Membrane oxygenator longevity was higher in argatroban-treated patients undergoing vvECMO.

BACKGROUND: In severe acute respiratory distress syndrome (ARDS), venovenous extracorporeal membrane oxygenation (vvECMO) can be a lifesaver. However, anticoagulation therapy is mandatory because the nonendothelial extracorporeal surface increases the risk of thromboembolic problems. Heparin is still the most common anticoagulant, but argatroban could be an alternative. This work investigates whether argatroban offers a therapeutic advantage over heparin during vvECMO. METHODS: We performed a retrospective cohort study of patients who underwent vvECMO for severe ARDS and received heparin or argatroban as anticoagulation therapy. Demographic variables, intensive care unit (ICU) treatment and outcome parameters were evaluated. The primary outcome parameter was the operating time of the membrane oxygenator normalized to the duration of vvECMO treatment. Secondary outcome parameters were transfusion requirements normalized to the duration of vvECMO therapy. RESULTS: Fifty seven patients from January 2019 to February 2021 underwent vvECMO and were included in this study. Thirty three patients received heparin and 24 patients argatroban as anticoagulatory therapy. The groups did not differ in demographics, ICU scoring systems, or comorbidities. Platelet counts and partial prothrombin time did not differ between the two groups during the first 6 days of vvECMO. The argatroban group had lower requirements for red blood cells, platelets and fresh frozen plasma. The mean runtime of the individual membrane oxygenator increased from 12.3 days (heparin group) to 16.6 days in the argatroban group. CONCLUSIONS: Our findings suggest that argatroban can be considered as anticoagulant during vvECMO.

Early vvECMO implantation may be associated with lower mortality in ARDS.

BACKGROUND: Venovenous extracorporeal membrane oxygenation (vvECMO) is used to treat hypoxia in patients with severe acute respiratory distress syndrome (ARDS). Nevertheless, uncertainty exists regarding the optimal timing of initiation of vvECMO therapy. We aimed to investigate the association between number of days of invasive mechanical ventilation (IMV) prior to vvECMO implantation and mortality. METHODS: In this retrospective observational study, we included patients treated at an academic intensive care unit with vvECMO for severe ARDS. The primary outcome was all-cause 28-day mortality. We conducted a multivariate logistic regression analysis to estimate the association between number of days of IMV prior to vvECMO implantation and mortality after adjustment for confounders. RESULTS: Out of 274 patients who underwent ECMO for severe ARDS, 158 patients (median age: 58 years) with relevant data were included in the analysis. The mean duration of IMV prior to vvECMO was significantly shorter in survivors than in nonsurvivors [survivors median: 1; interquartile range: 1-3; non-survivors median 4; interquartile range: 1-5.75; p = 0.0001). Logistic regression showed an association between the duration of ventilation prior to vvECMO and patient mortality. The odds ratio for the all-cause 28-day mortality and in-hospital mortality was significantly reduced in patients who received vvECMO within the first 5 days of IMV. CONCLUSIONS: Early vvECMO implantation may be associated with lower mortality in ARDS.

Inhaled prostacyclin therapy in the acute respiratory distress syndrome: a randomized controlled multicenter trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS. METHODS: We performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride (Placebo). The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events. RESULTS: Of 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n = 73) or sodium chloride (n = 77). Data from 144 patients were analyzed. The baseline PaO2/FiO2 ratio did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than Placebo (p = 0.17). Secondary analysis showed that the oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p = 0.04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups. CONCLUSIONS: The primary result of our study was negative. Our data suggest that inhaled prostacyclin might be beneficial treatment in patients with COVID-19 induced ARDS. TRIAL REGISTRATION: The study was approved by the Institutional Review Board of the Research Ethics Committee of the University of Tübingen (899/2018AMG1) and the corresponding ethical review boards of all participating centers. The trial was also approved by the Federal Institute for Drugs and Medical Devices (BfArM, EudraCT No. 2016003168-37) and registered at clinicaltrials.gov (NCT03111212) on April 6th 2017.

COVID-19 does not influence functional status after ARDS therapy.

