The current position of ß-blockers in hypertension: guidelines and clinical practice.

The benefits of improved clinical outcomes through blood pressure (BP) reduction have been proven in multiple clinical trials and meta-analyses. The new (2023) guideline from the European Society of Hypertension (ESH) includes ß-blockers within five main classes of antihypertensive agents suitable for initiation of antihypertensive pharmacotherapy and for combination with other antihypertensive agents. This is in contrast to the 2018 edition of ESH guidelines that recommended ß-blockers for use primarily in patients with compelling indications such as cardiovascular comorbidities, e.g. coronary heart disease, heart failure. This change was based on the fact that the magnitude of BP reduction is the most important factor for adverse cardiovascular outcomes, over and above the precise manner in which reduced BP is achieved. The ESH guideline also supports the use of ß-blockers for patients with resting heart rate (>80 bpm); high resting heart rate is a sign of sympathetic overactivity, an important driver of adverse cardiac remodelling in the setting of hypertension and heart failure. Hypertension management guidelines support for the use of combination therapies for almost all patients with hypertension, ideally within a single-pill combination to optimise adherence to therapy. Where a ß-blocker is prescribed, the inclusion of a dihydropyridine calcium channel blocker within a combination regimen is rational. These agents together reduce both peripheral and central BP, which epidemiological studies have shown is important for reducing the burden of premature morbidity and mortality associated with uncontrolled hypertension, especially strokes.

Exploring the Median Effective Dose of Ciprofol for Anesthesia Induction in Elderly Patients: Impact of Frailty on ED50.

Purpose: Explore the median effective dose of ciprofol for inducing loss of consciousness in elderly patients and investigate how frailty influences the ED50 of ciprofol in elderly patients. Patients and Methods: A total of 26 non-frail patients and 28 frail patients aged 65-78 years, with BMI ranging from 15 to 28 kg/m2, and classified as ASA grade II or III were selected. Patients were divided into two groups according to frailty: non-frail patients (CFS<4), frail patients (CFS≥4). With an initial dose of 0.3 mg/kg for elderly non-frail patients and 0.25 mg/kg for elderly frail patients, using the up-and-down Dixon method, and the next patient's dose was dependent on the previous patient's response. Demographic information, heart rate (HR), oxygen saturation (SpO2), mean blood pressure (MBP), and bispectral index (BIS) were recorded every 30 seconds, starting from the initiation of drug administration and continuing up to 3 minutes post-administration. Additionally, the total ciprofol dosage during induction, occurrences of hypotension, bradycardia, respiratory depression, and injection pain were recorded. Results: The calculated ED50 (95% confidence interval [CI]) and ED95 (95% CI) values for ciprofol-induced loss of consciousness were as follows: 0.267 mg/kg (95% CI 0.250-0.284) and 0.301 mg/kg (95% CI 0.284-0.397) for elderly non-frail patients; and 0.263 mg/kg (95% CI 0.244-0.281) and 0.302 mg/kg (95% CI 0.283-0.412) for elderly frail patients. Importantly, no patients reported intravenous injection pain, required treatment for hypotension, or experienced significant bradycardia. Conclusion: Frailty among elderly patients does not exert a notable impact on the median effective dose of ciprofol for anesthesia induction. Our findings suggest that anesthesiologists may forego the necessity of dosage adjustments when administering ciprofol for anesthesia induction in elderly frail patients.

Non-paroxysmal junctional tachycardia complicating disseminated intravascular coagulation during massive surgical hemorrhage: A case report.

RATIONALE: Non-paroxysmal junctional tachycardia (NPJT) is a self-limiting supraventricular tachycardia associated with primary heart disease, cardiac surgery, digitalis toxicity, and metabolic or electrolyte imbalances. However, NPJT caused enhanced normal automaticity even in the absence of structural heart disease can be fatal if not managed properly. PATIENT CONCERNS: A 74-year-old hypertensive female patient was scheduled for transureteroureterostomy and right ureteroneocystostomy under general anesthesia. DIAGNOSIS: The patient developed NPJT without visible P wave and severe hypotension due to adrenergic stimulation in response to massive hemorrhage during surgery. INTERVENTIONS: NPJT with hypotension was initially converted to sinus rhythm with normotension with administration of adenosine and esmolol. However uncontrolled surgical hemorrhage and administration of large dose of vasopressors eventually perpetuated NPJT refractory to antiarrhythmic drugs. OUTCOMES: Despite intravenous fluid resuscitation and massive transfusion, the patient was deteriorated hemodynamically due to uncontrolled bleeding and persistent NPJT, which resulted in hypovolemic shock and fatal disseminated intravascular coagulation (DIC). LESSONS: NPJT can occur by enhanced automaticity due to increased catecholamine during severe surgical hemorrhage. Although NPJT is generally self-limiting, it can be refractory to antiarrhythmic agents and accelerate hypotension if the surgical bleeding is uncontrolled. Therefore, aggressive management of the primary pathologic condition is crucial for the management of NPJT and hemodynamic collapse even in the absence of structural heart disease.

