Continuous Intravenous Infusion Research Articles

Safety and Effectiveness of an Anti-Xa-based Unfractionated Heparin Protocol for Impella Percutaneous Ventricular Assist Devices.

Background: Impella devices are used for mechanical circulatory support in patients with cardiogenic shock or those undergoing high-risk percutaneous coronary intervention (PCI). Anticoagulation protocols in this population are not well established and are complicated by concomitant use of purge solutions containing unfractionated heparin (UFH) and intravenous UFH continuous infusion (CI) for systemic anticoagulation. Objectives: To evaluate thrombotic and bleeding complications when using a novel UFH protocol with a reduced initial UFH CI dose of 6 units/kg/hour targeting an anti-Xa goal of 0.3 to 0.5 units/mL in patients receiving Impella support. Methods: This single-center, retrospective study included 41 patients on Impella support who received an UFH purge solution and/or an IV UFH infusion. The primary outcome was overall composite bleeding. Secondary outcomes included thrombotic events and systemic UFH exposure. An exploratory analysis was performed to identify risk factors for bleeding. Results: Anti-Xa values were in therapeutic range 46% of the time while on support (interquartile range 16.6%-75%), with a median IV UFH dose of 6 units/kg/hour. The overall bleeding rate was 29.2%, with 6 minor bleeds and 2 major bleeds with no fatal bleeding or intracranial hemorrhage. Rate of overall thrombosis was 4.9%, including 1 ischemic stroke and 1 occurrence of limb ischemia. Conclusion: Use of a modified UFH protocol to target an anti-Xa goal of 0.3 to 0.5 units/mL resulted in bleeding and thrombotic event rates similar to previous literature. This protocol utilizing an initial rate of 6 units/kg/hour may be a useful approach to achieve therapeutic anticoagulation while accounting for UFH exposure from the purge solution and minimizing need for frequent calculations.

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.

Time Limited Exposure to a ROR1 Targeting Bispecific T Cell Engager (NVG-111) Leads to Durable Responses in Subjects with Relapsed Refractory Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL)

Background: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is absent or expressed at low levels in normal adult tissues but overexpressed in a range of malignancies including CLL and MCL. NVG-111 is a humanized first in class, tandem scFv, ROR1xCD3 bispecific T cell engager. NVG-111 mediates potent killing of ROR1 + tumors by engaging a unique epitope on the Frizzled domain of ROR1 and redirecting T cell activity via the CD3 binder engineered for attenuated cytokine release. Methods: In this phase 1, first-in-human, dose-escalation study (ClinicalTrials.gov identifier: NCT04763083), NVG-111 was evaluated in relapsed/refractory CLL and MCL subjects with an ECOG PS of 0-2 who received ≥2 prior lines of treatment including a Bruton tyrosine kinase inhibitor (BTKi). Bayesian continual reassessment method with overdose control was implemented to guide escalation over a dose range of 0.3-45ug/day. Each subject received at least one dose of NVG-111, administered as a continuous intravenous infusion (cIV) over 21 days followed by 7 days off drug (=1 cycle). NVG-111 was administered in combination (N=8) with ibrutinib to subjects who had achieved a partial response to >1 year of ibrutinib therapy, or as monotherapy in subjects that progressed after covalent BTKi/B-cell lymphoma 2 inhibitor (BCL2i) (N=4). Primary objective was safety, with the secondary objectives being efficacy (overall response rates [ORR], minimal residual disease (MRD) measured by ERIC-compliant flow cytometry and duration of response [DoR]). Serum cytokine levels were determined using a human high sensitivity cytokine premixed magnetic Luminex assay and T cell function was longitudinally evaluated using cytometry by time of flight (CyTOF) analysis. Results: Between May 2021 and July 2023 12 subjects (10 males and 2 females, median age 60 years) completed a maximum of 6 cycles of treatment with NVG-111 (median=3 cycles [range 1-6 cycles]). Pharmacokinetic and pharmacodynamic data demonstrated systemic NVG-111 exposure and exposure-dependent NVG-111 targeting of ROR1 on circulating tumor cells. Adverse events (AEs) related to NVG-111 occurred in 10 subjects (83%), with the most common being nausea (58%), headaches (67%), and fatigue (33%), majority of which were grade 1 or 2. Grade 1(71%) or 2(29%) cytokine release syndrome (CRS) occurred in 58% of subjects during week 1 of cycle 1 except in one subject who had a second grade 1 CRS in cycle 2. Grade 3 dose limiting toxicities (DLTs) occurred in three subjects (25%) consisting of transient elevation of liver enzymes (ALT and AST) in one subject dosed at 3ug/day, immune effector cell-associated neurotoxicity syndrome-like symptoms (ICANS) in one subject dosed at 30ug/day and headache in one subject dosed at 45ug/day. All AEs were fully reversible with no late emergent grade 3 or greater toxicities. Evidence of T cell activation was observed in all 12 subjects with peak cytokine levels at the 30µg/day dose levels (mean±SEM): TNFα, 43±17pg/ml; IL6, 566±541pg/ml; IFNɣ, 18±12pg/ml; and IL10, 103±56pg/ml. Furthermore, T cell profiling showed an increase in cytotoxic CD8 + T cell activation marker expression during each NVG-111 treatment cycle without evidence of T cell exhaustion. Efficacy was evaluable in 11 subjects with objective clinical responses observed in 55% (6/11), including two subjects with clear evidence of single agent activity. Amongst these, three CLL subjects were rendered MRD negative in peripheral blood and one MCL subject achieved complete metabolic response by the Lugano criteria. Two subjects had stable disease but in one of these subjects there was a >50% reduction in peripheral blood lymphocytosis and a 40% reduction in lymphadenopathy. Despite time limited exposure to NVG-111, the restricted mean survival time for DoR is currently 13.6 months (SEM 3.07), the median is not yet calculable with response ongoing in four subjects. The median progression-free survival currently is 18.7 months (95% CI 2.6 - not calculable). Conclusion: These data provide clinical proof of concept for selective targeting of ROR1 with a TCE leading to objective evidence of antitumor activity with encouraging response durability even in CLL patients known to have defective T cell function. The safety profile was consistent with the mechanism of action. Further evaluation of this promising molecule is ongoing.

