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Refractory cardiogenic shock (CS) often requires veno-arterial extracorporeal membrane oxygenation (VA-ECMO) to sustain end-organ perfusion. Current animal models result in heterogenous cardiac injury and frequent episodes of refractory ventricular fibrillation. Thus, we aimed to develop an innovative, clinically relevant, and titratable model of severe cardiopulmonary failure. Six sheep (60 ± 6 kg) were anaesthetized and mechanically ventilated. VA-ECMO was commenced and CS was induced through intramyocardial injections of ethanol. Then, hypoxemic/hypercapnic pulmonary failure was achieved, through substantial decrease in ventilatory support. Echocardiography was used to compute left ventricular fractional area change (LVFAC) and cardiac Troponin I (cTnI) was quantified. After 5 h, the animals were euthanised and the heart was retrieved for histological evaluations. Ethanol (58 ± 23 mL) successfully induced CS in all animals. cTnI levels increased near 5000-fold. CS was confirmed by a drop in systolic blood pressure to 67 ± 14 mmHg, while lactate increased to 4.7 ± 0.9 mmol/L and LVFAC decreased to 16 ± 7%. Myocardial samples corroborated extensive cellular necrosis and inflammatory infiltrates. In conclusion, we present an innovative ovine model of severe cardiopulmonary failure in animals on VA-ECMO. This model could be essential to further characterize CS and develop future treatments.

Transpulmonary pressure can be estimated using esophageal balloon (EB) catheters, which come in a variety of manufacturing configurations. We assessed the performance of novel polyurethane EB designs, Aspisafe NG and NG+, against existing alternatives. We created a biomechanical model of the chest cavity using a plastic chamber and an ex-vivo porcine esophagus. The chamber was pressurized (− 20 and + 20 cmH 2 O) to simulate pleural pressures. We conducted tests with various EB inflation volumes and measured transesophageal pressure (TEP). TEP measurement was defined as accurate when the difference between pressure within the EB and chamber was 0 ± 1 cmH 2 O. We computed the minimal (V accuracy-min ) and maximal (V accuracy-max ) EB inflation volumes of accuracy. Inflation volumes were further validated using a surrogate method derived by the clinically validated positive pressure occlusion test (PPOT). When the esophageal balloons were filled with inflation volumes within the range provided by the manufacturers, the accuracy of TEP measurements was marginal. Our tests found median V accuracy-min across EB of 0.00–0.50 mL ( p  = 0.130), whereas V accuracy-max ranged 0.50–2.25 mL ( p  = 0.002). Post PPOT validation, median TEP was − 0.4 cmH 2 O (− 1.5 to 0.3) ( p  < 0.001 among catheters). The Aspisafe NG and NG+ were accurate in 81.7% and 77.8% of the measurements, respectively. We characterized two new EBs, which demonstrated good benchtop accuracy in TEP measurements. However, accuracy was notably influenced by the precise selection of EB inflation volumes.

Whilst the presence of 2 subphenotypes among the heterogenous Acute Respiratory Distress Syndrome (ARDS) population is becoming clinically accepted, subphenotype-specific treatment efficacy has yet to be prospectively tested. We investigated anti-inflammatory treatment in different ARDS models in sheep, previously shown similarities to human ARDS subphenotypes, in a preclinical, randomized, blinded study. Thirty anesthetized sheep were studied up to 48 h and randomized into: (a) OA: oleic acid (n = 15) and (b) OA-LPS: oleic acid and subsequent lipopolysaccharide (n = 15) to achieve a PaO 2 /FiO 2 ratio of < 150 mmHg. Then, animals were randomly allocated to receive treatment with methylprednisolone or erythromycin or none. Assessed outcomes were oxygenation, pulmonary mechanics, hemodynamics and survival. All animals reached ARDS. Treatment with methylprednisolone, but not erythromycin, provided the highest therapeutic benefit in Ph2 animals, leading to a significant increase in PaO 2 /FiO 2 ratio by reducing pulmonary edema, dead space ventilation and shunt fraction. Animals treated with methylprednisolone displayed a higher survival up to 48 h than all others. In animals treated with erythromycin, there was no treatment benefit regarding assessed physiological parameters and survival in both phenotypes. Treatment with methylprednisolone improves oxygenation and survival, more so in ovine phenotype 2 which resembles the human hyperinflammatory subphenotype.

