Critical Care

Background: Many patients in the ICU receive oxygen to secure blood and tissue oxygenation. Increasing evidence shows exposure to high fractions of inhaled oxygen (FiO2) being associated with adverse effects. In patients with severe ARDS, veno-venous Extracorporeal Membrane Oxygenation (VV-ECMO) can be implemented as a rescue therapy and PaO2 levels can be controlled by the blood flow of the VV-ECMO. Yet, optimal oxygenation targets in ARDS patients treated with VV-ECMO are unknown. Methods: Retrospective analysis of 443 patients with severe ARDS treated with VV-ECMO. Regression analyses were performed for mortality and time-weighted averages of PaO2 and FiO2. Furthermore, considering a possible non-linear relationship, a restricted cubic spline (RCS) model was performed for PaO2. Results: A simple logistic regression for mean PaO2 and ICU mortality showed a significant positive association (per mmHg OR 0.99 [95%CI 0.98-1.00], p=0.002). RCS analysis showed a U-shaped association of mortality and mean paO2 (paO2 69.70-90.24mmHg: OR 0.92 [95%CI 0.89-0.94], p<0.001; paO2 90.24-123.40mmHg: OR 1.09 [95%CI 1.06-1.13], p<0.001). A model including PaO2 as RCS variable and FiO2 showed significant associations of mortality with both variables (PaO2 69.70-90.24mmHg: OR 0.94 [95%CI 0.91-0.97], p<0.001; paO2 90.24-123.40 mmHg: OR 1.07 [95%CI 1.04-1.11], p<0.001; FiO2: OR 35.98 [95%CI 8.67-158.60], p<0.001, VIF<1.11). Conclusions: PaO2-levels in patients with ARDS and VV-ECMO have a U-shaped association with mortality. Optimal outcomes are observed in the 90-123 mmHg range, which is higher compared to non-ECMO settings. Whether this is explainable by increased tissue oxygenation with concurrent avoidance of pulmonary hypoxia should be subject of future research.

BackgroundSevere respiratory failure is a major complication of SARS-CoV-2 infection, and the need for mechanical ventilation (MV) is associated with a worse outcome. Whether some soluble biomarkers of lung injury can help predict MV requirement remains unclear. MethodsThis prospective, observational, monocentric cohort study consecutively enrolled patients with laboratory-confirmed COVID-19 pneumonia within 48 h of hospital admission. The serum concentrations of five key bronchoalveolar epithelial and endothelial biomarkers were determined at Day 0, 7 and 14: Krebs von den Lungen-6 (KL-6); soluble receptor for advanced glycation end-products (sRAGE); club cell protein 16 (CC16); angiopoietin-2 (Ang-2); and soluble CD146 (sCD146). The respiratory severity of COVID-19 pneumonia was defined by the maximal level of respiratory support received during hospitalization: oxygen (by mask or nasal prong); high flow oxygen therapy (HFOT); and MV. End-points were the need for MV during hospitalization and the time to liberation from oxygen. ResultsFifty-four COVID-19 patients were enrolled; 23 (43%) required MV, 13 (24%) HFOT, and 18 (33%) oxygen. At inclusion, levels of KL-6, sRAGE, and CC16 were significantly higher in MV compared with non-MV patients (p < 0.05), with sRAGE showing the greatest difference (2.4-fold increase). In multivariate logistic regression, sRAGE (OR per 100 pg/mL increase, 1.028 [95% CI, 1.004-1.054]; p = 0.022) and SpO2/FIO2 (OR, 0.984 [95% CI, 0.970-0.998]; p = 0.008) were identified as independent risk factors for MV. Furthermore, patients with an sRAGE [&ge;] 5449 pg/mL at inclusion had a lower probability of weaning from oxygen at Day 60 (HR, 0.36 [95% CI, 0.19-0.67]; p = 0.001). From Day 7 to Day 14, CC16 levels increased while sCD146 levels decreased in MV patients. ConclusionAmong five circulating biomarkers of bronchoalveolar injury, sRAGE showed the most favorable kinetic profile, rapidly increasing in MV patients. The early measurement of sRAGE and SpO2/FIO2 upon hospital admission may effectively identify COVID-19 patients at high risk of requiring MV and prolonged oxygen support.

