Intravenous Loading Research Articles

Digoxin Loading Doses and Serum Digoxin Concentrations for Rate Control of Atrial Arrhythmias in Critically Ill Patients.

Intravenous (IV) digoxin loading dose recommendations for rate control of atrial arrhythmias in critically ill patients are not well studied. When using digoxin in the setting of atrial fibrillation/atrial flutter (AF/AFL), a loading dose (LD) in either a fixed-dose regimen, weight-based dose, or pharmacokinetic-based calculation to target a serum digoxin concentration (SDC) of 0.8-1.5 ng/mL is recommended. The objective of this study was to assess the safety and effectiveness of digoxin LD used in critically ill patients for rate control of AF/AFL and to assess the SDC achieved. This single center retrospective cohort study included patients who received IV digoxin and had a SDC drawn. The primary endpoint was the median SDC achieved after a digoxin LD. Secondary outcomes included the frequency of SDCs ≥1.5 ng/mL and heart rate (HR) control. A total of 92 patients were included. The median total LD of digoxin for the entire cohort was 11mcg/kg (750 mcg). For 61% of the cohort, the LD was distributed over six-hour intervals. The median SDC after completion of the IV digoxin LD was 1.3 ng/mL (0.9, 1.7). The incidence of supratherapeutic SDC was 36% for the total cohort. A target HR < 110 beats per minute within 24 hours from digoxin LD was achieved in 60% of the cohort. In conclusion, a median total digoxin LD of 750 mcg in critically ill patients with AF/AFL, targeting a SDC < 1.5ng/mL may be considered for acute rate control, taking into account drug-drug interactions in the cardiac intensive care unit. Future studies are necessary to confirm our findings.

Diuretic responses to Ringer's solution and 20% albumin at different arterial pressures.

Intravenous volume loading is a common treatment when hypovolemia is a potential cause of oliguria. We studied whether the effectiveness of Ringer's solution and 20% albumin in inducing diuresis differs depending on the mean arterial pressure (MAP). For this purpose, volume kinetic analysis was performed based on urine output and hemoglobin-derived plasma dilution obtained during and after 136 infusions of Ringer and 85 infusions of 20% albumin. Covariance analysis quantified the diuretic response at different arterial pressures. The results show that the diuretic response to a known plasma volume expansion was greater for Ringer's solution above a MAP of 70 mmHg, while 20% albumin was significantly more effective at lower pressures (p < 0.03). Simulations of the urinary output in response to infusion of a predefined fluid volume yielded superior efficacy for 20% albumin when the MAP was low, while Ringer's was similarly effective when the MAP averaged 100 mmHg. In conclusion, urine output in response to plasma volume expansion with 20% albumin was similar to, or even stronger, than that of Ringer's solution when the MAP was below 70 mmHg.

Efficiency and safety of high-dose undiluted intravenous push levetiracetam loading doses compared to intravenous infusion in seizing patients: A retrospective cohort study.

Intravenous (IV) push (IVP) is an alternative administration method for levetiracetam, but evidence evaluating it compared to IV piggyback (IVPB) for loading doses in acutely seizing patients is limited, particularly in patients with status epilepticus (SE). This study aimed to compare the efficiency and safety of IVP versus IVPB levetiracetam loading doses. This was a single-center sequential retrospective study conducted in adult (≥18 years) patients who received an IV levetiracetam loading dose (>2000 mg or ≥20 mg/kg) for acute or suspected seizure. The primary outcome was time to administration, compared between doses given as IVP versus IVPB. Secondary outcomes included rates of adverse events (AEs), rescue benzodiazepine or antiseizure medication administration, intubation, and intensive care unit (ICU) admission between groups. A total of 246 patients were included; 116 received IVP and 130 received IVPB loading doses. Median age was 56 years; most patients were male (62%) and White (60%) and had witnessed seizures (67%). Doses were administered for SE in 32 (27.5%) and 46 (35.4%) patients in the IVP and IVPB arms, respectively. Median time to administration was shorter in the IVP group (12 vs. 38 min, p < .001). Bradycardia (1.7% vs. 2.3%, p = .99), hypotension (7.8% vs. 12%, p = .30), sedation (6% vs. 12.3%, p = .09), intubation (10% vs. 8%, p = .37), ICU admission (32% vs. 39%, p = .31), and rescue medication administration (8.6% vs. 14.6% p = .10) were similar between groups. In SE patients, IVP was associated with shorter time to administration (12 vs. 44 min, p = .003) and lower odds of ICU admission after adjustment for age, dose, Status Epilepticus Severity Score, and seizure history (adjusted odds ratio = .23, 95% confidence interval = .06-.81). IVP reduced time to levetiracetam administration versus IVPB and was not associated with more AEs. Rescue agent use, intubation, and ICU admission were similar between arms, but IVP may reduce ICU admissions in SE patients. Prospective studies should assess the effectiveness of IVP versus IVPB.

