Abstract
Purpose
Excessive tachycardia in resuscitated septic shock patients can impair hemodynamics and worsen patient outcome. We investigated whether heart rate (HR) control can be achieved without increased vasopressor requirements using the titratable highly selective, ultra-short-acting β1-blocker landiolol.
Methods
This randomized, open-label, controlled trial was conducted at 20 sites in 7 European countries from 2018 to 2022 and investigated the efficacy and safety of landiolol in adult patients with septic shock and persistent tachycardia. Patients were randomly assigned to receive either landiolol along with standard treatment (n = 99) or standard treatment alone (n = 101). The combined primary endpoint was HR response (i.e., HR within the range of 80−94 beats per minute) and its maintenance without increasing vasopressor requirements during the first 24 h after treatment start. Key secondary endpoints were 28-day mortality and adverse events.
Results
Out of 196 included septic shock patients, 98 received standard treatment combined with landiolol and 98 standard treatment alone. A significantly larger proportion of patients met the combined primary endpoint in the landiolol group than in the control group (39.8% [39/98] vs. 23.5% [23/98]), with a between-group difference of 16.5% (95% confidence interval [CI]: 3.4–28.8%; p = 0.013). There were no statistically significant differences between study groups in tested secondary outcomes and adverse events.
Conclusion
The ultra-short-acting beta-blocker landiolol was effective in reducing and maintaining HR without increasing vasopressor requirements after 24 h in patients with septic shock and persistent tachycardia. There were no differences in adverse events and clinical outcomes such as 28-day mortality vs. standard of care. The results of this study, in the context of previous trials, do not support a treatment strategy of stringent HR reduction (< 95 bpm) in an unselected septic shock population with persistent tachycardia. Further investigations are needed to identify septic shock patient phenotypes that benefit clinically from HR control.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00134-024-07587-1.
Keywords: Landiolol, Ultra-short-acting beta-blocker, Sepsis, Septic shock, Persistent tachycardia, Heart rate control
Take-home message
| Titrated intravenous landiolol increases the proportion of septic shock patients with persistent tachycardia, who have a reduced and maintained heart rate without a vasopressor increase after 24h without differences in adverse events and clinical outcomes. These results, in the context of previous trials, do not support a treatment strategy of stringent heart rate reduction (<95 bpm) in an unselected septic shock population with persistent tachycardia. Notably, lower mortality was observed in patients with atrial fibrillation. Further research should aim to identify characteristics of patients who benefit from heart rate control and who do not. |
Introduction
Septic shock-related inflammation results in hypovolemia and a reduction of cardiac output [1–3]. To maintain vital organ perfusion, massive sympathetic activation through the release of catecholamines is triggered leading to tachycardia, vasoconstriction, and increase in inotropism [4]. Current treatment guidelines [5, 6] recommend intravascular fluid administration and vasopressor therapy as the first step of hemodynamic management. However, in some patients, elevated heart rate (HR) persists, which may reflect sympathetic overstimulation [7–14]. Persistent tachycardia impairs preload and coronary perfusion and is associated with mortality and morbidity in a range of clinical conditions [15–18]. The threshold of 95 beats per minute (bpm) was reported as a predictive cut-off value to differentiate between survivors and non-survivors [19], while the range of 80−94 bpm is recognized as adequately balancing improved cardiac function and preserved systemic hemodynamics [9, 20]. These findings suggest that adequate HR control may improve the outcome of septic shock patients with tachycardia.
Beta1-selective beta-blockers, such as esmolol and landiolol, are considered suitable for the management of tachycardia in septic patients, as their administration resulted in improved stroke volume, lactate levels, a reduction of noradrenaline requirements, improvements in organ function, and survival rates [9, 20–23]. Due to their pharmacological properties, short-acting beta1-blockers in combination with vasopressors seem to be most appropriate approach to control HR during sepsis without systemic adverse effects [9, 20–32]. Other antiarrhythmic agents, such as ivabradine or amiodarone, showed HR reduction in clinical trials in septic shock patients but may lack the beneficial pleiotropic effects of beta-blockers, which include attenuating sympathetic overstimulation, increasing microcirculatory blood flow, blunting the inflammatory response, metabolic changes, and sepsis-associated coagulopathy [33, 34]. Beta-blockers were associated with superior clinical outcomes in a large retrospective study evaluating atrial fibrillation (AF) treatment in sepsis [35]. Non-selective beta-blockers are generally longer acting and may therefore be less suitable in the acute phase of sepsis [36]. The widespread use of beta-blockers is restrained due to possible induction of hypotension and bradycardia. High-quality data on the safety and efficacy of beta-blockade during septic shock are missing and recommendation on HR management in the current sepsis treatment guidelines remains limited. Landiolol has a shorter elimination half-life (4 min [37]) than esmolol (9 min [38]) and higher selectivity for beta1 receptors [4], resulting in lower negative inotropic effects [39–41] and reduced impact on blood pressure (BP) [42].
Up to date, only two multicenter studies were conducted with landiolol in septic patients. In the J-Land 3S study conducted in Japan, the administration of landiolol resulted in significantly more patients with sepsis-related tachyarrhythmia achieving a target HR of 60–94 bpm at 24 h while showing comparable safety profile to the control group. The study also reported a reduction in 28-day mortality: 12% in the control group vs 20% in the landiolol group (p = 0.22) [43]. However, the most recent study conducted in the United Kingdom (UK) (STRESS-L) was terminated prematurely after the enrolment of 37% of the planned patients, because landiolol was unlikely to demonstrate benefit in improving organ function and there was a signal for possible harm [44]. These studies reported inconsistent findings on the benefit and safety of landiolol in tachycardia patients with septic shock [9, 43]. Therefore, there is an urgent need for additional studies to provide comprehensive data on the efficacy and safety of landiolol in septic shock patients with persistent tachycardia and vasopressor therapy.
We aimed to evaluate, whether the administration of landiolol in patients with septic shock and persistent tachycardia (HR ≥ 95 bpm) is effective in reducing and maintaining HR, without increasing vasopressor requirements compared to standard treatment alone.
Methods
Ethics
The study was conducted in compliance with the Declaration of Helsinki and ICH Good Clinical Practice (GCP) guidelines. The study protocol [45] was approved by the relevant independent ethics committee at each participating center. Written informed consent was obtained from all patients or patient’s legal representative(s) before any intervention. The final study protocol and the Statistical Analysis Plan (SAP) are available in the electronic supplementary material (ESM). An Independent Data Monitoring Committee regularly reviewed the trial data.
