Iv Infusion Research Articles

Glycemic Management in Patients with COVID-19 Admitted to the Intensive Care Unit: Evaluation of Glycemic Control and Drug Therapy.

Emerging evidence describes the high incidence and strong impact of hyperglycemia on the outcomes of critically ill patients with a diagnosis of COVID-19. Given resource limitations during the COVID-19 pandemic, clinicians moved away from using continuous IV infusions of insulin to manage hyperglycemia. To evaluate glycemic control in critically ill patients receiving various medication regimens to manage their hyperglycemia. This retrospective cohort study involved 120 mechanically ventilated adult patients (> 18 years) with COVID-19 who were admitted to the intensive care unit (ICU) between February 2020 and December 2021. The following data were collected for the first 14 days of the ICU admission: blood glucose values (up to 4 times daily), hypoglycemia events, and antihyperglycemic medication regimens. The use of IV insulin infusions maintained glucose measurements within the target range of 4 to 10 mmol/L more often than any other medication regimen, with 60% of measured values falling within the target range. The use of a sliding-scale insulin regimen maintained 52% of glucose measurements within the target range. Oral hypoglycemic agents performed relatively poorly, with only 12% to 29% of glucose measurements within range. The coadministration of corticosteroids led to worse glycemic control across all medication regimens. This study confirmed that ICUs should continue using the standard protocol of IV insulin infusion to achieve recommended blood glucose targets in critically ill patients with COVID-19, particularly those receiving corticosteroids.

Pharmacokinetics, pharmacodynamics, and safety of GS-3583, a FLT3 agonist Fc fusion protein, from single-ascending-dose phase I study in healthy participants.

Conventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor-specific CD8+ T cells and their recruitment to tumor microenvironment. However, cDC1s are often underrepresented in the microenvironment. Systemic administration of Fms-like tyrosine kinase 3 ligand, a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to cDC1 expansion in the periphery and recruitment into the microenvironment. FLT3 pathway stimulation using GS-3583, a novel FLT3 agonistic Fc fusion protein, has the potential to promote T-cell mediated antitumor activity. This was a first-in-human, placebo-controlled study of GS-3583 in healthy participants to evaluate the safety, pharmacokinetics (PK), and pharmacodynamic (PD) of escalating single doses (75-2000 μg) of GS-3583. Each dose cohort enrolled 8-12 healthy participants who received GS-3583 or placebo as single IV infusion at 3:1 ratio. As part of the PD evaluation, the changes in the number of cDC1 cells were investigated. GS-3583 was well-tolerated in healthy participants up to the highest evaluated dose (2000 μg). There have been no serious or grade III or higher adverse events. PK analysis suggested a dose-dependent increase in GS-3583 exposure with target-mediated disposition characteristics at low doses. PD analysis shows that administration of GS-3583 resulted in transient, dose-dependent increases in cDC1 cells that returned to baseline within 3 weeks of drug administration. The pharmacokinetics and pharmacodynamics of GS-3583 following single dosing were characterized in this study which enabled subsequent phase Ib assessments in patients with advanced solid tumors.

The Acute Impact of Propofol on Blood-Brain Barrier Integrity in Mice.

We investigated whether short term infusion of propofol, a highly lipophilic agonist at GABAA receptors, which is in widespread clinical use as anesthetic and sedative, affects passive blood-brain barrier (BBB) permeability in vivo. Mice were anesthetized with an intraperitoneal injection of ketamine/xylazine followed by a continuous IV infusion of propofol in lipid emulsion through a tail vein catheter. Control groups received ketamine/xylazine anesthesia and an infusion of Intralipid, or ketamine/xylazine anesthesia only. [13C12]sucrose as a permeability marker was injected as IV bolus 15min after start of the infusions. Brain uptake clearance, Kin, of sucrose was calculated from the brain concentrations at 30min and the area under the plasma-concentration time curve. We also measured the plasma and brain concentration of propofol at the terminal time point. The Kin value for propofol-infused mice was significantly higher, by a factor of 1.55 and 1.87, compared to the Intralipid infusion and the ketamine/xylazine groups, respectively, while the control groups were not significantly different. No difference was seen in the expression levels of tight junction proteins in brain across all groups. The propofol plasma concentration at the end of infusion (10.7µM) matched the clinically relevant range of blood concentrations reported in humans, while concentration in brain was 2.5-fold higher than plasma. Propofol at clinical plasma concentrations acutely increases BBB permeability, extending our previous results with volatile anesthetics to a lipophilic injectable agent. This prompts further exploration, potentially refining clinical practices and ensuring safety, especially during extended propofol infusion schemes.

