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Abstract Background Pulmonary intravascular thrombus formation has been widely observed in patients with respiratory failure, for example, in patients with SARS-CoV-2 infection (COVID-19). The aim of this study was to evaluate the efficacy/safety of alteplase thrombolysis in COVID-19 severe hypoxemic respiratory failure. In this multicenter, open-label study, patients were randomized to receive alteplase (low- or high-dose) over 5 days plus standard of care (SOC), or SOC alone. The primary endpoint was time to clinical improvement (≥ 2-point decrease on WHO Clinical Progression Scale, or hospital discharge) up to Day 28. Secondary endpoints included all-cause mortality at Day 28, treatment failure at Day 28 and change in arterial oxygen partial pressure/fractional inspired oxygen (PaO2/FiO2) ratio at Day 6 versus baseline. Results Sixty-nine patients were randomized to alteplase (low- or high-dose) and 35 to SOC; 65% were on high-flow oxygen or non-invasive ventilation at baseline. Median time to clinical improvement was 25 days in the alteplase group and > 28 days (median not reached) in the SOC group. All-cause mortality was 8/69 (12%) versus 10/35 (29%) in the alteplase versus SOC groups, respectively (unadjusted risk difference [RD], − 17% [95% confidence interval (CI) − 34 to 0], p = 0.047; adjusted RD, − 16% [95% CI − 31 to 1], p = 0.058). The PaO2/FiO2 ratio (mean [standard deviation]) increased by + 30 (84) mmHg in the alteplase group and decreased by − 12 (59) mmHg in the SOC group (adjusted mean difference vs. SOC, p = 0.052). Differences were greater in patients receiving high-dose alteplase, and in those not receiving invasive ventilation. Eighteen patients (26.1%) in the alteplase group discontinued treatment due to adverse events. Major bleeding was more frequent with alteplase than with SOC (9 vs. 0 patients); no bleeding was fatal. The study closed early due to insufficient patient recruitment. Conclusion Alteplase was not associated with faster clinical recovery from COVID-19 severe hypoxemic respiratory failure. A numerical difference in survival and PaO2/FiO2 ratio was observed, particularly in patients not receiving invasive ventilation. These exploratory findings merit further investigation in larger patient cohorts that are adequately powered to confirm the hypotheses generated in this study regarding the impact of alteplase on treatment outcomes. Trial registration ClinicalTrials.gov: NCT04640194 (November 23, 2020); https://clinicaltrials.gov/study/NCT04640194 (early discontinuation due to insufficient patient recruitment).

Abstract Background Despite the growing body of evidence supporting the use of angiotensin II (ATII) in distributive shock, its integration into existing treatment algorithms requires careful consideration of factors related to patient comorbidities, hemodynamic parameters, cost-effectiveness, and risk–benefit balance. Moreover, several questions regarding its use in clinical practice warrant further investigations. To address these challenges, a group of Italian intensive care specialists (the panel) developed a consensus process using a modified Delphi technique. Methods The panel defined five clinical questions during an online scoping workshop and then provided a short list of statements related to each clinical question based on literature review and clinical experience. A total of 20 statements were collected. Two coordinators screened and selected the final list of statements to be included in the online survey, which consisted of 17 statements. The consensus was reached when ≥ 75% of respondents assigned a score within the 3-point range of 1–3 (disagreement) or 7–9 (agreement). Results Overall, a consensus on agreement was reached on 13 statements defining the existing gaps in scientific evidence, the possibility of evaluating the addition of drugs with different mechanisms of action for the treatment of refractory shock, the utility of ATII in reducing the catecholamine requirements in the treatment of vasopressor-resistant septic shock, and the effectiveness of ATII in treating patients in whom angiotensin-converting enzyme activity is reduced or pharmacologically blocked. It was widely shared that renin concentration can be used to identify patients who most likely benefit from ATII to restore vascular tone. Thus, the patients who might benefit most from using ATII were defined. Lastly, some potential barriers to the use of ATII were described. Conclusions ATII was recognized as a useful treatment to reduce catecholamine requirements in treating vasopressor-resistant septic shock. At the same time, the need for additional clinical trials to further elucidate the efficacy and safety of ATII, as well as investigations into potential mechanisms of action and optimization of treatment protocols in patients with refractory distributive shock, emerged.

Protamine, first isolated from salmon fish sperm and now produced through recombinant biotechnology, is an antidote that neutralizes the anticoagulant properties of heparin. Protamine function is based on the capacity to dissociate the heparin–antithrombin III (AT III) complex (an important link that promotes blood fluidification by inhibiting coagulation), forming the inactive heparin–protamine complex. Protamine has itself dose-dependent anticoagulant properties: It interferes with coagulation factors and platelet function; it stimulates fibrinolysis; it can lead to thrombocytopenia and reduction in thrombin-related platelet aggregation; it decreases platelet response to thrombin receptor agonist in a dose-dependent manner. In this review, we will focus on protamine and its interaction with heparin. Notably, protamine is able to antagonize not only unfractionated heparin (UFH) but also low molecular weight heparins to various degrees. Protamine-allergic and anaphylactoid systemic reactions may affect up to 1 in 10 people and should be prevented and treated early.

BackgroundWith machine learning (ML) carving a niche in diverse medical disciplines, its role in sepsis prediction, a condition where the ‘golden hour’ is critical, is of paramount interest. This study assesses the factors influencing the efficacy of ML models in sepsis prediction, aiming to optimize their use in clinical practice.MethodsWe searched Medline, PubMed, Google Scholar, and CENTRAL for studies published from inception to October 2023. We focused on studies predicting sepsis in real-time settings in adult patients in any hospital settings without language limits. The primary outcome was area under the curve (AUC) of the receiver operating characteristic. This meta-analysis was conducted according to PRISMA-NMA guidelines and Cochrane Handbook recommendations. A Network Meta-Analysis using the CINeMA approach compared ML models against traditional scoring systems, with meta-regression identifying factors affecting model quality.ResultsFrom 3,953 studies, 73 articles encompassing 457,932 septic patients and 256 models were analyzed. The pooled AUC for ML models was 0.825 and it significantly outperformed traditional scoring systems. Neural Network and Decision Tree models demonstrated the highest AUC metrics. Significant factors influencing AUC included ML model type, dataset type, and prediction window.ConclusionThis study establishes the superiority of ML models, especially Neural Network and Decision Tree types, in sepsis prediction. It highlights the importance of model type and dataset characteristics for prediction accuracy, emphasizing the necessity for standardized reporting and validation in ML healthcare applications. These findings call for broader clinical implementation to evaluate the effectiveness of these models in diverse patient groups.Systematic review registrationhttps://inplasy.com/inplasy-2023-12-0062/, identifier, INPLASY2023120062.

