RESUMEN

OBJECTIVE: This study compared the effects of norepinephrine or phenylephrine combined with restrictive infusion on the oxygenation during thoracoscopic one-lung ventilation (OLV). METHODS: Ninety patients were randomly divided into three groups: the norepinephrine group (Group N), the phenylephrine group (Group P), and the control group (Group C). Arterial partial pressure of oxygen (PaO2) and intrapulmonary shunt fraction (Qs/Qt) were measured with patients in lateral positions during two-lung ventilation (TLV) at 10 min (T1), and during OLV at 15 min (T2) and 45 min (T3). Lung tissue samples were analyzed for endothelin and COX-2 levels after surgery. RESULTS: At T3, Group P had significantly higher PaO2 and lower Qs/Qt than Groups N and C (all p < 0.05), with no significant differences between Groups N and C (all p > 0.05). Compared to T1, Groups N and C showed significantly lower PaO2 and higher Qs/Qt at T2 and T3 (all p < 0.05), with no significant differences in PaO2 and Qs/Qt at T3 compared with T2 (all p > 0.05). Group P patients had lower PaO2 and higher Qs/Qt at T2 and T3 compared to T1 (all p < 0.05), but at T3, PaO2 increased and Qs/Qt decreased compared to T2 (all p < 0.05). Lung tissue levels of endothelin and COX-2 were significantly elevated in group P compared to groups N and C (all p < 0.05). CONCLUSION: Combining phenylephrine with restrictive infusion during OLV improved oxygenation by increasing PaO2, decreasing Qs/Qt, and raising endothelin and COX-2 levels in lung tissue, thereby enhancing the HPV effect.

Phenylephrine with restrictive infusion improves oxygenation during one-lung ventilation by increasing PaO₂ and reducing Qs/Qt.The mechanism may involve the specific upregulation of pulmonary endothelin and cyclooxygenase-2 levels by phenylephrine, enhancing hypoxic pulmonary vasoconstriction.

RESUMEN

Stress has profound effects on health, yet how it damages tissues remains poorly understood. Here, we show that acute stress triggers rapid hair loss and initiates autoimmunity. Under stress, hyperactivated sympathetic nerves release excessive norepinephrine, causing necrosis in rapidly dividing hair follicle transit-amplifying cells (HF-TACs) while sparing most hair follicle stem cells (HFSCs). This differential sensitivity stems from differences in cell death pathways, metabolic strategies, and calcium homeostasis, which render HF-TACs more susceptible to norepinephrine-induced calcium surges. HF-TAC necrosis releases cellular debris that triggers macrophage-mediated clearance and dendritic cell activation, ultimately leading to the activation and amplification of autoreactive T cells that can attack the hair follicle under inflammatory insults. Our findings reveal mechanistically how stress causes immediate tissue damage in highly proliferative HF-TACs via sympathetic nerve-induced necrosis, which in turn fuels the activation of autoreactive T cells capable of mounting future attacks against the same tissue.

RESUMEN

The current drug delivery systems based on ferroptosis, which induce oxidative stress, are generally limited by the random generation and distribution of reactive oxygen species (ROS) without targeted delivery in the tumor microenvironment, resulting in unsatisfactory therapeutic outcomes. To address this issue, mitochondria were identified as ideal targets for anti-tumor treatment to enhance ROS attacks through the precise delivery of nanoagents. In this study, we developed a nanoagent named PNE-PEG-TPP-Fe by chelating triphenylphosphine (TPP)-modified polynorepinephrine (PNE) with Fe2 + . This nanoagent significantly enhanced ferroptosis of tumor cells by mitochondria targeting and increasing H2O2 concentration in mitochondria. Specifically, the lipophilic cationic TPP facilitates the nanoparticle translocation across both the cellular and mitochondrial membranes, enabling precise accumulation within the mitochondria. The PNE carrier can generate H2O2 and improve H2O2 level in mitochondria by catechol oxidation. Moreover, this nanoagent induces an excessive influx of Fe2+ into mitochondria, generating a substantial amount of ·OH by Fenton reaction, which can attack the mitochondrial membrane, disrupt the ferroptosis defense system in mitochondria, and enhance lipid peroxides generation and accumulation. This study underscores the potential benefits of selectively targeting mitochondria to enhance anti-cancer effects mediated by ferroptosis and has valuable prospect for anti-tumor therapies.

