|Year : 2014 | Volume
| Issue : 2 | Page : 114-120
Comparison between milrinone and levosimendan infusion in patients with peripartum cardiomyopathy
Hatem A Abdel Hamid1, Sanaa A. El-Tohamy2
1 Anesthesia and Intensive Care Department Faculty of Medicine, Ain Shams University, Egypt
2 Anesthesia and Intensive Care Department Faculty of Medicine, Zagazig University, Egypt
|Date of Submission||28-Oct-2013|
|Date of Acceptance||16-Nov-2013|
|Date of Web Publication||31-May-2014|
Hatem A Abdel Hamid
79 Mohey el din abdel hamid street, 8th District, Nasr City, Cairo
Source of Support: None, Conflict of Interest: None
Peripartum cardiomyopathy (PPCM) is a rare disorder of dilated cardiomyopathy in which no other cause of heart dysfunction can be identified within the final trimester of pregnancy or within 5 months after delivery. The aim of this prospective study was to assess the effect of 24-h infusion of levosimendan compared with milrinone on cardiac function and patient outcome.
Patients and methods
All patients enrolled in the study fulfilled the diagnostic criteria of PPCM. Patients were allocated randomly into one of two groups (15 patients each): group A received levosimendan infusion (a loading dose of 12 μg/kg intravenously for 10 min, followed by an intravenous infusion 0.1-0.2 μg/kg/min) and group B received milrinone infusion (a loading dose of 50 μg/kg administered intravenously for 10 min, followed by an intravenous infusion at a dosage titrated between 0.375 and 0.750 μg/kg/min) for 24 h after delivery. Hemodynamic and cardiac function parameters [stroke volume (SV), cardiac output (CO), and systemic vascular resistance] were monitored every 6 h for 24 h; also, cardiac biomarkers were monitored every 2 days thereafter until the day of discharge.
No significant difference was found in hemodynamic parameters between group A and group B. Milrinone-treated patients showed a significant increase in CO parameters (SV and cardiac index) compared with the levosimendan group; yet, no significant difference was found in systemic vascular resistance between the two study groups. Also, no significant differences were found in cardiac biomarkers or outcome prognosis parameters between milrinone and levosimendan groups.
PPCM is an uncommon, but life-threatening condition. Despite the significant improvement in CO parameters (SV and cardiac index) in milrinone-treated patients, there was no significant difference in hemodynamic parameters, cardiac biomarkers levels, and outcome prognosis compared with levosimendan infusion. This study paves the way for further researches to establish an optimized protocol for the management of such a challenging condition.
Keywords: Peripartum cardiomyopathy, levosimendan, milrinone, cardiac biomarkers, cardiac functions parameters, outcome prognosis
|How to cite this article:|
Abdel Hamid HA, El-Tohamy SA. Comparison between milrinone and levosimendan infusion in patients with peripartum cardiomyopathy. Ain-Shams J Anaesthesiol 2014;7:114-20
|How to cite this URL:|
Abdel Hamid HA, El-Tohamy SA. Comparison between milrinone and levosimendan infusion in patients with peripartum cardiomyopathy. Ain-Shams J Anaesthesiol [serial online] 2014 [cited 2021 Apr 11];7:114-20. Available from: http://www.asja.eg.net/text.asp?2014/7/2/114/133308
| Introduction|| |
Peripartum cardiomyopathy (PPCM) is an idiopathic cardiomyopathy that presents with heart failure secondary to left-ventricular systolic dysfunction that arises in the last trimester of pregnancy or up to 5 months after delivery, in the absence of any other cause of heart failure. PPCM is a diagnosis of exclusion. Although the left ventricle may not be dilated, the ejection fraction (EF) is almost always reduced below 45% and a left-ventricular end-diastolic dimension (LVEDD) is more than 27 mm . The clinical presentations of PPCM are most often dyspnea (90%), tachycardia (62%), and edema (60%) ; sometimes, there are unusual presentations, including multiple thromboembolic events  and acute hypoxia . The severity of symptoms in patients with PPCM can be classified according to the New York Heart Association system  as follows:
- Class I - disease with no symptoms.