Adrenal crises occur due to either a complete lack or an insufficient amount of cortisol and are usually triggered by stressors like infections, trauma, surgical interventions, and dental procedures. The physiological changes associated with major surgery are well-studied stressors linked to adrenal crisis. Extracorporeal membrane oxygenation (ECMO), a strategy employed to assist with circulatory support and gas exchange, is also a significant physiologically demanding stressor to the human body. In this study, we retrospectively assess the incidence and outcomes of patients with adrenal insufficiency who were cannulated for extracorporeal membrane oxygenation (ECMO) using the National Inpatient Sample (NIS) database. Patients who were cannulated for ECMO from 2016 to 2020 were identified and divided into two cohorts depending on the presence or absence of adrenal insufficiency. The two groups were compared for the primary outcome of inpatient mortality and secondary outcomes including rates of LVAD, heart transplant, lung transplantation, stroke, GI bleed, and renal failure. In our study, we found that mortality rates between the two groups were similar. All-cause inpatient mortality was 45% in both groups (p>0.9). We found no differences in the rates of heart transplantation, lung transplantation, or LVAD implantation between patients with and without adrenal insufficiency. We additionally find that mortality rates in our study mirror those from dedicated ECMO registries, further lending credence to our findings. Our study discusses important findings from a relatively understudied disease process, based on a large and representative population from multiple centers across the country.

ObjectivesNeutrophil elastase (NE) plays an important role in the pathogenesis of acute respiratory distress syndrome (ARDS). Sivelestat sodium, an NE inhibitor, has been approved in Japan for the treatment of patients with ARDS combined with systemic inflammatory response syndrome (SIRS). This trial was designed to evaluate the role of sivelestat sodium in mild-to-moderate ARDS combined with SIRS. MethodsWe conducted a multicentre, double-blind, randomized, placebo-controlled trial enrolling patients diagnosed with mild-to-moderate ARDS combined with SIRS admitted within 72 hours of ARDS onset (clinicaltrials.gov, NCT04909697). Patients were randomized in a 1:1 fashion to sivelestat or placebo. Trial drugs were administrated as a 24-hour continuous intravenous infusion at a rate of 0.2 mg/kg/h for 5 days. The primary outcome was PaO2/FiO2 ratio change on day 3 after randomization, which was defined as (PaO2/FiO2 ratio on day 3 - baseline PaO2/FiO2 ratio)/baseline PaO2/FiO2 ratio. ResultsThe study was stopped early at the recommendation of an independent Data and Safety Monitoring Board, which noted a between-group difference in mortality. A total of 162 patients were randomized, of whom 81 were assigned to receive sivelestat sodium and 81 placebo. On day 3, the PaO2/FiO2 ratio improved by 36% in the sivelestat group compared to 3% in the placebo group (difference, 0.27; 95% CI, 0.13 to 0.41, p < 0.001). In addition, The invasive mechanical ventilation-free days within 28 days was significantly longer in the sivelestat sodium group compared to the placebo group (median 26.9 days vs. 21.0 days, p = 0.004). The Kaplan-Meier curves showed a significant reduction in 90-day mortality in patients receiving sivelestat compared to those not receiving sivelestat (hazard ratio, 0.51; 95% CI, 0.26 to 0.99; log-rank p = 0.044). ConclusionIn patients with mild-to-moderate ARDS combined with SIRS, sivelestat sodium may improve oxygenation on day3, increase invasive mechanical ventilation-free days, and was associated with improved survival.

