Landiolol Infusion Research Articles

Landiolol for refractory ventricular fibrillation in out-of-hospital cardiac arrest: A randomized, double-blind, placebo-controlled, pilot trial

BackgroundOut-of-hospital cardiac arrest (OHCA) complicated by refractory ventricular fibrillation (VF) is associated with poor outcome. Beta-1-receptor selective blockade might overcome refractory VF and improve survival. This trial investigates the efficacy and safety of prehospital landiolol in OHCA and refractory VF. MethodsIn this randomized, double-blind, placebo-controlled pilot trial, patients with OHCA and recurrent or refractory VF (at least 3 defibrillation attempts and last rhythm shockable), pretreated with epinephrine and amiodarone, were allocated to receive add-on treatment with landiolol or placebo. Landiolol was given as a 20 mg bolus infusion. The primary efficacy outcome was time from trial drug infusion to sustained return of spontaneous circulation (ROSC). Safety outcomes included the onset of bradycardia and asystole. ResultsA total of 36 patients were enrolled, 19 were allocated to the landiolol group and 17 to the placebo group. Time from trial drug infusion to sustained ROSC was similar between treatment groups (39 min [landiolol] versus 41 min [placebo]). Sustained ROSC was numerically lower in the landiolol group compared with the placebo group (7 patients [36.8%] versus 11 patients [64.7%], respectively). Asystole within 15 min of trial drug infusion occurred significantly more often in the landiolol group than in the placebo group (7 patients [36.8%] and 0 patients [0.0%], respectively). ConclusionIn patients with OHCA and refractory VF who are pretreated with epinephrine and amiodarone, add-on bolus infusion of landiolol 20 mg did not lead to a shorter time to sustained ROSC compared with placebo. Landiolol might be associated with bradycardia and asystole.

#2545 Hemodialysis for salbutamol intoxication: patient case report

Abstract Background and Aims Salbutamol/albuterol is a moderately selective beta-2-adrenergic receptor agonist that acts as an airway smooth muscle relaxant. It is used to prevent and treat acute bronchospasm in various respiratory conditions. Due to its large volume of distribution, it is not considered dialysable. Method This is a clinical case report of inadvertent parenteral administration of salbutamol resulting in acute intoxication. Salvage renal replacement therapy was implemented due to the severity of the patient's clinical condition and the large amount of salbutamol administered. Multiple plasma measurements of salbutamol were taken during hemodialysis, allowing for a correlation to be made with the patient's clinical presentation. Results This case report presents an elderly patient with sepsis, Down syndrome, and liver cirrhosis. The patient required non-invasive ventilation due to worsening respiratory failure and was prescribed intravenous methylprednisolone. However, the patient inadvertently received 5mg of parenteral salbutamol (albuterol), which resulted in immediate severe arrhythmic tachycardia followed by hemodynamic collapse. After unsuccessful cardioversion and treatment with landiolol infusion, salvage hemodialysis was initiated to reduce the suspected highly elevated serum salbutamol levels. After 30 minutes, sinus rhythm with normocardia was observed. No rebound tachycardia was noted after the hemodialysis termination. However, due to severe septic shock, hypotension persisted, and vasoactive medications were adjusted. However, the measured levels of plasma salbutamol do not support the view that hemodialysis was the cause of the described improvement. The total amount of the drug cleared was exceedingly small, only 2.8% of the total dose. Data from the literature support our findings, even in the case of the life-threatening intoxication described. Conclusion The results confirm a large volume of distribution for salbutamol. The measured half-life time during hemodialysis (3.1 hours) is comparable to observed half-life times in therapeutic settings. The observed clinical benefit associated with dialysis appears to be fortuitous. This case report highlights the potential bias towards positive clinical outcomes and unproven therapies.

