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Methodist DeBakey Cardiovascular Journal 2023Vasoplegia is a condition characterized by persistent low systemic vascular resistance despite a normal or high cardiac index, resulting in profound and uncontrolled... (Review)
Review
Vasoplegia is a condition characterized by persistent low systemic vascular resistance despite a normal or high cardiac index, resulting in profound and uncontrolled vasodilation. Vasoplegia may occur due to various conditions, including cardiac failure, sepsis, and post-cardiac surgery. In the cardiac cohort, multiple risk factors for vasoplegia have been identified. Several factors contribute to the pathophysiology of this condition, and various mechanisms have been proposed, including nitric oxide, adenosine, prostanoids, endothelins, the renin-angiotensin-aldosterone system, and hydrogen sulfide. Early identification and prompt management of vasoplegia is crucial to prevent development of shock. This review expands upon the different vasopressors used in management of vasoplegia, including catecholamines such as norepinephrine, dopamine, epinephrine, phenylephrine, and other agents including vasopressin, methylene blue, angiotensin II, hydroxocobalamin, vitamin C, thiamine, and corticosteroids (ie, hydrocortisone). It also emphasizes the importance of conducting further research and making advancements in treatment regimens for vasoplegia.
Topics: Humans; Vasoplegia; Epinephrine; Norepinephrine; Phenylephrine; Sepsis
PubMed: 37547893
DOI: 10.14797/mdcvj.1245 -
Intensive Care Medicine Nov 2019Vasopressors are administered to critically ill patients with vasodilatory shock not responsive to volume resuscitation, and less often in cardiogenic shock, and... (Review)
Review
BACKGROUND
Vasopressors are administered to critically ill patients with vasodilatory shock not responsive to volume resuscitation, and less often in cardiogenic shock, and hypovolemic shock.
OBJECTIVES
The objectives are to review safety and efficacy of vasopressors, pathophysiology, agents that decrease vasopressor dose, predictive biomarkers, β1-blockers, and directions for research.
METHODS
The quality of evidence was evaluated using Grading of Recommendations Assessment, Development, and Evaluation (GRADE).
RESULTS
Vasopressors bind adrenergic: α1, α2, β1, β2; vasopressin: AVPR1a, AVPR1B, AVPR2; angiotensin II: AG1, AG2; and dopamine: DA1, DA2 receptors inducing vasoconstriction. Vasopressor choice and dose vary because of patients and physician practice. Adverse effects include excessive vasoconstriction, organ ischemia, hyperglycemia, hyperlactatemia, tachycardia, and tachyarrhythmias. No randomized controlled trials of vasopressors showed a significant difference in 28-day mortality rate. Norepinephrine is the first-choice vasopressor in vasodilatory shock after adequate volume resuscitation. Some strategies that decrease norepinephrine dose (vasopressin, angiotensin II) have not decreased 28-day mortality while corticosteroids have decreased 28-day mortality significantly in some (two large trials) but not all trials. In norepinephrine-refractory patients, vasopressin or epinephrine may be added. A new vasopressor, angiotensin II, may be useful in profoundly hypotensive patients. Dobutamine may be added because vasopressors may decrease ventricular contractility. Dopamine is recommended only in bradycardic patients. There are potent vasopressors with limited evidence (e.g. methylene blue, metaraminol) and novel vasopressors in development (selepressin).
CONCLUSIONS
Norepinephrine is first choice followed by vasopressin or epinephrine. Angiotensin II and dopamine have limited indications. In future, predictive biomarkers may guide vasopressor selection and novel vasopressors may emerge.
Topics: Angiotensin II; Critical Illness; Dopamine; Epinephrine; Humans; Methylene Blue; Norepinephrine; Phenylephrine; Shock; Terlipressin; Vasoconstrictor Agents; Vasopressins
PubMed: 31646370
DOI: 10.1007/s00134-019-05801-z -
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 -
Journal of Critical Care Feb 2021Calculating equipotent doses between vasopressor agents is necessary in clinical practice and research pertaining to the management of shock. This scoping review... (Review)
Review
PURPOSE
Calculating equipotent doses between vasopressor agents is necessary in clinical practice and research pertaining to the management of shock. This scoping review summarizes conversion ratios between vasopressors and provides a formula to incorporate into study designs.
