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CTIM-13. D2C7-IT IN COMBINATION WITH AN FC-ENGINEERED ANTI-HUMANCD40 MONOCLONAL ANTIBODY (2141-V11) ADMINISTERED INTRATUMORALLY VIA CONVECTION-ENHANCED DELIVERY (CED) FOLLOWED BY CERVICAL PERILYMPHATIC INJECTIONS (CPLIS) OF 2141-V11 IN PATIENTS WITH RECURRENT GLIOBLASTOMA (RGBM)

Abstract BACKGROUND The combination of D2C7-IT, an antibody toxin conjugate, and anti-mouseCD40 via CED generates robust antitumor immunity by killing tumor cells, activating microglia, reversing glioma-associated microglia and macrophage (GAMM)-mediated immune suppression, and empowering polyfunctional tumor antigen-specific CD8 T cells in glioma models. In addition to reprogramming GAMMs, anti-CD40 also activated dendritic cells and induced glioma-specific T cell responses in tumor draining lymph nodes. After establishing the phase 2 dose of the combination of D2C7-IT+2141-V11 when infused via CED, we initiated an assessment of the safety and efficacy of the combination of D2C7-IT+2141-V11 CED followed by repeated subcutaneous CPLIs of 2141-V11 ipsilateral to the tumor in patients with rGBM, IDH wild-type (NCT04547777). METHODS Eligible are adult patients with solitary supratentorial rGBM; ≥4weeks after chemotherapy, bevacizumab, or investigational agent; adequate organ function; and KPS ≥70%. Patients are treated with D2C7-IT (166μg) and 2141-V11 (3mg), both infused via CED, followed by CPLI of 2141-V11 at 2mg at weeks 2 and 4 post D2C7-IT+2141-V11 CED, followed by every 3 weeks for 1 year and then every 4-6 weeks. RESULTS As of May 22, 2024, 18 patients with rGBM (median age of 54) were treated with D2C7-IT+2141-V11 CED followed by CPLIs of 2141-V11. 83% patients remain alive (range 3.3-14.8 months from start of D2C7-IT CED infusion) with a median of 8 CPLIs of 2141-V11 received (range 3-19). No study related grade 4 or 5 adverse events (AEs) were observed. Grade 3 AEs related to D2C7-IT and/or 2141-V11 include one each of hydrocephalus, headache, seizure, and cerebral edema. AEs related exclusively to CPLIs of 2141-V11 consist of grade 1 injection site reaction (n=16). CONCLUSIONS The addition of CPLIs of 2141-V11 post CED of D2C7-IT+2141-V11 is feasible and has shown an acceptable toxicity profile. The safety and efficacy results will be updated.

Bioequivalence and pharmacokinetics of intravenous calcium during cesarean delivery.

Few studies have assessed the dose ratio of calcium gluconate to calcium chloride or defined the time course of change in serum ionized calcium concentration after intravenous injection. In a bioequivalence (dose ratio) trial, parturients undergoing cesarean delivery were randomly assigned to receive calcium chloride 0.5 grams or calcium gluconate 1.5 or 2 grams by 10-minute intravenous infusion. Venous serum ionized calcium concentration was measured prior to calcium infusion and approximately 5, 10, 15, 30, and 60 minutes after infusion start. We combined these data with serum ionized calcium concentration measurements in parturients who received 1 gram calcium chloride or saline placebo in two recent clinical trials to define the pharmacokinetics of intravenous calcium over the first hour during and after drug administration. The bioequivalence study enrolled 34 participants, from whom we collected 181 serum ionized calcium concentration measurements. The dose ratio of calcium gluconate to calcium chloride was 3.11 (95% CI: 2.77-3.48). Population pharmacokinetics of calcium were determined using 311 serum ionized calcium concentration measurements from 70 parturients. The pharmacokinetics of intravenous calcium were described by a two-compartment model with systemic clearance of 0.18 (95% CI: 0.07-0.27) L/min, distributional clearance of 1.25 (95%CI: 1.03-1.56) L/min, central volume of 10.9 (95% CI: 9.3-12.6) L, and peripheral volume of 16.5 (95% CI: 12.5-24.7) L. After adjusting for the dose ratio, calcium gluconate and calcium chloride had identical time courses. A one-gram infusion of calcium chloride results in a peak increase in serum ionized calcium concentration of 0.39 (0.38-0.42 mmol/L), which decreases by half 29 (23-40) minutes after initiation of the 10-minute infusion. We confirmed a 3:1 dose ratio of calcium gluconate to calcium chloride and estimated the pharmacokinetics over the first hour following intravenous delivery. These data inform clinical care and may guide future trials assessing calcium efficacy to reduce bleeding in obstetric patients. NCT05973747 (bioequivalence), NCT05027048, and NCT03867383 (trials included in pharmacokinetic assessment).

Simultaneous Determination of Methotrexate Concentrations in Human Plasma and Cerebrospinal Fluid Using Two-Dimensional Liquid Chromatography: Applications in Primary Central Nervous System Lymphoma.