Abstract The renin-angiotensin system (RAS) constitutes one of the principal mechanisms to maintain hemodynamic and fluid homeostasis. However, most research until now on RAS primarily focuses on its relationship with hypertension and its role in critically ill hypotensive populations is not well understood. With the approval of angiotensin II (Ang II) in the United States and Europe, following a phase 3 randomized controlled trial showing efficacy in catecholamine-resistant vasodilatory shock, there is growing interest in RAS in critically ill patients. Among the fundamental components of RAS, renin acts as the initial stimulus for the entire system. In the context of hypotension, its release increases in response to low blood pressure sensed by renal baroreceptors and attenuated negative Ang II feedback loop. Thus, elevated renin could reflect disease severity and predict poor outcomes. Studies investigating this hypothesis have validated the prognostic accuracy of renin in various critically ill populations, with several reports indicating its superiority to lactate for mortality prediction. Accordingly, renin reduction has been used to assess the effectiveness of Ang II administration. Furthermore, renin holds potential to identify patients who might benefit from Ang II treatment, potentially paving the way for personalized vasopressor management. Despite these promising data, most available evidence is derived from retrospective analysis and necessitates prospective confirmation. The absence of a rapid, point-of-care and reliable renin assay presents another hurdle to its integration into routine clinical practice. This narrative review aims to describe the current understanding and future directions of renin as a biomarker during resuscitation of critically ill patients.

Background: Postoperative agitation is common after non-cardiac surgery. It is associated with postoperative delirium and cognitive dysfunction, leading to prolonged hospital stay and delayed social readjustment. Prevention and treatment strategies are lacking. We assessed the efficacy of a novel approach, the Wash In/Wash Out procedure, in reducing post-anesthetic agitation. Methods: This multicenter, parallel-group, double-blind randomized controlled trial is enrolling 200 patients undergoing open abdominal surgery. Participants are randomly assigned to either a control group receiving standard recovery methods or an investigational group undergoing the Wash In/Wash Out procedure. In the Wash In/Wash Out procedure group, sevoflurane is stopped and then promptly restarted when the patient shows the first signs of awakening to achieve an end-tidal concentration of 1 minimum alveolar concentration (MAC) for 5 min. This stop-and-restart cycle is performed three times. The trial's primary outcome is the rate of postoperative agitation. Secondary outcomes include rate of postoperative delirium and cognitive dysfunction, postoperative nausea and vomiting, and length of intensive care and hospital stay. Discussion: The OPERA trial investigates the effect of the Wash In/Wash Out procedure to reduce post-anesthetic agitation in non-cardiac surgery. This study could offer a significant contribution to improving patient outcomes and optimizing recovery protocols in surgical settings.

Abstract Patients with septic shock who experience refractory hypotension despite adequate fluid resuscitation and high-dose noradrenaline have high mortality rates. To improve outcomes, evidence-based guidelines recommend starting a second vasopressor, such as vasopressin, if noradrenaline doses exceed 0.5 µg/kg/min. Recently, promising results have been observed in treating refractory hypotension with angiotensin II, which has been shown to increase mean arterial pressure and has been associated with improved outcomes. This narrative review aims to provide an overview of the pathophysiology of the renin-angiotensin system and the role of endogenous angiotensin II in vasodilatory shock with a focus on how angiotensin II treatment impacts clinical outcomes and on identifying the population that may benefit most from its use.

The coronavirus disease 2019 (COVID-19) pandemic led to an unprecedented burden on healthcare systems around the world and a severe global socioeconomic crisis, with more than 750 million confirmed cases and at least 7 million deaths reported by 31st December 2023. The DEFI-VID19 study (ClinicalTrials.gov NCT04335201), a phase II, single-arm, multicenter, open-label trial was designed in mid-2020 to assess the safety and efficacy of defibrotide in treating patients with COVID-19 pneumonia. Defibrotide was administered at a dose of 25 mg/kg/d intravenously, divided into four daily doses over a planned 14-day period for patients with COVID-19 pneumonia receiving non-invasive ventilation. The primary endpoint was Respiratory Failure Free Survival (RFFS); Overall Survival (OS), the number of post-recovery days, and adverse events were the secondary endpoints. For comparison, a contemporaneous control cohort receiving standard of care only was retrospectively selected by applying the eligibility criteria of the DEFI-VID19 trial. To adjust for the imbalance between the two cohorts in terms of baseline variable distributions, an outcome regression analysis was conducted. In adjusted analysis, patients receiving defibrotide reported a trend towards higher RFFS (HR=0.71[0.95CI: 0.34 to 1.29, P= .138]) and OS (HR=0.78[0.95CI: 0.33 to 1.53, P= .248]) and showed a significantly increased number of post-recovery days (difference in means: 3.61[ 0.95CI: 0.97 to 6.26, P= .0037]). Despite concomitant thromboprophylaxis with low molecular weight heparin, the safety profile of defibrotide proved to be favorable. Taken together, our findings suggest that defibrotide may represent a valuable addition to the COVID-19 therapeutic options.

Objectives Myocardial revascularisation and cardiopulmonary bypass (CPB) can cause ischaemia-reperfusion injury, leading to myocardial and other end-organ damage. Volatile anaesthetics protect the myocardium in experimental studies. However, there is uncertainty about whether this translates into clinical benefits because of the coadministration of propofol and its detrimental effects, restricting myocardial protective processes.Methods In this single-blinded, parallel-group randomised controlled feasibility trial, higher-risk patients undergoing elective coronary artery bypass graft (CABG) surgery with an additive European System for Cardiac Operative Risk Evaluation ≥5 were randomised to receive either propofol or total inhalational anaesthesia as single agents for maintenance of anaesthesia. The primary outcome was the feasibility of recruiting and randomising 50 patients across two cardiac surgical centres, and secondary outcomes included the feasibility of collecting the planned perioperative data, clinically relevant outcomes and assessments of effective patient identification, screening and recruitment.Results All 50 patients were recruited within 11 months in two centres, allowing for a 13-month hiatus in recruitment due to the COVID-19 pandemic. Overall, 50/108 (46%) of eligible patients were recruited. One patient withdrew before surgery and one patient did not undergo surgery. All but one completed in-hospital and 30-day follow-up.Conclusions It is feasible to recruit and randomise higher-risk patients undergoing CABG surgery to a study comparing total inhalational and propofol anaesthesia in a timely manner and with high acceptance and completion rates.Trial registration number NCT04039854.

Introduction: Growing evidence supports extracorporeal cardiopulmonary resuscitation (ECPR) for refractory out-of-hospital cardiac arrest (OHCA) patients, especially in experienced centres. We present characteristics, treatments, and outcomes of patients treated with ECPR in a high-volume cardiac arrest centre in the metropolitan area of Milan, Italy and determine prognostic factors. Methods: Refractory OHCA patients treated with ECPR between 2013 and 2022 at IRCCS San Raffaele Scientific Institute in Milan had survival and neurological outcome assessed at hospital discharge. Results: Out of 307 consecutive OHCA patients treated with ECPR (95% witnessed, 66% shockable, low-flow 70 [IQR 58–81] minutes), 17% survived and 9.4% had favourable neurological outcome. Survival and favourable neurological outcome increased to 51% (OR = 8.7; 95% CI, 4.3–18) and 28% (OR = 6.3; 95% CI, 2.8–14) when initial rhythm was shockable and low-flow (time between CPR initiation and ROSC or ECMO flow) ≤60 minutes and decreased to 9.5% and 6.3% when low-flow exceeded 60 minutes (72% of patients). At multivariable analysis, shockable rhythm (aOR for survival = 2.39; 95% CI, 1.04–5.48), shorter low-flow (aOR = 0.95; 95% CI, 0.94–0.97), intermittent ROSC (aOR = 2.5; 95% CI, 1.2–5.6), and signs of life (aOR = 3.7; 95% CI, 1.5–8.7) were associated with better outcomes. Survival reached 10% after treating 104 patients (p for trend