Recombinant Human Diamine Oxidase Against Histamine Induced Shock - Implications for Mast Cell Activation Syndrome

Background and Objective:Mastocytosis patients suffer from a clonal increase in mast cells which produce and release excessive amounts of histamine even under stable conditions (Keyzer et al. 1983). Unfortunately, symptom control with new kinase inhibitors is variable and modest at best. Mast cell activation syndrome may further enhance histamine release which can result in recurrent shocks (Böhm et al. 2019), or severe, protracted anaphylaxis refractory to epinephrine (Grafeneder et al. 2022). Previously we demonstrated that recombinant human diamine oxidase (rhDAO) fully degrades 100-fold elevated histamine concentrations in plasma samples from mastocytosis patients. In vivo rhDAO, with a mutated heparin binding motif (mHBM), was able to digest massively increased histamine levels, thereby improving indirect measures of shock such as a temperature drop in mice (Karer et al. 2022). As mice are insensitive to histamine (intravenous LD50 of 385mg/kg in mice compared with 0.18mg/kg in guinea pigs), this unfortunately limits their translational value. To assess the therapeutic potential of rhDAO_mHBM, we tested its efficacy for the prevention and treatment of histamine induced shock in guinea pigs, the only histamine sensitive rodent species. Methods:Guinea pigs received continuous intravenous infusions of 8 µg/kg/min histamine to model its release from activated circulating basophils or subcutaneous injections of 1mg/kg histamine to mimic peripheral histamine release by mast cells. We used intramuscular injections of 5µg/kg adrenaline as a benchmark, because it is recommended in guidelines for the treatment of anaphylaxis, although its efficacy had never been proven. Infusions of rhDAO_mHBM were given either prophylactically before- or therapeutically after - symptom onset. Mean arterial pressure was measured intra-arterially and rhDAO_mHBM levels were quantified by enzyme immunoassay and histamine concentrations by a liquid chromatography -tandem mass spectrometry (LC-MS/MS) method. The primary outcome variable was prevention of shock as defined by a >=30% drop in mean arterial blood pressure. Results:Guinea pigs pretreated with 4 mg/kg rhDAO_mHBM showed lower mean heart rate (p<0.01) and higher body core temperatures at the end of the intravenous histamine infusions compared to controls (p<0.05). Histamine infusions increased median urinary excretion of histamine and N-methyl-histamine 8.6- and 4.0-fold (p<0.05), respectively. Pretreatment with 4 mg/kg rhDAO_mHBM reduced urinary histamine (p<0.01) and N-methyl-histamine (p<0.01) concentrations compared with controls. Subcutaneous injections of 1 mg/kg histamine induced shock within 20 minutes in all control animals, and the experiments had to be terminated prematurely in several animals. Intramuscular injection of 5mcg/kg adrenaline (similar to human adrenaline auto-injector doses) after symptom onset was unable to prevent shock, confirming its lack of efficacy demonstrated previously in an anaphylaxis model in dogs (Mink et al. 2004). In contrast, prophylactic infusions of 4-8mg/kg rhDAO_mHBM prevented hypotensive shock in all treated animals (p<0.01). After an initial histamine induced drop in blood pressure, 8mg/kg rhDAO_mHBM restored blood pressure and prevented shock in all animals when injected at the time of symptom occurrence (p<0.01 Chi2 test). Figure 1 demonstrates the median drop in blood pressure and development of shock (indicated by the dashed line) by subcutaneous injection of 1mg/kg histamine (black squares), and the prevention of shock by rhDAO-mHBM given before (blue up triangles) or after (red circles) histamine injections. Conclusion: This is the first demonstration of the beneficial effects of rhDAO_mHBM in a histamine-sensitive species. rhDAO_mHBM is a novel therapeutic approach targeting histamine excess which effectively prevented shock, in contrast to intramuscular epinephrine. As the mechanism of action is not species specific, these findings can be translated from guinea pigs to humans: it will help to select optimal dosing of rhDAO_mHBM during clinical development for the prophylaxis in - and treatment of - mastocytosis patients suffering from histamine induced symptoms or mast cell activation syndrome, or patients with anaphylaxis induced by asparaginase, plasma products or other medications.

