Fabio Guarracino

Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock A Randomized Clinical Trial

IMPORTANCE β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects. OBJECTIVE To investigate the effect of the short-acting β-blocker esmolol in patients with severe septic shock. DESIGN, SETTING, AND PATIENTS Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit (ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. INTERVENTIONS We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment. MAIN OUTCOMES AND MEASURES Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and 96 hours; and adverse events and mortality occurring within 28 days after randomization. RESULTS Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was -28/min (IQR, -37 to -21) for the esmolol group vs -6/min (95% CI, -14 to 0) for the control group with a mean reduction of 18/min (P < .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, -1 to 10) vs 1 mL/m2 for the control group (IQR, -3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, -2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was -0.1 mmol/L (IQR, -0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, -0.3 for 0.6; P = .007); for norepinephrine, -0.11 μg/kg/min (IQR, -0.46 to 0.02) for the esmolol group vs -0.01 μg/kg/min (IQR, -0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P < .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P < .001). CONCLUSIONS AND RELEVANCE For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01231698.

International Evidence-Based Recommendations for Focused Cardiac Ultrasound

BACKGROUND Focused cardiac ultrasound (FoCUS) is a simplified, clinician-performed application of echocardiography that is rapidly expanding in use, especially in emergency and critical care medicine. Performed by appropriately trained clinicians, typically not cardiologists, FoCUS ascertains the essential information needed in critical scenarios for time-sensitive clinical decision making. A need exists for quality evidence-based review and clinical recommendations on its use. METHODS The World Interactive Network Focused on Critical UltraSound conducted an international, multispecialty, evidence-based, methodologically rigorous consensus process on FoCUS. Thirty-three experts from 16 countries were involved. A systematic multiple-database, double-track literature search (January 1980 to September 2013) was performed. The Grading of Recommendation, Assessment, Development and Evaluation method was used to determine the quality of available evidence and subsequent development of the recommendations. Evidence-based panel judgment and consensus was collected and analyzed by means of the RAND appropriateness method. RESULTS During four conferences (in New Delhi, Milan, Boston, and Barcelona), 108 statements were elaborated and discussed. Face-to-face debates were held in two rounds using the modified Delphi technique. Disagreement occurred for 10 statements. Weak or conditional recommendations were made for two statements and strong or very strong recommendations for 96. These recommendations delineate the nature, applications, technique, potential benefits, clinical integration, education, and certification principles for FoCUS, both for adults and pediatric patients. CONCLUSIONS This document presents the results of the first International Conference on FoCUS. For the first time, evidence-based clinical recommendations comprehensively address this branch of point-of-care ultrasound, providing a framework for FoCUS to standardize its application in different clinical settings around the world.

Percutaneous Mitral Annuloplasty: An Anatomic Study of Human Coronary Sinus and Its Relation With Mitral Valve Annulus and Coronary Arteries

Background— To allow performance of “stand-alone” mitral annuloplasty with minimal invasiveness, percutaneous techniques consisting of delivery into the coronary sinus (CS) of devices intended to shrink the mitral valve annulus have recently been tested in animal models. These techniques exploit the anatomic proximity of the CS and mitral valve annulus in ovine or dogs. Knowledge of a detailed anatomic relationship between the CS, coronary arteries, and mitral valve annulus in humans is essential to define the safety and efficacy of percutaneous techniques in clinical practice. We sought to determine the qualitative and quantitative anatomic relationships between CS and surrounding structures in human hearts. Methods and Results— The distance from the CS to the mitral valve annulus and the relationship between the CS and surrounding structures were studied in 61 excised cadaveric human hearts. Maximal distance from the CS to the mitral valve annulus was found to be up to 19 mm (mean, 9.7±3.2 mm). A diagonal or ramus branch, main circumflex artery, or its branches were located between anterior interventricular vein/CS and the mitral valve annulus in 16.4% and 63.9% of cases, respectively. Conclusions— Surgical anatomy suggests that in humans the CS is located behind the left atrial wall at a significant distance from the mitral valve annulus. Percutaneous mitral annuloplasty devices probably shrink the mitral valve annulus only by an indirect traction mediated by the left atrial wall; a theoretical risk of compressing coronary artery branches exists. Chronic studies are needed to address this problem and to determine long-term efficacy of such methods.

Echocardiography practice, training and accreditation in the intensive care: document for the World Interactive Network Focused on Critical Ultrasound (WINFOCUS).

