Critical Care

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.

RationaleHeterogeneity of sepsis limits discovery and targeting of treatments. Clustering approaches in critical illness have identified patient groups who may respond differently to therapies. These include in acute respiratory distress syndrome (ARDS) two inflammatory sub-phenotypes, using latent class analysis (LCA), and in sepsis two Sepsis Response Signatures (SRS), based on transcriptome profiling. It is unknown if inflammatory sub-phenotypes such as those identified in ARDS are present in sepsis and how sub-phenotypes defined with different techniques compare. ObjectivesTo identify inflammatory sub-phenotypes in sepsis using LCA and assess if these show differential treatment responses. These sub-phenotypes were compared to hierarchical clusters based on inflammatory mediators and to SRS sub-phenotypes. MethodsLCA was applied to clinical and biomarker data from two septic shock randomized trials. VANISH compared norepinephrine to vasopressin and hydrocortisone to placebo and LeoPARDS compared levosimendan to placebo. Hierarchical cluster analysis (HCA) was applied to 65, 21 and 11 inflammatory mediators measured in patients from the GAinS (n=124), VANISH (n=155) and LeoPARDS (n=484) studies. Measurements and Main ResultsLCA and HCA identified a sub-phenotype of patients with high cytokine levels and worse organ dysfunction and survival, with no interaction between LCA classes and trial treatment responses. Comparison of inflammatory and transcriptomic sub-phenotypes revealed some similarities but without sufficient overlap that they are interchangeable. ConclusionsA sub-phenotype with high levels of inflammation and increased disease severity is consistently identifiable in sepsis, with similarities to that described in ARDS. There was limited overlap with the transcriptomic sub-phenotypes.

OBJECTIVENearly 5 % of the patients with COVID-19 develop an acute respiratory distress syndrome (ARDS). Extravascular lung water index (EVLWI) is a marker of pulmonary oedema which is associated with mortality in ARDS. In this study we evaluate whether EVLWI is higher in patients with COVID-19 associated ARDS as compared to controls and whether EVLWI has the potential to monitor disease progression. METHODSFrom the day of intubation, EVLWI, cardiac function were monitored by transpulmonary thermodilution in n=25 patients with COVID-19 and compared to a control group of 49 non-COVID-19 ARDS-patients. RESULTSEVLWI in COVID-19-patients was noticeably elevated and significantly higher than in the control group (17 (11-38) vs. 11 (6-26) mL/kg; p<0.001). High pulmonary vascular permeability index values (2.9 (1.0-5.2) versus 1.9 (1.0-5.2); p=0.003) suggest inflammatory oedema. By contrast, the cardiac parameters SVI, GEF and GEDVI were comparable. High EVLWI values were associated with viral persistence, prolonged intensive care treatment and mortality (23.2{+/-}6.7% vs. 30.3{+/-}6.0%, p=0.025). CONCLUSIONSCompared to the control group, COVID-19 results in markedly elevated EVLWI-values in patients with ARDS. EVLWI reflects a non-cardiogenic pulmonary oedema in COVID-19 associated ARDS and could serve as parameter to monitor ARDS progression.

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.

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.

