Drug Infusion Research Articles

Anaesthesia for paediatric radiotherapy: A narrative review.

Radiotherapy is currently used in approximately one-third of children with cancer. Treatments are typically received as weekday outpatient appointments over 3-6 weeks. The treatment is painless but requires a still, co-operative patient who can lie alone in set positions, facilitated by the use of immobilisation devices, for up to 1 h. We conducted a literature search to identify relevant articles relating to radiotherapy treatment. Key search terms included: 'radiotherapy'; 'proton beam'; 'photon'; 'sedation'; 'anaesthesia'; and 'paediatric'. The abstracts of identified articles were assessed for relevance and their references reviewed for further relevant publications. The requirement for anaesthesia is almost exclusively limited to younger children, who are committed to daily anaesthetics over the duration of their treatment course. Centres tend to adopt a primary anaesthetic technique of either general anaesthesia using a supraglottic airway device or deep sedation, with spontaneous ventilation maintained. A full variety of anaesthetic drugs has been used with insufficient evidence to support a standardised primary approach but an apparent global trend towards propofol by infusion for sedation. Children may become acutely unwell during their treatment course and systems for escalation of clinical care in this event are vital. Distance from the patient for staff radiation shielding, patient positioning for treatment delivery and the use of immobilisation devices may provide additional access challenges in the event of an emergency. The requirement for anaesthesia for paediatric radiotherapy is typically confined to younger children. Patients may be unwell, with several specific considerations related to their cancer diagnosis and the impact of various treatments including surgery and chemotherapy, in addition to the radiotherapy. A multidisciplinary team approach to all aspects of care is imperative in this group of high-risk patients.

Using Implementation Science to Assess Barriers to Agreement on Sedation Goal Setting and Assessment.

Sedation assessment and goal setting using a validated assessment tool are key components of the ICU Liberation bundle. Appropriate integration of these bundle elements into daily practice remains challenging. Understanding barriers is an important step toward implementation of these best practice bundle elements. Two-phased explanatory mixed methods assessment carried out 2022-2023. Forty-bed quaternary PICU. Bedside nurses and prescribers caring for mechanically ventilated patients on sedative infusions. None. Forty-one nurses and 32 prescribers participated in the phase 1 pre-education assessments (2022). We identified lack of correlation between the providers' stated State Behavioral Scale (SBS) numerical goal and descriptive goal and hypothesized that this discrepancy was either due to a knowledge gap or disagreement on sedation goals. To investigate this hypothesis, we performed a phase 2 assessment (2022-2023), starting with a multipronged educational activity, followed by a repeat survey that included a qualitative interview. One hundred ninety nurses and 45 prescribers received the educational activity. Twenty-eight nurses and 22 prescribers participated in the phase 2 assessments with the qualitative interview. Although correlation of the sedation goal between providers improved, it remained poor. Subsequent qualitative interview data indicated that the reasons for persistent disagreement in the sedation goal for a given patient were related to individual providers' beliefs and attitudes toward sedation, rather than lack of understanding about using the SBS to set a target sedation goal. Barriers to setting and managing daily patient sedation goal in the PICU extend beyond providers' knowledge gaps. An improved understanding of underlying barriers is essential for successful implementation of evidence-based sedation guidelines.

Elimination of High-grade Gliomas Through Induced Cytolysis, Elucidated by Two Patient Cases.

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary malignant tumors in the central nervous system of adults. In practice, all patients with GBM experience relapse, and treatment options become limited following first-line therapy. We previously reported a new, successful treatment approach for a GBM patient, implemented in direct conjunction with surgical intervention. Here, we present an additional case demonstrating the success of this protocol, along with an overview of its underlying rationale and mechanisms. Following maximal safe tumor resection, our protocol involves the placement of two catheters in the tumor excision bed, connected to drug infusion pumps for continuous administration. The tumor's excision beds are irrigated for 90-120 hours with a slightly alkaline Tris-buffered solution containing L-2,4 diaminobutyric acid, an unnatural amino acid, and Prazosin, a proapoptotic drug widely used as an antihypertensive. Both patients demonstrated marked clinical improvement. Recent contrast-enhanced magnetic resonance imaging revealed no evidence of malignancy, with Case 1 remaining disease-free for seven years and Case 2 for two years of follow-up. This innovative approach not only enhances local drug delivery but also minimizes systemic side effects, addressing a critical challenge in GBM treatment. These cases highlight the potential of this protocol as an adjunct to standard therapies, offering a promising option for managing inoperable or recurrent GBM.