Pharmacokinetic and pharmacodynamic data from the NEOLEV1 and NEOLEV2 studies

ObjectivesTo confirm that levetiracetam (LEV) demonstrates predictable pharmacokinetics(PK) at higher doses and to study the pharmacodynamics(PD) of LEV.DesignPharmacokinetic data from the NEOLEV1 and NEOLEV2 trials were analysed using a non-linear...

L-carnitine for valproic acid-induced toxicity.

Review the effectiveness and dosing of L-carnitine for valproic-acid induced toxicity. A literature review of the pharmacokinetics and clinical use of L-carnitine was performed. Valproic acid is a fatty acid used for numerous therapeutic indications ranging from epilepsy to bipolar disorder. The metabolism of valproic acid produces both therapeutic and toxic metabolites. Whilst it has a good safety profile, adverse effects of valproic acid in chronic use include hepatotoxicity ranging from transient elevation of liver enzymes to fulminant liver failure and hyperammonaemia with resultant encephalopathy. L-carnitine is an essential cofactor for mitochondrial fatty acid metabolism, which is an important source of energy in cardiac and skeletal muscle. Physiological concentrations of L-carnitine are maintained in man by exogenous dietary intake and endogenous synthesis. Following exogenous oral administration of L-carnitine, the bioavailability ranges from 14% to 18%. After bolus intravenous administration of L-carnitine in doses ranging from 20 to 100 mg/kg, the volume of distribution is 0.2-0.3 L/kg, and the fraction excreted unchanged in urine is 0.73-0.95, suggesting that renal clearance of L-carnitine is dose dependent due to saturable renal reabsorption at supraphysiological concentrations. There is evidence supporting the use of L-carnitine in treating hyperammonaemia and hepatotoxicity following chronic therapeutic use and after acute overdose of valproic acid, but the optimal dose and route of administration is unknown. Based on the pharmacokinetics of L-carnitine, we advocate the administration of L-carnitine for valproic-acid induced hyperammonaemia or hepatotoxicity as an intravenous loading dose of 5 mg/kg followed by a continuous intravenous infusion instead of the oral or intravenous boluses that are currently advocated.

A Simulation-Based Assessment of Levetiracetam Concentrations Following Fixed and Weight-Based Loading Doses: A Meta-Regression and Pharmacokinetic Modeling Analysis.

Current recommendations for refractory status epilepticus (SE) unresponsive to benzodiazepines suggest a loading dose of levetiracetam (LEV) of 60 mg/kg to a maximum of 4500 mg. LEV therapeutic drug monitoring can help guide therapy and is garnering increasing attention. The objective of this study is to simulate the probability of target attainment (PTA) of fixed dose and weight-based loading doses of LEV with respect to established therapeutic target concentrations. Meta-regression of the current literature was performed to evaluate the relationship between intravenous LEV loading dose and seizure cessation in refractory SE patients. A previously published pharmacokinetic model was used to simulate the PTA capacity of competing single intravenous dosing schemes (fixed vs weight-based dosing) to achieve maximum (Cpeak) and 12-h (C12h) plasma concentrations that exceed 12 mg/L. The meta-regression indicated that dosage was not a statistically significant modulator of seizure control at dosages between 20 and 60 mg/kg. Stochastic simulations showed all dosing schemes achieved plasma Cpeak >12 mg/L, but C12h levels were <12 mg/L in subjects over 60 kg with a fixed dose ≤2000 mg or in subjects <60 kg with a weight-based dose <30 mg/kg. Dosages of 40 and 60 mg/kg provided ≥90% PTAs across all weights. Using a weight-based loading dose of 40 mg/kg, up to a suggested maximum of 4500 mg, improves the likelihood of achieving a sustained therapeutic drug concentration after the initial LEV dose, whereas fixed <3000 mg may not achieve the desired concentration before maintenance dosing.

Hemodynamic changes in the prone position according to fluid loading after anaesthesia induction in patients undergoing lumbar spine surgery: a randomized, assessor-blind, prospective study

Introduction A change from the supine to prone position causes hemodynamic alterations. We aimed to evaluate the effect of fluid preloading in the supine position, the subsequent hemodynamic changes in the prone position and postoperative outcomes. Patients and methods This prospective, assessor-blind, randomized controlled trial was conducted between March and June 2023. Adults scheduled for elective orthopaedic lumbar surgery under general anaesthesia were enrolled. In total, 80 participants were randomly assigned to fluid maintenance (M) or loading (L) groups. Both groups were administered intravenous fluid at a rate of 2 ml/kg/h until surgical incision; Group L was loaded with an additional 5 ml/kg intravenous fluid for 10 min after anaesthesia induction. The primary outcome was incidence of hypotension before surgical incision. Secondary outcomes included differences in the mean blood pressure (mBP), heart rate, pleth variability index (PVi), stroke volume variation (SVV), pulse pressure variation (PPV), stroke volume index and cardiac index before surgical incision between the two groups. Additionally, postoperative complications until postoperative day 2 and postoperative hospital length of stay were investigated. Results Hypotension was prevalent in Group M before surgical incision and could be predicted by a baseline PVi >16. The mBP was significantly higher in Group L immediately after fluid loading. The PVi, SVV and PPV were lower in Group L after fluid loading, with continued differences at 2–3 time points for SVV and PPV. Other outcomes did not differ between the two groups. Conclusion Fluid loading after inducing general anaesthesia could reduce the occurrence of hypotension until surgical incision in patients scheduled for surgery in the prone position. Additionally, hypotension could be predicted in patients with a baseline PVi >16. Therefore, intravenous fluid loading is strongly recommended in patients with high baseline PVi to prevent hypotension after anaesthesia induction and in the prone position. Trial number KCT0008294 (date of registration: 16 March 2023)

Safety and feasibility of intravenous sotalol loading for the prevention of ventricular arrhythmias.