In this study, we aimed to develop a method for the simultaneous quantification of methotrexate (MTX) samples extracted from human plasma and cerebrospinal fluid (CSF), using two-dimensional liquid chromatography (2D-LC). Furthermore, we intended to verify whether intravenous mannitol could increase MTX concentration in the CSF of patients. The mobile phase of PUMP1 consisted of 10.0 mmol/L ammonium acetate and acetonitrile. PUMP2 solution consisted of an aqueous solution of 10.0 mmol/L ammonium acetate. The mobile phase of PUMP3 comprised 50.0 mmol/L ammonium acetate and acetonitrile, with a flow rate of 1.0 mL/min. The developed method was successfully employed to simultaneously determine drug levels in plasma and CSF from the patients treated with MTX. CSF samples were obtained by lumbar puncture 0.5 - 2 h after starting the high-dose methotrexate (HD-MTX) infusion (over 4 h) and immediately before the intrathecal (IT) administration of MTX. Venous blood samples were drawn 4 h after the start of infusion. The calibration curve was linear, with a range of 0.07 - 2.38 µmol/L for CSF samples and a range of 0.11 - 5.51 µmol/L for plasma samples. Precision (> 95%) and accuracy (> 97%) were within the acceptance criteria for each quality control (QC) level. Inter- and intra-day accuracy and precision values met the acceptance criteria for each QC level. The correlation between MTX concentrations in the plasma and CSF was moderate (r = 0.502). No significant difference was observed in MTX concentration in CSF between patients using intravenous mannitol and those not using intravenous mannitol (P = 0.682). The developed method was useful for therapeutic drug monitoring of MTX and suitable for assessing the risks and benefits of chemotherapy in patients with primary central nervous system lymphoma. Intravenous mannitol did not increase MTX concentration in the CSF of patients.

Ketamine plus midazolam compared to midazolam infusion for the management of refractory status epilepticus

BackgroundData for the use of ketamine (Ket) in treatment of refractory and super-refractory status epilepticus (RSE, SRSE) is lacking despite its widespread growing use. We examined the efficacy of ketamine plus midazolam (MDZ) infusions for treating RSE versus midazolam alone. We hypothesized that ketamine initiation would result in earlier seizure termination. MethodsData was obtained from electronic health records (EHR) of adult patients who received intravenous anesthetic agents for RSE in our neurointensive care unit. Two cohorts were identified. The MDZ cohort received midazolam as the only intravenous anesthetic agent for RSE. The Ket+MDZ cohort received midazolam infusion followed by ketamine infusion. The primary outcomes were time from midazolam infusion start to SE end in both cohorts, and time from ketamine infusion start (Ket Start) to SE end in the Ket+MDZ cohort versus midazolam infusion start (MDZ start) to SE end in the MDZ cohort. Results73 patients were included (MDZ cohort n=17, Ket + MDZ cohort n=56). Cohorts did not differ significantly in age, sex, race, RSE etiology, or GCS on admission. Mean APACHE II score was higher in the Ket +MDZ cohort (26 ± 7.32SD) versus the MDZ cohort (22 ± 5.89SD)(P=.015). In survival analyses, cohorts did not differ significantly in time from midazolam start to SE end (HR=0.965, 95% CI=0.556-1.673, P=.899; median [IQR]: MDZ: 25hours [4.5-58]; Ket+MDZ: 21.5hours [IQR 13.5-49]). Time from Ket start (Ket+MDZ group) versus time from MDZ start (MDZ group) to SE end was significantly shorter in the Ket+MDZ cohort (HR=1.895, 95% CI=1.083-3.314, P=.025). The pattern of results was similar when including APACHE II and MDZ maximum dosage as covariates. ConclusionTime to SE end was significantly shorter after addition of ketamine infusion to midazolam infusion, versus after initiation of midazolam infusion monotherapy. Patients with higher disease severity favored Ket+MDZ. Randomized controlled trials are warranted in determining optimal anesthetics in RSE and SRSE.

An interactive dose optimizer based on population pharmacokinetic study to guide dosing of methotrexate in Chinese patients with osteosarcoma.

Osteosarcoma is a rare tumor with an incidence of 4.4 cases per million per year in adolescent. High-dose methotrexate (HD-MTX) is the standard first-line chemotherapeutic agent for osteosarcoma. However, its efficacy can vary significantly among individuals due to wide pharmacokinetic variability. Despite this, only a few population pharmacokinetics (popPK) models based on Chinese patients with osteosarcoma have been reported. Thus, this study aimed to develop a HD-MTX popPK model and an individual model-based dose optimizer for osteosarcoma therapy. A total of 680 MTX serum concentrations from 57 patients with osteosarcoma were measured at the end of MTX infusion and 10h, 24h, 48h, and 72h after the start of infusion. Using the first-order conditional estimation method with NONMEM, a popPK model was estimated. Goodness-of-fit plots, visual predictive checks, and bootstrap analysis were generated to evaluate the final model. A dose optimizer tool was developed based on the validated models using R Shiny. Additionally, clinical data from 12 patients with newly diagnosed osteosarcoma were collected and used as the validation set to preliminarily verify the predictive ability of the popPK model and the dose optimizer tool. Body surface area (BSA) was the most significant covariate for compartment distribution. Creatinine clearance (CrCL) and co-administration of NSAIDs were introduced as predictors for central compartmental and peripheral compartmental clearance, respectively. Co-administration of NSAIDs was associated with significantly higher MTX concentrations at 72h (p = 0.019). The dose optimizer tool exhibited a high consistency in predicting MTX AUC compared to the actual AUC (r = 0.821, p < 0.001) in the validation set. The dose optimizer tool could be used to estimate individual PK parameters, and optimize personalized MTX therapy in particular patients.

