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1.
BMJ Open ; 12(11): e065142, 2022 Nov 29.
Article in English | MEDLINE | ID: covidwho-2137779

ABSTRACT

INTRODUCTION: The variety, time patterns and long-term prognosis of persistent COVID-19 symptoms (long COVID-19) in patients who suffered from mild to severe acute COVID-19 are incompletely understood. Cohort studies will be combined to describe the prevalence of long COVID-19 symptoms, and to explore the pathophysiological mechanisms and impact on health-related quality of life. A prediction model for long COVID-19 will be developed and internally validated to guide care in future patients. METHODS AND ANALYSIS: Data from seven COVID-19 cohorts will be aggregated in the longitudinal multiple cohort CORona Follow Up (CORFU) study. CORFU includes Dutch patients who suffered from COVID-19 at home, were hospitalised without or with intensive care unit treatment, needed inpatient or outpatient rehabilitation and controls who did not suffer from COVID-19. Individual cohort study designs were aligned and follow-up has been synchronised. Cohort participants will be followed up for a maximum of 24 months after acute infection. Next to the clinical characteristics measured in individual cohorts, the CORFU questionnaire on long COVID-19 outcomes and determinants will be administered digitally at 3, 6, 12, 18 and 24 months after the infection. The primary outcome is the prevalence of long COVID-19 symptoms up to 2 years after acute infection. Secondary outcomes are health-related quality of life (eg, EQ-5D), physical functioning, and the prevalence of thromboembolic complications, respiratory complications, cardiovascular diseases and endothelial dysfunction. A prediction model and a patient platform prototype will be developed. ETHICS AND DISSEMINATION: Approval was obtained from the medical research ethics committee of Maastricht University Medical Center+ and Maastricht University (METC 2021-2990) and local committees of the participating cohorts. The project is supported by ZonMW and EuroQol Research Foundation. Results will be published in open access peer-reviewed scientific journals and presented at (inter)national conferences. TRIAL REGISTRATION NUMBER: NCT05240742.

2.
J Clin Epidemiol ; 152: 257-268, 2022 Oct 27.
Article in English | MEDLINE | ID: covidwho-2086388

ABSTRACT

OBJECTIVES: Many prediction models for coronavirus disease 2019 (COVID-19) have been developed. External validation is mandatory before implementation in the intensive care unit (ICU). We selected and validated prognostic models in the Euregio Intensive Care COVID (EICC) cohort. STUDY DESIGN AND SETTING: In this multinational cohort study, routine data from COVID-19 patients admitted to ICUs within the Euregio Meuse-Rhine were collected from March to August 2020. COVID-19 models were selected based on model type, predictors, outcomes, and reporting. Furthermore, general ICU scores were assessed. Discrimination was assessed by area under the receiver operating characteristic curves (AUCs) and calibration by calibration-in-the-large and calibration plots. A random-effects meta-analysis was used to pool results. RESULTS: 551 patients were admitted. Mean age was 65.4 ± 11.2 years, 29% were female, and ICU mortality was 36%. Nine out of 238 published models were externally validated. Pooled AUCs were between 0.53 and 0.70 and calibration-in-the-large between -9% and 6%. Calibration plots showed generally poor but, for the 4C Mortality score and Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) score, moderate calibration. CONCLUSION: Of the nine prognostic models that were externally validated in the EICC cohort, only two showed reasonable discrimination and moderate calibration. For future pandemics, better models based on routine data are needed to support admission decision-making.