The use of intravenous (IV) sotalol loading following recent U.S. Food and Drug Administration (FDA) approval of a 1-day loading protocol has reduced the obligatory 3-day hospital stay for sotalol initiation when given orally. Several studies have recently demonstrated the safety and feasibility of IV loading for patients with atrial arrhythmias. However, there is a paucity of data on the feasibility and safety of IV sotalol loading for patients with ventricular arrhythmias. This study aims to assess the safety, feasibility, and length of stay (LOS) outcomes of IV sotalol loading for the prevention of ventricular arrhythmias. A retrospective analysis was performed of all patients undergoing IV sotalol loading and oral sotalol initiation for ventricular arrhythmias, or IV sotalol loading for atrial arrhythmias between August 2021 and December 2023 at Northwestern University. Baseline characteristics, success of sotalol initiation/loading, changes in heart rate (HR) and QT/QTc, safety, and LOS were compared between patients undergoing sotalol loading/initiation for ventricular arrhythmias (IV vs. PO) and between patients undergoing IV sotalol loading for ventricular arrhythmias vs. for atrial arrhythmias. A total of 28 patients underwent sotalol loading/initiation for ventricular arrhythmias (N = 15 IV and N = 13 PO) and 41 patients underwent IV sotalol loading for atrial arrhythmias. Baseline characteristics of congestive heart failure history and left ventricular ejection fraction were worse in the ventricular arrhythmias group. There was no significant difference in the successful completion of IV sotalol loading for ventricular arrhythmias compared to oral sotalol initiation for ventricular arrhythmias or IV sotalol loading for atrial arrhythmias (86.7% vs. 92.3% vs. 90.2%, p = 0.88). There was a significant increase in ΔQTc following IV sotalol infusion for ventricular arrhythmias compared to following PO sotalol initiation for ventricular arrhythmias (46.4 ± 29.2ms vs. 8.9 ± 32.6ms, p = 0.004) and following IV sotalol infusion for atrial arrhythmias (46.4 ± 29.2ms vs. 24.0 ± 25.1ms, p = 0.018). ΔHR following IV sotalol infusion for ventricular arrhythmias was similar to ΔHR following PO sotalol initiation for ventricular arrhythmias and ΔHR following IV sotalol infusion for atrial arrhythmias (- 7.5 ± 8.7bpm vs. - 8.5 ± 13.9bpm vs. - 8.3 ± 13.2bpm, p = 0.87). There were no significant differences in discontinuation for QTc prolongation (6.7% vs. 1.7% vs. 2.4%, p = 0.64) and bradycardia (13.3% vs. 7.7% vs. 9.8%, p = 0.88) between IV sotalol loading for ventricular arrhythmias, PO sotalol initiation for ventricular arrhythmias, and IV sotalol loading for atrial arrhythmias. There were no instances of hypotension, life-threatening ventricular arrhythmias, heart failure, or death. Length of stay was significantly shorter for IV sotalol loading compared to PO sotalol initiation for ventricular arrhythmias (1.1 ± 0.36days vs. 4.2 ± 1.0days, p < 0.0001). IV sotalol loading appears feasible and safe for use in ventricular arrhythmias and results in a decreased length of stay. Despite increased comorbidities and greater increase in QTc interval following IV sotalol infusion in the ventricular arrhythmias group, there were no significant differences in successful completion of loading or adverse outcomes when compared to PO sotalol initiation for ventricular arrhythmias and IV loading for atrial arrhythmias.

Dexmedetomidine Versus Fentanyl on Time to Extubation in Patients with Morbid Obesity Undergoing Laparoscopic Sleeve Gastrectomy.