Analysis of Oxygen Concentration in the Oral Cavity During Intravenous Sedation with Intranasal Oxygen Administration for Dental Treatment.

Intravenous sedation (IVS) with propofol (PPF) is commonly performed in dental treatment, particular in patients with dentophobia, with gag reflex, or undergoing implant surgeries, as PPF has the advantages of rapid induction and recovery. However, PPF and other intravenous sedatives may cause respiratory depression. Thus, IVS with PPF requires oxygen administration. But airway burn may occur when high-concentration oxygen is stored in the oral cavity and catches fire. For these reasons, the present study aimed to elucidate the changes in oxygen concentration (OC) under IVS with PPF and oxygen administration. Nineteen healthy male volunteers participated in the study. None of them had missing teeth, nasal congestion, or temporomandibular joint dysfunction. They were sedated with a continuous PPF infusion dose of 6 mg/kg/hr for 25 min, followed by administration of 3 L/min oxygen via a nasal cannula. The OC was measured at two sites, namely, the median maxillary anterior teeth (MMAT) and median maxillary soft palate (MMSP), before PPF infusion (baseline) and 14, 15-18 (Term 1), 19, and 20-23 (Term 2) min after the start of infusion. Compared with the values at baseline, the OC in the MMSP significantly increased at each time point, whereas the OC in the MMAT significantly increased at Term 2. Furthermore, in the comparison of the OC before and after the use of a mouth prop, the OC exhibited an upward trend, but no statistically significant differences were observed between the two time points in the MMAT and MMSP. In IVS with PPF and oxygen administration, the OC in the pharynx increases as the sedative level deepens. Oxygen administration should be temporarily discontinued, and suction should be performed to decrease the OC in the oral cavity when sparking procedures during IVS with PPF and oxygen administration are performed.

Timing Is Everything: Recognizing the Importance of Infusion Duration in Preoperative Antimicrobial Prophylaxis

Background: For preoperative antimicrobials to be most effective in preventing surgical site infection, they must be administered early enough to reach a minimum tissue concentration that is specific to each drug. However, antibiotics have widely ranging infusion durations, from intravenous push over a few minutes to slow infusion over two hours. Heterogeneity in recommended infusion administration instructions, importance of infusion completion prior to incision, and complexity of healthcare systems present just some of the barriers to achieving appropriate preoperative antibiotic prophylaxis. We compared the percentage of infusion completion prior to case start before and after a multidisciplinary intervention. Methods: We performed a retrospective analysis of all patients undergoing a colorectal surgical procedure as defined by the National Healthcare Safety Network at a single university hospital from 10/19/22-10/18/23. A recognition that some antimicrobials were not finished infusing prior to surgery start prompted a multidisciplinary group including antibiotic stewardship, colorectal surgery, perioperative nursing, and anesthesiology to create and deploy an order set shortening metronidazole infusion duration from 60 to 30 minutes and initiating infusion in the preoperative area instead of the operating room. No change to the cefazolin intravenous push over 3-5 minutes was made. Goal antimicrobial infusion was defined as completed infusion within 120 minutes prior to incision, and calculations were made based on infusion start time and case start times. Rate of infusion completion was compared from the pre-intervention period to a post-intervention period from 10/19/23 through the end of the year. Results: For all colorectal surgeries in the pre-intervention period, 95% (n=418/440) of cefazolin doses and 0.002% (n=1/427) doses of metronidazole met goal infusion timing. At-goal infusion timing increased to 99% (n=84/85) of cefazolin doses and 68% (n=56/82) of metronidazole doses in the post-intervention period, resulting in a statistically significant improvement for metronidazole (Fischer’s exact test p &lt; 0 .00001). The average time to metronidazole infusion completion changed from 45 minutes after procedure start to 58 minutes before procedure start. Conclusions: Multidisciplinary team engagement and deployment of an order set incorporating changes in duration and workflow for metronidazole infusion improved all antimicrobial preoperative infusions for colorectal procedures. Increased awareness of completing antimicrobial infusion prior to the incision may improve preoperative antimicrobial administration.Disclosure: Lindsay Donohue: Advisor - Abbvie

