A focus group, semi-structured interview was conducted with twelve cross-specialty members of a shock team at a single tertiary cardiac centre in the UK. The focus group was audio-recorded, transcribed, and thematically analysed to capture and describe the clinicians' experience and perceptions of shock team discussions. RESULTS: Eight cardiac intensivists, two heart failure cardiologists, one cardiothoracic surgeon and one interventional cardiologist participated in the focus group. Four key themes were identified from the discussions: supportive decision making; team communication; governance and learning; and future directions. CONCLUSION: This study supports the notion that cross-specialty, real-time patient discussion may provide added value beyond protocolised decision making and account for the complexities of managing patients in a field where definitive, high-quality evidence to guide practice is currently limited.

A retrospective analysis of inpatient cardiac arrests over one year at a tertiary heart attack and cardiothoracic centre identifying potential candidates for an inpatient extracorporeal cardiopulmonary resuscitation service.

INTRODUCTION: Extracorporeal cardiopulmonary resuscitation (ECPR) is an internationally recognised treatment for refractory cardiac arrest, with evidence of improved outcomes in selected patient groups from cohort studies and case series. In order to establish the clinical need for an in-hospital extracorporeal cardiopulmonary resuscitation service at a tertiary cardiac centre, we analysed the inpatient cardiac arrest database for the previous 12 months. METHODS: Evidence-based inclusion criteria were used to retrospectively identify the number of patients potentially eligible for extracorporeal cardiopulmonary resuscitation over a 12-month period. RESULTS: A total of 261 inpatient cardiac arrests were analysed with 21 potential extracorporeal cardiopulmonary resuscitation candidates meeting the inclusion criteria (1.75 patients per month, or 8% of inpatient cardiac arrests (21/261)). The majority (71%) of these cardiac arrests occurred outside of normal working hours. Survival-to-discharge within this sub-group with conventional cardiopulmonary resuscitation was 19% (4/21). CONCLUSION: Sufficient numbers of refractory inpatient cardiac arrests occur to justify an extracorporeal cardiopulmonary resuscitation service, but a 24-h on-site extracorporeal membrane oxygenation team presents a significant financial and logistical challenge.

ECLS Training and Simulation - Evaluation of the 8th Educational Corner of the EuroELSO Congress 2019 Held in Barcelona.

Introduction: Simulation-based learning and hands-on learning are popular in medicine, particularly in areas where life-saving manoeuvres and team skills are required. Simulations can be provided in different environments: directly in hospitals (in situ), in dedicated facilities (simulation rooms) or, on occasion, at scientific meetings, thus taking advantage of the delegates' motivation. Simulation-based learning in extracorporeal life support is also increasingly relevant due to the inherent features of the often difficult and emergent decision-making, approaches and management involved, as well as to the challenging multidisciplinary teamwork. Aim: Based on these premises and on the constant rise in interest in starting new extracorporeal life support programmes, the EuroELSO organization has, since the beginning of its scientific activities, established an 'ad hoc' space (Educational Corner) for training and hands-on sessions with a limited number of attendees per session during its annual congress. Methods: Experienced trainers deliver repeated dedicated sessions on fundamental aspects of extracorporeal life support management. After several years of sessions, a questionnaire was prepared and delivered to the attendees at the 8th annual congress in Barcelona. Results: More than 90% of the responders indicated that they would recommend the workshop to their colleagues and that they received useful information during the workshops. Over 85% of the responders (85-97%) indicated that the workshops met the set educational goals and objectives and indicated that the simulation sessions would have a positive impact on their daily practice. Conclusion: The Educational Corner during the EuroELSO Congress has achieved great popularity, as shown by the number of attendees participating each year, and presumably improves many technical and behavioural skills among the attendees.

Postcardiotomy extracorporeal membrane oxygenation in a patient with Austrian syndrome.