Trial design and objectives
The LANDI-SEP trial was a multicenter, randomized, open-label, controlled phase IV trial in intensive care unit (ICU) patients with septic shock and persistent tachycardia (HR ≥ 95 bpm). The study was conducted at 20 sites in 7 European countries. The primary objective of the trial was to compare an HR response and its maintenance thereof without an increase in vasopressor requirements within the first 24 h of treatment between landiolol and control groups. Further assessments of efficacy and safety in the two study groups were set as secondary objectives.
Patients
Eligible to the study were adult patients (> 18 years) in the ICU with septic shock as defined by the Sepsis-3 Criteria [46], with persistent tachycardia (HR ≥ 95 bpm) despite a hemodynamic optimization phase of at least 12 h but a maximum of 36 h in which they received treatment according to the Surviving Sepsis Campaign (SSC) guidelines [6]. Patients with any form of compensatory tachycardia, as determined by the Investigator, were not eligible. Selection criteria are fully stated in supplemental Table 2-Study protocol [45]. Patients were randomized in a 1:1 ratio to landiolol or control group according to the randomization list generated by the study statistician. The presence of AF in the hemodynamic optimization period was used as a stratification factor. Treatments were assigned to individual patients based on block stratified randomization to ensure random assignment to treatments and balanced distribution of both treatment arms within each stratum. The intervention was open label due to the absence of a specific study treatment in the control group.
Interventions
Landiolol group
In addition to standard treatment based on SSC guidelines [6], patients started continuous infusion of landiolol hydrochloride within 2 h after randomization at a starting dose of 1 µg/kg/min. In the titration phase (0–24 h), the dose was increased at increments of 1 µg/kg/min to a maximum of 40 µg/kg/min at intervals of at least 20 min to reach a target HR of 80–94 bpm. After achievement of the target HR, landiolol was administered at any dose to maintain target HR until one the following events occurred: discontinuation of vasopressor infusion, death, serious adverse event (SAE) attributable to the study drug infusion, and patient’s discharge from ICU or day 28. Landiolol was administered until discontinuation of vasopressors to maximise its potential beneficial effects on sympathetic overstimulation [47].
Control group
Patients received standard treatment according to the SSC guidelines [6], which was not targeted to HR control. End of treatment was defined as one the following events: discontinuation of vasopressor infusion, death, and patient discharge from the ICU or day 28. Patients were discontinued from the study if they received beta-blocker treatment.
Procedures
Hemodynamic data [HR, systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP)] were documented hourly in the titration phase and every 12 h thereafter until end of treatment. Rate of vasopressor and inotrope infusion was recorded at every dose change. Detailed descriptions of the trial procedures are given in supplemental Table 3.
Study endpoints
Primary endpoint
The primary endpoint (PE) was a multi-component endpoint defined by achieving HR response (3 subsequent hourly HR values at 80–94 bpm or < 80 bpm and not clinically relevant), HR maintenance (defined as not recording 3 subsequent hourly HR values > 94 bpm or < 80 bpm after achievement of HR response), and no increase in vasopressor requirements during the first 24 h after treatment. Vasopressor response was defined as no increase of noradrenaline equivalent dose [48] at 24 h compared to the treatment start. HR values < 80 bpm were not deemed as response failure if the investigator considered the HR to be not clinically relevant (i.e., not assessed as relative bradycardia, without hemodynamic compromise). Individual endpoints, i.e., HR response (with or without maintenance) and vasopressors response, were also evaluated separately.
Secondary endpoints
Secondary endpoints included change in vasopressor requirements over the study period (dose and duration); 28-day/ICU mortality; duration of ICU/hospital stay; and Sequential Organ Failure Assessment (SOFA) score. The incidence rates of bradycardic episodes requiring intervention, adverse events (AEs), and SAEs were secondary safety endpoints.
Statistical analyses
Primary efficacy analysis
Absolute and relative frequencies of patients who achieved the PE were calculated. The comparison of study groups was conducted using a weighted Cochran–Mantel–Haenszel framework with two stratification factors: the presence of AF and site. The hypothesis that landiolol group is superior to control group in the proportion of patients who reached the PE was demonstrated if the lower limit of two-sided 95% confidence interval of difference pL–pC was above zero, where pL and pC are percentages of patients who reached the PE in landiolol and control groups, respectively. The PE was measured within 24 h after treatment initiation. Patients who died or were discontinued due to administration of beta-blockers during the first 24 h without reaching the PE were included in the analysis with the outcome that the PE was not reached.
Secondary efficacy and safety analyses
Secondary efficacy and safety analyses are fully described in the SAP (see electronic supplementary material).
Subgroup analyses
Subgroup analyses for the primary and secondary efficacy endpoints were defined post hoc for exploratory purposes and are specified in the SAP (see electronic supplementary material).
Results
Study participants
Between 24th February 2018 and 16th February 2022, we enrolled 196 patients (Fig. 1). Patient characteristics at baseline were similar in both study groups (Table 1). Landiolol doses and duration of administration are provided in supplemental Table 4.
Fig. 1.
Study flowchart
Table 1.
