Tranexamic Acid in Patients Undergoing Noncardiac Surgery.

BACKGROUND: Perioperative bleeding is common in patients undergoing noncardiac surgery. Tranexamic acid is an antifibrinolytic drug that may safely decrease such bleeding. METHODS: We conducted a trial involving patients undergoing noncardiac surgery. Patients were randomly assigned to receive tranexamic acid (1-g intravenous bolus) or placebo at the start and end of surgery (reported here) and, with the use of a partial factorial design, a hypotension-avoidance or hypertension-avoidance strategy (not reported here). The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. To establish the noninferiority of tranexamic acid to placebo for the composite cardiovascular outcome, the upper boundary of the one-sided 97.5% confidence interval for the hazard ratio had to be below 1.125, and the one-sided P value had to be less than 0.025. RESULTS: A total of 9535 patients underwent randomization. A composite bleeding outcome event occurred in 433 of 4757 patients (9.1%) in the tranexamic acid group and in 561 of 4778 patients (11.7%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.67 to 0.87; absolute difference, -2.6 percentage points; 95% CI, -3.8 to -1.4; two-sided P<0.001 for superiority). A composite cardiovascular outcome event occurred in 649 of 4581 patients (14.2%) in the tranexamic acid group and in 639 of 4601 patients (13.9%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, -1.1 to 1.7; one-sided P = 0.04 for noninferiority). CONCLUSIONS: Among patients undergoing noncardiac surgery, the incidence of the composite bleeding outcome was significantly lower with tranexamic acid than with placebo. Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established. (Funded by the Canadian Institutes of Health Research and others; POISE-3 ClinicalTrials.gov number, NCT03505723.).

Hypotension-Avoidance Versus Hypertension-Avoidance Strategies in Noncardiac Surgery : An International Randomized Controlled Trial.

BACKGROUND: Among patients having noncardiac surgery, perioperative hemodynamic abnormalities are associated with vascular complications. Uncertainty remains about what intraoperative blood pressure to target and how to manage long-term antihypertensive medications perioperatively. OBJECTIVE: To compare the effects of a hypotension-avoidance and a hypertension-avoidance strategy on major vascular complications after noncardiac surgery. DESIGN: Partial factorial randomized trial of 2 perioperative blood pressure management strategies (reported here) and tranexamic acid versus placebo. (ClinicalTrials.gov: NCT03505723). SETTING: 110 hospitals in 22 countries. PATIENTS: 7490 patients having noncardiac surgery who were at risk for vascular complications and were receiving 1 or more long-term antihypertensive medications. INTERVENTION: In the hypotension-avoidance strategy group, the intraoperative mean arterial pressure target was 80 mm Hg or greater; before and for 2 days after surgery, renin-angiotensin-aldosterone system inhibitors were withheld and the other long-term antihypertensive medications were administered only for systolic blood pressures 130 mm Hg or greater, following an algorithm. In the hypertension-avoidance strategy group, the intraoperative mean arterial pressure target was 60 mm Hg or greater; all antihypertensive medications were continued before and after surgery. MEASUREMENTS: The primary outcome was a composite of vascular death and nonfatal myocardial injury after noncardiac surgery, stroke, and cardiac arrest at 30 days. Outcome adjudicators were masked to treatment assignment. RESULTS: The primary outcome occurred in 520 of 3742 patients (13.9%) in the hypotension-avoidance group and in 524 of 3748 patients (14.0%) in the hypertension-avoidance group (hazard ratio, 0.99 [95% CI, 0.88 to 1.12]; P = 0.92). Results were consistent for patients who used 1 or more than 1 antihypertensive medication in the long term. LIMITATION: Adherence to the assigned strategies was suboptimal; however, results were consistent across different adherence levels. CONCLUSION: In patients having noncardiac surgery, our hypotension-avoidance and hypertension-avoidance strategies resulted in a similar incidence of major vascular complications. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research, National Health and Medical Research Council (Australia), and Research Grant Council of Hong Kong.

Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis: The MERCY Randomized Clinical Trial.

