scholarly journals Levosimendan to prevent acute organ dysfunction in sepsis: the LeoPARDS RCT

2018 ◽  
Vol 5 (6) ◽  
pp. 1-94 ◽  
Author(s):  
Anthony C Gordon ◽  
Shalini Santhakumaran ◽  
Farah Al-Beidh ◽  
Robert ML Orme ◽  
Gavin D Perkins ◽  
...  
Keyword(s):  
Septic Shock ◽  
Intensive Care ◽  
Placebo Group ◽  
Adverse Events ◽  
Organ Dysfunction ◽  
Standard Care ◽  
Absolute Difference ◽  
Serious Adverse Events ◽  
Supraventricular Tachyarrhythmias ◽  
Acute Organ Dysfunction

BackgroundIn septic shock, cardiovascular resuscitation using catecholamine vasopressors and inotropes is standard therapy, but catecholamines have important side effects. Levosimendan (Simdax®; Orion Pharma, Newbury, UK) is a calcium-sensitising drug with inotropic and other properties that may have a role in sepsis.ObjectivesTo determine, in adult septic shock, whether or not levosimendan reduces the incidence and severity of acute organ dysfunction, the effect of levosimendan on individual organ function and the safety profile of levosimendan.DesignMulticentre, randomised, double-blind, parallel-group, placebo-controlled study.SettingUK intensive care units.ParticipantsAdult patients with sepsis and cardiovascular failure requiring vasopressors to maintain blood pressure despite adequate fluid resuscitation.InterventionLevosimendan, at a dosage of 0.05–0.2 µg/kg/minute, compared with placebo for 24 hours, in addition to standard care, within 24 hours of meeting inclusion criteria.Main outcome measureThe primary outcome was mean Sequential Organ Failure Assessment (SOFA) score on the intensive care unit after randomisation to a maximum of 28 days. Secondary outcomes were time to extubation, survival up to 6 months and serious adverse events.ResultsIn total, 2382 patients were screened at 34 centres, of whom 516 were randomised to treatment, 259 to levosimendan and 257 to placebo. Baseline characteristics were well balanced across treatment arms. There was no significant difference in mean ± standard deviation (SD) SOFA score between the levosimendan group (6.7, SD 4.0) and the placebo group (6.1, SD 3.9) [mean difference 0.61, 95% confidence interval (CI) –0.07 to 1.29]. The 28-day mortality rate was 34.5% and 30.9% in the levosimendan and placebo groups, respectively (absolute difference 3.6%, 95% CI –4.5% to 11.7%). Patients in the levosimendan group were less likely to be successfully extubated over 28 days than patients in the placebo group (hazard ratio 0.77, 95% CI 0.60 to 0.97). More patients in the levosimendan group had supraventricular tachyarrhythmias (3.1% vs. 0.4%; absolute difference 2.7%, 95% CI 0.1% to 5.3%), but there was no overall difference in serious adverse events.ConclusionsIn the population of septic shock patients randomised to treatment in this study, the addition of levosimendan to standard medical care did not reduce organ dysfunction or mortality. Levosimendan was associated with a reduced likelihood of successful extubation and an increased risk of supraventricular tachyarrhythmias.LimitationsThis was a trial of levosimendan added to standard care rather than a comparison against an alternative inotrope such as dobutamine. No echocardiographic analyses were performed to provide detailed information about changes in myocardial function; therefore, this trial cannot provide guidance as to which inotrope (if any) is best to use in the management of sepsis if a very low cardiac index is present.Future workLevosimendan could be compared against dobutamine and placebo in patients with a very low cardiac output in sepsis to test which, if any, inotrope should be used in this select group.Trial registrationCurrent Controlled Trials ISRCTN12776039.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. Study drugs were provided by Orion Pharma and additional research funds were provided by Tenax Therapeutics. The study was supported by the NIHR Biomedical Research Centre based at Imperial College, London, and the UK Intensive Care Foundation.

scholarly journals New Definition of Sepsis

2013 ◽  
Vol 2 (1) ◽  
pp. 37
Author(s):  
Fuzhou Wang
Keyword(s):  
Septic Shock ◽  
Intensive Care ◽  
Systemic Inflammatory Response Syndrome ◽  
Inflammatory Response ◽  
Organ Dysfunction ◽  
Medical Science ◽  
Accurate Diagnosis ◽  
Causes Of Mortality ◽  
New Challenges ◽  
Definition Of

