Acute organ failure after heart transplantation is an extremely severe complication leading to multiorgan failure. Several theories have been proposed to explain the presentation of primary organ failure in the early postoperative period, including donor conditions, prolonged ischemia time, and acute cellular and humoral rejection (1). The therapeutical options in patients suffering from acute organ failure are limited to pharmacological or mechanical support. Pharmacological therapy with catecholamines is associated with elevated myocardial O2 consumption and potentially regional hypoperfusion leading to organ damage. Mechanical support including intra-aortic counterpulsation (IABP) and assist devices are invasive measures and therefore are associated with an increased complication rate (2).
Levosimendan is a Ca2+ sensitizer presenting a positive inotropic effect without increasing myocardial oxygen consumption. It also reduces peripheral vascular resistances by opening of ATP-dependent K+ channels.
Levosimendan has been shown to improve the outcome of patients with acute exacerbation of chronic heart failure (3, 4), with acute heart failure after myocardial infarction (5, 6), and in end-stage heart failure with associated pulmonary hypertension (7). The potential role of this drug in patients with acute graft failure after heart transplantation has not yet been described.
Case Report 1
A 17-year-old female with hypertrophic obstructive cardiomyopathy underwent heart transplantation. The donor was a 13-year-old polytraumatic injured boy. The donor organ was accepted despite a hypoxemic period at the time of explantation (Horowitz quotient 64) and thoracic trauma. After transplantation the patient needed pharmacological support with catecholamines (epinephrine 0.6 mg/h, milrinone 2.0 mg/h). The hemodynamic measurements showed a mean arterial pressure (MAP) of 74 mmHg, central venous pressure (CVP) of 13 mmHg, mean pulmonary arterial pressure (MPAP) of 29 mmHg, pulmonary capillary wedge pressure (PCWP) of 9 mmHg, cardiac index (CI) of 3.3 l/min/m2, systemic vascular resistance (SVR) of 870 dyn/sec/cm−5, and a pulmonary vascular resistance (PVR) of 290 dyn/sec/cm−5. Transesophageal echocardiography indicated a biventricular dilated heart with a severely reduced ejection fraction (EF; 25%) measured first by visual estimation and then using the modified biplane Simpson's method by two different observers; the septum showed paradoxical movements. Both ventricles had a diameter of 60 mm. The tricuspid valve presented an insufficiency II–III degree. After increasing pharmacological support, the hemodynamic and echocardiographic measurements improved but blood pressure was quickly rising to a MAP >100 mmHg. Sufficient immunosuppression was achieved by a combined tacrolimus and mycophenolate mofetil regimen. After two days, levosimendan was administered as continuous intravenous infusion for 24 hr (0.10 μg/kg·min). Thereafter, systematic echocardiographic measurements showed an improved cardiac performance. Pharmacological support was terminated within one day after treatment with levosimendan. The hemodynamic measurements revealed a MAP of 74 mmHg, a CVP of 13 mmHg, a MPAP of 19 mmHg, a PCWP of 13 mmHg, a CI of 3,0 l/min/m2, a SVR of 853 dyn/sec/cm−5, and a PVR of 190 dyn/sec/cm−5. The transesophageal echocardiography showed an ameliorated ejection fraction (55%). There were no regional wall motion abnormalities. Both ventricles had a diameter of 35 mm. The tricuspid valve presented an insufficiency I–II degrees. There was no relevant single organ failure during the hospital stay. The patient was transferred to general ward seven days after transplantation.
