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Introduction: Midazolam based continuous iv sedation became again prominent during the COVID-19 pandemic. However, this sedation therapy is associated with a high incidence of benzodiazepine-related delirium and an increased number of days spent in coma. Given the high midazolam dose requirements in some patients and due to the renal clearance (CL) of the active metabolite 1-OH-midazolam-glucuronide (OHmidazolamGluc), ICU patients with COVID-19 and continuous renal replacement therapy (CRRT) may are at risk of prolonged sedation. Therefore, the aim of the study was to investigate the CL of midazolam and metabolites in 5 critically ill COVID-19 patients with CRRT. Method(s): Pre-filter blood samples and ultrafiltrate samples were collected simultaneously. Midazolam, 1-OH-midazolam (OHmidazolam) and OHmidazolamGluc plasma samples were analysed by an UPLCMS/ MS method. CL of midazolam and metabolites were calculated by the delivered renal dose and sieving (SC) coefficient. Subsequently, the CL and delivered renal dose were corrected for downtime therapy and filter integrity by a filter urea ratio. Result(s): We included 4 cases of CVVHD and 2 cases of CVVHDF. Midazolam, OHmidazolam and OHmidazolamGluc concentrations in mug/l ranged from 0 to 6070, 0 to 295 and 1727 to 39,000, respectively. SCs ranged from 0.02 to 0.03 for midazolam, 0.05 to 0.06 for OHmidazolam and 0.23-0.43 for OHmidazolamGluc. The CL in ml/min by the delivered renal dose was 0.82-1.67 for midazolam, 2.20-3.46 for OHmidazolam and 4.0-27.65 for OHmidazolamGluc. The CL in ml/min by the corrected renal dose was 0.68-1.50, 1.83-2.33 and 3.40-25.4, respectively. The urea ratios were 0.53 to 1.0. Conclusion(s): Midazolam and OHmidazolam are not removed efficiently by CRRT and OHmidazolamGluc approximately up to 43%. Type of CRRT, filter integrity and downtime of CRRT affect the CL of midazolam and metabolites. Our results have implications for more personalized titration of midazolam in COVID-19 patients with CRRT, mainly to avoid oversedation.
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Introduction: One of the common causes of COVID-19 related death is acute respiratory distress syndrome (C-ARDS). Dexamethasone is the cornerstone in the therapy of C-ARDS and reduces mortality probably by suppressing inflammatory levels in ICU patients. Its anti-inflammatory effects may be concentration-related. However, no pharmacokinetic studies of dexamethasone have been conducted in ICU patients. Therefore, we designed a population pharmacokinetic study to gain a deeper understanding of the pharmacokinetics of dexamethasone in critically ill patients in order to identify relevant covariates that can be used to personalize dosing regimens and improve clinical outcomes. Method(s): This was a retrospective pilot study at the ICU of the Erasmus Medical Center. Blood samples were collected in adults at the ICU with COVID who were treated with fixed dose intravenous dexamethasone (6 mg/day). The data were analyzed using Nonlinear Mixed Effects Modelling (NONMEM) software for population pharmacokinetic analysis and clinically relevant covariates were selected and evaluated. Result(s): A total of 51 dexamethasone samples were measured in 18 patients. A two-compartment model with first-order kinetics best fitted the data. The mean population estimates for drug clearance and inter-compartment clearance were 2.85 L/h (IIV 62.9%) and 2.11 L/h, respectively, and central and peripheral volumes of distribution were 15.4 L and 12.3 L, respectively. The covariate analysis showed a significant correlation between dexamethasone clearance and CRP. Dexamethasone clearance decreased significantly with increasing CRP in the range of 0-50 mg/L and a correlation was observed with CRP up to 100 mg/L. Conclusion(s): The dexamethasone PK parameters of ICU COVID patients were quite different from those come from healthy populations. Inflammation might play an important role in dexamethasone clearance and the dosing should be more individualized in order to achieve best therapeutic effect in ICU patients.
