Giovanni Landoni

Pulmonary Vein Denervation Enhances Long-Term Benefit After Circumferential Ablation for Paroxysmal Atrial Fibrillation

Background—There are no data to evaluate the relationship between autonomic nerve function modification and recurrent atrial fibrillation (AF) after circumferential pulmonary vein ablation (CPVA). This study assesses the incremental benefit of vagal denervation by radiofrequency in preventing recurrent AF in a large series of patients undergoing CPVA for paroxysmal AF. Methods and Results—Data were collected on 297 patients undergoing CPVA for paroxysmal AF. Abolition of all evoked vagal reflexes around all pulmonary vein ostia was defined as complete vagal denervation (CVD) and was obtained in 34.3% of patients. Follow-up ended at 12 months. Heart rate variability attenuation, consistent with vagal withdrawal, was detectable for up to 3 months after CPVA, particularly in patients with reflexes and CVD, who were less likely to have recurrent AF than those without reflexes (P =0.0002, log-rank test). Only the percentage area of left atrial isolation and CVD were predictors of AF recurrence after CPVA (P <0.001 and P =0.025, respectively). Conclusions—This study suggests that adjunctive CVD during CPVA significantly reduces recurrence of AF at 12 months.

Renoprotective action of fenoldopam in high-risk patients undergoing cardiac surgery: A prospective, double-blind, randomized clinical trial

Background—Acute renal failure is a serious complication of cardiac surgery causing high morbidity and mortality. The aim of this study was to evaluate the usefulness of fenoldopam, a specific agonist of the dopamine-1 receptor, in patients at high risk of perioperative renal dysfunction. Methods and Results—A prospective single-center, randomized, double-blind trial was performed after local ethical committee approval and after written consent was obtained from 80 patients undergoing cardiac surgery. Patients received either fenoldopam at 0.05 &mgr;g/kg per minute or dopamine at 2.5 &mgr;g/kg per minute after the induction of anesthesia for a 24-hour period. All these patients were at high risk of perioperative renal dysfunction as indicated by Continuous Improvement in Cardiac Surgery Program score >10. Primary end point was defined as 25% creatinine increase from baseline levels after cardiac surgery. The 2 groups (fenoldopam versus dopamine) were homogeneous cohorts, and no difference in outcome was observed. Acute renal failure was similar: 17 of 40 (42.5%) in the fenoldopam group and 16 of 40 (40%) in the dopamine group (P=0.9). Peak postoperative serum creatinine level, intensive care unit and hospital stay, and mortality were also similar in the 2 groups. Conclusions—Despite an increasing number of reports of renal protective properties from fenoldopam, we observed no difference in the clinical outcome compared with dopamine in a high-risk population undergoing cardiac surgery.

Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies

Objective: Catecholaminergic inotropes have a place in the management of low output syndrome and decompensated heart failure but their effect on mortality is debated. Levosimendan is a calcium sensitizer that enhances myocardial contractility without increasing myocardial oxygen use. A meta-analysis was conducted to determine the impact of levosimendan on mortality and hospital stay. Data Sources: BioMedCentral, PubMed, Embase, and the Cochrane Central Register of clinical trials were searched for pertinent studies. International experts and the manufacturer were contacted. Study Selection: Articles were assessed by four trained investigators, with divergences resolved by consensus. Inclusion criteria were random allocation to treatment and comparison of levosimendan vs. control. There were no restrictions on dose or time of levosimendan administration or on language. Exclusion criteria were: duplicate publications, nonadult studies, oral administration of levosimendan, and no data on main outcomes. Data Extraction: Study end points, main outcomes, study design, population, clinical setting, levosimendan dosage, and treatment duration were extracted. Data Synthesis: Data from 5,480 patients in 45 randomized clinical trials were analyzed. The overall mortality rate was 17.4% (507 of 2,915) among levosimendan-treated patients and 23.3% (598 of 2,565) in the control group (risk ratio 0.80 [0.72; 0.89], p for effect <.001, number needed to treat = 17 with 45 studies included). Reduction in mortality was confirmed in studies with placebo (risk ratio 0.82 [0.69; 0.97], p = .02) or dobutamine (risk ratio 0.68 [0.52–0.88]; p = .003) as comparator and in studies performed in cardiac surgery (risk ratio 0.52 [0.35; 0.76] p = .001) or cardiology (risk ratio 0.75 [0.63; 0.91], p = .003) settings. Length of hospital stay was reduced in the levosimendan group (weighted mean difference = −1.31 [−1.95; −0.31], p for effect = .007, with 17 studies included). A trend toward a higher percentage of patients experiencing hypotension was noted in levosimendan vs. control (risk ratio 1.39 [0.97–1.94], p = .053). Conclusions: Levosimendan might reduce mortality in cardiac surgery and cardiology settings of adult patients.

