European Journal of Cardiovascular Medicine

Coronary artery bypass grafting (CABG) is the standard of care for revascularization in patients with multi-vessel coronary artery disease (CAD) and is performed either with the aid of cardiopulmonary bypass (on-pump) or without cardiopulmonary bypass (off- pump). [1] Low preoperative left ventricular ejection fraction (LVEF) is common in patients undergoing cardiac surgery. [2] Despite improvements in medical therapy and surgical techniques, management of patients with moderate to severe left ventricular dysfunction undergoing cardiac surgery remains challenging. [3] In patients undergoing cardiac surgery, reduced left ventricular ejection fraction is an important independent risk factor for perioperative morbidity and mortality. [4]

Several perioperative variables have been purposed as predictors of mortality, including acute renal failure and pneumonia, and are currently applied in everyday clinical practice to identify patients at higher risk. [5] Low EF per se is the strongest predictor of a poor outcome and is

included in all scoring system currently available. [6] Indeed, low LVEF is associated to postoperative low cardiac output syndrome (LCOS), need for inotropic support, acute renal failure, respiratory failure, pneumonia, atrial fibrillation, stroke, sepsis or endocarditis, deep sternal wound infection, bleeding requiring reoperation and gastrointestinal bleeding. [7]

Inotropes aim at increasing cardiac output by enhancing cardiac contractility. They constitute the third pharmacological pillar in the treatment of patients with decompensated heart failure, the other two being diuretics and vasodilators. [8] Three classes of parenterally administered inotropes are currently indicated for decompensated heart failure, (i) the beta adrenergic agonists, including dopamine and dobutamine and also the catecholamines epinephrine and norepinephrine, (ii) the phosphodiesterase III inhibitor milrinone and (iii) the calcium sensitizer levosimendan. [9] These three families of drugs share some pharmacologic traits, but differ profoundly in many of their pleiotropic effects. Identifying the patients in need of inotropic support and selecting the proper inotrope in each case remains challenging. [10]

Three major classes of inotropic agents have been clinically evaluated in patients with left ventricular dysfunction: a) agents that increase the intracellular concentration of cyclic adenosine monophosphate by stimulating the beta-adrenergic receptor or inhibiting phosphodiesterase; b) drugs that increase the intracellular calcium concentration; c) the new calcium-sensitizing drugs. Inotropes are used to improve systemic, as well as, regional perfusion and hence tissue oxygen delivery following CABG surgery. [11]

Postoperative myocardial stunning is a common phenomenon after cardiac surgery, even with the use of contemporary cardio-protective methods. So transient myocardial dysfunction easily sets in which is more pronounced in patients with impaired left ventricular function before surgery. Thereby needing postoperative inotropic support.

This is a prospective and randomized study was conducted Department of Cardiothoracic and Vascular Surgery at Yashoda hospital, Secunderabad.

Inclusion criteria

1. Patients aged between 30- 65 years
2. Patients with low ejection fraction (EF <40%)
3. Scheduled for elective off pump CABG
4. Patients who are willing to give consent

Exclusion criteria

1. Redo or Emergency operation
2. Concomitant cardiac procedures with CABG
3. Operation which was carried out via an incision other than median sternotomy. (e.g.,anterolateral left thoracotomy)
4. On-pump CABG
5. Known contraindication to off-pump CABG (e.g. calcified aorta, calcified coronaries and small target vessels)
6. Patient who are allergic to study drugs
7. Patients with moderate to Severe mitral regurgitation
8. Patients receiving preoperative pharmacological or Mechanical supporting devices
9. Severe Renal and Hepatic failure conditions.
10. Severe Hypotension prior to surgery(MAP < 60mm Hg)
11. Severe tachycardia prior to surgery(HR > 120bpm)
12. Patients who are not willing to give consent

STUDY PROCEDURE:

OPCAB was performed with the Acrobat- vaccum stabilizer system stabilizing device (MAQUET Cardiovascular) for target coronary artery stabilization. A mean systemic arterial pressure was maintained around 65 to 70 mm Hg throughout the procedure. An intracoronary shunt was used in all target coronaries greater than 1.25mm in diameter during construction of distal anastomosis. Humidified carbon dioxide blower /mister was used to disperse the blood from the anastomotic site while constructing the distal anastomoses. After getting approval from the hospital ethical committee, all patients included in the study were randomly divided into 2 groups of 50 each. All patients between age 30 and 65 years, with moderate to severe LV dysfunction scheduled for OPCAB, were included in the study. Patients with moderate to severe mitral regurgitation, redo or emergency CABG, patients receiving preoperative pharmacological or mechanical support were excluded from the study. Patients were randomly divided into two groups. Group I received levosimendan at 0.1 μg/kg/min and Group II received dobutamine at 5 μg/kg/min, as infusion started 12 hours prior to surgery.