Importance: Meropenem is a widely prescribed ß-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes. Objective: To determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis. Design, Setting, and Participants: A double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022. Interventions: Patients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304). Main Outcomes and Measures: The primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events. Results: All 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96 [95% CI, 0.81-1.13], P = .60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients). Conclusions and Relevance: In critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. Trial Registration: ClinicalTrials.gov Identifier: NCT03452839.

Volatile Anesthetics versus Total Intravenous Anesthesia for Cardiac Surgery.

BACKGROUND: Volatile (inhaled) anesthetic agents have cardioprotective effects, which might improve clinical outcomes in patients undergoing coronary-artery bypass grafting (CABG). METHODS: We conducted a pragmatic, multicenter, single-blind, controlled trial at 36 centers in 13 countries. Patients scheduled to undergo elective CABG were randomly assigned to an intraoperative anesthetic regimen that included a volatile anesthetic (desflurane, isoflurane, or sevoflurane) or to total intravenous anesthesia. The primary outcome was death from any cause at 1 year. RESULTS: A total of 5400 patients were randomly assigned: 2709 to the volatile anesthetics group and 2691 to the total intravenous anesthesia group. On-pump CABG was performed in 64% of patients, with a mean duration of cardiopulmonary bypass of 79 minutes. The two groups were similar with respect to demographic and clinical characteristics at baseline, the duration of cardiopulmonary bypass, and the number of grafts. At the time of the second interim analysis, the data and safety monitoring board advised that the trial should be stopped for futility. No significant difference between the groups with respect to deaths from any cause was seen at 1 year (2.8% in the volatile anesthetics group and 3.0% in the total intravenous anesthesia group; relative risk, 0.94; 95% confidence interval [CI], 0.69 to 1.29; P = 0.71), with data available for 5353 patients (99.1%), or at 30 days (1.4% and 1.3%, respectively; relative risk, 1.11; 95% CI, 0.70 to 1.76), with data available for 5398 patients (99.9%). There were no significant differences between the groups in any of the secondary outcomes or in the incidence of prespecified adverse events, including myocardial infarction. CONCLUSIONS: Among patients undergoing elective CABG, anesthesia with a volatile agent did not result in significantly fewer deaths at 1 year than total intravenous anesthesia. (Funded by the Italian Ministry of Health; MYRIAD ClinicalTrials.gov number, NCT02105610.).

Perioperative Noninvasive Ventilation After Adult or Pediatric Surgery: A Comprehensive Review.

Postoperative pulmonary complications and acute respiratory failure are among the leading causes of adverse postoperative outcomes. Noninvasive ventilation may safely and effectively prevent acute respiratory failure in high-risk patients after cardiothoracic surgery and after abdominal surgery. Moreover, noninvasive ventilation can be used to treat postoperative hypoxemia, particularly after abdominal surgery. Noninvasive ventilation also can be helpful to prevent or manage intraoperative acute respiratory failure during non-general anesthesia, primarily in patients with poor respiratory function. Finally, noninvasive ventilation is superior to standard preoxygenation in delaying desaturation during intubation in morbidly obese and in critically ill hypoxemic patients. The few available studies in children suggest that noninvasive ventilation could be safe and valuable in treating hypoxemic or hypercapnic acute respiratory failure after cardiac surgery; on the other hand, it could be dangerous after tracheoesophageal correction.

Six-Month Quality of Life in COVID-19 Intensive Care Unit Survivors.

