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Motivation: Acute kidney injury (AKI) is a syndrome that affects a large fraction of all critically ill patients, and early diagnosis to receive adequate treatment is as imperative as it is challenging to make early. Consequently, machine learning approaches have been developed to predict AKI ahead of time. However, the prevalence of AKI is often underestimated in state-of-the-art approaches, as they rely on an AKI event annotation solely based on creatinine, ignoring urine output., We construct and evaluate early warning systems for AKI in a multi-disciplinary ICU setting, using the complete KDIGO definition of AKI. We propose several variants of gradient-boosted decision tree (GBDT)-based models, including a novel time-stacking based approach. A state-of-the-art LSTM-based model previously proposed for AKI prediction is used as a comparison, which was not specifically evaluated in ICU settings yet., Results: We find that optimal performance is achieved by using GBDT with the time-based stacking technique (AUPRC = 65.7%, compared with the LSTM-based model's AUPRC = 62.6%), which is motivated by the high relevance of time since ICU admission for this task. Both models show mildly reduced performance in the limited training data setting, perform fairly across different subcohorts, and exhibit no issues in gender transfer., Following the official KDIGO definition substantially increases the number of annotated AKI events. In our study GBDTs outperform LSTM models for AKI prediction. Generally, we find that both model types are robust in a variety of challenging settings arising for ICU data., Availability and Implementation: The code to reproduce the findings of our manuscript can be found at: https://github.com/ratschlab/AKI-EWS., (© The Author(s) 2024. Published by Oxford University Press.)

Objective: Fluid bolus therapy (FBT) is ubiquitous in intensive care units (ICUs) after cardiac surgery. However, its physiological effects remain unclear., Design: : We performed an electronic health record-based quasi-experimental ICU study after cardiac surgery. We applied propensity score matching and compared the physiological changes after FBT episodes to matched control episodes where despite equivalent physiology no fluid bolus was given., Setting: The study was conducted in a multidisciplinary ICU of a tertiary-level academic hospital., Participants: The study included 2,736 patients who underwent Coronary Artery Bypass Grafting and/or heart valve surgery., Main Outcome Measures: Changes in cardiac output (CO) and mean arterial pressure (MAP) during the 60 minutes following FBT., Results: We analysed 3572 matched fluid bolus (FB) episodes. After FBT, but not in control episodes, CO increased within 10 min, with a maximum increase of 0.2 l/min (95%CI 0.1 to 0.2) or 4% above baseline at 40 min (p < 0.0001 vs. controls). CO increased by > 10% from baseline in 60.6% of FBT and 49.1% of control episodes (p < 0.0001). MAP increased by > 10% in 51.7% of FB episodes compared to 53.4% of controls. Finally, FBT was not associated with changes in acid-base status or oxygen delivery., Conclusion: In this quasi-experimental comparative ICU study in cardiac surgery patients, FBT was associated with statistically significant but numerically small increases in CO. Nearly half of FBT failed to induce a positive CO or MAP response., 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., (© 2023 The Authors.)

Sharing healthcare data is increasingly essential for developing data-driven improvements in patient care at the Intensive Care Unit (ICU). However, it is also very challenging under the strict privacy legislation of the European Union (EU). Therefore, we explored four successful open ICU healthcare databases to determine how open healthcare data can be shared appropriately in the EU. A questionnaire was constructed based on the Delphi method. Then, follow-up questions were discussed with experts from the four databases. These experts encountered similar challenges and regarded ethical and legal aspects to be the most challenging. Based on the approaches of the databases, expert opinion, and literature research, we outline four distinct approaches to openly sharing healthcare data, each with varying implications regarding data security, ease of use, sustainability, and implementability. Ultimately, we formulate seven recommendations for sharing open healthcare data to guide future initiatives in sharing open healthcare data to improve patient care and advance healthcare., (© 2023. The Author(s).)