A 43-year-old man with Austrian syndrome, the triad of infective endocarditis (IE), pneumonia and meningitis caused by Streptococcus pneumoniae, underwent emergency aortic and mitral valve replacement and closure of an aortic root abscess. Postoperatively, he required mechanical circulatory support with veno-arterial extracorporeal membrane oxygenation and an intra-aortic balloon pump. Several days after surgery, new mitral and aortic paraprosthetic leaks (PPLs) developed. These were managed conservatively, initially, but eventually required percutaneous closure 6 weeks after the initial operation. This has enabled the patient to recover to independent mobility, 20 weeks after the operation. This case illustrates a rare clinical syndrome and the devastating impact of IE. Moreover, it illustrates the successful application of extracorporeal membrane oxygenation in postcardiotomy cardiac failure and the successful treatment of PPL in a patient unfit for redo surgery.

Sub30: Protocol for the Sub30 feasibility study of a pre-hospital Extracorporeal membrane oxygenation (ECMO) capable advanced resuscitation team at achieving blood flow within 30 ​min in patients with refractory out-of-hospital cardiac arrest.

BACKGROUND: Out-of-hospital cardiac arrest carries a poor prognosis with survival less than 10% in many patient cohorts. Survival is inversely associated with duration of resuscitation as external chest compressions do not provide sufficient blood flow to prevent irreversible organ damage during a prolonged resuscitation. Extracorporeal membrane oxygenation (ECMO) instituted during cardiac arrest can provide normal physiological blood flows and is termed Extracorporeal Cardio-Pulmonary Resuscitation (ECPR). ECPR may improve survival when used with in-hospital cardiac arrests. This possible survival benefit has not been replicated in trials of out-of-hospital cardiac arrests, possibly because of the additional time it takes to transport the patient to hospital and initiate ECPR. Pre-hospital ECPR may shorten the time between cardiac arrest and physiological blood flows, potentially improving survival. It may also mitigate some of the neurological injury that many survivors suffer. METHODS: Sub30 is a prospective six patient feasibility study. The primary aim is to test whether it is possible to institute ECPR within 30 ​min of collapse in adult patients with refractory out of hospital cardiac arrest (OHCA). The secondary aims are to gather preliminary data on clinical outcomes, resource utilisation, and health economics associated with rapid ECPR delivery in order to plan any subsequent clinical investigation or clinical service. On study days a dedicated fast-response vehicle with ECPR capability will be tasked to out-of-hospital cardiac arrests in an area of London served by Barts Heart Centre. If patients suffer a cardiac arrest refractory to standard advanced resuscitation and meet eligibility criteria, ECPR will be started in the pre-hospital environment. DISCUSSION: Delivering pre-hospital ECPR within 30 ​min of an out-of-hospital cardiac arrest presents significant ethical, clinical, governance and logistical challenges. Prior to conducting an efficacy study of ECPR the feasibility of timely and safe application must be demonstrated first. Extensive planning, multiple high-fidelity multiagency simulations and a unique collaboration between pre-hospital and in-hospital institutions will allow us to test the feasibility of this intervention in London. The study has been reviewed, refined and endorsed by the International ECMO Network (ECMONet). TRIAL REGISTRATION: Clinicaltrials. gov NCT03700125, prospectively registered October 9, 2018.

A systematic literature review and meta-analysis of the effectiveness of extracorporeal-CPR versus conventional-CPR for adult patients in cardiac arrest.

INTRODUCTION: The probability of surviving a cardiac arrest remains low. International resuscitation guidelines state that extracorporeal cardiopulmonary resuscitation (ECPR) may have a role in selected patients suffering refractory cardiac arrest. Identifying these patients is challenging. This project systematically reviewed the evidence comparing the outcomes of ECPR over conventional-CPR (CCPR), before examining resuscitation-specific parameters to assess which patients might benefit from ECPR. METHOD: Literature searches of studies comparing ECPR to CCPR and the clinical parameters of survivors of ECPR were performed. The primary outcome examined was survival at hospital discharge or 30 days. A secondary analysis examined the resuscitation parameters that may be associated with survival in patients who receive ECPR (no-flow and low-flow intervals, bystander-CPR, initial shockable cardiac rhythm, and witnessed cardiac arrest). RESULTS: Seventeen of 948 examined studies were included. ECPR demonstrated improved survival (OR 0.40 (0.27-0.60)) and a better neurological outcome (OR 0.10 (0.04-0.27)) over CCPR during literature review and meta-analysis. Characteristics that were associated with improved survival in patients receiving ECPR included an initial shockable rhythm and a shorter low-flow time. Shorter no-flow, the presence of bystander-CPR and witnessed arrests were not characteristics that were associated with improved survival following meta-analysis, although the quality of input data was low. All data were non-randomised, and hence the potential for bias is high. CONCLUSION: ECPR is a sophisticated treatment option which may improve outcomes in a selected patient population in refractory cardiac arrest. Further comparative research is needed clarify the role of this potential resuscitative therapy.