3.
Front Cardiovasc Med ; 9: 929284, 2022.
Article in English | MEDLINE | ID: covidwho-2080116

ABSTRACT

Background: COVID-19 associated coagulopathy (CAC) is associated with an increase in thromboembolic events. Current guidelines recommend prophylactic heparins in the management of CAC. However, the efficacy of this strategy in the intensive care population remains uncertain. Objective: We aimed to measure thrombin generation (TG) to assess CAC in intensive care unit (ICU) patients receiving thromboprophylaxis with low molecular weight heparin (LMWH) or unfractionated heparin (UFH). In addition, we performed statistical modeling to link TG parameters to patient characteristics and clinical parameters. Lastly, we studied the potency of different anticoagulants as an alternative to LMWH treatment in ex vivo COVID-19 plasma. Patients/Methods: We included 33 patients with confirmed COVID-19 admitted at the ICU. TG was measured at least twice over the course of 6 weeks after admission. Thrombin generation parameters peak height and endogenous thrombin potential (ETP) were compared to healthy controls. Results were subsequently correlated with a patient characteristics and laboratory measurements. In vitro spiking in TG with rivaroxaban, dabigatran, argatroban and orgaran was performed and compared to LMWH. Results: Anti-Xa levels of all patients remained within the therapeutic range throughout follow-up. At baseline, the mean (SE) endogenous thrombin potential (ETP) was 1,727 (170) nM min and 1,620 (460) nM min for ellagic acid (EA) and tissue factor (TF), respectively. In line with this we found a mean (SE) peak height of 353 (45) nM and 264 (96) nM for EA and TF. Although fluctuating across the weeks of follow-up, TG parameters remained elevated despite thromboprophylaxis. In vitro comparison of LMWHs and direct thrombin inhibitors (e.g., agratroban, dabigatran) revealed a higher efficacy in reducing coagulation potential for direct thrombin inhibition in both ellagic acid (EA) and tissue factor (TF) triggered TG. Conclusion: In a sub-group of mechanically ventilated, critically ill COVID-19 patients, despite apparent adequate anti-coagulation doses evaluated by anti-Xa levels, thrombin generation potential remained high during ICU admission independent of age, sex, body mass index, APACHE II score, cardiovascular disease, and smoking status. These observations could, only partially, be explained by (anti)coagulation and thrombosis, inflammation, and multi-organ failure. Our in vitro data suggested that direct thrombin inhibition compared with LMWH might offer an alternate, more effective anticoagulant strategy in COVID-19.

4.
Sci Rep ; 12(1): 14517, 2022 08 25.
Article in English | MEDLINE | ID: covidwho-2016838

ABSTRACT

Patients with SARS-CoV-2 infection present with different lung compliance and progression of disease differs. Measures of lung mechanics in SARS-CoV-2 patients may unravel different pathophysiologic mechanisms during mechanical ventilation. The objective of this prospective observational study is to describe whether Electrical Impedance Tomography (EIT) guided positive end-expiratory pressure (PEEP) levels unravel changes in EIT-derived parameters over time and whether the changes differ between survivors and non-survivors. Serial EIT-measurements of alveolar overdistension, collapse, and compliance change in ventilated SARS-CoV-2 patients were analysed. In 80 out of 94 patients, we took 283 EIT measurements (93 from day 1-3 after intubation, 66 from day 4-6, and 124 from day 7 and beyond). Fifty-one patients (64%) survived the ICU. At admission mean PaO2/FiO2-ratio was 184.3 (SD 61.4) vs. 151.3 (SD 54.4) mmHg, (p = 0.017) and PEEP was 11.8 (SD 2.8) cmH2O vs. 11.3 (SD 3.4) cmH2O, (p = 0.475), for ICU survivors and non-survivors. At day 1-3, compliance was ~ 55 mL/cmH2O vs. ~ 45 mL/cmH2O in survivors vs. non-survivors. The intersection of overdistension and collapse curves appeared similar at a PEEP of ~ 12-13 cmH2O. At day 4-6 compliance changed to ~ 50 mL/cmH2O vs. ~ 38 mL/cmH2O. At day 7 and beyond, compliance was ~ 38 mL/cmH2O with the intersection at a PEEP of ~ 9 cmH2O vs. ~ 25 mL/cmH2O with overdistension intersecting at collapse curves at a PEEP of ~ 7 cmH2O. Surviving SARS-CoV-2 patients show more favourable EIT-derived parameters and a higher compliance compared to non-survivors over time. This knowledge is valuable for discovering the different groups.


