Objective— We hypothesized that reactive oxygen species (ROS) contribute to progression of aortic valve (AV) calcification/stenosis. Methods and Results— We investigated ROS production and effects of antioxidants tempol and lipoic acid (LA) in calcification progression in rabbits given 0.5% cholesterol diet +10 ⁴ IU/d Vit.D ₂ for 12 weeks. Superoxide and H ₂ O ₂ microfluorotopography and 3-nitrotyrosine immunoreactivity showed increased signals not only in macrophages but preferentially around calcifying foci, in cells expressing osteoblast/osteoclast, but not macrophage markers. Such cells also showed increased expression of NAD(P)H oxidase subunits Nox2, p22phox, and protein disulfide isomerase. Nox4, but not Nox1 mRNA, was increased. Tempol augmented whereas LA decreased H ₂ O ₂ signals. Importantly, AV calcification, assessed by echocardiography and histomorphometry, decreased 43% to 70% with LA, but increased with tempol ( P ≤0.05). Tempol further enhanced apoptosis and Nox4 expression. In human sclerotic or stenotic AV, we found analogous increases in ROS production and NAD(P)H oxidase expression around calcifying foci. An in vitro vascular smooth muscle cell (VSMC) calcification model also exhibited increased, catalase-inhibitable, calcium deposit with tempol, but not with LA. Conclusions— Our data provide evidence that ROS, particularly hydrogen peroxide, potentiate AV calcification progression. However, tempol exhibited a paradoxical effect, exacerbating AV/vascular calcification, likely because of its induced increase in peroxide generation.

Introduction: Mechanisms underlying inotropic failure in septic shock are incompletely understood. We previously identified the presence of exosomes in the plasma of septic shock patients. These exosomes are released mainly by platelets, produce superoxide, and induce apoptosis in vascular cells by a redox-dependent pathway. We hypothesized that circulating platelet-derived exosomes could contribute to inotropic dysfunction of sepsis. Methods: We collected blood samples from 55 patients with septic shock and 12 healthy volunteers for exosome separation. Exosomes from septic patients and healthy individuals were investigated concerning their myocardial depressant effect in isolated heart and papillary muscle preparations. Results: Exosomes from the plasma of septic patients significantly decreased positive and negative derivatives of left ventricular pressure in isolated rabbit hearts or developed tension and its first positive derivative in papillary muscles. Exosomes from healthy individuals decreased these variables non-significantly. In hearts from rabbits previously exposed to endotoxin, septic exosomes decreased positive and negative derivatives of ventricular pressure. This negative inotropic effect was fully reversible upon withdrawal of exosomes. Nitric oxide (NO) production from exosomes derived from septic shock patients was demonstrated by fluorescence. Also, there was an increase in myocardial nitrate content after exposure to septic exosomes. Conclusion: Circulating platelet-derived exosomes from septic patients induced myocardial dysfunction in isolated heart and papillary muscle preparations, a phenomenon enhanced by previous in vivo exposure to lipopolysaccharide. The generation of NO by septic exosomes and the increased myocardial nitrate content after incubation with exosomes from septic patients suggest an NO-dependent mechanism that may contribute to myocardial dysfunction of sepsis.

Anemia is frequent among patients with traumatic brain injury (TBI) and is associated with an increased risk of poor outcome. The optimal hemoglobin concentration to trigger red blood cell (RBC) transfusion in patients with TBI is not clearly defined. All eligible consecutive adult patients admitted to the intensive care unit (ICU) with moderate or severe TBI were randomized to a “restrictive” (hemoglobin transfusion threshold of 7 g/dL), or a “liberal” (threshold 9 g/dL) transfusion strategy. The transfusion strategy was continued for up to 14 days or until ICU discharge. The primary outcome was the mean difference in hemoglobin between groups. Secondary outcomes included transfusion requirements, intracranial pressure management, cerebral hemodynamics, length of stay, mortality and 6-month neurological outcome. A total of 44 patients were randomized, 21 patients to the liberal group and 23 to the restrictive group. There were no baseline differences between the groups. The mean hemoglobin concentrations during the 14-day period were 8.4 ± 1.0 and 9.3 ± 1.3 (p < 0.01) in the restrictive and liberal groups, respectively. Fewer RBC units were administered in the restrictive than in the liberal group (35 vs. 66, p = 0.02). There was negative correlation (r = − 0.265, p < 0.01) between hemoglobin concentration and middle cerebral artery flow velocity as evaluated by transcranial Doppler ultrasound and the incidence of post-traumatic vasospasm was significantly lower in the liberal strategy group (4/21, 3% vs. 15/23, 65%; p < 0.01). Hospital mortality was higher in the restrictive than in the liberal group (7/23 vs. 1/21; p = 0.048) and the liberal group tended to have a better neurological status at 6 months (p = 0.06). The trial reached feasibility criteria. The restrictive group had lower hemoglobin concentrations and received fewer RBC transfusions. Hospital mortality was lower and neurological status at 6 months favored the liberal group. ClinicalTrials.gov, NCT02203292 . Registered on 29 July 2014.

