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  1. Article ; Online: Evolution of Clinical Phenotypes of COVID-19 Patients During Intensive Care Treatment: An Unsupervised Machine Learning Analysis.

    Siepel, Sander / Dam, Tariq A / Fleuren, Lucas M / Girbes, Armand R J / Hoogendoorn, Mark / Thoral, Patrick J / Elbers, Paul W G / Bennis, Frank C

    Journal of intensive care medicine

    2023  Volume 38, Issue 7, Page(s) 612–629

    Abstract: Background: Identification of clinical phenotypes in critically ill COVID-19 patients could improve understanding of the disease heterogeneity and enable prognostic and predictive enrichment. However, previous attempts did not take into account temporal ...

    Abstract Background: Identification of clinical phenotypes in critically ill COVID-19 patients could improve understanding of the disease heterogeneity and enable prognostic and predictive enrichment. However, previous attempts did not take into account temporal dynamics with high granularity. By including the dimension of time, we aim to gain further insights into the heterogeneity of COVID-19.
    Methods: We used granular data from 3202 adult COVID patients in the Dutch Data Warehouse that were admitted to one of 25 Dutch ICUs between February 2020 and March 2021. Parameters including demographics, clinical observations, medications, laboratory values, vital signs, and data from life support devices were selected. Twenty-one datasets were created that each covered 24 h of ICU data for each day of ICU treatment. Clinical phenotypes in each dataset were identified by performing cluster analyses. Both evolution of the clinical phenotypes over time and patient allocation to these clusters over time were tracked.
    Results: The final patient cohort consisted of 2438 COVID-19 patients with a ICU mortality outcome. Forty-one parameters were chosen for cluster analysis. On admission, both a mild and a severe clinical phenotype were found. After day 4, the severe phenotype split into an intermediate and a severe phenotype for 11 consecutive days. Heterogeneity between phenotypes appears to be driven by inflammation and dead space ventilation. During the 21-day period, only 8.2% and 4.6% of patients in the initial mild and severe clusters remained assigned to the same phenotype respectively. The clinical phenotype half-life was between 5 and 6 days for the mild and severe phenotypes, and about 3 days for the medium severe phenotype.
    Conclusions: Patients typically do not remain in the same cluster throughout intensive care treatment. This may have important implications for prognostic or predictive enrichment. Prominent dissimilarities between clinical phenotypes are predominantly driven by inflammation and dead space ventilation.
    MeSH term(s) Humans ; COVID-19/therapy ; SARS-CoV-2 ; Unsupervised Machine Learning ; Critical Care ; Intensive Care Units ; Inflammation ; Phenotype ; Critical Illness/therapy
    Language English
    Publishing date 2023-02-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 632828-3
    ISSN 1525-1489 ; 0885-0666
    ISSN (online) 1525-1489
    ISSN 0885-0666
    DOI 10.1177/08850666231153393
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Determining and assessing characteristics of data element names impacting the performance of annotation using Usagi.

    de Groot, Rowdy / Püttmann, Daniel P / Fleuren, Lucas M / Thoral, Patrick J / Elbers, Paul W G / de Keizer, Nicolette F / Cornet, Ronald

    International journal of medical informatics

    2023  Volume 178, Page(s) 105200

    Abstract: Introduction: Hospitals generate large amounts of data and this data is generally modeled and labeled in a proprietary way, hampering its exchange and integration. Manually annotating data element names to internationally standardized data element ... ...

