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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 (V T ) of 3 mL/kg and positive end-expiratory pressure (PEEP) of 8 cm H 2 0, 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 H 2 O vs. 12.8 cm H 2 O, 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., Competing Interests: Declarations. Ethics approval and consent to participate: The project was approved by Queensland University of Technology (QUT) Animal Ethics Committee (Approval #16-1109). Ratified by the University of Queensland AEC (QUT/393/17/QUT), experiments were performed in accordance with the National Health and Medical Research Council (NHMRC) Australian Code of Practice for the Care and Use of Animals for Scientific Purposes (8th Edition 2013), the Animal Care and Protection Act 2001 (QLD) and complied with the ARRIVE Guidelines. Consent for publication: Not applicable. Competing interests: Professor John Fraser is the CEO of the Quantum Medical Innovation Fund and De Motu Cordis Pty Limited. He is also the co-founder of BiVACOR™ Pty Ltd. In addition, Prof. Fraser and his research group collaborate with Australian Red Cross Lifeblood, Fisher and Paykel healthcare, Mallinckrodt Pharmaceuticals and CSL. Professor Fraser receives reimbursement for travel costs when presenting research created collaboration with Fisher and Paykel Healthcare. Professor David McGiffin provides consultancy services to Abbott. This has no direct impact on the contents of the manuscript. The other authors do not have any conflict of interest., (© 2024. Crown.)

Competing Interests: Disclosure: The authors have no conflicts of interest to report.

Background: Escherichia 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., Aim: To develop a clinically relevant large-animal (ovine) live-bacterial infusion model for septic shock., Methods: Septic 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 × 10 5 -2 × 10 9  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., Results: The 2 × 10 7  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)]., Conclusions: This critically ill large-animal model was consistent in reproducing septic shock and will be applied in investigating advanced resuscitation and therapeutic interventions., (© 2024. The Author(s).)

Background: The commonest echocardiographic measurement, left ventricular ejection fraction, can not necessarily predict mortality of recipients following heart transplantation potentially due to afterload dependency. Afterload-independent left ventricular stroke work index (LVSWI) is alternatively recommended by the current guideline; however, pulmonary artery catheters are rarely inserted in organ donors in most jurisdictions. We propose a novel non-invasive echocardiographic parameter, Pressure-Strain Product (PSP), as a potential surrogate of catheter-based LVSWI. This study aimed to investigate if PSP could correlate with catheter-based LVSWI in an ovine model of brain stem death (BSD) donors. The association between PSP and myocardial mitochondrial function in the post-transplant hearts was also evaluated., Methods: Thirty-one female sheep (weight 47 ± 5 kg) were divided into two groups; BSD (n = 15), and sham neurologic injury (n = 16). Echocardiographic parameters including global circumferential strain (GCS) and global radial strain (GRS) and pulmonary artery catheter-based LVSWI were simultaneously measured at 8-timepoints during 24-h observation. PSP was calculated as a product of GCS or GRS, and mean arterial pressure for PSP circ or PSP rad , respectively. Myocardial mitochondrial function was evaluated following 6-h observation after heart transplantation., Results: In BSD donor hearts, PSP circ (n = 96, rho = .547, p < .001) showed the best correlation with LVSWI among other echocardiographic parameters. PSP circ returned AUC of .825 to distinguish higher values of cardiomyocyte mitochondrial function (cut-off point; mean value of complex 1,2 O 2 Flux) in post-transplant hearts, which was greater than other echocardiographic parameters., Conclusions: PSP circ could be used as a surrogate of catheter-based LVSWI reflecting mitochondrial function., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Left ventricular stroke work index (LVSWI) and cardiac power index (CPI) account for the haemodynamic load of the left ventricle and are promising prognostic values in cardiogenic shock. However, accurately and non-invasively measuring these parameters during veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is challenging and potentially biased by the extracorporeal circulation. This study aimed to investigate, in an ovine model of cardiogenic shock, whether Pressure-Strain Product (PSP), a novel speckle-tracking echocardiography parameter, (1) can correlate with pressure-volume catheter-based LVSWI and CPI, and (2) can be load-independent during the flow modification of V-A ECMO., Methods: Nine Dorset-cross ewes (51 ± 4 kg) were included. After cardiogenic shock was induced, full support V-A ECMO (X L/min based on 60 mL/kg/min) commenced. At seven time points during 24-h observation, echocardiographic parameters as well as pressure-volume catheter-based LVSWI and CPI were simultaneously measured with X and following X-1 L/min of ECMO flow. PSP was calculated by multiplying global circumferential strain or global radial strain, and mean arterial pressure, for PSPcirc or PSPrad, respectively., Results: PSPcirc showed a stronger correlation with LVSWI (correlation coefficient, CC = .360, p < .001) and CPI (CC = .283, p < .001) than other echocardiographic parameters. The predictability of PSPcirc for pressure-volume catheter-based LVSWI (AUC .82) and CPI (AUC .80) was also higher than other echocardiographic parameters. No statistically significant differences were identified between the two ECMO flow variations in PSPcirc (p = .558)., Conclusions: A novel echocardiographic parameter, PSP, may non-invasively predict pressure-volume catheter-based LVSWI and CPI in a load-independent manner in a cardiogenic shock supported by V-A ECMO., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Objective: The outcomes of COVID-19 patients on venovenous extracorporeal membrane oxygenation (VV-ECMO) varied. We aim to investigate the variability concerning location and timeframe. We conducted a retrospective analysis of data from 351 institutions in 53 countries. The primary outcome was survival to hospital discharge or death up to 90 days from ECMO start. The associations between calendar time (month and year) of ECMO initiation and the primary outcome were examined by Cox regression modeling. Multivariable survival analyses were adjusted for the time of ECMO start, age, body mass index, APACHE II, SOFA, and the duration of mechanical ventilation before ECMO., Results: 1060 adult COVID-19 patients enrolled in the COVID-19 Critical Care Consortium (COVID Critical) international registry and required VV-ECMO support. The study period is from January 2020 to December 2021. The median age was 51 years old, and 70% were male patients. Most patients were from Europe (39.3%) and North America (37.4%). The in-hospital mortality of the entire cohort was 47.12%. In North America and Europe, there was an increased probability of death from May 2020 through February 2021. Latin America showed a steady rate of survival until late in the study. South Asia, the Middle East, and Africa showed an increased chance of mortality around May 2020. In the Asian-Pacific region, after February 2021, there was an increased probability of death. The time of ECMO initiation and advanced patient age were associated with increased mortality., Conclusion: Variability in the outcomes of COVID-19 patients on VV-ECMO existed within different regions. This variability reflects the differences in resources, policies, patient selection, management, and possibly COVID-19 virus subtypes. Our findings might help guide global response in the future by early adoption of patient selection protocols, worldwide policies, and delivery of resources., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Gianluigi Li Bassi is a recipient of the BITRECS fellowship; the “BITRECS” project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 754,550 and from the “La Caixa” Foundation (ID 100010434), under the agreement LCF/PR/GN18/50310006. Jacky Y Suen is funded by the Advance Queensland fellowship program. Sung-Min Cho is funded by NIH (1K23HL157610) and serves as a consultant for Hyperfine. Peta Alexander is funded by U.S. DoD PRMRP Clinical Trial Award #W81XWH2210301, NIH (R13HD104432) and FDA UCSF-Stanford Center of Excellence in Regulatory Sciences and Innovation (U01FD004979/U01FD005978). Peta Alexander is Treasurer of ELSO Board of Directors.

