Continuous Intravenous Administration Research Articles

Guidance on Selecting Optimal Steady-State Tacrolimus Concentrations for Continuous IV Perfusion: Insights from Physiologically Based Pharmacokinetic Modeling.

Introduction: The dose-response relationships of tacrolimus have been primarily assessed through trough concentrations during intermittent administrations. In scenarios where oral administration (PO) is unfeasible, continuous intravenous (IV) administration is advised. Under these circumstances, only steady-state (Css) plasma or blood concentrations are measured, with the absence of distinct trough levels (Cmin). Consequently, the measured concentrations are frequently misinterpreted as trough concentrations, potentially resulting in sub-therapeutic true tacrolimus blood levels. This study employs physiologically based pharmacokinetic modeling (PBPK) to establish the Css/Cmin ratio for tacrolimus across various clinical scenarios. Method: Using a validated PBPK model, the tacrolimus dose (both PO and IV) and the Css/Cmin ratios corresponding to matching area under the blood concentration-time curve during a dosage interval (AUCτ) values were estimated under different conditions, including healthy subjects and individuals exhibiting cytochrome P450 3A (CYP3A) interactions or CYP3A5 polymorphisms, along with a demonstration of a real-life clinical application. Result: In healthy volunteers, the oral/intravenous (PO/IV) dose ratio was found to be 4.25, and the Css/Cmin ratio was 1.40. A specific clinical case substantiated the practical applicability of the Css/Cmin ratio as simulated by PBPK, demonstrating no immediate clinical complications related to the transplant. When considering liver donors versus recipients expressing CYP3A5, the tacrolimus AUCτ was notably affected, yielding a PO/IV dose ratio of 4.00 and a Css/Cmin ratio of 1.75. Furthermore, the concomitant administration of the CYP3A inhibitor itraconazole given PO resulted in a PO/IV ratio of 1.75 with and a Css/Cmin ratio of 1.28. Notably, the inhibitory effect of itraconazole was diminished when administered IV. Conclusions: Through the application of PBPK methodologies, this study estimates the PO/IV dose ratios and Css/Cmin ratios that can enhance dose adjustment and therapeutic drug monitoring during the switch between IV and PO administration of tacrolimus in transplant patients, ultimately guiding clinicians in real-time decision-making. Further validation with in vivo data is recommended to support these findings.

Apelin-13 reverses bupivacaine-induced cardiotoxicity: an experimental study

IntroductionCardiac arrest or arrhythmia caused by bupivacaine may be refractory to treatment. Apelin has been reported to directly increase the frequency of spontaneous activation and the propagation of action potentials, ultimately promoting cardiac contractility. This study aimed to investigate the effects of apelin-13 in reversing cardiac suppression induced by bupivacaine in rats. MethodsA rat model of cardiac suppression was established by a 3-min continuous intravenous infusion of bupivacaine at the rate of 5 mg.kg−1.min−1, and serial doses of apelin-13 (50, 150 and 450 μg.kg−1) were administered to rescue cardiac suppression to identify its dose-response relationship. We used F13A, an inhibitor of Angiotensin Receptor-Like 1 (APJ), and Protein Kinase C (PKC) inhibitor chelerythrine to reverse the effects of apelin-13. Moreover, the protein expressions of PKC, Nav1.5, and APJ in ventricular tissues were measured using Western blotting and immunofluorescence assay. ResultsCompared to the control rats, the rats subjected to continuous intravenous administration of bupivacaine had impaired hemodynamic stability. Administration of apelin-13, in a dose-dependent manner, significantly improved hemodynamic parameters in rats with bupivacaine-induced cardiac suppression (p < 0.05), and apelin-13 treatment also significantly upregulated the protein expressions of p-PKC and Nav1.5 (p < 0.05), these effects were abrogated by F13A or chelerythrine (p < 0.05). ConclusionExogenous apelin-13, at least in part, activates the PKC signaling pathway through the apelin/APJ system to improve cardiac function in a rat model of bupivacaine-induced cardiac suppression.

The role of dexmedetomidine administered via intravenous infusion as adjunctive therapy to mitigate postoperative delirium and postoperative cognitive dysfunction in elderly patients undergoing regional anesthesia: a meta-analysis of randomized controlled trials

