Administration Of Β-blockers Research Articles

Transvenous Radiofrequency Catheter Ablation for an Aldosterone-Producing Tumor of the Left Adrenal Gland: A First in Human Case Report

PurposeTo describe a novel technique of transvenous radiofrequency catheter ablation of an aldosterone-producing adenoma (APA) of the left adrenal gland using the GOS System (Japan Lifeline, Tokyo, Japan). Using the GOS system, a flexible radiofrequency tip catheter can be inserted into the adrenal central and tributary veins, the drainers for functional tumors.Materials and methodsAn APA at the left adrenal gland, which was diagnosed by segmental adrenal venous sampling following administration of 0.25 mg cosyntropin, was ablated using the GOS catheter inserted into adrenal tributary veins via a right femoral vein 7-Fr sheath. The effect of radiofrequency ablation on APA was assessed using the international consensus on surgical outcomes for unilateral primary aldosteronism (PA).ResultsNo device-related complications were observed. The patient was deeply sedated under blood pressure and heart rate control with continuous administration of β-blockers. Then, the tumor and surrounding adrenal gland were cauterized at 7000 J two times each in sequence. The output time was 7−11 min for each ablation and 80 min in total. For blood pressure and pulse rate control, esmolol hydrochloride and phentolamine mesylate were used. The contrast enhancement of APA disappeared on dynamic CT immediately after the procedure. PA was biochemically cured until 12 months after the procedure.ConclusionUsing the radiofrequency device with the GOS catheter and system is a method for cauterizing adrenal tumors from blood vessels. This approach resulted in a marked reduction in aldosterone concentrations and a complete biochemical cure of PA over the observation period.Graphical

Prognostic Impact of Early Administration of β-Blockers in Critically Ill Patients with Acute Myocardial Infarction.

In critically ill patients with acute myocardial infarction (AMI), the relationship between the early administration of β-blockers and the risks of in-hospital and long-term mortality remains controversial. Furthermore, there are conflicting evidences for the efficacy of the early administration of intravenous followed by oral β-blockers in AMI. We conducted a retrospective analysis of critically ill patients with AMI who received the early administration of β-blockers within 24hours of admission. The data were extracted from the Medical Information Mart for Intensive Care IV database. We enrolled 2467 critically ill patients with AMI in the study, with 1355 patients who received the early administration of β-blockers and 1112 patients who were non-users. Kaplan-Meier survival analysis and Cox proportional hazards models showed that the early administration of β-blockers was associated with a lower risk of in-hospital mortality (adjusted hazard ratio [aHR]0.52; 95% confidence interval [95%CI] 0.42-0.64), 1-year mortality (aHR0.54, 95%CI 0.47-0.63), and 5-year mortality (aHR0.60, 95%CI 0.52-0.69). Furthermore, the early administration of both oral β-blockers and intravenous β-blockers followed by oral β-blockers may reduce the mortality risk, compared with non-users. The risks of in-hospital and long-term mortality were significantly decreased in patients who underwent revascularization with the early administration of β-blockers. We found that the early administration of β-blockers could lower the risks of in-hospital and long-term mortality. Furthermore, the early administration of both oral β-blockers and intravenous β-blockers followed by oral β-blockers may reduce the mortality risk, compared with non-users. Notably, patients who underwent revascularization with the early administration of β-blockers showed the lowest risks of in-hospital and long-term mortality.

Investigating the Influence of High-Speed Gantry Rotation in Cardiac CT on Motion Artifacts in Aortic Stenosis Patients Not Premedicated with β-Blockers: The FAST-CCT Randomized Trial Protocol.

Coronary CT angiography (CCTA) is increasingly used as a non-invasive tool to assess coronary artery disease (CAD). However, CCTA is subject to motion artifacts, potentially limiting its clinical utility. Despite faster (0.35 and 0.28 s/rot) gantry rotation times, low (60-65 bpm) heartbeat is recommended, and the use of β-blockers is often needed. Technological advancements have resulted in the development of faster rotation speeds (0.23 s/rot). However, their added value in patients not premedicated with β-blockers remains unclear. This prospective single-center, two-arm, randomized, controlled trial aims to assess the influence of fast rotation on coronary motion artifacts, diagnostic accuracy of CCTA for CAD, and patient safety. We will randomize a total of 142 patients aged ≥ 50 scheduled for an aortic stenosis work-up to receive CCTA with either a fast (0.23) or standard (0.28 s/rot) gantry speed. rate of CCTAs with coronary motion artifacts hindering interpretation. assessable coronary segments rate, diagnostic accuracy against invasive coronary angiography (ICA), motion artifact magnitude per segment, contrast-to-noise ratio (CNR), and patient ionizing radiation dose. The local ethics committee has approved the protocol. Potential significance: FAST-CCT may improve motion artifact reduction and diagnosis quality, thus eliminating the need for rate control and β-blocker administration. gov identifier: NCT05709652.

