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Table of Contents
JANAK MEHTA AWARD  
Year : 2013  |  Volume : 16  |  Issue : 1  |  Page : 11-15
A comparison of hemodynamic effects of levosimendan and dobutamine in patients undergoing mitral valve repair / replacement for severe mitral stenosis


Department of Cardiac Anesthesiology, Sri Ramachandra Medical College, Chennai, Tamil Nadu, India

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Date of Submission13-Jan-2012
Date of Acceptance13-Sep-2012
Date of Web Publication2-Jan-2013
 

   Abstract 

Aims and Objectives: We aimed to compare the hemodynamic effects of levosimendan and dobutamine in patients undergoing mitral valve surgery on cardiopulmonary bypass (CPB). Materials and Methods: Sixty patients were divided into 2 groups of 30 each. Group-L patients received levosimendan 0.1 μg/kg/min and Group-D patients received dobutamine 5 μg/kg/min while weaning off CPB. Additional inotrope and/or vasoconstrictor were started based on hemodynamic parameters. Hemodynamic data were collected at the end and at 30 minutes after CPB, thereafter at 6, 12, 24, and 36 hours post-CPB. Mean arterial pressure (MAP), central venous pressure (CVP), heart rate (HR), cardiac index (CI), systemic vascular resistance index (SVRI), and lactate levels were measured. Results: Group-L showed increased requirement of inotropes and vasoconstrictors. The SVRI, CVP, and MAP were reduced more in Group-L. The CI was low in Group-L in the initial period when compared to Group-D. Later Group-L patients showed a statistically significant increase in CI even after 12 hrs of discontinuation of levosimendan infusion. The HR was increased more in Group-D. Lactate levels, intensive care unit stay, and duration of ventilation were similar in both groups. Conclusions: Levosimendan 0.1 μg/kg/min compared to dobutamine 5 μg/kg/min showed more vasodilation and lesser inotropic activity in patients undergoing mitral valve surgery for mitral stenosis. Levosimendan compared to dobutamine showed a statistically significant increase in CI even after 12 hrs of discontinuation. The requirement of another inotrope or vasopressor was frequent in levosimendan group.

Keywords: Cardiac index, Dobutamine, Hemodynamics, Levosimendan, Systemic vascular resistance index

How to cite this article:
Gandham R, Syamasundar A, Ravulapalli H, Karthekeyan RB, Vakamudi M, Kodalli R, Nandipati S. A comparison of hemodynamic effects of levosimendan and dobutamine in patients undergoing mitral valve repair / replacement for severe mitral stenosis. Ann Card Anaesth 2013;16:11-5

How to cite this URL:
Gandham R, Syamasundar A, Ravulapalli H, Karthekeyan RB, Vakamudi M, Kodalli R, Nandipati S. A comparison of hemodynamic effects of levosimendan and dobutamine in patients undergoing mitral valve repair / replacement for severe mitral stenosis. Ann Card Anaesth [serial online] 2013 [cited 2014 Sep 19];16:11-5. Available from: http://www.annals.in/text.asp?2013/16/1/11/105363



   Introduction Top


Surgery on cardiopulmonary bypass (CPB) with aortic clamping involves global myocardial ischemia resulting in different degrees of transitory ventricular dysfunction in the immediate post-operative period. [1],[2] Patients of critical mitral valve stenosis are known to present with low cardiac output following mitral valve surgery. Positive inotropic drugs and vasodilators are administered to treat this condition. Beta-adrenergic agonists and phosphodiesterase III/IV inhibitors induce good early hemodynamic improvement but may cause myocardial ischemia, arrhythmias and are associated with high mid-term mortality. [3],[4],[5] Levosimendan increases the sensitivity of myocardial contractile proteins to calcium resulting in positive inotropy. The use of this drug in the treatment of heart failure is based on its mechanisms of action, the improvement of myocardial contractility through the sensitization of troponin C to calcium, and systemic and coronary arterial and venous dilatation induced by activation of ATP-sensitive potassium channels of smooth muscle fibers. [3] Because of these actions levosimendan increases cardiac output, and coronary and renal blood flow. It also reduces the preload and afterload, has an anti-arrhythmic effect, and can revert myocardial stunning. [3] The present study was aimed to compare the hemodynamic effects of levosimendan and dobutamine in a group of patients undergoing mitral valve surgery on CPB. We also compared the outcomes in terms of duration of ventilation and intensive care unit stay and tissue perfusion in terms of lactate levels.