Baseline characteristics of the study participants
| Variable, statistics | Landiolol group (n = 98) | Control group (n = 98) |
|---|---|---|
| Age, mean (SD), years | 64.4 (12.5) | 65.2 (15.06) |
| Gender, n (%) | ||
| Female | 35 (36) | 43 (44) |
| Male | 63 (64) | 55 (56) |
| Atrial fibrillationa, n (%) | ||
| No | 72 (73) | 74 (76) |
| Yes | 26 (27) | 24 (24) |
| APACHE II score, mean (SD) | 24.9 (8) | 23.6 (8.6) |
| SOFA score, mean (SD) | 12.6 (3.54) | 12.1 (2.83) |
| Noradrenaline equivalent dose, mean (SD) | 0.51 (0.51) | 0.52 (0.54) |
| MAP, mean (SD), mmHg | 78.6 (10.2) | 79 (10.36) |
| SAP, mean (SD), mmHg | 119.5 (17.02) | 119.6 (16.62) |
| DAP, mean (SD), mmHg | 59.7 (9.49) | 60.1 (10.14) |
| HR, mean (SD), bpm | 116 (14.86) | 114.2 (13.5) |
| Cardiac rhythmb, n (%) | ||
| Missing | 8 | 7 |
| Arrhythmia | 24 (27) | 20 (22) |
| Sinus rhythm | 66 (73) | 71 (78) |
| Time since septic shock diagnosis, mean (SD), h | 23.95 (10.54) | 25.34 (7.68) |
| Renal replacement therapy, n (%) | 24 (24) | 22 (22) |
| Mechanical ventilation, n (%) | 83 (85) | 78 (80) |
| Left ventricular ejection fractionc, mean (SD), % | 55.2 (13.39) | 55.1 (12.46) |
| Velocity time integrald, mean (SD), cm | 19.4 (5.37) | 19.3 (5) |
| Arterial lactate level, mean (SD), mmol/L | 4 (3.3) | 3.9 (3.6) |
| Arterial pH, mean (SD) | 7.33 (0.11) | 7.35 (0.09) |
| Fluid balance, mean (SD), ml/day | 4719 (3842.2) | 4126 (3606.4) |
| Respiratory infection, n (%) | 42 (43) | 44 (45) |
| Abdominal infection, n (%) | 40 (41) | 30 (31) |
| Urinary tract infection, n (%) | 16 (16) | 11 (11) |
| Surgical infection, n (%) | 4 (4) | 9 (9) |
| Other infection, n (%) | 15 (15) | 18 (18) |
APACHE II score Acute Physiology and Chronic Health Evaluation score, SOFA score, Sequential Organ Failure Assessment score, MAP Mean Arterial Pressure, SAP Systolic Arterial Pressure, DAP Diastolic Arterial Pressure, HR Heart Rate, BMI Body Mass Index, SD Standard Deviation
aPresence of atrial fibrillation in the haemodynamic optimization period
bCardiac rhythm assessment at baseline
cN = 66
dN (Landiolol group) = 54, N (Control group) = 56
Primary efficacy endpoint
In the landiolol group, 39.8% [39/98] of patients achieved the primary combined endpoint compared to 23.5% [23/98] in the control group, with a difference between the interventions of 16.5% (95% confidence interval [CI] 3.4–28.8%; p = 0.013). 75.5% [74/98] patients in the landiolol group reached target HR when compared to 42.9% [42/98] in the control group, with a difference between the groups of 33% (95% CI 19.4–44.9%; p = < 0.001). The difference between the vasopressors response rates was not statistically significant between study groups (Table 2).
Table 2.
Primary efficacy analyses
| Response | Landiolol group (n = 98) | Control group (n = 98) | Overall (n = 196) | Effect estimate (95% CI) | P value |
|---|---|---|---|---|---|
| Primary response (multi-component)a, n (%) | 39 (39.8) | 23 (23.5) | 62 (31.6) | MD, 16.5% (3.4–28.8%) | 0.01 |
| Components of primary endpoint | |||||
| HR response (target HR reached and maintained)b, n (%) | 57 (58.2) | 29 (29.6) | 86 (43.9) | MD, 29% (15.1–41.3%) | < 0.001 |
| HR response (target HR reached, not necessarily maintained)c, n (%) | 74 (75.5) | 42 (42.9) | 116 (59.2) | MD, 33% (19.4–44.9%) | < 0.001 |
| Vasopressors responsed, n (%) | 56 (57.1) | 65 (66.3) | 121 (61.7) | MD, − 9.2% (− 22 to 4.4%) | 0.19 |
HR heart rate, CI confidence interval, MD mean difference
aPrimary response definition: achieving HR response (3 subsequent hourly HR values at 80 – 94 bpm or < 80 bpm and not clinically significant), HR maintenance (defined as not recording 3 subsequent hourly HR values > 94 bpm or < 80 bpm after achievement of HR response), and no increase in vasopressor requirements during the first 24 h after treatment
bHR response definition (target HR reached and maintained): 3 subsequent hourly HR values at 80 – 94 bpm or < 80 bpm and not clinically significant), HR maintenance (defined as not recording 3 subsequent hourly HR values > 94 bpm or < 80 bpm after achievement of HR response), and no increase in vasopressor requirements during the first 24 h after treatment
cHR response definition (target HR reached, not necessarily maintained): 3 subsequent hourly HR values at 80–94 bpm or < 80 bpm and not clinically significant during the first 24 h after treatment
dVasopressor response definition: no increase of noradrenaline equivalent dose at 24 h compared to the treatment start
Main secondary endpoints
Other efficacy measures
There were no statistically significant differences in 28-day and ICU mortalities between landiolol and control groups. Cox proportional hazards model from day 0 to day 28 showed no difference in survival between the study groups (HR 1.35 [95% CI 0.85–2.13], p = 0.20). No difference was observed between study groups for the durations of ICU stay (HR 1.17 [95% CI 0.70–1.94]; p = 0.55) and hospital stay (HR 0.80 [95% CI 0.41–1.54], p = 0.50) for patients alive on day 28. The secondary endpoints are summarized in Table 3. The duration of vasopressor administration was similar between study groups, with a mean (standard deviation, SD) duration of 5.64 (7.16) and 5.08 (5.20) days for the landiolol and control group, respectively. The mean (SD) total dose of noradrenaline over the treatment period was 194.6 (287.7) and 138.46 (158.7) mg for landiolol and control group, respectively. Inotropic agents were used in nine patients in the landiolol group with a mean (SD) duration of 3.95 (3.78) days and in nine patients in the control group with a mean (SD) duration of 1.32 (1.13) days. The average and total doses of vasopressors and inotropic agents administered in the study are summarized in supplemental Tables 5 and 6, respectively. Mean profiles of vasopressor doses administered during the titration phase and the study are displayed in Fig. 2e and f, respectively. SOFA scores were analysed descriptively for the visits before the end of study treatment and were comparable between study groups (supplemental Table 7). The levels of arterial lactate were comparable over the first 4 days of the study between the study groups (supplemental Table 8). While mean (SD) values for HR [bpm] were not different at baseline between the landiolol group [116 (14.86)], and control group [114.2 (13.50)], statistically significant differences were observed at 1 h after treatment start [101.8 (13.49) vs 111.3 (15.35), p < 0.001]. HR remained lower in the landiolol group compared to the control group at 24 h [90.2 (15.77) vs 101 (22.52), p < 0.001] and on day 2 [84.3 (13.64) vs 93.4 (17.03), p = 0.002] after treatment start. Thereafter, the HR in patients in the control group also stabilized and there was no significant difference in HR between the groups after day 2 (Fig. 2a, b). The values for MAP, SAP, and DAP were comparable between the study groups over the study period (Fig. 2c, d).
Table 3.
Secondary efficacy analyses
| Response | Landiolol group (n = 98) | Control group (n = 98) | Overall | Effect estimate (95% CI) | P value |
|---|---|---|---|---|---|
| 28-day mortality, n (%)a | 43 (43.9) | 39 (40.2) | 82 (42.1) | MD, 3.8% (− 9.9 to 17.3%) | 0.60 |
| ICU mortality, n (%)b | 43 (43.9) | 33 (34) | 76 (39) | MD, 9.9% (− 3.8 to 23%) | 0.16 |
| Duration of ICU stay for patients alive on day 28, median (95% CI), days | 14 (10.2–15.3) | 13.9 (10.2–20.4) | – | HR, 1.17 (0.70–1.94) | 0.55 |
| Duration of hospital stay for patients alive on day 28 | – | – | – | HR, 0.80 (0.41–1.54) | 0.50 |
CI confidence interval, HR hazard ratio, ICU intensive care unit, MD mean difference, SD standard deviation
aN (Landiolol group) = 98, N (Control group) = 97
Fig. 2.
