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EBioMedicine Dec 2022Management of the patient with sepsis comprises three key branches: control of the underlying infection, haemodynamic stabilization, and modulation of the host response.... (Review)
Review
Management of the patient with sepsis comprises three key branches: control of the underlying infection, haemodynamic stabilization, and modulation of the host response. Each aspect should be considered in all patients and, when relevant, managed at the same time. Infection control is applicable to all patients with sepsis and will include antibiotic therapy and often surgical intervention to remove an infectious source. Haemodynamic support involves fluid administration in all patients and vasoactive agents in patients with associated circulatory shock. Noradrenaline is the first choice vasopressor agent; inotropic agents, usually dobutamine, may be added in case of myocardial depression. No interventions directed at individual components of the host response to sepsis have yet been shown to improve outcomes, but glucocorticoids and vasopressin have a global impact on the response and can thus be considered in this category. A move toward more personalized treatment is needed across all three arms of sepsis management.
Topics: Humans; Shock, Septic; Sepsis; Vasoconstrictor Agents; Hemodynamics; Anti-Bacterial Agents
PubMed: 36470828
DOI: 10.1016/j.ebiom.2022.104318 -
Intensive Care Medicine Jun 2018We set out to summarize the current knowledge on vasoactive drugs and their use in the management of shock to inform physicians' practices. (Review)
Review
PURPOSE
We set out to summarize the current knowledge on vasoactive drugs and their use in the management of shock to inform physicians' practices.
METHODS
This is a narrative review by a multidisciplinary, multinational-from six continents-panel of experts including physicians, a pharmacist, trialists, and scientists.
RESULTS AND CONCLUSIONS
Vasoactive drugs are an essential part of shock management. Catecholamines are the most commonly used vasoactive agents in the intensive care unit, and among them norepinephrine is the first-line therapy in most clinical conditions. Inotropes are indicated when myocardial function is depressed and dobutamine remains the first-line therapy. Vasoactive drugs have a narrow therapeutic spectrum and expose the patients to potentially lethal complications. Thus, these agents require precise therapeutic targets, close monitoring with titration to the minimal efficacious dose and should be weaned as promptly as possible. Moreover, the use of vasoactive drugs in shock requires an individualized approach. Vasopressin and possibly angiotensin II may be useful owing to their norepinephrine-sparing effects.
Topics: Cardiotonic Agents; Dobutamine; Humans; Intensive Care Units; Norepinephrine; Shock; Shock, Septic; Vasoconstrictor Agents
PubMed: 29868972
DOI: 10.1007/s00134-018-5242-5 -
European Heart Journal Nov 2019Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive...
Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.
Topics: Acute Disease; Animals; Antioxidants; Calcium; Cardiotonic Agents; Case-Control Studies; Catecholamines; Clinical Trials as Topic; Diastole; Dobutamine; Dogs; Energy Metabolism; Excitation Contraction Coupling; Heart Failure; Humans; Mitochondria; Models, Animal; Myocardial Contraction; Nitrogen Oxides; Oxidation-Reduction; Phosphodiesterase Inhibitors; Placebos; Receptors, Adrenergic; Sarcomeres; Shock, Cardiogenic; Simendan; Swine; Systole; Urea
PubMed: 30295807
DOI: 10.1093/eurheartj/ehy600 -
The New England Journal of Medicine Oct 2014Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain.
METHODS
In this trial conducted at 51 centers (mostly in Australia or New Zealand), we randomly assigned patients presenting to the emergency department with early septic shock to receive either EGDT or usual care. The primary outcome was all-cause mortality within 90 days after randomization.