Comparison of clevidipine vs nicardipine in the treatment of hypertensive urgency and emergency in critically ill patients.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Evidence has suggested that clevidipine may provide faster blood pressure (BP) reduction with less volume than nicardipine in stroke and cardiothoracic surgery patients, but its use in hypertensive crises has not been well established. The primary objective of this study was to compare the treatment success of clevidipine and nicardipine in hypertensive crisis. This was a multicenter, retrospective cohort study including patients who received either clevidipine or nicardipine for treatment of hypertensive crisis. The primary outcome was the time from infusion start to attainment of goal BP, defined as the higher value of the guideline-directed 25% reduction in BP or the physician-ordered goal. Secondary outcomes were the time from infusion start to guideline-directed 25% reduction in BP, drug and total volume intake, the time from order entry to BP goal attainment, the number of BP and heart rate excursions, intensive care unit (ICU) length of stay, and study medication cost. In total, 182 patients were included in the study (103 receiving nicardipine and 79 receiving clevidipine). Time to goal BP was similar between the groups (35 vs 33 minutes for clevidipine vs nicardipine, respectively; P = 0.37). Time to guideline-directed 25% reduction was also similar (P = 0.42). Volume from study drug was significantly less with clevidipine (222 vs 518mL; P = 0.01); however, the total volume received in the ICU was similar (3,370 vs 3,383mL; P = 0.43). Percent time in the goal BP range was similar (43.1% vs 42.3%). The cost of clevidipine was $199.37 per vial (based on the average wholesale price as of June 2023). This cost was 682% higher than that for a bag of nicardipine. Time to goal BP was similar for clevidipine and nicardipine in this population. Any decreases in medication-associated volume with clevidipine were no longer evident when all volume sources were considered. These results show that clevidipine may not provide meaningful benefit in this heterogenous population. The difference in cost does not seem justified given the lack of improvement in clinically relevant outcomes.

Safety and feasibility analysis of rapid daratumumab infusion in Chinese patients with multiple myeloma.

With the increasing use of daratumumab (DARA)-containing regimens for multiple myeloma (MM) patients in China, the standard infusion time of DARA is long, with the potential for infusion-related reactions (IRRs) and increased hospitalization and use of resources. Shortening the duration of DARA infusion helps to optimize the hospital stay and enhance the patient treatment experience. The current, commonly used 90-min rapid DARA infusion regimen may not be applicable to Chinese MM patients, and therefore, we explored a new 110-min rapid DARA infusion regimen aimed at reducing the treatment burden on patients to guarantee therapeutic safety. MM inpatients treated with the DARA regimen were divided into two groups according to the number of times the DARA regimen was used: a standard infusion regimen for patients treated with the first two doses of DARA and a 110-min rapid infusion regimen for patients treated with more than two doses of DARA. Anti-allergy medications were routinely administered prior to the start of DARA infusion, patient consent, and authorization was obtained for all treatments, and statistical evaluation of the results was conducted via descriptive analyses, one-way ANOVA and chi-square tests. A total of 129 patients were included in this study: 68 in the standard infusion group, with 121 DARA infusions, and 129 in the rapid infusion group (patients who participated in the standard infusion subsequently participated in the rapid infusion), with 738 DARA infusions. The incidence of IRRs was 27.27% (36/121) in the standard infusion group and 1.35% (10/738) in the rapid infusion group, which were significantly different (p < 0.001). The incidence of IRRs after rapid infusion in other studies was <6%. The incidence of grade 1 IRRs in the rapid infusion group was 0.81% (6/738), the incidence of grade 2 IRRs was 0.54% (4/738), and there were no IRRs above grade 3; age, sex, and underlying disease had no effect on the choice of infusion method (p > 0.05). The mean infusion time after the occurrence of IRRs was also shorter in the rapid infusion group than in the standard infusion group (F = 24.781, p < 0.001). The 110-min rapid infusion DARA regimen is feasible and safe for use in Chinese MM patients.

Phase I study of the pharmacokinetics and safety of rezafungin in subjects with moderate/severe hepatic impairment and matched control subjects.

Rezafungin is a second-generation, once-weekly echinocandin antifungal approved for the treatment of invasive candidiasis, including candidemia. In phase II/III studies of rezafungin versus caspofungin, patients with severe hepatic impairment were excluded due to lack of caspofungin data in this population. This open-label, single-dose, phase I study evaluated the pharmacokinetics (primary objective) and safety of rezafungin in subjects with moderate or severe hepatic impairment versus matched, healthy subjects with normal hepatic function. Eight subjects each with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment were matched 1:1 with healthy subjects for age, sex, and body mass index. Each subject received a single 400-mg, intravenous, 1-h infusion of rezafungin. Plasma pharmacokinetic sampling was performed at various time points through 336 h postdose. Pharmacokinetic parameters were derived by non-compartmental analysis. Safety was assessed throughout. All 32 subjects received study treatment and were included in all analyses. Despite overlapping distributions of total plasma concentrations, based on geometric least-squares (LS) mean ratios, the area under the plasma concentration-time curve from time zero (prior to the start of infusion) to infinity (AUC0-∞) was 32% lower in subjects with moderate (LS mean ratio, 67.55; 90% confidence interval [CI]: 53.91, 84.65) and severe (LS mean ratio, 67.84; 90% CI: 57.49, 80.05) hepatic impairment versus matched healthy subjects. The maximum plasma concentration (Cmax) was 12% lower in moderate hepatic impairment and 28% lower in severe hepatic impairment groups. Linear regression showed no significant trend in the degree of hepatic impairment (based on Child-Pugh score) on AUC0-∞ or Cmax (p > 0.05). Treatment-emergent adverse events were reported in seven subjects (21.9%; three subjects in each of the hepatic impairment groups, and one healthy subject), none of which were severe, serious, or resulted in withdrawal. Rezafungin is well tolerated and can be administered to patients with moderate or severe hepatic impairment without the need for dose adjustment. The modest reduction in exposures in subjects with hepatic impairment is not clinically meaningful and is unlikely to impact efficacy.