Mean (SD) profiles of HR in the titration phase (a)/during the study up to day 14 (b), Mean (SD) profiles of blood pressure in the titration phase (c)/during the Study up to day 14 (d) and Mean (SE) norepinephrine equivalent dose during the titration phase (e)/during the study up to day 14 (f). bpm beats per minute, DAP diastolic arterial pressure, SAP systolic arterial pressure, mmHg millimetre of mercury
Safety analyses
A total of 166 AEs were reported in 66/98 (67.3%) patients in the landiolol group and 159 AEs in 65/98 (66.3%) patients in the control group (supplemental Table 9). 74 SAEs were reported in 54/98 (55.1%) patients in the landiolol group and 68 SAEs in 52/98 (53.1%) patients in the control group (supplemental Table 10). The most frequent AEs related to landiolol were hypotension in 5 (5.1%) and bradycardia in 2 (2%) patients. SAEs related to landiolol were low cardiac output syndrome (reduced ejection fraction and hypotension) and hypotension in 1 (1%) patient, respectively. Landiolol-related events resolved with dose reduction, dose interruption, or discontinuation of landiolol. No fatal event was considered related to landiolol treatment. Five bradycardic episodes requiring intervention occurred in four patients in the landiolol group, and three episodes in two patients were related to landiolol. All events resolved after landiolol discontinuation or dose reduction. New-onset arrhythmias were observed in 13.3% [13/98] and 17.3% [17/98] patients in the landiolol and control groups, respectively, with no significant difference between the groups (p = 0.55). Summary of safety analyses is provided in supplemental Table 11.
Additional and subgroup analyses
Subgroup analyses
In univariate, unadjusted analyses (supplemental Fig. 1), the percentage of patients achieving the combined PE was greater in the landiolol group in all subgroups of patients, except from patients affected with coronavirus disease 2019 (COVID-19), where sample size was small. Similar results as for the whole population were observed in the subgroups of patients with AF (supplemental Table 12) and in patients with LVEF > 65% at baseline (supplemental Table 13).
Discussion
The main finding of this study is that in septic shock patients with persistent tachycardia, the titrated highly selective, ultra-short-acting beta1-blocker landiolol represents an effective approach to reduce and control HR in patients requiring vasopressors. Notably, compared to the control group, a higher proportion of patients treated with landiolol reached the combined PE, i.e., HR reduction and maintenance without an increase in noradrenaline doses after 24 h, compared to the control group. The result was primarily based on the difference between the two groups in achieving and maintaining target HR, while vasopressor doses tended to be higher in the landiolol group. This was achieved despite 35.7% (35/98) patients in the control group receiving antiarrhythmic medication during the first 24 h. Landiolol administration led to prompt HR control and consistent differences in HR from baseline values compared to the control group within the first 24 h, while no significant impact on the blood pressure (BP) was observed. Compared to the control group, heart rate reduction was statistically significant during the first two days of landiolol treatment. In other words, patients in the control group suffered from higher HR for 48 h longer than landiolol treated patients. Following the study rationale, these findings support the reduction of adrenergic stress by landiolol. Primary response was consistent throughout all predefined and post hoc subgroups, except for patients with COVID-19.
Our study represents the largest population in currently published multicentre randomized trials on beta-blockers in septic shock patients. Baseline characteristics are representative of patients with septic shock and persistent tachycardia admitted to ICU. Patients with various primary locations of infection, age, gender, comorbidities, and overall health status allow for generalisability of trial findings. Illness severity was evidenced by the high APACHE II scores, noradrenaline equivalent doses, and arterial lactate values at baseline (Table 1). Landiolol administration was not associated with a reduction of vasopressor requirements or an improvement in survival compared to the control group. The 28-day mortality rate in our study for patients treated with landiolol (43.9%) was comparable to the STRESS-L study (37.1%) [44]. The latter study was stopped prematurely, because there was a signal of possible harm due to the low 28-day mortality rate of 25.4% in the control group (vs. 40% in the present study). While the representativeness of the control group of the STRESS-L study was brought into question [49], the mortality rates for landiolol reported in our and the STRESS-L study are in line with published data for general patients with septic shock [50, 51]. Notably, in a cohort of septic and septic shock patients, the J-Land 3S study showed a trend for lower mortality in patients treated with landiolol vs. standard of care [43, 52]. In our study, no differences in clinical outcomes such as 28-day mortality, duration of ICU/hospital stay or time of survival were shown between landiolol and standard of care even though comparable effects in HR reduction and maintenance of BP were observed under comparable landiolol doses. Importantly, the sample size of our study was not primarily powered for robust evaluations of these endpoints. However, several factors discussed below could have contributed to these results.
The protocol did not require detailed hemodynamic monitoring or advanced echocardiography. The lack of the insight into the hemodynamic profiles of individual patients could have led to the enrolment of patients with tachycardia, who did not benefit from HR reduction. Due to the lack of universally accepted criteria for the definition of non-compensatory tachycardia, methods of identification of such patients were at the investigator’s discretion. Observed decreases in BP in the early phase of landiolol treatment and increases in vasopressor doses suggest that some patients with compensatory tachycardia were indeed included. The lack of cardiac output measurement and orientation on achieving target HR prevented investigators to individualise treatment targets (e.g., to titrate landiolol to optimise cardiac output). While the incidence of hypotension was low in both study groups, we hypothesize that due to the adherence to the HR goal, investigators were more likely to increase vasopressor dose in these patients than to reduce landiolol dose. The stringent approach of targeting a fixed HR does not take full advantage of the titratability of an ultra-short-acting beta-blocker like landiolol and may have been too aggressive in patients with higher HR. The protocol allowed the enrolment of patients with other than sinus rhythm or pre-admission beta-blocker therapy, which might have also influenced the individual responses to treatment [53]. Post hoc subgroup analysis showed higher mortality risk for the landiolol group (47.2% [34/72]) compared to the control group (39.7% [29/73]) in patients with sinus tachycardia, while the opposite was observed in patients with AF (34.6% [9/26] vs 41.7% [10/24]) (supplemental Table 12). This finding, albeit not statistically significant, could also reflect the benefit of improved diastolic filling time in patients with the absence of the atrial kick. The use of inotropic agents was rare in our study with only nine patients in each group receiving dobutamine, levosimendan, or milrinone. In the Japanese study, around 40% of patients were administered dobutamine and phosphodiesterase III inhibitors in the landiolol group [52]. In the single-center study by Morelli et al. that reported a significant decrease in 28-day mortality using esmolol in a similar patient population, 49.4% of patients received levosimendan [9].
