| Abstract|| |
Background: Right ventricular (RV) dysfunction is an important predictor of both immediate and long-term outcomes in valve surgeries. Levosimendan has proven beneficial in improving RV function.
Aims: The objective was to study the effect of the addition of levosimendan to the conventional treatment on RV function in patients with RV dysfunction undergoing mitral valve (MV) surgeries.
Setting and Design: Prospective randomized double-blinded controlled study at a tertiary care institution.
Materials and Methods: Sixty adult patients aged 15–65 years, with preoperative transthoracic echocardiography (TTE) findings of RV dysfunction posted for elective MV surgery, were randomized into levosimendan (L) group and placebo (P) group. Patients in the L group were administered levosimendan at a rate of 0.1 mcg/kg/min after induction for 24 hrs, whereas patients in the P group were given multivitamin infusion at the same rate. Both the groups received standard inotropic therapy. The hemodynamic and echocardiographic parameters of RV function (RV size, Inferior vena cava (IVC) diameter, RV fractional area change (RVFAC) Tricuspid annular plane systolic excursion (TAPSE), and Systolic Pulmonary Artery Pressure (SPAP) were compared between the groups at 6 hrs, 24 hrs, and 7th day postoperatively.
Results: All hemodynamic and echocardiographic parameters of RV function like RV size, IVC diameter, RVFAC, TAPSE, and SPAP improved from baseline to 24 hrs in both groups. Levosimendan caused a significant improvement in RV function compared to the P group at 24 hrs and 7th day postoperatively.
Conclusions: The present study concludes that levosimendan is a promising option in patients with RV dysfunction undergoing MV surgeries.
Keywords: Inodilator, levosimendan, mitral valve surgery, right ventricular dysfunction, transesophageal echocardiography, transthoracic echocardiography
|How to cite this article:|
Bharathi K S, Pruthi G, Dhananjaya M, Simha PP. The effect of levosimendan on the right ventricular function in patients with right ventricular dysfunction undergoing mitral valve surgery. Ann Card Anaesth 2023;26:50-6
|How to cite this URL:|
Bharathi K S, Pruthi G, Dhananjaya M, Simha PP. The effect of levosimendan on the right ventricular function in patients with right ventricular dysfunction undergoing mitral valve surgery. Ann Card Anaesth [serial online] 2023 [cited 2023 Jan 30];26:50-6. Available from: https://www.annals.in/text.asp?2023/26/1/50/367010
| Introduction|| |
Right ventricular (RV) dysfunction is now widely accepted as an independent predictor of mortality in patients undergoing cardiac surgery. Because the severity of preoperative RV dysfunction affects both immediate and long-term outcomes of heart valve surgery, patients with abnormal RV contractility or morphology are considered to be at high perioperative risk. EuroSCORE I and II underestimate the risk of these patients because RV function is not considered in these risk scores. Peyrou et al. showed that the presence of RV dysfunction before cardiac surgery assessed by echocardiography predicts significant postoperative (PO) mortality irrespective of the EuroSCORE. As a result, to identify and safely manage these potentially complex patients, an anesthesiologist must have a good understanding of both RV physiology and the impact of RV dysfunction. Echocardiography plays a critical role in the perioperative care of these patients in diagnosing and evaluating the severity of RV dysfunction.
Inotropes have a well-established role in the perioperative therapy of RV dysfunction. The use of beta-adrenergic agonists like Dobutamine, Phosphodiesterase inhibitors like Milrinone has shown improvements in RV hemodynamics. However, these inotropes increase the risk of arrhythmias and also increase myocardial oxygen consumption resulting in cardiac ischemia, with subsequent damage to hibernating but viable myocardium. This potential harm associated with inotropic therapy has prompted a lot of debate in cardiac surgery. Indeed, the use of perioperative and PO inotropes has recently been found to be associated with increased mortality and major PO morbidity.