Utility of nicardipine in the management of hypertensive crises in adults with reduced ejection fractions

BackgroundNicardipine is commonly used in the management of hypertensive crises, except those involving cardiac contractility defects despite its ability to reduce afterload and pulmonary congestion. Consequently, there is limited literature evaluating nicardipine's role for this indication. The purpose of this study was to evaluate the efficacy and safety of nicardipine in adults with reduced ejection fractions presenting with acute heart failure with hypertension (AHF-H). MethodsThis was a retrospective study conducted at an academic Level 1 trauma center with an annual Emergency Department (ED) volume surpassing 100,000. The purpose of this study was to determine the efficacy and safety of nicardipine in adults with reduced ejection fractions presenting to the ED with AHF-H. Efficacy was determined by achievement of the physician prescribed blood pressure target range. The primary safety endpoints included the number of individuals who experienced bradycardia (< 60 beats per minute, bpm) or hypotension (systolic blood pressure, SBP, < 90 mmHg) while receiving nicardipine and for up to 15 min after its discontinuation. Patients were included if they were ≥ 18 years of age, received a continuous intravenous nicardipine infusion within six hours of presenting to the ED, and had an ejection fraction ≤ 40% per an echocardiogram obtained within three months of the study visit. Pregnant and incarcerated patients were excluded. ResultsOf the 500 patient charts reviewed, 38 met inclusion criteria. The median (interquartile, IQR) ejection fraction and brain natriuretic peptide (BNP) were 35% (25–40) and 731 pg/nL (418–3277), respectively. The median baseline heart rate and SBP were 90 bpm and 193 mmHg, respectively. The median physician specified SBP goal was 160 mmHg and all patients met this endpoint in a median time of 18 min. One (2.6%) patient in the total population developed both hypotension and bradycardia. This patient had an ejection fraction of 20%, was intubated, and received nicardipine in addition to esmolol for an aortic dissection without experiencing an adverse event until 30 min after dexmedetomidine was initiated. ConclusionIn this non-interventional study evaluating the use of nicardipine in patients with reduced ejection fractions presenting to the ED with AHF-H, nicardipine was found to be safe and effective. To our knowledge this is the largest study to date evaluating nicardipine in this patient population and positively contributes to the existing literature.

Furosemide continuous infusion versus repeated injection in the management of acute decompensated heart failure in infants with left to right shunt: a randomized trial

BackgroundFurosemide is the foremost drug used in the management of acute decompensated heart failure (ADHF). By tradition, it was administered as repeated intravenous boluses but fluctuations in intravascular volume and blood pressure were noticed in addition to the possibility of toxicity. Hence, continuous intravenous infusion was thought of as an alternative route of administration. In searching the literature, all previously published data concerning the pediatric age group was for infants and children following cardiac surgery. This study aims to compare the efficacy and safety of furosemide repeated injection versus continuous infusion during the management of ADHF in infants with left to right shunt.MethodsA prospective parallel-design randomized study was conducted on 54 infants with ADHF, Ross class IV, secondary to left to right shunt. Twenty-seven infants received repeated injections of furosemide and 27 infants had furosemide continuous infusion. Patients were followed clinically for weight, urine output, hours required for resolution of failure symptoms, serum creatinine, sodium and potassium, and length of hospital stay.ResultsNon-significant differences were observed between both groups regarding preadmission oral furosemide dose and serum creatinine level. A lower daily dose of furosemide was observed in the continuous infusion arm (3.5 ± 0.6 vs 4.7 ± 1.0, p = 0.001) with less fluctuation in urine output and significantly fewer hours required for resolution of failure symptoms (42.1 ± 9 vs 56 ± 18.5, p = 0.001). At the end of furosemide infusion, serum creatinine was significantly higher in the continuous infusion group (0.39 ± 0.06 vs 0.34 ± 0.1, p = 0.030). However, before hospital discharge, non-significant differences were noticed (0.32 ± 0.05 vs 0.33 ± 0.06, p = 0.584). Non-significant differences between both groups regarding serum sodium and potassium levels at the end of furosemide injection were detected (p = 0.289, 0.890, respectively).ConclusionContinuous infusion of furosemide can be safely administered to infants with ADHF, Ross class IV, secondary to left to right shunt with clinical gradual alleviation of fluid overload symptoms and less hemodynamic instability than repeated injections.Trial registrationThe study was approved by the Mansoura Faculty of Medicine institutional research board (MS/16.02.41) on August 3rd, 2016.