Efficacy and safety of esketamine combined with propofol for curative endoscopic resection in colorectum: a prospective, randomized controlled trial.

BACKGROUND: Curative endoscopic resection is widely used to treat colonic polyps and early stage cancers. The anesthetic strategy commonly involves the use of propofol combined with a small dose of opioids for sedation. Adverse respiratory or cardiovascular events such as hypotension often occur when attempting to achieve the necessary level of sedation. Several studies have suggested its advantages owing to the anesthetic, analgesic, and sympathomimetic properties of esketamine. However, there are no reports on curative colorectal endoscopic resection. We designed this randomized controlled trial to assess the efficacy and safety of esketamine combined with propofol for sedation in patients undergoing curative colorectal endoscopic resection. METHODS: A total of 166 patients who underwent curative colorectal endoscopic resection were randomly assigned to groups A (propofol + fentanyl) or E (propofol + esketamine). Ideal sedation was assessed using the MOAA/S scale and was achieved using TCI-propofol with different doses of fentanyl and esketamine. The propofol consumption and vasoactive drug dosages were recorded. Sedation-related times, adverse events, and satisfaction were recorded. RESULTS: Of the 160 patients, the total propofol consumption was significantly lower in group E (n = 81) (300 mg) than in group A (n = 79) (350 mg). Hypotension and bradycardia were significantly lower in Group E than in Group A. The groups showed no significant differences in other adverse events, induction time, recovery time, or patient or endoscopist satisfaction. CONCLUSION: Compared to fentanyl, esketamine helps decrease propofol consumption and increases cardiovascular stability during curative colorectal endoscopic resection in American Society of Anesthesiologists Class I-III patients without affecting anesthesia, patient and endoscopist satisfaction, or other adverse events. TRIAL REGISTRATION: The study was retrospectively registered at the Chinese Clinical Trial Registry ( www.chictr.org.cn ; registration number: ChiCTR2300069014 on 03/03/2023).

A new potential therapeutic approach for ALS: A case report with NGS analysis.

RATIONALE: Amyotrophic lateral sclerosis (ALS) poses a significant clinical challenge due to its rapid progression and limited treatment options, often leading to deadly outcomes. Looking for effective therapeutic interventions is critical to improve patient outcomes in ALS. PATIENT CONCERNS: The patient, a 75-year-old East Asian male, manifested an insidious onset of right-hand weakness advancing with dysarthria. Comprehensive Next-generation sequencing analysis identified variants in specific genes consistent with ALS diagnosis. DIAGNOSES: ALS diagnosis is based on El Escorial diagnostic criteria. INTERVENTIONS: This study introduces a novel therapeutic approach using artificial intelligence phenotypic response surface (AI-PRS) technology to customize personalized drug-dose combinations for ALS. The patient underwent a series of phases of AI-PRS-assisted trials, initially incorporating a 4-drug combination of Ibudilast, Riluzole, Tamoxifen, and Ropinirole. Biomarkers and regular clinical assessments, including nerve conduction velocity, F-wave, H-reflex, electromyography, and motor unit action potential, were monitored to comprehensively evaluate treatment efficacy. OUTCOMES: Neurophysiological assessments supported the ALS diagnosis and revealed the co-presence of diabetic polyneuropathy. Hypotension during the trial necessitated an adaptation to a 2-drug combinational trial (ibudilast and riluzole). Disease progression assessment shifted exclusively to clinical tests of muscle strength, aligning with the patient's well-being. LESSONS: The study raises the significance of personalized therapeutic strategies in ALS by AI-PRS. It also emphasizes the adaptability of interventions based on patient-specific responses. The encountered hypotension incident highlights the importance of attentive monitoring and personalized adjustments in treatment plans. The described therapy using AI-PRS, offering personalized drug-dose combinations technology is a potential approach in treating ALS. The promising outcomes warrant further evaluation in clinical trials for searching a personalized, more effective combinational treatment for ALS patients.

Provider Experience With the Use of Ketamine for Refractory Status Epilepticus.