Norepinephrine versus Ephedrine in Prevention of Hypotension after Spinal Anesthesia in Cesarean Section

Abstract Background Spinal anesthesia is the preferred anesthetic method for elective cesarean section in obstetric anesthesia practice. Cesarean sections normally require an anesthetic block at T4 level, so hypotension is reported in up to 80% of spinal anesthesia cases. Aim of the Work This study aims to compare norepinephrine versus ephedrine in Prevention of hypotension in CS under spinal anesthesia. Patients and Methods The study was a clinical Prospective, double–blinded and randomized study, the operating theatres of Ain Shams University Hospitals over one year. Results We administered the vasopressors by iv infusion when SBP drops 20% below the baseline. We found that no significant difference between both groups regarding fetal Apgar score. We compared two different vasopressors and we chose the regimen of iv infusion. Conclusion We found lower numbers of hypotension and hypertension episodes and less frequency of bradycardia and tachycardia in the patients treated with norepinephrine.

Centhaquine Increases Stroke Volume and Cardiac Output in Patients with Hypovolemic Shock.

Introduction: Centhaquine is a resuscitative agent that acts on α2B adrenergic receptors. Its effect on cardiac output in hypovolemic shock patients has not been reported. Methods: This pilot study was conducted in 12 hypovolemic shock patients treated with centhaquine who participated in an open-label phase IV study (NCT05956418). Echocardiography was utilized to measure stroke volume (SV), cardiac output (CO), left ventricular outflow tract velocity time integral (LVOT-VTI) and diameter (LVOTd), heart rate (HR), left ventricular ejection fraction (LVEF) and fractional shortening (LVFS), and inferior vena cava (IVC) diameter before (0 min) and 60, 120, and 300 min after centhaquine (0.01 mg/kg) iv infusion for 60 min. Results: SV was significantly increased after 60, 120, and 300 min. CO increased significantly after 120 and 300 min despite a decrease in HR. IVC diameter and LVOT-VTI at these time points significantly increased, indicating the increased venous return. LVEF and LVFS did not change, while the mean arterial pressure (MAP, mmHg) increased after 120 and 300 min. Positive correlations between IVC diameter and SV (R2 = 0.9556) and between IVC diameter and MAP (R2 = 0.8928) were observed, which indicated the effects of an increase in venous return on SV, CO, and MAP. Conclusions: Centhaquine-mediated increase in venous return is critical in enhancing SV, CO, and MAP in patients with hypovolemic shock; these changes could be pivotal for reducing shock-mediated circulatory failure, promoting tissue perfusion, and improving patient outcomes. Trial Registration: CTRI/2021/01/030263 and NCT05956418.

Human Amniotic Epithelial Cell Transplantation is Safe and Well Tolerated in Patients with Compensated Cirrhosis: A First-in-Human Trial.

Placenta-derived human amniotic epithelial cells (hAEC) exhibit anti-inflammatory and anti-fibrotic effects in cirrhosis models. We conducted a first-in-human phase I clinical trial to assess the safety and tolerability of hAEC in adults with compensated cirrhosis. We examined increasing and repeated doses of hAEC in 9 patients in 3 cohorts. Cohort 1 patients received 0.5 × 106/kg hAEC in one IV infusion. Cohort 2 patients received 1 × 106/kg hAEC in one IV infusion. The patients in cohort 3 received 1 × 106/kg hAEC on days 0 and 28. Here, we report follow-up to post-infusion day 56 (D56), during which no serious adverse events occurred. Six patients experienced no study-related adverse events, while 3 patients reported mild (grade 1) headaches that were possibly infusion-related. A transient decrease in serum platelet count occurred in all patients, which returned to baseline screening values by day 5. FIB-4 values to assess fibrosis were significantly lower at D56. Although not statistically significant, serum AST levels and liver stiffness measurements at D56 were lower than those at baseline. The hepatic venous pressure gradient, a measure of portal hypertension, declined in 4 patients, did not change in 3 patients, and increased in 2 patients. In conclusion, intravenous infusion of allogeneic hAEC in patients with compensated cirrhosis at the doses used in this study was safe and well tolerated, with no difference observed between 1 and 2 doses. Decreased hepatic inflammation, liver stiffness, and portal hypertension support larger studies aimed at identifying patients who may benefit from this therapy. Clinical Trial registration: The trial was prospectively entered on the Australian Clinical Trials Registry (ANZCTR12616000437460).

Clinical update related to the first-in-human trial of SYS6002 (CRB-701), a next-generation nectin-4 targeting antibody drug conjugate.