Study objectiveThis meta-analysis aimed to assess whether continuous intravenous administration of DEX during surgery can be part of the measures to prevent the onset of postoperative delirium and postoperative cognitive dysfunction in elderly individuals following regional anesthesia.MethodsWe searched the databases of PubMed, Embase, the Cochrane Library and China National Knowledge Infrastructure (by June 1, 2023) for all available randomized controlled trials assessing whether intravenous application of dexmedetomidine can help with postoperative delirium and postoperative cognitive dysfunction in the elderly with regional anesthesia. Subsequently, we carried out statistical analysis and graphing using Review Manager software (RevMan version 5.4.1) and STATA software (Version 12.0).Main resultsWithin the scope of this meta-analysis, a total of 18 randomized controlled trials were included. Among them, 10 trials aimed to assess the incidence of postoperative delirium as the primary outcome, while the primary focus of the other 8 trials was on the incidence of postoperative cognitive dysfunction. The collective evidence from these 10 studies consistently supports a positive relationship between the intravenous administration of dexmedetomidine and a decreased risk of postoperative delirium (RR: 0.48; 95%CI: 0.37 to 0.63, p < 0.00001, I2 = 0%). The 8 literature articles and experiments evaluating postoperative cognitive dysfunction showed that continuous intravenous infusion of dexmedetomidine during the entire surgical procedure exhibited a positive preventive effect on cognitive dysfunction among the elderly population with no obvious heterogeneity (RR: 0.35; 95%CI: 0.25 to 0.49,p < 0.00001, I2 = 0%).ConclusionAdministering dexmedetomidine intravenously during surgery can potentially play a significant role in preventing postoperative delirium and postoperative cognitive dysfunction in patients older than 60 years with regional anesthesia according to this meta-analysis.

Chimerism of avian IgY-scFv and truncated IgG-Fc: A novel strategy in cross-species antibody generation and enhancement.

Chicken single-chain fragment variable (IgY-scFv) is a functional fragment and an emerging development in genetically engineered antibodies with a wide range of biomedical applications. However, scFvs have considerably shorter serum half-life due to the absence of antibody Fc region compared with the full-length antibody, and usually requires continuous intravenous administration for efficacy. A promising approach to overcome this limitation is to fuse scFv with immunoglobulin G (IgG) Fc region, for better recognition and mediation by the neonatal Fc receptor (FcRn) in the host. In this study, engineered mammalian ΔFc domains (CH2, CH3, and intact Fc region) were fused with anti-canine parvovirus-like particles avian IgY-scFv to produce chimeric antibodies and expressed in the HEK293 cell expression system. The obtained scFv-CH2, scFv-CH3, and scFv-Fc can bind with antigen specifically and dose-dependently. Surface plasmon resonance investigation confirmed that scFv-CH2, scFv-CH3, and scFv-Fc had different degrees of binding to FcRn, with scFv-Fc showing the highest affinity. scFv-Fc had a significantly longer half-life in mice compared with the unfused scFv. The identified ΔFcs are promising for the development of engineered Fc-based therapeutic antibodies and proteins with longer half-lives. The avian IgY-scFv-mammalian IgG Fc region opens up new avenues for antibody engineering, and it is a novel strategy to enhance the rapid development and screening of functional antibodies in veterinary and human medicine.

Diagnosis and treatment of hepatorenal syndrome; a systematic review

Hepatorenal syndrome (HRS) is a severe form of functional renal failure associated with reduced renal blood flow, predominantly affecting patients with ascites and cirrhosis, showcasing normal kidney histology. This complication of advanced liver disease is marked by a grim prognosis, with survival typically spanning weeks or months. Diagnosis hinges on a blend of clinical and laboratory criteria, given the absence of definitive biomarkers. This systematic study sought to formulate guidelines for HRS diagnosis and treatment. Data, drawn from PubMed/Medline, Scopus databases, and Embase, encompassed English-language articles from 2010 to 2023, adhering to PRISMA guidelines. Among 457 studies, seven met eligibility criteria, employing surveys and national database analyses as prevalent methods. Current care standards involved albumin and terlipressin treatment, with continuous intravenous terlipressin administration proving equally effective and better-tolerated than boluses. Despite its 40-50% success rate, predictors included serum bilirubin and creatinine levels, blood pressure, and systemic inflammatory response syndrome presence. Liver transplant stands as the sole curative avenue, while alternative therapies like dopamine, noradrenaline, renal and liver replacement therapy, and transjugular intrahepatic portosystemic shunt are under evaluation. Ongoing research into advanced remedies is imperative, given current treatment limitations. Considerations such as antibiotic prophylaxis in severe cirrhosis with low protein ascitic fluid levels and volume expansion with albumin during spontaneous bacterial peritonitis and high-volume paracentesis further underscore the multifaceted approach required in managing HRS. This study advocates for continuous exploration of innovative therapies and emphasizes the pivotal role of liver transplant consideration for eligible patients.

Old drug, new tricks: polymer-based nanoscale systems for effective cytarabine delivery.

