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      Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome

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          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. 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. 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. Randomised controlled trials in people with myocardial infarction, heart failure or cardiac surgery complicated by cardiogenic shock or LCOS. We used standard methodological procedures expected by Cochrane. 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). 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. Inotropic and vasodilator strategies in people with cardiogenic shock or low cardiac output Review question We reviewed evidence of the treatment with different inotropic agents and vasodilative drugs for their effects on mortality in people with cardiogenic shock (CS) or low cardiac output syndrome (LCOS). Background CS and LCOS still remain life‐threatening complications. Inotropic and vasoactive drugs are potent, but potentially harmful agents. Their benefits and harms are associated with mortality. Study characteristics This evidence is current to June 2017. We included 13 studies with 2001 participants with CS or LCOS as complications of myocardial infarction, heart failure or cardiac surgery, with follow‐up periods between the length of the recovery period up to 12 months. Four studies were funded by a drug manufacturer. Key results We compared different approaches to standard therapies with possible addition of inotropic or vasoconstrictive drugs as levosimendan, dobutamine, enoximone, epinephrine. This review presents low‐quality evidence that levosimendan compared to dobutamine reduces short‐term mortality. The survival benefit with levosimendan vs. dobutamine is not confirmed on long‐term follow up. Very low‐quality evidence shows uncertainty around the effect of levosimendan compared to placebo or enoximone. Very low‐quality evidence shows uncertainty on the comparison of epinephrine with norepinephrine‐dobutamine, amrinone or enoximone with dobutamine, dopexamine with dopamine, and nitric oxide with placebo. Quality of evidence We have reduced confidence in the results of the studies that we analysed (low‐ or very low‐quality evidence) due to serious study limitations, very serious imprecision or indirectness.

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              EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population.

              The objective of the EuroHeart Failure Survey II (EHFS II) was to assess patient characteristics, aetiology, treatment, and outcome of acute heart failure (AHF) in Europe in relation to the guidelines on the diagnosis and treatment of AHF published by the European Society of Cardiology. Patients hospitalized for AHF were recruited by 133 centres in 30 European countries. Three thousand five hundred and eighty patients were entered into the database by the end of August 2005. Mean age was 70 years, and 61% of patients were male. New-onset AHF (de novo AHF) was diagnosed in 37%, of which 42% was due to acute coronary syndromes (ACS). Clinical classification according to the guidelines divided AHF patients into (i) decompensated HF (65%), (ii) pulmonary oedema (16%), (iii) HF and hypertension (11%), (iv) cardiogenic shock (4%), and (v) right HF (3%). Coronary heart disease, hypertension, and atrial fibrillation were the most common underlying conditions. Arrhythmias, valvular dysfunction, and ACS were each present as precipitating factor in one-third of cases. Preserved left ventricular ejection fraction (> or =45%) was observed in 34%. Valvular disorders were common, especially mitral regurgitation (MR) which was reported on echocardiography in 80% of patients. Median length of stay was 9 days, and in-hospital mortality 6.7%. At discharge, 80% of patients were on angiotensin-converting enzyme-inhibitors or angiotensin receptor blockers, whereas 61% were taking beta-blocker medication. Decompensated HF is the most common clinical presentation of AHF patients. More than one-third of AHF patients do not have a previous history of HF, and new-onset HF is often caused by ACS. Preserved systolic function is found in a substantial proportion of the patients. The prevalence of valvular dysfunction is strikingly high and contributes to the clinical presentation. The EHFS II on AHF verified that the use of evidence-based HF medication was well adopted to clinical practice.

                Author and article information

                Cochrane Database of Systematic Reviews
                January 29 2018
                [1 ]Martin-Luther-University Halle-Wittenberg; Department of Anaesthesiology and Surgical Intensive Care; Halle/Saale Germany
                [2 ]Martin-Luther-University Halle-Wittenberg; Institute of Medical Epidemiology, Biostatistics and Informatics; Halle/Saale Germany 06112
                [3 ]Carl von Basedow Klinikum Merseburg; Cardiology/Intensive Care Medicine; Weisse Mauer 42 Merseburg Germany 06217
                [4 ]Martin-Luther-University Halle-Wittenberg; Department of Internal Medicine III; Halle/Saale Germany
                [5 ]University Clinic Schleswig-Holstein, Campus Lübeck; Medical Clinic II (Kardiology, Angiology, Intensive Care Medicine); Ratzeburger Allee 160 Lubeck D-23538 Germany
                © 2018
                Self URI (article page): http://doi.wiley.com/10.1002/14651858.CD009669.pub3


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