Andexanet alpha versus four-factor prothrombin complex concentrate in DOACs anticoagulation reversal: an updated systematic review and meta-analysis.

BACKGROUND: There is currently a lack of evidence for the comparative effectiveness of Andexanet alpha and four-factor prothrombin complex concentrate (4F-PCC) in anticoagulation reversal of direct oral anticoagulants (DOACs). The primary aim of our systematic review was to verify which drug is more effective in reducing short-term all-cause mortality. The secondary aim was to determine which of the two reverting strategies is less affected by thromboembolic events. METHODS: A systematic review and meta-analysis was performed. RESULTS: Twenty-two studies were analysed in the systematic review and quantitative synthesis. In all-cause short-term mortality, Andexanet alpha showed a risk ratio (RR) of 0.71(95% CI 0.37-1.34) in RCTs and PSMs, compared to 4F-PCC (I2 = 81%). Considering the retrospective studies, the pooled RR resulted in 0.84 (95% CI 0.69-1.01) for the common effects model and 0.82 (95% CI 0.63-1.07) for the random effects model (I2 = 34.2%). Regarding the incidence of thromboembolic events, for RCTs and PSMs, the common and the random effects model exhibited a RR of 1.74 (95% CI 1.09-2.77), and 1.71 (95% CI 1.01-2.89), respectively, for Andexanet alpha compared to 4F-PCC (I2 = 0%). Considering the retrospective studies, the pooled RR resulted in 1.21 (95% CI 0.87-1.69) for the common effects model and 1.18 (95% CI 0.86-1.62) for the random effects model (I2 = 0%). CONCLUSION: Considering a large group of both retrospective and controlled studies, Andexanet alpha did not show a statistically significant advantage over 4F-PCC in terms of mortality. In the analysis of the controlled studies alone, Andexanet alpha is associated with an increased risk of thromboembolic events. CLINICAL TRIAL REGISTRATION: PROSPERO: International prospective register of systematic reviews, 2024, CRD42024548768.

Hemodynamic goals in sepsis and septic shock resuscitation: An umbrella review of systematic reviews and meta-analyses with trial sequential analysis.

OBJECTIVE: The objective of this study was to verify whether any parameter among those used as the target for haemodynamic optimisation (e.g., mean arterial pressure, central venous oxygen saturation, systolic or diastolic dysfunction, CO2 gap, lactates, right ventricular dysfunction, and PvaCO2/CavO2 ratio) is correlated with mortality in an undifferentiated population with sepsis or septic shock. METHODS: An umbrella review, searching MEDLINE, the Cochrane Database of Systematic Reviews, Health Technology Assessment Database, and the JBI Database of Systematic Reviews and Implementation Reports, was performed. We included systematic reviews and meta-analyses enrolling a population of unselected patients with sepsis or septic shock. The main outcome was mortality. Two authors conducted data extraction and risk-of-bias assessments independently. We used a random-effects model to pool binary and continuous data and summarised estimates of effect using equivalent odds ratios (eORs). We used the ROBIS tool to assess risk of bias and the assessment of multiple systematic reviews 2 score to assess global quality. DATA SYNTHESIS: 17 systematic reviews and meta-analyses (15 828 patients) were included in the quantitative analysis. Diastolic dysfunction (eOR: 1.42; 95% confidence interval [CI]: 1.14-1.76), PvaCO2/CavO2 ratio (eOR: 2.15; 95% CI: 1.37-3.37), and CO2 gap (eOR: 1.86; 95% CI: 1.07-3.25) showed a significant correlation with mortality. Lactates were the parameter with highest inconsistency (I2 = 92%). Central venous oxygen saturation and right ventricle dysfunction showed significant statistical excess test of significance (p-value = 0.009 and 0.005, respectively). None of the considered parameters showed statistically significant publication bias. CONCLUSIONS: According to this umbrella review, diastolic dysfunction is the haemodynamic variable that is most closely linked to the prognosis of septic patients. The PvaCO2/CavO2 ratio and the CO2gap are significantly related to the mortality of septic patients, but the poor quality of evidence or the low number of cases, studied so far, limit their clinical applicability. CLINICAL TRIAL REGISTRATION: PROSPERO: International prospective register of systematic reviews, 2023, CRD42023432813 (Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023432813).