RESUMEN

Mannheimia haemolytica (Mh) is an opportunistic pathogen that causes pneumonic infections in different ruminants. It is also part of the respiratory tract microbiome, but it descends into the lower respiratory tract under stress, causing shipping fever. The stress hormones epinephrine and norepinephrine have been suggested to induce Mh biofilm dispersion, but their roles in virulence have not been shown. In this study, the effects of these two hormones on Mh growth and on the expression of adhesins, proteases, and biofilm formation are evaluated. Physiological concentrations (1-5 ng/mL) of epinephrine and norepinephrine increase the growth of Mh and the expression of 42- and 75-kDa gelatin proteases, induce biofilm dispersion, and decrease biofilm protein and carbohydrate concentrations. At 50 or 500 ng/mL concentrations of epinephrine and norepinephrine, the expression of OmpA and OmpH adhesins and 42- and 100-kDa casein proteases increases. Bacterial adhesion to bovine monocytes or oral epithelial cells also increases, but antibodies against OmpH and OmpA diminish adhesion. Our results strongly suggest that epinephrine and norepinephrine modulate the expression of Mh virulence factors.

RESUMEN

BACKGROUND: Ephedrine, phenylephrine, and norepinephrine are commonly used to manage hypotension during the induction of anaesthesia. The objective of this study was to evaluate whether prophylactic administration of assumed equipotent doses of these vasopressors could maintain systolic arterial blood pressure (SAP) and heart rate (HR) within 80% of baseline for the first 5 min following induction of anaesthesia. METHODS: This randomised, double-blind, dose-controlled study was conducted at the Day Surgery Unit of Haugesund Hospital, Norway. One hundred and twenty-eight healthy women scheduled for gynaecological surgery were randomly allocated in a 1:1:1:1 ratio to receive prophylactic administration of ephedrine (0.1 mg/kg), phenylephrine (1 µg/kg), norepinephrine (0.1 mg/kg), or placebo (sodium chloride 9 mg/mL) at a volume of 0.1 mL/kg. Anaesthesia was induced using target-controlled infusion (TCI) of propofol and remifentanil. The initial 2.5 min constituted a sedation phase, after which the targets of propofol and remifentanil were increased, and the assigned vasopressor was administered. Beat-to-beat haemodynamic monitoring was performed using the LiDCOplus system. The primary outcome variables were the maximal decrease in SAP and HR within 5 min following bolus administration. Secondary outcome measures included changes in stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR). RESULTS: The absolute changes in SAP (mean ± standard deviation) following vasopressor administration were -27 ± 8.9 (ephedrine), -40 ± 11 (phenylephrine), -41 ± 13 (norepinephrine), and -42 ± 10 (placebo) mmHg. The differences (95% confidence interval [CI]) in the maximal SAP change between placebo and the vasopressors were as follows: ephedrine, -15 (-22, -9.9) mmHg; phenylephrine, -2.3 (-8.8, 4.2) mmHg; and norepinephrine, -1.7 (-8.3, 4.9) mmHg. Relative reductions in SAP from baseline to minimum values were -20% for ephedrine, -30% for phenylephrine, -30% for norepinephrine, and -32% for placebo. The absolute changes (median, interquartile range) in HR with ephedrine, phenylephrine, norepinephrine, and placebo were -10 (-6.2 to -18), -19 (-17 to -26), -23 (-20 to -33), and -15 (-9.5 to -21) bpm, respectively. Relative changes from baseline to minimum values in HR were -17% for ephedrine, -30% for phenylephrine, -37% for norepinephrine, and -22% for placebo. The differences in SV change between groups were small. CO was best preserved with ephedrine (-22% ± 11%), while phenylephrine and norepinephrine were associated with greater reductions (-38% ± 7.8% and -42% ± 9.8%, respectively). SVR increased most markedly in the norepinephrine group, followed by phenylephrine, with the smallest increase observed in the ephedrine group. CONCLUSION: Prophylactic administration of ephedrine effectively maintained SAP, HR, and CO within the first 5 min following bolus injection at induction with propofol and remifentanil. In contrast, bolus administration of norepinephrine and phenylephrine demonstrated a short duration of action, with SAP comparable to placebo at 5 min. Based on these findings, prophylactic administration of a bolus ephedrine is recommended, whereas prophylactic phenylephrine or norepinephrine injections may not be clinically preferable for bolus use in this context. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03864094, March 6, 2019 This trial assessed circulatory responses to three different commonly used vasoactive support (vasopressor) drugs given as a single bolus together anesthetic induction propofol and remifentanil, and this in a cardiovascularly healthy adult surgical cohort. Results demonstrated that pharmacodynamic patterns with the three different test drugs, along with a no-prophylactic vasopressor comparitor. Findings showed a favorable profile for ephedrine compared to phenylephrine or noradrenaline if choosing to give a vasopressor in this way.