Treatment of severe metformin-associated lactic acidosis with renal replacement therapy and tris-hydroxymethyl aminomethane: a case report

BackgroundType B lactic acidosis is a rare but serious side effect of metformin use. The risk of metformin-associated lactic acidosis is elevated in renal or liver impairment, heart failure and in metformin overdose. Metformin-associated lactic acidosis is treated with renal replacement therapy although this can be limited by metformin’s large volume of distribution and a patient’s hemodynamic instability. Tris-hydroxymethyl aminomethane is a buffer that rapidly equilibrates in liver cells and increases the intracellular pH of hepatocytes. Intracellular alkalosis increases lactate uptake by the liver and can promote gluconeogenesis which results in increased lactate metabolism and decreased lactate production. Unlike intravenous bicarbonate which can worsen acidosis due to carbon dioxide retention and hypocalcemia, tris-hydroxymethyl aminomethane does not generate large amounts of carbon dioxide and can improve cardiac contractility in experimental models.Case presentationWe present a case of a 43-year-old African American male who intentionally ingested 480,000 g of metformin. He developed severe metformin-associated lactic acidosis that was refractory to 21 hours of high flux hemodialysis. This was followed by an additional 12 hours of high flux hemodialysis augmented by continuous intravenous infusion of tris-hydroxymethyl aminomethane. After initiating tris-hydroxymethyl aminomethane, the patient had rapid reversal of lactic acidosis and was weaned off vasopressors and mechanical ventilation.ConclusionsWhile metformin-associated lactic acidosis can be treated with renal replacement therapy, severe cases of lactic acidosis may not be amenable to renal replacement therapy alone. Through its unique buffer mechanisms, tris-hydroxymethyl aminomethane can be used in conjunction with dialysis to rapidly improve acidosis associated with metformin.

Comparison of Early Postoperative Outcome Between Intermittent Intravenous Heparin versus Continuous Heparin Infusion after Initial Bolus Dose during Off-Pump Coronary Artery Bypass Surgery

Background: Heparin is an anticoagulant used invariably in all cardiac surgery. Heparin dosing and its reversal is determined by monitoring Activated Clotting Time (ACT). Surgery under cardiopulmonary bypass requires much more heparin than off-pump cardiac operations. Intermittent heparin dosing after initial bolus dose is widely practiced to maintain ACT level 200- 300 seconds in OPCAB. Fluctuation of ACT level from this range may causes adverse postoperative outcome. This study was aimed to compare early postoperative outcome between intermittent heparin dose and continuous heparin infusion after initial bolus dose during OPCAB. Methods: This comparative cross-sectional study was carried out in National Institute of Cardiovascular Diseases (NICVD) from January 2019 to December 2020. Total 110 patients were enrolled by purposive sampling and divided into 2 groups: group-A where 55 patients received intermittent heparin after initial bolus dose and group-B where 55 patients received continuous heparin infusion after initial bolus dose. Data were analyzed by statistical package for social science (SPSS) version 26.0 and p value &lt;0.05 was considered significant. Results: Baseline ACT level of group-A was 87.04±5.51 seconds and group-B was 87.31±5.74 seconds, which was not significant (p = 0.800). After bolus dose of Heparin, ACT level of group-A was 252.02 ± 25.131 seconds and group-B was 259.04 ± 12.645 seconds. Difference between the groups was not significant (p = 0.068). Mean maintenance ACT was 326.34±22.774 seconds in group-A and 258.67±12.285 seconds in group-B patient, which was significant (p&lt;0.001). Peroperatively 29% from group-A and 11% from group-B developed arrhythmia. Postoperative mean Troponin I level in group-A was 5.78± 1.15 and group-B was 5.32± 1.05 ng/dl, which is significant (p = 0.030). Postoperative blood loss was significantly higher in group-A than group-B (986.36± 398.31 vs 852.73±241.22, p=0.036). There was significantly better reduction of arrhythmia and ischemia in postoperative and on discharge ECG finding in group-B patients (p=0.002). On discharge echocardiography 31% from group-A and 13% from group-B had regional wall motion abnormality, which is significant (p=0.018). But there was no significant difference in LVEF% (52.65±5.99 vs 53.85±5.77, p = 0.287). There was only one mortality which was from group-A. The patient was suffering from critical left main disease and developed postoperative arrhythmia and low output syndrome. Conclusion: Early postoperative outcome of continuous heparin infusion is better than intermittent intravenous heparin after initial bolus dose during Off-pump coronary artery bypass surgery. So, during OPCAB use of continuous heparin infusion after bolus dose is eminent time worthy. Cardiovasc j 2023; 16(1): 17-23

