Publications by authors named "Iwan C C van der Horst"

203 Publications

Targeted Temperature Management in Out-of-Hospital Cardiac Arrest With Shockable Rhythm: A Post Hoc Analysis of the Coronary Angiography After Cardiac Arrest Trial.

Crit Care Med 2021 Sep 22. Epub 2021 Sep 22.

Department of Cardiology, Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands. Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands. Department of Intensive Care Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. Department of Cardiology, Amphia Hospital, Breda, The Netherlands. Department of Intensive Care Medicine, Amphia Hospital, Breda, The Netherlands. Department of Cardiology, Rijnstate Hospital, Arnhem, The Netherlands. Department of Intensive Care Medicine, Rijnstate Hospital, Arnhem, The Netherlands. Department of Cardiology, HAGA Hospital, Den Haag, The Netherlands. Department of Intensive Care Medicine, HAGA Hospital, Den Haag, The Netherlands. Department of Cardiology, Maasstad Hospital, Rotterdam, The Netherlands. Department of Cardiology, University Medical Centre Utrecht, Utrecht, The Netherlands. Department of Intensive Care Medicine, Maasstad Hospital, Rotterdam, The Netherlands. Department of Intensive Care Medicine, Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands. Department of Intensive Care Medicine, Maastricht University Medical Center, University Maastricht, Maastricht, The Netherlands. Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. Department of Intensive Care Medicine, Medisch Spectrum Twente, Enschede, The Netherlands. Department of Cardiology, Medisch Spectrum Twente, Enschede, The Netherlands. Department of Cardiology, Radboud University Medical Center, Nijmegen, The Netherlands. Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. Department of Cardiology, Amsterdam University Medical Center, location AMC, Amsterdam, The Netherlands. Department of Intensive Care Medicine, Amsterdam University Medical Center, location AMC, Amsterdam, The Netherlands. Department of Cardiology, OLVG, Amsterdam, The Netherlands. Department of Intensive Care Medicine, OLVG, Amsterdam, The Netherlands. Department of Cardiology, Noord West Ziekenhuisgroep, Alkmaar, The Netherlands. Department of Intensive Care Medicine, Noord West Ziekenhuisgroep, Alkmaar, The Netherlands. Department of Cardiology, Maastricht University Medical Center, Maastricht, The Netherlands. Department of Cardiology, Scheper Hospital, Emmen, The Netherlands. Department of Cardiology, Haaglanden Medical Center, Den Haag, The Netherlands. Department of Cardiology, Isala Hospital, Zwolle, The Netherlands. Department of Cardiology, Tergooi Hospital, Blaricum, The Netherlands. Department of Cardiology, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands. Department of Epidemiology and Data Science, Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands.

Objectives: The optimal targeted temperature in patients with shockable rhythm is unclear, and current guidelines recommend targeted temperature management with a correspondingly wide range between 32°C and 36°C. Our aim was to study survival and neurologic outcome associated with targeted temperature management strategy in postarrest patients with initial shockable rhythm.

Design: Observational substudy of the Coronary Angiography after Cardiac Arrest without ST-segment Elevation trial.

Setting: Nineteen hospitals in The Netherlands.

Patients: The Coronary Angiography after Cardiac Arrest trial randomized successfully resuscitated patients with shockable rhythm and absence of ST-segment elevation to a strategy of immediate or delayed coronary angiography. In this substudy, 459 patients treated with mild therapeutic hypothermia (32.0-34.0°C) or targeted normothermia (36.0-37.0°C) were included. Allocation to targeted temperature management strategy was at the discretion of the physician.

Interventions: None.

Measurements And Main Results: After 90 days, 171 patients (63.6%) in the mild therapeutic hypothermia group and 129 (67.9%) in the targeted normothermia group were alive (hazard ratio, 0.86 [95% CI, 0.62-1.18]; log-rank p = 0.35; adjusted odds ratio, 0.89; 95% CI, 0.45-1.72). Patients in the mild therapeutic hypothermia group had longer ICU stay (4 d [3-7 d] vs 3 d [2-5 d]; ratio of geometric means, 1.32; 95% CI, 1.15-1.51), lower blood pressures, higher lactate levels, and increased need for inotropic support. Cerebral Performance Category scores at ICU discharge and 90-day follow-up and patient-reported Mental and Physical Health Scores at 1 year were similar in the two groups.

Conclusions: In the context of out-of-hospital cardiac arrest with shockable rhythm and no ST-elevation, treatment with mild therapeutic hypothermia was not associated with improved 90-day survival compared with targeted normothermia. Neurologic outcomes at 90 days as well as patient-reported Mental and Physical Health Scores at 1 year did not differ between the groups.
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http://dx.doi.org/10.1097/CCM.0000000000005271DOI Listing
September 2021

Differences and Similarities Among Coronavirus Disease 2019 Patients Treated in Seven ICUs in Three Countries Within One Region: An Observational Cohort Study.

Crit Care Med 2021 Oct 12. Epub 2021 Oct 12.

Department of Intensive Care, Ziekenhuis Oost-Limburg, Genk, Belgium. UHasselt, Faculty of Medicine and Life Sciences, Diepenbeek, Belgium. Department of Intensive Care, Maastricht University Medical Center +, Maastricht, The Netherlands. Department of Intensive Care, Laurentius Ziekenhuis, Roermond, The Netherlands. Care and Public Health Research Institute, Maastricht University, Maastricht, The Netherlands. Department of Intensive Care, Jessa Hospital, Hasselt, Belgium. Department of Intensive Care, VieCuri Medisch Centrum, Venlo, The Netherlands. Department of Intensive Care, Zuyderland Medisch Centrum, Heerlen/Sittard, The Netherlands. Department of Surgery, Maastricht University Medical Center +, Maastricht, The Netherlands. School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands. Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands. Division for Acute and Emergency Medicine, Maastricht University Medical Center +, Maastricht, The Netherlands. Department of Intensive Care, University Hospital Rheinisch Westfälische Hochschule Aachen, Aachen, Germany.

Objectives: To investigate healthcare system-driven variation in general characteristics, interventions, and outcomes in coronavirus disease 2019 (COVID-19) patients admitted to the ICU within one Western European region across three countries.

Design: Multicenter observational cohort study.

Setting: Seven ICUs in the Euregio Meuse-Rhine, one region across Belgium, The Netherlands, and Germany.

Patients: Consecutive COVID-19 patients supported in the ICU during the first pandemic wave.

Interventions: None.

Measurements And Main Results: Baseline demographic and clinical characteristics, laboratory values, and outcome data were retrieved after ethical approval and data-sharing agreements. Descriptive statistics were performed to investigate country-related practice variation. From March 2, 2020, to August 12, 2020, 551 patients were admitted. Mean age was 65.4 ± 11.2 years, and 29% were female. At admission, Acute Physiology and Chronic Health Evaluation II scores were 15.0 ± 5.5, 16.8 ± 5.5, and 15.8 ± 5.3 (p = 0.002), and Sequential Organ Failure Assessment scores were 4.4 ± 2.7, 7.4 ± 2.2, and 7.7 ± 3.2 (p < 0.001) in the Belgian, Dutch, and German parts of Euregio, respectively. The ICU mortality rate was 22%, 42%, and 44%, respectively (p < 0.001). Large differences were observed in the frequency of organ support, antimicrobial/inflammatory therapy application, and ICU capacity. Mixed-multivariable logistic regression analyses showed that differences in ICU mortality were independent of age, sex, disease severity, comorbidities, support strategies, therapies, and complications.

