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Background: Acute kidney injury (AKI) is a serious and common complication of cardiac surgery, for which reduced kidney perfusion is a key contributing factor. Intravenous amino acids increase kidney perfusion and recruit renal functional reserve. However, the efficacy of amino acids in reducing the occurrence of AKI after cardiac surgery is uncertain., Methods: In a multinational, double-blind trial, we randomly assigned adult patients who were scheduled to undergo cardiac surgery with cardiopulmonary bypass to receive an intravenous infusion of either a balanced mixture of amino acids, at a dose of 2 g per kilogram of ideal body weight per day, or placebo (Ringer's solution) for up to 3 days. The primary outcome was the occurrence of AKI, defined according to the Kidney Disease: Improving Global Outcomes creatinine criteria. Secondary outcomes included the severity of AKI, the use and duration of kidney-replacement therapy, and all-cause 30-day mortality., Results: We recruited 3511 patients at 22 centers in three countries and assigned 1759 patients to the amino acid group and 1752 to the placebo group. AKI occurred in 474 patients (26.9%) in the amino acid group and in 555 (31.7%) in the placebo group (relative risk, 0.85; 95% confidence interval [CI], 0.77 to 0.94; P = 0.002). Stage 3 AKI occurred in 29 patients (1.6%) and 52 patients (3.0%), respectively (relative risk, 0.56; 95% CI, 0.35 to 0.87). Kidney-replacement therapy was used in 24 patients (1.4%) in the amino acid group and in 33 patients (1.9%) in the placebo group. There were no substantial differences between the two groups in other secondary outcomes or in adverse events., Conclusions: Among adult patients undergoing cardiac surgery, infusion of amino acids reduced the occurrence of AKI. (Funded by the Italian Ministry of Health; PROTECTION ClinicalTrials.gov number, NCT03709264.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Sedation protocols in patients undergoing complex endovascular aortic aneurysm repair are not fully investigated. The aim of this study was to compare a dexmedetomidine (DEX) based sedation protocol with a remifentanil-based sedation protocol., Methods: Seventy-nine consecutive patients undergoing complex endovascular aortic repair were enrolled and retrospectively analyzed. Forty-two received 0.03 mg/kg midazolam intravenous bolus with remifentanil (0.075-0.1 μg/kg/min for 10 minutes followed by continuous infusion 0.050-0.25 μg/kg/min) and 37 DEX (1 μg/kg over 10 minutes and continuous infusion 0.50-0.75 μg/kg/hour) to achieve an Observer Assessment of Alertness/Sedation Scale (OAAS) ≤4, a Richmond Agitation/Sedation Scale (RASS) ≤-2 and a Visual Analogic Scale (VAS) <4. The primary endpoint was patients' satisfaction. Secondary endpoints included assessment of sedation and pain, the incidence of perioperative hemodynamic or gas exchange imbalance, and 36 month-mortality., Results: Remifentanil group showed a higher satisfaction rate than DEX (P<0.001). Patients on DEX were more sedated than remifentanil according to OAAS (3 [2-3] vs. 4 [3-4]; P=0.001) and RASS (-2[-3/-2] vs. -2[-2/-2]; P=0.001) with no difference in VAS (2 [1-3] vs. 2 [1-3]; P=0.41). DEX provides reliable sedation with lower patient's satisfaction. A higher number of patients were discharged from the recovery room on vasopressors in the DEX group compare with the remifentanil group (5 vs. 0; P=0.045, respectively). The two groups showed a non-significant difference in the survival rate at 36-month (DEX 67% vs. remifentanil 73%; (P=0.90)., Conclusions: In this setting remifentanil provides reliable sedation with higher patient's satisfaction and less hemodynamic effect than DEX.

Introduction: Recent studies showed that balanced opioid-free anesthesia is feasible and desirable in several surgical settings. However, in thoracic surgery, scientific evidence is still lacking. Thus, we conducted the first systematic review and meta-analysis of opioid-free anesthesia in this field. Methods: The primary outcome was the occurrence of any complication. Secondary outcomes were the length of hospital stay, recovery room length of stay, postoperative pain at 24 and 48 h, and morphine equivalent consumption at 48 h. Results: Out of 375 potentially relevant articles, 6 studies (1 randomized controlled trial and 5 observational cohort studies) counting a total of 904 patients were included. Opioid-free anesthesia compared to opioid-based anesthesia, was associated with a lower rate of any complication (74 of 175 [42%] vs. 200 of 294 [68%]; RR = 0.76; 95% CI, 0.65−0.89; p < 0.001; I2 = 0%), lower 48 h morphine equivalent consumption (MD −14.5 [−29.17/−0.22]; p = 0.05; I2 = 95%) and lower pain at 48 h (MD −1.95 [−3.6/0.3]; p = 0.02, I = 98%). Conclusions: Opioid-free anesthesia in thoracic surgery is associated with lower postoperative complications, and less opioid demand with better postoperative analgesia at 48 h compared to opioid-based anesthesia.