Introduction: Iliopsoas haematoma (IPH) during extracorporeal membrane oxygenation (ECMO) is a rare bleeding complication that can be fatal due to its progression to abdominal compartment syndrome, but its incidence and risk factors are not well known. We have previously reported an IPH incidence rate of 16% in Japan. Among possible reasons for this high incidence, ethnicity has been hypothesised to play a role. Therefore, we used an international multi-centre cohort registry to test this hypothesis by determining the incidence rate of IPH., Methods: This study was performed using the COVID-19 Critical Care Consortium database, conducted in 30 countries across five continents between 3 January 2020, and 20 June 2022., Results: Overall, 1102 patients received ECMO for COVID-19-related acute respiratory distress syndrome. Of them, only seven were reported to have IPH, indicating an incidence rate of 0.64%, with comparable rates between the countries. The IPH group tended to have a higher mortality rate (71.4%) than the non-IPH group (51%)., Conclusions: Overall incidence of IPH in the studied COVID-19 ECMO cohort was 0.64%. Most cases were reported from Japan, Belgium, and Italy. In our study, this rare complication did not appear to be confined to Asian patients. Due to the high fatality rate, awareness about the occurrence of IPH should be recognised., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Peripheral intravenous catheters (PIVCs) are the most commonly used invasive medical device, yet despite best efforts by end-users, PIVCs experience unacceptably high early failure rates. We aimed to design a new PIVC that reduces the early failure rate of in-dwelling PIVCs and we conducted preliminary tests to assess its efficacy and safety in a porcine model of intravenous access., Methods: We used computer-aided design and simulation to create a PIVC with a ramped tip geometry, which directs the infused fluid away from the vein wall; we called the design the FloRamp™. We created FloRamp prototypes (test device) and tested them against a market-leading device (BD Insyte™; control device) in a highly-controlled setting with five insertion sites per device in four pigs. We measured resistance to infusion and visual infusion phlebitis (VIP) every 6 h and terminated the experiment at 48 h. Veins were harvested for histology and seven pathological markers were assessed., Results: Computer simulations showed that the optimum FloRamp tip reduced maximum endothelial shear stress by 60%, from 12.7 Pa to 5.1 Pa, compared to a typical PIVC tip and improved the infusion dynamics of saline in the blood stream. In the animal study, we found that 2/5 of the control devices were occluded after 24 h, whereas all test devices remained patent and functional. The FloRamp created less resistance to infusion (0.73 ± 0.81 vs 0.47 ± 0.50, p  = 0.06) and lower VIP scores (0.60 ± 0.93 vs 0.31 ± 0.70, p  = 0.09) than the control device, although neither findings were significantly different. Histopathology revealed that 5/7 of the assessed markers were lower in veins with the FloRamp., Conclusions: Herein we report preliminary assessment of a novel PIVC design, which could be advantageous in clinical settings through decreased device occlusion and reduced early failure rates., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: BJD, LJK and CS are named inventors on a patent describing the ramped tip design (WO/2020/237286). The study was funded by Flomatrix Pty Ltd of which CS is an employee and in which both BJD and CS hold equity. SK reports monies received by her employer QUT on her behalf from for educational consultancies with BD Medical and ITL Biomedical unrelated to this study. The remaining authors have no conflicts to report.

