Start Of Infusion Research Articles

Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies.

Adenosine inhibits the activation of most immune cells and platelets. Selective adenosine A2A receptor (A2AR) agonists such as regadenoson (RA) reduce inflammation in most tissues, including lungs injured by hypoxia, ischemia, transplantation, or sickle cell anemia, principally by suppressing the activation of invariant natural killer T (iNKT) cells. The anti-inflammatory effects of RA are magnified in injured tissues due to induction in immune cells of A2ARs and ecto-enzymes CD39 and CD73 that convert ATP to adenosine in the extracellular space. Here we describe the results of a five patient study designed to evaluate RA safety and to seek evidence of reduced cytokine storm in hospitalized COVID-19 patients. Five COVID-19 patients requiring supplemental oxygen but not intubation (WHO stages 4-5) were infused IV with a loading RA dose of 5 μg/kg/h for 0.5 h followed by a maintenance dose of 1.44 μg/kg/h for 6 hours, Vital signs and arterial oxygen saturation were recorded, and blood samples were collected before, during and after RA infusion for analysis of CRP, D-dimer, circulating iNKT cell activation state and plasma levels of 13 proinflammatory cytokines. RA was devoid of serious side effects, and within 24 hours from the start of infusion was associated with increased oxygen saturation (93.8 ± 0.58 vs 96.6 ± 1.08%, P<0.05), decreased D-dimer (754 ± 17 vs 518 ± 98 ng/ml, P<0.05), and a trend toward decreased CRP (3.80 ± 1.40 vs 1.98 ± 0.74 mg/dL, P = 0.075). Circulating iNKT cells, but not conventional T cells, were highly activated in COVID-19 patients (65% vs 5% CD69+). RA infusion for 30 minutes reduced iNKT cell activation by 50% (P<0.01). RA infusion for 30 minutes did not influence plasma cytokines, but infusion for 4.5 or 24 hours reduced levels of 11 of 13 proinflammatory cytokines. In separate mouse studies, subcutaneous RA infusion from Alzet minipumps at 1.44 μg/kg/h increased 10-day survival of SARS-CoV-2-infected K18-hACE2 mice from 10 to 40% (P<0.001). Infused RA is safe and produces rapid anti-inflammatory effects mediated by A2A adenosine receptors on iNKT cells and possibly in part by A2ARs on other immune cells and platelets. We speculate that iNKT cells are activated by release of injury-induced glycolipid antigens and/or alarmins such as IL-33 derived from virally infected type II epithelial cells which in turn activate iNKT cells and secondarily other immune cells. Adenosine released from hypoxic tissues, or RA infused as an anti-inflammatory agent decrease proinflammatory cytokines and may be useful for treating cytokine storm in patients with Covid-19 or other inflammatory lung diseases or trauma.

Comparative study between dexmedetomidine and fentanyl as adjuvants to bupivacaine for postoperative epidural analgesia in abdominal surgeries: A randomized controlled trial

ABSTRACT Background Epidural analgesia is an efficient strategy to relieve postoperative pain after abdominal surgeries. This study aimed to evaluate dexmedetomidine or fentanyl when added to bupivacaine, providing postoperative epidural analgesia after abdominal procedures. Patients and methods Epidural catheter was placed on 75 patients scheduled for lower abdominal procedures under general anesthesia, and they were randomly assigned into three equal groups. Epidural analgesia was activated before the procedure was completed by injection of bupivacaine (0.125%) plus dexmedetomidine or fentanyl or normal saline mixture, according to the study groups. After complete recovery from general anesthesia, the epidural block was evaluated. Then, the infusion started through an elastomeric pump with an infusion rate of 5 ml/hr and continued for 24 hr postoperatively. Group D Dexmedetomidine 1 ml (100 μg) plus normal saline 1 ml were added to bupivacaine (0.125%) 48 ml (a total volume of 50 ml). Group F: 2 ml (100 μg) fentanyl was added to bupivacaine (0.125%) 48 ml (a total volume of 50 ml). Group C: Normal saline 2 ml was added to bupivacaine (0.125%) 48 ml (a total volume of 50 ml). Measured outcomes Primary outcomes The onset of sensory analgesia (from the beginning of epidural infusion until scoring 1 on a 3-point scale) and the duration of analgesia (from the start of epidural infusion till the first demand for further pain medication) were observed and recorded. Secondary outcomes Postoperative pain was evaluated using a visual analogue scale (VAS), and the number of patients requesting additional analgesia with pethidine over paracetamol as well as the pethidine consumption during postoperative 24 hr were recorded. The hemodynamic parameters, including heart rate (HR) and mean arterial blood pressure (MAP), were monitored and recorded at baseline, 2, 6, 12, and 24 hr, and any adverse events were properly recorded and managed during the study period. Results The dexmedetomidine group showed an earlier onset and longer duration of analgesia, with a highly significant difference (P-value <0.001) than other groups. The study groups differed significantly concerning pethidine needs and consumption (P-value <0.05). The VAS revealed a considerable decrease in the dexmedetomidine group compared to other groups, with a significant difference (P-value <0.05) at the intervals of (baseline, 12 hr, and 24 hr) and a highly significant difference (P-value <0.001) at the intervals of (2 and 6 hr). Postoperative blood pressure and heart rate measurements in the dexmedetomidine group were lower than in other groups. MAP showed a statistically highly significant difference at 6 and 24 hr (P-value <0.001) and a significant difference after 12 hr (P-value <0.05), while HR showed a statistically significant difference after 6 hr (P-value <0.05) and a highly significant difference at 12 and 24 hr (P-value <0.001). Regarding postoperative adverse events, no statistical difference was detected between groups except in pruritis and dry mouth. Conclusion Dexmedetomidine is preferred to fentanyl when added to epidural bupivacaine to relieve pain after abdominal procedures.

Improving door-to-reperfusion time in acute ischemic stroke during the COVID-19 pandemic: experience from a public comprehensive stroke center in Brazil.