OBJECTIVE: Refractory status epilepticus (RSE) treated with anesthetic agents can be associated with complications including respiratory depression and hypotension. Ketamine is an emerging RSE treatment, but optimal dosing and timing are unknown. We studied provider attitudes and practices regarding the use of ketamine for RSE. METHODS: A literature review informed the creation of the survey, developed by professionals in epilepsy, pharmacy, and neurocritical care. The survey was distributed to members of the Critical Care EEG Monitoring and Research Consortium, Neurocritical Care Society, American Academy of Neurology Synapse community, American Epilepsy Society, and the Canadian League Against Epilepsy. Descriptive statistics were calculated. RESULTS: There were 109 respondents. First-line agents for RSE were midazolam (53%), propofol (42%), pentobarbital (2%), and ketamine (1%). Reasons for ketamine use included failure of midazolam/propofol to control seizures (81%) or hypotension on another anesthetic (35%). Perceived contraindications included hypertension (37%), elevated intracranial pressure (24%), and heart failure (18%). Perceived benefits included decreased use of vasopressors (53%) and more rapid RSE control when used adjunctively (49%). Routine ketamine users often treated more than 10 RSE cases per year, worked as intensivists or at academic institutions. Of the respondents, 59% found ketamine useful for RSE and 94% were interested in learning more about its use. CONCLUSIONS: Although most participants found ketamine helpful for RSE, it is mainly used as a second-line agent adjunctively with midazolam or propofol. Perceived ketamine benefits included decreased need for hemodynamic support and more rapid seizure control when used in conjunction with other anesthetics. Perceived contraindications centered on cardiac and intracranial pressure concerns.

Effect of Dexmedetomidine on Intraoperative Hemodynamics and Blood Loss in Patients Undergoing Spine Surgery: A Systematic Review and Meta-Analysis.

Objective Dexmedetomidine (Dex) is a highly selective α2 adrenoceptor agonist that reduces blood pressure and heart rate. However, its ability to provide stable hemodynamics and a clinically significant reduction in blood loss in spine surgery is still a matter of debate. This study aimed to investigate the effects of Dex on intraoperative hemodynamics and blood loss in patients undergoing spine surgery.Methods The Web of Science, MEDLINE, EMBASE, and the Cochrane Library were searched up to February 2023 for randomized controlled trials (RCTs) including patients undergoing spine surgeries under general anaesthesia and comparing Dex and saline. A fixed- or random-effect model was used depending on heterogeneity.Results Twenty-one RCTs, including 1388 patients, were identified. Dex added the overall risk of intraoperative hypotension (odds ratio [OR]: 2.11; 95% confidence interval [CI]: 1.24 - 3.58; P=0.006) and bradycardia (OR: 2.48; 95%CI: 1.57 - 3.93; P=0.0001). The use of a loading dose of Dex led to significantly increased risks of intraoperative hypotension (OR: 2.00; 95%CI: 1.06 - 3.79; P=0.03) and bradycardia (OR: 2.28; 95%CI: 1.42 - 3.66; P=0.0007). For patients receiving total intravenous anesthesia, there was an increased risk of hypotension (OR: 2.90; 95%CI: 1.24 - 6.82; P=0.01) and bradycardia (OR: 2.66; 95%CI: 1.53 - 4.61; P=0. 0005). For patients in the inhalation anesthesia group, only an increased risk of bradycardia (OR: 4.95; 95%CI: 1.41 - 17.37; P=0.01) was observed. No significant increase in the risk of hypotension and bradycardia was found in the combined intravenous-inhalation anesthesia group. The incidence of severe hypotension (OR: 2.57; 95%CI: 1.05 - 6.32; P=0.04), but not mild hypotension, was increased. Both mild (OR: 2.55; 95%CI: 1.06 - 6.15; P=0.04) and severe (OR: 2.45; 95%CI: 1.43 - 4.20; P=0.001) bradycardia were associated with a higher risk. The overall analyses did not reveal significant reduction in intraoperative blood loss. However, a significant decrease in blood loss was observed in total inhalation anesthesia subgroup (mean difference [MD]: -82.97; 95%CI: -109.04 - -56.90; P<0.001).Conclusions Dex increases the risks of intraoperative hypotension and bradycardia in major spine surgery. The administration of a loading dose of Dex and the utilization of various anesthesia maintenance methods may potentially impact hemodynamic stability and intraoperative blood loss.

Randomized Double-Blinded Comparison of Intermittent Boluses Phenylephrine and Norepinephrine for the Treatment of Postspinal Hypotension in Patients with Severe Pre-Eclampsia During Cesarean Section.

