Introduction

Tachyarrhythmias, such as atrial fibrillation (AF), ventricular tachycardia (VT), and sinus tachycardia, occur commonly in patients admitted to the Intensive Cardiac Care Unit (ICCU). Specifically, tachycardia worsens cardiac performance in patients with acute decompensated heart failure (ADHF) and cardiogenic shock (CS) by decreasing diastolic filling and increasing the oxygen demand.1, 2

Additionally, haemodynamically unstable patients frequently require inotropic support with catecholamines, which are known to induce adverse haemodynamic effects, such as excess sinus tachycardia, arrhythmias, increased oxygen demand, and afterload increase.3

Landiolol hydrochloride (Landiobloc, AMOMED Pharma, Italy) is an ultra-short-acting highly β1-selective adrenergic receptor blocker. It is similar to esmolol, but it has a greater chronotropic effect and a lesser negative inotropic effect.4

Given the results of the J-Land study, landiolol has become a milestone for rate control in AF and reduced cardiac function.5 Recently, the safety and efficacy of landiolol have been investigated in patients with recurrent haemodynamically unstable VT, despite concerns about this indication.6, 7

This report presents five cases of critically ill patients treated with a combination of inotropes and a low dose of landiolol (3–16 mcg/kg/min), admitted to our ICCU between November 2020 and May 2021.

We sought to document the safety and beneficial effect of landiolol on cardiac rhythm in patients with severe left ventricular (LV) dysfunction and ADHF deteriorating to CS.

Case report

The main baseline patient characteristics and information on catecholamines and landiolol treatment are listed in Table 1. Changes in vital, haemodynamic, and echocardiographic parameters and cardiac biomarkers after landiolol infusion are summarized in Table 2.

Table 1. Baseline patient characteristics Case no. 1 2 3 4 5 Mean ±SD or n Age, years 55 50 44 53 20 44.4 ± 14.3 Gender M M M M F M/F 4/1 Height, cm 180 180 180 175 155 174 ± 10.8 Weight, kg 120 130 74 60 50 86.8 ± 36.1 Duration HF Chronic Chronic Chronic Chronic Chronic NYHA III III III III II

NYHA III–IV 4

NYHA II 1

Clinical profile (Stevenson et al., classification) Wet and warm Wet and cold Wet and cold Wet and cold Dry and cold

