Sepsis and delayed cerebral ischemia are associated and have a cumulative effect on poor functional outcome in aneurysmal subarachnoid hemorrhage.

Objective: Although sepsis and delayed cerebral ischemia (DCI) are severe complications in patients with aneurysmal subarachnoid hemorrhage (aSAH) and share pathophysiological features, their interrelation and additive effect on functional outcome is uncertain. We investigated the association between sepsis and DCI and their cumulative effect on functional outcome in patients with aSAH using current sepsis-3 definition. Methods: Patients admitted to our hospital between 11/2014 and 11/2018 for aSAH were retrospectively analyzed. The main explanatory variable was sepsis, diagnosed using sepsis-3 criteria. Endpoints were DCI and functional outcome at hospital discharge (modified Rankin Scale (mRS) 0-3 vs. 4-6). Propensity score matching (PSM) and multivariable logistic regressions were performed. Results: Of 238 patients with aSAH, 55 (23.1%) developed sepsis and 74 (31.1%) DCI. After PSM, aSAH patients with sepsis displayed significantly worse functional outcome (p < 0.01) and longer ICU stay (p = 0.046). Sepsis was independently associated with DCI (OR = 2.46, 95%CI: 1.28-4.72, p < 0.01). However, after exclusion of patients who developed sepsis before (OR = 1.59, 95%CI: 0.78-3.24, p = 0.21) or after DCI (OR = 0.85, 95%CI: 0.37-1.95, p = 0.70) this statistical association did not remain. Good functional outcome gradually decreased from 56.3% (76/135) in patients with neither sepsis nor DCI, to 43.8% (21/48) in those with no sepsis but DCI, to 34.5% (10/29) with sepsis but no DCI and to 7.7% (2/26) in patients with both sepsis and DCI. Conclusion: Our study demonstrates a strong association between sepsis, DCI and functional outcome in patients with aSAH and suggests a complex interplay resulting in a cumulative effect towards poor functional outcome, which warrants further studies.

Effects of prone positioning on lung mechanical power components in patients with acute respiratory distress syndrome: a physiologic study.

BACKGROUND: Prone positioning (PP) homogenizes ventilation distribution and may limit ventilator-induced lung injury (VILI) in patients with moderate to severe acute respiratory distress syndrome (ARDS). The static and dynamic components of ventilation that may cause VILI have been aggregated in mechanical power, considered a unifying driver of VILI. PP may affect mechanical power components differently due to changes in respiratory mechanics; however, the effects of PP on lung mechanical power components are unclear. This study aimed to compare the following parameters during supine positioning (SP) and PP: lung total elastic power and its components (elastic static power and elastic dynamic power) and these variables normalized to end-expiratory lung volume (EELV). METHODS: This prospective physiologic study included 55 patients with moderate to severe ARDS. Lung total elastic power and its static and dynamic components were compared during SP and PP using an esophageal pressure-guided ventilation strategy. In SP, the esophageal pressure-guided ventilation strategy was further compared with an oxygenation-guided ventilation strategy defined as baseline SP. The primary endpoint was the effect of PP on lung total elastic power non-normalized and normalized to EELV. Secondary endpoints were the effects of PP and ventilation strategies on lung elastic static and dynamic power components non-normalized and normalized to EELV, respiratory mechanics, gas exchange, and hemodynamic parameters. RESULTS: Lung total elastic power (median [interquartile range]) was lower during PP compared with SP (6.7 [4.9-10.6] versus 11.0 [6.6-14.8] J/min; P < 0.001) non-normalized and normalized to EELV (3.2 [2.1-5.0] versus 5.3 [3.3-7.5] J/min/L; P < 0.001). Comparing PP with SP, transpulmonary pressures and EELV did not significantly differ despite lower positive end-expiratory pressure and plateau airway pressure, thereby reducing non-normalized and normalized lung elastic static power in PP. PP improved gas exchange, cardiac output, and increased oxygen delivery compared with SP. CONCLUSIONS: In patients with moderate to severe ARDS, PP reduced lung total elastic and elastic static power compared with SP regardless of EELV normalization because comparable transpulmonary pressures and EELV were achieved at lower airway pressures. This resulted in improved gas exchange, hemodynamics, and oxygen delivery. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00017449). Registered June 27, 2019. https://drks.de/search/en/trial/DRKS00017449.

Preload Responsiveness in Patients With Acute Respiratory Distress Syndrome Managed With Extracorporeal Membrane Oxygenation.

