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Efficacy and Safety of Esmolol in Treatment of Patients with Septic Shock.

ABSTRACT: Previous studies have suggested that ?1-receptor blockers benefit septic shock patients. This study aimed to determine whether ?1-receptor blockers benefit tissue perfusion in sepsis and to identify parameters to reduce the risk of this drug in sepsis.Consecutive septic shock patients were recruited from the Intensive Care Unit of Peking Union Medical College Hospital within 48 h of diagnosis. All patients were hemodynamically stable and satisfactorily sedated with a heart rate (HR) ?100 beats/min. Esmolol therapy achieved the target HR of 10-15% lower than the baseline HR. Clinical and physiological data of patients were collected prospectively within 1 h prior to esmolol therapy and 2 h after achieving the targeted HR.Sixty-three patients were recruited. After esmolol therapy, blood pressure was unaltered, whereas stroke volume (SV) was increased compared with before esmolol therapy (43.6 ± 22.7 vs. 49.9 ± 23.7 ml, t = -2.3, P = 0.047). Tissue perfusion, including lactate levels (1.4 ± 0.8 vs. 1.1 ± 0.6 mmol/L, t = 2.6, P = 0.015) and the central venous-to-arterial carbon dioxide difference (5.6 ± 3.3 vs. 4.3 ± 2.2 mmHg, t = 2.6 P = 0.016), was also significantly decreased after esmolol therapy. For patients with increased SV (n = 42), cardiac efficiency improved, and esmolol therapy had a lower risk for a decrease in cardiac output (CO). Therefore, pretreatment cardiac systolic and diastolic parameters with (n = 42)/without (n = 21) an increase in SV were compared. Mitral lateral annular plane systolic excursion (MAPSElat) in patients with increased SV was significantly higher than that in those without increased SV (1.3 ± 0.3 vs. 1.1 ± 0.2 cm, t = 2.4, P = 0.034).SV of septic shock patients is increased following esmolol therapy. Although CO is also decreased with HR, tissue perfusion is not worse. MAPSElat can be used to predict an increase in SV before esmolol use.ClinicalTrials.gov, NCT01920776; https://clinicaltrials.gov/ct2/show/NCT01920776?term=NCT01920776&rank=1.

SUBMITTER: Du W

PROVIDER: S-EPMC4960954 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Efficacy and Safety of Esmolol in Treatment of Patients with Septic Shock.

Du Wei W Wang Xiao-Ting XT Long Yun Y Liu Da-Wei DW

Chinese medical journal 20160701 14

<h4>Background</h4>Previous studies have suggested that β1-receptor blockers benefit septic shock patients. This study aimed to determine whether β1-receptor blockers benefit tissue perfusion in sepsis and to identify parameters to reduce the risk of this drug in sepsis.<h4>Methods</h4>Consecutive septic shock patients were recruited from the Intensive Care Unit of Peking Union Medical College Hospital within 48 h of diagnosis. All patients were hemodynamically stable and satisfactorily sedated ...[more]

PMID: 27411452

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Project description:BackgroundHigh adrenergic tone appears to be associated with mortality in septic shock, while adrenergic antagonism may improve survival. In preparation for a randomized trial, we conducted a prospective, single-arm pilot study of esmolol infusion for patients with septic shock and tachycardia that persists after adequate volume expansion.MethodsFrom April 2016 to March 2017, we enrolled patients admitted to an intensive care unit with sepsis who were receiving vasopressor infusion and were tachycardic despite adequate volume expansion. All patients received a continuous intravenous infusion of esmolol, targeted to heart rate 80-90/min, while receiving vasopressors. The feasibility outcomes were proportion of eligible patients consented, compliance with pre-infusion safety check, and compliance with the titration protocol. The primary clinical outcome was organ-failure-free days (OFFD) at 28 days.ResultsWe enrolled 7 of 10 eligible patients. Mean age was 46 (± 19) years, and mean admission APACHE II was 28 (± 8). Median norepinephrine infusion rate at the initiation of esmolol infusion was 0.20 (0.14-0.23) μg/kg/min. Compliance with the safety check was 100%; compliance with components of the titration protocol was 98-100%. OFFD were 26 (24.5-26); all patients survived to day 90. Median peak esmolol infusion was 50 (25-50) μg/kg/min. Median peak norepinephrine infusion rate during esmolol infusion was 0.46 (0.13-0.50) μg/kg/min. Four patients achieved target heart rate. Protocol-defined stop events, suggesting possible intolerance to a given infusion rate, occurred in three patients, all of whom were receiving at least 50 μg/kg/min of esmolol.ConclusionsIn a pilot, single-arm study, we report the first published experience with esmolol infusion in tachycardic patients with septic shock in the United States. These findings support a phase 2 trial of esmolol infusion for septic shock. Lower infusion rates of esmolol infusion may be better tolerated and more feasible than higher infusion rates for such a trial.Trial registrationThis study was retrospectively registered at ClinicalTrials.gov (NCT02841241) on 19 July 2016.