Fenoldopam Reduces the Need for Renal Replacement Therapy and In-Hospital Death in Cardiovascular Surgery: A Meta-Analysis

OBJECTIVE Acute renal failure is a common and threatening complication in patients undergoing cardiovascular surgery. To determine the efficacy of fenoldopam in the prevention of acute renal failure, the authors performed a systematic review of randomized, controlled trials and propensity-matched studies in patients undergoing cardiovascular surgery. DESIGN Meta-analysis. SETTING Hospitals. PARTICIPANTS A total of 1,059 patients from 13 randomized and case-matched studies were included in the analysis. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Google Scholar, PubMed, and scientific sessions were searched (updated November 2006). Authors and external experts were contacted. Four unblinded reviewers selected controlled trials that used fenoldopam in the prevention or treatment of acute renal failure in cardiovascular surgery. Four reviewers independently abstracted patient data, treatment characteristics, and outcomes. Pooled estimates showed that fenoldopam consistently and significantly reduced the need for renal replacement therapy (odds ratio = 0.37 [0.23-0.59], p < 0.001) and in-hospital death (odds ratio = 0.46 [0.29-0.75], p = 0.01). These benefits were associated with shorter intensive care unit stay (weighted mean difference [WMD] = -0.93 days [-1.27; -0.58], p = 0.002). Sensitivity analyses, tests for small study bias, and heterogeneity assessment further confirmed the main analysis. CONCLUSIONS This meta-analysis provides evidence that fenoldopam may confer significant benefits in preventing renal replacement therapy and reducing mortality in patients undergoing cardiovascular surgery.

Levosimendan : molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan

The molecular background of the Ca(2+)-sensitizing effect of levosimendan relates to its specific interaction with the Ca(2+)-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K(+) channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP-sensitive K(+) channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug-receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators.

Reducing Mortality in Cardiac Surgery With Levosimendan: A Meta-analysis of Randomized Controlled Trials

OBJECTIVES The authors performed a meta-analysis to evaluate whether levosimendan is associated with improved survival in patients undergoing cardiac surgery. DESIGN A meta-analysis. SETTING Hospitals. PARTICIPANTS A total of 440 patients from 10 randomized controlled studies were included in the analysis. INTERVENTIONS None. MEASURMENTS AND MAIN RESULTS: Four investigators independently searched BioMedCentral and PubMed. Inclusion criteria were random allocation to treatment, comparison of levosimendan versus control, and cardiac surgery patients. Exclusion criteria were duplicate publications, nonhuman experimental studies, and no mortality data. The primary endpoint was postoperative mortality. Levosimendan was associated with a significant reduction in postoperative mortality (11/235 [4.7%] in the levosimendan group v 26/205 [12.7%] in the control arm, odds ratio = 0.35 [0.18-0.71], p for effect = 0.003, p for heterogeneity = 0.22, I(2) = 27.4% with 440 patients included), cardiac troponin release, and atrial fibrillation. No difference was found in terms of myocardial infarction, acute renal failure, time on mechanical ventilation, intensive care unit, and hospital stay. CONCLUSIONS Levosimendan has cardioprotective effects that could result in a reduced postoperative mortality. A large randomized controlled study is warranted in this setting.