Diaphragm ultrasound evaluation during weaning from mechanical ventilation in COVID-19 patients: a pragmatic, cross-section, multicenter study.

BACKGROUND: Diaphragmatic dysfunction is a major factor responsible for weaning failure in patients that underwent prolonged invasive mechanical ventilation for acute severe respiratory failure from COVID-19. This study hypothesizes that ultrasound measured diaphragmatic thickening fraction (DTF) could provide corroborating information for weaning COVID-19 patients from mechanical ventilation. METHODS: This was an observational, pragmatic, cross-section, multicenter study in 6 Italian intensive care units. DTF was assessed in COVID-19 patients undergoing weaning from mechanical ventilation from 1st March 2020 to 30th June 2021. Primary aim was to evaluate whether DTF is a predictive factor for weaning failure. RESULTS: Fifty-seven patients were enrolled, 25 patients failed spontaneous breathing trial (44%). Median length of invasive ventilation was 14 days (IQR 7-22). Median DTF within 24 h since the start of weaning was 28% (IQR 22-39%), RASS score (- 2 vs - 2; p = 0.031); Kelly-Matthay score (2 vs 1; p = 0.002); inspiratory oxygen fraction (0.45 vs 0.40; p = 0.033). PaO2/FiO2 ratio was lower (176 vs 241; p = 0.032) and length of intensive care stay was longer (27 vs 16.5 days; p = 0.025) in patients who failed weaning. The generalized linear regression model did not select any variables that could predict weaning failure. DTF was correlated with pH (RR 1.56 × 1027; p = 0.002); Kelly-Matthay score (RR 353; p < 0.001); RASS (RR 2.11; p = 0.003); PaO2/FiO2 ratio (RR 1.03; p = 0.05); SAPS2 (RR 0.71; p = 0.005); hospital and ICU length of stay (RR 1.22 and 0.79, respectively; p < 0.001 and p = 0.004). CONCLUSIONS: DTF in COVID-19 patients was not predictive of weaning failure from mechanical ventilation, and larger studies are needed to evaluate it in clinical practice further. Registered: ClinicalTrial.gov (NCT05019313, 24 August 2021).

Level of Diffusion and Training of Lung Ultrasound during the COVID-19 Pandemic - A National Online Italian Survey (ITALUS) from the Lung Ultrasound Working Group of the Italian Society of Anesthesia, Analgesia, Resuscitation, and Intensive Care (SIAARTI).

PURPOSE: The goal of this survey was to describe the use and diffusion of lung ultrasound (LUS), the level of training received before and during the COVID-19 pandemic, and the clinical impact LUS has had on COVID-19 cases in intensive care units (ICU) from February 2020 to May 2020. MATERIALS AND METHODS: The Italian Lung Ultrasound Survey (ITALUS) was a nationwide online survey proposed to Italian anesthesiologists and intensive care physicians carried out after the first wave of the COVID-19 pandemic. It consisted of 27 questions, both quantitative and qualitative. RESULTS: 807 responded to the survey. The median previous LUS experience was 3 years (IQR 1.0-6.0). 473 (60.9 %) reported having attended at least one training course on LUS before the COVID-19 pandemic. 519 (73.9 %) reported knowing how to use the LUS score. 404 (52 %) reported being able to use LUS without any supervision. 479 (68.2 %) said that LUS influenced their clinical decision-making, mostly with respect to patient monitoring. During the pandemic, the median of patients daily evaluated with LUS increased 3-fold (p < 0.001), daily use of general LUS increased from 10.4 % to 28.9 % (p < 0.001), and the daily use of LUS score in particular increased from 1.6 % to 9.0 % (p < 0.001). CONCLUSION: This survey showed that LUS was already extensively used during the first wave of the COVID-19 pandemic by anesthesiologists and intensive care physicians in Italy, and then its adoption increased further. Residency programs are already progressively implementing LUS teaching. However, 76.7 % of the sample did not undertake any LUS certification.