Subject(s)
COVID-19 , Electric Impedance , Humans , Positive-Pressure Respiration/methods , SARS-CoV-2 , Tomography/methods , Tomography, X-Ray Computed/methods
5.
BMJ ; 378: e070022, 2022 07 04.
Article in English | MEDLINE | ID: covidwho-1932663

ABSTRACT

OBJECTIVE: To assess the benefits and harms of different types and doses of anticoagulant drugs for the prevention of venous thromboembolism in patients who are acutely ill and admitted to hospital. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Cochrane CENTRAL, PubMed/Medline, Embase, Web of Science, clinical trial registries, and national health authority databases. The search was last updated on 16 November 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Published and unpublished randomised controlled trials that evaluated low or intermediate dose low-molecular-weight heparin, low or intermediate dose unfractionated heparin, direct oral anticoagulants, pentasaccharides, placebo, or no intervention for the prevention of venous thromboembolism in acutely ill adult patients in hospital. MAIN OUTCOME MEASURES: Random effects, bayesian network meta-analyses used four co-primary outcomes: all cause mortality, symptomatic venous thromboembolism, major bleeding, and serious adverse events at or closest timing to 90 days. Risk of bias was also assessed using the Cochrane risk-of-bias 2.0 tool. The quality of evidence was graded using the Confidence in Network Meta-Analysis framework. RESULTS: 44 randomised controlled trials that randomly assigned 90 095 participants were included in the main analysis. Evidence of low to moderate quality suggested none of the interventions reduced all cause mortality compared with placebo. Pentasaccharides (odds ratio 0.32, 95% credible interval 0.08 to 1.07), intermediate dose low-molecular-weight heparin (0.66, 0.46 to 0.93), direct oral anticoagulants (0.68, 0.33 to 1.34), and intermediate dose unfractionated heparin (0.71, 0.43 to 1.19) were most likely to reduce symptomatic venous thromboembolism (very low to low quality evidence). Intermediate dose unfractionated heparin (2.63, 1.00 to 6.21) and direct oral anticoagulants (2.31, 0.82 to 6.47) were most likely to increase major bleeding (low to moderate quality evidence). No conclusive differences were noted between interventions regarding serious adverse events (very low to low quality evidence). When compared with no intervention instead of placebo, all active interventions did more favourably with regard to risk of venous thromboembolism and mortality, and less favourably with regard to risk of major bleeding. The results were robust in prespecified sensitivity and subgroup analyses. CONCLUSIONS: Low-molecular-weight heparin in an intermediate dose appears to confer the best balance of benefits and harms for prevention of venous thromboembolism. Unfractionated heparin, in particular the intermediate dose, and direct oral anticoagulants had the least favourable profile. A systematic discrepancy was noted in intervention effects that depended on whether placebo or no intervention was the reference treatment. Main limitations of this study include the quality of the evidence, which was generally low to moderate due to imprecision and within-study bias, and statistical inconsistency, which was addressed post hoc. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020173088.


Subject(s)
Thrombosis , Venous Thromboembolism , Anticoagulants/adverse effects , Bayes Theorem , Hemorrhage/chemically induced , Hemorrhage/drug therapy , Heparin/adverse effects , Heparin, Low-Molecular-Weight/adverse effects , Hospitals , Humans , Network Meta-Analysis , Randomized Controlled Trials as Topic , Thrombosis/drug therapy , Venous Thromboembolism/drug therapy
6.
J Thorac Imaging ; 37(4): 217-224, 2022 Jul 01.
Article in English | MEDLINE | ID: covidwho-1909064