RESUMEN

Traumatic brain injury (TBI), as a significant central nervous system damage disease with high frequency in the world, leads to a huge number of patients with impaired health and lower quality of life every year. Lung injury is a common and dangerous consequence, which dramatically raises the mortality of patients. Discovering the pathophysiology of lung injury after TBI and discovering viable therapeutic targets has become an important need for clinical diagnosis and therapy. Neurotransmitters, as the fundamental chemical agents of the nervous system for signal transmission, not only govern neuronal activity and apoptosis in TBI but also significantly influence the pathophysiological mechanisms of lung injury subsequent to TBI. The imbalance is intricately linked to the onset and progression of lung damage. This paper systematically reviews the clinical characteristics and predominant pathogenesis of lung injury following TBI, emphasizing the role of key neurotransmitters, including glutamate (Glu), γ-aminobutyric acid (GABA), norepinephrine (NE), dopamine (DA), and acetylcholine (ACh), in lung injury post-TBI. It examines their influence on inflammatory response, vascular permeability, and pulmonary circulation function. Additionally, the paper evaluates the research advancements and potential applications of targeted therapeutic strategies for various neurotransmitter systems, such as receptor antagonists, transporter inhibitors, and neurotransmitter analogues. This research aims to offer a theoretical framework for clarifying the neural regulatory mechanisms of lung injury following TBI and to establish a basis for the development of novel therapeutic strategies and enhancement of the prognosis of the patients.

RESUMEN

Norepinephrine (NE) serves as a vital neurotransmitter, regulating various physiological and cognitive processes in the central nervous system. NE detection is crucial for improving diagnostic and therapeutic monitoring. The current study elucidates the molecular interactions of NE with a two-dimensional multielement aluminum quasicrystal (2D-Al70Co10Fe5Ni10Cu5 (2D-Al QC)) through vibrational spectroscopy and theoretical simulations including geometry optimization, charge transfer dynamics, and bond length variations. The interaction dynamics are monitored in real-time at the atomic scale by in situ liquid cell transmission electron microscopy (LCTEM). The results confirm the binding of the -OH group of NE molecules with the aluminum atoms of the 2D-Al QC by Al-O bonding. Based on this binding mechanism, an electrochemical sensor is developed using the 2D-Al QC, for ultrasensitive and selective detection of NE. The sensor exhibits two distinct linear detection ranges: a higher range from 1 nM to 1 µM, and a lower range from 1 pM to 500 pM. The sensor achieves ultralow detection limits of 0.42 ± 0.02 nM and 0.17 ± 0.04 pM, with corresponding quantification limits of 1.28 ± 0.02 nM and 0.5 ± 0.04 pM. The sensor demonstrates outstanding selectivity against potential interferents, excellent reproducibility across seven electrodes with minimal variation of 3%, and sustained performance over 90 days with a negligible deviation of 4.6%. This work highlights the potential of 2D-Al QC-based electrochemical sensors as a robust, scalable platform for neurotransmitter detection, paving the way for enhanced point-of-care diagnostics and neurochemical monitoring.

RESUMEN

Alzheimer's disease (AD) is a degenerative brain disease that presents with neurological symptoms and memory loss, with no clear treatment. Catecholamines, including dopamine, epinephrine, and norepinephrine, can inhibit or degrade the abnormal aggregation of proteins that cause diseases; however, developing these catecholamines as medication is difficult. This study aimed to demonstrate that increasing the levels of catecholamines in the brain may help improve symptoms of AD. We tested whether an increase in catecholamines by bupropion, a dopamine and norepinephrine re-uptake inhibitor, improves the symptoms of AD. Dopamine and norepinephrine showed similar effects in inhibiting amyloid ß (Aß) aggregation and the decomposition of Aß aggregates as curcumin, a positive control. Dopamine and norepinephrine blocked Aß aggregates-induced abnormal hippocampal long-term potentiation. The intraperitoneal administration of bupropion increased the concentrations of dopamine and norepinephrine in the hippocampus from 1 to 6 h after administration. In the Aß-induced memory decline model, bupropion showed a dose-dependent improvement in learning and memory. In 5XFAD mice administered bupropion for 2 months, significant improvements in memory and Aß deposition were also found compared to vehicle-treated 5XFAD mice. These results suggest that the symptoms of AD can be improved or delayed by increasing the amount of dopamine and norepinephrine using bupropion.