A restrictive fluid strategy is recommended in patients with acute respiratory distress syndrome (ARDS) managed with venovenous extracorporeal membrane oxygenation (VV ECMO). However, there are no established predictors for preload responsiveness in these patients. In 20 ARDS patients managed with VV ECMO, transesophageal echocardiography was used to repeatedly evaluate dynamic parameters of the left (velocity and stroke volume variation) and right ventricular outflow tract (velocity [respiratory variations of the maximal Doppler velocity in the truncus pulmonalis {ΔV max TP}] and velocity time integral [respiratory variation of the velocity time integral measured in the truncus pulmonalis {ΔVTI_TP}] variation in the truncus pulmonalis), the diameter variation in the superior and inferior vena cava and stroke volume variation measured by pulse contour analysis (SVV_PCA). Patients were categorized as responders and nonresponders according to an increase in stroke volume measured by echocardiography during a Passive Leg Raise Test with a cutoff value ≥10%. The final analysis includes 86 measurements. Predictive values for preload responsiveness were found for ΔV max TP (area under the curve [AUC] of 0.64), ΔVTI_TP (AUC 0.67), and SVV_PCA (AUC 0.74). In conclusion, SVV_PCA and, to a lesser extent, ΔV max TP and ΔVTI_TP are the most accurate parameters to predict preload responsiveness in ARDS patients managed with VV ECMO. Transesophageal echocardiography offers no advantages over pulse contour analysis for predicting preload responsiveness and provides only intermittent monitoring and assessment.

S-Adenosylhomocysteine Is a Useful Metabolic Factor in the Early Prediction of Septic Disease Progression and Death in Critically Ill Patients: A Prospective Cohort Study.

A common final pathway of pathogenetic mechanisms in septic organ dysfunction and death is a lack or non-utilization of oxygen. Plasma concentrations of lactate serve as surrogates for the oxygen-deficiency-induced imbalance between energy supply and demand. As S-adenosylhomocysteine (SAH) was shown to reflect tissue hypoxia, we compared the ability of SAH versus lactate to predict the progression of inflammatory and septic disease to septic organ dysfunction and death. Using univariate and multiple logistic regression, we found that SAH but not lactate, taken upon patients' inclusion in the study close to ICU admission, significantly and independently contributed to the prediction of disease progression and death. Due to the stronger increase in SAH in relation to S-adenosylmethionine (SAM), the ratio of SAM to SAH, representing methylation potential, was significantly decreased in patients with septic organ dysfunction and non-survivors compared with SIRS/sepsis patients (2.8 (IQR 2.3-3.9) vs. 8.8 (4.9-13.8); p = 0.003) or survivors (4.9 (2.8-9.5) vs. 8.9 (5.1-14.3); p = 0.026), respectively. Thus, SAH appears to be a better contributor to the prediction of septic organ dysfunction and death than lactate in critically ill patients. As SAH is a potent inhibitor of SAM-dependent methyltransferases involved in numerous vital biochemical processes, the impairment of the SAM-to-SAH ratio in severely critically ill septic patients and non-survivors warrants further studies on the pathogenetic role of SAH in septic multiple organ failure.

The Use of an Inspiration-Synchronized Vibrating Mesh Nebulizer for Prolonged Inhalative Iloprost Administration in Mechanically Ventilated Patients-An In Vitro Model.

Mechanically ventilated patients suffering from acute respiratory distress syndrome (ARDS) frequently receive aerosolized iloprost. Because of prostacyclin's short half-life, prolonged inhalative administration might improve its clinical efficacy. But, this is technically challenging. A solution might be the use of inspiration-synchronized vibrating mesh nebulizers (VMNsyn), which achieve high drug deposition rates while showing prolonged nebulization times. However, there are no data comparing prolonged to bolus iloprost nebulization using a continuous vibrating mesh nebulizer (VMNcont) and investigating the effects of different ventilation modes on inspiration-synchronized nebulization. Therefore, in an in vitro model of mechanically ventilated adults, a VMNsyn and a VMNcont were compared in volume-controlled (VC-CMV) and pressure-controlled continuous mandatory ventilation (PC-CMV) regarding iloprost deposition rate and nebulization time. During VC-CMV, the deposition rate of the VMNsyn was comparable to the rate obtained with the VMNcont, but 10.9% lower during PC-CMV. The aerosol output of the VMNsyn during both ventilation modes was significantly lower compared to the VMNcont, leading to a 7.5 times longer nebulization time during VC-CMV and only to a 4.2 times longer nebulization time during PC-CMV. Inspiration-synchronized nebulization during VC-CMV mode therefore seems to be the most suitable for prolonged inhalative iloprost administration in mechanically ventilated patients.

