Intermediate dose enoxaparin in hospitalized patients with moderate-severe COVID-19: a pilot phase II single-arm study, INHIXACOVID19.

BACKGROUND: Randomized clinical trials in non-critically ill COVID-19 patients showed that therapeutic-dose heparin increased survival with reduced organ support as compared with usual-care thromboprophylaxis, albeit with increased bleeding risk. The purpose of the study is to assess the safety of intermediate dose enoxaparin in hospitalized patients with moderate to severe COVID-19. METHODS: A phase II single-arm interventional prospective study including patients receiving intermediate dose enoxaparin once daily according to body weight: 60 mg for 45-60 kg, 80 mg for 61-100 kg or 100 mg for > 100 kg for 14 days, with dose adjustment according to anti-factor Xa activity (target range: 0.4-0.6 UI/ml); an observational cohort (OC) included patients receiving enoxaparin 40 mg day for comparison. Follow-up was 90 days. Primary outcome was major bleeding within 30 and 90 days after treatment onset. Secondary outcome was the composite of all-cause 30 and 90-day mortality rates, disease severity at the end of treatment, intensive care unit (ICU) admission and length of ICU stay, length of hospitalization. All outcomes were adjudicated by an independent committee and analyzed before and after propensity score matching (PSm). RESULTS: Major bleeding was similar in IC (1/98 1.02%) and in the OC (none), with only one event observed in a patient receiving concomitantly anti-platelet therapy. The composite outcome was observed in 53/98 patients (54%) in the IC and 132/203 (65%) patients in the OC (p = 0.07) before PSm, while it was observed in 50/90 patients (55.6%) in the IC and in 56/90 patients (62.2%) in the OC after PSm (p = 0.45). Length of hospitalization was lower in the IC than in OC [median 13 (IQR 8-16) vs 14 (11-21) days, p = 0.001], however it lost statistical significance after PSm (p = 0.08). At 30 days, two patients had venous thrombosis and two pulmonary embolism in the OC. Time to first negative RT-PCR were similar in the two groups. CONCLUSIONS: Weight adjusted intermediate dose heparin with anti-FXa monitoring is safe with potential positive impact on clinical course in COVID-19 non-critically ill patients. TRIAL REGISTRATION: The study INHIXACOVID19 was registred on ClinicalTrials.gov with the trial registration number (TRN) NCT04427098 on 11/06/2020.

Association between respiratory distress time and invasive mechanical ventilation in COVID-19 patients: A multicentre regional cohort study.

AIM: To determine whether the duration of respiratory distress symptoms in severe COVID-19 pneumonia affects the need for invasive mechanical ventilation and clinical outcomes. MATERIALS AND METHODS: An observational multicentre cohort study of patients hospitalised in five COVID-19-designated ICUs of the University Hospitals of Emilia-Romagna Region. Patients included were adults with pneumonia due to SARS-CoV-2 with PaO2/FiO2 ratio <300 mmHg, respiratory distress symptoms, and need for mechanical ventilation (invasive or non-invasive). Exclusion criteria were an uncertain time of respiratory distress, end-of-life decision, and mechanical respiratory support before hospital admission. MEASUREMENTS AND MAIN RESULTS: We analysed 171 patients stratified into tertiles according to respiratory distress duration (distress time, DT) before application of mechanical ventilation support. The rate of patients requiring invasive mechanical ventilation was significantly different (p < 0.001) among the tertiles: 17/57 patients in the shortest duration, 29/57 in the intermediate duration, and 40/57 in the longest duration. The respiratory distress time significantly increased the risk of invasive ventilation in the univariate analysis (OR 5.5 [CI 2.48-12.35], p = 0.003). Multivariable regression analysis confirmed this association (OR 10.7 [CI 2.89-39.41], p < 0.001). Clinical outcomes (mortality and hospital stay) did not show significant differences between DT tertiles. DISCUSSION: Albeit preliminary and retrospective, our data raised the hypothesis that the duration of respiratory distress symptoms may play a role in COVID-19 patients' need for invasive mechanical ventilation. Furthermore, our observations suggested that specific strategies may be directed towards identifying and managing early symptoms of respiratory distress, regardless of the levels of hypoxemia and the severity of the dyspnoea itself.

Thoracic ultrasound for pleural effusion in the intensive care unit: a narrative review from diagnosis to treatment.