Sleeve gastrectomy (SG) is an effective method for managing obesity. While opioids are used for their hemodynamic stability and their ability to reduce intraoperative stress, they also have reported side effects. Dexmedetomidine (DEX), an α2 adrenergic receptor agonist, is noted for its analgesic and anesthetic-sparing effects, leading to a higher quality of recovery. The study aims to compare the effects of fentanyl and dexmedetomidine (DEX) on the recovery of morbidly obese patients following laparoscopic sleeve gastrectomy (SG). This randomized, double-blind study involved 64 patients, equally divided into two groups. The Dexmedetomidine group (Group D) received an intravenous (IV) loading dose of dexmedetomidine (1 μg/kg) over 15 minutes before anesthesia induction, followed by a 10 mL saline 0.9% infusion over 60 seconds during induction. Post-intubation, dexmedetomidine was administered at 0.5 μg/kg/h. The Fentanyl group (Group F) received a volume-matched saline 0.9% IV over 15 minutes pre-induction and fentanyl (1 μg/kg) diluted in 10 ml saline 0.9% IV over 60 seconds during induction. After intubation, a continuous fentanyl infusion was maintained at a rate of 1 μg/kg/hr. Extubation time was significantly shorter in the Dexmedetomidine group (Group D) at 8.25 ± 2.7 minutes compared to the Fentanyl group (Group F) at 10.47 ± 2.17 minutes, with a P-value of 0.001. Intraoperative heart rate and mean arterial blood pressure were also significantly lower in Group D than in Group F. Visual analogue scale (VAS) pain scores were significantly lower in Group D compared to Group F upon arrival at the post-anesthesia care unit and at 2 hours postoperatively (P-value < 0.05). Additionally, the morphine dose consumed in the first 12 hours after surgery was significantly lower in Group D (5.75 ± 2.20 mg) compared to Group F (8 ± 2.38 mg), with a P-value of 0.001. For morbidly obese patients undergoing laparoscopic sleeve gastrectomy, dexmedetomidine (DEX) proves to be an effective anesthetic choice. It not only reduces extubation time but also lowers early postoperative visual analogue scale (VAS) pain scores and opioid consumption within the first 12 hours following surgery.

To Study Perioperative Changes in Plasma Phenytoin Levels in Patients with Brain Tumor Undergoing Craniotomy and Its Correlation with Postoperative Seizures

Abstract Introduction Phenytoin, although commonly used for postoperative seizure prophylaxis, exhibits variable results in mitigating seizure frequency following craniotomy. These discrepancies may be linked to a reduction in plasma phenytoin levels subsequent to the surgical intervention. Aims This prospective study aims to characterize changes in plasma phenytoin levels after craniotomy and their relationship with intraoperative blood loss. Methods Fifty consecutive patients were enrolled in this study after obtaining written informed consent. These patients had either been on oral phenytoin for at least 7 days or had received an intravenous loading dose before undergoing craniotomy. Serum phenytoin levels were measured 24 hours preoperatively, immediately before craniotomy (prior to skin incision), postcraniotomy (after skin closure), and 24 hours postcraniotomy. Additionally, intraoperative blood loss was calculated using a modified Gross formula. Results Immediately following craniotomy, there was a statistically significant mean decline of 28.16% in serum phenytoin levels. Furthermore, the analysis revealed a robust positive correlation between the decrease in phenytoin concentration level and several factors, including blood loss during surgery, the duration of the surgical procedure, intravenous fluids administered during surgery, and the occurrence of postoperative seizures. Conclusion This study underscores the potential utility of routinely measuring perioperative serum phenytoin levels in high-risk patients to prevent postcraniotomy seizures. Moreover, it suggests that patients with substantial intraoperative blood loss may benefit from an additional bolus dose of phenytoin toward the end of the surgical procedure.

Comparison of Detomidine or Romifidine in Combination with Morphine for Standing Magnetic Resonance Imaging in Horses.

The aim of this study was to determine the most appropriate sedation protocol for a standing magnetic resonance imaging (MRI) examination in horses, comparing continuous rate infusions (CRIs) of detomidine and romifidine combined with a single bolus of morphine. Sixteen horses referred for standing low-field open-magnet MRI were randomly assigned to one of two sedation protocols. The horses were premedicated with 0.03 mg/kg of intramuscular acepromazine, and those animals belonging to Group D received an intravenous (IV) loading dose of detomidine (0.01 mg/kg) 30 min later, while those of Group R received romifidine (0.04 mg/kg). If the horses were inadequately sedated, an additional dose of IV detomidine (0.005 mg/kg) or romifidine (0.02 mg/kg) was administered, according to the animal's group. During the MRI, a single IV bolus of morphine (0.05 mg/kg) was administered, and according to which group it belonged to, the animal started the administration of detomidine (0.01 mg/kg/h) or romifidine (0.02 mg/kg/h). Heart rate (HR), respiratory rate (RR), rectal temperature (RT), depth of sedation, and degree of ataxia were evaluated every 10 min during MRI. Two horses belonging to Group D and four horses from Group R needed additional sedation before entering the MRI unit because they were unsatisfactorily sedated. No side effects were observed following morphine bolus administration. During the MRI procedure, five horses in Group R received an additional IV romifidine bolus (0.01 mg/kg) because the depth of sedation score was 1 and the ataxia score was 0. Any substantial differences were recorded between the two treatments in terms of HR, RR, and RT. In conclusion, at the doses used, a detomidine-morphine combination following a CRI of detomidine appears more suitable than a romifidine-morphine combination following a CRI of romifidine for maintaining an adequate depth of sedation and adequate immobility in horses undergoing standing MRI.

Immediate and sustained terminal complement inhibition with ravulizumab in patients with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder.

