A simple and robust parametric shared frailty model for recurrent events with the competing risk of death: An application to the Carvedilol Prospective Randomized Cumulative Survival trial.

Many non-fatal events can be considered recurrent in that they can occur repeatedly over time, and some researchers may be interested in the trajectory and relative risk of non-fatal events. With the competing risk of death, the treatment effect on the mean number of recurrent events is non-identifiable since the observed mean is a function of both the recurrent event and terminal event processes. In this paper, we assume independence between the non-fatal and the terminal event process, conditional on the shared frailty, to fit a parametric model that recovers the trajectory of, and identifies the effect of treatment on, the non-fatal event process in the presence of the competing risk of death. Simulation studies are conducted to verify the reliability of our estimators. We illustrate the method and perform model diagnostics using the Carvedilol Prospective Randomized Cumulative Survival trial which involves heart-failure events.

Which should you choose for post operative atrial fibrillation, carvedilol or metoprolol? A systemic review and meta-analysis.

BACKGROUND: Postoperative atrial fibrillation (POAF) is the most common arrhythmic complication following cardiac surgery. Current guidelines suggest beta-blockers for the prevention of POAF. In comparing metoprolol succinate with carvedilol, the later has sparked interest in its usage as an important medication for POAF prevention. METHODS: We considered randomized controlled studies (RCTs) and retrospective studies that evaluated the efficacy of carvedilol versus metoprolol for the prevention of POAF. After literature search, data extraction, and quality evaluation, pooled data were analyzed using either the fixed-effect or random-effect model using Review Manager 5.3. The Cochrane risk of bias tool was used to assess the bias of included studies. The incidence of POAF was the primary endpoint, while mortality rate and bradycardia were secondary outcomes. RESULTS: In meta-analysis 5 RCTs and 2 retrospective studies with a total of 1000 patients were included. The overall effect did not favor the carvedilol over metoprolol groups in terms of mortality rate [risk ratio 0.45, 95 % CI (0.1-1.97), P=0.29] or incidence of bradycardia [risk ratio 0.63, 95 % CI (0.32-1.23), P=0.17]. However, the incidence of POAF was lower in patients who received carvedilol compared to metoprolol [risk ratio 0.54, 95 % CI (0.42-0.71), P < 0.00001]. CONCLUSION: In patients undergoing cardiac surgery, carvedilol may minimize the occurrence of POAF more effectively than metoprolol. To definitively establish the efficacy of carvedilol compared to metoprolol and other beta-blockers in the prevention of POAF, a large-scale, well-designed randomized controlled trials are required.

Efficacy of a single dose of esmolol to prevent extubation-related complications during emergence from anesthesia: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Few trials have examined the efficacy of esmolol to attenuate hemodynamic and respiratory responses during extubation. However, the most appropriate dose of esmolol and an optimal protocol for administering this beta-blocker are uncertain. METHODS: Ninety patients ASA physical status I, II, and III (aged 18...60 years) scheduled to procedures with general anesthesia and tracheal extubation were selected. Patients were randomized into esmolol and placebo group to evaluate the efficacy and safety of a single bolus dose of esmolol (2...mg.kg-1) on cardiorespiratory responses during the peri-extubation period. The primary outcome was the rate of tachycardia during extubation. RESULTS: The rate of tachycardia was significantly lower in esmolol-treated patients compared to placebo-treated patients (2.2% vs. 48.9%, relative risk (RR): 0.04, 95% confidence interval (95% CI)...=...0.01 to 0.32, p...=...0.002). The rate of hypertension was also significantly lower in the esmolol group (4.4% vs. 31.1%, RR: 0.14, 95% CI 0.03 to 0.6, p...=...0.004). Esmolol-treated patients were associated with higher extubation quality compared to patients who received placebo (p...<...0.001), with an approximately two-fold increase in the rate of patients without cough (91.1%) in the esmolol group compared to the placebo group (46.7%). The rate of bucking was approximately 5-fold lower in the esmolol group (8.9% vs. 44.5%, respectively, RR: 0.20 (95% CI, 0.1 to 0.5, p...=...0.002, with an NNT of 2.8). CONCLUSION: A single bolus dose of esmolol is an effective and safe therapeutic strategy to attenuate cardiorespiratory responses during the peri-extubation period.