Sepsis or septic shock is one of the major causes of mortality in intensive care medicine. How to define and how to make an accurate diagnosis possess critical implications for patients and intensive caregivers. With the development of modern medical science, new challenges rose for how to re-define sepsis and also revision is needed. Should we add organ dysfunction to the diagnostic criteria of systemic inflammatory response syndrome, and whether are there early symptoms or signs of organ dysfunction need to be considered critically. May be the new definition of sepsis can save more lives.

scholarly journals Effect of SGLT-2 Inhibitors on Cardiovascular Outcomes Among Patients With Heart Failure and Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis of Randomized Controlled Trials

2020 ◽  
Author(s):  
Yuan Lu ◽  
Yu Yang ◽  
Yong Fan ◽  
Chenzong Li ◽  
Min Zhang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Adverse Events ◽  
Standard Care ◽  
Sensitivity Analyses ◽  
Controlled Trials ◽  
Serious Adverse Events ◽  
Randomized Controlled ◽  
Patients With Heart Failure

Abstract Background Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are significantly effective in reducing cardiovascular events in patients with type 2 diabetes mellitus (T2DM). However, the magnitude of the effect of SGLT-2i on cardiovascular outcomes in established heart failure (HF) patients with T2DM remains undefined. Methods We systematically searched the PubMed, Embase, Cochrane Central and Web of Science databases for articles published prior to 09 April 2020 to identify randomized controlled trials that compared SGLT-2i with placebo in patients with heart failure concomitant with T2DM. Efficacy outcomes included the composite of cardiovascular death (CVD) or hospitalization for heart failure (HHF), individual CVD, individual HHF, and all-cause mortality (ACM). Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were pooled across trials by using the generic inverse variance method. Sensitivity analyses were conducted by excluding specific studies or using risk ratios (RRs) with 95% CIs as measures of the effect size. Serious adverse events served as safety outcomes. Results A total of 5 large trials comprising 6945 patients with HF and T2DM were enrolled. Pooled data demonstrated that SGLT-2i significantly reduced the risk for the primary composite outcome of CVD or HHF by 13% (HR: 0.87, 95% CI: 0.83–0.91, I2: 0%, P < 0.00001) in patients with HF concomitant with T2DM. Similarly, the use of SGLT-2i was associated with a statistically significant 14% reduction in HHF (pooled HR: 0.86, 95% CI: 0.81–0.91, I2: 0%, P < 0.00001) and a 10% reduction in ACM (pooled HR: 0.90, 95% CI: 0.86–0.96, I2: 16%, P < 0.0005) but was not significantly associated with a reduction in CVD (HR: 0.91, 95% CI: 0.81–1.02, I2: 60%, P = 0.11). Sensitivity analyses indicted consistent results. Compared with placebo plus standard care, the SGLT-2i group had a lower proportion of serious adverse events (weighted proportions: 44.3% vs 50.3%; RR 0.88, 95% CI 0.82–0.95, I2: 22%, p = 0∙006). Conclusions SGLT-2i significantly reduced the risk of HHF and ACM in a broad range of HF patients concomitant with T2DM. Compared with standard care, SGLT-2i plus standard therapy was associated with a reduction in serious adverse events.

Sepsis

2020 ◽  
Author(s):  
Steven P LaRosa ◽  
Steven M. Opal
Keyword(s):  
Intensive Care Unit ◽  
Septic Shock ◽  
Severe Sepsis ◽  
Intensive Care ◽  
Organ Dysfunction ◽  
Fluid Resuscitation ◽  
Multiorgan Failure ◽  
Sepsis Management ◽  
The Past ◽  
Sepsis And Septic Shock

Sepsis, along with the multiorgan failure that often accompanies this condition, is a leading cause of mortality in the intensive care unit. Although modest improvements in the prognosis have been made over the past two decades and promising new therapies continue to be investigated, innovations in the management of septic shock are still required. This chapter discusses the definitions, epidemiology, and pathogenesis (including microbial factors, host-derived mediators, and organ dysfunction) relating to sepsis. Management of severe sepsis and septic shock is also described.  This review contains 5 figures, 11 tables, and 99 references. Keywords:Organ dysfunction, sepsis, septic shock, infection, bacteremia, fluid resuscitation, vasopressor

Efficacy and Safety of PEGPH20 in Pancreatic Cancer: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 17 ◽  
Author(s):  
Vinod Solipuram ◽  
Harish Gopalakrishna ◽  
Gayatri Naira ◽  
Akhila Mohan
Keyword(s):  
Pancreatic Cancer ◽  
Placebo Group ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Cochrane Library ◽  
Thromboembolic Events ◽  
Serious Adverse Events ◽  
Significant Difference