Abstract Background This study was conducted to test the hypothesis that phosphocreatine (PCr), administered intravenously and as cardioplegia adjuvant in patients undergoing cardiac surgery with prolonged aortic cross clamping and cardiopulmonary bypass (CPB) time, would decrease troponin I concentration after surgery. Methods In this randomized, double-blind, placebo-controlled pilot study we included 120 patients undergoing double/triple valve repair/replacement under cardiopulmonary bypass in the cardiac surgery department of a tertiary hospital. The treatment group received: intravenous administration of 2 g of PCr after anesthesia induction; 2.5 g of PCr in every 1 L of cardioplegic solution (concentration = 10 mmol/L); intravenous administration of 2 g of PCr immediately after heart recovery following aorta declamping; 4 g of PCr at intensive care unit admission. The control group received an equivolume dose of normosaline. Results The primary endpoint was peak concentration of troponin I after surgery. Secondary endpoints included peak concentration of serum creatinine, need for, and dosage of inotropic support, number of defibrillations after aortic declamping, incidence of arrhythmias, duration of Intensive Care Unit (ICU) stay, length of hospitalization. There was no difference in peak troponin I concentration after surgery (PCr, 10,508 pg/ml [IQR 6,838–19,034]; placebo, 11,328 pg/ml [IQR 7.660–22.894]; p = 0.24). There were also no differences in median peak serum creatinine (PCr, 100 µmol/L [IQR 85.0–117.0]; placebo, 99.5 µmol/L [IQR 90.0–117.0]; p = 0.87), the number of patients on vasopressor/inotropic agents (PCr, 49 [88%]; placebo, 57 [91%]; p = 0.60), the inotropic score on postoperative day 1 (PCr, 4.0 (0–7); placebo, 4.0 (0–10); p = 0.47), mean SOFA score on postoperative day 1 (PCr, 5.25 ± 2.33; placebo, 5,45 ± 2,65; p = 0.83), need for defibrillation after declamping of aorta (PCr, 22 [39%]; placebo, 25 [40%]; p = 0.9),, duration of ICU stay and length of hospitalization as well as 30-day mortality (PCr, 0 (0%); placebo,1 (4.3%); p = 0.4). Conclusion PCr administration to patients undergoing double/triple valve surgery under cardiopulmonary bypass is safe but is not associated with a decrease in troponin I concentration. Phosphocreatine had no beneficial effect on clinical outcomes after surgery. Trial registration The study is registered at ClinicalTrials.gov with the Identifier: NCT02757443. First posted (published): 02/05/2016.

Abstract Introduction Polymorphonuclear cell influx into the interstitial and bronchoalveolar spaces is a cardinal feature of severe coronavirus disease 2019 (COVID-19), principally mediated by interleukin-8 (IL-8). We sought to determine whether reparixin, a novel IL-8 pathway inhibitor, could reduce disease progression in patients hospitalized with severe COVID-19 pneumonia. Methods In this Phase 3, randomized, double-blind, placebo-controlled, multicenter study, hospitalized adult patients with severe COVID-19 pneumonia were randomized 2:1 to receive oral reparixin 1200 mg three times daily or placebo for up to 21 days or until hospital discharge. The primary endpoint was the proportion of patients alive and free of respiratory failure at Day 28, with key secondary endpoints being the proportion of patients free of respiratory failure at Day 60, incidence of intensive care unit (ICU) admission by Day 28 and time to recovery by Day 28. Results Of 279 patients randomized, 182 received at least one dose of reparixin and 88 received placebo. The proportion of patients alive and free of respiratory failure at Day 28 was similar in the two groups {83.5% versus 80.7%; odds ratio 1.63 [95% confidence interval (CI) 0.75, 3.51]; p = 0.216}. There were no statistically significant differences in the key secondary endpoints, but a numerically higher proportion of patients in the reparixin group were alive and free of respiratory failure at Day 60 (88.7% versus 84.6%; p = 0.195), fewer required ICU admissions by Day 28 (15.8% versus 21.7%; p = 0.168), and a higher proportion recovered by Day 28 compared with placebo (81.6% versus 74.9%; p = 0.167). Fewer patients experienced adverse events with reparixin than placebo (45.6% versus 54.5%), most mild or moderate intensity and not related to study treatment. Conclusions This trial did not meet the primary efficacy endpoints, yet reparixin showed a trend toward limiting disease progression as an add-on therapy in COVID-19 severe pneumonia and was well tolerated. Trial Registration ClinicalTrials.gov: NCT04878055, EudraCT: 2020-005919-51. Graphical Abstract

Background Early postoperative neurocognitive disorders (ePND), include both emergence delirium, which is defined as very early onset postoperative delirium, and emergence agitation, defined as motor arousal. Although research on anesthesia emergence is limited, ePND are likely associated with unfavorable outcomes. This meta-analysis assessed the effect of ePND on clinically relevant outcomes. Methods A systematic search of studies published between 2002 and 2022 on MEDLINE, PubMed, Google Scholar, and the Cochrane Library was performed. Studies that included adults with emergence agitation and/or delirium and reported at least one of the following outcomes: mortality, postoperative delirium, length of post-anesthesia care unit stay, or length of hospital stay were included. The internal validity, risk of bias, and certainty of the evidence were assessed. Results A total of 16,028 patients from 21 prospective observational studies and one case-control retrospective study were included in this meta-analysis. The occurrence rate of ePND was 13% (data excluding the case-control study). The mortality rate was 2.4% in patients with ePND vs. 1.2% in the normal emergence group (risk ratio [RR]: 2.6, P = 0.01, very low quality of evidence). Postoperative delirium occurred in 29% of patients with ePND and 4.5% of patients with normal emergence (RR: 9.5, P < 0.001, I2 = 93%). Patients with ePND had a prolonged length of post-anesthesia care unit stay (P = 0.004) and length of hospital stay (P < 0.001). Conclusions This meta-analysis suggests that ePND are associated with twice the risk of mortality and a 9-fold increased risk of postoperative delirium.

Abstract Background Propofol is one of the most widely used hypnotic agents in the world. Nonetheless, propofol might have detrimental effects on clinically relevant outcomes, possibly due to inhibition of other interventions' organ protective properties. We performed a systematic review and meta-analysis of randomized controlled trials to evaluate if propofol reduced survival compared to any other hypnotic agent in any clinical setting. Methods We searched eligible studies in PubMed, Google Scholar, and the Cochrane Register of Clinical Trials. The following inclusion criteria were used: random treatment allocation and comparison between propofol and any comparator in any clinical setting. The primary outcome was mortality at the longest follow-up available. We conducted a fixed-effects meta-analysis for the risk ratio (RR). Using this RR and 95% confidence interval, we estimated the probability of any harm (RR > 1) through Bayesian statistics. We registered this systematic review and meta-analysis in PROSPERO International Prospective Register of Systematic Reviews (CRD42022323143). Results We identified 252 randomized trials comprising 30,757 patients. Mortality was higher in the propofol group than in the comparator group (760/14,754 [5.2%] vs. 682/16,003 [4.3%]; RR = 1.10; 95% confidence interval, 1.01–1.20; p = 0.03; I2 = 0%; number needed to harm = 235), corresponding to a 98.4% probability of any increase in mortality. A statistically significant mortality increase in the propofol group was confirmed in subgroups of cardiac surgery, adult patients, volatile agent as comparator, large studies, and studies with low mortality in the comparator arm. Conclusions Propofol may reduce survival in perioperative and critically ill patients. This needs careful assessment of the risk versus benefit of propofol compared to other agents while planning for large, pragmatic multicentric randomized controlled trials to provide a definitive answer. Graphical Abstract