Cardiopulmonary function, anesthetic effects, quality of arousal, hematology, and blood biochemistry during continuous intravenous infusion of a combination solution of xylazine, butorphanol, and propofol in calves.

General anesthesia in calves is easier to perform under field conditions, total intravenous anesthesia (TIVA) than using inhalation anesthesia. In the present study, cardiopulmonary function, anesthetic effects, quality of arousal, hematology, and blood biochemistry were assessed during continuous infusion of a combination solution of 0.01% xylazine, 0.001% butorphanol, and 0.2% propofol (XBP) at doses of 6 (G6; 10μg/kg/min xylazine, 1μg/kg/min butorphanol, 200μg/kg/min propofol) and 9mL/kg/h (G9; 15μg/kg/min xylazine, 1.5μg/kg/min butorphanol 300μg/kg/min propofol). For both groups, five castrated Holstein calves received intravenous injections of xylazine (0.2mg/kg) and propofol (2mg/kg), followed by a continuous infusion of XBP for 60min to maintain anesthesia. Respiratory management consisted of tracheal intubation followed by spontaneous inhalation of pure oxygen. Cardiopulmonary, anesthesia, hematology, and blood biochemistry variables were assessed at rest (baseline) and every 5 or 15min after the start of the XBP infusion. Quality of arousal was assessed based on the swallowing reflex recovery time from the stop of XBP infusion, and the sternal position time and standing time after atipamezole administration. XBP produced adequate sedation, analgesia, and muscle relaxation in all calves and maintained stable anesthesia for 60min. As XBP infusion time passed, rectal temperature and heart rate became lower, and mean arterial blood pressure increased. In both groups, hematologic and blood biochemical effects were mild. The quality of arousal was not different, and all calves were standing. The results of the present study suggested that XBP is useful for TIVA in calves.

A Practical Dosing Algorithm for Deep Neuromuscular Blockade during Total Intravenous Anesthesia: ROCURITHM.

The number of trials investigating the effects of deep neuromuscular blockade (NMB) on surgical conditions and patient outcomes is steadily increasing. Consensus on which surgical procedures benefit from deep NMB (a posttetanic count [PTC] of 1 to 2) and how to implement it has not been reached. The European Society of Anaesthesiology and Intensive Care does not advise routine application but recommends use of deep NMB to improve surgical conditions on indication. This study investigates the optimal dosing strategy to reach and maintain adequate deep NMB during total intravenous anesthesia. Data from three trials investigating deep NMB during laparoscopic surgery with total intravenous anesthesia (n = 424) were pooled to analyze the required rocuronium dose, when to start continuous infusion, and how to adjust. The resulting algorithm was validated (n = 32) and compared to the success rate in ongoing studies in which the algorithm was not used (n = 180). The mean rocuronium dose based on actual bodyweight for PTC 1 to 2 was (mean ± SD) 1.0 ± 0.27 mg · kg-1 ·h-1 in the trials, in which mean duration of surgery was 116 min. An induction dose of 0.6 mg ·kg-1 led to a PTC of 1 to 5 in a quarter of patients after a mean of 11 min. The remaining patients were equally divided over too shallow (additional bolus and direct start of continuous infusion) or too deep; a 15-min wait after PTC of 0 for return of PTC to 1 or higher. Using the proposed algorithm, a mean 76% of all 5-min measurements throughout surgery were on target PTC 1 to 2 in the validation cohort. The algorithm performed significantly better than anesthesiology residents without the algorithm, even after a learning curve from 0 to 20 patients (42% on target, P ≤ 0.001, Cohen's d = 1.4 [95% CI, 0.9 to 1.8]) to 81 to 100 patients (61% on target, P ≤ 0.05, Cohen's d = 0.7 [95% CI, 0.1 to 1.2]). This study proposes a dosing algorithm for deep NMB with rocuronium in patients receiving total intravenous anesthesia.