Landiolol and Organ Failure in Patients With Septic Shock

Patients with septic shock undergo adrenergic stress, which affects cardiac, immune, inflammatory, and metabolic pathways. β-Blockade may attenuate the adverse effects of catecholamine exposure and has been associated with reduced mortality. To assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (>24 hours) vasopressor support. An open-label, multicenter, randomized trial involving 126 adults (≥18 years) with tachycardia (heart rate ≥95/min) and established septic shock treated for at least 24 hours with continuous norepinephrine (≥0.1 μg/kg/min) in 40 UK National Health Service intensive care units. The trial ran from April 2018 to December 2021, with early termination in December 2021 due to a signal of possible harm. Sixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion. The primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group. The trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled (mean age, 55.6 years [95% CI, 52.7 to 58.5 years]; 58.7% male). The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, -0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, -4.4% to 27.8%]; P = .16). Mortality at day 90 after randomization was 43.5% (27 of 62) in the landiolol group and 28.6% (18 of 63) in the standard care group (absolute difference, 15% [95% CI, -1.7% to 31.6%]; P = .08). There were no differences in the number of patients having at least one adverse event. Among patients with septic shock with tachycardia and treated with norepinephrine for more than 24 hours, an infusion of landiolol did not reduce organ failure measured by the SOFA score over 14 days from randomization. These results do not support the use of landiolol for managing tachycardia among patients treated with norepinephrine for established septic shock. EU Clinical Trials Register Eudra CT: 2017-001785-14; isrctn.org Identifier: ISRCTN12600919.

Managing postoperative atrial fibrillation after open-heart surgery using transdermal β1 blockers

BackgroundPostoperative atrial fibrillation (POAF) after open-heart surgery is a non-negligible complication. We aimed to describe the efficacy of a transdermal patch of bisoprolol for managing POAF and flutter in thoracic surgical procedures.MethodsWe analyzed the data of 384 patients who underwent open-heart surgery at our hospital and received oral bisoprolol to prevent POAF. Among them, 65 patients (16.9%) also received a 4-mg transdermal patch of bisoprolol to control the heart rate due to POAF. We applied the bisoprolol transdermal patch when the heart rate was > 80 bpm and removed it at ≤ 60 bpm; an additional patch was applied when the heart rate was > 140 bpm. Heparin calcium injections were administered twice daily for anticoagulation between 2 and 6 days postoperatively.ResultsThe average number of prescriptions for transdermal patches of bisoprolol during hospitalization was 1.8 ± 1.1 (1–5). The median first prescription date was on postoperative day 2 (range: days 0–37). Sinus rhythm recovered within 24 h in 18 patients (27.7%). Eight patients (12.3%) were switched to continuous landiolol infusion because of persistent tachycardia. In three patients, the transdermal patch was removed owing to severe bradycardia. Fifteen patients experienced persistent atrial fibrillation and were treated with electrical cardioversion during hospitalization. We did not observe any serious complications that could be directly attributed to bisoprolol transdermal patch use.ConclusionsSingle-use bisoprolol transdermal patch may help control the heart rate during the initial treatment of POAF after open-heart surgery.

Heart rate control with landiolol hydrochloride in infants with ventricular dysfunction and pulmonary hypertension.

Sinus tachycardia potentially leads to a deterioration of cardiac function in critically ill infants. The ultrashort-acting beta-blocker landiolol hydrochloride is a new pharmacological option for a selective heart rate (HR) control in patients with sinus tachycardia and heart failure. This study was a monocentric retrospective medical chart review study at the University Children's Hospital Bonn (Germany) from 01 January 2018 until 30 June 2020. This study included a cohort of 62 term and preterm infants with a diagnosis of ventricular dysfunction and/or pulmonary hypertension (PH), in combination with preexisting tachycardia and treatment with landiolol hydrochloride. Infants were allocated to subgroups according to weeks of gestational age (GA): born at <35weeks of GA (Group A) and born at >35weeks of GA (Group B). Tachycardia was defined depending on GA (<35weeks of GA: >170b.p.m.; 35weeks of GA: >150b.p.m.). The primary endpoint was defined as percentage of patients achieving HR normalization during the first 24h of landiolol treatment. Twenty-nine infants were allocated to Group A and 33 infants to Group B. The overall median GA of the infants was 35.3 (23.3/41.3), with 53% female infants. The primary endpoint was achieved in 57 patients (91.9%). The median time to reach target HR was 1.8 (0.3-24) h. The median starting dose of landiolol was 8.8 (3.9-25.3) μk/kg/min, with a median dosing during the first 24h of landiolol treatment of 9.9 (2.8-35.4) μk/kg/min. The median landiolol dose while achieving the target HR was 10 (2.4-44.4) μk/kg/min. The right ventricular dysfunction improved significantly in both groups 24h after onset of landiolol infusion (P=0.001 in Group A and P=0.045 in Group B). The left ventricular and biventricular dysfunction improved significantly 24h after onset of landiolol infusion in infants of Group B (P=0.004 and P=0.006, respectively). The severity of PH improved significantly after 24h in infants of Group A (P<0.001). During landiolol treatment, no severe drug-related adverse event was noted. The use of landiolol hydrochloride for HR control of non-arrhythmic tachycardia in critically ill infants is well tolerated. Reduction of HR can be guided quickly and landiolol treatment is associated with an improvement of ventricular dysfunction and PH.