Efficacy of a single dose of esmolol to prevent extubation-related complications during emergence from anesthesia: a randomized, double-blind, placebo-controlled trial

Abstract Background Few trials have examined the efficacy of esmolol to attenuate hemodynamic and respiratory responses during extubation. However, the most appropriate dose of esmolol and an optimal protocol for administering this beta-blocker are uncertain. Methods Ninety patients ASA physical status I, II, and III (aged 18-60 years) scheduled to procedures with general anesthesia and tracheal extubation were selected. Patients were randomized into esmolol and placebo group to evaluate the efficacy and safety of a single bolus dose of esmolol (2 mg.kg-1) on cardiorespiratory responses during the peri-extubation period. The primary outcome was the rate of tachycardia during extubation. Results The rate of tachycardia was significantly lower in esmolol-treated patients compared to placebo-treated patients (2.2% vs. 48.9%, relative risk (RR): 0.04, 95% confidence interval (95% CI) = 0.01 to 0.32, p= 0.002). The rate of hypertension was also significantly lower in the esmolol group (4.4% vs. 31.1%, RR: 0.14, 95% CI 0.03 to 0.6, p= 0.004). Esmolol-treated patients were associated with higher extubation quality compared to patients who received placebo (p< 0.001), with an approximately two-fold increase in the rate of patients without cough (91.1%) in the esmolol group compared to the placebo group (46.7%). The rate of bucking was approximately 5-fold lower in the esmolol group (8.9% vs. 44.5%, respectively, RR: 0.20 (95% CI, 0.1 to 0.5, p= 0.002, with an NNT of 2.8). Conclusion A single bolus dose of esmolol is an effective and safe therapeutic strategy to attenuate cardiorespiratory responses during the peri-extubation period.

Carvedilol ameliorates dexamethasone-induced myocardial injury in rats independent of its action on the α1-adrenergic receptor.

The current study aimed to investigate the cardiotoxic effect of dexamethasone-high-dose in rats, the therapeutic effect of carvedilol and the role of α1-adrenergic receptor (α1AR). The experiment involved 6 groups: control, dexamethasone (10 mg/kg), carvedilol (10 mg/kg), phenylephrine (1 mg/kg), phenylephrine plus carvedilol and propranolol (30 mg/kg). Drugs and vehicles were given for 7 days. Dexamethasone was given with the drugs in the last 4 groups. On the 8th-day and after overnight fasting, serum and cardiac samples were collected. Serum levels of cardiac troponin I and creatine kinase-myoglobin as well as cardiac levels of diacylglycerol, malondialdehyde, kinase activity of Akt, transforming growth factor-ß, Smad3 and alpha smooth muscle actin were measured. Cardiac samples were also used for histopathological examination using hematoxylin-eosin and Sirius red stains, in addition to immunohistochemical examination using ß-arrestin2 antibody. Dexamethasone induced cardiac injury via increasing oxidative stress, apoptosis and profibrotic signals. Carvedilol significantly reduced the dexamethasone-induced cardiotoxicity. Using phenylephrine, a competitive α1-agonist, with carvedilol potentiated the cardioprotective actions of carvedilol. Propranolol, a ß-blocker without activity on α1ARs, showed higher cardiac protection than carvedilol. Dexamethasone-high-dose upregulates cardiac oxidative stress, apoptotic and profibrotic signals and induces cardiac injury. Blocking the α1-adrenergic receptor by carvedilol attenuates its cardioprotective effects against dexamethasone-induced cardiotoxicity.

Esmolol for intractable ventricular arrhythmias in major amitriptyline toxicity.

A massive tricyclic overdose of 10 g of amitriptyline resulted in cardiovascular collapse with multiple episodes of ventricular tachycardia and ventricular fibrillation despite aggressive attention to current recommended therapy of sodium bicarbonate and hypertonic saline, and correction of electrolytes. Second-line antiarrhythmic therapies failed to reduce the recurrent deterioration to malignant ventricular rhythms. Progression to extracorporeal support was avoided by the use of a titrated esmolol infusion. We discuss the physiological rationale by which esmolol may prevent tachyarrhythmia and fibrillation in severe amitriptyline toxicity.

Benefits of esmolol in adults with sepsis and septic shock: An updated meta-analysis of randomized controlled trials.