RESULTS
Of the 1600 enrolled patients, 796 were assigned to the EGDT group and 804 to the usual-care group. Primary outcome data were available for more than 99% of the patients. Patients in the EGDT group received a larger mean (±SD) volume of intravenous fluids in the first 6 hours after randomization than did those in the usual-care group (1964±1415 ml vs. 1713±1401 ml) and were more likely to receive vasopressor infusions (66.6% vs. 57.8%), red-cell transfusions (13.6% vs. 7.0%), and dobutamine (15.4% vs. 2.6%) (P<0.001 for all comparisons). At 90 days after randomization, 147 deaths had occurred in the EGDT group and 150 had occurred in the usual-care group, for rates of death of 18.6% and 18.8%, respectively (absolute risk difference with EGDT vs. usual care, -0.3 percentage points; 95% confidence interval, -4.1 to 3.6; P=0.90). There was no significant difference in survival time, in-hospital mortality, duration of organ support, or length of hospital stay.
CONCLUSIONS
In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days. (Funded by the National Health and Medical Research Council of Australia and the Alfred Foundation; ARISE ClinicalTrials.gov number, NCT00975793.).
Topics: Adult; Aged; Combined Modality Therapy; Critical Illness; Dobutamine; Emergency Service, Hospital; Erythrocyte Transfusion; Female; Fluid Therapy; Humans; Length of Stay; Male; Middle Aged; Renal Replacement Therapy; Respiration, Artificial; Shock, Septic; Survival Analysis; Vasoconstrictor Agents
PubMed: 25272316
DOI: 10.1056/NEJMoa1404380 -
The Cochrane Database of Systematic... Jan 2018Cardiogenic shock (CS) and low cardiac output syndrome (LCOS) as complications of acute myocardial infarction (AMI), heart failure (HF) or cardiac surgery are... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cardiogenic shock (CS) and low cardiac output syndrome (LCOS) as complications of acute myocardial infarction (AMI), heart failure (HF) or cardiac surgery are life-threatening conditions. While there is a broad body of evidence for the treatment of people with acute coronary syndrome under stable haemodynamic conditions, the treatment strategies for people who become haemodynamically unstable or develop CS remain less clear. We have therefore summarised here the evidence on the treatment of people with CS or LCOS with different inotropic agents and vasodilative drugs. This is the first update of a Cochrane review originally published in 2014.
OBJECTIVES
To assess efficacy and safety of cardiac care with positive inotropic agents and vasodilator strategies in people with CS or LCOS due to AMI, HF or cardiac surgery.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase and CPCI-S Web of Science in June 2017. We also searched four registers of ongoing trials and scanned reference lists and contacted experts in the field to obtain further information. No language restrictions were applied.
SELECTION CRITERIA
Randomised controlled trials in people with myocardial infarction, heart failure or cardiac surgery complicated by cardiogenic shock or LCOS.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We identified 13 eligible studies with 2001 participants (mean or median age range 58 to 73 years) and two ongoing studies. We categorised studies into eight comparisons, all against cardiac care and additional other active drugs or placebo. These comparisons investigated the efficacy of levosimendan versus dobutamine, enoximone or placebo, epinephrine versus norepinephrine-dobutamine, amrinone versus dobutamine, dopexamine versus dopamine, enoximone versus dopamine and nitric oxide versus placebo.All trials were published in peer-reviewed journals, and analysis was done by the intention-to-treat (ITT) principle. Twelve of 13 trials were small with few included participants. Acknowledgement of funding by the pharmaceutical industry or missing conflict of interest statements emerged in five of 13 trials. In general, confidence in the results of analysed studies was reduced due to serious study limitations, very serious imprecision or indirectness. Domains of concern, which show a high risk of more than 50%, include performance bias (blinding of participants and personnel) and bias affecting the quality of evidence on adverse events.Levosimendan may reduce short-term mortality compared to a therapy with dobutamine (RR 0.60, 95% CI 0.37 to 0.95; 6 studies; 1776 participants; low-quality evidence; NNT: 16 (patients with moderate risk), NNT: 5 (patients with CS)). This initial short-term survival benefit with levosimendan vs. dobutamine is not confirmed on long-term follow up. There is uncertainty (due to lack of statistical power) as to the effect of levosimendan compared to therapy with placebo (RR 0.48, 95% CI 0.12 to 1.94; 2 studies; 55 participants, very low-quality evidence) or enoximone (RR 0.50, 95% CI 0.22 to 1.14; 1 study; 32 participants, very low-quality evidence).All comparisons comparing other positive inotropic, inodilative or vasodilative drugs presented uncertainty on their effect on short-term mortality with very low-quality evidence and based on only one RCT. These single studies compared epinephrine with norepinephrine-dobutamine (RR 1.25, 95% CI 0.41 to 3.77; 30 participants), amrinone with dobutamine (RR 0.33, 95% CI 0.04 to 2.85; 30 participants), dopexamine with dopamine (no in-hospital deaths from 70 participants), enoximone with dobutamine (two deaths from 40 participants) and nitric oxide with placebo (one death from three participants).