Effects of individualised positive end-expiratory pressure titration on respiratory and haemodynamic parameters during the Trendelenburg position with pneumoperitoneum: A randomised crossover physiologic trial.

BACKGROUND: The Trendelenburg position with pneumoperitoneum during surgery promotes dorsobasal atelectasis formation, which impairs respiratory mechanics and increases lung stress and strain. Positive end-expiratory pressure (PEEP) can reduce pulmonary inhomogeneities and preserve end-expiratory lung volume (EELV), resulting in decreased inspiratory strain and improved gas-exchange. The optimal intraoperative PEEP strategy is unclear. OBJECTIVES: To compare the effects of individualised PEEP titration strategies on set PEEP levels and resulting transpulmonary pressures, respiratory mechanics, gas-exchange and haemodynamics during Trendelenburg position with pneumoperitoneum. DESIGN: Prospective, randomised, crossover single-centre physiologic trial. SETTING: University hospital. PATIENTS: Thirty-six patients receiving robot-assisted laparoscopic radical prostatectomy. INTERVENTIONS: Randomised sequence of three different PEEP strategies: standard PEEP level of 5 cmH 2 O (PEEP 5 ), PEEP titration targeting a minimal driving pressure (PEEP ΔP ) and oesophageal pressure-guided PEEP titration (PEEP Poeso ) targeting an end-expiratory transpulmonary pressure ( PTP ) of 0 cmH 2 O. MAIN OUTCOME MEASURES: The primary endpoint was the PEEP level when set according to PEEP ΔP and PEEP Poeso compared with PEEP of 5 cmH 2 O. Secondary endpoints were respiratory mechanics, lung volumes, gas-exchange and haemodynamic parameters. RESULTS: PEEP levels differed between PEEP ΔP , PEEP Poeso and PEEP5 (18.0 [16.0 to 18.0] vs. 20.0 [18.0 to 24.0]vs. 5.0 [5.0 to 5.0] cmH 2 O; P  < 0.001 each). End-expiratory PTP and lung volume were lower in PEEP ΔP compared with PEEP Poeso ( P  = 0.014 and P  < 0.001, respectively), but driving pressure, lung stress, as well as respiratory system and dynamic elastic power were minimised using PEEP ΔP ( P  < 0.001 each). PEEP ΔP and PEEP Poeso improved gas-exchange, but PEEP Poeso resulted in lower cardiac output compared with PEEP 5 and PEEP ΔP . CONCLUSION: PEEP ΔP ameliorated the effects of Trendelenburg position with pneumoperitoneum during surgery on end-expiratory PTP and lung volume, decreased driving pressure and dynamic elastic power, as well as improved gas-exchange while preserving cardiac output. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00028559, date of registration 2022/04/27). https://drks.de/search/en/trial/DRKS00028559.

The Outcome Relevance of Pre-ECMO Liver Impairment in Adults with Acute Respiratory Distress Syndrome.

We hypothesize that (1) a significant pre-ECMO liver impairment, which is evident in the presence of pre-ECMO acute liver injury and a higher pre-ECMO MELD (model for end-stage liver disease) score, is associated with increased mortality; and (2) the requirement of veno-veno-arterial (V-VA) ECMO support is linked to a higher prevalence of pre-ECMO acute liver injury, a higher pre-ECMO MELD score, and increased mortality. We analyze 187 ECMO runs (42 V-VA and 145 veno-venous (V-V) ECMO) between January 2017 and December 2020. The SAPS II score is calculated at ICU admission; hepatic function and MELD score are assessed at ECMO initiation (pre-ECMO) and during the first five days on ECMO. SOFA, PRESERVE and RESP scores are calculated at ECMO initiation. Pre-ECMO cardiac failure, acute liver injury, ECMO type, SAPS II and MELD, SOFA, PRESERVE, and RESP scores are associated with mortality. However, only the pre-ECMO MELD score independently predicts mortality (p = 0.04). In patients with a pre-ECMO MELD score > 16, V-VA ECMO is associated with a higher mortality risk (p = 0.0003). The requirement of V-VA ECMO is associated with the development of acute liver injury during ECMO support, a higher pre-ECMO MELD score, and increased mortality.

Exploring the Synergistic Potential of Radiomics and Laboratory Biomarkers for Enhanced Identification of Vulnerable COVID-19 Patients.