BACKGROUND: Sepsis affects millions of patients annually, resulting in substantial health and economic burdens globally. The role of esmolol potentially plays in the treatment of sepsis and septic shock in adult patients remains controversial. METHODS: We undertook a systematic search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases from their inception to May 12, 2022, for randomized controlled trials that evaluated the efficacy of esmolol for sepsis and septic shock. A random-effects meta-analysis was performed. Two investigators independently screened articles, extracted data, and assessed the quality of included studies. RESULTS: Eight studies from 7 randomized controlled trials were included in our meta-analysis of 503 patients with sepsis and/or septic shock. Compared with standard treatment, esmolol significantly decreased 28-day mortality (risk ratio 0.68, 95% confidence interval [CI] 0.52-0.88; P = .004), heart rate (standardized mean difference [SMD] -1.83, 95% CI -2.95 to -0.70, P = .001), tumor necrosis factor-a (SMD -0.48, 95% CI -0.94 to -0.02, P = .04), and the troponin I level (SMD -0.59, 95% CI -1.02 to -0.16, P = .008) 24 hours after treatment. No significant effect was found in terms of length of intensive care unit stay; mean arterial pressure, lactic acid, central venous pressure, or central venous oxygen saturation, interleukin 6, or white blood cell levels; stroke volume index; or the PaO2/FiO2 ratio. CONCLUSIONS: Esmolol treatment may be safe and effective in decreasing 28-day mortality, controlling heart rate, and providing cardioprotective function, but has no effect on lung injury in patients with sepsis or septic shock after early fluid resuscitation. Improvement in cardiac function may be related to changes in serum inflammatory mediators. No significant adverse effects on tissue perfusion and oxygen utilization were observed.

Beneficial effects of carvedilol modulating potassium channels on the control of glucose.

The increased prevalence of hypertensive patients with type 2 diabetes mellitus (T2DM) is evident worldwide, leading to a higher risk of cardiovascular disease onset, which is substantially associated with disabilities and mortality in the clinic. In order to achieve the satisfyingly clinical outcomes and prognosis, the comprehensive therapies have been conducted with a beneficial effect on both blood pressure and glucose homeostasis, and clinical trials reveal that some kind of antihypertensive drugs such as angiotensin converting enzyme inhibitors (ACE-I) may, at least in part, meet the dual requirement during the disease management. As a nonselective ß-blocker, carvedilol is employed for treating many cardiovascular diseases in clinical practice, including hypertension, angina pectoris and heart failure, and also exhibit the effectiveness for glycemic control and insulin resistance. Apart from alleviating sympathetic nervous system activity, several causes, such as lowering oxygen reactive species, may contribute to the effects of carvedilol on controlling plasma glucose levels, suggesting a feature of this drug having multiple targets. Interestingly, numerous distinct K+ channels expressed in pancreatic ß-cells and peripheral insulin-sensitive tissues, which play a sentential role in glucose metabolism, are subjected to extensive modulation of carvdilol, establishing a linkage between K+ channels and drug's effects on the control of glucose. A variety of evidence shows that the impact of carvedilol on different K+ channels, including Kv, KAch, KATP and K2 P, can lead to positive influences for glucose homeostasis, contributing to its clinical beneficial effectiveness in treatment of hypertensive patients with T2DM. This review focus on the control of plasma glucose conferred by carvedilol modulation on K+ channels, providing the novel mechanistic explanation for drug's actions.

[Heart rate control in shock]. / Herzfrequenzkontrolle im Schock.

Heart rate is well established in the diagnosis of shock; however, the mechanisms regulating heart rate, systemic resistance and blood pressure remain unclear. The concept of heart rate control in shock-related tachycardia has been known for about 50 years. Elevated heart rates in septic shock have been identified as an indicator of increasingly inefficient hemodynamics, worsening perfusion and organ function as well as of an unfavourable prognosis. Many drugs used for heart rate control also lower blood pressure. The challenge of this therapeutic concept is achieving optimal heart rate control without provoking critical hypotension. Only in recent years has the development of highly cardioselective, short- and ultrashort-acting ß­blockers such as esmolol and landiolol made it possible to prove the feasibility and usefulness of heart rate control in certain types of shock.

Effects of esmolol continuous infusion on blood loss in patients undergoing posterior lumbar internal fixation surgery: A prospective randomized study.