BackgroundThe fungal cell-wall constituent (1,3)-{beta}-d-glucan (BDG) is a pathogen-associated molecular pattern (PAMP) that can stimulate innate immunity. We hypothesized that BDG from colonizing fungi in critically-ill patients may translocate into the systemic circulation and thus be associated with host inflammatory responses and outcomes. MethodsWe enrolled 453 mechanically-ventilated patients with acute respiratory failure with no evidence of invasive fungal infection (IFI). From serial plasma samples, we measured BDG, innate immunity and epithelial permeability biomarkers. From lower respiratory tract and stool samples we quantified bacterial and fungal DNA load using culture-independent techniques. ResultsA positive BDG test (>60pg/ml) at baseline was detected in 19% of patients. BDG levels were significantly associated with markers of innate immunity (interleukin-6, tumor necrosis factor receptor-1 and procalcitonin), epithelial barrier disruption (receptor for advanced glycation end-products and fatty-acid binding protein-2, for lung and gut respectively) and with higher probability of classification in an adverse prognosis hyperinflammatory subphenotype (all p<0.05). No differences in fungal or bacterial DNA load were found by BDG test positivity. Positive BDG testing was associated with higher incidence of acute kidney injury, fewer ventilator free days and worse 30-day survival (adjusted p<0.05). Patients with positive BDG test on follow-up sampling (>3 days from intubation) had higher mortality than patients with persistently negative test on follow-up (p<0.05). ConclusionsThis is the first study to demonstrate the prognostic role of BDG in critically ill patients with no evidence of IFI. Translocation of BDG into systemic circulation may contribute to inflammation and clinical outcomes. Funding supportNational Institutes of Health [K23 HL139987 (GDK); U01 HL098962 (AM); P01 HL114453 (BJM); R01 HL097376 (BJM); K24 HL123342 (AM); U01 HL137159 (DVM, PVB); R01 LM012087 (DVM, PVB); R01 HL142084 (JSL); R01 HL136143 (JSL); F32 HL137258 (JWE); F32 HL142172 (WB); K08 HS025455 (IJB); K23 GM122069 (FS)].

At the end of March 2020, there were in excess of 800.000 confirmed cases of coronavirus disease 2019 (COVID-19) worldwide. Several reports suggest that, in severe cases, COVID-19 may cause a hyperinflammatory "cytokine storm". However, unlike SARS-CoV infection, high levels of anti-inflammatory mediators have also been reported in COVID-19 patients. One study reported that 16% of COVID-19 patients who died developed secondary infection, which might indicate an immune-suppressed state. We explored kinetics of mHLA-DR expression, the most widely used marker of innate immune suppression in critically ill patients, in COVID-19 patients admitted to the ICU. Twenty-four confirmed COVID-19 patients were included, of which 75% was male and 79% had comorbidities. All patients were mechanically ventilated and exhibited large high levels of inflammatory parameters such as CRP and PCT. mHLA-DR expression levels were mostly within the normal range of 15000-45000 mAb/cell and showed no change over time. COVID-19 patients displayed notably higher mHLA-DR expression levels compared with bacterial septic shock patients. None of the COVID-19 patients developed a secondary infection. In conclusion, despite a pronounced inflammatory response, mHLA-DR expression kinetics indicate no overt innate immune suppression in COVID-19 patients. These data signify that innate immune suppression as a negative feedback mechanism following PAMP-induced inflammation appears not to be present in COVID-19.

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.

IntroductionD-dimer concentration has been used to identify candidates for intensified anticoagulant treatment for both venous thromboembolism prevention and mitigation of the microthrombotic complications associated with COVID-19. Thromboelastography (TEG) maximum amplitude (MA) has been validated as an indicator of hypercoagulability and MA [&ge;] 68 mm has been utilized as a marker of hypercoagulability in other conditions. We evaluated the relationship between coagulation, inflammatory, and TEG parameters in patients with COVID-19 on extracorporeal membrane oxygenation (ECMO). MethodsWe performed a single center retrospective analysis of consecutive patients that received ECMO for the treatment of COVID-19. TEG, inflammatory, and coagulation markers were compared in patients with and without thrombotic complications. Correlation tests were performed to identify the coagulation and inflammatory markers that best predict hypercoagulability as defined by an elevated TEG MA. Results168 TEGs were available in 24 patients. C-reactive protein and fibrinogen were significantly higher in patients that developed a thrombotic event versus those that did not (p=0.038 and p=0.043 respectively). D-dimer was negatively correlated with TEG MA (p<0.001) while fibrinogen was positively correlated (p<0.001). A fibrinogen > 441 mg/dL had a sensitivity of 91.2% and specificity of 85.7% for the detection of MA [&ge;] 68 mm. ConclusionsIn critically ill patients with COVID-19, D-dimer concentration had an inverse relationship with hypercoagulability as measured by TEG MA. D-dimer elevation may reflect severity of COVID-19 related sepsis rather than designate patients likely to benefit from anticoagulation. Fibrinogen concentration may represent a more useful marker of hypercoagulability in this population.

