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Rutger A Middelburg,1,2 M Sesmu Arbous,2,3 Judith G Middelburg,4 Johanna G van der Bom1,2 1Center for Clinical Transfusion Research, Sanquin Research, Leiden, the Netherlands; 2Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; 3Department of Intensive Care Medicine, Leiden University Medical Center, Leiden, the Netherlands; 4Department of Radiation Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands Abstract: Evidence-based medicine has become associated with a preference for randomized trials. Randomization is a powerful tool against both known and unknown confounding. However, due to cost-induced constraints in size, randomized trials are seldom able to provide the subgroup analyses needed to gain much insight into effect modification. To apply results to an individual patient, effect modification needs to be considered. Results from randomized trials are therefore often difficult to apply in daily clinical practice. Confounding by indication, which randomization aims to prevent, is caused by more severely ill patients being less or more likely to be treated. Therefore, the prognostic indicators that physicians use to make treatment decisions become confounders. However, these same prognostic indicators are also effect modifiers. This is in fact exactly why they are relevant to decision-making. We use simple, fictive numerical examples to illustrate these concepts. Then we argue that if we would record all relevant variables, it would simultaneously solve the problem of confounding by indication and allow quantification of effect modification. It has previously been argued that it is practically more feasible to “simply” randomize treatment allocation, than to adequately correct for confounding by indication. We will argue that, in the current age of evidence-based medicine and highly regulated randomized trials, this balance has shifted. We therefore call for better observational clinical research. However, careless acceptance of results from poorly performed observational research can lead clinicians seriously astray. Therefore, a more interactive approach toward the medical literature might be needed, where more room is made for scientific discussion and interpretation of results, instead of one-way reporting. Keywords: treatment, personalized, effectiveness, effect modification, risk factors, confounding by indication

The article presents a case study of two women: a 30-year-old who suffered postpartum haemorrhage and developed hepatic encephalopathy; and a 35-year-old who suffered intra-uterine fetal death and developed hepatic coma. Topics discussed include carrying out of orthotopic liver transplantation (OLT) and auxiliary liver transplantation (AUX) of respective women, developing and treating of acute fatty liver of pregnancy (AFLP) and improvements in fetal mortality and maternal mortality rate.

Background: Postoperative infections remain a crucial challenge in health care, resulting in high morbidity, mortality, and costs. Accurate identification and labeling of patients with postoperative bacterial infections is crucial for developing prediction models, validating biomarkers, and implementing surveillance systems in clinical practice., Objective: This scoping review aimed to explore methods for identifying patients with postoperative infections using electronic health record (EHR) data to go beyond the reference standard of manual chart review., Methods: We performed a systematic search strategy across PubMed, Embase, Web of Science (Core Collection), the Cochrane Library, and Emcare (Ovid), targeting studies addressing the prediction and fully automated surveillance (ie, without manual check) of diverse bacterial infections in the postoperative setting. For prediction modeling studies, we assessed the labeling methods used, categorizing them as either manual or automated. We evaluated the different types of EHR data needed for the surveillance and labeling of postoperative infections, as well as the performance of fully automated surveillance systems compared with manual chart review., Results: We identified 75 different methods and definitions used to identify patients with postoperative infections in studies published between 2003 and 2023. Manual labeling was the predominant method in prediction modeling research, 65% (49/75) of the identified methods use structured data, and 45% (34/75) use free text and clinical notes as one of their data sources. Fully automated surveillance systems should be used with caution because the reported positive predictive values are between 0.31 and 0.76., Conclusions: There is currently no evidence to support fully automated labeling and identification of patients with infections based solely on structured EHR data. Future research should focus on defining uniform definitions, as well as prioritizing the development of more scalable, automated methods for infection detection using structured EHR data., (©Siri Lise van der Meijden, Anna M van Boekel, Harry van Goor, Rob GHH Nelissen, Jan W Schoones, Ewout W Steyerberg, Bart F Geerts, Mark GJ de Boer, M Sesmu Arbous. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 10.09.2024.)

Background: Statins exert pleiotropic anti-inflammatory and antioxidant effects in addition to their cholesterol-lowering properties. This study aimed to investigate whether statin use is associated with improved outcomes of sepsis., Methods: Data from sepsis patients were extracted from the Medical Information Mart for Intensive Care IV database. Patients with a history of receiving prescriptions for statins (i.e. atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) were matched with non-users using propensity-score matching, to balance confounding factors between the groups. Mendelian Randomization (MR) analyses were performed using information from the UK Biobank dataset to explore the potential causal link between low-density lipoprotein cholesterol (LDL-C) levels and LDL-C lowering effects via genetically inhibiting β‑hydroxy β-methylglutaryl-coenzyme A reductase and the susceptibility to sepsis, and the sepsis-related 28-day mortality., Main Results: 90-day mortality rate was lower among the 10,323 statin users when compared to matched non-users [hazard ratio (HR): 0.612, 95 % CI: 0.571 to 0.655]. In-hospital mortality was also lower for statin users compared to non-users (11.3% vs. 17.8 %, p < 0.0001, HR: 0.590, 95 % CI: 0.548 to 0.634). Statin use was associated with better outcome in all investigated subpopulations apart from patients with severe liver disease. MR analyses further pointed toward pleiotropic effects beyond lipid-lowering effects of statins on sepsis-related outcomes., Conclusions: Statin use is associated with improved outcomes following sepsis-related ICU admission, most likely from its pleiotropic properties, characterized by lower 90-day and in-hospital mortality among statin users., Competing Interests: Declaration of competing interest The authors declare no competing interests or external funding., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Currently, there is no marker of efficacy of red blood cell (RBC) transfusion. This study describes the impact of RBC transfusion on mitochondrial oxygen tension (mitoPO 2 ) and mitochondrial oxygen consumption (mitoVO 2 ) in critically ill patients with anemia., Methods: Critically ill patients with a hemoglobin concentration < 10 g/dL, for whom a single RBC unit had been ordered, were included. MitoPO 2 was measured with the COMET device immediately before RBC transfusion, 0.5 h, 1 h, 3 h, and 24 h after RBC transfusion. MitoVO 2 was calculated from dynamic mitoPO 2 measurements during cessation of local oxygen supply., Results: Sixty-three patients participated, median age 64.0 (interquartile range (IQR) 52.3-72.8) years, median hemoglobin concentration before transfusion 7.4 (IQR 7.1-7.7) g/dL. Median mitoPO 2 values were 55.0 (IQR 49.6-63.0) mmHg before RBC transfusion, 51.0 (IQR 41.5-61.2) directly after and 67.3 (IQR 41.6-83.7) at 24 h after RBC transfusion. Median mitoVO 2 values were 3.3 (IQR 2.1-5.9) mmHg/s before RBC transfusion, 3.7 (IQR 2.0-5.1) mmHg/s directly after, and 3.1 (IQR 2.5-4.8) mmHg/s 24 h after RBC transfusion. In the higher Hb concentration group (> 7 g/dL), we saw a dissociation of the effect of RBC transfusion on mitoPO 2 versus on mitoVO 2 values. MitoPO 2 and mitoVO 2 values were not associated with commonly used parameters of tissue perfusion and oxygenation., Conclusion: RBC transfusion did not alter mitoPO 2 and mitoVO 2 in critically ill patients with anemia. MitoPO 2 and mitoVO 2 values were not notably associated with Hb concentrations, parameters of severity of illness and markers of tissue perfusion or oxygenation. Given the high baseline value, it cannot be excluded nor confirmed whether RBC can improve low mitoPO 2 . Trial registration number NCT03092297 (registered 27 March 2017)., (© 2024. The Author(s).)