Cytarabine, an antimetabolite antineoplastic agent, has been utilized to treat various cancers. However, because of its short half-life, low stability, and limited bioavailability, achieving an optimal plasma concentration requires continuous intravenous administration, which can lead to toxicity in normal cells and tissues. Addressing these limitations is crucial to optimize the therapeutic efficacy of cytarabine while minimizing its adverse effects. The use of novel drug delivery systems, such as polymer-based nanocarriers have emerged as promising vehicles for targeted drug delivery due to their unique properties, including high stability, biocompatibility, and tunable release kinetics. In this review, we examine the application of various polymer-based nanocarriers, including polymeric nanoparticles, polymeric micelles, dendrimers, polymer-drug conjugates, and nano-hydrogels, for the delivery of cytarabine. The article highlights the limitations of conventional cytarabine administration which often lead to suboptimal therapeutic outcomes and systemic toxicity. The rationale for using polymer-based nanocarriers is discussed, highlighting their ability to overcome challenges by providing controlled drug release, improved stability, and enhanced targeting capabilities. In summary, this review offers a valuable resource for drug delivery scientists by providing insights into the design principles, formulation strategies, and potential applications of polymer-based nanocarriers that can enhance the therapeutic efficacy of cytarabine.

Efficacy, safety, and pharmacokinetics of MR13A11A, a generic of remifentanil, for pain management of Japanese patients in the intensive care unit: a double-blinded, fentanyl-controlled, randomized, non-inferiority phase 3 study

BackgroundThe aims of this study were to evaluate the efficacy, safety, and pharmacokinetics (PK) of continuous intravenous administration of remifentanil in mechanically ventilated patients in the intensive care unit (ICU).MethodsThis was a multicenter, randomized, double-blinded, fentanyl-controlled, non-inferiority phase 3 study. Patients aged ≥ 20 years requiring 6 h to 10 days mechanical ventilation in an ICU and requiring pain relief were randomly assigned in a 1:1 ratio to receive either remifentanil (n = 98) or fentanyl (n = 98). Dose was titrated from an infusion rate of 1 mL/h (remifentanil: 0.025 µg/kg/min, fentanyl: 0.1 µg/kg/h) until the target level of analgesia (behavioral pain scale [BPS] ≤ 5 or numerical rating score [NRS] ≤ 3) was achieved by escalating the dose in 1 mL/h increasing. Administration was then adjusted to maintain the target level of analgesia until weaning from the ventilator. The primary endpoint was the proportion of patients who did not require rescue fentanyl. Safety was assessed according to standard procedures. PK of remifentanil in the arterial blood was assessed in 24 patients.ResultsThe proportion of patients achieving the primary endpoint in the remifentanil and fentanyl groups was 100% (92/92) and 97.8% (88/90), respectively. The difference between the groups was 2.2% (95% confidence interval, − 0.8–5.3) and non-inferiority of remifentanil to fentanyl was verified (p < 0.0001). The incidences of any adverse events in the remifentanil and fentanyl groups was 34 of 92 patients (37.0%) and 34 of 90 patients (37.8%), respectively. Adverse drug reactions was 12 in 92 patients (13.0%) and 15 in 90 patients (16.7%), respectively. In the PK analysis, blood remifentanil concentration decreased within 10 min to almost 50% of the end of administration, suggesting rapid offset of action following discontinuation of remifentanil.ConclusionsRemifentanil can be used safely for pain management in mechanically ventilated Japanese patients in the ICU.Trial registration: Japan Registry of Clinical Trials, jRCT2080224954. Registered 20 November 2019, https://jrct.niph.go.jp/latest-detail/jRCT2080224954.

The Area Under Tacrolimus Concentrations on Day 14-28 Is the Independent Predictor of the Development of Chronic Gvhd in Patients without Severe Acute Gvhd after Unrelated Allogeneic HSCT