84 Evaluating the effects of hind gut acidosis in sheep on rumen fermentation ex vivo

Abstract The objective was to determine the effect of hindgut acidosis in sheep on rumen fermentation ex vivo. Eleven ruminally and cecally cannulated ewes [body weight (BW) = 49 ± 4 kg] were assigned to one of two treatments: a constant infusion of deionized water (CON; 26 mL/kg BW per 24 h) or starch solution (STA; 3 g wheat starch/kg BW per 24 h) in the cecum to induce hindgut acidosis. Rumen fluid was collected from each ewe on the d before and four d after the start of cecal infusion for an ex vivo fermentation. There were four flasks for each ewe with two flasks per substrate. The two substrates were forage-based (FB; 40% grass hay pellet, 35% whole shell corn, 15% dried distiller’s grain, and 10% alfalfa cubes) and concentrate-based (CB; 75% whole shell corn, 15% dried distiller’s grain, and 10% alfalfa cubes). Flasks contained 2.5 grams of substrate and 150 mL of inoculum (2:1 ratio of McDougall’s buffer and rumen fluid). Four sealed ANKOM F57 bags were filled with 0.25g DM of substrate and placed into flasks to determine in vitro dry matter disappearance (IVDMD). The flasks were incubated at 39°C for 24 h, with sample aliquots collected at h 0, 8, and 24 to determine pH, volatile fatty acids (VFA), and ammonia. Data were analyzed using the MIXED procedure of SAS 9.4. For all response variables, values from the run before cecal infusion initiation were included in the model as a covariate. Ammonia, pH, and VFA were analyzed with the effects of treatment, time, and their interaction. For the CB substrate, there was no effect (P = 0.90) of cecal infusion on ammonia concentration; however, there was a time effect (P = 0.01) with h 24 having a greater ammonia concentration than h 8. For the FB substrate, there was a tendency for STA to have lesser (P = 0.10) ammonia than CON. There was no effect (P ≥ 0.78) of cecal infusion treatment on pH for both substrates; however, there was a time effect (P = 0.01) with pH decreasing over time. In both substrates, there were no effects (P ≥ 0.23) of cecal infusion treatment on IVDMD, VFA concentration, acetate, or propionate molar concentration. However, butyrate molar concentration tended to be less (P = 0.07) for STA ewes for the CB substrate. No treatment differences were observed in butyrate for the FB substrate (P = 0.35). Results indicate that induced hindgut acidosis in sheep did not affect rumen fermentation ex vivo.

IGF-1 infusion increases growth in fetal sheep when euinsulinemia is maintained.

Insulin-like growth factor 1 (IGF-1) is a critical fetal anabolic hormone. IGF-1 infusion to the normally growing sheep fetus increases the weight of some organs but does not consistently increase body weight. However, IGF-1 infusion profoundly decreases fetal plasma insulin concentrations, which may limit fetal growth potential. In this study, normally growing late-gestation fetal sheep received an intravenous infusion of either: IGF-1 (IGF), IGF-1 with insulin and dextrose to maintain fetal euinsulinemia and euglycemia (IGF+INS), or vehicle control (CON) for 1 week. The fetus underwent a metabolic study immediately prior to infusion start and after 1 week of the infusion to measure uterine and umbilical uptake rates of nutrients and oxygen. IGF+INS fetuses were 23% heavier than CON (P = 0.0081) and had heavier heart, liver, and adrenal glands than IGF and CON (P < 0.01). By design, final fetal insulin concentrations in IGF were 62% and 65% lower than IGF+INS and CON, respectively. Final glucose concentrations were similar in all groups. IGF+INS had lower final oxygen content than IGF and CON (P < 0.0001) and lower final amino acid concentrations than CON (P = 0.0002). Final umbilical oxygen uptake was higher in IGF+INS compared to IGF and CON (P < 0.05). Final umbilical uptake of several essential amino acids was higher in IGF+INS compared to CON (P < 0.05). In summary, maintaining euinsulinemia and euglycemia during fetal IGF-1 infusion is necessary to maximally support body growth. We speculate that IGF-1 and insulin stimulate placental nutrient transport to support fetal growth.

Pre-clinical evaluation of effectiveness of infusion solutions with different osmolarity during acute blood loss in experiments on rats

The aim of the research was to experimentally evaluate the effectiveness of infusion solutions with different osmolarity during acute blood loss in experiments on rats. Material and methods. Experiments approved by the local Ethics Committee, have been done on 30 male rats line Vistar (320 ± 35 g). Design of the research included anesthesia, simulation of acute blood loss to 50 % of circulating blood volume, its replenishment with experimental infusion solutions based on polyglycan derivatives (estimated osmolarity 1026.6, 1784.2, 2566.6 mOsm/l), research of survivability, functional state of cardiovascular and respiratory systems, blood acid-base status and gas partial pressure 5, 30, 60, 120, 180 min after the beginning of replenishment of circulating blood volume. The infusion solution Hemostabil was used as a comparison product. Results. The highest survival rate, restoration of hemodynamics and acid-base state and blood acid-base status and gas partial pressure were obtained as a result of infusion of solution with osmolarity 1026.6 mOsm/l. In this group of animals survivability accounted for 100 %, arterial pressure restored in 5 minutes after the start of infusion, indicators of blood acid-base status and gas partial pressure normalized in 120 min of experiment. All of the results had statistically significant differences (p &lt; 0.05) relative to values in other experimental groups. Conclusions. Sample of solution with osmolarity 1026.6 mOsm/l is the most effective in restoration of hemodynamics of rats with the blood loss up to 50 % of circulating blood volume. The expediency of the researches of safety of this infusion solution based on polyglucan derivatives in the capacity of medication for replenishment acute blood loss is substantiated.

