Search

Importance: Typical cysteine-altering NOTCH3 (NOTCH3cys) variants are highly prevalent (approximately 1 in 300 individuals) and are associated with a broad spectrum of small vessel disease (SVD), ranging from early-onset stroke and dementia (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) to nonpenetrance. A staging system that captures the full NOTCH3-SVD severity spectrum is needed and currently lacking., Objective: To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3-SVD severity spectrum., Design, Setting, and Participants: A cohort study was performed in which the NOTCH3-SVD severity staging system was developed using a discovery cohort (2019-2020) and validated in independent international CADASIL cohorts (1999-2023) and the UK Biobank. Clinical and imaging data were collected from participants originating from 23 international CADASIL cohorts and from the UK Biobank. Eligibility criteria were presence of a NOTCH3cys variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3cys-positive cases from families with CADASIL; the validation set included 1713 NOTCH3cys-positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3cys-positive individuals. Data from 2-year (2019-2023) and 18-year (1999-2017) follow-up studies were also analyzed. Data analysis was performed from July 2023 to August 2024., Main Outcomes and Measures: Percentage of cases following the sequence of events of the NOTCH3-SVD stages, and the association between the stages and ischemic stroke, intracerebral hemorrhage, global cognition, processing speed, brain volume, brain microstructural damage, and serum neurofilament light chain (NfL) level., Results: The NOTCH3-SVD staging system encompasses 9 disease stages or substages, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Of all 1908 cases, which included 195 in the discovery cohort (mean [SD] age, 52.4 [12.2] years) and 1713 in the validation cohorts (mean [SD] age, 53.1 [13.0] years), 1789 (94%) followed the sequence of events defined by the NOTCH3-SVD staging system. The NOTCH3-SVD stages were associated with neuroimaging outcomes in the NOTCH3cys-positive cases in the CADASIL cohorts and in the UK Biobank and with cognitive outcomes and serum NfL level in cases from the CADASIL cohorts. The NOTCH3-SVD staging system captured disease progression and was associated with 18-year survival., Conclusions and Relevance: The NOTCH3-SVD staging system captures the full disease spectrum, from asymptomatic individuals with a NOTCH3cys variant to patients with end-stage disease. The NOTCH3-SVD staging system is a simple but effective tool for uniform disease staging in the clinic and in research.

Background: For mechanically ventilated critically ill COVID-19 patients, prone positioning has quickly become an important treatment strategy, however, prone positioning is labor intensive and comes with potential adverse effects. Therefore, identifying which critically ill intubated COVID-19 patients will benefit may help allocate labor resources., Methods: From the multi-center Dutch Data Warehouse of COVID-19 ICU patients from 25 hospitals, we selected all 3619 episodes of prone positioning in 1142 invasively mechanically ventilated patients. We excluded episodes longer than 24 h. Berlin ARDS criteria were not formally documented. We used supervised machine learning algorithms Logistic Regression, Random Forest, Naive Bayes, K-Nearest Neighbors, Support Vector Machine and Extreme Gradient Boosting on readily available and clinically relevant features to predict success of prone positioning after 4 h (window of 1 to 7 h) based on various possible outcomes. These outcomes were defined as improvements of at least 10% in PaO 2 /FiO 2 ratio, ventilatory ratio, respiratory system compliance, or mechanical power. Separate models were created for each of these outcomes. Re-supination within 4 h after pronation was labeled as failure. We also developed models using a 20 mmHg improvement cut-off for PaO 2 /FiO 2 ratio and using a combined outcome parameter. For all models, we evaluated feature importance expressed as contribution to predictive performance based on their relative ranking., Results: The median duration of prone episodes was 17 h (11-20, median and IQR, N = 2632). Despite extensive modeling using a plethora of machine learning techniques and a large number of potentially clinically relevant features, discrimination between responders and non-responders remained poor with an area under the receiver operator characteristic curve of 0.62 for PaO 2 /FiO 2 ratio using Logistic Regression, Random Forest and XGBoost. Feature importance was inconsistent between models for different outcomes. Notably, not even being a previous responder to prone positioning, or PEEP-levels before prone positioning, provided any meaningful contribution to predicting a successful next proning episode., Conclusions: In mechanically ventilated COVID-19 patients, predicting the success of prone positioning using clinically relevant and readily available parameters from electronic health records is currently not feasible. Given the current evidence base, a liberal approach to proning in all patients with severe COVID-19 ARDS is therefore justified and in particular regardless of previous results of proning., (© 2022. The Author(s).)