Abstract Vasopressors and fluids are the cornerstones for the treatment of shock. The current international guidelines on shock recommend norepinephrine as the first-line vasopressor and vasopressin as the second-line vasopressor. In clinical practice, due to drug availability, local practice variations, special settings, and ongoing research, several alternative vasoconstrictors and adjuncts are used in the absence of precise equivalent doses. Norepinephrine equivalence (NEE) is frequently used in clinical trials to overcome this heterogeneity and describe vasopressor support in a standardized manner. NEE quantifies the total amount of vasopressors, considering the potency of each such agent, which typically includes catecholamines, derivatives, and vasopressin. Intensive care studies use NEE as an eligibility criterion and also an outcome measure. On the other hand, NEE has several pitfalls which clinicians should know, important the lack of conversion of novel vasopressors such as angiotensin II and also adjuncts such as methylene blue, including a lack of high-quality data to support the equation and validate its predictive performance in all types of critical care practice. This review describes the history of NEE and suggests an updated formula incorporating novel vasopressors and adjuncts.

Background: Inflammation during and after surgery can lead to organ damage including acute kidney injury. Colchicine, an established inexpensive anti-inflammatory medication, may help to protect the organs from pro-inflammatory damage. This protocol describes a kidney substudy of the colchicine for the prevention of perioperative atrial fibrillation (COP-AF) study, which is testing the effect of colchicine versus placebo on the risk of atrial fibrillation and myocardial injury among patients undergoing thoracic surgery. Objective: Our kidney substudy of COP-AF will determine whether colchicine reduces the risk of perioperative acute kidney injury compared with a placebo. We will also examine whether colchicine has a larger absolute benefit in patients with pre-existing chronic kidney disease, the most prominent risk factor for acute kidney injury. Design and Setting: Randomized, superiority clinical trial conducted in 40 centers in 11 countries from 2018 to 2023. Patients: Patients (~3200) aged 55 years and older having major thoracic surgery. Intervention: Patients are randomized 1:1 to receive oral colchicine (0.5 mg tablet) or a matching placebo, given twice daily starting 2 to 4 hours before surgery for a total of 10 days. Patients, health care providers, data collectors, and outcome adjudicators will be blinded to the randomized treatment allocation. Methods: Serum creatinine concentrations will be measured before surgery and on postoperative days 1, 2, and 3 (or until hospital discharge). The primary outcome of the substudy is perioperative acute kidney injury, defined as an increase (from the prerandomization value) in serum creatinine concentration of either ≥26.5 μmol/L (≥0.3 mg/dL) within 48 hours of surgery or ≥50% within 7 days of surgery. The primary analysis (intention-to-treat) will examine the relative risk of acute kidney injury in patients allocated to receive colchicine versus placebo. We will repeat the primary analysis using alternative definitions of acute kidney injury and examine effect modification by pre-existing chronic kidney disease, defined as a prerandomization estimated glomerular filtration rate (eGFR)

IntroductionMicroRNAs (miRs) emerged as promising diagnostic and therapeutic biomarkers in cardiovascular diseases. The potential clinical utility of platelet miRs in the setting of left ventricular assist device (LVAD) support is unexplored.MethodsWe prospectively measured the expression levels of 12 platelet miRs involved in platelet activation, coagulation, and cardiovascular diseases in LVAD patients by quantitative real-time polymerase chain reaction. Data were longitudinally measured before LVAD implant and after 1, 6, and 12 months of LVAD support, and compared with those measured in healthy volunteers (controls). In silico analysis was also performed to identify pathways targeted by differentially expressed miRs.ResultsData from 15 consecutive patients and 5 controls were analyzed. Pre-implant expression levels of platelet miR-126, miR-374b, miR-223, and miR-320a were significantly different in patients vs. controls. The expression levels of platelet miR-25, miR-144, miR-320, and miR-451a changed significantly over the course of LVAD support; in silico analysis revealed that these miRs are implicated in both cardiac- and coagulation-associated pathways. Furthermore, the patients who suffered from bleeding (n = 5, 33%) had significantly higher pre-implant expression levels of platelet miR-151a and miR-454 with respect to the patients who did not. The same miRs were also differentially expressed in bleeders following LVAD implantation early before the clinical manifestation of the events.DiscussionThis study provides a proof-of-concept evidence of significant modulation of platelet miRs expression driven by LVADs. The possible existence of a platelet miRs signature predictive of the development of bleeding events warrants further validation studies.

Background: Women researchers might experience obstacles in academic environments and might be underrepresented in the authorship of articles published in peer-reviewed journals. Material and Methods: This is a cross-sectional analysis of female-led RCTs describing all interventions reducing mortality in critically ill and perioperative patients from 1981 to December 31, 2020. We searched PubMed/MEDLINE and EMBASE with the keywords RCTs and mortality. The gender of the first author was extracted and descriptive analysis was performed including the year of publication, impact factor, country of the first author, and methodological aspects. Results: We analyzed 340 RCTs, of which 42 (12%) were led by female researchers. The presence of women increased from 8% (14/172) until 2010 up to 17% (28/168) in 2010 and beyond. The United States, the United Kingdom, and Brazil were the main countries of origin of female researchers. Women authors conducted mainly single-center and single-nation studies as compared to male authors. The median impact factor of the target journal was 6 (3-27) in women vs. 7 (3-28) in men, with a p-value of 0.67; Critical Care Medicine, JAMA, and The New England Journal of Medicine were the most frequent target journals for both women and men. Conclusion: In the last 40 years, only one out of eight RCTs had a woman as the first author but the presence of women increased up to 17% by 2010 and beyond. The impact factor of publication target journals was high and not different between genders.

Background: Percutaneous dilation tracheostomy is an aerosol-generating procedure carrying a documented infectious risk during respiratory virus pandemics. For this reason, during the COVID-19 outbreak, surgical tracheostomy was preferred to the percutaneous one, despite the technique related complications increased risk. Methods: We describe a new sequence for percutaneous dilation tracheostomy procedure that could be considered safe both for patients and healthcare personnel. A fiberscope was connected to a video unit to allow bronchoscopy. Guidewire positioning was performed as usual. While the established standard procedure continues with the creation of the stoma without any change in mechanical ventilation, we retracted the bronchoscope until immediately after the access valve in the mount tube, allowing normal ventilation. After 3 minutes of ventilation with 100% oxygen, mechanical ventilation was stopped without disconnecting the circuit. During apnea, the stoma was created by dilating the trachea and the tracheostomy cannula was inserted. Ventilation was then resumed. We evaluated the safeness of the procedure by recording any severe desaturation and by performing serological tests to all personnel. Results: Thirty-six patients (38%) of 96 underwent tracheostomy; 22 (23%) percutaneous dilation tracheostomies with the new approach were performed without any desaturation. All personnel (150 operators) were evaluated for serological testing: 9 (6%) had positive serology but none of them had participated in tracheostomy procedures. Conclusion: This newly described percutaneous dilation tracheostomy technique was not related to severe desaturation events and we did not observe any positive serological test in health workers who performed the tracheostomies.