BackgroundAcute respiratory distress syndrome (ARDS) is a life-threatening lung condition that requires admission to an intensive care unit (ICU). Sepsis is one of the leading causes of ARDS and understanding protein regulation during sepsis could reveal key mechanisms that predispose patients to ARDS. We performed genome-wide association studies (GWAS) on ARDS biomarkers levels to identify protein quantitative trait loci (pQTLs) and genes which could be associated with ARDS risk. MethodsGWAS were performed in 209 patients with sepsis from the GEN-SEP cohort to determine the association of imputed genotypes with 10 serum biomarker levels relevant to ARDS. Measurements were obtained by ELISA within the first 24 hours (T1), 48-72 hours (T2), and 7 days (T7) after the diagnosis of sepsis. We conducted a multi-trait analysis to aggregate the GWAS results for each biomarker at three time points. We prioritized genes in the significant loci (p<5x10-8) and evaluated the association between rare variants and ARDS in whole-exome sequencing data from 272 patients with sepsis-associated ARDS and 550 sepsis controls from GEN-SEP. We analyzed the aggregated association of pQTLs with ICU mortality, multiple organ failure, and ARDS risk using polygenic scores (PGS) in independent patients (n=621) from GEN-SEP. ResultsWe identified 27 significant independent loci and prioritized 56 genes. Seven of these were previously associated with respiratory infections and diseases (LINGO2, MC4R, MCTP1, NUAK1, PIEZO2, PTPRD, and TMEMc5). Defects in another prioritized gene, FOXN1, cause an inborn error of immunity. Rare variants in PTPRD, which was previously involved in COVID-19 severity and pulmonary hypertension, were significantly associated with ARDS (p=3.11x10-4). PGS of PAI-1 levels was significantly associated with ICU mortality. ConclusionsWe prioritized genes of interest governing ARDS biomarker levels and identified PTPRD as a novel gene associated with ARDS risk. In addition, we demonstrate the value of biomarker PGS for predicting sepsis mortality. O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/26344107v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1654886org.highwire.dtl.DTLVardef@7c8865org.highwire.dtl.DTLVardef@1dea651org.highwire.dtl.DTLVardef@791901_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

BackgroundTherapeutic effects of steroids on acute respiratory distress syndrome (ARDS) requiring mechanical ventilation (MV) have been reported. However, predictive indicators of early weaning from MV post-treatment have not yet been defined, making treating established ARDS challenging. Interleukin (IL)-6 has been associated with the pathogenesis of ARDS. ObjectiveOur aim was to clarify clinical utility of IL-6 level in ventilated patients with established ARDS. MethodsClinical, treatment, and outcome data were evaluated in 119 invasively ventilated patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated ARDS. Plasma levels of IL-6 and C-reactive protein (CRP) were measured on days 1, 4, and 7 after intubation. ResultsFifty-two patients were treated with dexamethasone (steroid group), while the remaining 67 patients were not (non-steroid group). Duration of MV use was significantly shorter in the steroid group compared to non-steroid group (11.5{+/-}0.6 vs. 16.1{+/-}1.0 days, P = 0.0005, respectively) along with significantly decreased levels of IL-6 and CRP. Even when restricted to the steroid group, among variables post-MV, IL-6 level on day 7 was most closely correlated with duration of MV use (Spearmans rank correlation coefficient [{rho}] = 0.73, P < 0.0001), followed by CRP level on day 7 and the percentage change in IL-6 or CRP levels between day 1 and day 7. Moreover, among these variables, IL-6 levels on day 7 showed the highest accuracy for withdrawal from MV within 11 days (AUC: 0.88), with optimal cutoff value of 20.6 pg/mL. Consistently, the rate of MV weaning increased significantly earlier in patients with low IL-6 ([&le;] 20.6 pg/mL) than in those with high IL-6 (> 20.6 pg/mL) (log-rank test P < 0.0001). ConclusionsIn invasively ventilated patients with established ARDS due to SARS-CoV-2, plasma IL-6 levels served as a predictor of early withdrawal from MV after dexamethasone administration.

PurposeEnhanced understanding of the dynamic changes in the dysregulated inflammatory response in COVID-19 may help improve patient selection and timing for immunomodulatory therapies. MethodsWe enrolled 323 COVID-19 inpatients on different levels of baseline respiratory support: i) Low Flow Oxygen (37%), ii) Non-Invasive Ventilation or High Flow Oxygen (NIV_HFO, 29%), iii) Invasive Mechanical Ventilation (IMV, 27%), and iv) Extracorporeal Membrane Oxygenation (ECMO, 7%). We collected plasma samples upon enrollment and days 5 and 10 to measure host-response biomarkers. We classified subjects into inflammatory subphenotypes using two validated predictive models. We examined clinical, biomarker and subphenotype trajectories and outcomes during hospitalization. ResultsIL-6, procalcitonin, and Angiopoietin-2 were persistently elevated in patients at higher levels of respiratory support, whereas sRAGE displayed the inverse pattern. Patients on NIV_HFO at baseline had the most dynamic clinical trajectory, with 26% eventually requiring intubation and exhibiting worse 60-day mortality than IMV patients at baseline (67% vs. 35%, p<0.0001). sRAGE levels predicted NIV failure and worse 60-day mortality for NIV_HFO patients, whereas IL-6 levels were predictive in IMV or ECMO patients. Hyper-inflammatory subjects at baseline (<10% by both models) had worse 60-day survival (p<0.0001) and 50% of them remained classified as hyper-inflammatory on follow-up sampling at 5 days post-enrollment. Receipt of combined immunomodulatory therapies (steroids and anti-IL6 agents) was associated with markedly increased IL-6 and lower Angiopoietin-2 levels (p<0.05). ConclusionsLongitudinal study of systemic host responses in COVID-19 revealed substantial and predictive inter-individual variability, influenced by baseline levels of respiratory support and concurrent immunomodulatory therapies.