Pleural effusion (PLEFF), mostly caused by volume overload, congestive heart failure, and pleuropulmonary infection, is a common condition in critical care patients. Thoracic ultrasound (TUS) helps clinicians not only to visualize pleural effusion, but also to distinguish between the different types. Furthermore, TUS is essential during thoracentesis and chest tube drainage as it increases safety and decreases life-threatening complications. It is crucial not only during needle or tube drainage insertion, but also to monitor the volume of the drained PLEFF. Moreover, TUS can help diagnose co-existing lung diseases, often with a higher specificity and sensitivity than chest radiography and without the need for X-ray exposure. We review data regarding the diagnosis and management of pleural effusion, paying particular attention to the impact of ultrasound. Technical data concerning thoracentesis and chest tube drainage are also provided.

Desmopressin after cardiac surgery in bleeding patients. A multicenter randomized trial.

BACKGROUND: Previous studies showed that desmopressin decreases post-operative blood loss in patients undergoing cardiac surgery. These studies were small and never studied the effect of desmopressin in patients with active bleeding. Objective of the study was to determine whether desmopressin reduces red blood cells transfusion requirements in patients with active bleeding after cardiac surgery who had been pre-treated with tranexamic acid. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study randomized elective patients with bleeding after cardiac surgery despite pre-treatment with tranexamic acid, to receive placebo (saline solution) or a single administration of desmopressin (0.3 µg/kg in saline solution). The primary endpoint was the number of patients requiring red blood cells transfusion after randomization and during hospital stay. Secondary end points were: blood loss from chest tubes during the first 24 h after study drug administration, hours of mechanical ventilation, intensive care unit stay, and in-hospital mortality. RESULTS: The study was interrupted after inclusion of 67% of the planned patients for futility. The number of patients requiring red blood cells transfusion after randomization was 37/68 (54%) in desmopressin group and 33/67 (49%) in placebo group (P = 0.34) with no difference in blood loss: 575 (interquartile 422-770) ml in desmopressin group and 590 (476-1013) ml in placebo group (P = 0.42), mechanical ventilation, intensive care unit stay or mortality. CONCLUSIONS: This multicenter randomized trial demonstrated that, in patients pre-treated with tranexamic acid, desmopressin should not be expected to improve treatment of patients who experience bleeding after cardiac surgery.

Sevoflurane vs. propofol in patients with coronary disease undergoing mitral surgery: a randomised study.

BACKGROUND: Myocardial ischemic damage is reduced by volatile anaesthetics in patients undergoing low-risk coronary artery bypass graft surgery; few and discordant results exist in other settings. We therefore performed a randomised controlled trial (sevoflurane vs. propofol) to compare cardiac troponin release in patients with coronary disease undergoing mitral surgery. METHODS: Patients with coronary artery disease undergoing mitral surgery were randomly allocated to receive either sevoflurane (50 patients) or propofol (50 patients) as main hypnotic. The primary endpoint of the study was peak post-operative cardiac troponin release defined as the maximum value among the post-operative values measured at intensive care unit arrival, 4 h later, on the first and second post-operative day. RESULTS: There was no significant difference in post-operative peak troponin release, the median (25th-75th percentiles) values being 14.9 (10.1-22.1) ng/ml and 14.5 (8.8-17.6) ng/ml in the sevoflurane and propofol groups, respectively (P = 0.4). Fentanyl administration was different between the two groups: 1347 ± 447 µg in patients receiving sevoflurane and 1670 ± 469 µg in those receiving propofol, P = 0.002. The 1-year follow-up identified two patients who died in the propofol group (one myocardial infarction and one low cardiac output syndrome) and one in the sevoflurane group (myocardial infarction). CONCLUSION: In this study, patients with coronary artery disease undergoing mitral surgery did not benefit from the cardioprotective properties of halogenated anaesthetics. Sevoflurane anaesthesia was not associated to lower cardiac troponin release when compared with propofol anaesthesia.

Mortality reduction in cardiac anesthesia and intensive care: results of the first International Consensus Conference.