Lung ultrasound in ruling out COVID-19 pneumonia in the ED: a multicentre prospective sensitivity study.

PURPOSE: Early diagnosis of COVID-19 has a crucial role in confining the spread among the population. Lung ultrasound (LUS) was included in the diagnostic pathway for its high sensitivity, low costs, non-invasiveness and safety. We aimed to test the sensitivity of LUS to rule out COVID-19 pneumonia (COVIDp) in a population of patients with suggestive symptoms. METHODS: Multicentre prospective observational study in three EDs in Northeastern Italy during the first COVID-19 outbreak. A convenience sample of 235 patients admitted to the ED for symptoms suggestive COVIDp (fever, cough or shortness of breath) from 17 March 2020 to 26 April 2020 was enrolled. All patients underwent a sequential assessment involving: clinical examination, LUS, CXR and arterial blood gas. The index test under investigation was a standardised protocol of LUS compared with a pragmatic composite reference standard constituted by: clinical gestalt, real-time PCR test, radiological and blood gas results. Of the 235 enrolled patients, 90 were diagnosed with COVIDp according to the reference standard. RESULTS: Among the patients with suspected COVIDp, the prevalence of SARS-CoV-2 was 38.3%. The sensitivity of LUS for diagnosing COVIDp was 85.6% (95% CI 76.6% to 92.1%); the specificity was 91.7% (95% CI 86.0% to 95.7%). The positive predictive value and the negative predictive value were 86.5% (95%CI 78.8% to 91.7%) and 91.1% (95% CI 86.1% to 94.4%) respectively. The diagnostic accuracy of LUS for COVIDp was 89.4% (95% CI 84.7% to 93.0%). The positive likelihood ratio was 10.3 (95% CI 6.0 to 17.9), and the negative likelihood ratio was 0.16 (95% CI 0.1 to 0.3). CONCLUSION: In a population with high SARS-CoV-2 prevalence, LUS has a high sensitivity (and negative predictive value) enough to rule out COVIDp in patients with suggestive symptoms. The role of LUS in diagnosing patients with COVIDp is perhaps even more promising. Nevertheless, further research with adequately powered studies is needed. TRIAL REGISTRATION NUMBER: NCT04370275.

Antimicrobial Stewardship in the Covid-19 Pandemic.

During COVID-19 pandemic, implementing and maintaining an antimicrobial stewardship protocol obtained both low rates of MDR microorganisms and low antimicrobial use in an 800-bed hospital network in northern Italy. Infectious diseases specialist consulting was crucial to maintain this protocol active.

Classification and analysis of outcome predictors in non-critically ill COVID-19 patients.

BACKGROUND: Early detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients who could develop a severe form of COVID-19 must be considered of great importance to carry out adequate care and optimise the use of limited resources. AIMS: To use several machine learning classification models to analyse a series of non-critically ill COVID-19 patients admitted to a general medicine ward to verify if any clinical variables recorded could predict the clinical outcome. METHODS: We retrospectively analysed non-critically ill patients with COVID-19 admitted to the general ward of the hospital in Pordenone from 1 March 2020 to 30 April 2020. Patients' characteristics were compared based on clinical outcomes. Through several machine learning classification models, some predictors for clinical outcome were detected. RESULTS: In the considered period, we analysed 176 consecutive patients admitted: 119 (67.6%) were discharged, 35 (19.9%) dead and 22 (12.5%) were transferred to intensive care unit. The most accurate models were a random forest model (M2) and a conditional inference tree model (M5) (accuracy = 0.79; 95% confidence interval 0.64-0.90, for both). For M2, glomerular filtration rate and creatinine were the most accurate predictors for the outcome, followed by age and fraction-inspired oxygen. For M5, serum sodium, body temperature and arterial pressure of oxygen and inspiratory fraction of oxygen ratio were the most reliable predictors. CONCLUSIONS: In non-critically ill COVID-19 patients admitted to a medical ward, glomerular filtration rate, creatinine and serum sodium were promising predictors for the clinical outcome. Some factors not determined by COVID-19, such as age or dementia, influence clinical outcomes.