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.

BackgroundTo investigate the prevalence and outcomes of acute gastrointestinal injury (AGI) in critically ill patients with coronavirus disease 2019 (COVID-19). MethodsIn this clinical retrospective study, demographic data, laboratory parameters, AGI grades, clinical severity and outcomes were collected. The primary endpoints were AGI incidence and 28-day mortality, the secondary endpoints were organ dysfunction and septic shock incidence. ResultsFrom February 10 to March 10 2020, 83 critically ill patients of 1314 patients with COVID-19 were enrolled. Seventy-two (86.7%) patients had AGI during hospital stay, of them, 30 had AGI grade I, 35 had AGI grade II, 5 had AGI grade III, and 2 had AGI grade IV. The incidence of AGI grade II and above was 50.6%. As of March 16, 40 (48.2%) patients died within 28 days of admission, the median hospital stay was 12.0 days, ranging from 3 days to 27 days. Multiple organ dysfunction syndrome developed in 58 (69.9%) patients, septic shock in 16 (19.3%) patients. Patients with worse AGI grades had worse clinical variables, higher septic shock incidence and 28-day mortality. Sequential organ failure assessment scores (SOFA) (95% CI, 1.374-2.860; P <0.001), white blood cell (WBC) counts (95% CI, 1.037-1.379; P =0.014), duration of mechanical ventilation (MV) (95% CI, 1.020-1.340; P =0.025) were risk factors for the development of AGI grade II and above. Non-survivors were accompanied by higher incidence of AGI grade III to IV than survivors (17.5% vs. 0.0%, P =0.004). ConclusionsThe AGI incidence was 86.7%, and hospital mortality was 48.2% in critically ill patients with COVID-19. SOFA scores, WBC counts, and duration of MV were risk factors for the development of AGI grade II and above. Patients with worse AGI grades had worse clinical severity variables, higher septic shock incidence and 28-day mortality.

BackgroundPulmonary vascular pressures are freq[ABS]suently elevated in critically ill patients and are associated with worse outcomes. However, whether elevated pressures persist and their impact on outcomes after critical illness is unknown. Research QuestionsWhat factors asre associated with persistently elevated pulmonary vascular pressures? What are the outcomes associated with persistently elevated pulmonary vascular pressures? Study Design and MethodsThis is a single center retrospective cohort study of critically ill patients during the year 2021. Adult patients with a measured tricuspid regurgitant velocity[&ge;]2.8 m/s during critical illness and had a repeat echocardiogram done after hospital discharge were included. Kaplan Meier and logistic regression were used for mortality and multivariate analysis. ResultsOf 540 patients, 257 (47.6%) had an elevated TRV. Of 51 patients with a repeat echocardiogram, 33 (64.7%) had an elevated repeat TRV. These patients had higher heart rates (91{+/-}23 vs 73{+/-}14 bpm, p<0.01), lower hemoglobin levels (8.42{+/-}1.76 vs 10.0{+/-}2.16, p=0.02), decreased TAPSE (1.90 {+/-} 0.52 mm vs 2.23 {+/-} 0.43, p = 0.03), increased RV middle diameter(3.27{+/-}0.85 vs 2.72{+/-}0.78, p=0.04) and decreased left ventricular stroke volume (61.76{+/-}15.10 vs 84.36{+/-}27.09, p=0.01) compared to those with a normal repeat TRV. Hemoglobin (p=0.03, 95% CI: 0.30-0.90) and SVI (p=0.03, 95% CI: 0.77-0.98) were associated with elevated repeat TRV levels. Elevated TRV on repeat echocardiogram was not associated with worse survival (log-rank test, p=0.33). InterpretationElevated pulmonary vascular pressures persisted after critical illness in a large number of patients, although the impact of persistently elevated pulmonary vascular pressures is uncertain.