Dry and cold 1

Wet and cold 3

Wet and warm 1

HR, b.p.m. 70 130 140 135 120 119 ± 28.4 SBP, mmHg 90 100 130 70 88 95.6 ± 2.1 DBP, mmHg 60 60 70 45 50 57 ± 9.8 LVEF, % 15 19 15 15 25 17.8 ± 4.4 CVP, mmHg 20 17 25 1 5 13.6 ± 10.2 ScVO2, % 60 41 43 66 72 56.4 ± 13.8 NT-proBNP, pg/mL 2465 20 000 1553 32 754 13 130 13 980.4 ± 13 004.3 Creatinine, mg/dL 1.3 3.3 0.8 1.57 1.1 1.6 ± 1 Type of arrhythmia VT/VF VT Persistent AF ST Paroxysmal AF Oral therapy before admission Beta-blockers + + + + + ACE-I/ARBs + + + + Diuretics + + + + + Aldosterone blockers + + + Amiodarone + + Inotropic therapy CAI 0 95 5 14 7 24.2 ± 40 Landiolol dose (mcg/kg/min) 10 3 9 16 6 8.8 ± 5 Duration of landiolol infusion, h 96 96 48 96 72 81.6 ± 21.5 ACE-I, angiotensin-converting enzyme inhibitors; AF, atrial fibrillation; ARBs, angiotensin receptor blockers; CVP, central venous pressure; DBP, diastolic blood pressure; HF, heart failure; HR, heart rate; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; ScVO2, central venous oxygen saturation; SD, standard deviation; ST, sinus tachycardia; VF, ventricular fibrillation; VT, ventricular tachycardia. CAI = dopamine dose (μg/kg/min) + dobutamine dose (μg/kg/min) + 100 × epinephrine dose (μg/kg/min) + 100 × norepinephrine dose (μg/kg/min) + 10 × phosphodiesterase 3 inhibitor dose (μg/kg/min). High-dose catecholamine use was defined as use of CAI > 10. Table 2. Response to intravenous treatment with landiolol Case no. 1 2 3 4 5 Mean ± SD HR, b.p.m. 60 85 90 99 66 80 ± 16.4 SBP, mmHg 110 100 120 110 100 108 ± 8.4 DBP, mmHg 60 60 70 60 50 60 ± 7 LVEF, % 25 21 35 18 25 24.8 ± 6.4 CVP, mmHg 10 5 9 1 1 5.2 ± 4.3 ScVO2, % 74 54 77 65 61 66.2 ± 9.4 NT-proBNP, pg/mL 747 6746 1284 6401 7008 4437.2 ± 3136.7 Creatinine, mg/dL 1.2 1.6 0.7 1.26 1.0 1.2 ± 0.3 Inotropic therapy CAI 0 5 0 9 3 3.4 ± 3.8 CVP, central venous pressure; DBP, diastolic blood pressure; HR, heart rate; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; SBP, systolic blood pressure; ScVO2, central venous oxygen saturation; SD, standard deviation. CAI = dopamine dose (μg/kg/min) + dobutamine dose (μg/kg/min) + 100 × epinephrine dose (μg/kg/min) + 100 × norepinephrine dose (μg/kg/min) + 10 × phosphodiesterase 3 inhibitor dose (μg/kg/min). High-dose catecholamine use was defined as use of CAI > 10. Case 1

A 55-year-old man affected by hypertrophic cardiomyopathy (CM) with ejection fraction (EF) of 45% was admitted to our ICCU with episodes of sustained VT and ventricular fibrillation (VF) with several appropriate implantable cardioverter-defibrillator (ICD) interventions. On arrival, arrhythmic storm was uncontrolled despite amiodarone infusion. Landiolol infusion was then initiated at 10 μg/kg/min, and it was rapidly effective in maintaining sinus rhythm (SR) without arrhythmic relapses. The prolonged arrhythmic storm had caused ADHF with a severe EF deterioration up to 15%. Non-invasive mechanical ventilation (NIMV) and concomitant infusion of furosemide and vasodilators were started. Landiolol was well tolerated without hypotension, and an improvement in tissue perfusion, pulmonary congestion, and EF was achieved. We also observed significantly decreased in central venous pressure (CVP), venous oxygen saturation (SvO2), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels. Four days later, a transcatheter VT ablation was successfully performed and the patient was discharged on Day 10.

Case 2

A 50-year-old patient was admitted to the ICCU with CS and pulmonary oedema. He had a known history of heart failure, classed as ‘New York Heart Association’ (NYHA) III, due to ischaemic CM with biventricular dysfunction (LVEF < 25%). Following our step-wise management algorithm of CS, we started vasoactive agents infusion (epinephrine and sodium nitroprusside) and NIMV.8 Two hours later, we deployed a trans-femoral intra-aortic balloon pump (IABP) because haemodynamics did not improve.

Continuous veno-venous haemofiltration (CVVH) was initiated due to acute kidney injury. On Day 10, a levosimendan infusion improved haemodynamics and the IABP was successfully removed. Due to his comorbidities, especially severe obesity and advanced chronic kidney disease, the patient was not eligible for a heart transplant; LV assist device implantation was also excluded because of severe right ventricular dysfunction. Therefore, the ongoing pharmacological support was gradually reduced and switched to a low dose of milrinone for palliative purposes.