Psychoneuro-oncology: How chronic stress grows cancer.

Chronic stress is an inextricable part of modern daily living; practically all human diseases, particularly cancer, are negatively affected by it. Numerous studies have shown that stressors, depression, social isolation, and adversity correlate with a worse prognosis for patients with cancer, with increased symptoms, early metastasis, and a shortened life span. Prolonged or very intense adverse life episodes are perceived and assessed by the brain and translated into physiologic responses mediated through relays to the hypothalamus and locus coereleus. This response triggers the activation of the hypothalamus-pituitary-adrenal axis (HPA) and the peripheral nervous system (PNS) with the secretion of glucocorticosteroids/epinephrine and norepinephrine (NE). These hormones and neurotransmitters affect immune surveillance and the immune response to malignancies by skewing immunity from a type 1 to a type 2 response; this process not only impedes the detection and killing of cancer cells but induces immune cells to facilitate cancer growth and systemic spread. It may be mediated by the engagement of norepinephrine to β-adrenergic receptors, which can be partially reversed by the administration of β-blockers.

β-Blockade before Noncardiac Surgery: The Devil Is in the Details.

β-Blockade before Noncardiac Surgery: The Devil Is in the Details.

Influence of β- blockers on the activity of some anti-epileptic drugs on convulsions induced by picrotoxin in mice

Adrenergic β-receptor blockers are widely used in clinic for the management of cardiovascular disease and some other illnesses. However, this group of drugs known to cause central nervous system side effects such as drowsiness, sleep disturbance, hallucination, migraine and tremors. As anti-epileptic drugs exert their action mainly through the inhibition of the central nervous system to decrease the firing and the excitability of neurons. Accordingly, β-blockers might influence the pharmacological activity of anti-epileptic drugs. Aim:The aims of this study is to investigate the influence of β –blockerson the anti-convulsant activity of two anti-epileptic drugs, i.e. phenytoin and phenobarbital. Methods: Three beta blockers with different β-receptor blocking selectivity and degree of solubility (atenolol, metoprolol, and propranolol) were injected intraperitoneally (IP) into mice either alone or in combination with phenytoin or phenobarbital. After 30 min mice were injected with picrotoxin (8mg/kg) to induce convulsions. Convulsion parameters recorded were; the onset of jerks, number of tonic and clonic convulsions, and % mortality. Results: Picrotoxin produced 100% death in all control animals. However, mosttheanimals treated with antiepileptics alone or in combination with β-blockers were protected from death. The effect of phenytoin on the onset of convulsions was significantlyenhanced when it combined with β-blockers. However, in regard to phenobarbital only the increase was noticed with propranolol. Giving phenytoin with β-blockers improves its effect in reducing clonic convulsion, whereas, no change in phenobarbital activity when administered together with β-blockers. Combination of either phenytoin or phenobarbital with β-blockers did not result in any significant change in their ability to reduce tonic convulsions except when phenytoin co-administered with metoprolol a significant decrease was observed. Conclusion: The administration of β-blockers in concomitant with phenytoin and phenobarbital increased their anticonvulsant activity. However, β-blockers alone could have some protective effect against convulsions.

Effects of Β‒Blocker Administration on Cardiac Function: A Coronary Computed Tomography Angiography Study.

β-blockers are widely used for lowering heart rate (HR) during coronary computed tomography angiography (CCTA); however, they should be used with caution for patients with heart failure as they may have a negative inotropic effect. To clarify the effects of β-blockers (oral and intravenous injection) on cardiac function using CCTA. A total of 244 patients (men: women = 166: 78; mean age, 64.4 years old) suspected of having ischemic cardiac disease and had undergone echocardiography within 3 months before and after CCTA were included in the study. Systematic errors in ejection fraction (EF) were corrected by calculating ΔEF from the EF difference between echocardiography and CCTA in patients not using β- blockers. Univariate and multivariate analyses were performed for factors affecting ΔEF. In addition, HR between, before, and during CCTA were compared by Wilcoxon's test. Temporary oral or intravenous administration of β-blockers at the CCTA had no significant effects on EF (p = 0.70), whereas HR was significantly decreased (p < 0.001). However, regular administration of β-blockers increases the EF on CCTA. The administration of β-blockers immediately before CCTA affects HR but not EF. Premedication with β-blockers can be safely used for patients who undergo CCTA, and CCTA is useful for EF evaluation, independent of the use of β-blockers.

Effect of β-blocker on patients with moderate functional mitral regurgitation undergoing surgical aortic valve replacement.

The optimal treatment for severe aortic valve disease complicated with moderate function mitral regurgitation (FMR) remains controversial. Although isolated surgical aortic valve replacement (SAVR) is reasonable, previous studies also show that moderate FMR might deteriorate after surgical treatment and result in poorer prognosis. Because the left ventricular remodelling plays a critical role in the development of FMR, these patients might potentially benefit from the administration of β-blocker (BB). Unfortunately, relevant clinical evidence is lacking. This study aimed to investigate the impact of post-operative administration of BB on the outcomes of moderate FMR patients undergoing isolated SAVR. In this single-centre cohort study, patients who underwent isolated SAVR and complicated with pre-operative moderate FMR during 2010 and 2019 at our centre were retrospectively recruited. Patients were divided into two groups according to postoperative administration of BB (BB group vs. control group). The cumulative survival rates were calculated using the Kaplan-Meier method and tested by the log-rank test, followed by inverse probability treatment weighting (IPTW) analysis to further control the between-group imbalances. The primary outcome was the major adverse cardiovascular and cerebrovascular events (MACCE), a composite endpoint of all-cause death, repeat heart valve surgery, non-fatal myocardial infarction, stroke, and hospitalization for heart failure. A total of 165 patients were enrolled, 57 (34.6%) of whom were female, and the mean age was 59.2±12.2years. Eighty (48.5%) patients received post-operative BB therapy. The median follow-up time was 18.4months. The administration of BB was not associated with lower risk of MACCE [hazard ratio (HR): 0.68, 95% confidence interval (CI): 0.29-1.62, P=0.388] or all-cause death (HR: 1.03, 95% CI: 0.30-0.56, P=0.967). In the IPTW dataset, the total number of patients were 326.89, and the outcomes regarding the risk of MACCE (HR: 0.79, 95% CI: 0.31-1.97, P=0.607) and all-cause death (HR: 1.33, 95% CI:0.35-5.05, P=0.674) were in line with the unmatched analysis. The follow-up echocardiographic results were available for 72.2% of the overall cohort, and the use of BB was observed to be associated with higher improvement rate of follow-up FMR according to the IPTW analysis (92.2% vs. 98.3%, P=0.033). The administration of BB after SAVR was not associated with lower risk of MACCE for patients of severe aortic valve disease complicated with moderate FMR, but was potentially beneficial for improving FMR.

Evaluating systemic administration effect of propranolol on osseointegration around titanium implants: A histomorphometric study in dogs

Dental implants are known as a widely accepted and predictable method to replace missing teeth. Many factors, including using a class of drugs, such as β-blockers, can improve the osseointegration of dental implants. This study aimed to investigate the relationship between administrating propranolol and osseointegration in dental implants. This experimental animal study was performed on four native male street dogs of 11-13 kg of weight and 16-20 months of age. The specimens underwent teeth extraction. After that, the dogs were randomly divided into two groups. The first group contains two control dogs which would receive oral saline. The second contains two dogs which would receive oral tablets of propranolol daily. After a period of healing, three titanium implants were inserted in each of speciments' left mandibular quadrant, and treatment was resumed with propranolol and saline administration in case and control group, respectively. After 4 weeks, one of control group dogs and one of case group were anesthetized, and dental implants were removed alongside the peripheral bone marrow using a trephine drill. Meanwhile, the other two dogs (1 control and 1 propranolol administered dogs) were anesthetized after 9 weeks of implant placement, and the same procedure was carried out. Due to the histomorphometric assessment, the mean score of bone implant contact (BIC) in week 4 was significantly higher in case group compared to control one (68.33% vs. 20.22%). In week 9, the mean BIC score was higher in case group compared to control group (68.60% vs. 50.17%); meanwhile, in contrast to week 4, it was not statistically significant. In both case and control groups, the formation of woven and lamellar bone was more significant in week 4 rather than week 9. Administration of systemic β-blockers can improve dental implants osseointegration process.

β-Blockers Reduced the Target Lesion Revascularization After Percutaneous Coronary Intervention Using an Everolimus-eluting Stent

The effect of β-adrenergic blockers on everolimus-eluting stent (EES) implantation is unknown. We aimed to investigate how β-blockers affect the outcomes of EES by using the Tokyo-MD PCI registry data and analyse real-world data in this drug-eluting stent era in Japan.We selected 1,899 patients who underwent EES implantation. We compared patients with β-blocker administration versus those without, at follow-up regarding the incidence rate of ischemia-driven target lesion revascularization (ID-TLR), all-cause death, cardiac death, acute myocardial infarction (AMI), and stent thrombosis (ST).Patients in the β-blocker group had higher coronary risks than those in the non-β-blocker group. Although no significant difference was observed in the five-year incidence of all-cause death, cardiac death, AMI, and ST between the two groups, the incidence of ID-TLR was significantly lower in the β-blocker group (4.5% vs. 6.6%; p=0.04). β-Blocker administration (hazard ratio=0.61; p=0.016) was negatively associated with ID-TLR via multivariate analysis.β-Blocker administration reduced ID-TLR after percutaneous coronary intervention using an EES despite the greater comorbid risks and more severe disease lesions.

Atrial fibrillation after cardiac surgery: Implementation of a prevention care bundle on intensive care unit improves adherence to current perioperative guidelines and reduces incidence

Atrial fibrillation after cardiac surgery (AFACS) is a very frequent complication affecting 30–50% of all patients. It is associated with an increase in morbidity, mortality and hospital and intensive care unit (ICU) length of stay. We aimed to implement an AFACS prevention care bundle based on a recently published practice advisory, focusing on early postoperative (re)introduction of β-blockers. Baseline AFACS incidence and β-blocker administration practices in our centre were audited for all patients undergoing valve surgery or coronary artery bypass graft (CABG) during a 6 weeks period. The AFACS prevention care bundle – an easy to follow graphical tool – was subsequently introduced to the cardiac ICU by a multidisciplinary team and audited following a model of improvement approach. After exclusion of patients with preoperative AF, differences between pre- and post-implementation groups were compared with Chi 2 and Fisher's exact tests for categorical, and One-way ANOVA for continuous variables, using SPSS. A total of 384 patients were analysed. Patient and surgery characteristics did not differ between groups. Significantly, more patients received postoperative β-blockers after bundle implementation (82.7% pre- vs. 91.3% post-bundle, P = 0.019) with a higher proportion on day 1 (36.7% pre- vs. 67% post-bundle, P < 0.001). The incidence of AFACS was significantly reduced from 35.4% to 23.3% ( P = 0.009), with a particularly marked reduction in the age group 65–75 years and for isolated aortic valve and CABG surgery. There was no significant reduction in hospital length of stay for this cohort. Introduction of an AFACS prevention care bundle using a graphical tool improved adherence to current guidelines with regards to early β-blocker administration and significantly reduced AFACS incidence. Future care bundles should include preoperative interventions and might reduce hospital length of stay.

Long-term impact of β-blocker in elderly patients without myocardial infarction after percutaneous coronary intervention.

AimsLittle is known about the long‐term outcomes of β‐blockers use in patients with coronary artery disease (CAD) without myocardial infarction (MI) and reduced ejection fraction (rEF). However, more attention should be paid to the oral administration of β‐blockers in elderly patients who are susceptible to heart failure (HF), sinus node dysfunction, or rate response insufficiency. We aimed to evaluate the long‐term impact of β‐blockers in elderly patients with CAD without MI or systolic HF who have undergone percutaneous coronary intervention.Methods and resultsA total of 1018 consecutive elderly patients with CAD (mean age, 72 ± 7 years; 77% men) who underwent their first intervention between 2010 and 2018 were included in this study. According to the presence or absence of the use of β‐blockers, 514 patients (50.5%) were allocated to the β‐blocker group, and 504 (49.5%) to the non‐β‐blocker group. We evaluated the incidence of 4‐point major adverse cardiovascular events (4P‐MACE), including cardiovascular death, non‐fatal MI, non‐fatal stroke, admission for HF, target vessel revascularization (TVR), and all‐cause death. We focused on the association between chronotropic incompetence of β‐blockers and incidence of a new HF and analysed the results using an exercise electrocardiogram regularly performed in the outpatient department after percutaneous coronary intervention. During a median follow‐up duration of 5.1 years, 83 patients (8.3%) developed 4P‐MACE, including cardiovascular death in 17, non‐fatal MI in 13, non‐fatal stroke in 25, and admission for HF in 39 patients. Additionally, 124 patients (12.2%) had a TVR and 104 (10.2%) died of other causes. Kaplan–Meier analysis showed that the cumulative incidence rate of 4P‐MACE in the β‐blocker group was significantly higher than that in the non‐β‐blocker group (15.4% vs. 10.0%, log‐rank test, P = 0.015). Above all, the cumulative incidence rate of admission for HF in the β‐blocker group was significantly higher (8.8% vs. 3.2%, log‐rank test, P < 0.001). The β‐blocker group had significantly lower resting heart rate, stress heart rate, and stress‐rest Δ heart rate on exercise electrocardiogram. Multivariate Cox hazard analysis revealed that EF, β‐blocker use, stress‐rest Δ heart rate, and CKD were strong independent predictors of admission for HF.ConclusionsLong‐term β‐blocker use was significantly associated with an increased risk of adverse cardiovascular events in elderly patients with CAD without MI or systolic HF. In particular, the chronotropic incompetence action of β‐blockers could increase the risk of admission for HF in elderly patients with CAD without MI and systolic HF, and the present findings warrant further investigation.

Intranasal Dexmedetomidine in Elderly Patients (Aged > 65 Years) During Maxillofacial Surgery: Sedative Properties and Safety Analysis

Light sedation rather than intravenous sedation is preferred when patients have a low heart rate and blood pressure during maxillofacial surgery. Intranasal administration of dexmedetomidine is reported to be efficacious and safe in adults. However, dexmedetomidine could be unsuitable for routine clinical use in elderly patients because many of these patients take β-blockers, which increase the cardiovascular effects of dexmedetomidine. The objectives of the study were to evaluate the sedative properties and safety of intranasal dexmedetomidine, regardless of concurrent β-blocker treatment, in elderly patients who underwent maxillofacial surgery. This study was a retrospective analysis of 535 patients aged > 65 years (American Society of Anesthesiologists physical status I or II) who were undergoing maxillofacial surgery. Very anxious patients and those with hypertension received intranasal 1 µg/kg dexmedetomidine through an intranasal mucosal atomization device before anesthesia (local ropivacaine). Intranasal administration of dexmedetomidine decreased the requirement for midazolam before surgery (18 of 252 vs 63 of 283, P < .0001), but increased the requirement for norepinephrine (102 of 252 vs 8 of 283, P < .0001) during or after the surgery. A combination of a β-blocker and intranasal administration of dexmedetomidine reduced the hemodynamic parameters for an extended period. Intranasal administration of dexmedetomidine resulted in bradycardia and hypotension, regardless of concurrent β-blocker treatment. Intranasal 1 µg/kg dexmedetomidine was associated with a high sedation score during the operation, but also with bradycardia and hypotension.

Blood Pressure Recovery After Dobutamine Antagonism: Partial With Landiolol, None With Esmolol.

We investigated the hemodynamic effects of 2 short-acting β1 -blockers, landiolol and esmolol, in the continuous presence of dobutamine in a prospective, single-center, randomized, crossover study in 16 healthy White volunteers. Dobutamine was infused at a rate sufficient to increase the heart rate by at least 30 beats per minute, followed by a 60-minute infusion of 50 μg/kg/min esmolol or 10 μg/kg/min landiolol on top of the unchanged dobutamine infusion. Concentrations of β-blockers and their metabolites in blood, heart rate, and blood pressure were followed for 180 minutes. Landiolol reduced the dobutamine-induced heart rate and blood pressure increases better than esmolol. After discontinuation of β-blocker administration, heart rate recovered swiftly to preinfusion values in both study arms. Systolic and diastolic blood pressure recovered partially after landiolol but showed a continued reduction after esmolol. No serious adverse events were observed. The heart rate effect is characteristic for β-blockers, whereas the blood pressure effects are likely due to direct and indirect β-blocker effects as well as influences on various ion channels. This may explain why landiolol that is devoid of effects on renin and sodium, calcium, and potassium channels behaves different from esmolol with respect to blood pressure recovery.