IntroductionThe SARS-CoV-2 disease outbreak has now become a pandemic. Critical patients with COVID-19 require basic and advanced respiratory support. Therefore, the objective was to describe the ventilatory support strategies in SARS-CoV-2 during intensive therapy. Materials and methodsA systematic review of observational studies of the available scientific literature was performed in accordance with the recommendations of the Cochrane collaboration and the criteria of the PRISMA Declaration. ResultsFifteen observational studies were included that gave a study population of 4,081 patients. Mechanical ventilation is the main respiratory support treatment for critically ill patients, which should be administered as soon as normal oxygenation cannot be maintained, and despite the fact that there is no current consensus on the parameters of mechanical ventilation, the evidence collected suggests the use of Fio2 on average 50%, PEEP of 14 cmH2O, lung compliance of 29-37 ml per cm of water, driving pressure between 12-14 cm of water and a plateau pressure of 22-25 cm of water. ConclusionsIL-6 is shown as a possible marker of respiratory failure and a worse prognosis as well as obesity. In addition, the use of prone position, neuromuscular blockade, pulmonary vasodilators, ECMO, and mechanical ventilation based on the clinical conditions and needs of the patient with COVID-19 are strategies that could benefit patients entering intensive therapy for SARS-CoV-2.

BackgroundAcute respiratory distress syndrome (ARDS) is associated with high mortality in Intensive Care Units (ICU). A previous genome-wide association study (GWAS) identified the vascular endothelial growth factor receptor 1 (VEGFR1) gene in ARDS risk. We performed a GWAS on soluble VEGFR1 (sVEGFR1) levels to identify protein quantitative trait loci (pQTLs) and genes of interest for ARDS. MethodsSerum samples (n=292) within the first 24 (T1), 72 hours (T2), and 7 days (T7) after sepsis diagnosis were collected while in the ICU. sVEGFR1 levels were measured and tested for association. We combined fine mapping, colocalisation and gene-set mapping analyses to prioritise genes and test low-frequency variation association with ARDS (n=822). We analysed the association of sVEGFR1 pQTLs with mortality and ARDS susceptibility using polygenic scores (PGS). Finally, the causality of VEGFR1 in ARDS was assessed using two-sample Mendelian randomisation (MR) analyses. ResultsWe found a pQTL for T2 sVEGFR1 levels at TCF20 (rs134871, p=4.66x10-8). Fine mapping prioritised rs762995 as a likely pathogenic variant and CYP2D6 as the most likely functional gene. The locus colocalised with eQTLs for TCF20 and CYP2D6. Low-frequency missense variation in TCF20 was associated with sepsis-associated ARDS susceptibility (p=3.0x10-3). sVEGFR1 levels PGS were associated with decreased ARDS susceptibility and mortality. MR analyses did not evidence causality. ConclusionsWe identified biologically relevant pQTLs of VEGFR1 levels during sepsis in TCF20 and identified CYP2D6 as the gene more biologically implicated. Low frequency missense variation in TCF20 and sVEGFR1 levels PGS models were associated with sepsis outcomes. What is already known on this topicAcute respiratory distress syndrome (ARDS) is an acute condition, characterised by respiratory failure, an acute inflammatory response and the development of non-cardiogenic oedema. There is a need for target pharmacological strategies and advances in the risk stratification methods that can improve patient management. What this study addsWe performed the first GWAS of sVEGFR1 levels in patients with sepsis. The integration of different complementary genomic approaches has allowed us to reveal a regulatory variant of sVEGFR1 during sepsis, suggesting a role in ARDS susceptibility and mortality. In exome-wide low-frequency variation analyses, we identified TCF20 as a novel gene of interest for ARDS. How this study might affect research, practice or policyThis study emphasises the value of proteogenomic approaches in improving our understanding of ARDS pathogenesis and detecting novel risk genes to advance patient risk stratification.