Case Report 2
A 65-year-old male with ischemic cardiomyopathy was transplanted. The donor was a 55-year-old female who died from subarachnoidal bleeding. The time of ischemia was 4.5 hr. After transplantation the patient needed pharmacological support with high doses of catecholamines (epinephrine 1.0 mg/h, norepinephrine 1.0, milrinone 2.0 mg/h). Additionally, prostaglandin was inhaled regularly. The hemodynamic measurements revealed a MAP of 65 mmHg, a CVP of 17 mmHg, a MPAP of 31 mmHg, a PCWP of 12 mmHg, a CI of 4.2 l/min/m2, a SVR of 379 dyn/sec/cm−5, and a PVR of 110 dyn/sec/cm−5. The transesophageal echocardiography instead showed a right ventricular dilatation with a severely reduced ejection fraction (25%); the left ventricle was hypovolemic with a good ventricular function. The right ventricle had a diameter of 62 mm; the left ventricle had a diameter of 30 mm. The tricuspid valve presented an insufficiency II–III degrees. After increasing pharmacological support the hemodynamic and the echocardiographic measurements could not be dramatically improved. Tacrolimus and mycophenolate mofetil were used as immunosuppressive regimen. After three days, levosimendan was administered as continuous intravenous infusion for 24 hr (0.10 μg/kg·min). Echocardiographic investigations performed regularly during treatment revealed an improved cardiac performance. Pharmacological support was terminated within three days after treatment with levosimendan. The hemodynamic measurements showed a MAP of 74 mmHg, a CVD of 14 mmHg, a MPAP of 23 mmHg, a PCWP of 14 mmHg, a CI of 3,0 l/min/m2, a SVR of 743 dyn/sec/cm−5, and a PVR of 176 dyn/sec/cm−5. The transesophageal echocardiography showed an ameliorated right ventricular function with an ejection fraction of EF 55%. There were no significant regional wall motion abnormalities. The right ventricle had a diameter of 38 mm. The tricuspid valve presented an insufficiency I degree. Renal failure occurred directly after transplantation, and the patient needed dialysis. The patient was transferred to general ward 12 days after transplantation.
Acute graft failure is a severe complication after cardiac transplantation, which is associated with a poor short- and long-term outcome. Different pathophysiological pathways contribute to primary heart failure after transplantation including myocardial stunning resulting from prolonged cold ischemia as well as right heart failure and arrhythmias induced from reperfusion injury or inadequate preservation (8). Donor-recipient–related factors, including suspected myocardial contusion or depressed cardiac function following brain death, may induce a primary dysfunction of the graft (9, 10).
Current treatment options include catecholamine therapy and mechanical support. Catecholamines as well as phosphodiesterase inhibitors improve cardiac performance by increasing intracellular Ca2+ concentrations, thereby raising myocardial O2 consumption and worsening stunning. Furthermore, intravenous inotropic agents may be associated with proarrhythmic effects in some patients (11), thus worsening the prognosis of patients with a depressed cardiac function after transplantation. Mechanical circulation support in acute heart failure after transplantation includes in first stage the implantation of an intra-aortic counterpulsation device. Further mechanical support in case of rapid deterioration of the patient could be achieved by the implantation of a left ventricular assist device, a continuous axial flow pump, or a biventricular assist device. All these alternatives show a high perioperative risk as well as an increased risk of hematological and neurological complications (12).
Levosimendan (Simdax; Abbot GesmbH, Vienna, Austria) is a new inotropic agent used in the treatment of acute and chronic left ventricular failure. Levosimendan, a Ca2+ sensitizer, has been shown to improve options for the treatment of acute heart failure as its mechanism of action is not affecting the oxygen consumption, being able to enhance the contractility of the myocardium by binding to cardiac troponin C (TnC). This high affinity interaction stabilizes TnC allowing a prolonged systolic interaction of actin-myosin filaments and an increase of the sensitivity of the myofilaments to calcium. The reduction of the myocardial oxygen demand may potentially decrease the myocardial damage in a compromised hemodynamic situation. Furthermore, the concomitant risk of arrhythmias related to the use of catecholamines may also be reduced as levosimendan allows a rapid reduction of these drugs. Tollner et al. suggested the use of levosimendan in patients undergoing heart transplantation (13). In the cases presented, levosimendan was able to reduce the need for catecholamine support dramatically within 24 hr after the infusion had been started. Left and right ventricular performance improved significantly after treatment. Although levosimendan proved to be useful in the treatment of our patients, further clinical studies are needed to determine its role as a therapeutical option in patients suffering from primary graft failure after heart transplantation.
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