Introduction: Pancreatic cancer is an aggressive tumor that had an estimated 57,600 new cases and 47,050 deaths in 2020 in the US alone. Recent studies have targeted tumor microenvironment (TME) for better delivery of systemic chemotherapy like PEGPH20, which degrades hyaluronic acid in the extracellular matrix (ECM). A meta-analysis of these Randomized controlled trials (RCTs) to test the efficacy of PEGPH20 was performed. Methods: A systematic search was performed using PubMed, Embase, and Cochrane library without language limitations from inception to July 30, 2020. A total of 59 articles was identified, and 3 RCTs were included in the final analysis. The primary outcome was progression-free survival (PFS), and secondary outcomes were overall survival (OS), deaths from adverse events, thromboembolic events, serious adverse events (SAE), and febrile neutropenia. Results: There was no statistically significant improvement in PFS (HR= 0.94; 95%CI (0.79, 1.11)) in the PEGPH20 group when compared to the standard treatment/placebo group. There was no significant difference among OS (HR= 0.99, 95%CI (0.83, 1.17), deaths from adverse events (RR=0.97; 95%CI (0.54, 1.73)), thromboembolic events (RR= 1.49; 95%CI (0.92, 2.44)), and febrile neutropenia (RR= 0.88; 95%CI (0.45, 1.72), however, there was statistically significant increase in SAE (RR = 1.59; 95%CI (1.01, 2.52) in the PEGPH20 group compared to the placebo group. Conclusion: This meta-analysis showed that PEGPH20 did not improve the PFS or OS. Moreover, there is an increased incidence of serious adverse events with the use of PEGPH20 compared to standard therapies.

Effectiveness of enteral ivabradine for heart rate control in septic shock: A randomised controlled trial

2021 ◽  
pp. 0310057X2110099
Author(s):  
Priyankar K Datta ◽  
Vimi Rewari ◽  
Rashmi Ramachandran ◽  
Preet M Singh ◽  
Bikash R Ray ◽  
...  
Keyword(s):  
Heart Rate ◽  
Septic Shock ◽  
Adverse Events ◽  
Standard Therapy ◽  
Controlled Trial ◽  
Cardiac Pacemaker ◽  
Stroke Volume Index ◽  
Volume Index ◽  
Serious Adverse Events ◽  
Group I

Persistent tachycardia in patients with septic shock predicts poor outcome. This study sought to investigate the effect of the cardiac pacemaker current inhibitor ivabradine on heart rate and cardio-circulatory function in patients with septic shock. After informed consent, 60 patients with septic shock and persistent tachycardia (heart rate >95 /minute) were prospectively randomly assigned to receive either standard therapy for septic shock (group S) or standard therapy along with enteral ivabradine (group I) for the initial 96 hours after enrolment. Primary outcome was the difference in heart rate between the two groups during the first 96 hours. Secondary outcomes included the effect of ivabradine on haemodynamic, oxygenation, myocardial function and organ function parameters, incidence of adverse events and 30-day overall survival. Heart rate was lower in group I compared to group S (median difference in area under the curve –25.6 (95% confidence intervals –31.4 to –15.9) /minute; P <0.001). Vasopressor requirements, blood lactate levels, Sequential Organ Failure Assessment scores and E/e′ ratio were lower in group I compared to group S. Stroke volume index and ejection fraction were higher in group I while cardiac index and oxygen delivery parameters were maintained similar to group S. There was no difference in 30-day mortality or in the incidence of serious adverse events. Enteral ivabradine is effective in reducing heart rate, and improving haemodynamic parameters and cardiac function in patients with septic shock and persistent tachycardia, without increasing the incidence of adverse events.

scholarly journals Saccharomyces boulardii to Prevent Antibiotic-Associated Diarrhea: A Randomized, Double-Masked, Placebo-Controlled Trial

2016 ◽  
Vol 3 (1) ◽  
Author(s):  
Stephan Ehrhardt ◽  
Nan Guo ◽  
Rebecca Hinz ◽  
Stefanie Schoppen ◽  
Jürgen May ◽  
...  
Keyword(s):  
Placebo Group ◽  
Clostridium Difficile ◽  
Adverse Events ◽  
Antibiotic Treatment ◽  
Controlled Trial ◽  
Saccharomyces Boulardii ◽  
Serious Adverse Events ◽  
Antibiotic Associated Diarrhea ◽  
Clostridium Difficile Associated Diarrhea ◽  
Systemic Antibiotic Treatment