3151 Background: SYS6002 (CRB-701) is a novel, nectin-4 targeting antibody drug conjugate (ADC) that take advantage of a third generation, site-specific cleavable linker with novel conjugation chemistry. This technology is designed to establish a stable linker across antibody and payload, to produce an ADC with a homogenous drug antibody ratio of 2.0, with the additional aim to reduce the concentration of free-MMAE and thereby improve known payload related toxicities. SYS6002 (CRB-701) also contains a novel monoclonal antibody with a prolonged half-life that can support Q3W dosing. Methods: This is a multicenter, open-label, single-arm, phase I study using Bayesian optimal interval design. Eligible patients were aged ≥18 years with histologically confirmed Nectin-4 positive solid tumors (no Nectin-4 testing was required for urothelial carcinoma [UC]) who had failed or were intolerant to standard of care options. In the dose escalation, patients were given SYS6002 (dose level 0.2, 0.6, 1.2, 1.8, 2.7, 3.6, and 4.5 mg/kg) administered Q3W by intravenous infusion. The primary endpoints were safety, tolerability, and the recommended phase 2 dose. Results: As of January 2024, SYS6002 (CRB-701) has established a differentiated safety profile across a broad dose range (0.2-3.6 mg/kg) with no dose limiting toxicities and the majority of adverse events representing grade 1 or 2. No low-grade peripheral neuropathy, skin rash or fatigue, known toxicities that rate limit the usage of enfortumab vedotin (EV) have occurred. Herein, we report the anti-tumor activity of SYS6002 (CRB-701) in patients with nectin-4 positive solid tumors with a median of 4 prior therapies. The first confirmed stable disease was observed at 0.6 mg/kg and the first confirmed partial response was at 1.2 mg/kg. Anti-tumor activity in nectin-4 positive patients at doses ≥ 2.7 mg/kg ( n=6) would suggest an overall unconfirmed objective response rate of 50%, and among them, the ORR of patients with UC was 50% (1/2), and that of patients with cervical cancer reached 67% (2/3). Across this group of patients, 4/6 had moderate to high nectin-4 expression (H-score ≥ 150) and 3 achieved a partial response, suggesting SYS6002 (CRB-701) could achieve a highly differentiated ORR of 75% in patients with moderate to high Nectin-4 expression. After single IV infusion of SYS6002 0.2-3.6 mg/kg, the exposure of TAb, ADC and MMAE generally increased in a dose proportional manner. The half-lives of TAb, ADC and MMAE were 4-6 days, 4-5 days and 5-10 days, respectively. SYS6002 (CRB-701) exhibited a longer ADC half-life and lower free-MMAE exposures relative to EV at comparable dose levels. Conclusions: SYS6002 (CRB-701) demonstrates promising anti-tumor activity with a well-tolerated safety profile in patients with advanced nectin-4 positive solid tumors. Dose escalation at 4.5 mg/kg Q3W and dose expansion at 3.6 mg/kg Q3W are ongoing. Clinical trial information: ChiCTR2200066256.

Advanced optical photothermal infrared spectroscopy for comprehensive characterization of microplastics from intravenous fluid delivery systems

Growing attention is being directed towards exploring the potential harmful effects of microplastic (MP) particles on human health. Previous reports on human exposure to MPs have primarily focused on inhalation, ingestion, transdermal routes, and, potentially, transplacental transfer. The intravenous transfer of MP particles in routine healthcare settings has received limited exploration in existing literature. Standard hospital IV system set up with 0.9 % NaCl in a laminar flow hood with MP contamination precautions. Various volumes of 0.9 % NaCl passed through the system, some with a volumetric pump. Fluid filtered with Anodisc filters washed with isopropyl alcohol. The IV cannula was immersed in Mili-Q water for 72 h to simulate vein conditions. Subsequently, the water was filtered and washed. Optical photothermal infrared (O-PTIR) microspectroscopy is used to examine filters for MP particles. All filters examined from the IV infusion system contained MP particles, including MPs from the polymer materials used in the manufacture of the IV delivery systems (polydimethylsiloxane, polypropylene, polystyrene, and polyvinyl chloride) and MP particles arising from plastic resin additives (epoxy resin, polyamide resin, and polysiloxane-containing MPs). The geometric mean from the extrapolated result data indicated that approximately 0.90 MP particles per mL of 0.9 % NaCl solution can be administered through a conventional IV infusion system in the absence of a volumetric pump. However, with the implementation of a pump, this value may increase to 1.57 particles per mL. Notably, over 72 h, a single cannula was found to release approximately 558 MP particles including polydimethylsiloxane, polysiloxane-containing MPs, polyamide resin, and epoxy resin. Routine IV infusion systems release microplastics. MP particles are also released around IV cannulas, suggesting transfer into the circulatory system during standard IV procedures.