    Abstract Introduction: Hospitals generate large amounts of data and this data is generally modeled and labeled in a proprietary way, hampering its exchange and integration. Manually annotating data element names to internationally standardized data element identifiers is a time-consuming effort. Tools can support performing this task automatically. This study aimed to determine what factors influence the quality of automatic annotations.
    Methods: Data element names were used from the Dutch COVID-19 ICU Data Warehouse containing data on intensive care patients with COVID-19 from 25 hospitals in the Netherlands. In this data warehouse, the data had been merged using a proprietary terminology system while also storing the original hospital labels (synonymous names). Usagi, an OHDSI annotation tool, was used to perform the annotation for the data. A gold standard was used to determine if Usagi made correct annotations. Logistic regression was used to determine if the number of characters, number of words, match score (Usagi's certainty) and hospital label origin influenced Usagi's performance to annotate correctly.
    Results: Usagi automatically annotated 30.5% of the data element names correctly and 5.5% of the synonymous names. The match score is the best predictor for Usagi finding the correct annotation. It was determined that the AUC of data element names was 0.651 and 0.752 for the synonymous names respectively. The AUC for the individual hospital label origins varied between 0.460 to 0.905.
    Discussion: The results show that Usagi performed better to annotate the data element names than the synonymous names. The hospital origin in the synonymous names dataset was associated with the amount of correctly annotated concepts. Hospitals that performed better had shorter synonymous names and fewer words. Using shorter data element names or synonymous names should be considered to optimize the automatic annotating process. Overall, the performance of Usagi is too poor to completely rely on for automatic annotation.
    MeSH term(s) Humans ; COVID-19/epidemiology ; Netherlands
    Language English
    Publishing date 2023-08-29
    Publishing country Ireland
    Document type Journal Article
    ZDB-ID 1466296-6
    ISSN 1872-8243 ; 1386-5056
    ISSN (online) 1872-8243
    ISSN 1386-5056
    DOI 10.1016/j.ijmedinf.2023.105200
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Large-scale ICU data sharing for global collaboration: the first 1633 critically ill COVID-19 patients in the Dutch Data Warehouse.

    Fleuren, Lucas M / de Bruin, Daan P / Tonutti, Michele / Lalisang, Robbert C A / Elbers, Paul W G

    Intensive care medicine

    2021  Volume 47, Issue 4, Page(s) 478–481

    MeSH term(s) COVID-19 ; Critical Illness ; Data Warehousing ; Humans ; Information Dissemination ; Intensive Care Units ; Netherlands
    Language English
    Publishing date 2021-02-17
    Publishing country United States
    Document type Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 80387-x
    ISSN 1432-1238 ; 0340-0964 ; 0342-4642 ; 0935-1701
    ISSN (online) 1432-1238
    ISSN 0340-0964 ; 0342-4642 ; 0935-1701
    DOI 10.1007/s00134-021-06361-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Machine learning in intensive care medicine: ready for take-off?

    Fleuren, Lucas M / Thoral, Patrick / Shillan, Duncan / Ercole, Ari / Elbers, Paul W G

    Intensive care medicine

    2020  Volume 46, Issue 7, Page(s) 1486–1488

    MeSH term(s) Critical Care ; Humans ; Intensive Care Units ; Machine Learning ; Medicine
    Language English
    Publishing date 2020-05-12
    Publishing country United States
    Document type Letter
    ZDB-ID 80387-x
    ISSN 1432-1238 ; 0340-0964 ; 0342-4642 ; 0935-1701
    ISSN (online) 1432-1238
    ISSN 0340-0964 ; 0342-4642 ; 0935-1701
    DOI 10.1007/s00134-020-06045-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Augmented intelligence facilitates concept mapping across different electronic health records.

    Dam, Tariq A / Fleuren, Lucas M / Roggeveen, Luca F / Otten, Martijn / Biesheuvel, Laurens / Jagesar, Ameet R / Lalisang, Robbert C A / Kullberg, Robert F J / Hendriks, Tom / Girbes, Armand R J / Hoogendoorn, Mark / Thoral, Patrick J / Elbers, Paul W G

    International journal of medical informatics

    2023  Volume 179, Page(s) 105233

    Abstract: Introduction: With the advent of artificial intelligence, the secondary use of routinely collected medical data from electronic healthcare records (EHR) has become increasingly popular. However, different EHR systems typically use different names for ... ...