- Class II - mild symptoms/effect on function or symptoms only with extreme exertion.
- Class III - symptoms with minimal exertion.
- Class IV - symptoms at rest.
Standard heart failure treatment is recommended for PPCM until the EF recovers. Medications include angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers, b-blockers, and diuretics. However, caution must be exercised as ACEI and angiotensin receptor blockers are contraindicated in pregnancy. A few patients may eventually benefit from cardiac resynchronization therapy, internal defibrillators, or cardiac transplantation . An important therapeutic option to be considered is anticoagulation. Pregnancy results in a hypercoagulable state that extends ∼3 months postpartum. During this time, patients with PPCM and depressed systolic function are at a high risk for thrombus formation and thromboembolic events . No specific treatment has been identified to significantly alter the morbidity of PPCM. Small trials have reported the benefits of pentoxifylline, intravenous immunoglobulin, and bromocriptine. Pentoxifylline decreased tumor necrosis factor levels and increased EF in patients with PPCM . Intravenous immunoglobulin improved EF compared with standard treatment in a retrospective study of six cases compared with a control group . Case reports of recovery from PPCM with bromocriptine treatment have been described .
Among cardiac biomarkers, elevations of troponin T (TropT) level appear to have prognostic significance in patients presenting with PPCM. A TropT level of 0.04 ng/ml predicts persistence of systolic dysfunction with a sensitivity of 55% and a specificity of 91% .
Normally, atrial natriuretic peptide (ANP) is stored in large concentrations in the atria, with much less in the ventricles, whereas brain natriuretic peptide (BNP) is derived to a much greater extent from the cardiac ventricles. The ventricles secrete a large amount of BNP, although they store only a small quantity . Plasma concentrations of ANP are usually higher than that of BNP, but in cardiac failure, BNP concentrations increase much more than ANP concentrations so that in severe heart failure plasma BNP often exceeds plasma ANP. This differential release rate may make BNP concentrations a more sensitive indicator of left-ventricular dysfunction than ANP concentrations .
Milrinone (Primacor) is a derivative of amrinone. Both compounds share a bipyridine ring structure and increase the contractility of isolated heart muscle. However, the inotropic potency of milrinone is 10-30 times greater than that of its parent compound . The mechanism of this inotropic effect remains unclear. Milrinone is a potent inhibitor of cardiac cAMP phosphodiesterase, with a resultant increase in cardiac cAMP levels. In addition to its direct cardiac effects, milrinone also relaxes vascular smooth muscle in experimental preparations at considerably higher doses than required to produce a positive inotropic response. It increases cardiac output (CO) and reduces systemic vascular resistance (SVR) and pulmonary capillary wedge pressure. The drug exerts its hemodynamic effects without excessive changes in heart rate or increases in myocardial oxygen consumption . Following an intravenous infusion, Primacor has a volume of distribution of 0.38 l/kg and a mean terminal elimination half-life of 2.3 h .
Levosimendan (Simdax) is an inodilator with an alternative mode of action to the traditionally used agents. It exerts positive inotropic effects by binding to cardiac troponin C, sensitizing myofilaments to calcium by enhancing the sensitivity of troponin C to calcium without increasing intracellular calcium concentration ,. Levosimendan also has vasodilatory properties and a cardiac afterload reduction effect. In clinical studies, levosimendan increased CO and reduced cardiac filling pressures, and was associated with reducing cardiac symptoms, risk of death, and hospitalization ,.
Levosimendan induces hemodynamic improvement without an increase in myocardial oxygen consumption . Levosimendan is 97-98% bound to plasma proteins, primarily to albumin. It has an elimination half-life of 1 h. However, the half-lives of its two circulating metabolites, OR-1855 and its acetylated form OR-1896, range between 70 and 80 h. These metabolites reach their maximum serum concentration 2 days after the completion of a 24-h intravenous levosimendan infusion.
| Patients and methods|| |
Over a 3-years period, this prospective study was carried out in the ICU in Obstetric & Gynecology Governmental Hospital in Dammam/KSA after approval of the study protocol by the hospital authority on 30 female patients aged 35 ± 10 years within the childbearing period. All patients enrolled in the study fulfilled the diagnostic criteria of PPCM on the basis of the Demakis et al.'s  diagnostic criteria [Table 1]. The randomization was determined using a computer-generated randomization sequence (http://www.randomizer.org) and was concealed using sealed prenumbered opaque envelopes prepared by an administrative assistant not involved in the study.
Upon admission to the ICU, the patient's age, height, and weight were recorded after monitoring of baseline data. Baseline assessment of left-ventricular ejection fraction (LVEF) and LVEDD was performed through bedside echocardiography. All patients received the conventional treatment for congestive heart failure including the use of diuretics and ACEIs. If EF is less than 35%, anticoagulation is indicated, as there is a greater risk of developing left-ventricular thrombi. Inotropic agents (study medications) are used in patients with a low output state, indicated by signs of hypoperfusion (cold, clammy skin, vasoconstriction, acidosis, renal impairment, liver dysfunction, and impaired mentation) and those with congestion that persists despite administration of vasodilators and/or diuretics. For fetal safety study, infusion of medications was started after delivery and lactating women were excluded from the study. Patients were assigned randomly to group A (n = 15); they received a loading dose of levosimendan (Simdax; Orion Pharma, Finland [Orion Corporation, Orionintie 1A, 02200 Espoo, PO Box 65, FI-02101 Espoo, Finland]) 12 ∝g/kg intravenously for 10 min, followed by an intravenous infusion (0.1-0.2 μg/kg/min) for 24 h. Group B (n = 15) received a loading dose of milrinone (Primacor; Sanofi-Aventis [Sanofi-Aventis, 55 Corporate Drive Bridgewater, NJ 08807, USA]) 50 μg/kg administered intravenously for 10 min, followed by an intravenous infusion at a dosage titrated between 0.375 and 0.75 μg/kg/min for 24 h.
For each patient, a radial artery catheter (gage 20 Arrow Arterial Catheterization Catheter AV04020; Arrow [Arrow International, Inc., 2400 Bernville Road Reading, PA 19605, USA]) and a central venous line (ARROW-Howes Multi-Lumen Central Venous Catheterization Set; Arrow) were inserted. All patients were monitored by ECG, pulse oximetry (SpO 2 ), and respiratory rate, with continuous invasive monitoring of arterial blood pressure using an Hp V 570 (Palo Alto, California, USA).
Noninvasive monitoring of stroke volume (SV), CO, and SVR is performed with the plethysmography-based thoracic electrical bioimpedance technique using (Bioz Impedance Cardiography; Cardiodynamics, San Diego, California, USA), with four pregelled dual sensors yielding a real-time digital display of all the previously mentioned parameters; two electrodes are placed on both sides of the neck and both sides of the lower thorax.
Hemodynamic and cardiac function parameters were monitored every 6 h for 24 h.
BNP was measured using the point-of-care Biosite Triage (Biosite, San Diego, California, USA) BNP test. This system uses a single-use cartridge to measure each sample specimen and utilizes two antibodies, one of which is fluorescently tagged. The assay requires 15 min of reaction time. TropT was measured by an electrochemiluminescence immunoassay using an hs-cTnT assay on the Modular Analytics E 170 (Roche Diagnostics [Roche Diagnostics Corporation, 9115 Hague Road Indianapolis, Indiana 46250, USA]). All these variables were monitored every 2 days thereafter until the day of discharge or death of the patients.
Outcome prognosis was assessed in terms of the average length of ICU stay in addition to survival or death in the ICU. Survival was defined as leaving the hospital alive and able to resume all previous daily activities.
Epi Info (Centers for Disease Control and Prevention, Atlanta, Georgia, USA) was used for calculation of the sample size guided by α error of 5%, 95% confidence interval, and power of the test of 80%.