OBJECTIVES: Because there is increasing evidence of serious deterioration in long-term quality of life (QoL) in coronavirus 2019 (COVID-19) intensive care unit (ICU) survivors, the authors identified predictors of poor quality of life in these patients. DESIGN: Prospective cohort study. SETTING: Research hospital repurposed into a COVID-19 center. PARTICIPANTS: Consecutive patients admitted in COVID-19 ICUs between March and June 2020. INTERVENTIONS: An SF-36 questionnaire, which included physical and mental items, was used six months after patient's discharge. MEASUREMENTS AND MAIN RESULTS: A total of 403 patients were managed in the ICU, with a hospital mortality of 181 of 403 (44.9%), and 16 (4.0%) patients died within six months. Among the 125 questionnaire responders, only 32.0% and 52% had a normal quality of life in terms of the physical and mental component of health. Multivariate analysis identified low-molecular-weight heparin treatment in the ICU as the only modifiable factor associated with an increase in physical component of QoL odds ratio (OR) 3.341 (95% confidence interval 1.298-8.599), p = 0.012, and age ≥52 years OR 0.223 and female sex OR 0.321 were significantly associated with a decrease in the physical component. Medical history of cerebrovascular insufficiency was significantly associated with a decrease in mental component of QoL OR 0.125, and the only factor associated with an increase in the mental health component was body mass index ≥27.6 kg/m2 OR 7.466. CONCLUSIONS: In COVID-19 ICU survivors the authors identified treatment with low- molecular-weight heparin as a predictor of improved physical component of QoL at 6 months.

Effect of Volatile Anesthetics on Myocardial Infarction After Coronary Artery Surgery: A Post Hoc Analysis of a Randomized Trial.

OBJECTIVE: To investigate the effect of volatile anesthetics on the rates of postoperative myocardial infarction (MI) and cardiac death after coronary artery bypass graft (CABG). DESIGN: A post hoc analysis of a randomized trial. SETTING: Cardiac surgical operating rooms. PARTICIPANTS: Patients undergoing elective, isolated CABG. INTERVENTIONS: Patients were randomized to receive a volatile anesthetic (desflurane, isoflurane, or sevoflurane) or total intravenous anesthesia (TIVA). The primary outcome was hemodynamically relevant MI (MI requiring high-dose inotropic support or prolonged intensive care unit stay) occurring within 48 hours from surgery. The secondary outcome was 1-year death due to cardiac causes. MEASUREMENTS AND MAIN RESULTS: A total of 5,400 patients were enrolled between April 2014 and September 2017 (2,709 patients randomized to the volatile anesthetics group and 2,691 to TIVA). The mean age was 62 ± 8.4 years, and the median baseline ejection fraction was 57% (50-67), without differences between the 2 groups. Patients in the volatile group had a lower incidence of MI with hemodynamic complications both in the per-protocol (14 of 2,530 [0.6%] v 27 of 2,501 [1.1%] in the TIVA group; p = 0.038) and as-treated analyses (16 of 2,708 [0.6%] v 29 of 2,617 [1.1%] in the TIVA group; p = 0.039), but not in the intention-to-treat analysis (17 of 2,663 [0.6%] v 28 of 2,667 [1.0%] in the TIVA group; p = 0.10). Overall, deaths due to cardiac causes were lower in the volatile group (23 of 2,685 [0.9%] v 40 of 2,668 [1.5%] than in the TIVA group; p = 0.03). CONCLUSIONS: An anesthetic regimen, including volatile agents, may be associated with a lower rate of postoperative MI with hemodynamic complication in patients undergoing CABG. Furthermore, it may reduce long-term cardiac mortality.

Corticosteroids for Patients With Coronavirus Disease 2019 (COVID-19) With Different Disease Severity: A Meta-Analysis of Randomized Clinical Trials.

OBJECTIVES: Efficacy and safety of corticosteroids in patients with 2019-nCoV (novel coronavirus 2019) infection still are debated. Because large randomized clinical trials (RCTs) and a well-conducted meta-analysis on the use of corticosteroids, focused on patients with coronavirus disease (COVID-19) in intensive care units, recently were published, a meta-analysis of RCTs on corticosteroids therapy in patients with different disease severity was performed to evaluate the effect on survival. DESIGN: A meta-analyses of RCTs was performed. SETTING: Patients admitted to hospital. PARTICIPANTS: Patients with coronavirus disease. INTERVENTIONS: Administration of corticosteroids. MEASUREMENTS AND MAIN RESULTS: A search was performed for RCTs of adult patients with acute hypoxemic failure related to 2019-nCoV infection who received corticosteroids versus any comparator. The primary endpoint was mortality rate. Five RCTs involving 7,692 patients were included. Overall mortality of patients treated with corticosteroids was slightly but significantly lower than mortality of controls (26% v 28%, relative risk {RR} = 0.89 [95% confidence interval {CI} 0.82-0.96], p = 0.003). The same beneficial effect was found in the subgroup of patients requiring mechanical ventilation (RR = 0.85 [95% CI 0.72-1.00], p = 0.05 number needed to treat {NNT} = 19). Remarkably, corticosteroids increased mortality in the subgroup of patients not requiring oxygen (17% v 13%, RR = 1.23 [95% CI 1.00-1.62], p = 0.05 number needed to harm {NNH} = 29). Tests for comparison between mechanically ventilated subgroups and those not requiring oxygen confirmed that treatment with corticosteroids had a statistically significant different effect on survival. Patients treated with corticosteroids had a significantly lower risk of need for mechanical ventilation. CONCLUSIONS: Corticosteroids may be considered in severe critically ill patients with COVID-19 but must be discouraged in patients not requiring oxygen therapy. Urgently, further trials are warranted before implementing this treatment worldwide.