Project description:IntroductionSeptic shock is often characterized by tachycardia and a hyperdynamic hemodynamic profile. Use of the beta antagonist esmolol has been proposed as a therapy to lower heart rate, thereby improving diastolic filling time and improving cardiac output, resulting in a reduction in vasopressor support.MethodsWe conducted a two-center, open-label, randomized, Phase II trial comparing esmolol to placebo in septic shock patients with tachycardia. The primary endpoint was improvement in hemodynamics as measured by the difference in norepinephrine equivalent dose (NED) between groups at 6 hours after initiation of study drug. Secondary outcomes included assessing differences in inflammatory biomarkers and oxygen consumption (VO2).ResultsA total of 1,122 patients were assessed for eligibility and met inclusion criteria; 42 underwent randomization, and 40 received study interventions (18 in the esmolol arm and 22 in the usual care arm). The mean NED at 6 h was 0.30 ± 0.17 mcg/kg/min in the esmolol arm compared to 0.21 ± 0.19 in the standard care arm (P = 0.15). There was no difference in number of shock free days between the esmolol (2, IQR 0, 5) and control groups (2.5, IQR 0, 6) (P = 0.32). There were lower levels of C-reactive protein at 12 and 24 h in the esmolol arm, as well as a statistically significant difference in trend over time between groups. There were no differences in terms of IL-4, IL-6, IL-10, and TNFα. Among a subset who underwent VO2 monitoring, there was decreased oxygen consumption in the esmolol patients; the mean difference between groups at 24 h was -2.07 mL/kg/min (95% CI -3.82, -0.31) (P = 0.02), with a significant difference for the trend over time (P < 0.01).ConclusionAmong patients with septic shock, infusion of esmolol did not improve vasopressor requirements or time to shock reversal. Esmolol was associated with decreased levels of C-reactive protein over 24 h.Trial registrationwww.clinicaltrials.gov. Registered February 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02369900.

Project description:BackgroundSeveral studies have shown that heart rate control with selective beta-1 blockers in septic shock is safe. In these trials, esmolol was administered 24 h after onset of septic shock in patients who remained tachycardic. While an earlier use of beta-blockers might be beneficial, such use remains challenging due to the difficulty in distinguishing between compensatory and non-compensatory tachycardia. Therefore, the Esmosepsis study was designed to study the effects of esmolol aimed at reducing the heart rate by 20% after the initial resuscitation process in hyperkinetic septic shock patients on (1) cardiac index and (2) systemic and regional hemodynamics as well as inflammatory patterns.MethodsNine consecutive stabilized tachycardic hyperkinetic septic shock patients treated with norepinephrine for a minimum of 6 h were included. Esmolol was infused during 6 h in order to decrease the heart rate by 20%. The following data were recorded at hours H0 (before esmolol administration), H1-H6 (esmolol administration) and 1 h after esmolol cessation (H7): systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, central venous pressure, heart rate, PICCO transpulmonary thermodilution, sublingual and musculo-cutaneous microcirculation, indocyanine green clearance and echocardiographic parameters, diuresis, lactate, and arterial and venous blood gases.ResultsEsmolol was infused 9 (6.4-11.6) hours after norepinephrine introduction. Esmolol was ceased early in 3 out of 9 patients due to a marked increase in norepinephrine requirement associated with a picture of persistent cardiac failure at the lowest esmolol dose. For the global group, during esmolol infusion, norepinephrine infusion increased from 0.49 (0.34-0.83) to 0.78 (0.3-1.11) µg/min/kg. The use of esmolol was associated with a significant decrease in heart rate from 115 (110-125) to 100 (92-103) beats/min and a decrease in cardiac index from 4.2 (3.1-4.4) to 2.9 (2.5-3.7) l/min/m-2. Indexed stroke volume remained unchanged. Cardiac function index and global ejection fraction also markedly decreased. Using echocardiography, systolic, diastolic as well as left and right ventricular function parameters worsened. After esmolol cessation, all parameters returned to baseline values. Lactate and microcirculatory parameters did not change while the majority of pro-inflammatory proteins decreased in all patients.ConclusionIn the very early phase of septic shock, heart rate reduction using fast esmolol titration is associated with an increased risk of hypotension and decreased cardiac index despite maintained adequate tissue perfusion (NCT02068287).

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Efficacy and Safety of Esmolol in Treatment of Patients with Septic Shock.

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Efficacy and Safety of Esmolol in Treatment of Patients with Septic Shock.

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