A sample size of 30 patients was found to be sufficient to carry out the study. Significance level was at α = 0.05 (type error I). The minimal sample size was 18. Statistical analysis was carried out using the computer software statistical package for the social science (version 17.0; SPSS Inc., Chicago, Illinois, USA). Quantitative (numerical) variables were described as mean ± SD. Qualitative (categorical) data were described as number of cases and percent. Error bars represent 95% confidence interval. Analysis of unpaired numerical variable was carried out using an unpaired the Student t-test, whereas analysis of paired numerical variables was carried out using a repeated-measure general linear model analysis of variance. Analysis of categorical data was carried out using Fisher's exact test or the c2 -test, whenever appropriate. The significance level was set at P value of 0.05 or less, and P value of 0.01 or less was considered highly significant.
| Results|| |
Thirty adult female ICU patients fulfilling the clinical criteria for PPCM  were enrolled in the study. The demographic baseline characteristics of the study population are presented in [Table 2].
No significant difference was found in the hemodynamic parameters between the two groups; yet, the milrinone group showed a significant improvement in noninvasive CO parameters (SV and cardiac index) compared with the levosimendan group. However, no significant difference was found in SVR between the two study groups. In terms of cardiac biomarkers (BNP and TropT), both were decreased at comparable rates in both groups in response to study medications, without a significant difference between the two groups. Finally, no significant difference was found in outcome prognosis parameters in the levosimendan and milrinone groups [Table 3],[Table 4],[Table 5],[Table 6] and [Table 7].
|Table 3: Baseline echocardiographic fi ndings upon admission of the study population|
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|Table 7: Prognostic presentation of the two study groups in relation to outcome prognosis|
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| Discussion|| |
PPCM is a rare cardiomyopathy of unknown cause that is life threatening. PPCM remains a diagnosis of exclusion and echocardiography provides clues to diagnosis in a symptomatic patient. Decompensated PPCM requires a multidisciplinary approach and hence represents a serious challenge.
In the current study, we determined the influence of using two inotropic agents (levosimendan and milrinone) infused after delivery for two groups of patients fulfilling the diagnostic criteria of PPCM. We traced the hemodynamic parameters (blood pressure and heart rate) response as well as SV, cardiac index, and SVR that were measured noninvasively using the impedance cardiography technique. Another aim of the study was to compare the effect of the two study medications on cardiac biomarkers levels (BNP and TropT) as well as outcome prognosis parameters in terms of mortality and average length of ICU stay.
Mebazaa et al.  have reported a reduction in the plasma BNP concentration in levosimendan-treated patients with acutely decompensated heart failure. Consistent with this finding, BNP levels were lower during levosimendan treatment in the present study.
Twomley et al.  reported that BNP and TropT levels have been shown to be markedly elevated in patients with PPCM, although these markers are not unique to PPCM, and yet appear to have prognostic significance in this setting. These results are in agreement with our current study, which showed a decrease in serum concentrations of BNP and TropT serum concentrations in response to the infusion of study medications.
The measurement of serum concentration of TropT is a simple and useful method to detect myocyte injury . Myocardial biopsies in PPCM showed that the most prominent findings were hypertrophy of myocardial fibers and varying degrees of fibrosis. The mechanisms of myocyte injury in PPCM are not fully understood. It may be caused by virus, infection, autoimmune mechanisms, hormonal changes, genetic disorders, and toxemia .
Also, Hu et al.  reported that a cardiac TropT concentration measured within 2 weeks of the onset of PPCM was correlated negatively with follow-up LVEF and that it has a moderate predictive capacity for persistent left-ventricular dysfunction at the 6-month follow-up (a TropT concentration of more than 0.04 ng/ml predicted persistent left-ventricular dysfunction). In the present study, the TropT concentration decreased in response to levosimendan and milrinone infusion, but we did not follow patients for 6 months with cardiac biomarkers or echocardiography because this was beyond the scope of our protocol. Also, no previous study has compared the rate of decrease of TropT and BNP in response to levosimendan and milrinone infusion.
Adamopoulos et al.  studied the effect of levosimendan on the inflammatory pathway and the hemodynamics in acutely decompensated heart failure and found that systolic left-ventricular function as evaluated by the EF and cardiac index was significantly improved in levosimendan-treated patients, which was consistent with our results. Also, Adamopoulos and colleagues found that levosimendan induces beneficial immunoinflammatory responses (reduction in tumor necrosis factor, IL-6, and NT-pro-BNP); thus, it may interfere with the cellular and biochemical pathways implicated in the progression of acute heart failure.