ABSTRACT

PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is regarded as a multisystemic disease. Patients with preexisting cardiovascular disease have an increased risk for a more severe disease course. This study aimed to investigate if a higher degree of coronary artery calcifications (CAC) on a standard chest computed tomography (CT) scan in mechanically ventilated patients was associated with a more severe multiorgan failure over time. MATERIALS AND METHODS: All mechanically ventilated intensive care unit patients with SARS-CoV-2 infection who underwent a chest CT were prospectively included. CT was used to establish the extent of CAC using a semiquantitative grading system. We categorized patients into 3 sex-specific tertiles of CAC: lowest, intermediate, and highest CAC score. Daily, the Sequential Organ Failure Assessment (SOFA) scores were collected to evaluate organ failure over time. Linear mixed-effects regression was used to investigate differences in SOFA scores between tertiles. The models were adjusted for age, sex, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, cardiovascular risk factors, and chronic liver, lung, and renal disease. RESULTS: In all, 71 patients were included. Patients in the highest CAC tertile had, on average, over time, 1.8 (0.5-3.1) points higher SOFA score, compared with the lowest CAC tertile ( P =0.005). This association remained significant after adjustment for age, sex, and APACHE II score (1.4 [0.1-2.7], P =0.042) and clinically relevant after adjustment for cardiovascular risk factors (1.3 [0.0-2.7], P =0.06) and chronic diseases (1.3 [-0.2 to 2.7], P =0.085). CONCLUSION: A greater extent of CAC is associated with a more severe multiorgan failure in mechanically ventilated coronavirus disease 2019 patients.


Subject(s)
COVID-19 , Coronary Artery Disease , COVID-19/complications , Coronary Artery Disease/complications , Coronary Artery Disease/diagnostic imaging , Critical Care , Female , Humans , Intensive Care Units , Longitudinal Studies , Male , Prognosis , Retrospective Studies , Risk Factors , SARS-CoV-2
7.
J Hypertens ; 40(7): 1278-1287, 2022 07 01.
Article in English | MEDLINE | ID: covidwho-1908998

ABSTRACT

OBJECTIVES: In coronavirus disease 2019 (COVID-19), cardiovascular risk factors and myocardial injury relate to increased mortality. We evaluated the extent of cardiac sequelae 6 months after hospital discharge in patients surviving ICU hospitalization for COVID-19. METHODS: All survivors of Maastricht-ICU were invited for comprehensive cardiovascular evaluation 6 months after discharge from ICU. Cardiac screening included an electrocardiogram, cardiac biomarkers, echocardiography, cardiac magnetic resonance (CMR) and, wherever indicated, cardiac computed tomography or coronary angiogram. RESULTS: Out of 52 survivors, 81% ( n  = 42) participated to the cardiovascular follow-up [median follow-up of 6 months, interquartile range (IQR) 6.1-6.7]. Eight patients (19%) had newly diagnosed coronary artery disease (CAD), of which two required a percutaneous intervention. Echocardiographic global longitudinal strain (GLS) was abnormal in 24% and CMR-derived GLS was abnormal in 12%, despite normal left ventricular ejection fraction in all. None of the patients showed elevated T 1 relaxation times and five patients (14%) had an elevated T 2 relaxation time. Late gadolinium enhancement (LGE) reflecting regional myocardial fibrosis was increased in eight patients (21%), of which three had myocarditis and three had pericarditis. CONCLUSION: Cardiovascular follow-up at 6 months after ICU-admission for severe COVID-19 revealed that one out of five invasively mechanically ventilated survivors had CAD, a quarter had subclinical left ventricular dysfunction defined as reduced echocardiographic GLS, and 42% of the patients had CMR abnormalities (reduced LVEF, reduced GLS, LGE presence, and elevated T 2 ). On the basis of these findings, long-term cardiovascular follow-up is strongly recommended in all post-IC COVID-19 patients. CLINICAL TRIAL REGISTRATION: Trial Register number [NL8613]) https://www.trialregister.nl/trial/8613Video abstract:http://links.lww.com/HJH/B899 .


Subject(s)
COVID-19 , Coronary Artery Disease , COVID-19/complications , Contrast Media , Coronary Artery Disease/diagnostic imaging , Gadolinium , Humans , Magnetic Resonance Imaging, Cine/methods , Predictive Value of Tests , Stroke Volume , Ventricular Function, Left
8.
Artif Organs ; 46(7): 1249-1267, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1819876

