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Inoprotection review.

Thank you for the excellent review article by Dr Soeding et al (1). Levosimendan is a relatively new drug and is not yet available in the United States. The article reported the clinical trials REVIVE II and SURVIVE as showing improvements in morbidity and mortality. These trials have not yet been published in full: however, the following is taken from the Abbott press release (2).

REVIVE II was not primarily designed to assess mortality. A secondary endpoint was mortality at 90 days for which there was no statistically significant difference between treatment arms, although there were a greater number of deaths in the levosimendan arm (levosimendan 45 vs. standard therapy 35).

The most common treatment-emergent cardiovascular adverse events in REVIVE II were hypotension (50% vs. 36%), ventricular tachycardia (25% vs. 17%), cardiac failure (23% vs. 27%) and atrial fibrillation (8% vs. 2%) in the levosimendan plus standard therapy arm versus the standard therapy alone arm, respectively.

The statement "levosimendan is not associated with an increased incidence of arrhythmia" is therefore questionable. I also wonder how any drug can increase the heart rate, stroke volume and cardiac output, but not increase oxygen consumption? Is there another energy source available to cardiac myocytes?


(1.) Soeding PF, Royse CF, Wright CE, Royse AG, Angus JA. Inoprotection: the perioperative role of levosimendan. Anaesth Intensive Care 2007; 35: 845-862.

(2.) Abbott Reports Improved Clinical Course with Levosimendan (Simdax[R]) When Added to Standard Therapy in Acute Decompensated Heart Failure Trial. From US/60.5:5/ Press_Release_0237.htm Accessed December 2007.


Bondi, New South Wales

Inoprotection review--Reply

We thank D. Heffernan for his interest in our article. The article was aimed at drawing attention to the emerging pharmacological role of levosimendan in the perioperative period, with a report of clinical experience to date. Despite the observation that levosimendan was associated with arrhythmia in the REVIVE II study, the clinical trend in other studies has been improvement in cardiac performance without arrhythmogenesis. This has been for patients with heart failure and those undergoing cardiac surgery. In the REVIVE II study itself, patients improved clinically with a reduced length of stay when treated with levosimendan. Studies cited in our paper indicate levosimendan to have a favourable electrophysiological profile. However, the question of whether levosimendan has phosphodiesterase III inhibitory activity predisposing to arrhythmia is often posed. Levosimendan appears to reduce the susceptibility to ischaemic arrythmias when compared to milrinone. In a canine model of acute regional ischaemia (1), levosimendan reduced the incidence of ventricular arrhythmia and improved survival. As a therapeutic agent, levosimendan has the potential to minimise myocardial injury via [K.sub.ATP] channel activation and, in addition, improve local coronary flow and reduce infarct size during ischaemia. Notwithstanding, further trials will indicate whether these advantages translate into improved clinical outcome and careful monitoring of adverse endpoints such as arrhythmia is a prerequisite.

A number of the actions of levosimendan contribute to improved oxygen handling and reduced cardiac work during myocardial contraction. Energy expenditure occurs with excitation-contraction coupling and calcium reuptake within the myocyte. Heart failure is characterised by abnormal intracellular calcium handling, with elevated cytosolic diastolic calcium levels and blunted systolic levels due to poor calcium re-uptake and release. By acting at the mitochondrial level, levosimendan will theoretically stabilise oxygen utilisation and cellular metabolism within the ischaemic myocyte. Intracellular membrane transport mechanisms would then be optimised to maintain the calcium transient and force of contraction. At the myofilament level, calcium sensitisation is a stereo-specific action, not dependant on oxygen utilisation, and this enhances the binding of calcium to increase contraction force. And importantly, the vasodilatory action of levosimendan reduces both right and left ventricular afterload, reducing the work of each stroke volume.


(1.) Papp JG, Pollesello P, Varro, Vegh AS. Effect of levosimendan and milrinone on regional myocardial ischemia/reperfusion-induced arrhythmias in dogs. J Cardiovasc Pharmacol Ther 2006;11:129-135.




Melbourne, Victoria
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Article Details
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Title Annotation:Correspondence
Author:Heffernan, D.; Soeding, P.F.; Royse, C.F.; Wright, C.E.; Royse, A.G.; Angus, J.A.
Publication:Anaesthesia and Intensive Care
Article Type:Letter to the editor
Date:Mar 1, 2008
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