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.

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.

Randomized Evidence for Reduction of Perioperative Mortality: An Updated Consensus Process.

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.

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.

Mortality in Multicenter Critical Care Trials: An Analysis of Interventions With a Significant Effect.

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.

Effect of fenoldopam on use of renal replacement therapy among patients with acute kidney injury after cardiac surgery: a randomized clinical trial.

IMPORTANCE: No effective pharmaceutical agents have yet been identified to treat acute kidney injury after cardiac surgery. OBJECTIVE: To determine whether fenoldopam reduces the need for renal replacement therapy in critically ill cardiac surgery patients with acute kidney injury. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-blind, placebo-controlled, parallel-group study from March 2008 to April 2013 in 19 cardiovascular intensive care units in Italy. We randomly assigned 667 patients admitted to intensive care units after cardiac surgery with early acute kidney injury (≥50% increase of serum creatinine level from baseline or oliguria for ≥6 hours) to receive fenoldopam (338 patients) or placebo (329 patients). We used a computer-generated permuted block randomization sequence for treatment allocation. All patients completed their follow-up 30 days after surgery, and data were analyzed according to the intention-to-treat principle. INTERVENTIONS: Continuous infusion of fenoldopam or placebo for up to 4 days with a starting dose of 0.1 µg/kg/min (range, 0.025-0.3 µg/kg/min). MAIN OUTCOMES AND MEASURES: The primary end point was the rate of renal replacement therapy. Secondary end points included mortality (intensive care unit and 30-day mortality) and the rate of hypotension during study drug infusion. RESULTS: The study was stopped for futility as recommended by the safety committee after a planned interim analysis. Sixty-nine of 338 patients (20%) allocated to the fenoldopam group and 60 of 329 patients (18%) allocated to the placebo group received renal replacement therapy (P = .47). Mortality at 30 days was 78 of 338 (23%) in the fenoldopam group and 74 of 329 (22%) in the placebo group (P = .86). Hypotension occurred in 85 (26%) patients in the fenoldopam group and in 49 (15%) patients in the placebo group (P = .001). CONCLUSIONS AND RELEVANCE: Among patients with acute kidney injury after cardiac surgery, fenoldopam infusion, compared with placebo, did not reduce the need for renal replacement therapy or risk of 30-day mortality but was associated with an increased rate of hypotension. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00621790.

Randomized evidence for reduction of perioperative mortality.

OBJECTIVE: With more than 220 million major surgical procedures performed annually, perioperative interventions leading to even minor mortality reductions would save thousands of lives per year. This international consensus conference aimed to identify all nonsurgical interventions that increase or reduce perioperative mortality as suggested by randomized evidence. DESIGN AND SETTING: A web-based international consensus conference. PARTICIPANTS: More than 1,000 physicians from 77 countries participated in this web-based consensus conference. INTERVENTIONS: Systematic literature searches (MEDLINE/PubMed, June 8, 2011) were used to identify the papers with a statistically significant effect on mortality together with contacts with experts. Interventions were considered eligible for evaluation if they (1) were published in peer-reviewed journals, (2) dealt with a nonsurgical intervention (drug/technique/strategy) in adult patients undergoing surgery, and (3) provided a statistically significant mortality increase or reduction as suggested by a randomized trial or meta-analysis of randomized trials. MEASUREMENTS AND MAIN RESULTS: Fourteen interventions that might change perioperative mortality in adult surgery were identified. Interventions that might reduce mortality include chlorhexidine oral rinse, clonidine, insulin, intra-aortic balloon pump, leukodepletion, levosimendan, neuraxial anesthesia, noninvasive respiratory support, hemodynamic optimization, oxygen, selective decontamination of the digestive tract, and volatile anesthetics. In contrast, aprotinin and extended-release metoprolol might increase mortality. CONCLUSIONS: Future research and health care funding should be directed toward studying and evaluating these interventions.

Hybrid three-stage repair of mega-aortic syndrome with the Lupiae technique: 10-year results.

