Luca Cabrini

Anaesthetic drugs and survival: a Bayesian network meta-analysis of randomized trials in cardiac surgery

BACKGROUND Many studies have compared desflurane, isoflurane, sevoflurane, total i.v. anaesthesia (TIVA), or all in cardiac surgery to assess their effects on patient survival. METHODS We performed standard pairwise and Bayesian network meta-analyses; the latter allows indirect assessments if any of the anaesthetic agents were not compared in head-to-head trials. Pertinent studies were identified using BioMedCentral, MEDLINE/PubMed, Embase, and the Cochrane Library (last updated in June 2012). RESULTS We identified 38 randomized trials with survival data published between 1991 and 2012, with most studies (63%) done in coronary artery bypass grafting (CABG) patients with standard cardiopulmonary bypass. Standard meta-analysis showed that the use of a volatile agent was associated with a reduction in mortality when compared with TIVA at the longest follow-up available [25/1994 (1.3%) in the volatile group vs 43/1648 (2.6%) in the TIVA arm, odds ratio (OR)=0.51, 95% confidence interval (CI) 0.33-0.81, P-value for effect=0.004, number needed to treat 74, I(2)=0%] with results confirmed in trials with low risk of bias, in large trials, and when including only CABG studies. Bayesian network meta-analysis showed that sevoflurane (OR=0.31, 95% credible interval 0.14-0.64) and desflurane (OR=0.43, 95% credible interval 0.21-0.82) were individually associated with a reduction in mortality when compared with TIVA. CONCLUSIONS Anaesthesia with volatile agents appears to reduce mortality after cardiac surgery when compared with TIVA, especially when sevoflurane or desflurane is used. A large, multicentre trial is warranted to confirm that long-term survival is significantly affected by the choice of anaesthetic.

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.

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

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

Noninvasive ventilation and survival in acute care settings: a comprehensive systematic review and metaanalysis of randomized controlled trials.

Objective:Noninvasive ventilation is increasingly applied to prevent or treat acute respiratory failure, but its benefit on survival is still controversial for many indications. We performed a metaanalysis of randomized controlled trials focused on the effect of noninvasive ventilation on mortality. Data Sources:BioMedCentral, PubMed, Embase, and the Cochrane Central Register of clinical trials (updated December 31, 2013) were searched. Study Selection:We included all the randomized controlled trials published in the last 20 years performed in adults, reporting mortality, comparing noninvasive ventilation to any other treatment for prevention or treatment of acute respiratory failure or as a tool allowing an earlier extubation. Studies with unclear methodology, comparing two noninvasive ventilation modalities, or in palliative settings were excluded. Data Extraction:We extracted data on mortality, study design, population, clinical setting, comparator, and follow-up duration. Data Synthesis:Seventy-eight studies were analyzed. Noninvasive ventilation was associated with a reduction in mortality (12.6% in the noninvasive ventilation group vs 17.8% in the control arm; risk ratio = 0.73 [0.66–0.81]; p < 0.001; number needed to treat = 19 with 7,365 patients included) at the longest available follow-up. Mortality was reduced when noninvasive ventilation was used to treat (14.2% vs 20.6%; risk ratio = 0.72; p < 0.001; number needed to treat = 16, with survival improved in pulmonary edema, chronic obstructive pulmonary disease exacerbation, acute respiratory failure of mixed etiologies, and postoperative acute respiratory failure) or to prevent acute respiratory failure (5.3% vs 8.3%; risk ratio = 0.64 [0.46–0.90]; number needed to treat = 34, with survival improved in postextubation ICU patients), but not when used to facilitate an earlier extubation. Overall results were confirmed for hospital mortality. Patients randomized to noninvasive ventilation maintained the survival benefit even in studies allowing crossover of controls to noninvasive ventilation as rescue treatment. Conclusions:This comprehensive metaanalysis suggests that noninvasive ventilation improves survival in acute care settings. The benefit could be lost in some subgroups of patients if noninvasive ventilation is applied late as a rescue treatment. Whenever noninvasive ventilation is indicated, an early adoption should be promoted.

Percutaneous tracheostomy, a systematic review.

Percutaneous dilatational tracheostomy (PDT) is a common procedure in intensive care units and the identification of the best technique is very important. We performed a systematic review and meta‐analysis of randomized studies comparing different PDT techniques in critically ill adult patients to investigate if one technique is superior to the others with regard to major and minor intraprocedural complications.

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.