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Introduction: COVID-19 patients with non-resolving ARDS may benefit from treatment with high-dose steroids (HDS), because of a presumed persistent systemic and alveolar hyperinflammation. At ICU admission, it is unknown which patients require HDS. Obtaining insights in their inflammatory state by using biomarkers and determining their association with the effect of HDS could support decisionmaking. The goal of this study is to compare the patient characteristics and biomarker profiles at ICU admission of the patients that received HDS to the patients who did not. Method(s): This was a retrospective cohort study including COVID-19 patients admitted to the ICU of the Erasmus MC between 2020 and 2022. The primary intervention was treatment with HDS, defined as 1000 mg methylprednisolone or > 40 mg prednisolone for three consecutive days. We compared demographics, comorbidities, biomarkers and mortality between patients treated with HDS and without. Logistic regression multivariate analyses was used to analyze which biomarkers were associated with initiation of HDS. Result(s): We included 151 patients, of which 48 were treated with HDS at a median of 6 days after ICU admission (Table 1). There were no significant differences in demographics and comorbidities. Patients treated with HDS had a significantly longer ICU length of stay (p < 0.001) and higher hospital mortality rate (p < 0.001). LDH (p = 0.02) and ferritin (p = 0.05) levels on admission were significantly higher in patients treated with HDS, whereas their CRP was significantly lower (p = 0.02). In multivariate regression analysis, these were not independently associated with the initiation of HDS. Conclusion(s): At ICU admission, demographics and comorbidities did not differ between patients treated with HDS and without. There were no factors associated with the initiation of HDS in COVID-19 patients in the ICU. Further studies on the association between the inflammatory state, mortality, and the effect of HDS are required to understand which patients may benefit from HDS.
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Background: A central hallmark of ARDS is hypoxemic respiratory failure due to increased pulmonary capillary leakage. The kinase inhibitor imatinib was shown to reverse vascular leak. This study aimed to investigate the effect of intravenous imatinib on pulmonary edema in patients with COVID-19 ARDS. Method(s): This multicentre, randomised, double-blind, placebo-controlled clinical trial (ClinicalTrial.gov identifier NCT04794088) included adult patients admitted to the ICU with moderate or severe COVID-19 ARDS. Patients were randomised 1:1 to receive 200mg intravenous imatinib or placebo twice daily for seven days or until ICU discharge. The change in extravascular lung water index between day 1 and day 4, measured using a PiCCO catheter, was chosen as the primary endpoint. Secondary outcomes included the PaO2/FiO2 ratio, number of ventilator free days, length of ICU admission and 28-day mortality rate. Study drug safety was assessed by daily screening of the patient records for adverse and serious adverse event occurrence and by performing ECGs and targeted clinical laboratory tests to monitor renal, liver and cardiac function. Result(s): Between March 2021 and 2022, 67 predominantly male (58%) patients with a mean age of 63+/-10 years were randomized to receive imatinib or placebo. No adverse events were considered to be related to study drug administration. At the moment of the submission, data cleaning is still ongoing. Conclusion(s): Thus far, intravenous imatinib administration seems safe and feasible in patients with COVID-19 related ARDS.