To assess the pharmacokinetics and pharmacodynamics of the long-acting terminal complement 5 (C5) inhibitor ravulizumab in adults with anti-aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) in the phase 3, open-label CHAMPION-NMOSD trial (NCT04201262). Patients aged 18 years or older received a weight-based intravenous loading dose of ravulizumab (2,400-3,000 mg) on day 1, followed by weight-based maintenance doses (3,000-3,600 mg) on day 15 and once every 8 weeks thereafter. Pharmacokinetic assessments were maximum observed concentration (Cmax, assessed at the end of the infusion) and concentration at the end of the dosing interval (Ctrough, assessed before dosing) for ravulizumab. Pharmacodynamic assessment was time-matched observed free C5 concentration in serum up to 50 weeks. The pharmacokinetic/pharmacodynamic analysis included 58 patients treated with ravulizumab. Serum ravulizumab concentrations at or above the therapeutic threshold (175 μg/mL) were achieved in all patients after administration of the first dose and maintained for 50 weeks. At week 50, the mean (standard deviation) Cmax (n = 51) and Ctrough (n = 52) were 1,887.6 (411.38) and 764.4 (217.68) μg/mL, respectively. Immediate and complete terminal complement inhibition (free C5 serum concentrations < 0.5 μg/mL) was achieved by the end of the first ravulizumab infusion and sustained throughout the treatment period. No treatment-emergent antibodies to ravulizumab were observed. No impact on ravulizumab pharmacokinetics was seen for age, sex, race, hematocrit, hemoglobin, markers of renal and liver impairment, or medications commonly used by patients with NMOSD. Body weight and BMI were significant covariates of ravulizumab pharmacokinetics. Serum ravulizumab concentrations were maintained above the therapeutic threshold in all patients through 50 weeks of treatment. Ravulizumab achieved immediate and complete terminal complement inhibition that was sustained throughout the treatment period in adults with AQP4+ NMOSD.

Trials in Progress: The Randomized, Double-Blind, Placebo-Controlled Phase 1b CROSSWALK-a and Phase 2a CROSSWALK-c Trials - Crovalimab for the Treatment and Prevention of Vaso-Occlusive Episodes in Sickle Cell Disease

Background and Significance In sickle cell disease (SCD), a single point mutation in the beta-globin gene results in hemoglobin S (HbS) production, which can polymerize upon deoxygenation. Polymerization distorts the red blood cell (RBC) membrane and generates sickled RBCs, contributing to microvascular occlusions, which may present as acute, painful vaso-occlusive episodes (VOEs). For patients (pts) with SCD, 70% of emergency department visits and 90% of hospitalizations are VOE-related. 1,2 Despite existing treatments for VOE prevention, considerable morbidity and mortality remain; acute VOE treatment is limited to supportive care due to a lack of targeted therapies. Accumulating nonclinical data suggest a multimodal role for complement dysregulation in SCD pathophysiology, including in vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage. 3 Crovalimab is a novel, engineered, anti-complement C5 monoclonal antibody that allows for small-volume subcutaneous (SC) injection after an initial intravenous (IV) loading dose. 4 Here, we describe two randomized, double-blind, placebo-controlled trials evaluating crovalimab in pts with SCD: CROSSWALK-a (Phase 1b; NCT04912869) and CROSSWALK-c (Phase 2a; NCT05075824). Study Design and Methods CROSSWALK-a evaluates the safety of crovalimab in managing acute uncomplicated VOEs. CROSSWALK-c evaluates the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs. Pts 12-55 years old, weighing ≥40 kg with a confirmed diagnosis of sickle cell anemia (homozygous HbSS or heterozygous HbS/β 0 thalassemia) and vaccinated against N. meningitidis, H. influenzae type B and S. pneumoniae are eligible (Fig. 1 and 2). Concurrent SCD-directed therapies are allowed. CROSSWALK-a Pts must present with an acute uncomplicated VOE requiring hospitalization and parenteral opioid analgesics, and have had ≤10 VOEs in the 12 months prior to randomization. Eligible pts will be randomized 2:1 to receive a single IV weight-based tiered dose of crovalimab or placebo, and monitored during hospitalization and in an 84-day observational period followed by a safety follow-up period for a total study duration of 322 days (10.5 months). The primary objective of CROSSWALK-a is to evaluate safety up to Day 84, including: Incidence and severity of adverse eventsIncidence and severity of infusion-related reactions and hypersensitivityChange from baseline in targeted vital signs and clinical laboratory test results Efficacy, pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity, and exploratory biomarker endpoints will also be evaluated. CROSSWALK-c Pts with 2-10 VOEs in the 12 months prior to randomization are eligible. Eligible pts will be randomized 1:1 to receive weight-based tiered doses of crovalimab or placebo, consisting of initial loading doses (IV: Day 1; SC: Day 2 and weekly for Weeks 2-4) and monthly maintenance SC doses Weeks 5-49 for 48 weeks of treatment. The primary objective of CROSSWALK-c is to evaluate crovalimab efficacy vs placebo up to 48 weeks, on the basis of: The annualized rate of medical facility VOEs Key secondary efficacy objectives are: Annualized rate of home VOEsAnnualized rate of acute chest syndromeAnnualized rate of days hospitalized for medical facility VOEsPt-reported fatigue in adults Safety, PK, PD, immunogenicity, and exploratory biomarker endpoints will also be evaluated. Primary results will be published upon trial readout.