Abstract Background For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes. Methods The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization. Discussion Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality. Trial registration ClinicalTrials.gov NCT03505723. Registered on 23 April 2018.

Background/Aims: The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide spectrum of effects, including acute kidney injury (AKI) in up to 40% of hospitalized patients. Given the established relationship between AKI and poor prognosis, whether AKI might be a prognostic indicator for patients admitted to the hospital for SARS-CoV-2 infection would allow for a straightforward risk stratification of these patients. Methods: We analyzed data of 623 patients admitted to San Raffaele Hospital (Milan, IT) between February 25 and April 19, 2020, for laboratory-confirmed SARS-CoV-2 infection. Incidence of AKI at hospital admission was calculated, with AKI defined according to the KDIGO criteria. Multivariable Cox regression models assessed the association between AKI and overall mortality and admission to the intensive care unit (ICU). Results: Overall, 108 (17%) patients had AKI at hospital admission for SARS-CoV-2 infection. After a median follow-up for survivors of 14 days (interquartile range: 8, 23), 123 patients died, while 84 patients were admitted to the ICU. After adjusting for confounders, patients who had AKI at hospital admission were at increased risk of overall mortality compared to those who did not have AKI (hazards ratio [HR]: 2.00; p = 0.0004), whereas we did not find evidence of an association between AKI and ICU admission (HR: 0.95; p = 0.9). Conclusions: These data suggest that AKI might be an indicator of poor prognosis for patients with SARS-CoV-2 infection, and as such, given its readily availability, it might be used to improve risk stratification at hospital admission.

BackgroundMicrovascular lung vessels obstructive thromboinflammatory syndrome has been proposed as a possible mechanism of respiratory failure in COVID-19 patients. However, it has only been observed in post-mortem studies and has never been documented in vivo, probably because of a lack of CT scan sensitivity in small pulmonary arteries. The aim of the present study was to assess the safety, tolerability, and diagnostic value of optical coherence tomography (OCT) for the assessment of patients with COVID-19 pneumonia for pulmonary microvascular thromboinflammatory syndrome.MethodsThe COVID-OCT trial was a multicenter, open-label, prospective, interventional clinical study. Two cohorts of patients were included in the study and underwent pulmonary OCT evaluation. Cohort A consisted of patients with COVID-19 with a negative CT scan for pulmonary thrombosis and elevated thromboinflammatory markers (D-dimer > 10,000 ng/mL or 5,000 < D-dimer < 10,000 ng/mL and one of: C-reactive Protein > 100 mg/dL, IL-6 > 6 pg/mL, or ferritin > 900 ng/L). Cohort B consisted of patients with COVID-19 and a CT scan positive for pulmonary thrombosis. The primary endpoints of the study were: (i) to evaluate the overall safety of OCT investigation in patients with COVID-19 pneumonia, and (ii) to report on the potential value of OCT as a novel diagnostic tool for the diagnosis of microvascular pulmonary thrombosis in COVID-19 patients.ResultsA total of 13 patients were enrolled. The mean number of OCT runs performed in each patient was 6.1 ± 2.0, both in ground glass and healthy lung areas, achieving a good evaluation of the distal pulmonary arteries. Overall, OCT runs identified microvascular thrombosis in 8 patients (61.5%): 5 cases of red thrombus, 1 case of white thrombus, and 2 cases of mixed thrombus. In Cohort A, the minimal lumen area was 3.5 ± 4.6 mm2, with stenosis of 60.9 ± 35.9% of the area, and the mean length of thrombus-containing lesions was 5.4 ± 3.0 mm. In Cohort B, the percentage area obstruction was 92.6 ± 2.6, and the mean thrombus-containing lesion length was 14.1 ± 13.9 mm. No peri-procedural complications occurred in any of the 13 patients.ConclusionOCT appears to be a safe and accurate method of evaluating the distal pulmonary arteries in hospitalized COVID-19 patients. Here, it enabled the first in vivo documentation of distal pulmonary arterial thrombosis in patients with elevated thromboinflammatory markers, even when their CT angiogram was negative for pulmonary thrombosis.Clinical trial registrationClinicalTrial.gov, identifier NCT04410549.

BackgroundHypercoagulability and thrombo-inflammation are the main reasons for death in COVID-19 patients. It is unclear whether there is a difference between D-dimer levels in patients without or with COVID-19 acute respiratory distress syndrome (ARDS).MethodsWe searched PubMed, EMBASE, and ClinicalTrails.gov databases looking for studies reporting D-dimer levels in patients without or with COVID-19 ARDS. Secondary endpoints included length of hospital stay, and mortality data at the longest follow-up available.ResultsWe included 12 retrospective and 3 prospective studies with overall 2,828 patients, of whom 1,404 (49.6%) had non-COVID-19 ARDS and 1,424 had COVID-19 ARDS. D-dimer levels were not significantly higher in non-COVID-19 ARDS than in COVID-19 ARDS patients (mean 7.65 mg/L vs. mean 6.20 mg/L MD 0.88 [CI: -0.61 to 2.38] p = 0.25; I² = 85%) while the length of hospital stay was shorter (non-COVID-19 mean 37.4 days vs. COVID-19 mean 48.5 days, MD -10.92 [CI: -16.71 to -5.14] p < 0.001; I² = 44%). No difference in mortality was observed: non-COVID-19 ARDS 418/1167 (35.8%) vs. COVID-19 ARDS 467/1201 (38.8%).ConclusionsWe found no difference in the mean D-dimer levels between non-COVID-19 ARDS and COVID-19 ARDS patients.

Ventricular arrhythmias still represent an important cause of morbidity and mortality, especially in patients with heart failure and reduced left ventricular ejection fraction. Amiodarone is a Class III Vaughan-Williams anti-arrhythmic drug widely used in ventricular arrhythmias for its efficacy and low pro-arrhythmogenic effect. On the other hand, a significant limitation in its use is represented by toxicity. In this review, the pharmacology of the drug is discussed to provide the mechanistic basis for its clinical use. Moreover, all the latest evidence on its role in different clinical settings is provided, including the prevention of sudden cardiac death, implanted cardioverter defibrillators, ischemic and non-ischemic cardiomyopathies. A special focus is placed on everyday clinical practice learning points, such as dosage, indications, and contraindications from the latest guidelines.

The demand for cardiac surgery procedures is increasing globally. Thanks to an improvement in survival driven by medical advances, patients with liver disease undergo cardiac surgery more often. Liver disease is associated with the development of heart failure, especially in patients with advanced cirrhosis. Cardiovascular risk factors can also contribute to the development of both cardiomyopathy and liver disease and heart failure itself can worsen liver function. Despite the risk that liver disease and cirrhosis represent for the perioperative management of patients who undergo cardiac surgery, liver function is often not included in common risk scores for preoperative evaluation. These patients have worse short and long-term survival when compared with other cardiac surgery populations. Preoperative evaluation of liver function, postoperative management and close postoperative follow-up are crucial for avoiding complications and improving results. In the present narrative review, we discuss the pathophysiological components related with postoperative complications and mortality in patients with liver disease who undergo cardiac surgery and provide recommendations for the perioperative management.