Objectives: Epinephrine is frequently used as an inotropic and vasopressor agent in critically ill patients requiring hemodynamic support. Data from observational trials suggested that epinephrine use is associated with a worse outcome as compared with other adrenergic and nonadrenergic vasoactive drugs. We performed a systematic review and meta-analysis of randomized controlled trials to investigate the effect of epinephrine administration on outcome of critically ill patients., Data Sources: PubMed, EMBASE, and Cochrane central register were searched by two independent investigators up to March 2019., Study Selection: Inclusion criteria were: administration of epinephrine as IV continuous infusion, patients admitted to an ICU or undergoing major surgery, and randomized controlled trials. Studies on epinephrine administration as bolus (e.g., during cardiopulmonary resuscitation), were excluded. The primary outcome was mortality at the longest follow-up available., Data Extraction: Two independent investigators examined and extracted data from eligible trials., Data Synthesis: A total of 5,249 studies were assessed, with a total of 12 studies (1,227 patients) finally included in the meta-analysis. The majority of the trials were performed in the setting of septic shock, and the most frequent comparator was a combination of norepinephrine plus dobutamine. We found no difference in all-cause mortality at the longest follow-up available (197/579 [34.0%] in the epinephrine group vs 219/648 [33.8%] in the control group; risk ratio = 0.95; 95% CI, 0.82-1.10; p = 0.49; I = 0%). No differences in the need for renal replacement therapy, occurrence rate of myocardial ischemia, occurrence rate of arrhythmias, and length of ICU stay were observed., Conclusions: Current randomized evidence showed that continuous IV administration of epinephrine as inotropic/vasopressor agent is not associated with a worse outcome in critically ill patients.

Objective: Of the 230 million patients undergoing major surgical procedures every year, more than 1 million will die within 30 days. Thus, any nonsurgical interventions that help reduce perioperative mortality might save thousands of lives. The authors have updated a previous consensus process to identify all the nonsurgical interventions, supported by randomized evidence, that may help reduce perioperative mortality., Design and Setting: A web-based international consensus conference., Participants: The study comprised 500 clinicians from 61 countries., Interventions: A systematic literature search was performed to identify published literature about nonsurgical interventions, supported by randomized evidence, showing a statistically significant impact on mortality. A consensus conference of experts discussed eligible papers. The interventions identified by the conference then were submitted to colleagues worldwide through a web-based survey., Measurements and Main Results: The authors identified 11 interventions contributing to increased survival (perioperative hemodynamic optimization, neuraxial anesthesia, noninvasive ventilation, tranexamic acid, selective decontamination of the gastrointestinal tract, insulin for tight glycemic control, preoperative intra-aortic balloon pump, leuko-depleted red blood cells transfusion, levosimendan, volatile agents, and remote ischemic preconditioning) and 2 interventions showing increased mortality (beta-blocker therapy and aprotinin). Interventions then were voted on by participating clinicians. Percentages of agreement among clinicians in different countries differed significantly for 6 interventions, and a variable gap between evidence and clinical practice was noted., Conclusions: The authors identified 13 nonsurgical interventions that may decrease or increase perioperative mortality, with variable agreement by clinicians. Such interventions may be optimal candidates for investigation in high-quality trials and discussion in international guidelines to reduce perioperative mortality., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Democracy-based medicine is a combination of evidence-based medicine (systematic review), expert assessment, and worldwide voting by physicians to express their opinions and self-reported practice via the Internet. The authors applied democracy-based medicine to key trials in critical care medicine., Design and Setting: A systematic review of literature followed by web-based voting on findings of a consensus conference., Participants: A total of 555 clinicians from 61 countries., Interventions: The authors performed a systematic literature review (via searching MEDLINE/PubMed, Scopus, and Embase) and selected all multicenter randomized clinical trials in critical care that reported a significant effect on survival and were endorsed by expert clinicians. Then they solicited voting and self-reported practice on such evidence via an interactive Internet questionnaire. Relationships among trial sample size, design, and respondents' agreement were investigated. The gap between agreement and use/avoidance and the influence of country origin on physicians' approach to interventions also were investigated., Measurements and Main Results: According to 24 multicenter randomized controlled trials, 15 interventions affecting mortality were identified. Wide variabilities in both the level of agreement and reported practice among different interventions and countries were found. Moreover, agreement and reported practice often did not coincide. Finally, a positive correlation among agreement, trial sample size, and number of included centers was found. On the contrary, trial design did not influence clinicians' agreement., Conclusions: Physicians' clinical practice and agreement with the literature vary among different interventions and countries. The role of these interventions in affecting survival should be further investigated to reduce both the gap between evidence and clinical practice and transnational differences., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Recent literature has drawn attention to the potential inadequacy of frequentist analysis and threshold p values as tools for reporting outcomes in clinical trials. The fragility index, which is a measure of how many events the statistical significance of a result depends on, has been suggested as a means to aid the interpretation of trial results. This study aimed to calculate the fragility index of clinical trials in critical care medicine reporting a statistically significant effect on mortality (increasing or decreasing mortality)., Data Sources: Literature search (PubMed/MEDLINE) to identify all multicenter randomized controlled trials in critical care medicine., Study Selection: We identified 862 trials; of which 56 fulfilled eligibility criteria and were included in our analysis., Data Extraction: Calculation of fragility index for trials reporting a statistically significant effect on mortality, and analysis of the relationship between trial characteristics and fragility index., Data Synthesis: The median fragility index was 2 (interquartile range, 1-3.5), and greater than 40% of trials had a fragility index of less than or equal to 1. 12.5% of trials reported loss to follow-up greater than their fragility index. Trial sample size was positively correlated, and reported p value was negatively correlated, with fragility index., Conclusions: In critical care trials reporting statistically significant effects on mortality, the findings often depend on a small number of events. Critical care clinicians should be wary of basing decisions on trials with a low fragility index. We advocate the reporting of fragility index for future trials in critical care to aid interpretation and decision making by clinicians.