   Materials and Methods Top


The study was approved by the hospital ethics committee. All patients undergoing mitral valve surgery for mitral stenosis under 60 years of age were considered for inclusion. The patients having associated moderate to severe mitral regurgitation, other valvular pathologies, renal dysfunction (serum creatinine >2 mg/dl and/or chronic kidney disease), undergoing combined mitral valve surgery with coronary artery bypass graft surgery, or redo mitral valve surgery or re-exploration for surgical causes were excluded. Written informed consent was obtained from all the patients. Randomization was done by computerized allocation of patients to both the groups. Pre-anesthetic assessment was done the day before surgery. Demographic data and the transthoracic echocardiography data including valve area (determined by planimetry), pulmonary artery pressure, and left ventricular ejection fraction were recorded. All patients received oral diazepam 10 mg and pantoprazole 40 mg previous night and on the morning of surgery. Patients were induced with midazolam 0.15 mg/kg, fentanyl 2-3 μg/kg and thiopentone titrated to the loss of eyelash reflex. Vecuronium 0.1 mg/kg was used to facilitate endotracheal intubation. Radial artery was cannulated for arterial pressure monitoring. Cardiac output was monitored using FloTrac sensor (Edwards lifesciences services LLC Irvine, CA 92614-5686 USA) and Vigileo monitor software (ver. 0302 pic v 1.0 Edwards life sciences). Right internal jugular vein was cannulated and systemic vascular resistance was measured after obtaining the central venous pressure (CVP). The cardiac index (CI) and systemic vascular resistance index (SVRI) were also measured. The myocardial contractility, mitral valve function and preload were assessed by transesophageal echocardiography (TEE) at the time of separation from CPB. The surgical techniques (ttk chitra prosthetic valve or annuloplasty ring) used were recorded in all patients.

Surgery was performed on CPB with moderate hypothermia (28°C to 32°C) and cold blood cardioplegic cardiac arrest. At separation from CPB, group-D patients received infusion of dobutamine 5 μg/kg/min and group-L received levosimendan infusion 0.1 μg/ kg/ min. The study drug levosimendan and dobutamine were diluted in such a way that equal infusion rates were achieved for comparable patients. Both the drug syringes were prepared by another person blinded from the study. Syringes and extension tubing were covered with brown paper to blind the anesthesiologist. Drugs were administered once patient was rewarmed to 34°C and aortic clamp was released. Protocol and criteria for addition of another inotrope or vasopressor (adrenaline or noradrenaline) is described in flow diagram. While continuing a flow of 0.5 l/min on CPB, the CVP, the mean arterial pressure (MAP), SVRI, CI and left ventricular (LV) and right ventricular (RV) function and mitral valve function were assessed and the vasopressor or inotropic agent was selected as described in the flow diagram.



If MAP was more than 50 mmHg and LV and RV function were adequate as assessed by TEE in mid esophageal four chamber view, the study drug was continued.

If MAP was less than 50 mmHg, CI <1 dyne-sec-m 2 /cm 5 with adequate LV and RV function on TEE imaging, but SVRI less than 1200 units, noradrenaline 0.05 μg/kg/min was added in addition to group inotrope.

If MAP was less than 50 mmHg, CI <1 dyne-sec-m 2 /cm 5 with inadequate LV and RV function on TEE imaging and SVRI more than 1200 units, adrenaline 0.05 μg/kg/min was added in addition to group inotrope.

In both groups, the HR, CVP, CI, and SVRI were monitored at baseline, immediately and at 30 minutes after CPB, thereafter at 6, 12, 24 and 36 hours after CPB. Aortic clamp time and CPB time were recorded for all patients. Tracheal extubation was performed when patients were hemodynamically stable, temperature was >36°C, chest tube drainage was less than 50 ml per hour, urine output was greater than 0.5 ml per kg per hour, and patients were breathing spontaneously with adequate blood gases as per institution protocol. Both the study drugs and additional inotrope/vasoconstrictor were tapered once the patients were extubated and hemodynamically stable. Presence of any arrhythmia was recorded.

Statistics

The sample size required was determined by the criterion that an increase in the CI of >20% over baseline is obtained after 24 hours of treatment for α error of 5% and a β error of 10%. The determined sample size was 30 patients in levosimendan (L) group and 30 patients in dobutamine (D) group. Numerical results are presented as mean ± SD; mean was compared by the students 't' test; categorical data were compared using chi square test. Significance was set at a P value < 0.05.