Short acting intravenous beta-blocker as a first line of treatment for atrial fibrillation after cardiac surgery: a prospective observational study.

Post-operative atrial fibrillation (POAF) defined as a new-onset of atrial fibrillation (AF) following surgery occurs frequently after cardiac surgery. For non-symptomatic patients, rate control strategy seems to be as effective as rhythm control one in surgical patients. Landiolol is a new highly cardio-selective beta-blocker agent with interesting pharmacological properties that may have some interest in this clinical situation. This is a prospective, monocentric, observational study. All consecutive adult patients (age >18 years old) admitted in the intensive care unit following cardiac surgery with a diagnosed episode of AF were eligible. Success of landiolol administration was defined by a definitive rate control from the beginning of infusion to the 72th h. We also evaluated rhythm control following landiolol infusion. Safety analysis was focused on haemodynamic, renal and respiratory side effects. From 1 January 2020 to 30 June 2021, we included 54 consecutive patients. A sustainable rate control was obtained for 49 patients (90.7%). Median time until a sustainable rate control was 4 h (1, 22). Median infusion rate of landiolol needed for a sustainable rate control was 10 µg/kg/min (6, 19). Following landiolol infusion, median time until pharmacological cardioversion was 24 h. During landiolol infusion, maintenance of mean arterial pressure target requires a concomitant very low dose of norepinephrine. We did not find any other side effects. Low dose of landiolol used for POAF treatment was effective and safe for a rapid and sustainable rate and rhythm control after cardiac surgery.

Effects of Landiolol on Macrocirculatory Parameters and Left and Right Ventricular Performances Following Cardiac Surgery: A Randomized Controlled Trial

Postoperative atrial fibrillation (POAF) is a major complication after cardiac surgery, and an early postoperative introduction of beta-blockers is recommended to reduce its incidence. Landiolol, a new intravenous short-acting beta-1 blocker, could present a useful and safe macrohemodynamic profile after cardiac surgery. Detailed metabolic and hemodynamic effects of landiolol on cardiac performance, however, remain poorly documented. The authors aimed to investigate the dose-dependent hemodynamic and metabolic effects of landiolol in that specific setting. A prospective, randomized, double-blind study versus placebo. A tertiary university hospital. Adult patients scheduled for elective cardiac surgery with cardiopulmonary bypass. Incremental doses of intravenous landiolol (0.5, 1, 2, 5, and 10 μg/kg/min) were given within the 2 hours after arrival in the intensive care unit. Macrocirculatory parameters and cardiac performances were derived from transpulmonary thermodilution and transthoracic echocardiography. Metabolic data were obtained from arterial blood tests. From January to November 2019, 58 patients were analyzed and divided into a landiolol group (n=30) and a control group (n=28). Heart rate significantly decreased in the landiolol group (p < 0.01), whereas mean arterial pressure and stroke volume remained unchanged. No significant modification was found in both left and right systolic and diastolic performances. Metabolic variables were similar in both groups. New-onset POAF occurred in 9 (32%) versus 5 (17%) patients in the control and landiolol groups, respectively (p=0.28). Infusion of landiolol in the range of 0.5-to-10 μg/kg/min during the early postoperative period presents a good macrohemodynamic safety profile in cardiac surgical patients and could be useful to prevent POAF.

