“Levosimendan for the prevention of acute organ dysfunction in sepsis,” NEJM, 2016, UK
Background: Levosimendan is a calcium-sensitizing drug marketed under the trade name Simdax that is approved in Europe and South American for use in acute decompensated heart failure. It increases cardiac contractility through calcium sensitization of troponin C and vasodilates by opening potassium channels in vascular smooth muscle cells. It is felt to only minimally increase myocardial oxygen demand. Small trials have suggested that it may improve organ perfusion and hemodynamics in sepsis.
Question: Does the addition of levosimendan to standard care in patients with septic shock reduce the severity of organ dysfunction?
Study Type: Multicenter, randomized, double-blind, placebo-controlled trial in 34 ICUs in the UK.
Study Population: Adult patients who required vasopressor support for ≥4hrs for septic shock were eligible for the trial. Exclusion criteria included >24 hrs of vasopressor support prior to enrollment, ESRD, Child-Pugh C liver disease, history of torsades, DNR, weight >125kg, and pregnancy.
Study Groups: Patients randomized to levosimendan or placebo for 24 hours. Additional inotropic medications were allowed if felt necessary by the treating clinician. Orion Pharmaceuticals provided the study drug but was not otherwise involved in the trial.
Primary Outcome: Mean daily SOFA score while in the ICU for a maximum of 28 days.
Results: 516 patients were randomized. The majority of screened patients were excluded because they were outside the 24hr window since meeting inclusion criteria. Notable baseline characteristics: Caucasian (93%), recent surgery (37%), APACE II (25), lung as primary source of infection (39%), beta-blockers at baseline (19%), mechanical ventilation (81%), dobutamine (9%). There was no difference in the mean SOFA score during ICU stay (6.68 +/-3.96 in the levosimendan group and 6.06 +/- 3.89 in the placebo group). Patients given levosimendan required more norepinephrine, were less likely to be liberated from mechanical ventilation, and more likely to experience SVT. Levosimendan did not improve outcomes in any of the pre-specified subgroups including patients with low cardiac output, impaired O2 delivery to tissue, and those on high-dose vasopressors. There was no difference in any mortality measure. Of note, cardiac index was similar throughout the trial in both groups (largely between 3.1-3.5 L/min/m2).
Caveats: Mostly Caucasian patients, does not answer the question of whether levosimendan may be helpful in the initial resuscitation of septic shock (median time from shock to randomization in this trial was 16 hrs), does not answer the question of whether a supranormal cardiac index is helpful in septic shock (both groups had a similar CI and very few patients in the intervention arm would have fit into the “cardiac index” arm of the 1995 NEJM trial we reviewed where CI goal was >4.5), does not answer the question of whether an inotrope is helpful in septic shock as the addition of levosimendan was offset in part by increased dobutamine use in the control arm, cardiac index was only measured in a subset of patients (30%) and measured using a variety of methods (PiCCO, esophageal Doppler, PAC) raising questions about generalizability and accuracy, more dobutamine use in the standard care arm then is seen at NMH.
Take-home Point: The addition of levosimendan to standard care in patients with septic shock does not improve outcomes and may be harmful.
Commentary: For me, an odd hypothesis to think that levosimendan would provide much physiologic benefit in this patient group: resuscitated septic patients who had been on vasopressors for a median of 16 hours and had adequate DO2 (as assessed by a median ScVO2 of 75 at the time of enrollment) especially as another inotrope was allowed in both arms. I would have been more interested in a protocol focused on early resuscitation, perhaps specifically in patients with a low ScVO2 or known cardiac dysfunction comparing levosimendan to placebo (without additional dobutamine) or a three-armed trial with levosimendan vs dobutamine vs placebo (as levosimendan’s ability to only minimally raise myocardial O2 demand offers some potential advantages over dobutamine). In any case, this trial, and others strongly suggest that a supranormal DO2 (or attempts to achieve one) are of little benefit in patients with sepsis. This trial is also a good reminder to take systematic reviews of small trials with a big grain of salt (see “Levosimendan reduces mortality in patients with severe sepsis and septic shock: a meta-analysis of randomized trials,” J Critical Care, 2015).