Conclusions: COVID-19 patients admitted to ICUs within one region, the Euregio Meuse-Rhine, differed significantly in general characteristics, applied interventions, and outcomes despite presumed genetic and socioeconomic background, admission diagnosis, access to international literature, and data collection are similar. Variances in healthcare systems' organization, particularly ICU capacity and admission criteria, combined with a rapidly spreading pandemic might be important drivers for the observed differences. Heterogeneity between patient groups but also healthcare systems should be presumed to interfere with outcomes in coronavirus disease 2019.
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http://dx.doi.org/10.1097/CCM.0000000000005314DOI Listing
October 2021

Hemostasis and fibrinolysis in COVID-19 survivors 6 months after intensive care unit discharge.

Res Pract Thromb Haemost 2021 Aug 24;5(6):e12579. Epub 2021 Sep 24.

Central Diagnostic Laboratory Maastricht University Medical Centre+ Maastricht the Netherlands.

Background: The prothrombotic phenotype has been extensively described in patients with acute coronavirus disease 2019 (COVID-19). However, potential long-term hemostatic abnormalities are unknown.

Objective: To evaluate the changes in routine hemostasis laboratory parameters and tissue-type plasminogen activator (tPA) rotational thromboelastometry (ROTEM) 6 months after COVID-19 intensive care unit (ICU) discharge in patients with and without venous thromboembolism (VTE) during admission.

Methods: Patients with COVID-19 of the Maastricht Intensive Care COVID cohort with tPA ROTEM measurement at ICU and 6-month follow-up were included. TPA ROTEM is a whole blood viscoelastic assay that illustrates both clot development and fibrinolysis due to simultaneous addition of tissue factor and tPA. Analyzed ROTEM parameters include clotting time, maximum clot firmness (MCF), lysis onset time (LOT), and lysis time (LT).

Results: Twenty-two patients with COVID-19 were included and showed extensive hemostatic abnormalities before ICU discharge. TPA ROTEM MCF (75 mm [interquartile range, 68-78]-59 mm [49-63];  ≤ .001), LOT (3690 seconds [2963-4418]-1786 seconds [1465-2650];  ≤ .001), and LT (7200 seconds [6144-7200]-3138 seconds [2591-4389];  ≤ .001) normalized 6 months after ICU discharge. Of note, eight and four patients still had elevated fibrinogen and D-dimer concentrations at follow-up, respectively. In general, no difference in median hemostasis parameters at 6-month follow-up was observed between patients with (n=14) and without (n=8) VTE, although fibrinogen appeared to be lower in the VTE group (VTE-, 4.3 g/L [3.7-4.7] vs VTE+, 3.4 g/L [3.2-4.2];  = .05).

Conclusions: Six months after COVID-19 ICU discharge, no persisting hypercoagulable or hypofibrinolytic profile was detected by tPA ROTEM. Nevertheless, increased D-dimer and fibrinogen concentrations persist up to 6 months in some patients, warranting further exploration of the role of hemostasis in long-term morbidity after hospital discharge.
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http://dx.doi.org/10.1002/rth2.12579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463660PMC
August 2021

Targeting Autoregulation-Guided Cerebral Perfusion Pressure after Traumatic Brain Injury (COGiTATE): A Feasibility Randomized Controlled Clinical Trial.

J Neurotrauma 2021 Oct 16;38(20):2790-2800. Epub 2021 Aug 16.

Department of Intensive Care Medicine, University Maastricht (KEMTA), Maastricht University Medical Center+, Maastricht, The Netherlands.

Managing traumatic brain injury (TBI) patients with a cerebral perfusion pressure (CPP) near to the cerebral autoregulation (CA)-guided "optimal" CPP (CPPopt) value is associated with improved outcome and might be useful to individualize care, but has never been prospectively evaluated. This study evaluated the feasibility and safety of CA-guided CPP management in TBI patients requiring intracranial pressure monitoring and therapy (TBIicp patients). The CPPopt Guided Therapy: Assessment of Target Effectiveness (COGiTATE) parallel two-arm feasibility trial took place in four tertiary centers. TBIicp patients were randomized to either the Brain Trauma Foundation (BTF) guideline CPP target range (control group) or to the individualized CA-guided CPP targets (intervention group). CPP targets were guided by six times daily software-based alerts for up to 5 days. The primary feasibility end-point was the percentage of time with CPP concordant (±5 mm Hg) with the set CPP targets. The main secondary safety end-point was an increase in therapeutic intensity level (TIL) between the control and intervention group. Twenty-eight patients were randomized to the control and 32 patients to the intervention group. CPP in the intervention group was in the target range for 46.5% (interquartile range, 41.2-58) of the monitored time, significantly higher than the feasibility target specified in the published protocol (36%;  < 0.001). There were no significant differences between groups for TIL or for other safety end-points. Conclusively, targeting an individual and dynamic CA-guided CPP is feasible and safe in TBIicp patients. This encourages a prospective trial powered for clinical outcomes.
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http://dx.doi.org/10.1089/neu.2021.0197DOI Listing
October 2021

Deep Learning for Identification of Acute Illness and Facial Cues of Illness.

Front Med (Lausanne) 2021 26;8:661309. Epub 2021 Jul 26.

Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

The inclusion of facial and bodily cues (clinical gestalt) in machine learning (ML) models improves the assessment of patients' health status, as shown in genetic syndromes and acute coronary syndrome. It is unknown if the inclusion of clinical gestalt improves ML-based classification of acutely ill patients. As in previous research in ML analysis of medical images, simulated or augmented data may be used to assess the usability of clinical gestalt. To assess whether a deep learning algorithm trained on a dataset of simulated and augmented facial photographs reflecting acutely ill patients can distinguish between healthy and LPS-infused, acutely ill individuals. Photographs from twenty-six volunteers whose facial features were manipulated to resemble a state of acute illness were used to extract features of illness and generate a synthetic dataset of acutely ill photographs, using a neural transfer convolutional neural network (NT-CNN) for data augmentation. Then, four distinct CNNs were trained on different parts of the facial photographs and concatenated into one final, stacked CNN which classified individuals as healthy or acutely ill. Finally, the stacked CNN was validated in an external dataset of volunteers injected with lipopolysaccharide (LPS). In the external validation set, the four individual feature models distinguished acutely ill patients with sensitivities ranging from 10.5% (95% CI, 1.3-33.1% for the skin model) to 89.4% (66.9-98.7%, for the nose model). Specificity ranged from 42.1% (20.3-66.5%) for the nose model and 94.7% (73.9-99.9%) for skin. The stacked model combining all four facial features achieved an area under the receiver characteristic operating curve (AUROC) of 0.67 (0.62-0.71) and distinguished acutely ill patients with a sensitivity of 100% (82.35-100.00%) and specificity of 42.11% (20.25-66.50%). A deep learning algorithm trained on a synthetic, augmented dataset of facial photographs distinguished between healthy and simulated acutely ill individuals, demonstrating that synthetically generated data can be used to develop algorithms for health conditions in which large datasets are difficult to obtain. These results support the potential of facial feature analysis algorithms to support the diagnosis of acute illness.
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http://dx.doi.org/10.3389/fmed.2021.661309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350122PMC
July 2021

Predicting mortality of individual patients with COVID-19: a multicentre Dutch cohort.

BMJ Open 2021 07 19;11(7):e047347. Epub 2021 Jul 19.

Department of Internal Medicine, Flevoziekenhuis, Almere, Flevoland, The Netherlands.

Objective: Develop and validate models that predict mortality of patients diagnosed with COVID-19 admitted to the hospital.

Design: Retrospective cohort study.