Objectives: To develop and validate a prediction model for 1-year mortality in patients with a hematologic malignancy acutely admitted to the ICU., Design: A retrospective cohort study., Setting: Five university hospitals in the Netherlands between 2002 and 2015., Patients: A total of 1097 consecutive patients with a hematologic malignancy were acutely admitted to the ICU for at least 24 h., Interventions: None., Measurements and Main Results: We created a 13-variable model from 22 potential predictors. Key predictors included active disease, age, previous hematopoietic stem cell transplantation, mechanical ventilation, lowest platelet count, acute kidney injury, maximum heart rate, and type of malignancy. A bootstrap procedure reduced overfitting and improved the model's generalizability. This involved estimating the optimism in the initial model and shrinking the regression coefficients accordingly in the final model. We assessed performance using internal-external cross-validation by center and compared it with the Acute Physiology and Chronic Health Evaluation II model. Additionally, we evaluated clinical usefulness through decision curve analysis. The overall 1-year mortality rate observed in the study was 62% (95% CI, 59-65). Our 13-variable prediction model demonstrated acceptable calibration and discrimination at internal-external validation across centers ( C -statistic 0.70; 95% CI, 0.63-0.77), outperforming the Acute Physiology and Chronic Health Evaluation II model ( C -statistic 0.61; 95% CI, 0.57-0.65). Decision curve analysis indicated overall net benefit within a clinically relevant threshold probability range of 60-100% predicted 1-year mortality., Conclusions: Our newly developed 13-variable prediction model predicts 1-year mortality in hematologic malignancy patients admitted to the ICU more accurately than the Acute Physiology and Chronic Health Evaluation II model. This model may aid in shared decision-making regarding the continuation of ICU care and end-of-life considerations., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

The objective of this study was to investigate the relationship between sublingual microcirculatory parameters and the severity of the disease in critically ill coronavirus disease 2019 (COVID-19) patients in the initial period of Intensive Care Unit (ICU) admission in a phase of the COVID-19 pandemic where patients were being treated with anti-inflammatory medication. In total, 35 critically ill COVID-19 patients were included. Twenty-one critically ill COVID-19 patients with a Sequential Organ Failure Assessment (SOFA) score below or equal to 7 were compared to 14 critically ill COVID-19 patients with a SOFA score exceeding 7. All patients received dexamethasone and tocilizumab at ICU admission. Microcirculatory measurements were performed within the first five days of ICU admission, preferably as soon as possible after admission. An increase in diffusive capacity of the microcirculation (total vessel density, functional capillary density, capillary hematocrit) and increased perfusion of the tissues by red blood cells was found in the critically ill COVID-19 patients with a SOFA score of 7-9 compared to the critically ill COVID-19 patients with a SOFA score ≤ 7. No such effects were found in the convective component of the microcirculation. These effects occurred in the presence of administration of anti-inflammatory medication., (© 2024. The Author(s).)

Purpose: To investigate the development in quality of ICU care over time using the Dutch National Intensive Care Evaluation (NICE) registry., Materials and Methods: We included data from all ICU admissions in the Netherlands from those ICUs that submitted complete data between 2009 and 2021 to the NICE registry. We determined median and interquartile range for eight quality indicators. To evaluate changes over time on the indicators, we performed multilevel regression analyses, once without and once with the COVID-19 years 2020 and 2021 included. Additionally we explored between-ICU heterogeneity by calculating intraclass correlation coefficients (ICC)., Results: 705,822 ICU admissions from 55 (65%) ICUs were included in the analyses. ICU length of stay (LOS), duration of mechanical ventilation (MV), readmissions, in-hospital mortality, hypoglycemia, and pressure ulcers decreased significantly between 2009 and 2019 (OR <1). After including the COVID-19 pandemic years, the significant change in MV duration, ICU LOS, and pressure ulcers disappeared. We found an ICC ≤0.07 on the quality indicators for all years, except for pressure ulcers with an ICC of 0.27 for 2009 to 2021., Conclusions: Quality of Dutch ICU care based on seven indicators significantly improved from 2009 to 2019 and between-ICU heterogeneity is medium to small, except for pressure ulcers. The COVID-19 pandemic disturbed the trend in quality improvement, but unaltered the between-ICU heterogeneity., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Stroke patients admitted to an intensive care unit (ICU) follow a particular survival pattern with a high short-term mortality, but if they survive the first 30 days, a relatively favourable subsequent survival is observed., Objectives: The development and validation of two prognostic models predicting 30-day mortality for ICU patients with ischaemic stroke and for ICU patients with intracerebral haemorrhage (ICH), analysed separately, based on parameters readily available within 24 h after ICU admission, and with comparison with the existing Acute Physiology and Chronic Health Evaluation IV (APACHE-IV) model., Design: Observational cohort study., Setting: All 85 ICUs participating in the Dutch National Intensive Care Evaluation database., Patients: All adult patients with ischaemic stroke or ICH admitted to these ICUs between 2010 and 2019., Main Outcome Measures: Models were developed using logistic regressions and compared with the existing APACHE-IV model. Predictive performance was assessed using ROC curves, calibration plots and Brier scores., Results: We enrolled 14 303 patients with stroke admitted to ICU: 8422 with ischaemic stroke and 5881 with ICH. Thirty-day mortality was 27% in patients with ischaemic stroke and 41% in patients with ICH. Important factors predicting 30-day mortality in both ischaemic stroke and ICH were age, lowest Glasgow Coma Scale (GCS) score in the first 24 h, acute physiological disturbance (measured using the Acute Physiology Score) and the application of mechanical ventilation. Both prognostic models showed high discrimination with an AUC 0.85 [95% confidence interval (CI), 0.84 to 0.87] for patients with ischaemic stroke and 0.85 (0.83 to 0.86) in ICH. Calibration plots and Brier scores indicated an overall good fit and good predictive performance. The APACHE-IV model predicting 30-day mortality showed similar performance with an AUC of 0.86 (95% CI, 0.85 to 0.87) in ischaemic stroke and 0.87 (0.86 to 0.89) in ICH., Conclusion: We developed and validated two prognostic models for patients with ischaemic stroke and ICH separately with a high discrimination and good calibration to predict 30-day mortality within 24 h after ICU admission., Trial Registration: Trial registration: Dutch Trial Registry ( https://www.trialregister.nl/ ); identifier: NTR7438., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society of Anaesthesiology and Intensive Care.)