Introduction: In unrelated allogeneic hematopoietic stem cell transplantation (UR-SCT), chronic graft-versus-host disease (GVHD) is a critical complication that affects not only patients' quality of life but also post-transplant outcome. Acute GVHD is a major risk factor for the subsequent development of chronic GVHD. The combination of tacrolimus and short-term methotrexate (TAC+sMTX) has been widely used as a GVHD prophylaxis for UR-SCT in Japan. Previous reports have shown that tacrolimus blood concentrations early after transplantation are associated with the development of acute GVHD, but not with that of chronic GVHD. On the other hand, among UR-SCT recipients who did not develop severe acute GVHD, the relationship between tacrolimus blood concentrations and the development of chronic GVHD remains unclear. Methods: To examine the association between tacrolimus blood concentrations and post-transplant outcomes, the area under the tacrolimus concentration on day 0-14 (AUTC 0-14) and day 14-28 (AUTC 14-28) was calculated simply as the sum of the area of the trapezoid for the corresponding period ( Figure). Tacrolimus was initiated by continuous intravenous administration from day -1 in all patients, and no patients were switched to oral administration prior to day 28. Short-term methotrexate was administered at 10 mg/m 2 on day 1 and 7 mg/m 2 on day 3, day 6, and day 11. Among all 151 adult patients with hematopoietic malignancies who underwent first UR-SCT with GVHD prophylaxis of TAC+sMTX between 2010 and 2022 at the Jikei University Hospital, the following were excluded from the analysis: developing grade III-to-IV acute GVHD, using prednisolone or methyl-prednisolone ≥0.5 mg/kg within day 100, engraftment failure, death before day 100, and relapse before day 100. Results: A total of 68 patients were included in the analysis. Median age was 50.5 (range, 16-68) years. Twenty-seven (40%) patients had acute myeloid leukemia, and 18 (27%) had acute lymphoblastic leukemia. Fifty-five (81%) were in complete remission/chronic phase/early stage. The donor source consisted of 42 (62%) bone marrow transplantation (BMT), 20 (29%) cord blood transplantation (CBT), and 6 (9%) peripheral blood stem cell transplantation (PBSCT). BMT recipients transplanted from 22 (52%) HLA 8/8 matched donor, 19 (45%) HLA 7/8 matched donor, and one (3%) HLA 6/8 matched donor. CBT recipients transplanted from 15 (75%) HLA 4/6 matched donor and 5 (25%) HLA 5/6 matched donor. PBSCT recipients transplanted from 5 (83%) HLA 8/8 matched donor and one (17%) HLA 7/8 matched donor. Fifteen (22%) patients were administered additional low-dose anti-thymocyte globulin (ATG) as GVHD prophylaxis. Fifteen male patients transplanted from female donors (22%). Thirty-nine (57%) patients received myeloablative conditioning regimen. The median time from UR-SCT to neutrophil engraftment was 19 days (range, 11-34). Regarding acute GVHD, 46 patients (68%) developed none, 13 patients (19%) developed grade I, and 9 patients (13%) developed grade II. The median observation period for all 68 patients was 48.2 months (4.0 years). The 4-year cumulative incidence (CI) of chronic GVHD was 51%, of which 24% were moderate-to-severe. The CI of moderate-to-severe chronic GVHD was not associated with age, disease status, donor source, HLA incompatibility, ATG use, female to male, intensity of conditioning regimen, and grade I-to-II acute GVHD development. AUTC 14-28 &amp;lt;200 was the only risk factor (AUTC 14-28&amp;lt;200: 32% vs AUTC 14-28≥200: 11%; p=0.047). Multivariate analysis also showed that AUTC 14-28 &amp;lt;200 was the independent factor for development of moderate-to-severe chronic GVHD ( p=0.04). In all 68 patients, 4-year CI of relapse was 20%, 4-year CI of non-relapse mortality was 10%, 4-year GVHD-free, relapse-free, survival (GRFS) was 50%, and 4-year Overall survival was 80%, all of which did not differ between AUTC 14-28 &amp;lt;200 and AUTC 14-28 ≥200 groups. Conclusion: In UR-SCT, our data showed that AUTC 14-28 &amp;lt;200 may be an independent risk factor for developing moderate-to-severe chronic GVHD, even in patients who did not develop severe acute GVHD.

An Open-Label, Multicenter, Single-Arm, Phase I Dose Escalation Study of OP-2100, an Orally Bioavailable Prodrug of Decitabine, for Patients with Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

CONCLUSIONS Hypomethylating agents (HMA) are commonly used to treat high-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).Decitabine (DEC), one of the HMAs, is S phase-specifically incorporated into DNA to exert its effect, and sustained plasma concentration may increase its efficacy (Saunthararajah et al. J Clin Invest. 2015). Therefore, we developed OP-2100, an orally bioavailable prodrug of DEC. It showed equal efficacy to conventional HMAs in various blood cancer mouse models and exhibited a favorable safety profile in healthy mice (Watanabe et al. Blood. 2020; Ureshino et al. Mol Cancer Ther. 2021). In addition, it exhibited a sustained-release pharmacokinetic (PK) profile when orally administered to monkeys. In a phase I study, OP-2100 monotherapy showed the expected PK profile on patients with relapsed or refractory higher-risk MDS and CMML, and we reported the preliminary result. We designed a single-arm, multicenter phase I study for Japanese patients with MDS or CMML with intermediate-risk, high-risk, or very high-risk by Revised International Prognostic Scoring System (IPSS-R) and relapsed, refractory, or intolerant to standard therapy. The primary objective was to determine the maximum tolerated dose following the incidence of dose-limiting toxicity (DLT) in the first cycle, whereas the secondary objectives were to evaluate the safety, PK, and efficacy. Treatment-emergent adverse events (TEAEs) and response to therapy were assessed per NCI CTCAE v5.0 and IWG 2018 response criteria, respectively. Oral administration of OP-2100 as a single agent was continued for the patients daily on days 1-5 of each 28-day cycle until meeting discontinuation criteria, including disease progression. The dose level was defined as 30, 50, 80, and 120 mg/day. The initial dose of 50 mg/day was determined based on the highest non-severely toxic dose of OP-2100 in monkeys and the PK of DACOGEN TM in humans. This study was implemented in the 3+3 design according to DLT incidence. The plasma concentration of DEC and OP-2100 was measured on days 1 and 5. Furthermore, the LINE-1 methylation, a common HMA pharmacodynamics marker, was measured. This study is registered in the Japan Registry for Clinical Trials (jRCT2071220035). In total 3 patients with a history of azacitidine treatment for MDS were registered in the 50-mg initial cohort. These patients had been categorized as intermediate to high-risk in the IPSS-R, respectively. Table 1 shows patient characteristics. Out of 3, 2 patients did not experience DLT, while the 3rd one suffered from Grade 4 neutropenia, which was confirmed as DLT. As of April 30, the most common TEAEs were cytopenia of leukopenia, neutropenia, and thrombocytopenia, all of which were Grade 3 or 4. Other adverse events of Grade 3 or 4 include anemia, lymphopenia, COVID-19, and fall. In terms of efficacy, 2 patients had stable disease, while one had progressive, according to the IWG2018 response criteria. However, the 2 patients with stable disease still received administration up to 9 and 5 cycles, respectively (Figure 1). The PK profile of DEC after OP-2100 administration indicated sustained release, with an area under the curve (AUC) similar to that of DACOGEN TM (5-day regimen, 1-h continuous intravenous administration at 20 mg/m 2) and C max approximately 1/5. The LINE-1 methylation exhibited the similar behavior as conventional HMAs. The PK profile of DEC released from the prodrug after 50 mg of OP-2100 oral administration in 3 patients showed a similar AUC to that of the 5-day regimen of DACOGEN TM, and then C max showed a low with sustained plasma concentration. Among the 3 patients, OP-2100 could be administered for at least 5 cycles in 2 patients. To determine maximum tolerated dose, enrollment for this study is ongoing.