Objective: As data science and artificial intelligence continue to rapidly gain traction, the publication of freely available ICU datasets has become invaluable to propel data-driven clinical research. In this guide for clinicians and researchers, we aim to: 1) systematically search and identify all publicly available adult clinical ICU datasets, 2) compare their characteristics, data quality, and richness and critically appraise their strengths and weaknesses, and 3) provide researchers with suggestions, which datasets are appropriate for answering their clinical question., Data Sources: A systematic search was performed in Pubmed, ArXiv, MedRxiv, and BioRxiv., Study Selection: We selected all studies that reported on publicly available adult patient-level intensive care datasets., Data Extraction: A total of four publicly available, adult, critical care, patient-level databases were included (Amsterdam University Medical Center data base [AmsterdamUMCdb], eICU Collaborative Research Database eICU CRD], High time-resolution intensive care unit dataset [HiRID], and Medical Information Mart for Intensive Care-IV). Databases were compared using a priori defined categories, including demographics, patient characteristics, and data richness. The study protocol and search strategy were prospectively registered., Data Synthesis: Four ICU databases fulfilled all criteria for inclusion and were queried using SQL (PostgreSQL version 12; PostgreSQL Global Development Group) and analyzed using R (R Foundation for Statistical Computing, Vienna, Austria). The number of unique patient admissions varied between 23,106 (AmsterdamUMCdb) and 200,859 (eICU-CRD). Frequency of laboratory values and vital signs was highest in HiRID, for example, 5.2 (±3.4) lactate values per day and 29.7 (±10.2) systolic blood pressure values per hour. Treatment intensity varied with vasopressor and ventilatory support in 69.0% and 83.0% of patients in AmsterdamUMCdb versus 12.0% and 21.0% in eICU-CRD, respectively. ICU mortality ranged from 5.5% in eICU-CRD to 9.9% in AmsterdamUMCdb., Conclusions: We identified four publicly available adult clinical ICU datasets. Sample size, severity of illness, treatment intensity, and frequency of reported parameters differ markedly between the databases. This should guide clinicians and researchers which databases to best answer their clinical questions., Competing Interests: Dr. Dam received funding from AmsterdamUMC and the Netherlands Organization for Health Research and Development (project number 10430012010003). Dr. Celi received support for article research from the National Institutes of Health. Dr. Faltys received funding from the Swiss National Fund. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

In the CNS, amino acid (AA) neurotransmitters and neurotransmitter precursors are subject to tight homeostatic control mediated by blood-brain barrier (BBB) solute carrier amino acid transporters (AATs). Since the BBB is composed of multiple closely apposed cell types and opportunities for human in vivo studies are limited, we used in vitro and computational approaches to investigate human BBB AAT activity and regulation. Quantitative real-time PCR (qPCR) of the human BBB endothelial cell model hCMEC/D3 (D3) was used to determine expression of selected AAT, tight junction (TJ), and signal transduction (ST) genes under various culture conditions. L-leucine uptake data were interrogated with a computational model developed by our group for calculating AAT activity in complex cell cultures. This approach is potentially applicable to in vitro cell culture drug studies where multiple "receptors" may mediate observed responses. Of 7 Leu AAT genes expressed by D3 only the activity of SLC7A5-SLC3A2/LAT1-4F2HC (LAT1), SLC43A2/LAT4 (LAT4) and sodium-dependent AATs, SLC6A15/B 0 AT2 (B 0 AT2), and SLC7A7/y + LAT1 (y + LAT1) were calculated to be required for Leu uptake. Therefore, D3 Leu transport may be mediated by a potentially physiologically relevant functional cooperation between the known BBB AAT, LAT1 and obligatory exchange (y + LAT1), facilitative diffusion (LAT4), and sodium symporter (B 0 AT2) transporters.