Safety and Efficacy of Landiolol Hydrochloride in Children with Tachyarrhythmia of Various Etiologies

The safety and efficacy of landiolol have not been fully elucidated in pediatric patients. This study aimed to clarify the safety and efficacy of landiolol in a pediatric cohort. We retrospectively assessed the clinical features of 21 pediatric patients who were administered landiolol at our hospital. We also investigated the rates of sinus rhythm conversion and heart rate response. The median patient age was 7 months (interquartile range 1–13 months). The etiology of tachyarrhythmia was junctional ectopic tachycardia in 10 patients (47.6%), atrial tachycardia in 10 patients (47.6%), and ventricular tachycardia in 1 patient (4.8%). Of the 21 children, 18 (85.7%) had congenital heart defects, including 14 (77.8%) in whom a landiolol infusion was performed perioperatively. The landiolol infusion was effective in 18 pediatric patients (85.7%), as measured by the conversion to sinus rhythm or a reduced heart rate. Atrial tachycardia in the perioperative period was terminated in all patients. Of 7 patients with tachyarrhythmias unrelated to the perioperative period, landiolol was effective in 5. No adverse effects were reported in any patient. Landiolol infusion is effective and safe in pediatric patients with tachyarrhythmia of various etiologies, especially those with atrial tachyarrhythmia during the perioperative period.

Pharmacodynamic and pharmacokinetic behavior of landiolol during dobutamine challenge in healthy adults

BackgroundTo study the pharmacokinetic and -dynamic behavior of landiolol in the presence of dobutamine in healthy subjects of European ancestry.MethodsWe conducted a single-center, prospective randomized study in 16 healthy subjects each receiving an infusion of dobutamine sufficient to increase heart rate by 30 bpm followed by a 60 min infusion of 10 μg/kg/min landiolol.ResultsDobutamine-induced increases in heart rate were stable for at least 20 min before a 60 min landiolol- infusion was started. The dobutamine effects were rapidly antagonized by landiolol within 16 min. A further slight decrease in heart rate during 20–60 min of the landiolol infusion occurred as well. Upon termination of landiolol infusion, heart rate and blood pressure recovered rapidly in response to the persisting dobutamine infusion but did not return to the maximum values before landiolol infusion. The pharmacokinetic parameters of landiolol in presence of dobutamine showed a short half-life (3.5 min) and a low distribution volume (0.3 l/kg). No serious adverse events were observed.ConclusionLandiolol can antagonize the dobutamine-induced increases in heart rate and blood pressure in a fast way. A rapid bradycardic effect until steady-state plasma levels is followed by a slow heart rate reduction. The latter can be attributed to an early desensitization to dobutamine. Consequently, after termination of landiolol, the heart rate did not achieve maximum pre-landiolol values. The pharmacokinetics of landiolol during dobutamine infusion are similar when compared to short- and long-term data in Caucasian subjects. Landiolol in the given dose can thus serve as an antagonist of dobutamine-induced cardiac effects.Trial registrationRegistration number 2010–023311-34 at the EU Clinical Trials Register, registration date 2010-12-21.

Efficacy of early intravenous landiolol, an ultrashort-acting beta-blocker on infarct size and its safety in patients with myocardial infarction undergoing primary PCI: a randomized, controlled study

Abstract Background Previous clinical studies showed that early intravenous metoprolol before reperfusion in patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI reduced infarct size. However, intravenous beta-blockers in acute phase of STEMI can be associated with adverse effects such as cardiogenic shock and atrioventricular block. Landiolol is an ultrashort-acting beta-blocker with a half-life of 3 min that is eight times more cardioselective than esmolol. Purpose We evaluate the efficacy of intravenous infusion of landiolol on infarct size and its safety in STEMI patients undergoing primary PCI. Methods This study is a multicenter randomized control trial. A total of 47 patients with Killip class II or less STEMI undergoing PCI within 12 hours of symptoms onset were randomized to receive intravenous landiolol (n=23) or not (control, n=24). Patients allocated to landiolol group delivered an intravenous continuous dose of 3μg/min/kg before reperfusion and then continued until a total dose of 50mg. All patients started oral metoprolol or carvedilol within 12 hours. The primary end point was myocardial salvage index (MSI) on magnetic resonance imaging performed 5 to 7 days after PCI. MSI was defined as the difference between the area at risk and the area of necrosis analyzed using a commercial software. Results Magnetic resonance imaging was performed in 35 patients (17 patients in landiolol group and 18 patients in the control group), and ischemia duration time was 229 minutes in the landiolol group and the 242 minutes in control. In adjusting for confounding variables, the areas of myocardium at risk were not difference in both groups (54.4g in the landiolol group, and 46.8g in the control group; p=0.31). However, MSI in the landiolol group was significantly reduced than that in the control group (36.8% and 57.0%; p&amp;lt;0.001). In both group blood pressure was not difference in recruitment (142mmHg in landiolol group, and 144 in control) and starting PCI (163mmHg in landiolol group, and 165 in control). Regarding safety, the composite of death, malignant ventricular arrhythmia, cardiogenic shock, and atrioventricular block at 24 hours did not differ between the landiolol and the control groups (8.7% and 8.3%, respectively, p=0.93). Conclusion Early intravenous landiolol before starting primary PCI reduced infarct size in STEMI patients without significant hemodynamic adverse effects. Funding Acknowledgement Type of funding source: None

Efficacy and Safety of Landiolol in Patients With Ventricular Tachyarrhythmias With or Without Renal Impairment - Subanalysis of the J-Land II Study.