However, the patient experienced further haemodynamic deterioration, complicated by recurrent sustained VT with multiple ICD interventions, refractory to amiodarone infusion. A low dose infusion of landiolol (3 mcg/kg/min) was subsequently started and successfully suppressed VT episodes without changing the systolic blood pressure (SBP). The treatment (landiolol, milrinone, and epinephrine) was continued for 96 h and was well tolerated. During landiolol infusion, we saw a significant decrease in LV filling pressure and CVP. NT-proBNP and serum lactate (lac 1.3 mmol/L) also decreased, and hepatic and kidney function slowly returned to baseline. A mild improvement in LV contractility and stroke volume index (SVi) was noted and enabled epinephrine discontinuation. On Day 21, the patient was transferred to the Cardiology Ward with the discharge plan, supported by milrinone, of palliative care.

Case 3

A 44-year-old male patient self-presented to the emergency department (ED) with pulmonary oedema in chronic heart failure (NYHA III). He was affected by non-ischaemic dilated CM with LVEF < 25% and persistent AF.

On admission to the ICU, the patient required epinephrine infusion to maintain a mean arterial pressure (MAP) > 65 mmHg. The ventricular response of his AF was >140 b.p.m., and a landiolol infusion was started at 9 mcg/kg/min and continued for 48 h. Notably, 2 h after landiolol initiation, heart rate (HR) dropped to 90 b.p.m. without hypotension. During the following 24 h, the patient's clinical conditions improved (serum lactate persistently <2 mmol/L and SvO2 > 65%, CVP 9 mmHg), enabling progressive weaning from epinephrine. NT-proBNP notably also decreased without a remarkable rise in cardiac troponin.

On the day of discharge from the ICU, a transthoracic echocardiography showed improved cardiac contractility (LVEF 39%) with accompanying severe mitral regurgitation and electrocardiogram and continuous monitoring reported permanent AF with a better ventricular response rate.

Case 4

The patient was a 53-year-old man referred to our ICCU with acute pulmonary oedema and CS. He was on the waiting list for heart transplant because of a primitive dilated CM with LVEF 20%. Due to recurrent episodes of VT, he was on antiarrhythmic treatment with mexiletine and high-dose metoprolol. Clinical examination on admission revealed severely impaired haemodynamics and multiorgan failure. NIMV, intravenous infusion of epinephrine, milrinone, and furosemide were immediately started, whereas oral treatment with metoprolol was interrupted. Re-introduction of metoprolol during CS was contraindicated due to the acute haemodynamic instability, requiring sustained inotropic support. With this vasoactive support, the patient's clinical condition progressively improved over the next 48 h, but HR progressively increased up to 135 b.p.m., leading to several inappropriate ICD shocks on sinus tachycardia. A concomitant haemodynamic deterioration occurred, with significant hypotension (SBP 70 mmHg), low cardiac index (CI; 1.7 L/min/m2), oliguria, and lactic acidosis. Therefore, intravenous continuous infusion of landiolol was initiated at 10 μg/kg/min in addition to epinephrine and milrinone. Two hours after the initiation of the landiolol infusion, HR was 110 b.p.m. and an improvement in haemodynamics was observed. During the next few days, as landiolol was titrated to 16 μg/kg/min, HR decreased to 80 b.p.m., while CI improved up to 3 L/min/m2 and the epinephrine dosage was reduced. The landiolol infusion was continued for 96 h and a remarkable reduction in NT-proBNP and plasma creatinine was achieved. Because the patient was still dependent on inotropic support, he was then implanted with a paracorporeal LV assist device as a bridge to heart transplantation.