Ventilator-associated pneumonia (VAP) is a frequent complication of mechanical ventilation and is associated with substantial morbidity and mortality. Accurate diagnosis of VAP relies in part on subjective diagnostic criteria. Surveillance according to ventilator-associated event (VAE) criteria may allow quick and objective benchmarking. Our objective was to create an automated surveillance tool for VAE tiers I and II on a large data collection, evaluate its diagnostic accuracy and retrospectively determine the yearly baseline VAE incidence. We included all consecutive intensive care unit admissions of patients with mechanical ventilation at Bern University Hospital, a tertiary referral center, from January 2008 to July 2016. Data was automatically extracted from the patient data management system and automatically processed. We created and implemented an application able to automatically analyze respiratory and relevant medication data according to the Centers for Disease Control protocol for VAE-surveillance. In a subset of patients, we compared the accuracy of automated VAE surveillance according to CDC criteria to a gold standard (a composite of automated and manual evaluation with mediation for discrepancies) and evaluated the evolution of the baseline incidence. The study included 22'442 ventilated admissions with a total of 37'221 ventilator days. 592 ventilator-associated events (tier I) occurred; of these 194 (34%) were of potentially infectious origin (tier II). In our validation sample, automated surveillance had a sensitivity of 98% and specificity of 100% in detecting VAE compared to the gold standard. The yearly VAE incidence rate ranged from 10.1-22.1 per 1000 device days and trend showed a decrease in the yearly incidence rate ratio of 0.96 (95% CI, 0.93-1.00, p = 0.03). This study demonstrated that automated VAE detection is feasible, accurate and reliable and may be applied on a large, retrospective sample and provided insight into long-term institutional VAE incidences. The surveillance tool can be extended to other centres and provides VAE incidences for performing quality control and intervention studies., (© 2021. The Author(s).)

Intensive-care clinicians are presented with large quantities of measurements from multiple monitoring systems. The limited ability of humans to process complex information hinders early recognition of patient deterioration, and high numbers of monitoring alarms lead to alarm fatigue. We used machine learning to develop an early-warning system that integrates measurements from multiple organ systems using a high-resolution database with 240 patient-years of data. It predicts 90% of circulatory-failure events in the test set, with 82% identified more than 2 h in advance, resulting in an area under the receiver operating characteristic curve of 0.94 and an area under the precision-recall curve of 0.63. On average, the system raises 0.05 alarms per patient and hour. The model was externally validated in an independent patient cohort. Our model provides early identification of patients at risk for circulatory failure with a much lower false-alarm rate than conventional threshold-based systems.

Treating diseases nonpharmacologically, using targeted neurostimulation instead of systemic drugs, is a hallmark of the burgeoning field of bioelectronic medicine. In this review, we provide a brief overview of the discovery and function of the prototypical neuroimmune reflex, the "inflammatory reflex." We discuss various biomarkers developed and used to translate early physiological discoveries into dosing parameters used in experimental settings, from the treatment of animal models of disease through a proof-of-concept clinical study in rheumatoid arthritis (RA). Finally, we relate how unique aspects of this form of therapy enabled the design of a next-generation implanted pulse generator using integrated electrodes, currently under evaluation in a U.S.-based clinical study for patients with drug refractory RA., (Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved.)

Macrophage cytokine production is regulated by neural signals, for example in the inflammatory reflex. Signals in the vagus and splenic nerves are relayed by choline acetyltransferase + T cells that release acetylcholine, the cognate ligand for alpha7 nicotinic acetylcholine subunit-containing receptors (α7nAChR), and suppress TNF release in macrophages. Here, we observed that electrical vagus nerve stimulation with a duration of 0.1-60 s significantly reduced systemic TNF release in experimental endotoxemia. This suppression of TNF was sustained for more than 24 h, but abolished in mice deficient in the α7nAChR subunit. Exposure of primary human macrophages and murine RAW 264.7 macrophage-like cells to selective ligands for α7nAChR for 1 h in vitro attenuated TNF production for up to 24 h in response to endotoxin. Pharmacological inhibition of adenylyl cyclase (AC) and knockdown of adenylyl cyclase 6 (AC6) or c-FOS abolished cholinergic suppression of endotoxin-induced TNF release. These findings indicate that action potentials in the inflammatory reflex trigger a change in macrophage behavior that requires AC and phosphorylation of the cAMP response element binding protein (CREB). These observations further our mechanistic understanding of neural regulation of inflammation and may have implications for development of bioelectronic medicine treatment of inflammatory diseases.