Background: Post hoc analysis was used to investigate the effects of renal function on the efficacy and safety of landiolol using data from the J-Land II study, which evaluated landiolol in patients with hemodynamically unstable ventricular tachycardia (VT) or ventricular fibrillation (VF) who were refractory to Class III antiarrhythmic drugs.Methods and Results: Patient data from the J-Land II study (n=29) were stratified by renal function (estimated glomerular filtration rate [eGFR] <45 and ≥45 mL/min/1.73 m2) and analyzed. Continuous landiolol infusion (1 μg/kg/min, i.v.) was initiated after VT/VF was suppressed with electrical defibrillation; subsequent dose adjustments were made (1–40 μg/kg/min). The primary efficacy endpoint was the proportion of patients free from recurrent VT/VF during the assessment period. Safety endpoints were also assessed. In the eGFR <45 and ≥45 mL/min/1.73 m2 groups, the median doses of landiolol during the assessment period were 9.44 and 8.97 μg/kg/min, the proportions of patients free from recurrent VT/VF were 69.2% and 81.8%, and adverse events occurred in 9 and 10 of 13 patients in each group, respectively. There were no apparent differences in the efficacy or safety of landiolol between the 2 groups.Conclusions: The data suggest that renal function may not affect the efficacy and safety of landiolol for hemodynamically unstable VT or VF.

P4605Landiolol, a beta-blocker, optimizes cardiac energetics and peripheral microhemodynamics better than ivabradine while reducing heart rate at hemodynamic resuscitation of experimental septic shock

Abstract Background Septic shock is associated with sympathetic over-activation characterized by tachycardia, which is associated with poor survival. Though several kinds of drugs are available to reduce heart rate (HR), it is not clear which drug should be used to reduce HR effectively in initial hemodynamic resuscitation in septic shock. Purpose The aim of this study was to experimentally investigate comparative effects of landiolol (a β-blocker) and ivabradine (an If-channel inhibitor) on initial hemodynamic resuscitation in a canine model of endotoxin shock. Methods We used 19 anesthetized dogs. Seven dogs were allocated to control (CT) group, six dogs to landiolol (BB) group, and six dogs to ivabradine (IVA) group. In all the groups, endotoxin shock was induced by intravenous infusion of Escherichia coli lipopolysaccharide (4 mg/kg) over 1 h. After induction of endotoxin shock, we started hemodynamic resuscitation to restore mean arterial pressure (AP) and cardiac output (CO) by infusing noradrenaline (NA) and Ringer acetate solution (RiA). Dose of NA and RiA were automatically titrated with use of a computer-controlled drug infusion system that we developed previously. Hemodynamic resuscitation was continued for 4 h. During resuscitation, the BB group was given landiolol infusion at a low-dose range (1–10 μg/kg/min, manually titrated), while the IVA group was given ivabradine at 0.25 mg/kg bolus-injected every 2 h. Results The drug infusion system automatically restored AP to 70 mmHg and CO to greater than 90% of baseline level in all the groups. The restored AP and CO were not significantly different among the three groups (Figure A, B). There were no significant differences in the computer-controlled infusion rate of NA and cumulated volume of RiA infused among the three groups (Figure C). During the first 2 h of resuscitation, HR was significantly reduced in the BB and IVA groups in comparison to the CT group (Figure D). However, only in the BB group, cardiac oxygen consumption was significantly lower than that in the CT group (Figure E). Blood lactate level decreased significantly after hemodynamic resuscitation only within the BB group (Figure F). Figure 1 Conclusions In the initial hemodynamic resuscitation of septic shock, both low-dose landiolol infusion and ivabradine injection may be used to reduce HR. However, to optimize cardiac energetics and peripheral microhemodynamics, low-dose landiolol infusion may be preferable to ivabradine injection. Acknowledgement/Funding This work was supported by JSPS KAKENHI Grant Number 15K01307, 18K12126.