IntroductionThere is a paucity of data that can be used to guide the management of critically ill patients with COVID-19. In response, a research and data-sharing collaborative—The COVID-19 Critical Care Consortium—has been assembled to harness the cumulative experience of intensive care units (ICUs) worldwide. The resulting observational study provides a platform to rapidly disseminate detailed data and insights crucial to improving outcomes.Methods and analysisThis is an international, multicentre, observational study of patients with confirmed or suspected SARS-CoV-2 infection admitted to ICUs. This is an evolving, open-ended study that commenced on 1 January 2020 and currently includes >350 sites in over 48 countries. The study enrols patients at the time of ICU admission and follows them to the time of death, hospital discharge or 28 days post-ICU admission, whichever occurs last. Key data, collected via an electronic case report form devised in collaboration with the International Severe Acute Respiratory and Emerging Infection Consortium/Short Period Incidence Study of Severe Acute Respiratory Illness networks, include: patient demographic data and risk factors, clinical features, severity of illness and respiratory failure, need for non-invasive and/or mechanical ventilation and/or extracorporeal membrane oxygenation and associated complications, as well as data on adjunctive therapies.Ethics and disseminationLocal principal investigators will ensure that the study adheres to all relevant national regulations, and that the necessary approvals are in place before a site may contribute data. In jurisdictions where a waiver of consent is deemed insufficient, prospective, representative or retrospective consent will be obtained, as appropriate. A web-based dashboard has been developed to provide relevant data and descriptive statistics to international collaborators in real-time. It is anticipated that, following study completion, all de-identified data will be made open access.Trial registration numberACTRN12620000421932 (http://anzctr.org.au/ACTRN12620000421932.aspx).

Differential hypoxaemia (DH) is common in patients supported by femoral veno-arterial extracorporeal membrane oxygenation (V-A ECMO) and can cause cerebral hypoxaemia. To date, no models have studied the direct impact of flow on cerebral damage. We investigated the impact of V-A ECMO flow on brain injury in an ovine model of DH. After inducing severe cardiorespiratory failure and providing ECMO support, we randomised six sheep into two groups: low flow (LF) in which ECMO was set at 2.5 L min −1 ensuring that the brain was entirely perfused by the native heart and lungs, and high flow (HF) in which ECMO was set at 4.5 L min −1 ensuring that the brain was at least partially perfused by ECMO. We used invasive (oxygenation tension—PbTO 2 , and cerebral microdialysis) and non-invasive (near infrared spectroscopy—NIRS) neuromonitoring, and euthanised animals after five hours for histological analysis. Cerebral oxygenation was significantly improved in the HF group as shown by higher PbTO 2 levels (+ 215% vs − 58%, p  = 0.043) and NIRS (67 ± 5% vs 49 ± 4%, p  = 0.003). The HF group showed significantly less severe brain injury than the LF group in terms of neuronal shrinkage, congestion and perivascular oedema ( p  < 0.0001 ) . Cerebral microdialysis values in the LF group all reached the pathological thresholds, even though no statistical difference was found between the two groups. Differential hypoxaemia can lead to cerebral damage after only a few hours and mandates a thorough neuromonitoring of patients. An increase in ECMO flow was an effective strategy to reduce such damages.