Propofol Affords No Protection against Delayed Cerebral Ischemia in a Mouse Model of Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) is an important contributor to poor outcomes in aneurysmal subarachnoid hemorrhage (SAH) patients. We previously showed that volatile anesthetics such as isoflurane, sevoflurane and desflurane provided robust protection against SAH-induced DCI, but the impact of a more commonly used intravenous anesthetic agent, propofol, is not known. The goal of our current study is to examine the neurovascular protective effects of propofol on SAH-induced DCI. Twelve-week-old male wild-type mice were utilized for the study. Mice underwent endovascular perforation SAH or sham surgery followed one hour later by propofol infusion through the internal jugular vein (2 mg/kg/min continuous intravenous infusion). Large artery vasospasm was assessed three days after SAH. Neurological outcome assessment was performed at baseline and then daily until animal sacrifice. Statistical analysis was performed via one-way ANOVA and two-way repeated measures ANOVA followed by the Newman-Keuls multiple comparison test with significance set at p < 0.05. Intravenous propofol did not provide any protection against large artery vasospasm or sensory-motor neurological deficits induced by SAH. Our data show that propofol did not afford significant protection against SAH-induced DCI. These results are consistent with recent clinical studies that suggest that the neurovascular protection afforded by anesthetic conditioning is critically dependent on the class of anesthetic agent.

THE TREATMENT OF HEPATORENAL SYNDROME WITH TERLIPRESSIN: CONTINUOUS INTRAVENOUS INFUSION VS INTRAVENOUS BOLUSES A RANDOMISED CONTROLLED STUDY ON SYNDROME

Objective: Hepatorenal syndrome (HRS) is a severe complication of cirrhosis, with terlipressin and albumin being the most common treatment. The study aimed to compare the effectiveness and safety of continuous intravenous infusion vs. intravenous boluses of terlipressin in treating type 1 h.&#x0D; Methods: A randomized controlled trial was conducted on cirrhosis patients with type 1 h. Patients were allocated to receive terlipressin via continuous infusion (TERLI-INF group) or intravenous boluses (TERLI-BOL group). Demographic, clinical, and laboratory data were collected, and treatment details were recorded. The primary endpoint was the frequency of drug-related adverse events. Secondary endpoints included therapy responsiveness and 90-day transplant-free survival.&#x0D; Results: Both groups exhibited similar baseline characteristics. While treatment length and cumulative albumin doses were comparable, TERLI-INF patients received lower terlipressin doses. Severe treatment-related adverse events differed between groups. Univariate analysis identified several baseline parameters significantly associated with response to terlipressin. The study supports continuous terlipressin infusion's superiority in treating type 1 h, with lower adverse event rates and improved patient response.&#x0D; Conclusion: The study concludes that continuous intravenous terlipressin infusion is safer and more effective in treating type 1 h in decompensated cirrhosis patients compared to intravenous boluses. Lower terlipressin dosages were effective in continuous infusion, indicating improved safety. The MELD score was an independent predictor of response, and therapy responsiveness was associated with improved 90 d survival.

NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial

Pancreatic ductal adenocarcinoma remains one of the most lethal malignancies, with few treatment options. NAPOLI 3 aimed to compare the efficacy and safety of NALIRIFOX versus nab-paclitaxel and gemcitabine as first-line therapy for metastatic pancreatic ductal adenocarcinoma (mPDAC). NAPOLI 3 was a randomised, open-label, phase 3 study conducted at 187 community and academic sites in 18 countries worldwide across Europe, North America, South America, Asia, and Australia. Patients with mPDAC and Eastern Cooperative Oncology Group performance status score 0 or 1 were randomly assigned (1:1) to receive NALIRIFOX (liposomal irinotecan 50 mg/m2, oxaliplatin 60 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2, administered sequentially as a continuous intravenous infusion over 46 h) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2, administered intravenously, on days 1, 8, and 15 of a 28-day cycle. Balanced block randomisation was stratified by geographical region, performance status, and liver metastases, managed through an interactive web response system. The primary endpoint was overall survival in the intention-to-treat population, evaluated when at least 543 events were observed across the two treatment groups. Safety was evaluated in all patients who received at least one dose of study treatment. This completed trial is registered with ClinicalTrials.gov, NCT04083235. Between Feb 19, 2020 and Aug 17, 2021, 770 patients were randomly assigned (NALIRIFOX, 383; nab-paclitaxel-gemcitabine, 387; median follow-up 16·1 months [IQR 13·4-19·1]). Median overall survival was 11·1 months (95% CI 10·0-12·1) with NALIRIFOX versus 9·2 months (8·3-10·6) with nab-paclitaxel-gemcitabine (hazard ratio 0·83; 95% CI 0·70-0·99; p=0·036). Grade 3 or higher treatment-emergent adverse events occurred in 322 (87%) of 370 patients receiving NALIRIFOX and 326 (86%) of 379 patients receiving nab-paclitaxel-gemcitabine; treatment-related deaths occurred in six (2%) patients in the NALIRIFOX group and eight (2%) patients in the nab-paclitaxel-gemcitabine group. Our findings support use of the NALIRIFOX regimen as a possible reference regimen for first-line treatment of mPDAC. Ipsen. For the plain language summary see Supplementary Materials section.