RESUMEN

Learning maternal odors is crucial for mammalian newborns, who must locate the mother's nipples to survive. In the newborn rabbit, the mammary pheromone (MP) present in the milk not only allows the pups to locate the nipples, but also promotes associative memory of neutral odorants. The noradrenergic system modulates neonatal learning in humans and rodents, but its role in newborn rabbits has never been investigated. Intraperitoneal injection of propranolol, a ß-adrenoceptors antagonist, blocked acquisition, but not memory consolidation or retrieval, of MP-induced odor memory. Moreover, gene expression analyses revealed that propranolol attenuated c-Fos neuronal activation induced by odor learning in the olfactory bulb and to a lesser extent in the anterior piriform cortex, but not in the hippocampus, of rabbit pups. Interestingly, propranolol had no effect on c-Fos activation induced by MP alone indicating a specific effect of propranolol on neuronal activation induced by associative learning. These effects were not associated with a change in ß-adrenoceptors expression in these brain areas. This highlights the crucial role of noradrenergic system in neonatal odor learning in mammals and suggest that the MP promotes odor learning by activating ß-adrenoceptors in olfactory brain areas in rabbit pups. This pheromone-induced memory provides a great opportunity to explore the neurobiology of neonatal learning.

RESUMEN

OBJECTIVES: This study aimed to explore how phenylephrine (PE) and norepinephrine (NE) affect renin-angiotensin-aldosterone system (RAAS) components and postoperative complications in patients undergoing acute abdomen emergency surgery. DESIGN: A randomized controlled trial. SETTING: The Anesthesiology Department at the Affiliated Hospital of Xuzhou Medical University. PATIENTS: We enrolled 156 patients 18 years older who were undergoing emergency acute abdominal surgery under general anesthesia. INTERVENTIONS: Patients were randomized to receive PE (PE group) or NE (NE group) to maintain their mean arterial pressure at 70-80 mm Hg during operation. MEASUREMENTS AND MAIN RESULTS: The plasma renin level increased in the immediate postoperative period in the NE group (median difference [MD]: 21 µIU/mL (interquartile range [IQR]: 5-51], p = 0.020), but not in the PE group (MD: 7 µIU/mL [IQR: -1 to 33], p = 0.336). However, the plasma renin levels were significantly decreased in both groups at 24 hours postoperation. Furthermore, in both groups, the levels of angiotensin II and aldosterone were reduced at 24 hours postoperation. The upper quartile of the plasma renin level before surgery was associated with higher vasopressor requirements and higher acute kidney injury (AKI) incidence. Furthermore, the groups showed no significant difference in AKI incidence (relative risk [RR]: 1.50 [95% CI, 0.65-3.47], p = 0.569), myocardial injury (RR: 1.11 [95% CI, 0.64-1.93], p = 0.497), and 30-day mortality rate (RR: 1.00 [95% CI, 0.44-2.27], p = 1.000). CONCLUSIONS: PE and NE exert similar effects on RAAS components and postoperative complications. A higher plasma renin level before surgery is associated with greater vasopressor requirement and a higher incidence of postoperative complications.