    Abstract Introduction: With the advent of artificial intelligence, the secondary use of routinely collected medical data from electronic healthcare records (EHR) has become increasingly popular. However, different EHR systems typically use different names for the same medical concepts. This obviously hampers scalable model development and subsequent clinical implementation for decision support. Therefore, converting original parameter names to a so-called ontology, a standardized set of predefined concepts, is necessary but time-consuming and labor-intensive. We therefore propose an augmented intelligence approach to facilitate ontology alignment by predicting correct concepts based on parameter names from raw electronic health record data exports.
    Methods: We used the manually mapped parameter names from the multicenter "Dutch ICU data warehouse against COVID-19" sourced from three types of EHR systems to train machine learning models for concept mapping. Data from 29 intensive care units on 38,824 parameters mapped to 1,679 relevant and unique concepts and 38,069 parameters labeled as irrelevant were used for model development and validation. We used the Natural Language Toolkit (NLTK) to preprocess the parameter names based on WordNet cognitive synonyms transformed by term-frequency inverse document frequency (TF-IDF), yielding numeric features. We then trained linear classifiers using stochastic gradient descent for multi-class prediction. Finally, we fine-tuned these predictions using information on distributions of the data associated with each parameter name through similarity score and skewness comparisons.
    Results: The initial model, trained using data from one hospital organization for each of three EHR systems, scored an overall top 1 precision of 0.744, recall of 0.771, and F1-score of 0.737 on a total of 58,804 parameters. Leave-one-hospital-out analysis returned an average top 1 recall of 0.680 for relevant parameters, which increased to 0.905 for the top 5 predictions. When reducing the training dataset to only include relevant parameters, top 1 recall was 0.811 and top 5 recall was 0.914 for relevant parameters. Performance improvement based on similarity score or skewness comparisons affected at most 5.23% of numeric parameters.
    Conclusion: Augmented intelligence is a promising method to improve concept mapping of parameter names from raw electronic health record data exports. We propose a robust method for mapping data across various domains, facilitating the integration of diverse data sources. However, recall is not perfect, and therefore manual validation of mapping remains essential.
    Language English
    Publishing date 2023-09-22
    Publishing country Ireland
    Document type Journal Article
    ZDB-ID 1466296-6
    ISSN 1872-8243 ; 1386-5056
    ISSN (online) 1872-8243
    ISSN 1386-5056
    DOI 10.1016/j.ijmedinf.2023.105233
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Book ; Online: Integrating Expert ODEs into Neural ODEs

    Qian, Zhaozhi / Zame, William R. / Fleuren, Lucas M. / Elbers, Paul / van der Schaar, Mihaela

    Pharmacology and Disease Progression

    2021  

    Abstract: Modeling a system's temporal behaviour in reaction to external stimuli is a fundamental problem in many areas. Pure Machine Learning (ML) approaches often fail in the small sample regime and cannot provide actionable insights beyond predictions. A ... ...

    Abstract Modeling a system's temporal behaviour in reaction to external stimuli is a fundamental problem in many areas. Pure Machine Learning (ML) approaches often fail in the small sample regime and cannot provide actionable insights beyond predictions. A promising modification has been to incorporate expert domain knowledge into ML models. The application we consider is predicting the progression of disease under medications, where a plethora of domain knowledge is available from pharmacology. Pharmacological models describe the dynamics of carefully-chosen medically meaningful variables in terms of systems of Ordinary Differential Equations (ODEs). However, these models only describe a limited collection of variables, and these variables are often not observable in clinical environments. To close this gap, we propose the latent hybridisation model (LHM) that integrates a system of expert-designed ODEs with machine-learned Neural ODEs to fully describe the dynamics of the system and to link the expert and latent variables to observable quantities. We evaluated LHM on synthetic data as well as real-world intensive care data of COVID-19 patients. LHM consistently outperforms previous works, especially when few training samples are available such as at the beginning of the pandemic.
    Keywords Computer Science - Machine Learning ; Statistics - Machine Learning
    Subject code 006
    Publishing date 2021-06-05
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Right dose, right now: bedside, real-time, data-driven, and personalised antibiotic dosing in critically ill patients with sepsis or septic shock-a two-centre randomised clinical trial.