MATERIALS AND METHODS
Medline, Embase and Web of Science databases were searched from inception to 21st October 2020. Additional papers were obtained through bibliography searches of retrieved articles. Two investigators assessed articles for eligibility. Clinical trials comparing the potency of at least two intravenous vasopressors (norepinephrine, epinephrine, dopamine, phenylephrine, vasopressin, metaraminol or angiotensin II), with regard to an outcome of blood pressure, were selected.
RESULTS
Of 16,315 articles, 21 were included for synthesis. The range of conversion ratios equivalent to one unit of norepinephrine were: epinephrine (0.7-1.4), dopamine (75.2-144.4), metaraminol (8.3), phenylephrine (1.1-16.3), vasopressin (0.3-0.4) and angiotensin II (0.07-0.13). The following formula may be considered for the calculation of norepinephrine equivalents (NE) (all in mcg/kg/min, except vasopressin in units/min): NE = norepinephrine + epinephrine + phenylephrine/10 + dopamine/100 + metaraminol/8 + vasopressin*2.5 + angiotensin II*10.
CONCLUSION
A summary of equipotent ratios for common vasopressors used in clinical practice has been provided. Our formula may be considered to calculate NE for studies in the intensive care unit.
Topics: Epinephrine; Humans; Norepinephrine; Phenylephrine; Shock; Vasoconstrictor Agents
PubMed: 33220576
DOI: 10.1016/j.jcrc.2020.11.002 -
Journal of Critical Care Feb 2021Vasopressors are commonly administered through Central Venous Catheters (CVCs) as it is considered unsafe to administer them via peripheral IVs, mainly due to the...
CONTEXT
Vasopressors are commonly administered through Central Venous Catheters (CVCs) as it is considered unsafe to administer them via peripheral IVs, mainly due to the concern of local tissue injury. Unlike peripheral IVs, midline catheters provide a wider lumen with the catheter tip ending in a large peripheral vein. The use of vasopressors through midline catheters has not yet been evaluated.
OBJECTIVE
The primary objective of this study is to determine the safety and efficacy of long term administration of vasopressors through a midline catheter.
DESIGN
This is a retrospective study between 2016 and 2019 looking at the outcomes of midline catheters.
SETTING
45 bed Tertiary level ICU in a 600-bed teaching hospital.
PATIENTS
A total of 248 patients received vasopressors via midline catheters.
RESULTS
The average midline dwell time was 14.7 ± 12.8 days and the average duration of continuous vasopressor infusion was 7.8 ± 9.3 days. Vasopressors used with their average dose (AD) were norepinephrine (n = 165, 16.8 CE ± 10.7 μg/min), epinephrine (n = 56, 9.1 CE ± 6.0 μg/min), vasopressin (n = 123, 0.05 CE ± 0.02 units/min), phenylephrine (n = 158, 91.4 CE ± 64.7 μg/min) and Angiotensin II (50 CE ± 27.6 ng/kg/min). Early Complication rate was 3.6% due to Bloodstream infection (n = 6), drug extravasation (n = 1), thrombophlebitis (n = 1) and arterial puncture (n = 1). Late Complication rate was 0.8% (n = 2) due to midline-associated DVTs. There were no complications related to ineffective drug delivery or limb endangerment.
CONCLUSIONS
Many medical centers are attempting to limit the use of central venous catheters (CVCs) to avoid central line-associated bloodstream infections (CLABSIs). This study demonstrates that midline catheters are a safe alternative to CVCs, for the safe and efficacious administration of vasopressors for prolonged periods of time.
