IMPORTANCE: Hospitalized patients with COVID-19 are at risk for venous and arterial thromboembolism and death. Optimal thromboprophylaxis dosing in high-risk patients is unknown. OBJECTIVE: To ...evaluate the effects of therapeutic-dose low-molecular-weight heparin (LMWH) vs institutional standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: The HEP-COVID multicenter randomized clinical trial recruited hospitalized adult patients with COVID-19 with D-dimer levels more than 4 times the upper limit of normal or sepsis-induced coagulopathy score of 4 or greater from May 8, 2020, through May 14, 2021, at 12 academic centers in the US. INTERVENTIONS: Patients were randomized to institutional standard prophylactic or intermediate-dose LMWH or unfractionated heparin vs therapeutic-dose enoxaparin, 1 mg/kg subcutaneous, twice daily if creatinine clearance was 30 mL/min/1.73 m2 or greater (0.5 mg/kg twice daily if creatinine clearance was 15-29 mL/min/1.73 m2) throughout hospitalization. Patients were stratified at the time of randomization based on intensive care unit (ICU) or non-ICU status. MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was venous thromboembolism (VTE), arterial thromboembolism (ATE), or death from any cause, and the principal safety outcome was major bleeding at 30 ± 2 days. Data were collected and adjudicated locally by blinded investigators via imaging, laboratory, and health record data. RESULTS: Of 257 patients randomized, 253 were included in the analysis (mean SD age, 66.7 14.0 years; men, 136 53.8%; women, 117 46.2%); 249 patients (98.4%) met inclusion criteria based on D-dimer elevation and 83 patients (32.8%) were stratified as ICU-level care. There were 124 patients (49%) in the standard-dose vs 129 patients (51%) in the therapeutic-dose group. The primary efficacy outcome was met in 52 of 124 patients (41.9%) (28.2% VTE, 3.2% ATE, 25.0% death) with standard-dose heparins vs 37 of 129 patients (28.7%) (11.7% VTE, 3.2% ATE, 19.4% death) with therapeutic-dose LMWH (relative risk RR, 0.68; 95% CI, 0.49-0.96; P = .03), including a reduction in thromboembolism (29.0% vs 10.9%; RR, 0.37; 95% CI, 0.21-0.66; P < .001). The incidence of major bleeding was 1.6% with standard-dose vs 4.7% with therapeutic-dose heparins (RR, 2.88; 95% CI, 0.59-14.02; P = .17). The primary efficacy outcome was reduced in non-ICU patients (36.1% vs 16.7%; RR, 0.46; 95% CI, 0.27-0.81; P = .004) but not ICU patients (55.3% vs 51.1%; RR, 0.92; 95% CI, 0.62-1.39; P = .71). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, therapeutic-dose LMWH reduced major thromboembolism and death compared with institutional standard heparin thromboprophylaxis among inpatients with COVID-19 with very elevated D-dimer levels. The treatment effect was not seen in ICU patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04401293
Background Coronavirus disease 2019 (COVID-19) is associated with venous and arterial thromboembolism (VTE and ATE) and all-cause mortality (ACM) in hospitalized patients. High-quality data are ...needed on postdischarge outcomes in patients with cardiovascular disease.
Objectives To analyze outcomes and identify risk factors for ATE, VTE, and ACM in a high-risk subgroup of hospitalized COVID-19 patients with baseline cardiovascular disease.
Methods We investigated postdischarge rates and associated risk factors of ATE, VTE, and ACM in 608 hospitalized COVID-19 patients with coronary artery disease, carotid artery stenosis (CAS), peripheral arterial disease (PAD), or ischemic stroke.
Results Through 90 days postdischarge, outcome rates were: ATE 27.3% (10.2% myocardial infarction, 10.1% ischemic stroke, 13.2% systemic embolism, 12.7% major adverse limb event); VTE 6.9% (4.1% deep vein thrombosis, 3.6% pulmonary embolism); composite of ATE, VTE, or ACM 35.2% (214/608). Multivariate analysis showed significant association between this composite endpoint and age >75 years (odds ratio OR: 1.90, 95% confidence interval CI: 1.22–2.94, p = 0.004), PAD (OR: 3.23, 95% CI: 1.80–5.81, p ≤ 0.0001), CAS (OR: 1.74, 95% CI: 1.11–2.75, p = 0.017), congestive heart failure (CHF) (OR: 1.84, 95% CI: 1.02–3.35, p = 0.044), previous VTE (OR: 3.08, 95% CI: 1.75–5.42, p < 0.0001), and intensive care unit (ICU) admission (OR: 2.93, 95% CI: 1.81–4.75, p < 0.0001).