    Roggeveen, Luca F / Guo, Tingjie / Fleuren, Lucas M / Driessen, Ronald / Thoral, Patrick / van Hest, Reinier M / Mathot, Ron A A / Swart, Eleonora L / de Grooth, Harm-Jan / van den Bogaard, Bas / Girbes, Armand R J / Bosman, Rob J / Elbers, Paul W G

    Critical care (London, England)

    2022  Volume 26, Issue 1, Page(s) 265

    Abstract: Background: Adequate antibiotic dosing may improve outcomes in critically ill patients but is challenging due to altered and variable pharmacokinetics. To address this challenge, AutoKinetics was developed, a decision support system for bedside, real- ... ...

    Abstract Background: Adequate antibiotic dosing may improve outcomes in critically ill patients but is challenging due to altered and variable pharmacokinetics. To address this challenge, AutoKinetics was developed, a decision support system for bedside, real-time, data-driven and personalised antibiotic dosing. This study evaluates the feasibility, safety and efficacy of its clinical implementation.
    Methods: In this two-centre randomised clinical trial, critically ill patients with sepsis or septic shock were randomised to AutoKinetics dosing or standard dosing for four antibiotics: vancomycin, ciprofloxacin, meropenem, and ceftriaxone. Adult patients with a confirmed or suspected infection and either lactate > 2 mmol/L or vasopressor requirement were eligible for inclusion. The primary outcome was pharmacokinetic target attainment in the first 24 h after randomisation. Clinical endpoints included mortality, ICU length of stay and incidence of acute kidney injury.
    Results: After inclusion of 252 patients, the study was stopped early due to the COVID-19 pandemic. In the ciprofloxacin intervention group, the primary outcome was obtained in 69% compared to 3% in the control group (OR 62.5, CI 11.4-1173.78, p < 0.001). Furthermore, target attainment was faster (26 h, CI 18-42 h, p < 0.001) and better (65% increase, CI 49-84%, p < 0.001). For the other antibiotics, AutoKinetics dosing did not improve target attainment. Clinical endpoints were not significantly different. Importantly, higher dosing did not lead to increased mortality or renal failure.
    Conclusions: In critically ill patients, personalised dosing was feasible, safe and significantly improved target attainment for ciprofloxacin.
    Trial registration: The trial was prospectively registered at Netherlands Trial Register (NTR), NL6501/NTR6689 on 25 August 2017 and at the European Clinical Trials Database (EudraCT), 2017-002478-37 on 6 November 2017.
    MeSH term(s) Adult ; Anti-Bacterial Agents ; COVID-19 ; Ciprofloxacin/therapeutic use ; Critical Illness/therapy ; Humans ; Pandemics ; Sepsis/drug therapy ; Shock, Septic/drug therapy
    Chemical Substances Anti-Bacterial Agents ; Ciprofloxacin (5E8K9I0O4U)
    Language English
    Publishing date 2022-09-05
    Publishing country England
    Document type Journal Article ; Randomized Controlled Trial
    ZDB-ID 2041406-7
    ISSN 1466-609X ; 1364-8535
    ISSN (online) 1466-609X
    ISSN 1364-8535
    DOI 10.1186/s13054-022-04098-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Why physiology will continue to guide the choice between balanced crystalloids and normal saline: a systematic review and meta-analysis.

    Zwager, Charlotte L / Tuinman, Pieter Roel / de Grooth, Harm-Jan / Kooter, Jos / Ket, Hans / Fleuren, Lucas M / Elbers, Paul W G

    Critical care (London, England)

    2019  Volume 23, Issue 1, Page(s) 366

    Abstract: Background: Crystalloids are the most frequently prescribed drugs in intensive care medicine and emergency medicine. Thus, even small differences in outcome may have major implications, and therefore, the choice between balanced crystalloids versus ... ...