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Background: Thrombosis is a frequent and severe complication in COVID-19 patients admitted to the intensive care unit (ICU). Lupus anticoagulant (LA) is a strong acquired risk factor for thrombosis in various diseases and is frequently observed in COVID-19 patients. Whether LA is associated with thrombosis in patients with severe COVID-19 is currently unclear. Aim(s): To investigate if LA is associated with thrombosis in critically ill COVID-19 patients. Method(s): The presence of LA and other antiphospholipid antibodies was assessed in COVID-19 patients admitted to the ICU. Informed consent was obtained by an opt-out approach and the study was approved by the local medical ethical committee. LA was determined with dilute Russell's Viper Venom Time (dRVVT) and LA-sensitive Activated Partial Thromboplastin Time (aPTT) reagents. Statistical analysis to study the association of LA and other antiphospholipid antibodies with thrombosis occurrence was performed using logistic regression. Result(s): Out of 169 COVID-19 patients, 116 (69%) tested positive for at least one antiphospholipid antibody upon admission to the ICU. Forty (24%) patients tested positive for LA;of whom 29 (17%) tested positive with a dRVVT, 19 (11%) tested positive with an LA-sensitive aPTT and eight (5%) tested positive on both tests. Fifty-eight (34%) patients developed thrombosis after ICU admission. The odds ratio (OR) for thrombosis in patients with LA based on a dRVVT was 2.4 (95%-CI: 1.1-5.4), which increased to 5.1 (95%-CI: 1.7-15.4) in patients on or below the median age of this study population (64 years). LA-positivity based on a dRVVT or LA-sensitive aPTT was only associated with thrombosis in patients younger than 65 years (OR: 4.2, 95%-CI: 1.5-11.7). Conclusion(s): LA on admission is strongly associated with thrombosis in critically ill COVID-19 patients, especially in patients <65 years of age.
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Background: Variation in fibrinogen caused by degradation or extension of the Aalpha chain affects the fibrin network structure and interaction of fibrin(ogen) with cells. The plasma level of these fibrinogen variants might be altered during COVID-19, potentially affecting disease severity or the risk of thrombosis. Aim(s): To investigate the level of fibrinogen Aalpha chain variants in plasma of COVID-19 patients. Method(s): Using the Clauss assay, we measured plasma levels of functional fibrinogen. ELISAs were used to measure antigen levels of total, intact (non-degraded Aalpha chain), and extended Aalpha chain fibrinogen (alphaE) in intensive care unit (ICU) patients with COVID-19 (with and without thrombosis, at two time points), COVID-19 ward patients without thrombosis, ICU patients with pneumococcal infection, and healthy controls. Ethical approval was obtained and written informed consent was obtained or an opt-out procedure was in place. Result(s): Higher levels of functional and intact fibrinogen were observed in COVID-19 ICU patients (before diagnosis of thrombosis) with (n = 18) and without thrombosis (n = 19) and ICU patients with pneumococcal infection (n = 6) than in COVID-19 ward patients (n = 10) and healthy controls (n = 7) (Figure 1). Total fibrinogen levels were higher in all ICU patients compared to healthy controls. Interestingly, the percentage of alphaE fibrinogen was significantly higher in COVID-19 ICU patients who do and do not develop thrombosis than in healthy controls. COVID-19 ICU patients who develop thrombosis also showed significantly higher percentages of alphaE fibrinogen than COVID-19 ward patients. After diagnosis of thrombosis, functional fibrinogen levels were significantly higher in COVID-19 ICU patients with thrombosis than in those without, while no differences were observed in intact, total, or alphaE fibrinogen (Figure 2). Conclusion(s): Our results show that severe COVID-19 is associated with increased percentages of alphaE fibrinogen, which may be the cause or consequence of severe disease, but does not explain the development of thrombosis. (Figure Presented).
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Background: SARS-CoV- 2 infection is associated with an increased incidence of thrombosis. Aim(s): By studying the fibrin network structure of COVID-19 patients, we aimed to unravel pathophysiological mechanisms that contribute to this increased risk of thrombosis. This may contribute to optimal prevention and treatment of COVID-19 related thrombosis. Method(s): In this case-control study, we collected plasma samples from intensive care unit (ICU) patients with COVID-19, with and without confirmed thrombosis, between April and December 2020. Additionally, we collected plasma from COVID-19 patients admitted to general wards without thrombosis, from ICU patients with pneumococcal infection, and from healthy controls. Fibrin fiber diameters and fibrin network density were quantified in plasma clots imaged with stimulated emission depletion (STED) microscopy and confocal microscopy. Finally, we determined the sensitivity to fibrinolysis. Ethical approval was obtained and written informed consent was obtained or an opt-out procedure was in place. Result(s): COVID-19 ICU patients (n = 37) and ICU patients with pneumococcal disease (n = 7) showed significantly higher fibrin network densities and longer plasma clot lysis times than healthy controls (n = 7) (Figure 1). No differences were observed between COVID-19 ICU patients with and without thrombosis, or ICU patients with pneumococcal infection. At a second time point, after thrombosis or at a similar time point in patients without thrombosis, we observed thicker fibers and longer lysis times in COVID-19 ICU patients with thrombosis (n = 19) than in COVID-19 ICU patients without thrombosis (n = 18). Conclusion(s): Our results suggest that severe COVID-19 is associated with a changed fibrin network structure and decreased susceptibility to fibrinolysis. Since these changes were not exclusive to COVID-19 patients, they may not explain the increased thrombosis risk. (Figure Presented).