Abstract Background.  Antibiotic-associated diarrhea (AAD) and Clostridium difficile-associated diarrhea (CDAD) are common complications of antibiotic use. Data on the efficacy of probiotics to prevent AAD and CDAD are unclear. We aimed to evaluate the efficacy of Saccharomyces boulardii to prevent AAD and CDAD in hospitalized adult patients. Methods.  We conducted a multicenter, phase III, double-masked, randomized, placebo-controlled trial in hospitalized patients who received systemic antibiotic treatment in 15 hospitals in Germany between July 2010 and October 2012. Participants received Perenterol forte 250 mg capsules or matching placebo twice per day within 24 hours of initiating antibiotic treatment, continued treatment for 7 days after antibiotic discontinuation, and were then observed for 6 weeks. Results.  Two thousand four hundred forty-four patients were screened. The trial was stopped early for futility after inclusion of 477 participants. Two hundred forty-six patients aged 60.1 ± 16.5 years and 231 patients aged 56.5 ± 17.8 were randomized to the S boulardii group and the placebo group, respectively, with 21 and 19 AADs in the respective groups (P = .87). The hazard ratio of AAD in the S boulardii group compared with the placebo group was 1.02 (95% confidence interval, .55–1.90; P = .94). Clostridium difficile-associated diarrhea occurred in 0.8% of participants (4 of 477). Nine serious adverse events were recorded in the S boulardii group, and 3 serious adverse events were recorded in the placebo group. None were related to study participation. Conclusions.  We found no evidence for an effect of S boulardii in preventing AAD or CDAD in a population of hospitalized patients without particular risk factors apart from systemic antibiotic treatment. ClinicalTrials.gov Identifier.  NCT01143272.

OP164 Extracorporeal Cytokine Adsorption Therapy: An Update Systematic Review Of Clinical Efficacy And Safety For Two Indications

2021 ◽  
Vol 37 (S1) ◽  
pp. 3-3
Author(s):  
Gregor Goetz ◽  
Katharina Hawlik ◽  
Claudia Wild
Keyword(s):  
Intensive Care Unit ◽  
Cardiac Surgery ◽  
Intensive Care ◽  
Length Of Stay ◽  
Adverse Events ◽  
Clinical Benefit ◽  
Organ Function ◽  
Serious Adverse Events ◽  
Potential Clinical Benefit ◽  
Length Of Hospitalization

IntroductionThe idea of using extracorporeal cytokine adsorption therapy (ECAT) is to remove cytokines from the blood in order to restore a balanced immune response. Yet, it is unclear as to whether the use of ECAT improves patient-relevant outcomes. Hence, the aim of this article is to synthesize the currently available evidence with regard to a potential clinical benefit of ECAT used in cardiac surgery or sepsis.MethodsWe conducted an updated systematic review summarizing the body of evidence with regard to a potential clinical benefit of ECAT. The study followed the PRISMA statement and the European Network for Health Technology Assessment (EUnetHTA) guidelines. The quality of the individual studies and the strength of the available evidence was assessed using the Cochrane risk of bias tool (v.1) and the GRADE approach respectively. Mortality, organ function, length of stay in the intensive care unit and length of hospitalization, as well as adverse events, were defined as critical outcomes.ResultsFor the preventive treatment of ECAT in patients undergoing cardiac surgery, we found very low-quality inconclusive evidence for mortality (5 randomized controlled trials (RCTs), n = 163), length of stay in the intensive care unit (5 RCTs, n = 163), and length of hospitalization (3 RCTs, n = 101). In addition, very low-quality inconclusive evidence was found for (serious) adverse events (4 RCTs, n = 148). For the therapeutic treatment of ECAT in patients with sepsis/ septic shock, we found very low-quality inconclusive evidence for mortality up to 60-day follow-up (2 RCTs, n = 117), organ function (2 RCTs, n = 117) and length of stay in the intensive care unit (1 study, n = 20). Similarly, very low-quality inconclusive evidence was found for (serious) adverse events (2 RCTs, n = 117). There are currently eighteen ongoing RCTs on the use of ECAT.ConclusionsThere is a lack of reliable data on the clinical benefit of using ECAT as an add-on treatment preventively in cardiac surgery and therapeutically in patients with sepsis or septic shock. While theoretical advantages are anticipated, the current available evidence is inconclusive and was not able to establish the efficacy and safety of ECAT in combination with standard care in the investigated indications. In light of the available RCTs, we strongly recommend the consideration of studies with patient-relevant endpoints and adequate statistical power, instead of investing further research funds on small studies that may not shed more light onto the potential clinical benefit of ECAT. The results of ongoing RCTs are awaited to guide the decision on whether further research funds should be invested in ECAT research or to conclude that the intervention may not show clinical benefits for patients.