Safety was comparable between the landiolol and control group with respect to AE and SAE rates. There was no difference in the incidence of new-onset arrhythmia between groups, but this may have been influenced by the wide use of antiarrhythmic medication in the control group (supplemental Table 14). Hypotension and bradycardia related to landiolol administration were rare with only 5, respectively, 3 patients experiencing such events. All events were resolved after prompt intervention by the treating physician.
Our results in the context of previous trials with beta-blockers in septic shock suggest that the enrolled population comprises patients who could clinically benefit from HR control, but also those in whom tachycardia should not be specifically treated. The goal of future research is to identify those subgroups, in which personalised treatment with a titratable rapidly acting beta-blocker landiolol can be a powerful tool. For example, the subgroup of patients with a hyperdynamic heart at baseline (LVEF > 65%) showed numerically lower mortality at day 28 compared to control in our study (supplemental Table 13). A randomized-controlled trial investigating the use of landiolol in this patient population with overall increased mortality is currently ongoing (NCT04748796). Future research might focus on the group of patients with AF, as demonstrated in the respective subgroup of this study (supplemental Table 12), as well as patients with preexisting chronic beta-blocker therapy, as suggested by the data of Fuchs et al. [53]. To identify these specific conditions, more detailed monitoring of hemodynamics at baseline and during the treatment in future trials seems paramount, and so is a more stringent exclusion of patients, who might not benefit. While correct identification of patients with non-compensatory tachycardia remains challenging, a recent post hoc analysis by Morelli et al. identified the systolic and dicrotic pressure difference as a potential discriminator for the origin of the tachycardia [54].
Limitations
Potential limitations of the trial include the open-label design and the lack of requirement for more detailed hemodynamic monitoring, which may have led to enrolment of patients with a compensatory sinus tachycardia who did not benefit from HR reduction. Also, the evaluation of the effect of landiolol on cardiac function remains limited. Our study was designed to explore hemodynamic responses, but it was not powered to investigate mortality or other robust patient-centred outcomes. The primary endpoint evaluated in our study has not been validated as a surrogate marker for clinical outcomes. Furthermore, study centres varied in their previous experience with intravenous beta-blocker use in this patient population. The study was recruiting throughout the initial phase of the COVID-19 pandemic, which might have had an impact on patient care especially in the landiolol group that contrary to the control group required additional attention of doctors and nurses. More patients with COVID-19 were included in the landiolol group and this was the only subgroup in which primary outcome tended to be worse with landiolol treatment.
Conclusion
Titrated administration of the highly selective, ultra-short-acting beta1-blocker landiolol in patients with septic shock and persistent tachycardia was effective in reducing and maintaining HR without increasing vasopressor requirements within the first 24 h. There were no differences in adverse events and clinical outcomes, such as 28-day mortality, duration of ICU/hospital stay or time of survival, between patients treated with landiolol vs. sole standard of care. These results, in the context of previous trials, do not support a treatment strategy of stringent HR reduction (< 95 bpm) in an unselected septic shock population with persistent tachycardia. Subgroup analysis showed a trend for lower mortality in patients with atrial fibrillation but reverse trend for higher mortality in patients with sinus tachycardia. Further investigations are needed to identify septic shock patient phenotypes that benefit clinically from HR control.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors thank the members of Data and Safety Monitoring Board Martin Balík, Alain Rudiger, and Michael Freissmuth, for their inputs and time dedicated to Landi-SEP trial.
Investigators: František Duška: Department of Anesthesia and Intensive Care, Charles University, 3rd Medical Faculty and University Hospital Královské Vinohrady, Czech Republic; Sebastian Rehberg: Department of Anesthesiology, Intensive Care, Emergency Medicine, Transfusion Medicine and Pain Therapy, University Hospital of Bielefeld, Campus Bielefeld-Bethel, Protestant Hospital of the Bethel Foundation, Bielefeld, Germany; Sandra Frank: Department of Anesthesiology, LMU University Hospital, LMU Munich, Munich, Germany; Vladimír Černý: Department of Anesthesiology, Perioperative Medicine and Intensive Care, Masaryk Hospital, Labem, Czech Republic; Radek Cihlář: Department of Anesthesiology and Intensive Care, Hospital České Budějovice, České Budějovice, Czech Republic; Gianni Biancofiore: University School of Medicine Pisa, Department of Anesthesiology and Transplant Intensive Care Unit, Pisa, Italy; Fabio Guarracino: Azienda Ospedaliero Universitaria Pisana, Department of Anesthesia and Critical Care Medicine, Cardiothoracic and vascular Anesthesiology and Intensive Care, Pisa, Italy; Andreas Schober: Department of Cardiology, Klinik Floridsdorf & Karl Landsteiner Institute for Cardiovascular and Critical Care Research, Wien, Austria; Helmut Trimmel: Department of Anesthesiology, Emergency Medicine and General Intensive Care, State Hospital Wiener Neustadt, Wiener Neustadt, Austria; Thomas Pernerstorfer: Department of Anesthesiology and Intensive Care, Ordensklinikum Linz GmbH, Barmherzige Schwestern, Linz, Austria; Christian Siebers: Department of Anesthesiology and Intensive Care, Hospital of Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany; Pavel Dostál and Jan Brujevic: Department of Anesthesiology and Intensive Care Medicine, Charles University, Faculty of Medicine in Hradec Kralove, and Department of Anesthesiology and Intensive Care Medicine, University Hospital Hradec Králové, Hradec Králové, Czech Republic; Andrea Morelli: Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, University of Rome, "La Sapienza", Policlinico Umberto Primo, Rome, Italy; Michael Joannidis: Division of Emergency Medicine and Intensive Care, Department of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria; Ingrid Pretsch: Clinic of Internal Medicine II, Division of Cardiology and Intensive Care, Paracelsus Medical University of Salzburg, Salzburg, Austria; Christian Fuchs: Department of Anesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Greifswald, Greifswald, Germany; Tim Rahmel: Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Knappschaftskrankenhaus Bochum, Bochum, Germany; Matej Podbregar: General Hospital Celje, Internal Intensive Care Department, Celje, and Medical Faculty, University of Ljubljana, Slovenia; Éva Duliczki: Szabolcs-Szatmár-Bereg County Hospitals and University Teaching Hospital Jósa András Teaching Hospital, Anesthesiology and Intensive Care Unit, Nyíregyháza, Hungary; Kadri Tamme: Tartu University Hospital, Clinic of Anesthesiology and Intensive Care, 1st. Intensive Care Unit, Tartu, Estonia; Gottfried Heinz: Medical University Vienna, Department of Internal Medicine II., Division of Cardiology, Vienna, Austria; Claudia Spies: Charité—Berlin University Medicine, Department of Anesthesiology and Operative Intensive Care Medicine, Berlin, Germany; Francesca Pratesi: Azienda Ospedaliero Universitaria Pisana, Department of Anesthesiology and Resuscitation 6, Pisa, Italy; Andrej Markota: University Medical Center Maribor, Medical Intensive Care Unit, Maribor, Slovenia; Gintautas Kekstas: Vilnius University Hospital Santaros klinikos, Center of Anesthesiology, Intensive Care and Pain Management, Vilnius, Lithuania; Ákos Csomós: MH Egészségügyi Központ—Honvédkórház Központi Aneszteziológiai és Intenzív Osztály Budapest, Hungary; Gabriella Kecskés: Petz Aladár Megyei Oktató Kórház Központi Aneszteziológiai és Intenzív Terápiás Osztály, Györ, Hungary; Peter Sarkany: B-A-Z Megyei Központi Kórház és Egyetemi Oktatókórház, Központi Aneszteziológiai és Intenzív Terápiás Osztály, Miskolc, Hungary; Bela Fülesdi: University of Debrecen, Intensive care unit, Móricz Zsigmond, Debrecen, Hungary; Rafal Wojtowicz: Central Clinical Hospital of the MSWIA in Warsaw, Clinical Department of Intensive Care and Anesthesiology, Warsaw, Poland.