Beta-blocker could show the prognostic impact in heart failure patients even on the regular hemodialysis

Abstract Background β-blockers are recommended as standard medications for patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF). However, this favorable prognostic effect of β-blockers has not been fully validated in patients receiving regular hemodialysis. Indeed, prior clinical trials have generally excluded such very high-risk population for adverse cardiovascular events. Main reasons for that are the limited number of regular hemodialysis patients in the Western nations, and too high rates of clinical events. Purpose This study aimed to clarify the prognostic benefit of β-blocker in patients on regular hemodialysis who were hospitalized due to HF. Methods This observational study included 1,930 consecutive patients who were hospitalized for worsening of HF and discharged alive from 2013 to 2019. Of them, 151 patients who underwent regular hemodialysis were ultimately analyzed. They were divided into 2 groups depending on the prescription of β-blocker at the discharge; β-blocker group (n=115) and No-β-blocker group (n=36). The primary endpoint of this study was a composite of death from any cause and rehospitalization due to HF. Results During the observation period with 501 days of median follow-up (IQR: 197–954 days), the primary endpoint was occurred in 45 patients (39%) who were receiving β-blockers, while in 24 patients (67%) who were not. Kaplan-Meier analysis showed a significantly lower rate of the primary endpoint in patients in the β-blocker group (Log-rank, p&amp;lt;0.001, Figure). After the adjustment for age, sex, LVEF, systolic blood pressure, heart rate and atrial fibrillation, the administration of β-blocker was still an independent predictor for the primary endpoint in patients who underwent regular hemodialysis (hazard ratio; 0.46, 95% confidence interval; 0.26–0.82). Further analysis each for the population with reduced LVEF (&amp;lt;45%) and preserved LVEF (&amp;gt;45%) showed that the main result of the current study was consistent with that in the reduced LVEF group (Log-rank, p=0.005), but was diminished in the preserved LVEF group (p=0.13). Conclusion The prescription of β-blocker at discharge in HF patients with regular hemodialysis was associated with lower risk of adverse cardiovascular events, mainly in the patients with reduced LVEF. From the findings of our study, we should consider the administration of β-blockers in HF patients, even they are on the regular hemodialysis. Funding Acknowledgement Type of funding sources: None. Figure 1

Effects of long-term oral administration of β-blocker on septic myocardial injury and prognosis

To investigate the effect of long-term oral administration of β-blocker on septic myocardial injury and prognosis. A retrospective study was conducted. Patients who were admitted to the emergency intensive care unit (EICU) and intensive care unit (ICU) of Tongde Hospital of Zhejiang Province from January 2015 to June 2020 were enrolled. A total of 289 patients who met the criteria of myocardial injury induced by sepsis were included in the analysis. Among them, 187 patients who had never taken β-blocker within 3 months before diagnosis were divided in the non-β-blocker group, and 102 patients who took β-blocker daily for more than 3 months before diagnosis were in the β-blocker group. The physiological and biochemical characteristics were compared between the two groups, including heart rate, mean arterial pressure (MAP) at the time of diagnosis, cardiac troponin I (cTnI), brain natriuretic peptide (BNP), MB isoenzyme of creatine kinase (CK-MB), blood lactic acid (Lac), central venous oxygen saturation (ScvO2), sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation II (APACHE II) score within 24 hours of diagnosis, left ventricular ejection fraction (LVEF), early and late mitral orifice diastolic peak flow velocity ratio (E/A), utilization rate of vasoactive drugs during hospitalization and 28-day mortality. The heart rate in the β-blocker group at the time of diagnosis was significantly lower than that in the non-β-blocker group (bpm: 107±8 vs. 110±7, P < 0.01), and the levels of cTnI and BNP within 24 hours of diagnosis were significantly lower than those in the non-β-blocker group [cTnI (μg/L): 0.191 (0.220) vs. 0.291 (0.300), BNP (ng/L): 627 (133) vs. 690 (201), both P < 0.05]. However, there were no significant differences in MAP, CK-MB, Lac, ScvO2, SOFA score, APACHE II score, LVEF, E/A, vasoactive drug utilization rate, and 28-day mortality between the β-blocker and non-β-blocker groups [MAP (mmHg, 1 mmHg = 0.133 kPa): 70.6±3.9 vs. 69.9±3.8, CK-MB (μg/L): 4.24 (3.33) vs. 4.32 (3.13), Lac (mmol/L): 3.50 (1.80) vs. 3.50 (1.90), ScvO2: 0.729±0.032 vs. 0.735±0.041, SOFA score: 7.74±2.34 vs. 7.25±2.23, APACHE II score: 17.19±5.13 vs. 18.27±6.12, LVEF: 0.567±0.058 vs. 0.557±0.051, E/A: 0.71 (0.20) vs. 0.69 (0.20), vasoactive drug utilization rate: 60.8% (62/102) vs. 56.7% (106/187), 28-day mortality: 23.5% (24/102) vs. 25.7% (48/187), all P > 0.05]. Long-term oral administration of β-blocker reduce myocardial injury in septic patients, and has no effect on disease severity and prognosis.