There is no consensus on which drugs/techniques/strategies can affect mortality in the perioperative period of cardiac surgery. With the aim of identifying these measures, and suggesting measures for prioritized future investigation we performed the first International Consensus Conference on this topic. The consensus was a continuous international internet-based process with a final meeting on 28 June 2010 in Milan at the Vita-Salute University. Participants included 340 cardiac anesthesiologists, cardiac surgeons, and cardiologists from 65 countries all over the world. A comprehensive literature review was performed to identify topics that subsequently generated position statements for discussion, voting, and ranking. Of the 17 major topics with a documented mortality effect, seven were subsequently excluded after further evaluation due to concerns about clinical applicability and/or study methodology. The following topics are documented as reducing mortality: administration of insulin, levosimendan, volatile anesthetics, statins, chronic ß-blockade, early aspirin therapy, the use of pre-operative intra-aortic balloon counterpulsation, and referral to high-volume centers. The following are documented as increasing mortality: administration of aprotinin and aged red blood cell transfusion. These interventions were classified according to the level of evidence and effect on mortality and a position statement was generated. This International Consensus Conference has identified the non-surgical interventions that merit urgent study to achieve further reductions in mortality after cardiac surgery: insulin, intra-aortic balloon counterpulsation, levosimendan, volatile anesthetics, statins, chronic ß-blockade, early aspirin therapy, and referral to high-volume centers. The use of aprotinin and aged red blood cells may result in increased mortality.

Mortality reduction in cardiac anesthesia and intensive care: results of the first International Consensus Conference.

BACKGROUND: There is no consensus on which drugs/techniques/strategies can affect mortality in the perioperative period of cardiac surgery. With the aim of identifying these measures, and suggesting measures for prioritized future investigation we performed the first international consensus conference on this topic. METHODS: The consensus was a continuous international internet-based process with a final meeting on June 28th 2010 in Milan at the Vita-Salute University. Participants included 340 cardiac anesthesiologists, cardiac surgeons and cardiologists from 65 countries all over the world. A comprehensive literature review was performed to identify topics that subsequently generated position statements for discussion, voting and ranking. RESULTS: Of the 17 major topics with a documented mortality effect, seven were subsequently excluded after further evaluation due to concerns about clinical applicability and/or study methodology. The following topics are documented as reducing mortality: administration of insulin, levosimendan, volatile anesthetics, statins, chronic beta-blockade, early aspirin therapy, the use of preoperative intra-aortic balloon counterpulsation and referral to high-volume centers. The following are documented as increasing mortality: administration of aprotinin and aged red blood cell transfusion. These interventions were classified according to the level of evidence and effect on mortality and a position statement was generated. CONCLUSION: This international consensus conference has identified the non-surgical interventions that merit urgent study to achieve further reductions in mortality after cardiac surgery: insulin, intra-aortic balloon counterpulsation, levosimendan, volatile anesthetics, statins, chronic beta-blockade, early aspirin therapy, and referral to high-volume centers. The use of aprotinin and aged red blood cells may result in increased mortality.

Levosimendan reduces mortality in critically ill patients. A meta-analysis of randomized controlled studies.

AIM: Critically ill patients often need catecholamines, but these agents could be associated with an increased risk of death and other adverse cardiac events. Levosimendan is a calcium sensitizer that is able to enhance myocardial contractility without increasing myocardial oxygen use. We conducted a meta-analysis to determine the impact of levosimendan on mortality in critically ill patients. METHODS: Four investigators independently searched BioMedCentral and PubMed to identify all randomized trials that compared levosimendan vs. control with no restriction in dose or time of administration. Exclusion criteria were duplicate publications, non-human experimental studies, and no information on the primary outcome (mortality). RESULTS: Data from a total of 3,350 patients from 27 randomized controlled studies were included in the analysis. Levosimendan was associated with a significant reduction in mortality (333/1893 [17.6%] in the levosimendan group vs. 326/1457 [22.4%] in the control arm, OR=0.74 [0.62-0.89], P for effect=0.001) and in the rate of myocardial infarction (3/493 [0.6%] in the levosimendan group vs. 14/356 [3.9%] in the control arm P=0.007), with a significant increase in the rate of hypotension (164/1484 [11.1%] in the levosimendan group vs. 106/1093 [9.7%] in the control arm P=0.02). CONCLUSION: Levosimendan has cardioprotective effects that could result in a reduced mortality in critically ill patients. A large randomized controlled study is warranted in this setting.

Transcatheter implantation of an aortic valve: anesthesiological management.

