Isoproterenol Improves Hemodynamics And Right Ventricle-Pulmonary Artery Coupling After Heart Transplantation.

BACKGROUND: Right ventricular failure (RVF) is a major cause of early mortality after heart transplantation (HT). Isoproterenol has chronotropic, inotropic, and vasodilatory properties which might improve right ventricle function in this setting. We aimed to investigate the hemodynamic effects of isoproterenol on patients with post-HT RVF. METHODS: We conducted a one-year retrospective observational study including patients receiving isoproterenol and dobutamine for early RVF after HT. A comprehensive multiparametric hemodynamic evaluation was performed successively at three times: no isoproterenol, low doses: 0.025 µg/kg/min and high doses: 0.05 µg/kg/min (henceforth respectively called no-iso, low-iso and high-iso). RESULTS: From June 2022 to June 2023, 25 patients, median [IQR25-75] age 54 [38-61] years, were included. Before isoproterenol introduction, all patients received dobutamine and 15 (60%) were on veno-arterial extracorporeal membrane oxygenation. Isoproterenol significantly increased heart rate from 84 [77-99] (no-iso) to 91 [88-106] (low-iso) and 102 [90-122] bpm (high-iso, p<0.001). Similarly, cardiac index raised from 2.3 [1.4-3.1] to 2.7 [1.8-3.4] and 3 [1.9-3.7] l/min/m2 (p<0.001) with concomitant increase of indexed stroke volume (28 [17-34] to 31 [20-34] and 33 [23-35] mL/m2, p<0.05). Effective pulmonary arterial elastance and pressures were not modified by isoproterenol. Pulmonary vascular resistance tended to decrease from 2.9 (1.4-3.6) WU to 2.3 (1.3-3.5) WU, p=0.06. Right ventricular ejection fraction/systolic PAP evaluating RV-PA coupling increased after isoproterenol from 0.8 to 0.9 and 1 %.mmHg-1 (p=0.001). CONCLUSIONS: In post-HT RVF, isoproterenol exhibits chronotropic and inotropic effects, thereby improving RV-PA coupling and resulting in a clinically relevant increase in the cardiac index.

Improved Extracorporeal Cardiopulmonary Resuscitation (ECPR) Outcomes Is Associated with a Restrictive Patient Selection Algorithm.

INTRODUCTION: Out-of-hospital cardiac arrest (OHCA) is a leading cause of mortality. Despite decades of intensive research and several technological advancements, survival rates remain low. The integration of extracorporeal cardiopulmonary resuscitation (ECPR) has been recognized as a promising approach in refractory OHCA. However, evidence from recent randomized controlled trials yielded contradictory results, and the criteria for selecting eligible patients are still a subject of debate. METHODS: This study is a retrospective analysis of refractory OHCA patients treated with ECPR. All adult patients who received ECPR, according to the hospital algorithm, from 2013 to 2021 were included. Two different algorithms were used during this period. A "permissive" algorithm was used from 2013 to mid-2016. Subsequently, a revised algorithm, more "restrictive", based on international guidelines, was implemented from mid-2016 to 2021. Key differences between the two algorithms included reducing the no-flow time from less than three minutes to zero minutes (implying that the cardiac arrests must occur in the presence of a witness with immediate CPR initiation), reducing low-flow duration from 100 to 60 min, and lowering the age limit from 65 to 55 years. The aim of this study is to compare these two algorithms (permissive (1) and restrictive (2)) to determine if the use of a restrictive algorithm was associated with higher survival rates. RESULTS: A total of 48 patients were included in this study, with 23 treated under Algorithm 1 and 25 under Algorithm 2. A significant difference in survival rate was observed in favor of the restrictive algorithm (9% vs. 68%, p < 0.05). Moreover, significant differences emerged between algorithms regarding the no-flow time (0 (0-5) vs. 0 (0-0) minutes, p < 0.05). Survivors had a significantly shorter no-flow and low-flow time (0 (0-0) vs. 0 (0-3) minutes, p < 0.01 and 40 (31-53) vs. 60 (45-80) minutes, p < 0.05), respectively. CONCLUSION: The present study emphasizes that a stricter selection of OHCA patients improves survival rates in ECPR.

Thiamine as a metabolic resuscitator in septic shock: a meta-analysis of randomized controlled trials with trial sequential analysis.

