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Author(s): Marijke Peetermans [sup.1] [sup.2], Ipek Guler [sup.3], Philippe Meersseman [sup.1], Alexander Wilmer [sup.1] [sup.2], Joost Wauters [sup.1] [sup.2], Bart Meyns [sup.4], Alexander P. J. Vlaar [sup.5] [sup.6], Alain Combes [...], Purpose The impact of body mass index (BMI) on outcomes in respiratory failure necessitating extracorporeal membrane oxygenation (ECMO) has been poorly described. We aimed to assess: (i) whether adults with class II obesity or more (BMI [greater than or equal to] 35 kg/m.sup.2) have worse outcomes than lean counterparts, (ii) the form of the relationship between BMI and outcomes, (iii) whether a cutoff marking futility can be identified. Methods A retrospective analysis of the Extracorporeal Life Support Organization (ELSO) Registry from 1/1/2010 to 31/12/2020 was conducted. Impact of BMI [greater than or equal to] 35 kg/m.sup.2 was assessed with propensity-score (PS) matching, inverse propensity-score weighted (IPSW) and multivariable models (MV), adjusting for a priori identified confounders. Primary outcome was in-hospital mortality. The form of the relationship between BMI and outcomes was studied with generalized additive models. Outcomes across World Health Organisation (WHO)-defined BMI categories were compared. Results Among 18,529 patients, BMI [greater than or equal to] 35 kg/m.sup.2 was consistently associated with reduced in-hospital mortality [PS-matched: OR: 0.878(95%CI 0.798-0.966), p = 0.008; IPSW: OR: 0.899(95%CI 0.827-0.979), p = 0.014; MV: OR: 0.900(95%CI 0.834-0.971), p = 0.007] and shorter hospital length of stays. In patients with BMI [greater than or equal to] 35 kg/m.sup.2, cardiovascular (17.3% versus 15.3%), renal (37% versus 30%) and device-related complications (25.7% versus 20.6%) increased, whereas pulmonary complications decreased (7.6% versus 9.3%). These findings were independent of confounders throughout PS-matched, IPSW and MV models. The relationship between BMI and outcomes was non-linear and no cutoff for futility was identified. Conclusion Patients with obesity class II or more treated with ECMO for respiratory failure have lower mortality risk and shorter stays, despite increased cardiovascular, device-related, and renal complications. No upper limit of BMI indicating futility of ECMO treatment could be identified. BMI as single parameter should not be a contra-indication for respiratory ECMO. more...

Author(s): Alexander P. J. Vlaar [sup.1] [sup.2] Author Affiliations: (1) grid.509540.d, 0000 0004 6880 3010, Department of Intensive Care Medicine, Amsterdam UMC, , Room, C3-430, Meibergdreef 9, location AMC, 1105 [...] more...

Rationale: Systemic molecular phenotypes of critical illness are prognostically informative, yet their temporal kinetics and implications of changing phenotypes remain incompletely understood. Objectives: To determine the temporal nature of the Hyperinflammatory and Hypoinflammatory phenotypes and assess the impact of transition between the phenotypes on mortality. Methods: We used data from one prospective observational cohort (MARS [Molecular Diagnosis and Risk Stratification of Sepsis]) and two randomized controlled trials in acute respiratory distress syndrome (ALVEOLI [Assessment of Low Tidal Volume and Elevated End-Expiratory Pressure to Obviate Lung Injury]) and sepsis (CLOVERS [Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis]). Critically ill patients with biomarkers available at multiple time points (Days 0–4) were included. We used a validated classifier model incorporating plasma IL-8, protein C, and serum bicarbonate to assign phenotypes on each day. We determined the association of longitudinal phenotype transition and 90-day all-cause mortality. Measurements and Main Results: Data from 2,407, 527, and 868 patients were included in MARS, ALVEOLI, and CLOVERS, respectively. In MARS, 36.0% were classified by the parsimonious model as Hyperinflammatory at Day 0, decreasing to 15.6% by Day 2 and 6.3% by Day 4. In ALVEOLI and CLOVERS, 26.4% and 24.8% of patients were Hyperinflammatory at Day 0, decreasing to 13.4% and 5.7% at Day 3, respectively. In all three cohorts, switching classification from Hyperinflammatory (Day 0) to Hypoinflammatory over time was associated with significantly improved mortality compared with persistently Hyperinflammatory patients. Mediation analysis indicated that only a minor proportion of this improvement could be attributed to ameliorating organ failure. Conclusions: The prevalence of the Hyperinflammatory phenotype, as assigned using a parsimonious biomarker classifier model, decreases over the first several days of critical illness, irrespective of acute respiratory distress syndrome diagnosis. The transition from Hyperinflammatory to Hypoinflammatory mediates a trajectory toward recovery beyond the resolution of organ failure. [ABSTRACT FROM AUTHOR] more...

