case report

Levosimendan reverses right-heart failure in a 51-year-old patient after heart transplantation 11 3

Summary Primary graft failure in the early postopera-tive period after heart transplantation, remains a main cause of a poor outcome. Current treatment options include pharmacological (catecholamines and phos-phodiesterase inhibitors) and mechanical assist device support. Pharmacological support with catecholamines is related to elevated myocardial oxygen consumption and regional hypoperfusion leading to organ damage. On the other hand, levosimendan, as a calcium-sensitiz-ing agent increases cardiac contractility without altering intracellular Ca2+ levels and increase in oxygen demand.

We present a case of a 51-year-old man, who was suf-fering from acute right-heart failure in the early postop-erative period after heart transplantation. As a rescue therapy at the late stage of a low cardiac output state, levosimendan was started as continuous infusion at 0.1 μg/kg/min for 12 h and thereafter, at 0.2 μg/kg/min for the following 36  h. Levosimendan demonstrated an advanced pharmacological option as was portrayed in this case, where the right ventricle was under a pro-longed severe depression and acutely overloaded after heart transplantation.

Keywords Transplantation  · Right ventricular dysfunc-tion · Levosimendan · Primary organ failure

Levosimendan macht das Rechtsherzversagen bei einem 51-jährigen Patienten nach der Herztransplantation rückgängig

Zusammenfassung Das primäre Versagen des Trans-plantates in der frühen postoperativen Phase nach einer Herztransplantation bleibt die Hauptursache für eine schlechte Prognose. Derzeitige Behandlungsmöglichkei-ten umfassen sowohl pharmakologische (Katecholamine und Inhibition der Phosphodiesterase) als auch mecha-nische „assist device support“ Methoden. Pharmako-logische Unterstützung mit Katecholaminen steht in Zusammenhang mit erhöhtem myokardialen Sauerstoff-verbrauch und regionaler Hypoperfusion, was Organ-schäden zur Folge hat. Andererseits erhöht Levosimendan als Calcium-Sensibilisierungsagens die Herzkontraktilität ohne Einfluss auf Veränderungen des intrazellulären Ca2+ Spiegels und Erhöhung des Sauerstoffbedarfes.

Wir stellen den Fall eines 51-jährigen Mannes dar, der in der frühen postoperativen Phase nach einer Herz-transplantation ein akutes Rechtsherzversagen erlitt. In der Spätphase eines Low-Cardiac-Output-Syndroms wurde als Notfalltherapie Levosimendan mit einer Dau-erinfusion von 0,1 μg/kg/min über 12 h eingeführt und danach für die folgenden 36 h mit 0,2 μg/kg/min fortge-setzt. In diesem Fall zeigte Levosimendan eine erweiterte pharmakologische Option, wobei sich der rechte Ventri-kel unter einer länger anhaltenden höhergradig redu-zierten Rechtsventrikelfunktion befand und akut nach einer Herztransplantation überlastet war.

Schlüsselwörter Transplantation  · Dysfunktion der rechten Herzkammer · Levosimendan · Primäres Organ-versagen

S. Barisin, MD, PhD () · V. Djuzel, MDClinical Department of Cardiovascular Anesthesia and Intensive Care, University Department of Anesthesiology, Resuscitation and Intensive Care, Dubrava University Hospital,Av. G. Suska 6, 10000 Zagreb, Croatiae-mail: abarisin@kbd.hr

A. Barisin, MD, PhDDepartment of Medicine, Medikol Polyclinic,Zagreb, Croatia

I. Rudez, MD, PhDDepartment of Cardiac Surgery, University Department of Surgery, Dubrava University Hospital, Zagreb, Croatia

Received: 24 November 2012 / Accepted: 18 February 2014© Springer-Verlag Wien 2014

Wien Klin WochenschrDOI 10.1007/s00508-014-0528-2

Levosimendan reverses right-heart failure in a 51-year-old patient after heart transplantation

Stjepan Barisin · Viktor Djuzel · Ana Barisin · Igor Rudez

case report

2 Levosimendan reverses right-heart failure in a 51-year-old patient after heart transplantation 1 3

Introduction

Primary graft failure in the early postoperative period after heart transplantation remains a main cause of poor outcome, however the potential factors causing it, are not thoroughly understood [1]. The therapeutic options in patients suffering from acute organ failure are limited to pharmacological (catecholamines and phosphodies-terase inhibitors) or mechanical support [2].