New dosing paradigms in bioelectronic medicine applications, such as low duty cycle stimulation of the vagus nerve to treat inflammatory disorders, enable architectural shifts in active implantable devices that benefit patients. Herein, we describe various features of the MicroRegulator (MR), an innovative neurostimulation system that includes a unique electrode-integrated implantable nerve stimulator. To verify efficient activation of neuronal targets within the vagus nerve, a geometric emulator of the MR (identical form and electrical contact properties as the clinical MR device) was tested in situ and neurophysiologic outcomes were compared to a control electrode in wide clinical use. The data demonstrated comparable patterns of compound potentials evoked from the MR emulator and the control electrode, with the MR emulator requiring a lower threshold current to depolarize the nerve. To verify chronic mechanical safety, the MR emulator was implanted for 2 months on the vagus nerves of canines. Blood flow through the major cervical vessels was unaffected, and pathologic and histologic findings included normal foreign body encapsulation and an absence of demyelination and nerve damage. Together these finding support the feasibility of the MR system for clinical translation.

Rheumatoid arthritis (RA) is a heterogeneous, prevalent, chronic autoimmune disease characterized by painful swollen joints and significant disabilities. Symptomatic relief can be achieved in up to 50% of patients using biological agents that inhibit tumor necrosis factor (TNF) or other mechanisms of action, but there are no universally effective therapies. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in animal models. One well-characterized cytokine-inhibiting mechanism, termed the "inflammatory reflex," is dependent upon vagus nerve signals that inhibit cytokine production and attenuate experimental arthritis severity in mice and rats. It previously was unknown whether directly stimulating the inflammatory reflex in humans inhibits TNF production. Here we show that an implantable vagus nerve-stimulating device in epilepsy patients inhibits peripheral blood production of TNF, IL-1β, and IL-6. Vagus nerve stimulation (up to four times daily) in RA patients significantly inhibited TNF production for up to 84 d. Moreover, RA disease severity, as measured by standardized clinical composite scores, improved significantly. Together, these results establish that vagus nerve stimulation targeting the inflammatory reflex modulates TNF production and reduces inflammation in humans. These findings suggest that it is possible to use mechanism-based neuromodulating devices in the experimental therapy of RA and possibly other autoimmune and autoinflammatory diseases.

Introduction: The inflammatory reflex is a physiological mechanism through which the nervous system maintains immunologic homeostasis by modulating innate and adaptive immunity. We postulated that the reflex might be harnessed therapeutically to reduce pathological levels of inflammation in rheumatoid arthritis by activating its prototypical efferent arm, termed the cholinergic anti-inflammatory pathway. To explore this, we determined whether electrical neurostimulation of the cholinergic anti-inflammatory pathway reduced disease severity in the collagen-induced arthritis model., Methods: Rats implanted with vagus nerve cuff electrodes had collagen-induced arthritis induced and were followed for 15 days. Animals underwent active or sham electrical stimulation once daily from day 9 through the conclusion of the study. Joint swelling, histology, and levels of cytokines and bone metabolism mediators were assessed., Results: Compared with sham treatment, active neurostimulation of the cholinergic anti-inflammatory pathway resulted in a 52% reduction in ankle diameter (p = 0.02), a 57% reduction in ankle diameter (area under curve; p = 0.02) and 46% reduction overall histological arthritis score (p = 0.01) with significant improvements in inflammation, pannus formation, cartilage destruction, and bone erosion (p = 0.02), accompanied by numerical reductions in systemic cytokine levels, not reaching statistical significance. Bone erosion improvement was associated with a decrease in serum levels of receptor activator of NF-κB ligand (RANKL) from 132±13 to 6±2 pg/mL (mean±SEM, p = 0.01)., Conclusions: The severity of collagen-induced arthritis is reduced by neurostimulation of the cholinergic anti-inflammatory pathway delivered using an implanted electrical vagus nerve stimulation cuff electrode, and supports the rationale for testing this approach in human inflammatory disorders.