Feasibility and safety values of activated clotting time-guided systemic heparinization in coil embolization for unruptured intracranial aneurysms.

This study aimed to evaluate the feasibility and safety values of activated clotting time (ACT)-guided systemic heparinization in reducing periprocedural thrombosis and bleeding complications during coil embolization of unruptured intracranial aneurysms. A total of 228 procedures performed on 213 patients between 2016 and 2021 were included in the retrospective analysis. The target ACT was set at 250 s. Logistic regression was performed to assess predictors for the occurrence of thrombosis and bleeding. Receiver operating characteristic (ROC) analyses were employed to determine the optimal cut-off values for ACT, heparinization, and procedure time. Most (85.1%) of procedures were stent-assisted embolization. The mean baseline ACT was 128.8 ± 45.7 s. The mean ACT at 20 min after the initial intravenous heparin loading of 78.2 ± 18.8 IU/kg was 185 ± 46.4 s. The mean peak ACT was 255.6 ± 63.8 s with 51.3% (117 cases) achieving the target ACT level. Peak ACT was associated with symptomatic thrombosis (OR per second, 1.008; 95% CI, 1.000-1.016; P = 0.035) (cut-off value, 275 s; area under ROC (AUROC), 0.7624). Total administered heparin dose per body weight was negatively associated with symptomatic thrombosis (OR per IU/kg, 0.972; 95% CI, 0.949-0995; P = 0.018) (cut-off value, 294 IU/kg; AUROC, 0.7426) but positively associated with significant bleeding (OR, 1.008 per IU/kg; 95% CI, 1.005-1.012; P <0 .001) (cut-off value, 242 IU/kg; AUROC, 0.7391). Procedure time was significantly associated with symptomatic thrombosis (OR per minute, 1.05; 95% CI, 1.017-1.084; P value = 0.002) (cut-off value, 158 min; area under ROC, 0.8338). This study demonstrated that ACT-guided systemic heparinization was feasible to achieve the target ACT value and proposes probable safety thresholds to prevent periprocedural complications through reducing procedure time during coil embolization of unruptured intracranial aneurysms in the stent era.

Effect of constant rate infusion of detomidine with and without vatinoxan on blood glucose and insulin concentrations in horses

ObjectiveTo assess the effects of an α2-adrenoceptor agonist (detomidine) constant rate infusion (CRI) with and without an α2-adrenoceptor antagonist (vatinoxan) CRI on blood insulin and glucose concentrations, heart rate, intestinal borborygmi, and sedation during and after infusion in horses. Study designRandomized, blinded, crossover, experimental study. AnimalsA total of nine healthy, adult Finnhorse mares. MethodsHorses were treated with an intravenous (IV) detomidine loading dose (0.01 mg kg–1), followed by CRI (0.015 mg kg–1 hour–1), and the same doses of detomidine combined with an IV vatinoxan loading dose (0.15 mg kg–1), followed by CRI (detomidine and vatinoxan; 0.05 mg kg–1 hour–1) with an 18 day washout period. Infusion time was 60 minutes and horses were monitored for 240 minutes after the infusion. Heart rate, borborygmi score and sedation were assessed, and blood glucose, insulin and triglyceride concentrations were measured. Data were analyzed using repeated measures ancova and Wilcoxon signed-rank tests. Values of p < 0.05 were considered statistically significant. ResultsInsulin concentration decreased during (median nadir 1.7, range 0.0–2.9 μIU mL–1 at 60 minutes, p < 0.0001) and increased after detomidine CRI (median 36.6, range 11.7–78.4 μIU mL–1 at 180 minutes, p = 0.0001) significantly compared with detomidine and vatinoxan CRI. A significant elevation of blood glucose (peak 11.5 ± 1.6 mmol L–1 at 60 minutes, p < 0.0001) was detected during detomidine CRI. Vatinoxan alleviated the insulin changes and abolished the significant increase in blood glucose. Vatinoxan alleviated the decrease in heart rate (p = 0.0001) during detomidine infusion. No significant differences were detected in sedation scores between treatments. Conclusions and clinical relevanceVatinoxan attenuated the negative adverse effects of detomidine CRI and thus is potentially beneficial when used in combination with an α2-adrenoceptor agonist CRI in horses.