The global COVID-19 pandemic has had a devastating effect on global health, resulting in a strain on healthcare services worldwide. The faster a patient with acute ischemic stroke (AIS) receives reperfusion treatment, the greater the odds of a good functional outcome. To maintain the time-dependent processes in acute stroke care, strategies to reorganize infrastructure and optimize human and medical resources were needed. Data from AIS patients who received thrombolytic therapy were prospectively assessed in the emergency department (ED) of Hospital de Clínicas de Porto Alegre from 2019 to 2021. Treatment times for each stage were measured, and the reasons for a delay in receiving thrombolytic therapy were evaluated. A total of 256 patients received thrombolytic therapy during this period. Patients who arrived by the emergency medical service (EMS) had a lower median door-to-needle time (DNT). In the multivariable analysis, the independent predictors of DNT >60 min were previous atrial fibrillation (OR 7) and receiving thrombolysis in the ED (OR 9). The majority of patients had more than one reason for treatment delay. The main reasons were as follows: delay in starting the CT scan, delay in the decision-making process after the CT scan, and delay in reducing blood pressure. Several actions were implemented during the study period. The most important factor that contributed to a decrease in DNT was starting the bolus and continuous infusion of tPA on the CT scan table (decreased the median DNT from 74 to 52, DNT ≤ 60 min in 67% of patients treated at radiology service vs. 24% of patients treated in the ED). The DNT decreased from 78 min to 66 min in 2020 and 57 min in 2021 (p = 0.01). Acute stroke care continued to be a priority despite the COVID-19 pandemic. The implementation of a thrombolytic bolus and the start of continuous infusion on the CT scan table was the main factor that contributed to the reduction of DNT. Continuous monitoring of service times is essential for improving the quality of the stroke center and achieving better functional outcomes for patients.

Slope until reaching the plateau: a new predictor of valve response obtained by lumbar infusion test for idiopathic normal pressure hydrocephalus.

Diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is based on clinical, radiological, and hydrodynamic data of cerebrospinal fluid (CSF) obtained by invasive methods such as lumbar infusion test, which is used to determine the resistance to CSF outflow (Rout). However, Rout has limitations, and its value as predictor of valve response is questioned. Other variables can be obtained by lumbar infusion test, such as the time to reach the plateau (TRP) and the slope until reaching the plateau (SRP). The objectives were to determine if SRP could be a predictor of response to ventriculoperitoneal shunt (VPS) and what variable (Rout versus SRP) would have greater predictive value. Patients with probable iNPH who underwent a lumbar infusion test and were indicated for a VPS were retrospectively studied. Two groups were established, responders and non-responders. Rout, TRP (period between the start of infusion until reaching the plateau measured in seconds) and SRP ((plateau pressure-opening pressure)/TRP) were obtained. For Rout and SRP, the receiver operating curves (ROC) with its areas under the curve (AUC) were calculated. One hundred ten patients were included, being 86 responders (78.20%). Shunt responders had a significantly greater Rout (17.02 (14.45-20.23) versus 13.34 (12.10-16.28) mmHg/ml/min, p = 0.002) and SRP (0.049 (0.043-0.054) versus 0.031 (0.026-0.036) mmHg/sec, p < 0.001) and smaller TRP (641.28 (584.83-697.73) versus 777.65 (654.03-901.27) sec, p = 0.028) than non-responders. The AUC for SRP was greater than the AUC for Rout (0.763 (95 % CI 0.655-0.871, p < 0.001) versus 0.673 (95 % CI 0.595-0.801, p = 0.008), respectively), but the differences were not significant (p = 0.180). SRP could be considered predictor of response to VPS, and its accuracy tends to be better than Rout. So, this variable may be a useful tool to select shunt candidates among patients with probable iNPH.

Pharmacokinetics of SPR206 in Plasma, Pulmonary Epithelial Lining Fluid, and Alveolar Macrophages following Intravenous Administration to Healthy Adult Subjects.

SPR206 is a next-generation polymyxin being developed for the treatment of multidrug-resistant (MDR) Gram-negative infections. This Phase 1 bronchoalveolar lavage (BAL) study was conducted to evaluate SPR206's safety and pharmacokinetics in plasma, pulmonary epithelial lining fluid (ELF), and alveolar macrophages (AM) in healthy volunteers. Subjects received a 100 mg intravenous (IV) dose of SPR206 infused over 1 h every 8 h for 3 consecutive doses. Each subject underwent 1 bronchoscopy with BAL at 2, 3, 4, 6, or 8 h after the start of the third IV infusion. SPR206 concentrations in plasma, BAL, and cell pellet were measured with a validated LC-MS/MS assay. Thirty-four subjects completed the study and 30 completed bronchoscopies. Mean SPR206 peak concentrations (Cmax) in plasma, ELF, and AM were 4395.0, 735.5, and 860.6 ng/mL, respectively. Mean area under the concentration-time curve (AUC0-8) for SPR206 in plasma, ELF, and AM was 20120.7, 4859.8, and 6026.4 ng*h/mL, respectively. The mean ELF to unbound plasma concentration ratio was 0.264, and mean AM to unbound plasma concentration ratio was 0.328. Mean SPR206 concentrations in ELF achieved lung exposures above the MIC for target Gram-negative pathogens for the entire 8-h dosing interval. Overall, SPR206 was well tolerated; 22 subjects (64.7%) reported at least 1 treatment-emergent adverse event (TEAE). Of the 40 reported TEAEs, 34 (85.0%) were reported as mild in severity. The most frequent TEAEs were oral paresthesia (10 subjects [29.4%]) and nausea (2 subjects [5.9%]). This study demonstrates pulmonary penetration of SPR206 and supports further development of SPR206 for the treatment of patients with serious infections caused by MDR Gram-negative pathogens.