Background: Functional Magnetic Resonance Imaging (fMRI) is often used in preoperative assessment before epilepsy surgery, tumor or cavernous malformation resection, or cochlear implantation. As it requires complete immobility, sedation is needed for uncooperative patients., Objective: The aim of this study was to compare the fMRI cortical activation pattern after auditory stimuli in propofol-sedated 5- to 8-year-old children with that of similarly aged nonsedated children., Methods: When possible, children underwent MRI without sedation, otherwise it was induced with i.v. propofol 2 mg·kg(-1) and maintained with i.v. propofol 4-5 mg·kg(-1) ·h(-1) . Following diagnostic MRI, fMRi was carried out, randomly alternating two passive listening tasks (a fairy-tale and nonsense syllables)., Results: We studied 14 awake and 15 sedated children. During the fairy-tale task, the nonsedated children's blood-oxygen-level-dependent (BOLD) signal was bilaterally present in the posterior superior temporal gyrus (STG), Wernicke's area, and Broca's area. Sedated children showed similar activation, with lesser extension to Wernicke's area, and no activation in Broca's area. During the syllable task, the nonsedated children's BOLD signal was bilaterally observed in the STG and Wernicke's area, in Broca's area with leftward asymmetry, and in the premotor area. In sedated children, cortical activation was present in the STG, but not in the frontal lobes. BOLD signal change areas in sedated children were less extended than in nonsedated children during both the fairy-tale and syllable tasks. Modeling the temporal derivative during both the fairy-tale and syllable tasks, nonsedated children showed no response while sedated children did., Conclusions: After auditory stimuli, propofol-sedated 5- to 8-year-old children exhibit an fMRI cortical activation pattern which is different from that in similarly aged nonsedated children., (© 2016 John Wiley & Sons Ltd.)

Introduction: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, severe and potentially fatal cutaneous adverse drug reaction (the mortality rate is up to 10 %) associated with numerous and apparently heterogeneous drugs. The aetiology is unknown., Objective: To report Italian cases of DRESS over a 10-year period., Methods: We searched the National Pharmacovigilance Network (NPN) for the term 'drug reaction with eosinophilia and systemic symptoms' from 1 January 2004 to 1 January 2014, to identify all reports of DRESS. Each case was checked to avoid duplication., Results: In the NPN, we identified 91 serious cases of DRESS: 68 were spontaneous, still-unpublished reports, while 23 additional cases were derived from screening of the scientific literature, performed by marketing authorization holders. Notably, the single common element linking all cases of DRESS was intake of a drug containing an aromatic ring., Conclusion: Thanks to the largest national DRESS case series ever reported, we were able to hypothesize, for the first time, that there is an association between use of drugs containing an aromatic ring in their chemical structure and DRESS. This might aid understanding of the aetiology of DRESS and facilitate diagnosis.