Background: The prediction of in-hospital mortality for ICU patients with COVID-19 is fundamental to treatment and resource allocation. The main purpose was to develop an easily implemented score for such prediction., Methods: This was an observational, multicenter, development, and validation study on a national critical care dataset of COVID-19 patients. A systematic literature review was performed to determine variables possibly important for COVID-19 mortality prediction. Using a logistic multivariable model with a LASSO penalty, we developed the Rapid Evaluation of Coronavirus Illness Severity (RECOILS) score and compared its performance against published scores., Results: Our development (validation) cohort consisted of 1480 (937) adult patients from 14 (11) Dutch ICUs admitted between March 2020 and April 2021. Median age was 65 (65) years, 31% (26%) died in hospital, 74% (72%) were males, average length of ICU stay was 7.83 (10.25) days and average length of hospital stay was 15.90 (19.92) days. Age, platelets, PaO2/FiO2 ratio, pH, blood urea nitrogen, temperature, PaCO2, Glasgow Coma Scale (GCS) score measured within +/-24 h of ICU admission were used to develop the score. The AUROC of RECOILS score was 0.75 (CI 0.71-0.78) which was higher than that of any previously reported predictive scores (0.68 [CI 0.64-0.71], 0.61 [CI 0.58-0.66], 0.67 [CI 0.63-0.70], 0.70 [CI 0.67-0.74] for ISARIC 4C Mortality Score, SOFA, SAPS-III, and age, respectively)., Conclusions: Using a large dataset from multiple Dutch ICUs, we developed a predictive score for mortality of COVID-19 patients admitted to ICU, which outperformed other predictive scores reported so far., (© 2021 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Introduction: Determining the optimal timing for extubation can be challenging in the intensive care. In this study, we aim to identify predictors for extubation failure in critically ill patients with COVID-19., Methods: We used highly granular data from 3464 adult critically ill COVID patients in the multicenter Dutch Data Warehouse, including demographics, clinical observations, medications, fluid balance, laboratory values, vital signs, and data from life support devices. All intubated patients with at least one extubation attempt were eligible for analysis. Transferred patients, patients admitted for less than 24 h, and patients still admitted at the time of data extraction were excluded. Potential predictors were selected by a team of intensive care physicians. The primary and secondary outcomes were extubation without reintubation or death within the next 7 days and within 48 h, respectively. We trained and validated multiple machine learning algorithms using fivefold nested cross-validation. Predictor importance was estimated using Shapley additive explanations, while cutoff values for the relative probability of failed extubation were estimated through partial dependence plots., Results: A total of 883 patients were included in the model derivation. The reintubation rate was 13.4% within 48 h and 18.9% at day 7, with a mortality rate of 0.6% and 1.0% respectively. The grandient-boost model performed best (area under the curve of 0.70) and was used to calculate predictor importance. Ventilatory characteristics and settings were the most important predictors. More specifically, a controlled mode duration longer than 4 days, a last fraction of inspired oxygen higher than 35%, a mean tidal volume per kg ideal body weight above 8 ml/kg in the day before extubation, and a shorter duration in assisted mode (< 2 days) compared to their median values. Additionally, a higher C-reactive protein and leukocyte count, a lower thrombocyte count, a lower Glasgow coma scale and a lower body mass index compared to their medians were associated with extubation failure., Conclusion: The most important predictors for extubation failure in critically ill COVID-19 patients include ventilatory settings, inflammatory parameters, neurological status, and body mass index. These predictors should therefore be routinely captured in electronic health records., (© 2021. The Author(s).)