Introduction: Obesity is associated with a worse prognosis in COVID-19 patients with acute respiratory distress syndrome (ARDS). Veno-venous (V-V) Extracorporeal Membrane Oxygenation (ECMO) can be a rescue option, however, the direct impact of morbid obesity in this select group of patients remains unclear. Methods: This is an observational study of critically ill adults with COVID-19 and ARDS supported by V-V ECMO. Data are from 82 institutions participating in the COVID-19 Critical Care Consortium international registry. Patients were admitted between 12 January 2020 to 27 April 2021. They were stratified based on Body Mass Index (BMI) at 40 kg/m 2 . The endpoint was survival to hospital discharge. Results: Complete data available on 354 of 401 patients supported on V-V ECMO. The characteristics of the high BMI (>40 kg/m 2 ) and lower BMI (≤40 kg/m 2 ) groups were statistically similar. However, the 'high BMI' group were comparatively younger and had a lower APACHE II score. Using survival analysis, older age (Hazard Ratio, HR 1.49 per-10-years, CI 1.25-1.79) and higher BMI (HR 1.15 per-5 kg/m 2 increase, CI 1.03 - 1.28) were associated with a decreased patient survival. A safe BMI threshold above which V-V ECMO would be prohibitive was not apparent and instead, the risk of an adverse outcome increased linearly with BMI. Conclusion : In COVID-19 patients with severe ARDS who require V-V ECMO, there is an increased risk of death associated with age and BMI. The risk is linear and there is no BMI threshold beyond which the risk for death greatly increases., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Left ventricular stroke work index (LVSWI) and afterload-related cardiac performance (ACP) consider left ventricular (LV) afterload and could be better prognosticators in septic cardiomyopathy. However, their invasive nature prevents their routine clinical applications. This study aimed to investigate (1) whether a proposed speckle-tracking echocardiography parameter, Pressure-Strain Product (PSP), can non-invasively predict catheter-based LVSWI, ACP and serum lactate in an ovine model of septic cardiomyopathy; and (2) whether PSP can distinguish the sub-phenotypes of acute respiratory distress syndrome (ARDS) with or without sepsis-like conditions., Methods: Sixteen sheep with ARDS were randomly assigned to either (1) sepsis-like (n = 8) or (2) non-sepsis-like (n = 8) group. Each ARDS and sepsis-like condition was induced by intravenous infusion of oleic acid and lipopolysaccharide, respectively. Pulmonary artery catheter-based LVSWI (the product of stroke work index, mean arterial pressure and .0136), ACP (the percentage of cardiac output measured to cardiac output predicted as normal) and serum lactate were measured simultaneously with transthoracic echocardiography. Two PSP indices were calculated by multiplying the mean arterial blood pressure and either global circumferential strain (PSPcirc) or radial strain (PSPrad)., Results: PSPcirc showed a significant correlation with LVSWI (r 2  = .66, p < .001) and ACP (r 2  = .82, p < .001) in the sepsis-like group. Although PSP could not distinguish subphenotypes, PSPcirc predicted LVSWI (AUC .86) and ACP (AUC .88), and PSPrad predicted serum lactate (AUC .75) better than LV ejection fraction, global circumferential and radial strain., Conclusions: A novel PSP has the potential to non-invasively predict catheter-based LVSWI and ACP, and was associated with serum lactate in septic cardiomyopathy., (© 2023 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Mortality and morbidity of Acute Respiratory Distress Syndrome (ARDS) are largely unaltered. A possible new approach to treatment of ARDS is offered by the discovery of inflammatory subphenotypes. In an ovine model of ARDS phenotypes, matching key features of the human subphenotypes, we provide an imaging characterization using computer tomography (CT). Nine animals were randomized into (a) OA (oleic acid, hypoinflammatory; n = 5) and (b) OA-LPS (oleic acid and lipopolysaccharides, hyperinflammatory; n = 4). 48 h after ARDS induction and anti-inflammatory treatment, CT scans were performed at high (H) and then low (L) airway pressure. After CT, the animals were euthanized and lung tissue was collected. OA-LPS showed a higher air fraction and OA a higher tissue fraction, resulting in more normally aerated lungs in OA-LPS in contrast to more non-aerated lung in OA. The change in lung and air volume between H and L was more accentuated in OA-LPS, indicating a higher recruitment potential. Strain was higher in OA, indicating a higher level of lung damage, while the amount of lung edema and histological lung injury were largely comparable. Anti-inflammatory treatment might be beneficial in terms of overall ventilated lung portion and recruitment potential, especially in the OA-LPS group., (© 2024. The Author(s).)

