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Circulation Mar 2022Recent studies have established that CCR2 (C-C chemokine receptor type 2) marks proinflammatory subsets of monocytes, macrophages, and dendritic cells that contribute to...
BACKGROUND
Recent studies have established that CCR2 (C-C chemokine receptor type 2) marks proinflammatory subsets of monocytes, macrophages, and dendritic cells that contribute to adverse left ventricle (LV) remodeling and heart failure progression. Elucidation of the effector mechanisms that mediate adverse effects of CCR2 monocytes, macrophages, and dendritic cells will yield important insights into therapeutic strategies to suppress myocardial inflammation.
METHODS
We used mouse models of reperfused myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation to investigate CCL17 (C-C chemokine ligand 17). We used knockout mice, flow cytometry, RNA sequencing, biochemical assays, cell trafficking studies, and in vivo cell depletion to identify the cell types that generate CCL17, define signaling pathways that controlled its expression, delineate the functional importance of CCL17 in adverse LV remodeling and heart failure progression, and determine the mechanistic basis by which CCL17 exerts its effects.
RESULTS
We demonstrated that CCL17 is expressed in CCR2 macrophages and cluster of differentiation 11b conventional dendritic cells after myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation. We clarified the transcriptional signature of CCL17 macrophages and dendritic cells and identified granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling as a key regulator of CCL17 expression through cooperative activation of STAT5 (signal transducer and activator of transcription 5) and canonical NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling. deletion resulted in reduced LV remodeling, decreased myocardial fibrosis and cardiomyocyte hypertrophy, and improved LV systolic function after myocardial infarction and angiotensin II and phenylephrine infusion. We observed increased abundance of regulatory T cells (Tregs) in the myocardium of injured knockout mice. CCL17 inhibited Treg recruitment through biased activation of CCR4. CCL17 activated Gq signaling and CCL22 (C-C chemokine ligand 22) activated both Gq and ARRB (β-arrestin) signaling downstream of CCR4. CCL17 competitively inhibited CCL22 stimulated ARRB signaling and Treg migration. We provide evidence that Tregs mediated the protective effects of deletion on myocardial inflammation and adverse LV remodeling.
CONCLUSIONS
These findings identify CCL17 as a proinflammatory mediator of CCR2 macrophages and dendritic cells and suggest that inhibition of CCL17 may serve as an effective strategy to promote Treg recruitment and suppress myocardial inflammation.
Topics: Angiotensin II; Animals; Chemokine CCL17; Diphtheria Toxin; Heart Failure; Humans; Inflammation; Ligands; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Phenylephrine; T-Lymphocytes, Regulatory; Ventricular Remodeling
PubMed: 35113652
DOI: 10.1161/CIRCULATIONAHA.121.055888 -
The American Journal of Emergency... Nov 2022To evaluate practice patterns, efficacy, and safety of push dose pressors (PDP) in critically ill patients outside of the operating room (OR) at a large academic medical...
PURPOSE
To evaluate practice patterns, efficacy, and safety of push dose pressors (PDP) in critically ill patients outside of the operating room (OR) at a large academic medical center.
MATERIALS AND METHODS
This was a single-center, retrospective cohort study (June 2018 to July 2020) conducted at a 1273-bed academic medical center. The primary outcome was efficacy, defined as a 25% increase in systolic blood pressure, and the cohort was analyzed according to PDP response (i.e. responders versus non-responders). A logistic regression model was used to assess predictors of response to PDPs. Safety outcomes included the incidence of hypertension, bradycardia, and tachycardia.
RESULTS
1727 patients were included in the final analysis. The median doses of phenylephrine and epinephrine administered were 400 μg (IQR 200-888 μg) and 50 μg (IQR 20-100 μg). The primary outcome was achieved in 102 (71.8%) patients in the epinephrine group and 1140 (55.9%) of patients in the phenylephrine group. Adverse effects after PDP receipt were minimal, with the most common being hypertension in 6.6% and 13.4% of the phenylephrine and epinephrine groups respectively.
CONCLUSIONS
This study demonstrates that PDP phenylephrine and epinephrine are safe and efficacious in treating the acute hypotensive period.
Topics: Humans; Adult; Critical Illness; Retrospective Studies; Vasoconstrictor Agents; Phenylephrine; Epinephrine; Hypertension
PubMed: 36108346
DOI: 10.1016/j.ajem.2022.08.055 -
Anesthesiology Apr 2024The treatment of intraoperative hypotension with phenylephrine may impair cerebral perfusion through vasoconstriction, which has been linked to postoperative delirium....
BACKGROUND
The treatment of intraoperative hypotension with phenylephrine may impair cerebral perfusion through vasoconstriction, which has been linked to postoperative delirium. The hypothesis was that intraoperative administration of phenylephrine, compared to ephedrine, is associated with higher odds of postoperative delirium.
METHODS
A total of 103,094 hospitalized adults undergoing general anesthesia for noncardiac, non-neurosurgical procedures between 2008 and 2020 at two tertiary academic healthcare networks in Massachusetts were included in this multicenter hospital registry study. The primary exposure was the administration of phenylephrine versus ephedrine during surgery, and the primary outcome was postoperative delirium within 7 days. Multivariable logistic regression analyses adjusted for a priori defined confounding variables including patient demographics, comorbidities, and procedural factors including magnitude of intraoperative hypotension were applied.