Objective: Septic shock is one of the most common reasons for admission to the Intensive Care Unit (ICU) and is associated with high mortality. Fundamentally, its management rests on antibiotics, fluid therapy and vasopressor use while many adjunctive therapies have shown disappointing results. Thiamine has recently gained interest as a metabolic resuscitator, though recent trials have tempered this enthusiasm, more specifically when thiamine is associated with ascorbic acid. However, thiamine use alone has been poorly investigated. Design: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) in septic shock patients to assess the effects of thiamine without ascorbic acid as an adjunctive therapy. Setting: PubMed, Embase and the Cochrane library databases were searched from inception to April of 2023. Data were extracted independently by two authors. The main outcome was mortality. Subjects: We included RCTs comparing standard care using thiamine alone, to standard care or placebo, in patients admitted to the ICU with sepsis or septic shock. Main results: We included 5 RCTs (n = 293 patients). In this analysis, use of thiamine alone did not significantly change mortality, RR 0.87 (95%CI 0.65; 1.16, I2 = 21%) p = 0.34. Conclusion: Current RCTs did not show an improvement in mortality when using thiamine in septic shock patients as an adjunctive therapy. However, these trials are largely underpowered for a definitive conclusion to be drawn. Further studies are therefore needed to assess the effects of thiamine without ascorbic acid as an adjunctive therapy.

Early renal recovery after acute kidney injury in patients on venoarterial extracorporeal membrane oxygenation: A retrospective study.

PURPOSE: The impact of VA-ECMO on early renal recovery (within 7 days after ECMO onset) in patients with pre-ECMO acute kidney injury and cardiogenic shock is unknown. MATERIAL AND METHODS: This retrospective single-center study included adult patients with cardiogenic shock rescued by VA-ECMO and severe AKI occurring before ECMO implantation (pre-ECMO AKI). Patients with early renal recovery (defined as at least a 50% decrease in peak serum creatinine or weaning from renal replacement therapy) were compared to patients without early renal recovery. RESULTS: During 7 years, 145 patients with severe pre-ECMO AKI were included. Eighty-two patients had no early renal recovery whereas 63 had early renal recovery within 7 days after VA-ECMO onset. The median time to early renal recovery was 4 (3,6) days. Nephrotoxic antibiotics (HR = 0.35 [95% CI, 0.21-0.59], p < 0.001), median fluid balance during the first 7 days of VA-ECMO (HR = 0.77 [95% CI, 0.64-0.93], p = 0.008), pre-ECMO AKI stage 3 (HR = 0.36 [95% CI, 0.20-0.64], p < 0.001) and median vasoactive-inotropic score (HR = 0.99 [95% CI, 0.98,1.00], p = 0.035) were independently associated with no early renal recovery. CONCLUSIONS: Only 43% of patients with severe pre-ECMO AKI had early renal recovery after VA-ECMO initiation.

PupillOmetry for preDIction of DeliriUM in ICU (PODIUM): protocol for a prospective multicentre cohort study.

INTRODUCTION: Delirium is a severe complication that is associated with short-term adverse events, prolonged hospital stay and neurological sequelae in survivors. Automated pupillometry is an easy-to-use device that allows for accurate objective assessment of the pupillary light responses in comatose patients in the intensive care unit (ICU). Whether automated pupillometry might predict delirium in critically ill patients is not known. We hypothesise that automated pupillometry could predict the occurrence of delirium in critically ill patients without primary brain injury, requiring more than 48 hours of invasive mechanical ventilation in the ICU. METHODS AND ANALYSIS: The PupillOmetry for preDIction of DeliriUM in ICU (PODIUM) study is a prospective cohort study, which will be conducted in eight French ICUs in the Paris area. We aim to recruit 213 adult patients requiring invasive mechanical ventilation for more than 48 hours. Automated pupillometry (Neurological Pupil Index; NPi-200, Neuroptics) will be assessed two times per day for 7 days. Delirium will be assessed using the Confusion Assessment Method in ICU two times per day over 14 days in non-comatose patients (Richmond Agitation and Sedation Scale ≥-3).The predictive performances of the seven automated pupillometry parameters (ie, pupillary diameter, variation of the pupillary diameter, pupillary constriction speed, pupillary dilatation speed, photomotor reflex latency, NPi and symmetry of pupillary responses) measured to detect the delirium occurrence within 14 days will be the main outcomes. Secondary outcomes will be the predictive performances of the seven automated pupillometry parameters to detect complications related to delirium, ICU length of stay, mortality, functional and cognitive outcomes at 90 days. ETHICS AND DISSEMINATION: The PODIUM study has been approved by an independent ethics committee, the Comité de Protection des Personnes (CPP) OUEST IV-NANTES (CPP21.02.15.45239 32/21_3) on 06 April 2021). Participant recruitment started on 15 April 2022. Results will be published in international peer-reviewed medical journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT05248035; clinicaltrials.gov.