Quantifying the variability in the assessment of reproductive hormone levels

To quantify how representative a single measure of reproductive hormone level is of the daily hormonal profile using data from detailed hormonal sampling in the saline placebo-treated arm conducted over several hours. Retrospective analysis of data from previous interventional research studies evaluating reproductive hormones. Clinical Research Facility at a tertiary reproductive endocrinology centre at Imperial College Hospital NHS Foundation Trust. Overall, 266 individuals, including healthy men and women (n = 142) and those with reproductive disorders and states (n = 124 [11 with functional hypothalamic amenorrhoea, 6 with polycystic ovary syndrome, 62 women and 32 men with hypoactive sexual desire disorder, and 13 postmenopausal women]), were included in the analysis. Data from 266 individuals who had undergone detailed hormonal sampling in the saline placebo-treated arms of previous research studies was used to quantify the variability in reproductive hormones because of pulsatile secretion, diurnal variation, and feeding using coefficient of variation (CV) and entropy. The ability of a single measure of reproductive hormone level to quantify the variability in reproductive hormone levels because of pulsatile secretion, diurnal variation, and nutrient intake. The initial morning value of reproductive hormone levels was typically higher than the mean value throughout the day (percentage decrease from initial morning measure to daily mean: luteinizing hormone level 18.4%, follicle-stimulating hormone level 9.7%, testosterone level 9.2%, and estradiol level 2.1%). Luteinizing hormone level was the most variable (CV 28%), followed by sex-steroid hormone levels (testosterone level 12% and estradiol level 13%), whereas follicle-stimulating hormone level was the least variable reproductive hormone (CV 8%). In healthy men, testosterone levels fell between 9:00 am and 5:00 pm by 14.9% (95% confidence interval 4.2, 25.5%), although morning levels correlated with (and could be predicted from) late afternoon levels in the same individual (r2 = 0.53, P<.0001). Testosterone levels were reduced more after a mixed meal (by 34.3%) than during ad libitum feeding (9.5%), after an oral glucose load (6.0%), or an intravenous glucose load (7.4%). Quantification of the variability of a single measure of reproductive hormone levels informs the reliability of reproductive hormone assessment.

Myocardial work index and myofilament calcium sensitivity: possible hand in hand markers of contractility in aortic valve stenosis patients - a translational study

Abstract Background In aortic valve stenosis, conventional echocardiographic parameters, such as ejection fraction (EF), are heavily influenced by the increased afterload caused by the valvular disease. Myocardial work index (GWI) quantifies myocardial deformation depending on the momentary LV pressure, potentially serving as a marker of LV contractility independent of loading conditions. Similarly, myofilament Ca2+ sensitivity (pCa50) followed the alterations of LV contractility in a rat model of pressure overload-induced heart failure. Therefore, GWI and pCa50 may also show correlation, as both can be reliable measures of contractility in diseases of chronically elevated LV afterload. Purpose Accordingly, our first aim was to assess the association of pCa50 and GWI in a rat model of pressure overload-induced heart failure and sham operated animals. We also aimed to evaluate the changes in GWI after myocardial Ca2+ sensitizing with levosimendan in aortic valve stenosis patients. Methods Firstly, on the thoracic aortic banded (n=2) and sham operated (n=3) rats speckle-tracking echocardiography and invasive LV pressure measurements were performed to calculate GWI. Using single permeabilized cardiomyocytes, pCa50 was calculated by myofilament force measurement. Secondly, to test our hypothesis in a clinical setting, 23 severe aortic valve stenosis patients (age 76±9 years, 39% female) were enrolled who received levosimendan therapy. Conventional and advanced echocardiographic measurements were performed before and after a 24-hour intravenous loading dose. We determined global longitudinal strain by speckle-tracking echocardiography, then using LV pressure curves estimated from systolic blood pressure and mean transaortic gradient, we quantified non-invasive global myocardial work index (GWI). Results In the animal study, GWI and pCa50 strongly correlated in the rats (r=0.942; p=0.017). In the clinical study, patients with a baseline EF &amp;lt;35% (n=12) had significantly increased GWI after the levosimendan therapy (533±347 vs. 660±419 mmHg%; p=0.004), while those who initially had an EF &amp;gt;35% (n=11) did not show any change (998±342 vs. 1003±275 mmHg%; p= 0.788). Also, the pre-levosimendan GWI showed a strong inverse correlation with the relative GWI change after the loading dose (r=-0.708; p=0.003). Conclusions We showed in an experimental setting, that GWI and pCa50 correlated in a rat model of pressure overload-induced heart failure and in sham operated controls. In the clinical setting, patients with severely decreased baseline EF and GWI benefited more from the Ca2+ sensitizing therapy, having better LV function after it, while those with better baseline function did not show improvement. Therefore, patients with worse baseline GWI initially might have had decreased Ca2+ sensitivity, which implies a possible correlation between GWI and pCa50 in patients with aortic valve stenosis, resembling the experimental findings.Correlation of pCa50 - GWICorrelation of GWI - relative GWI change

Bihemispheric Seizure Without Generalization.