No Measurable Transfer of Oxytocin-Receptor Agonist Merotocin Detected in Human Breast Milk.

Objective: The study aimed to assess the transfer of merotocin from systemic circulation to breast milk in early postpartum women and women with established lactation. Methods: This was a two-part, multicenter, open-label, parallel-group study. Merotocin was administered as a single 90-minute intravenous (iv) infusion mimicking the intranasal pharmacokinetic profile. In Part A, 12 early postpartum women received doses of either 4 μg (n = 6) or 16 μg (n = 6) of merotocin within 4 days of delivery. In Part B, six women with established lactation received 20 μg of merotocin. The total concentration of merotocin in plasma and breast milk and its metabolites excreted in breast milk were measured at various time points. Adverse events (AEs) were also assessed for both parts of the study. Results: In both early postpartum and established lactation groups (mean age, 26.3 years; 83.3% Caucasian), merotocin and its metabolites in breast milk were below the limit of quantification (25.0 pg/mL) at all time points. Sixteen treatment-emergent AEs occurred in early postpartum women only, including seven events of uterine spasm and three of breast engorgement. There was one moderate event, whereas all the other events were considered mild. Conclusion: Merotocin was undetectable in breast milk after single iv administration of up to 20 μg in early postpartum women and women with established lactation.

Successful management of ventricular bigeminy using lidocaine in a horse anaesthetised for emergency laparotomy

AbstractA 13‐year‐old mare was referred to the Equine Hospital of the University of Liege for colic, 1 week after foaling and was submitted to emergency laparotomy. During anaesthesia, the horse developed ventricular bigeminy that did not compromise haemodynamic stability. Lidocaine (two intravenous [iv] boluses of 1 mg/kg, followed by iv infusion of 1–2 mg/kg/h) effectively terminated the arrhythmia and the animal recovered uneventfully. Although cardiac arrhythmias associated with gastrointestinal disorders are mostly attributed to endotoxaemia, cardiac workup performed postoperatively should not be overlooked. The mare was discharged 23 days after surgery.

Abstract 5604: Modulating DNA repair through endo-exonuclease inhibition: a new therapeutic paradigm in oncology

Abstract DNA damage repair (DDR) mechanisms are crucial for the maintenance of genomic stability and are emerging as potential therapeutic targets for cancer. Endo-exonuclease (EE)1 plays a key role in this process and increase EE expression has been observed in the cancer cells examined. In this context, we identified a dicationic diarylfuran, pentamidine, which is an antiparasitic drug that has been used clinically to treat opportunistic infections such as Pneumocystis carinii. Pentamidine is an inhibitor of the endo-exonuclease as determined by enzyme kinetic assay and is known to be active on cancer cells. In a proof of concept study2, tumor with increased EE expression (determined by IHC) showed the best response to this drug. We have now identified novel mono- and di-amidine analogs of pentamidine that are more effective than the parent drug in both in vitro and in vivo studies. Furthermore, pre-clinical animal studies of our lead candidate, MTDX203, showed an increased anti-cancer activity with a higher safety index than pentamidine. Based on a predictive PK/PD model, a human iv infusion dose administered twice weekly at ~0.4 mpk (i.e. 28 mg/day, ~10% of pentamidine effective iv dose) is expected to be clinically effective. Our work establishes the EE as a therapeutic target for cancer and identifies a new First in Class of novel anti-cancer agents. 1Chow et al. (2004) MCT 3:911-9182 NCT01378143: Pentamidine (OCZ103-OS) in Patients With Unresectable and Locally Recurrent or Metastatic Colorectal Cancer Undergoing Standard Chemotherap Citation Format: Terry Chow, Jianmin Duan, Patrick Colin, Colin Bier. Modulating DNA repair through endo-exonuclease inhibition: a new therapeutic paradigm in oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5604.

Cabozantinib (Cabometyx)


 CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.
 The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.
 This review assesses:
 
 Cabozantinib (Cabometyx): 40 mg once daily, oral tablet
 Nivolumab (Opdivo): 240 mg every 2 weeks, 30-minute IV infusion, or 480 mg every 4 weeks, 30-minute IV infusion.
 
 
 Indication: Cabozantinib, in combination with nivolumab, is indicated for the first-line treatment of adult patients with advanced (not amenable to curative surgery or radiation therapy) or metastatic renal cell carcinoma.