    Abstract Background: Crystalloids are the most frequently prescribed drugs in intensive care medicine and emergency medicine. Thus, even small differences in outcome may have major implications, and therefore, the choice between balanced crystalloids versus normal saline continues to be debated. We examined to what extent the currently accrued information size from completed and ongoing trials on the subject allow intensivists and emergency physicians to choose the right fluid for their patients.
    Methods: Systematic review and meta-analysis with random effects inverse variance model. Published randomized controlled trials enrolling adult patients to compare balanced crystalloids versus normal saline in the setting of intensive care medicine or emergency medicine were included. The main outcome was mortality at the longest follow-up, and secondary outcomes were moderate to severe acute kidney injury (AKI) and initiation of renal replacement therapy (RRT). Trial sequential analyses (TSA) were performed, and risk of bias and overall quality of evidence were assessed. Additionally, previously published meta-analyses, trial sequential analyses and ongoing large trials were analysed for included studies, required information size calculations and the assumptions underlying those calculations.
    Results: Nine studies (n = 32,777) were included. Of those, eight had data available on mortality, seven on AKI and six on RRT. Meta-analysis showed no significant differences between balanced crystalloids versus normal saline for mortality (P = 0.33), the incidence of moderate to severe AKI (P = 0.37) or initiation of RRT (P = 0.29). Quality of evidence was low to very low. Analysis of previous meta-analyses and ongoing trials showed large differences in calculated required versus accrued information sizes and assumptions underlying those. TSA revealed the need for extremely large trials based on our realistic and clinically relevant assumptions on relative risk reduction and baseline mortality.
    Conclusions: Our meta-analysis could not find significant differences between balanced crystalloids and normal saline on mortality at the longest follow-up, moderate to severe AKI or new RRT. Currently accrued information size is smaller, and the required information size is larger than previously anticipated. Therefore, completed and ongoing trials on the topic may fail to provide adequate guidance for choosing the right crystalloid. Thus, physiology will continue to play an important role for individualizing this choice.
    MeSH term(s) Acute Kidney Injury/mortality ; Acute Kidney Injury/physiopathology ; Acute Kidney Injury/therapy ; Critical Care/methods ; Critical Care/standards ; Crystalloid Solutions/administration & dosage ; Crystalloid Solutions/adverse effects ; Humans ; Renal Replacement Therapy/mortality ; Renal Replacement Therapy/trends ; Saline Solution/administration & dosage ; Saline Solution/adverse effects
    Chemical Substances Crystalloid Solutions ; Saline Solution
    Language English
    Publishing date 2019-11-21
    Publishing country England
    Document type Journal Article ; Meta-Analysis ; Systematic Review
    ZDB-ID 2041406-7
    ISSN 1466-609X ; 1364-8535
    ISSN (online) 1466-609X
    ISSN 1364-8535
    DOI 10.1186/s13054-019-2658-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Why we should sample sparsely and aim for a higher target: Lessons from model-based therapeutic drug monitoring of vancomycin in intensive care patients.

    Guo, Tingjie / van Hest, Reinier M / Fleuren, Lucas M / Roggeveen, Luca F / Bosman, Rob J / van der Voort, Peter H J / Girbes, Armand R J / Mathot, Ron A A / van Hasselt, Johan G C / Elbers, Paul W G

    British journal of clinical pharmacology

    2020  Volume 87, Issue 3, Page(s) 1234–1242

    Abstract: Aims: To explore the optimal data sampling scheme and the pharmacokinetic (PK) target exposure on which dose computation is based in the model-based therapeutic drug monitoring (TDM) practice of vancomycin in intensive care (ICU) patients.: Methods: ... ...