There is no consensual definition of refractory shock. The use of more than 0.5 mcg/kg/min of norepinephrine or epinephrine to maintain target blood pressure is often used in clinical trials as a threshold. Nearly 6% of critically ill patients will develop refractory shock, which accounts for 18% of deaths in intensive care unit. Mortality rates are usually greater than 50%. The assessment of fluid responsiveness and cardiac function can help to guide therapy, and inotropes may be used if hypoperfusion signs persist after initial resuscitation. Arginine vasopressin is frequently used in refractory shock, although definite evidence to support this practice is still missing. Its associations with corticosteroids improved outcome in observational studies and are therefore promising alternatives. Other rescue therapies such as terlipressin, methylene blue, and high-volume isovolemic hemofiltration await more evidence before use in routine practice.

Introduction: One of the possible mechanisms by which the new coronavirus (SARS-Cov2) could induce brain damage is the impairment of cerebrovascular hemodynamics (CVH) and intracranial compliance (ICC) due to the elevation of intracranial pressure (ICP). The main objective of this study was to assess the presence of CVH and ICC alterations in patients with COVID-19 and evaluate their association with short-term clinical outcomes. Methods: Fifty consecutive critically ill COVID-19 patients were studied with transcranial Doppler (TCD) and non-invasive monitoring of ICC. Subjects were included upon ICU admission; CVH was evaluated using mean flow velocities in the middle cerebral arteries (mCBFV), pulsatility index (PI), and estimated cerebral perfusion pressure (eCPP), while ICC was assessed by using the P2/P1 ratio of the non-invasive ICP curve. A CVH/ICC score was computed using all these variables. The primary composite outcome was unsuccessful in weaning from respiratory support or death on day 7 (defined as UO). Results: At the first assessment (n = 50), only the P2/P1 ratio (median 1.20 [IQRs 1.00–1.28] vs. 1.00 [0.88–1.16]; p = 0.03) and eICP (14 [11–25] vs. 11 [7–15] mmHg; p = 0.01) were significantly higher among patients with an unfavorable outcome (UO) than others. Patients with UO had a significantly higher CVH/ICC score (9 [8–12] vs. 6 [5–7]; p < 0.001) than those with a favorable outcome; the area under the receiver operating curve (AUROC) for CVH/ICC score to predict UO was 0.86 (95% CIs 0.75–0.97); a score > 8.5 had 63 (46–77)% sensitivity and 87 (62–97)% specificity to predict UO. For those patients undergoing a second assessment (n = 29), after a median of 11 (5–31) days, all measured variables were similar between the two time-points. No differences in the measured variables between ICU non-survivors (n = 30) and survivors were observed. Conclusions: ICC impairment and CVH disturbances are often present in COVID-19 severe illness and could accurately predict an early poor outcome.

OBJECTIVE: The present study was designed to answer several concerns disclosed by systematic reviews indicating no evidence to support the use of computed tomography angiography (CTA) in the diagnosis of brain death (BD). Therefore, the aim of this study was to assess the effectiveness of CTA for the diagnosis of BD and to define the optimal tomographic criteria of intracranial circulatory arrest.METHODS: A unicenter, prospective, observational case-control study was undertaken. Comatose patients (Glasgow Coma Scale score ≤ 5), even those presenting with the first signs of BD, were included. CTA scanning of arterial and venous vasculature and transcranial Doppler (TCD) were performed. A neurological determination of BD and consequently determination of case (BD group) or control (no-BD group) was conducted. All personnel involved with assessing patients were blinded to further tests results. Accuracy of BD diagnosis determined by using CTA was calculated based on the criteria of bilateral absence of visualization of the internal cerebral veins and the distal middle cerebral arteries, the 4-point score (4PS), and an exclusive criterion of absence of deep brain venous drainage as indicated by the absence of deep venous opacification on CTA, the venous score (VS), which considers only the internal cerebral veins bilaterally.RESULTS: A total of 106 patients were enrolled in this study; 52 patients did not have BD, and none of these patients had circulatory arrest observed by CTA or TCD (100% specificity). Of the 54 patients with a clinical diagnosis of BD, 33 met the 4PS (61.1% sensitivity), whereas 47 met the VS (87% sensitivity). The accuracy of CTA was time related, with greater accuracy when scanning was performed less than 12 hours prior to the neurological assessment, reaching 95.5% sensitivity with the VS.CONCLUSIONS: CTA can reliably support a diagnosis of BD. The criterion of the absence of deep venous opacification, which can be assessed by use of the VS criteria investigated in this study, can confirm the occurrence of cerebral circulatory arrest.Clinical trial registration no.: 12500913400000068 (clinicaltrials.gov)