Artificial intelligence in anesthesiology: a bibliometric analysis

AbstractThe application of artificial intelligence (AI) in anesthesiology has become increasingly widespread. However, no previous study has analyzed this field from the bibliometric analysis dimension. The objective of this paper was to assess the global research trends in AI in anesthesiology using bibliometric software. Literatures relevant to AI and anesthesiology were retrieved from the Web of Science until 10 April 2024 and were visualized and analyzed using Excel, CiteSpace, and VOSviewer. After screening, 491 studies were included in the final bibliometric analysis. The growth rate of publications, countries, institutions, authors, journals, literature co-citations, and keyword co-occurrences was computed. The number of publications increased annually since 2018, with the most significant contributions from the USA, China, and England. The top 3 institutions were Yuan Ze University, National Taiwan University, and Brunel University London. The top three journals were Anesthesia & Analgesia, BMC Anesthesiology, and the British Journal of Anaesthesia. The researches on the application of AI in predicting hypotension have been extensive and represented a hotspot and frontier. In terms of keyword co-occurrence cluster analysis, keywords were categorized into four clusters: ultrasound-guided regional anesthesia, postoperative pain and airway management, prediction, depth of anesthesia (DoA), and intraoperative drug infusion. This analysis provides a systematic analysis on the literature regarding the AI-related research in the field of anesthesiology, which may help researchers and anesthesiologists better understand the research trend of anesthesia-related AI.

Reduction of postoperative pain and opioid consumption by VVZ-149, first-in-class analgesic molecule: A confirmatory phase 3 trial of laparoscopic colectomy.

VVZ-149 is a small molecule that inhibits the glycine transporter type 2 and the serotonin receptor 5-hydroxytryptamine 2A. In this Phase 3 study, we investigated the efficacy and safety of VVZ-149 as a single-use injectable analgesic for treating moderate to severe postoperative pain after laparoscopic colectomy. Randomized, parallel group, double-blind, Phase 3 clinical trial (Trial no. NCT05764525). 5 tertiary referral centers in South Korea. 284 patients undergoing laparoscopic colectomy. A continuous 10-h intravenous infusion of VVZ-149 (n=141) or placebo (n=143) administered after emergence from anesthesia. Pain intensity was assessed using a numeric rating scale (NRS) from the start of infusion for 48h. The primary efficacy measure was the Sum of Pain Intensity Difference (SPID) for the first 12h after the start of drug infusion. Other efficacy measures included SPID at other time points, opioid consumption via on-demand patient-controlled analgesia (PCA) and rescue medication, and proportion of patients who did not require rescue opioids for 48h post-dose. Pain relief as measured by SPID was significantly improved by 35% in the VVZ-149 group compared to the placebo group at 6h (p=0.0193) and 12h (p=0.0047) after the start of infusion. Significantly lower pain intensity scores were observed between 4-10h in the VVZ-149 group compared to the placebo group (p=0.0007), reaching mild pain (mean NRS <4) at 8h. VVZ-149 alleviated pain during the first 12h post-dose with 30.8% less opioid consumption and 60.2% fewer PCA requests when compared with placebo. A higher proportion of patients receiving VVZ-149 were rescue opioid-free during 2-6h (p=0.0026) and 6-12h (p=0.0024) compared with the placebo group. VVZ-149 administration in post-colectomy patients was generally safe and well tolerated. When compared to placebo, VVZ-149 infusion demonstrated a significant reduction of pain within the first 12h after surgery with a substantial decrease in opioid use. VVZ-149 rapidly lowers the pain intensity starting at as early as 4h post-dose, allowing subjects to experience mild pain levels from 8h through 48h. Therefore, the analgesic effect of VVZ-149 was shown to effectively relieve pain and reduce opioid use for treating moderate to severe pain in the early postoperative care setting. Trial Number NCT05764525.