A 70-year-old male without prior psychiatric history presented with recurrent episodes (<60seconds each, every 5-10minutes) of left hemibody and right lower extremity jerking movements concerning for seizure with preserved awareness (Video). Examination showed left hemiparesis (leg > arm) in addition to right lower extremity weakness. Computed tomography showed a right parafalcine acute subdural hematoma (SDH). Clinical events did not recur after intravenous lorazepam (4mg) and levetiracetam load (3500mg), and his weakness improved. He was continued on levetiracetam and has since remained seizure free for 16months. A 60-minute awake/sleep electroencephalogram (EEG) obtained 12hours after administration of antiseizure medications showed low amplitude theta slowing (posterior predominant) in the range of 5-7Hz. There was no apparent epileptiform activity or other abnormalities during the awake and sleep recording or photic stimulation. Focal seizures originate from pathologic disruption of neuronal activity within an isolated brain region, almost exclusively from a single hemisphere. Focal seizures may generalize bilaterally with associated impaired awareness. This is the first visual report demonstrating focal, bihemispheric clinical seizures, without generalization or impaired awareness. Rarely patients with generalized motor involvement from seizures have had retained consciousness and memory. The parafalcine SDH likely promoted epileptogenicity of the bilateral hemispheres. Acute and chronic SDH commonly present with seizures. Although there were no supportive electrographic findings, parasagittal epileptogenic lesions may be difficult for both clinical and electrographic localization. Post-event paresis with clinical improvement in the hours after event cessation supports clinical seizure.

(149) Use of Intravenous Valproic Acid Loading in the Emergency Department for Acute Mania: Case Report and Literature Review

(149) Use of Intravenous Valproic Acid Loading in the Emergency Department for Acute Mania: Case Report and Literature Review

FRI069 Treatment With Mibavademab, A Novel Leptin Receptor Agonist, Is Associated With Improvement In Weight And Associated Comorbidities In Congenital Leptin Deficiency

Abstract Disclosure: E. Ozsu: None. L. Akin: None. M. Aydin: None. M. Berberoglu: None. D. Stein: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. O. Pagovich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Olenchock: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Podgrabinska: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. C.A. Harris: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J. Mendell: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R. SinhaRoy: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J. Altarejos: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Akinci: Advisory Board Member; Self; Amryt Pharmaceuticals, Regeneron, Third Rock Ventures. Consulting Fee; Self; Third Rock ventures, Regeneron, Amryt Pharmaceuticals. Speaker; Self; Astra Zeneca, Lilly, MSD, Novartis, Novo Nordisk, Sanofi Aventis. E.A. Oral: Advisory Board Member; Self; Third Rock Ventures, Regeneron, Rejuveneate Bio. Consulting Fee; Self; Amryt Pharmaceuticals, Regeneron. Grant Recipient; Self; Regeneron, Novo Nordisk, GI Dynamics, Ionis Pharmaceuticals, Fractyl, Rhythm Pharmaceuticals. Other; Self; Amryt Pharmaceuticals. Background: Congenital leptin deficiency (CLD) is a form of extreme obesity caused by biallelic pathogenic variants in the leptin gene. Recombinant human leptin normalizes weight and neuroendocrine/metabolic abnormalities in CLD, however, daily dosing is required with a risk of immunogenicity. Mibavademab is an investigational human leptin receptor agonist monoclonal antibody. Case report: A Turkish male infant came to medical attention due to rapid weight gain at 2 months of age and work-up led to identification of homozygous variant in the leptin gene causing CLD. He was treated with Metreleptin for 11 months starting at age 2. When weight regain despite Metreleptin therapy was noted, neutralizing antibody (Nab) was found to be strongly positive. He continued to gain weight rapidly causing impaired mobility, and required nightly oxygen with BIPAP. He was hospitalized frequently with upper respiratory tract infections and needed ICU care four times during the 5th year of his life. At age 5 years and 9 months and body weight of 89.9 kg (BMI SD:5.7), the compassionate use application to use Mibavademab was approved by the local ethics board and the Ministry of Health. The patient received an intravenous loading dose of Mibavademab followed by weekly subcutaneous (SC) administration of Mibavademab. SC dose and diet intake were carefully adjusted based on drug levels, and intended vs. observed weight loss. Results: Weight reduction was first observed in the first week of treatment, which was rapid with an average velocity of 7.1 kg/month until month 7. Upon dose adjustment, velocity decreased to 3.1 kg/month. Weight stabilization was achieved at month 11 at a weight of 28.9 kg (BMI SD:1.0) while using Mibavademab every two weeks. Overall, drug levels were significantly higher than projected in the first 28 weeks and then brought to predicted stable levels upon dose adjustments. Despite the rapid weight loss, improved mobility and age-appropriate growth were observed. There were no signs of precocious puberty. Glucose tolerance, insulinemia, and liver parameters all improved favorably over treatment period and there were no safety signals. The patient discontinued BIPAP treatment and sleep assumed a normal pattern without hypoxia. Conclusions: Compassionate treatment with Mibavademab for up to 60 weeks was associated with improvements in body weight and metabolic parameters, and was well-tolerated in a young child with CLD and Nab against metreleptin. Substantial benefits in mobility, social engagement, and respiratory status were also noted without adverse events. Mibavademab represents a potential new therapeutic option for patients with CLD and this first experience will provide guidance for treatment of similar patients. Presentation: Friday, June 16, 2023