Lung, Heart, Vascular, and Diaphragm Ultrasound Examination of COVID-19 Patients: A Comprehensive Approach.

Lung ultrasound (LU) has a multitude of features and capacities that make it a useful medical tool to assist physicians contending with the pandemic spread of novel coronavirus disease-2019 (COVID-19) caused by coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, an LU approach to patients with suspected COVID-19 is being implemented worldwide. In noncritical COVID-19 patients, 2 new LU signs have been described and proposed, the "waterfall" and the "light beam" signs. Both signs have been hypothesized to increase the diagnostic accuracy of LU for COVID-19 interstitial pneumonia. In critically ill patients, a distinct pattern of LU changes seems to follow the disease's progression, and this information can be used to guide decisions about when a patient needs to be ventilated, as occurs in other disease states similar to COVID-19. Furthermore, a new algorithm has been published, which enables the automatic detection of B-lines as well as quantification of the percentage of the pleural line associated with lung disease. In COVID-19 patients, a direct involvement of cardiac function has been demonstrated, and ventilator-induced diaphragm dysfunction might be present due to the prolonged mechanical ventilation often involved, as reported for similar diseases. For this reason, cardiac and diaphragm ultrasound evaluation are highly important. Last but not least, due to the thrombotic tendency of COVID-19 patients, particular attention also should be paid to vascular ultrasound. This review is primarily devoted to the study of LU in COVID-19 patients. The authors explain the significance of its "light and shadows," bearing in mind the context in which LU is being used-the emergency department and the intensive care setting. The use of cardiac, vascular, and diaphragm ultrasound is also discussed, as a comprehensive approach to patient care.

Accuracy of Ultrasonographic Measurements of Inferior Vena Cava to Determine Fluid Responsiveness: A Systematic Review and Meta-Analysis.

OBJECTIVE: Fluid responsiveness is the ability to increase the cardiac output in response to a fluid challenge. Only about 50% of patients receiving fluid resuscitation for acute circulatory failure increase their stroke volume, but the other 50% may worsen their outcome. Therefore, predicting fluid responsiveness is needed. In this purpose, in recent years, the assessment of the inferior vena cava (IVC) through ultrasound (US) has become very popular. The aim of our work was to systematically review all the previously published studies assessing the accuracy of the diameter of IVC or its respiratory variations measured through US in predicting fluid responsiveness. DATA SOURCES: We searched in the MEDLINE (PubMed), Embase, Web of Science databases for all relevant articles from inception to September 2017. STUDY SELECTION: Included articles specifically addressed the accuracy of IVC diameter or its respiratory variations assessed by US in predicting the fluid responsiveness in critically ill ventilated or not, adult or pediatric patients. DATA EXTRACTION: We included 26 studies that investigated the role of the caval index (IVC collapsibility or distensibility) and 5 studies on IVC diameter. DATA SYNTHESIS: We conducted a meta-analysis for caval index with 20 studies: The pooled area under the curve, logarithmic diagnostic odds ratio, sensitivity, and specificity were 0.71 (95% confidence interval [CI]: 0.46-0.83), 2.02 (95% CI: 1.29-2.89), 0.71 (95% CI: 0.62-0.80), and 0.75 (95% CI: 0.64-0.85), respectively. CONCLUSION: An extreme heterogeneity of included studies was highlighted. Ultrasound evaluation of the diameter of the IVC and its respiratory variations does not seem to be a reliable method to predict fluid responsiveness.