First-in-Human Phase I Clinical Trial of the Adenosine A1R/A3R Agonist AST-004 in Healthy Subjects.

AST-004 is a small-molecule adenosine A1/A3 receptor agonist that has exhibited significant cerebroprotective efficacy in preclinical models of acute ischemic stroke and traumatic brain injury. The primary objectives of this clinical phase I first-in-human study were to evaluate the safety and tolerability profile of single ascending intravenous doses in healthy subjects. The secondary objectives were to characterize the single-dose pharmacokinetic profiles in plasma, cerebrospinal fluid (CSF), and urine. In part 1 of the study, AST-004 was administered in ascending dose cohorts of 5, 25, 50, 75, and 100 mg, with 6 subjects in each cohort receiving the study drug and 2 receiving placebo. In part 2, all 12 subjects received a 100 mg IV infusion of the study drug followed by a single CSF collection per subject via lumbar puncture at 20, 40, or 60 minutes after infusion. A total of 42 subjects received AST-004, with no severe or serious adverse events observed. Twelve of these subjects experienced a treatment-emergent adverse event, the most frequent across groups being headache. In part 2, pharmacokinetic analyses confirmed that AST-004 was distributed in the CSF, with the CSF-to-plasma ratio increasing over the 3 timepoints sampled. The mean half-life was 1.1 to 1.4 hours for doses of 25 to 100 mg, and the geometric mean maximum plasma concentration obtained in the highest dosing cohort (100 mg) was 2232±428 ng/mL. AST-004 was safe and well-tolerated at plasma concentrations 3 to 8× higher than those associated with significant efficacy in astrocyte's preclinical primate stroke efficacy studies, with CSF concentrations highest at the 60-minute collection timepoint, the last timepoint tested. This study supports additional clinical investigations, including evaluation of an extended infusion to support the phase 2 program in stroke and traumatic brain injury.

Successive Infusion of Parenteral Drugs: Negligent Supervision of Treatments of a Medical Team and Principle of Reliance

Successive Infusion of Parenteral Drugs: Negligent Supervision of Treatments of a Medical Team and Principle of Reliance

Successive Infusion of Parenteral Drugs: The Violation of Warning on Drug Label

Successive Infusion of Parenteral Drugs: The Violation of Warning on Drug Label

Inflammatory Markers Significantly Increased in Patients Treated with Obinotuzumab for Lymphoproliferative Diseases.

Background: The purpose of this study was to analyze the behaviors of inflammatory markers, such as procalcitonin and C-reactive protein (CRP), during treatment with obinotuzumab (an anti-CD20 antibody). Methods: Our non-randomized observational study prospectively evaluated a cohort of 22 adult patients with lymphoproliferative neoplasms, chronic lymphocytic leukemia (CLL), and follicular lymphoma (FL) with indications for obinotuzumab therapy. Results: All patients had their blood drawn to determine blood counts, CRP, and procalcitonin, as well as body temperature measurements and blood cultures performed for bacterial infections on day 0 before administration of the anti-CD20 antibody. Subsequently, on days 1 to 7 after administration, blood was drawn daily at a fixed time of 8:00 a.m. for blood counts and CRP and PCT values, and blood cultures were performed. In addition, on days 1 to 7, body temperature was measured at fixed times (i.e., 8:00 a.m. and 8:00 p.m.). In all of these patients, significant increases in inflammatory markers, such as CRP and procalcitonin, were observed shortly after drug infusion. There was a statistically significant change in the serum PCT concentration (p < 0.0001), which significantly increased on days 1 to 4 compared to the initial measurement 0. Conclusions: The increases in inflammatory markers shortly after obinotuzumab (anti-CD20 antibody) administration can be significantly high but are most often not related to the onset of infection and do not lead to any ill consequences in the treatment of lymphoproliferative disease.

Dexmedetomidine versus propofol for postoperative recovery after cardiac surgery: a historical cohort study.