Background: Norepinephrine has fewer negative effects on heart rate (HR) and cardiac output (CO) for treating postspinal hypotension (PSH) compared with phenylephrine during cesarean section. However, it remains unclear whether fetuses from patients with severe pre-eclampsia could benefit from the superiority of CO. The objective of this study was to compare the safety and efficacy of intermittent intravenous boluses of phenylephrine and norepinephrine used in equipotent doses for treating postspinal hypotension in patients with severe pre-eclampsia during cesarean section. Methods: A total of 80 patients with severe pre-eclampsia who developed PSH predelivery during cesarean section were included. Eligible patients were randomized at a 1:1 ratio to receive either phenylephrine or norepinephrine for treating PSH. The primary outcome was umbilical arterial pH. Secondary outcomes included other umbilical cord blood gas values, Apgar scores at 1 and 5 min, changes in hemodynamic parameters including CO, mean arterial pressure (MAP), HR, stroke volume (SV), and systemic vascular resistance (SVR), the number of vasopressor boluses required, and the incidence of bradycardia, hypertension, nausea, vomiting, and dizziness. Results: No significant difference was observed in umbilical arterial pH between the phenylephrine and norepinephrine groups (7.303±0.38 vs 7.303±0.44, respectively; P=0.978). Compared with the phenylephrine group, the overall CO (P=0.009) and HR (P=0.015) were greater in the norepinephrine group. The median [IQR] total number of vasopressor boluses required was comparable between the two groups (2 [1 to 3] and 2 [1 to 3], respectively; P=0.942). No significant difference was found in Apgar scores or the incidence of maternal complications between groups. Conclusion: A 60 µg bolus of phenylephrine and a 4.5 µg bolus of norepinephrine showed similar neonatal outcomes assessed by umbilical arterial pH and were equally effective when treating PSH during cesarean section in patients with severe pre-eclampsia. Norepinephrine provided a higher maternal CO and a lower incidence of bradycardia.

Norepinephrine versus phenylephrine on cerebral tissue oxygen saturation during prophylactic infusion to prevent spinal hypotension for Caesarean birth.

BACKGROUND: Phenylephrine may cause a reduction in maternal cerebral tissue oxygen saturation (SctO2) during Caesarean birth to prevent spinal hypotension; however, the effect of norepinephrine has not been assessed. We hypothesized that norepinephrine was more effective than phenylephrine in maintaining SctO2 when preventing spinal hypotension during Caesarean birth. METHODS: We conducted a randomized, double-blind, controlled study. Sixty patients were randomly assigned to prophylactic norepinephrine or phenylephrine to maintain blood pressure during spinal anesthesia for Caesarean birth. SctO2, systolic blood pressure, and heart rate were recorded. The primary outcome was the incidence of a 10% reduction of intraoperative SctO2 from baseline or more during Caesarean birth. RESULTS: The norepinephrine group had a lower incidence of more than 10% reduction of intraoperative SctO2 from baseline than that of the phenylephrine group (13.3% vs 40.0%, P = .02). The change in SctO2 after 5 minutes of norepinephrine infusion was higher than that after phenylephrine infusion (-3.4 ±â€…4.7 vs -6.2 ±â€…5.6, P = .04). The change in SctO2 after 10 minutes of norepinephrine infusion was higher than that after phenylephrine infusion (-2.5 ±â€…4.4 vs -5.4 ±â€…4.6, P = .006). The norepinephrine group showed greater left- and right-SctO2 values than the phenylephrine group at 5 to 10 minutes. However, the change in systolic blood pressure was comparable between the 2 groups. CONCLUSION: Norepinephrine was more effective than phenylephrine in maintaining SctO2 when preventing spinal hypotension during Caesarean birth. However, the changes in clinical outcomes caused by differences in SctO2 between the 2 medications warrant further studies.

RNA Interference With Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trial.