BackgroundSepsis-Induced Myocardial Injury (SIMI) is a serious complication with high in-hospital and 28-day mortality. Dexmedetomidine (DEX), a selective 2-adrenergic receptor agonist, has shown anti-inflammatory and cardioprotective effects, but its impact on SIMI prognosis is unclear. MethodsThis retrospective study used the MIMIC-IV database, including SIMI patients diagnosed per Sepsis-3 criteria. Propensity score matching (PSM) balanced baseline characteristics, and Cox regression analyzed the association between DEX use and mortality outcomes. External validation was performed using the MIMIC-III database. ResultsAmong 3,921 SIMI patients (375 DEX, 3,546 non-DEX), DEX use showed a trend toward lower 28-day mortality (HR 0.49, 95% CI 0.23-1.05, p = 0.068) and in-hospital mortality (HR 0.45, 95% CI 0.20-1.02, p = 0.055). After PSM, mortality remained lower in the DEX group. ICU and hospital stays were longer in the DEX group, but CRRT use showed no significant differences. External validation confirmed these findings. ConclusionDEX use may reduce 28-day and in-hospital mortality in SIMI patients, providing preliminary evidence for its potential benefits. Further large-scale studies are needed to confirm these results.

PurposeDysregulated immune response is a key driver of disease progression in sepsis and known to be associated with impaired cellular metabolism. This association has been studied mostly in the late stage sepsis patients. Here, we investigate whether such impairment in cellular metabolism is present in uncomplicated infection patients who do not develop sepsis. MethodsForty sepsis (fulfilled Sepsis-3 criteria) and 27 uncomplicated infection patients were recruited from the emergency department along with 20 healthy volunteers. Whole blood was collected for measurement of gene expression, cytokine levels and cellular metabolic functions (including mitochondrial respiration, oxidative stress and apoptosis). ResultsOur analysis revealed the impairment of mitochondrial respiration in uncomplicated infection and sepsis patients (p value <0.05), with greater degree of impairment noted in the established sepsis. The impairment was significantly correlated with increased mitochondrial oxidative stress level; the latter was increased in uncomplicated infection and more so in established sepsis patients. Further analysis revealed that the oxidative stress level correlated significantly with cytokine level (tumor necrosis factor-) and gene expression levels (CYCS, TP53, SLC24A24 and TSPO). ConclusionsThese findings suggest that impaired immune cell metabolism is present in infection patients without presenting sepsis, thereby opening potential window for early diagnosis and intervention (e.g. antioxidant therapy) in such patients.

BackgroundSepsis is a major public health challenge, and reliable biomarkers are essential for distinguishing sepsis from other conditions. Neutrophil Gelatinase-Associated Lipocalin (Neutrophil gelatinase-associated lipocalin (NGAL)) has shown promise as a diagnostic marker due to its role in the immune response. This study evaluates plasma NGAL as a diagnostic tool at the time of ICU admission. MethodsWe analysed plasma NGAL and C-reactive protein (CRP) levels in 4732 adult patients admitted to four ICUs between 2015 and 2018. All patients were retrospectively screened for Sepsis-3 criteria at ICU admission. The discriminative performance of NGAL and CRP for sepsis was assessed using receiver operating characteristic (ROC) analysis, with NGAL levels adjusted for Chronic kidney disease (CKD) and age. Patients were stratified by renal function. ResultsPlasma NGAL levels were significantly higher in septic patients (p<0.001). For the whole cohort, NGAL alone yielded an Area under the curve (AUC) of 0.67 (Confidence interval (CI) 0.66-0.69), CRP yielded an AUC of 0.72 (CI 0.71-0.73, p<0.001), and combining NGAL with CRP nominally improved discriminative performance (AUC 0.74 vs 0.72, p<0.001). Stratified analyses indicated that NGAL, together with CRP, significantly outperformed CRP alone in patients with no kidney injury and those with Acute Kidney Injury (AKI) only. In contrast, differences were not significant in patients with CKD only or CKD and AKI. ConclusionIn this large cohort, NGAL showed modest discrimination for sepsis, with a nominal improvement when combined with CRP. These findings do not indicate that NGAL meaningfully improves sepsis diagnosis in the ICU.