RESUMEN

Recalled memories become transiently labile and require stabilization1-3. The mechanism for stabilizing memories of survival-critical experiences, which are often emotionally salient and repeated, remains unclear4. Here we identify an astrocytic ensemble that is transcriptionally primed by emotional experience and functionally triggered by repeated experience to stabilize labile memory. Using a novel brain-wide Fos tagging and imaging method, we found that astrocytic Fos ensembles were preferentially recruited in regions with neuronal engrams5 and were more widespread during fear recall than during conditioning. We established the induction mechanism of the astrocytic ensemble, which involves two steps: (1) an initial fear experience that induces day-long, slow astrocytic state changes with noradrenaline receptor upregulation; and (2) enhanced noradrenaline responses during recall, a repeated experience, enabling astrocytes to integrate coincident signals from local engrams and long-range noradrenergic projections, which induce secondary astrocytic state changes, including the upregulation of Fos and the neuromodulatory molecule IGFBP2. Pharmacological and genetic perturbation of the astrocytic ensemble signalling modulate engrams, and memory stability and precision. The astrocytic ensemble thus acts as a multiday trace in a subset of astrocytes after experience-dependent neural activity, which are eligible to capture future repeated experiences for stabilizing memories.

RESUMEN

PURPOSE: Previous studies have investigated the kinetics and affinities of norepinephrine transporter (NET)-targeting radiotracers, including [123I]MIBG, but the role of organic cation transporters (OCTs) remains unclear. This study aimed to evaluate how the structural design of selective NET-targeting tracers affects OCT-mediated non-specific uptake, identifying factors influencing both NET and OCT affinity. METHODS: Cellular uptake assays were conducted using SK-N-SH cells expressing human NET, and human OCT1-, OCT2-, and OCT3-expressing cells with [3H]norepinephrine, [3H]MPP+, and [131I]MIBG. Competitive uptake assays used non-radioactive reference compounds for several NET-targeting radiopharmaceuticals (MIBG, HED, EPI, PHEN, LMI1195, and PHPG), along with a new PET radiotracer [18F]AF78, and its two analogs with meta-iodide [18F]AF78(I) or hydroxyl group [18F]AF78(OH). Dynamic PET imaging in non-human primates assessed the in vivo uptake of [18F]AF78 after NET inhibition with desipramine. RESULTS: Monoamine-based tracers (EPI, PHEN, HED) exhibited high NET selectivity with minimal OCTs interaction, while guanidine-containing tracers (e.g., MIBG, LMI1195) displayed substantial OCTs affinity. Lower lipophilicity in guanidine-containing compounds, influenced by substitutions on the benzene ring (e.g., PHPG, AF78), correlated with weaker OCT interactions. PET imaging confirmed that cardiac uptake of [18F]AF78 is sensitive to desipramine pretreatment (***P < 0.0005), indicating its NET-specificity, while persistent hepatic retention suggests an OCT-mediated transport mechanism. CONCLUSION: This study highlights the critical influence of the compounds' chemical structure on NET and OCT affinities. Structural modifications that reduce OCT-mediated uptake while maintaining high NET affinity could improve the specificity and theranostic potential of NET-targeting ligands. These findings provide insights for designing next-generation radiotracers with enhanced selectivity and clinical utility.

RESUMEN

Impairments of locus coeruleus (LC) are implicated in anxiety/depression and Alzheimer's disease (AD). Increases in cytosolic noradrenaline (NA) concentration and monoamine oxidase A (MAO-A) activity initiate the LC impairment through production of NA metabolite, 3,4-dihydroxyphenyl-glycolaldehyde (DOPEGAL), by MAO-A. However, how NA accumulates in soma/dendritic cytosol of LC neurons has never been addressed despite the fact that NA is virtually absent in cytosol while NA is produced exclusively in cytoplasmic vesicles from dopamine by dopamine-ß-hydroxylase. Since reuptake of autocrine-released NA following spike activity is the major source of NA accumulation, we investigated whether and how chronic stress can increase the spike activity accompanied by NA autocrine. Overexcitation of LC neurons is normally prevented by the autoinhibition mediated by activation of α2A-adrenergic receptor (AR)-coupled inwardly rectifying potassium-current (GIRK-I) with autocrine-released NA. Patch-clamp study revealed that NA-induced GIRK-I in LC neurons was decreased in chronic restraint stress (RS) mice, while a similar decrease was gradually caused by repeated excitation. Chronic RS caused internalization of α2A-ARs expressed in cell membrane in LC neurons and decreased protein/mRNA levels of α2A-ARs/GIRKs in membrane fraction. Subsequently, chronic RS increased the protein levels of MAO-A, DOPEGAL-induced asparagine endopeptidase (AEP), and tau N368. These results suggest that chronic RS-induced overexcitation due to the internalization of α2A-ARs/GIRK is accompanied by [Ca2+]i increases, subsequently increasing Ca2+-dependent MAO-A activity and NA autocrine. Thus, it is likely that internalization of α2A-AR increased cytosolic NA, as reflected in AEP increases, by facilitating reuptake of autocrine-released NA. The suppression of α2A-AR internalization may have a translational potential for anxiety/AD treatment.