Perioperative Dexmedetomidine Supplement Decreases Delirium Incidence After Adult Cardiac Surgery: A Randomized, Double-Blind, Controlled Study.

OBJECTIVE: Conflicting data exist on the effect of dexmedetomidine on delirium. For the present study, a randomized trial was performed to investigate the effect of perioperative dexmedetomidine on the rate of postoperative delirium after cardiac surgery. DESIGN: A randomized controlled trial. SETTING: University hospital. PARTICIPANTS: Patients (n = 169) undergoing elective cardiac surgery (coronary artery bypass graft surgery, valve surgery, or combined surgery) with cardiopulmonary bypass. INTERVENTIONS: Patients received a sevoflurane-based general anesthesia and were randomly assigned 1:1 to receive a dexmedetomidine infusion that started in the operating room (0.7 µg/kg/h) and continued into the intensive care unit (0.4 µg/kg/h) or an equivolume infusion of placebo. MEASUREMENTS AND MAIN RESULTS: A decrease in the rate of delirium in the dexmedetomidine group compared with the placebo group was demonstrated (6 of 84 [7.1%] v 16 of 85 [18.8%]; p = 0.02; odds ratio [OR] 0.33 [95% confidence interval {CI} 0.12-0.90]). Reduced intensive care unit and hospital lengths of stay also were observed (18 [18-22] hours v 22 [18-39] hours; p = 0.002 and 17 [7-20] days v 19 [8-21] days; p = 0.04, respectively). Mortality at 30 days was 2 (2.4%) in both groups. On multivariate analysis, only dexmedetomidine administration (OR 0.24 [95% CI 0.08-0.74]) and cardiopulmonary bypass time (OR 1.02 [95% CI 1.01-1.03] for increases of 1 min) were independent predictors of delirium development. CONCLUSIONS: Dexmedetomidine administered during and after general anesthesia for cardiac surgery with cardiopulmonary bypass decreased the rate of postoperative delirium and intensive care unit and hospital lengths of stay.

Levosimendan for Hemodynamic Support after Cardiac Surgery.

BACKGROUND: Acute left ventricular dysfunction is a major complication of cardiac surgery and is associated with increased mortality. Meta-analyses of small trials suggest that levosimendan may result in a higher rate of survival among patients undergoing cardiac surgery. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving patients in whom perioperative hemodynamic support was indicated after cardiac surgery, according to prespecified criteria. Patients were randomly assigned to receive levosimendan (in a continuous infusion at a dose of 0.025 to 0.2 µg per kilogram of body weight per minute) or placebo, for up to 48 hours or until discharge from the intensive care unit (ICU), in addition to standard care. The primary outcome was 30-day mortality. RESULTS: The trial was stopped for futility after 506 patients were enrolled. A total of 248 patients were assigned to receive levosimendan and 258 to receive placebo. There was no significant difference in 30-day mortality between the levosimendan group and the placebo group (32 patients [12.9%] and 33 patients [12.8%], respectively; absolute risk difference, 0.1 percentage points; 95% confidence interval [CI], -5.7 to 5.9; P=0.97). There were no significant differences between the levosimendan group and the placebo group in the durations of mechanical ventilation (median, 19 hours and 21 hours, respectively; median difference, -2 hours; 95% CI, -5 to 1; P=0.48), ICU stay (median, 72 hours and 84 hours, respectively; median difference, -12 hours; 95% CI, -21 to 2; P=0.09), and hospital stay (median, 14 days and 14 days, respectively; median difference, 0 days; 95% CI, -1 to 2; P=0.39). There was no significant difference between the levosimendan group and the placebo group in rates of hypotension or cardiac arrhythmias. CONCLUSIONS: In patients who required perioperative hemodynamic support after cardiac surgery, low-dose levosimendan in addition to standard care did not result in lower 30-day mortality than placebo. (Funded by the Italian Ministry of Health; CHEETAH ClinicalTrials.gov number, NCT00994825 .).