Levosimendan (Simdax®, Orion, SF), is a calcium-sensitizing agent that increases cardiac output without increasing oxygen demand. Its beneficial effects have already been described in patients with acute right-heart failure after cardiac surgery [3, 4]. We report a case of severe and prolonged acute right ventricular (RV) fail-ure after cardiac transplantation, which was significantly reversed with levosimendan as it was being used as a res-cue therapy.

Case report

A 51-year-old man with dilatative cardiomyopathy sec-ondary to ischemia, with a left ventricular ejection frac-tion (LVEF) of 25 %, right ventricular ejection fraction (RVEF) of 11 %, and pulmonary vascular resistance (PVR) of 2.4 wood units, had undergone heart transplanta-tion. The donor was a 60-year-old woman who died from subarachnoidal hemorrhage. The surgical procedure was carried out in normothermia with the use of cardio-pulmonary bypass circuit (CPB). The time of ischemia was 99 min. The heart was reperfused for 45 min before weaning from CPB. After starting the patient on an iso-prenaline infusion at 0.25  μg/kg/min, the patient man-aged to function independently for only 12  min after weaning from CPB, due to RV dilatation, sonographically verified by transesophageal echocardiography (TEE), presenting with a severely reduced ejection fraction (EF) and submassive tricuspidal regurgitation. The left ven-tricle was hypovolemic with a good function. The second attempt at weaning, now with an infusion of isoprena-line at 0.5 μg/kg/min and intermittent intravenous (i.v.) boluses of norepinephrine, was also unsuccessful. The third attempt at weaning was successful with infusions of isoprenaline at 0.25 μg/kg/min, dobutamine at 5 μg/kg/min, nitroglycerine at 0.05 μg/kg/min, and an infusion of norepinephrine at 0.4 μg/kg/min being infused directly into the left atrium. However, despite the successful weaning, a low output state remained. The total pump time was 178 min (124, 33, and 21 min). Prior to intensive care unit (ICU) admission, the TEE still showed a massive tricuspid regurgitation (TR), RV dilatation (diameter was 46 mm) with an EF of approximately 20 % and a hypovo-lemic left ventricle with a preserved EF and a septal shift into the left ventricle.

At ICU admission, the hemodynamic param-eters worsened, with systemic hypotension as low as 70/40  mmHg, tachycardia of 140  beats/min, and with serum lactate levels of 9.25. Hemodynamic measure-

ment in the low cardiac output state showed a mean arte-rial pressure (MAP) of 55 mmHg, central venous pressure (CVP) of 26  mmHg, mean pulmonary arterial pressure (MPAP) of 27  mmHg, pulmonary capillary wedge pres-sure (PCWP) of 23  mmHg, cardiac index (CI) of 1.1  L/min/m2, left ventricular stroke work index (LVSWI) of 14 g m/m2, right ventricular stroke work index (RVSWI) of 0.1  g  m/m2, systemic vascular resistance (SVR) of 1190  dyn/sec/cm−5, and pulmonary vascular resistance (PVR) of 205  dyn/sec/cm−5. In addition to the infusion of norepinephrine at 0.5 μg/kg/min into the left atrium, isoprenaline at 0.5  μg/kg/min into the CV catheter, on the second day, we also increased the infusion of dobu-tamine to 6  μg/kg/min. This condition of a low cardiac output state with metabolic acidosis persisted for the fol-lowing 2 days with further deterioration on the 3rd day. As the surgeons decided not to implement a mechanical support, the lead author of the paper during his duty in the ICU insisted on purchasing and applying levosimen-dan as a last option. Once levosimendan was available, as a rescue therapy, it was administered as a continu-ous infusion at 0.1 μg/kg/min for 12 h and thereafter at 0.2  μg/kg/min for the following 36  h. Prior to adminis-tration of levosimendan, the MPAP was 52 mmHg, mixed venous oxygen saturation (SvO2) was 52 %, cardiac index (CI) was 1.7 L/min/m2, and RVSWI was 0.2 g m/m2. A few hours after initiation of levosimendan (3rd day of ICU stay), hemodynamic parameters had recovered with a further tendency of improvement in the following days (Fig. 1). On the sixth day after transplantation, transtho-racic echocardiography of the heart was carried out and it showed an RV basal diameter of 42 mm and left ven-tricle diameter of 23 mm, with paradoxic septal motion and submassive TR. Immunosupression was started on the first day after transplantation by induction with pro-nisone, antithymocyte globuline, and mycophenolate mofetil. Cyclosporine was started on the third postop-erative day. From the fourth postoperative day we had to put the patient on continuous hemofiltration due to anuria, while from the tenth to the thirteenth poostop-erative day, the patient was intermittently hemofiltrated every 12 h. The patient regained diuresis with furosemide stimulation. On the third postoperative day, due to the patient having a fever of 39.1 °C we started the patient on meropenem. Subsequently, Enterobacter spp. was isolated from the bronchial aspirate. We also isolated methycillin-resistant Staphylococcus aureus (MRSA) in the blood samples so the patient was started intermit-tently on vancomycin from the ninth postoperative day. The patient was weaned from the respirator on the ninth day after surgery and on the tenth day the patient was extubated. The hemodynamic profile and SvO2 com-pletely recovered and measured 74 % on day 12 after starting the patient on levosimendan. Hemodynamic measurements on day 12 were: MAP of 78 mmHg, CVP of 17 mmHg, MPAP of 24 mmHg, PCWP of 18 mmHg, CI at 3.6 L/min/m2, LVSWI at 25 g m/m2, RVSWI at 5 g m/m2, SVR of 690  dyn/sec/cm−5, and PVR of 93  dyn/sec/cm−5. The transthoracic echocardiography showed a RV