Hepatic ischemia-reperfusion syndrome and its effect on the cardiovascular system: The role of treprostinil, a synthetic prostacyclin analog.

Hepatic ischemia-reperfusion syndrome has been the subject of intensive study and experimentation in recent decades since it is responsible for the outcome of several clinical entities, such as major hepatic resections and liver transplantation. In addition to the organ's post reperfusion injury, this syndrome appears to play a central role in the dysfunction of distant tissues and systems. Thus, continuous research should be directed toward finding effective therapeutic options to improve the outcome and reduce the postoperative morbidity and mortality rates. Treprostinil is a synthetic analog of prostaglandin I2, and its experimental administration has shown encouraging results. It has already been approved by the Food and Drug Administration in the United States for pulmonary arterial hypertension and has been used in liver transplantation, where preliminary encouraging results showed its safety and feasibility by using continuous intravenous administration at a dose of 5 ng/kg/min. Treprostinil improves renal and hepatic function, diminishes hepatic oxidative stress and lipid peroxidation, reduces hepatictoll-like receptor 9 and inflammation, inhibits hepatic apoptosis and restores hepatic adenosine triphosphate (ATP) levels and ATP synthases, which is necessary for functional maintenance of mitochondria. Treprostinil exhibits vasodilatory properties and antiplatelet activity and regulates proinflammatory cytokines; therefore, it can potentially minimize ischemia-reperfusion injury. Additionally, it may have beneficial effects on cardiovascular parameters, and much current research interest is concentrated on this compound.

Effect of Repeated Bolus and Continuous Glucose Infusion on DNA Damage and Oxidative Stress Biomarkers in Healthy Male Volunteers.

Glucose variability (GV), which describes fluctuations in blood glucose levels within the day, is a phenomenon that is increasingly becoming the target of scientific attention when it comes to increased risk of coronary heart disease. Effects of GV may contribute to the development of metabolic syndrome and type 2 diabetes. Hyperglycemia can lead to oxidative stress resulting in molecular damage due to accumulation of reactive oxygen species (ROS). To discover more about the immediate effects of GV, continuous vs. bolus intravenous glucose administration was applied to 10 healthy men aged 21-30 years over a time frame of 48 h. Whole blood and plasma were analyzed for DNA damage using a comet assay with 3 different treatments (lysis buffer, H2O2, and the lesion-specific enzyme formamidopyrimidine DNA glycosylase (FPG)) as well as for the oxidative stress markers protein carbonyls (PC), unconjugated bilirubin (UCB), and ferric reducing antioxidant power (FRAP). A significant time effect was found in the three DNA damage treatments as well as in PC and UCB possibly due to circadian changes on oxidative stress, but no intervention group effect was observed for any of the markers. In conclusion, bolus vs. continuous glucose administration had no significant acute effect on DNA damage and markers of oxidative stress in healthy men.

Influence of Long-Term Continuous Intravenous Administration of Pentoxifylline on Endothelial-Related Coagulation in Critically Ill Patients: Retraction.

Influence of Long-Term Continuous Intravenous Administration of Pentoxifylline on Endothelial-Related Coagulation in Critically Ill Patients: Retraction.