The impact of postoperative dexmedetomidine sedation on outcomes following cardiac surgery remains controversial. We sought to compare postoperative sedation techniques with dexmedetomidine vs propofol infusions on postoperative recovery outcomes following cardiac surgery to assess whether dexmedetomidine is associated with longer time to achieve recovery milestones. In this historical cohort study, we abstracted the electronic medical records of a convenience sample of cardiac surgery patients either receiving dexmedetomidine (0.5-1.5µg·kg-1·hr-1) or propofol (5-80µg·kg-1·min-1) infusions for postoperative sedation. The study period included time periods where the standard postoperative sedation practice included dexmedetomidine (March 2019-January 2022) or propofol (January 2022-June 2022) infusions. Measured outcomes for both groups included time to tracheal extubation and intensive care unit and hospital length of stay. Two thousand and sixty-five patients receiving dexmedetomidine and 510 patients receiving propofol were included. Postoperative sedation after cardiac surgery with dexmedetomidine was associated with a 1.8-hr longer time to tracheal extubation than propofol (98.3% confidence interval, 1.5 to 2.1; P < 0.001). Dexmedetomidine administration for postoperative sedation in a convenience sample of over 2,000 cardiac surgery patients was associated with a longer time to tracheal extubation than propofol.

Impact of hospital-physician vertical integration on physician-administered drug spending and utilization.

We estimate the effects of hospital-physician vertical integration on spending and utilization of physician-administered drugs for hematology-oncology, ophthalmology, and rheumatology. Using a 100% sample of Medicare fee-for-service medical claims from 2013 to 2017, we find that vertical integration shifts treatments away from physician offices and toward hospital outpatient departments. These shifts are accompanied by increases in physician-administered drug administration spending per procedure for all three specialties. Spending on Part B drugs also increasesfor hematologist-oncologists. At the same time, physician treatment intensity, as measured by the number of beneficiaries who receive drug infusions/injections and the number of drug infusions, decreases across all three specialties. These results suggest that the incentives of the Medicare reimbursement system, particularly site-of-care payment differentials and outpatient drugreimbursement rates, interact with vertical integration to lead to higher overall spending. Policies and merger guidelines should attempt to restrain spending increases attributed to vertical integration.

DDEL-06. CONVECTION-ENHANCED DELIVERY OF SEVEN DIFFERENT MOLECULES SHOW LARGE DIFFERENCES IN CONVECTIVE PROPERTIES BETWEEN MOLECULES. INFORMED DECISION MAKING FOR OPTIMIZED CATHETER PLACEMENT AND SUBSEQUENT INFUSION STRATEGIES

Abstract INTRODUCTION Glioblastoma (GBM) trials based on convection-enhanced drug delivery (CED) bypassing the blood-brain barrier have failed to prove efficient until now. Many factors influence CED. In this study we evaluated CED of seven different molecules using dynamic PET/MRI during infusion. This enabled in-depth evaluation of drug distribution and concentration gradients providing a more precise understanding of the Vd/Vi ratio and the extent of efficacy level across the Vd zone. Novel surgical catheter placement software algorithms, results in more informed-decision-making for catheter positioning and subsequent infusion planning strategies. METHODS Pigs were implanted with neuroinfuse™ drug delivery systems enabling intermittent drug infusions. Gadolinium, [124I]-UdR, [55Co]Co-DOTA-hEGF, [55Co]Co-DOTA-SP4, [18F]PSMA-1007 and three differently sized [64Cu]-labelled nanocarriers were evaluated in both pigs with and without a brain resection cavity. Gadolinium distribution was followed by MRI. PET imaging was used for the rest. To inform clinical trial design, strategic catheter placement and volumes to be infused, planning was investigated on several historical GBM cases. RESULTS Vd/Vi ratios ranged between 1.00 – 3.77. where large-sized liposomes performed best. Catheters stayed patent during weeks of repeated infusions. In the resected animals no leakage of drugs into the brain resection cavity was observed. Effective 3D modelling of novel catheter infusion planning aids provided visualized representations of tailor-made infusion plumes, capable of being suitably positioned to optimize surgical planning of catheters and transcutaneous reaccess port. CONCLUSION Large differences in convective properties between different molecules were observed. Large-sized liposomes as drug-carrier system showed superior performance to all other molecules. Vd/Vi ratios for promising drugs should be determined before initiating future clinical CED trials. Infusion concentration gradients to facilitate more precise Vd/Vi ratios provided important performance metrics for visualised infusion planning aids of a novel chronic drug delivery system, illustrating informed decision making for optimised catheter placement and subsequent infusion strategies is clinically translatable for GBM indications.