BACKGROUND: Mega-aortic syndrome (MAS) is a rare disease carrying a poor prognosis if treated conservatively. Open repairs of these aneurysms are invasive, while totally endovascular repairs are associated with higher rates of late reintervention due to endoleaks, compromising long-term prognosis. We describe the 10-year results of a hybrid three-stage approach to MAS using the Lupiae technique. METHODS: Between 2006 and 2016, 27 patients with MAS extending from the ascending aorta to the iliac arteries (MAS type III) underwent: (I) a surgical aortic arch debranching, using the Vascutek Lupiae™ multibranched graft to create a proximal Dacron landing zone; (II) an abdominal aorta debranching to create a distal Dacron landing zone and (III) the implantation of multiple endovascular stents to exclude any residual aneurysm between the two landing zones. RESULTS: One patient died following the first stage, and another following the second stage of the repair (overall mortality 7.4%). The interval between the first and the second stage was 58.3±16.1 days. The interval between the second and the third stage was 47.7±13.1 days. Four-year survival was 88.6%±6.2% while 10-year survival was 51.7%±17.9%. One patient had a type III endoleak after the third stage that self-resolved within 6 months without intervention. No patient had type I or II endoleaks and none underwent redo procedures. Mean follow-up was 5.9±3.6 years and completeness was 100%. CONCLUSIONS: Three-stage hybrid repairs using the Lupiae technique can be safely performed in MAS type III patients. Short intervals between the stages should mitigate the risk of rupture during the waiting periods and may enhance patient compliance, but to achieve this, the burden and the complexity of the first stage must be carefully weighted. Our strategy improves the long-term survival of these patients compared to their natural history and is less invasive than an open repair. The adoption of Dacron landing zones appears to be associated with very low rates of reintervention due to endoleaks.

Hybrid three-stage repair of mega aorta with Lupiae technique: tips and tricks.

Mega aorta syndrome (MAS) poses a complex clinical challenge: the involvement of the ascending aorta, aortic arch, descending thoracic and abdominal aorta with extension below the origin of renal arteries requires almost total replacement of the aorta. The modality of treatment remains still controversial. Different aortic debranching techniques have been developed to re-route the origin of epiaortic and visceral vessels and achieve an optimal landing zone for implantation of subsequent endovascular grafts. We illustrate the Lupiae technique as a further evolution of the aortic debranching and hybrid repair of a mega aorta. It was developed with the purpose to exclude a very long segment of diseased aorta by implanting two or more endoprostheses between two surgically-generated landing zones. We describe a series of 27 patients treated by this hybrid three-stage mega-aorta repair; the tips and tricks discussed here facilitate a safe and effective procedure, enable treatment of frail patients and help to avoid life-threatening complications.

Results of mitral valve repair for Barlow disease (bileaflet prolapse) via right minithoracotomy versus conventional median sternotomy: a randomized trial.

OBJECTIVE: The results of mitral repair for complex Barlow valves are adequate and support earlier intervention. It is unknown whether these results are reproducible in the context of minimally invasive surgery via right minithoracotomy. METHODS: We randomized patients with Barlow mitral disease (bileaflet prolapse) to have conventional open repair via median sternotomy (MS group) or minimally invasive (MI group) repair. Repair was done using polytetrafluoroethylene chordal reimplantation for both leaflets. In the MI group, we adopted right minithoracotomy, peripheral cannulation, external aortic clamping, and surgery under direct vision. RESULTS: Both groups comprised 70 patients. The operative and the cardiopulmonary bypass times were significantly longer in the MI group (P = .003 and P = .012). Mitral repair was successful in 98.5% MI patients and 100% MS patients. Operative mortality was comparable. The mean mechanical ventilation time, intensive care unit stay, and hospital stay were lower in the MI group (P = .014, P =.02, and P = .03,). Mean pain score was lower in the MI group at postoperative days 2 and 4. At follow-up, the freedom from moderate (2+) or severe (3+ or 4+) mitral regurgitation was 98% versus 97% (P = .9). Two patients underwent reoperation (1 in each group) for late failure of repair. The Kaplan-Meier analysis confirmed these results. CONCLUSIONS: Our data indicate that the optimal standard-of-care results of mitral repair for complex disease (Barlow) are reproducible in the minimally invasive settings through right minithoracotomy and direct vision. The minimally invasive technique can be proposed for complex mitral disease and early referral of these patients can be encouraged.

