Levosimendan in intensive care and emergency medicine: literature update and expert recommendations for optimal efficacy and safety.

The inodilator levosimendan, in clinical use for over two decades, has been the subject of extensive clinical and experimental evaluation in various clinical settings beyond its principal indication in the management of acutely decompensated chronic heart failure. Critical care and emergency medicine applications for levosimendan have included postoperative settings, septic shock, and cardiogenic shock. As the experience in these areas continues to expand, an international task force of experts from 15 countries (Austria, Belgium, China, Croatia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Spain, Sweden, Switzerland, and the USA) reviewed and appraised the latest additions to the database of levosimendan use in critical care, considering all the clinical studies, meta-analyses, and guidelines published from September 2019 to November 2021. Overall, the authors of this opinion paper give levosimendan a "should be considered" recommendation in critical care and emergency medicine settings, with different levels of evidence in postoperative settings, septic shock, weaning from mechanical ventilation, weaning from veno-arterial extracorporeal membrane oxygenation, cardiogenic shock, and Takotsubo syndrome, in all cases when an inodilator is needed to restore acute severely reduced left or right ventricular ejection fraction and overall haemodynamic balance, and also in the presence of renal dysfunction/failure.

Systematic review and literature appraisal on methodology of conducting and reporting critical-care echocardiography studies: a report from the European Society of Intensive Care Medicine PRICES expert panel.

BACKGROUND: The echocardiography working group of the European Society of Intensive Care Medicine recognized the need to provide structured guidance for future CCE research methodology and reporting based on a systematic appraisal of the current literature. Here is reported this systematic appraisal. METHODS: We conducted a systematic review, registered on the Prospero database. A total of 43 items of common interest to all echocardiography studies were initially listed by the experts, and other "topic-specific" items were separated into five main categories of interest (left ventricular systolic function, LVSF n = 15, right ventricular function, RVF n = 18, left ventricular diastolic function, LVDF n = 15, fluid management, FM n = 7, and advanced echocardiography techniques, AET n = 17). We evaluated the percentage of items reported per study and the fraction of studies reporting a single item. RESULTS: From January 2000 till December 2017 a total of 209 articles were included after systematic search and screening, 97 for LVSF, 48 for RVF, 51 for LVDF, 36 for FM and 24 for AET. Shock and ARDS were relatively common among LVSF articles (both around 15%) while ARDS comprised 25% of RVF articles. Transthoracic echocardiography was the main echocardiography mode, in 87% of the articles for AET topic, followed by 81% for FM, 78% for LVDF, 70% for LVSF and 63% for RVF. The percentage of items per study as well as the fraction of study reporting an item was low or very low, except for FM. As an illustration, the left ventricular size was only reported by 56% of studies in the LVSF topic, and half studies assessing RVF reported data on pulmonary artery systolic pressure. CONCLUSION: This analysis confirmed sub-optimal reporting of several items listed by an expert panel. The analysis will help the experts in the development of guidelines for CCE study design and reporting.

Hydroxyl radicals and oxidative stress: the dark side of Fe corrosion.

Fe-based materials are considered for the manufacture of temporary implants that degrade through the corrosion of Fe by oxygen. Here we document the generation of hydroxyl radicals (HO) during this corrosion process, and their deleterious impacts on human endothelial (ECs) and smooth muscle cells (SMCs) in vitro. The generation of HO was documented by two independent acellular assays, terephtalic acid hydroxylation (fluorescence) and spin trapping technique coupled with electron paramagnetic resonance spectroscopy. All Fe-based materials tested exhibited a strong potential to generate HO. The addition of catalase prevented the formation of HO. Cellular responses were assessed in two ECs and SMCs lines using different cytotoxicity assays (WST-1 and CellTiter-Glo). Cells were exposed directly to Fe powder in the presence/absence of catalase, or to extracts obtained from the corrosion of Fe. Cell viability was dose-dependently affected by the direct contact with Fe materials, but not in the presence of catalase or after indirect exposure to cell extracts. The deleterious effect of HO on ECs and SMCs was confirmed by the dose-dependent increase of the transcripts of the oxidative stress gene heme oxygenase-1 4 h or 6 h after direct exposure to the particles, but not in presence of catalase or after indirect exposure. The demonstration of HO production during corrosion and consequent oxidative stress on human ECs and SMCs newly reveals a deleterious consequence of Fe-corrosion that should be integrated in the assessment of the biocompatibility of Fe-based alloys.

Proteolysis in septic shock patients: plasma peptidomic patterns are associated with mortality.

BACKGROUND: Uncontrolled proteolysis contributes to cell injury and organ dysfunction in animal models of circulatory shock. We investigated in humans the relationship between septic shock, proteolysis, and outcome. METHODS: Intensive care patients with septic shock (n=29) or sepsis (n=6) and non-hospitalised subjects (n=9) were recruited as part of the prospective observational trial 'ShockOmics' (ClinicalTrials.gov Identifier NCT02141607). A mass spectrometry-based approach was used to analyse the plasma peptidomes and the origin of circulating peptides from proteolysis in the enrolled subjects. RESULTS: Evidence of systemic proteolysis was indicated by a larger number of circulating peptides in septic shock patients, compared with septic patients and non-hospitalised healthy subjects. The peptide count and abundance in the septic shock patients were greater in patients who died (n=6) than in survivors (n=23), suggesting an association between magnitude of proteolysis and outcome. In silico analysis of the peptide sequences and of the sites of cleavage on the proteins of origin indicated a predominant role for serine proteases, such as chymotrypsin, and matrix metalloproteases in causing the observed proteolytic degradation. CONCLUSIONS: Systemic proteolysis is a novel fundamental pathological mechanism in septic shock. Plasma peptidomics is proposed as a new tool to monitor clinical trajectory in septic shock patients. CLINICAL TRIAL REGISTRATION: NCT02141607.

Time course of iron metabolism in critically ill patients.

BACKGROUND: Altered iron metabolism plays a central role in the development of anaemia in critically ill patients but the time course of iron status in septic and non-septic critically ill patients has not been well defined. METHODS: Prospective study in a 34-bed medico-surgical ICU. The complete blood count, iron, ferritin, transferrin, and transferrin receptor concentrations, transferrin saturation and C-reactive protein (CRP) concentrations were measured on days 1, 3 and 5 of the ICU stay in 95 consecutive ICU patients (33 with sepsis and 62 without). RESULTS: Despite an identical complete blood count on day 1, septic patients had significantly lower iron concentrations (21 [13-34] vs 50[28-75] microg/dL, p<0.001), transferrin concentrations (169[121-215] vs 214[173-247] mg/dL; p=0.003), and transferrin saturation (11[7-15] vs 19[11-25]%; p= 0.004), and higher ferritin concentrations (432[184-773] vs 204[78-354] ng/mL; p=0.002) than non-septic patients. These alterations were associated with a lower reticulocyte count (42[29-61] vs 58[48-77] x 10(3)/mm3; p=0.028). On day 1, CRP concentrations, which were higher in septic than in non-septic patients (20.0[13.5-27.5] vs 2.3[0.7-5.9] mg/dL; p<0.001), were directly correlated with ferritin concentrations (rho=0.55, p<0.001) and inversely correlated with transferrin concentrations (rho=-0.49, p=0.0001) and transferrin saturation (rho=-0.49, p=0.0001). After 3 days, iron and transferrin concentrations were identical in septic and non-septic patients. Iron metabolism remained altered in both populations until the 5th day. CONCLUSIONS: Iron status is rapidly altered in critically ill patients, especially in septic patients. These alterations persist during the course of the disease and are associated with decreased erythropoiesis.