Background: The application of sepsis subtypes to enhance personalized medicine in critically ill patients is hindered by the lack of validation across diverse cohorts and the absence of a simple classification model. We aimed to validate the previously identified SENECA clinical sepsis subtypes in multiple large ICU cohorts, and to develop parsimonious classifier models for δ-type adjudication in clinical practice. Methods: Data from four cohorts between 2008 and 2023 were used to assign α, β, γ and δ-type in patients fulfilling the Sepsis-3 criteria using clinical variables: (I) The Molecular diAgnosis and Risk stratification of Sepsis (MARS, n = 2449), (II) a contemporary continuation of the MARS study (MARS2, n = 2445) (III) the Dutch National Intensive Care Evaluation registry (NICE, n = 28,621) and (IV) the Medical Information Mart for Intensive Care including (MIMIC-IV, n = 18,661). K-means clustering using clinical variables was conducted to assess the optimal number of classes and compared to the SENECA subtypes. Parsimonious models were built in the SENECA derivation cohort to predict subtype membership using logistic regression, and validated in MARS and MIMIC-IV. Results: Among 52.226 patients with sepsis, the subtype distribution in MARS, MARS2 and NICE was 2–6% for the α-type, 1–5% for the β-type, 49–65% for the γ-type and 26–48% for the δ-type compared to 33%, 27%, 27% and 13% in the original SENECA derivation cohort, whereas subtype distribution in MIMIC-IV was more similar at 25%, 24%, 27% and 25%, respectively. In-hospital mortality rates were significantly different between the four cohorts for α, γ and δ-type (p < 0.001). Method-based validation showed moderate overlap with the original subtypes in both MARS and MIMIC-IV. A parsimonious model for all four subtypes had moderate to low accuracy (accuracy 62.2%), while a parsimonious classifier model with 3 variables (aspartate aminotransferase, serum lactate, and bicarbonate) had excellent accuracy in predicting the δ-type patients from all other types in the derivation cohort and moderate accuracy in the validation cohorts (MARS: area under the receiver operator characteristic curve (AUC) 0.93, 95% CI [0.92–0.94], accuracy 85.5% [84.0–86.8%]; MIMIC-IV: AUC 0.86 [0.85–0.87], accuracy 82.9% [82.4–83.4%]). Conclusions: The distribution and mortality rates of clinical sepsis subtypes varied between US and European cohorts. A three-variable model could accurately identify the δ-type sepsis patients. [ABSTRACT FROM AUTHOR] more...

Author(s): Alexander P. J. Vlaar [sup.1], Joanna C. Dionne [sup.2] [sup.3] [sup.4] [sup.21], Sanne de Bruin [sup.1], Marije Wijnberge [sup.1] [sup.5], S. Jorinde Raasveld [sup.1], Frank E. H. P. van [...], Purpose To develop evidence-based clinical practice recommendations regarding transfusion practices and transfusion in bleeding critically ill adults. Methods A taskforce involving 15 international experts and 2 methodologists used the GRADE approach to guideline development. The taskforce addressed three main topics: transfusion support in massively and non-massively bleeding critically ill patients (transfusion ratios, blood products, and point of care testing) and the use of tranexamic acid. The panel developed and answered structured guideline questions using population, intervention, comparison, and outcomes (PICO) format. Results The taskforce generated 26 clinical practice recommendations (2 strong recommendations, 13 conditional recommendations, 11 no recommendation), and identified 10 PICOs with insufficient evidence to make a recommendation. Conclusions This clinical practice guideline provides evidence-based recommendations for the management of massively and non-massively bleeding critically ill adult patients and identifies areas where further research is needed. more...