Clinical pharmacokinetic study of tacrolimus in continuous intravenous administration for lung transplantation.

Tacrolimus is a cornerstone of immunosuppression after lung transplantation. However, there are no clear guidelines on how to administer the drug and the duration to achieve the required therapeutic range in the early phase of lung transplantation. This is a single-center cohort study of adult patients who had lung transplantation. Tacrolimus was administered beginning with a low dose of 0.01 mg/kg/day immediately after transplantation. In addition, the designated clinical pharmacist conducted a daily intervention with trough concentrations to achieve the target of 10-15 ng/mL. Time in the therapeutic range (TTRin, %), time to the therapeutic range (TTRto, days), and coefficient of variation (CoV) of tacrolimus were evaluated for the 2-week post-transplant period. A total of 67 adult patients who had received first-time lung transplantation were included in the analysis. The median percentage of tacrolimus TTRin was 35.7% (21.4-42.9%) for the 2-week postoperative period. The median day of TTRto was 7 days (5-9 days), and the median tacrolimus trough concentration was 10.02 ng/mL (7.87-12.26 ng/mL) for the 2-week postoperative period. The median CoV of tacrolimus was 49.7% (40.8-61.6%). Acute kidney injury following tacrolimus infusion occurred in 23 (34.3%) patients, but there was no neurotoxicity or acute cellular rejection within 1 month of the postoperative period. In conclusion, continuous intravenous administration with the daily measure and dose titration of tacrolimus trough concentrations allowed the therapeutic range of tacrolimus to be reached within 1 week without significant adverse events, although the pharmacokinetic parameters were highly variable over time.

10 clinical tips for advancing patient safety when using syringe pump systems for microinfusion intravenous drug therapy.

10 clinical tips for advancing patient safety when using syringe pump systems for microinfusion intravenous drug therapy.

Heart of the Matter: Reversal of Systolic Heart Failure and Long Term Remission in Primary Cardiac Lymphoma with Multi-Agent Chemotherapy with Continuous Intravenous Administration of Doxorubicin

Heart of the Matter: Reversal of Systolic Heart Failure and Long Term Remission in Primary Cardiac Lymphoma with Multi-Agent Chemotherapy with Continuous Intravenous Administration of Doxorubicin

Comparison of Changes in Chest Wall Mechanics and Respiratory Timing Between Patient-Controlled Epidural Analgesia and Intravenous Patient-Controlled Analgesia After Laparoscopic Gastrectomy: A Randomized Controlled Trial.

Upper abdominal surgery is associated with postoperative diaphragmatic dysfunction. Whether patient-controlled epidural analgesia (PCEA) is superior to intravenous patient-controlled analgesia (IV-PCA) in preventing postoperative diaphragmatic dysfunction is still unclear in laparoscopic gastric surgery. Sixteen patients undergoing laparoscopic gastrectomy randomly received either PCEA or IV-PCA. The primary outcomes were the change in chest wall mechanics and respiratory timing, measured by respiratory inductive plethysmography(Respitrace; Ambulatory Monitoring Inc., Ardsley, New York, United States) before and after surgery, and analyzed by a data acquisition system (PowerLab; ADInstruments, Dunedin, New Zealand). Inspiratory time (Ti), expiratory time (Te), total respiratory cycle time (Ttot), proportion of inspiratory time over total respiratory cycle time (Ti/Ttot), respiratory rate (RR), and abdominal contribution to tidal volume (AB/VT [%]) were calculated from the stored data. AB/VT, relative volume contribution of diaphragm to tidal breathing, represents an index of diaphragmatic function.Because the diaphragm is the main contributor to tidal volume, decreases in AB/VT indicate diaphragm dysfunction. Changes in outcomes over time between the two groups were analyzed using a linear mixed model, and two-sided p values < 0.05 were considered statistically significant. The secondary outcomes were postoperative pain score(visual analog scale (VAS)), bowel function recovery, and hospital stay duration. Postoperative AB/VT in the IV-PCA group was significantly decreased compared to preoperative levels. AB/VT in the PCEA group was significantly higher than the IV-PCA group on postoperative day (POD) 1. Change in AB/VT over time between the PCEA group and the IV-PCA group differed significantly (p = 0.01). A decrease of AB/VT during POD 1 to 3 was observed in the IV-PCA group but not in the PCEA group. As for respiratory timing, there were significant increases in RR with a reduction of Te and Ttot compared to preoperative levels on POD 1 in the PCEA group. There were significant decreases in RR and Ti/Ttot with an increase of Te and Ttot compared to preoperative levels on POD 1 in the IV-PCA group. There was a significant difference in the change of the Ttot over time between the two groups (p = 0.046). There were no significant differences in the changes of Te, Ti/Ttot, Ti, and RR over time between the two groups. There was no significant difference in VAS over time at rest and mobilization, recovery of bowel function, and hospital stay between the two groups. Continuous ropivacaine infusion with PCEA partially attenuated diaphragmatic dysfunction after laparoscopic gastrectomy, while pain relief by continuous intravenous administration of fentanyl could not attenuate diaphragmatic dysfunction. This suggests that PCEA might ameliorate postoperative diaphragmatic dysfunction after laparoscopic gastrectomy.