ECMELLA as a bridge to heart transplantation in refractory ventricular fibrillation: A case report.

Background: Extracorporeal membrane oxygenation (ECMO) is an effective cardiorespiratory support technique in refractory cardiac arrest (CA). In patients under veno-arterial ECMO, the use of an Impella device, a microaxial pump inserted percutaneously, is a valuable strategy through a left ventricular unloading approach. ECMELLA, a combination of ECMO with Impella, seems to be a promising method to support end-organ perfusion while unloading the left ventricle. Case summary: The present case report describes the clinical course of a patient with ischemic and dilated cardiomyopathy who presented with refractory ventricular fibrillation (VF) leading to CA in the late postmyocardial infarction (MI) period, and who was successfully treated with ECMO and IMPELLA as a bridge to heart transplantation. Discussion: In the case of CA on VF refractory to conventional resuscitation maneuvers, early extracorporeal cardiopulmonary resuscitation (ECPR) associated with an Impella seems to be the best strategy. It provides organ perfusion, left ventricular unloading, and ability for neurological evaluation and VF catheter ablation before allowing heart transplantation. It is the treatment of choice in cases of end-stage ischaemic cardiomyopathy and recurrent malignant arrhythmias.

Setting and Monitoring of Mechanical Ventilation During Venovenous ECMO.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2023. Other selected articles can be found online at  https://www.biomedcentral.com/collections/annualupdate2023 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from  https://link.springer.com/bookseries/8901 .

Extracorporeal membrane oxygenation in COVID-19 associated acute respiratory distress syndrome: A narrative review.

Venovenous extracorporeal membrane oxygenation (VV-ECMO) is an established rescue therapy in the management of refractory acute respiratory distress syndrome (ARDS). Although ECMO played an important role in previous respiratory viral epidemics, concerns about the benefits and usefulness of this technique were raised during the coronavirus disease 2019 (COVID-19) pandemic. Indeed, the mortality rate initially reported in small case series from China was concerning and exceeded 90%. A few months later, the critical care community published the findings from several observational cohorts on the use of extracorporeal membrane oxygenation (ECMO) in COVID-19-related ARDS. Contrary to the preliminary results, data from the first surge supported the use of ECMO in experienced centers because the mortality rate was comparable to those from the ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) trial or other large prospective studies. However, the mortality rate of the population with severe disease evolved during the pandemic, in conjunction with changes in the management of the disease and the occurrence of new variants. The results from subsequent studies confirmed that the outcomes mainly depend on strict patient selection and center expertise. In comparison with non-COVID-related ARDS, the duration of ECMO for COVID-related ARDS was longer and increased over time. Clinicians and decision-makers must integrate this finding in the ECMO decision-making process to plan their ICU capacity and resource allocation. This narrative review summarizes the current evidence and specific considerations for ECMO use in COVID-19-associated ARDS.

Senescent stromal cells: roles in the tumor microenvironment.

Cellular senescence forms a barrier to tumorigenesis, by inducing cell cycle arrest in damaged and mutated cells. However, once formed, senescent cells often emit paracrine signals that can either promote or suppress tumorigenesis. There is evidence that, in addition to cancer cells, subsets of tumor stromal cells, including fibroblasts, endothelial cells, and immune cells, undergo senescence. Such senescent stromal cells can influence cancer development and progression and represent potential targets for therapy. However, understanding of their characteristics and roles is limited and few studies have dissected their functions in vivo. Here, we discuss current knowledge and pertinent questions regarding the presence of senescent stromal cells in cancers, the triggers that elicit their formation, and their potential roles within the tumor microenvironment.

Updates in the management of respiratory virus infections in ICU patients: revisiting the non-SARS-CoV-2 pathogens.

INTRODUCTION: Although viruses are an underestimated cause of community-acquired pneumonias (CAP) and hospital-acquired pneumonias (HAP)/ventilator-associated pneumonias (VAP) in intensive care unit (ICU) patients, they have an impact on morbidity and mortality. AREAS COVERED: In this perspective article, we discuss the available data regarding the management of severe influenza CAP and herpesviridae HAP/VAP. We review diagnostic and therapeutic strategies in order to give clear messages and address unsolved questions. EXPERT OPINION: Influenza CAP affects yearly thousands of people; however, robust data regarding antiviral treatment in the most critical forms are scarce. While efficacy of oseltamivir has been investigated in randomized controlled trials (RCT) in uncomplicated influenza, only observational data are available in ICU patients. Herpesviridae are an underestimated cause of HAP/VAP in ICU patients. Whilst incidence of herpesviridae identification in samples from lower respiratory tract of ICU patients is relatively high (from 20% to 50%), efforts should be made to differentiate local reactivation from true lung infection. Only few randomized controlled trials evaluated the efficacy of antiviral treatment in herpesviridae reactivation/infection in ICU patients and all were exploratory or negative. Further studies are needed to evaluate the impact of such treatment in specific populations.