BackgroundAcute Respiratory Failure (ARF) is a serious complication of various diseases, characterized by a high mortality rate. Aspirin influences cyclooxygenase, which have a crucial role in inflammation, blood clotting, and immune system modulation. ARF is characterized by an uncontrolled inflammatory and pro-coagulant response, but aspirin can mitigate this inflammatory response by inhibiting platelet function, potentially leading to improved outcomes.Numerous studies have produced conflicting data concerning the impact of aspirin on individuals suffering from Acute Respiratory Failure. We performed an analysis of the MIMIC IV database to explore the association between aspirin use and the outcomes in ARF patients, as well as to ascertain the optimal dosing regimen for aspirin treatment. Materials and methodsARF patients clinical data were extracted from MIMICIV2.2. Propensity score matching was utilized to ensure comparability of baseline characteristics between the group receiving aspirin and the group not receiving aspirin. Subsequently, the link between aspirin and patient death was examined through the application of Kaplan-Meier estimations and Cox proportional hazard regression analyses. ResultsWe identified a cohort of 6,663 individuals suffering from ARF from the MIMIC IV database.Following propensity score matching in a sample of 4,008 participants, multivariate Cox proportional hazards analysis revealed a lower hazard of dying within 90 days for those in the aspirin group versus the non-users group (adjusted Hazard Ratio: 0.723; 95% Confidence Interval: 0.652 to 0.802). Additionally, the Kaplan-Meier survival curves indicated that the 90-day survival rate was higher among aspirin users compared to non-users (log-rank test p< 0.001). And the median duration of survival for patients undergoing aspirin therapy was considerably extended compared to those who did not receive it, amounting to 15.60 days versus 10.36 days, respectively In the aspirin group, the median ICU stay length was longer than non-users group (6.93 days vs. 6.08 days, p <0.001).Patients in the aspirin use group had a significantly shorter duration of mechanical ventilation compared to those in the non-aspirin use group(54.95 days vs. 58.00 days, p <0.001). ConclusionAspirin may reduce the 30-day or 90-day mortality risk in ARF patients and also shorten the duration of mechanical ventilation. Aspirin could be an effective medication in the treatment of ARF patients.

BackgroundAcute respiratory distress syndrome (ARDS) is a complex, heterogeneous, and deadly condition often resulting from pulmonary lesions due to sepsis, among other causes. There is a lack of targeted therapies to specifically treat the patients. Common genetic factors in the population (frequency >1%) have been associated with ARDS susceptibility, but systematic genetic screens of the role of rare genetic variants are lacking. We used the network of known molecular interactions to identify ARDS risks from clusters of biologically related genes containing qualifying variants (QVs) with frequency <1% likely affecting function. MethodsWe conducted whole-exome sequencing in sepsis patients from the GEN-SEP cohort (n=822, of which 272 developed ARDS). A network-based heterogeneity clustering algorithm was used to identify significant gene clusters (p<1x10-5). Gene-set enrichment analysis and logistic regression models aggregating QVs were used for characterization of gene clusters and findings validation. ResultsWe identified 19 significant clusters (plowest=3.29x10-10), each containing an average of 102 genes (11.6% mean similarity). QVs in eight gene clusters were associated with sepsis-associated ARDS (plowest=2.35x10-4) but were not associated with 28-day survival. Clusters were enriched in several biological pathways, notably the Interferon signaling and Toll-like receptor cascades. ConclusionsThese results support a marked genetic heterogeneity underlying ARDS susceptibility and the presence of risk variants involving multiple biological processes that are associated with sepsis outcomes. This evidence paves the way for future development of preventive and therapeutic approaches targeting those pathways to reduce the risk for sepsis-associated ARDS.