Long-term effects with policosanol on lipid profile according to hypercholesterolemia severity in older patients

2021 ◽  
Vol 4 (1) ◽  
pp. 026-38
Author(s):  
Julio C. Fernández-Travieso ◽  
José Illnait-Ferrer ◽  
Sarahí Mendoza-Castaño ◽  
Lilia Fernández-Dorta ◽  
Rafael Gámez-Menéndez ◽  
...  
Keyword(s):  
Placebo Group ◽  
Adverse Events ◽  
Lipid Profile ◽  
Total Cholesterol ◽  
Older Patients ◽  
Lower Amount ◽  
Coronary Risk Factors ◽  
Serious Adverse Events ◽  
Old Patients ◽  
Proportional Intensity

Background: End-point based studies have demonstrated a direct relationship between coronary disease and elevated serum levels of low density lipoprotein cholesterol (LDL-C) and total cholesterol, as well as the benefits of lowering LDL-C with statins on clinical end-points. Policosanol is a mixture of very long chain fatty alcohols purified from sugar cane wax, with dislipidemia controlling effects, proved in numerous clinical assays in which patients with different conditions were included. The efficacy and tolerability of policosanol in the elderly have been also investigated in several clinical trials, being effective, safe and well tolerated. Objectives: To investigate the effects of policosanol treatment during three years on lipid profile with a proportional intensity to the initial dislipidemia severity in older hypercholesterolemic patients. Methods: The present analysis was obtained from the data of all patients treated with policosanol included in a previous prevention study. One thousand, ford hundred seventy old patients of both sexes, between 60 to 85 years old, with type II hypercholesterolemia, and ³ 1 non-lipid coronary risk factors, were randomized in two groups and treated with policosanol or placebo, during three years. Significant changes on lipid profile with a proportional intensity to the initial dislipidemia severity were considered primary efficacy variables. The analysis was done by Intention-to-treat method. Results: An analysis of the response intensity show that after treatment, reductions of LDL-C, total cholesterol and triglycerides were greater, and according to the initial hypercholesterolemia severity, so that, patients with severe hypercholesterolemia showed the better responses, followed by moderate and mild hypercholesterolemia. An opposite pattern, however, was observed for HDL-C serum concentration. Triglycerides did not respond in the same way. The frequency of vascular serious adverse events was lower in the policosanol group (15 events) compared with those on placebo group (49 events). There were 109 patients who experienced serious adverse events: 83 (11.3 %) in placebo and 26 (3.5 %) in policosanol group (p<0.0001). Twenty-three deaths occurred up to study completion: 19 patients belonging to placebo group (2.6 %) and 4 to the policosanol group (0.5 %). Conclusions: The treatment with policosanol produce positive changes on serum lipid profile according to hypercholesterolemia severity and with a significant lower amount of vascular serious adverse events, mortality, and frequency of total adverse events in older patients.

Sepsis

2020 ◽  
Author(s):  
Steven P LaRosa ◽  
Steven M. Opal
Keyword(s):  
Intensive Care Unit ◽  
Septic Shock ◽  
Severe Sepsis ◽  
Intensive Care ◽  
Organ Dysfunction ◽  
Fluid Resuscitation ◽  
Multiorgan Failure ◽  
Sepsis Management ◽  
The Past ◽  
Sepsis And Septic Shock

Sepsis, along with the multiorgan failure that often accompanies this condition, is a leading cause of mortality in the intensive care unit. Although modest improvements in the prognosis have been made over the past two decades and promising new therapies continue to be investigated, innovations in the management of septic shock are still required. This chapter discusses the definitions, epidemiology, and pathogenesis (including microbial factors, host-derived mediators, and organ dysfunction) relating to sepsis. Management of severe sepsis and septic shock is also described.  This review contains 5 figures, 11 tables, and 99 references. Keywords:Organ dysfunction, sepsis, septic shock, infection, bacteremia, fluid resuscitation, vasopressor

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