Conclusion COVID-19 inpatients with cardiovascular disease experience high rates of ATE, VTE, or ACM through 90 days postdischarge. Age >75 years, PAD, CAS, CHF, previous VTE, and ICU admission are independent risk factors.
Inflammation in traumatic spinal cord injury (SCI) has been proposed to promote damage acutely and oppose functional recovery chronically. However, we do not yet understand the signals that initiate ...or prolong inflammation in persons with SCI. High-Mobility Group Box 1 (HMGB1) is a potent systemic inflammatory cytokine-or damage-associated molecular pattern molecule (DAMP)-studied in a variety of clinical settings. It is elevated in pre-clinical models of traumatic spinal cord injury (SCI), where it promotes secondary injury, and strategies that block HMGB1 improve functional recovery. To investigate the potential translational relevance of these observations, we measured HMGB1 in plasma from adults with acute (≤ 1 week post-SCI, n = 16) or chronic (≥ 1 year post-SCI, n = 47) SCI. Plasma from uninjured persons (n = 51) served as controls for comparison. In persons with acute SCI, average HMGB1 levels were significantly elevated within 0-3 days post-injury (6.00 ± 1.8 ng/mL, mean ± standard error of the mean SEM) or 4-7 (6.26 ± 1.3 ng/mL, mean ± SEM), compared with controls (1.26 ± 0.24 ng/mL, mean ± SEM; p ≤ 0.001 and p ≤ 0.01, respectively). In persons with chronic SCI who were injured for 15 ± 1.5 years (mean ± SEM), HMGB1 also was significantly elevated, compared with uninjured persons (3.7 ± 0.69 vs. 1.26 ± 0.24 ng/mL, mean ± SEM; p ≤ 0.0001). Together, these data suggest that HMGB1 may be a common, early, and persistent danger signal promoting inflammation in individuals with SCI.
Pregnant women with chronic hypertension are at risk for increased blood pressure and superimposed preeclampsia (SPE) in late pregnancy. Alterations in the renin-aldosterone system are a feature of ...normal pregnancy; however, their role in chronic hypertension with and without SPE is less clear. We performed a prospective, longitudinal trial of 108 women with chronic hypertension and measured plasma renin activity (PRA), 24-hour urine sodium, urine potassium, and urine aldosterone (Ualdo) at 12, 20, 28, and 36 weeks and postpartum. SPE developed in 34% of pregnancies. PRA was lower in women who developed SPE at weeks 28 (5.99 versus 6.22 ng/mL per hour; P<0.001) and 36 (5.71 versus 7.74 ng/mL per hour; P=0.002). Ualdo was lower in women with SPE compared with those without SPE at 28 weeks (59.6 versus 81.3 μg/d; P=0.039). Mean arterial pressure was inversely related to both PRA (r=−0.23; P<0.0001) and Ualdo (r=−0.11; P=0.029). PRA and Ualdo were positively associated with each other (r=0.5327; P<0.0001) after adjusting for urine potassium, urine sodium, serum potassium, and mean arterial pressure. PRA and Ualdo were lower in women of black race compared with other racial groups (P<0.001). Our results demonstrate that in women with chronic hypertension PRA and Ualdo increase in early pregnancy and subsequently decrease in women who develop SPE. These findings are consistent with the hypothesis that sodium retention may contribute to the elevation in blood pressure in SPE.
Twin pregnancy and risk of postpartum hemorrhage Blitz, Matthew J.; Yukhayev, Anar; Pachtman, Sarah L. ...
The journal of maternal-fetal & neonatal medicine,
11/2020, Letnik:
33, Številka:
22
Journal Article
Recenzirano
Objective: To identify maternal and peripartum characteristics in twin gestations that are associated with postpartum hemorrhage (PPH) in which one or more units of packed red blood cells (PRBCs) ...were either administered or recommended but declined (PPH + PRBC).
Methods: This retrospective cohort study evaluated all women with twin gestations who delivered at greater than 23 weeks of gestational age at a single, tertiary medical center from 2011 to 2016. Patients were included if they had documentation of estimated blood loss (EBL) at delivery and complete inpatient medical records available for review. Patients with incomplete records or an intrauterine fetal demise of one or both twins were excluded. The primary outcome was PPH + PRBC. Secondary outcomes included PPH with delivery EBL ≥1500 ml, PPH with atony and uterotonic administration, PPH with maternal hemorrhagic morbidity (MHM), and PPH with severe maternal morbidity (SMM). MHM was a composite outcome defined as PPH associated with any of the following: atony requiring uterotonics, any PRBC transfusion (≥1 unit), uterine or hypogastric artery ligation, hysterectomy, compression sutures, intrauterine balloon tamponade, uterine artery embolization, and/or exploratory laparotomy. SMM was a composite outcome defined as PPH associated with any of the following: administration of ≥4 units of PRBC, administration of ≥2 units of PRBC, and ≥2 units of fresh frozen plasma (FFP), return to operating room for any major procedure (excludes dilation and curettage), any peripartum hysterectomy, uterine artery embolization, intrauterine balloon tamponade or compression suture placed and administration of ≥2 units of PRBC, and/or intensive care unit (ICU) admission for invasive monitoring/treatment. A multivariable logistic regression analysis was performed.