Delivery decision in pregnant women rescued by ECMO for severe ARDS: a retrospective multicenter cohort study.

BACKGROUND: Although rarely addressed in the literature, a key question in the care of critically pregnant women with severe acute respiratory distress syndrome (ARDS), especially at the time of extracorporeal membrane oxygenation (ECMO) decision, is whether delivery might substantially improve the mother's and child's conditions. This multicenter, retrospective cohort aims to report maternal and fetal short- and long-term outcomes of pregnant women with ECMO-rescued severe ARDS according to the timing of the delivery decision taken before or after ECMO cannulation. METHODS: We included critically ill women with ongoing pregnancy or within 15 days after a maternal/child-rescue-aimed delivery supported by ECMO for a severe ARDS between October 2009 and August 2021 in four ECMO centers. Clinical characteristics, critical care management, complications, and hospital discharge status for both mothers and children were collected. Long-term outcomes and premature birth complications were assessed. RESULTS: Among 563 women on venovenous ECMO during the study period, 11 were cannulated during an ongoing pregnancy at a median (range) of 25 (21-29) gestational weeks, and 13 after an emergency delivery performed at 32 (17-39) weeks of gestation. Pre-ECMO PaO2/FiO2 ratio was 57 (26-98) and did not differ between the two groups. Patients on ECMO after delivery reported more major bleeding (46 vs. 18%, p = 0.05) than those with ongoing pregnancy. Overall, the maternal hospital survival was 88%, which was not different between the two groups. Four (36%) of pregnant women had a spontaneous expulsion on ECMO, and fetal survival was higher when ECMO was set after delivery (92% vs. 55%, p = 0.03). Among newborns alive, no severe preterm morbidity or long-term sequelae were reported. CONCLUSION: Continuation of the pregnancy on ECMO support carries a significant risk of fetal death while improving prematurity-related morbidity in alive newborns with no difference in maternal outcomes. Decisions regarding timing, place, and mode of delivery should be taken and regularly (re)assess by a multidisciplinary team in experienced ECMO centers.

Unsupervised clustering reveals phenotypes of AKI in ICU COVID-19 patients.

Background: Acute Kidney Injury (AKI) is a very frequent condition, occurring in about one in three patients admitted to an intensive care unit (ICU). AKI is a syndrome defined as a sudden decrease in glomerular filtration rate. However, this unified definition does not reflect the various mechanisms involved in AKI pathophysiology, each with its own characteristics and sensitivity to therapy. In this study, we aimed at developing an innovative machine learning based method able to subphenotype AKI according to its pattern of risk factors. Methods: We adopted a three-step pipeline of analyses. First, we looked for factors associated with AKI using a generalized additive model. Second, we calculated the importance of each identified AKI related factor in the estimated AKI risk to find the main risk factor for AKI, at the single patient level. Lastly, we clusterized AKI patients according to their profile of risk factors and compared the clinical characteristics and outcome of every cluster. We applied this method to a cohort of severe COVID-19 patients hospitalized in the ICU of the Geneva University Hospitals. Results: Among the 248 patients analyzed, we found 7 factors associated with AKI development. Using the individual expression of these factors, we identified three groups of AKI patients, based on the use of Lopinavir/Ritonavir, baseline eGFR, use of dexamethasone and AKI severity. The three clusters expressed distinct characteristics in terms of AKI severity and recovery, metabolic patterns and hospital mortality. Conclusion: We propose here a new method to phenotype AKI patients according to their most important individual risk factors for AKI development. When applied to an ICU cohort of COVID-19 patients, we were able to differentiate three groups of patients. Each expressed specific AKI characteristics and outcomes, which probably reflect a distinct pathophysiology.

Management of High-Risk Pulmonary Embolism: What Is the Place of Extracorporeal Membrane Oxygenation?

