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

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

Preclinical Studies on Mechanisms Underlying the Protective Effects of Propranolol in Traumatic Brain Injury: A Systematic Review.

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity amongst trauma patients. Its treatment is focused on minimizing progression to secondary injury. Administration of propranolol for TBI maydecrease mortality and improve functional outcomes. However, it is our sense that its use has not been universally adopted due to low certainty evidence. The literature was reviewed to explore the mechanism of propranolol as a therapeutic intervention in TBI to guide future clinical investigations. Medline, Embase, and Scopus were searched for studies that investigated the effect of propranolol on TBI in animal models from inception until June 6, 2023. All routes of administration for propranolol were included and the following outcomes were evaluated: cognitive functions, physiological and immunological responses. Screening and data extraction were done independently and in duplicate. The risk of bias for each individual study was assessed using the SYCLE's risk of bias tool for animal studies. Three hundred twenty-three citations were identified and 14 studies met our eligibility criteria. The data suggests that propranolol may improve post-TBI cognitive and motor function by increasing cerebral perfusion, reducing neural injury, cell death, leukocyte mobilization and p-tau accumulation in animal models. Propranolol may also attenuate TBI-induced immunodeficiency and provide cardioprotective effects by mitigating damage to the myocardium caused by oxidative stress. This systematic review demonstrates that propranolol may be therapeutic in TBI by improving cognitive and motor function while regulating T lymphocyte response and levels of myocardial reactive oxygen species. Oral or intravenous injection of propranolol following TBI is associated with improved cerebral perfusion, reduced neuroinflammation, reduced immunodeficiency, and cardio-neuroprotection in preclinical studies.

Propranolol monotherapy in angiosarcoma - A window-of-opportunity study (PropAngio).

BACKGROUND: Angiosarcoma is a rare and aggressive cancer of the endothelial cells. Propranolol, a non-selective ß-blocker, was able to initiate apoptosis in angiosarcoma cell lines and its anti-tumor activity has been described in several case reports. The aim of this trial was to prospectively evaluate the anti-tumor activity of propranolol monotherapy in patients with angiosarcoma before proceeding to standard of care treatment. METHODS: Propranolol was dosed 80 mg to 240 mg/day for 3 to 6 weeks according to a dose titration schedule. The primary endpoint was clinical response (response according to RECIST 1.1 or stable disease with improvement of cutaneous lesions) in at least three patients. Exploratory objectives included histologic response (>30% decrease in Ki-67), FDG PET response, and ß-receptor expression levels. RESULTS: Fourteen patients were enrolled. The median duration of treatment was 26 days (range 21-42 days). The median highest propranolol dose was 160 mg/day (range 80 - 240 mg). Two patients showed clinical response (14%, 95% CI 3-100%). One of these patients showed a partial metabolic response on PET-CT. None of the tumors showed histologic response. The most common adverse event was grade 1/2 bradycardia (86%). There were no grade ≥ 3 adverse events. ADRB2 was overexpressed in 16 out of 18 tumors, in both responders and non-responders. None of the tumors showed ADRB1 overexpression. CONCLUSIONS: This window-of-opportunity trial did not show clinical efficacy of propranolol monotherapy. However, two out of 14 patients did show clinical benefit. ADRB1/2 expression did not correlate with clinical response.

Can the hemodynamic model in heart failure be restored based on analysis of ventricular-arterial coupling?

The hemodynamic model was inappropriate to explain the disappointing effect of vasodilation and the beneficial effect of beta-blockade in chronic heart failure. A more nuanced hemodynamic analysis, taking both steady and pulsatile hemodynamics into consideration, improves insight into these apparently enigmatic effects. Of particular interest is the velocity of early systolic flow as a determinant of left ventricular afterload. Several drugs, in particular beta-blockers, directly or indirectly, influence the velocity of early systolic flow. Thus, the hemodynamic model in heart failure may deserve reconsideration.

Secondary Prevention of Esophageal Variceal Bleeding Is Often Imperfect: A National, Population-Based Cohort Study of 3592 Patients.