#3589 OXALATE METABOLISM IN PRIMARY HYPEROXALURIA TYPE 1 TREATED WITH LUMASIRAN IMMEDIATELY AFTER BIRTH: STILL NOT EARLY ENOUGH

Abstract Background and Aims Severe primary hyperoxaluria type 1 (PH1) with rapid onset nephrocalcinosis and renal function loss in early infancy required so far combined liver and kidney transplant. RNA interfering drugs are the new challenge for these children. Here we present the first case of a newborn affected by PH1 treated with RNA-interfering Lumasiran 6 hours after birth. Method Diagnosis of PH1 (homozygous mutation AGXT c.731T&amp;gt;C9 [p.Ile244Thr]) was done at 11 weeks of pregnancy on chorionic villus due to family history. Parents are first cousins, both heterozygous carriers of the mutation. Their first child is homozygous, affected by PH1, in dialysis for massive nephrocalcinosis since two months of life, kidney-liver transplanted at 14 months, with multiple comorbidities, severe retinal oxalate deposition, early ischemic stroke and post-transplant lympho-proliferative disease. Mother blood Oxalate, Glycolate and Urinary Oxalate during pregnancy proved normal (3 umol/L and 4 umol/L; 35 umol/mmol). Fetal morphology at ultrasound was normal, showing a male fetus large for gestational age, due to gestational diabetes, and polyhydramnios. At 37w cesarean section was performed. Birth weight 4120 g; Length 49.9 cm (99° centile for gestational age). Apgar score 9/9. Cord blood and amniotic fluid were obtained for Oxalate dosage and Sanger sequencing for diagnosis confirmation. Umbilical central venous line and bladder catheter were placed for immediate start of infusions and serial sampling. Results PH1 was confirmed due to Homozygous mutation AGXT c.731T&amp;gt;C9 [p.(Ile244Thr)]. Oxalate on cord blood was 15 umol/L (nv &amp;lt;10), on amniotic fluid 55 umol/L (nv 19-71), on first urine 401 umol/mmolCr (nv &amp;lt; 300 umol/mmolCr). Blood Oxalate at 6h of life rose to 32 umol/L, Glycolate to 107 umol/L and urinary Oxalate to 573 umol/mmolCr. Serum Creatinin was normal (0.3 mg/dl). At 6 hours of life the child was treated with Glycolate Oxidase RNAi Lumasiran at the dose 6 mg/kg subcutaneously, in combination with Pyridoxin 10 mg/kg/day. Hyperhydration (240 ml/kg/day) was maintained iv for 16 days in combination with oral water and potassium citrate (500 mg in 500 ml/day) above breast feeding. Blood Oxalate was serially assessed every 48 hrs showing a peak level of 108 umol/l (nv &amp;lt;10) at day 6, higher than the supersaturation level of 60 umol/L, then a gradual decline (65-56-62 umol/L at 10-20-30 days respectively). Lumasiran 6 mg/kd was repeated at 30 and 60 days according to schedule, then at 3 mg/kg every month. After the second dose of Lumasiran a steeper decline of blood Oxalate was observed (31-17 umol/L at 45-60 days respectively) reaching the upper normal limit of 12 umol/L after three doses, at 80 days. Urinary Oxalate in spite of Lumasiran early start rose until a maximum of 4173 umol/mmolCr (nv for age &amp;lt;300 umol/mmolCr) at 13 days and gradually declined to 765 umol/mmolCr at 80 days, after three doses. Blood and urine Glycolate initially paralleled Oxalate then increased after each Lumasiran dose. Renal ultrasound normal at birth, showed only minimal hyperechogenic spots during the first 2 months, then mild bilateral hyperechogenic papillary deposits without signs of nephrocalcinosis/stones. Renal function at 3 months of life is normal (serum Creatinine 0.2 mg/dl); child growth on the higher centiles (7 kg), with no adverse events. Conclusion Blood and urine Oxalate serial analysis in a severe case of PH1 treated immediately after birth show that Glycolate Oxidase inhibition has a latency of at least 15 days, even when no previous deposits are present. In these days extremely high level of urine and blood Oxalate, far higher than supersaturation level, are reached, in spite of normal renal function, hyperhydration, B6 and citrate supplementation. This case confirms that familiar severe forms of PH1 should be treated immediately after birth with Lumasiran in combination with aggressive supportive therapy to avoid irreversible nephrocalcinosis and renal failure. Prenatal treatment of these cases might be considered in future.

Reducing infusion center wait times in a resource-limited setting.

6567 Background: Time toxicity is increasingly recognized as an important factor in quality of life in cancer patients, and this effect may be amplified in under-resourced oncology settings. In the safety-net oncology center at Parkland Health (PH), wait time from infusion appointment check-in to treatment start was 147 minutes in June 2022, which led to significant patient frustration, delays in care, and staff dissatisfaction. We aimed to decrease wait time by 20% by December 2022. Methods: Baseline wait time data for patients getting infusions in the oncology infusion center was collected daily from the electronic medical record (EMR) time stamps of check in and infusion start (first IV medication given), and the average time was calculated. A value stream map detailing the steps required to start infusion with time stamps was produced. Stakeholders were queried to identify causes of delay, an Ishikawa diagram was constructed, and a priority matrix was developed to determine the most impactful interventions. The first PDSA cycle (July-Oct 2023) intervention consisted of working group formation and implementation of separate infusion pathway for patients getting injections (“fast track”). The second PDSA cycle (Nov-Dec 2023) intervention was rescheduling infusion-only patients to the least congested times of the day to relieve the bottleneck that occurred in the late mornings for patients with labs or provider visit prior to infusion. Patients and infusion center providers were surveyed about their perception of wait times. Results: Average wait times decreased from 147 minutes to 131 minutes during first PDSA cycle, a 10.8% improvement from baseline. From Nov-Dec 2023 during second PDSA cycle, wait time improved to 127 minutes, a 15.7% improvement from baseline. The average daily number of infusions and injections increased from 106/day baseline to 115/day by Dec 2023; an increase of 8.5%. Qualitative surveys of patients and infusion providers endorsed increased satisfaction with infusion process. Conclusions: Using established quality improvement methods, we improved average wait times for Parkland Health oncology infusion patients by 15.7% over a 6 month period. While we did not meet our goal, we increased daily capacity to treat patients by 8.5% while improving overall infusion wait time. We also improved perceptions of quality of care.

Early therapeutic effects of an Angiopoietin-1 mimetic peptide in middle-aged rats with vascular dementia.