Effective Dose of Landiolol, an Ultra-Short-Acting β-Blocker, to Decrease Heart Rate During On-Pump, Beating Coronary Artery Bypass Grafting

Decreasing the heart rate (HR) using landiolol, an ultra-short-acting β-blocker, is helpful for completing a meticulous distal anastomosis during on-pump or off-pump, beating coronary artery bypass grafting (CABG) surgery. We determine the effectiveness of landiolol to decrease the HR because the most effective dose has not been established. Observational open-label pharmacodynamics cohort study. Single center, Hamamatsu University Hospital. 28 patients undergoing on-pump, beating CABG. Landiolol 5 μg/kg/min was started (time 0) and then increased to 15, 25, and 35 μg/kg/min at 10-min intervals during left internal thoracic artery (LITA) to left anterior descending artery (LAD) anastomosis. Pharmacodynamics were characterized using a sigmoidal inhibitory maximum effect model to determine the percent decrease in HR according to the landiolol dose. Baseline (mean ± SD) HR (85 ± 10 beats/min) decreased to 81 ± 9, 71 ± 10, 67 ± 9, and 67 ± 9 beats/min, respectively, at the four landiolol infusion points evaluated. Estimated maximum percent decrease in HR from the baseline effective dose value (ED0) was -21.5 (-25.3 to -17.8) [mean (95% confidence interval)]%. ED50, ED90, and ED95 were 9.5 (9.0-10.1), 25.0 (22.5-27.6), and 35.2 (30.3-40.1) μg/kg/min, respectively. Landiolol maximally decreased HR just over 20% of the baseline HR. Hence, landiolol 25 μg/kg/min is likely a sufficient dose during LITA-LAD anastomosis during on-pump, beating CABG.

Landiolol in patients with septic shock resident in an intensive care unit (LANDI-SEP): study protocol for a randomized controlled trial

BackgroundIn patients with septic shock, the presence of an elevated heart rate (HR) after fluid resuscitation marks a subgroup of patients with a particularly poor prognosis. Several studies have shown that HR control in this population is safe and can potentially improve outcomes. However, all were conducted in a single-center setting. The aim of this multicenter study is to demonstrate that administration of the highly beta1-selective and ultrashort-acting beta blocker landiolol in patients with septic shock and persistent tachycardia (HR ≥ 95 beats per minute [bpm]) is effective in reducing and maintaining HR without increasing vasopressor requirements.MethodsA phase IV, multicenter, prospective, randomized, open-label, controlled study is being conducted. The study will enroll a total of 200 patients with septic shock as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria and tachycardia (HR ≥ 95 bpm) despite a hemodynamic optimization period of 24–36 h. Patients are randomized (1:1) to receive either standard treatment (according to the Surviving Sepsis Campaign Guidelines 2016) and continuous landiolol infusion to reach a target HR of 80–94 bpm or standard treatment alone. The primary endpoint is HR response (HR 80–94 bpm), the maintenance thereof, and the absence of increased vasopressor requirements during the first 24 h after initiating treatment.DiscussionDespite recent studies, the role of beta blockers in the treatment of patients with septic shock remains unclear. This study will investigate whether HR control using landiolol is safe, feasible, and effective, and further enhance the understanding of beta blockade in patients with septic shock.Trial registrationEU Clinical Trials Register; EudraCT, 2017-002138-22. Registered on 8 August 2017.

Study design for control of HEART rate in inFant and child tachyarrhythmia with heart failure Using Landiolol (HEARTFUL): A prospective, multicenter, uncontrolled clinical trial