ABSTRACT

OBJECTIVE: Myocardial damage occurs in up to 25% of coronavirus disease 2019 (COVID-19) cases. While veno-venous extracorporeal life support (V-V ECLS) is used as respiratory support, mechanical circulatory support (MCS) may be required for severe cardiac dysfunction. This systematic review summarizes the available literature regarding MCS use rates, disease drivers for MCS initiation, and MCS outcomes in COVID-19 patients. METHODS: PubMed/EMBASE were searched until October 14, 2021. Articles including adults receiving ECLS for COVID-19 were included. The primary outcome was the rate of MCS use. Secondary outcomes included mortality at follow-up, ECLS conversion rate, intubation-to-cannulation time, time on ECLS, cardiac diseases, use of inotropes, and vasopressors. RESULTS: Twenty-eight observational studies (comprising both ECLS-only populations and ECLS patients as part of larger populations) included 4218 COVID-19 patients (females: 28.8%; median age: 54.3 years, 95%CI: 50.7-57.8) of whom 2774 (65.8%) required ECLS with the majority (92.7%) on V-V ECLS, 4.7% on veno-arterial ECLS and/or Impella, and 2.6% on other ECLS. Acute heart failure, cardiogenic shock, and cardiac arrest were reported in 7.8%, 9.7%, and 6.6% of patients, respectively. Vasopressors were used in 37.2%. Overall, 3.1% of patients required an ECLS change from V-V ECLS to MCS for heart failure, myocarditis, or myocardial infarction. The median ECLS duration was 15.9 days (95%CI: 13.9-16.3), with an overall survival of 54.6% and 28.1% in V-V ECLS and MCS patients. One study reported 61.1% survival with oxy-right ventricular assist device. CONCLUSION: MCS use for cardiocirculatory compromise has been reported in 7.3% of COVID-19 patients requiring ECLS, which is a lower percentage compared to the incidence of any severe cardiocirculatory complication. Based on the poor survival rates, further investigations are warranted to establish the most appropriated indications and timing for MCS in COVID-19.


Subject(s)
COVID-19 , Heart Failure , Heart-Assist Devices , Adult , COVID-19/therapy , Female , Heart Failure/complications , Heart-Assist Devices/adverse effects , Humans , Middle Aged , Shock, Cardiogenic , Treatment Outcome
9.
Am J Cardiol ; 170: 118-127, 2022 05 01.
Article in English | MEDLINE | ID: covidwho-1783146

ABSTRACT

Myocardial injury in COVID-19 is associated with in-hospital mortality. However, the development of myocardial injury over time and whether myocardial injury in patients with COVID-19 at the intensive care unit is associated with outcome is unclear. This study prospectively investigates myocardial injury with serial measurements over the full course of intensive care unit admission in mechanically ventilated patients with COVID-19. As part of the prospective Maastricht Intensive Care COVID cohort, predefined myocardial injury markers, including high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and electrocardiographic characteristics were serially collected in mechanically ventilated patients with COVID-19. Linear mixed-effects regression was used to compare survivors with nonsurvivors, adjusting for gender, age, APACHE-II score, daily creatinine concentration, hypertension, diabetes mellitus, and obesity. In 90 patients, 57 (63%) were survivors and 33 (37%) nonsurvivors, and a total of 628 serial electrocardiograms, 1,565 hs-cTnT, and 1,559 NT-proBNP concentrations were assessed. Log-hs-cTnT was lower in survivors compared with nonsurvivors at day 1 (ß -0.93 [-1.37; -0.49], p <0.001) and did not change over time. Log-NT-proBNP did not differ at day 1 between both groups but decreased over time in the survivor group (ß -0.08 [-0.11; -0.04] p <0.001) compared with nonsurvivors. Many electrocardiographic abnormalities were present in the whole population, without significant differences between both groups. In conclusion, baseline hs-cTnT and change in NT-proBNP were strongly associated with mortality. Two-thirds of patients with COVID-19 showed electrocardiographic abnormalities. Our serial assessment suggests that myocardial injury is common in mechanically ventilated patients with COVID-19 and is associated with outcome.


Subject(s)
COVID-19 , SARS-CoV-2 , Biomarkers , COVID-19/epidemiology , Humans , Natriuretic Peptide, Brain , Peptide Fragments , Prospective Studies , Respiration, Artificial , Troponin T
10.
Crit Care Med ; 50(4): 595-606, 2022 04 01.
Article in English | MEDLINE | ID: covidwho-1764676

ABSTRACT

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.