BackgroundRespiratory distress requiring intubation is the most serious complication associated with coronavirus disease 2019 (COVID-19). MethodsIn this retrospective study, we used survival analysis to determine whether or not mortality following intubation was associated with hormone exposure in patients treated at New York Presbyterian/ Columbia University Irving Medical Center. Here, we report the overall hazards ratio for each hormone for exposure before and after intubation for intubated and mechanically ventilated patients. ResultsAmong the 189,987 patients, we identified 948 intubation periods across 791 patients who were diagnosed with COVID-19 or infected with SARS-CoV2 and 3,497 intubation periods across 2,981 patients who were not. Melatonin exposure after intubation was statistically associated with a positive outcome in COVID-19 (demographics and comorbidities adjusted HR: 0.131, 95% CI: 7.76E-02 - 0.223, p-value = 8.19E-14) and non-COVID-19 (demographics and comorbidities adjusted HR: 0.278, 95% CI: 0.142 - 0.542, p-value = 1.72E-04) intubated patients. Additionally, melatonin exposure after intubation was statically associated with a positive outcome in COVID-19 patients (demographics and comorbidities adjusted HR: 0.127, 95% CI: 6.01E-02 - 0.269, p-value = 7.15E-08). ConclusionsMelatonin exposure after intubation is significantly associated with a positive outcome in COVID-19 and non-COVID-19 patients. Additionally, melatonin exposure after intubation is significantly associated with a positive outcome in COVID-19 patients requiring mechanical ventilation. While our models account for many covariates, including clinical history and demographics, it is impossible to rule out confounding or collider biases within our population. Further study into the possible mechanism of this observation is warranted.

RationaleTo explore the association and implications of using Heart rate variability (HRV) derived from continuous bedside monitoring as a surrogate for detection of Acute Respiratory Failure (ARF) in critically ill sepsis patients. ObjectiveTo analyze HRV measures derived from continuous physiological data captured before ARF-onset to determine whether statistically significant markers can be characterized when compared to sepsis controls. MethodsRetrospective HRV analysis of sepsis patients admitted to Emory Healthcare ICUs was performed between ARF and age and gender-matched controls. HRV measures such as time domain, frequency domain, nonlinear, and complexity measures were analyzed up to 1 hour before the onset of ARF, and a random event time in the sepsis-controls. Statistical significance was computed by the Wilcoxon Rank Sum test. ResultsA total of 89 intensive care unit (ICU) patients with sepsis were included in this retrospective cohort study. Time-domain HRV measures including pNN50 (the fraction of consecutive NN intervals that differ by more than 50 ms), RMSSD (root-mean-square differences of successive NN intervals), standard deviation, interquartile range, variance, and approximate entropy for Beat-to-Beat intervals strongly distinguished ARF patients from the controls group. HRV measures for nonlinear and frequency domains were significantly altered (p<0.05) among sepsis patients with ARF compared to controls. Frequency measures such as low frequency (LF), very low frequency (VLF), high frequency (HF), and SD1/SD2 ratio nonlinear measure (SD1:SD2) also showed a significant (p<0.05) increase in the ARF group patients. Multiscale entropy complexity was lower for ARF patients compared to the control counterparts. Detrended fluctuation analysis (DFA) showed a decreasing trend in ARF patients. ConclusionsHRV was significantly impaired across sepsis patients who developed ARF when compared to sepsis controls, indicating a potential prognostic utility for earlier identification of the need for mechanical ventilation and management of patients suspected with sepsis.

IntroductionSepsis-induced organ failure is caused by a dysregulated host response characterized by mitochondrial and microcirculatory abnormalities. Early detection of perfusion deficits is critical to preventing progression to shock and organ failure. While capillary refill time (CRT) and other single-parameter assessments are used, a comprehensive, multimodal evaluation of peripheral perfusion has not yet been applied in clinical settings. The purpose of the MAP-SEPS trial is to ascertain whether such a multimodal approach can enhance early identification of sepsis and organ dysfunction in critically ill ICU patients. Methods and analysisMAP-SEPS is a prospective observational study enrolling a minimum of 50 adult ICU patients without sepsis on admission. Patients will be monitored over 72 hours using a multimodal protocol that includes clinical (CRT, skin temperature, mottling score, urine output), biochemical (lactate, ScvO{square}, Pv- aCO{square}, arterial/interstitial glucose), and near-infrared spectroscopy assessments. Standardized macrohemodynamic monitoring and echocardiography will be performed, along with advanced calculations of venous return dynamics, cardiac efficiency, and arterial/venous resistance. Data will be collected at predefined intervals and analyzed using mixed-effects linear regression models. The primary objective is to assess the predictive value of these hemodynamic and perfusion parameters for early detection of sepsis and organ failure. Secondary outcomes include ICU and hospital length of stay, mechanical ventilation duration, and mortality at 28 and 90 days. Ethics and disseminationThe study has been approved by the Ethics Committee of the General Hospital Tzaneio and complies with the Declaration of Helsinki. Peer-reviewed papers, conference presentations, and clinical seminars will all be used to disseminate the findings, contributing to better bedside evaluation techniques for septic patients.