Statistical methods

Data will be presented as absolute numbers, mean, and standard deviation, or percentages. Values of continuous variables will be expressed as a mean ± standard deviation (SD). Categorical variables are represented as frequency distributions and single percentages. Normally distributed continuous variables will be compared using a Student t-test, non-normally distributed continuous variables using the Mann-Whitney U test, and categorical variables will be compared by χ2 and Fisher's exact test, where appropriate. All statistical tests will be two-sided. Results will be considered statistically significant at a level of p less than 0.05. All analysis will be performed using SAS version 9.2 (SAS institute, Cary, NC) software.

The study enrolled 100 patients of which 50 patients were randomized to Dobutamine group and 50 patients to Levosimendan  group. The mean age of the patients was 55.56±7.73 in Dobutamine group and 55.24±7.99 in Levosimendan group (p=0.83). Out of 50 patients in Dobutamine group 14 (28%) were females and 36 (72%) were males compared to Levosimendan group where 12(24%) were females and 38(76%) were males , (p=0.64).

The baselines characteristics such as DM (p=0.40), HTN (p=0.16), NYHA class (p=0.25), preoperative MI (p=0.31), prior PTCA (p=0.29), preoperative CVA (p=0.29) and PAD (p=1.00) were compared between the groups and were found to be statistically insignificant (table 1).

      Table 1:  Analysis of Baseline characteristics between Dobutamine and Levosimendan Groups

CAD: coronary artery disease; CVA: cerebrovascular accident; DM: diabetes mellitus; D: dobutamine; DVD: double vessel disease;; HTN: hypertenstion; LVEF: left ventricular ejection fraction;; L : levosimendan ; MI: myocardial infarction; NYHA: new York heart association; PAD: peripheral arterial disease; PTCA: percutaneous transluminal coronary angioplasty; SVD single vessel disease; TVD: triple vessel disease

     Table 2: Analysis of Intraoperative characteristics between Dobutamine and Levesimendan

CPB: cardiopulmonary bypass; D: dobutamine; IABP: intra aortic balloon pump; L: levosimendan; LIMA: left internal mammary artery; SVG: saphenous vein graft; NA: noradrenaline

Intraoperative characteristics were analysed between the groups. Significant difference was observed between the groups in the usage of grafts (dobutamine 3.38±0.85 vs levosimendan 3.68±0.68), p=0.05. IABP was used in 3 (6%) patients in dobutamine group and 2(4%) patients in levosimendan group, p=0.64 the distribution of conduits in respective target artery territories.

  Table 3: Analysis of postoperative outcomes between Dobutamine and Levosimendan

D: dobutamine; ICU: intensive care unit; LCOS: low cardiac output syndrome; L: levosimendan; LVEF: left ventricular ejection fraction; POD: post-operative day

One (2%) mortality was observed in dobutamine group and none in levosimendan group (p=0.31) and no statistically significant difference was found between the groups. Atrial fibrillation occurred more in dobutamine group (22%) compared to levosmendan group (8%), (p=0.04), means of ICU (3.24±0.84 vs 2.74±0.77, p=0.002) and hospital stay (7.12±1.02 vs was 6.76±0.77, p=0.04) were more in dobutamine group compared to levosimendan group. Significant difference was observed between the groups in terms of atrial fibrillation , Ventilator support, ICU stay and hospital stay (Table 3).

                 Table 4: Heart rate between Dobutamine and Levosimendan groups

Means of basal heart rates as compared between the groups at 1 hr, 6 hrs, 12 hrs and 24 hrs respectively Table -4. Levosimendan shows significant reduction in heart rates at 12 (p=0.001) and 24 hrs (<.0001) compared to those receiving Dobutamine.

                 Table 5: Mean Arterial Pressure (MAP) between Dobutamine and Levosimendan groups

The Means of Arterial pressures were compared between the groups at 1,6,12 and 24 hrs respectively (Table -5). Mean arterial pressure decreased significantly in Levosimendan group at 12 hrs ( P=<.0001) and 24 hrs(P= <.0001).

Table 6: Mean pulmonary capillary wedge pressure (PCWP) between Dobutamine and Levosimendan groups

Statistically significant reduction in Means of PCWP was observed in Levosimendan group compared to Dobutamine group at 12 (p=<.0001) and 24 hrs (P=<.0003). Table 6.