Veno‐arterial extracorporeal membrane oxygenation (VA‐ECMO) is used in case of potentially reversible cardiac failure and restores systemic hemodynamics. However, whether this is followed by improvement of microcirculatory perfusion is unknown. Moreover, critically ill patients have possible pre‐existing microcirculatory perfusion disturbances. Therefore, this review provides an overview of alterations in sublingual microcirculatory perfusion in critically ill adult patients receiving VA‐ECMO support. Pubmed, Embase (Ovid), Cochrane Central Register of Controlled Trials, and Web of Science were systematically searched according to PRISMA guidelines. Studies reporting sublingual microcirculatory perfusion measurements in adult patients supported by VA‐ECMO were included. Outcome parameters included small vessel density (SVD), perfused vessel density (PVD), perfused small vessel density (PSVD), proportion of perfused vessels (PPV), microvascular flow index (MFI) and the heterogeneity index (HI). The protocol was registered at PROSPERO (CRD42021243930). The search identified 1215 studies of which 11 were included. Cardiogenic shock was the most common indication for VA‐ECMO (n=8). Three studies report increased PSVD, PPV, and MFI 24 hours after initiation of ECMO compared to pre‐ECMO. Nonetheless, microcirculatory perfusion stabilized thereafter. Four out of four studies showed higher PSVD and PPV in survivors compared to non‐survivors. Over time, survivors showed recovery of microcirculatory perfusion within hours of initiation of ECMO, whereas this was absent in non‐survivors. Notwithstanding the limited sample, VA‐ECMO seems to improve microcirculatory perfusion shortly after initiation of ECMO, especially in survivors. Further research in larger cohorts is needed to clarify the longitudinal effects of ECMO on microcirculatory perfusion. [ABSTRACT FROM AUTHOR] more...

Background: This Intensive Care Medicine Rapid Practice Guideline (ICM‐RPG) provides an evidence‐based recommendation to address the question: in adult patients in intensive care units (ICUs), should we use small‐volume or conventional blood collection tubes? Methods: We included 23 panelists in 8 countries and assessed and managed financial and intellectual conflicts of interest. Methodological support was provided by the Guidelines in Intensive Care, Development, and Evaluation (GUIDE) group. We conducted a systematic review, including evidence from observational and randomized studies. Using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, we evaluated the certainty of evidence and developed recommendations using the Evidence‐to‐Decision framework. Results: We identified 8 studies (1 cluster and 2 patient‐level randomized trials; 5 observational studies) comparing small‐volume to conventional tubes. We had high certainty evidence that small‐volume tubes reduce daily and cumulative blood sampling volume; and moderate certainty evidence that they reduce the risk of transfusion and mean number of red blood cell units transfused, but these estimates were limited by imprecision. We had high certainty that small‐volume tubes have a similar rate of specimens with insufficient quantity. The panel considered that the desirable effects of small‐volume tubes outweigh the undesirable effects, are less wasteful of resources, and are feasible, as demonstrated by successful implementation across multiple countries, although there are upfront implementation costs to validate small‐volume tubes on laboratory instrumentation. Conclusion: This ICM‐RPG panel made a strong recommendation for the use of small‐volume sample collection tubes in adult ICUs based on overall moderate certainty evidence. [ABSTRACT FROM AUTHOR] more...

Extracorporeal membrane oxygenation (ECMO) is a life-saving intervention for patients with circulatory and/or pulmonary failure; however, the rate of complications remains high. ECMO induces systemic inflammation, which may activate and damage the endothelium, thereby causing edema and organ dysfunction. Advancing our understanding in this area is crucial for improving patient outcomes during ECMO. The goal of this review is to summarize the current evidence of the effects of ECMO on endothelial activation and damage in both animals and patients. PubMed and Embase databases were systematically searched for both clinical and animal studies including ECMO support. The outcome parameters were markers of endothelial activation and damage or (in)direct measurements of endothelial permeability, fluid leakage and edema. In total, 26 studies (patient n = 16, animal n = 10) fulfilled all eligibility criteria, and used VA-ECMO (n = 13) or VV-ECMO (n = 6), or remained undefined (n = 7). The most frequently studied endothelial activation markers were adhesion molecules (ICAM-1) and selectins (E- and P-selectin). The levels of endothelial activation markers were comparable to or higher than in healthy controls. Compared to pre-ECMO or non-ECMO, the majority of studies showed stable or decreased levels. Angiopoietin-2, von Willebrand Factor and extracellular vesicles were the most widely studied circulating markers of endothelial damage. More than half of the included studies showed increased levels when compared to normal ranges, and pre-ECMO or non-ECMO values. In healthy animals, ECMO itself leads to vascular leakage and edema. The effect of ECMO support in critically ill animals showed contradicting results. ECMO support (further) induces endothelial damage, but endothelial activation does not, in the critically ill. Further research is necessary to conclude on the effect of the underlying comorbidity and type of ECMO support applied on endothelial dysfunction. [ABSTRACT FROM AUTHOR] more...