Abstract A005: Enhanced DNA damage and disruption of repair by iodinated thymidine analogues with Tipiracil for clinical radiation sensitization

Abstract IUdR incorporation into cellular DNA enhances radiation induced DNA damage and impairs repair pathways. IUdR has been explored as a clinical radiation sensitizer in Phase I and II clinical trials of sarcomas and gliomas, showing clinical activity. A major barrier to acceptance of this therapy has been the poor pharmacokinetic (PK) profile of IUdR which has a blood plasma half-life of less than 10 minutes. Continuous IV infusion of IUdR has been used to achieve clinically relevant DNA incorporation into tumor cells, but technical limitations of delivery and acute toxicities in rapidly proliferating normal tissues presented barriers to advancing this approach. To improve the PK profile of IUdR, a prodrug strategy has been employed leading to the development of ropidoxuridine (IPdR), which improved the PK profile, demonstrated oral bioavailability of the active metabolite IUdR, showed less normal tissue toxicity, and provided tumor radiation sensitization. IPdR plus XRT has been tested in Phase 0 and Phase 1 clinical trials and a phase II trial is proposed for glioblastoma treatment. We report here a second approach to improve the PK profile of orally administered IUdR by combining these iodinated thymidine analogs with the metabolism inhibitor, Tipiracil (TPI) which inhibits thymidine phosphorylase, the primary enzyme responsible for irreversible IUdR degradation, and is currently used in the FDA approved combination drug Lonsurf. Oral co-administration of IUdR and TPI in rats dramatically improved the PK profile of IUdR, increasing the half-life of the compound to 1.5 hours and boosting the maximum plasma concentration by approximately 8-fold. We studied the effects of Tipiracil on the metabolism of IUdR by varying the molecular ratio of IUdR/TPI from 2:1 up to a ratio of 10:1 and discovered that the plasma concentration of IUdR plateaued between a ratio of 5:1 and 10:1. This new combination therapy of IUdR/TPI yields a PK profile of IUdR that is relevant to clinical treatment in combination with RT and offers to expand potential clinical radiation sensitizer applications. Citation Format: Scott Grindrod, Alfredo Velana, Tyvin Rich, Mira Jung, Dalong Pang, Anatoly Dritschilo. Enhanced DNA damage and disruption of repair by iodinated thymidine analogues with Tipiracil for clinical radiation sensitization [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A005.

Comparative Evaluation of Two Different Doses of Dexmedetomidine for Intra Operative Moderate Sedation During Spinal Anesthesia

Background: Intravenous (IV) sedation is often used to relieve anxiety or stress during surgery under regional anesthesia. Subarachnoid block is a widely followed regional anaesthesia technique, especially in lower abdominal and lower limb surgeries. Intense sensory and motor block, continuous supine position and the inability to move the body also brings a feeling of discomfort and phobia in many patients. Sedation has been shown to increase patient satisfaction during regional anaesthesia. Dexmedetomidine is well suited for conscious sedation as patient can be quickly aroused and oriented on demand. Aim of this study was to compare infusion doses of 0.3μg/kg/hr and 0.5μg/kg/hr, after loading dose of 1μg/kg of injection (inj).dexmedetomidine in order to obtain a better regimen for patients undergoing procedures under spinal anaesthesia in terms of sedation and hemodynamic stability.
 Objective: To compare efficacy of dexmedetomidine for intraoperative sedation and hemodynamic stability at doses of 0.3μg/kg/hr and 0.5μg/kg/hr after loading dose of 1 μg/kg in patients operated under spinal anaesthesia.
 Methods: Adult 80 Patients were randomly divided into two groups, (Group D-0.3) and (Group D-0.5). They were given spinal anaesthesia with 0.5% hyperbaric bupivacaine and initial dose of inj.dexmedetomidine 1 μg/kg was infused over 10 minutes. Group D-0.3 received maintenance dose of inj.dexmedetomidine of 0.3μg/kg/hr and Group D-0.5 received maintenance dose of 0.5μg/kg/hr. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), respiratory rate (RR), spO2 and sedation using observer’s assessment of alertness/sedation (OASS) were recorded at baseline, after loading dose, before spinal anesthesia, after spinal anesthesia at every 5 minutes upto 30 minutes, followed by every 15 minutes till the end of surgery and every 5 minutes upto 15 minutes after surgery. Data were compared using chi-square and unpaired t test. 
 Results: The mean age for Group D-0.3 is 43.9+11 and for Group D-0.5 is 35.3+20. There is no statistically significant difference in demographic profile between two groups. It was also observed that there is no statistically significant difference in HR, SBP, DBP, MAP, RR and SpO2 in all point of time (p>0.05). According to sedation score in group D-0.3 72% patients were sleeping comfortably but easily arousable and 8% patients were in deep sleep, while in group D-0.5 70% were sleeping comfortably but easily arousable and 15% in deep sleep.
 Conclusion: After a loading dose of 1 μg/kg intravenously, an iv infusion of dexmedetomidine at a lower rate, i.e. 0.3μg/kg/hr is equally effective in providing sedation for patients undergoing surgeries under spinal anesthesia as 0.5μg/kg/hr.