               Table 7: Mean pulmonary artery pressure (MPAP) between Dobutamine and Levosimendan

Levosimendan was superior to Dobutamine in lowering of mean pulmonary artery pressures (MPAP) and showed significant statistical differences between the Levosimendan and dobutamine groups at 6 hrs (p=<0.10) , at 12 hrs (p=<.0001), at 24 hrs (p=<.0001) Table 7 shows median change in MPAP in 24 hrs between Levosimendan and Dobutamine

This study showed that the means of preoperative LVEF were comparable between the groups. There was no statistically significant difference between the groups in the terms of baseline characteristics.  Cheetah trial [12] compared LCOS in patients with a preoperative left ventricular ejection fraction of less than 25%, and receiving Levosimendan and those not receiving it. The results of this study were comparable to our study groups.

LEVO-CTS [13] the study was a phase III clinical trial on 882 patients on scheduled or urgent cardiac surgery, CABG and/or mitral valve surgery with or without other valves. all patients were at risk of developing postoperative LCOS. Levosimendan group had statistically significantly less LCOS events (18% vs. 26%, p = 0.007) and needed less inotropic support (55% vs. 63%, p = 0.02), and cardiac index improved more (2.86±0.61 vs. 2.68±0.65 l/min/m2; p < 0.001) in levosimendan treated patients. On the contrary the need for other ionotropic support in this study was minimal in both the groups and showed no significant statistical difference (P-0.90).

LiCorn [14] the LiCorn trial assessed the efficacy of a preoperative infusion of levosimendan in reducing postoperative LCOS in 336 patients with poor LVEF undergoing CABG. There was no difference in mortality or length of ICU stay. More patients in the levosimendan group experienced hypotension (57% vs. 48%, p = 0.11) and atrial fibrillation (50% vs. 40%, p = 0.09) but not statistically significantly. Present study also in alignment with the results of all LEVO-CTS, LiCorn, ChEETah in terms of less mortality and shorter length of ICU stay in Levosimendan. But in the present study occurrence of atrial fibrillation was less in levosmendan group when compared to dobutamine group and showed significant difference between the groups (p=0.04).

The meta-analysis by harrison et al. [15] was performed before the completion of the ChEETah, LEVo-CTS and LiCorn studies. The authors divided the patients by their

preoperative ejection fraction and a total of 1155 patients were included. Those with a mean EF < 40% were designated as low-EF. The authors concluded that the use of levosimendan was associated with reduced mortality and other adverse outcomes in patients undergoing cardiac surgery, and these benefits were greatest in patients with

reduced EF (< 40%). a Bayesian network meta-analysis evaluated the role of different inodilators in cardiac surgery [16] also this meta-analysis was performed before the completion ChEETah, LEVo-CTS and LiCorn studies and it included data on 2647 patients. The analysis found that only the use of levosimendan was associated with a decrease in mortality when compared with placebo (posterior mean of odds ratio 0.48, 95% CI 0.28-0.80). Present study in contrast to the above study showed no statistical significance between both the groups in terms of Mortality ( P-0.31)

The double-blind, randomised trial by Shah and colleagues [17]tested preoperatively administered levosimendan 200 μg/kg infusion for 24 h against placebo for off-pump CABG in 50 patients with left ventricular dysfunction (LVEF <30%) . As compared to the control group, the levosimendan-treated patients had higher cardiac index and low PCWP during the operative and early postoperative periods. Requirements for inotropes, IABP and CPB support were lower for levosimendan group, both ICU and hospital length of stay were also reduced. In this study also IABP usage, ICU stay was less in Levosimendan group compared to dobutamine group. Hence, our study is in concurrence with this study.

Kandaswamy et al [18] conducted a randomized study in eighty patients divided into two groups of 40 each. Group I received levosimendan at 0.1 µg/kg/min and Group II received dobutamine at 5 µg/kg/min. The HR, MAP, PCWP, SVRI, and PVRI were lower in Group I when compared to Group II. Group I patients showed a statistically significant increase in LVSWI, RVSWI, and CI, when compared to Group II. Comparatively, Group I patients maintained higher SvO2 and lower lactate levels. Duration of ventilation, Intensive Care Unit (ICU), and hospital stay were lower in Group I. Current study shows the results similar with Kandaswamy et al where Means of ICU stay, MAP (P=0.01), MPAP (0.01) and PCWP (0.01) showed significant differences favouring the use of Levosimendan over Dobutamine after 12 hrs of infusion.

Pre-treatment with Levosimendan in patients undergoing surgical myocardial revascularization with left ventricular dysfunction resulted in lower postoperative mortality, a shorter length of Ventilation support, ICU stay and Hospital stay with significant improvement in cardiac indices compared with Dobutamine treatment.

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