Subject(s)
COVID-19/therapy , Critical Care/methods , Intensive Care Units , APACHE , Aged , COVID-19/mortality , Cohort Studies , Europe/epidemiology , Female , Humans , Intensive Care Units/organization & administration , Intensive Care Units/statistics & numerical data , Logistic Models , Male , Middle Aged , Patient Acuity , Patient Transfer , Treatment Outcome
11.
Sci Rep ; 12(1): 734, 2022 01 14.
Article in English | MEDLINE | ID: covidwho-1625506

ABSTRACT

Although male Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) patients have higher Intensive Care Unit (ICU) admission rates and a worse disease course, a comprehensive analysis of female and male ICU survival and underlying factors such as comorbidities, risk factors, and/or anti-infection/inflammatory therapy administration is currently lacking. Therefore, we investigated the association between sex and ICU survival, adjusting for these and other variables. In this multicenter observational cohort study, all patients with SARS-CoV-2 pneumonia admitted to seven ICUs in one region across Belgium, The Netherlands, and Germany, and requiring vital organ support during the first pandemic wave were included. With a random intercept for a center, mixed-effects logistic regression was used to investigate the association between sex and ICU survival. Models were adjusted for age, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, comorbidities, and anti-infection/inflammatory therapy. Interaction terms were added to investigate effect modifications by sex with country and sex with obesity. A total of 551 patients (29% were females) were included. Mean age was 65.4 ± 11.2 years. Females were more often obese and smoked less frequently than males (p-value 0.001 and 0.042, respectively). APACHE II scores of females and males were comparable. Overall, ICU mortality was 12% lower in females than males (27% vs 39% respectively, p-value < 0.01) with an odds ratio (OR) of 0.62 (95%CI 0.39-0.96, p-value 0.032) after adjustment for age and APACHE II score, 0.63 (95%CI 0.40-0.99, p-value 0.044) after additional adjustment for comorbidities, and 0.63 (95%CI 0.39-0.99, p-value 0.047) after adjustment for anti-infection/inflammatory therapy. No effect modifications by sex with country and sex with obesity were found (p-values for interaction > 0.23 and 0.84, respectively). ICU survival in female SARS-CoV-2 patients was higher than in male patients, independent of age, disease severity, smoking, obesity, comorbidities, anti-infection/inflammatory therapy, and country. Sex-specific biological mechanisms may play a role, emphasizing the need to address diversity, such as more sex-specific prediction, prognostic, and therapeutic approach strategies.


Subject(s)
COVID-19/epidemiology , Pandemics , Aged , Female , Hospitalization , Humans , Intensive Care Units , Male , Middle Aged , Retrospective Studies , Risk Factors , Severity of Illness Index
12.
Ann Med ; 53(1): 402-409, 2021 12.
Article in English | MEDLINE | ID: covidwho-1574118

ABSTRACT

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.


Subject(s)
COVID-19/mortality , Emergency Service, Hospital/statistics & numerical data , Aged , COVID-19/diagnosis , Feasibility Studies , Female , Hospital Mortality , Humans , Length of Stay/statistics & numerical data , Logistic Models , Male , Middle Aged , Netherlands/epidemiology , Prognosis , ROC Curve , Retrospective Studies , Risk Assessment/methods , SARS-CoV-2/isolation & purification
13.
Sensors (Basel) ; 21(23)2021 Dec 05.
Article in English | MEDLINE | ID: covidwho-1555018