Therapeutic Hypothermia in Critically Ill Patients: A Systematic Review and Meta-Analysis of High Quality Randomized Trials.

OBJECTIVES: To investigate the effect of the application of therapeutic hypothermia (32-35°C) on survival and major clinical endpoints in critically ill patients. DATA SOURCES: We searched online database and clinical trial registries dated up to April 30, 2019, and references of relevant studies. STUDY SELECTION: Low risk of bias randomized trials which compared hypothermia applied for at least 24 hours and conventional therapy in critically ill patients were included. We excluded trials investigating therapeutic hypothermia in indications already supported by international guidelines (adult cardiac arrest and hypoxic-ischemic encephalopathy of newborns) or intraoperative hypothermia. DATA EXTRACTION: Titles and abstracts were reviewed independently by two authors. If the articles seemed eligible, full-text articles were reviewed, and data were abstracted using a structured template. DATA SYNTHESIS: Our search retained 14 low risk of bias randomized trials (2,670 patients) performed in three different settings: traumatic brain injury, serious infections, and stroke. Therapeutic hypothermia was associated with an increase in mortality at longest follow-up available (432/1,375 [31%] vs 330/1,295 [25%]; risk ratio, 1.24; 95% CI, 1.10-1.39; p = 0.0004; I = 0%). Pooled results showed no difference of good neurologic outcome among survivors between the two treatment arms (493/1,142 [43%] vs 486/1,067 [46%]; risk ratio, 1.04; 95% CI, 0.97-1.12; p = 0.27; I = 1%). Arrhythmias were significantly increased among patients undergoing therapeutic hypothermia. We found no difference between groups in pneumonia, serious infections, any infection, hemorrhage, renal failure, deep vein thrombosis, and uncontrollable intracranial hypertension. CONCLUSIONS: High-quality randomized evidence indicates that therapeutic hypothermia is associated with higher mortality and no difference in good neurologic outcome compared with normothermia in critically ill patients. Although there still might be a possibility that therapeutic hypothermia is beneficial in a specific setting, routine application of therapeutic hypothermia would better be avoided outside the settings indicated by international guidelines (adult cardiac arrest and hypoxic-ischemic encephalopathy of newborns).

Management of Challenging Cardiopulmonary Bypass Separation.

SEPARATION from cardiopulmonary bypass (CPB) after cardiac surgery is a progressive transition from full mechanical circulatory and respiratory support to spontaneous mechanical activity of the lungs and heart. During the separation phase, measurements of cardiac performance with transesophageal echocardiography (TEE) provide the rationale behind the diagnostic and therapeutic decision-making process. In many cases, it is possible to predict a complex separation from CPB, such as when there is known preoperative left or right ventricular dysfunction, bleeding, hypovolemia, vasoplegia, pulmonary hypertension, or owing to technical complications related to the surgery. Prompt diagnosis and therapeutic decisions regarding mechanical or pharmacologic support have to be made within a few minutes. In fact, a complex separation from CPB if not adequately treated leads to a poor outcome in the vast majority of cases. Unfortunately, no specific criteria defining complex separation from CPB and no management guidelines for these patients currently exist. Taking into account the above considerations, the aim of the present review is to describe the most common scenarios associated with a complex CPB separation and to suggest strategies, pharmacologic agents, and para-corporeal mechanical devices that can be adopted to manage patients with complex separation from CPB. The routine management strategies of complex CPB separation of 17 large cardiac centers from 14 countries in 5 continents will also be described.