Calcitonin gene-related peptide causes migraine aura

BackgroundAlthough the involvement of calcitonin gene-related peptide (CGRP) in migraines is well-established, its specific role in investigating the aura phase, which often precedes the headache, remains largely unexplored. This study aims to instigate CGRP’s potential in triggering aura, thus establishing its role in the early stages of migraine.MethodsIn this open-label, non-randomized, single-arm trial, 34 participants with migraine with aura received continuous intravenous infusion of CGRP (1.5 µg/min) over 20 min on a single experimental day. Participants were required to be free of headache and report no use of acute medications 24 h before infusion start. The primary endpoint was the incidence of migraine aura during the 12-hour observational period after the start of infusion.ResultsThirteen (38%) of 34 participants developed migraine aura after CGRP infusion. In addition, 24 (71%) of 34 participants developed migraine headache following CGRP infusion.ConclusionsOur findings suggest that CGRP could play an important role in the early phases of a migraine attack, including during the aura phase. These insights offer a new perspective on the pathogenesis of migraines with aura. They underscore the need for additional research to further explore the role of CGRP in these initial stages of a migraine attack, and potentially inform future development of therapeutic interventions.Trial registrationClinicalTrials.gov Identifier: NCT04592952.Graphical

Challenges in the management of hyperinsulinemic hypoglycemia in a preterm neonate - A case report and literature review

Hyperinsulinemic hypoglycemia (HH) includes a diverse group of disorders characterized by dysregulated insulin secretion, exhibiting clinical, genetic, and morphological heterogeneity. It is associated with permanent brain damage. Hence, a timely diagnosis and prompt management are essential to safeguard against complications such as epilepsy, cerebral palsy, and neurodevelopmental deficits. We report the challenges faced in the management of HH in a preterm neonate. A baby girl was born to a G2A1 mother at 31 weeks of gestation due to preterm onset of labor with premature rupture of membranes. The baby had persistent and refractory hypoglycemia requiring oral and parenteral medications such as diazoxide, hydrochlorothiazide, hydrocortisone, nifedipine, glucagon infusion, and subcutaneous octreotide. Genetic testing unveiled a homozygous pathogenic mutation of the ABCC8 gene with autosomal recessive (AR) inheritance. As the AR inheritance always presents with diffuse lesions, a 18F-fluoro-dihydroxyphenylalanine positron emission computed tomography (18F-DOPA PET) scan was not done to differentiate focal and diffuse lesions. The baby underwent laparoscopic near-total pancreatectomy and was discharged on subcutaneous octreotide. Continuous intravenous glucagon infusion may help reduce the infusion rate of glucose needed to maintain normoglycemia. Diazoxide unresponsiveness in a baby with HH needs genetic studies. AR inheritance always presents as diffuse lesions. Hence, an 18F-DOPA PET scan can be deferred to differentiate the diffuse and focal forms.

Role of dexmedetomidine in modifying immune paralysis in patients with septic shock: randomized controlled trial

BackgroundImmune paralysis can be defined as a hypoinflammatory state associated with the incapacity of the immune system to release proinflammatory mediators despite the clearance of pathogens by antimicrobials. Persistent immune paralysis leads to failure to eradicate primary infections with a substantial increase in the risk of multiorgan dysfunction and mortality. The state of immune paralysis is caused mainly by the diminished ability of monocytes to release proinflammatory cytokines in response to endotoxin. This phenomenon is known as endotoxin tolerance. This study aimed to assess the role of dexmedetomidine in modifying immune paralysis in septic shock patients.MethodsTwenty-four patients with septic shock were randomized into two groups of 12 patients. A continuous intravenous infusion of dexmedetomidine started at 0.15 µg kg−1 hr−1 and adjusted by 0.15 µg kg−1 h−1 to a maximum of 0.75 µg kg−1 h−1 (10 ml h−1), while midazolam was started at 1 mg h−1 (2 mL hr−1) and adjusted by 1 mg h−1 to a maximum of 5 mg h−1 (10 mL h−1). All infusions were adjusted by increments of 2 mL/hr−1 to maintain blinding. Serum levels of CD42a+/CD14+, HLADR+/CD14+, CRP, IL-6, IL-10 and TNF-α were measured at baseline (T1), 12 h (T2), and 24 h (T3).ResultsTreatment with dexmedetomidine yielded no significant difference in CD42a+/CD14+, HLADR+/CD14, CD24b-MFI, HLADR-MFI, IL6 and TREM1 at all time points when compared with midazolam treatment. There was no significant difference in TLR levels between the two groups. Cardiac output in the dexmedetomidine group showed a significant decrease at 6, 12 and 24 h (P = 0.033, 0.021, and 0.005, respectively) compared with that in the midazolam group.ConclusionOur results indicated that dexmedetomidine did not affect CD42a+/CD14+ and HLA-DR+/CD14+ expression in septic patients. Furthermore, cytokine production and inflammatory biomarkers did not change with dexmedetomidine infusion.Trial registration Clinical trial.gov registry (NCT03989609) on June 14, 2019, https://register.clinicaltrials.gov.