BackgroundSystemic hemodynamics and specific ventilator settings have been shown to predict survival during venoarterial extracorporeal membrane oxygenation (VA ECMO). While these factors are intertwined with right ventricular (RV) function, the independent relationship between RV function and survival during VA ECMO is unknown. ObjectivesTo identify the relationship between RV function with mortality and duration of ECMO support. MethodsCardiac ECMO runs in adults from the Extracorporeal Life Support Organization (ELSO) Registry between 2010 and 2022 were queried. RV function was quantified via pulmonary artery pulse pressure (PAPP) for pre-ECMO and on-ECMO periods. A multivariable model was adjusted for Society for Cardiovascular Angiography and Interventions (SCAI) stage, age, gender, and concurrent clinical data (i.e., pulmonary vasodilators and systemic pulse pressure). The primary outcome was in-hospital mortality. ResultsA total of 4,442 ECMO runs met inclusion criteria and had documentation of hemodynamic and illness severity variables. The mortality rate was 55%; non-survivors were more likely to be older, have a worse SCAI stage, and have longer pre-ECMO endotracheal intubation times (P < 0.05 for all) than survivors. Improving PAPP from pre-ECMO to on-ECMO time ({Delta} PAPP) was associated with reduced mortality per 10 mm Hg increase (OR: 0.91 [95% CI: 0.86-0.96]; P=0.002). Increasing on-ECMO PAPP was associated with longer time on ECMO per 10 mm Hg (Beta: 15 [95% CI: 7.7-21]; P<0.001). ConclusionsEarly improvements in RV function from pre-ECMO values were associated with mortality reduction during cardiac ECMO. Incorporation of {Delta} PAPP into risk prediction models should be considered.

Positive end expiratory pressure (PEEP) is routinely used as part of lung protective ventilation strategies in the treatment of acute respiratory distress syndrome (ARDS). In the case of ARDS arising due to COVID-19 (CARDS), there is some debate as to whether the atypical pathophysiological characteristics of the disease which lead to hypoxaemia could warrant a modified approach to ventilator management, particularly with regards to PEEP settings. Here we review the available evidence for the existence of a unique underlying lung pathophysiology in CARDS, and for the suitability of standard approaches to setting PEEP, in both the invasive and non-invasive ventilation settings. We show how detailed computational models informed by this evidence can shed light on the available data, and help to interpret recent results in the literature.

BackgroundSepsis remains a major clinical challenge for which successful treatment requires greater precision in identifying patients at increased risk of adverse outcomes requiring different therapeutic approaches. Predicting clinical outcomes and immunological endotyping of septic patients has generally relied on using blood protein or mRNA biomarkers, or static cell phenotyping. Here, we sought to determine whether functional immune responsiveness would yield improved precision. MethodsAn ex vivo whole blood enzyme-linked immunosorbent (ELISpot) assay for cellular production of interferon-{gamma} (IFN-{gamma}) was evaluated in 107 septic and 68 non-septic patients from five academic health centers using blood samples collected on days 1, 4 and 7 following ICU admission. ResultsCompared with 46 healthy subjects, unstimulated and stimulated whole blood IFN{gamma} expression were either increased or unchanged, respectively, in septic and nonseptic ICU patients. However, in septic patients who did not survive 180 days, stimulated whole blood IFN{gamma} expression was significantly reduced on ICU days 1, 4 and 7 (all p<0.05), due to both significant reductions in total number of IFN{gamma}-producing cells and amount of IFN{gamma} produced per cell (all p<0.05). Importantly, IFN{gamma} total expression on day 1 and 4 after admission could discriminate 180-day mortality better than absolute lymphocyte count (ALC), IL-6 and procalcitonin. Septic patients with low IFN{gamma} expression were older and had lower ALC and higher sPD-L1 and IL-10 concentrations, consistent with an immune suppressed endotype. ConclusionsA whole blood IFN{gamma} ELISpot assay can both identify septic patients at increased risk of late mortality, and identify immune-suppressed, sepsis patients. Trial RegistryBecause the study is a prospective observational study, and not a clinical trial, registration with clinical trials.gov is not required.