Introduction: Data on out-of-hospital cardiac arrest (OHCA) is limited in Italy, and there has never been a comprehensive systematic appraisal of the available evidence. Therefore, this review aims to explore the incidence, characteristics, and outcome of OHCA in Italy. Methods: We systematically searched PubMed, Embase, Google Scholar, ResearchGate, and conference proceedings up to September 23, 2022. Studies investigating OHCA in Italy and reporting at least one outcome related to cardiac arrest were considered eligible. The primary outcome was survival at the longest follow-up available. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal tool. A random-effects model proportion meta-analysis was performed to calculate the pooled outcomes with 95% confidence interval (CI). Results: We included 42 studies (43,042 patients) from 13 of the 20 Italian regions published between 1995 and 2022. Only five studies were deemed to be at low risk of bias. The overall average incidences of OHCA attended by emergency medical services and with resuscitation attempted were 86 (range: 10–190) and 55 (range: 6–108) per 100,000 populations per year, respectively. Survival at the longest follow-up available was 9.0% (95% CI, 6.7–12%; 30 studies and 15,195 patients) in the overall population, 25% (95% CI, 21–30%; 16 studies and 2,863 patients) among patients with shockable rhythms, 28% (95% CI, 20–37%; 8 studies and 1,292 patients) among the Utstein comparator group. Favourable neurological outcome was 5.0% (95% CI, 3.6–6.6%; 16 studies and 9,675 patients). Return of spontaneous circulation was achieved in 19% (95% CI, 16–23%; 40 studies and 30,875 patients) of cases. Bystanders initiated cardiopulmonary resuscitation in 26% (95% CI, 21–32%; 33 studies and 23,491 patients) of cases but only in 3.2% (95% CI, 1.9–4.9%; 9 studies and 8,508 patients) with an automated external defibrillator. The mean response time was 10.2 (95% CI, 8.9–11.4; 25 studies and 23,997 patients) minutes. Conclusions: Survival after OHCA in Italy occurred in one of every ten patients. Bystanders initiated cardiopulmonary resuscitation in only one-third of cases, rarely with a defibrillator. Different areas of the country collected data, but an essential part of the population was not included. There was high heterogeneity and large variation in outcomes results and reporting, limiting the confidence in the estimates of incidence and outcome. Creating and maintaining a nationwide registry is a priority.

Abstract Purpose COVID-19 is characterized by dysregulated immune response, respiratory failure and a relevant mortality rate among hospitalized patients. Interleukin-6 (IL-6) is involved in COVID-19-associated cytokine storm, and several trials investigated whether its inhibition could improve patients’ outcome. We performed a meta-analysis of randomized trials (RCT) to test this hypothesis. Materials and methods Two independent investigators searched PubMed, Scopus, ClnicalTrials.gov and medRxiv up to September 1st, 2021. Inclusion criteria were: administration of tocilizumab or sarilumab; COVID-19 adult patients with pneumonia; and being a RCT. Primary outcome was mortality at the longest follow-up. Secondary outcomes included intubation rate and incidence of adverse events. Two independent investigators extracted data from eligible trials. Results Of the 763 studies assessed, 15 RCTs were included (9,320 patients), all were multicentre, and the majority open-label vs standard treatment. IL-6 inhibitors were associated with reduced all-cause mortality at the longest follow-up (1315/5,380 [24.4%] in the IL-6 inhibitors group versus 1080/3,814 [28.3%] in the control group, RR = 0.90; 95% CI 0.84 to 0.96; p for effect = 0.003, I 2 = 0%, with 13 studies included), with reduction in 28/30-day mortality and intubation rates, and with no increase in adverse events and secondary infections. Conclusion IL-6 inhibitors reduced longest follow-up mortality and intubation in COVID-19 patients. Findings need to be confirmed in high-quality RCTs.

Abstract The efficacy of non-invasive ventilation (NIV) in acute respiratory failure secondary to SARS-CoV-2 infection remains controversial. Current literature mainly examined efficacy, safety and potential predictors of NIV failure provided out of the intensive care unit (ICU). On the contrary, the outcomes of ICU patients, intubated after NIV failure, remain to be explored. The aims of the present study are: (1) investigating in-hospital mortality in coronavirus disease 2019 (COVID-19) ICU patients receiving endotracheal intubation after NIV failure and (2) assessing whether the length of NIV application affects patient survival. This observational multicenter study included all consecutive COVID-19 adult patients, admitted into the twenty-five ICUs of the COVID-19 VENETO ICU network (February–April 2020), who underwent endotracheal intubation after NIV failure. Among the 704 patients admitted to ICU during the study period, 280 (40%) presented the inclusion criteria and were enrolled. The median age was 69 [60–76] years; 219 patients (78%) were male. In-hospital mortality was 43%. Only the length of NIV application before ICU admission (OR 2.03 (95% CI 1.06–4.98), p = 0.03) and age (OR 1.18 (95% CI 1.04–1.33), p

Abstract As for all newly-emergent pathogens, SARS-CoV-2 presents with a relative paucity of clinical information and experimental models, a situation hampering both the development of new effective treatments and the prediction of future outbreaks. Here, we find that a simple virus-free model, based on publicly available transcriptional data from human cell lines, is surprisingly able to recapitulate several features of the clinically relevant infections. By segregating cell lines (n = 1305) from the CCLE project on the base of their sole angiotensin-converting enzyme 2 (ACE2) mRNA content, we found that overexpressing cells present with molecular features resembling those of at-risk patients, including senescence, impairment of antibody production, epigenetic regulation, DNA repair and apoptosis, neutralization of the interferon response, proneness to an overemphasized innate immune activity, hyperinflammation by IL-1, diabetes, hypercoagulation and hypogonadism. Likewise, several pathways were found to display a differential expression between sexes, with males being in the least advantageous position, thus suggesting that the model could reproduce even the sex-related disparities observed in the clinical outcome of patients with COVID-19. Overall, besides validating a new disease model, our data suggest that, in patients with severe COVID-19, a baseline ground could be already present and, as a consequence, the viral infection might simply exacerbate a variety of latent (or inherent) pre-existing conditions, representing therefore a tipping point at which they become clinically significant.

Abstract Background We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the association of higher positive end-expiratory pressure (PEEP), as opposed to lower PEEP, with hospital mortality in adult intensive care unit (ICU) patients undergoing invasive mechanical ventilation for reasons other than acute respiratory distress syndrome (ARDS). Methods We performed an electronic search of MEDLINE, EMBASE, Scopus, Cochrane Central Register of Controlled Trials, CINAHL, and Web of Science from inception until June 16, 2021 with no language restrictions. In addition, a research-in-progress database and grey literature were searched. Results We identified 22 RCTs (2225 patients) comparing higher PEEP (1007 patients) with lower PEEP (991 patients). No statistically significant association between higher PEEP and hospital mortality was observed (risk ratio 1.02, 95% confidence interval 0.89–1.16; I 2 = 0%, p = 0.62; low certainty of evidence). Among secondary outcomes, higher PEEP was associated with better oxygenation, higher respiratory system compliance, and lower risk of hypoxemia and ARDS occurrence. Furthermore, barotrauma, hypotension, duration of ventilation, lengths of stay, and ICU mortality were similar between the two groups. Conclusions In our meta-analysis of RCTs, higher PEEP, compared with lower PEEP, was not associated with mortality in patients without ARDS receiving invasive mechanical ventilation. Further large high-quality RCTs are required to confirm these findings.