BackgroundPersistent tachycardia in pediatric patients after congenital heart surgery further deteriorates their hemodynamic condition, and may become fatal. Therefore, immediate control of the tachycardia is mandatory in these patients. For this purpose, quick-acting, short-acting, titratable intravenous agents are required. However, there are no agents with such characteristics among the drugs approved for control of pediatric arrhythmias in Japan, and thus novel and effective medications for these patients are awaited. Landiolol, an ultrashort-acting β-blocker, was approved in 2013 for tachyarrhythmias in adult patients with heart failure. However, its efficacy and safety in pediatric patients remain unclear. The aim of this prospective, multicenter, open-label phase IIb/III study is to investigate the efficacy and safety of landiolol in pediatric patients with tachyarrhythmias as well as heart failure. MethodsEligible patients are aged ≥ 3 months and <15 years, and have tachyarrhythmia (atrial fibrillation, atrial flutter, supraventricular tachycardia) as well as heart failure. The primary endpoint of the study is ≥20% reduction from baseline heart rate or return to normal sinus rhythm within 2h after starting intravenous administration of landiolol. Patients will receive intravenous infusion of landiolol, starting at 1μg/kg/min. The dose will be increased by 1μg/kg/min every 15–20min until the tachycardia rate has decreased by >20% or tachycardia has terminated, and the dose will then be maintained or further increased depending on the patient's condition. The study was started in April 2015 and will end within a few years. ConclusionsThe study was designed and designated the “HEARTFUL study” in the hope of establishing a basis for control of HEART rate in inFant and child tachyarrhythmia Using Landiolol in children with heart failure.

Efficacy of Intravenous Administration of Landiolol in Patients With Acute Heart Failure and Supraventricular Tachyarrhythmia.

BackgroundPatients with acute heart failure (HF) complicated by supraventricular tachyarrhythmia (SVT) often receive continuous intravenous infusion of landiolol or diltiazem for rate control. It is unclear whether the interval from initiation of infusion to commencement of oral beta-blocker (BB) therapy differs for these two drugs.MethodsFrom January 2013 to July 2015, 94 consecutive patients were hospitalized for acute HF complicated by SVT. After 35 patients were excluded, the remaining 59 were divided into groups treated with diltiazem or landiolol. We investigated the blood pressure, heart rate, New York Heart Association classification, brain natriuretic peptide, chest X-ray film, echocardiographic findings (ejection fraction (EF)), time until commencement of oral BB therapy, and hospital stay.ResultsThere were no significant between-group differences of heart rate, blood pressure, or the severity of HF. The time until commencing oral BB therapy was significantly shorter in the landiolol group compared with the diltiazem group (median: 2 vs. 4 days, P = 0.002), but there was no significant difference in hospital stay. This interval was significantly shorter in patients with a reduced EF in the landiolol group (median: 2 days) compared with those with a reduced EF in the diltiazem group (median: 5 days, P = 0.008), and patients with a preserved EF in the landiolol group tended to have a shorter interval (median: 2 days) than those with a preserved EF in the diltiazem group (median: 4 days, P = 0.092).ConclusionsSwitching to oral BBs was accomplished earlier with landiolol than with diltiazem.

Landiolol infusion during general anesthesia does not prevent postoperative atrial fibrillation in patients undergoing lung resection.

We aimed to determine whether intraoperative low-dose infusion of landiolol, an ultra-short-acting beta blocker, can prevent postoperative atrial fibrillation (POAF) after lung resection. A double-blind, randomized, controlled, preliminary study was performed in university academic hospital, single center. Fifty lung surgical patients were key-opened before enrollment of the originally planned 100 patients, who were randomized in a 1:1 ratio in each treatment arm. Landiolol was infused with a dosage of 5 μg/kg/min during general anesthesia in the landiolol group, which was compared with the placebo control group with no landiolol. Atrial fibrillation (AF)-free survival curves were generated by means of Kaplan-Meier estimates and differences in survival were compared with the use of the log-rank test. We examined independent predictors of POAF by the multivariate logistic regression analysis using the perioperative parameters detected with the univariate analysis. The AF events were recorded for 7days with Holter monitor in 5 of 25 patients in the landiolol group and 4 of 25 patients in the control group. Kaplan-Meier analysis showed that the landiolol group could not avoid the incidence of POAF in comparison with the placebo saline group (P=0.806). The multivariate logistic regression analysis for prevalence of POAF identified only one statistically significant predictor: interleukin-6 (IL-6) sampled at 6h after end of surgery. We failed to demonstrate that low-dose infusion of landiolol during general anesthesia could prevent the incidence of AF after lung resection. Only IL-6 sampled at 6h after end of surgery significantly predicted POAF among pulmonary surgical patients.