BACKGROUND: Severe courses and high hospitalization rates were ubiquitous during the first pandemic SARS-CoV-2 waves. Thus, we aimed to examine whether integrative diagnostics may aid in identifying vulnerable patients using crucial data and materials obtained from COVID-19 patients hospitalized between 2020 and 2021 (n = 52). Accordingly, we investigated the potential of laboratory biomarkers, specifically the dynamic cell decay marker cell-free DNA and radiomics features extracted from chest CT. METHODS: Separate forward and backward feature selection was conducted for linear regression with the Intensive-Care-Unit (ICU) period as the initial target. Three-fold cross-validation was performed, and collinear parameters were reduced. The model was adapted to a logistic regression approach and verified in a validation naïve subset to avoid overfitting. RESULTS: The adapted integrated model classifying patients into "ICU/no ICU demand" comprises six radiomics and seven laboratory biomarkers. The models' accuracy was 0.54 for radiomics, 0.47 for cfDNA, 0.74 for routine laboratory, and 0.87 for the combined model with an AUC of 0.91. CONCLUSION: The combined model performed superior to the individual models. Thus, integrating radiomics and laboratory data shows synergistic potential to aid clinic decision-making in COVID-19 patients. Under the need for evaluation in larger cohorts, including patients with other SARS-CoV-2 variants, the identified parameters might contribute to the triage of COVID-19 patients.

Bacterial Co- or Superinfection in Patients Treated in Intensive Care Unit with COVID-19- and Influenza-Associated Pneumonia.

Viral pneumonia is frequently complicated by bacterial co- or superinfection (c/s) with adverse effects on patients' outcomes. However, the incidence of c/s and its impact on the outcomes of patients might be dependent on the type of viral pneumonia. We performed a retrospective observational study in patients with confirmed COVID-19 pneumonia (CP) or influenza pneumonia (IP) from 01/2009 to 04/2022, investigating the incidence of c/s using a competing risk model and its impact on mortality in these patients in a tertiary referral center using multivariate logistic regressions. Co-infection was defined as pulmonary pathogenic bacteria confirmed in tracheal aspirate or bronchoalveolar lavage within 48 h after hospitalization. Superinfection was defined as pulmonary pathogenic bacteria detected in tracheal aspirate or bronchoalveolar lavage 48 h after hospitalization. We examined 114 patients with CP and 76 patients with IP. Pulmonary bacterial co-infection was detected in 15 (13.2%), and superinfection was detected in 50 (43.9%) of CP patients. A total of 5 (6.6%) co-infections (p = 0.2269) and 28 (36.8%) superinfections (p = 0.3687) were detected in IP patients. The overall incidence of c/s did not differ between CP and IP patients, and c/s was not an independent predictor for mortality in a study cohort with a high disease severity. We found a significantly higher probability of superinfection for patients with CP compared to patients with IP (p = 0.0017).

Effects of changes in veno-venous extracorporeal membrane oxygenation blood flow on the measurement of intrathoracic blood volume and extravascular lung water index: a prospective interventional study.

In severe acute respiratory distress syndrome (ARDS), veno-venous extracorporeal membrane oxygenation (V-V ECMO) has been proposed as a therapeutic strategy to possibly reduce mortality. Transpulmonary thermodilution (TPTD) enables monitoring of the extravascular lung water index (EVLWI) and cardiac preload parameters such as intrathoracic blood volume index (ITBVI) in patients with ARDS, but it is not generally recommended during V-V ECMO. We hypothesized that the amount of extracorporeal blood flow (ECBF) influences the calculation of EVLWI and ITBVI due to recirculation of indicator, which affects the measurement of the mean transit time (MTt), the time between injection and passing of half the indicator, as well as downslope time (DSt), the exponential washout of the indicator. EVLWI and ITBVI were measured in 20 patients with severe ARDS managed with V-V ECMO at ECBF rates from 6 to 4 and 2 l/min with TPTD. MTt and DSt significantly decreased when ECBF was reduced, resulting in a decreased EVLWI (26.1 [22.8-33.8] ml/kg at 6 l/min ECBF vs 22.4 [15.3-31.6] ml/kg at 4 l/min ECBF, p < 0.001; and 13.2 [11.8-18.8] ml/kg at 2 l/min ECBF, p < 0.001) and increased ITBVI (840 [753-1062] ml/m2 at 6 l/min ECBF vs 886 [658-979] ml/m2 at 4 l/min ECBF, p < 0.001; and 955 [817-1140] ml/m2 at 2 l/min ECBF, p < 0.001). In patients with severe ARDS managed with V-V ECMO, increasing ECBF alters the thermodilution curve, resulting in unreliable measurements of EVLWI and ITBVI. German Clinical Trials Register (DRKS00021050). Registered 14/08/2018. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00021050.