IntroductionA great number of anti-inflammatory drugs have been suggested in the treatment of SARS-CoV-2 infection. Reparixin, a non-competitive allosteric inhibitor of the CXCL8 (IL-8) receptors C-X-C chemokine receptor type 1 (CXCR1) and C-X-C chemokine receptor type 2 (CXCR2), has already been tried out as a treatment in different critical settings. Due to the contrasting existing literature, we decided to perform the present meta-analysis of randomized controlled trials (RCTs) to investigate the effect of the use of reparixin on survival in patients at high risk for in-hospital mortality.MethodsWe created a search strategy to include any human RCTs performed with reparixin utilization in patients at high risk for in-hospital mortality, excluding oncological patients. Two trained, independent authors searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) for appropriate studies. Furthermore, references of review articles and included RCTs were screened to identify more studies. No language restrictions were enforced. To assess the risk of bias of included trials, the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) was used.ResultsOverall, six studies were included and involved 406 patients (220 received reparixin and 186 received the comparator). The all-cause mortality in the reparixin group was significantly lower than that in the control group [5/220 (2.3%) in the reparixin group vs. 12/186 (6.5%) in the control group, odds ratio = 0.33 (95% confidence interval 0.12 to 0.96), p-value for effect 0.04, p for heterogeneity 0.20, I2 = 36%]. In addition, no difference in the rate of pneumonia, sepsis, or non-serious infections was shown between the two groups.ConclusionOur meta-analysis of randomized trials suggests that short-term inhibition of CXCL8 activity improved survival in patients at high risk for in-hospital mortality without increasing the risk of infection.Meta-analysis registrationPROSPERO, identifier CRD42021254467.

Anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccination is the world’s most important strategy for stopping the pandemic. Vaccination challenges the body’s immune response and can be complicated by hypersensitivity reactions. The autonomic nervous system can modulate the inflammatory immune response, therefore constituting a potential marker to characterize individuals at high risk of hypersensitivity reactions. Autonomic nervous system functionality was assessed through measurement of the heart rate variability (HRV) in subjects with a history of severe allergic reactions and 12 control subjects. HRV parameters included the mean electrocardiograph RR interval and the standard deviation of all normal R–R intervals (SDNN). All measurements were performed immediately before the anti-SARS-CoV-2 vaccination. The median RR variability was lower in the study than in the control group: 687 ms (645–759) vs. 821 ms (759–902); p = 0.02. The SDNN was lower in the study group than in the control group: 32 ms (23–36) vs. 50 ms (43–55); p < 0.01. No correlation was found between age and the SDNN. Autonomic nervous system activity is unbalanced in people with a severe allergy background.

Abstract SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), is responsible for the largest pandemic facing humanity since the Spanish flu pandemic in the early twentieth century. Since there is no specific antiviral treatment, optimized support is the most relevant factor in the patient's prognosis. In the hospital setting, the identification of high-risk patients for clinical deterioration is essential to ensure access to intensive treatment of severe conditions in a timely manner. The initial management of hypoxemia includes conventional oxygen therapy, high-flow nasal canula oxygen, and non-invasive ventilation. For patients requiring invasive mechanical ventilation, lung-protective ventilation with low tidal volumes and plateau pressure is recommended. Cardiovascular complications are frequent and include myocardial injury, thrombotic events, myocarditis, and cardiogenic shock. Acute renal failure is a common complication and is a marker of poor prognosis, with significant impact in costs and resources allocation. Regarding promising therapies for COVID-19, the most promising drugs until now are remdesivir and corticosteroids although further studies may be needed to confirm their effectiveness. Other therapies such as, tocilizumab, anakinra, other anti-cytokine drugs, and heparin are being tested in clinical trials. Thousands of physicians are living a scenario that none of us have ever seen: demand for hospital exceed capacity in most countries. Until now, the certainty we have is that we should try to decrease the number of infected patients and that an optimized critical care support is the best strategy to improve patient’s survival.

Background: In the first wave of the novel coronavirus (severe acute respiratory syndrome coronavirus 2) infections, Italy experienced a heavy burden of hospital admissions for acute respiratory distress syndromes associated with the novel coronavirus disease (COVID-19). Early evidence suggested that females are less affected than males. Objective: This study aimed to assess the gender-related differences in presentation and severity among COVID-19 patients admitted to IRCCS San Raffaele Hospital, Milan, Italy. Materials and Methods: This prospective observational study included all patients admitted to the hospital between February 25 and April 19, 2020, with a positive real-time reverse-transcriptase polymerase chain reaction for COVID-19. The following data were collected: date of admission, gender, age and details of intensive care unit admission and outcomes. Results: A total of 901 patients with COVID-19 were admitted to the hospital and provided consent for the study. Of these, 284 were female (31.5%). The percentage of admitted female patients significantly increased over time (25.9% of all admissions in the first half of the study period vs. 37.1% in the second half; P < 0.001). Females accounted for 14.4% of all COVID-19 intensive care unit admissions. There was no gender-based difference in the overall hospital mortality: 20.1% for females and 19.2% for males (P = 0.8). Conclusions: In our hospital, which was in the epicenter of the first wave of COVID-19 pandemic in Italy, female patients were few, presented late and were less critical than male patients.

Abstract Background Treatment decisions on critically ill patients with circulatory shock lack consensus. In an international survey, we aimed to evaluate the indications, current practice, and therapeutic goals of inotrope therapy in the treatment of patients with circulatory shock. Methods From November 2016 to April 2017, an anonymous web-based survey on the use of cardiovascular drugs was accessible to members of the European Society of Intensive Care Medicine (ESICM). A total of 14 questions focused on the profile of respondents, the triggering factors, first-line choice, dosing, timing, targets, additional treatment strategy, and suggested effect of inotropes. In addition, a group of 42 international ESICM experts was asked to formulate recommendations for the use of inotropes based on 11 questions. Results A total of 839 physicians from 82 countries responded. Dobutamine was the first-line inotrope in critically ill patients with acute heart failure for 84% of respondents. Two-thirds of respondents (66%) stated to use inotropes when there were persistent clinical signs of hypoperfusion or persistent hyperlactatemia despite a supposed adequate use of fluids and vasopressors, with (44%) or without (22%) the context of low left ventricular ejection fraction. Nearly half (44%) of respondents stated an adequate cardiac output as target for inotropic treatment. The experts agreed on 11 strong recommendations, all of which were based on excellent (> 90%) or good (81–90%) agreement. Recommendations include the indications for inotropes (septic and cardiogenic shock), the choice of drugs (dobutamine, not dopamine), the triggers (low cardiac output and clinical signs of hypoperfusion) and targets (adequate cardiac output) and stopping criteria (adverse effects and clinical improvement). Conclusion Inotrope use in critically ill patients is quite heterogeneous as self-reported by individual caregivers. Eleven strong recommendations on the indications, choice, triggers and targets for the use of inotropes are given by international experts. Future studies should focus on consistent indications for inotrope use and implementation into a guideline for circulatory shock that encompasses individualized targets and outcomes.