case report

Levosimendan reverses right-heart failure in a 51-year-old patient after heart transplantation 31 3

common cause of cardiovascular collapse during wean-ing from CPB are acute left or right-heart failure or signif-icant vasodilatation. Myocardial stunning, arrhythmias induced from reperfusion, inadequate preservation, or donor-recipient-related factors, such as myocardial contusion or depressed cardiac function following brain death, may contribute to acute primary graft failure [5, 6]. Except for a suboptimal graft due to the left ventricular concentric hypertrophy, in this case there were no other obvious factors which could precipitate acute right ven-tricular failure after heart transplantation. Primary graft failure accounts for 42 % of the in-hospital mortality after heart transplantation [7].

The treatment of acute RV failure frequently requires a multimodal approach with continuous hemodynamic monitoring for timely detection of problems associ-ated with RV failure. Current treatment options include pharmacological (catecholamines and phosphodiester-ase inhibitors) and mechanical assist device support. In this case, after the second attempt at weaning failed, the attending anesthesiologist decided on a combina-tion of dobutamine and isoprenaline instead of milri-none due to concerns that the use of milrinone might further aggravate the existing hypotension and vasodi-latation. At that moment, due to a low systemic blood pressure of 78/43  mmHg, the patient was receiving an infusion of norepinephrine in a dose of 0.4  μg/kg/min infused directly into the left atrium! Namely, it is well known that in comparison with dobutamine, milrinone produces a more significant reduction in MAP and SVR [8, 9]. The third weaning was successful with high-dose catecholamines, but with a persistent low cardiac out-put state remaining for the first three postoperative days in the ICU. Unfortunately due to the unavailability of levosimendan, it could not be applied earlier than the third day. Then, as a rescue therapy, levosimendan was introduced in a continuous infusion. A bolus dose of levosimendan, was omitted due to an existent refractory hypotension and a prolonged low-output state due to RV failure. The pharmacokinetics of levosimendan are simi-lar after single-dose administration or after continuous infusion through 7 days [10]. As patients with New York Heart Association functional class IV symptoms of heart failure, tolerate an extended infusion of levosimendan quite well and due to established medium term survival rates in patients with severe postcardiotomy heart failure after levosimendan administration, we decided to put the patient on a 48-h continuous infusion of levosimen-dan (0.1 μg/kg/min through 12 h, followed by 0.2 μg/kg/min during the following 36  h) [11, 12]. After adminis-tration of levosimendan, we witnessed a slow but stable improvement of hemodynamic parameters, particularly the RVSWI. The CI increased to 2  L/min/m2, 8 h after levosimendan administration, SvO2 increased to 63 % the following day, and the RVSWI was 4 g m/m2 on the ninth day. Norepinephrine was discontinued on day 9 and dobutamine on day 13 after levosimendan administra-tion (Fig. 1). We decided not to use milrinone for treating severe acute right-heart failure, due to clinically proven

ejection fraction of 33 % with tricuspid annular plane systolic excursion (TAPSE) of about 12 mm, and TR more than 2–3. There were no significant regional wall motion abnormalities. Five endomyocardial biopsies showed no signs of organ rejection (four biopsies were International Society for Heart Transplantation (ISHLT) grade 0, while one was ISHLT grade 1). The patient was transferred to the cardiosurgical ward on the fifteenth day after trans-plantation and was discharged from the hospital on postoperative day 34. During the 3-month follow-up, repeated endomyocardial biopsies have been normal.