RATIONALE: Health-related quality of life after surviving acute respiratory distress syndrome has come into focus in recent years, especially during the coronavirus disease 2019 pandemic. OBJECTIVES: A total of 144 patients with acute respiratory distress syndrome caused by COVID-19 or of other origin were recruited in a randomized multicenter trial. METHODS: Clinical data during intensive care treatment and data up to 180 days after study inclusion were collected. Changes in the Sequential Organ Failure Assessment score were used to quantify disease severity. Disability was assessed using the Barthel index on days 1, 28, 90, and 180. MEASUREMENTS: Mortality rate and morbidity after 180 days were compared between patients with and without COVID-19. Independent risk factors associated with high disability were identified using a binary logistic regression. MAIN RESULTS: The SOFA score at day 5 was an independent risk factor for high disability in both groups, and score dynamic within the first 5 days significantly impacted disability in the non-COVID group. Mortality after 180 days and impairment measured by the Barthel index did not differ between patients with and without COVID-19. CONCLUSIONS: Resolution of organ dysfunction within the first 5 days significantly impacts long-term morbidity. Acute respiratory distress syndrome caused by COVID-19 was not associated with increased mortality or morbidity.

[Echocardiographic Assessment of Perioperative Right and Left Ventricular Function]. / Perioperative Echokardiografie der rechts- und linksventrikulären Funktion.

The perioperative quantification of left and right ventricular function is cornerstone to provide optimal patient care. Echocardiography has emerged as the most important cardiac imaging modality in this setting, mainly due to its rapid availability, non-invasiveness and cost-efficiency. Both the transthoracic and the transesophageal acoustic windows offer manifold modes, e.g., doppler-based measurements or M-mode display, to assess systolic and diastolic ventricular function. An association with patient outcome and corresponding prognostic implications could be demonstrated for the majority of those parameters. Hence, a profound understanding of these measurements is key to delineate sufficient from failing left or right ventricular function and guide treatment decisions. This article gives the reader an overview over the most important measurements, reference values and pitfalls.

Neuronal guidance proteins in cardiovascular inflammation.

Cardiovascular pathologies are often induced by inflammation. The associated changes in the inflammatory response influence vascular endothelial biology; they complicate the extent of ischaemia and reperfusion injury, direct the migration of immune competent cells and activate platelets. The initiation and progression of inflammation is regulated by the classical paradigm through the system of cytokines and chemokines. Therapeutic approaches have previously used this knowledge to control the extent of cardiovascular changes with varying degrees of success. Neuronal guidance proteins (NGPs) have emerged in recent years and have been shown to be significantly involved in the control of tissue inflammation and the mechanisms of immune cell activation. Therefore, proteins of this class might be used in the future as targets to control the extent of inflammation in the cardiovascular system. In this review, we describe the role of NGPs during cardiovascular inflammation and highlight potential therapeutic options that could be explored in the future.

Machine learning identifies ICU outcome predictors in a multicenter COVID-19 cohort.

BACKGROUND: Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes. METHODS: A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. RESULTS: 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict "survival". Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients' age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. CONCLUSIONS: Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration "ClinicalTrials" (clinicaltrials.gov) under NCT04455451.

Extubation and Noninvasive Ventilation of Patients Supported by Extracorporeal Life Support for Cardiogenic Shock: A Single-Center Retrospective Observational Cohort Study.

BACKGROUND: Temporary extracorporeal life support (ECLS) by venoarterial extracorporeal membrane oxygenation is an emerging therapy for patients with severe, ongoing cardiogenic shock. After stabilization of the hemodynamic status and end-organ function, sedation weaning, extubation, and noninvasive ventilation (NIV) can be attempted. The goal of this study was to analyze the feasibility of extubation and NIV during versus after ECLS for cardiogenic shock. METHODS: Single-center retrospective observational study of 132 patients undergoing ECLS due to severe cardiogenic shock between January 2015 and December 2016 at a tertiary care university hospital. RESULTS: Patients received ECLS due to acute myocardial infarction (20.6%), ongoing cardiogenic shock (15.2%), postoperative low-cardiac-output syndrome (24.2%), and extracorporeal cardiopulmonary resuscitation (40.2%). Overall, intensive care unit survival was 44.7%. Sixty-nine (52.3%) patients could never be extubated. Forty-three (32.6%) were extubated while on ECLS support (group 1) and 20 (15.1%) were extubated after weaning from ECLS (group 2). Patients extubated during ECLS had a significantly shorter total time on ventilator (P = .003, mean difference: -284 hours [95% confidence limits: -83 to -484]) and more invasive ventilation free days (P = .0018; mean difference 8 days [95%CL: 2-14]). Mortality and NIV failure rates were similar between groups. CONCLUSIONS: Extubation and NIV are feasible in patients who stabilize during ECLS therapy. Further studies need to address whether extubation has the potential to improve patients outcome or if the feasibility to extubate is a surrogate for disease severeness.