Introduction: Peripheral veno-arterial extracorporeal membrane oxygenation (VA ECMO) creates a retrograde flow along the aorta competing with the left ventricle (LV) in the so-called 'mixing zone' (MZ). Detecting it is essential to understand which of the LV or the ECMO flow perfuses the upper body - particularly the brain and the coronary arteries - in case of differential hypoxemia (DH)., Methods: We described a mock circulation loop (MCL) that enabled experimental research on DH. We recreated the three clinical situations relevant to clinicians: where the brain is either totally perfused by the ECMO or the LV or both. In a second step, we used this model to investigate two scenarios to diagnose DH: (i) pulse pressure and (ii) thermodilution via injection of cold saline in the ECMO circuit., Results: The presented MCL was able to reproduce the three relevant mixing zones within the aortic arch, thus allowing to study DH. Pulse pressure was unable to detect location of the MZ. However, the thermodilution method was able to detect whether the brain was totally perfused by the ECMO or not., Conclusion: We validated an in-vitro differential hypoxemia model of cardiogenic shock supported by VA ECMO. This MCL could be used as an alternative to animal studies for research scenarios., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., (© 2023. Springer Nature Limited.)

Background: The global shortage of donor hearts available for transplantation is a major problem for the treatment of end-stage heart failure. The ischemic time for donor hearts using traditional preservation by standard static cold storage (SCS) is limited to approximately 4 hours, beyond which the risk for primary graft dysfunction (PGD) significantly increases. Hypothermic machine perfusion (HMP) of donor hearts has been proposed to safely extend ischemic time without increasing the risk of PGD., Methods: Using our sheep model of 24 hours brain death (BD) followed by orthotopic heart transplantation (HTx), we examined post-transplant outcomes in recipients following donor heart preservation by HMP for 8 hours, compared to donor heart preservation for 2 hours by either SCS or HMP., Results: Following HTx, all HMP recipients (both 2 hours and 8 hours groups) survived to the end of the study (6 hours after transplantation and successful weaning from cardiopulmonary bypass), required less vasoactive support for hemodynamic stability, and exhibited superior metabolic, fluid status and inflammatory profiles compared to SCS recipients. Contractile function and cardiac damage (troponin I release and histological assessment) was comparable between groups., Conclusions: Overall, compared to current clinical SCS, recipient outcomes following transplantation are not adversely impacted by extending HMP to 8 hours. These results have important implications for clinical transplantation where longer ischemic times may be required (e.g., complex surgical cases, transport across long distances). Additionally, HMP may allow safe preservation of "marginal" donor hearts that are more susceptible to myocardial injury and facilitate increased utilization of these hearts for transplantation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Evidence of cerebrovascular complications in COVID-19 requiring venovenous extracorporeal membrane oxygenation (ECMO) is limited. Our study aims to characterize the prevalence and risk factors of stroke secondary to COVID-19 in patients on venovenous ECMO., Design: We analyzed prospectively collected observational data, using univariable and multivariable survival modeling to identify risk factors for stroke. Cox proportional hazards and Fine-Gray models were used, with death and discharge treated as competing risks., Setting: Three hundred eighty institutions in 53 countries in the COVID-19 Critical Care Consortium (COVID Critical) registry., Patients: Adult COVID-19 patients who were supported by venovenous ECMO., Interventions: None., Measurements and Main Results: Five hundred ninety-five patients (median age [interquartile range], 51 yr [42-59 yr]; male: 70.8%) had venovenous ECMO support. Forty-three patients (7.2%) suffered strokes, 83.7% of which were hemorrhagic. In multivariable survival analysis, obesity (adjusted hazard ratio [aHR], 2.19; 95% CI, 1.05-4.59) and use of vasopressors before ECMO (aHR, 2.37; 95% CI, 1.08-5.22) were associated with an increased risk of stroke. Forty-eight-hour post-ECMO Pa co2 -pre-ECMO Pa co2 /pre-ECMO Pa co2 (relative ΔPa co2 ) of negative 26% and 48-hour post-ECMO Pa o2 -pre-ECMO Pa o2 /pre-ECMO Pa o2 (relative ΔPa o2 ) of positive 24% at 48 hours of ECMO initiation were observed in stroke patients in comparison to relative ΔPa co2 of negative 17% and relative ΔPa o2 of positive 7% in the nonstroke group. Patients with acute stroke had a 79% in-hospital mortality compared with 45% mortality for stroke-free patients., Conclusions: Our study highlights the association of obesity and pre-ECMO vasopressor use with the development of stroke in