A Systematic Review and International Web-Based Survey of Randomized Controlled Trials in the Perioperative and Critical Care Setting: Interventions Reducing Mortality.

The authors aimed to identify interventions documented by randomized controlled trials (RCTs) that reduce mortality in adult critically ill and perioperative patients, followed by a survey of clinicians' opinions and routine practices to understand the clinicians' response to such evidence. The authors performed a comprehensive literature review to identify all topics reported to reduce mortality in perioperative and critical care settings according to at least 2 RCTs or to a multicenter RCT or to a single-center RCT plus guidelines. The authors generated position statements that were voted on online by physicians worldwide for agreement, use, and willingness to include in international guidelines. From 262 RCT manuscripts reporting mortality differences in the perioperative and critically ill settings, the authors selected 27 drugs, techniques, and strategies (66 RCTs, most frequently published by the New England Journal of Medicine [13 papers], Lancet [7], and Journal of the American Medical Association [5]) with an agreement ≥67% from over 250 physicians (46 countries). Noninvasive ventilation was the intervention supported by the largest number of RCTs (n = 13). The concordance between agreement and use (a positive answer both to "do you agree" and "do you use") showed differences between Western and other countries and between anesthesiologists and intensive care unit physicians. The authors identified 27 clinical interventions with randomized evidence of survival benefit and strong clinician support in support of their potential life-saving properties in perioperative and critically ill patients with noninvasive ventilation having the highest level of support. However, clinician views appear affected by specialty and geographical location.

A Systematic Review and International Web-Based Survey of Randomized Controlled Trials in the Perioperative and Critical Care Setting: Interventions Increasing Mortality.

OBJECTIVE: Reducing mortality is a key target in critical care and perioperative medicine. The authors aimed to identify all nonsurgical interventions (drugs, techniques, strategies) shown by randomized trials to increase mortality in these clinical settings. DESIGN: A systematic review of the literature followed by a consensus-based voting process. SETTING: A web-based international consensus conference. PARTICIPANTS: Two hundred fifty-one physicians from 46 countries. INTERVENTIONS: The authors performed a systematic literature search and identified all randomized controlled trials (RCTs) showing a significant increase in unadjusted landmark mortality among surgical or critically ill patients. The authors reviewed such studies during a meeting by a core group of experts. Studies selected after such review advanced to web-based voting by clinicians in relation to agreement, clinical practice, and willingness to include each intervention in international guidelines. MEASUREMENTS AND MAIN RESULTS: The authors selected 12 RCTs dealing with 12 interventions increasing mortality: diaspirin-crosslinked hemoglobin (92% of agreement among web voters), overfeeding, nitric oxide synthase inhibitor in septic shock, human growth hormone, thyroxin in acute kidney injury, intravenous salbutamol in acute respiratory distress syndrome, plasma-derived protein C concentrate, aprotinin in high-risk cardiac surgery, cysteine prodrug, hypothermia in meningitis, methylprednisolone in traumatic brain injury, and albumin in traumatic brain injury (72% of agreement). Overall, a high consistency (ranging from 80% to 90%) between agreement and clinical practice was observed. CONCLUSION: The authors identified 12 clinical interventions showing increased mortality supported by randomized controlled trials with nonconflicting evidence, and wide agreement upon clinicians on a global scale.

Effect of Levosimendan on Renal Outcome in Cardiac Surgery Patients With Chronic Kidney Disease and Perioperative Cardiovascular Dysfunction: A Substudy of a Multicenter Randomized Trial.