AUTHORS' CONCLUSIONS
Apart from low quality of evidence data suggesting a short-term mortality benefit of levosimendan compared with dobutamine, at present there are no robust and convincing data to support a distinct inotropic or vasodilator drug-based therapy as a superior solution to reduce mortality in haemodynamically unstable people with cardiogenic shock or LCOS.Considering the limited evidence derived from the present data due to a generally high risk of bias and imprecision, it should be emphasised that there remains a great need for large, well-designed randomised trials on this topic to close the gap between daily practice in critical care medicine and the available evidence. It seems to be useful to apply the concept of 'early goal-directed therapy' in cardiogenic shock and LCOS with early haemodynamic stabilisation within predefined timelines. Future clinical trials should therefore investigate whether such a therapeutic concept would influence survival rates much more than looking for the 'best' drug for haemodynamic support.
Topics: Aged; Cardiac Output, Low; Cardiotonic Agents; Cause of Death; Dobutamine; Enoximone; Humans; Hydrazones; Middle Aged; Myocardial Infarction; Nitric Oxide; Pyridazines; Randomized Controlled Trials as Topic; Shock, Cardiogenic; Simendan; Vasodilator Agents
PubMed: 29376560
DOI: 10.1002/14651858.CD009669.pub3 -
Circulation May 2023Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a paramount treatment for patients with heart failure (HF), irrespective of underlying reduced or... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a paramount treatment for patients with heart failure (HF), irrespective of underlying reduced or preserved ejection fraction. However, a definite cardiac mechanism of action remains elusive. Derangements in myocardial energy metabolism are detectable in all HF phenotypes, and it was proposed that SGLT2i may improve energy production. The authors aimed to investigate whether treatment with empagliflozin leads to changes in myocardial energetics, serum metabolomics, and cardiorespiratory fitness.
METHODS
EMPA-VISION (Assessment of Cardiac Energy Metabolism, Function and Physiology in Patients With Heart Failure Taking Empagliflozin) is a prospective, randomized, double-blind, placebo-controlled, mechanistic trial that enrolled 72 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF; n=36; left ventricular ejection fraction ≤40%; New York Heart Association class ≥II; NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥125 pg/mL) and HF with preserved ejection fraction (HFpEF; n=36; left ventricular ejection fraction ≥50%; New York Heart Association class ≥II; NT-proBNP ≥125 pg/mL). Patients were stratified into respective cohorts (HFrEF versus HFpEF) and randomly assigned to empagliflozin (10 mg; n=35: 17 HFrEF and 18 HFpEF) or placebo (n=37: 19 HFrEF and 18 HFpEF) once daily for 12 weeks. The primary end point was a change in the cardiac phosphocreatine:ATP ratio (PCr/ATP) from baseline to week 12, determined by phosphorus magnetic resonance spectroscopy at rest and during peak dobutamine stress (65% of age-maximum heart rate). Mass spectrometry on a targeted set of 19 metabolites was performed at baseline and after treatment. Other exploratory end points were investigated.