OBJECTIVE: To determine the intravenous (i.v.) dose of esmolol needed to attenuate blood loss in patients undergoing posterior lumbar internal fixation (PLIF) surgery. METHODS: This study randomized patients to either the E5 or E10 group. Patients in the E5 group received a 0.25 mg/kg i.v. loading dose of esmolol before anaesthesia, followed by an infusion of 5 µg/kg/min throughout the operation. Patients in the E10 group received a 0.5 mg/kg i.v. loading dose of esmolol before anaesthesia, followed by an infusion of 10 µg/kg/min throughout the operation. RESULTS: The study analysed 33 patients: 16 in the E5 group and 17 in the E10 group. The mean ± SD blood loss at the end of surgery was significantly greater in the E5 than E10 group (586.3 ± 160.1 versus 347.7 ± 138.0 ml, respectively). The total amount of patient-controlled analgesia (PCA) used was significantly higher in the E5 than E10 group at 8 (26.1 ± 12.0 versus 17.5 ± 8.3 ml, respectively), 24 (58.4 ± 21.3 versus 44.1 ± 16.2 ml, respectively) and 48 h after surgery (90.0 ± 22.5 versus 69.3 ± 22.1 ml, respectively). CONCLUSION: A continuous infusion of 10 µg/kg/min of esmolol can safely reduce blood loss during PLIF surgery. It was also shown to reduce postoperative PCA consumption.

Application of Esmolol to Control Heart Rate and Artificial Intelligence Reconstruction Analysis for Rapid Zero-Cooperation Emergency Coronary CTA.

Objective: To investigate a rapid and effective method for the examination of coronary CTA in emergency patients requiring coronary CTA examination, who have faster heart rate (≧80 bpm) or cannot cooperate with the examination due to the inability of breath holding at poor physical conditions. Methods: Before coronary CTA examination, with the ECG monitoring, intravenous injection of esmolol was given to achieve rapid heart rate reduction. Without the patient's cooperation, coronary CTA examination was then performed in a quick and effective manner using the 640-slice high-speed CT. The diagnosis report was obtained through the subsequent reconstruction analysis using artificial intelligence software. Conclusion: Esmolol injection can rapidly reduce the heart rate of normal people during exercise and at rest, and the steady blood concentration can be reached in 2 minutes. The half-life is about 5 minutes, with short duration and fewer side effects on patients. The diagnostic rate of coronary artery segment using (excellent + good) CTA image of the patients with esmolol and artificial intelligence analysis in the experimental group was 95.4%, while the diagnostic rate was 91.1% in the control group, and there was no significant statistical difference between the two groups (P > 0.05). Esmolol injection can rapidly reduce heart rate in patients with high heart rate, without holding breath or long-term preoperative preparation; the combination with the analysis of subsequent artificial intelligence reconstruction is a new method for rapid and effective coronary CTA examination in all patients.

Esmolol to Treat the Hemodynamic Effects of Septic Shock: A Randomized Controlled Trial.

INTRODUCTION: Septic 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. METHODS: We 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). RESULTS: A 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 ±â€Š0.17 mcg/kg/min in the esmolol arm compared to 0.21 ±â€Š0.19 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). CONCLUSION: Among 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 REGISTRATION: www.clinicaltrials.gov. Registered February 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02369900.

Use of esmolol for control of tachycardia in 28 dogs and cats (2003-2020).

OBJECTIVE: To describe the indications and clinical response for dogs and cats treated with esmolol. DESIGN: Retrospective case series from 2003 to 2020. SETTING: Single university veterinary teaching hospital. ANIMALS: Twenty-two dogs and 6 cats. INTERVENTIONS: Animals received either a bolus or bolus and continuous rate infusion of the ultrashort-acting beta receptor antagonist, esmolol. MEASUREMENTS AND MAIN RESULTS: Twenty-two animals were treated for either a supraventricular or sinus tachycardia, 5 were treated for a ventricular tachycardia, and 1 was treated for atrial fibrillation. Esmolol was most frequently used in dogs (N = 9) who had ingested a toxin such as albuterol, amphetamine, or chocolate. Esmolol was administered at median bolus dose of 330 µg/kg (range 10-1000 µg/kg) and continued as a continuous rate infusion in 15 animals at a median dose of 50 µg/kg/min. Defining success as a reduction in heart rate of 20% or greater, esmolol therapy was considered successful in 13 of 28 animals (46%). Animals treated for a toxicosis were more likely to have a successful rate reduction than those treated for other causes (P = 0.006). Nineteen animals survived to discharge. Both treatment success (P = 0.046) and treatment for a toxicosis (P = 0.003) were associated with survival. CONCLUSIONS: Esmolol administration was well tolerated by dogs and cats with tachycardia due to intoxication. Heart rate reduction by at least 20% was achieved in 46% of cases. Animals with toxin ingestion were more likely to be discharged from the hospital.

Validation of Fenoterol to Study ß2-Adrenoceptor Function in the Rat Urinary Bladder.