OBJECTIVE: Acute kidney injury (AKI) occurs frequently after cardiac surgery. Levosimendan might reduce the incidence of AKI in patients undergoing cardiac surgery. The authors investigated whether levosimendan administration could reduce AKI incidence in a high-risk cardiac surgical population. DESIGN: Post hoc analysis of a multicenter randomized trial. SETTING: Cardiac surgery operating rooms and intensive care units of 14 centers in 3 countries. PARTICIPANTS: The study comprised 90 patients who underwent mitral valve surgery with an estimated glomerular filtration rate <60 mL/min/1.73 m2 and perioperative myocardial dysfunction. INTERVENTIONS: Patients were assigned randomly to receive levosimendan (0.025-0.2 µg/kg/min) or placebo in addition to standard inotropic treatment. MEASUREMENTS AND MAIN RESULTS: Forty-six patients were assigned to receive levosimendan and 44 to receive placebo. Postoperative AKI occurred in 14 (30%) patients in the levosimendan group versus 23 (52%) in the placebo group (absolute difference -21.8; 95% confidence interval -41.7 to -1.97; p = 0.035). The incidence of major complications also was lower (18 [39%]) in the levosimendan group versus that in the placebo group (29 [66%]) (absolute difference -26.8 [-46.7 to -6.90]; p = 0.011). A trend toward lower serum creatinine at intensive care unit discharge was observed in the levosimendan group (1.18 [0.99-1.49] mg/dL) versus that in the placebo group (1.39 [1.05-1.76] mg/dL) (95% confidence interval -0.23 [-0.49 to 0.01]; p = 0.07). CONCLUSIONS: Levosimendan may improve renal outcome in cardiac surgery patients with chronic kidney disease undergoing mitral valve surgery who develop perioperative myocardial dysfunction. Results of this exploratory analysis should be investigated in future properly designed randomized controlled trials.

Nonsurgical Strategies to Reduce Mortality in Patients Undergoing Cardiac Surgery: An Updated Consensus Process.

OBJECTIVE: A careful choice of perioperative care strategies is pivotal to improve survival in cardiac surgery. However, there is no general agreement or particular attention to which nonsurgical interventions can reduce mortality in this setting. The authors sought to address this issue with a consensus-based approach. DESIGN: A systematic review of the literature followed by a consensus-based voting process. SETTING: A web-based international consensus conference. PARTICIPANTS: More than 400 physicians from 52 countries participated in this web-based consensus conference. INTERVENTIONS: The authors identified all studies published in peer-reviewed journals that reported on interventions with a statistically significant effect on mortality in the setting of cardiac surgery through a systematic Medline/PubMed search and contacts with experts. These studies were discussed during a consensus meeting and those considered eligible for inclusion in this study were voted on by clinicians worldwide. MEASUREMENTS AND MAIN RESULTS: Eleven interventions finally were selected: 10 were shown to reduce mortality (aspirin, glycemic control, high-volume surgeons, prophylactic intra-aortic balloon pump, levosimendan, leuko-depleted red blood cells transfusion, noninvasive ventilation, tranexamic acid, vacuum-assisted closure, and volatile agents), whereas 1 (aprotinin) increased mortality. A significant difference in the percentages of agreement among different countries and a variable gap between agreement and clinical practice were found for most of the interventions. CONCLUSIONS: This updated consensus process identified 11 nonsurgical interventions with possible survival implications for patients undergoing cardiac surgery. This list of interventions may help cardiac anesthesiologists and intensivists worldwide in their daily clinical practice and can contribute to direct future research in the field.

Nuclear DNA as Predictor of Acute Kidney Injury in Patients Undergoing Coronary Artery Bypass Graft: A Pilot Study.

OBJECTIVE: To measure the release of plasma nuclear deoxyribonucleic acid (DNA) and to assess the relationship between nuclear DNA level and acute kidney injury occurrence in patients undergoing cardiac surgery. SETTING: Cardiovascular anesthesiology and intensive care unit of a large tertiary-care university hospital. DESIGN: Prospective observational study. PARTICIPANTS: Fifty adult patients undergoing cardiac surgery. INTERVENTIONS: Nuclear DNA concentration was measured in the plasma. The relationship between the level of nuclear DNA and the incidence of acute kidney injury after coronary artery bypass grafting was investigated. MEASUREMENTS AND MAIN RESULTS: Cardiac surgery leads to significant increase in plasma nuclear DNA with peak levels 12 hours after surgery (median [interquartile range] 7.0 [9.6-22.5] µg/mL). No difference was observed between off-pump and on-pump surgical techniques. Nuclear DNA was the only predictor of acute kidney injury between baseline and early postoperative risk factors. CONCLUSIONS: The authors found an increase of nuclear DNA in the plasma of patients who had undergone coronary artery bypass grafting, with a peak after 12 hours and an association of nuclear DNA with postoperative acute kidney injury.