BACKGROUND AND AIMS: Secondary prevention of esophageal variceal bleeding is important to improve prognosis, but uptake of guidelines is unknown in a real-world setting. Here, we determined the proportion of patients receiving appropriate nonselective beta-blocker treatment and repeat upper endoscopy after a first episode of esophageal variceal bleeding within a reasonable time frame. METHODS: Population-based registers were used to identify all patients with a first episode of esophageal variceal bleeding in Sweden from 2006 to 2020. Crosslinkage between registers was performed to receive information on the cumulative incidence of patients with a dispensation of nonselective beta-blockers and repeat upper endoscopy within 120 days from baseline. Overall mortality was investigated using Cox regression. RESULTS: In total, 3592 patients were identified, with a median age of 63 (interquartile range, 54-71) years. The cumulative incidence of a dispensation of nonselective beta-blockers and a repeat endoscopy within 120 days was 33%. A total of 77% received either of these treatments. Overall mortality was high, with 65% of patients dying after esophageal variceal bleeding during the full follow-up period (median 1.7 years). We observed an improved overall mortality during the later years of the study period (adjusted hazard ratio for the 2016-2020 period compared with the 2006-2010 period, 0.80; 95% confidence interval, 0.71-0.89). Patients with receipt of nonselective beta-blockers and repeat upper endoscopy had better overall survival compared with those without (adjusted hazard ratio, 0.80; 95% confidence interval, 0.72-0.90). CONCLUSIONS: Secondary prevention of esophageal variceal bleeding has not been widely undertaken, with many patients not receiving guideline-supported interventions within a reasonable time frame. This highlights a need to raise awareness on appropriate prevention strategies to clinicians and patients.

Beta-adrenergic receptor blockade in angiosarcoma: Which beta-blocker to choose?

Beta-blockers are currently studied to improve therapeutic options for patients with angiosarcoma. However, most of these patients have no cardiovascular co-morbidity and it is therefore crucial to discuss the most optimal pharmacological properties of beta-blockers for this population. To maximize the possible effectiveness in angiosarcoma, the use of a non-selective beta-blocker is preferred based on in vitro data. To minimize the risk of cardiovascular adverse events a beta-blocker should ideally have intrinsic sympathomimetic activity or vasodilator effects, e.g. labetalol, pindolol or carvedilol. However, except for one case of carvedilol, only efficacy data of propranolol is available. In potential follow-up studies labetalol, pindolol or carvedilol can be considered to reduce the risk of cardiovascular adverse events.

Beta adrenergic blockade and clinical outcomes in patients with colorectal cancer: A systematic review and meta-analysis.

OBJECTIVE: Preclinical and in vitro studies have shown that beta blockade affect colorectal cancer growth and metastasis through the sympathetic nervous system. There is no consensus on the effect of beta blockade on clinical outcomes in patients with colorectal cancer. We conducted a systematic review and meta-analysis to assess the impact of beta blockade on clinical outcomes in patients with colorectal cancer. METHOD: A systematic review and meta-analysis was conducted through a comprehensive search of the PubMed, EMBASE and the Cochrane Central Library databases for all studies to compare clinical outcomes in colorectal cancer patients based on the use of beta blockade. Pooled data of survival was analyzed. RESULTS: Fourteen studies involving 85993 patients were included in our meta-analysis. The use of beta blockade was associated with improvements in cancer-specific mortality (N = 59621; HR 0.87; 95%CI, 0.76-0.99; P = 0.04)and overall 1-year mortality (N = 37442; HR 0.54; 95%CI, 0.43-0.67; P < 0.00001),while there was no significant difference in overall survival (N = 37975; HR 0.95; 95%CI, 0.85-1.05; P = 0.28). In patients with stage IV colorectal cancer,the use of beta blockade was significantly associated with improvement in progression-free survival (N = 749; HR 0.76; 95%CI, 0.62-0.92; P = 0.005). CONCLUSION: In this meta-analysis, beta blockade use was associated with a reduction in cancer-specific mortality. The correlation was particularly significant for PFS improvement in patients with stage IV colorectal cancer. beta blockade may be an option for patients with advanced colorectal cancer.

Adrenergic Modulation of Erythropoiesis After Trauma.