RESUMEN

BACKGROUND: Fibromyalgia is a chronic pain condition without an established aetiology. However, noradrenergic dysfunction is a possible mechanism to explain the constellation of symptoms associated with fibromyalgia. Noradrenaline synthesis in the locus coeruleus (LC) results in a paramagnetic by-product, neuromelanin. Recently, a magnetic resonance imaging sequence sensitive to neuromelanin has been used to assay LC signal intensity, a proxy for noradrenergic system function. Here, we use MR imaging to investigate the noradrenergic-locus coeruleus system in participants with fibromyalgia and healthy controls. METHODS: Forty-six participants with fibromyalgia and 41 healthy controls were recruited for a cross-sectional characterisation of LC signal intensity at 3 T, quantified from a 2D gradient echo acquisition. Participants completed the Revised Fibromyalgia Impact Questionnaire, as well as measures of anxiety, depression, sleep and the THINC-it cognitive battery. RESULTS: An independent groups t-test revealed no differences in LC signal intensity between participants with fibromyalgia and healthy controls. For the participants with fibromyalgia, partial correlations accounting for age showed no association between LC signal intensity and fibromyalgia history, fibromyalgia symptom severity, anxiety, depression, insomnia or cognitive performance. Almost 90% of participants with fibromyalgia had been exposed to medications targeting noradrenergic function complicating the interpretation of these findings. CONCLUSIONS: LC signal intensity as measured by MR did not distinguish participants with fibromyalgia and healthy controls, nor was it associated with core fibromyalgia pain symptoms or associated symptoms. Dynamic measures of noradrenergic function may be required to understand noradrenergic contributions to fibromyalgia. SIGNIFICANCE STATEMENT: This study is the first report using MR measured signal intensity of the LC to examine noradrenergic function in participants with fibromyalgia. There was no difference in signal intensity when comparing patients to controls, nor did it associate with any symptoms or associated features of fibromyalgia. This suggests that lifetime noradrenergic function may not distinguish fibromyalgia.

RESUMEN

Detection of neurochemicals voltammetrically can be challenging in complex matrices like tissue. Norepinephrine (NE) is a neurotransmitter in the brain and is directly released by the sympathetic nervous system in the periphery. Fast-scan cyclic voltammetry (FSCV) is an electrochemical technique previously used to detect NE from sympathetic neurons in lymphoid tissues. Mesenteric lymph nodes present a unique challenge to FSCV due to their complex tissue matrix, which includes immune cells and neurons. These cells release various neuropeptides, cytokines, and other chemical signaling molecules, which can interfere with FSCV. Notably, Neuropeptide Y (NPY) from sympathetic neurons, and Substance P (SubP) and Calcitonin Gene-Related Peptide (CGRP) from sensory neurons are common peptides that are released locally near NE sites. These peptides are regulated by and interact with NE through complex neuronal circuits, potentially impacting FSCV NE detection. We demonstrate that increasing levels of each peptide alter voltammetric NE detection. We observed that the NE oxidation potential shifts with each peptide in vitro, and NE cyclic voltammograms exhibit unique peak broadening specific to NPY compared to SubP and CGRP, indicating that each peptide affects the carbon fiber microelectrode (CFME) differently. Overall, we show significant convolution of voltammetric NE peaks in the presence of peptides, providing evidence that future developments in materials to reduce protein fouling could significantly improve the robustness and accuracy of NE FSCV detection.