Pneumonia in the first week after polytrauma is associated with reduced blood levels of soluble herpes virus entry mediator.

Background: Pneumonia develops frequently after major surgery and polytrauma and thus in the presence of systemic inflammatory response syndrome (SIRS) and organ dysfunction. Immune checkpoints balance self-tolerance and immune activation. Altered checkpoint blood levels were reported for sepsis. We analyzed associations of pneumonia incidence in the presence of SIRS during the first week of critical illness and trends in checkpoint blood levels. Materials and methods: Patients were studied from day two to six after admission to a surgical intensive care unit (ICU). Blood was sampled and physician experts retrospectively adjudicated upon the presence of SIRS and Sepsis-1/2 every eight hours. We measured the daily levels of immune checkpoints and inflammatory markers by bead arrays for polytrauma patients developing pneumonia. Immune checkpoint time series were additionally determined for clinically highly similar polytrauma controls remaining infection-free during follow-up. We performed cluster analyses. Immune checkpoint time trends in cases and controls were compared with hierarchical linear models. For patients with surgical trauma and with and without sepsis, selected immune checkpoints were determined in study baseline samples. Results: In polytrauma patients with post-injury pneumonia, eleven immune checkpoints dominated subcluster 3 that separated subclusters 1 and 2 of myeloid markers from subcluster 4 of endothelial activation, tissue inflammation, and adaptive immunity markers. Immune checkpoint blood levels were more stable in polytrauma cases than controls, where they trended towards an increase in subcluster A and a decrease in subcluster B. Herpes virus entry mediator (HVEM) levels (subcluster A) were lower in cases throughout. In unselected surgical patients, sepsis was not associated with altered HVEM levels at the study baseline. Conclusion: Pneumonia development after polytrauma until ICU-day six was associated with decreased blood levels of HVEM. HVEM signaling may reduce pneumonia risk by strengthening myeloid antimicrobial defense and dampening lymphoid-mediated tissue damage. Future investigations into the role of HVEM in pneumonia and sepsis development and as a predictive biomarker should consider the etiology of critical illness and the site of infection.

Machine learning for the prediction of preclinical airway management in injured patients: a registry-based trial.

OBJECTIVE: The aim of this study was to determine the feasibility of using machine learning to establish the need for preclinical airway management for injured patients based on a standardized emergency dataset. METHODS: A registry-based, retrospective analysis was conducted of adult trauma patients who were treated by physician-staffed emergency medical services in southwestern Germany between 2018 and 2020. The primary outcome was to assess the feasibility of using the random forest (RF) and Naive Bayes (NB) machine learning algorithms to predict the need for preclinical airway management. The secondary outcome was to use a principal component analysis to determine the attributes that can be used and advanced for future model development. RESULTS: In total, 25,556 adults with multiple injuries were identified, including 1,451 patients (5.7%) who required airway management. Key attributes were auscultation, injury pattern, oxygen therapy, thoracic drainage, noninvasive ventilation, catecholamines, pelvic sling, colloid infusion, initial vital signs, preemergency status, and shock index. The area under the receiver operating characteristics curve was between 0.96 (RF; 95% confidence interval [CI], 0.96-0.97) and 0.93 (NB; 95% CI, 0.92-0.93; P<0.01). For the prediction of airway management, RF yielded a higher precision-recall area than NB (0.83 [95% CI, 0.8-0.85] vs. 0.66 [95% CI, 0.61-0.72], respectively; P<0.01). CONCLUSION: To predict the need for preclinical airway management in injured patients, attributes that are commonly recorded in standardized datasets can be used with machine learning. In future models, the RF algorithm could be used because it has robust prediction accuracy.