Importance: Angiotensinogen is the most upstream precursor of the renin-angiotensin-aldosterone system, a key pathway in blood pressure (BP) regulation. Zilebesiran, an investigational RNA interference therapeutic, targets hepatic angiotensinogen synthesis. Objective: To evaluate antihypertensive efficacy and safety of different zilebesiran dosing regimens. Design, Setting, and Participants: This phase 2, randomized, double-blind, dose-ranging study of zilebesiran vs placebo was performed at 78 sites across 4 countries. Screening initiation occurred in July 2021 and the last patient visit of the 6-month study occurred in June 2023. Adults with mild to moderate hypertension, defined as daytime mean ambulatory systolic BP (SBP) of 135 to 160 mm Hg following antihypertensive washout, were randomized. Interventions: Randomization to 1 of 4 subcutaneous zilebesiran regimens (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months) or placebo (once every 3 months) for 6 months. Main Outcomes and Measures: The primary end point was between-group difference in least-squares mean (LSM) change from baseline to month 3 in 24-hour mean ambulatory SBP. Results: Of 394 randomized patients, 377 (302 receiving zilebesiran and 75 receiving placebo) comprised the full analysis set (93 Black patients [24.7%]; 167 [44.3%] women; mean [SD] age, 57 [11] years). At 3 months, 24-hour mean ambulatory SBP changes from baseline were -7.3 mm Hg (95% CI, -10.3 to -4.4) with zilebesiran, 150 mg, once every 6 months; -10.0 mm Hg (95% CI, -12.0 to -7.9) with zilebesiran, 300 mg, once every 3 months or every 6 months; -8.9 mm Hg (95% CI, -11.9 to -6.0) with zilebesiran, 600 mg, once every 6 months; and 6.8 mm Hg (95% CI, 3.6-9.9) with placebo. LSM differences vs placebo in change from baseline to month 3 were -14.1 mm Hg (95% CI, -19.2 to -9.0; P < .001) with zilebesiran, 150 mg, once every 6 months; -16.7 mm Hg (95% CI, -21.2 to -12.3; P < .001) with zilebesiran, 300 mg, once every 3 months or every 6 months; and -15.7 mm Hg (95% CI, -20.8 to -10.6; P < .001) with zilebesiran, 600 mg, once every 6 months. Over 6 months, 60.9% of patients receiving zilebesiran had adverse events vs 50.7% patients receiving placebo and 3.6% had serious adverse events vs 6.7% receiving placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients (principally injection site reactions and mild hyperkalemia) and 8.0% of placebo-treated patients. Conclusions and Relevance: In adults with mild to moderate hypertension, treatment with zilebesiran across a range of doses at 3-month or 6-month intervals significantly reduced 24-hour mean ambulatory SBP at month 3. Trial Registration: ClinicalTrials.gov Identifier: NCT04936035.

Successful treatment of severe calcium channel blocker poisoning, new experience with the guidance of invasive hemodynamic monitoring in a 17-year-old girl: a case report.

BACKGROUND: Calcium channel blocker poisoning is one of the most lethal cardiac drugs overdoses. Calcium and high-dose insulin infusion are the first-line therapy for symptomatic patients, and Intralipid emulsion infusion is useful for refractory cases. CASE PRESENTATION: In this report, we describe a 17-year-old Iranian girl who took 250 mg of the drug for a suicidal attempt and presented with refractory hypotension and non-cardiogenic pulmonary edema treated successfully with the guidance of invasive hemodynamic parameters. CONCLUSION: For complicated cases, in addition to supportive care and adjuvant therapy such as high-dose insulin and Intralipid, it is mandatory to utilize advanced hemodynamic monitoring to treat hypotension in severe calcium channel blocker poisoning to guide the treatment.

Administration of methylene blue in septic shock: pros and cons.

Septic shock typically requires the administration of vasopressors. Adrenergic agents remain the first choice, namely norepinephrine. However, their use to counteract life-threatening hypotension comes with potential adverse effects, so that non-adrenergic vasopressors may also be considered. The use of agents that act through different mechanisms may also provide an advantage. Nitric oxide (NO) is the main driver of the vasodilation that leads to hypotension in septic shock, so several agents have been tested to counteract its effects. The use of non-selective NO synthase inhibitors has been of questionable benefit. Methylene blue, an inhibitor of soluble guanylate cyclase, an important enzyme involved in the NO signaling pathway in the vascular smooth muscle cell, has also been proposed. However, more than 25 years since the first clinical evaluation of MB administration in septic shock, the safety and benefits of its use are still not fully established, and it should not be used routinely in clinical practice until further evidence of its efficacy is available.

Comparative Study Between Dexmedetomidine with Bupivacaine and Bupivacaine Alone in Erector Spinae Plane Block for Postoperative Pain Control of Posterior Lumbosacral Spine Fixation Surgeries: A Randomized Controlled Trial.