An In Vitro Platform for Pharmacokinetic Quantification and Optimization of Cerebrospinal Fluid Filtration and Drug Circulation

Abstract Modification of cerebrospinal fluid (CSF) transport dynamics is an expanding method for treating central nervous system injury and diseases. One application of this route is to modify the distribution of solutes in the CSF; however, few tools currently exist for this purpose. The present study describes the use of a subject-specific in vitro CSF phantom to perform a parametric evaluation of the Neurapheresis™ CSF Management System (NP) for both CSF filtration and intrathecal drug circulation. An in vitro CSF phantom was constructed which included realistic anatomy for the complete subarachnoid space (SAS). This platform was configured to test multiple parametric modifications of a dual-lumen catheter and filtration system. Calibrated mapping of tracer distribution and area under the curve (AUC) measurements were used to compare filtration and intrathecal-circulation schemes using the NP device versus the clinical standards of care. The NP device showed potential advantages over lumbar drain (LD) for clearance of simulated subarachnoid hemorrhage (SAH), especially in the spinal canal. Use of the NP device in combination with simulated intracerebroventricular (ICV) drug infusion resulted in an increased extent and uniformity of tracer spread compared to ICV alone. NP improved clearance of simulated subarachnoid hemorrhage compared to LD and increased uniformity of tracer concentration via simulated ICV, providing support for NP use in these scenarios. The in vitro CSF phantom system presented here quantitatively described the effects of parametric boundary modification on solute distribution in the intrathecal space.

Effect of Ketamine on the Bispectral Index, Spectral Edge Frequency, and Surgical Pleth Index During Propofol-Remifentanil Anesthesia: An Observational Prospective Trial.

Ketamine administration during stable propofol anesthesia is known to be associated with an increase in bispectral index (BIS) but a "deepening" in the level of hypnosis. This study aimed to evaluate the association between the effect-site concentration of ketamine (CeK) and 2 electroencephalogram (EEG)-derived parameters, the BIS and spectral edge frequency (SEF95), after the administration of a ketamine bolus. Secondary aims included investigating the BIS and SEF95 variations with time and changes in the surgical pleth index (SPI). We conducted an observational, prospective, single-center study analyzing intraoperative data from 14 adult female patients undergoing breast oncologic surgery. During stable propofol-remifentanil target-controlled infusion (TCI) anesthesia, a ketamine analgesic bolus was delivered with the target CeK set to 1 μg.mL-1 (Domino model) corresponding to a dose of 0.57 mg.kg-1 (interquartile range [IQR] 0.56-0.57 mg.kg-1). Once the CeK reached a value of 1 μg.mL-1, the target CeK was set to 0 μg.mL-1. We determined the median BIS, SEF95, and SPI trends with time and as a function of the modeled CeK. BIS and SEF95 showed no significant change from when ketamine was administered to when CeK=1 μg.mL-1, but a significant increase was observed at lower CeKs. The maximum BIS was reached at 16.0 minutes [10.2-22.7 minutes] after CeK=1 μg.mL-1, at CeK=0.22 μg.mL-1 [0.12-0.41 μg.mL-1]. The peak SEF95 value was observed at 10.0 minutes [8.62-14.1 minutes] after CeK=1 μg.mL-1, at CeK=0.43 μg.mL-1 [0.25-0.50 μg.mL-1]. No significant association was found between CeK and the registered SPI values. Our results show that BIS and SEF95, but not SPI, follow a CeK-dependent trend after administering a ketamine bolus. Interestingly, their peak values were not reached at CeK=1 μg.mL-1, but after several minutes after the drug infusion at CeKs in the 0.2 to 0.5 μg.mL-1 range. This may be explained by the specific pharmacodynamics of ketamine and its varying effects at different concentrations, as well as by the time delay associated with the calculation of the BIS.