Outpatient Management of Sickle Cell Vaso-Occlusive Crisis As a Strategy of Decreasing Emergency Department Visits

Background: Complications of sickle cell disease (SCD), including vaso-occlusive crises (VOC), usually require emergency room visits or even hospitalization for management. Outpatient treatment programs have been developed for management of VOC, however the literature is limited as to the efficacy of these models. Previously, patients in Edmonton, Canada followed by the Hemoglobinopathy Clinic would have to present to the emergency department (ED) for assessment of and management of VOC. Since 2019, patients experiencing early VOC symptoms were able to present to the Medical Outpatient Unit (MOU), an infusion clinic shared with other benign and malignant hematology conditions, to be assessed and receive treatment. This study retrospectively evaluated the outcomes of this treatment strategy. Hypothesis: Outpatient management of VOC is an effective way to assess patients and provide appropriate treatment, thereby reducing the frequency of ED presentations for SCD patients. Methods: Patients were able to schedule their own appointments and were encouraged to present early before they developed severe symptoms. They would be assessed by a nurse, who could then release orders from their personalized pain plan, which is a standing set of orders from an SCD clinic physician. Examples of orders include intravenous fluids and pain medications. Based on the severity of symptoms, patients could also be referred to the ED or for assessment by a physician or nurse practitioner. Chart review of patients aged 18 years or older with SCD followed by the Edmonton Hemoglobinopathy Clinic and who presented to MOU from November 2019 to December 2022 for management of VOC was completed. Information gathered included if the patient was on hydroxyurea at the time, investigations ordered, treatments administered, if NP or physician assessment was required, and disposition following the encounter. Encounters within 7 days were counted as one episode and assumed to be the same VOC event. Visits to ED for this cohort were counted and compared to the number of ED visits from 2016 to 2018. Results: 26 SCD patients had at least one MOU encounter for VOC or prophylaxis resulting in a total of 136 encounters (median 2, maximum 25). These accounted for 96 separate episodes of VOC (median 2, maximum 19), with a median of 1 encounter to MOU per episode (maximum 5). Patient demographics had a mean age of 32 years as of the beginning of the study (maximum 65, minimum 16) with 14 males (54%) and 12 females (46%). Patient diagnoses included 10 with HbSS (38%), 12 with HbSC (46%), 3 with HbSD (12%), and 1 with HbSB° (4%). 21 of 26 patients (81%) were on hydroxyurea at some point during this time period. IV fluids were administered in 129 encounters (95%), and pain medications were given in 64 encounters (47%), with opioid medications being given in 24 encounters (18%). 109 encounters had assessment by a nurse only (80%), while 24 were also assessed by a nurse practitioner (18%) and only 3 required assessment by a physician (2%). Patients were discharged home in 134 of 136 encounters (99%), with only 2 encounters resulting in assessment in ED. 70 of 96 episodes of VOC treated in MOU did not have presentation to ED within 30 days (73%). Total ED visits for this cohort decreased from 59 in 2016-2018 to 38 during the time of this study. Conclusion: Treatment of VOC in an outpatient setting was effective for assessment and treatment and decreased ED visits in our cohort. While retrospective, these results suggest outpatient treatment of VOC can be completed safely and efficiently in a shared infusion unit and may be generalized to other centres with outpatient IV infusion programs.