The easier, the better: age, creatinine, ejection fraction score for operative mortality risk stratification in a series of 29,659 patients undergoing elective cardiac surgery.

OBJECTIVE: Age, preoperative creatinine value, and ejection fraction are easily arranged in the age, creatinine, ejection fraction score to predict operative mortality in elective cardiac operations, as recently shown. We validate the age, creatinine, ejection fraction score in a large multicentric study. METHODS: We analyzed 29,659 consecutive patients who underwent elective cardiac operations in 14 Italian institutions during the period from 2004 to 2009. The operative (30-day) mortality rate was recorded for the entire population and for subgroups of patients based on the risk distribution. The predicted mortality was assessed using the additive and logistic European System for Cardiac Operative Risk Evaluations, and the age, creatinine, ejection fraction score. Accuracy and clinical performance of the different models were tested. RESULTS: The observed mortality rate was 2.77% (95% confidence interval, 2.59-2.96). The predicted mortality rate was 2.84% (95% confidence interval, 2.79-2.88) for the age, creatinine, ejection fraction score (not significantly different from the observed rate), 6.26% for the additive European System for Cardiac Operative Risk Evaluation, and 9.67% for the logistic European System for Cardiac Operative Risk Evaluation (both significantly overestimated). For all deciles of risk distribution, the European System for Cardiac Operative Risk Evaluation significantly overestimated mortality risk; the age, creatinine, ejection fraction score slightly overestimated the mortality risk in very low-risk patients and significantly underestimated the mortality risk in very high-risk patients, correctly estimating the risk in 7 of 10 deciles. The accuracy of the age, creatinine, ejection fraction score was acceptable (area under the curve of 0.702). In a separate analysis, this value increased to 0.74 by excluding centers that reported no operative mortality. These values were similar or worse for the European System for Cardiac Operative Risk Evaluation. CONCLUSIONS: The age, creatinine, ejection fraction score provides an accuracy level comparable to that of the European System for Cardiac Operative Risk Evaluation, with far superior clinical performance.

Minimally invasive epicardial ablation of lone atrial fibrillation in pediatric patient.

We describe a case of epicardial surgical ablation of drug refractory lone atrial fibrillation in a pediatric patient. Minimally invasive radiofrequency equipment was used off-pump through a right mini-thoracotomy. Electrical isolation of the pulmonary veins cuffs was obtained. The preoperative electrophysiological study identified a macro re-entrant circuit around the pulmonary veins orifices as the mechanism of arrhythmia triggering. At follow-up, the patient is in stable sinus rhythm and there is no evidence of pulmonary vein stenosis. The minimally invasive, off-pump ablation of lone atrial fibrillation is feasible and reliable, even in children who may pose incremental technical challenges. This technique may represent an additional tool for the current treatment algorithms to treat lone atrial fibrillation.

Hybrid treatment of thoracoabdominal aortic aneurysms with the use of a new prosthesis.

We report the case of a 72-year-old woman with thoracoabdominal aortic aneurysm who underwent hybrid surgical and endovascular procedure. First, debranching of the aortic arch and implantation of a new multi-branched prosthesis with transdiaphragmatic celiac artery and superior mesenteric artery revascularization was performed. Two weeks later the procedure was successfully completed with aneurysmal exclusion by deployment of multiple stent grafts. The postoperative course was uneventful. A two-staged surgical and endovascular approach with the use of a new prosthesis reduces the risk of endoluminal graft endoleak and may constitute an attractive alternative to conventional surgery in management of high-risk thoracoabdominal aortic aneurysms.