Background: Previously, we reported a decreased mortality rate among patients with COVID-19 who were admitted at the ICU during the final upsurge of the second wave (February-June 2021) in the Netherlands. We examined whether this decrease persisted during the third wave and the phases with decreasing incidence of COVID-19 thereafter and brought up to date the information on patient characteristics., Methods: Data from the National Intensive Care Evaluation (NICE)-registry of all COVID-19 patients admitted to an ICU in the Netherlands were used. Patient characteristics and rates of in-hospital mortality (the primary outcome) during the consecutive periods after the first wave (periods 2-9, May 25, 2020-January 31, 2023) were compared with those during the first wave (period 1, February-May 24, 2020)., Results: After adjustment for patient characteristics and ICU occupancy rate, the mortality risk during the initial upsurge of the third wave (period 6, October 5, 2021-January, 31, 2022) was similar to that of the first wave (OR adj  = 1.01, 95%-CI [0.88-1.16]). The mortality rates thereafter decreased again (e.g., period 9, October 5, 2022-January, 31, 2023: OR adj  = 0.52, 95%-CI [0.41-0.66]). Among the SARS-CoV-2 positive patients, there was a huge drop in the proportion of patients with COVID-19 as main reason for ICU admission: from 88.2% during the initial upsurge of the third wave to 51.7%, 37.3%, and 41.9% for the periods thereafter. Restricting the analysis to these patients did not modify the results on mortality., Conclusions: The results show variation in mortality rates among critically ill COVID-19 patients across the calendar time periods that is not explained by differences in case-mix and ICU occupancy rates or by varying proportions of patients with COVID-19 as main reason for ICU admission. The consistent increase in mortality during the initial, rising phase of each separate wave might be caused by the increased virulence of the contemporary virus strain and lacking immunity to the new strain, besides unmeasured patient-, treatment- and healthcare system characteristics., (© 2024. The Author(s).)

Purpose: Sepsis is one of the leading causes of morbidity and mortality worldwide with approximately 50 million annual cases. There is ongoing debate on the clinical benefit of hydrocortisone in the prevention of death in septic patients. Here we evaluated the association between hydrocortisone treatment and mortality in patients diagnosed with sepsis in a large-scale clinical dataset., Methods: Data from patients between 2008 and 2019 were extracted from the retrospective Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients who received hydrocortisone after diagnosis were matched using propensity-score matching with patients who did not, to balance confounding (by indication and contraindication) factors between the groups. 90-day mortality and survivors' length of hospital stay was compared between patients who did or did not receive hydrocortisone., Results: A total of 31,749 septic patients were included in the study (mean age: 67, men: 57.3%, in-hospital mortality: 15.6%). 90-day mortality was higher among the 1802 patients receiving hydrocortisone when compared with the 6348 matched non-users (hazard ratio: 1.35, 95% CI: 1.24-1.47). Hydrocortisone treatment was also associated with increased in-hospital mortality (40.9% vs. 27.6%, p < 0.0001) and prolonged hospital stay in those who survived until discharge (median 12.6 days vs. 10.8 days, p < 0.0001). Stratification for age, gender, ethnicity, occurrence of septic shock, and the need for vasopressor drug administration such as (nor)epinephrine did not reveal sub-population(s) benefiting of hydrocortisone use., Conclusion: Hydrocortisone treatment is associated with increased risk of death as well as prolonged hospital stay in septic patients. Although residual confounding (by indication) cannot be ruled out completely due to the observational nature of the study, the present study suggests clinical implication of hydrocortisone use in patients with sepsis., Competing Interests: Declaration of Competing Interest I, Mohan Li, hereby declare that there is no conflict of interest pertaining to the research work titled " Hydrocortisone-associated death and hospital length of stay in patients with sepsis: A retrospective cohort of large-scale clinical care data" submitted for consideration to be published in Biomedicine & Pharmacotherapy. Throughout the course of this research, no financial or non-financial relationships or activities that could potentially influence or bias the findings, interpretations, or conclusions of this work have been present. Additionally, there are no affiliations with any organization, company, or individual that might create a conflict of interest in connection with this research. I confirm that this Declaration of Interest is accurate and complete to the best of my knowledge., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: An asymptomatic respiratory viral infection during cardiac surgery could lead to pulmonary complications and increased mortality. For elective surgery, testing for respiratory viral infection before surgery or vaccination could reduce the number of these pulmonary complications. The aim of this study was to investigate the association between influenzalike illness (ILI) seasons and prolonged mechanical ventilation and inhospital mortality in a Dutch cohort of adult elective cardiac surgery patients., Methods: Cardiac surgery patients who were admitted to the intensive care unit between January 1, 2014, and February 1, 2020, were included. The primary endpoint was the duration of invasive mechanical ventilation in the ILI season compared with baseline season. Secondary endpoints were the median Pao 2 to fraction of inspired oxygen ratio on days 1, 3, and 7 and postoperative inhospital mortality., Results: A total of 42,277 patients underwent cardiac surgery, 12,994 (30.7%) in the ILI season, 15,843 (37.5%) in the intermediate season, and 13,440 (31.8%) in the baseline season. No hazard rates indicative of a longer duration of invasive mechanical ventilation during the ILI season were found. No differences were found for the median Pao 2 to fraction of inspired oxygen ratio between seasons. However, inhospital mortality was higher in the ILI season compared with baseline season (odds ratio 1.67; 95% CI, 1.14-2.46)., Conclusions: Patients undergoing cardiac surgery during the ILI season were at increased risk of inhospital mortality compared with patients in the baseline season. No evidence was found that this difference is caused by direct postoperative pulmonary complications., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: A multitude of diagnostic and predictive algorithms have been designed for COVID-19. However, currently no score can accurately quantify and track day-to-day disease severity in hospitalised patients with COVID-19. We aimed to design such a score to improve pathophysiological insight in COVID-19., Methods: Development of the Severity of COronavirus Disease Assessment (SCODA) score was based on the 4C Mortality score but patient demographic variables that remain constant during admission were excluded. Instead, parameters associated with breathing and oxygenation were added to reflect the daily condition. The SCODA score was subsequently applied to the BEAT-COVID cohort to describe COVID-19 severity over time and to determine the timing of clinical recovery for each patient, an important marker in pathophysiological studies. The BEAT-COVID study included patients with PCR confirmed COVID-19 who were hospitalized between April 2020 and March 2021 in the Leiden University Medical Center, The Netherlands., Results: The SCODA score consists of 6 clinical and 2 routine lab parameters. 191 patients participated in the BEAT-COVID study. Median age was 66, and 74.4% was male. The modal timepoint at which recovery was clinically initiated occurred on days 8 and 24 since symptom onset for non-ICU and ICU-patients, respectively., Conclusions: We developed a daily score which can be used to track disease severity of patients admitted due to COVID-19. This score is useful for improving insight in COVID-19 pathophysiology, its clinical course and to evaluate interventions. In a future stage this score can also be used in other (emerging) infectious respiratory diseases., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Joosten et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: BG is currently CEO and majority shareholder of Healthplus.ai B.V. and subsidiaries. BG has also consulted for and received research grants from Philips NV and Edwards Lifesciences LLC. SvdM works as a data scientist and PhD at Healthplus.ai and LUMC. SvdM owns share options in Healthplus.ai.