Setting: A multicentre cohort across 10 Dutch hospitals including patients from 27 February to 8 June 2020.

Participants: SARS-CoV-2 positive patients (age ≥18) admitted to the hospital.

Main Outcome Measures: 21-day all-cause mortality evaluated by the area under the receiver operator curve (AUC), sensitivity, specificity, positive predictive value and negative predictive value. The predictive value of age was explored by comparison with age-based rules used in practice and by excluding age from the analysis.

Results: 2273 patients were included, of whom 516 had died or discharged to palliative care within 21 days after admission. Five feature sets, including premorbid, clinical presentation and laboratory and radiology values, were derived from 80 features. Additionally, an Analysis of Variance (ANOVA)-based data-driven feature selection selected the 10 features with the highest F values: age, number of home medications, urea nitrogen, lactate dehydrogenase, albumin, oxygen saturation (%), oxygen saturation is measured on room air, oxygen saturation is measured on oxygen therapy, blood gas pH and history of chronic cardiac disease. A linear logistic regression and non-linear tree-based gradient boosting algorithm fitted the data with an AUC of 0.81 (95% CI 0.77 to 0.85) and 0.82 (0.79 to 0.85), respectively, using the 10 selected features. Both models outperformed age-based decision rules used in practice (AUC of 0.69, 0.65 to 0.74 for age >70). Furthermore, performance remained stable when excluding age as predictor (AUC of 0.78, 0.75 to 0.81).

Conclusion: Both models showed good performance and had better test characteristics than age-based decision rules, using 10 admission features readily available in Dutch hospitals. The models hold promise to aid decision-making during a hospital bed shortage.
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http://dx.doi.org/10.1136/bmjopen-2020-047347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290951PMC
July 2021

Appropriateness of empirical antibiotic therapy and added value of adjunctive gentamicin in patients with septic shock: a prospective cohort study in the ICU.

Infect Dis (Lond) 2021 Nov 22;53(11):830-838. Epub 2021 Jun 22.

Department of Intensive Care Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.

Objectives: To determine the appropriateness of empiric antibiotic therapy and the possible benefit of adding short-course gentamicin in septic shock patients with abdominal, urogenital, or an unknown focus. Secondary objectives were the effect of gentamicin addition on shock reversal and the incidence of a fungal infection.

Methods: Microbiological cultures, antibiotic treatment, and antibiotic resistance patterns of the cultured microorganisms were recorded during the first 5 days of admission. Inappropriate antibiotic therapy was defined as a prescription within the first 24 h that did not cover cultured bacteria during the first 5 days of admission and was determined in the overall group and in patients receiving adjunctive gentamicin (combination therapy) versus patients receiving monotherapy. Binomial logistic regression analysis was used to investigate the association of gentamicin addition with shock reversal.

Results: Of 203 septic shock patients, with abdominal ( = 143), urogenital ( = 27) or unknown ( = 33) focus, 115 patients received monotherapy, and 88 patients received combination therapy. Inappropriate therapy occurred in 29 patients (14%), more frequently in monotherapy (17%) versus combination therapy (10%). Combination therapy would have been effective in 55% of patients with inappropriate monotherapy. We found no association between gentamicin addition and shock reversal ( = .223). A fungal infection was present in 22 patients (11%).

Conclusion: Inappropriate empirical antibiotic therapy occurs in 17% of septic shock patients receiving monotherapy. In 55% of these patients, additional gentamicin would have resulted in appropriate therapy. When clinical course is unfavourable, lowering the threshold for administering adjunctive aminoglycoside and antifungal therapy should be considered.
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http://dx.doi.org/10.1080/23744235.2021.1942543DOI Listing
November 2021

Systemic inflammation down-regulates glyoxalase-1 expression: an experimental study in healthy males.

Biosci Rep 2021 Jul;41(7)

Department of Intensive Care Medicine, Maastricht University Medical Center +, Maastricht, The Netherlands.

Background: Hypoxia and inflammation are hallmarks of critical illness, related to multiple organ failure. A possible mechanism leading to multiple organ failure is hypoxia- or inflammation-induced down-regulation of the detoxifying glyoxalase system that clears dicarbonyl stress. The dicarbonyl methylglyoxal (MGO) is a highly reactive agent produced by metabolic pathways such as anaerobic glycolysis and gluconeogenesis. MGO leads to protein damage and ultimately multi-organ failure. Whether detoxification of MGO into D-lactate by glyoxalase functions appropriately under conditions of hypoxia and inflammation is largely unknown. We investigated the effect of inflammation and hypoxia on the MGO pathway in humans in vivo.

Methods: After prehydration with glucose 2.5% solution, ten healthy males were exposed to hypoxia (arterial saturation 80-85%) for 3.5 h using an air-tight respiratory helmet, ten males to experimental endotoxemia (LPS 2 ng/kg i.v.), ten males to LPS+hypoxia and ten males to none of these interventions (control group). Serial blood samples were drawn, and glyoxalase-1 mRNA expression, MGO, methylglyoxal-derived hydroimidazolone-1 (MG-H1), D-lactate and L-lactate levels, were measured serially.

Results: Glyoxalase-1 mRNA expression decreased in the LPS (β (95%CI); -0.87 (-1.24; -0.50) and the LPS+hypoxia groups; -0.78 (-1.07; -0.48) (P<0.001). MGO was equal between groups, whereas MG-H1 increased over time in the control group only (P=0.003). D-Lactate was increased in all four groups. L-Lactate was increased in all groups, except in the control group.

Conclusion: Systemic inflammation downregulates glyoxalase-1 mRNA expression in humans. This is a possible mechanism leading to cell damage and multi-organ failure in critical illness with potential for intervention.
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http://dx.doi.org/10.1042/BSR20210954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411911PMC
July 2021

Identifying and characterizing high-risk clusters in a heterogeneous ICU population with deep embedded clustering.

Sci Rep 2021 06 8;11(1):12109. Epub 2021 Jun 8.

Department of Intensive Care, Maastricht University Medical Centre+, University Maastricht, Maastricht, The Netherlands.

Critically ill patients constitute a highly heterogeneous population, with seemingly distinct patients having similar outcomes, and patients with the same admission diagnosis having opposite clinical trajectories. We aimed to develop a machine learning methodology that identifies and provides better characterization of patient clusters at high risk of mortality and kidney injury. We analysed prospectively collected data including co-morbidities, clinical examination, and laboratory parameters from a minimally-selected population of 743 patients admitted to the ICU of a Dutch hospital between 2015 and 2017. We compared four clustering methodologies and trained a classifier to predict and validate cluster membership. The contribution of different variables to the predicted cluster membership was assessed using SHapley Additive exPlanations values. We found that deep embedded clustering yielded better results compared to the traditional clustering algorithms. The best cluster configuration was achieved for 6 clusters. All clusters were clinically recognizable, and differed in in-ICU, 30-day, and 90-day mortality, as well as incidence of acute kidney injury. We identified two high mortality risk clusters with at least 60%, 40%, and 30% increased. ICU, 30-day and 90-day mortality, and a low risk cluster with 25-56% lower mortality risk. This machine learning methodology combining deep embedded clustering and variable importance analysis, which we made publicly available, is a possible solution to challenges previously encountered by clustering analyses in heterogeneous patient populations and may help improve the characterization of risk groups in critical care.
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http://dx.doi.org/10.1038/s41598-021-91297-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187398PMC
June 2021

Serial markers of coagulation and inflammation and the occurrence of clinical pulmonary thromboembolism in mechanically ventilated patients with SARS-CoV-2 infection; the prospective Maastricht intensive care COVID cohort.