COVID-19 patients on venovenous ECMO. Also, the importance of relative decrease in Pa co2 and moderate hyperoxia within 48 hours after ECMO initiation were additional risk factors., Competing Interests: Drs. Kelly’s, Heinsar’s, and Suen’s institutions received funding from the Bill and Melinda Gates Foundation. Drs. Kelly, Heinsar, Suen, and Fraser received support for article research from the Bill and Melinda Gates Foundation. Dr. Heinsar received funding from The Prince Charles Hospital Foundation. Dr. Suen is funded by the Advance Queensland fellowship program. Dr. Li Bassi is a recipient of the Biomedicine International training research programme for excellent clinician-scientists (BITRECS) fellowship; the “BITRECS” project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 754550 and from the “La Caixa” Foundation (identification number 100010434), under the agreement LCF/PR/GN18/50310006. Dr. Jacobs received funding from SpecialtyCare and the American Academy of Dermatology. Dr. Fraser’s institution received funding from Fisher & Paykel, Mallinckrodt Pharmaceuticals, and Lendlease; he received funding from De Motu Cordis, Philips Electronics, International Society for Heart and Lung Transplantation, and General Practice Training Queensland. Dr. Lorusso’s institution received funding from Medtronic, LivaNova, Getinge, Eurosets, Corcym, Hemocue, and Xenios. Dr. Cho received support for article research from the National Institutes of Health; he is funded by the National Heart, Lung, and Blood Institute 1K23HL157610. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objective: Pulsatile-flow veno-arterial extracorporeal membrane oxygenation (V-A ECMO) has shown encouraging results for microcirculation resuscitation and left ventricle unloading in patients with refractory cardiogenic shock. We aimed to comprehensively assess different V-A ECMO parameters and their contribution to hemodynamic energy production and transfer through the device circuit., Methods: We used the i-cor® ECMO circuit, which composed of Deltastream DP3 diagonal pump and i-cor® console (Xenios AG), the Hilite 7000 membrane oxygenator (Xenios AG), venous and arterial tubing and a 1 L soft venous pseudo-patient reservoir. Four different arterial cannulae (Biomedicus 15 and 17 Fr, Maquet 15 and 17 Fr) were used. For each cannula, 192 different pulsatile modes were investigated by adjusting flow rate, systole/diastole ratio, pulsatile amplitudes and frequency, yielding 784 unique conditions. A dSpace data acquisition system was used to collect flow and pressure data., Results: Increasing flow rates and pulsatile amplitudes were associated with significantly higher hemodynamic energy production (both p < 0.001), while no significant associations were seen while adjusting systole-to-diastole ratio (p = 0.73) or pulsing frequency (p = 0.99). Arterial cannula represents the highest resistance to hemodynamic energy transfer with 32%-59% of total hemodynamic energy generated being lost within, depending on pulsatile flow settings used., Conclusions: Herein, we presented the first study to compare hemodynamic energy production with all pulsatile ECLS pump settings and their combinations and widely used yet previously unexamined four different arterial ECMO cannula. Only increased flow rate and amplitude increase hemodynamic energy production as single factors, whilst other factors are relevant when combined., (© 2023 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

The right ventricle (RV) has a critical role in hemodynamics and right ventricular failure (RVF) often leads to poor clinical outcome. Despite the clinical importance of RVF, its definition and recognition currently rely on patients' symptoms and signs, rather than on objective parameters from quantifying RV dimensions and function. A key challenge is the geometrical complexity of the RV, which often makes it difficult to assess RV function accurately. There are several assessment modalities currently utilized in the clinical settings. Each diagnostic investigation has both advantages and limitations according to its characteristics. The purpose of this review is to reflect on the current diagnostic tools, consider the potential technological advancements and propose how to improve the assessment of right ventricular failure. Advanced technique such as automatic evaluation with artificial intelligence and 3-dimensional assessment for the complex RV structure has a potential to improve RV assessment by increasing accuracy and reproducibility of the measurements. Further, noninvasive assessments for RV-pulmonary artery coupling and right and left ventricular interaction are also warranted to overcome the load-related limitations for the accurate evaluation of RV contractile function. Future studies to cross-validate the advanced technologies in various populations are required., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Ro, Sato, Ijuin, Sela, Fior, Heinsar, Kim, Chan, Nonaka, Lin, Bassi, Platts, Obonyo, Suen and Fraser.)

Refractory cardiogenic shock is increasingly being treated with veno-arterial extracorporeal membrane oxygenation (V-A ECMO), without definitive proof of improved clinical outcomes. Recently, pulsatile V-A ECMO has been developed to address some of the shortcomings of contemporary continuous-flow devices. To describe current pulsatile V-A ECMO studies, we conducted a systematic review of all preclinical studies in this area. We adhered to PRISMA and Cochrane guidelines for conducting systematic reviews. The literature search was performed using Science Direct, Web of Science, Scopus, and PubMed databases. All preclinical experimental studies investigating pulsatile V-A ECMO and published before July 26, 2022 were included. We extracted data relating to the 1) ECMO circuits, 2) pulsatile blood flow conditions, 3) key study outcomes, and 4) other relevant experimental conditions. Forty-five manuscripts of pulsatile V-A ECMO were included in this review detailing 26 in vitro , two in silico , and 17 in vivo experiments. Hemodynamic energy production was the most investigated outcome (69%). A total of 53% of studies used a diagonal pump to achieve pulsatile flow. Most literature on pulsatile V-A ECMO focuses on hemodynamic energy production, whereas its potential clinical effects such as favorable heart and brain function, end-organ microcirculation, and decreased inflammation remain inconclusive and limited., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

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., (© 2023. The Author(s).)

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.

Extracorporeal membrane oxygenation (ECMO), a critical life-sustaining tool, faces significant challenges for the maintenance of normal haemostasis due to the large volume of circulating blood continuously in contact with artificial surfaces, hyperoxia and excessive shear stresses of the extracorporeal circuit. From a biomaterials perspective, it has been hypothesised that drug eluting coatings composed of haemocompatible hydrogels loaded with an anticoagulant drug could potentially enhance the haemocompatibility of the circuit. Poly(ethylene glycol) (PEG) has been well established as a biocompatible and anti-fouling material with wide biomedical application. Unfractionated heparin is the most commonly used anticoagulant for ECMO. In the present study, the feasibility of using heparin-loaded PEG-based hydrogels as anti-thrombogenic surface coatings for ECMO was investigated. The hydrogels were synthesised by photopolymerisation using poly(ethylene glycol) diacrylate (PEGDA) as the crosslinking monomer and poly(ethylene glycol) methacrylate (PEGMA) as the hydrophilic monomer, with heparin loaded into the pre-gel solution. Factors which could affect the release of heparin were investigated, including the ratio of PEGDA/PEGMA, water content, loading level of heparin and the flow of fluid past the hydrogel. Our results showed that increased crosslinker content and decreased water content led to slower heparin release. The hydrogels with water contents of 60 wt% and 70 wt% could achieve a sustained heparin release by adjusting the ratio of PEGDA/PEGMA. The anticoagulation efficacy of the released heparin was evaluated by measuring the activated clotting time of whole blood. The hydrogels with desirable heparin release profiles were prepared onto poly(4-methyl-1-pentene) (PMP) films with the same chemical composition as the PMP ECMO membranes. The coatings showed sustained heparin release with a cumulative release of 70-80% after 7 days. Haemocompatibility tests demonstrated that PEG hydrogel coatings significantly reduced platelet adhesion and prolonged plasma recalcification time. These results suggest that heparin-loaded PEG hydrogels are potential anti-thrombogenic coatings for ECMO.

Background: Fluid resuscitation is the standard treatment to restore circulating blood volume and pressure after massive haemorrhage and shock. Packed red blood cells (PRBC) are transfused to restore haemoglobin levels. Restoration of microcirculatory flow and tissue oxygen delivery is critical for organ and patient survival, but these parameters are infrequently measured. Patient Blood Management is a multidisciplinary approach to manage and conserve a patient's own blood, directing treatment options based on broad clinical assessment beyond haemoglobin alone, for which tissue perfusion and oxygenation could be useful. Our aim was to assess utility of non-invasive tissue-specific measures to compare PRBC transfusion with novel crystalloid treatments for haemorrhagic shock., Methods: A model of severe haemorrhagic shock was developed in an intensive care setting, with controlled haemorrhage in sheep according to pressure (mean arterial pressure 30-40 mmHg) and oxygen debt (lactate > 4 mM) targets. We compared PRBC transfusion to fluid resuscitation with either PlasmaLyte or a novel crystalloid. Efficacy was assessed according to recovery of haemodynamic parameters and non-invasive measures of sublingual microcirculatory flow, regional tissue oxygen saturation, repayment of oxygen debt (arterial lactate), and a panel of inflammatory and organ function markers. Invasive measurements of tissue perfusion, oxygen tension and lactate levels were performed in brain, kidney, liver, and skeletal muscle. Outcomes were assessed during 4 h treatment and post-mortem, and analysed by one- and two-way ANOVA., Results: Each treatment restored haemodynamic and tissue oxygen delivery parameters equivalently (p > 0.05), despite haemodilution after crystalloid infusion to haemoglobin concentrations below 70 g/L (p < 0.001). Recovery of vital organ-specific perfusion and oxygen tension commenced shortly before non-invasive measures improved. Lactate declined in all tissues and correlated with arterial lactate levels (p < 0.0001). The novel crystalloid supported rapid peripheral vasodilation (p = 0.014) and tended to achieve tissue oxygen delivery targets earlier. PRBC supported earlier renal oxygen delivery (p = 0.012) but delayed peripheral perfusion (p = 0.034)., Conclusions: Crystalloids supported vital organ oxygen delivery after massive haemorrhage, despite haemodilution to < 70 g/L, confirming that restrictive transfusion thresholds are appropriate to support oxygen delivery. Non-invasive tissue perfusion and oximetry technologies merit further clinical appraisal to guide treatment for massive haemorrhage in the context of Patient Blood Management., (© 2022. The Author(s).)

Previous experience has shown that transporting patients on extracorporeal membrane oxygenation (ECMO) is a safe and effective mode of transferring critically ill patients requiring maximum mechanical ventilator support to a quaternary care center. The coronavirus disease 2019 (COVID-19) pandemic posed new challenges. This is a multicenter, retrospective study of 113 patients with confirmed severe acute respiratory syndrome coronavirus 2, cannulated at an outside hospital and transported on ECMO to an ECMO center. This was performed by a multidisciplinary mobile ECMO team consisting of physicians for cannulation, critical care nurses, and an ECMO specialist or perfusionist, along with a driver or pilot. Teams practised strict airborne contact precautions with eyewear while caring for the patient and were in standard Personal Protective Equipment. The primary mode of transportation was ground. Ten patients were transported by air. The average distance traveled was 40 miles (SD ±56). The average duration of transport was 133 minutes (SD ±92). When stratified by mode of transport, the average distance traveled for ground transports was 36 miles (SD ±52) and duration was 136 minutes (SD ±93). For air, the average distance traveled was 66 miles (SD ±82) and duration was 104 minutes (SD ±70). There were no instances of transport-related adverse events including pump failures, cannulation complications at outside hospital, or accidental decannulations or dislodgements in transit. There were no instances of the transport team members contracting COVID-19 infection within 21 days after transport. By adhering to best practices and ACE precautions, patients with COVID-19 can be safely cannulated at an outside hospital and transported to a quaternary care center without increased risk to the transport team., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2021.)