Vascular Dementia (VaD) refers to dementia caused by cerebrovascular disease and/or reduced blood flow to the brain and is the second most common form of dementia after Alzheimer's disease. We previously found that in middle-aged rats subjected to a multiple microinfarction (MMI) model of VaD, treatment with AV-001, a Tie2 receptor agonist, significantly improves short-term memory, long-term memory, as well as improves preference for social novelty compared to control MMI rats. In this study, we tested the early therapeutic effects of AV-001 on inflammation and glymphatic function in rats subjected to VaD. Male, middle-aged Wistar rats (10-12 m), subjected to MMI, were randomly assigned to MMI and MMI + AV-001 treatment groups. A sham group was included as reference group. MMI was induced by injecting 800 ± 200, 70-100 μm sized, cholesterol crystals into the internal carotid artery. Animals were treated with AV-001 (1 μg/Kg, i.p.) once daily starting at 24 h after MMI. At 14 days after MMI, inflammatory factor expression was evaluated in cerebrospinal fluid (CSF) and brain. Immunostaining was used to evaluate white matter integrity, perivascular space (PVS) and perivascular Aquaporin-4 (AQP4) expression in the brain. An additional set of rats were prepared to test glymphatic function. At 14 days after MMI, 50 μL of 1% Tetramethylrhodamine (3 kD) and FITC conjugated dextran (500 kD) at 1:1 ratio were injected into the CSF. Rats (4-6/group/time point) were sacrificed at 30 min, 3 h, and 6 h from the start of tracer infusion, and brain coronal sections were imaged using a Laser scanning confocal microscope to evaluate tracer intensities in the brain. Treatment of MMI with AV-001 significantly improves white matter integrity in the corpus callosum at 14 days after MMI. MMI induces significant dilation of the PVS, reduces AQP4 expression and impairs glymphatic function compared to Sham rats. AV-001 treatment significantly reduces PVS, increases perivascular AQP4 expression and improves glymphatic function compared to MMI rats. MMI significantly increases, while AV-001 significantly decreases the expression of inflammatory factors (tumor necrosis factor-α (TNF-α), chemokine ligand 9) and anti-angiogenic factors (endostatin, plasminogen activator inhibitor-1, P-selectin) in CSF. MMI significantly increases, while AV-001 significantly reduces brain tissue expression of endostatin, thrombin, TNF-α, PAI-1, CXCL9, and interleukin-6 (IL-6). AV-001 treatment of MMI significantly reduces PVS dilation and increases perivascular AQP4 expression which may contribute to improved glymphatic function compared to MMI rats. AV-001 treatment significantly reduces inflammatory factor expression in the CSF and brain which may contribute to AV-001 treatment induced improvement in white matter integrity and cognitive function.

The effect of Lu AG09222 on PACAP38- and VIP-induced vasodilation, heart rate increase, and headache in healthy subjects: an interventional, randomized, double-blind, parallel-group, placebo-controlled study

BackgroundPituitary adenylate cyclase-activating polypeptide (PACAP), structurally related to vasoactive intestinal peptide (VIP), is one of the important mediators in the pathogenesis of migraine and is known to dilate cranial arteries and induce headache and migraine. Our objective was to determine whether Lu AG09222—an investigational humanized monoclonal antibody directed against PACAP ligand—would inhibit the PACAP-signaling cascade by abolishing its vasodilatory and headache-inducing abilities.MethodsIn a randomized, double-blind, parallel-group, single-dose, placebo-controlled study of Lu AG09222, healthy volunteers aged 18–45 years without history of headache disorders were randomly allocated to three treatment sequences (1:2:2) on two experimental infusion visits with 9 ± 3 days’ interval: placebo + saline + saline (n = 5), placebo + PACAP38 + VIP (n = 10), and Lu AG09222 + PACAP38 + VIP (n = 10). The primary outcome measure was area under the curve (AUC) of the change in superficial temporal artery (STA) diameter from 0 to 120 min after start of infusion of PACAP38. The study was conducted at the Danish Headache Center in Copenhagen, Denmark.ResultsIn participants who received Lu AG09222 + PACAP38 infusion, there was a significantly lower STA diameter (mean (SE) [95% CI] AUC ‒35.4 (4.32) [‒44.6, ‒26.3] mm × min; P < 0.0001) compared to participants who received placebo + PACAP38 infusion. Secondary and explorative analysis revealed that PACAP38 infusion induced an increase in facial blood flow, heart rate and mild headache, and indicated that these PACAP38-induced responses were inhibited by Lu AG09222.ConclusionsThis proof-of-mechanism study demonstrated that Lu AG09222 inhibited PACAP38-induced cephalic vasodilation and increases in heart rate, and reduced concomitant headache. Lu AG09222 may be a potential therapy against migraine and other PACAP-mediated diseases.Trial registrationClinicalTrials.gov: NCT04976309. Registration date: July 19, 2021.Graphical

Efficacy of early intrauterine balloon tamponade for immediate postpartum hemorrhage after vaginal delivery: a randomized clinical trial