Echocardiography is increasingly used in the management of the critically ill patient as a non-invasive diagnostic and monitoring tool. Whilst in few countries specialized national training schemes for intensive care unit (ICU) echocardiography have been developed, specific guidelines for ICU physicians wishing to incorporate echocardiography into their clinical practice are lacking. Further, existing echocardiography accreditation does not reflect the requirements of the ICU practitioner. The WINFOCUS (World Interactive Network Focused On Critical UltraSound) ECHO-ICU Group drew up a document aimed at providing guidance to individual physicians, trainers and the relevant societies of the requirements for the development of skills in echocardiography in the ICU setting. The document is based on recommendations published by the Royal College of Radiologists, British Society of Echocardiography, European Association of Echocardiography and American Society of Echocardiography, together with international input from established practitioners of ICU echocardiography. The recommendations contained in this document are concerned with theoretical basis of ultrasonography, the practical aspects of building an ICU-based echocardiography service as well as the key components of standard adult TTE and TEE studies to be performed on the ICU. Specific issues regarding echocardiography in different ICU clinical scenarios are then described.Obtaining competence in ICU echocardiography may be achieved in different ways – either through completion of an appropriate fellowship/training scheme, or, where not available, via a staged approach designed to train the practitioner to a level at which they can achieve accreditation. Here, peri-resuscitation focused echocardiography represents the entry level – obtainable through established courses followed by mentored practice. Next, a competence-based modular training programme is proposed: theoretical elements delivered through blended-learning and practical elements acquired in parallel through proctored practice. These all linked with existing national/international echocardiography courses. When completed, it is anticipated that the practitioner will have performed the prerequisite number of studies, and achieved the competency to undertake accreditation (leading to Level 2 competence) via a recognized National or European examination and provide the appropriate required evidence of competency (logbook). Thus, even where appropriate fellowships are not available, with support from the relevant echocardiography bodies, training and subsequently accreditation in ICU echocardiography becomes achievable within the existing framework of current critical care and cardiological practice, and is adaptable to each countries needs.

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.

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.

Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery

BACKGROUND The calcium sensitizer levosimendan has anti-ischaemic effects mediated via the opening of sarcolemmal and mitochondrial ATP-sensitive potassium channels. These properties suggest potential application in clinical situations where cardioprotection would be beneficial, such as cardiac surgery. We thus decided to investigate whether pharmacological pre-treatment with levosimendan reduces intensive care unit (ICU) length of stay in patients undergoing elective myocardial revascularization under cardiopulmonary bypass. METHODS One hundred and six patients undergoing elective coronary artery bypass grafting were randomly assigned in a double-blind manner to receive levosimendan or placebo. Levosimendan (24 microg kg(-1)) or placebo was administered as a slow i.v. bolus over a 10 min period before the initiation of bypass. RESULTS Tracheal intubation time and the length of ICU stay were significantly reduced in the levosimendan group (P<0.01). The number of patients needing inotropic support for >12 h was significantly higher in the control group (18.0% vs 3.8%; P=0.021). Compared with control patients, levosimendan-treated patients had lower postoperative troponin I concentrations (P<0.0001) and a higher cardiac power index (P<0.0001). CONCLUSIONS Pre-treatment with levosimendan in patients undergoing surgical myocardial revascularization resulted in less myocardial injury, a reduction in tracheal intubation time, less requirement for inotropic support, and a shorter length of ICU stay.

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.

Cardiac protection by volatile anaesthetics: A multicentre randomized controlled study in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass

Background and objectives: To evaluate the effects of total intravenous anaesthesia vs. volatile anaesthesia on cardiac troponin release in coronary artery bypass grafting with cardiopulmonary bypass, we performed a multicentre randomized controlled study to compare postoperative cardiac troponin release in patients receiving two different anaesthesia plans. Methods: We randomly assigned 75 patients to propofol (intravenous anaesthetic) and 75 patients to desflurane (volatile anaesthetic) in addition to an opiate‐based anaesthesia for coronary artery bypass grafting. Peak postoperative troponin I release was measured as a marker of myocardial necrosis. Results: There was a significant (P < 0.001) difference in the postoperative median (25th‐75th percentiles) peak of troponin I in patients receiving propofol 5,5 (2,3‐9,5) ng dL−1 when compared to patients receiving desflurane 2,5 (1,1‐5,3) ng dL−1. The median (interquartile) troponin I area under the curve analysis confirmed the results: 68 (30.5‐104.8) vs. 36.3 (17.9‐86.6) h ng dL−1 (P = 0.002). Patients receiving volatile anaesthetics had reduced need for postoperative inotropic support (24/75, 32.0% vs. 31/75, 41.3%, P = 0.04), and tends toward a reduction in number of Q‐wave myocardial infarction, time on mechanical ventilation, intensive care unit and overall hospital stay. Conclusions: Myocardial damage measured by cardiac troponin release could be reduced by volatile anaesthetics in coronary artery bypass surgery.