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Background: The COVID-19 pandemic continues to overwhelm intensive care units (ICUs) worldwide, and improved prediction of mortality among COVID-19 patients could assist decision making in the ICU setting. In this work, we report on the development and validation of a dynamic mortality model specifically for critically ill COVID-19 patients and discuss its potential utility in the ICU. Methods: We collected electronic medical record (EMR) data from 3222 ICU admissions with a COVID-19 infection from 25 different ICUs in the Netherlands. We extracted daily observations of each patient and fitted both a linear (logistic regression) and non-linear (random forest) model to predict mortality within 24 h from the moment of prediction. Isotonic regression was used to re-calibrate the predictions of the fitted models. We evaluated the models in a leave-one-ICU-out (LOIO) cross-validation procedure. Results: The logistic regression and random forest model yielded an area under the receiver operating characteristic curve of 0.87 [0.85; 0.88] and 0.86 [0.84; 0.88], respectively. The recalibrated model predictions showed a calibration intercept of -0.04 [-0.12; 0.04] and slope of 0.90 [0.85; 0.95] for logistic regression model and a calibration intercept of -0.19 [-0.27; -0.10] and slope of 0.89 [0.84; 0.94] for the random forest model. Discussion: We presented a model for dynamic mortality prediction, specifically for critically ill COVID-19 patients, which predicts near-term mortality rather than in-ICU mortality. The potential clinical utility of dynamic mortality models such as benchmarking, improving resource allocation and informing family members, as well as the development of models with more causal structure, should be topics for future research.
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Introduction: Mitochondrial dysfunction has been linked to the persistent hypoxia and altered aerobic glycolytic metabolism seen in COVID-19 patients. This observational pilot study assessed mitochondrial function in COVID-19 patients and healthy controls (HC) utilizing in vivo and ex vivo techniques. Methods: This single center observational study examined COVID-19 patients on two time points, the first within 72 h after intensive care admission (T1), and the second seven days after T1 (T2). HC were age and sex matched to the included COVID-19 patients. In vivo epidermal mitochondrial oxygen utilization was analyzed using the COMET (Cellular Oxygen METabolism) monitor, which employs the protoporphyrin- IX triplet state technique. Ex vivo measurements consisted of in vitro mitochondrial respiration analyzed by the Oroboros O2k respirometer and free mitochondrial DNA (fMtDNA) which was isolated from plasma and quantified by qPCR. Results: 16 COVID-19 sepsis patients and 16 HC were included. The median MitoVO2 of COVID-19 patients on T1 was 4.6 mmHg s-1 [IQR;3.6-6.0], 4.6 mmHg s-1 [IQR;3.9-5.8] on T2 and 5.3 mmHg s-1 [IQR;4.5-6.3] in the HC. Basal platelet respiration did not differ substantially between the three groups, whilst PBMC basal respiration was increased by approximately 80% in the T1 group when contrasted to T2 and the HC. fMtDNA was 14 times higher in the T1 group and 5 times higher in the T2 group when compared to the HC. Conclusions: fMtDNA levels were increased in COVID-19 patients, but were not associated with decreased mitochondrial O2 consumption in vivo in the skin, and ex vivo in platelets or PBMC. This suggests the presence of mitochondrial stress, with concurrent preservation of mitochondrial respiration and function. It must be noted that due to the timing of T1, the optimal measurement window could have been missed. Therefore, the role of mitochondrial dysfunction in COVID-19 should be further evaluated at different time points.