Desmopressin reduces transfusion needs after surgery: a meta-analysis of randomized clinical trials.

Background:Perioperative pathologic microvascular bleeding is associated with increased morbidity and mortality and could be reduced by hemostatic drugs. At the same time, safety concerns regarding existing hemostatic agents include excess mortality. Numerous trials investigating desmopressin have lacked power to detect a beneficial effect on transfusion of blood products. The authors performed a meta-analysis of 38 randomized, placebo-controlled trials (2,488 patients) investigating desmopressin in surgery and indicating at least perioperative blood loss or transfusion of blood products. Methods:Pertinent studies were searched in BioMed Central, CENTRAL, and PubMed (updated May 1, 2008). Further hand or computerized searches involved recent (2003–2008) conference proceedings. Results:In most of the included studies, 0.3 &mgr;g/kg desmopressin was used prophylactically over a 15- to 30-min period. In comparison with placebo, desmopressin was associated with reduced requirements of blood product transfusion (standardized mean difference = −0.29 [−0.52 to −0.06] units per patient; P = 0.01), which were more pronounced in the subgroup of noncardiac surgery and were without a statistically significant increase in thromboembolic adverse events (57/1,002 = 5.7% in the desmopressin group vs. 45/979 = 4.6% in the placebo group; P = 0.3). Conclusions:Desmopressin slightly reduced blood loss (almost 80 ml per patient) and transfusion requirements (almost 0.3 units per patient) in surgical patients, without reduction in the proportion of patients who received transfusions. This meta-analysis suggests the importance of further large, randomized controlled studies using desmopressin in patients with or at risk of perioperative pathologic microvascular bleeding.

Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study.

IntroductionThe purpose of the present study was to investigate microcirculatory blood flow in patients with septic shock treated with levosimendan as compared to an active comparator drug (i.e. dobutamine). The primary end point was a difference of ≥ 20% in the microvascular flow index of small vessels (MFIs) among groups.MethodsThe study was designed as a prospective, randomized, double-blind clinical trial and performed in a multidisciplinary intensive care unit. After achieving normovolemia and a mean arterial pressure of at least 65 mmHg, 40 septic shock patients were randomized to receive either levosimendan 0.2 μg·kg-1·min-1 (n = 20) or an active comparator (dobutamine 5 μg·kg-1·min-1; control; n = 20) for 24 hours. Sublingual microcirculatory blood flow of small and medium vessels was assessed by sidestream dark-field imaging. Microcirculatory variables and data from right heart catheterization were obtained at baseline and 24 hours after randomization. Baseline and demographic data were compared by means of Mann-Whitney rank sum test or chi-square test, as appropriate. Microvascular and hemodynamic variables were analyzed using the Mann-Whitney rank sum test.ResultsMicrocirculatory flow indices of small and medium vessels increased over time and were significantly higher in the levosimendan group as compared to the control group (24 hrs: MFIm 3.0 (3.0; 3.0) vs. 2.9 (2.8; 3.0); P = .02; MFIs 2.9 (2.9; 3.0) vs. 2.7 (2.3; 2.8); P < .001). The relative increase of perfused vessel density vs. baseline was significantly higher in the levosimendan group than in the control group (dMFIm 10 (3; 23)% vs. 0 (-1; 9)%; P = .007; dMFIs 47 (26; 83)% vs. 10 (-3; 27); P < .001). In addition, the heterogeneity index decreased only in the levosimendan group (dHI -93 (-100; -84)% vs. 0 (-78; 57)%; P < .001). There was no statistically significant correlation between systemic and microcirculatory flow variables within each group (each P > .05).ConclusionsCompared to a standard dose of 5 μg·kg-1·min-1 of dobutamine, levosimendan at 0.2 μg·kg-1·min-1 improved sublingual microcirculatory blood flow in patients with septic shock, as reflected by changes in microcirculatory flow indices of small and medium vessels.Trial registrationNCT00800306.

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.