Results: A total of 1081 women with twin gestations were included. PPH + PRBC occurred in 4.4% (n = 48), delivery EBL ≥1500 ml occurred in 3.9% (n = 42), and atony with uterotonic administration occurred in 12.1% (n = 131) of the study population. The rate of MHM and SMM were 13.9% (n = 150) and 1.9% (n = 20), respectively. Although the rate of cesarean delivery was high overall (83.2%), it was nearly universal in the PPH + PRBC group (97.9%; p < .02). PPH + PRBC occurred at a rate of 0.5% (n = 1/182) among vaginally delivered twins compared to 5.2% (n = 47/899) among those delivered by cesarean (p < .03). The final multivariable logistic regression model to predict PPH + PRBC identified six significant maternal and peripartum factors: nulliparity, either pregestational or gestational diabetes, intrapartum magnesium sulfate, admission hematocrit <30%, admission platelets <100 000/µL and administration of general anesthesia.
Conclusions: A number of maternal and peripartum factors are associated with PPH in twin gestations. Optimization of maternal hematologic parameters and chronic medical conditions, and reduction in the rate of cesarean delivery in twin pregnancies may decrease the risk of postpartum hemorrhage.
Many intervertebral disc diseases cause low back pain (LBP). Proinflammatory cytokines and matrix metalloproteinases (MMPs) participate in disc pathology. In this study, we examined levels of serum ...cytokines and MMPs in human subjects with diagnoses of disc herniation (DH), spinal stenosis (SS), or degenerative disc disease (DDD) relative to levels in control subjects. Comparison between subjects with DH and those with other diagnoses (Other Dx, grouped from SS and DDD) was performed to elaborate a pathological mechanism based on circulating cytokine levels.
Study participants were recruited from a spine neurosurgery practice (n = 80), a back pain management practice (n = 27), or a control cohort (n = 26). Serum samples were collected before treatment and were assayed by multiplex assays for levels of interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ, tumor necrosis factor-α, MMP-1, MMP-3, and MMP-9. Inflammatory and degradative mediator levels were compared for subjects with LBP and control subjects, by diagnosis and by treatment groups, controlling for effects of sex, age, and reported history of osteoarthritis. Spearman's correlation coefficient was used to examine relationships with age, body mass index (BMI), symptom duration, and smoking history.
Serum levels of IL-6 were significantly higher in subjects with LBP compared with control subjects. Participants with LBP due to Other Dx had significantly higher levels of IL-6 than DH and controls. Serum levels of MMP-1 were significantly lower in LBP subjects, specifically those with DH, than in control subjects. Positive correlations were found between IL-6 levels and BMI, symptom duration, and age. MMP-1 levels were positively correlated with age.
The findings of the present clinical study are the results of the first examination of circulating cytokine levels in DDD and SS and provide evidence for a more extensive role of IL-6 in disc diseases, where patients with DDD or SS have higher serum cytokine levels than those with DH or control subjects. These findings suggest that LBP subjects have low-grade systemic inflammation, and biochemical profiling of circulating cytokines may assist in refining personalized diagnoses of disc diseases.
Increased left ventricular wall thickness is a hallmark of cardiac amyloidosis (CA). Several other disease states, including hypertrophic cardiomyopathy (HCM), share this common feature. Myocardial ...strain has emerged as a diagnostic and prognostic tool to differentiate causes of increased left ventricular wall thickness. We sought to determine if regional strain differences were present in CA when compared with HCM when indexed to wall thickness as well as adjusting for important factors such as ejection fraction (EF), age, sex, and hypertension.
We performed a multicenter, retrospective analysis of 122 patients in 3 groups: CA (n=40), HCM (n=44), and controls (n=38). Using commercially available software, we determined peak systolic strain measurements in the base, mid, and apical segments in all 3 cardinal directions of radial strain, circumferential strain, and longitudinal strain. The regional strain was indexed to wall thickness to create a strain to wall thickness (STT) ratio. Analysis of Variance was performed to examine the association of each strain parameter with the disease group, adjusting for age, sex, hypertension, and EF. Multinomial logistic regression was performed to determine which combination of variables can potentially be used to best model the disease group.