Objections: Development of acute lung injury after cardiac surgery is associated with an unfavourable outcome. Acute respiratory distress syndrome in general is, besides cytokine and interleukin activation, associated with activation of platelets, monocytes and neutrophils. In relation to pulmonary outcome after cardiac surgery, leucocyte and platelet activation is described in animal studies only. Therefore, we explored the perioperative time course of platelet and leucocyte activation in cardiac surgery and related these findings to acute lung injury assessed via PaO2/FiO2 (P/F) ratio measurements., Methods: A prospective cohort study was performed, including 80 cardiac surgery patients. At five time points, blood samples were directly assessed by flow cytometry. For time course analyses in low (< 200) versus high (≥200) P/F ratio groups, repeated measurement techniques with linear mixed models were used., Results: Already before the start of the operation, platelet activatability (P = 0.003 for thrombin receptor-activator peptide and P = 0.017 for adenosine diphosphate) was higher, and the expression of neutrophil activation markers was lower (CD18/CD11; P = 0.001, CD62L; P = 0.013) in the low P/F group. After correction for these baseline differences, the peri- and postoperative thrombin receptor-activator peptide-induced thrombocyte activatability was decreased in the low P/F ratio group (P = 0.008), and a changed pattern of neutrophil activation markers was observed., Conclusions: Prior to surgery, an upregulated inflammatory state with higher platelet activatability and indications for higher neutrophil turnover were demonstrated in cardiac surgery patients who developed lung injury. It is difficult to distinguish whether these factors are mediators or are also aetiologically related to the development of lung injury after cardiac surgery. Further research is warranted., Trial Registration: Clinical Registration number: ICTRP: NTR 5314, 26-05-2015., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: Artificial intelligence-based clinical decision support (AI-CDS) tools have great potential to benefit intensive care unit (ICU) patients and physicians. There is a gap between the development and implementation of these tools., Objective: We aimed to investigate physicians' perspectives and their current decision-making behavior before implementing a discharge AI-CDS tool for predicting readmission and mortality risk after ICU discharge., Methods: We conducted a survey of physicians involved in decision-making on discharge of patients at two Dutch academic ICUs between July and November 2021. Questions were divided into four domains: (1) physicians' current decision-making behavior with respect to discharging ICU patients, (2) perspectives on the use of AI-CDS tools in general, (3) willingness to incorporate a discharge AI-CDS tool into daily clinical practice, and (4) preferences for using a discharge AI-CDS tool in daily workflows., Results: Most of the 64 respondents (of 93 contacted, 69%) were familiar with AI (62/64, 97%) and had positive expectations of AI, with 55 of 64 (86%) believing that AI could support them in their work as a physician. The respondents disagreed on whether the decision to discharge a patient was complex (23/64, 36% agreed and 22/64, 34% disagreed); nonetheless, most (59/64, 92%) agreed that a discharge AI-CDS tool could be of value. Significant differences were observed between physicians from the 2 academic sites, which may be related to different levels of involvement in the development of the discharge AI-CDS tool., Conclusions: ICU physicians showed a favorable attitude toward the integration of AI-CDS tools into the ICU setting in general, and in particular toward a tool to predict a patient's risk of readmission and mortality within 7 days after discharge. The findings of this questionnaire will be used to improve the implementation process and training of end users., (©Siri L van der Meijden, Anne A H de Hond, Patrick J Thoral, Ewout W Steyerberg, Ilse M J Kant, Giovanni Cinà, M Sesmu Arbous. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 05.01.2023.)

Background: We investigated whether COVID-19 leads to persistent impaired pulmonary function, fibrotic-like abnormalities or psychological symptoms 12 months after discharge and whether severely ill patients (ICU admission) recover differently than moderately ill patients., Methods: This single-centre cohort study followed adult COVID-19 survivors for a period of one year after discharge. Patients underwent pulmonary function tests 6 weeks, 3 months and 12 months after discharge and were psychologically evaluated at 6 weeks and 12 months. Computed tomography (CT) was performed after 3 months and 12 months., Results: 66 patients were analysed, their median age was 60.5 (IQR: 54-69) years, 46 (70%) patients were male. 38 (58%) patients had moderate disease and 28 (42%) patients had severe disease. Most patients had spirometric values within normal range after 12 months of follow-up. 12 (23%) patients still had an impaired lung diffusion after 12 months. Impaired pulmonary diffusion capacity was associated with residual CT abnormalities (OR 5.1,CI-95: 1.2-22.2), shortness of breath (OR 7.0, CI-95: 1.6-29.7) and with functional limitations (OR 5.8, CI-95: 1.4-23.8). Ground-glass opacities resolved in most patients during follow-up. Resorption of reticulation, bronchiectasis and curvilinear bands was rare and independent of disease severity. 81% of severely ill patients and 37% of moderately ill patients showed residual abnormalities after 12 months (OR 8.1, CI-95: 2.5-26.4). A minority of patients had symptoms of post-traumatic stress disorder, anxiety, depression and cognitive failure during follow-up., Conclusion: Some patients still had impaired lung diffusion 12 months after discharge and fibrotic-like residual abnormalities were notably prevalent, especially in severely ill patients., Competing Interests: Conflict of interest None., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Vasoplegia is a common complication after cardiac surgery and is associated with poor prognosis. It is characterised by refractory hypotension despite normal or even increased cardiac output. The pathophysiology is complex and includes the systemic inflammatory response caused by cardiopulmonary bypass (CPB) and surgical trauma. Patients with end-stage heart failure (HF) are at increased risk for developing vasoplegia. The CytoSorb adsorber is a relatively new haemoadsorption device which can remove circulating inflammatory mediators in a concentration based manner. The CytoSorb-HF trial aims to evaluate the efficacy of CytoSorb haemoadsorption in limiting the systemic inflammatory response and preventing postoperative vasoplegia in HF patients undergoing cardiac surgery with CPB., Methods and Analysis: This is an investigator-initiated, single-centre, randomised, controlled clinical trial. In total 36 HF patients undergoing elective cardiac surgery with an expected CPB duration of more than 120 min will be randomised to receive CytoSorb haemoadsorption along with standard surgical treatment or standard surgical treatment alone. The primary endpoint is the change in systemic vascular resistance index with phenylephrine challenge after CPB. Secondary endpoints include inflammatory markers, sublingual microcirculation parameters and 30-day clinical indices. In addition, we will assess the cost-effectiveness of using the CytoSorb adsorber. Vascular reactivity in response to phenylephrine challenge will be assessed after induction, after CPB and on postoperative day 1. At the same time points, and before induction and on postoperative day 4 (5 time points in total), blood samples will be collected and the sublingual microcirculation will be recorded. Study participants will be followed up until day 30., Ethics and Dissemination: The trial protocol was approved by the Medical Ethical Committee of Leiden The Hague Delft (METC LDD, registration number P20.039). The results of the trial will be published in peer-reviewed medical journals and through scientific conferences., Trial Registration Number: NCT04812717., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We previously reported the added value of 24-hour lactate concentration alone and in combination with 24-hour lactate clearance and lactate concentration at admission for the prediction of inhospital mortality in critically ill patients with sepsis. We aimed to validate this finding., Derivation Cohort: The derivation cohort from Leiden, The Netherlands, consisted of 451 critically ill patients with sepsis., Validation Cohort: The validation cohort consisted of 4,440 critically ill adult patients with sepsis from the Medical Information Mart for Intensive Care cohort admitted to the ICU of Beth Israel Deaconness Medical Center, Boston, MA, between January 2006 and 2018., Prediction Model: Predictors of mortality were: age, chronic comorbidities, length of stay pre-ICU, Glasgow Coma Scale, and Acute Physiology Score. Lactate concentration at 24-hour alone, in combination with 24-hour lactate clearance and in combination with lactate concentration at admission, was added to assess improvement of the prediction model. The outcome was inhospital mortality., Results: Inhospital mortality occurred in 160 patients (36%) in the derivation cohort and in 2,347 patients (53%) in the validation cohort. The Acute Physiology and Chronic Health Evaluation (APACHE) IV model had a moderate discriminative performance (recalibrated C -statistic, 0.62; 95% CI, 0.60-0.63). Addition of 24-hour lactate concentration increased the recalibrated C -statistic to 0.64 (95% CI, 0.62-0.66). The model with 24-hour lactate concentration and lactate concentration at admission showed the best fit as depicted by the smallest Akaike Information Criterion in both the derivation and validation data., Conclusion: The 24-hour lactate concentration and lactate concentration at admission contribute modestly to prediction of inhospital mortality in critically ill patients with sepsis. Future updates and possible modification of APACHE IV should consider the incorporation of lactate concentration at baseline and at 24 hours., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Opioid overdoses are increasing in the Netherlands, and there may be other harms associated with prescription opioid use. We investigated the relationship between prescription opioid use and unplanned ICU admission and death., Methods: This is an analysis of linked government registries of the adult Dutch population (age ≥18 years) alive on January 1, 2018. The co-primary outcomes were ICU admission and death up to 1 year. Crude event rates and event-specific adjusted hazard rates (aHRs) with 95% confidence intervals (CIs) were calculated using multivariable analysis for people with and without exposure to an opioid prescription., Results: We included 13 813 173 individuals, of whom 32 831 were admitted to the ICU and 152 259 died during the 1 year follow-up. Rates of ICU admission and death amongst people who reimbursed an opioid prescription were 5.87 and 62.2 per 1000 person-years, and rates of ICU admission and death in those without a prescription were 2.03 and 6.34, respectively. Exposed individuals had a higher rate of both ICU admission (aHR 2.53; 95% CI: 2.45-2.60) and death (aHR 7.11; 95% CI: 7.02-7.19) compared with unexposed individuals. Both outcomes were more frequent amongst prescription opioid users across a range of subgroups., Conclusions: The rate of ICU admission and death was higher amongst prescription opioid users than non-users in the full cohort and in subgroups. These findings represent an important public health concern., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Building Machine Learning (ML) models in healthcare may suffer from time-consuming and potentially biased pre-selection of predictors by hand that can result in limited or trivial selection of suitable models. We aimed to assess the predictive performance of automating the process of building ML models (AutoML) in-hospital mortality prediction modelling of triage COVID-19 patients at ICU admission versus expert-based predictor pre-selection followed by logistic regression., Methods: We conducted an observational study of all COVID-19 patients admitted to Dutch ICUs between February and July 2020. We included 2,690 COVID-19 patients from 70 ICUs participating in the Dutch National Intensive Care Evaluation (NICE) registry. The main outcome measure was in-hospital mortality. We asessed model performance (at admission and after 24h, respectively) of AutoML compared to the more traditional approach of predictor pre-selection and logistic regression., Findings: Predictive performance of the autoML models with variables available at admission shows fair discrimination (average AUROC = 0·75-0·76 (sdev = 0·03), PPV = 0·70-0·76 (sdev = 0·1) at cut-off = 0·3 (the observed mortality rate), and good calibration. This performance is on par with a logistic regression model with selection of patient variables by three experts (average AUROC = 0·78 (sdev = 0·03) and PPV = 0·79 (sdev = 0·2)). Extending the models with variables that are available at 24h after admission resulted in models with higher predictive performance (average AUROC = 0·77-0·79 (sdev = 0·03) and PPV = 0·79-0·80 (sdev = 0·10-0·17))., Conclusions: AutoML delivers prediction models with fair discriminatory performance, and good calibration and accuracy, which is as good as regression models with expert-based predictor pre-selection. In the context of the restricted availability of data in an ICU quality registry, extending the models with variables that are available at 24h after admission showed small (but significantly) performance increase., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Describe the differences in characteristics and outcomes between COVID-19 and other viral pneumonia patients admitted to Dutch ICUs., Materials and Methods: Data from the National-Intensive-Care-Evaluation-registry of COVID-19 patients admitted between February 15th and January 1th 2021 and other viral pneumonia patients admitted between January 1st 2017 and January 1st 2020 were used. Patients' characteristics, the unadjusted, and adjusted in-hospital mortality were compared., Results: 6343 COVID-19 and 2256 other viral pneumonia patients from 79 ICUs were included. The COVID-19 patients included more male (71.3 vs 49.8%), had a higher Body-Mass-Index (28.1 vs 25.5), less comorbidities (42.2 vs 72.7%), and a prolonged hospital length of stay (19 vs 9 days). The COVID-19 patients had a significantly higher crude in-hospital mortality rate (Odds ratio (OR) = 1.80), after adjustment for patient characteristics and ICU occupancy rate the OR was respectively 3.62 and 3.58., Conclusion: Higher mortality among COVID-19 patients could not be explained by patient characteristics and higher ICU occupancy rates, indicating that COVID-19 is more severe compared to other viral pneumonia. Our findings confirm earlier warnings of a high need of ICU capacity and high mortality rates among relatively healthy COVID-19 patients as this may lead to a higher mental workload for the staff., Competing Interests: Declaration of Competing Interest All authors state that there were no conflict of interest. The NICE foundation pays the department of Medical Informatics to process and analyze data for the registry. This institution is not paid specifically for this study but it is part of the task agreement to perform analyses like this on data from the NICE registry., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: To assess trends in the quality of care for COVID-19 patients at the ICU over the course of time in the Netherlands., Methods: Data from the National Intensive Care Evaluation (NICE)-registry of all COVID-19 patients admitted to an ICU in the Netherlands were used. Patient characteristics and indicators of quality of care during the first two upsurges (N = 4215: October 5, 2020-January 31, 2021) and the final upsurge of the second wave, called the 'third wave' (N = 4602: February 1, 2021-June 30, 2021) were compared with those during the first wave (N = 2733, February-May 24, 2020)., Results: During the second and third wave, there were less patients treated with mechanical ventilation (58.1 and 58.2%) and vasoactive drugs (48.0 and 44.7%) compared to the first wave (79.1% and 67.2%, respectively). The occupancy rates as fraction of occupancy in 2019 (1.68 and 1.55 vs. 1.83), the numbers of ICU relocations (23.8 and 27.6 vs. 32.3%) and the mean length of stay at the ICU (HRs of ICU discharge = 1.26 and 1.42) were lower during the second and third wave. No difference in adjusted hospital mortality between the second wave and the first wave was found, whereas the mortality during the third wave was considerably lower (OR = 0.80, 95% CI [0.71-0.90])., Conclusions: These data show favorable shifts in the treatment of COVID-19 patients at the ICU over time. The adjusted mortality decreased in the third wave. The high ICU occupancy rate early in the pandemic does probably not explain the high mortality associated with COVID-19., (© 2022. The Author(s).)

Background: The COVID-19 pandemic continues to overwhelm intensive care units (ICUs) worldwide, and improved prediction of mortality among COVID-19 patients could assist decision making in the ICU setting. In this work, we report on the development and validation of a dynamic mortality model specifically for critically ill COVID-19 patients and discuss its potential utility in the ICU., Methods: We collected electronic medical record (EMR) data from 3222 ICU admissions with a COVID-19 infection from 25 different ICUs in the Netherlands. We extracted daily observations of each patient and fitted both a linear (logistic regression) and non-linear (random forest) model to predict mortality within 24 h from the moment of prediction. Isotonic regression was used to re-calibrate the predictions of the fitted models. We evaluated the models in a leave-one-ICU-out (LOIO) cross-validation procedure., Results: The logistic regression and random forest model yielded an area under the receiver operating characteristic curve of 0.87 [0.85; 0.88] and 0.86 [0.84; 0.88], respectively. The recalibrated model predictions showed a calibration intercept of -0.04 [-0.12; 0.04] and slope of 0.90 [0.85; 0.95] for logistic regression model and a calibration intercept of -0.19 [-0.27; -0.10] and slope of 0.89 [0.84; 0.94] for the random forest model., Discussion: We presented a model for dynamic mortality prediction, specifically for critically ill COVID-19 patients, which predicts near-term mortality rather than in-ICU mortality. The potential clinical utility of dynamic mortality models such as benchmarking, improving resource allocation and informing family members, as well as the development of models with more causal structure, should be topics for future research., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: There are limited published data on the epidemiology of skin and soft tissue infections (SSTIs) requiring intensive care unit (ICU) admission. This study intended to describe the annual prevalence, characteristics, and outcomes of critically ill adult patients admitted to the ICU for an SSTI., Methods: This was a registry-based retrospective cohort study, using data submitted to the Australian and New Zealand Intensive Care Society Adult Patient Database for all admissions with SSTI between 2006 and 2017. The inclusion criteria were as follows: primary diagnosis of SSTI and age ≥16 years. The exclusion criteria were as follows: ICU readmissions (during the same hospital admission) and transfers from ICUs from other hospitals. The primary outcome was in-hospital mortality, and the secondary outcomes were ICU mortality and length of stay (LOS) in the ICU and hospital with independent predictors of outcomes., Results: Admissions due to SSTI accounted for 10 962 (0.7%) of 1 470 197 ICU admissions between 2006 and 2017. Comorbidities were present in 25.2% of the study sample. The in-hospital mortality was 9% (991/10 962), and SSTI necessitating ICU admission accounted for 0.07% of in-hospital mortality of all ICU admissions between 2006 and 2017. Annual prevalence of ICU admissions for SSTI increased from 0.4% to 0.9% during the study period, but in-hospital mortality decreased from 16.1% to 6.8%. The median ICU LOS was 2.1 days (interquartile range = 3.4), and the median hospital LOS was 12.1 days (interquartile range = 20.6). ICU LOS remained stable between 2006 and 2017 (2.0-2.1 days), whereas hospital LOS decreased from 15.7 to 11.2 days. Predictors for in-hospital mortality included Australian and New Zealand Risk of Death scores [odds ratio (OR): 1.07; confidence interval (CI) (1.05, 1.09); p < 0.001], any comorbidity except diabetes [OR: 2.00; CI (1.05, 3.79); p = 0.035], and admission through an emergency response call [OR: 2.07; CI (1.03, 4.16); p = 0.041]., Conclusions: SSTIs are uncommon as primary ICU admission diagnosis. Although the annual prevalence of ICU admissions for SSTI has increased, in-hospital mortality and hospital LOS have decreased over the last decade., Competing Interests: Conflict of Interest The authors declare that they have no competing interests., (Copyright © 2021 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: Short-term follow-up of COVID-19 patients reveals pulmonary dysfunction, myocardial damage and severe psychological distress. Little is known of the burden of these sequelae, and there are no clear recommendations for follow-up of COVID-19 patients.In this multi-disciplinary evaluation, cardiopulmonary function and psychological impairment after hospitalization for COVID-19 are mapped., Methods: We evaluated patients at our outpatient clinic 6 weeks after discharge. Cardiopulmonary function was measured by echocardiography, 24-hours ECG monitoring and pulmonary function testing. Psychological adjustment was measured using questionnaires and semi-structured clinical interviews. A comparison was made between patients admitted to the general ward and Intensive care unit (ICU), and between patients with a high versus low functional status., Findings: Eighty-one patients were included of whom 34 (41%) had been admitted to the ICU. New York Heart Association class II-III was present in 62% of the patients. Left ventricular function was normal in 78% of patients. ICU patients had a lower diffusion capacity (mean difference 12,5% P  = 0.01), lower forced expiratory volume in one second and forced vital capacity (mean difference 14.9%; P <0.001; 15.4%; P <0.001; respectively). Risk of depression, anxiety and PTSD were 17%, 5% and 10% respectively and similar for both ICU and non-ICU patients., Interpretation: Overall, most patients suffered from functional limitations. Dyspnea on exertion was most frequently reported, possibly related to decreased DLCOc. This could be caused by pulmonary fibrosis, which should be investigated in long-term follow-up. In addition, mechanical ventilation, deconditioning, or pulmonary embolism may play an important role., Competing Interests: There is no conflict of interest for the present manuscript., (© 2021 The Author(s).)