Author(s): Nicole P. Juffermans [sup.1] [sup.2], Cécile Aubron [sup.3], Jacques Duranteau [sup.4], Alexander P. J. Vlaar [sup.1] [sup.5], Daryl J. Kor [sup.6], Jennifer A. Muszynski [sup.7], Philip C. Spinella [sup.8], [...], Red blood cell transfusions are a frequent intervention in critically ill patients, including in those who are receiving mechanical ventilation. Both these interventions can impact negatively on lung function with risks of transfusion-related acute lung injury (TRALI) and other forms of acute respiratory distress syndrome (ARDS). The interactions between transfusion, mechanical ventilation, TRALI and ARDS are complex and other patient-related (e.g., presence of sepsis or shock, disease severity, and hypervolemia) or blood product-related (e.g., presence of antibodies or biologically active mediators) factors also play a role. We propose several strategies targeted at these factors that may help limit the risks of associated lung injury in critically ill patients being considered for transfusion. more...

Background: Reported bleeding incidences following central venous catheter (CVC) placement highly depend on methods of bleeding assessment. To determine the direction and magnitude of the bias associated with retrospective data collection, we used data from the PACER randomized controlled trial and a previous retrospective cohort study. Study Design and Methods: A patient‐level comparison of CVC‐related bleeding severity was made among (1) the prospectively collected clinical bleeding assessment of the PACER trial, (2) centralized assessment of CVC insertion site photographs, and (3) retrospective chart review. Interrater reliability for photographic bleeding assessment and retrospective chart review was assessed using Cohen's κ. The magnitude of underreporting of both methods compared to prospective clinical bleeding assessment at different cutoff points of clinically relevant bleeding was assessed using McNemar's test. Results: Interrater reliability was acceptable for both methods (κ = 0.583 and κ = 0.481 for photographic assessment and retrospective chart review, respectively). Photographic bleeding assessment led to significant underreporting of bleeding complications at all cutoff points. Retrospective chart review led to significant underreporting of minor bleeding complications, with an odds ratio (95% CI) of 0.17 (0.044–0.51) for the cutoff point grade 1 (i.e., self‐limiting or requiring at most 20 min of manual compression) or higher. There was no significant underreporting of major bleeding complications with retrospective chart review. Discussion: Centralized photographic bleeding assessment and retrospective chart review lead to biased bleeding assessment compared to prospective clinical bleeding assessment. [ABSTRACT FROM AUTHOR] more...

Author(s): Marit J. van Gils 1,*, Ayesha Lavell 2, Karlijn van der Straten 1,3, Brent Appelman 4, Ilja Bontjer 1, Meliawati Poniman 1, Judith A. Burger 1, Melissa Oomen 1, [...], Background Emerging and future SARS-CoV-2 variants may jeopardize the effectiveness of vaccination campaigns. Therefore, it is important to know how the different vaccines perform against diverse SARS-CoV-2 variants. Methods and findings In a prospective cohort of 165 SARS-CoV-2 naive health care workers in the Netherlands, vaccinated with either one of four vaccines (BNT162b2, mRNA-1273, AZD1222 or Ad26.COV2.S), we performed a head-to-head comparison of the ability of sera to recognize and neutralize SARS-CoV-2 variants of concern (VOCs; Alpha, Beta, Gamma, Delta and Omicron). Repeated serum sampling was performed 5 times during a year (from January 2021 till January 2022), including before and after booster vaccination with BNT162b2. Four weeks after completing the initial vaccination series, SARS-CoV-2 wild-type neutralizing antibody titers were highest in recipients of mRNA-1273, followed by recipients of BNT162b2 (geometric mean titers (GMT) of 358 [95% CI 231-556] and 214 [95% CI 153-299], respectively; p Conclusions Overall, this study shows that the mRNA vaccines appear superior to adenovirus vector-based vaccines in inducing neutralizing antibodies against VOCs four weeks after initial vaccination and after booster vaccination, which implies the use of mRNA vaccines for both initial and booster vaccination. more...

Author(s): Andres Alban [sup.1], Stephen E. Chick [sup.1] [sup.2], Dave A. Dongelmans [sup.3], Alexander P. J. Vlaar [sup.3], Danielle Sent [sup.4], Alexander F. van der Sluijs, W. Joost Wiersinga Author [...] more...