Pulmonary embolism (PE) is a common disease with an annual incidence rate ranging from 39-115 per 100,000 inhabitants. It is one of the leading causes of cardiovascular mortality in the USA and Europe. While the clinical presentation and severity may vary, it is a life-threatening condition in its most severe form, defined as high-risk or massive PE. Therapeutic options in high-risk PE are limited. Current guidelines recommend the use of systemic thrombolytic therapy as first-line therapy (Level Ib). However, this treatment has important drawbacks including bleeding complications, limited efficacy in patients with recurrent PE or cardiac arrest, and formal contraindications. In this context, the use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) in the management of high-risk PE has increased worldwide in the last decade. Strategies, including VA-ECMO as a stand-alone therapy or as a bridge to alternative reperfusion therapies, are associated with acceptable outcomes, especially if implemented before cardiac arrest. Nonetheless, the level of evidence supporting ECMO and alternative reperfusion therapies is low. The optimal management of high-risk PE patients will remain controversial until the realization of a prospective randomized trial comparing those cited strategies to systemic thrombolysis.

The Impact of Sample Size Misestimations on the Interpretation of ARDS Trials: Systematic Review and Meta-analysis.

BACKGROUND: Indeterminate randomized controlled trials (RCTs) in ARDS may arise from sample size misspecification, leading to abandonment of efficacious therapies. RESEARCH QUESTIONS: If evidence exists for sample size misspecification in ARDS RCTs, has this led to rejection of potentially beneficial therapies? Does evidence exist for prognostic enrichment in RCTs using mortality as a primary outcome? STUDY DESIGN AND METHODS: We identified 150 ARDS RCTs commencing recruitment after the 1994 American European Consensus Conference ARDS definition and published before October 31, 2020. We examined predicted-observed sample size, predicted-observed control event rate (CER), predicted-observed average treatment effect (ATE), and the relationship between observed CER and observed ATE for RCTs with mortality and nonmortality primary outcome measures. To quantify the strength of evidence, we used Bayesian-averaged meta-analysis, trial sequential analysis, and Bayes factors. RESULTS: Only 84 of 150 RCTs (56.0%) reported sample size estimations. In RCTs with mortality as the primary outcome, CER was overestimated in 16 of 28 RCTs (57.1%). To achieve predicted ATE, interventions needed to prevent 40.8% of all deaths, compared with the original prediction of 29.3%. Absolute reduction in mortality ≥ 10% was observed in 5 of 28 RCTs (17.9%) but was predicted in 21 of 28 RCTs (75.0%). For RCTs with mortality as the primary outcome, no association was found between observed CER and observed ATE (pooled OR: ß = -0.04; 95% credible interval, -0.18 to 0.09). We identified three interventions that are not currently standard of care with a Bayesian-averaged effect size of > 0.20 and moderate strength of existing evidence: corticosteroids, airway pressure release ventilation, and noninvasive ventilation. INTERPRETATION: Reporting of sample size estimations was inconsistent in ARDS RCTs, and misspecification of CER and ATE was common. Prognostic enrichment strategies in ARDS RCTs based on all-cause mortality are unlikely to be successful. Bayesian methods can be used to prioritize interventions for future effectiveness RCTs.

Use of Carboxyhemoglobin as an Early Sign of Oxygenator Dysfunction in Patients Supported by Extracorporeal Membrane Oxygenation.

Introduction: Plasma free hemoglobin is the gold standard for monitoring hemolysis in extracorporeal membrane oxygenation (ECMO) but its routine use has some limitations. Carboxyhemoglobin (HbCO) is also a marker of intravascular hemolysis. We aimed to investigate HbCO as a marker of both hemolysis and oxygenator dysfunction in patients supported by ECMO. Methods: Retrospective analysis of patients on ECMO in an adult ICU in a tertiary hospital. HbCO was recorded every 6 h in the 48 h before and after oxygenator change in adult patients on ECMO support with an oxygenator dysfunction and replacement. Results: The investigation of 27 oxygenators replacements in 19 patients demonstrated that HbCO values progressively increased over time and then significantly decreased after oxygenator change. Median oxygenator lifespan was 14 days [interquartile range (IQR) 8-21] and there was no correlation between HbCO and oxygenator lifespan [Spearman coefficient 0.23 (p = 0.23)]. HbCO values at oxygenator change [HbCO median 2.7 (IQR 2.5-3.5)] were significantly higher than the HbCO values 1 week before [HbCO median 2.07 (IQR 1.86-2.8)] (p value < 0.001). Conclusion: Our data highlight the potential role of HbCO as a novel marker for ECMO oxygenator dysfunction.

Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions.

OBJECTIVE: Cellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development. DESIGN: To uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment. RESULTS: We found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma. CONCLUSIONS: These findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.