Scalp cooling therapy for chemotherapy-induced hair loss in patients with breast or gynecological cancers-an Asian tertiary institution experience.

Scalp cooling therapy (SCT) improves chemotherapy-induced alopecia (CIA), but there are few published data about its efficacy in an Asian-predominant population. We report our tertiary institution experience of SCT in patients with breast or gynaecological cancers undergoing chemotherapy. The Paxman scalp cooling system was employed for eligible women with breast or gynaecological cancers receiving anthracycline or taxane-based chemotherapy. Only patients with Grade (G) 0-1 alopecia by common terminology criteria for adverse events (CTCAE) version 4.0 were eligible initially, but patients with G2 alopecia were later included in the study. SCT was performed at each chemotherapy cycle, commencing 30min prior to and continuing up to 90min after completion of the drug infusion. Patients were assessed at the start and end of each session for hair preservation (defined as G0-2 alopecia) and comfort level of SCT (rated on a 5-point visual scale). The primary end point was success of hair preservation or hair regrowth after completion of all cycles of chemotherapy. Eighty-three patients were enrolled over a period of 18months from December 2017 to October 2019, with a total of 510 scalp cooling cycles performed. 94.0% (n = 78) of patients reported a comfort score of 3 and above, indicating that the procedure was comfortable, upon a 5-point visual scale. Patients receiving weekly paclitaxel had highest success in hair preservation at 76.7% (23/30 patients), with a lower rate of hair preservation observed for the 3 weekly paclitaxel regimen (50%, 2/4 patients). In contrast, only 1 patient (5.3%, 1/19 patients) who underwent chemotherapy with anthracycline and cyclophosphamide achieved hair preservation. SCT is well tolerated in an Asian-predominant population. Among women with breast or gynaecological cancers receiving taxane and/or anthracycline based chemotherapy, those who underwent SCT were about 50% more likely to achieve hair preservation or hair regrowth, as compared to historical controls.

No benefit from the addition of low-dose ketamine infusion to standard evidence-based care of patients with multiple rib fractures.

Multiple rib fractures from blunt thoracic trauma cause significant morbidity. Optimal current management includes multimodal analgesia, pulmonary hygiene, and early mobilization. Low-dose ketamine infusion (LDKI) has been proposed as an adjunctive analgesic in this setting. A prior study reported decreased pain scores with LDKI in patients with multiple rib fractures. We hypothesized that LDKI would decrease morphine milligram equivalents (MMEs) in patients with multiple rib fractures. A prospective randomized placebo-controlled trial was performed in adult (18 years or older) patients with three or more rib fractures. A prestudy power analysis calculated an 80% chance of identifying a 15% decrease in MMEs with 50 subjects. The study was approved by the institutional review board and informed consent obtained in all subjects. Demographic (age, sex) and injury specific information (Injury Severity Score, number of rib fractures) were obtained. Subjects were randomized 1:1 to receive continuous LDKI (0.1 mg/kg/h) or placebo infusion (0.9% NaCl) for ≤48 hours. All patients received a standard evidence-based multidisciplinary protocol for rib fractures management. Primary outcome measure was MME use or pulmonary complications. Statistical comparison of LDKI versus placebo was performed using the Mann-Whitney U test. All 50 enrolled subjects (placebo, 25; LDKI, 25) received study drug infusion. The two groups were well matched for age, Injury Severity Score, and number of rib fractures. We observed no differences in the Day 1 (p = 0.961), Day 2 (p = 0.373), or total MMEs (p = 0.946) between groups. Similar total MME use was observed when subjects who received ≥40 hours of study drug and were compared (p = 0.924). Use of LDKI did not alter subsequent need for opiate analgesics postinfusion, hospital length of stay, pulmonary complications, or need for readmission. The addition of LDKI to an established multimodal, evidence-based protocol for management of multiple rib fractures did not decrease opiate usage or impact pulmonary complications. Therapeutic/Care Managaement; Level I.

