Introduction

Most inotropes used in the clinics function by increasing the levels of cytosolic calcium (Ca⁺²), whereas levosimendan (LS) stimulates myocardial contractility without raising the intracellular Ca⁺² concentration [₁₂]. LS increases the Ca⁺² response to myofilament by binding to cardiac troponin C. As a result, myocardial contraction increases without a higher myocardial O₂ consumption [₂₃₄]. LS also exhibits vasodilator effect through the activation of adenosine triphosphate-dependent potassium (K⁺) channels [₅₆]. LS is distinguished from other inotropic agents by this dual mechanism and considered as a good choice in high-risk patients undergoing cardiac surgery.

LS, a new inodilator used in the treatment of decompensate heart failure, has been reported to be effective in patients with high perioperative risks, with abnormal left ventricular function, and who face difficulties in weaning off cardiopulmonary bypass [₂].

Cause of its many beneficial effects, the use of LS in cardiac surgery arises. However, experiences about the use of LS in pediatric patients are limited. We aimed to report our LS administration in a case of 3 years old child who developed heart failure during cardiopulmonary bypass removal period.

Case presentation

A 3 years old, 11 kg female child was admitted to our center who had a total revision of tetralogy of Fallot four months ago. Any postoperative complaints or symptoms were not present since we find out a large progressive aneurysm in the echocardiographic evaluation of the otogen pericardial patch which was prepared with gluteraldehide.

The laboratory blood tests, including platelet count, protrombin time, activated partial tromboplastin time were normal. The patient’s chest X-ray and electrocardiography were normal also. The echocardiography reported; EF was 74 % and LV diameters were 22/13mm, pulmonary valvular infindubular stenosis. The patient was given 0.5 mg/kg midazolam per oral for premedication.

Preoperative TA: 100/70mmHg, HR: 100 pulse per min, sat O2: 98%. Before the initiation of anesthesia 200ml Isolex-P was given by intravenous infusion. In the operating room noninvasive blood pressure, pulse oximetry and three lead electrocardiograms (ECG) monitorization was provided. Induction of anesthesia was done with 2 mg/kg ketamin and 0.5mg/kg atracurium, 20 µg/kg atropine was administered also. After endotracheal entubation, invasive blood pressure of the left radial artery and central venous pressure monitoring of the right internal jugular vein was successfully. After the excision of the pericardial patch the repair of the right ventricular outflow was done with e-PTFE graft. At the end of cardiopulmonary bypass (CPB) surgery deep hypotension occurred. In spite of dopamine (15 µg/kg/min), dobutamine (15 µg/kg/min) and adrenalin (1mg/h) infusions, myocardium failed to maintain normotension. Diuresis was suboptimal in our patient also. Upon these LS infusion was started with the loading dose of 12 µg/kg over 10 minutes. Later, 0.2 µg/kg/min maintenance dosage was applied. In an hour we observed 200cc diuresis and the vital signs were taken under control. LV infusion was completed after 24 hours postoperatively in our intensive care unit. Six hours later we started to reduce the analogous inotropic support (dopamine 10µg/kg/min, dobutamine 10µg/kg/min, adrenalin 0.5mg/h) since the hemodynamic parameters were satisfactory. Twelve hours later another reduction was applied. Since the well tolerance of the myocardium we were able to stop the other inotropic drug infusions after 48 hours and the patient was discharged from the hospital 10 days after the surgery.

Discussion

LS has superior pharmacologic features when compared to conventional inotropic agents. Dobutamine increases cAMP production by stimulating cardiac β receptors, and leads to signals which trigger the increase of intracellular Ca⁺² levels. Increase in Ca⁺² levels produce a positive inotropic effect by stimulating cardiac contractile proteins. Besides its effectiveness in the treatment of decompensation symptoms, side effects of dobutamine, such as greater myocardial O₂ consumption, arrhythmia possibility, tachyphylaxis, and drug dependency, carry hemodynamic risks. It is also advisable not to administer dobutamine together with β-blockers [₁₂₇₈]. Like dobutamine, dopamine also exhibits a positive inotropic effect on the myocardium by stimulating the β₁-adrenergic receptors. However, contrary to dobutamine, dopamine exerts an additional indirect effect by releasing stored noradrenalin. In low doses, it leads to diuresis by stimulating the renal dopamine receptors, while in high doses it causes vasoconstriction by stimulating α-receptors. Dopamine may lead to tachycardia and arrhythmias [₁₂₉]. Catecholamines like epinephrine and isoproterenol may also generate a risk for increases in myocardial O₂ consumption, heart rate and after-load, as well as arrhythmia through similar action mechanisms. On the other hand, phosphodiesterase inhibitors such as amrinone, milrinone and enoximone inhibit the enzyme which facilitates the breakdown of cAMP and thereby increase the intracellular Ca⁺². Similarly to β-adrenergic agonists, they increase the levels of cAMP, which is a second intracellular messenger with inotropic effects on the heart. In some patients, phosphodiesterase inhibitors have been reported to trigger tachycardia, arrhythmia and tolerance, and most probably increase mortality associated with higher intracellular Ca⁺² levels compared to placebo [₁₂₈].

LS enhances the sensitivity of myofilaments to calcium during cardiac systole by calcium dependent binding to troponin C. This interaction strengthens the actin-myosin cross-bridges through the stabilization of calcium-induced conformational changes in tropomyosin. LS accomplishes this effect by enhancing the intracellular Ca⁺² sensitivity of troponin C without increasing the intracellular Ca⁺² concentrations [_210111213]. Since LS does not increase intracellular Ca⁺² levels, its arrhythmogenic potential is reported to be low [₂₁₄]. The hemodynamic effects of LS were found to be higher in patients who used β-blockers. Its superiority over other inotropic agents can also be evidenced with this feature [₁₅].

Over the past years, there have been a growing number of patients who underwent cardiac surgery with high perioperative risks or with left ventricular disorders. This condition led to an increase in the use of vasodilators and inotropic support in order to correct tissue perfusion during the perioperative period or support the weaning off from cardiopulmonary bypass. As mentioned above, conventional use of inotropic agents like epinephrine, dobutamine and milrinone during the perioperative period is limited for myocardial O₂ consumption due to proarrhythmia or significant increases in neurohormonal activation. LS, a new inodilator used in the treatment of decompensate heart failure, has been reported to be effective in patients with high perioperative risks, with abnormal left ventricular function, and who face difficulties in weaning off cardiopulmonary bypass [₂].

There are so many reports of LS use in adult patients. However, experiences about the use of LS in paediatric patients are limited.

Namachivayam P et all [₁₆] observed 15 children aged between 7 days to 18 years old retrospectively. The patients had myocardial dysfunction despite taking inotrop drug infusions. 11 of these children were given a single dose, 3 of them were given 2 repeated doses and 1 of them was given 4 repeated doses of LS. In the following days the inotropic support of 10 children was stopped and that of 3 was reduced. They reported that the ejection fractions increased from 29.8% to 40.5% but there were no significant impairment those of whom had end stage heart failure before the infusions. But the fractions of the children with acute heart failure increased by 63%.

They concluded that LS can be safely administered to infants and children with severe heart failure. LS allowed for substantial reduction in catecholamine infusions in children with end-stage or acute heart failure and also produced an objective improvement in myocardial performance in children with acute heart failure.

Egan JR et al. [₁₇] reported a retrospective study in their pediatric intensive care unit in which 19 patients with low cardiac output who underwent cardiopulmonary bypass surgery and were administered LS. They observed that using LS reduced arteriyel lactate levels, improved the hemodynamic data, increased the mean arterial pressure and reduced conventional inotrop drug use. And as a conclusion they reported LS as a safe drug in pediatric patients.

Turanlathi M and et al. [₁₈] evaluated the pharmacokinetics, hemodynamic effects, and safety of LS in children with congenital heart disease. Thirteen children between the ages of 3 months and 7 yrs coming for preoperative cardiac catheterization were enrolled into their study. All children received 12 µg/kg LS as an intravenous infusion given over 10 min during the catheterization. The pharmacokinetic profile of LS in children with congenital heart disease was similar to that in adult patients with congestive heart failure. The minimal hemodynamic efficacy after the 12 µg /kg LS bolus was probably due to a small dose relative to body surface area.

In our case we achieved correlative evidence with the studies shown above. We observed that LV which has a very extensive use in adult patients could be used successfully in selected pediatric cases.

In conclusion; our clinical experiences with LS has shown that it reduces conventional inotropic agents dosages and could be a satisfactory agent in myocardial depression therapy which occurred in CPB surgery intraoperatively also in pediatric patients. However the need for serial randomized controlled studies in pediatric patients about the use of LS is indisputable.

Correspondence to

Uzm.Dr.Murat AKSUN Erzene Mah. 116/10 Sok. No:7/11 Bornova-İZMİR/TURKEY Tel: 0552 3631614 – Fax:0232 2434848 e-mail= murataksun@yahoo.com