Objectives: We aimed to identify all treatments that affect mortality in adult critically ill patients in multicenter randomized controlled trials. We also evaluated the methodological aspects of these studies, and we surveyed clinicians' opinion and usual practice for the selected interventions., Data Sources: MEDLINE/PubMed, Scopus, and Embase were searched. Further articles were suggested for inclusion from experts and cross-check of references., Study Selection: We selected the articles that fulfilled the following criteria: publication in a peer-reviewed journal; multicenter randomized controlled trial design; dealing with nonsurgical interventions in adult critically ill patients; and statistically significant effect in unadjusted landmark mortality. A consensus conference assessed all interventions and excluded those with lack of reproducibility, lack of generalizability, high probability of type I error, major baseline imbalances between intervention and control groups, major design flaws, contradiction by subsequent larger higher quality trials, modified intention to treat analysis, effect found only after adjustments, and lack of biological plausibility., Data Extraction: For all selected studies, we recorded the intervention and its comparator, the setting, the sample size, whether enrollment was completed or interrupted, the presence of blinding, the effect size, and the duration of follow-up., Data Synthesis: We found 15 interventions that affected mortality in 24 multicenter randomized controlled trials. Median sample size was small (199 patients) as was median centers number (10). Blinded trials enrolled significantly more patients and involved more centers. Multicenter randomized controlled trials showing harm also involved significantly more centers and more patients (p = 0.016 and p = 0.04, respectively). Five hundred fifty-five clinicians from 61 countries showed variable agreement on perceived validity of such interventions., Conclusions: We identified 15 treatments that decreased/increased mortality in critically ill patients in 24 multicenter randomized controlled trials. However, design affected trial size and larger trials were more likely to show harm. Finally, clinicians view of such trials and their translation into practice varied.

Background: High-quality evidence and derived guidelines, as typically published in major academic journals, are a major process that shapes physician decision-making worldwide. However, for many aspects of medical practice, there is a lack of High-quality evidence or an overload of somewhat contradictory low-quality information, which makes decision-making a difficult, uncertain, and unpredictable process. When the issues in question are important and evidence limited or controversial, the medical community seeks to establish common ground for "best practice" through consensus conferences and consensus statements or guidelines. Such consensus statements are seen as a useful tool to establish expert agreement, define the boundaries of acceptable practice, provide priorities for the research agenda, and obtain opinions from different countries and healthcare systems. This standard approach, however, can be criticized for being elitist, noninclusive, and poorly representative of the community of clinicians who will have to make decisions about the implementation of such recommendations., Objective: Accordingly, the authors propose a new model based on a combination of a local core meeting (detailed review and expert input) followed by a worldwide web-based network assessment (democracy-based consensus). The authors already have applied this approach to develop consensus on all nonsurgical interventions that increase or reduce perioperative mortality in critically ill patients and in those with acute kidney injury., Methods: The methodology was based on 5 sequential local and web-based steps., Results: Both a panel of experts and a large number of professionals from all over the world were involved, giving birth to a new type of "democracy-based consensus.", Conclusions: This new type of "democracy-based consensus" has the potential to increase grass-root clinician involvement, expand the reach to less-developed countries, provide a more global perspective on proposed interventions, and perhaps more importantly, increase awareness, ownership, and the statistical likelihood of subsequent implementation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: Standard inotropic treatment is often necessary in end-stage heart failure but may be harmful. We performed a meta-analysis of randomized controlled trials to investigate the effect of repeated administration of levosimendan on survival in patients with chronic heart failure., Methods and Results: Four investigators independently searched in CENTRAL, Google Scholar MEDLINE/PubMed, Scopus and the Cochrane Central Register of clinical trials to identify any randomized study ever performed with intermittent levosimendan intravenous administration in adult patients with chronic heart failure with no restrictions on dose or time of administration. Data from a total of 326 patients from six randomized controlled studies using intermittent levosimendan in a cardiological setting were included in the analysis. Levosimendan was associated with a significant reduction in mortality at the longest follow-up available [32 of 168 (19 %) in the levosimendan group 46 of 133 (35 %) in the control arm, RR = 0.55 (95 % CI 0.37-0.84), p for effect = 0 0.005, p for heterogeneity = 0.3, I (2) = 23.4 %, NNT = 6 with 5 studies included]. Brain natriuretic peptide values, ejection fraction and number of patients with New York Heart Association ≥ III status were similar in survivors of both groups., Conclusions: A large randomized trial is necessary to confirm the promising beneficial effects of intermittent levosimendan administration on the mid-term survival of patients with chronic heart failure.