Background Acute respiratory distress syndrome (ARDS) requiring veno-venous extracorporeal membrane oxygenation (VV-ECMO) is associated with high mortality. One of the primary challenges in translating preclinical findings into effective clinical treatments lies in developing animal models that accurately replicate clinical scenarios. Thus, we aimed to develop a clinically relevant novel ovine model of severe ARDS with VV-ECMO support, with the primary aim of assessing feasibility through 48-h survival, while monitoring safety and clinical relevance. Methods Six sheep (52.7 ± 1.5 kg) were anesthetized and mechanically ventilated. Severe ARDS was induced by oleic acid and lipopolysaccharide (0.5 µg/kg). Lung-protective mechanical ventilation commenced once the PaO 2 /FiO 2 ratio deteriorated to less than 150 mmHg, with additional doses of oleic acid administered if the PaO 2 /FiO 2 improved. Severe ARDS criteria, triggering ECMO initiation, were defined as PaO 2 /FiO 2  < 100 mmHg, PaCO 2  > 60 mmHg, or refractory respiratory acidosis (T0) before commencing VV-ECMO (T1), followed by a 48-h observation. The primary outcome was survival at 48 h to assess the feasibility of a novel model. All complications were also recorded, and lung tissues were obtained upon autopsy. Assessments followed the American Thoracic Society (ATS) Workshop Report 2022 recommendations, including histological assessments, alveolar–capillary barrier evaluations, and inflammatory and physiological responses. Data were analysed using the Friedman test. Results All sheep survived the 48-h follow-up. No complications were recorded throughout the study. In all sheep, although PaO 2 /FiO 2 reached 126 (interquartile range: IQR 103–149) mmHg, lung-protective mechanical ventilation strategies improved PaO 2 /FiO 2 to 181 (IQR: 167–185) mmHg within 60 min, requiring additional oleic acid doses to reach injury criteria. All sheep developed hallmark features of experimental ARDS including histological evidence (filling of the alveolar space with proteinaceous alveolar fluid and debris and increasing histologic injury score), impaired alveolar–capillary barrier (elevated total protein in bronchoalveolar lavage fluid (BAL) and increased lung wet-to-dry weight ratio), inflammatory response (increase in IL6, IL-8 and neutrophil numbers in BAL), and physiologic dysfunction (e.g., impaired oxygenation, reduction in lung compliance). Conclusions We developed a novel animal model of ARDS that closely replicates ARDS management, including lung-protective mechanical ventilation before the initiation of VV-ECMO, ensuring a prolonged 48-h survival observation without any complications. This model meets all four key features of ARDS as recommended by the latest ATS guidelines and provides an innovative platform to support clinical translation.

Open-lung ventilation during cardiopulmonary bypass (CPB) in patients undergoing heart transplantation (HTx) is a potential strategy to mitigate postoperative acute respiratory distress syndrome (ARDS). We utilized an ovine HTx model to investigate whether open-lung ventilation during CPB reduces postoperative lung damage and complications. Eighteen sheep from an ovine HTx model were included, with ventilatory interventions randomly assigned during CPB: the OPENVENT group received low tidal volume (VT) of 3 mL/kg and positive end-expiratory pressure (PEEP) of 8 cm H20, while no ventilation was provided in the NOVENT group as per standard of care. The recipient sheep were monitored for 6 h post-surgery. The primary outcome was histological lung damage, scored at the end of the study. Secondary outcomes included pulmonary shunt, driving pressure, hemodynamics and inflammatory lung infiltration. All animals completed the study. The OPENVENT group showed significantly lower histological lung damage versus the NOVENT group (0.22 vs 0.27, p = 0.042) and lower pulmonary shunt (19.2 vs 32.1%, p = 0.001). In addition, the OPENVENT group exhibited a reduced driving pressure (9.6 cm H2O vs. 12.8 cm H2O, p = 0.039), lower neutrophil (5.25% vs 7.97%, p ≤ 0.001) and macrophage infiltrations (11.1% vs 19.6%, p < 0.001). No significant differences were observed in hemodynamic parameters. In an ovine model of HTx, open-lung ventilation during CPB significantly reduced lung histological injury and inflammatory infiltration. This highlights the value of an open-lung approach during CPB and emphasizes the need for further clinical evidence to decrease risks of lung injury in HTx patients.