Multidisciplinary and standardized management of patients with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

BACKGROUND: The appropriate management of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) remains uncertain. We aimed to evaluate the effect of implementing a standardized protocol for detection and management of DCI after aSAH on cerebral infarction and functional outcome. METHODS: We studied two cohorts of aSAH patients, one before (pre-implementation cohort: January 2012 to August 2014) and one after (post-implementation cohort: January 2016 to July 2018) implementation of a multidisciplinary approach, with standardized neurological and radiological assessment and risk-based medical treatment of DCI. We assessed the presence of new hypodensities on CT within 6 weeks after aSAH and categorized cerebral infarction into overall and DCI-related infarctions (hypodensities not within 48 h after IA repair and not attributable to aneurysm occlusion or intraparenchymal hematoma). Functional outcome was assessed at 3 months using the extended Glasgow outcome scale (eGOS), dichotomized into unfavorable (eGOS: 1-5) and favorable (eGOS: 6-8). We calculated odds ratios (OR) with corresponding 95% confidence intervals (CI's), and adjusted for age, WFNS grade, Fisher score, and treatment modality (aOR). RESULTS: In the post-implementation (n = 158) versus the pre-implementation (n = 143) cohort the rates for overall cerebral infarction were 29.1% vs 46.9% (aOR: 0.41 [0.24-0.69]), for DCI-related cerebral infarction 17.7% vs. 31.5% (aOR: 0.41 [0.23-0.76]), and for unfavorable functional outcome at 3 months 37.3% vs. 53.8% (aOR: 0.30 [0.17-0.54]). For patients with DCI, the rates for unfavorable functional outcomes at 3 months in the post-implementation versus the pre-implementation cohort were 42.3% vs. 77.8% (aOR: 0.1 [0.03-0.27]). CONCLUSIONS: A multidisciplinary approach with more frequent and standardized neurological assessment, standardized CT and CT perfusion monitoring, as well as tailored application of induced hypertension and invasive rescue therapy strategies, is associated with a significant reduction of cerebral infarction and unfavorable functional outcome after aneurysmal aSAH.

Comparative Analyses of the Impact of Different Criteria for Sepsis Diagnosis on Outcome in Patients with Spontaneous Subarachnoid Hemorrhage.

Data on sepsis in patients with a subarachnoid hemorrhage (SAH) are scarce. We assessed the impact of different sepsis criteria on the outcome in an SAH cohort. Adult patients admitted to our ICU with a spontaneous SAH between 11/2014 and 11/2018 were retrospectively included. In patients developing an infection, different criteria for sepsis diagnosis (Sepsis-1, Sepsis-3_original, Sepsis-3_modified accounting for SAH-specific therapy, alternative sepsis criteria compiled of consensus conferences) were applied and their impact on functional outcome using the modified Rankin Scale (mRS) on hospital discharge and in-hospital mortality was evaluated. Of 270 SAH patients, 129 (48%) developed an infection. Depending on the underlying criteria, the incidence of sepsis and septic shock ranged between 21-46% and 9-39%. In multivariate logistic regression, the Sepsis-1 criteria were not associated with the outcome. The Sepsis-3 criteria were not associated with the functional outcome, but in shock with mortality. Alternative sepsis criteria were associated with mortality for sepsis and in shock with mortality and the functional outcome. While Sepsis-1 criteria were irrelevant for the outcome in SAH patients, septic shock, according to the Sepsis-3 criteria, adversely impacted survival. This impact was higher for the modified Sepsis-3 criteria, accounting for SAH-specific treatment. Modified Sepsis-3 and alternative sepsis criteria diagnosed septic conditions of a higher relevance for outcomes in patients with an SAH.

Key Signature Genes of Early Terminal Granulocytic Differentiation Distinguish Sepsis From Systemic Inflammatory Response Syndrome on Intensive Care Unit Admission.

Infection can induce granulopoiesis. This process potentially contributes to blood gene classifiers of sepsis in systemic inflammatory response syndrome (SIRS) patients. This study aimed to identify signature genes of blood granulocytes from patients with sepsis and SIRS on intensive care unit (ICU) admission. CD15+ cells encompassing all stages of terminal granulocytic differentiation were analyzed. CD15 transcriptomes from patients with sepsis and SIRS on ICU admission and presurgical controls (discovery cohort) were subjected to differential gene expression and pathway enrichment analyses. Differential gene expression was validated by bead array in independent sepsis and SIRS patients (validation cohort). Blood counts of granulocyte precursors were determined by flow cytometry in an extension of the validation cohort. Despite similar transcriptional CD15 responses in sepsis and SIRS, enrichment of canonical pathways known to decline at the metamyelocyte stage (mitochondrial, lysosome, cell cycle, and proteasome) was associated with sepsis but not SIRS. Twelve of 30 validated genes, from 100 selected for changes in response to sepsis rather than SIRS, were endo-lysosomal. Revisiting the discovery transcriptomes revealed an elevated expression of promyelocyte-restricted azurophilic granule genes in sepsis and myelocyte-restricted specific granule genes in sepsis followed by SIRS. Blood counts of promyelocytes and myelocytes were higher in sepsis than in SIRS. Sepsis-induced granulopoiesis and signature genes of early terminal granulocytic differentiation thus provide a rationale for classifiers of sepsis in patients with SIRS on ICU admission. Yet, the distinction of this process from noninfectious tissue injury-induced granulopoiesis remains to be investigated.