Discussion

In this case, levosimendan, as a rescue therapy, led to the reversal of severe acute right-heart failure after trans-plantation with a compromised donor heart. The most

Fig. 1 Hemodynamic values and vasoactive drugs. In both graphs the X-axis shows time in days before and from the in-troduction of levosimendan (0-day). Top graph: the left Y-axis shows pressure in mmHg (MAP) and percentage (SvO2). The right Y-axis shows. L/min/m2 (CI) and g m/m2 (RVSWI). Bot-tom graph: the left Y-axis shows doses of the infusions of va-soactive drugs in μg/kg/min (norepinephrine, levosimendan, isoprenaline, and nitroglicerine). The right Y-axis shows dose of the infusion of dobutamine. SvO2—mixed venous oxygen saturation in the pulmonary artery, MAP—mean arterial pres-sure, CI—cardiac index, RVSWI—right ventricular stroke work index

case report

4 Levosimendan reverses right-heart failure in a 51-year-old patient after heart transplantation 1 3

References

1. Mitropoulos FA, Odim J, Marelli D, et al. Outcome of hearts with cold ischemic time greater than 300  min. A case-matched study. Eur J Cardiothorac Surg. 2005;28(1):143–8.

2. Hauer D, Beiras-Fernandez A, Kur F, Weis M, Schmoeckel M, Weis FC. The management of severe primary graft failure after cardiac transplantation. J Cardiothorac Vasc Anesth. 2009;23(2):203–5.

3. Morais RJ. Levosimendan in severe right ventricular failure following mitral valve replacement. J Cardiothorac Vasc Anesth. 2006;20(1):82–4.

4. Mebazaa A, Karpati P, Renaud E, Algotsson L. Acute right ventricular failure—from pathophysiology to new treat-ments. Intensive Care Med. 2004;30(2):185–96.

5. Beiras-Fernandez A, Weis FC, Fuchs H, Meiser BM, Reich-art B, Weis M. Levosimendan treatment after primary organ failure in heart transplantation: a direct way to recov-ery? Transplantation. 2006;82(8):1101–3.

6. Jahania MS, Mullett TW, Sanchez JA, Narayan P, Lasley RD, Mentzer RM Jr. Acute allograft failure in thoracic organ transplantation. J Card Surg. 2000;15(2):122–8.

7. Beiras-Fernandez A, Kur F, Kaczmarek I, et al. Levosimen-dan for primary graft failure after heart transplantation: a 3-year follow-up. Transplant Proc. 2011;43(6):2260–2.

8. Colucci WS, Wright RF, Jaski BE, Fifer MA, Braunwald E. Milrinone and dobutamine in severe heart failure: differ-ing hemodynamic effects and individual patient respon-siveness. Circulation. 1986;73(3):75–83.

9. Banfor PN, Preusser LC, Campbell TJ, et al. Comparative effects of levosimendan, OR-1896, OR-1855, dobutamine, and milrinone on vascular resistance, indexes of cardiac function, and O2 consumption in dogs. Am J Physiol Heart Circ Physiol. 2008;294:238–48.

10. Antila S, Kivikko M, Lehtonen L, et al. Pharmacokinetics of levosimendan and its circulating metabolites in patients with heart failure after an extended continuous infusion of levosimendan. Br J Clin Pharmacol. 2004;57(4):412–5.

11. Kivikko M, Antila S, Eha J, Lehtonen L, Pentikäinen PJ. Pharmacodynamics and safety of a new calcium sensitizer, levosimendan, and its metabolites during an extended infusion in patients with severe heart failure. J Clin Phar-macol. 2002;42(1):43–51.

12. Braun JP, Jasulaitis D, Moshirzadeh M, et al. Levosimen-dan may improve survival in patients requiring mechanical assist devices for post-cardiotomy heart failure. Crit Care. 2006;10:569–75.

13. Lilleberg J, Ylonene V, Lehtonen L, Toivonen L. The cal-cium sensitizer levosimendan and cardiac arrhythmias: an analysis of the safety database of heart failure treatment studies. Scand Cardiovasc J. 2004;38(2):80–4.

14. Kivikko M, Antila S, Eha J, Lehtonen L, Pentikäinen PJ. Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure. Int J Clin Pharmacol Ther. 2002;40(10):465–71.

15. Westphal M, Morelli A, Van Aken H. Dear levosimen-dan. the right ventricle will thank you! Crit Care Med. 2007;35(3):952–3.

16. Missant C, Rex S, Segers P, Wouters PF. Levosimendan improves right ventriculovascular coupling in a porcine model of right ventricular dysfunction. Crit Care Med. 2007;35(3):707–15.

17. Puttonen J, Kantele S, Kivikko M, et al. Effect of severe failure and haemodialysis on the pharmacokinetics of levosimendan and its metabolites. Clin Pharmacokinet. 2007;46(3):235–46.

advantages of levosimendan compared with milrinone. Namely, low-dose levosimendan has a significant ino-tropic effect, while it does not increase the incidence of arrhythmias, nor does it increase myocardial oxy-gen consumption. Levosimendan, also has a prolonged action due to its pharmacologically active metabolite OR-1896 [13, 14]. Also, its inotropic effect is not linked to increased myocardial oxygen demand or impaired myocardial relaxation [15]. To date, there is no published evidence that any other vasoactive drug except for levosi-mendan, is capable of restoring right ventriculovascular coupling by simultaneously increasing RV contractility, with significantly increased right coronary artery blood flow and reducing RV afterload [16].

Consequential to renal hypoperfusion due to RV fail-ure and high-dose vasoconstrictors, the patient had developed acute renal failure at the time of initiating levosimendan administration. The pharmacokinetic profile suggests that the dose of drug in this state can be reduced. Namely, an elimination half-life (t1/2

) of levosimendan is longer in patients undergoing hemo-dialysis compared with healthy volunteers (1.5 ± 0.09 vs 0.91 ± 0.03 h), as is the case with its metabolite OR-1896 (96.5 ± 19.5 vs 61.6 ± 5.2 h) [17]. It is important to note that in the state of severe acute right-heart failure, the admin-istration of levosimendan is all the more justified because levosimendan along with its metabolites has sustained reno-protective effects persisting up to 3 months [18]. These effects occur via vasodilatation through adenosine triphosphate-sensitive potassium channels, improve-ment in estimated glomerular filtration rate, while due to their anti-inflammatory properties it may protect against tubular injury [19]. A day after discontinuation of nor-epinephrine, i.e. 10 days after initiation of levosimendan administration, the patient was no longer dependent on renal-replacement therapy and his diuresis needed pharmacological stimulation with furosemide.

In the presented case, with regard to its hemodynamic effects in low-output states, levosimendan should have been introduced earlier in the course of therapy, in fact it should have been introduced immediately in the oper-ating theatre rather than on the third postoperative day in the ICU. Its administration reduced the need for cate-cholamine support and significantly improved RV perfor-mance after treatment. Therefore, we support the claim of Toller and Stranz. [20], on the use of levosimendan in patients with RV dysfunction during and after heart transplantation. Our therapy suggests that levosimendan could represent an advanced pharmacological option, as it has been shown in this case, where the patient’s right ventricle was severely depressed and acutely overloaded after heart transplantation.

Conflict of interestEach author certifies that they have no commercial asso-ciations that might pose a conflict of interest in regards to the submitted article.

case report

Levosimendan reverses right-heart failure in a 51-year-old patient after heart transplantation 51 3

20. Toller WG, Stranz C. Levosimendan, a new inotropic and vasodilator agent. Anesthesiology. 2006;104(3):556–69.

18. Zemljic G, Bunc M, Yazdanbakhsh AP, Vrtovec B. Levosi-mendan improves renal function in patients with advanced chronic heart failure awaiting cardiac transplantation. J Cardiac Fail. 2007;13(6):417–21.

19. Yilmaz MB, Yalta K, Yontar C, et al. Levosimendan improves renal function in patients with acute decompensated heart failure: comparison with dobutamine. Cardiovasc Drugs Ther. 2007;21(6):431–5.