The effectiveness of dexmedetomidine cardioprotection during vascular surgery in high cardiac risk patients

The objective was to study the occurrence of perioperative cardiovascular complications (CVС) and clinical and laboratory cardioprotection parameters in patients treated with dexmedetomidine infusion in perioperative period of vascular surgery.Materials and methods. The study involved 204 patients with high cardiac risk (revised cardiac risk index &gt; 2, risk of perioperative myocardial infarction or cardiac arrest &gt; 1%) who underwent elective vascular surgery. The patients were randomly divided into two groups. Group I patients received perioperative infusion of dexmedetomidine at a dose 0.40 [0.34–0.47] mg/kg/h during 7.0 [6.0–8.0]) hours. Group II was a control group. In the perioperative period, the occurrence of CVC, the blood level of the N-terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) and cardiospecific troponin I (cTnI) were analyzed. The data were statistically processed, using the Fisher’s exact test, Mann–Whitney test and logistic regression.Results. Perioperative CVC without taking into account arterial hypotension were recorded in 3 (2.9%) patients in group I and in 14 (13.7%) patients in group II (p = 0.009). Arterial hypotension was recorded in 14 (13.7%) patients in group I and in 5 (4.9%) patients in group II (p = 0.051). Perioperative dexmedetomidine infusion reduced the risk of CVC, except for arterial hypotension (OR 0.1905, 95% CI 0.0530–0.6848, p = 0.011) and increased the risk of arterial hypotension (OR 3.5787, 95% CI 1.1254–11.3796, p = 0.031). The cTnI level in patients of groups I and II was 0.017 [0.011–0.024] and 0.019 [0.011–0.028] ng/ml (p = 0.196) before surgery, 0.02 [0.011–0.029] and 0.02 [0.015–0.039] ng/ml (p = 0.050) after surgery, 0.018 [0.014–0.024] and 0.028 [0.018–0.033] ng/ml (p = 0.0002) before discharge from the hospital. At the same stages, the level of NT-proBNP was 221.5 [193.3–306.5] and 237.8 [171.3–310.1] pg/ml (p = 0.572), 237.0 [205–303.5] and 289.0 [217.5–409.5] pg/ml (p = 0.007), 250.5 [198.8–302.0] and 259.6 [171.0–421.6] pg/ml (p = 0.933).Conclusion. In patients at high cardiac risk undergoing vascular surgery, perioperative dexmedetomidine infusion reduces the risk of a composite outcome including cardiac mortality, nonfatal myocardial infarction, myocardial ischemia, pulmonary embolism, stroke, hypertension, and arrhythmias, while the risk of arterial hypotension increases significantly. The perioperative dynamics of cTnI and NT-proBNP require further research. The start of dexmedetomidine infusion in 2.7% of cases is accompanied by severe bradycardia, requiring discontinuation of the infusion.

Safety of perioperative intravenous lidocaine in liver surgery - A pilot study.

Perioperative lidocaine infusion has many interesting properties such as analgesic effects in the context of enhanced recovery after surgery. However, its use is limited in liver surgery due to its hepatic metabolism. This prospective, monocentric study was conducted from 2020 to 2021. Patients undergoing liver surgery were included. They received a lidocaine infusion protocol until the beginning of hepatic transection (bolus dose of 1.5 mg kg-1, then a continuous infusion of 2 mg kg-1 h-1). Plasma concentrations of lidocaine were measured four times during and after lidocaine infusion. Twenty subjects who underwent liver resection were analyzed. There was 35% of preexisting liver disease before tumor diagnosis, and 75% of liver resection was defined as "major hepatectomy." Plasmatic levels of lidocaine were in the therapeutic range. No blood sample showed a concentration above the toxicity threshold: 1.6 (1.3-2.1) μg ml-1 one hour after the start of infusion, 2.5 (1.7-2.8) μg ml-1 at the end of hepatic transection, 1.7 (1.3-2.0) μg ml-1 one hour after the end of infusion, and 1.2 (0.8-1.4) μg ml-1 at the end of surgery. Comparative analysis between the presence of a preexisting liver disease or not and the association of intraoperative vascular clamping or not did not show significant difference concerning lidocaine blood levels. Perioperative lidocaine infusion seems safe in the field of liver surgery. Nevertheless, additional prospective studies need to assess the clinical usefulness in terms of analgesia and antitumoral effects.

Electroencephalogram monitoring during ketamine antidepressant treatment: a pilot study

Introduction Depression is a major cause of disability world-wide. Up to a third of patients have a treatment-resistant form (TRD), presenting a major challenge. Ketamine has been introduced as a novel rapid-acting antidepressant effective in this population. However, at present, ketamine treatment is not routinely informed by any objective neural markers. Basic research has shown promising electroencephalogram (EEG) changes including a decrease in alpha power. However, clinical translation is lacking.ObjectivesAssess the feasibility of identifying EEG correlates of ketamine infusions in a routine outpatient setting with a low-cost, easily usable system.MethodsThe study was carried out at the Oxford Health Foundation Trust Ketamine Clinic (ethics reference 22/EM/0226). N=18 EEG recordings from N=12 patients were collected (5 women, mean age 44, range 33-62, IV dose 0.5-1mg/kg over 40min). 4-channel EEG was collected with a Muse-S headband at 256Hz, from 5min before to 55min after infusion start. 5s epochs were rejected if gyroscope data indicated head movement above 10 deg/s or if amplitude was above 200μV. A spectrogram (4s window, 3s overlap) as well as band-limited power (theta: 4-8Hz, alpha: 8-13Hz, beta: 13-25Hz) were computed. Significance of changes was found with a repeated measures analysis of variance (RM-ANOVA) on power in 5min segments together with post-hoc Tukey’s P-values.ResultsAcross the ketamine infusion recordings, there was a significant effect of time (F=3.65, P=0.0105) and Channel*Time interaction (F=3.80, P&lt;0.001) on the EEG spectrum. Effects were largest on temporal electrodes, particularly TP9 in the alpha and theta bands (Figure 1, Table 1).Table 1:Effect sizes (Cohen’s d) and FDR-corrected ANOVA P-values for ketamine effects on each EEG channel and frequency band. P&lt;0.05 was considered significant (bold). n.s. = not significant (P&gt;0.2). Channel / Band TP9AF7AF8TP10Theta1.16 (P=0.019)0.11 (n.s.)0.11 (n.s.)0.42 (P=0.113)Alpha1.41 (P&lt;0.001)0.12 (n.s.)0.17 (n.s.)0.605 (P=0.113)Beta1.19 (P=0.112)0.03 (n.s.)0.08 (n.s.)0.21 (n.s.)Image:ConclusionsIn a routine outpatient setting, sub-anaesthetic ketamine infusions in TRD patients were associated with decreased fronto-temporal EEG alpha and theta power. Future work should assess the potential of low-cost routine EEG, and alpha desaturation specifically, to inform individualised ketamine treatment.Disclosure of InterestNone Declared