Objectives: Assessment of all-cause mortality of intracerebral hemorrhage and ischemic stroke patients admitted to the ICU and comparison to the mortality of other critically ill ICU patients classified into six other diagnostic subgroups and the general Dutch population., Design: Observational cohort study., Setting: All ICUs participating in the Dutch National Intensive Care Evaluation database., Patients: All adult patients admitted to these ICUs between 2010 and 2015; patients were followed until February 2017., Interventions: None., Measurements and Main Results: Of all 370,386 included ICU patients, 7,046 (1.9%) were stroke patients, 4,072 with ischemic stroke, and 2,974 with intracerebral hemorrhage. Short-term mortality in ICU-admitted stroke patients was high with 30 days mortality of 31% in ischemic stroke and 42% in intracerebral hemorrhage. In the longer term, the survival curve gradient among ischemic stroke and intracerebral hemorrhage patients stabilized. The gradual alteration of mortality risk after ICU admission was assessed using left-truncation with increasing minimum survival period. ICU-admitted stroke patients who survive the first 30 days after suffering from a stroke had a favorable subsequent survival compared with other diseases necessitating ICU admission such as patients admitted due to sepsis or severe community-acquired pneumonia. After having survived the first 3 months after ICU admission, multivariable Cox regression analyses showed that case-mix adjusted hazard ratios during the follow-up period of up to 3 years were lower in ischemic stroke compared with sepsis (adjusted hazard ratio, 1.21; 95% CI, 1.06-1.36) and severe community-acquired pneumonia (adjusted hazard ratio, 1.57; 95% CI, 1.39-1.77) and in intracerebral hemorrhage patients compared with these groups (adjusted hazard ratio, 1.14; 95% CI, 0.98-1.33 and adjusted hazard ratio, 1.49; 95% CI, 1.28-1.73)., Conclusions: Stroke patients who need intensive care treatment have a high short-term mortality risk, but this alters favorably with increasing duration of survival time after ICU admission in patients with both ischemic stroke and intracerebral hemorrhage, especially compared with other populations of critically ill patients such as sepsis or severe community-acquired pneumonia patients.

Introduction: COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. Reports on the incidence of thrombotic complications are however not available., Methods: We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital., Results: We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020. All patients received at least standard doses thromboprophylaxis. The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%). PE was the most frequent thrombotic complication (n = 25, 81%). Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic complications., Conclusion: The 31% incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high. Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence., Competing Interests: Disclosures Frederikus Klok reports research grants from Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi-Sankyo, MSD and Actelion, the Dutch Heart foundation and the Dutch Thrombosis association, all outside the submitted work. Menno Huisman reports grants from ZonMW Dutch Healthcare Fund, and grants and personal fees from Boehringer-Ingelheim, Pfizer-BMS, Bayer Health Care, Aspen, Daiichi-Sankyo, all outside the submitted work. Marieke Kruip reports unrestricted research grants from Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Pfizer, Sobi, and The Netherlands Organisation for Health Research and Development (ZonMW). The other authors having nothing to disclose., (Copyright © 2020. Published by Elsevier Ltd.)

Introduction: We recently reported a high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 admitted to the intensive care units (ICUs) of three Dutch hospitals. In answering questions raised regarding our study, we updated our database and repeated all analyses., Methods: We re-evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction and/or systemic arterial embolism in all COVID-19 patients admitted to the ICUs of 2 Dutch university hospitals and 1 Dutch teaching hospital from ICU admission to death, ICU discharge or April 22nd 2020, whichever came first., Results: We studied the same 184 ICU patients as reported on previously, of whom a total of 41 died (22%) and 78 were discharged alive (43%). The median follow-up duration increased from 7 to 14 days. All patients received pharmacological thromboprophylaxis. The cumulative incidence of the composite outcome, adjusted for competing risk of death, was 49% (95% confidence interval [CI] 41-57%). The majority of thrombotic events were PE (65/75; 87%). In the competing risk model, chronic anticoagulation therapy at admission was associated with a lower risk of the composite outcome (Hazard Ratio [HR] 0.29, 95%CI 0.091-0.92). Patients diagnosed with thrombotic complications were at higher risk of all-cause death (HR 5.4; 95%CI 2.4-12). Use of therapeutic anticoagulation was not associated with all-cause death (HR 0.79, 95%CI 0.35-1.8)., Conclusion: In this updated analysis, we confirm the very high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 pneumonia., Competing Interests: Declaration of competing interest Frederikus Klok reports research grants from Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi-Sankyo, MSD and Actelion, the Dutch Heart foundation and the Dutch Thrombosis association, all outside the submitted work. Menno Huisman reports grants from ZonMW Dutch Healthcare Fund, and grants and personal fees from Boehringer-Ingelheim, Pfizer-BMS, Bayer Health Care, Aspen, Daiichi-Sankyo, all outside the submitted work. Marieke Kruip reports unrestricted research grants from Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Pfizer, Sobi, and The Netherlands Organisation for Health Research and Development (ZonMW). The other authors having nothing to disclose., (Copyright © 2020. Published by Elsevier Ltd.)