Author contributions
Concept and design: MU, CK, KK, GK, SR, AM, HT, MJ, VČ, PD, CS, FG and GB. Protocol evaluation: SR, MU, CK, KK and GK. Drafting of the manuscript: MU and JS. Acquisition of data: SR, SF, VČ, RC, GB, FG, AS, HT, TP, CS, PD, AM, MJ, IP, CF, TR, MP, ED, KT and FD. Revision of the manuscript: SR, SF, VČ, RC, RB, GB, FG, AS, HT, TP, CS, PD, AM, MJ, IP, CF, TR, MP, ED, KT, MU, JS, CK, KK, NKB, GK and FD.
Funding
Open Access funding enabled and organized by Projekt DEAL. The study was sponsored by AOP Orphan Pharmaceuticals GmbH.
Data availability statement
The data that support the findings of this study are openly available in EU Clinical Trials Register at https://www.clinicaltrialsregister.eu/, EudraCT Number: 2017-002138-22.
Declarations
Conflicts of interest
All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. MU, JS, CK, KK, NKB are employees of AOP Orphan Pharmaceuticals GmbH. GK is a Board Director of AOP Health International Management AG.
Footnotes
The members of the LANDI‐SEP Study Group are listed in the Acknowledgment section of the manuscript.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Sebastian Rehberg, Email: Sebastian.Rehberg@uni-bielefeld.de.
the LANDI-SEP Study Group:
Jan Brujevic, Gottfried Heinz, Claudia Spies, Francesca Pratesi, Andrej Markota, Gintautas Kekstas, Ákos Csomós, Gabriella Kecskés, Peter Sarkany, Bela Fülesdi, and Rafal Wojtowicz
References
- 1.Bhagat K, Hingorani AD, Palacios M, Charles IG, Vallance P (1999) Cytokine-induced venodilatation in humans in vivo: eNOS masquerading as iNOS. Cardiovasc Res 41:754–764 [DOI] [PubMed] [Google Scholar]
- 2.Marx G, Vangerow B, Burczyk C, Gratz KF, Maassen N, Cobas Meyer M, Leuwer M, Kuse E, Rueckholdt H (2000) Evaluation of noninvasive determinants for capillary leakage syndrome in septic shock patients. Intensive Care Med 26:1252–1258 [DOI] [PubMed] [Google Scholar]
- 3.Parrillo JE (1993) Pathogenetic mechanisms of septic shock. N Engl J Med 328:1471–1477 [DOI] [PubMed] [Google Scholar]
- 4.Lescroart M, Pequignot B, Kimmoun A, Klein T, Levy B (2022) Beta-blockers in septic shock: what is new? J Intensive Med 2:150–155 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, Machado FR, McIntyre L, Ostermann M, Prescott HC, Schorr C, Simpson S, Wiersinga WJ, Alshamsi F, Angus DC, Arabi Y, Azevedo L, Beale R, Beilman G, Belley-Cote E, Burry L, Cecconi M, Centofanti J, Coz Yataco A, De Waele J, Dellinger RP, Doi K, Du B, Estenssoro E, Ferrer R, Gomersall C, Hodgson C, Moller MH, Iwashyna T, Jacob S, Kleinpell R, Klompas M, Koh Y, Kumar A, Kwizera A, Lobo S, Masur H, McGloughlin S, Mehta S, Mehta Y, Mer M, Nunnally M, Oczkowski S, Osborn T, Papathanassoglou E, Perner A, Puskarich M, Roberts J, Schweickert W, Seckel M, Sevransky J, Sprung CL, Welte T, Zimmerman J, Levy M (2021) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 47:1181–1247 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP (2017) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med 45:486–552 [DOI] [PubMed] [Google Scholar]
- 7.Dunser MW, Hasibeder WR (2009) Sympathetic overstimulation during critical illness: adverse effects of adrenergic stress. J Intensive Care Med 24:293–316 [DOI] [PubMed] [Google Scholar]
- 8.Leibovici L, Gafter-Gvili A, Paul M, Almanasreh N, Tacconelli E, Andreassen S, Nielsen AD, Frank U, Cauda R, Group TS (2007) Relative tachycardia in patients with sepsis: an independent risk factor for mortality. QJM. 100:629–634 [DOI] [PubMed] [Google Scholar]
- 9.Morelli A, Ertmer C, Westphal M, Rehberg S, Kampmeier T, Ligges S, Orecchioni A, D’Egidio A, D’Ippoliti F, Raffone C, Venditti M, Guarracino F, Girardis M, Tritapepe L, Pietropaoli P, Mebazaa A, Singer M (2013) Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA 310:1683–1691 [DOI] [PubMed] [Google Scholar]
- 10.Rudiger A, Singer M (2013) The heart in sepsis: from basic mechanisms to clinical management. Curr Vasc Pharmacol 11:187–195 [PubMed] [Google Scholar]
- 11.Sander O, Welters ID, Foex P, Sear JW (2005) Impact of prolonged elevated heart rate on incidence of major cardiac events in critically ill patients with a high risk of cardiac complications. Crit Care Med. 33:81–88 [DOI] [PubMed] [Google Scholar]
- 12.Schmidt H, Muller-Werdan U, Hoffmann T, Francis DP, Piepoli MF, Rauchhaus M, Prondzinsky R, Loppnow H, Buerke M, Hoyer D, Werdan K (2005) Autonomic dysfunction predicts mortality in patients with multiple organ dysfunction syndrome of different age groups. Crit Care Med 33:1994–2002 [DOI] [PubMed] [Google Scholar]
- 13.Schmittinger CA, Torgersen C, Luckner G, Schroder DC, Lorenz I, Dunser MW (2012) Adverse cardiac events during catecholamine vasopressor therapy: a prospective observational study. Intensive Care Med 38:950–958 [DOI] [PubMed] [Google Scholar]
- 14.Werdan K, Schmidt H, Ebelt H, Zorn-Pauly K, Koidl B, Hoke RS, Heinroth K, Muller-Werdan U (2009) Impaired regulation of cardiac function in sepsis, SIRS, and MODS. Can J Physiol Pharmacol 87:266–274 [DOI] [PubMed] [Google Scholar]
- 15.Copie X, Hnatkova K, Staunton A, Fei L, Camm AJ, Malik M (1996) Predictive power of increased heart rate versus depressed left ventricular ejection fraction and heart rate variability for risk stratification after myocardial infarction. Results of a two-year follow-up study. J Am Coll Cardiol 27:270–276 [DOI] [PubMed] [Google Scholar]