Many questions remain about the appropriate use of intrauterine balloon devices in postpartum hemorrhage after vaginal delivery refractory to first-line uterotonics. Available data suggest that early use of intrauterine balloon tamponade might be beneficial. This study aimed to compare the effect of intrauterine balloon tamponade used in combination with second-line uterotonics vs intrauterine balloon tamponade used after the failure of second-line uterotonic treatment on the rate of severe postpartum hemorrhage in women with postpartum hemorrhage after vaginal delivery refractory to first-line uterotonics. This multicenter, randomized, controlled, parallel-group, nonblinded trial was conducted at 18 hospitals and enrolled 403 women who had just given birth vaginally at 35 to 42 weeks of gestation. The inclusion criteria were a postpartum hemorrhage refractory to first-line uterotonics (oxytocin) and requiring a second-line uterotonic treatment with sulprostone (E1 prostaglandin). In the study group, the sulprostone infusion was combined with intrauterine tamponade by an ebb balloon performed within 15 minutes of randomization. In the control group, the sulprostone infusion was started alone within 15 minutes of randomization, and if bleeding persisted 30 minutes after the start of sulprostone infusion, intrauterine tamponade using the ebb balloon was performed. In both groups, if the bleeding persisted 30 minutes after the insertion of the balloon, an emergency radiological or surgical invasive procedure was performed. The primary outcome was the proportion of women who either received ≥3 units of packed red blood cells or had a calculated peripartum blood loss of >1000 mL. The prespecified secondary outcomes were the proportions of women who had a calculated blood loss of ≥1500 mL, any transfusion, an invasive procedure and women who were transferred to the intensive care unit. The analysis of the primary outcome with the triangular test was performed sequentially throughout the trial period. At the eighth interim analysis, the independent data monitoring committee concluded that the incidence of the primary outcome did not differ between the 2 groups and stopped inclusions. After 11 women were excluded because they met an exclusion criterion or withdrew their consent, 199 and 193 women remained in the study and control groups, respectively, for the intention-to-treat analysis. The women's baseline characteristics were similar in both groups. Peripartum hematocrit level change, which was needed for the calculation of the primary outcome, was missing for 4 women in the study group and 2 women in the control group. The primary outcome occurred in 131 of 195 women (67.2%) in the study group and 142 of 191 women (74.3%) in the control group (risk ratio, 0.90; 95% confidence interval, 0.79-1.03). The groups did not differ substantially for rates of calculated peripartum blood loss pf ≥1500 mL, any transfusion, invasive procedure, and admission to an intensive care unit. Endometritis occurred in 5 women (2.7%) in the study group and none in the control group (P=.06). The early use of intrauterine balloon tamponade did not reduce the incidence of severe postpartum hemorrhage compared with its use after the failure of second-line uterotonic treatment and before recourse to invasive procedures.

High versus low frequency transcutaneous acupoint electrical stimulation as an adjunct therapy to prevent nausea and vomiting in the first 24 hours after infusion of high-grade emetic chemotherapy: A randomized controlled trial

Background: Transcutaneous acupoint electrical stimulation (TAES) has been tested as antiemetic therapy. Objective: Evaluation of the effectiveness of two different frequencies of the electrical current as adjunctive therapy in the prevention of nausea and vomiting. Methods: This placebo-controlled clinical trial compared the incidence of nausea and vomiting (within the first 24 hours after high-grade emetic chemotherapy infusion) of 61 women (54 ± 11 years) with breast cancer undergoing three modes of TAES: high frequency (HF:150 Hz), low frequency (LF:10 Hz), and placebo (P). Electrodes were fixed at the acupuncture point PC6 and a symmetric bipolar current (pulse width 200 μs) was applied in a single 30-minute session prior to the start of chemotherapy infusion. All patients receive fixed antiemetic treatment infusions (ondansetron 8 mg) and rescue medication instructions, if necessary, according to the routine for infusions of cyclophosphamide associated with anthracycline. Results: The incidence of nausea was 47% in P, 45% in HF and 26% in LF. Although not significant, the intervention with LF-TAES at PC6 acupoint reached relevant values in reducing the relative risk of developing nausea (RR = 0.51; CI 95% = 0.18 to 1.44; p = 0.18) and a trend toward improved reported well-being (p = 0.06) and a lower Edmonton Symptom Rating Scale score (p = 0.08). The incidence of vomiting and the consumption of rescue antiemetic doses were very similar between the groups. Conclusion: New studies with LF and HF of TAES as adjuvant therapy for the prevention of nausea and vomiting should be carried out to confirm this hypothesis.

A Case of Kounis Syndrome Caused by Anaphylaxis During Surgery

Kounis syndrome is a hypersensitivity coronary disorder associated with several triggers, such as drugs, foods, environmental, coronary stents and other factors. It was originally proposed by the Greek cardiologist Nicholas Kounis in 1991. Kounis syndrome is a life-threatening and challenging emergency disease, which is constantly being recognized and studied. It is a disease that is constantly being recognized and Kounis syndrome can be classified into three types, involving coronary artery spasm, plaque rupture or stent thrombosis respectively. Most patients with coronary artery spasm caused by allergies can recover completely after active treatment, and the prognosis is good. If not, it may cause severe myocardial damage and even myocardial infarction, which threatens the patient's life. In our case, a 56-year-old female patient was scheduled to undergo right pelvic resection. A few minutes after the start of intravenous succinylated gelatin infusion, she was experienced a decrease in heart rate, blood pressure, oxygen saturation and ST elevation on 2-lead. An anaphylactic reaction was suspected after rapid differential diagnosis and gradually recovered with treatment. In this context, a rapid differential diagnosis and a highly suspicious become essential, because the management of Kounis syndrome is different from the traditional acute coronary syndrome. Kounis syndrome requires simultaneous diagnosis and treatment of both allergic reaction and acute coronary syndrome based on their manifestations and risk factors. This case describes the onset, development, and recovery of Kounis syndrome in this patient in detail, and illustrates the classification, pathophysiology, and treatment of Kounis syndrome. It is hoped that through the management of this case, the occurrence of Kounis syndrome can be rapidly identified and treated accordingly so that avoiding disaster for patients.

Comparison of Hemodynamic Effects of Dobutamine and Ephedrine Infusions in Isoflurane-Anesthetized Horses.

The objective of this study was to compare the hemodynamic effects of dobutamine and ephedrine during the management of anesthesia-related hypotension in healthy horses. Thirteen horses underwent general anesthesia with isoflurane and were randomly divided into two different groups, one of which received a dobutamine constant rate infusion (CRI) (1 µg/kg bwt/min) and the other received an ephedrine CRI (20 µg/kg bwt/min) when hypotension (<60 mmHg) was identified, following up to 15 min after the blood pressure reached 70 mmHg. All horses were equipped with a pulmonary artery catheter and a peripheral artery catheter, and multiparameter monitoring commenced as soon as they were under mechanical ventilation. Hemodynamic parameters were recorded, while tissue perfusion markers (peripheral oxygen saturation, arterial oxygen partial pressure, arterial carbon dioxide partial pressure, arterial pH, arterial plasma bicarbonate concentration, arterial oxygen saturation, mixed venous oxygen saturation, mixed venous oxygen content, arterial oxygen content, arteriovenous oxygen difference, oxygen delivery index, oxygen consumption index, and oxygen extraction ratio), serum lactate concentration, and troponin I concentrations were analyzed before the start of infusions (T0), when the blood pressure reached 70 mmHg (T1), and 15 min after T1 (T2). The time to restore the arterial pressure was similar in both groups (p > 0.05); however, the heart rate was higher in the ephedrine group (p = 0.0098), and sinus bradyarrhythmia occurred in the dobutamine group. Furthermore, both experimental protocols increased cardiac output (p = 0.0012), cardiac index (p = 0.0013), systemic vascular resistance (p = 0.008), systemic vascular resistance index (p < 0.001), and ameliorated perfusion markers. In the dobutamine group, the pulmonary artery wedge pressure (p < 0.001) and systolic index (p = 0.003) were elevated, while the arteriovenous oxygen difference was reduced in the ephedrine group (p = 0.02). Troponin I was used as a myocardial injury indicator, and did not differ between moments or between groups (p > 0.05). We concluded that both drugs were effective and safe to treat anesthetic hypotension under the conditions of this study.