AIM: Transcatheter aortic valve implantation (TAVI) is an emergent alternative technique to surgery in high-risk patients with aortic stenosis. Here, we describe the anesthesiological management of patients undergoing TAVI at our institution over an 18-month period. METHODS: After a proper assessment of surgical risk and comorbidities, 69 patients underwent TAVI with the transfemoral/subclavian approach. Both Edwards-Sapien and Corevalve prostheses were implanted. The anesthetic regimen consisted of general anesthesia or local anesthesia plus sedation. RESULTS: Twenty-seven patients received general anesthesia, and 42 received local anesthesia plus sedation. Procedural complications included prosthesis embolization (2), ascending aorta dissection (1), ventricular fibrillation following rapid ventricular pacing (8), vascular access site complications (17), and the valve-in-valve procedure (1). Three patients had to be converted from local anesthesia to general anesthesia (one patient had refractory ventricular fibrillation, and two patients were restless). All patients were alive at the 30-day follow-up. Mechanical ventilation time was 8.5+/-0.03 h. Mean ICU stay was 20.1+/-2.89 h. Postoperative complications included acute renal dysfunction (11), advanced atrioventricular block (9), and stroke (1). Thirty-six out of 42 (86%) patients were alive at the 6-month follow-up. CONCLUSIONS: TAVI is feasible in high-risk patients who would not be able to undergo surgical valve replacement. Hemodynamic management is the main concern of intraoperative anesthesiological management. General or local anesthesia plus sedation are both valid alternative techniques that can be titrated according to patient characteristics. Close postoperative monitoring in the ICU is required.

Fenoldopam to prevent renal replacement therapy after cardiac surgery. Design of the FENO-HSR study.

INTRODUCTION: Acute kidney injury requiring renal replacement therapy is a serious complication following cardiac surgery associated with poor clinical outcomes. Until now no drug showed nephroprotective effects. Fenoldopam is a dopamine-1 receptor agonist which seems to be effective in improving postoperative renal function. The aim of this paper is to describe the design of the FENO-HSR study, planned to assess the effect of a continuous infusion of fenoldopam in reducing the need for renal replacement therapy in patients with acute kidney injury after cardiac surgery. METHODS: We're performing a double blind, placebo-controlled multicentre randomized trial in over 20 Italian hospitals. Patients who develop acute renal failure defined as R of RIFLE score following cardiac surgery are randomized to receive a 96-hours continuous infusion of either fenoldopam (0.025-0.3 µg/kg/min) or placebo. RESULTS: The primary endpoint will be the rate of renal replacement therapy. Secondary endpoints will be: mortality, time on mechanical ventilation, length of intensive care unit and hospital stay, peak serum creatinine and the rate of acute renal failure (following the RIFLE score). CONCLUSIONS: This trial is planned to assess if fenoldopam could improve relevant outcomes in patients undergoing cardiac surgery who develop acute renal dysfunction. Results of this double-blind randomized trial could provide important insights to improve the management strategy of patients at high risk for postoperative acute kidney injury.

A comparison of epidural vs. paravertebral blockade in thoracic surgery.

AIM: Epidural analgesia is considered to be the best method of pain relief after major surgery despite its side-effects, which include hypotension, respiratory depression, urinary retention, incomplete or failed block, and, in rare cases, paraplegia. Paravertebral block is an alternative technique that may offer a comparable analgesic effect and a better side-effect profile. This study measured postoperative pain and respiratory function in patients randomized to receive either paravertebral block or epidural analgesia for pain control after thoracic surgery. METHODS: Twenty-four adult patients undergoing thoracic surgery were enrolled in a prospective and randomized clinical study. Patients were randomly allocated to receive either postoperative continuous paravertebral analgesia (N=12) or epidural analgesia (N=12) starting at pleura closure. Postoperative use of morphine, visual analogue scores, and spirometer data were collected for 72 hours after surgery as markers of pain relief. RESULTS: There was a statistically significant (P=0.003) increase in median (25th-75th percentiles) patient-controlled use of morphine, with values of 36 (22-42) mg in the paravertebral group vs. 9 (2-22) mg in the epidural group. This increase in morphine usage in the paravertebral group was statistically significant at 6, 24, 48, and 72 hours after surgery. Postoperative pain measured with the visual analogue score was not significantly different in the two groups. Spirometer values at 72 h were better in the epidural group than in the paravertebral group (P=0.03). CONCLUSIONS: Epidural analgesia is more efficient than paravertebral continuous block at reducing pain after thoracic surgery.

Prospective randomized, blind comparison of ropivacaine and levobupivacaine for superficial plexus anesthesia in carotid endoarterectomy.