Our Italian experience using lung ultrasound for identification, grading and serial follow-up of severity of lung involvement for management of patients with COVID-19.

Lung ultrasound (LU) has rapidly become a tool for assessment of patients stricken by the novel coronavirus 2019 (COVID-19). Over the past two and a half months (January, February, and first half of March 2020) we have used this modality for identification of lung involvement along with pulmonary severity in patients with suspected or documented COVID-19 infection. Use of LU has helped us in clinical decision making and reduced the use of both chest x-rays and computed tomography (CT).

Multiple Electrode Aggregometry After Cardiopulmonary Bypass to Assess Platelet (Dys)-Function and Transfusion Threshold: A Concordance Study.

OBJECTIVE: Cardiac surgery patients have a high risk of postoperative bleeding. Historically, the platelet count has been one of the main parameters used to establish the need for platelet transfusions, and the recent introduction of point-of-care tests for platelet function has allowed clinicians to rationalize platelet transfusion needs by assessing the platelet (dys-)function of the patient. For the present study, the authors evaluated how the introduction of one of these systems-the adenosine diphosphate (ADP) test, performed using a Multiplate electrode analyzer (Roche Diagnostics, Basel, Switzerland)-into their clinical practice had modified their platelet transfusion practice. The relationship between the platelet count and the functional evaluation of platelet aggregation (via the ADP test) also was examined. DESIGN: This was a retrospective, single-center, observational study. SETTING: Cardiac surgery department of a tertiary care center in North-east Italy. PARTICIPANTS: Cardiac surgery patients requiring cardiac bypass in 2017 and 2019. INTERVENTIONS: The primary outcome was to compare platelet transfusion practice before and after the implementation of a platelet function test (the ADP test) into the institution's transfusion algorithm, which replaced the platelet count as the trigger. Secondary outcomes were assessing whether the incorporation of the ADP test into their transfusion algorithm brought about a reduction in the frequency of platelet transfusions compared with previous rates (when only platelets counts were used); assessing patient blood loss in the first 12 postoperative hours; and ascertaining the percentage of patients requiring surgical reexplorations. MEASUREMENTS AND MAIN RESULTS: The study comprised 110 patients undergoing cardiac surgery from the platelet count period (2017) and 110 patients from the ADP test period (2019). Agreement between platelet counts versus ADP tests in determining the need for platelet transfusion was moderate (κ = 0.483; 95% confidence interval [CI] 0.239-0.728), and the general linear regression relationship between platelet counts and the ADP test (Akaike information criterion = 2536; p < 0.001) was determined. Since the introduction of ADP testing, a highly significant reduction in platelet transfusions has occurred: 41.82% (platelet count period) versus 13.64% (ADP test period) (p < 0.001); average blood loss in the 12 hours postsurgery also was less in the ADP test period (p < 0.001) at 300 mL (95% CI 150-730) compared with 440 mL in the platelet count period (95% CI 135-900). Furthermore, a decreasing trend was observed in the number of patients requiring reexploration to optimize hemostasis in the first 12 hours postsurgery (6.36% v 2.73%); however, this trend did not achieve statistical significance (p = 0.195). CONCLUSION: The application of new Multiplate analyzer technologies, like the ADP test, have the potential to reduce platelet transfusion rates in cardiac surgery patients compared with the use of platelet counts alone; this point-of-care test may constitute an important strategy to help spare the use of allogeneic blood products. Additional studies are needed to confirm this trend and establish the best cutoff values to apply.

Functional fibrinogen (FLEV-TEG) versus the Clauss method in an obstetric population: a comparative study.