Levosimendan is a positive inotrope and vasodilator that belongs to the new class of drugs known as myofilament calcium sensitizers. Unlike the catecholamines and phosphodiesterase (PDE) inhibitors, this improvement in contractility is achieved without the detrimental effects of increased intracellular calcium concentration, increased myocardial energy demand, or increased incidence of cardiac arrhythmias. Levosimendan improves right ventricular-pulmonary artery (RV-PA) coupling in experimental acute RV failure more than dobutamine. These effects have been demonstrated clinically with improvements in RV function and reduction in pulmonary vascular resistance (PVR) in ischemic RV failure, adult respiratory distress syndrome (ARDS), and chronic pulmonary hypertension (PH). However, there is a scarcity of data on the effect of levosimendan in patients with RV dysfunction who undergo elective mitral valve surgery.
In the present study, we aim to measure the effect of levosimendan along with a standard inotropic regimen on RV function in patients with RV dysfunction undergoing mitral valve surgery with the help of perioperative hemodynamic and echocardiographic parameters like RV size, Inferior vena cava (IVC) diameter, RV fractional area change (RVFAC) Tricuspid annular plane systolic excursion (TAPSE), Systolic Pulmonary Artery Pressure (SPAP).
| Materials and Methods|| |
A randomized control trial was conducted in a tertiary care hospital after obtaining informed written consent from the patients, 60 adult patients aged between 15 and 65 years, posted for elective Mitral valve repair or replacement surgery were included in the study. Patients with preoperative transthoracic echocardiography (TTE) findings of RV dysfunction, that is, TAPSE <15 mm and RVFAC <35% with or without clinical features of RV failure were enrolled for the study. (The approval from the ethics committee was obtained. Approval date: 26th February, 2016).
Exclusion criteria for the study were pregnant and breastfeeding female patients, patients with alcohol abuse, neurological deficits, and psychiatric disorders. Based on a power analysis (minimum detectable difference of means = 20%, expected SD of residuals = 20%, desired power = 80%, and an α error = 5%), a sample size of n = 20 was calculated to be sufficient to detect a 20% increase in RVFAC in the legomena group. However, in the present study, 30 patients were included in each group.
Demographic data and the Transthoracic echocardiography (TTE) data including RV size, IVC size, TAPSE, FAC, and SPAP were recorded preoperatively in all the patients. The pre-anesthetic assessment was done the day before surgery. Patients were randomized into the levosimendan group (L) and the placebo group (P) based on the closed envelope technique. All patients received oral Alprazolam 0.5 mg and pantoprazole 40 mg the previous night and on the morning of surgery. Radial artery cannulation was done before induction for arterial pressure monitoring. Patients were induced with midazolam 0.1 mg/kg, fentanyl 2-3 μg/kg, and propofol titrated to the loss of eyelash reflex. Vecuronium 0.1 mg/kg was used to facilitate endotracheal intubation and normocapnic ventilation was established. The right internal jugular vein was cannulated and the central venous pressure (CVP) was measured. Central venous application of the study medication was commenced immediately after induction of anesthesia. Patients in the L group were administered levosimendan at a rate of 0.1 mcg/kg/min whereas patients in the P group were treated with water-soluble multivitamin concentrate diluted in normal saline to match the color of the levosimendan preparation at the same infusion rate.
The transesophageal echocardiography (TEE) was used to quantify the RV function intra-operatively before cardiopulmonary bypass (CPB) and 30 min after CPB after mitral valve replacement/repair. The RV size is measured by M-mode in mid oesophageal 4 chamber view. The RV systolic function was compared between the groups using two parameters, the Fractional Area Change (FAC) and Tricuspid Annular Plane Systolic Excursion (TAPSE) at various time intervals. SPAP was calculated by adding mean right atrial pressure (derived from the IVC diameter) to the peak flow velocity of the tricuspid regurgitant jet.