- 16.Diaz A, Bourassa MG, Guertin MC, Tardif JC (2005) Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J 26:967–974 [DOI] [PubMed] [Google Scholar]
- 17.Disegni E, Goldbourt U, Reicher-Reiss H, Kaplinsky E, Zion M, Boyko V, Behar S (1995) The predictive value of admission heart rate on mortality in patients with acute myocardial infarction. SPRINT study group. Secondary prevention reinfarction Israeli Nifedipine trial. J Clin Epidemiol 48:1197–1205 [DOI] [PubMed] [Google Scholar]
- 18.Dyer AR, Persky V, Stamler J, Paul O, Shekelle RB, Berkson DM, Lepper M, Schoenberger JA, Lindberg HA (1980) Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol 112:736–749 [DOI] [PubMed] [Google Scholar]
- 19.Kumar A, Schupp E, Bunnell E, Ali A, Milcarek B, Parrillo JE (2008) Cardiovascular response to dobutamine stress predicts outcome in severe sepsis and septic shock. Crit Care 12:R35 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Morelli A, Donati A, Ertmer C, Rehberg S, Kampmeier T, Orecchioni A, D’Egidio A, Cecchini V, Landoni G, Pietropaoli P, Westphal M, Venditti M, Mebazaa A, Singer M (2013) Microvascular effects of heart rate control with esmolol in patients with septic shock: a pilot study. Crit Care Med 41:2162–2168 [DOI] [PubMed] [Google Scholar]
- 21.Shang X, Wang K, Xu J, Gong S, Ye Y, Chen K, Lian F, Chen W, Yu R (2016) The effect of esmolol on tissue perfusion and clinical prognosis of patients with severe sepsis: a prospective cohort study. Biomed Res Int 2016:1038034 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Tao Y, Jingyi W, Xiaogan J, Weihua L, Xiaoju J (2015) Effect of esmolol on fluid responsiveness and hemodynamic parameters in patients with septic shock. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 27:885–889 [PubMed] [Google Scholar]
- 23.Wang S, Li M, Duan J, Yi L, Huang X, Chen D, Li G (2017) Effect of esmolol on hemodynamics and clinical outcomes in patients with septic shock. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 29:390–395 [DOI] [PubMed] [Google Scholar]
- 24.Aboab J, Sebille V, Jourdain M, Mangalaboyi J, Gharbi M, Mansart A, Annane D (2011) Effects of esmolol on systemic and pulmonary hemodynamics and on oxygenation in pigs with hypodynamic endotoxin shock. Intensive Care Med 37:1344–1351 [DOI] [PubMed] [Google Scholar]
- 25.Balik M, Rulisek J, Leden P, Zakharchenko M, Otahal M, Bartakova H, Korinek J (2012) Concomitant use of beta-1 adrenoreceptor blocker and norepinephrine in patients with septic shock. Wien Klin Wochenschr 124:552–556 [DOI] [PubMed] [Google Scholar]
- 26.Chen JX, Sun J, Liu YY, Jia BH (2013) Effects of adrenergic beta-1 antagonists on hemodynamics of severe septic patients. Zhonghua Yi Xue Za Zhi 93:1243–1246 [PubMed] [Google Scholar]
- 27.Kimmoun A, Louis H, Al Kattani N, Delemazure J, Dessales N, Wei C, Marie PY, Issa K, Levy B (2015) beta1-adrenergic inhibition improves cardiac and vascular function in experimental septic shock. Crit Care Med 43:e332-340 [DOI] [PubMed] [Google Scholar]
- 28.Suzuki T, Morisaki H, Serita R, Yamamoto M, Kotake Y, Ishizaka A, Takeda J (2005) Infusion of the beta-adrenergic blocker esmolol attenuates myocardial dysfunction in septic rats. Crit Care Med 33:2294–2301 [DOI] [PubMed] [Google Scholar]
- 29.Wang Z, Wu Q, Nie X, Guo J, Yang C (2015) Combination therapy with milrinone and esmolol for heart protection in patients with severe sepsis: a prospective, randomized trial. Clin Drug Investig 35:707–716 [DOI] [PubMed] [Google Scholar]
- 30.Wei C, Louis H, Schmitt M, Albuisson E, Orlowski S, Levy B, Kimmoun A (2016) Effects of low doses of esmolol on cardiac and vascular function in experimental septic shock. Crit Care 20:407 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Xinqiang L, Weiping H, Miaoyun W, Wenxin Z, Wenqiang J, Shenglong C, Juhao Z, Hongki Z (2015) Esmolol improves clinical outcome and tissue oxygen metabolism in patients with septic shock through controlling heart rate. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 27:759–763 [PubMed] [Google Scholar]
- 32.Yang S, Liu Z, Yang W, Zhang G, Hou B, Liu J, Shi Q (2014) Effects of the beta-blockers on cardiac protection and hemodynamics in patients with septic shock: a prospective study. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 26:714–717 [DOI] [PubMed] [Google Scholar]
- 33.Nuding S, Schroder J, Presek P, Wienke A, Muller-Werdan U, Ebelt H, Werdan K (2018) Reducing elevated heart rates in patients with multiple organ dysfunction syndrome with the if (funny channel current) inhibitor ivabradine. Shock 49:402–411 [DOI] [PubMed] [Google Scholar]
- 34.Khataminia M, Najmeddin F, Najafi A, Sharifnia H, Ahmadi A, Sahebnasagh A, Mojtahedzadeh M (2021) Effect of heart rate control with amiodarone infusion on hemodynamic and clinical outcomes in septic shock patients with tachycardia: a prospective, single-arm clinical study. J Pharm Health Care Sci 7:37 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Walkey AJ, Evans SR, Winter MR, Benjamin EJ (2016) Practice patterns and outcomes of treatments for atrial fibrillation during sepsis: a propensity-matched cohort study. Chest 149:74–83 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Kuo MJ, Chou RH, Lu YW, Guo JY, Tsai YL, Wu CH, Huang PH, Lin SJ (2021) Premorbid beta1-selective (but not non-selective) beta-blocker exposure reduces intensive care unit mortality among septic patients. J Intensive Care 9:40 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Summary of Product Characteristics (2022) Rapibloc 300 mg powder for solution for infusion. AOP Orphan Ltd. Available at https://www.medicines.org.uk/emc/. Last updated on 23 Jun 2022