Severe traumatic injury results in a cascade of systemic changes which negatively affect normal erythropoiesis. Immediately after injury, acute blood loss leads to anemia, however, patients can remain anemic for as long as 6 months after injury. Research on the underlying mechanisms of such alterations of erythropoiesis after trauma has focused on the prolonged hypercatecholaminemia seen after trauma. Supraphysiologic elevation of catecholamines leads to an inhibitive effect on erythropoiesis. There is evidence to show that alleviation of the neuroendocrine stress response following trauma reduces these inhibitory effects. Both beta blockade and alpha-2 adrenergic receptor stimulation have demonstrated increased growth of hematopoietic progenitor cells as well as increased pro-erythropoietic cytokines after trauma. This review will describe prior research on the neuroendocrine stress response after trauma and its consequences on erythropoiesis, which offer insight into underlying mechanisms of prolonged anemia postinjury. We will then discuss the beneficial effects of adrenergic modulation to improve erythropoiesis following injury and propose future directions for the field.

Therapeutic Properties of Highly Selective ß-blockers With or Without Additional Vasodilator Properties: Focus on Bisoprolol and Nebivolol in Patients With Cardiovascular Disease.

Bisoprolol and nebivolol are highly selective ß1-adrenoceptor antagonists, with clinical indications in many countries within the management of heart failure with reduced left ventricular ejection fraction (HFrEF), ischaemic heart disease (IHD), and hypertension. Nebivolol has additional vasodilator actions, related to enhanced release of NO in the vascular wall. In principle, this additional mechanism compared with bisoprolol might lead to more potent vasodilatation, which in turn might influence the effectiveness of nebivolol in the management of HFrEF, IHD and hypertension. In this article, we review the therapeutic properties of bisoprolol and nebivolol, as representatives of "second generation" and "third generation" ß-blockers, respectively. Although head-to-head trials are largely lacking, there is no clear indication from published studies of an additional effect of nebivolol on clinical outcomes in patients with HFrEF or the magnitude of reductions of BP in patients with hypertension.

Effect of the beta-adrenergic blockade on intestinal lactate production and glycogen concentration in dogs infused with hexoses.

OBJECTIVES: To investigate effect of beta adrenergic blockade on intestinal lactate production and glycogen concentration in dogs infused with hexoses. METHODS: Experiments were carried out on 35 fasted male anaesthetized dogs weighing between 9 and 16 kg. The animals were divided into 7 (5 dogs per group) groups. Group I dogs served as control and infused with normal saline, groups II-IV were intravenously infused with glucose (1.1 mg/kg/min), fructose (1.1 mg/kg/min) and galactose (1.1 mg/kg/min) respectively while groups V-VII animals were pretreated with propranolol (0.5 mg/kg) and were infused with glucose, fructose or galactose respectively. A vein draining the proximal segment of the jejunum was cannulated along with right and left femoral arteries and veins. Glucose uptake was calculated as the product of jejunal blood flow and the difference between arterial and venous glucose levels (A-V glucose), part of the jejunum tissue was homogenized for estimation of glycogen concentration, and plasma lactate was assayed using lactate colorimetric kit. RESULTS: The result showed significant increase in venous lactate production in response to glucose (78.30 ± 4.57 mg/dL), fructose (60.72 ± 1.82 mg/dL) and galactose (71.70 ± 1.30 mg/dL) when compared with the control group (51.75 ± 1.32 mg/dL) at (p<0.05) with no significant difference in animals pretreated with propranolol. There was no significant difference in glycogen concentration (p>0.05) in animals infused with hexoses only compared with propanolol pretreated group. CONCLUSIONS: Results suggests that one of the possible fates of the enormous amount of glucose taken up by the intestine is conversion to lactate and not glycogen and ß-adrenergic receptor does not affect it.

ß-Blockade for Patients with Hypertension, Ischemic Heart Disease or Heart Failure: Where are We Now?

ß-blockers are a heterogeneous class of drugs, with varying selectivity/specificity for ß1 vs ß2 receptors, intrinsic sympathomimetic activity (ISA), and vasodilatory properties (through ß2 stimulation, α receptor blockade or nitric oxide release). These drugs are indicated for the management of arterial hypertension, heart failure or ischemic heart disease (IHD; eg angina pectoris or prior myocardial infarction). Most of the benefit of ß-blockade in these conditions arises from blockade of the ß1 receptor, and, in practice, the addition of ISA appears to reduce the potential for improved clinical outcomes in people with heart failure or IHD. Aspects of the benefit/risk balance of ß-blockers remain controversial, and recent meta-analyses have shed new light on this issue. We have reviewed the current place of cardioselective ß-blockade in hypertension, IHD and heart failure, with special reference to the therapeutic profile of a highly selective ß1-adrenoceptor blocker, bisoprolol.