   Results Top


This prospective, randomized, double-blind study included 60 patients undergoing mitral valve surgery under CPB from July 2011 to December 2011. [Table 1] shows the clinical and demographic data of all patients included in the study. The demographic data was comparable between the two groups. Both groups were comparable regarding valve area, ejection fraction, incidence of severe pulmonary artery hypertension, CPB and aortic clamp time, and surgical technique employed. The ICU stay and duration of ventilation were also similar in both groups. The MAP reduced more in the levosimendan group compared to dobutamine group, which was statistically significant at weaning from CPB, and at 30 minutes, 6 hours, and 12 hours post CPB. This decrease in MAP was maintained even after its discontinuation. Treatment with dobutamine showed no significant changes in this respect. [Table 2] shows the MAP, the CVP, and the SVRI at various time intervals. The HR was higher in dobutamine group, which was statistically significant. The HR normalized with tapering of inotropes. Levosimendan group patients showed a sustained increase in CI at 24 and 36 hours postoperatively compared to dobutamine group, which was statistically significant. [Table 3] shows HR, and CI of patients monitored at various time intervals. Seven patients needed adrenaline infusion, and 14 patients needed noradrenaline infusion in the levosimendan group, whereas only 2 patients needed adrenaline and 2 patients needed noradrenaline infusion in dobutamine group as shown in [Table 4]. This difference in the requirement of inotropic agent and vasoconstrictor infusion was statistically significant. Post-operative atrial fibrillation was recorded in patients in whom preoperatively atrial fibrillation was found. No malignant ventricular arrhythmias were recorded in any patient. Serum lactate levels indicative of tissue perfusion were increased in both groups intra-operatively and settled towards baseline by 24 hours [Table 4].
Table 1: Patient characteristics and clinical parameters in 2 groups


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Table 2: MAP, CVP and SVRI at various time intervals


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Table 3: HR, CI and lactate levels at various time intervals


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Table 4: Number of patients in whom adrenaline or nor adrenaline was required


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   Discussion Top


Post-operative myocardial stunning defined as transitory myocardial dysfunction induced by ischemia through clamping of the aorta followed by reperfusion involves depletion of high energy phosphates, intracellular calcium overload, generation of free radicals, and impairment of the coronary microcirculation. [2] Myocardial stunning, anesthetic agents, vasodilation and hyperthermia caused by the inflammatory response associated with CPB, all contributes to hemodyanamic instability in the early post-operative period. [6] The recovery from this phenomenon starts after one hour of termination of CPB, and continues till 24 hours post-CPB. [1] Patients with this condition usually respond to positive inotropic agents. [1] Beta-adrenergic agonists and phosphodiesterase III/IV inhibitors induce hemodynamic improvement, but favor myocardial ischemia, arrhythmias, and are associated with high mid-term mortality in non-surgically treated patients with heart failure. [3],[4],[5] Few studies on the use of levosimendan in the immediate post-cardiac surgery patients have been undertaken. [7],[8],[9],[10] In the present study levosimendan was started at 0.1 μg/kg/min without a bolus dose to avoid profound hypotension. [11] Dobutamine was chosen as the inotropic control drug since its effects on low cardiac output syndrome following surgery involving CPB are well described. [12],[13] In our study, levosimendan showed sustained increase in CI even after 36 hrs post-CPB, helping to improve the myocardial dysfunction associated with CPB. Julian et al., [14] in their study found significant hypotension with levosimendan infusion 0.2 μg/kg/min with a bolus dose of 12 μg/kg. In our study, we did not find significant hypotension since we selected a smaller infusion dose of levosimendan and avoided its bolus dose. In contrast to the study of Julian et al., [14] our study showed less increase in HR in levosimendan group compared to dobutamine group. Although we have not measured the pulmonary vascular resistance index and pulmonary artery (PA) pressures, levosimendan could have benefited our study patients since increase in PA pressures is known in patients with severe mitral stenosis. The prolonged effects of levosimendan are owed to the pharmacokinetic properties of its metabolites, especially the molecule known as OR-1896. This has a pharmacodynamic profile identical to that of levosimendan, with a half life of approximately 80 hours and activity period of 2 weeks. [11],[15],[16],[17] Seven patients in levosimendan group needed adrenaline for maintaining adequate MAP and CI indicating that 0.1 μg/kg/min levosimendan did not produce enough inotropy. This might be attributed to decrease in dosage of levosimendan. Fourteen patients in the levosimendan group were started on nor-adrenaline infusion to increase the SVRI indicating that levosimendan infusion even at 0.1 μg/kg/min without a bolus dose produces significant vasodilation. Conversely, only 2 patients needed adrenaline infusion and 2 patients needed noradrenaline infusion in dobutamine group indicating relatively less vasodilation with dobutamine.


   Conclusion Top


Levosimendan 0.1 μg/kg/min produces more vasodilation and lesser inotropic activity as compared to dobutamine 5 μg/kg/min in the post bypass period in patients undergoing mitral valve surgery for mitral stenosis. Levosimendan showed a statistically significant increase in CI even after 12 hours of stopping the infusion when compared to dobutamine. The requirement of another inotrope or vasopressor was more frequent in levosimendan group than in dobutamine group. There was no significant difference in the lactate levels and duration of ventilation and ICU stay in both the groups.