Vasoactive Inotropic Score as a Prognostic Factor during (Cardio-) Respiratory ECMO.

The vasoactive inotropic score (VIS) is calculated as a weighted sum of all administered vasopressor and inotropic medications and quantifies the amount of pharmacological cardiovascular support in patients with the most severe combined cardiopulmonary failure supported with extracorporeal membrane oxygenation (ECMO). This study evaluated (1) whether VIS prior to the initiation of ECMO is an independent predictor of survival in these patients and (2) whether VIS might guide the selection of the appropriate extracorporeal cannulation modality (Veno-Venous 'V-V' or Veno-VenoArterial 'V-VA'). In this study, 39 V-VA and 182 V-V ECMO runs were retrospectively analyzed. VIS immediately prior to ECMO initiation (pre-ECMO) was 40 (10/113) in all patients, 30 (10/80) in patients with V-V ECMO and 207 (60/328) in patients with V-VA ECMO. Pre-ECMO VIS was an independent predictor of survival in univariate (AUC = 0.68, p = 0.001) and multi-variable analyses (p = 0.02). Pre-ECMO VIS was clearly associated with mortality (p = 0.001) in V-V ECMO group; however, V-VA ECMO disrupted this association (p = 0.18). Therefore, in conjunction with echocardiography, VIS might assist in selecting the appropriate ECMO cannulation strategy as patients with a pre-ECMO VIS ≥ 61.4 had significantly lower odds of survival compared to those with lower VIS.

Ultraprotective versus apneic ventilation in acute respiratory distress syndrome patients with extracorporeal membrane oxygenation: a physiological study.

BACKGROUND: Even an ultraprotective ventilation strategy in severe acute respiratory distress syndrome (ARDS) patients treated with extracorporeal membrane oxygenation (ECMO) might induce ventilator-induced lung injury and apneic ventilation with the sole application of positive end-expiratory pressure may, therefore, be an alternative ventilation strategy. We, therefore, compared the effects of ultraprotective ventilation with apneic ventilation on oxygenation, oxygen delivery, respiratory system mechanics, hemodynamics, strain, air distribution and recruitment of the lung parenchyma in ARDS patients with ECMO. METHODS: In a prospective, monocentric physiological study, 24 patients with severe ARDS managed with ECMO were ventilated using ultraprotective ventilation (tidal volume 3 ml/kg of predicted body weight) with a fraction of inspired oxygen (FiO2) of 21%, 50% and 90%. Patients were then treated with apneic ventilation with analogous FiO2. The primary endpoint was the effect of the ventilation strategy on oxygenation and oxygen delivery. The secondary endpoints were mechanical power, stress, regional air distribution, lung recruitment and the resulting strain, evaluated by chest computed tomography, associated with the application of PEEP (apneic ventilation) and/or low VT (ultraprotective ventilation). RESULTS: Protective ventilation, compared to apneic ventilation, improved oxygenation (arterial partial pressure of oxygen, p < 0.001 with FiO2 of 50% and 90%) and reduced cardiac output. Both ventilation strategies preserved oxygen delivery independent of the FiO2. Protective ventilation increased driving pressure, stress, strain, mechanical power, as well as induced additional recruitment in the non-dependent lung compared to apneic ventilation. CONCLUSIONS: In patients with severe ARDS managed with ECMO, ultraprotective ventilation compared to apneic ventilation improved oxygenation, but increased stress, strain, and mechanical power. Apneic ventilation might be considered as one of the options in the initial phase of ECMO treatment in severe ARDS patients to facilitate lung rest and prevent ventilator-induced lung injury. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00013967). Registered 02/09/2018. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013967 .

Effects of different positive end-expiratory pressure titration strategies during prone positioning in patients with acute respiratory distress syndrome: a prospective interventional study.