    Abstract Aims: To explore the optimal data sampling scheme and the pharmacokinetic (PK) target exposure on which dose computation is based in the model-based therapeutic drug monitoring (TDM) practice of vancomycin in intensive care (ICU) patients.
    Methods: We simulated concentration data for 1 day following four sampling schemes, C
    Results: PK parameters were unbiasedly estimated in all investigated scenarios and the 6-day average NRMSE were 32.5%/38.5% (CL/V, where CL is clearance and V is volume of distribution) in the trough sampling scheme and 27.3%/26.5% (CL/V) in the rich sampling scheme. Regarding POT, the sampling scheme had marginal influence, while target exposure showed clear impacts that the maximum POT of 71.5% was reached when doses were computed based on AUC
    Conclusions: For model-based TDM of vancomycin in ICU patients, sampling more frequently than taking only trough samples adds no value and dosing based on AUC
    MeSH term(s) Anti-Bacterial Agents/therapeutic use ; Area Under Curve ; Bayes Theorem ; Critical Care ; Drug Monitoring ; Humans ; Vancomycin
    Chemical Substances Anti-Bacterial Agents ; Vancomycin (6Q205EH1VU)
    Language English
    Publishing date 2020-08-17
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 188974-6
    ISSN 1365-2125 ; 0306-5251 ; 0264-3774
    ISSN (online) 1365-2125
    ISSN 0306-5251 ; 0264-3774
    DOI 10.1111/bcp.14498
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Machine learning for the prediction of sepsis: a systematic review and meta-analysis of diagnostic test accuracy.

    Fleuren, Lucas M / Klausch, Thomas L T / Zwager, Charlotte L / Schoonmade, Linda J / Guo, Tingjie / Roggeveen, Luca F / Swart, Eleonora L / Girbes, Armand R J / Thoral, Patrick / Ercole, Ari / Hoogendoorn, Mark / Elbers, Paul W G

    Intensive care medicine

    2020  Volume 46, Issue 3, Page(s) 383–400

    Abstract: Purpose: Early clinical recognition of sepsis can be challenging. With the advancement of machine learning, promising real-time models to predict sepsis have emerged. We assessed their performance by carrying out a systematic review and meta-analysis.!## ...

    Abstract Purpose: Early clinical recognition of sepsis can be challenging. With the advancement of machine learning, promising real-time models to predict sepsis have emerged. We assessed their performance by carrying out a systematic review and meta-analysis.
    Methods: A systematic search was performed in PubMed, Embase.com and Scopus. Studies targeting sepsis, severe sepsis or septic shock in any hospital setting were eligible for inclusion. The index test was any supervised machine learning model for real-time prediction of these conditions. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, with a tailored Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist to evaluate risk of bias. Models with a reported area under the curve of the receiver operating characteristic (AUROC) metric were meta-analyzed to identify strongest contributors to model performance.
    Results: After screening, a total of 28 papers were eligible for synthesis, from which 130 models were extracted. The majority of papers were developed in the intensive care unit (ICU, n = 15; 54%), followed by hospital wards (n = 7; 25%), the emergency department (ED, n = 4; 14%) and all of these settings (n = 2; 7%). For the prediction of sepsis, diagnostic test accuracy assessed by the AUROC ranged from 0.68-0.99 in the ICU, to 0.96-0.98 in-hospital and 0.87 to 0.97 in the ED. Varying sepsis definitions limit pooling of the performance across studies. Only three papers clinically implemented models with mixed results. In the multivariate analysis, temperature, lab values, and model type contributed most to model performance.
    Conclusion: This systematic review and meta-analysis show that on retrospective data, individual machine learning models can accurately predict sepsis onset ahead of time. Although they present alternatives to traditional scoring systems, between-study heterogeneity limits the assessment of pooled results. Systematic reporting and clinical implementation studies are needed to bridge the gap between bytes and bedside.
    MeSH term(s) Diagnostic Tests, Routine ; Humans ; Machine Learning ; Retrospective Studies ; Sepsis/diagnosis ; Shock, Septic
    Language English
    Publishing date 2020-01-21
    Publishing country United States
    Document type Journal Article ; Meta-Analysis ; Review ; Systematic Review
    ZDB-ID 80387-x
    ISSN 1432-1238 ; 0340-0964 ; 0342-4642 ; 0935-1701
    ISSN (online) 1432-1238
    ISSN 0340-0964 ; 0342-4642 ; 0935-1701
    DOI 10.1007/s00134-019-05872-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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