Background: As posterior lumbosacral spine fixation surgeries are common spine procedures done nowadays due to different causes and mostly accompanied with moderate-to-severe postoperative pain, so should find effective postoperative analgesia for these patients. This study aimed to observe analgesic effect of dexmedetomidine combined with bupivacaine versus bupivacaine alone for erector spinae plane block ESPB for postoperative pain control of posterior lumbosacral spine fixation surgeries. Methods: Double-blind randomized controlled study including 90 patients who were randomly allocated into 3 groups (30 patients for each): Dexmedetomidine combined with bupivacaine (DB group), bupivacaine (B group), and saline (control) (S group). US-guided ESPB was performed preoperatively bilaterally in all patients of the 3 groups. All patients received intravenous patient-controlled postoperative analgesia with morphine and 1 gm intravenous paracetamol every 8 hours. Primary clinical outcomes were active (while mobilization) and passive (at rest) visual analog scale (VAS) pain score at first 24 hours measured every 2 hours, opioid consumption (number of PCA presses), and need for rescue analgesia. Other clinical outcomes included active and passive VAS pain score at second 24 hours, measured every 4 hours, opioid consumption, need for rescue analgesia, postoperative opioid side effects, and intraoperative dexmedetomidine side effects as bradycardia and hypotension. Results: Active and passive VAS pain scores, postoperative opioid consumption, need for rescue analgesia, and postoperative opioid side effects were significantly lower in DB group when compared to other groups (B and S groups). There were no additional intraoperative dexmedetomidine side effects as bradycardia and hypotension. The estimated effect-size r was -0.58 and Cohen's d was -1.46. Conclusion: Addition of dexmedetomidine to bupivacaine 0.25% in ESPB for postoperative pain control in patients of posterior lumbosacral spine fixation surgeries resulted in lower active and passive VAS pain scores, decreased postoperative opioid consumption, need for rescue analgesia and postoperative opioid side effects without additional intraoperative dexmedetomidine side effects. Clinicaltrialsgov Identifier: NCT05590234.

Safety and Tolerability of Starting Aripiprazole Lauroxil With Aripiprazole Lauroxil NanoCrystal Dispersion in 1 Day Followed by Aripiprazole Lauroxil Every 2 Months Using Paliperidone Palmitate Monthly as an Active Control in Patients With Schizophrenia: A Post Hoc Analysis of a Randomized Controlled Trial.

Background: Aripiprazole lauroxil (AL) 1064 mg every 2 months following initiation using the AL NanoCrystal Dispersion formulation (ALNCD) plus 30-mg oral aripiprazole was efficacious and well tolerated in a 25-week, randomized, double-blind phase 3 trial in adults with acute schizophrenia. This post hoc analysis further characterized the safety of AL 1064 mg administered every 2 months and that of active control paliperidone palmitate (PP) 156 mg monthly based on occurrence, timing, and severity of adverse events (AEs) associated with antipsychotic medications.Methods: This study was conducted between November 2017 and March 2019. AL or PP was initiated during an inpatient stay of ≥ 2 weeks with transition to outpatient treatment thereafter. Rates of AEs of clinical interest, including injection site reactions (ISRs), motor AEs, sedation, hypotension, prolactin level increase, weight gain, and suicidal ideation/behavior, were summarized through weeks 4, 9, and 25 for each treatment.Results: Of 200 patients who received ≥ 1 dose of study treatment, 99 (49.5%) completed the study (AL, 57%; PP, 43%). Mean (SD) baseline Positive and Negative Syndrome Scale total scores were 94.1 (9.04) and 94.6 (8.41) in the AL and PP treatment groups, respectively. AEs were reported by 69/99 (70%) patients administered AL and 72/101 (71%) administered PP; most AEs were mild or moderate in severity. ISRs (AL, 18.2%; PP, 26.7%) occurred primarily on days 1 and 8. All akathisia/restlessness AEs (AL, 10.1%; PP, 11.9%) occurred during the first 4 weeks; <10% of patients (either treatment) experienced hypotension, sedation, or suicidal ideation/behavior events. Weight gain of ≥ 7% from baseline occurred in 9.3% of AL- and 23.8% of PP-treated patients. Median prolactin concentrations changed by -4.60 and -3.55 ng/mL among AL-treated males and females, respectively, and did not exceed 2 times normal levels in any AL-treated patients. In PP-treated patients, changes were 21.20 and 80.40 ng/mL and concentrations exceeded 2 times normal in 38% and 88% of males and females, respectively.Conclusions: No new early- or late-emerging safety concerns were observed through 25 weeks of treatment with AL 1064 mg every 2 months following initiation using ALNCD plus 30-mg oral aripiprazole. Results were consistent with known safety profiles of AL and PP and support the safety of AL 1064 mg every 2 months initiated using ALNCD plus 30-mg oral aripiprazole.Trial Registration: ClinicalTrials.gov identifier: NCT03345979.

Pharmacoutilization and adherence to sacubitril/valsartan in real world: the REAL.IT study in HFrEF.