ABSTRACT

This study introduces machine learning predictive models to predict the future values of the monitored vital signs of COVID-19 ICU patients. The main vital sign predictors include heart rate, respiration rate, and oxygen saturation. We investigated the performances of the developed predictive models by considering different approaches. The first predictive model was developed by considering the following vital signs: heart rate, blood pressure (systolic, diastolic and mean arterial, pulse pressure), respiration rate, and oxygen saturation. Similar to the first approach, the second model was developed using the same vital signs, but it was trained and tested based on a leave-one-subject-out approach. The third predictive model was developed by considering three vital signs: heart rate (HR), respiration rate (RR), and oxygen saturation (SpO2). The fourth model was a leave-one-subject-out model for the three vital signs. Finally, the fifth predictive model was developed based on the same three vital signs, but with a five-minute observation rate, in contrast with the aforementioned four models, where the observation rate was hourly to bi-hourly. For the five models, the predicted measurements were those of the three upcoming observations (on average, three hours ahead). Based on the obtained results, we observed that by limiting the number of vital sign predictors (i.e., three vital signs), the prediction performance was still acceptable, with the average mean absolute percentage error (MAPE) being 12%,5%, and 21.4% for heart rate, oxygen saturation, and respiration rate, respectively. Moreover, increasing the observation rate could enhance the prediction performance to be, on average, 8%,4.8%, and 17.8% for heart rate, oxygen saturation, and respiration rate, respectively. It is envisioned that such models could be integrated with monitoring systems that could, using a limited number of vital signs, predict the health conditions of COVID-19 ICU patients in real-time.


Subject(s)
COVID-19 , Humans , Intensive Care Units , SARS-CoV-2 , Vital Signs
14.
Res Pract Thromb Haemost ; 5(6): e12579, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1437084

ABSTRACT

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]; P ≤ .001), LOT (3690 seconds [2963-4418]-1786 seconds [1465-2650]; P ≤ .001), and LT (7200 seconds [6144-7200]-3138 seconds [2591-4389]; P ≤ .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]; P = .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.

15.
BMJ Open ; 11(7): e047347, 2021 07 19.
Article in English | MEDLINE | ID: covidwho-1318029

ABSTRACT

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.


Subject(s)
COVID-19 , Cohort Studies , Humans , Logistic Models , Retrospective Studies , SARS-CoV-2
16.
BMC Med Ethics ; 22(1): 73, 2021 06 17.
Article in English | MEDLINE | ID: covidwho-1277937

ABSTRACT

BACKGROUND: The COVID-19 pandemic has created ethical challenges for intensive care unit (ICU) professionals, potentially causing moral distress. This study explored the levels and causes of moral distress and the ethical climate in Dutch ICUs during COVID-19. METHODS: An extended version of the Measurement of Moral Distress for Healthcare Professionals (MMD-HP) and Ethical Decision Making Climate Questionnaire (EDMCQ) were online distributed among all 84 ICUs. Moral distress scores in nurses and intensivists were compared with the historical control group one year before COVID-19. RESULTS: Three hundred forty-five nurses (70.7%), 40 intensivists (8.2%), and 103 supporting staff (21.1%) completed the survey. Moral distress levels were higher for nurses than supporting staff. Moral distress levels in intensivists did not differ significantly from those of nurses and supporting staff. "Inadequate emotional support for patients and their families" was the highest-ranked cause of moral distress for all groups of professionals. Of all factors, all professions rated the ethical climate most positively regarding the culture of mutual respect,  ethical awareness and support. "Culture of not avoiding end-of-life-decisions" and "Self-reflective and empowering leadership" received the lowest mean scores. Moral distress scores during COVID-19 were significantly lower for ICU nurses (p < 0.001) and intensivists (p < 0.05) compared to one year prior. CONCLUSION: Levels and causes of moral distress vary between ICU professionals and differ from the historical control group. Targeted interventions that address moral distress during a crisis are desirable to improve the mental health and retention of ICU professionals and the quality of patient care.


Subject(s)
COVID-19 , Attitude of Health Personnel , Critical Care , Humans , Intensive Care Units , Morals , Pandemics , SARS-CoV-2 , Stress, Psychological , Surveys and Questionnaires
17.
Thromb J ; 19(1): 35, 2021 May 31.
Article in English | MEDLINE | ID: covidwho-1249557

ABSTRACT

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.