Development of an automated closed-loop β-blocker delivery system to stably reduce myocardial oxygen consumption without inducing circulatory collapse in a canine heart failure model: a proof of concept study

Beta-blockers are well known to reduce myocardial oxygen consumption (MVO2) and improve the prognosis of heart failure (HF) patients. However, its negative chronotropic and inotropic effects limit their use in the acute phase of HF due to the risk of circulatory collapse. In this study, as a first step for a safe β-blocker administration strategy, we aimed to develop and evaluate the feasibility of an automated β-blocker administration system. We developed a system to monitor arterial pressure (AP), left atrial pressure (PLA), right atrial pressure, and cardiac output. Using negative feedback of hemodynamics, the system controls AP and PLA by administering landiolol (an ultra-short-acting β-blocker), dextran, and furosemide. We applied the system for 60 min to 6 mongrel dogs with rapid pacing-induced HF. In all dogs, the system automatically adjusted the doses of the drugs. Mean AP and mean PLA were controlled within the acceptable ranges (AP within 5 mmHg below target; PLA within 2 mmHg above target) more than 95% of the time. Median absolute performance error was small for AP [median (interquartile range), 3.1% (2.2–3.8)] and PLA [3.6% (2.2–5.7)]. The system decreased MVO2 and PLA significantly. We demonstrated the feasibility of an automated β-blocker administration system in a canine model of acute HF. The system controlled AP and PLA to avoid circulatory collapse, and reduced MVO2 significantly. As the system can help the management of patients with HF, further validations in larger samples and development for clinical applications are warranted.

β-Blockers for traumatic brain injury: A systematic review and meta-analysis.

Paroxysmal sympathetic hyperactivity (PSH) and catecholamine surge, which are associated with poor outcome, may be triggered by traumatic brain injury (TBI).β Adrenergic receptor blockers (β-blockers), as potential therapeutic agents to prevent paroxysmal sympathetic hyperactivity and catecholamine surge, have been shown to improve survival after TBI. The principal aim of this study was to investigate the effect of β-blockers on outcomes in patients with TBI. For this systematic review and meta-analysis, we searched MEDLINE, EMBASE, and Cochrane Library databases from inception to September 25, 2020, for randomized controlled trials, nonrandomized controlled trials, and observational studies reporting the effect of β-blockers on the following outcomes after TBI: mortality, functional measures, and cardiopulmonary adverse effects of β-blockers (e.g., hypotension, bradycardia, and bronchospasm). With use of random-effects model, we calculated pooled estimates, confidence intervals (CIs), and odds ratios (ORs) of all outcomes. Fifteen studies with 12,721 patients were included. Exposure to β-blockers after TBI was associated with a significant reduction in adjusted in-hospital mortality (OR, 0.39; 95% CI, 0.30-0.51; I2 = 66.3%; p < 0.001). β-Blockers significantly improved the long-term (≥6 months) functional outcome (OR, 1.75; 95% CI, 1.09-2.80; I2 = 0%; p = 0.02). Statistically significant difference was not seen for cardiopulmonary adverse events (OR, 0.91; 95% CI, 0.55-1.50; I2 = 25.9%; p = 0.702). This meta-analysis demonstrated that administration of β-blockers after TBI was safe and effective. Administration of β-blockers may therefore be suggested in the TBI care. However, more high-quality trials are needed to investigate the use of β-blockers in the management of TBI. Systematic review and meta-analysis, level III.

Metoprolol Impairs β1-Adrenergic Receptor-Mediated Vasodilation in Rat Cerebral Arteries: Implications for β-Blocker Therapy.