Impact of institutional interventions on the rate of paclitaxel hypersensitivity reactions.

Paclitaxel is associated with hypersensitivity reactions (HSRs). Intravenous premedication regimens have been devised to decrease the incidence and severity of HSRs. At our institution oral histamine 1 receptor antagonists (H1RA) and histamine 2 receptor antagonists (H2RA) were adopted as standard. Standardizations were implemented for consistent premedication use in all disease states. The purpose of this retrospective study was to compare the incidence and severity of HSRs before and after standardization. Patients who received paclitaxel from 20 April 2018 to 8 December 2020 having an HSR were included in analysis. An infusion was flagged for review if a rescue medication was administered after the start of the paclitaxel infusion. The incidences of all HSR prior to and post-standardization were compared. A subgroup analysis of patients receiving paclitaxel for the first and second time was performed. There were 3499infusions in the pre-standardization group and 1159infusions in the post-standardization group. After review, 100 HSRs pre-standardization and 38 HSRs post-standardization were confirmed reactions. The rate of overall HSRs was 2.9% in the pre-standardization group and 3.3% in the post-standardization group (p = 0.48). HSRs, during the first and second doses of paclitaxel, occurred in 10.2% of the pre-standardization and 8.5% of the post-standardization group (p = 0.55). This retrospective interventional study demonstrated that same-day intravenous dexamethasone, oral H1RA, and oral H2RA are safe premedication regimens for paclitaxel. No change in the severity of reactions was seen. Overall, better adherence to premedication administration was seen post-standardization.

Abstract 4533: Serum protein changes in patients with desmoid tumors responsive to the TBL1 inhibitor, tegavivint

Abstract Background: A Phase 1/2 clinical trial (NCT03459469) of the small molecule tegavivint in patients with desmoid tumors (DTs), demonstrated drug safety and tolerability with evidence of clinical activity. Transducin Beta-Like Protein 1 (TBL1) is a necessary co-activator for beta-catenin’s oncogenic activity. Wnt-activation promotes formation of a TBL1: beta-catenin complex that protects β-catenin from degradation in the nucleus and promotes Wnt-target gene activation. Tegavivint binds TBL1 preventing the interaction with beta-catenin, which results in nuclear beta-catenin degradation and inhibition of downstream transcription. For patients whose desmoid tumors responded to tegavivint we assayed changes in serum-based proteins, selected based on their cancer-related function and dysregulation by aberrant Wnt/beta-catenin signaling, to potentially identify suitable biomarkers that may be useful in future studies. Methods: Whole blood and tumor tissue was collected from desmoid patients before and after administration of tegavivint at dose levels ranging from 1 to 5 mg/kg administered via a 4-hour intravenous (IV) infusion on days 1, 8, and 15 of a 28-day cycle. Collection timepoints were pre-dose and up 1 week (wk.) following the start of the infusion. Secreted protein levels were profiled in the serum using Luminex multiplex technology. Changes in protein levels were compared to the tegavivint pharmacokinetic (PK) profiles. Tissue samples were analyzed for gene expression changes. Results: Preliminary analyses demonstrated that the majority of tegavivint treated patients with an objective response to tegavivint showed a consistent and expected pattern in serum levels of known Wnt/beta-catenin regulated proteins. Decreases in levels of DKK1, FGF-2, MMP-1, PDGF-AA and VEGF-A and an increase in CCL5 levels were observed. In treated patient serum, protein level changes were detected as early as 2 hours (h) following the start of infusion and continued to progress in the predicted direction at 24 h. At the 5 mg/kg dose, all selected biomarkers remained decreased (or in the case of CCL5, increased) during the dosing interval, with a tegavivint half-life of 48.6 h and Cmin (trough value) 1 wk. post treatment above in vitro IC50 values. Gene expression changes were found in tumor tissue in comparing pre- to post-tegavivint treatment. Conclusion: A panel of beta-catenin regulated proteins and transcripts were identified as candidate pharmacodynamic biomarkers in patients whose desmoid tumor responded to tegavivint. Alterations in these serum proteins continued throughout the dosing interval and, for several proteins, a potential dose response correlation was observed. Further characterization of the relationship between tegavivint plasma levels, serum biomarkers, transcriptional changes and clinical responses in additional patients and time points will be presented. Citation Format: Stephen Horrigan, Kimberly R. Holloway, David Stenehjem, Casey Cunningham. Serum protein changes in patients with desmoid tumors responsive to the TBL1 inhibitor, tegavivint. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4533.

Early vasopressin infusion improves oxygenation in infants with congenital diaphragmatic hernia.