Case 5

A 20-year-old woman was referred to the ICCU with ADHF. Her cardiovascular history begun 2 years prior when she was diagnosed with non-obstructive hypertrophic CM and Wolff–Parkinson–White syndrome, as a pattern of Danon disease. The patient rapidly deteriorated; consequently, she was placed on the waiting list for heart transplant. On arrival, an atrial rhythm at HR of 100–130 b.p.m. with frequent episodes of atrioventricular nodal re-entrant tachycardia at 160 b.p.m. and concomitant hypotension (SBP 85 mmHg) were noted. Amiodarone infusion was ineffective and the patient rapidly deteriorated to a low cardiac output syndrome. Echocardiography showed biventricular hypertrophy with severe dysfunction and low estimated SVi (20 mL/m2). Intravenous infusion of a medium-dose epinephrine and a low-dose landiolol (6 μg/kg/min) was started. Two hours after landiolol initiation, SR was restored. The concomitant infusion of landiolol and epinephrine was well tolerated without recurrence of prolonged episodes of supraventricular tachycardia and with an improvement in SVi to 30 mL/m2. Laboratory tests also revealed lower NT-proBNP levels and a rise in SvO2, associated with improved tissue perfusion. Consequently, a progressive reduction of the epinephrine dosage was possible. Five days after ICCU admission, the patient was dependent on inotropes, but still stable. Heart transplant was performed on Day 45.

Discussion

In this report, five patients with refractory tachyarrhythmias during ADHF and CS were successfully treated with a continuous infusion of landiolol.

Tachycardia significantly limits the cardiovascular capacity in severe LV dysfunction and heart failure by shortening the diastolic filling period and decreasing SVi. In addition, it increases intracellular cardiomyocyte Ca2+ handling, contributing to further LV dysfunction.9

Additionally, despite stabilizing haemodynamics, ventricular–arterial (V–A) decoupling may persist in patients with CS.3, 10 This decoupling is further exacerbated both by an increase in afterload through the administration of inotropes/vasoconstrictor agents and by tachycardia.11

Given the side effects of adrenergic stimulation (tachyarrhythmias, increased cardiac oxygen consumption, and immune dysregulation), ‘breaking’ the adrenergic stressors with β-blocking could help to stabilize the cardiovascular function, although it may initially sound contradictory.

Bearing in mind that arterial elastance is related to HR and total peripheral resistances, β-blockade leads to both reduced afterload and prolonged duration of diastole (caused by HR reduction), which in turn allows increased LV filling, resulting in an increased stroke volume.

We believe that this physiological rationale is an indispensable prerequisite for the introduction of landiolol with optimized CS therapy.

The use of beta-blockers frequently results in rapid hypotension due to their negative inotropic activity. However, the highly β1 selectivity of landiolol allowed the maintenance of relative stable systolic and diastolic BP values, even in patients who received higher doses (9–16 μg/kg/min). Landiolol, compared with other beta-blockers, presents faster pharmacokinetics, higher potency, and cardioselectivity (β1/β2-selectivity 255:33) with less potent negative inotropic effect. These characteristics make it suitable to manage arrhythmias in critical patients without further deterioration of the cardiac function.

In our patients, landiolol infusion was effective in either restoring SR or reducing HR, as shown in Figure 1A. Interestingly, in three cases, approximately 120 min after landiolol infusion, tachyarrhythmias were converted to SR, emphasizing its potential role in this scenario. In all cases, the infusion was well tolerated and hypotension did not occur (Figure 1B). Conversely, HR reduction increased LV stroke volume, leading to a global haemodynamic improvement, which enabled a reduction in the infused catecholamine dose (Figure 1C).

Changes in heart rate (HR, Panel A), systolic blood pressure (SBP, Panel B), and dose of epinephrine (Panel C) during landiolol infusion in the patients studied.

In accordance with other recent studies, the combination therapy of landiolol and milrinone improved cardiac function and decreased HR for two of the patients studied.12, 13

Conclusions

Based on our observations and current evidence, we suggest that the combination of inotropes/vasoconstrictor agents and a low dose of landiolol may be a new option to manage tachycardias and tachyarrhythmias in patients with CS, without any negative impact on cardiac function.7, 14 However, the positive haemodynamic effects (increase in SVi or LVEF) were still presumably driven mainly by inotrope support rather than landiolol administration.