Background: The Coronavirus disease 2019 (COVID-19) pandemic has underlined the urgent need for reliable, multicenter, and full-admission intensive care data to advance our understanding of the course of the disease and investigate potential treatment strategies. In this study, we present the Dutch Data Warehouse (DDW), the first multicenter electronic health record (EHR) database with full-admission data from critically ill COVID-19 patients., Methods: A nation-wide data sharing collaboration was launched at the beginning of the pandemic in March 2020. All hospitals in the Netherlands were asked to participate and share pseudonymized EHR data from adult critically ill COVID-19 patients. Data included patient demographics, clinical observations, administered medication, laboratory determinations, and data from vital sign monitors and life support devices. Data sharing agreements were signed with participating hospitals before any data transfers took place. Data were extracted from the local EHRs with prespecified queries and combined into a staging dataset through an extract-transform-load (ETL) pipeline. In the consecutive processing pipeline, data were mapped to a common concept vocabulary and enriched with derived concepts. Data validation was a continuous process throughout the project. All participating hospitals have access to the DDW. Within legal and ethical boundaries, data are available to clinicians and researchers., Results: Out of the 81 intensive care units in the Netherlands, 66 participated in the collaboration, 47 have signed the data sharing agreement, and 35 have shared their data. Data from 25 hospitals have passed through the ETL and processing pipeline. Currently, 3464 patients are included in the DDW, both from wave 1 and wave 2 in the Netherlands. More than 200 million clinical data points are available. Overall ICU mortality was 24.4%. Respiratory and hemodynamic parameters were most frequently measured throughout a patient's stay. For each patient, all administered medication and their daily fluid balance were available. Missing data are reported for each descriptive., Conclusions: In this study, we show that EHR data from critically ill COVID-19 patients may be lawfully collected and can be combined into a data warehouse. These initiatives are indispensable to advance medical data science in the field of intensive care medicine., (© 2021. The Author(s).)

Background: The identification of risk factors for adverse outcomes and prolonged intensive care unit (ICU) stay in COVID-19 patients is essential for prognostication, determining treatment intensity, and resource allocation. Previous studies have determined risk factors on admission only, and included a limited number of predictors. Therefore, using data from the highly granular and multicenter Dutch Data Warehouse, we developed machine learning models to identify risk factors for ICU mortality, ventilator-free days and ICU-free days during the course of invasive mechanical ventilation (IMV) in COVID-19 patients., Methods: The DDW is a growing electronic health record database of critically ill COVID-19 patients in the Netherlands. All adult ICU patients on IMV were eligible for inclusion. Transfers, patients admitted for less than 24 h, and patients still admitted at time of data extraction were excluded. Predictors were selected based on the literature, and included medication dosage and fluid balance. Multiple algorithms were trained and validated on up to three sets of observations per patient on day 1, 7, and 14 using fivefold nested cross-validation, keeping observations from an individual patient in the same split., Results: A total of 1152 patients were included in the model. XGBoost models performed best for all outcomes and were used to calculate predictor importance. Using Shapley additive explanations (SHAP), age was the most important demographic risk factor for the outcomes upon start of IMV and throughout its course. The relative probability of death across age values is visualized in Partial Dependence Plots (PDPs), with an increase starting at 54 years. Besides age, acidaemia, low P/F-ratios and high driving pressures demonstrated a higher probability of death. The PDP for driving pressure showed a relative probability increase starting at 12 cmH 2 O., Conclusion: Age is the most important demographic risk factor of ICU mortality, ICU-free days and ventilator-free days throughout the course of invasive mechanical ventilation in critically ill COVID-19 patients. pH, P/F ratio, and driving pressure should be monitored closely over the course of mechanical ventilation as risk factors predictive of these outcomes.