Intracoronary administration of levosimendan in patients with acute coronary syndromes and decreased le ft ventricular ejection fraction undergoing coronary artery bypass gra ft surgery

In cardiac surgery patients, intracoronary (IC) administration of levosimendan can provide optimal drug spread, enabling effective manifestation of favorable drug effects and avoiding potentially harmful systemic hypotension. This could be beneficial in acute coronary syndromes (ACS) with decreased left ventricular ejection fraction (LVEF). We present ten cases of IC administration of levosimendan in ACS manifested as ST segment elevation myocardial infarction, non-ST segment elevation myocardial infarction or unstable angina pectoris. All patients underwent coronary artery bypass graft (CABG) surgery, performed as an “off-pump” or “onpump”/“off-clamp” procedure (latter one with the use of cardiopulmonary bypass on the beating heart). Levosimendan was administered as an IC bolus (125-250 μg) in each coronary artery graft (2-3 grafts). Intravenous (IV) levosimendan infusion continued (0.1-0.2 μg•kg-1•min-1) after graft placements (24-48 h), with IV infusion of norepinephrine (0.1 mg•ml-1), if needed. Cardiac function was assessed using LVEF (%) (Teicholz), thermodilution cardiac index (CI) (ml•m-2), and systemic vascular resistance (SVR) (dynes•sec•cm-5). Nonparametric Wilcoxon signed-ranks test [presented as median (MED) with interquartile range (IQR)] indicated a significant difference between preoperative vs. immediate postoperative CI, SVR, and LVEF in all cases [2.2 (1.9-2.5) vs. 3.1 (2.93.4) ml•m-2, 1173.0 (1062.7-1278.2) vs. 882.5 (763.5-993.0) dynes•sec•cm-5, 44.5 (36.0-46.7) vs. 53.5 (45.7-59.2) %, respectively] (P=0.005), i.e. IC administration of levosimendan was associated with prompt improvement of intraoperative hemodynamics and cardiac contractility. IC administration of levosimendan may be a promising alternative method for improving decreased cardiac function in acute cardiac ischemia, besides necessary surgical revascularization.


INTRODUCTION
Patients with acute coronary syndrome (ACS), undergoing surgical myocardial revascularization, are susceptible to contractile myocardial dysfunction with hemodynamic compromise, often necessitating inotropic and/or mechanical circulatory support.(1,2) Consequently, perioperative preservation of heart function and the use of optimal inotropic agents are becoming strongly emphasized.(2,3) A calcium-sensitizing drug, levosimendan, has emerged as a novel inotropic agent with vasodilator properties and potent cardioprotective effects, all especially beneficial in coronary artery disease (CAD).(2,4) The perioperative use of levosimendan in cardiac surgery patients has been associated with a reduction in myocardial injury, improvement of hemodynamics and clinical outcomes, and reduction in additional inotropic and/ or mechanical circulatory support.(1,4) In the majority of studies, levosimendan is usually administered as a continuous intravenous (IV) infusion over 24 h.(4) However, IV use of levosimendan could be limited by extensive systemic vasodilatation and hypotension, particularly in CAD.

MATERIALS AND METHODS
The study was approved by the local Ethics Committee of the University Hospital Split.

Technical aspects of IC levosimendan administration
CABG surgery was performed as an "offpump" or "on-pump"/"off-clamp" proce-dure, the latter with the use of cardiopulmonary bypass (CPB) on the beating heart.Levosimendan was administered as an IC bolus injected in each coronary artery graft.Levosimendan was first diluted (12.5 mg in 50 ml of 5% glucose solution, 250 μg•ml-1).Two ml of this drug solution was mixed with the patients heparinized blood in a 20 ml syringe (25 μg•ml-1).Prepared content from the syringe was forwarded to the surgery team in sterile conditions.A surgeon administered 5-10 ml (125-250 μg) in each coronary artery graft (2-3 grafts).After the completion of CABG surgery, IV infusion of levosimendan continued (0.1-0.2 μg•kg-1•min-1) to prolong drug delivery (24-48 h), with IV infusion of norepinephrine (0.1 mg•ml-1), if needed.