Therapeutic effects of 7- to 14-day subanesthetic ketamine infusions for chronic pain on standardized psychiatric measures.

Background: We have previously shown that subanesthetic ketamine infusions effectively reduce refractory pain. However, the effects of ketamine infusions on comorbid conditions of depression and anxiety have not been explored in this patient population. Methods: We investigated the effects of ketamine on mood and anxiety in patients with refractory chronic pain treated with 7-14days of subanesthetic continuous intravenous ketamine infusions, using well-validated clinical scales. Results: There was a significant 52% reduction in pain severity and 33% reduction in pain interference scores following ketamine treatment. Ketamine treatment also reduced scores on the depression module of the Patient Health Questionnaire (PHQ-9) by 28% and scores on the Generalised Anxiety and Depression Assessment (GAD-7) by 36%. Conclusion: Multiday subanesthetic ketamine infusions effectively reduce pain, anxiety and depression in patients with complex chronic pain.

Abstract P396: Blood Pressure Of Individuals With Salt Sensitivity But Not Salt Resistance Is Increased After Acute Na + Loading

Kidney function is influenced by salt intake and may adapt rapidly to dietary salt variations by modulating pressure-natriuresis. In particular, salt-sensitive (SS) individuals respond to a high-salt diet with a large rise in blood pressure (BP), indicative of a blunted pressure-natriuresis relationship, while 7-12% of the normotensive population have reduced BP with Na + loading, a condition termed inverse salt sensitivity. We compared effects of acute intravenous Na + loading on renal function in normotensive salt-resistant (SR) (11) and SS (5) individuals, as described below. After subjects were prepared in metabolic balance at 100 mmol Na + /d, they underwent Phase I renal function studies (0700h-1100h); Phase II oral sodium citrate load (1100h) followed by a continuous intravenous infusion of 0.9% saline (1100h-1300h); Phase III post-control monitoring period (1300h-1500h). During the entire protocol, BP and heart rate were monitored every 10 min. Blood and urine samples were obtained every hour and analyzed for Na + , K + , creatinine, osmolality and pH. Renal function tests included GFR, filtered Na + load (F Na ), urinary Na + exretion (U Na V), fractional Na + reabsorption (FR Na ), and fractional Na + excretion (FE Na ). Mean BP was calculated using 6 measurements/hour. SS systolic (SBP) and diastolic BP (DBP) were significantly higher than in subjects with SR throughout the procedure (at 1100h SS 137±6.3 vs SR 114±2.6 mmHg, p&lt;0.001 two-way ANOVA). Phase II changes in BP were calculated by subtracting BP at 1100h; there were no significant changes for SR BP. With Na + infusion, SS SBP and DBP increased and remained elevated through the end of the procedure. The increase of SS DBP at 1500h was significantly higher than that of SR (85.8±5.5 vs 65.9±1.6 mmHg, p&lt;0.05 t-test). Both GFR and F Na were increased in SR, while there were no changes in SS after Na + infusion (GFR SR Y=2.9*X-28.37; SS Y=0.61*X-11.45). FR Na was increased in SR, but decreased in SS. The difference between slopes was significant (SS Y=-1.92*X+21.56; SR Y=0.64*X-6.8, P&lt;0.01). After 1 h of Na + loading, FE Na decreased to 1.3 in SS but increased to 1.6 in SR (P=0.089 t-test). The results indicate that renal function of individuals with SS responds differently to acute intravenous Na + loading than those with SR.

General anesthesia alters the diversity and composition of the lung microbiota in rat

BackgroundThe lung microbiome plays a crucial role in human health and disease. Extensive studies have demonstrated that the disturbance of the lung microbiome influences immune response, cognition, and behavior. The goal of this study was to investigate the effect of general anesthetics on lung microbiome. MethodsEight-week-old male SD rats received a continuous intravenous infusion of propofol or inhalation of isoflurane for 4 h. 16S rRNA gene amplification from BALF samples was used to investigate the changes in the lung microbiome after interventions. We further performed neurobehavioral assessments to find the differential strains’ association with behavior disorder after isoflurane anesthesia. ResultsThe absolute and relative quantitation of 16S rRNA sequencing data showed that isoflurane altered the diversity and abundance of the lung microbiome in rats more than propofol. Elusimicrobia increased significantly in the isoflurane group. Both EPM and OFT results showed that rats exhibited depression-like behaviors after inhalation of isoflurane. In addition, significant differences were found in the COG/KO/MetaCyc/KEGG pathway enrichment analyses among the groups. ConclusionContinuous inhalation of isoflurane changed the diversity and composition of the lung microbiota in rats, resulting in post-anesthesia depression.