BackgroundSepsis-related organ dysfunction results from complex interactions between systemic hemodynamics, microcirculatory alterations, and cellular metabolic failure. Conventional resuscitation strategies guided by global parameters may miss persistent tissue hypoperfusion, a phenomenon termed "hemodynamic incoherence." The PRISM trial was designed to determine whether individualized management guided by advanced multimodal circulatory and perfusion monitoring improves outcomes in septic shock. MethodsThe PRISM trial is a multicenter, randomized, controlled, open-label study with blinded outcome assessment. Adults with septic shock (Sepsis-3 criteria) are randomized (1:1) to structured multimodal monitoring versus standard care. The intervention integrates advanced systemic hemodynamic indices --including mean circulatory filling pressure analogue and other determinants of venous return, heart efficiency, cardiac power output, power efficiency, and volume efficiency-- with a comprehensive perfusion panel (capillary refill time, mottling score, temperature gradients, lactate kinetics, central venous oxygen saturation, venous-arterial carbon dioxide difference, near-infrared spectroscopy-derived skeletal muscle tissue oxygen saturation, and arterial-interstitial glucose gradients). A predefined treatment algorithm links abnormal thresholds to therapeutic interventions. The primary endpoint is change in SOFA and SAPS II scores from baseline to 72 hours. Secondary endpoints include 28-day mortality, ICU and hospital length of stay, ventilator- and vasopressor-free days, lactate clearance, and safety outcomes. DiscussionBy combining advanced hemodynamic physiology with structured multimodal perfusion monitoring, the PRISM trial tests whether individualized, pathophysiology-guided resuscitation can overcome hemodynamic incoherence and improve patient-centered outcomes in septic shock.

Prone position ventilation has been shown to decrease mortality and improve oxygenation in ARDS patients. With best of our knowledge, no study reported physiological effect of prone position in SARS-CoV-2 infected ARDS patients. In this prospective observational study, data of n=20 consecutive laboratory confirmed SARS-CoV-2 patients with severe ARDS as per Berlin definition was included. Data of 20 patients analyzed with a median (Interquartile range, IQR) age of 56 (45.5-67) y and median (IQR) P/F ratio of 56 (54-66) with a median (IQR) PEEP of 12 (12-14) before initiation of prone position. Seventy-five percentage (95% CI 53.1-88.8) patients were prone responders at 16h prone session and 50 (95% CI 29.9-70.1) % patients were sustained responders. There was a significant decrease in plateau airway pressure (p<0.0001), peak airway pressure (p<0.0001) and driving pressure(p<0.0001) and increase in static compliance (p=0.001), P/F ratio (p<0.0001), PaO2 (p=0.0002)and SpO2 (p=0.0004) at 4h and 16h since initiation of prone session and also after return of supine position. Prone position in SARS-CoV-2 infected severe ARDS patients is associated with improvement in lung compliance and oxygenation in two-third of the patients and persisted in half of the patients.

