Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis (LeoPARDS)
A.C. Gordon, G.D. Perkins, M. Singer, D.F. McAuley, R.M.L. Orme,S. Santhakumaran, A.J. Mason, M. Cross, F. Al‐Beidh, J. Best‐Lane, D. Brealey, C.L. Nutt, J.J. McNamee, H. Reschreiter, A. Breen, K.D. Liu, and D. Ashby. Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis. N Engl J Med. 2016 Oct 5. [Epub ahead of print]
Back ground & Clinical Question:
Levosimendan was demonstrated to improve laboratory markers of improved organ perfusion in experimental studies in both human and animal subjects. Moreover, there is an extensive range of possible beneficial effects (immune modulation, anti-inflammatory etc.) of Levosimendan. With such a vast area of applicability and probably outcome benefits, a multicenter randomized trial was planned to test effect of Levosimendan on the organ dysfunction associated with septic shock.
Multicenter, double blind, randomized, placebo-controlled, randomized trial.
Setting (Population, Timeframe & Enrolment):
Conducted in 34 general adult intensive care units (ICUs) in United Kingdom from January 2014 to December 2015. A total of 516 patients (259 Levosimendan group) were enrolled with an approximated power of 90%.
Study enrolled adult patients (≥18 years) who required vasopressor support for at least 4 hours for the management of sepsis despite fluid resuscitation (Septic shock). Patients managed according to the Survival Sepsis Campaign Guidelines. Patient recruitment was allowed until 24 hours of meeting the enrollment criteria.
Intervention common to both groups:
Study drug/Placebo- Patients were assigned to receive a blinded infusion of Levosimendan or placebo for 24 hours.
Dose- Starting dose 0.1 mgm/kg/min and was increased to a maximum of 0.2 mgm/kg/min if there was no rate limiting side effects. Intravenous fluid and vasopressors were adjusted to a MAP 65-70mm Hg.
Mean daily Sequential Organ Failure Assessment (SOFA) score measured from admission to maximum 28 days. CNS variables of SOFA score were not included. Individual SOFA components were also analysed to assess the effect of Levosimendan on individual system.
There was no significant difference in the mean (±SD) SOFA score between the levosimendan group and the placebo group. The mean daily cardiovascular SOFA score was higher in Levosimendan group.
Patients treated with Levosimendan were less likely to be successfully weaned off from mechanical ventilation. Incidence of supra ventricular tachycardia (SVT) was significantly higher with Levosimendan. There was no significant inter group difference in number of catecholamine and ventilator free days, number of major kidney event over a period of 28 days, mortality rates at 28 days, at ICU discharge and at hospital discharge, length of stay .
Addition of Levosimendan to standard care in septic shock did not improve organ dysfunction, rather increased the probability of SVT and delayed weaning from mechanical ventilation.
Multicenter randomized double blind trial.
Benefits of Levosimendan are well demonstrated in patients with decompensated heart failure. Only 24 patients (9.2%) in intervention group had heart failure.
Maximum number of patients (52.2%) had significant CNS dysfunction (mentioned as organ failure at baseline characteristics). Total SOFA score in this trial excluded the neurological dysfunction which would have been interesting if included. Moreover, the rational for excluding CNS variable in the SOFA score calculation was attributed to sedation in intubated patients. It was postulated that it would have been difficult for assessing the neurological state in these patients. The best documented neurological status before or during the daily evaluation for SOFA score would have been a good surrogate marker to compare.
There was a significant difference in base line stroke volume of the patients in two groups which might account for some degree of poor outcome in Levosimendan group. This was an important baseline character which required matching. This trial failed to do so.
The drug was continued for a 24-hour period and was postulated that the active metabolite of levosimendan is long acting and could lead to a prolonged drug effect. This is only hypothetical and highly unpredictable in critically ill patients. No laboratory data was used to demonstrate it. A longer duration of infusion would have resulted in a better outcome and there was no prefixed end point to cessation of infusion apart from a 24 hour time line.
There was no objective screening (i.e Echocardiography) performed at enrollment to specifically include patients with sepsis induced myocardial dysfunction.
Levosimendan was compared to a placebo in this trial. The control should ideally be an inotrope near similar and in clinical use (i.e Dobutamine) for the same purpose for which Levosimendan is being tested in this trial.
Relevance to current practice:
Using Levosimendan in Septic shock for prevention and progression of organ dysfunction is very rare. Dobutamine is the preferred agent as recommended by Survival Sepsis Campaign guidelines. Levosimendan cannot be recommended for this purpose currently.
Literature before this study and basis of the current trial:
Sepsis causes calcium desensitization leading to myocardial depression. By stabilizing the calcium-troponin C complex, levosimendan inhibits troponin I and prolongs the actin-myosin cross-bridge association rate. Thereby increasing inotropy. At the sametime it does not affect the relaxation (no negative luciotropy). Thus it does not increase myocardial oxygen demand in expense of increase inotropy. The beneficial effects of levosimendan may also be related to a vasodilatory effect mediated by a K +ATP- channel opening effect, which may decrease right and left ventricular afterload.
A small randomized trial demonstrated better hemodynamics and regional perfusion with Levosimendan compared to dobutamine in patients with septic myocardial depression.(1) The same group of authors latter demostrateded that there was a significant increase in sublingual microcirculatory flow with Levosimendan compared to Dobutamine.(2) Further small studies demonastrated a better splanchnic blood flow with Levosimendan compared to Dobutamine when added to Dopamine in Septic patients.(3) Levosimendan was also demonstrated to have prominent anti-inflammatory effect and decreased the oxidative burst in polymorphonuclear cells.(4,5) It also decreased the IL-6 level which is a proinflammatory mediator in patients with decompensated heart failure.(6) A recent meta-analysis involving 246 patients demonstrated a significant improvement in mortality in patients with septic shock (Number needed to treat = 7) when treated with Levosimendan compared to standard inotropic therapy. (7)
Morelli A, De Castro S, Teboul J-L, et al. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med 2005;31:638-644.
Morelli A, Donati A, Ertmer C, et al. Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study. Crit Care 2010;14:R232-R232.
Memiş D, Inal MT, Sut N. The effects of levosimendan vs dobutamine added to dopamine on liver functions assessed with noninvasive liver function monitoring in patients with septic shock. J Crit Care 2012;27:318.e1-e6.
Wang Q, Yokoo H, Takashina M, et al. Anti-inflammatory profile of levosimendan in cecal ligation-induced septic mice and in lipopolysaccharide-stimulated macrophages. Crit Care Med 2015;43:e508-e520.
Hasslacher J, Bijuklic K, Bertocchi C, et al. Levosimendan inhibits release of reactive oxygen species in polymorphonuclear leukocytes in vitro and in patients with acute heart failure and septic shock: a prospective observational study. Crit Care 2011;15:R166-R166.
Parissis JT, Adamopoulos S, Antoniades C, et al. Effects of levosimendan on circulating pro-inflammatory cytokines and soluble apoptosis mediators in patients with decompensated advanced heart failure. Am J Cardiol 2004;93:1309-1312.
Zangrillo A, Putzu A, Monaco F, et al. Levosimendan reduces mortality in patients with severe sepsis and septic shock: a meta-analysis of randomized trials. J Crit Care 2015;30:908-913
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