BACKGROUND: Hemostasis is the dynamic equilibrium between coagulation and fibrinolysis. During pregnancy, the balance shifts toward a hypercoagulative state; however placental abruption and abnormal placentations may lead to rapidly evolving coagulopathy characterized by the increased activation of procoagulant pathways. These processes can result in hypofibrinogenemia, with fibrinogen levels dropping to 2 g/L or less and an associated increased risk of post-partum hemorrhage. The aim of the present study was to evaluate the concordance between two methods of functional fibrinogen measurement: the Thromboelastography (TEG) method (also known as FLEV) vs. the Clauss method. Three patient groups were considered: healthy volunteers; non-pathological pregnant patients; and pregnant patients who went on to develop postpartum hemorrhage. METHODS: A prospective observational study. Inclusion criteria were: healthy volunteer women of childbearing age, non-pathological pregnant women at term, and pregnant hemorrhagic patients subjected to elective or urgent caesarean section (CS), with blood loss exceeding 1000 mL. Exclusion criteria were age < 18 years, a history of coagulopathy, and treatment with contraceptives, anticoagulants, or antiplatelet agents. RESULTS: Bland-Altman plots showed a significant overestimation with the FLEV method in all three patient groups: bias was - 133.36 mg/dL for healthy volunteers (95% IC: - 257.84; - 8.88. Critical difference: 124.48); - 56.30 mg/dL for healthy pregnant patients (95% IC: - 225.53; 112.93. Critical difference: 169.23); and - 159.05 mg/dL for hemorrhagic pregnant patients (95% IC: - 333.24; 15.148. Critical difference: 174.19). Regression analyses detected a linear correlation between FLEV and Clauss for healthy volunteers, healthy pregnant patients, and hemorrhagic pregnant patients (R2 0.27, p value = 0.002; R2 0.31, p value = 0.001; R2 0.35, p value = 0.001, respectively). ANOVA revealed a statistically significant difference in fibrinogen concentration between all three patients groups when assayed using the Clauss method (p value < 0.001 for all the comparisons), but no statistically significant difference between the two patients groups of pregnant women when using the FLEV method. CONCLUSIONS: The FLEV method does not provide a valid alternative to the Clauss method due to the problem of fibrinogen overestimation, and for this reason it should not be recommended for the evaluation of patients with an increased risk of hypofibrinogenemia.

Derivation and Validation of a Biomarker-Based Clinical Algorithm to Rule Out Sepsis From Noninfectious Systemic Inflammatory Response Syndrome at Emergency Department Admission: A Multicenter Prospective Study.

OBJECTIVES: To derive and validate a predictive algorithm integrating a nomogram-based prediction of the pretest probability of infection with a panel of serum biomarkers, which could robustly differentiate sepsis/septic shock from noninfectious systemic inflammatory response syndrome. DESIGN: Multicenter prospective study. SETTING: At emergency department admission in five University hospitals. PATIENTS: Nine-hundred forty-seven adults in inception cohort and 185 adults in validation cohort. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A nomogram, including age, Sequential Organ Failure Assessment score, recent antimicrobial therapy, hyperthermia, leukocytosis, and high C-reactive protein values, was built in order to take data from 716 infected patients and 120 patients with noninfectious systemic inflammatory response syndrome to predict pretest probability of infection. Then, the best combination of procalcitonin, soluble phospholipase A2 group IIA, presepsin, soluble interleukin-2 receptor α, and soluble triggering receptor expressed on myeloid cell-1 was applied in order to categorize patients as "likely" or "unlikely" to be infected. The predictive algorithm required only procalcitonin backed up with soluble phospholipase A2 group IIA determined in 29% of the patients to rule out sepsis/septic shock with a negative predictive value of 93%. In a validation cohort of 158 patients, predictive algorithm reached 100% of negative predictive value requiring biomarker measurements in 18% of the population. CONCLUSIONS: We have developed and validated a high-performing, reproducible, and parsimonious algorithm to assist emergency department physicians in distinguishing sepsis/septic shock from noninfectious systemic inflammatory response syndrome.