AIMS: The current European Society of Cardiology (ESC) guidelines provide clear indications for the treatment of acute and chronic heart failure (HF). Nevertheless, there is a constant need for real-world evidence regarding the effectiveness, adherence, and persistence of drug therapy. We investigated the use of sacubitril/valsartan for the treatment of HF with reduced ejection fraction in real-world clinical practice in Italy. METHODS AND RESULTS: An observational, retrospective, non-interventional cohort study based on electronic medical records from nine specialized hospital HF centres in Italy was carried out on patients with prescription of sacubitril/valsartan. Overall, 948 patients had a prescription of sacubitril/valsartan, with 924 characterized over 6 months and followed up for 12 months. Pharmacoutilization data at 1 year of follow-up were available for 225 patients {mean age 69.7 years [standard deviation (SD) = 10.8], 81.8% male}. Of those, 398 (45.2%) reached the target dose of sacubitril/valsartan of 97/103 mg in a mean time of 6.9 (SD = 6.2) weeks. Blood pressure and hypotension in 61 patients (65%) and worsening of chronic kidney disease in 10 patients (10.6%) were the main reasons for not reaching the target dose. Approximatively 50% of patients had a change in sacubitril/valsartan dose during follow-up, and 158 (70.2%) were persistent with the treatment during the last 3 months of follow-up. A sensitivity analysis (persistence during the last 4 months of follow-up) showed persistence for 162 patients (72.0%). Adherence data, available for 387 patients, showed full adherence for 205 (53%). Discontinuation (102/717 patients, 14.2%) was mainly due to hypotension and occurred after a mean time of 34.3 (SD = 28.7) weeks. During follow-up, out of 606 patients with available data, 434 patients (71.6%) had an HF add-on drug or drugs concomitant with sacubitril/valsartan. HF-related hospitalization during follow-up was numerically higher in non-persistent (16/67 patients, 23.9%) vs. patients persistent to sacubitril/valsartan (30/158, 19%) (P = 0.405). CONCLUSIONS: Real-world data on the use of sacubitril/valsartan in clinical practice in Italy show a rapid titration to the target dose, high therapeutic adherence enabling a good level of therapeutic management in line with ESC guidelines for patients with reduced ejection fraction.

Risk factors and outcomes of persistent post-transplant hypotension among simultaneous pancreas and kidney transplant recipients.

BACKGROUND: The risk factors and outcomes associated with post- transplant hypotension after simultaneous pancreas and kidney (SPK) Transplantation are poorly defined. METHODS: SPK recipients at our center between 2010 and 2021 with functioning pancreas and kidney grafts for >6 months were included. Recipients were then divided into three groups based on active medications for the treatment of hypo-or hypertension at 6-months post-transplant: those with normal blood pressure (NBP) not requiring medication (NBP group), those on antihypertensive medications (HTN group), and those on medications for hypotension (fludrocortisone and/or midodrine) (Hypotensive group). RESULTS: A total of 306 recipients were included in the study: 54 (18%) in the NBP group, 215 (70%) in the HTN group, and 37 (12%) in the Hypotensive group. On multivariate analysis, the use of T-depleting induction (aHR = 9.64, p = .0001, 95% Cl = 3.12-29.75), pre-transplant use of hypotensive medications (aHR = 4.53, p = .0003, 95% Cl = 1.98-10.38), and longer duration of dialysis (aHR = 1.02, p = .01, 95% Cl = 1.00-1.04) were associated with an increased risk of post-transplant hypotension. Post-transplant hypotension was not associated with an increased risk of death-censored kidney or pancreatic allograft failure, or patient death. CONCLUSION: Hypotension was common even 6 months post-SPK transplantation. With appropriate management, hypotension was not associated with detrimental graft or patient outcomes.

Hypotension and respiratory events related to electrical cardioversion for atrial fibrillation or atrial flutter in the emergency department.

INTRODUCTION: Electrical cardioversion for atrial fibrillation/atrial flutter (AF/AFL) is common in the ED. Our previous work showed that hypotension and respiratory events were important adverse events that occurred in patients undergoing electrical cardioversion for AF/AFL. The purpose of this study was to examine if (1) beta-blockers or calcium channel blocker use prior to ECV were associated with hypotension and (2) medications used for procedural sedation were associated with respiratory events. METHODS: This was a secondary analysis of pooled study data from four previous multicentred studies on AF/AFL. We conducted a multivariable logistic regression to examine predictors of hypotension and respiratory adverse events. RESULTS: There were 1736 patients who received ECV. A hypotensive event occurred in 62 (3.6%) patients. There was no significant difference in the odds of a hypotensive event in patients who received a beta-blocker or calcium channel blocker in the ED compared to no rate control. Procedural sedation with fentanyl (OR 2.01 95% CI 1.15-3.51) and home beta-blocker use (OR 1.92, 95% CI 1.14-3.21) were significantly associated with hypotensive events. A respiratory event occurred in 179 (10.3%) patients. Older age (OR 2.02, 95% CI 1.30- 3.15) and receiving midazolam for procedural sedation were found to be significantly associated with respiratory events (OR 1.99, 95% CI 1.02-3.88). CONCLUSION: Beta-blocker or calcium channel blocker use prior to ECV for AF/AFL was not associated with hypotension. However, sedation with fentanyl and home beta-blocker use was associated with hypotension. The use of midazolam for procedural sedation was significantly associated with respiratory events.