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Coronavirus disease 2019 (COVID-19) is still an ongoing pandemic and has already resulted in millions of deaths worldwide. Since it is frequently associated with thrombotic complications, most hospitalised patients receive some form of anticoagulant therapy. Lately, bleeding events in patients with COVID-19 have also been increasingly reported. It is not yet clear whether these are also part of the spectrum of coagulation dysfunction in COVID-19. We report two cases of patients with COVID-19 with a large spontaneous haemorrhage during therapeutic anticoagulant therapy, after a long-term stay in the ICU. We propose several hypotheses for the occurrence of bleeding in COVID-19. Physicians should be aware of this risk, especially when patients are being treated with anticoagulants, because changes in the patient's condition during the course of the disease could lead to a relative overdose. We advise regular reassessment of anticoagulation dosage in patients with COVID-19.
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Introduction: SARS-CoV-2 is responsible for a global pandemic, with almost 200 million confirmed cases. SARS-CoV-2 infection can lead to various disease states, from only mild symptoms in the majority of cases to severe disease, which is associated with an increased incidence of venous thromboembolism (VTE). We hypothesized that an altered fibrin network structure contributes to VTE in COVID-19 patients by affecting thrombus stability and fibrinolysis sensitivity. By studying the fibrin network of COVID-19 patients, we aimed to unravel the mechanisms that contribute to the increased risk of VTE in COVID-19 patients. Methods: Between April 2020 and December 2020, we collected plasma samples from patients with COVID-19 admitted to the intensive care unit (ICU) of the Erasmus Medical Center. We included patients with confirmed VTE diagnosed on CT-angiography, and COVID-19 patients without confirmed VTE during ICU admission. Samples were collected on admission to the ICU and after confirmed VTE or at similar time points in ICU patients without confirmed VTE. In addition, we collected plasma from COVID-19 patients at admission to general wards without confirmed VTE and from healthy controls. Clots were formed by mixing citrated plasma with thrombin (final concentration 1 U/ml) and calcium (17 mM). We imaged the clots using stimulated emission depletion (STED) microscopy, a super-resolution technique in which a depletion laser is used to selectively switch off fluorophores surrounding the focal point, thereby increasing the resolution. In these images, fibrin fiber diameters were measured using the Local Thickness plugin of ImageJ. Fiber density was quantified as percentage of area in Z-stacks of confocal microscopy images. Finally, a clot lysis assay based on turbidity was used to determine sensitivity to fibrinolysis (clot lysis time) and clot density (difference between maximum and baseline absorbance). Differences in fibrin network properties between groups were tested using One-Way ANOVA with Bonferroni post-hoc tests and linear regression with and without adjustment for fibrinogen levels. Results: We included 21 COVID-19 ICU patients with confirmed VTE, 20 COVID-19 ICU patients without confirmed VTE, 10 COVID-19 ward patients and 7 healthy controls. Mean age was comparable between the groups, while BMI was higher in COVID-19 patients than in healthy controls (Table 1). Levels of fibrinogen, D-dimer and anti-Xa were significantly higher in COVID-19 ICU patients than in COVID-19 ward patients and healthy controls. FVIII levels were significantly higher in COVID-19 ICU patients than in healthy controls, while FXIII levels were significantly lower. On admission to the ICU, clot density was significantly higher in COVID-19 ICU patients with and without confirmed VTE than in healthy controls (Figure 1 and Table 2). However, after