Benlolo et al.  used levosimendan in a patient with PPCM and observed a decrease in pulmonary capillary wedge pressure, followed by a definitive increase in cardiac SV, and the patient recovered from the episode of heart failure. Benlolo et al. reported that hemodynamic improvements persisted after levosimendan infusion ended, and these prolonged effects were likely attributable to the production of an active metabolite with a long half-life (OR-1896, t1/2 = 80 h) that was detected in human milk. 
The hemodynamic response to infusion of levosimendan and milrinone in the current study showed increases in both systolic as well as diastolic blood pressure and a decrease in heart rate within 6 h of infusion compared with the baseline hemodynamic parameters. These results were in agreement with a study carried out by Hewing et al. , who reported that current inotropes in use including adrenoreceptor agonists (dopamine, dobutamine, norepinephrine, epinephrine), phosphodiesterase III inhibitors (milrinone, enoximone), and Ca 2+ sensitizers (levosimendan) yield short-term hemodynamic improvements. These data were also supported by the study carried out by Parissis et al. , who concluded that classical inotropes, such as b-agonists (dobutamine, dopamine) and phosphodiesterase inhibitors (milrinone), seem to improve clinical symptoms and hemodynamics of acutely decompensated chronic heart failure patients.
The beneficial hemodynamic effects of milrinone in congestive heart failure were confirmed in a study carried out by Timmis et al. . The drug improved left-ventricular systolic function as a result of simultaneous positive inotropism and vasodilatation. Milrinone exerts vasodilatory effects in patients with heart failure, and the reduction in left-ventricular afterload contributes significantly toward the drug's overall action to increase SV.
In a study carried out by Bregagnollo et al.  on 20 patients with DCM and New York Heart Association class III and IV heart failure, the hemodynamic and vasodilating effects of milrinone administered intravenously were evaluated and showed a significant improvement in the parameters of cardiac performance analyzed, with an increase in CO and CI; a significant improvement in myocardial contractility; and a reduction in pulmonary capillary wedge pressure (PCWP), mean arterial pressure (MAP), SVR, and pulmonary vascular resistance (PVR), with no significant changes in heart rate .
Instead of traditional inotropes, such as milrinone (phosphodiesterase inhibitor), which are known to improve contractility, but at the cost of increased myocardial oxygen demand with a consequent risk of ischemia and arrhythmia, the myofilament calcium sensitizer levosimendan is a promising alternative inotropic agent. Levosimendan improves cardiac muscle contractile force, vascular smooth muscle relaxation, coronary blood flow, and CO through calcium sensitization of the contractile filament and opening of potassium channel without increasing oxygen consumption of the heart muscles .
Lechner et al.  observed an increase in the cardiac index over time in the levosimendan group, but not in the milrinone group, in children during open heart surgery.
All these results are comparable with our study on improvement in CO parameters; yet, specific study of the difference between milrinone and levosimendan in PPCM has not been carried out in previous studies, which is an avenue for future researches.
In a prospectively randomized study carried out by Biteker et al.  on 24 consecutive women with PPCM, Biteker and colleagues concluded that the addition of levosimendan to conventional therapy did not improve outcome in patients with PPCM (25% of patients died during the study period), whereas in our study, the mortality rate in the levosimendan group was 20%. The echocardiographic baseline data were different between the Biteker and colleagues' study and our study (LVEDD was 6.7 vs. 5.6 cm, respectively, and LVEF was 25 vs. 33.5%, respectively); also, Biteker and colleagues followed patients for 12 to 38 months, whereas in the present study, we followed patients during the length of hospital stay and survival was defined as leaving the hospital alive and able to resume all previous activities.
| Conclusion|| |
PPCM is an uncommon but life-threatening condition. This study shows that milrinone infusion led to significant improvement in cardiac parameters (SV and cardiac index); yet, there was no significant difference in hemodynamic parameters, cardiac biomarkers levels, and outcome prognosis in comparison with levosimendan infusion. This study paves the way for further researches to establish an optimized protocol for the management of such a challenging condition.
| Acknowledgements|| |
Conflicts of interest
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]