Tirofiban in the treatment of cancer-associated ischemic stroke.

It is still unknown whether early tirofiban treatment improves prognosis in patients with cancer-related ischemic stroke without intravenous thrombolytic therapy. The purpose of this study was to assess the safety and efficacy of tirofiban in patients with cancer-associated ischemic stroke. A retrospective analysis was performed on 75 patients with cancer and mild to moderate ischemic stroke, 34 of whom received tirofiban treatment and 41 aspirin treatment. The aspirin group received aspirin 100 mg QD, while the tirofiban group received continuous intravenous administration of tirofiban at a dosage of 0.1 μg/kg/min for 48 hours before switching to oral aspirin. The 24-hour and 7-day National Institute of Health Stroke Scale (NIHSS) scores for the tirofiban group were lower than those for the aspirin group (p=0.017 and p=0.035, respectively). The proportion of intracerebral hemorrhage occurring within 7 days did not differ significantly between the two groups (p>0.05), and neither did the 90-day Modified Rankin Scale (mRS) scores nor the incidence of ischemic stroke. Early administration of tirofiban in the treatment of mild to moderate ischemic stroke is safe, which can reduce 24-hour and 7-day NIHSS scores and has potential value.

670 DEXMEDETOMIDINE SEDATION FOR PULMONARY VEIN ISOLATION PROCEDURE

Abstract Background Peri-procedural anesthesia for catheter ablation of atrial fibrillation (AF) varies from conscious sedation to general anesthesia. Current guidelines do not suggest any specific strategy, thus the choice between different protocols is mainly driven by local expertise, operator and/or patient preference and availability of a dedicated anesthesiology team. Propofol is often the drug of choice despite the risk of respiratory depression. Few data have recently reported operator-directed nurse-administered dexmedetomidine (DEX) sedation as an effective and safe strategy. Aim of the study To evaluate the outcomes of operator-directed nurse-administered DEX sedation in AF ablation (pulmonary vein isolation-PVI). Method Between May 2022 and August 2022, 41 consecutive patients (male 83%, median age 64 years, IQR 57-71) with drug-refractory paroxysmal (n.27;66%) or persistent AF (n.14;34%) underwent first PVI procedure under DEX sedation. Our sedation protocol consisted of continuous intravenous administration of DEX (0.2–0,7 µg/kg/hr) titrated throughout the procedure to achieve mild to moderate sedation (Modified Observer's Assessment of Alertness and Sedation Scale 2-3). A single dose of Ondansetron (4 mg) was administered in the beginning of procedure. Adjunctive doses of fentanyl (cumulative dose 50-100 µg) were administered before the beginning of radiofrequency (RF) delivery and in case of inadequate control of the pain. A low dose propofol bolus (&amp;lt;1mg/kg) was eventually added for electrical cardioversion (ECV). Sedation-related complications were evaluated, including sustained hypoxemia (SpO2 &amp;lt;90%), need of anesthesiologist support and persistent hypotension (SBP &amp;lt; 90 mmHg). The day after the procedure, patients’ satisfaction and pain (0-100 scale) were assessed by a standardized questionnaire. Results Pulmonary vein isolation was performed either with Low Power Long Duration (LPLD, n.17;41,46%) or High-Power Short Duration (HPSD, n.24;58,54%) RF protocol. Median procedure time was 135’ (IQR 110-170’). Median DEX dose was 0,30 µg/kg/hr (IQR 0,27-0,33 µg/kg/hr). Median fentanyl dose was 75 µg (IQR 50-100 µg). In patients needing for ECV (n. 16; 39%), median propofol dose was 60 mg (IQR 47,5–105 mg). Thirteen patients (31,7%) had one or more significant risk factor (obesity, severe heart failure, pulmonary comorbidity, coronary artery disease) for anesthesia-related complications. Median pain scale value was 20 (IQR 10-50). Majority of patients (90,2%, n.37) reported mild to moderate pain (pain &amp;lt;60/100) during the procedure and satisfaction was overall high (median value 90, IQR 80-100), with a 90,2% of patients declaring a satisfaction of 60/100 or more. These results were independent from baseline characteristics (sex, age, AF type, HF, CAD, pulmonary comorbidity, obesity) and procedural aspects (LPLD vs HPSD, procedure time, need for ECV). A strong linear correlation was found between patients’ satisfaction and reported pain (r=-0,59). Only 1 (2,4%) sedation-related complication occurred, consisting in sustained post procedural hypotension treated with volume repletion. Conclusions in our experience, dexmedetomidine (DEX) sedation protocol during catheter ablation of atrial fibrillation is associated to high patients’ satisfaction and no respiratory complications. It seems to be also feasible in patients at higher risk for anesthesia-related complications (severe heart failure, BMI &amp;gt; 30 kg/m2), generally excluded from previous studies.