Pediatric Patients with High-Risk B-Cell ALL in First Complete Remission May Benefit from Less Toxic Immunotherapy with Blinatumomab - Results from Randomized Controlled Phase 3 Trial AIEOP-BFM ALL 2017

Background: One of the key questions in trial AIEOP-BFM ALL 2017 focused on the reduction of treatment-related complications by replacing parts of the highly intensive consolidation phase by two courses of Blinatumomab (Blina) in a prospective randomized trial. Herein, we report the toxicity profile of B-cell acute lymphoblastic leukemia (B-ALL) patients (pts) with high-risk (HR) characteristics pending final outcome data. Patients and Methods: 728 pts with HR B-ALL were enrolled from July 15, 2018 to October 31, 2022 in this multicenter trial run in 8 different countries. Patients were included in the HR group in view of the presence of at least one of the following criteria: induction failure; high levels of minimal residual disease (MRD) at day 15 of induction, or at the end of induction (EOI), or at the end of consolidation (EOC); presence of KMT2A::AFF1, of IKZF1+ and positive MRD at EOI (Stanulla et al, JCO 2018), TCF3::HLF, or hypodiploidy. B-ALL pts with one or several of these characteristics represented 20.8% of all pts aged 0-18 years of age with B-ALL. After a 4-drug induction phase, and two weeks of consolidation treatment, patients were randomized to receive Bortezomib in addition to standard consolidation (not part of this report). Before treatment continued with intensive consolidation block HR-1', MRD was analyzed in order to identify patients eligible for subsequent hematopoietic stem cell transplantation (HSCT) based on MRD results. After block HR-1', all B-ALL HR pts were randomized to receive either two courses of consolidation (blocks HR-2', and HR-3'), or two 28-day courses of Blina at 15µg/m 2/d administered by continuous IV infusion (with a 2-week treatment-free interval). Two intrathecal injections of methotrexate (MTX) for CNS prophylaxis were given on days 1 and 29 of each Blina course, respectively. Out of 728 HR B-ALL pts, 619 pts were eligible for randomization [reasons for non-eligibility were: Event (death or relapse) before randomization was due (26), Down syndrome (25; scheduled for a non-randomized intervention with Blina), presence of TCF3::HLF (3; could receive any alternative therapy including Blina), discontinuation/substantial change of preceding therapy (23) or other protocol exclusion criteria (32)]. 572 pts were randomized (92.4% of those eligible). One pt assigned to the experimental arm (EA) and 4 pts assigned to the control arm (CA) received the other arms, respectively. Results: Toxicity was evaluated in randomized pts according to treatment administered during the randomized phase, respectively, until next element started: 268 pts were treated in the control and 281 in the EA (see Table). 16 of them switched in/after the first Blina cycle to the HR blocks due to toxicity or poor response to Blina (due to increasing MRD, >=1x10 -4). Medically relevant adverse reactions of special interest (ARSI) according to MedDRA (specified in the protocol) were evaluated in the randomized treatment phases (CA: HR-2‘/HR-3‘ block, EA: 2 Blina cycles). ARSI were recorded in 61 of 268 pts in the CA (22.8%, 71 ARSI) and in 29 of 281 pts in the EA (10.3% [p<0.001], 33 ARSI); 3 of the 33 ARSI in the EA were related to HR blocks and were observed in 3 of the 16 pts that switched to HR blocks. Life-threatening SAR were seen in 14 pts of the control group (5.2%) and in no patient in the EA (p<0.001). Conclusions: Taken together, these results show for the first time in newly diagnosed pts with HR B ALL, the favorable toxicity profile previously reported with Blinatumomab in pediatric relapsed ALL (Locatelli F et al, JAMA 2021; Brown P et al, JAMA 2021). We have demonstrated that the toxicity profile of Blinatumomab is much more favorable as compared to the intensive chemotherapy approach using HR-blocks. If upcoming analyses of outcome data will show no inferiority of the EA, blinatumomab replacement of some of the intensive chemotherapy blocks will become the new standard of care for treatment if newly diagnosed patients with HR B-ALL.

Evaluation of the Safety of Slow IV Push Versus Slow IV Infusion Administration of 23.4% Sodium Chloride.

Increased intracranial pressure due to cerebral edema is a medical emergency in which 23.4% sodium chloride (23.4% NaCl) may be a lifesaving intervention. Currently, safety data is limited on slow IV push (IVP) administration. The purpose of this study was to evaluate the safety of IVP administration of 23.4% NaCl and determine the number of infusion-related adverse events (IRAEs) compared to slow IV infusion (SIV) administration. We performed a retrospective review of patients who received a dose of 23.4% NaCl at the (removed institution) from January 2015 to June 2020 as either SIV over 30 minutes or IVP over 2-5 minutes. In total, 81 patients, 55 in the IVP group and 26 in the SIV group, were included in the analysis. There was a significantly faster time from order entry to dose completion (IVP 25 [13,58] vs SIV 73 [55,113] minutes, P < .001). There was no difference in IRAEs between the groups (IVP 17 [31%] vs SIV 6 [23%], P = .466). Hypotension was most common (IVP 13 [24%] vs SIV 5 [19%], P = .656) followed by bradycardia (IVP 6 [11%] vs SIV 1 [4%], P = .291). There were no extravasations reported. Overall, among a cohort of patients with cerebral edema, we found no difference in the incidence of IRAEs between SIV and IVP administration of 23.4% NaCl, and found a faster time to complete administration fssor the latter. In emergent scenarios where time may impact neurologic function, 23.4% NaCl administered IVP may be an alternative to SIV administration.