Microdosing of alteplase leads to thrombolysis in an in vitro flow model of cardiac microvascular obstruction

Abstract Background Cardiac microvascular obstruction (MVO) is a frequent injury of the myocardial microcirculation after successful recanalisation of the occluded coronary artery in myocardial infarction. At least in part, MVO is caused by embolised microthrombi of less than 200 µm diameter [1]. MVO leads to hypoperfusion of the myocardium and negatively affects patient outcomes. However, there is no effective treatment for MVO [2, 3]. Thrombolytic drugs are a promising approach, but they are difficult to deliver to the MVO area, and an increased risk of bleeding limits their use. In a previous study using an in vitro fluidic multi-scale model for MVO [4, 5], it was shown that controlled flow infusion (CFI) with a novel drug-delivering catheter could be used to effectively deliver highly concentrated intracoronary microdoses of a thrombolytic drug to the MVO area [6]. We now aim to investigate how such locally administered drug microdoses can induce thrombolysis as a possible therapeutic approach for MVO treatment. Methods A microfluidic chip (Fig.1) was used to study thrombolysis under flow using different microdoses of the thrombolytic drug alteplase. The chip consists of a tapered straight channel, which traps injected porcine microthrombi without causing complete channel occlusion (Fig. 1A). To mimic intracoronary CFI (consisting of temporary balloon occlusion of a coronary vessel for 90 seconds while drug is injected distally through a catheter) in vitro, microthrombi were incubated (without flow) directly in the chip for 90 seconds with various microdoses of alteplase (Fig. 2A, C). The chip was subsequently perfused with porcine plasma for 25 min (matched for physiological shear stress of 30 dyn/cm²). Conventional intravenous (IV) drug infusion (10 mg dose) resulting in a low systemic alteplase concentration, was mimicked by perfusing microthrombi with porcine plasma containing 2 µg/ml alteplase (Fig. 2B, C). Results Thrombolysis after CFI was concentration dependent, with the lowest microdose (0.3 mg) achieving 24% lysis of the thrombus area and the highest microdose (1.5 mg) achieving 60% lysis. In contrast, conventional IV drug infusion (corresponding to 10 mg alteplase IV dose) only achieved 10% lysis and was not significantly higher than the control perfused with pure porcine plasma. Conclusion Our findings suggest that intracoronary CFI is more efficient at achieving porcine microthrombus lysis than the current standard of IV bolus infusion (2 µg/ml alteplase in the circulating blood). Intracoronary CFI microdosing of fibrinolytic drugs using a drug-delivering catheter is a promising therapeutic approach for treating embolising MVO with a reduced systemic drug burden. Importantly, our intracoronary CFI approach achieves locally 6–40 times higher drug concentrations than a conventional IV drug infusion while reducing the total drug dose 60–300 times (Fig. 2C).

Ex vivo evaluation of the whole heart function allowing selective investigation of the right and left heart

Objectives. The aim was to demonstrate a reliable ex vivo method to test the function of the whole heart. Design. Pigs of varying sizes (44–80 kg) were exposed to dose response of adrenaline. Blood pressures and cardiac output were measured. The explanted hearts were tested in a novel ex vivo system to see if we could replicate the in vivo values at maximal adrenaline stimulation. The perfusion solution was STEEN Solution™ with erythrocytes and continuous infusion of essential drugs. In contrast to normal body circulation which is sequential, the heart evaluation system is divided into left and right heart circuits which are operating in parallel, making it possible to test the right and left heart individually or as a whole. The system provides coronary flow measurements. The nonlinear dynamic resistances are constructed to stabilize systolic and diastolic pressures in a broad range and independently from cardiac output. It is important for the functional evaluation to avoid pumping help for the heart; therefore, atrial vortexes are constructed to minimize pump flow directionality and energy from entering atria. Results. Ex vivo evaluation was able to match the maximal in vivo effect of adrenaline on cardiac output and blood pressures. After 2 h of evaluation, the blood gases and lactate were normal and free haemoglobin was zero. Autopsy of the hearts showed no macroscopic pathology. Conclusions. The system is able to give a reliable functional evaluation of the heart ex vivo.

Risk factors for central line-associated bloodstream infection in the pediatric intensive care setting despite standard prevention measures.