 
   References Top

1.Breisblatt WM, Stein KL, Wolfe CJ, Follansbee WP, Capozzi J, Armitage JM, et al. Acute myocardial dysfunction and recovery: A common occurrence after coronary bypass surgery. J Am Coll Cardiol 1990;15:1261-9.  Back to cited text no. 1
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2.Doyle AR, Dhir AK, Moors AH, Latimer RD. Treatment of perioperative low cardiac output syndrome. Ann Thorac Surg 1995;59:S3-11.  Back to cited text no. 2
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3.Tamargo J, López-Sendón J. Rationale and clinical evidence for the effects of new pharmacological treatments for heart failure. Rev Esp Cardiol 2004;57:447-64.  Back to cited text no. 3
    
4.Cody RJ. Do positive inotropic agents adversely affect the survival of patients with chronic congestive heart failure? I. Introduction. J Am Coll Cardiol 1988;12:559-61.  Back to cited text no. 4
    
5.Chatterjee K, Wolfe CL, deMarco T. Nonglicoside inotropes in congestive heart failure: Are they beneficial or harmful? Cardiol Clin 1994;12:63-72.  Back to cited text no. 5
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6.Laffey JG, Boyland JF, Cheng DC. The systemic inflammatory response to cardiac surgery. Anesthesiology 2002;97:215-52.  Back to cited text no. 6
    
7.Lilleberg J, Nieminen MS, Akkila J, Heikkilae L, Kuitunen A, Lehtonen L. Effects of a new calcium sensitizer, levosimendan, on the haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting. Eur Heart J 1998;19:660-8.  Back to cited text no. 7
    
8.Nijhawan N, Nicolosi AC, Montgomery MW, Aggarwal A, Pagel PS, Warltier DC. Levosimendan enhances cardiac performance after cardiopulmonary bypass: A prospective, randomized placebo-controlled trial. J Cardiovasc Pharmacol 1998;34:219-28.  Back to cited text no. 8
    
9.Labriola C, Siro-Brigiani M, Carrata F, Santangelo E, Amantea B. Hemodynamic effects of levosimendan in patients with low-output heart failure after cardiac surgery. Int J Clin Pharmacol Ther 2004;42:204-11.  Back to cited text no. 9
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10.Delange Segura L, Jerez Anera M, Carmona Aurioles J, Rodríguez Fernández S. Levosimendan as inotropic support during coronary surgery with extracorporeal circulation in a patient with severely depressed ventricular function. Rev Esp Anestesiol Reanim 2003;50:423-4.  Back to cited text no. 10
    
11.Fernández AL, García-Bengochea JB, Ledo R, Vega M, Amaro A, Álvarez J, et al. ally invasive surgical implantation of left ventricular epicardial leads for ventricular resynchronization using video-assisted thoracoscopy. Rev Esp Cardiol 2004;57:313-9.  Back to cited text no. 11
    
12.Nieminen MS, Böhm M, Cowie MR, Drexler H, Filippatos GS, Jondeau G, et al. Executive summary of the guidelines on the diagnosis and treatment of acute heart failure. Rev Esp Cardiol 2005;58:389-429.  Back to cited text no. 12
    
13.Feneck RO, Sherry KM, Withington PS, Oduro-Dominah A. Comparision of the hemodynamic effects of milrinone with dobutamine in patients after cardiac surgery. J Cardiothorac Vasc Anesth 2001;15:306-15.  Back to cited text no. 13
    
14.Álvarez J, Bouzada M, Fernández AL, Caruezo V, Taboada M, Rodríguez J, et al. Hemodynamic effects of levosimendan compared with dobutamine in patients with low cardiac output after cardiac surgery. Rev Esp Cardiol 2006;59:338-45.  Back to cited text no. 14
    
15.Kivikko M, Lehtonen L. Levosimendan: A new inodilatory drug for the treatment of decompensated heart failure. Curr Pharm Des 2005;11:435-55.  Back to cited text no. 15
    
16.Kivikko M, Lehtonen L, Colucci WS. Sustained hemodynamic effects of intravenous levosimendan. Circulation 2003;107:81-6.  Back to cited text no. 16
    
17.Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): A randomised double-blind trial. Lancet 2002;360:196-202.  Back to cited text no. 17
    

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Correspondence Address:
Ravikumar Gandham
Department of Anesthesiology and Critical Care, Sri Rama Chandra University, Chennai, Tamil Nadu
India
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DOI: 10.4103/0971-9784.105363

PMID: 23287080

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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