Increasing the depth of vestibular sulcus using a disposable IV infusion set tube in apically positioned flap surgery: A technical note

AbstractAimIn this technical note, it was aimed to provide an appropriate retention, better stability and function for our patient's denture by the technique applied newly.Materials and MethodsThe authors offer a new and effective method using a part of disposable IV infusion set tube and single mini titanium screw stabilizing of apically positioned flap in order to secure vestibule sulcus depth gained.Results and ConclusionOne‐year follow‐up of our patient showed that our technique provided a consistent and predictable increase in attached gingival width and could be used successfully in the treatment of insufficient vestibular depth cases.

Abstract 18979: Calm Before the Storm: Exploring the Risk of Torsades De Pointes With Dexmedetomidine Administration

Introduction: Corrected QT interval (QTc) prolongation is the known side effect of multiple medications especially in antipsychotic and antiarrhythmic family. Patients with either inherited or secondary prolonged QTc should be monitored closely as they can develop life threatening complications like Torsades de-pointes and ventricular fibrillation. Here we present a case of cardiac arrest secondary to dexmedetomidine. Case: A 49-year-old female with history of bipolar disorder was admitted to intensive unit for seizure after intentional ingestion of uncounted amount of diphenhydramine pills. Patient was intubated for airway protection and started on propofol. Her vitals at the time of admission included the pulse rate of 76, blood pressure of 102/49 mmHg. Her urine drug screen was positive for TCA and cannabinoids. Her ECG at the time of admission was significant for prolonged QTC of 600msec that improved to 460msec in the consecutive ECGs after administration of total of 4mg intravenous magnesium. Continuous EEG was negative for seizure and she was weaned off sedation. After awakening, she became agitated, after pushes of benzodiazepines, was eventually started on dexmedetomidine. Twenty minutes after starting low dose dexmedetomidine, patient was noted to be in cardiac arrest. Reviewing telemetry prior to event, revealed the R on T phenomenon and Torsades de pointes that lasted for few seconds with progression into ventricular fibrillation. Discussion: Currently dexmedetomidine is labeled with a low to possible risk of Torsade de pointes and QTC prolongation. Dexmedetomidine induced Torsade de pointes might be explained by bradycardia in patients which causes further prolongation of QT interval. Studies have shown that continuous IV infusion of dexmedetomidine at rate of 0.3 mcg/kg/hour can worsen QTC prolongation. Conclusions: In this case we present a case of VFib arrest secondary to Torsade after twenty minutes of infusion of dexmedetomidine without any sign of bradycardia prior to the event. This carries a significant importance as it shows this drug carries a potential risk of QTc prolongation similar to previous studies. Whether this side effect is dose dependent or not requires further investigation.

Comparison of efficacy between subcutaneous and intravenous application of moss-aGal in the mouse model of Fabry disease.

Fabry disease (FD, OMIM 301500) is a rare X-linked inherited lysosomal storage disorder associated with reduced activities of α-galactosidase A (aGal, EC 3.2.1.22). The current standard of care for FD is based on enzyme replacement therapy (ERT), in which a recombinantly produced version of αGal is intravenously (iv) applied to Fabry patients in biweekly intervals. Though the iv application is clinically efficacious, periodical infusions are inconvenient, time- and resource-consuming and they negatively impact the patients' quality of life. Subcutaneous (sc) injection, in contrast, is an established route of administration for treatment of chronic conditions. It opens the beneficial option of self-administration, thereby improving patients' quality of life and at the same time reducing treatment costs. We have previously shown that Moss-α-Galactosidase (moss-aGal), recombinantly produced in the moss Physcomitrium patens, is efficient in degrading accumulated Gb3 in target organs of murine model of FD and in the phase I clinical study, we obtained first efficacy evidence in human patients following single iv infusion. Here, we tested the efficacy of subcutaneous administration of moss-aGal and compared it with the results observed following iv infusion in Fabry mice. The obtained findings demonstrate that subcutaneously applied moss-aGal is correctly transported to target organs and efficacious in degrading Gb3 deposits there and thus suggest the possibility of using this route of administration for therapy of Fabry disease.