adjustment for fibrinogen levels, this difference disappears. Clot lysis time was significantly longer in clots from COVID-19 ICU patients than in clots from healthy controls, regardless of fibrinogen levels (Table 2). COVID-19 ICU patients with confirmed VTE also showed a significant longer clot lysis time than COVID-19 ward patients. Interestingly, in the clot lysis assay, fibrinolysis did not occur in 25% of COVID-19 ICU patients with VTE versus 9.5% of COVID-19 ICU patients without VTE (Figure 2). This fibrinolysis shutdown was never observed in clots from healthy controls and COVID-19 ward patients. Fibrin fiber diameters were comparable between the groups. In the clots from plasma samples collected at admission to the ICU, there were no differences between COVID-19 ICU patients with and without VTE (Figure 2). However, when comparing clots prepared from plasma collected at the second time point (after VTE or at a similar time point for patients without VTE), we observed significant longer clot lysis times in patients with confirmed VTE (97.4 [88.5-158.8] min) than in patients without confirmed VTE (80.0 [76.0-97.8] min) (p=0.03). Finally, there were no significant changes between clots fro plasma before and after VTE or between the two time points in patients without VTE, except for a decreased clot lysis time over time for COVID-19 ICU patients without confirmed VTE. Conclusion: Our results suggest that SARS-CoV-2 infection increases clot density and decreases clot susceptibility to fibrinolysis, and that these changes relate to the severity of the disease. [Formula presented] Disclosures: Kruip: Daiichi Sankyo: Research Funding;Bayer: Honoraria, Research Funding.
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Background : An increased incidence of thrombo-embolic events has been described in Coronavirus Disease 2019 (COVID-19) patients, especially in critically-ill patients. In response, ISTH guidelines consider use of intermediate-dose low-molecular-weight heparins (LMWH) in critically-ill COVID-19 patients. Therefore, twice daily nadroparin dosing can been applied to prevent thrombo-embolic events. Although population pharmacokinetic (PK) parameters of nadroparin are unknown in ICU COVID-19 patients, these parameters would allow evaluation of the proposed dosing schemes from current guidelines. Aims : To construct a population PK model describing anti-Xa levels subsequent to nadroparin administration, allowing assessment of population PK parameters and their associated interpatient variability (IIV) in COVID-19 Intensive Care Unit (ICU)-patients. Methods : Retrospective data of 65 ICU patients with at least one positive SARS-CoV-2 RT-PCR test were included (Table 1/Results). At start of ICU admission, patients received twice daily 5700 IU nadroparin according to local protocol. Anti-Xa sampling was applied routinely daily. Population PK parameters were estimated using nonlinear mixed-effect modelling (NONMEM v7.4.1). Data collection was approved by the local ethics committee Results : Anti-Xa level versus time profiles were adequately described using a population PK model with one elimination and one absorption compartment (Figure 2). Including a transit-compartment did not result in significantly better data description. Population PK parameter estimates and IIV (%) were: Absorption rate: 0.245 h -1 , clearance (CL): 2010 mL/h (33.9%), V1: 10.0 L. CL increased exponentially with rising CRP, D-dimer and renal function (CKD-EPI eGFR). When applying corticosteroids or vasopressors, CL was decreased by 22.4% and 20.3% respectively. Conclusions : In critically-ill COVID-19 patients, measured anti-Xa levels were adequately described by the established population PK model. Our model shows that nadroparin clearance, reported as anti-Xa levels, is influenced by inflammation. This model will be used to evaluate limited sampling schemes for anti-Xa to facilitate blood sampling in clinical practice.