Surgery was performed on CPB with moderate hypothermia (28°C to 32°C) and cold blood cardioplegic cardiac arrest. Aortic clamp time and CPB times were recorded for all patients. Hemodynamic parameters like heart rate (HR), CVP and mean arterial pressure (MAP) were recorded hourly. At the end of CPB, the inotropic-vasoactive strategy was decided by the attending anesthesiologist, according to the underlying pathology, the preoperative myocardial function, the duration of CPB, and cross-clamping and the hemodynamic and TEE assessment. Patients received either milrinone 0.33 to 1 μg/kg/min or Dobutamine 5 μg/kg/min or epinephrine 0.02 to 0.05 μg/kg/min along with vasoactive drugs like norepinephrine, dopamine, or vasopressin titrated to maintain a MAP of 70 mmHg during the first 24 hrs. We have not interfered with the anesthesiologist/surgeon's choice of the inotropes. The inotropic score was calculated by using the formula Vasoactive Inotropic Score (VIS) = Dopamine dose (μg/kg/min) + Dobutamine dose (μg/kg/min) + 100 x Epinephrine dose (μg/kg/min) + 10 x Milrinose dose (μg/kg/min) + 10,000 x Vasopressin dose (U/kg/min) + 100 x Norepinephrine dose (μg/kg/min). Levosimendan is not included in the inotropic score as it is blinded. The VIS score at 0, 6, 12, and 24 hrs postoperatively were calculated and then the mean VIS score for the 24 hrs was compared between L and P groups. Tracheal extubation was performed when patients met the standard criteria of extubation as per institution protocol. The presence of any arrhythmia was also noted. Postoperatively TTE was used to measure RV function by measuring RV size, IVC diameter, RVFAC, TAPSE, and SPAP at 6 hrs, 24 hrs, and after 7 days.
Statistical analysis was performed using SPSS 23.0 version (IBM Corp., Armonk, N.Y., USA). All categorical variables were expressed as frequency and percentages and continuous variables were expressed as mean + SD. Normality was checked by using the Shapiro-Wilk test. The student's t-test was used to test significant differences between two means and paired student t-test was used for intragroup analysis. The Chi-square test was used to test the association between categorical variables. P value <0.05 was considered statistically significant.
| Results|| |
The demographic and preoperative clinical data from the two groups were comparable. [Table 1]. The HRs of the two groups were comparable at different time intervals [Figure 1] The MAP increased statistically significantly in the L group compared to the P group beginning at the 4th hour of the PO period until the 24th hour of PO. [Figure 2] The difference in CVP between both groups was not statistically significant. [Figure 3]
|Figure 1: Comparison of heart rate (beats/min) between the study groups at different time intervals|
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|Figure 2: Comparison of Mean Arterial Pressure (MAP) (mmHg) between the study groups at different time intervals|
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|Figure 3: Comparison of Central Venous Pressure (CVP) (cmH2O) between the study groups at different time intervals|
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The mean RV size in both L and P groups as measured by M-mode, decreased significantly from baseline to post CPB, at 6 hrs, 24 hrs, and 7th day PO (p < 0.05). However, there was no statistically significant difference between the groups. [p (intergroup) = 0.22 at 24 hrs, P (intergroup) = 0.10 at 7th day PO]. [Table 2]
|Table 2: Comparison of echocardiographic parameters of right ventricular function between the two groups and within the groups at different time intervals|
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There is an increase in FAC values from pre-CPB to 24 hrs PO in both groups. However, when compared to the control group, levosimendan caused a statistically significant increase in FAC at all time intervals (p = 0.00). The increase in FAC in the L group lasted till the 7th POD, whereas it did not in the P group [Table 2].
The was a significant increase in TAPSE at the 24th hour and 7th POD in the L group compared to the P group. (P = 0.01 at the 24th hour, p = 0.00 at the 7th day PO) [Table 2].
When compared to the control group, levosimendan caused a significant reduction in IVC size at 24 hrs (p = 0.00), however, this size reduction was not significant at the 7th PO Day (p = 0.40) [Table 2].
There is a statistically significant reduction in the SPAP in the L group at the 6th hr. and 24th hrs. PO when compared to the P group. The fall in the SPAP in the L group is more rapid compared to the control group, though it did not persist till the 7th POD [Table 2].
[Table 2] also compares the intragroup parameters that assess RV size, RVFAC, TAPSE, IVC size, and SPAP from baseline to 7th POD. All the parameters of RV function improved from baseline to 7th POD with the addition of levosimendan to the conventional inotropes (p < 0.05 at all times).