RESUMEN

BACKGROUND: Intraoperative hypotension is a strong predictor of adverse outcomes in major abdominal surgery. However, data on the occurrence of intraoperative hypotension during the induction of general anesthesia are scarce. We hypothesized that early prevention of postinduction hypotension using a vasopressor could reduce postoperative adverse outcomes. METHODS: In this single-center randomized trial at Amiens Hospital University (Amiens, France), adults older than 50 yr with American Society of Anesthesiologists (Schaumburg, Illinois) Physical Status II or greater undergoing major abdominal surgery were assigned to ephedrine or norepinephrine groups. In the ephedrine group, titration with iterative boluses of ephedrine (3 mg · ml -1 ) was performed at the induction if intraoperative hypotension occurred. In the norepinephrine group, continuous intravenous injection of norepinephrine (0.016 mg · ml -1 ) was started at a rate of 0.48 mg · h -1 from the induction of anesthesia and was titrated if intraoperative hypotension occurred. The primary endpoint was any medico-surgical complication within 30 days (Clavien-Dindo score of 1 or greater). Secondary endpoints included hospital stay length, acute kidney injury, 1-month mortality, and cardiovascular, respiratory, neurologic, and infectious complications. Results were assessed by blinded evaluators. RESULTS: A total of 500 patients were randomized, and 473 were included in the intention-to-treat analysis. The cumulative episodes of intraoperative hypotension were significantly lower in the norephedrine group in comparison to the ephedrine group (respectively, 35 [15%] vs. 176 [74%]; P < 0.001). The primary endpoint occurred in 137 patients (58%) in the ephedrine group and 103 patients (44%) in the norepinephrine group (relative risk, 0.58 [0.40 to 0.83]; P = 0.004). No significant differences were observed in secondary endpoints, except for pulmonary complications, which were lower in the norepinephrine group than in the ephedrine group (respectively; 40 [17%] vs. 74 [31%]; relative risk, 0.46 [0.29; 0.70]; P < 0.001). CONCLUSIONS: Prophylactic titrated norepinephrine infusion to prevent postinduction hypotension was more effective than repeated ephedrine boluses and may reduce postoperative complications in major abdominal surgery.

RESUMEN

Exercise training (ET) is increasingly recognized as a beneficial non-pharmacological intervention for cardiovascular diseases. Our previous results demonstrated that the thoracic perivascular adipose tissue (tPVAT) of heart failure (HF) rats underwent a phenotypic shift from brown to white adipose tissue, accompanied by impaired anticontractile function and oxidative stress. Thus, the present study aimed to investigate the effects of combined aerobic and resistance ET on the vasoactive properties of tPVAT in a HF rat model following myocardial infarction (MI). Wistar rats were subjected to either coronary artery ligation or sham operation (SO). Four weeks after surgery, the rats were divided into four groups: untrained (u) and exercise-trained (t) SO or HF. An 8-week ET program significantly improved running distance and maximum load lifting in the SO and HF groups, ameliorating tPVAT dysfunction and inducing browning only in the HF group. Additionally, ET enhanced the nitric oxide bioavailability, restored oxidative stress and pro-inflammatory cytokine levels (interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1), and increased anti-inflammatory interleukin-10 levels in tPVAT. Furthermore, it increased noradrenaline (NE) content and ß3-adrenoceptor (AR) gene expression in tPVAT, optimizing the NE/ß3-AR/ adiponectin/AMP-activated protein kinase (AMPK)/endothelial nitric oxide synthase pathway locally. These findings highlight the potential of ET as a non-pharmacological approach to managing PVAT and vascular adjustments in HF.

RESUMEN

STUDY OBJECTIVE: To determine whether an individualized blood pressure strategy based on low-dose noradrenaline infusion could reduce cytokines/stress level, thus reducing the acute kidney injury (AKI) complication. DESIGN: A prospective, randomized, controlled trial. SETTING: The study was performed in First Affiliated Hospital of Anhui Medical University, China, from December 2021 to July 2023. PATIENTS: 108 patients older than 60 years with ASA class II-III and scheduled to hepatobiliary and pancreatic surgery were enrolled. INTERVENTION: Patients were randomly assigned in a 1:1 ratio to either a standard or individualized treatment group. Individualized management strategy aimed at achieving a mean arterial pressure (MAP) within 20 % of the reference value or standard management strategy of treating MAP less than 65 mmHg. MEASUREMENTS: The primary outcome was tumor necrosis factor-α (TNF-α) at 24 h after surgery. The secondary outcomes included other inflammatory cytokine IL-6 and IL-10 levels and the incidence of postoperative AKI within 7-day after surgery. MAIN RESULTS: 100 patients completed the trial and were included in the modified intention-to-treat analysis. The primary outcome TNF-α at 24 h was increased to 16.65 (7.36) pg/ml assigned to the individualized treatment strategy vs 21.23 (7.70) pg/ml in standard treatment group (difference -4.58, 95 %CI -7.56 to -1.58, P = 0.003). A relatively mild increase from baseline were found after surgery in IL-6 and cortisol level except for IL-10. 3 patients (6 %) in the individualized treatment group and 10 (20 %) in the standard treatment group had AKI (Relative Risk 3.33; 95 % CI, 0.95 to 11.39; P = 0.037). CONCLUSION: Among elderly patients undergoing major surgery, an individualized mean arterial pressure strategy management based on low-dose norepinephrine reduced surgical stress responses and attenuated the release of proinflammatory cytokines TNF-α and IL-6. It was also associated with a lower risk of AKI.