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INTRODUCTION: In the first wave, thrombotic complications were common in COVID-19 patients. It is unknown whether state-of-the-art treatment has resulted in less thrombotic complications in the second wave. METHODS: We assessed the incidence of thrombotic complications and overall mortality in COVID-19 patients admitted to eight Dutch hospitals between September 1st and November 30th 2020. Follow-up ended at discharge, transfer to another hospital, when they died, or on November 30th 2020, whichever came first. Cumulative incidences were estimated, adjusted for competing risk of death. These were compared to those observed in 579 patients admitted in the first wave, between February 24th and April 26th 2020, by means of Cox regression techniques adjusted for age, sex and weight. RESULTS: In total 947 patients with COVID-19 were included in this analysis, of whom 358 patients were admitted to the ICU; 144 patients died (15%). The adjusted cumulative incidence of all thrombotic complications after 10, 20 and 30 days was 12% (95% confidence interval (CI) 9.8-15%), 16% (13-19%) and 21% (17-25%), respectively. Patient characteristics between the first and second wave were comparable. The adjusted hazard ratio (HR) for overall mortality in the second wave versus the first wave was 0.53 (95%CI 0.41-0.70). The adjusted HR for any thrombotic complication in the second versus the first wave was 0.89 (95%CI 0.65-1.2). CONCLUSIONS: Mortality was reduced by 47% in the second wave, but the thrombotic complication rate remained high, and comparable to the first wave. Careful attention to provision of adequate thromboprophylaxis is invariably warranted.
Subject(s)
COVID-19/complications , Pulmonary Embolism/etiology , Thrombosis/etiology , Venous Thromboembolism/etiology , Aged , Aged, 80 and over , COVID-19/mortality , Cohort Studies , Critical Illness/mortality , Female , Hospitalization , Humans , Incidence , Male , Middle Aged , Netherlands/epidemiology , Proportional Hazards Models , SARS-CoV-2/isolation & purificationABSTRACT
INTRODUCTION: We recently reported a high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 admitted to the intensive care units (ICUs) of three Dutch hospitals. In answering questions raised regarding our study, we updated our database and repeated all analyses. METHODS: We re-evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction and/or systemic arterial embolism in all COVID-19 patients admitted to the ICUs of 2 Dutch university hospitals and 1 Dutch teaching hospital from ICU admission to death, ICU discharge or April 22nd 2020, whichever came first. RESULTS: We studied the same 184 ICU patients as reported on previously, of whom a total of 41 died (22%) and 78 were discharged alive (43%). The median follow-up duration increased from 7 to 14 days. All patients received pharmacological thromboprophylaxis. The cumulative incidence of the composite outcome, adjusted for competing risk of death, was 49% (95% confidence interval [CI] 41-57%). The majority of thrombotic events were PE (65/75; 87%). In the competing risk model, chronic anticoagulation therapy at admission was associated with a lower risk of the composite outcome (Hazard Ratio [HR] 0.29, 95%CI 0.091-0.92). Patients diagnosed with thrombotic complications were at higher risk of all-cause death (HR 5.4; 95%CI 2.4-12). Use of therapeutic anticoagulation was not associated with all-cause death (HR 0.79, 95%CI 0.35-1.8). CONCLUSION: In this updated analysis, we confirm the very high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 pneumonia.
Subject(s)
Arterial Occlusive Diseases/epidemiology , Coronavirus Infections/complications , Pneumonia, Viral/complications , Pulmonary Embolism/epidemiology , Thrombophilia/etiology , Venous Thrombosis/epidemiology , Acute Disease , Anticoagulants/therapeutic use , Arterial Occlusive Diseases/etiology , Brain Ischemia/epidemiology , Brain Ischemia/etiology , COVID-19 , Critical Illness , Embolism/epidemiology , Embolism/etiology , Female , Follow-Up Studies , Hospitals, Teaching/statistics & numerical data , Hospitals, University/statistics & numerical data , Humans , Incidence , Male , Middle Aged , Myocardial Infarction/epidemiology , Myocardial Infarction/etiology , Netherlands/epidemiology , Pandemics , Pulmonary Embolism/etiology , Thrombophilia/drug therapy , Venous Thrombosis/etiologyABSTRACT
INTRODUCTION: COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. Reports on the incidence of thrombotic complications are however not available. METHODS: We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital. RESULTS: We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020. All patients received at least standard doses thromboprophylaxis. The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%). PE was the most frequent thrombotic complication (n = 25, 81%). Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic complications. CONCLUSION: The 31% incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high. Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence.