CASE REPORT Successful Combination of Landiolol and Levosimendan in Patients with Decompensated Heart Failure A Report of 3 Cases Wojciech Dabrowski,1 MD, Dorota Siwicka-Gieroba,1 MD, Ewa Piasek,1 MD, Todd T Schlegel,2,3 MD and Andrzej Jaroszynski,4 MD Summary Tachycardia and supraventricular tachyarrhythmias often impair cardiovascular capacity in patients with de- compensated heart failure (dHF) treated with inotropes. Normalization of heart rhythm or rate typically im- proves diastolic filling and stroke volume (SV). Thus, isochronal administration of an ultra-short-acting and highly selective β1-blockers, such as landiolol, along with inotropic calcium-sensitizer medications, such as levosimendan, could benefit patients with dHF. We present a case series of three patients with severe dHF and low ejection fraction who were successfully treated with a combination of landiolol and levosimendan. The co-administration of landiolol and levosimendan was well tolerated, improved cardiac function, normalized SV, and enabled the reduction of norepinephrine dos- ing in all patients. Additionally, the combination improved the vectorcardiographic spatial QRS-T angle and de- creased the corrected QT interval. All patients were successfully discharged from the intensive care unit (ICU). A combination of levosimendan and landiolol was safe and well-tolerated. This combination may be a new option for successful treatment of patients with acute dHF complicated by sinus or supraventricular tachycar- dias. (Int Heart J 2020; 61: 384-389) Key words: Critically ill, Cardiac tachyarrhthmias, Sepsis, Spatial QRS-T angle, Corrected QT interval achycardias including supraventricular tachyar- dences of atrial fibrillation and tachycardia, whereas oth- rhythmias such as atrial fibrillation are frequently ers suggest that the incidence of ventricular arrhythmias observed in patients with decompensated heart following treatment with levosimendan is no different T 1,2) 9,10) failure (dHF), increasing the risk of mortality. The de- from that with other medications used in dHF. One ex- velopment of atrial tachyarrhythmia is often associated perimental study also showed a severe proarrhythmic ef- with an irregular ventricular rhythm and an absence of an fect of levosimendan, its administration increasing the in- atrial kick, leading to a decrease in cardiac output with ducibility of life-threatening arrhythmias in a dose- consequent worsening of cardiac hemodynamic func- dependent manner.11) Levosimendan also tends to prolong tion.1-5) Therefore, the normalization of heart rhythm or the rate-corrected QT interval in healthy volunteers, al- rate can often play a crucial role in the correction of car- though such an effect has not always been observed in pa- diac dysfunction. Some of the medications frequently used tients with heart failure treated with therapeutic doses.12) in patients with dHF failure also commonly induce tachy- Therefore, some authors have suggested a combination of cardia. levosimendan and β-blockers, particularly in patients with Levosimendan is a calcium-sensitizing inotropic a tendency to tachyarrhythmia.13,14) agent that increases cardiac contractility without increas- Landiolol is a new, ultra-short-acting β1-receptor an- ing oxygen consumption.6) It also presents an anti- tagonist useful for both treatment and prevention of su- stunning and anti-ischemic effect via the opening of the praventricular tachyarrhythmias. Landiolol at the dose of KATP channels in cardiac mitochondria, potentially decreas- 1-10 μg/kg/minute is also more effective than digoxin in ing mortality.7) Levosimendan is recommended by the controlling the ventricular response rate during atrial fib- European Society of Cardiology for patients with acute rillation in patients with heart failure.15) Several studies dHF.8) However, some studies have documented that treat- have documented its beneficial effect on cardiac rhythm in ment with levosimendan is associated with higher inci- patients with severe acute heart failure and tachycar- From the 1Department of Anaesthesiology and Intensive Care Medical University of Lublin, Poland, 2Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden, 3Nicollier-Schlegel SARL, Trélex, Switzerland and 4Department of Nephrology, Institute of Medical Science, Jan Kochanowski University of Kielce, Poland. Address for correspondence: Wojciech Dabrowski, MD, Department of Anaesthesiology and Intensive Care Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland. E-mail: [email protected] Received for publication August 15, 2019. Revised and accepted October 25, 2019. Released in advance online on J-STAGE March 4, 2020. doi: 10.1536/ihj.19-420 All rights reserved by the International Heart Journal Association. 384 IntHeartJ March 2020 LANDIOLOL AND LEVOSIMENDAN IN THE CRITICALLY ILL 385 dia.16-18) Landiolol restores stroke volume (SV) in septic shock and decreases stroke volume variation, probably be- cause of a decrease in the difference between maximum and minimum SV during breathing.17,18) Based on these ac- tions, we can assume that a combination of a strong inotropic agent, such as levosimendan, and the ultra- selective β1-blocker landiolol may improve cardiac hemo- dynamic function by increasing cardiac output (CO) via improved ventricular filling following the correction of heart rhythm and/or rate. In this study, we report cases of three patients treated with a combination of levosimendan and landiolol for severe shock with tachyarrhythmia. Case Reports In all cases, hemodynamic parameters were measured for all three presented patients, including this patient, us- ing an EV 1000 platform (Edwards Lifesciences, Irvine, CA, USA) that also incorporates thermodilution. Spatial QRS-T angle and corrected QT (QTc) intervals were also automatically calculated in the same patients, by using a Cardiax computerized 12-lead electrocardiographic system (IMED, Budapest, Hungary), as previously described.19) The results of all measurements for all three patients, per- formed each morning for 5 serial days, are presented in Figure 1. Case 1: A 70-year-old woman (78 kg) was admitted to the intensive care unit (ICU) with critical acute cardiac failure and left ventricular ejection fraction (LVEF) < 25% complicated by pulmonary edema. This case was included within a larger prospective observational study, performed at the First Clinic of Intensive Care at the Medical Uni- versity of Lublin, Poland (KE-0254/172/2019). Patient was mechanically ventilated with FiO2 0.7 and PEEP + 10 cmH2O. Ten days before admission to the ICU, she had undergone coronary artery bypass surgery (CABG) with extracorporeal circulation for acute coronary symptoms. Her comorbidities included hypertension and type II dia- betes. The cardiac surgery was uncomplicated, and the pa- tient required dobutamine infusion from the end of extra- corporeal circulation to the 8 postoperative hour. Doses of dobutamine were gradually reduced from 7 μg/kg/min. The postoperative period was also without serious compli- cations. A day before the admission into ICU, tachycardia with severe suffocation and rapid decrease in arterial oxy- gen tension to 58 mmHg were noted. The patient required oxygen supplementation with oxygen face-mask, and she was then intubated and mechanically ventilated with 70% of oxygen. The patient was admitted into cardiac- postoperative intensive care and received an initial dose of amiodarone at 5 mg/kg/1 hour, continuing by 0.01 mg/kg/ min. The norepinephrine infusion was started to maintain mean arterial blood pressure (MAP) between 60-70 mmHg. The treatment with amiodarone was unsuccessful. A coronary angiogram was performed just before admis- sion to ICU and the presence of important disorders in Figure 1. Changes in heart rate (HR), cardiac index (CI), stroke vol- ume index (SVI), dose of norepinephrine, and vectorcardiography blood flow were excluded. Hemodynamic measurements variables such as spatial QRS-T angle and corrected QT (QTc) interval showed low cardiac index (CI) (Figure 1) with high ex- in studied patients. The observations were made at five time points: 5 travascular water index (ELWI = 13.8 mL/kg). Systemic min before treatment with a combination of landiolol and levosimen- vascular resistance index (SVRI = 2776 dyne-s-m2/cm5) dan, and 24, 48, 72, and 96 hours after the beginning of treatment. was maintained with continuous norepinephrine infusion IntHeartJ 386 DABROWSKI, ET AL March 2020 at 0.41 μg/kg/minute, with MAP being maintained be- antibiotic therapy was started. Based on KIDIGO criteria, tween 60 and 70 mmHg. Laboratory measurements acute kidney injury with anuria was diagnosed and con- showed high plasma troponin I concentration (529 ng/L) tinuous renal replacement therapy was started. Laboratory and N-terminal fragment of prohormone B-type natriuretic studies showed high plasma procalcitonin concentration peptide (Nt-proBNP = 14,931 pg/mL). Immediately after (PCT = 32 ng/mL), high Nt-proBNP (6520 pg/mL), and admission to the ICU, the patient received an intravenous leukocytosis (WBC = 17,200/mL). Transthoracic echocar- infusion of dobutamine at 9 μg/kg/minute. The dobu- diography showed global impaired cardiac contractility tamine infusion did not improve CI, but increased tachyar- with an LVEF of ~20%. Based on clinical symptoms and rhythmia. Diuresis was maintained by continuous fu- hemodynamic findings, intravenous infusion of levosimen- rosemide (Furosemide, Polfa, Pl) infusion