Guidelines on the management of acute respiratory distress syndrome.

The Faculty of Intensive Care Medicine and Intensive Care Society Guideline Development Group have used GRADE methodology to make the following recommendations for the management of adult patients with acute respiratory distress syndrome (ARDS). The British Thoracic Society supports the recommendations in this guideline. Where mechanical ventilation is required, the use of low tidal volumes (<6 ml/kg ideal body weight) and airway pressures (plateau pressure <30 cmH2O) was recommended. For patients with moderate/severe ARDS (PF ratio<20 kPa), prone positioning was recommended for at least 12 hours per day. By contrast, high frequency oscillation was not recommended and it was suggested that inhaled nitric oxide is not used. The use of a conservative fluid management strategy was suggested for all patients, whereas mechanical ventilation with high positive end-expiratory pressure and the use of the neuromuscular blocking agent cisatracurium for 48 hours was suggested for patients with ARDS with ratio of arterial oxygen partial pressure to fractional inspired oxygen (PF) ratios less than or equal to 27 and 20 kPa, respectively. Extracorporeal membrane oxygenation was suggested as an adjunct to protective mechanical ventilation for patients with very severe ARDS. In the absence of adequate evidence, research recommendations were made for the use of corticosteroids and extracorporeal carbon dioxide removal.

Routine CT scanning of patients retrieved to a tertiary centre on veno-venous extracorporeal membrane oxygenation: a retrospective risk benefit analysis.

INTRODUCTION: Comprehensive clinical examination can be compromised in patients on veno-venous extracorporeal membrane oxygenation (VV-ECMO). Adjunctive diagnostic imaging strategies range from bedside imaging only to routine computed tomography (CT). The risk-benefit of either approach remains to be evaluated. Patients retrieved to the Royal Brompton Hospital (RBH) on VV-ECMO routinely undergo admission CT imaging of head, chest, abdomen and pelvis. This study aimed to identify how frequently changes in therapy or adverse events could be attributed to routine CT scanning. METHODS: Demographic and clinical data were gathered retrospectively from patients retrieved to RBH on VV-ECMO (January 2014-2016). Scans were categorized as 'routine' or requested to clarify a specific clinical uncertainty. Clinical records were reviewed to identify attributable management changes and CT- related adverse events. Seventy-two patients were retrieved on VV-ECMO (median age 44 years) and 65 scanned on admission (mean radiation dose 2344mGy-cm). Routine head CT head yielded novel clinical information in 11 patients, 10 of whom had unexpected intracranial haemorrhage and, subsequently, had their anticoagulation withheld. Routine thoracic CT identified unexpected positive findings in three patients (early fibrosis, pulmonary vasculitis, pneumomediastinum), eliciting management variation in one (steroid administration). Routine abdomen/pelvis CT identified new information in three patients (adrenal haemorrhage, hepatosteatosis, splenic infarction), changing the management in one (withholding anticoagulation). RESULTS: CT scanning was not associated with consequential adverse events (e.g. accidental decannulation, gas entrainment into the circuit, hypoxia, hypotension). Median transfer/scan time was 78 minutes, requiring five ITU staff-members. In our cohort, a policy of routine head CT changed the management in 17% of patients; the yield from routine chest, abdomen and pelvis CT was modest. CT transfer was safe, but resource intensive. CONCLUSION: Prospective studies should evaluate whether routine CT impacts outcome.