Congenital Diaphragmatic Hernia (CDH) is a complex disease including a diaphragmatic defect, lung hypoplasia, and pulmonary hypertension. Despite its increasing use in neonates, the literature on the use of vasopressin in neonates is limited. The aim of this work is to analyze the changes in clinical and hemodynamic variables in a cohort of CDH infants treated with vasopressin. Among CDH infants managed at the Neonatal Intensive Care Unit (NICU) of our hospital from May 2014 to January 2019, all infants who were treated with vasopressin, because of systemic hypotension and pulmonary hypertension, were enrolled in this retrospective study. The primary outcome was the change in oxygenation index (OI) after the start of the infusion of vasopressin. The secondary outcomes were the changes in cerebral andsplanchnic fractional tissue oxygen extraction (FTOEc and FTOEs) at near-infrared spectroscopy, to understand the balance between oxygen supply and tissue oxygen consumption after the start of vasopressin infusion. We also reported as secondary outcomes the changes in ratio of arterial oxygen partial pressure (PaO2) to fraction of inspired oxygen (FiO2), heart rate, mean arterial pressure, serum pH, and serum sodium. We included 27 patients with isolated CDH who received vasopressin administration. OI dramatically dropped when vasopressin infusion started, with a significant reduction according to ANOVA for repeated measures (p = 0.003). A global significant improvement in FTOEc and FTOEs was detected (p = 0.009 and p = 0.004, respectively) as a significant reduction in heart rate (p = 0.019). A global significant improvement in PaO2/FiO2 ratio was observed (p < 0.001) and also at all time points: at 6 h since infusion (p = 0.015), 12 h (p = 0.009), and 24 h (p = 0.006), respectively. A significant reduction in sodium levels was observed as expected side effect (p = 0.012). No significant changes were observed in the remaining outcomes. Our data suggest that starting early vasopressin infusion in CDH infants with pulmonary hypertension could improve oxygenation index and near-infrared spectroscopy after 12 and 24 h of infusion. These pilot data represent a background for planning future larger randomized trials to evaluate the efficacy and safety of vasopressin for the CDH population.

Влияние гексанового экстракта Serenoa repens на функцию мочевого пузыря при частичной инфравезикальной обструкции.

Introduction. It is believed that the «target» of the hexane extract of Serenoa repens (HESR) is the prostate gland itself. However, there is evidence in the literature that the therapeutic effect of HESR can be carried out at the level of the bladder. We hypothesized about the direct effect of HESR on the obstructive bladder, preventing the development of its dysfunction. Material and methods. The study was conducted on 30 white mongrel female rats. Bladder outlet obstruction (BOO) was modeled by applying a ligature to the urethra on 18G catheter. The animals were divided into groups: experimental – HESR (n = 10); sham/placebo (n = 15) and control (n = 5). From the day following the operation, rats of the experimental series daily received aqueous alcohol suspension of HESR (27.6 mg/kg) intragastrically through a probe, and the sham group received the same volume of 3.5% alcohol solution. After 2 weeks, the survival rate of the animals, the functional state of the bladder, daily diuresis, biochemical changes in blood and urine characterizing the functional state of the kidneys were evaluated. Bladder function was assessed according to infusion cystometry. After examination, the animals were euthanized and the bladders was removed to determine its mass and histological examination. Results. Within 2 weeks in the sham group 10 (67%) rats died due to renal failure, while in the HESR group – only 3 (30%). An obvious overfilling of the bladder in the main and sham groups was revealed. Bladder volume was larger in the HESR group compared to the sham (p&lt;0.05) one. The daily diuresis of the animals of the main group was also higher compared to the sham group, and the decrease in diuresis in the sham group was lower compared to the control (p=0.045). The functional state of the bladder was assessed by filling cystometry. In the sham group, an increase in intravesical pressure occurred immediately after the start of fluid infusion and its growth was accompanied by irregular fluctuations, which is a manifestation of secondary detrusor hyperactivity, while in the HESR group, a gradual increase in pressure without fluctuations up to large volumes of fluid was observed. The dynamics of the volume/pressure index in the main group was close to normal, which indicates better compliance of the wall of the hypertrophied bladder during HESR therapy. The use of HESR contributed to better preservation of kidney function. In terms of daily diuresis, glomerular filtration rate, tubular reabsorption of sodium, daily excretion of urea and creatinine in the urine, statistically significant differences were established between the main and sham groups. In the sham group, a more pronounced activity of creatine phosphokinase was noted compared to the HESR group (p&lt;0.05), which indicates a significant damage to kidney and bladder cells (cytolysis) during BOO. Animals of both groups showed pronounced detrusor hypertrophy. If in the sham group the mass of the bladder exceeded the average value of the control group by 5.7 times, then in the HESR group it was 10.5 times. Histological studies confirmed the development of bladder hypertrophy, which was statistically significantly more pronounced in the HESR group: an increase in the thickness of the detrusor (p&lt;0.001) and bladder wall (p&lt;0.05). At the same time, the area of perimuscular sclerosis foci was significantly larger in the sham group (p&lt;0.05), which indicates bladder decompensation. Thickening of the bladder wall also occurred due to the submucosal layer, which was more noticeable in the sham series (p&lt;0.05) and was associated with the presence of edema, inflammatory infiltrates, and sclerosis in this area. In half of the cases of the sham series, de-epithelialized areas of the bladder mucosa were observed, while in the HESR group they were absent. In the experimental series, in all samples, a pronounced expansion of the vessels of the submucosal layer was noted. At the same time, if in the experimental group inflammatory infiltration was detected only within the submucosal layer, then in half of the cases of the sham series, diffuse infiltration of the entire bladder wall was detected. Conclusion. In BOO detrusor hypertrophy, the use of HESR contributes to the better preservation of the functional parameters of the bladder (compliance and evacuation ability), reduces the degree of inflammation and sclerosis of the bladder wall, prevents the development of decompensation of the bladder and, thereby, contributes to the preservation of kidney function. A significant decrease in the frequency of development and the degree of detrusor hyperactivity against HESR makes it possible to think about it’s direct effect on the smooth muscle cells of the bladder wall and/or on the way of regulating their contractile activity. The mechanisms of the HESR effects on the BOO bladder are currently unclear. This is probably of a complex nature, where the anti-inflammatory effects of Serenoa Repens are expected to play a primary role.