RESUMEN

INTRODUCTION: One goal of therapeutic efforts in sepsis/septic shock is rapid shock reversal that might be enhanced by adjunctive hemoadsorption by CytoSorb®. We hypothesized that shortening the time the adsorbers are used, reduces the time to shock reversal. METHODS: In a retrospective study, we compared two groups of 16 and 17 patients with sepsis/septic shock treated with short change interval (sci) of 14.2 (12.9, 15.2) h/adsorber or long change interval (lci) of 21.7 (17.6, 24.0) h/adsorber. RESULTS: Time to shock reversal, defined as the time from hemoadsorption start to the end of norepinephrine treatment, was similar between groups (sci: 5 (3.8, 12.7), lci: 10.8 (6.5, 18.5) days; p = 0.210) and did not correlate with the change interval. At baseline, the change interval correlated inversely with interleukin-6 (IL-6; p < 0.001). From baseline to day 5 the significant decrease of thrombocytes was more pronounced in the sci group. DISCUSSION: Shortening the CytoSorb® change interval did not promote faster shock reversal, but imbalances in baseline imply patients in the sci group to have been sicker. Hemodynamic instability and high IL-6 levels prompted intensivists to use shorter change intervals. Possibly the increased number of adsorber binding sites was too low to be effective, or the observed spread between the short and lci was ineffective, or shortening of the change interval improved the outcomes of patients with higher risk profiles at baseline. The calculation of an effective hemoadsorption dose, be it by the amount of blood purified, or binding sites, or a combination hereof, remains speculative. TRIAL REGISTRATION: Not applicable.

RESUMEN

Polycystic ovary syndrome (PCOS) is a multifactorial endocrine disorder associated with vascular dysfunction and increased cardiovascular risk. This study aims to investigate the dysregulation of vascular tone in PCOS, focusing on the imbalance between vasodilators (nitric oxide [NO] and apelin) and vasoconstrictors (noradrenaline and reduced prostacyclin). By examining these factors, the study seeks to elucidate their contribution to endothelial dysfunction and cardiovascular complications in PCOS patients. Forty-four patients diagnosed with PCOS according to the 2003 Rotterdam Criteria, along with 44 healthy controls, were included in the study. Ultrasound evaluations were performed on all volunteers. Serum NO, apelin, noradrenaline, and prostacyclin levels were measured using commercial enzyme-linked immunosorbent assay (ELISA) kits. Additionally, routine biochemical, hormonal, and glycated hemoglobin analyses were conducted on all samples. There was no statistically significant difference between the PCOS and control groups in terms of marital status, age, and body mass index (BMI) (p > 0.05). Compared to the control group (83.85 ± 22.65 µmol/L, 190.88 ± 16.44 ng/L, and 24.63 ± 4.59 ng/L, respectively), NO, apelin, and noradrenaline concentrations were significantly higher in patients with PCOS (104.35 ± 44.96 µmol/L, 379.57 ± 40.11 ng/L, and 27.48 ± 5.36 ng/L, respectively) (p < 0.01). In contrast, prostacyclin concentrations were significantly lower in patients with PCOS (5.85 ± 1.28 ng/L) compared to the control group (6.78 ± 1.99 ng/L) (p = 0.011). Additionally, a statistically significant difference was found between the PCOS and control groups in FSH, LH, testosterone, SHBG, glucose, and HDL levels (p < 0.05). The disrupted balance between vasodilation and vasoconstriction in PCOS, driven by altered levels of NO, apelin, noradrenaline, and prostacyclin, contributes to endothelial dysfunction and increased cardiovascular risk. These molecular disturbances underline the need for targeted therapeutic strategies aimed at restoring vascular homeostasis in PCOS patients.