Eighth World Congress of Intensive and Critical Care Medicine
Sydney, Australia
October 2001
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The 8th WCICCM was attended by nearly 3,500 professionals from 87 countries—including delegates from Angola and Argentina to Venezuela and Western Samoa.

At the Sydney meeting, one important issue that surfaced was that problem of how can cardiac output be increased without increasing cardiac work and myocardial oxygen. While traditional agents for treating heart failure address specific patient needs, these agents also have drawbacks (Table 1). For example, diuretics reduce filling pressure, but they can decrease stroke volume as well. And inotropes such as dobutamine and milrinone increase cardiac output, but they also increase cardiac work. This latter effect can result in arrhythmias and tachycardia, and may be linked to an increased risk for death.

Table 1
Limitations of conventional pharmacological approaches to treating heart failure

Therapy

Limitations

Diuretics

Reduce filling pressure, but can decrease stroke volume as well; use may be limited by presence of hypotension

  • In combination with nitrates, furosemide can mask or cause hypovolaemia, thus leading to harmful sympathetic responses, e.g., increased vascular resistance, which in turn causes an increase in cardiac work.

Inotropes/inodilators

Increase cardiac output, but increased cardiac work may lead to harmful consequences

  • beta-adrenergic agonists, e.g., dobutamine, may increase O2 consumption, thus leading to arrhythmias or tachycardia.
  • Phosphodiesterase inhibitors, e.g., milrinone, may also increase O2 consumption, thus increasing likelihood of arrhythmias; this therapy is associated with increased post-hospitalisation deaths.

Considering all currently available inotropes—dobutamine, epinephrine, isoprenaline, dopamine, dopexamine, and milrinone—“There is no good evidence that any of these drugs yield significant help,” commented Prof.
D. Bennett (UK). Given the drawbacks of conventional pharmacological therapy for heart failure, intensivists have long been limited with the prospect of selecting the least harmful regimen for each patient.

A new pharmacological approach to treatment of heart failure: levosimendan

In a sponsored symposium, Prof. M. Singer (UK) introduced a new agent for treatment of patients with acutely decompensated heart failure. Levosimendan, a drug with a dual mechanism of action,was developed for treatment of patients with acutely decompensated heart failure. Levosimendan dual actions are to (1) increase vasodilation for decreased preload and afterload along with enhanced coronary blood flow, and (2) calcium sensitisation for enhanced cardiac contractility. Because calcium sensitisation averts diastolic calcium overload in myocytes, levosimendan increases cardiac output without a significant rise in myocardial oxygen demand.

Prof. Singer described results of three studies that support levosimendan clinical efficacy; these studies involved nearly 900 patients who were hospitalised for cardiac decompensation due to acutely worsened chronic heart failure (dose-titration and LIDO studies) or to myocardial infarction (RUSSLAN study). When administered intravenously for short-term therapy, levosimendan enhanced cardiac output, reduced systemic vascular resistance, and lowered pulmonary artery wedge pressure—without evidence of tachycardia or arrhythmias noted with inotropes that increase cardiac workload (Figure 1). Importantly, mortality 31 days after treatment was halved in chronic heart failure patients treated with levosimendan compared to dobutamine (p=0.049), and this significant difference was sustained throughout 180 days after treatment (p=0.029). Similar benefits were seen among patients with acute heart failure following myocardial infarction, with notable positive survival benefits at 14 and 180 days after therapy. In testing to date, a low incidence of levosimendan-treated patients experiencing hypotension was readily managed.

Figure 1.
Cardiovascular effects of levosimendan

CO, cardiac output;
SVR, systemic vascular resistance; PAWP, pulmonary artery wedge pressure; CVP, central venous pressure;
BP, blood pressure


In summary, clinical studies show the beneficial effects of the calcium sensitiser levosimendan on cardiac performance, haemodynamic parameters, and survival for patients who are otherwise likely to experience worsening heart failure. Notably, the novel mechanism of levosimendan promotes these actions without increasing myocardial oxygen demand, thus averting arrhythmias and ischaemia characteristic of therapy with inotropes that act through adrenergic pathways.

 

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