Thromb J 2021 May 31;19(1):35. Epub 2021 May 31.

Department of Intensive Care Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands.

Background: The incidence of pulmonary thromboembolism is high in SARS-CoV-2 patients admitted to the Intensive Care. Elevated biomarkers of coagulation (fibrinogen and D-dimer) and inflammation (c-reactive protein (CRP) and ferritin) are associated with poor outcome in SARS-CoV-2. Whether the time-course of fibrinogen, D-dimer, CRP and ferritin is associated with the occurrence of pulmonary thromboembolism in SARS-CoV-2 patients is unknown. We hypothesise that patients on mechanical ventilation with SARS-CoV-2 infection and clinical pulmonary thromboembolism have lower concentrations of fibrinogen and higher D-dimer, CRP, and ferritin concentrations over time compared to patients without a clinical pulmonary thromboembolism.

Methods: In a prospective study, fibrinogen, D-dimer, CRP and ferritin were measured daily. Clinical suspected pulmonary thromboembolism was either confirmed or excluded based on computed tomography pulmonary angiography (CTPA) or by transthoracic ultrasound (TTU) (i.e., right-sided cardiac thrombus). In addition, patients who received therapy with recombinant tissue plasminogen activator were included when clinical instability in suspected pulmonary thromboembolism did not allow CTPA. Serial data were analysed using a mixed-effects linear regression model, and models were adjusted for known risk factors (age, sex, APACHE-II score, body mass index), biomarkers of coagulation and inflammation, and anticoagulants.

Results: Thirty-one patients were considered to suffer from pulmonary thromboembolism ((positive CTPA (n = 27), TTU positive (n = 1), therapy with recombinant tissue plasminogen activator (n = 3)), and eight patients with negative CTPA were included. After adjustment for known risk factors and anticoagulants, patients with, compared to those without, clinical pulmonary thromboembolism had lower average fibrinogen concentration of - 0.9 g/L (95% CI: - 1.6 - - 0.1) and lower average ferritin concentration of - 1045 μg/L (95% CI: - 1983 - - 106) over time. D-dimer and CRP average concentration did not significantly differ, 561 μg/L (- 6212-7334) and 27 mg/L (- 32-86) respectively. Ferritin lost statistical significance, both in sensitivity analysis and after adjustment for fibrinogen and D-dimer.

Conclusion: Lower average concentrations of fibrinogen over time were associated with the presence of clinical pulmonary thromboembolism in patients at the Intensive Care, whereas D-dimer, CRP and ferritin were not. Lower concentrations over time may indicate the consumption of fibrinogen related to thrombus formation in the pulmonary vessels.
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http://dx.doi.org/10.1186/s12959-021-00286-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165953PMC
May 2021

Serial EXTEM, FIBTEM, and tPA Rotational Thromboelastometry Observations in the Maastricht Intensive Care COVID Cohort-Persistence of Hypercoagulability and Hypofibrinolysis Despite Anticoagulation.

Front Cardiovasc Med 2021 26;8:654174. Epub 2021 Apr 26.

Central Diagnostic Laboratory, Maastricht University Medical Centre+, Maastricht, Netherlands.

Coronavirus Disease 2019 (COVID-19) patients often present with thromboembolic events. In COVID-19 patients, routine hemostatic assays cannot correctly identify patients at risk for thromboembolic events. Viscoelastic testing with rotational thromboelastometry (ROTEM) might improve the characterization of COVID-19-associated coagulopathy. To unravel underlying coagulopathy and fibrinolysis over time as measured by serial assessment heparin-independent (FIBTEM and EXTEM) and fibrinolysis illustrating (tissue plasminogen activator; tPA) ROTEM assays. Between April 23 and June 12, consecutive adult patients enrolled within the Maastricht Intensive Care COVID (MaastrICCht) cohort were included, and a comprehensive set of clinical, physiological, pharmaceutical, and laboratory variables were collected daily. Twice per week, EXTEM, FIBTEM, and tPA ROTEM were performed. Clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), lysis onset time (LOT), and lysis time (LT) were determined to assess clot development and breakdown and were compared to routine hemostatic assays. In 36 patients, 96 EXTEM/FIBTEM and 87 tPA ROTEM tests were performed during a 6-week follow-up. CT prolongation was present in 54% of EXTEM measurements, which were not matched by prothrombin time (PT) in 37%. Respectively, 81 and 99% of all EXTEM and FIBTEM MCF values were above the reference range, and median MCF remained elevated during follow-up. The ROTEM fibrinolysis parameters remained prolonged with median LOT consequently >49 min and unmeasurable LT in 56% of measurements, suggesting a severe hypofibrinolytic phenotype. ROTEM tests in COVID-19 ICU patients show hypercoagulability and severe hypofibrinolysis persisting over at least 6 weeks.
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http://dx.doi.org/10.3389/fcvm.2021.654174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107372PMC
April 2021

Functional Outcomes and Their Association With Physical Performance in Mechanically Ventilated Coronavirus Disease 2019 Survivors at 3 Months Following Hospital Discharge: A Cohort Study.

Crit Care Med 2021 10;49(10):1726-1738

Department of Intensive Care Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands.

Objectives: We performed a comprehensive health assessment in mechanically ventilated coronavirus disease 2019 survivors to assess the impact of respiratory and skeletal muscle injury sustained during ICU stay on physical performance at 3 months following hospital discharge.

Design: Preregistered prospective observational cohort study.

Setting: University hospital ICU.

Patients: All mechanically ventilated coronavirus disease 2019 patients admitted to our ICU during the first European pandemic wave.

Measurements And Main Results: At 3 months after hospital discharge, 46 survivors underwent a comprehensive physical assessment (6-min walking distance, Medical Research Council sum score and handgrip strength), a full pulmonary function test, and a chest CT scan which was used to analyze skeletal muscle architecture. In addition, patient-reported outcomes measures were collected. Physical performance assessed by 6-minute walking distance was below 80% of predicted in 48% of patients. Patients with impaired physical performance had more muscle weakness (Medical Research Council sum score 53 [51-56] vs 59 [56-60]; p < 0.001), lower lung diffusing capacity (54% [44-66%] vs 68% of predicted [61-72% of predicted]; p = 0.002), and higher intermuscular adipose tissue area (p = 0.037). Reduced lung diffusing capacity and increased intermuscular adipose tissue were independently associated with physical performance.

Conclusions: Physical disability is common at 3 months in severe coronavirus disease 2019 survivors. Lung diffusing capacity and intermuscular adipose tissue assessed on CT were independently associated with walking distance, suggesting a key role for pulmonary function and muscle quality in functional disability.
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http://dx.doi.org/10.1097/CCM.0000000000005089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439632PMC
October 2021

The effect of immediate coronary angiography after cardiac arrest without ST-segment elevation on left ventricular function. A sub-study of the COACT randomised trial.

Resuscitation 2021 07 28;164:93-100. Epub 2021 Apr 28.

Department of Intensive care medicine, Noord West Ziekenhuisgroep, Alkmaar, The Netherlands.

Background: The effect of immediate coronary angiography and percutaneous coronary intervention (PCI) in patients who are successfully resuscitated after cardiac arrest in the absence of ST-segment elevation myocardial infarction (STEMI) on left ventricular function is currently unknown.

Methods: This prespecified sub-study of a multicentre trial evaluated 552 patients, successfully resuscitated from out-of-hospital cardiac arrest without signs of STEMI. Patients were randomized to either undergo immediate coronary angiography or delayed coronary angiography, after neurologic recovery. All patients underwent PCI if indicated. The main outcomes of this analysis were left ventricular ejection fraction and end-diastolic and systolic volumes assessed by cardiac magnetic resonance imaging or echocardiography.