Identify risk factors for central line-associated bloodstream infections (CLABSI) in pediatric intensive care settings in an era with high focus on prevention measures. Matched, case-control study. Quaternary children's hospital. Cases had a CLABSI during an intensive care unit (ICU) stay between January 1, 2015 and December 31, 2020. Controls were matched 4:1 by ICU and admission date and did not develop a CLABSI. Multivariable, mixed-effects logistic regression. 129 cases were matched to 516 controls. Central venous catheter (CVC) maintenance bundle compliance was >70%. Independent CLABSI risk factors included administration of continuous non-opioid sedative (adjusted odds ratio (aOR) 2.96, 95% CI [1.16, 7.52], P = 0.023), number of days with one or more CVC in place (aOR 1.42 per 10 days [1.16, 1.74], P = 0.001), and the combination of a chronic CVC with administration of parenteral nutrition (aOR 4.82 [1.38, 16.9], P = 0.014). Variables independently associated with lower odds of CLABSI included CVC location in an upper extremity (aOR 0.16 [0.05, 0.55], P = 0.004); non-tunneled CVC (aOR 0.17 [0.04, 0.63], P = 0.008); presence of an endotracheal tube (aOR 0.21 [0.08, 0.6], P = 0.004), Foley catheter (aOR 0.3 [0.13, 0.68], P = 0.004); transport to radiology (aOR 0.31 [0.1, 0.94], P = 0.039); continuous neuromuscular blockade (aOR 0.29 [0.1, 0.86], P = 0.025); and administration of histamine H2 blocking medications (aOR 0.17 [0.06, 0.48], P = 0.001). Pediatric intensive care patients with chronic CVCs receiving parenteral nutrition, those on non-opioid sedative infusions, and those with more central line days are at increased risk for CLABSI despite current prevention measures.

Chemical Profiling, Enzyme Inhibitory Activity and Antioxidant Capacity of South African Herbal Teas: Buddleja saligna, Lippia javanica, L. scaberrima and Phyla dulcis.

Herbal teas are used in South Africa as digestives to lower glycaemia and for other indications. However, the chemical composition of the infusions and their effect on enzymes related to metabolic syndrome is poorly known. The composition of infusions and methanol extracts of B. saligna (Scrophulariaceae), Lippia javanica, L. scaberrima, and Phyla dulcis (Verbenaceae) was assessed and the effect of the infusions and extract was determined towards α-glucosidase, α-amylase, and pancreatic lipase. The commercial herbal products were extracted separately with MeOH or hot water to obtain the extract/infusion for comparative studies. Total phenolic, total flavonoid and antioxidant capacity were assessed. The fingerprints of the MeOH extracts and infusions were compared by HPLD-DAD. The extract constituents were tentatively identified by HPLC-MS/MS and NMR analyses. From the extracts/infusions, 57 compounds were identified, including iridoids, phenylpropanoid glycosides, flavonoids, and caffeic acid derivatives, among others. The MeOH extracts and infusions showed strong inhibition towards α-glucosidase with IC50 in the range of 0.13-0.84 µg/mL for the phenolic-enriched infusion extract (PEI) and 0.47-0.50 µg/mL for the MeOH extracts, respectively. The P. dulcis PEI showed higher inhibition towards α-glucosidase, and the MeOH extract of L. scaberrima was better than the PEI. At 100 µg/mL, the PEI from the four herbal teas reduces the activity of α-amylase by 23.03-28.61%, with L. javanica as the most active tea. Three of the species are high in phenylpropanoid glycosides, while P. dulcis contains rosmarinic acid. Some 26 compounds were identified in the infusion from B. saligna, 28 from L. scaberrima, and 21 from P. dulcis. Four of them are common in all the teas, namely decaffeoylverbascoside, verbascoside, isoverbascoside, and tuberonic acid hexoside. Ten compounds occur in two of the teas and seventeen, fifteen, and eleven compounds were detected only in B. saligna, L. scaberrima, and P. dulcis, respectively. Most of the compounds are reported for the first time from the crude drug infusions. The results give some support for the traditional use of herbal teas as digestives and/or indications for diabetes. The chemical fingerprints set the basis for quality control of the crude drugs, based on the main constituents and differential compounds occurring in the samples.