The effects of normoxic endurance exercise on erythropoietin (EPO) production and the impact of selective ß1 and non-selective ß1 + ß2 adrenergic receptor blockade.

PURPOSE: Habitual endurance exercise results in increased erythropoiesis, which is primarily controlled by erythropoietin (EPO), yet studies demonstrating upregulation of EPO via a single bout of endurance exercise have been equivocal. This study compares the acute EPO response to 30 min of high versus 90 min of moderate-intensity endurance exercise and whether that response can be upregulated via selective adrenergic receptor blockade. METHODS: Using a counterbalanced, cross-over design, fifteen participants (age 28 ± 8) completed two bouts of running (30-min, high intensity vs 90-min, moderate intensity) matched for overall training stress. A separate cohort of fourteen participants (age 31 ± 6) completed three bouts of 30-min high-intensity cycling after ingesting the preferential ß1-adrenergic receptor (AR) antagonist bisoprolol, the non-preferential ß1 + ß2 antagonist nadolol or placebo. Venous blood was collected before, during, and after exercise, and serum EPO levels were determined by ELISA. RESULTS: No detectable EPO response was observed during or after high intensity running, however, in the moderate-intensity trial EPO was significantly elevated at both during-exercise timepoints (+ 6.8% ± 2.3% at 15 min and + 8.7% ± 2.2% at 60 min). No significant change in EPO was observed post-cycling or between the trials involving ßAR blockade. CONCLUSION: Neither training mode (running or cycling), nor beta-blockade significantly influenced the EPO response to 30 min of high-intensity exercise, however, 90 min of moderate-intensity running elevated EPO during exercise, returning to baseline immediately post-exercise. Identifying the optimal mode, duration and intensity required to evoke an EPO response to exercise may help tailor exercise prescriptions designed to maximize EPO response for both performance and clinical applications.

The effects of beta-blockers in patients with stress cardiomyopathy.

Beta-blockers are often used in the treatment of patients with stress cardiomyopathy without firm evidence of benefit. We conducted a retrospective case note review investigating the effects of beta-blockers on QT interval and heart rate in patients with stress cardiomyopathy over 3 days of hospital admission. We found no evidence of effects on QT interval from beta-blocker treatment in this condition.

Is lactate lower in septic patients who are prescribed beta blockers? Retrospective cohort study of an intensive care population.

OBJECTIVE: Elevated serum lactate has long been considered an important marker of sepsis severity. Increasing evidence supports catecholamine-stimulated aerobic glycolysis being a major contributor to the hyperlactataemia seen in sepsis. Beta-blockade may blunt such catecholamine mediated rise in lactate analogous to the way it can mask tachycardia. This could impact the way we evaluate sepsis severity and adequacy of initial treatment. The objective of this study is to investigate whether septic patients who were on beta-blocker treatment at presentation have lower serum lactate level. METHODS: Using a retrospective cohort design we gathered data on patients admitted to our base hospital intensive care unit with APACHE III diagnosis of sepsis and septic shock during the 2017 calendar year. Serum lactate, current medications, presenting vital signs, illness severity scores, laboratory data and mortality outcome were extracted from patients' medical record and the unit's clinical database. RESULTS: Of 189 records analysed, 49 patients were concurrently prescribed beta-blockers. More beta-blocked patients were male, beta-blocked patients were older, and a greater proportion of beta blocked patients had their first lactate measured as an inpatient. After regression to correct for identified significant covariates mean serum lactate was 0.87 (95% confidence interval 0.05-1.69) mmol/L lower in those prescribed beta blockers. CONCLUSIONS: In our cohort pre-existing beta blocker treatment was associated with lower serum lactate measurements in patients presenting with sepsis. Pre-existing beta blocker treatment may reduce serum lactate at presentation in patients with sepsis.

Mechanisms of Beta-Blocker Induced Psoriasis, and Psoriasis De Novo at the Cellular Level.