Effect of Intra Operative Intravenous Lidocaine Infusion on Control of Pain and Recovery of Intestinal Function Following Surgical Appendectomy

Abstract Background Intravenous lidocaine infusion has been shown to facilitate postoperative recovery after major abdominal surgery. This current randomized controlled study will assess the effect of intraoperative intravenous lidocaine infusion on pain intensity, bowel function and cytokine response after surgical appendectomy. Aim of the Work To determine the role of intraoperative lidocaine infusion in reducing perioperative pain and analgesia requirement and enhancing the recovery of intestinal function in patients undergoing surgical Appendectomy. Patients and Methods The current prospective randomized double-blinded study was conducted at the surgery department, Faculty of Medicine, Ain Shams University and it included 40 patients who were undergone urgent open appendectomy and met the selection criteria. They were classified into 2 groups: Group L: patient who received IV bolus injection of lidocaine (1.5 mg/kg slowly over 10 min) 30 minutes before the skin incisions followed by a continuous IV infusion at the rate of 2 mg/kg/h via infusion pump(B-BRAUN), Group S (control): patient who received 0.9% normal saline in equal volume and in the same manner. Results There was statistically significant difference between the studied groups regarding time to pass flatus. Patients within lidocaine group pass flatus significantly earlier than those with control group. There is statistically non-significant difference between the studied groups regarding postoperative complications. Conclusion From the current study, it was concluded that perioperative IV lidocaine injection had significant effect in reduction of postoperative pain and increased the main pain free period also noticed IV lidocaine decreased opioid requirement and time to pass flatus so shorten hospital stay. Perioperative IV lidocaine had no effect on postoperative complications and IV lidocaine during incision and extubation attenuated hemodynamic response.

A clinical trial of zosuquidar plus gemtuzumab ozogamicin (GO) in relapsed or refractory acute myeloid leukemia (RR AML): evidence of efficacy based on leukemic blast P-glycoprotein functional phenotype.

To evaluate safety, tolerability, potential efficacy, and pharmacodynamics (PD) of zosuquidar (Zos) in combination with gemtuzumab ozogamicin (GO) in elderly patients with relapsed or refractory (RR) acute myeloid leukemia (AML). Patients with RR AML (N = 41) were treated with Zos as a 48-h continuous intravenous infusion initiated 4h prior to a 2-h infusion of GO on days 1 and 15. P-glycoprotein (P-gp) status of the patients' leukemic blasts and PD determinations were assessed with ex vivo bioassays. Patient outcomes were analyzed for the total cohort and as stratified into P-gp-positive (P-gp +) and P-gp-negative (P-gp‒) subgroups. The eligible cohort exhibited a 34% overall remission rate (ORR), a composite of patients that exhibited complete remission (CR), CR with incomplete platelet recovery, or morphologic remission. Patients with 1st relapsed disease exhibited 40% ORR. P-gp phenotype did not significantly predict ORR. However, the P-gp + subgroup exhibited a greater median overall survival (OS) of 6.0months vs. 1.8months for patients in the P-gp‒ subgroup (p = 0.01). PD analyses revealed 90-95% inhibition of blast P-gp function during Zos infusion. Treatment related toxicities were observed and resolved with decrease or discontinued Zos or GO dosages. Zos plus GO elicited appreciable ORR for an elderly patient population with RR AML. The greater OS of the P-gp + subgroup vs. the P-gp‒ subgroup suggests that patients with P-gp + leukemic blasts were being more effectively targeted by GO with Zos co-therapy. The poorer OS of the P-gp‒ subgroup suggests activity of Zos-insensitive multidrug resistant mechanisms. NCT00233909; First posted October 06, 2005.

Analgesic Effects of Magnesium Sulphate as an Adjuvant to Fentanyl for Monitored Anaesthesia Care During Hysteroscopy.

Magnesium sulphate (MgSO4) is conventionally used in the treatment of eclampsia, refractive arrhythmias, asthma, etc. In our study, we aimed to study the analgesic effects of MgSO4 as an adjuvant to fentanyl and reduce the intraoperative opioid requirement to decrease their adverse effects. A total of 122 patients scheduled for hysteroscopy were randomly divided into two groups. Patients in the magnesium group (group A) received intravenous MgSO4 50 mg/kg in 100 ml of isotonic saline over 15 minutes before anaesthesia induction and then 15 mg/kg per hour by continuous intravenous infusion. Patients in the control group (group B) received an equal volume of isotonic saline as a placebo. All the patients were induced with fentanyl and propofol. Perioperative haemodynamic monitoring and postoperative assessment of pain were done. Only 18% of the patients in group A required rescue analgesics as compared to 39.3% of patients in group B. The patients receiving MgSO4 displayed lower verbal numeric rating scale scores in the postoperative period. In addition, the intraoperative requirement of fentanyl (101 (21.33) vs. 144 (28.4) µg, mean (SD)) and propofol (121 (13.3) vs. 140 (16.5) mg, mean (SD)) was significantly lower in group A as compared to that in group B. MgSO4, when administered as an adjuvant to opioids, provided effective postoperative analgesia thereby reducing the need for rescue analgesics. It also decreases intraoperative fentanyl consumption and its dose-related side effects.