RESULTS
Empagliflozin treatment did not change cardiac energetics (ie, PCr/ATP) at rest in HFrEF (adjusted mean treatment difference [empagliflozin - placebo], -0.25 [95% CI, -0.58 to 0.09]; =0.14) or HFpEF (adjusted mean treatment difference, -0.16 [95% CI, -0.60 to 0.29]; =0.47]. Likewise, there were no changes in PCr/ATP during dobutamine stress in HFrEF (adjusted mean treatment difference, -0.13 [95% CI, -0.35 to 0.09]; =0.23) or HFpEF (adjusted mean treatment difference, -0.22 [95% CI, -0.66 to 0.23]; =0.32). No changes in serum metabolomics or levels of circulating ketone bodies were observed.
CONCLUSIONS
In patients with either HFrEF or HFpEF, treatment with 10 mg of empagliflozin once daily for 12 weeks did not improve cardiac energetics or change circulating serum metabolites associated with energy metabolism when compared with placebo. Based on our results, it is unlikely that enhancing cardiac energy metabolism mediates the beneficial effects of SGLT2i in HF.
REGISTRATION
URL: https://www.
CLINICALTRIALS
gov; Unique identifier: NCT03332212.
Topics: Humans; Heart Failure; Stroke Volume; Ventricular Function, Left; Prospective Studies; Dobutamine; Energy Metabolism; Adenosine Triphosphate
PubMed: 37070436
DOI: 10.1161/CIRCULATIONAHA.122.062021 -
The Cochrane Database of Systematic... Nov 2020Cardiogenic shock (CS) and low cardiac output syndrome (LCOS) are potentially life-threatening complications of acute myocardial infarction (AMI), heart failure (HF) or... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cardiogenic shock (CS) and low cardiac output syndrome (LCOS) are potentially life-threatening complications of acute myocardial infarction (AMI), heart failure (HF) or cardiac surgery. While there is solid evidence for the treatment of other cardiovascular diseases of acute onset, treatment strategies in haemodynamic instability due to CS and LCOS remains less robustly supported by the given scientific literature. Therefore, we have analysed the current body of evidence for the treatment of CS or LCOS with inotropic and/or vasodilating agents. This is the second update of a Cochrane review originally published in 2014.
OBJECTIVES
Assessment of efficacy and safety of cardiac care with positive inotropic agents and vasodilator agents in CS or LCOS due to AMI, HF or after cardiac surgery.
SEARCH METHODS
We conducted a search in CENTRAL, MEDLINE, Embase and CPCI-S Web of Science in October 2019. We also searched four registers of ongoing trials and scanned reference lists and contacted experts in the field to obtain further information. No language restrictions were applied.
SELECTION CRITERIA
Randomised controlled trials (RCTs) enrolling patients with AMI, HF or cardiac surgery complicated by CS or LCOS.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures according to Cochrane standards.
MAIN RESULTS
We identified 19 eligible studies including 2385 individuals (mean or median age range 56 to 73 years) and three ongoing studies. We categorised studies into 11 comparisons, all against standard cardiac care and additional other drugs or placebo. These comparisons investigated the efficacy of levosimendan versus dobutamine, enoximone or placebo; enoximone versus dobutamine, piroximone or epinephrine-nitroglycerine; epinephrine versus norepinephrine or norepinephrine-dobutamine; dopexamine versus dopamine; milrinone versus dobutamine and dopamine-milrinone versus dopamine-dobutamine. All trials were published in peer-reviewed journals, and analyses were done by the intention-to-treat (ITT) principle. Eighteen of 19 trials were small with only a few included participants. An acknowledgement of funding by the pharmaceutical industry or missing conflict of interest statements occurred in nine of 19 trials. In general, confidence in the results of analysed studies was reduced due to relevant study limitations (risk of bias), imprecision or indirectness. Domains of concern, which showed a high risk in more than 50% of included studies, encompassed performance bias (blinding of participants and personnel) and bias affecting the quality of evidence on adverse events. All comparisons revealed uncertainty on the effect of inotropic/vasodilating drugs on