Beta-blockers are a commonly prescribed medication, but the increase in use goes hand in hand with increasing side effects; one of particular interest lately has been its dermatological reactions. Although rare, beta-blockers can exacerbate pre-existing psoriasis and also cause de novo psoriasis in patients naïve to the disease. The mechanism by which this occurs is still unclear, although numerous articles have been published throughout the years as to how this unusual effect takes place. The most common mechanism suggests that beta-blockers cause intracellular changes in calcium, affecting both keratinocyte proliferation and granulocyte function via decreased cyclic adenosine monophosphate (cAMP) levels. Several inflammatory mediators are known to play a role, as well as reduced expression and desensitization of the beta-adrenergic receptor itself. We discuss these posed pathways in-depth and how each contributes to the worsening or formation of new psoriasis. With this knowledge, future physicians may be more mindful of this side effect should it occur, and why they occur, to better manage our patients on this widely used medication.

The effects of selective beta-adrenergic blockade on bone marrow dysfunction following severe trauma and chronic stress.

INTRODUCTION: Propranolol has been shown to improve erythroid progenitor cell growth and anemia following trauma and this study sought to investigate the mechanisms involved by evaluating the effects of selective beta blockade. METHODS: Male Sprague-Dawley rats were subjected to lung contusion, hemorrhagic shock and chronic stress (LCHS/CS) ± daily selective beta-1, beta-2, or beta-3 blockade (B1B, B2B, B3B). Bone marrow cellularity and growth of erythroid progenitor colonies, hemoglobin, plasma granulocyte colony-stimulating factor (G-CSF), hematopoietic progenitor cell mobilization, and daily weight were assessed. RESULTS: Selective beta-2 and beta-3 blockade improved bone marrow cellularity, erythroid progenitor colony growth and hemoglobin levels, while decreasing plasma G-CSF, progenitor cell mobilization and weight loss following LCHS/CS. CONCLUSIONS: Attenuating the neuroendocrine stress response with the use of selective beta-2 and 3 adrenergic blockade may be an alternative to improve bone marrow erythroid function following trauma.

Long-Term Analysis of Functional Outcomes in Traumatic Brain Injury Patients.

INTRODUCTION: Traumatic brain injury (TBI) remains a significant cause of morbidity and mortality. The purpose of this study is to examine outcomes after discharge and identify factors from the index admission that may contribute to long-term mortality. METHODS: The study population is composed of patients who survived to discharge from a previously published study examining TBI. Demographics, injury severity, and length of stay were abstracted from the index study. Phone surveys of surviving patients were performed to evaluate each patient's Glasgow Outcome Scale-Extended (GOSE). Patients who were deceased at the time of the survey were compared with those who were alive. RESULTS: 1615 patients were alive at the end of the first study period and 211 (13%) comprised the study population. Overall, the median age was 54 years, and the majority were male (74%). The median time to follow-up was 80 months. The population was severely injured, with a median injury severity score (ISS) of 25 and a median head abbreviated injury score (AIS) of 4. Overall mortality was 57%. The group that survived at the time of the survey was younger, more injured, less likely to have received beta-blockers (BB) during the index admission, and had a longer time to follow-up. After adjusting for ISS, age, base deficit, and BB, age was the only variable predictive of mortality (HR 1.03; HL 1.02-1.04). CONCLUSION: Despite being more severely injured, younger patients were more likely to survive to follow-up. Further investigation is needed to determine if aggressive care in older TBI patients in the acute phase leads to good long-term outcomes.

Electrical storm: A focused review for the emergency physician.

BACKGROUND: Electrical storm is a dangerous condition presenting to the Emergency Department that requires rapid diagnosis and management. OBJECTIVE: This article provides a review of the diagnosis and management of electrical storm for the emergency clinician. DISCUSSION: Electrical storm is defined as ≥3 episodes of sustained ventricular tachycardia, ventricular fibrillation, or shocks from an implantable cardioverter defibrillator within 24 h. Patients may present with a wide array of symptoms. Initial evaluation should include an electrocardiogram with a rhythm strip and continuous cardiac monitoring, a medication history, assessment of hemodynamic stability, and identification of potential triggers. Management includes an antiarrhythmic and a beta blocker. Refractory patients may benefit from double-sequential defibrillation or more invasive procedures such as intra-aortic balloon pumps, catheter ablation and extracorporeal membrane oxygenation for critically ill patients. These patients will typically require admission to an intensive care unit. CONCLUSION: Electrical storm is a condition associated with significant morbidity and mortality. It is important for clinicians to be aware of the current evidence regarding the evaluation and management of these patients.