Results: Data on left ventricular function was available for 397 patients. The mean (± standard deviation) left ventricular ejection fraction was 45.2% (±12.8) in the immediate angiography group and 48.4% (±13.2) in the delayed angiography group (mean difference: -3.19; 95% confidence interval [CI], -6.75 to 0.37). Median left ventricular end-diastolic volume was 177 ml in the immediate angiography group compared to 169 ml in the delayed angiography group (ratio of geometric means: 1.06; 95% CI, 0.95-1.19). In addition, mean left ventricular end-systolic volume was 90 ml in the immediate angiography group compared to 78 ml in the delayed angiography group (ratio of geometric means: 1.13; 95% CI 0.97-1.32).

Conclusion: In patients successfully resuscitated after out-of-hospital cardiac arrest and without signs of STEMI, immediate coronary angiography was not found to improve left ventricular dimensions or function compared with a delayed angiography strategy.

Clinical Trial Registration: Netherlands Trial Register number, NTR4973.
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http://dx.doi.org/10.1016/j.resuscitation.2021.04.020DOI Listing
July 2021

Cognitive biases, environmental, patient and personal factors associated with critical care decision making: A scoping review.

J Crit Care 2021 08 20;64:144-153. Epub 2021 Apr 20.

Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Intensive Care Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands.

Purpose: Cognitive biases and factors affecting decision making in critical care can potentially lead to life-threatening errors. We aimed to examine the existing evidence on the influence of cognitive biases and factors on decision making in critical care.

Materials And Methods: We conducted a scoping review by searching MEDLINE for articles from 2004 to November 2020. We included studies conducted in physicians that described cognitive biases or factors associated with decision making. During the study process we decided on the method to summarize the evidence, and based on the obtained studies a descriptive summary of findings was the best fit.

Results: Thirty heterogenous studies were included. Four main biases or factors were observed, e.g. cognitive biases, personal factors, environmental factors, and patient factors. Six (20%) studies reported biases associated with decision making comprising omission-, status quo-, implicit-, explicit-, outcome-, and overconfidence bias. Nineteen (63%) studies described personal factors, twenty-two (73%) studies described environmental factors, and sixteen (53%) studies described patient factors.

Conclusions: The current evidence on cognitive biases and factors is heterogenous, but shows they influence clinical decision. Future studies should investigate the prevalence of cognitive biases and factors in clinical practice and their impact on clinical outcomes.
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http://dx.doi.org/10.1016/j.jcrc.2021.04.012DOI Listing
August 2021

Does postoperative cognitive decline after coronary bypass affect quality of life?

Open Heart 2021 04;8(1)

Department of Cardiothoracic Surgery, University Medical Centre Groningen, Groningen, The Netherlands.

Objective: This study aimed to explore the influence of coronary artery bypass grafting (CABG) on both postoperative cognitive dysfunction and quality of life (QoL) and the association between the two patient-related outcomes.

Methods: In a prospective, observational cohort study, patients with elective, isolated CABG were included. Cognitive function was assessed using the Cogstate computerised cognitive test battery preoperatively, 3 days and 6 months after surgery. QoL was measured preoperatively and at 6 months using the RAND-36 questionnaire including the Physical Component Score (PCS) and the Mental Component Score (MCS). Regression analysis, with adjustment for confounders, was used to evaluate the association between postoperative cognitive dysfunction and QoL.

Results: A total of 142 patients were included in the study. Evidence of persistent cognitive dysfunction was observed in 33% of patients after 6 months. At 6 months, the PCS had improved in 59% and decreased in 21% of patients, and the MCS increased in 49% and decreased in 29%. Postoperative cognitive changes were not associated with QoL scores.

Conclusions: Postoperative cognitive dysfunction and decreased QoL are common 6 months after surgery, although cognitive function and QoL were found to have improved in many patients at 6 months of follow-up. Impaired cognitive function is not associated with impaired QoL at 6 months.

Trial Registration Number: NCT03774342.
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http://dx.doi.org/10.1136/openhrt-2020-001569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070880PMC
April 2021

Performance of prediction models for short-term outcome in COVID-19 patients in the emergency department: a retrospective study.

Ann Med 2021 12;53(1):402-409

Department of Internal Medicine, Division of General Internal Medicine, Section Acute Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.

Introduction: Coronavirus disease 2019 (COVID-19) has a high burden on the healthcare system. Prediction models may assist in triaging patients. We aimed to assess the value of several prediction models in COVID-19 patients in the emergency department (ED).

Methods: In this retrospective study, ED patients with COVID-19 were included. Prediction models were selected based on their feasibility. Primary outcome was 30-day mortality, secondary outcomes were 14-day mortality and a composite outcome of 30-day mortality and admission to medium care unit (MCU) or intensive care unit (ICU). The discriminatory performance of the prediction models was assessed using an area under the receiver operating characteristic curve (AUC).

Results: We included 403 patients. Thirty-day mortality was 23.6%, 14-day mortality was 19.1%, 66 patients (16.4%) were admitted to ICU, 48 patients (11.9%) to MCU, and 152 patients (37.7%) met the composite endpoint. Eleven prediction models were included. The RISE UP score and 4 C mortality scores showed very good discriminatory performance for 30-day mortality (AUC 0.83 and 0.84, 95% CI 0.79-0.88 for both), significantly higher than that of the other models.

Conclusion: The RISE UP score and 4 C mortality score can be used to recognise patients at high risk for poor outcome and may assist in guiding decision-making and allocating resources.
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http://dx.doi.org/10.1080/07853890.2021.1891453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919920PMC
December 2021

Ensemble machine learning prediction and variable importance analysis of 5-year mortality after cardiac valve and CABG operations.

Sci Rep 2021 02 10;11(1):3467. Epub 2021 Feb 10.

Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Despite having a similar post-operative complication profile, cardiac valve operations are associated with a higher mortality rate compared to coronary artery bypass grafting (CABG) operations. For long-term mortality, few predictors are known. In this study, we applied an ensemble machine learning (ML) algorithm to 88 routinely collected peri-operative variables to predict 5-year mortality after different types of cardiac operations. The Super Learner algorithm was trained using prospectively collected peri-operative data from 8241 patients who underwent cardiac valve, CABG and combined operations. Model performance and calibration were determined for all models, and variable importance analysis was conducted for all peri-operative parameters. Results showed that the predictive accuracy was the highest for solitary mitral (0.846 [95% CI 0.812-0.880]) and solitary aortic (0.838 [0.813-0.864]) valve operations, confirming that ensemble ML using routine data collected perioperatively can predict 5-year mortality after cardiac operations with high accuracy. Additionally, post-operative urea was identified as a novel and strong predictor of mortality for several types of operation, having a seemingly additive effect to better known risk factors such as age and postoperative creatinine.
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http://dx.doi.org/10.1038/s41598-021-82403-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876023PMC
February 2021

A new tool to assess Clinical Diversity In Meta-analyses (CDIM) of interventions.

J Clin Epidemiol 2021 07 6;135:29-41. Epub 2021 Feb 6.

Copenhagen Trial Unit (CTU), Centre for Clinical Intervention Research, Capital Region of Denmark, Denmark.

Objective: To develop and validate Clinical Diversity In Meta-analyses (CDIM), a new tool for assessing clinical diversity between trials in meta-analyses of interventions.

Study Design And Setting: The development of CDIM was based on consensus work informed by empirical literature and expertise. We drafted the CDIM tool, refined it, and validated CDIM for interrater scale reliability and agreement in three groups.