all-cause mortality with a low to very low quality of evidence. In detail, the findings were: levosimendan versus dobutamine (short-term mortality: RR 0.60, 95% CI 0.36 to 1.03; participants = 1701; low-quality evidence; long-term mortality: RR 0.84, 95% CI 0.63 to 1.13; participants = 1591; low-quality evidence); levosimendan versus placebo (short-term mortality: no data available; long-term mortality: RR 0.55, 95% CI 0.16 to 1.90; participants = 55; very low-quality evidence); levosimendan versus enoximone (short-term mortality: RR 0.50, 0.22 to 1.14; participants = 32; very low-quality evidence; long-term mortality: no data available); epinephrine versus norepinephrine-dobutamine (short-term mortality: RR 1.25; 95% CI 0.41 to 3.77; participants = 30; very low-quality evidence; long-term mortality: no data available); dopexamine versus dopamine (short-term mortality: no deaths in either intervention arm; participants = 70; very low-quality evidence; long-term mortality: no data available); enoximone versus dobutamine (short-term mortality RR 0.21; 95% CI 0.01 to 4.11; participants = 27; very low-quality evidence; long-term mortality: no data available); epinephrine versus norepinephrine (short-term mortality: RR 1.81, 0.89 to 3.68; participants = 57; very low-quality evidence; long-term mortality: no data available); and dopamine-milrinone versus dopamine-dobutamine (short-term mortality: RR 1.0, 95% CI 0.34 to 2.93; participants = 20; very low-quality evidence; long-term mortality: no data available). No information regarding all-cause mortality were available for the comparisons milrinone versus dobutamine, enoximone versus piroximone and enoximone versus epinephrine-nitroglycerine.
AUTHORS' CONCLUSIONS
At present, there are no convincing data supporting any specific inotropic or vasodilating therapy to reduce mortality in haemodynamically unstable patients with CS or LCOS. Considering the limited evidence derived from the present data due to a high risk of bias and imprecision, it should be emphasised that there is an unmet need for large-scale, well-designed randomised trials on this topic to close the gap between daily practice in critical care of cardiovascular patients and the available evidence. In light of the uncertainties in the field, partially due to the underlying methodological flaws in existing studies, future RCTs should be carefully designed to potentially overcome given limitations and ultimately define the role of inotropic agents and vasodilator strategies in CS and LCOS.
Topics: Aged; Cardiac Output, Low; Cardiotonic Agents; Cause of Death; Dobutamine; Enoximone; Epinephrine; Humans; Hydrazones; Middle Aged; Myocardial Infarction; Nitric Oxide; Placebos; Pyridazines; Randomized Controlled Trials as Topic; Shock, Cardiogenic; Simendan; Vasodilator Agents
PubMed: 33152122
DOI: 10.1002/14651858.CD009669.pub4 -
Journal of Nuclear Medicine Technology Jun 2019Pharmacology principles provide key understanding that underpins the clinical and research roles of nuclear medicine practitioners in nuclear cardiology. The scope of... (Review)
Review
Pharmacology principles provide key understanding that underpins the clinical and research roles of nuclear medicine practitioners in nuclear cardiology. The scope of practice of the nuclear medicine technologist demands knowledge and understanding of indications, contraindications, warnings, precautions, proper use, drug interactions, and adverse reactions for each medication to be used. This article is the fifth in a series of articles that aims to enhance the understanding of pharmacologic principles relevant to nuclear medicine. This article will build on the introductory concepts, terminology, and principles of pharmacology explored in the first 2 articles in the series. Specifically, this article will focus on the pharmacologic principles and complex relationship associated with interventional, adjunctive, and cessation medications in nuclear cardiology. Future articles will address the pharmacology related to the emergency crash cart and contrast medium associated with CT and MRI.
Topics: Cardiology; Humans; Nuclear Medicine; Pharmacology; Stress, Physiological
PubMed: 30770476
DOI: 10.2967/jnmt.118.219675