Beneficial effect of early infusion of landiolol, a very short-acting beta-1 adrenergic receptor blocker, on reperfusion status in acute myocardial infarction

BackgroundAn early IV beta blocker during primary percutaneous coronary intervention (PCI) has been shown to reduce infarct size in ST-segment elevation acute myocardial infarction (STEMI), although the underlying mechanism is unknown. The aim of this study was to investigate the efficacy of early infusion of landiolol, the short-acting beta-1 adrenergic receptor blocker, on the reperfusion status in a STEMI. MethodsWe conducted a prospective, single-group trial of landiolol during the primary PCI for a STEMI. Landiolol was started intravenously just before reperfusion. The reperfusion status and outcomes in 55 treated patients were compared with those in 60 historical controls treated without landiolol. The optimal reperfusion was assessed by an ST-segment resolution (STR), coronary flow, and myocardial brush grade (MBG) after reperfusion. ResultsPatients in the landiolol group achieved a higher rate of an STR (64% vs. 42%, p=0.023) and MBG 2/3 (64% vs. 45%, p=0.045), whereas coronary flow was comparable between the two groups. A multivariate analysis showed that landiolol use was an independent predictor of an STR (odds ratio 2.99, 95% confidence interval 1.25–7.16, p=0.014). The incidence of non-sustained ventricular tachycardia (27% vs. 50%, p=0.014), hypotension (15% vs. 32%, p=0.046), and progression to Killip class grade III or IV (0% vs. 10%, p=0.028) were lower in the landiolol group. ConclusionEarly infusion of landiolol during the primary PCI was associated with optimal reperfusion and a lower incidence of adverse events in comparison with the control group.

Perioperative Landiolol Infusion Reduces the Incidence of Atrial Fibrillation after Pulmonary Lobectomy: Postoperative Randomized Controlled Study

Background and Objective: Atrial fibrillation is a common complication after lung resection. We sought to determine the relationship between low-dose landiolol only intraoperatively administration and the incidence of atrial fibrillation development in patients who did not have atrial fibrillation before undergoing lung resection. Methods: Forty-five patients undergoing lung resection (lobectomy or bilobectomy), as indicated for lung cancer at Nippon Medical Hospital, between August 2012 and September 2013. Two patients were excluded from the final analysis. Patients were given either intravenous landiolol (n = 22) or placebo (n = 21) during lobectomy or bilobectomy only intraoperatively. This is prospective, randomized, placebo-controlled study. Main Outcome Measures: The primary end point was the incidence of sustained atrial fibrillation (≥30 min). Results: Postoperative atrial fibrillation occurred in 1 (4.5%) of the 22 patients in the landiolol group and 6 (28.6%) of the 21 patients in the placebo group. No serious adverse effects such as bradycardia and hypotention secondary to landiolol were observed. Conclusion: Low-dose landiolol infusion intraoperatively reduced the incidence of clinically significant atrial fibrillation in patients undergoing pulmonary lobectomy.

Impact of a β-blocker and/or acute hemodilution on cerebral oxygenation during apneic hypoxia.

β-blockers reduce the tolerance for acute hemodilution by decreasing cerebral oxygenation and may contribute to the incidence of stroke. We hypothesized that β-blockers also increase the risk for cerebral hypoxia when apneic hypoxia occurs. After induction of isoflurane, 14 swine (mean ± SD =25.3 ± 0.8 kg) were studied using 200 μg/kg/min of landiolol or saline (control group) in three sequential stages: before, during, and after landiolol (saline) infusion. In each stage, after 5 min of mechanical ventilation with 100% oxygen, apnea was induced until the time to < 70% oxygen saturation. Hemodynamic and blood gas variables were measured, and the cerebral tissue oxygenation index (TOI) was recorded by near infrared spectroscopy (apnea experiment). After these steps, hemodilution was induced by hemorrhage of 600 ml and infusion of the same volume of hydroxyethylstarch, and the apnea experiments were then conducted before, during, and after landiolol (saline) infusion similarly to before hemodilution. Landiolol decreased TOI at 1 min after apnea and at SpO2 < 70% by 3.3% and 7.0% from each corresponding value at baseline, and by 13.1% and 20.3% during hemodilution. Landiolol shifted the relationship between TOI and arterial hemoglobin oxygen saturation (SaO2 ) or arterial partial pressure of oxygen (PaO2 ) to the left; and reduced TOI at similar arterial blood oxygenation. This phenomenon was marked during hemodilution. Landiolol reduces cerebral tissue oxygenation during apneic hypoxia. β-blockers increase the risk for cerebral hypoxia when apneic hypoxia occurs, especially during acute hemodilution.