Topics: Catheter-Related Infections; Catheterization, Central Venous; Catheterization, Peripheral; Central Venous Catheters; Humans; Phenylephrine; Retrospective Studies; Vasoconstrictor Agents
PubMed: 33049486
DOI: 10.1016/j.jcrc.2020.09.024 -
American Journal of Physiology. Heart... Aug 2023Heart failure (HF) is a leading cause of morbidity and mortality particularly in older adults and patients with multiple metabolic comorbidities. Heart failure with...
Heart failure (HF) is a leading cause of morbidity and mortality particularly in older adults and patients with multiple metabolic comorbidities. Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome with multisystem organ dysfunction in which patients develop symptoms of HF as a result of high left ventricular (LV) diastolic pressure in the context of normal or near normal LV ejection fraction (LVEF; ≥50%). Challenges to create and reproduce a robust rodent phenotype that recapitulates the multiple comorbidities that exist in this syndrome explain the presence of various animal models that fail to satisfy all the criteria of HFpEF. Using a continuous infusion of angiotensin II and phenylephrine (ANG II/PE), we demonstrate a strong HFpEF phenotype satisfying major clinically relevant manifestations and criteria of this pathology, including exercise intolerance, pulmonary edema, concentric myocardial hypertrophy, diastolic dysfunction, histological signs of microvascular impairment, and fibrosis. Conventional echocardiographic analysis of diastolic dysfunction identified early stages of HFpEF development and speckle tracking echocardiography analysis including the left atrium (LA) identified strain abnormalities indicative of contraction-relaxation cycle impairment. Diastolic dysfunction was validated by retrograde cardiac catheterization and analysis of LV end-diastolic pressure (LVEDP). Among mice that developed HFpEF, two major subgroups were identified with predominantly perivascular fibrosis and interstitial myocardial fibrosis. In addition to major phenotypic criteria of HFpEF that were evident at early stages of this model (3 and 10 days), accompanying RNAseq data demonstrate activation of pathways associated with myocardial metabolic changes, inflammation, activation of extracellular matrix (ECM) deposition, microvascular rarefaction, and pressure- and volume-related myocardial stress. Heart failure with preserved ejection fraction (HFpEF) is an emerging epidemic affecting up to half of patients with heart failure. Here we used a chronic angiotensin II/phenylephrine (ANG II/PE) infusion model and instituted an updated algorithm for HFpEF assessment. Given the simplicity in generating this model, it may become a useful tool for investigating pathogenic mechanisms, identification of diagnostic markers, and for drug discovery aimed at both prevention and treatment of HFpEF.
Topics: Animals; Mice; Heart Failure; Stroke Volume; Angiotensin II; Ventricular Function, Left; Cardiomyopathies; Disease Models, Animal; Fibrosis; Phenylephrine
PubMed: 37204871
DOI: 10.1152/ajpheart.00038.2023 -
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 -
Molecules (Basel, Switzerland) May 2021Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete.... (Review)
Review
Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the detailed mechanisms of enzymatic reactions where experimental research measurements are not possible. Theories invoked by a variety of scientists indicate that enzymes work as structural scaffolds that serve to bring together and orient the reactants so that the reaction can proceed with minimum energy. Enzyme models can be utilized for mimicking enzyme catalysis and the development of novel prodrugs. Prodrugs are used to enhance the pharmacokinetics of drugs; classical prodrug approaches focus on alternating the physicochemical properties, while chemical modern approaches are based on the knowledge gained from the chemistry of enzyme models and correlations between experimental and calculated rate values of intramolecular processes (enzyme models). A large number of prodrugs have been designed and developed to improve the effectiveness and pharmacokinetics of commonly used drugs, such as anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), antihypertension (atenolol), antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. This article describes the works done on enzyme models and the computational methods used to understand enzyme catalysis and to help in the development of efficient prodrugs.
Topics: Acyclovir; Atenolol; Atovaquone; Catalysis; Chemistry, Pharmaceutical; Decitabine; Dopamine; Enzymes; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Molecular Conformation; Nucleosides; Phenylephrine; Prodrugs; Protons; Quantum Theory; Software; Technology, Pharmaceutical; Temperature; Tranexamic Acid
PubMed: 34071328
DOI: 10.3390/molecules26113248