RéSUMé: INTRODUCTION: La cardioversion électrique pour la fibrillation auriculaire / flutter auriculaire (AF / AFL) est fréquente aux urgences. Nos travaux précédents ont montré que l'hypotension et les événements respiratoires étaient des événements indésirables importants qui se sont produits chez les patients subissant une cardioversion électrique pour AF / AFL. Le but de cette étude était d'examiner si 1) les bêtabloquants ou les inhibiteurs calciques utilisés avant l'ECV étaient associés à l'hypotension et 2) les médicaments utilisés pour la sédation procédurale sont associés à des événements respiratoires. MéTHODES: Il s'agissait d'une analyse secondaire des données d'études regroupées de quatre études multicentriques précédentes sur l'AF/AFL. Nous avons effectué une régression logistique multivariée pour examiner les prédicteurs de l'hypotension et des événements indésirables respiratoires. RéSULTATS: Il y avait 1736 patients qui ont reçu ECV. Un événement hypotenseur s'est produit dans 62 (3,6%) patients. Il n'y avait pas de différence significative dans la probabilité d'un événement hypotenseur chez les patients qui ont reçu un bêtabloquant ou un inhibiteur calcique à l'urgence par rapport à aucun contrôle de taux. La sédation procédurale avec du fentanyl (RC 2,01 à 95 %, IC 1,15 à 3,51) et l'utilisation de bêtabloquants à domicile (RC 1,92, IC à 95 %, 1,14 à 3,21) étaient significativement associées à des événements hypotensifs. Un événement respiratoire est survenu chez 179 (10,3 %) patients. Un âge plus avancé (RC 2,02, IC à 95 % : 1,30 à 3,15) et la réception de midazolam pour sédation procédurale étaient significativement associés à des événements respiratoires (RC 1,99, IC à 95 % 1,02-3,88). CONCLUSIONS: L'utilisation d'un bêtabloquant ou d'un inhibiteur calcique avant l'ECV pour l'AF/AFL n'était pas associée à l'hypotension. Cependant, la sédation avec du fentanyl et l'utilisation de bêtabloquants à domicile étaient associées à l'hypotension. L'utilisation du midazolam pour la sédation procédurale était significativement associée aux événements respiratoires.

Higher NT-proBNP levels and the risk of intradialytic hypotension at hemodialysis initiation.

INTRODUCTION: Elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) is a potent predictor of adverse outcomes in hemodialysis initiation. These patients often experience intradialytic hypotension, which may partially reflect cardiac dysfunction, but the association of NT-proBNP with intradialytic hypotension is not clear. METHODS: We performed a post hoc analysis of a randomized trial that tested mannitol versus placebo in 52 patients initiating hemodialysis (NCT01520207). NT-proBNP was measured prior to the first and third sessions (n = 87). Mixed-effects models (adjusting for randomized treatment, sex, race, age, diabetes, heart failure, catheter use, pre-dialysis systolic blood pressure, pre-dialysis weight, ultrafiltration volume, serum sodium, bicarbonate, urea nitrogen, phosphate, albumin, hemoglobin, and session length) were fit to examine the association of NT-proBNP with systolic blood pressure decline (pre-dialysis minus nadir systolic blood pressure). Additionally, mixed-effects Poisson models were fit to examine the association with intradialytic hypotension (≥20 mmHg decline in systolic blood pressure). FINDINGS: Mean age was 55 ± 16 years; 33% had baseline heart failure. The median NT-proBNP was 5498 [25th-75th percentile 2011, 14,790] pg/mL; 26 sessions (30%) were complicated by intradialytic hypotension. In adjusted models, each unit higher log-NT-proBNP was associated with 6.0 mmHg less decline in systolic blood pressure (95%CI -9.2 to -2.8). Higher pre-dialysis NT-proBNP, per log-unit, was associated with a 52% lower risk of intradialytic hypotension (IRR 0.48, 95%CI 0.23-0.97), without evidence for effect modification by randomized treatment (P-interaction = 0.17). DISCUSSION: In patients initiating hemodialysis, higher NT-proBNP is associated with less decline in intradialytic systolic blood pressure and lower risk of intradialytic hypotension. Future studies should investigate if higher pre-dialysis NT-proBNP levels may identify patients who might tolerate more aggressive ultrafiltration.