The analysis of the usage of inotropes in both the groups revealed that the number of patients in whom milrinone, dobutamine, and epinephrine used in the P group were 7, 12, and 9 whereas it was 4, 2, and 7 in the L group. The dosage of these inotropes used was also significantly more in the P group along with the use of vasoactive drugs like norepinephrine, dopamine, and vasopressin. VIS scores were calculated at 0, 6, 12, and 24 hrs. PO and mean VIS score was calculated for each patient. The mean VIS score for the first 24 hrs. of the postoperative period was 17.95 in the L group whereas it was 43.05 in the P group. The reduction in the inotropic score in the L group for the first 24 hrs was statistically significant. (p = 0.00). [Table 3]
|Table 3: Comparison of inotropic score in the first 24 hrs, postoperative ventilatory hours, and postoperative hospital length of stay (days) between the study groups|
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The PO ventilatory hours were significantly low in the L group (p = 0.01). However, there is no statistically significant difference in the duration of hospital stay between the groups. [Table 3]. Six patients in the levosimendan group and eleven in the control group developed atrial fibrillation which was treated with intravenous Amiodarone infusion. However, this was not statistically significant. There were no deaths in the L group, but three deaths in the P group. Two deaths occurred on the seventh PO Day due to renal failure, and one death occurred on the sixth day due to sepsis. However, this was not statistically significant.
| Discussion|| |
Right heart failure induced by Pulmonary Hypertension has a mortality rate of up to 48% in intensive care units (ICUs), which is higher than that of left heart failure. Towheed et al. in their study published the short-term outcomes following left-sided valvular surgery in RV dysfunction. Compared with normal RV function, patients with RV dysfunction had higher 30-day mortality (22.6% versus 3.8%; P = 0.01) and were found to be at higher risk for developing multisystem failure/shock (13.2% versus 3.2%; P = 0.01).
RV dysfunction associated with valvular heart diseases is a complex cardiovascular condition, and to manage such a challenging situation we now have a triple-action compound, levosimendan that exerts positive inotropic, vasodilatory, and anti-ischemic effects at the same time. Compared with other inotropic agents, this positive effect is not linked to increased myocardial oxygen demand or impaired myocardial relaxation. By combining PVR reduction with raising RV contractility, levosimendan has been shown to improve ventriculoarterial coupling, as analyzed in animal models of right ventricular failure. Leather et al. in an experimental study, showed that levosimendan increased the RV contractility indices dP/dtmax, Emax, and the slope of the preload recruitable stroke work index (Mw) in normal anesthetized pigs. Although the existing evidence on this topic is limited, it supports the idea that levosimendan is a beneficial agent for treating RV dysfunction caused by pulmonary hypertension worsened by valvular heart disease, particularly mitral valve disease. The same was supported by Mads D. Vildbrad et al., in his experimental rat model in which PH is artificially induced. Levosimendan showed a direct acute positive inotropic effect on the hypertrophic and failing RV of the rat. Hansen et al., also demonstrated that levosimendan improves RV stroke work and myocardial external efficiency in the failing RV without increasing myocardial oxygen consumption.
The results of the present study are in agreement with the study conducted by Tewari et al., where they compared conventional treatment (Dobutamine and Noradrenaline) with levosimendan infusion for 48 hrs in 50 patients with mitral stenosis and pulmonary hypertension and found that the levosimendan group had an increase in TAPSE, FAC, and S' velocity. The participants in their study were not diagnosed with preoperative RV failure, whereas all the sixty participants in our study are diagnosed to have RV dysfunction preoperatively.
Kundra et al. compared the effects of levosimendan by intravenous and inhalational routes in their study in adult patients with pulmonary hypertension who underwent mitral valve replacement and reported a significant reduction in SPAP in both the group of patients. They also observed that SVR was significantly decreased with intravenous levosimendan, but no significant decrease in SVR was observed with inhalational levosimendan proving an additional advantage of using the drug by inhalation route.