A randomized controlled trial of levosimendan to reduce mortality in high-risk cardiac surgery patients (CHEETAH): Rationale and design.

OBJECTIVE: Patients undergoing cardiac surgery are at risk of perioperative low cardiac output syndrome due to postoperative myocardial dysfunction. Myocardial dysfunction in patients undergoing cardiac surgery is a potential indication for the use of levosimendan, a calcium sensitizer with 3 beneficial cardiovascular effects (inotropic, vasodilatory, and anti-inflammatory), which appears effective in improving clinically relevant outcomes. DESIGN: Double-blind, placebo-controlled, multicenter randomized trial. SETTING: Tertiary care hospitals. INTERVENTIONS: Cardiac surgery patients (n = 1,000) with postoperative myocardial dysfunction (defined as patients with intraaortic balloon pump and/or high-dose standard inotropic support) will be randomized to receive a continuous infusion of either levosimendan (0.05-0.2 µg/[kg min]) or placebo for 24-48 hours. MEASUREMENTS AND MAIN RESULTS: The primary end point will be 30-day mortality. Secondary end points will be mortality at 1 year, time on mechanical ventilation, acute kidney injury, decision to stop the study drug due to adverse events or to start open-label levosimendan, and length of intensive care unit and hospital stay. We will test the hypothesis that levosimendan reduces 30-day mortality in cardiac surgery patients with postoperative myocardial dysfunction. CONCLUSIONS: This trial is planned to determine whether levosimendan could improve survival in patients with postoperative low cardiac output syndrome. The results of this double-blind, placebo-controlled randomized trial may provide important insights into the management of low cardiac output in cardiac surgery.

Sevoflurane Versus Total Intravenous Anesthesia for Isolated Coronary Artery Bypass Surgery With Cardiopulmonary Bypass: A Randomized Trial.

OBJECTIVE: Several studies have suggested that the cardioprotective effects of halogenated anesthetics in cardiac surgery result in reduced cardiac biomarker release compared with total intravenous anesthesia (TIVA). These findings came from relatively small randomized clinical trials and meta-analyses. The authors of this study hypothesized that the beneficial effects of volatile anesthetics translate into a reduced length of hospital stay after coronary artery bypass grafting surgery (CABG) with cardiopulmonary bypass. DESIGN: A randomized controlled trial. SETTING: Two university hospitals. PARTICIPANTS: Adult patients undergoing elective CABG surgery with cardiopulmonary bypass. INTERVENTIONS: Patients were assigned randomly to 2 following groups: propofol-based TIVA group (n = 431) and sevoflurane group (n = 437). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was hospital length of stay, and the secondary endpoint included postoperative troponin T and N-terminal pro-brain natriuretic peptide release and mortality. In the sevoflurane group, a reduced length of hospital stay was observed compared with the propofol-based TIVA group (10 [9-11] days v 14 [10-16], p<0.001) as were reductions in cardiac troponin T release (0.18 ng/mL v 0.57 ng/mL at 24 hours, p<0.001), in N-terminal pro-brain natriuretic peptide release (633 pg/mL v 878 pg/mL at 24 hours, p<0.001; 482 pg/mL v 1,036 pg/mL at 48 hours, p<0.001), and in mortality at 1-year follow up (17.8% v 24.8%, p = 0.03). CONCLUSIONS: Anesthesia with sevoflurane reduced cardiac biomarker release and length of hospital stay after CABG with cardiopulmonary bypass surgery compared with propofol-based TIVA with a possible reduction in 1-year mortality.

Worldwide Opinion on Multicenter Randomized Interventions Showing Mortality Reduction in Critically Ill Patients: A Democracy-Based Medicine Approach.

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.