Fenoterol is a ß2-adrenoceptor (AR)-selective agonist that is commonly used to investigate relaxation responses mediated by ß2-AR in smooth muscle preparations. Some data have questioned this because fenoterol had low potency in the rat urinary bladder when a muscarinic agonist was used as a pre-contraction agent and because some investigators proposed that fenoterol may act in part via ß3-AR. We designed the present study to investigate whether fenoterol is a proper pharmacological tool to study ß2-AR-mediated relaxation responses in the rat urinary bladder. Firstly, we have compared the effect of pre-contraction agents on fenoterol potency and found that fenoterol potency was about 1.5 log units greater against KCl than carbachol (pEC50 7.19 ± 0.66 and 5.62 ± 1.09 of KCl and of carbachol, respectively). To test the selectivity of fenoterol, we have determined the effects of the ß2-AR antagonist ICI 118,551 and the ß3-AR antagonist L 748,337 on relaxation responses to fenoterol. While 300 nM L 748,337 had little effect on the potency of fenoterol (pEC50 6.56 ± 0.25 and 6.33 ± 0.61 in the absence and presence of L 748,337, respectively), the relaxation curve for fenoterol was right-shifted in the presence 300 nM ICI 118,551 (pEC50 5.03 ± 0.18). Thus, we conclude that fenoterol is a proper pharmacological tool to assess ß2-AR-mediated responses in the rat urinary bladder and most likely in other smooth-muscle preparations containing multiple subtypes of the ß-AR.

Effects of lidocaine and esmolol on hemodynamic response to tracheal intubation: a randomized clinical trial.

INTRODUCTION AND OBJECTIVES: Although lidocaine is widely used to prevent cardiovascular changes resulting from laryngoscopy and orotracheal intubation, it is still unclear whether there are more efficacious drugs. This study aimed to compare the beta-blocker esmolol with lidocaine regarding the effects on hemodynamic response after orotracheal intubation. METHODS: The study has a prospective, randomized, double-blind, superiority design, and assessed 69 participants between 18 and 70 years of age, ASA I-II, scheduled for elective or emergency surgery under general anesthesia with orotracheal intubation. Participants were randomly allocated to receive 1.5 mg.kg-1 esmolol bolus followed by 0.1 mg.kg-1.min-1 esmolol infusion (n = 34) or 1.5 mg.kg-1 lidocaine bolus followed by 1.5 mg.kg-1.h-1 lidocaine infusion (n = 35). We recorded changes in heart rate, arterial blood pressure and incidence of adverse events. RESULTS: Post-intubation tachycardia episodes were significantly less frequent in the esmolol group (5.9% vs. 34.3%; Relative Risk (RR) 0.17; 95% Confidence Interval (95% CI) 0.04-0.71; Number Needed to Treat (NNT) 3.5; p = 0.015. After orotracheal intubation, mean heart rate was significantly lower in the esmolol group (74.5 vs. 84.5, p = 0.006). Similar results were observed in the subsequent 3 and 6 minutes (75.9 vs. 83.9, p = 0.023 and 74.6 vs. 83.0, p = 0.013, respectively). CONCLUSION: Esmolol was a safe and more effective intervention to reduce incidence of tachycardia and control heart rate immediately after tracheal intubation when compared to lidocaine.

Bucindolol Decreases Atrial Fibrillation Burden in Patients With Heart Failure and the ADRB1 Arg389Arg Genotype.

[Figure: see text].

The use of ß-blockers in patients with heart failure and comorbidities: Doubts, certainties and unsolved issues.

ß-blockers represent a mainstay in the pharmacological approach to patients affected by heart failure with reduced ejection fraction (HFrEF). However, underuse of this class of drugs is still reported, especially in the presence of cardiovascular and non-cardiovascular comorbidities, even if they are not contraindications for prescription of a ß-blocker. The prognostic benefit of ß-blockers is relevant in the presence of comorbidities, and achievement of the maximum tolerated dose is an important goal to increase their favorable prognostic role. The aim of the present review is to analyze the available evidence on the use of ß-blockers in HFrEF patients with the most common comorbidities. In particular, we will discuss the role and most appropriate beta-blocker in patients with pulmonary disease (bisoprolol, metoprolol, nebivolol), diabetes (carvedilol and nebivolol), atrial fibrillation (all indicated for rate control, with metoprolol as the first choice followed by bisoprolol, nebivolol, and carvedilol), erectile dysfunction (bisoprolol and nebivolol), peripheral arterial disease (nebivolol), and other conditions, in order to clarify the correct use of this class of drugs in the clinical practice.