Efficacy and Safety of Intravenous Vernakalant in Rapid Cardioversion of Recent Onset Atrial Fibrillation: A Retrospective Single-Centre Study.

We use vernakalant, an intravenous anti-arrhythmic, to cardiovert paroxysmal atrial fibrillation (AF) into sinus rhythm. It is a relatively atrium-selective, early-activating potassium and frequency-dependent sodium channel blocker with a half-life of 2 to 3 hours. Due to concerns regarding its safety profile, it is not Food and Drug Administration (FDA)-approved. This study aims to assess the efficacy of intravenous vernakalant in cardioversion of paroxysmal AF and the safety of its use. Patients with paroxysmal AF who presented to the American University of Beirut Medical Center (AUBMC) between 2015 and 2020 and received vernakalant for cardioversion were included. Patients did not receive vernakalant if they had any of the following: QTc > 440 ms, heart rate < 50 bpm, acute coronary syndrome within the last 30 days, second- and third-degree atrioventricular (AV) block in the absence of a pacemaker, severe aortic stenosis (AS), use of intravenous antiarrhythmics (class I and class III) within four hours of vernakalant infusion, systolic blood pressure <100 mmHg, and heart failure (New York Heart Association (NYHA) III or NYHA IV class). The primary endpoint is conversion to sinus rhythm for at least one minute within 90 minutes of the start of the vernakalant infusion. The secondary endpoint included the presence of these side effects: bradycardia, QTc prolongation, AV block, ventricular arrhythmias, hypotension, taste alteration/dysgeusia, sneezing, nausea, vomiting, paresthesia, cardiogenic shock, or death. The study included 23 patients with paroxysmal AF (15 men, mean age 54 ± 14 years). Fourteen patients (61%) cardioverted to sinus rhythm within 90 minutes of the start of the Vernakalant infusion. Seven patients (30%) reverted to sinus rhythm within 15 minutes after the first infusion. After treatment with vernakalant, four patients (17%) developed sinus bradycardia, and four patients (17%) developed first-degree AV block. No patient had a QTc greater than 460 ms. None of the patients experienced sinus pauses, high-grade AV block, ventricular arrhythmias, hypotension, dysgeusia, sneezing, nausea, vomiting, paresthesia, cardiogenic shock, or death. Vernakalant had 61% efficacy in the rapid cardioversion of paroxysmal AF to sinus rhythm, was well tolerated, and had a low rate of adverse events in our study population.

Predicted effect-site concentrations of remimazolam for i-gel insertion: a prospective randomized controlled study.

This study is the first to report 50% and 95% effect-site concentrations (EC50 and EC95, respectively) of the new short-acting benzodiazepine, remimazolam, for the successful insertion of i-gels with co-administration of fentanyl. Thirty patients (38 ± 5 years old, male/female = 4/26) were randomly assigned into five groups to receive one of five different remimazolam doses (0.1, 0.15, 0.2, 0.25, and 0.3mg/kg bolus followed by infusion of 1, 1.5, 2, 2.5, and 3mg/kg/h, respectively, for 10min), which were designed to maintain a constant effect-site concentration of remimazolam at the time of i-gel insertion. At 6min after the start of remimazolam infusion, all patients received 2µg/kg fentanyl. i-gel insertion was attempted at 10min and the success or failure of insertion were assessed by the patient response. Probit analysis was used to estimate the EC50 and EC95 values of remimazolam with 95% confidence intervals (CIs). In the five remimazolam dose groups, two, two, four, five, and six of the six patients in each group had an i-gel successfully inserted. Two patients in the lowest remimazolam dose group were conscious at the time of i-gel insertion and were counted as failures. The EC50 and EC95 values of remimazolam were 0.88 (95% CI, 0.65-1.11) and 1.57 (95% CI, 1.09-2.05) µg/ml, respectively. An effect-site concentration of ≥ 1.57µg/ml was needed to insert an i-gel using remimazolam anesthesia, even with 2µg/kg fentanyl. Trial registration: The study was registered in Japan Registry of Clinical Trials on 19 April 2021, Code jRCTs041210009.