Results: CDIM measures clinical diversity on a scale that includes four domains with 11 items overall: setting (time of conduct/country development status/units type); population (age, sex, patient inclusion criteria/baseline disease severity, comorbidities); interventions (intervention intensity/strength/duration of intervention, timing, control intervention, cointerventions); and outcome (definition of outcome, timing of outcome assessment). The CDIM is completed in two steps: first two authors independently assess clinical diversity in the four domains. Second, after agreeing upon scores of individual items a consensus score is achieved. Interrater scale reliability and agreement ranged from moderate to almost perfect depending on the type of raters.

Conclusion: CDIM is the first tool developed for assessing clinical diversity in meta-analyses of interventions. We found CDIM to be a reliable tool for assessing clinical diversity among trials in meta-analysis.
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http://dx.doi.org/10.1016/j.jclinepi.2021.01.023DOI Listing
July 2021

Biological subphenotypes of acute respiratory distress syndrome may not reflect differences in alveolar inflammation.

Physiol Rep 2021 02;9(3):e14693

Department of Intensive Care, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, The Netherlands.

Biological subphenotypes have been identified in acute respiratory distress syndrome (ARDS) based on two parsimonious models: the "uninflamed" and "reactive" subphenotype (cluster-model) and "hypo-inflammatory" and "hyper-inflammatory" (latent class analysis (LCA) model). The distinction between the subphenotypes is mainly driven by inflammatory and coagulation markers in plasma. However, systemic inflammation is not specific for ARDS and it is unknown whether these subphenotypes also reflect differences in the alveolar compartment. Alveolar inflammation and dysbiosis of the lung microbiome have shown to be important mediators in the development of lung injury. This study aimed to determine whether the "reactive" or "hyper-inflammatory" biological subphenotype also had higher concentrations of inflammatory mediators and enrichment of gut-associated bacteria in the lung. Levels of alveolar inflammatory mediators myeloperoxidase (MPO), surfactant protein D (SPD), interleukin (IL)-1b, IL-6, IL-10, IL-8, interferon gamma (IFN-ƴ), and tumor necrosis factor-alpha (TNFα) were determined in the mini-BAL fluid. Key features of the lung microbiome were measured: bacterial burden (16S rRNA gene copies/ml), community diversity (Shannon Diversity Index), and community composition. No statistically significant differences between the "uninflamed" and "reactive" ARDS subphenotypes were found in a selected set of alveolar inflammatory mediators and key features of the lung microbiome. LCA-derived subphenotypes and stratification based on cause of ARDS (direct vs. indirect) showed similar profiles, suggesting that current subphenotypes may not reflect the alveolar host response. It is important for future research to elucidate the pulmonary biology within each subphenotype properly, which is arguably a target for intervention.
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http://dx.doi.org/10.14814/phy2.14693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865405PMC
February 2021

Current use of inotropes in circulatory shock.

Ann Intensive Care 2021 Jan 29;11(1):21. Epub 2021 Jan 29.

Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, USA.

Background: Treatment decisions on critically ill patients with circulatory shock lack consensus. In an international survey, we aimed to evaluate the indications, current practice, and therapeutic goals of inotrope therapy in the treatment of patients with circulatory shock.

Methods: From November 2016 to April 2017, an anonymous web-based survey on the use of cardiovascular drugs was accessible to members of the European Society of Intensive Care Medicine (ESICM). A total of 14 questions focused on the profile of respondents, the triggering factors, first-line choice, dosing, timing, targets, additional treatment strategy, and suggested effect of inotropes. In addition, a group of 42 international ESICM experts was asked to formulate recommendations for the use of inotropes based on 11 questions.

Results: A total of 839 physicians from 82 countries responded. Dobutamine was the first-line inotrope in critically ill patients with acute heart failure for 84% of respondents. Two-thirds of respondents (66%) stated to use inotropes when there were persistent clinical signs of hypoperfusion or persistent hyperlactatemia despite a supposed adequate use of fluids and vasopressors, with (44%) or without (22%) the context of low left ventricular ejection fraction. Nearly half (44%) of respondents stated an adequate cardiac output as target for inotropic treatment. The experts agreed on 11 strong recommendations, all of which were based on excellent (> 90%) or good (81-90%) agreement. Recommendations include the indications for inotropes (septic and cardiogenic shock), the choice of drugs (dobutamine, not dopamine), the triggers (low cardiac output and clinical signs of hypoperfusion) and targets (adequate cardiac output) and stopping criteria (adverse effects and clinical improvement).

Conclusion: Inotrope use in critically ill patients is quite heterogeneous as self-reported by individual caregivers. Eleven strong recommendations on the indications, choice, triggers and targets for the use of inotropes are given by international experts. Future studies should focus on consistent indications for inotrope use and implementation into a guideline for circulatory shock that encompasses individualized targets and outcomes.
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http://dx.doi.org/10.1186/s13613-021-00806-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846624PMC
January 2021

Biological Subphenotypes of Acute Respiratory Distress Syndrome Show Prognostic Enrichment in Mechanically Ventilated Patients without Acute Respiratory Distress Syndrome.

Am J Respir Crit Care Med 2021 06;203(12):1503-1511

Department of Intensive Care Medicine.

Recent studies showed that biological subphenotypes in acute respiratory distress syndrome (ARDS) provide prognostic enrichment and show potential for predictive enrichment. To determine whether these subphenotypes and their prognostic and potential for predictive enrichment could be extended to other patients in the ICU, irrespective of fulfilling the definition of ARDS. This is a secondary analysis of a prospective observational study of adult patients admitted to the ICU. We tested the prognostic enrichment of both cluster-derived and latent-class analysis (LCA)-derived biological ARDS subphenotypes by evaluating the association with clinical outcome (ICU-day, 30-day mortality, and ventilator-free days) using logistic regression and Cox regression analysis. We performed a principal component analysis to compare blood leukocyte gene expression profiles between subphenotypes and the presence of ARDS. We included 2,499 mechanically ventilated patients (674 with and 1,825 without ARDS). The cluster-derived "reactive" subphenotype was, independently of ARDS, significantly associated with a higher probability of ICU mortality, higher 30-day mortality, and a lower probability of successful extubation while alive compared with the "uninflamed" subphenotype. The blood leukocyte gene expression profiles of individual subphenotypes were similar for patients with and without ARDS. LCA-derived subphenotypes also showed similar profiles. The prognostic and potential for predictive enrichment of biological ARDS subphenotypes may be extended to mechanically ventilated critically ill patients without ARDS. Using the concept of biological subphenotypes for splitting cohorts of critically ill patients could add to improving future precision-based trial strategies and lead to identifying treatable traits for all critically ill patients.
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http://dx.doi.org/10.1164/rccm.202006-2522OCDOI Listing
June 2021

Incidence, prognostic factors, and outcomes of venous thromboembolism in critically ill patients: data from two prospective cohort studies.

Crit Care 2021 01 12;25(1):27. Epub 2021 Jan 12.

Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: The objective of this study was to describe the prevalence, incidence, prognostic factors, and outcomes of venous thromboembolism in critically ill patients receiving contemporary thrombosis prophylaxis.

Methods: We conducted a pooled analysis of two prospective cohort studies. The outcomes of interest were in-hospital pulmonary embolism or lower extremity deep vein thrombosis (PE-LDVT), in-hospital nonleg deep vein thrombosis (NLDVT), and 90-day mortality. Multivariable logistic regression analysis was used to evaluate the association between predefined baseline prognostic factors and PE-LDVT or NLDVT. Cox regression analysis was used to evaluate the association between PE-LDVT or NLDVT and 90-day mortality.