RESULTS
Between the two healthcare networks, 78,982 (76.6%) patients received phenylephrine, and 24,112 (23.4%) patients received ephedrine during surgery; 770 patients (0.8%) developed delirium within 7 days. The median (interquartile range) total intraoperative dose of phenylephrine was 1.0 (0.2 to 3.3) mg and 10.0 (10.0 to 20.0) mg for ephedrine. In adjusted analyses, the administration of phenylephrine, compared to ephedrine, was associated with higher odds of developing postoperative delirium within 7 days (adjusted odds ratio, 1.35; 95% CI, 1.06 to 1.71; and adjusted absolute risk difference, 0.2%; 95% CI, 0.1 to 0.3%; P = 0.015). A keyword and manual chart review-based approach in a subset of 45,465 patients further validated these findings (delirium incidence, 3.2%; adjusted odds ratio, 1.88; 95% CI, 1.49 to 2.37; P < 0.001). Fractional polynomial regression analysis further indicated a dose-dependent effect of phenylephrine (adjusted coefficient, 0.08; 95% CI, 0.02 to 0.14; P = 0.013, per each μg/kg increase in the cumulative phenylephrine dose).
CONCLUSIONS
The administration of phenylephrine compared to ephedrine during general anesthesia was associated with higher odds of developing postoperative delirium. Based on these data, clinical trials are warranted to determine whether favoring ephedrine over phenylephrine for treatment of intraoperative hypotension can reduce delirium after surgery.
Topics: Adult; Humans; Phenylephrine; Ephedrine; Vasoconstrictor Agents; Emergence Delirium; Retrospective Studies; Hypotension
PubMed: 37725759
DOI: 10.1097/ALN.0000000000004774 -
Anaesthesia Jan 2018
Topics: Adult; Anesthesia, Obstetrical; Anesthesia, Spinal; Cesarean Section; Consensus; Ephedrine; Female; Humans; Hypotension; Phenylephrine; Practice Guidelines as Topic; Pregnancy; Vasoconstrictor Agents
PubMed: 29090733
DOI: 10.1111/anae.14080 -
Journal of Cataract and Refractive... Jul 2019
Topics: Cataract; Humans; Iris; Ketorolac; Miosis; Operative Time; Phenylephrine
PubMed: 31262476
DOI: 10.1016/j.jcrs.2019.04.035 -
British Journal of Anaesthesia May 2022
Randomized Controlled Trial
Prophylactic norepinephrine or phenylephrine infusion for bradycardia and post-spinal anaesthesia hypotension in patients with preeclampsia during Caesarean delivery: a randomised controlled trial.
Topics: Anesthesia, Obstetrical; Anesthesia, Spinal; Bradycardia; Cesarean Section; Female; Humans; Hypotension; Norepinephrine; Phenylephrine; Pre-Eclampsia; Pregnancy; Vasoconstrictor Agents
PubMed: 35190176
DOI: 10.1016/j.bja.2022.01.027 -
International Journal of Obstetric... Feb 2017
Topics: Adrenergic alpha-Agonists; Anesthesia, Obstetrical; Anesthesia, Spinal; Cardiotonic Agents; Cesarean Section; Female; Humans; Hypotension; Norepinephrine; Phenylephrine; Pregnancy
PubMed: 28089182
DOI: 10.1016/j.ijoa.2017.01.002 -
Expert Opinion on Pharmacotherapy Aug 2022Priapism is a compartment syndrome, defined as an unwanted penile erection lasting longer than 4 h, unrelated to sexual stimulation, and persistent even after... (Review)
Review
INTRODUCTION
Priapism is a compartment syndrome, defined as an unwanted penile erection lasting longer than 4 h, unrelated to sexual stimulation, and persistent even after ejaculation/orgasm. Ischemic priapism is considered a urologic emergency requiring time-sensitive management. Studies have documented that untreated priapism is associated with progressive ischemic histological changes in the corpora cavernosa, such as widespread smooth muscle necrosis, blood vessel and nerve attrition, and trabecular fibrosis. Treatment options include conservative management, corporal irrigation, pharmacologic therapy, and surgery. We herein provide an overview of the emergency pharmacology for priapism.
AREAS COVERED
The American Urological Association (AUA) and the European Association of Urology (EAU) both recommend penile aspiration in conjunction with intracavernosal injection of sympathomimetics as the initial management of ischemic priapism. We have performed a retrospective review of the literature from 1914 to 2022 by using PubMed and a review of the treatment guidelines from the AUA and the EAU to discuss the various therapies for ischemic priapism in the emergent setting.
EXPERT OPINION
After a thorough overview of the literature regarding the treatment of ischemic priapism in the emergent setting, we conclude that intracavernosal phenylephrine is superior to other agents due to its demonstrated efficacy and limited systemic side effects.
Topics: Humans; Male; Penile Erection; Penis; Phenylephrine; Priapism; Sympathomimetics
PubMed: 35815373
DOI: 10.1080/14656566.2022.2099271 -
Anesthesia and Analgesia Mar 2018
Topics: Anesthesia, Spinal; Cesarean Section; Female; Humans; Hypotension; Phenylephrine; Pregnancy
PubMed: 29239952
DOI: 10.1213/ANE.0000000000002725 -
Minerva Anestesiologica Oct 2020
Topics: Humans; Phenylephrine; Vasoconstrictor Agents
PubMed: 32613813
DOI: 10.23736/S0375-9393.20.14716-3