BackgroundAcute 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. MethodsWe 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. 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. FindingsOf 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 oxygenation index did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than NaCl (p=0{middle dot}17). Oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p=0{middle dot}04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups. InterpretationAlthough the primary result of our study was negative, our data suggest that inhaled prostacyclin might be a more beneficial treatment than standard care for patients with ARDS.

BackgroundUntangling the heterogeneity of sepsis in children and identifying clinically relevant phenotypes could lead to the development of enrichment strategies and targeted therapies. In this study, our aim was to analyze the organ dysfunction-based trajectories of children with sepsis-associated multiple organ dysfunction syndrome (MODS) to identify and characterize reproducible and clinically relevant sepsis phenotypes using a data-driven approach. MethodsWe collected data from patients admitted with suspected infections to 13 pediatric intensive care units (PICUs) in the U.S. between 2012-2018. We used subgraph-augmented nonnegative matrix factorization to identify candidate trajectory-driven phenotypes based on the type, severity, and progression of organ dysfunction in the first 72 hours of PICU admission. We analyzed the candidate phenotypes to determine reproducibility as well as prognostic, therapeutic, and biological relevance. ResultsOverall, 38,732 children had suspected infection, of which 15,246 (39.4%) had sepsis-associated MODS. Amongst patients with sepsis-associated MODS, 1,537 (10.1%) died in the hospital. We identified an organ dysfunction trajectory-based phenotype (which we termed persistent hypoxemia and shock) that was highly reproducible, had features of systemic inflammation and coagulopathy, and was independently associated with higher mortality. In a propensity score matched analysis, patients with the persistent hypoxemia and shock phenotype appeared to have a higher likelihood to benefit from adjuvant therapy with hydrocortisone and albumin than other patients. When compared to other high-risk clinical syndromes, the persistent hypoxemia and shock phenotype only overlapped with 50 to 60% of patients with septic shock, those with moderate-to-severe pediatric acute respiratory distress syndrome, or those in the top tertile of organ dysfunction burden, suggesting that it represents a distinct clinical phenotype of sepsis-associated MODS with a disproportionately high risk of mortality. ConclusionsWe derived and validated the persistent hypoxemia and shock phenotype, a trajectory-based organ dysfunction phenotype which is highly reproducible, clinically relevant, and associated with heterogeneity of treatment effect to common adjuvant therapies. Further validation is warranted. Future studies are needed to validate this phenotype, assess whether it can be predicted earlier in the course, study possible biological mechanisms underlying it, and investigate candidate therapeutic targets.

Severe coronavirus disease 2019 (Covid-19) is characterized by lung injury, cytokine storm and increased neutrophil-to-lymphocyte ratio (NLR). Current therapies focus on reducing viral replication and inflammatory responses, but no specific treatment exists to prevent the development of severe Covid-19 in infected individuals. Angiotensin-converting enzyme-2 ACE-2) is the receptor for SARS-CoV-2, the virus causing Covid-19, but it is also critical for maintaining the correct functionality of lung epithelium and endothelium. Coronaviruses induce activation of a disintegrin and metalloprotease 17 (ADAM17) and shedding of ACE-2 from the cell surface resulting in exacerbated inflammatory responses. Thus, we hypothesized that ADAM17 inhibition ameliorates Covid-19-related lung inflammation. We employed a pre-clinical mouse model using intra-tracheal instillation of a combination of polyinosinic:polycytidylic acid (poly-I:C) and the receptor-binding domain of the SARS-CoV-2 spike protein (RBD-S) to mimic lung damage associated with Covid-19. Histological analysis of inflamed mice confirmed the expected signs of lung injury including edema, fibrosis, vascular congestion and leukocyte infiltration. Moreover, inflamed mice also showed an increased NLR as observed in critically ill Covid-19 patients. Administration of the ADAM17 inhibitors apratastat and TMI-1 significantly improved lung histology and prevented leukocyte infiltration. Reduced leukocyte recruitment could be explained by reduced production of pro-inflammatory cytokines and lower levels of the endothelial adhesion molecules ICAM-1 and VCAM-1. Additionally, the NLR was significantly reduced by ADAM17 inhibition. Thus, we propose inhibition of ADAM17 as a novel promising treatment strategy in SARS-CoV-2-infected individuals to prevent the progression towards severe Covid-19.