Fenoldopam and Acute Renal Failure in Cardiac Surgery: A Meta-Analysis of Randomized Placebo-Controlled Trials

OBJECTIVE Because at present no pharmacologic prevention or treatment of acute kidney injury seems to be available, the authors updated a meta-analysis to investigate the effects of fenoldopam in reducing acute kidney injury in patients undergoing cardiac surgery, focusing on randomized placebo-controlled studies only. DESIGN A meta-analysis of randomized, placebo-controlled trials. SETTING Hospitals. PARTICIPANTS A total of 440 patients from 6 studies were included in the analysis. INTERVENTIONS None. The ability of fenoldopam to reduce acute kidney injury in the perioperative period when compared with placebo was investigated. MEASUREMENTS AND MAIN RESULTS Google Scholar and PubMed were searched (updated January 1, 2012). Authors and external experts were contacted. Pooled estimates showed that fenoldopam consistently and significantly reduced the risk of acute kidney injury (odds ratio [OR] = 0.41; 95% confidence interval [CI], 0.23-0.74; p = 0.003), with a higher rate of hypotensive episodes and/or use of vasopressors (30/109 [27.5%] v 21/112 [18.8%]; OR = 2.09; 95% CI, 0.98-4.47; p = 0.06) and no effect on renal replacement therapy, survival, and length of intensive care unit or hospital stay. CONCLUSIONS This analysis suggests that fenoldopam reduces acute kidney injury in patients undergoing cardiac surgery. Because the number of the enrolled patients was small and there was no effect on renal replacement therapy or survival, a large, multicenter, and appropriately powered trial is needed to confirm these promising results.

Impact of impedance threshold devices on cardiopulmonary resuscitation: A systematic review and meta-analysis of randomized controlled studies

Objectives:Vital organ hypoperfusion significantly contributes to the dismal survival rates observed with manual cardiopulmonary resuscitation after cardiac arrest. The impedance threshold device is a valve which reduces air entry into lungs during chest recoil between chest compressions, producing a potentially beneficial decrease in intrathoracic pressure and thus increasing venous return to the heart. This review provides an update on the impedance threshold device and underlines its effect on short-term survival. Data Source:MedCentral, CENTRAL, PubMed, and conference proceedings were searched (updated March 27, 2007). Authors and external experts were contacted. Study Selections:Three unblinded reviewers selected randomized trials using an impedance threshold device in cardiopulmonary resuscitation of nontraumatic out-of-hospital cardiac arrests. Four reviewers independently abstracted patient, treatment and outcome data. Data Extraction:A total of 833 patients from five high quality randomized studies were included in the analysis. Data Synthesis:Pooled estimates showed that the impedance threshold device consistently and significantly improved return to spontaneous circulation (202/438 [46%] for impedance threshold device group vs. 159/445 [36%] for control, relative risk [RR] = 1.29 [1.10–1.51], p = .002), early survival (139/428 [32%] vs. 97/433 [22%], RR = 1.45 [1.16–1.80], p = .0009) and favorable neurologic outcome (39/307 [13%] vs. 18/293 [6%], RR = 2.35 [1.30–4.24], p = .004) with no effect on favorable neurologic outcome in survivors (39/60 [65%] vs. 18/44 [41%]) nor an improved survival at the longest available follow up (35/428 [8.2%] vs. 24/433 [5.5%]). Conclusions:This meta-analysis of randomized controlled studies suggests that the impedance threshold device improves early outcome in patients with out-of-hospital cardiac arrest undergoing cardiopulmonary resuscitation.

Reducing Mortality in Acute Kidney Injury Patients: Systematic Review and International Web-Based Survey

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.

Remifentanil in Cardiac Surgery: A Meta-analysis of Randomized Controlled Trials

OBJECTIVE The authors conducted a review of randomized controlled trials to identify advantages in clinically relevant outcomes in patients undergoing cardiac surgery with remifentanil. DESIGN Meta-analysis. SETTING Hospitals. PARTICIPANTS A total of 1,473 patients from 16 randomized trials. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULT PubMed, BioMedCentral, and conference proceedings were searched (updated May 2010) for randomized trials that compared remifentanil with fentanyl or sufentanil in cardiac anesthesia. Four independent reviewers performed data extraction, with divergences resolved by consensus. Overall analysis showed that the use of remifentanil was associated with a significant reduction in postoperative mechanical ventilation (WMD = -139 min [-244, -32], p for effect = 0.01, p for heterogeneity < 0.001, I(2) = 89%); length of hospital stay (WMD = -1.08 days [-1.60, -0.57], p for effect < 0.0001, p for heterogeneity = 0.004, I(2) = 71%); and cardiac troponin-I release (WMD = -2.08 ng/mL [-3.93, -0.24], p for effect = 0.03, p for heterogeneity < 0.02, I(2) = 74%). No difference was noted in mortality (3/344 [0.87%] in the remifentanil group vs [1.06%] the control group, OR 0.76 [0.17-3.38], p for effect = 0.72, p for heterogeneity = 0.35, I(2) = 5%). CONCLUSIONS Remifentanil reduces cardiac troponin release, time of mechanical ventilation, and length of hospital stay in patients undergoing cardiac surgery.