Eucalcemia during lipopolysaccharide challenge in postpartum dairy cows: I. Clinical, inflammatory, and metabolic response

Hypocalcemia induced by immune activation is a conserved response across mammalian species; however, administration of Ca is discouraged in other species as it is associated with increased morbidity and mortality. Early postpartum cows experience a decrease in circulating Ca concentration following acute inflammation. Corrective Ca therapy during the transition period, particularly in dairy cows experiencing acute disease, is common practice. However, the effect of Ca administration on the inflammatory response during acute immune activation is unknown. Our objective was to compare the clinical, inflammatory, and metabolic response to an intravenous (IV) lipopolysaccharide (LPS) challenge between postpartum cows infused, or not, with IV Ca to maintain eucalcemia. Cows (n = 14, 8 ± 1 d in milk) were enrolled in a matched-pair randomized controlled design to receive IV Ca (IVCa) or sterile 0.9% NaCl (CTRL) during an IV LPS challenge (0.040 or 0.045 µg of LPS/kg of body weight over 1 h). Ionized Ca (iCa) was monitored cow-side, and IV Ca infusion was adjusted in a eucalcemic clamp for 12 h following the start of LPS infusion. Cows were monitored during the 24 h following challenge and serial blood samples were collected to quantify concentrations of glucose, β-hydroxybutyrate, nonesterified fatty acids, urea nitrogen, cytokines, acute-phase proteins, and cortisol. Blood iCa concentration decreased to 0.87 ± 0.03 mM in CTRL during challenge, and by design, iCa concentration was maintained within 3% of baseline in IVCa. Body temperature, heart rate, and respiratory rate were monitored for 24 h following the start of challenge and did not differ between groups. A treatment × time interaction was identified such that serum cortisol concentrations increased in both groups at 2 h but decreased to a greater extent at 6 h in IVCa compared with CTRL. Rumination time (min/h) over the first 12 h following challenge was greater in IVCa, but total rumination time in the 24 h following challenge did not differ from CTRL. Serum glucose and nonesterified fatty acid concentrations decreased, and β-hydroxybutyrate and urea nitrogen concentrations increased over time, but did not differ between groups. Acute leukopenia occurred in both groups at 4 h before leukocytosis was observed at 24 h with total white blood cell counts returning to baseline within 72 h. Plasma concentrations of tumor necrosis factor (TNF) and interleukin-10 (IL-10) increased within 1 h following the start of challenge and did not differ between groups. Serum haptoglobin and serum amyloid A concentrations increased within the 24 h following challenge and were elevated through 72 h but did not differ between groups. Eucalcemia during the acute systemic inflammatory response did not alter the TNF or IL-10 cytokine response, or the acute-phase protein SAA and haptoglobin response in this LPS challenge model; however, eucalcemia was associated with a more rapid decline in cortisol response and greater rumination time in the first 12 h following challenge. We did not find evidence that eucalcemia exacerbated the inflammatory response in early postpartum cows, but Ca administration may alter the clinical response to acute systemic inflammation.

Intestinal Synthesis and Lymphatic Secretion of Apolipoprotein A–IV Vary with Chain Length of Intestinally Infused Fatty Acids in Rats

To evaluate the hypothesis that stimulation of intestinal apolipoprotein (apo) A–IV by dietary fat depends upon assembly and transport of chylomicrons, we examined the effect of duodenal infusion of fatty acids of graded chain length on mucosal synthesis and lymphatic output of lipid and apo A–IV. Rats with duodenal cannulas and mesenteric lymph fistulas were given 8-h duodenal infusions of lipid emulsions containing either butyric (4:0), caprylic (8:0), lauric (12:0), myristic (14:0), stearic (18:0), oleic (18:1), linoleic (18:2) or arachidonic (20:4) acids, or tributyrin, tricaprylin or triolein. Lymph outputs of triglyceride, phospholipid and apo A–IV were measured at 0, 2, 4, 5, 6, 7 and 8 h after the start of lipid infusion. Significant increases in lymph lipid (triglyceride, phospholipid) and apo A–IV output were observed in response to long-chain fatty acids (14:0, 18:0, 18:1, 18:2, 20:4) or triolein; short- or medium-chain fatty acids (4:0, 8:0, 12:0) or tributyrin or tricaprylin produced no significant increase in lymph lipid output above basal levels. Similarly, increased jejunal mucosal synthesis of apo A–IV was observed in response to duodenal infusion of oleic acid but not butyric or caprylic acid. These results provide direct support for the hypothesis that stimulation of apo A–IV by dietary fat depends upon transport of absorbed lipid via chylomicrons in lymph.

The Effect of BMI on Pharmacokinetic and Pharmacodynamic Parameters of Insulin Degludec: Results from an Euglycemic Glucose Clamp Study.

This study evaluated the effect of body mass index (BMI) on pharmacokinetic (PK) and pharmacodynamic (PD) parameters of insulin degludec in healthy Chinese males, depending on an euglycemic glucose clamp study. Sixty-five healthy male subjects were divided into four groups according to quartile of BMI value. Group A: BMI ≤ 20.7 kg/m2; group B: 20.7 < BMI ≤ 22.5 kg/m2; group C: 22.5 < BMI ≤ 23.6 kg/m2; group D: BMI > 23.6 kg/m2. Each volunteer received a single subcutaneous dose (0.4 U/kg) of insulin degludec and accepted a 24-h euglycemic glucose clamp study. The primary PK parameters were maximum observed drug concentration (Cmax) and the area under the curve (AUCINS) for the specified time intervals. The primary PD parameters were the time to the start of glucose infusion (Tonset), maximal glucose infusion rate (GIRmax) and area under the curve (AUCGIR) for the specified time intervals. The differences of these PK/PD parameters were compared among groups. Cmax and the AUC of insulin (0-6 h, 6-12 h and 0-24 h) were more than onefold higher in group A than those in groups B, C, D, and the concentration-time curve of group A was significantly shifted to the left compared with the other three groups. The GIRmax, total AUCGIR, and AUCGIR for each time interval were significantly higher in group A than those in other three groups. The proportion of AUCGIR in group A was the lowest proportion among four groups seen in the late stage. Multiple linear regression analysis showed that BMI was negatively correlated with AUCGIR,0-24 h. Insulin degludec in healthy Chinese male subjects with BMI ≤ 20.7 kg/m2 had a faster absorption, clearance, and a stronger glucose-lowering effect, but a steeper decrease of insulin action in the late stage after dosing.