Coronavirus disease 2019 (COVID-19) mortality is associated with hypoxaemia, multiorgan failure, and thromboinflammation. However severity of disease varies considerably and understanding physiological changes that may link to poor outcomes is important. Although increased serum ferritin has been observed in COVID-19 patients consistent with inflammation, other iron parameters have not been examined to our knowledge. Because iron is required for immunity and oxygen utilisation, and dysregulated iron homeostasis has been observed in COPD, we investigated serum iron concentrations in 30 patients with COVID-19 requiring ICU admission. All patients had low serum iron but patients with severe hypoxemic respiratory failure had more profound hypoferraemia. The area under the curve for receiver operating characteristic curves for serum iron to identify severe hypoxemia was 0{middle dot}95; the optimal Youden Index for distinguishing between severe and non-severe hypoxemia was a serum iron concentration of 2{middle dot}9 mol/L. By linear regression, serum iron was associated with lymphocyte count and PaO2/FiO2. In conclusion, profound hypoferraemia identifies COVID-19 patients with severe hypoxaemia. Serum iron is a simple biomarker that could be usefully employed to stratify patients and monitor disease. Severe hypoferraemia may plausibly impair critical iron-dependent processes such as lymphocyte responses and hypoxia sensing, contributing to pathology, and is potentially treatable.

The COVID19 pandemic is likely to cause more than a million of deaths worldwide, primarily due to complications from COVID19-associated acute respiratory distress syndrome (ARDS). Controversy surrounds the circulating cytokine/chemokine profile of COVID19-associated ARDS, with some groups suggesting that it is similar to non-COVID19 ARDS patients and others observing substantial differences. Moreover, while a hyperinflammatory phenotype associates with higher mortality in non-COVID19 ARDS, there is little information on the inflammatory landscapes association with mortality in COVID19 ARDS patients. Even though the circulating leukocytes transcriptomic signature has been associated with distinct phenotypes and outcomes in critical illness including ARDS, it is unclear whether the mortality-associated inflammatory mediators from COVID19 patients are transcriptionally regulated in the leukocyte compartment. Here, we conducted a prospective cohort study of 41 mechanically ventilated patients with COVID19 infection using highly calibrated methods to define the levels of plasma cytokines/chemokines and their gene expressions in circulating leukocytes. Plasma IL1RA and IL8 were found positively associated with mortality while RANTES and EGF negatively associated with that outcome. However, the leukocyte gene expression of these proteins had no statistically significant correlation with mortality. These data suggest a unique inflammatory signature associated with severe COVID19.

BackgroundLymphocytopenia is frequent in critically ill patients and has been associated with an increased risk of nosocomial infections and death in the ICU. Immunotherapies to promote recovery of lymphocyte counts have therefore been proposed. However, it is unknown if lymphocytopenia is a direct cause of ICU-acquired infections and death, or merely a marker of disease severity. We set out to study the prevalence, temporal evolution, and clinical correlates of lymphocytopenia in ICU patients, and estimate the attributable risk of lymphocytopenia in ICU-acquired infections. MethodsWe assessed the association between persistent lymphocytopenia (absolute lymphocyte counts <1x10^9/L on day 4) and ICU-acquired infections using multivariable competing risk Cox-regression analyses. ResultsAmong 2302 patients admitted to a Dutch tertiary ICU having sepsis, trauma, or major surgery between 2011 and 2018, persistent lymphocytopenia was observed in 980 (42.6%) subjects. Lymphocyte counts remained relatively stable during early ICU admission, and the median duration of lymphocytopenia was 3 (IQR 1-6) days among exposed patients. ICU-acquired infections occurred in 239 (18.1%) patients without and 214 (21.8%) patients with persistent lymphocytopenia (p=0.03). However, in multivariable survival analysis persistent lymphocytopenia was not associated with infection occurrence, either directly (adjusted cause-specific HR 1.08, 95% CI, 0.90-1.31) or indirectly (subdistribution HR 1.09, 95% CI, 0.91-1.32). Sensitivity analyses did not alter these findings. ConclusionPersistent lymphocytopenia was not associated with a higher incidence rate of nosocomial infections in critically ill patients. This challenges the rationale for using absolute lymphocyte counts as a therapeutic target to prevent ICU-acquired infections.