Results: A total of 2208 patients were included. The prevalence of any venous thromboembolism during 3 months before ICU admission was 3.6% (95% CI 2.8-4.4%). Out of 2166 patients, 47 (2.2%; 95% CI 1.6-2.9%) developed PE-LDVT and 38 patients (1.8%; 95% CI 1.2-2.4%) developed NLDVT. Renal replacement therapy (OR 3.5 95% CI 1.4-8.6), respiratory failure (OR 2.0; 95% CI 1.1-3.8), and previous VTE (OR 3.6; 95% CI 1.7-7.7) were associated with PE-LDVT. Central venous catheters (OR 5.4; 95% CI 1.7-17.8) and infection (OR 2.2; 95% CI 1.1-4.3) were associated with NLDVT. Occurrence of PE-LDVT but not NLDVT was associated with increased 90-day mortality (HR 2.7; 95% CI 1.6-4.6, respectively, 0.92; 95% CI 0.41-2.1).

Conclusion: Thrombotic events are common in critically ill patients, both before and after ICU admittance. Development of PE-LDVT but not NLDVT was associated with increased mortality. Prognostic factors for developing PE-LDVT or NLDVT despite prophylaxis can be identified at ICU admission and may be used to select patients at higher risk in future randomized clinical trials.

Trial Registration: NCT03773939.
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http://dx.doi.org/10.1186/s13054-021-03457-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801861PMC
January 2021

Plasma neutrophil gelatinase-associated lipocalin at intensive care unit admission as a predictor of acute kidney injury progression.

Clin Kidney J 2020 Dec 17;13(6):994-1002. Epub 2020 Feb 17.

Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Acute kidney injury (AKI) is a common complication in patients during intensive care unit (ICU) admission. AKI is defined as an increase in serum creatinine (SCr) and/or a reduction in urine output. SCr is a marker of renal function with several limitations, which led to the search for biomarkers for earlier AKI detection. Our aim was to study the predictive value of plasma neutrophil gelatinase-associated lipocalin (NGAL) at admission as a biomarker for AKI progression during the first 48 h of ICU admission in an unselected, heterogeneous ICU patient population.

Methods: We conducted a prospective observational study in an academic tertiary referral ICU population. We recorded AKI progression in all ICU patients during the first 48 h of ICU admission in a 6-week period. Plasma NGAL was measured at admission but levels were not reported to the attending clinicians. As possible predictors of AKI progression, pre-existing AKI risk factors were recorded. We examined the association of clinical parameters and plasma NGAL levels at ICU admission with the incidence and progression of AKI within the first 48 h of the ICU stay.

Results: A total of 361 patients were included. Patients without AKI progression during the first 48 h of ICU admission had median NGAL levels at admission of 115 ng/mL [interquartile range (IQR) 81-201]. Patients with AKI progression during the first 48 h of ICU admission had median NGAL levels at admission of 156 ng/mL (IQR 97-267). To predict AKI progression, a multivariant model with age, sex, diabetes mellitus, body mass index, admission type, Acute Physiology and Chronic Health Evaluation score and SCr at admission had an area under the receiver operating characteristics (ROC) curve of 0.765. Adding NGAL to this model showed a small increase in the area under the ROC curve to 0.783 (95% confidence interval 0.714-0.853).

Conclusions: NGAL levels at admission were higher in patients with progression of AKI during the first 48 h of ICU admission, but adding NGAL levels at admission to a model predicting this AKI progression showed no significant additive value.
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http://dx.doi.org/10.1093/ckj/sfaa002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769547PMC
December 2020

Response to "Early hydroxychloroquine but not chloroquine use reduces ICU admission in COVID-19 patients".

Int J Infect Dis 2021 02 9;103:560-561. Epub 2020 Dec 9.

Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht University, P.O. Box 85500, 3584 CX Utrecht, The Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, Roger Williams Building 69-75 Chenies Mews, London WC1E 6HX, United Kingdom; Health Data Research UK and Institute of Health Informatics, University College London, 222 Euston Road, London NW1 2DA, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.ijid.2020.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725132PMC
February 2021

Clinical diagnoses vs. autopsy findings in early deceased septic patients in the intensive care: a retrospective cohort study.

Virchows Arch 2021 Jun 11;478(6):1173-1178. Epub 2020 Dec 11.

Department of Intensive Care Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands.

Early death in sepsis occurs frequently; however, specific causes are largely unknown. An autopsy can contribute to ascertain causes of death. The objective of the study was to determine discrepancies in clinical diagnosis and postmortem findings in septic intensive care unit (ICU) patients deceased within 48 h after ICU admission. All septic ICU patients who deceased within 48 h after ICU admission were identified and included. Four intensivists determined the clinical cause of death by medical record review. An autopsy was performed within 24 h of death. Clinical diagnosis and postmortem findings were compared and classified as autopsy-identified missed clinical diagnoses and autopsy-refuted diagnoses. Class I and II missed major diagnoses using the Goldman criteria were scored. Between 2012 and 2017, 1107 septic patients were admitted to ICU. Of these, 344 patients (31%) died, of which 97 patients (28%) deceased within 48 h. In 32 (33%) early deceased patients, an autopsy was agreed. There were 26 autopsy-identified missed clinical diagnoses found, mostly myocardial infarction (n = 4) and pneumonia (n = 4). In four patients (13%), a class I discrepancy was found. In fourteen patients (42%), a class II discrepancy was found. In conclusion, an autopsy is an important diagnostic tool that can identify definite causes of death. These diagnoses deviate from diagnoses established during admission in early deceased sepsis patients.
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http://dx.doi.org/10.1007/s00428-020-02984-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203528PMC
June 2021

Data on sex differences in one-year outcomes of out-of-hospital cardiac arrest patients without ST-segment elevation.

Data Brief 2020 Dec 12;33:106521. Epub 2020 Nov 12.

Department of Intensive care medicine, Maastricht University Medical Center, University Maastricht, Maastricht, the Netherlands.

Sex differences in out-of-hospital cardiac arrest (OHCA) patients are increasingly recognized. Although it has been found that post-resuscitated women are less likely to have significant coronary artery disease (CAD) than men, data on follow-up in these patients are limited. Data for this data in brief article was obtained as a part of the randomized controlled Coronary Angiography after Cardiac Arrest without ST-segment elevation (COACT) trial. The data supplements the manuscript "Sex differences in out-of-hospital cardiac arrest patients without ST-segment elevation: A COACT trial substudy" were it was found that women were less likely to have significant CAD including chronic total occlusions, and had worse survival when CAD was present. The dataset presented in this paper describes sex differences on interventions, implantable-cardioverter defibrillator (ICD) shocks and hospitalizations due to heart failure during one-year follow-up in patients successfully resuscitated after OHCA. Data was derived through a telephone interview at one year with the patient or general practitioner. Patients in this randomized dataset reflects a homogenous study population, which can be valuable to further build on research regarding long-term sex differences and to further improve cardiac care.
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http://dx.doi.org/10.1016/j.dib.2020.106521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691722PMC
December 2020

The "sex gap" in COVID-19 trials: a scoping review.

EClinicalMedicine 2020 Dec 30;29:100652. Epub 2020 Nov 30.

Department of Obstetrics and Gynaecology, Maastricht University Medical Centre (MUMC+), Maastricht, the Netherlands.