Ratios of STT at all 3 levels were significantly different with respect to the cardinal directions of radial, circumferential, and longitudinal strain in a multivariable analysis adjusting for age, sex, and hypertension. Specifically, with respect to the basal segments, the STT ratio across CA, HCM, and normal were significantly different in radial (1.13±0.34 vs. 3.79±0.22 vs. 4.12±0.38; P<0.0001), circumferential (-0.79±0.10 vs. -1.62±0.07 vs. -2.25±0.11; P<0.0001), and longitudinal directions (-0.41±0.09 vs. -1.03±0.06 vs. -1.41±0.10; P<0.0001). When adjusting for age, sex, hypertension and EF, only the base was significantly different between the CA and HCM groups in the radial (1.49±0.37 vs. 3.53±0.24; P<0.0001), circumferential -1.04±0.10 vs. -1.44±0.06; P<0.005), and longitudinal (-0.55±0.10 vs -0.94±0.06; P=0.007) directions. Using multinomial logistic regression, the use of age, left ventricular EF, global longitudinal strain, and basal radial strain yielded a diagnostic model with an area under the receiver operating characteristic curve (AUC) of 0.98. A model excluding age, despite being likely an independent predictor in our cohort, yielded an overall AUC of 0.90. When excluding age, the overall AUC was 0.91 and specifically when discriminating CA from HCM was 0.95.
Regional myocardial strain indexed to wall thickness with an STT ratio can differentiate between etiologies of increased left ventricular wall thickness. Differences in myocardial deformation may be independent of wall thickness. Differences in basal strain when indexed to wall thickness in all 3 cardinal directions between CA and HCM are independent of EF. Multinomial logistic regression analysis using strain parameters differentiates CA and HCM with excellent diagnostic accuracy.
Macrophage migration inhibitory factor (MIF) is a multifunctional protein that exhibits an intrinsic thiol protein oxidoreductase activity and proinflammatory activities. In the present study to ...examine intracellular MIF redox function, exposure of MIF-deficient cardiac fibroblasts to oxidizing conditions resulted in a 2.3-fold increase (p < 0.001) in intracellular ROS that could be significantly reduced by adenoviral-mediated reexpression of recombinant MIF. In an animal model of myocardial injury by ischemia/reperfusion (I/R), MIF-deficient hearts exhibited higher levels of oxidative stress than did wild-type hearts, as measured by significantly higher oxidized glutathione levels (decreased GSH/GSSG ratio), increased protein oxidation, reduced aconitase activity, and increased mitochondrial injury (increased cytochrome c release). The increased myocardial oxidative stress after I/R was reflected by larger infarct size (INF) in MIF-deficient hearts versus wild-type (WT) hearts (21 ± 6% vs. 8 ± 3% INF/LV; p < 0.05). In vivo hemodynamic measurements showed that left ventricular (LV) contractile function of MIF-deficient hearts subjected to 15-min ischemia failed to recover during reperfusion compared with WT hearts (LV developed pressure and ± dP/dt; p = 0.02). These data represent the first in vivo evidence in support of a cardioprotective role of MIF in the postischemic heart by reducing oxidative stress.
In patients with aneurysmal subarachnoid hemorrhage (aSAH), poor outcomes have been shown to be correlated with subsequent cerebral vasospasm (CV) and delayed cerebral ischemia (DCI). The ...identification of novel biomarkers may aid in the prediction of which patients are vulnerable to developing vasospasm, cerebral ischemia, and neurological deterioration.
In this prospective clinical study at North Shore University Hospital, patients with aSAH or normal pressure hydrocephalus (NPH) with external ventricular drains were enrolled. The concentration of macrophage migration inhibitory factor (MIF) in CSF was assessed for correlation with CV or DCI, the primary outcome measures.
Twenty-five patients were enrolled in the aSAH group and 9 were enrolled in the NPH group. There was a significant increase in aggregate CSF MIF concentration in patients with aSAH versus those with NPH (24.4 ± 19.2 vs 2.3 ± 1.1 ng/ml, p < 0.0002). Incidence of the day of peak MIF concentration significantly correlated with the onset of clinical vasospasm (rho = 0.778, p < 0.0010). MIF concentrations were significantly elevated in patients with versus those without evidence of DCI (18.7 ± 4.93 vs 8.86 ± 1.28 ng/ml, respectively, p < 0.0025). There was a significant difference in MIF concentrations between patients with infection versus those without infection (16.43 ± 4.21 vs 8.5 ± 1.22 ng/ml, respectively, p < 0.0119).
Preliminary evidence from this study suggests that CSF concentrations of MIF are correlated with CV and DCI. These results, however, could be confounded in the presence of clinical infection. A study with a larger patient sample size is necessary to corroborate these findings.
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