Mesenchymal Stem Cell Therapy for Severe COVID-19 ARDS.

BACKGROUND: The COVID-19 pandemic reached Germany in spring 2020. No proven treatment for SARS-CoV-2 was available at that time, especially for severe COVID-19-induced ARDS. We determined whether the infusion of mesenchymal stromal cells (MSCs) would help to improve pulmonary function and overall outcome in patients with severe COVID-19 ARDS. We offered MSC infusion as an extended indication to all critically ill COVID-19 patients with a Horovitz index <100. We treated 5 out of 23 patients with severe COVID-19 ARDS with an infusion of MSCs. One million MSCs/kg body weight was infused over 30 minutes, and the process was repeated in 3 patients twice and in 2 patients 3 times. RESULT: Four out of 5 MSC-treated patients compared to 50% of control patients (9 out of 18) received ECMO support (80%). The MSC group showed a higher Murray score on admission than control patients, reflecting more severe pulmonary compromise (3.5 ± 0.2 versus 2.8 ± 0.3). MSC infusion was safe and well tolerated. The MSC group had a significantly higher Horovitz score on discharge than the control group. Compared to controls, patients with MSC treatment showed a significantly lower Murray score upon discharge than controls. In the MSC group, 4 out of 5 patients (80%) survived to discharge and exhibited good pulmonary function, whereas only 8 out of 18 patients (45%) in the control group survived to discharge. CONCLUSION: MSC infusion is a safe treatment for COVID-19 ARDS that improves pulmonary function and overall outcome in this patient population.

Transcription-independent Induction of ERBB1 through Hypoxia-inducible Factor 2A Provides Cardioprotection during Ischemia and Reperfusion.

BACKGROUND: During myocardial ischemia, hypoxia-inducible factors are stabilized and provide protection from ischemia and reperfusion injury. Recent studies show that myocyte-specific hypoxia-inducible factor 2A promotes myocardial ischemia tolerance through induction of epidermal growth factor, amphiregulin. Here, the authors hypothesized that hypoxia-inducible factor 2A may enhance epidermal growth factor receptor 1 (ERBB1) expression in the myocardium that could interface between growth factors and its effect on providing tolerance to ischemia and reperfusion injury. METHODS: Human myocardial tissues were obtained from ischemic heart disease patients and normal control patients to compare ERBB1 expression. Myocyte-specific Hif2a or ErbB1 knockout mice were generated to observe the effect of Hif2a knockdown in regulating ERBB1 expression and to examine the role of ERBB1 during myocardial ischemia and reperfusion injury. RESULTS: Initial studies of myocardial tissues from patients with ischemic heart disease showed increased ERBB1 protein (1.12 ± 0.24 vs. 13.01 ± 2.20, P < 0.001). In contrast, ERBB1 transcript was unchanged. Studies using short hairpin RNA repression of Hif2A or Hif2a Myosin Cre+ mice directly implicated hypoxia-inducible factor 2A in ERBB1 protein induction during hypoxia or after myocardial ischemia, respectively. Repression of RNA-binding protein 4 abolished hypoxia-inducible factor 2A-dependent induction of ERBB1 protein. Moreover, ErbB1 Myosin Cre+ mice experienced larger infarct sizes (22.46 ± 4.06 vs. 46.14 ± 1.81, P < 0.001) and could not be rescued via amphiregulin treatment. CONCLUSIONS: These findings suggest that hypoxia-inducible factor 2A promotes transcription-independent induction of ERBB1 protein and implicates epidermal growth factor signaling in protection from myocardial ischemia and reperfusion injury.

[Disturbances of the Potassium Homeostasis]. / Störungen des Kaliumhaushalts.

Potassium is a key cation in the human organism and largely responsible for the resting membrane potential of excitable cells. 98% of the potassium pool resides within the cells and only 2% in the extracellular space. Thus, blood sample measurements of potassium do not necessarily reflect the total potassium state. The extracellular potassium concentration however is tightly regulated, either through potassium elimination via the kidney or shift between the intra- or extracellular compartment. Changes in the blood serum potassium concentration are defined as hypokalemia (< 3,5 mmol/l) or hyperkalemia (> 5,0 mmol/l). Hypokalemia is caused by a low-potassium diet, gastrointestinal losses or polyuric renal failure. Hyperkalemia can follow excessive intake, severe tissue damage or oliguric or anuric renal failure. Acute alteration of the extracellular potassium concentration should spark immediate action by the perioperative physician. In particular, hyperkalemic states require immediate attention and therapeutic interventions. In this review, we give an overview of the pathophysiology of potassium changes and provide a practical approach to their management.

Differential Tissue-Specific Function of Adora2b in Cardioprotection.

The adenosine A2b receptor (Adora2b) has been implicated in cardioprotection from myocardial ischemia. As such, Adora2b was found to be critical in ischemic preconditioning (IP) or ischemia/reperfusion (IR) injury of the heart. Whereas Adora2b is present on various cells types, the tissue-specific role of Adora2b in cardioprotection is still unknown. To study the tissue-specific role of Adora2b signaling on inflammatory cells, endothelia, or myocytes during myocardial ischemia in vivo, we intercrossed floxed Adora2b mice with Lyz2-Cre(+), VE-cadherin-Cre(+), or myosin-Cre(+) transgenic mice, respectively. Mice were exposed to 60 min of myocardial ischemia with or without IP (four times for 5 min) followed by 120 min of reperfusion. Cardioprotection by IP was abolished in Adora2b(f/f)-VE-cadherin-Cre(+) or Adora2b(f/f)-myosin-Cre(+), indicating that Adora2b signaling on endothelia or myocytes mediates IP. In contrast, primarily Adora2b signaling on inflammatory cells was necessary to provide cardioprotection in IR injury, indicated by significantly larger infarcts and higher troponin levels in Adora2b(f/f)-Lyz2-Cre(+) mice only. Cytokine profiling of IR injury in Adora2b(f/f)-Lyz2-Cre(+) mice pointed toward polymorphonuclear neutrophils (PMNs). Analysis of PMNs from Adora2b(f/f)-Lyz2-Cre(+) confirmed PMNs as one source of identified tissue cytokines. Finally, adoptive transfer of Adora2b(-/-) PMNs revealed a critical role of Adora2b on PMNs in cardioprotection from IR injury. Adora2b signaling mediates different types of cardioprotection in a tissue-specific manner. These findings have implications for the use of Adora2b agonists in the treatment or prevention of myocardial injury by ischemia.

Explainable Boosting Machine approach identifies risk factors for acute renal failure.

BACKGROUND: Risk stratification and outcome prediction are crucial for intensive care resource planning. In addressing the large data sets of intensive care unit (ICU) patients, we employed the Explainable Boosting Machine (EBM), a novel machine learning model, to identify determinants of acute kidney injury (AKI) in these patients. AKI significantly impacts outcomes in the critically ill. METHODS: An analysis of 3572 ICU patients was conducted. Variables such as average central venous pressure (CVP), mean arterial pressure (MAP), age, gender, and comorbidities were examined. This analysis combined traditional statistical methods with the EBM to gain a detailed understanding of AKI risk factors. RESULTS: Our analysis revealed chronic kidney disease, heart failure, arrhythmias, liver disease, and anemia as significant comorbidities influencing AKI risk, with liver disease and anemia being particularly impactful. Surgical factors were also key; lower GI surgery heightened AKI risk, while neurosurgery was associated with a reduced risk. EBM identified four crucial variables affecting AKI prediction: anemia, liver disease, and average CVP increased AKI risk, whereas neurosurgery decreased it. Age was a progressive risk factor, with risk escalating after the age of 50 years. Hemodynamic instability, marked by a MAP below 65 mmHg, was strongly linked to AKI, showcasing a threshold effect at 60 mmHg. Intriguingly, average CVP was a significant predictor, with a critical threshold at 10.7 mmHg. CONCLUSION: Using an Explainable Boosting Machine enhance the precision in AKI risk factors in ICU patients, providing a more nuanced understanding of known AKI risks. This approach allows for refined predictive modeling of AKI, effectively overcoming the limitations of traditional statistical models.

Semaphorin 7A coordinates neutrophil response during pulmonary inflammation and sepsis.

ABSTRACT: Pulmonary defense mechanisms are critical for host integrity during pneumonia and sepsis. This defense is fundamentally dependent on the activation of neutrophils during the innate immune response. Recent work has shown that semaphorin 7A (Sema7A) holds significant impact on platelet function, yet its role on neutrophil function within the lung is not well understood. This study aimed to identify the role of Sema7A during pulmonary inflammation and sepsis. In patients with acute respiratory distress syndrome (ARDS), we were able to show a correlation between Sema7A and oxygenation levels. During subsequent workup, we found that Sema7A binds to the neutrophil PlexinC1 receptor, increasing integrins, and L-selectin on neutrophils. Sema7A prompted neutrophil chemotaxis in vitro and the formation of platelet-neutrophil complexes in vivo. We also observed altered adhesion and transmigration of neutrophils in Sema7A-/-animals in the lung during pulmonary inflammation. This effect resulted in increased number of neutrophils in the interstitial space of Sema7A-/- animals but reduced numbers of neutrophils in the alveolar space during pulmonary sepsis. This finding was associated with significantly worse outcome of Sema7A-/- animals in a model of pulmonary sepsis. Sema7A has an immunomodulatory effect in the lung, affecting pulmonary sepsis and ARDS. This effect influences the response of neutrophils to external aggression and might influence patient outcome. This trial was registered at www.ClinicalTrials.gov as #NCT02692118.

The Intriguing Role of Hypoxia-Inducible Factor in Myocardial Ischemia and Reperfusion: A Comprehensive Review.

Hypoxia-inducible factors (HIFs) play a crucial role in cellular responses to low oxygen levels during myocardial ischemia and reperfusion injury. HIF stabilizers, originally developed for treating renal anemia, may offer cardiac protection in this context. This narrative review examines the molecular mechanisms governing HIF activation and function, as well as the pathways involved in cell protection. Furthermore, we analyze the distinct cellular roles of HIFs in myocardial ischemia and reperfusion. We also explore potential therapies targeting HIFs, emphasizing their possible benefits and limitations. Finally, we discuss the challenges and opportunities in this research area, underscoring the need for continued investigation to fully realize the therapeutic potential of HIF modulation in managing this complex condition.

[Risk of cannulation site bleeding during physical therapy mobilization during extracorporeal membrane oxygenation : A retrospective analysis in patients with acute respiratory failure]. / Blutungsrisiko im Kanülenbereich bei physiotherapeutischer Mobilisation unter extrakorporaler Membranoxygenierung : Eine retrospektive Analyse bei Patient*innen mit akutem Lungenversagen.

BACKGROUND: Patients suffering from acute respiratory distress syndrome receive extracorporeal membrane oxygenation (ECMO) as the last possible therapy. At the University Hospital Tübingen, these patients also receive physical therapy during this phase from a specially trained team to counteract physical deconditioning. OBJECTIVES: In this work, the risk of cannula site bleeding during physiotherapy mobilization is investigated and aspects regarding safety are described. METHODS: From 2013 to 2018, 83 patients matching the inclusion criteria were treated at the Anesthesiology Intensive Care Unit at the University Hospital Tübingen. The datasets were retrospectively analyzed by means of a case-control study. For comparison, the patients were divided into a passive and an active group according to the achieved level of mobilization. Bleeding events, ECMO implantation duration, and other aspects were taken into consideration in the analysis. RESULTS AND CONCLUSION: There were two bleeding events in the passive and two bleeding events in the active group, but these were not related to physical therapy mobilization. The ECMO implantation duration varied between 1 and 77 days. Physical therapy mobilization by a specially trained interdisciplinary team did not increase the risk of bleeding at the cannulation site.

Echocardiography as a Tool to Assess Cardiac Function in Critical Care-A Review.

In critically ill patients, hemodynamic disturbances are common and often lead to a detrimental outcome. Frequently, invasive hemodynamic monitoring is required for patients who are hemodynamically unstable. Although the pulmonary artery catheter enables a comprehensive assessment of the hemodynamic profile, this technique carries a substantial inherent risk of complications. Other less invasive techniques do not offer a full range of results to guide detailed hemodynamic therapies. An alternative with a lower risk profile is transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE). After training, intensivists can obtain similar parameters on the hemodynamic profile using echocardiography, such as stroke volume and ejection fraction of the right and left ventricles, an estimate of the pulmonary artery wedge pressure, and cardiac output. Here, we will review individual echocardiography techniques that will help the intensivist obtain a comprehensive assessment of the hemodynamic profile using echocardiography.