BACKGROUND: The authors performed a study to evaluate if the onset time, duration of sensory block, and quality of postoperative analgesia in superficial cervical plexus anesthesia with 0.5% levobupivacaine (1 mg/kg) was greater than 0.75% ropivacaine (1.5 mg/kg). DESIGN: randomized, double-blind study. SETTING: University teaching hospital. PARTICIPANTS: 28 consecutive patients undergoing elective carotid thromboendoarterectomy were randomized into two groups. INTERVENTIONS: patients received either 1 mg/kg of 0.5% levobupivacaine (N.=15), or 1.5 mg/kg of 0.75% ropivacaine (N.=13). We assessed the onset time (pinprick test), duration of sensory block, and postoperative analgesia with the two drugs. RESULTS: Onset time of sensory block was 20+/-6 min with ropivacaine and 29+/-8 min with levobupivacaine (P=0.003). Intraoperatively we used different total doses of lidocaine, with the median (interquartile range) dose of 50 (40-100) mg for ropivacaine and 130 (60-180) mg for levobupivacaine (P=0.05). The first pain medication was requested after 12+/-0.4 h by ropivacaine patients and after 11+/-1.6 h by levobupivacaine patients (P=0.5). CONCLUSION: No beneficial effect was noted in the quality of nerve block or patient's satisfaction for 0.5% levobupivacaine when compared to 0.75% ropivacaine.

Cardiac protection by volatile anesthetics. A review.

All volatile anesthetics have cardiac depressant effects that decrease myocardial oxygen demand and may thus improve the myocardial oxygen balance during ischemia. Recent experimental evidence has clearly demonstrated that, in addition to these indirect effects, volatile anesthetic agents also directly protect from ischemic myocardial damage. Implementation of these effects during clinical anesthesia can provide an additional tool for treatment or prevention of ischemic cardiac dysfunction during the perioperative period. A recent meta-analysis showed that desflurane and sevoflurane reduce postoperative mortality and the incidence of myocardial infarction following cardiac surgery, with significant advantages in terms of postoperative cardiac troponin release, need for inotropic support, and time on mechanical ventilation, as well as in time spent in the intensive care unit and overall hospital stay. Multicenter, randomized clinical trials previously demonstrated that desflurane could reduce the postoperative release of cardiac troponin I, the need for inotropic support, and the number of patients requiring prolonged hospitalization following coronary artery bypass graft surgery, either with or without cardiopulmonary bypass. However, evidence in non-coronary surgical settings is contradictory and will be reviewed in this paper, together with the mechanism of cardiac protection by volatile agents.

Cardiac protection by volatile anesthetics in non-cardiac surgery? A meta-analysis of randomized controlled studies on clinically relevant endpoints.

INTRODUCTION: Volatile anesthetics improve post-ischemic recovery. A meta-analysis suggested that the cardioprotective properties of desflurane and sevoflurane could reduce mortality and cardiac morbidity in cardiac surgery. Recent American College of Cardiology / American Heart Association Guidelines recommended volatile anesthetic agents during non-cardiac surgery for the maintenance of general anesthesia in patients at risk for myocardial infarction but whether these cardioprotective properties exist in non-cardiac surgery settings is controversial. We therefore performed a meta-analysis of randomized studies to investigate this issue. METHODS: Two investigators independently searched PubMed. Inclusion criteria were random allocation to treatment, comparison of a total intravenous anesthesia regimen vs an anesthesia plan including desflurane or sevoflurane, performed on adult patients undergoing non-cardiac surgery. The primary endpoints were the incidence of perioperative myocardial infarction and death. RESULTS: A total of 6219 patients from 79 randomized trials were identified. No myocardial infarctions or deaths were reported in any of the studies we examined. CONCLUSIONS: This meta-analysis highlights a weakness in the literature and the results can be used to design future studies: the cardioprotective properties of desflurane and sevoflurane have never been studied in noncardiac surgery. No randomized study, among those which compared desflurane or sevoflurane to intravenous anesthetics, has addressed major outcomes such as myocardial infarction or mortality. Large, multicentre, randomized clinical trials including patients undergoing high-risk non-cardiac surgery and reporting clinically relevant outcomes such as myocardial infarction and mortality are needed.

Percutaneous aortic valve implantation: the anesthesiologist perspective.

Percutaneous aortic valve implantation is an emergent technique alternative to surgical aortic valve replacement in high risk patients with aortic stenosis. Percutaneous aortic valve implantation techniques are undergoing rapid development and currently represent a dynamic field of research. Perioperative optimal strategies keep on evolving too. At a review of the literature, only three previous papers on Pubmed focused specifically on anesthesiological challenges of percutaneous aortic valve implantation. In one of them our first 6 months experience was reported. In this new paper we describe the anesthesiological management of percutaneous aortic valve implantation at our Centre, reporting the results of our implantation program from November 2007 to February 2009.