PSUN370 Refractory Hypoglycemia Associated with a Metastatic Neuroendocrine Tumor Producing Multiple Hormones

Abstract Introduction Neuroendocrine tumors are rare. They are derived from hormone-producing and nerve cells mostly found in GI tract, lung or pancreas. In about half of the cases, work-up does not detect any tumor-related hormone secretion. Even less common, the tumor produces several hormones which may be associated with clinical symptoms. Clinical Case A frail 81-year-old male with mild-to-moderate dementia and no history of diabetes presented to the emergency department with complaints of generalized weakness, fatigue, weight loss, poor appetite, diarrhea and shortness of breath for 1-2 weeks. Physical examination was pertinent for cachexia, general pallor, dry oral mucosa and having heme positive stool. Initial laboratory work-up found anemia (Hg 5.8g/dl), low glucose of 43 mg/dL, hypoalbuminemia (Alb 1.9 gm/dL). CT angiogram of abdomen did not show any active bleed but showed incidental diffuse hepatic lesions favoring metastatic disease, pancreatic ductal dilatation and fluid-filled loops of small and large bowel compatible with enteritis. Subsequent endoscopy and colonoscopy were negative for malignancy. Findings of multiple liver lesions prompted a CT-guided liver biopsy which showed a metastatic, well differentiated neuroendocrine tumor WHO grade II/III with positive stains for chromogranin A, synaptophysin, cytokeratin Oscar (Ki-67 less than 20%). MRCP abdomen examination of pancreas showed no focal pancreatic lesions but was suboptimal due to motion artefacts and lack of contrast. Workup for the tumor revealed increased serum serotonin (772 ng/ml), increased 5-HIAA (3,175 ng/ml), increased chromogranin A (48,436 ng/ml) and an increased 24hr Urine 5-HIAA (162mg/24hr). Further workup for the persistent and hypoglycemia showed a random cortisol 24.6mcg/dl. During hypoglycemia, insulin and C-peptide levels were 4.3 uU/L and 1.4ng/ml indicating inappropriately "normal" insulin production consistent with an insulinoma. IGF 1 and IGF 2 levels were withing the normal range. The hypoglycemia was initially managed with continuous intravenous administration of dextrose and optimization of oral intake, glucagon and octreotide 50 mcg every 8 hours. However, the response to octreotide was insufficient and we were unable to wean the patient off the dextrose. Subsequently we started prednisone 20 mg oral daily and glucose tablets which allowed us to discontinue the intravenous dextrose and the octreotide. Patient was discharged home on hospice care. Conclusion Hypoglycemia is a potentially life-threatening condition necessitating prompt action including the administration of intravenous dextrose. The results of the workup indicate that the neuroendocrine tumor produced excessive amounts of both serotonin and insulin contributing to prolonged refractory hypoglycemia. Treatment of this rare condition is challenging and often empirical. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Intravenous nicardipine for Japanese patients with acute intracerebral hemorrhage: an individual participant data analysis

The effects of acute systolic blood pressure levels achieved with continuous intravenous administration of nicardipine for Japanese patients with acute intracerebral hemorrhage on clinical outcomes were determined. A systematic review and individual participant data analysis of articles were performed based on prospective studies involving adults developing hyperacute intracerebral hemorrhage who were treated with intravenous nicardipine. Outcomes included death or disability at 90 days, defined as the modified Rankin Scale score of 4–6, and hematoma expansion, defined as an increase 6 mL or more from baseline to 24 h computed tomography. Of the total 499 Japanese patients (age 64.9 ± 11.8 years, 183 women, initial BP 203.5 ± 18.3/109.1 ± 17.2 mmHg) studied, death or disability occurred in 35.6%, and hematoma expansion occurred in 15.6%. Mean hourly systolic blood pressure during the initial 24 h was positively associated with death or disability (adjusted odds ratio 1.25, 95% confidence interval 1.03–1.52 per 10 mmHg) and hematoma expansion (1.49, 1.18–1.87). These odds ratios were relatively high as compared to the reported ones for overall global patients of this individual participant data analysis [1.12 (95% confidence interval 1.00–1.26) and 1.16 (1.02–1.32), respectively]. In conclusion, lower levels of systolic blood pressure by continuous intravenous nicardipine were associated with lower risks of hematoma expansion and 90-day death or disability in Japanese patients with hyperacute intracerebral hemorrhage. The impact of systolic blood pressure lowering on better outcome seemed to be stronger in Japanese patients than the global ones.