The practice of prescribing β-blockers to lower blood pressure and mitigate perioperative cardiovascular events has been questioned because of reports of an increased risk of stroke. The benefit of β-blocker therapy primarily relies on preventing activation of cardiac β1-adrenergic receptors (ARs). However, we reported that β1ARs also mediate vasodilator responses of rat cerebral arteries (CAs), implying that β-blockers may impair cerebral blood flow under some conditions. Here, we defined the impact of metoprolol (MET), a widely prescribed β1AR-selective antagonist, on adrenergic-elicited diameter responses of rat CAs ex vivo and in vivo. MET (1-10 µmol/l) prevented β1AR-mediated increases in diameter elicited by dobutamine in cannulated rat CAs. The β1AR-mediated dilation elicited by the endogenous adrenergic agonist norepinephrine (NE) was reversed to a sustained constriction by MET. Acute oral administration of MET (30 mg/kg) to rats in doses that attenuated resting heart rate and dobutamine-induced tachycardia also blunted β1AR-mediated dilation of CAs. In the same animals, NE-induced dilation of CAs was reversed to sustained constriction. Administration of MET for 2 weeks in drinking water (2 mg/ml) or subcutaneously (15 mg/kg per day) also resulted in NE-induced constriction of CAs in vivo. Thus, doses of MET that protect the heart from adrenergic stimulation also prevent β1AR-mediated dilation of CAs and favor anomalous adrenergic constriction. Our findings raise the possibility that the increased risk of ischemic stroke in patients on β-blockers relates in part to adrenergic dysregulation of cerebrovascular tone. SIGNIFICANCE STATEMENT: β-Blocker therapy using second-generation, cardioselective β-blockers is associated with an increased risk of stroke, but the responsible mechanisms are unclear. Here, we report that either acute or chronic systemic administration of a cardioselective β-blocker, metoprolol, mitigates adrenergic stimulation of the heart as an intended beneficial action. However, metoprolol concomitantly eliminates vasodilator responses to adrenergic stimuli of rat cerebral arteries in vivo as a potential cause of dysregulated cerebral blood flow predisposing to ischemic stroke.

Efficacy of Timolol in a Novel Intranasal Thermosensitive Gel for Hereditary Hemorrhagic Telangiectasia–Associated Epistaxis

Other than nasal moisturizers, no standard-of-care medical therapy exists for epistaxis in hereditary hemorrhagic telangiectasia (HHT). With epistaxis as the greatest cause of morbidity in patients with HHT, there is a need to identify effective topical therapies. To determine the efficacy and safety of an intranasal timolol thermosensitive gel vs placebo thermosensitive gel in treating HHT-associated epistaxis. This double-blind, placebo-controlled randomized clinical trial was conducted from October 29, 2019, to May 20, 2020, at a tertiary care center. A total of 27 patients with HHT and moderate-to-severe epistaxis were recruited and included in this prespecified analysis: 14 in the timolol group and 13 in the placebo group. Inclusion criteria included (1) age 18 years or older, (2) clinical or genetic diagnosis of HHT, (3) screening Epistaxis Severity Score (ESS) of 4 or greater and 2 or more nosebleeds cumulatively lasting at least 5 minutes per week, (4) stable epistaxis pattern over the preceding 3 months, and (5) no change in epistaxis treatment or nasal hygiene regimen in the preceding month. Exclusion criteria included (1) contraindications to systemic β-blocker administration, (2) use of medications interacting with timolol, (3) use of antiangiogenic medications in the last month before recruitment, and (4) use of anticoagulants, antiplatelets, or fibrinolytic therapies within the last month. Novel thermosensitive intranasal timolol (0.1%) gel vs placebo thermosensitive gel applied twice daily to each nostril for 8 weeks. The primary outcome was the median change in ESS and percentage of participants reaching the minimal clinically important difference in ESS. Secondary outcomes were changes in Clinical Global Impression-Severity and Clinical Global Impression-Improvement scores, Nasal Outcome Score for Epistaxis in Hereditary Hemorrhagic Telangiectasia, and hemoglobin level. Of 27 participants randomized (median [range] age, 55 [20-76] years; 14 women [52%]; 25 White [93%]), a total of 23 patients with HHT completed the primary outcome measure. Within the timolol gel and placebo gel groups, respectively, the median change (range) in ESS was 2.32 (0.22 to 5.97) vs 1.96 (-0.91 to 5.98), and 9 of 11 (82%) vs 9 of 12 (75%) participants experienced a clinically meaningful improvement in ESS. Twenty-two of the 23 participants (96%) reported improvement via the Clinical Global Impression-Improvement score, with 81% vs 58% of participants reporting reduced severity of epistaxis in the timolol vs placebo group, respectively. Of participants completing the Nasal Outcome Score for Epistaxis in HHT at follow-up visit, 7 of 10 (70%) in the timolol group achieved a clinically important difference vs 5 of 10 (50%) in the placebo group. There was no change in hemoglobin level between or within groups. Zero participants in the placebo group and 2 of 13 (15%) in the timolol group withdrew because of adverse events. Thermosensitive gel, alone or in combination with timolol, was highly effective in reducing HHT-associated epistaxis. The timolol group had greater improvement in epistaxis and quality of life than the placebo group, but effect estimates were imprecise, and no definitive conclusions on the superiority of timolol can be drawn. Physicians treating patients with HHT-associated epistaxis should consider a thermosensitive gel (with or without timolol) for their patients. ClinicalTrials.gov Identifier: NCT04139018.