Objectives: The study investigated the impact of prone positioning during venovenous extracorporeal membrane oxygenation support for coronavirus disease 2019 acute respiratory failure on the patient outcome., Design: An observational study of venovenous extracorporeal membrane oxygenation patients. We used a multistate survival model to compare the outcomes of patients treated with or without prone positioning during extracorporeal membrane oxygenation, which incorporates the dynamic nature of prone positioning and adjusts for potential confounders., Setting: Seventy-two international institutions participating in the Coronavirus Disease 2019 Critical Care Consortium international registry., Patients: Coronavirus disease 2019 patients who were supported by venovenous extracorporeal membrane oxygenation during the study period., Intervention: None., Measurements and Main Results: There were 232 coronavirus disease 2019 patients at 72 participating institutions who were supported with venovenous extracorporeal membrane oxygenation during the study period from February 16, 2020, to October 31, 2020. Proning was used in 176 patients (76%) before initiation of extracorporeal membrane oxygenation and in 67 patients (29%) during extracorporeal membrane oxygenation. Survival to hospital discharge was 33% in the extracorporeal membrane oxygenation prone group versus 22% in the extracorporeal membrane oxygenation supine group. Prone positioning during extracorporeal membrane oxygenation support was associated with reduced mortality (hazard ratio, 0.31; 95% CI, 0.14-0.68)., Conclusions: Our study highlights that prone positioning during venovenous extracorporeal membrane oxygenation support for refractory coronavirus disease 2019-related acute respiratory distress syndrome is associated with reduced mortality. Given the observational nature of the study, a randomized controlled trial of prone positioning on venovenous extracorporeal membrane oxygenation is needed to confirm these findings., Competing Interests: Dr. Jacobs received funding from SpecialtyCare and the American Academy of Dermatology. Dr. Heinsar received funding via PhD scholarship from the University of Queensland. Dr. Bassi’s institution received funding from Fisher & Paykel. Dr. Dalton received funding from Innovative Extracorporeal Membrane Oxygenation (ECMO) Concepts; she disclosed the off-label product use of ECMO equipment. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Heart transplantation (HTx) from brainstem dead (BSD) donors is the gold-standard therapy for severe/end-stage cardiac disease, but is limited by a global donor heart shortage. Consequently, innovative solutions to increase donor heart availability and utilisation are rapidly expanding. Clinically relevant preclinical models are essential for evaluating interventions for human translation, yet few exist that accurately mimic all key HTx components, incorporating injuries beginning in the donor, through to the recipient. To enable future assessment of novel perfusion technologies in our research program, we thus aimed to develop a clinically relevant sheep model of HTx following 24 h of donor BSD., Methods: BSD donors (vs. sham neurological injury, 4/group) were hemodynamically supported and monitored for 24 h, followed by heart preservation with cold static storage. Bicaval orthotopic HTx was performed in matched recipients, who were weaned from cardiopulmonary bypass (CPB), and monitored for 6 h. Donor and recipient blood were assayed for inflammatory and cardiac injury markers, and cardiac function was assessed using echocardiography. Repeated measurements between the two different groups during the study observation period were assessed by mixed ANOVA for repeated measures., Results: Brainstem death caused an immediate catecholaminergic hemodynamic response (mean arterial pressure, p = 0.09), systemic inflammation (IL-6 - p = 0.025, IL-8 - p = 0.002) and cardiac injury (cardiac troponin I, p = 0.048), requiring vasopressor support (vasopressor dependency index, VDI, p = 0.023), with normalisation of biomarkers and physiology over 24 h. All hearts were weaned from CPB and monitored for 6 h post-HTx, except one (sham) recipient that died 2 h post-HTx. Hemodynamic (VDI - p = 0.592, heart rate - p = 0.747) and metabolic (blood lactate, p = 0.546) parameters post-HTx were comparable between groups, despite the observed physiological perturbations that occurred during donor BSD. All p values denote interaction among groups and time in the ANOVA for repeated measures., Conclusions: We have successfully developed an ovine HTx model following 24 h of donor BSD. After 6 h of critical care management post-HTx, there were no differences between groups, despite evident hemodynamic perturbations, systemic inflammation, and cardiac injury observed during donor BSD. This preclinical model provides a platform for critical assessment of injury development pre- and post-HTx, and novel therapeutic evaluation., (© 2021. The Author(s).)

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., (© 2021. The Author(s).)

Acute fulminant myocarditis (AFM) occurs as an inflammatory response to an initial myocardial insult. Its rapid and deadly progression calls for prompt diagnosis with aggressive treatment measures. The demonstration of its excellent recovery potential has led to increasing use of mechanical circulatory support, especially extracorporeal membrane oxygenation (ECMO). Arrhythmias, organ failure, elevated cardiac biomarkers, and decreased ventricular function at presentation predict requirement for ECMO. In these patients, ECMO should be considered earlier as the clinical course of AFM can be unpredictable and can lead to rapid haemodynamic collapse. Key uncertainties that clinicians face when managing children with AFM such as timing of initiation of ECMO and left ventricular decompression need further investigation.

In vitro hemolysis testing is commonly used to determine hemocompatibility of ExtraCorporeal Membrane Oxygenation (ECMO). However, poor reproducibility remains a challenging problem, due to several unidentified influencing factors. The present study investigated potential factors, such as flow rates, the use of anticoagulants, and gender of blood donors, which could play a role in hemolysis. Fresh human whole blood was anticoagulated with either citrate (n = 6) or heparin (n = 12; 6 female and 6 male blood donors). Blood was then circulated for 360 min at 4 L/min or 1.5 L/min. Regardless of flow rate conditions, hemolysis remained unchanged over time in citrated blood, but significantly increased after 240 min circulation in heparinized blood ( p ≤ 0.01). The ratio of the normalized index of hemolysis ( NIH ) of heparinized blood to citrated blood was 11.7-fold higher at 4 L/min and 16.5-fold higher at 1.5 L/min. The difference in hemolysis between 1.5 L/min and 4 L/min concurred with findings of previous literature. In addition, the ratio of NIH of male heparinized blood to female was 1.7-fold higher at 4 L/min and 2.2-fold higher at 1.5 L/min. Our preliminary results suggested that the choice of anticoagulant and blood donor gender could be critical factors in hemolysis studies, and should be taken into account to improve testing reliability during ECMO.