Introduction: The recently developed protoporphyrin IX-triple state lifetime technique measures mitochondrial oxygenation tension (mitoPO 2 ) in vivo at the bedside. MitoPO 2 might be an early indicator of oxygen disbalance in cells of critically ill patients and therefore may support clinical decisions regarding red blood cell (RBC) transfusion. We aim to investigate the effect of RBC transfusion and the associated changes in haemoglobin concentration on mitoPO 2 and other physiological measures of tissue oxygenation and oxygen balance in critically ill patients with anaemia. We present the protocol and pilot results for this study., Methods and Analysis: We perform a prospective multicentre observational study in three mixed intensive care units in the Netherlands with critically ill patients with anaemia in whom an RBC transfusion is planned. The skin of the anterior chest wall of the patients is primed with a 5-aminolevulinic acid patch for 4 hours for induction of mitochondrial protoporphyrin-IX to enable measurements of mitoPO 2 , which is done with the COMET monitoring device. At multiple predefined moments, before and after RBC transfusion, we assess mitoPO 2 and other physiological parameters of oxygen balance and tissue oxygenation. Descriptive statistics will be used to describe the data. A linear mixed-effect model will be used to study the association between RBC transfusion and mitoPO 2 and other traditional parameters of oxygenation, oxygen delivery and oxygen balance. Missing data will be imputed using multiple imputation methods., Ethics and Dissemination: The institutional ethics committee of each participating centre approved the study (reference P16.303), which will be conducted according to the 1964 Helsinki declaration and its later amendments. The results will be submitted for publication in peer-reviewed journals and presented at scientific conferences., Trial Registration Number: NCT03092297., Competing Interests: Competing interests: EGM is founder and shareholder of Photonics Healthcare B.V. (Utrecht, The Netherlands). Photonics Healthcare develops and commercialises the COMET measuring system for mitochondrial oxygen measurements. The other authors have no conflicts of interest to declare., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Corticosteroids are often administered prophylactically to attenuate the inflammatory response associated with cardiac surgery using cardiopulmonary bypass (CPB). However, the efficacy and safety profile of corticosteroids remain uncertain. The primary aim of this systematic review and meta-analysis was to investigate the effect of corticosteroids on mortality in adult cardiac surgery using CPB. Secondary aims were to examine the effect of corticosteroids on myocardial adverse events, pulmonary adverse events, atrial fibrillation, surgical site infection, gastrointestinal bleeding and duration of stay in the intensive care unit and hospital. Randomized controlled trials (RCTs) were systematically searched in electronic databases (MEDLINE, EMBASE, CINAHL, CENTRAL and Web of Science) from their inception until March 2019. Observational studies, case reports, case series and literature reviews were excluded. Sixty-two studies (n = 16 457 patients) were included in this meta-analysis. There was no significant difference in mortality between the corticosteroid and placebo groups [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.81-1.14; P = 0.65, participants = 14 693, studies = 24, evidence of certainty: moderate]. Compared to those receiving a placebo, patients who were given corticosteroids had a significantly higher incidence of myocardial adverse events (OR 1.17, 95% CI 1.03-1.33; P = 0.01, participants = 14 512, studies = 23) and a lower incidence of pulmonary adverse events (OR 0.86, 95% CI 0.75-0.98; P = 0.02, participants = 13 426, studies = 17). The incidences of atrial fibrillation (OR 0.87, 95% CI 0.81-0.94; P < 0.001, participants = 14 148, studies = 24) and surgical site infection (OR 0.81, 95% CI 0.73-0.90; P < 0.001, participants = 13 946; studies = 22) were all lower in patients who were given corticosteroids. In the present meta-analysis of 62 RCTs (16 457 patients), including the 2 major RCTs (SIRS and DECS trials: 12 001 patients), we found that prophylactic corticosteroids in cardiac surgery did not reduce mortality. The clinical significance of an increase in myocardial adverse events remains unclear as the definition of a relevant myocardial end point following cardiac surgery varied greatly between RCTs., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

We investigated the added predictive value of lactate and lactate clearance to the Acute Physiology and Chronic Health Evaluation IV model for predicting in-hospital mortality in critically ill patients with sepsis., Design: Retrospective observational cohort study., Setting: Mixed ICU of Leiden University Medical Center, The Netherlands., Patients: Critically ill patients adult patients with sepsis who have been admitted to the ICU of Leiden University Medical Center, The Netherlands, from 2006 to January 2018., Interventions: None., Measurements and Main Results: We fitted a baseline model with the Acute Physiology and Chronic Health Evaluation IV predictors and added 13 prespecified combinations of lactate and lactate clearance at 0, 6 and 24 hours after admission to create a set of extended models to compare with the baseline Acute Physiology and Chronic Health Evaluation IV model. Among 603 ICU admissions, 451 patients met the inclusion criteria. A total of 160 patients died in-hospital, of which 106 died in the ICU. Their lactate and lactate clearance measurements were higher at all time points than those of survivors. The Akaike Information Criterion score improved in 10 of 13 prespecified extended models, with best performance for models that included lactate at 24 hours, alone or in combination with lactate at admission or lactate clearance at 24 hours. We compared the observed and predicted probabilities of in-hospital mortality of the baseline Acute Physiology and Chronic Health Evaluation IV model with the best model in our data, lactate at 24 hours added to the Acute Physiology and Chronic Health Evaluation IV model. This resulted in an increase in specificity of 29.9% (95% CI, 18.9-40.9%)., Conclusions: Lactate measurements at 24 hours after admission add predictive value to the prediction of mortality with Acute Physiology and Chronic Health Evaluation IV among ICU patients with sepsis. External validation is needed to develop extended prediction models., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Purpose: Unclear recommendations in transfusion guidelines may possibly lead to inconsistency in treatment of patients admitted to the intensive care unit. This study aimed to uncover variation in red blood cell (RBC) transfusion decisions in the ICU worldwide., Methods: Members of the European Society of Intensive Care Medicine (ESICM) were requested to complete an online questionnaire which included four different hypothetical clinical scenarios. The scenarios represented patients with acute myocardial infarction (AMI), abdominal sepsis, traumatic brain injury (TBI) and post-surgical complications. Hemoglobin level was 7∙3 g/dL in all scenarios. The questionnaire explored the physicians' transfusion decision in each clinical scenario and identified patient characteristics that were most influential in the transfusion decision., Results: In total 211 members participated in the study, of whom 142 (67%) completed the entire survey. Most variation was observed in the clinical scenario of sepsis, in which 49% decided to transfuse and 51% decided not to. In the clinical scenarios of AMI, TBI and post-surgical complications this was respectively; 75/25%, 35/65% and 66/34%., Conclusions: Critical care physicians differed in outcome of RBC transfusion decisions and weighed patient characteristics differently. These findings indicate that variation in transfusion practice amongst critical care physicians exists., (Copyright © 2019 Elsevier Inc. All rights reserved.)