- 38.Summary of Product Characteristics (2010) Esmolol hydrochloride 2500 Mg powder for concentrate for solution for infusion. AOP Orphan Ltd. Available at https://www.medicines.org.uk/emc/. Last updated on 30 Sep 2019
- 39.Ikeshita K, Nishikawa K, Toriyama S, Yamashita T, Tani Y, Yamada T, Asada A (2008) Landiolol has a less potent negative inotropic effect than esmolol in isolated rabbit hearts. J Anesth 22:361–366 [DOI] [PubMed] [Google Scholar]
- 40.Muraki K, Nakagawa H, Nagano N, Henmi S, Kawasumi H, Nakanishi T, Imaizumi K, Tokuno T, Atsuki K, Imaizumi Y, Watanabe M (1996) Effects of ONO-1101, a novel beta-antagonist, on action potential and membrane currents in cardiac muscle. J Pharmacol Exp Ther 278:555–563 [PubMed] [Google Scholar]
- 41.Sugiyama A, Takahara A, Hashimoto K (1999) Electrophysiologic, cardiohemodynamic and beta-blocking actions of a new ultra-short-acting beta-blocker, ONO-1101, assessed by the in vivo canine model in comparison with esmolol. J Cardiovasc Pharmacol 34:70–77 [DOI] [PubMed] [Google Scholar]
- 42.Plosker GL (2013) Landiolol: a review of its use in intraoperative and postoperative tachyarrhythmias. Drugs 73:959–977 [DOI] [PubMed] [Google Scholar]
- 43.Kakihana Y, Nishida O, Taniguchi T, Okajima M, Morimatsu H, Ogura H, Yamada Y, Nagano T, Morishima E, Matsuda N, Group JLSS (2020) Efficacy and safety of landiolol, an ultra-short-acting beta1-selective antagonist, for treatment of sepsis-related tachyarrhythmia (J-Land 3S): a multicentre, open-label, randomised controlled trial. Lancet Respir Med. 8:863–872 [DOI] [PubMed] [Google Scholar]
- 44.Whitehouse T, Hossain A, Perkins GD, Gordon AC, Bion J, Young D, McAuley D, Singer M, Lord J, Gates S, Veenith T, MacCallum NS, Yeung J, Innes R, Welters I, Boota N, Skilton E, Ghuman B, Hill M, Regan SE, Mistry D, Lall R, Collaborators S-L (2023) Landiolol and organ failure in patients with septic shock: the STRESS-L randomized clinical trial. JAMA 330:1641–1652 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Unger M, Morelli A, Singer M, Radermacher P, Rehberg S, Trimmel H, Joannidis M, Heinz G, Cerny V, Dostal P, Siebers C, Guarracino F, Pratesi F, Biancofiore G, Girardis M, Kadlecova P, Bouvet O, Zorer M, Grohmann-Izay B, Krejcy K, Klade C, Krumpl G (2018) Landiolol in patients with septic shock resident in an intensive care unit (LANDI-SEP): study protocol for a randomized-controlled trial. Trials 19:637 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC (2016) The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315:801–810 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Rudiger A, Singer M (2016) Decatecholaminisation during sepsis. Crit Care 20:309 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Goradia S, Sardaneh AA, Narayan SW, Penm J, Patanwala AE (2021) Vasopressor dose equivalence: a scoping review and suggested formula. J Crit Care 61:233–240 [DOI] [PubMed] [Google Scholar]
- 49.Mantzarlis K, Vazgiourakis V, Makris D (2024) Use of landiolol for patients with septic shock and organ failure. JAMA 331:705 [DOI] [PubMed] [Google Scholar]
- 50.Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, Angus DC, Rubenfeld GD, Singer M, Sepsis Definitions Task F (2016) Developing a new definition and assessing new clinical criteria for septic shock: for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315:775–787 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Bauer M, Gerlach H, Vogelmann T, Preissing F, Stiefel J, Adam D (2020) Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019- results from a systematic review and meta-analysis. Crit Care 24:239 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Matsuda N, Nishida O, Taniguchi T, Okajima M, Morimatsu H, Ogura H, Yamada Y, Nagano T, Ichikawa A, Kakihana Y, Group JLSS (2020) Impact of patient characteristics on the efficacy and safety of landiolol in patients with sepsis-related tachyarrhythmia: Subanalysis of the J-Land 3S randomised controlled study. EClinicalMedicine 28:100571 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.Fuchs C, Wauschkuhn S, Scheer C, Vollmer M, Meissner K, Kuhn SO, Hahnenkamp K, Morelli A, Grundling M, Rehberg S (2017) Continuing chronic beta-blockade in the acute phase of severe sepsis and septic shock is associated with decreased mortality rates up to 90 days. Br J Anaesth 119:616–625 [DOI] [PubMed] [Google Scholar]
- 54.Morelli A, Romano SM, Sanfilippo F, Santonocito C, Frati G, Chiostri M, Agro FE, Ertmer C, Rehberg SW, Vieillard-Baron A (2020) Systolic-dicrotic notch pressure difference can identify tachycardic patients with septic shock at risk of cardiovascular decompensation following pharmacological heart rate reduction. Br J Anaesth 125:1018–1024 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are openly available in EU Clinical Trials Register at https://www.clinicaltrialsregister.eu/, EudraCT Number: 2017-002138-22.