Background: Many studies investigate the role of pharmacological treatments on disease course in Corona Virus Disease 2019 (COVID-19). Sex disparities in genetics, immunological responses, and hormonal mechanisms may underlie the substantially higher fatality rates reported in male COVID-19 patients. To optimise care for COVID-19 patients, prophylactic and therapeutic studies should include sex-specific design and analyses. Therefore, in this scoping review, we investigated whether studies on pharmacological treatment in COVID-19 were performed based on a priori sex-specific design or post-hoc sex-specific analyses.

Methods: We systematically searched PubMed, EMBASE, UpToDate, clinical trial.org, and MedRxiv for studies on pharmacological treatment for COVID-19 until June 6th, 2020. We included case series, randomized controlled trials, and observational studies in humans (≥18 years) investigating antiviral, antimalarial, and immune system modulating drugs. Data were collected on 1) the proportion of included females, 2) whether sex stratification was performed (a priori by design or post-hoc), and 3) whether effect modification by sex was investigated.

Findings: 30 studies were eligible for inclusion, investigating remdesivir ( = 2), lopinavir/ritonavir ( = 5), favipiravir ( = 1), umifenovir ( = 1), hydroxychloroquine/chloroquine ( = 8), convalescent plasma ( = 6), interleukin-6 (IL-6) pathway inhibitors ( = 5), interleukin-1 (IL-1) pathway inhibitors ( = 1) and corticosteroids ( = 3). Only one study stratified its data based on sex in a post-hoc analysis, whereas none did a priori by design. None of the studies investigated effect modification by sex. A quarter of the studies included twice as many males as females.

Interpretation: Analyses assessing potential interference of sex with (side-)effects of pharmacological therapy for COVID-19 are rarely reported. Considering sex differences in case-fatality rates and genetic, immunological, and hormonal mechanisms, studies should include sex-specific analyses in their design to optimise COVID-19 care.

Funding: None.
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http://dx.doi.org/10.1016/j.eclinm.2020.100652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701906PMC
December 2020

The PRICES statement: an ESICM expert consensus on methodology for conducting and reporting critical care echocardiography research studies.

Intensive Care Med 2021 01 4;47(1):1-13. Epub 2020 Dec 4.

Intensive Care Medicine Unit, Assistance Publique-Hôpitaux de Paris, University Hospital Ambroise Paré, 92100, Boulogne-Billancourt, France.

Purpose: Echocardiography is a common tool for cardiac and hemodynamic assessments in critical care research. However, interpretation (and applications) of results and between-study comparisons are often difficult due to the lack of certain important details in the studies. PRICES (Preferred Reporting Items for Critical care Echocardiography Studies) is a project endorsed by the European Society of Intensive Care Medicine and conducted by the Echocardiography Working Group, aiming at producing recommendations for standardized reporting of critical care echocardiography (CCE) research studies.

Methods: The PRICE panel identified lists of clinical and echocardiographic parameters (the "items") deemed important in four main areas of CCE research: left ventricular systolic and diastolic functions, right ventricular function and fluid management. Each item was graded using a critical index (CI) that combined the relative importance of each item and the fraction of studies that did not report it, also taking experts' opinion into account.

Results: A list of items in each area that deemed essential for the proper interpretation and application of research results is recommended. Additional items which aid interpretation were also proposed.

Conclusion: The PRICES recommendations reported in this document, as a checklist, represent an international consensus of experts as to which parameters and information should be included in the design of echocardiography research studies. PRICES recommendations provide guidance to scientists in the field of CCE with the objective of providing a recommended framework for reporting of CCE methodology and results.
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http://dx.doi.org/10.1007/s00134-020-06262-5DOI Listing
January 2021

Decreased serial scores of severe organ failure assessments are associated with survival in mechanically ventilated patients; the prospective Maastricht Intensive Care COVID cohort.

J Crit Care 2021 04 17;62:38-45. Epub 2020 Nov 17.

Department of Intensive Care, Maastricht University Medical Centre+, P. Debyelaan 25, 6202 AZ Maastricht, the Netherlands; Care and Public Health Research Institute (CAPHRI), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, the Netherlands. Electronic address:

Background: The majority of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are admitted to the Intensive Care Unit (ICU) for mechanical ventilation. The role of multi-organ failure during ICU admission as driver for outcome remains to be investigated yet.

Design And Setting: Prospective cohort of mechanically ventilated critically ill with SARS-CoV-2 infection.

Participants And Methods: 94 participants of the MaastrICCht cohort (21% women) had a median length of stay of 16 days (maximum of 77). After division into survivors (n = 59) and non-survivors (n = 35), we analysed 1555 serial SOFA scores using linear mixed-effects models.

Results: Survivors improved one SOFA score point more per 5 days (95% CI: 4-8) than non-survivors. Adjustment for age, sex, and chronic lung, renal and liver disease, body-mass index, diabetes mellitus, cardiovascular risk factors, and Acute Physiology and Chronic Health Evaluation II score did not change this result. This association was stronger for women than men (P-interaction = 0.043).

Conclusions: The decrease in SOFA score associated with survival suggests multi-organ failure involvement during mechanical ventilation in patients with SARS-CoV-2. Surviving women appeared to improve faster than surviving men. Serial SOFA scores may unravel an unfavourable trajectory and guide decisions in mechanically ventilated patients with SARS-CoV-2.
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http://dx.doi.org/10.1016/j.jcrc.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669472PMC
April 2021

Monitoring of Unfractionated Heparin in Severe COVID-19: An Observational Study of Patients on CRRT and ECMO.

TH Open 2020 Oct 19;4(4):e365-e375. Epub 2020 Nov 19.

Central Diagnostic Laboratory, Maastricht University Medical Centre, Maastricht, the Netherlands.

 Severe cases of coronavirus disease 2019 (COVID-19) can require continuous renal replacement therapy (CRRT) and/or extracorporeal membrane oxygenation (ECMO). Unfractionated heparin (UFH) to prevent circuit clotting is mandatory but monitoring is complicated by (pseudo)-heparin resistance. In this observational study, we compared two different activated partial thromboplastin time (aPTT) assays and a chromogenic anti-Xa assay in COVID-19 patients on CRRT or ECMO in relation to their UFH dosages and acute phase reactants.  The aPTT (optical [aPTT-CS] and/or mechanical [aPTT-STA] clot detection methods were used), anti-Xa, factor VIII (FVIII), antithrombin III (ATIII), and fibrinogen were measured in 342 samples from 7 COVID-19 patients on CRRT or ECMO during their UFH treatment. Dosage of UFH was primarily based on the aPTT-CS with a heparin therapeutic range (HTR) of 50-80s. Associations between different variables were made using linear regression and Bland-Altman analysis.  Dosage of UFH was above 35,000IU/24 hours in all patients. aPTT-CS and aPTT-STA were predominantly within the HTR. Anti-Xa was predominantly above the HTR (0.3-0.7 IU/mL) and ATIII concentration was >70% for all patients; mean FVIII and fibrinogen were 606% and 7.5 g/L, respectively. aPTT-CS correlated with aPTT-STA (  = 0.68) with a bias of 39.3%. Correlation between aPTT and anti-Xa was better for aPTT-CS (0.78 ≤   ≤ 0.94) than for aPTT-STA (0.34 ≤   ≤ 0.81). There was no general correlation between the aPTT-CS and ATIII, FVIII, fibrinogen, thrombocytes, C-reactive protein, or ferritin.  All included COVID-19 patients on CRRT or ECMO conformed to the definition of heparin resistance. A patient-specific association was found between aPTT and anti-Xa. This association could not be explained by FVIII or fibrinogen.
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http://dx.doi.org/10.1055/s-0040-1719083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676995PMC
October 2020
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