Patients
Our first case (45-year-old female in acute STEMI), was done unintentionally in an urgent manner, due to acute onset of myocardial stunning during weaning from CPB. Surgical revascularization started as Off-pump coronary artery bypass (OP-CAB),, but after the first bypass was completed, the patient experienced sudden hemodynamic instability.An intra-aortic balloon pump (IABP) was positioned without expected improvement.Urgent CPB was initiated in order to place two additional grafts.During the very challenging process of weaning (hemodynamic compromise, several weaning attempts), we decided to administer an IC bolus of levosimendan in each coronary artery graft (in consultancy with colleagues from abroad).Soon after, the patient was successfully weaned from CPB with evident intraoperative improvement of hemodynamics and overall cardiac function.We continued with IC levosimendan administration in several subsequent acute STEMI cases with troponin I over 50 ng•ml-1 (5 cases).Additionally, as we continued, we found this method to be beneficial in more complicated cases of advanced chronic CAD manifested in acute form, as unstable AP (4 cases) or acute NSTEMI (1 case), with moderately elevated troponin I.

Perioperative evaluation of cardiac function and outcomes
Cardiac function was obtained with perioperative heart ultrasound estimation of LVEF (%) (Teicholz), thermodilution cardiac index (CI) (ml•m-2), and systemic vascular resistance (SVR) (dynes•sec•cm-5).Troponin I (ng•ml-1) was measured pre-operatively and checked regularly.Time to extubation, intensive care unit (ICU) and hospital discharge were expressed in postoperative days (POD).POD 1 represented the first day following the day of surgery.

Statistical analysis
The results were analyzed using statistical program SPSS 14.0 with nonparametric Wilcoxon signed-ranks test for comparisons of preoperative vs. immediate postoperative values (or ICU discharge values for troponin I) of CI, SVR, LVEF, and troponin I variables in all patients.Data were presented as median (MED) with interquartile range (IQR).Statistical significance was set at P<0.05.

DISCUSSION
In this short report, IC administration of levosimendan was associated with evident improvement in intraoperative hemodynamics and overall cardiac function.Jamali et al. have previously found that IC levosimendan administration enhances contractile function of stunned myocardium.(10) Several subsequent animal studies pointed to its cardioprotective and antiapoptotic effects.(6,7) In humans, IC administration of levosimendan improved systolic and diastolic cardiac function, in ischemic and non-ischemic acute heart failure, without significant systemic hypotension.(8,9) Our main reason for IC administration of levosimendan was globally hypokinetic myocardium with reduced overall cardiac function evident in every patient.Patients who underwent an "on pump"/"off-clamp" procedure were successfully weaned from CPB.In "off pump" cases, an IC bolus was first administered after the placement of the first graft, enabling hemodynamic stability and procedure continuation.In previous studies, IC levosimendan was used in variable doses, as an IC bolus or short continuous IC infusion.(7-9) An ongoing clinical trial chose a 12 μg•kg-1 dose of IC levosimendan infusion at the induction of cardioplegia (after opening of the aortic cross-clamp in aortic valve/CABG surgery).( 4) Our 125-250 μg IC bolus administered in each coronary artery graft (2-3 grafts) during surgical revascularization, corresponded approximately to the 6-12 μg•kg-1 dose of IC levosimendan administered to each patient.Many questions arise regarding the right timing for IC levosimendan administration, optimal dose, category of patients that could benefit, and the relevant outcome measures.Further randomized control studies and/or more case series are needed to provide the correct answers.
In conclusion, as we used an IV infusion of levosimendan (following graft placements) and surgical revascularization, it is not possible to define the exact contribution of IC levosimendan to the final clinical outcome.However, we believe that IC administration of levosimendan may be a useful alternative method for improving decreased cardiac function in acute onset cardiac ischemia, in addition to necessary surgical revascularization.

table 2
characteristics, clinical findings and outcomes in each of ten patients are presented in table 1. Comparing preoperative vs. immediate postoperative CI, SVR, and LVEF in all patients (