18.
Front Cardiovasc Med ; 8: 654174, 2021.
Article in English | MEDLINE | ID: covidwho-1226974

ABSTRACT

Background: 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. Objective: 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. Patients/Methods: 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. Results: 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. Conclusion: ROTEM tests in COVID-19 ICU patients show hypercoagulability and severe hypofibrinolysis persisting over at least 6 weeks.

19.
Crit Care Med ; 49(10): 1726-1738, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1221494

ABSTRACT

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.


Subject(s)
COVID-19/complications , Recovery of Function/physiology , Respiration, Artificial/adverse effects , Survivors/statistics & numerical data , Aged , COVID-19/therapy , Cohort Studies , Female , Follow-Up Studies , Humans , Length of Stay/statistics & numerical data , Male , Middle Aged , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Physical Functional Performance , Prospective Studies , Respiration, Artificial/methods , Respiration, Artificial/statistics & numerical data , Survivors/psychology , Time Factors
20.
Lancet Rheumatol ; 2(12): e764-e773, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1003183

ABSTRACT

BACKGROUND: Severe COVID-19 is characterised by inflammation and coagulation in the presence of complement system activation. We aimed to explore the potential benefit and safety of selectively blocking the anaphylatoxin and complement protein C5a with the monoclonal antibody IFX-1 (vilobelimab), in patients with severe COVID-19. METHODS: We did an exploratory, open-label, randomised phase 2 trial (part of the adaptive phase 2/3 PANAMO trial) of intravenous IFX-1 in adults with severe COVID-19 at three academic hospitals in the Netherlands. Eligibility criteria were age 18 years or older; severe pneumonia with pulmonary infiltrates consistent with pneumonia, a clinical history of severe shortness of breath within the past 14 days, or a need for non-invasive or invasive ventilation; severe disease defined as a ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO2/FiO2) between 100 mm Hg and 250 mm Hg in the supine position; and severe acute respiratory syndrome coronavirus 2 infection confirmed by RT-PCR. Patients were randomly assigned 1:1 to receive IFX-1 (up to seven doses of 800 mg intravenously) plus best supportive care (IFX-1 group) or best supportive care only (control group). The primary outcome was the percentage change in PaO2/FiO2 in the supine position between baseline and day 5. Mortality at 28 days and treatment-emergent and serious adverse events were key secondary outcomes. The primary analysis was done in the intention-to-treat population and safety analyses were done in all patients according to treatment received. This trial is registered at ClinicalTrials.gov (NCT04333420). FINDINGS: Between March 31 and April 24, 2020, 30 patients were enrolled and randomly assigned to the IFX-1 group (n=15) or the control group (n=15). During the study it became clear that several patients could not be assessed regularly in the supine position because of severe hypoxaemia. It was therefore decided to focus on all PaO2/FiO2 assessments (irrespective of position). At day 5 after randomisation, the mean PaO2/FiO2 (irrespective of position) was 158 mm Hg (SD 63; range 84-265) in the IFX-1 group and 189 mm Hg (89; 71-329) in the control group. Analyses of the least squares mean relative change in PaO2/FiO2 at day 5 showed no differences between treatment groups (17% change in the IFX-1 group vs 41% in the control group; difference -24% [95% CI -58 to 9], p=0·15. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0-31) for the IFX-1 group and 27% (4-49) for the control group (adjusted hazard ratio for death 0·65 [95% CI 0·10-4·14]). The frequency of serious adverse events were similar between groups (nine [60%] in the IFX-1 group vs seven [47%] in the control group) and no deaths were considered related to treatment assignment. However, a smaller proportion of patients had pulmonary embolisms classed as serious in the IFX-1 group (two [13%]) than in the control group (six [40%]). Infections classed as serious were reported in three (20%) patients in the IFX-1 group versus five (33%) patients in the control group. INTERPRETATION: In this small exploratory phase 2 part of the PANAMO trial, C5a inhibition with IFX-1 appears to be safe in patients with severe COVID-19. The secondary outcome results in favour of IFX-1 are preliminary because the study was not powered on these endpoints, but they support the investigation of C5a inhibition with IFX-1 in a phase 3 trial using 28-day mortality as the primary endpoint. FUNDING: InflaRx.

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