Background: Most of the drugs used in anesthesia are off-label in children even if they present solid clinical evidence in adults. This lack of authorization is caused by multiple factors including the difficulty in conducting research in this area (due to the ethical concerns and/or the low number of available participants, the high variability of the outcome measures) and the lack of economic interest of the pharmaceutical companies (due to the limited market)., Objective: Define a list of medicinal products commonly used off-label in pediatrics anesthesia to be reimbursed by Italian National Health System., Methods and Results: We hereby describe the methodological framework used to allow reimbursed use of a list of medicinal products, widely used off-label in pediatric patients, ensuring the best therapeutic results with the lowest possible risk for children. A task force of pediatric anesthesiologists from Italy petitioned the Italian Medicines Agency (AIFA) to allow a number of commonly utilized but off-label drugs for pediatric anesthesia to be reimbursed for specific indications. For each drug, both the supporting literature and expert opinion were used, and the resulting list of drugs allowed to be used/reimbursed officially by AIFA was significantly expanded. This paper documents one approach to the problem of off-label use of drugs for pediatric patients that can be a model for future efforts., Conclusion: Continuous efforts are needed from government institutions and sponsors on drug development and on drug approval process in pediatrics, as research on drug effectiveness and safety is mandatory in children as in adults. At the same time, clinicians must become more familiar with the drug-approval process, participate to sponsored trials, and perform ztrials themselves., (© 2014 John Wiley & Sons Ltd.)

Non-invasive ventilation (NIV) has been used to prevent or to treat perioperative acute respiratory failure (ARF). Intraoperative prophylactic and therapeutic use of NIV could be of interest to patients with anticipated difficulty in postoperative weaning from mechanical ventilation or to patients refusing tracheal intubation. Intraoperative NIV might also be useful when deep sedation is required, as this can cause respiratory depression. PubMed, Embase, Google Scholar, and Cochrane Library were searched for pertinent studies. Inclusion criteria were NIV use during surgery and adult patients; the exclusion criteria were NIV application only in the preoperative or postoperative periods, paediatric patients, NIV applied as negative pressure ventilation. Thirty papers including 618 patients were included for final analysis. Intraoperative therapeutic NIV to treat ARF was reported for 92 patients and in all those cases, including six Caesarean sections, surgery was completed uneventfully. Intraoperative prophylactic NIV to avoid ARF was described in 24 patients with severe respiratory limitation and in 502 healthy patients during deep sedation. Three patients could not be successfully ventilated due to upper airway obstruction, but no further complication was reported. Intraoperative NIV appears feasible, safe, and potentially useful, particularly when tracheal intubation is best avoided. However, high-quality, randomized studies are required.

Objective: To identify all interventions that increase or reduce mortality in patients with acute kidney injury (AKI) and to establish the agreement between stated beliefs and actual practice in this setting., Design and Setting: Systematic literature review and international web-based survey., Participants: More than 300 physicians from 62 countries., Interventions: Several databases, including MEDLINE/PubMed, were searched with no time limits (updated February 14, 2012) to identify all the drugs/techniques/strategies that fulfilled all the following criteria: (a) published in a peer-reviewed journal, (b) dealing with critically ill adult patients with or at risk for acute kidney injury, and (c) reporting a statistically significant reduction or increase in mortality., Measurements and Main Results: Of the 18 identified interventions, 15 reduced mortality and 3 increased mortality. Perioperative hemodynamic optimization, albumin in cirrhotic patients, terlipressin for hepatorenal syndrome type 1, human immunoglobulin, peri-angiography hemofiltration, fenoldopam, plasma exchange in multiple-myeloma-associated AKI, increased intensity of renal replacement therapy (RRT), CVVH in severely burned patients, vasopressin in septic shock, furosemide by continuous infusion, citrate in continuous RRT, N-acetylcysteine, continuous and early RRT might reduce mortality in critically ill patients with or at risk for AKI; positive fluid balance, hydroxyethyl starch and loop diuretics might increase mortality in critically ill patients with or at risk for AKI. Web-based opinion differed from consensus opinion for 30% of interventions and self-reported practice for 3 interventions., Conclusion: The authors identified all interventions with at least 1 study suggesting a significant effect on mortality in patients with or at risk of AKI and found that there is discordance between participant stated beliefs and actual practice regarding these topics., (Copyright © 2013 Elsevier Inc. All rights reserved.)