BACKGROUND: Prone positioning in combination with the application of low tidal volume and adequate positive end-expiratory pressure (PEEP) improves survival in patients with moderate to severe acute respiratory distress syndrome (ARDS). However, the effects of PEEP on end-expiratory transpulmonary pressure (Ptpexp) during prone positioning require clarification. For this purpose, the effects of three different PEEP titration strategies on Ptpexp, respiratory mechanics, mechanical power, gas exchange, and hemodynamics were evaluated comparing supine and prone positioning. METHODS: In forty consecutive patients with moderate to severe ARDS protective ventilation with PEEP titrated according to three different titration strategies was evaluated during supine and prone positioning: (A) ARDS Network recommendations (PEEPARDSNetwork), (B) the lowest static elastance of the respiratory system (PEEPEstat,RS), and (C) targeting a positive Ptpexp (PEEPPtpexp). The primary endpoint was to analyze whether Ptpexp differed significantly according to PEEP titration strategy during supine and prone positioning. RESULTS: Ptpexp increased progressively with prone positioning compared with supine positioning as well as with PEEPEstat,RS and PEEPPtpexp compared with PEEPARDSNetwork (positioning effect p < 0.001, PEEP strategy effect p < 0.001). PEEP was lower during prone positioning with PEEPEstat,RS and PEEPPtpexp (positioning effect p < 0.001, PEEP strategy effect p < 0.001). During supine positioning, mechanical power increased progressively with PEEPEstat,RS and PEEPPtpexp compared with PEEPARDSNetwork, and prone positioning attenuated this effect (positioning effect p < 0.001, PEEP strategy effect p < 0.001). Prone compared with supine positioning significantly improved oxygenation (positioning effect p < 0.001, PEEP strategy effect p < 0.001) while hemodynamics remained stable in both positions. CONCLUSIONS: Prone positioning increased transpulmonary pressures while improving oxygenation and hemodynamics in patients with moderate to severe ARDS when PEEP was titrated according to the ARDS Network lower PEEP table. This PEEP titration strategy minimized parameters associated with ventilator-induced lung injury induction, such as transpulmonary driving pressure and mechanical power. We propose that a lower PEEP strategy (PEEPARDSNetwork) in combination with prone positioning may be part of a lung protective ventilation strategy in patients with moderate to severe ARDS. TRIAL REGISTRATION: German Clinical Trials Register ( DRKS00017449 ). Registered June 27, 2019. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00017449.

Ground truth labels challenge the validity of sepsis consensus definitions in critical illness.

BACKGROUND: Sepsis is the leading cause of death in the intensive care unit (ICU). Expediting its diagnosis, largely determined by clinical assessment, improves survival. Predictive and explanatory modelling of sepsis in the critically ill commonly bases both outcome definition and predictions on clinical criteria for consensus definitions of sepsis, leading to circularity. As a remedy, we collected ground truth labels for sepsis. METHODS: In the Ground Truth for Sepsis Questionnaire (GTSQ), senior attending physicians in the ICU documented daily their opinion on each patient's condition regarding sepsis as a five-category working diagnosis and nine related items. Working diagnosis groups were described and compared and their SOFA-scores analyzed with a generalized linear mixed model. Agreement and discriminatory performance measures for clinical criteria of sepsis and GTSQ labels as reference class were derived. RESULTS: We analyzed 7291 questionnaires and 761 complete encounters from the first survey year. Editing rates for all items were > 90%, and responses were consistent with current understanding of critical illness pathophysiology, including sepsis pathogenesis. Interrater agreement for presence and absence of sepsis was almost perfect but only slight for suspected infection. ICU mortality was 19.5% in encounters with SIRS as the "worst" working diagnosis compared to 5.9% with sepsis and 5.9% with severe sepsis without differences in admission and maximum SOFA. Compared to sepsis, proportions of GTSQs with SIRS plus acute organ dysfunction were equal and macrocirculatory abnormalities higher (p < 0.0001). SIRS proportionally ranked above sepsis in daily assessment of illness severity (p < 0.0001). Separate analyses of neurosurgical referrals revealed similar differences. Discriminatory performance of Sepsis-1/2 and Sepsis-3 compared to GTSQ labels was similar with sensitivities around 70% and specificities 92%. Essentially no difference between the prevalence of SIRS and SOFA ≥ 2 yielded sensitivities and specificities for detecting sepsis onset close to 55% and 83%, respectively. CONCLUSIONS: GTSQ labels are a valid measure of sepsis in the ICU. They reveal suspicion of infection as an unclear clinical concept and refute an illness severity hierarchy in the SIRS-sepsis-severe sepsis spectrum. Ground truth challenges the accuracy of Sepsis-1/2 and Sepsis-3 in detecting sepsis onset. It is an indispensable intermediate step towards advancing diagnosis and therapy in the ICU and, potentially, other health care settings.