In a study conducted by Guerrero Orriach et al., nine patients with tricuspid valve disease and/or RV dysfunction received preoperative levosimendan. The echocardiograms on the following day revealed improvements in TAPSE and RV ejection fraction in patients with tricuspid valve prostheses. In the present study, we not only studied 60 patients with RV dysfunction, the largest number so far studied but also included more parameters of RV function like RV size, RVFAC, IVC diameter as well as SPAP in addition to TAPSE. All the parameters have shown statistically significant improvement in RV function with the addition of levosimendan compared to Placebo. The studies of Gandham et al. compared hemodynamic effects of levosimendan and dobutamine for patients undergoing mitral valve repair/replacement for severe mitral stenosis and found that levosimendan reduced MAP more than dobutamine at weaning from CPB, at 30 min, 6 hrs, and 12 hrs post-CPB. Despite discontinuation, this MAP decrease was sustained. In the present study, no decrease in MAP was observed when levosimendan was used in addition to conventional inotropic therapy. The increase in the MAP in the levosimendan group might be related to the use of adequate fluid loading and the use of levosimendan as an additive to the conventional inotropic regime. In a study by Russ et al., a 24-hr infusion of the inodilator levosimendan resulted in beneficial hemodynamic effects for patients with cardiogenic shock following acute myocardial infarction with a decrease in PVR and increase in CI while not affecting MAP.
Our study also has similar results as that of Parissis et al. where improvements in RV systolic and diastolic functions continue after levosimendan infusion as expressed by conventional echocardiographic and TDI-derived parameters in patients with acute decompensated HF. We calculated the inotropic score in both the groups over 24 hrs and found that levosimendan infusion has caused a significant reduction in the inotropic score which will be a major clinical advantage in the form of reduced mortality and morbidity as indicated in many studies., There is no statistically significant increase in the incidence of arrhythmias or increased usage of Amiodarone between the L and P groups. Poelzl et al. in their study proved the safety and effectiveness of levosimendan in patients with predominant right heart failure.
Guerrero-Orriach et al. demonstrated that preoperative administration of levosimendan in patients with RV dysfunction, pulmonary hypertension, and high perioperative risk would improve cardiac function and would also have a protective effect on renal and neurological function. In a meta-analysis that includes the efficacy and safety of levosimendan in patients with acute right heart failure by Qiu et al., the patients treated with levosimendan for 24 hours showed a significant increase in tricuspid annular plane systolic excursion and ejection fraction as well as a significant reduction in SPAP and PVR. The above meta-analysis strongly supports the use of levosimendan for patients with RV dysfunction undergoing valve surgeries. Zangrillo et al., in their meta-analysis of randomized controlled studies, showed that levosimendan reduced cardiac troponin release after cardiac surgery. Niu et al., in their meta-analysis, proposed that perioperative levosimendan therapy is associated with a lower incidence of acute kidney injury after cardiac surgery. Landoni et al., showed improved mortality with the use of perioperative levosimendan. Since all of the meta-analyses on operative use of levosimendan to date,,, show positive benefits from levosimendan, there is a strong rationale for further expansion of usage of this drug in the perioperative period. A Bayesian network meta-analysis where the effect of inodilatory agents on mortality was studied, shows that levosimendan has over 90% probability to be the best in improving survival in cardiac surgery when compared with PDE inhibitors, dobutamine, and placebo.
| Conclusion|| |
The present study strongly suggests that levosimendan may be promising in patients with RV dysfunction coming for Mitral valve repair/replacement surgeries. The study has demonstrated that in patients with RV dysfunction undergoing MV surgeries a 24-hr infusion of levosimendan significantly improved the RV function as evidenced by both hemodynamic as well as the 2D echocardiographic parameters. This improvement in the RV function was noted up to the 7th PO day.
The authors would like to express our gratitude to Mr. Karamjot Singh (University of Essex, Data Science) for his support with the statistical and data visualization aspects of the study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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K S Bharathi
Associate Professor, Department of Cardiac Anaesthesiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, K.R.S. Road, Mysore - 570016, Karnataka
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]