Abstract Background The detrimental effects of inotropes are well-known, and in many fields they are only used within a goal-directed therapy approach. Nevertheless, standard management in many centers includes administering inotropes to all patients undergoing cardiac surgery to prevent low cardiac output syndrome and its implications. Randomized evidence in favor of a patient-tailored, inotrope-sparing approach is still lacking. We designed a randomized controlled noninferiority trial in patients undergoing cardiac surgery with normal ejection fraction to assess whether an dobutamine-sparing strategy (in which the use of dobutamine was guided by hemodynamic evidence of low cardiac output associated with signs of inadequate tissue perfusion) was noninferior to an inotrope-to-all strategy (in which all patients received dobutamine). Results A total of 160 patients were randomized to the dobutamine-sparing strategy (80 patients) or to the dobutamine-to-all approach (80 patients). The primary composite endpoint of 30-day mortality or occurrence of major cardiovascular complications (arrhythmias, acute myocardial infarction, low cardiac output syndrome and stroke or transient ischemic attack) occurred in 25/80 (31%) patients of the dobutamine-sparing group (p = 0.74) and 27/80 (34%) of the dobutamine-to-all group. There were no significant differences between groups regarding the incidence of acute kidney injury, prolonged mechanical ventilation, intensive care unit or hospital length of stay. Discussion Although it is common practice in many centers to administer inotropes to all patients undergoing cardiac surgery, a dobutamine-sparing strategy did not result in an increase of mortality or occurrence of major cardiovascular events when compared to a dobutamine-to-all strategy. Further research is needed to assess if reducing the administration of inotropes can improve outcomes in cardiac surgery. Trial registration ClinicalTrials.gov, NCT02361801. Registered Feb 2nd, 2015. https://clinicaltrials.gov/ct2/show/NCT02361801

Context: Protamine is routinely administered to neutralize the anticlotting effects of heparin, traditionally at a dose of 1 mg for every 100 IU of heparin—a 1:1 ratio protamine sparing effects—but this is based more on experience and practice than literature evidence. The use of Hemostasis Management System (HMS) allows an individualized heparin and protamine titration. This usually results in a decreased protamine dose, thus limiting its side effects, including paradox anticoagulation. Aims: This study aims to assess how the use of HMS allows to reduction of protamine administration while restoring the basal activated clotting time (ACT) at the end of cardiac surgery. Settings and Design: A retrospective observational study in a tertiary care university hospital. Subjects and Methods: We analyzed data from 42 consecutive patients undergoing cardiopulmonary bypass (CPB) for cardiac surgery. For all patients HMS tests were performed before and after CPB, to determine how much heparin was needed to reach target ACT, and how much protamine was needed to reverse it. Results: At the end of cardiopulmonary bypass, 2.2 ± 0.5 mg/kg of protamine was sufficient to reverse heparin effects. The protamine-to-heparin ratio was 0.56:1 over heparin total dose (a 44% reduction) and 0.84:1 over heparin initial dose (a 16% reduction). Conclusion: A lower dose of protamine was sufficient to revert heparin effects after cardiopulmonary bypass. While larger studies are needed to confirm these findings and detect differences in clinically relevant outcomes, the administration of a lower protamine dose is endorsed by current guidelines and may help to avoid the detrimental effects of protamine overdose, including paradox bleeding.

Background The aim of this study was to test the hypothesis that the use of inhalational anesthesia leads to higher suppression of the cell-mediated immunity compared to total intravenous anesthesia in patients undergoing kidney cancer surgery under combined low thoracic epidural analgesia and general anesthesia. Methods Patients were randomly allocated to either propofol-based (intravenous anesthetic) or sevoflurane-based (volatile anesthetic) anesthesia group with 10 patients in each group, along with epidural analgesia in both groups. Amounts of natural killer (NK) cells, total T lymphocytes, and T lymphocyte subpopulations in the blood samples collected from the patients before surgery, at the end of the surgery and postoperative days 1, 3 and 7 were determined by flow cytometric analysis. The NK cell count served as the primary endpoint of the study, whereas the total T lymphocyte count and cell counts for T lymphocyte subpopulations were used as the secondary endpoint. Results Our study showed that there were no significant differences in the amount of NK cells, total T lymphocytes, regulatory T cells, and T-helper cells, cytotoxic T lymphocytes, and their subpopulations between the propofol- and sevoflurane-based anesthesia groups when the anesthesia was administered in combination with epidural analgesia. Conclusions The results of this pilot study did not support the hypothesis that the use of inhalational anesthesia leads to higher suppression of the cell-mediated immunity than that of total intravenous anesthesia in patients undergoing kidney cancer surgery under combined low thoracic epidural analgesia and general anesthesia.

Abstract Background The prognostic role of low postoperative serum albumin levels (SAL) after cardiac surgery (CS) remains unclear in patients with normal preoperative SAL. Our aim was to evaluate the influence of SAL on the outcome of CS. Methods Prospective observational study. Patients undergoing CS with normal preoperative SAL and nutritional status were included and classified into different subgroups based on SAL at 24 h after CS. We assessed outcomes (i.e., in-hospital mortality, postoperative complications and long-term survival) and results were analyzed among the different subgroups of SAL. Results We included 2818 patients. Mean age was 64.5 ± 11.6 years and body mass index 28.0 ± 4.3Kg·m− 2. 5.8%(n = 162) of the patients had normal SAL levels(≥35 g·L− 1), 32.8%(n = 924) low deficit (30–34.9 g·L− 1), 44.3%(n = 1249) moderate deficit (25–29.9 g·L− 1), and 17.1%(n = 483) severe deficit(

Introduction: Weaning from cardiopulmonary bypass (CPB) is a critical step of any cardiac surgical procedure and often requires pharmacologic intervention. Calcium ions are pivotal elements for the excitation-contraction coupling process of cardiac myocytes. Thus, calcium administration might be helpful during weaning from CPB. Methods: We describe a multicenter, placebo-controlled, double blind randomized clinical trial to assess the effect of calcium chloride on the need for inotropic support among adult patients during weaning from CPB. The experimental group (409 patients) will receive 15 mg/kg of calcium chloride. The control group (409 patients) will receive an equivalent volume of 0.9% sodium chloride. Both drugs will be administered intravenously as a bolus at the beginning of weaning from CPB. Results: The primary outcome will be the need for inotropic support between termination of CPB and completion of surgery. Secondary outcomes will be: duration of inotropic support, vasoactive-inotropic score 30 min after transfer to intensive care unit and on postoperative day 1, plasma alpha-amylase on postoperative day 1, plasma Ca2+ concentration immediately before and 10–15 min after calcium chloride administration, non-fatal myocardial infarction, blood loss on postoperative day 1, need for transfusion of red blood cells, signs of myocardial ischemia on electrocardiogram after arrival to intensive care unit, all-cause mortality at 30 days or during hospital stay if this is longer than 30 days. Discussion: This trial is designed to assess whether intravenous calcium chloride administration could reduce the need for inotropic support after cardiopulmonary bypass weaning among adults undergoing cardiac surgery.