BackgroundEscherichia coli is the most common cause of human bloodstream infections and bacterial sepsis/septic shock. However, translation of preclinical septic shock resuscitative therapies remains limited mainly due to low-fidelity of available models in mimicking clinical illness. To overcome the translational barrier, we sought to replicate sepsis complexity by creating an acutely critically-ill preclinical bacterial septic shock model undergoing active 48-h intensive care management.AimTo develop a clinically relevant large-animal (ovine) live-bacterial infusion model for septic shock.MethodsSeptic shock was induced by intravenous infusion of the live antibiotic resistant extra-intestinal pathogenic E. coli sequence type 131 strain EC958 in eight anesthetised and mechanically ventilated sheep. A bacterial dose range of 2 × 105–2 × 109 cfu/mL was used for the dose optimisation phase (n = 4) and upon dose confirmation the model was developed (n = 5). Post-shock the animals underwent an early-vasopressor and volume-restriction resuscitation strategy with active haemodynamic management and monitoring over 48 h. Serial blood samples were collected for testing of pro-inflammatory (IL-6, IL-8, VEGFA) and anti-inflammatory (IL-10) cytokines and hyaluronan assay to assess endothelial integrity. Tissue samples were collected for histopathology and transmission electron microscopy.ResultsThe 2 × 107 cfu/mL bacterial dose led to a reproducible distributive shock within a pre-determined 12-h period. Five sheep were used to demonstrate consistency of the model. Bacterial infusion led to development of septic shock in all animals. The baseline mean arterial blood pressure reduced from a median of 91 mmHg (71, 102) to 50 mmHg (48, 57) (p = 0.004) and lactate levels increased from a median of 0.5 mM (0.3, 0.8) to 2.1 mM (2.0, 2.3) (p = 0.02) post-shock. The baseline median hyaluronan levels increased significantly from 25 ng/mL (18, 86) to 168 ng/mL (86, 569), p = 0.05 but not the median vasopressor dependency index which increased within 1 h of resuscitation from zero to 0.39 mmHg−1 (0.06, 5.13), p = 0.065, and. Over the 48 h, there was a significant decrease in the systemic vascular resistance index (F = 7.46, p = 0.01) and increase in the pro-inflammatory cytokines [IL-6 (F = 8.90, p = 0.02), IL-8 (F = 5.28, p = 0.03), and VEGFA (F = 6.47, p = 0.02)].ConclusionsThis critically ill large-animal model was consistent in reproducing septic shock and will be applied in investigating advanced resuscitation and therapeutic interventions.

Despite decades of comprehensive research, Acute Respiratory Distress Syndrome (ARDS) remains a disease with high mortality and morbidity worldwide. The discovery of inflammatory subphenotypes in human ARDS provides a new approach to study the disease. In two different ovine ARDS lung injury models, one induced by additional endotoxin infusion (phenotype 2), mimicking some key features as described in the human hyperinflammatory group, we aim to describe protein expression among the two different ovine models. Nine animals on mechanical ventilation were included in this study and were randomized into (a) phenotype 1, n = 5 (Ph1) and (b) phenotype 2, n = 4 (Ph2). Plasma was collected at baseline, 2, 6, 12, and 24 h. After protein extraction, data-independent SWATH-MS was applied to inspect protein abundance at baseline, 2, 6, 12, and 24 h. Cluster analysis revealed protein patterns emerging over the study observation time, more pronounced by the factor of time than different injury models of ARDS. A protein signature consisting of 33 proteins differentiated among Ph1/2 with high diagnostic accuracy. Applying network analysis, proteins involved in the inflammatory and defense response, complement and coagulation cascade, oxygen binding, and regulation of lipid metabolism were activated over time. Five proteins, namely LUM, CA2, KNG1, AGT, and IGJ, were more expressed in Ph2.

Background:Postvention services aim to support individuals bereaved by suicide, prevent further suicides and reduce adverse mental health in this at-risk population.Aim:The aim of this study was to evaluate the perceived effectiveness of postvention services in the UK and develop a model for anyone seeking to create a new postvention service.Methods:A mixed methods design was used to assess perceived effectiveness and develop recommendations. Fifty-eight interviews were conducted with nine services, including beneficiaries, commissioners, service Chief Executive Officers (CEOs), referrers, and Suicide Liaison Employees (SLOs). Interviews were analysed twice using thematic analysis, once to generate themes from each service and then again to create themes from each participant group. Two services’ audit data on beneficiary demographics and evaluation outcome measures (CORE-10 and SWEMWBS) were analysed using paired samples t-tests.Results:This study found that well-being significantly improved between the initial assessment and recent assessment. Themes that emerged included: 1) “what do you need from us?”; 2) accessibility of postvention; 3) the ongoing debate surrounding data collection; 4) sustainability and longevity; 5) Shared learning of challenges and improvements for postvention services.Conclusion:Postvention services in England are having a positive impact on people bereaved by suicide and the wider community, by offering a tailor-made service that have adopted a public health approach to align postvention with suicide prevention programs. However, the longevity of these services was a concern due to funding and lack of evidence of their effectiveness. Evaluation would evidence their value and support the development of new services. Postvention services could be costeffective in reducing the use of statutory services for people bereaved by suicide and reducing further suicides. A model for new services and further research is discussed.