Patient-Related Factors Associated with Adverse Outcomes Following Weaning from Veno-Arterial Extracorporeal Membrane Oxygenation.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (vaECMO) removal reflects a critical moment and factors of adverse outcomes are incompletely understood. Thus, we studied various patient-related factors during vaECMO removal to determine their association with outcomes. METHODS: A total of 58 patients from a university hospital were included retrospectively. Demographic, clinical, and echocardiographic parameters were recorded while under vaECMO support, as well as the need for inotropic and vasoactive-inotropic scores (VIS). Successful weaning was defined as 28-day survival without reinitiation of vaECMO. RESULTS: Patient age differed significantly between patients with a successful and a failed vaECMO weaning (54 ± 14 vs. 62 ± 12 years, p = 0.029). In univariable logistic regression, age (OR 0.952 (0.909-0.997), p = 0.038), the necessities for inotropic agents at the time of echocardiography (OR 0.333 (0.113-0.981), p = 0.046), and vaECMO removal (OR 0.266 (0.081-0.877), p = 0.030) as well as the dobutamine dose during removal (OR 0.649 (0.473-0.890), p = 0.007), were significantly associated with a successful weaning from vaECMO. Age (HR 1.048 (1.006-1.091), p = 0.024) and the VIS (HR 1.030 (1.004-1.056), p = 0.025) at the time of vaECMO removal were independently associated with survival in bivariable Cox regression. In Kaplan-Meier analysis, a VIS of >5.1 at vaECMO removal was associated with impaired survival (log-rank p = 0.025). CONCLUSIONS: In this cohort, age and the extent of vasoactive-inotropic agents were associated with adverse outcomes following vaECMO, whereas echocardiographic biventricular function during vaECMO support was not.

Adora2b signaling on bone marrow derived cells dampens myocardial ischemia-reperfusion injury.

BACKGROUND: Cardiac ischemia-reperfusion (I-R) injury represents a major cause of cardiac tissue injury. Adenosine signaling dampens inflammation during cardiac I-R. The authors investigated the role of the adenosine A2b-receptor (Adora2b) on inflammatory cells during cardiac I-R. METHODS: To study Adora2b signaling on inflammatory cells, the authors transplanted wild-type (WT) bone marrow (BM) into Adora2b(-/-) mice or Adora2b(-/-) BM into WT mice. To study the role of polymorphonuclear leukocytes (PMNs), neutrophil-depleted WT mice were treated with an Adora2b agonist. After treatments, mice were exposed to 60 min of myocardial ischemia and 120 min of reperfusion. Infarct sizes and troponin I concentrations were determined by triphenyltetrazolium chloride staining and enzyme-linked immunosorbent assay, respectively. RESULTS: Transplantation of WT BM into Adora2b(-/-) mice decreased infarct sizes by 19 ± 4% and troponin I by 87.5 ± 25.3 ng/ml (mean ± SD, n = 6). Transplantation of Adora2b(-/-) BM into WT mice increased infarct sizes by 20 ± 3% and troponin I concentrations by 69.7 ± 17.9 ng/ml (mean ± SD, n = 6). Studies on the reperfused myocardium revealed PMNs as the dominant cell type. PMN depletion or Adora2b agonist treatment reduced infarct sizes by 30 ± 11% or 26 ± 13% (mean ± SD, n = 4); however, the combination of both did not produce additional cardioprotection. Cytokine profiling showed significantly higher cardiac tumor necrosis factor α concentrations in Adora2b(-/-) compared with WT mice (39.3 ± 5.3 vs. 7.5 ± 1.0 pg/mg protein, mean ± SD, n = 4). Pharmacologic studies on human-activated PMNs revealed an Adora2b-dependent tumor necrosis factor α release. CONCLUSION: Adora2b signaling on BM-derived cells such as PMNs represents an endogenous cardioprotective mechanism during cardiac I-R. The authors' findings suggest that Adora2b agonist treatment during cardiac I-R reduces tumor necrosis factor α release of PMNs, thereby dampening tissue injury.