Showing papers on "Epinephrine published in 2021"
TL;DR: The regulation of cardiac and vascular function by adrenergic receptors is regulated by the action of the endogenous catecholamines norepinephrine and epinephrine on Adrenergic receptors.
Abstract: Activation of the sympathetic nervous system is responsible for the body's "fight or flight" reaction. The physiological responses to the activation of the sympathetic nervous system and adrenal medulla are mediated through the action of the endogenous catecholamines norepinephrine (or noradrenaline) and epinephrine (or adrenaline) on adrenergic receptors. Adrenergic receptors belong to the superfamily of G protein-coupled receptors (GPCR). Adrenoceptors are divided into alpha1, alpha2, beta1, beta2 and beta3 receptors. Norepinephrine stimulates both subtypes of α receptors and β1 receptors. Epinephrine stimulates all subtypes ofα and β adrenoreceptors. α1 adrenergic receptors, coupled to stimulatory Gq proteins, activate the enzyme phospholipase C and are mainly found in the smooth muscle cells of blood vessels and urinary tract, where they induce constriction. α2 receptors are coupled to inhibitory Gi proteins, that inactivate adenylyl cyclase, decreasing cyclic adenosine monophosphate (AMP) production. They are mainly found in the central nervous system, where their activation results in a decreased arterial blood pressure. β1 adrenoreceptors predominate in the heart, activate the Gs-adenylyl cyclase -cAMP-protein kinase A signaling cascade, and induce positive inotropic and chronotropic effects. β2 adrenoreceptors are distributed extensively throughout the body, but are expressed predominantly in bronchial smooth muscle cells. β2 adrenergic receptors activate adenylyl cyclase, dilate blood vessels and bronchioles, relax the muscles of the uterus, bladder and gastrointestinal duct, and also decrease platelet aggregation and glycogenolysis. β3 receptors can couple interchangeably to both stimulating and inhibiting G proteins. They are abundantly expressed in white and brown adipose tissue, and increase fat oxidation, energy expenditure and insulin-mediated glucose uptake. This review details the regulation of cardiac and vascular function by adrenergic receptors.
61 citations
TL;DR: Structural comparison revealed that the catecholamine-binding pockets are identical between β1AR and β2AR, but the extracellular vestibules have different shapes and electrostatic properties, which influence the path norepinephrine takes to the orthosteric pocket and contribute to the different association rates and thus different affinities.
Abstract: Beta adrenergic receptors (βARs) mediate physiologic responses to the catecholamines epinephrine and norepinephrine released by the sympathetic nervous system. While the hormone epinephrine binds β1AR and β2AR with similar affinity, the smaller neurotransmitter norepinephrine is approximately tenfold selective for the β1AR. To understand the structural basis for this physiologically important selectivity, we solved the crystal structures of the human β1AR bound to an antagonist carazolol and different agonists including norepinephrine, epinephrine and BI-167107. Structural comparison revealed that the catecholamine-binding pockets are identical between β1AR and β2AR, but the extracellular vestibules have different shapes and electrostatic properties. Metadynamics simulations and mutagenesis studies revealed that these differences influence the path norepinephrine takes to the orthosteric pocket and contribute to the different association rates and thus different affinities.
50 citations
Humboldt University of Berlin1, Ludwig Maximilian University of Munich2, Dresden University of Technology3, Sofia Medical University4, Federal University of São Paulo5, Hospital Clínico San Carlos6, Paracelsus Private Medical University of Salzburg7, Cork University Hospital8, University of Freiburg9, University of Giessen10, National and Kapodistrian University of Athens11, University of Manchester12, Saarland University13, Pomeranian Medical University14, University Hospital of Basel15, University of Erlangen-Nuremberg16, Hannover Medical School17
TL;DR: It is validated that patients with intermediate baseline serum tryptase levels and without skin involvement have higher risk of severe VIA, and patients receiving beta-blockers or ACE-I had a higherrisk of developing severe cardiovascular symptoms in VIA and non-VIA cases.
Abstract: Background Venom-induced anaphylaxis (VIA) is a common, potentially life-threatening hypersensitivity reaction associated with (1) a specific symptom profile, 2) specific cofactors, and 3) specific management. Identifying the differences in phenotypes of anaphylaxis is crucial for future management guidelines and development of a personalized medicine approach. Objective This study aimed to evaluate the phenotype and risk factors of VIA. Methods Using data from the European Anaphylaxis Registry (12,874 cases), we identified 3,612 patients with VIA and analyzed their cases in comparison with sex- and age-matched anaphylaxis cases triggered by other elicitors (non-VIA cases [n = 3,605]). Results VIA more frequently involved more than 3 organ systems and was associated with cardiovascular symptoms. The absence of skin symptoms during anaphylaxis was correlated with baseline serum tryptase level and was associated with an increased risk of a severe reaction. Intramuscular or intravenous epinephrine was administered significantly less often in VIA, in particular, in patients without a history of anaphylaxis. A baseline serum tryptase level within the upper normal range (8-11.5 ng/mL) was more frequently associated with severe anaphylaxis. Conclusion Using a large cohort of VIA cases, we have validated that patients with intermediate baseline serum tryptase levels (8-11 ng/mL) and without skin involvement have a higher risk of severe VIA. Patients receiving β-blockers or angiotensin-converting enzyme inhibitors had a higher risk of developing severe cardiovascular symptoms (including cardiac arrest) in VIA and non-VIA cases. Patients experiencing VIA received epinephrine less frequently than did cases with non-VIA.
40 citations
TL;DR: A systematic review and meta-analysis of published studies reporting epinephrine treatment for anaphylaxis in which data relating to the number of doses administered were available was conducted in this paper.
Abstract: Background Regulatory bodies recommend that all patients at risk of anaphylaxis be prescribed 2 epinephrine autoinjectors, which they should carry at all times. This is in contrast to some guidelines. The proportion of anaphylaxis reactions that are treated with multiple doses of epinephrine has not been systematically evaluated. Objective Our aim was to undertake a systematic review and meta-analysis of published studies reporting epinephrine treatment for anaphylaxis in which data relating to the number of doses administered were available. Methods We searched the Medline, Embase, and Cochrane databases for relevant studies reporting at least 10 anaphylaxis events (due to food or venom) from 1946 until January 2020. Data were extracted in duplicate for the meta-analysis, and the risk of bias was assessed. The study was registered under the PROSPERO identifier CRD42017069109. Results A total of 86 studies (36,557 anaphylaxis events) met the inclusion criteria (20 of the studies [23%] were prospective studies; 64 [74%] reported reactions in the community, and 22 [26%] included food challenge data). Risk of bias was assessed as low in 50 studies. Overall, 7.7% of anaphylaxis events from any cause (95% CI = 6.4-9.1) were treated with multiple doses of epinephrine. When only epinephrine-treated reactions for which subsequent doses were administered by a health care professional were considered, 11.1% of food-induced reactions (95% CI = 9.4-13.2) and 17.1% of venom-induced reactions (95% CI = 11.3-25.0) were treated with more than 1 epinephrine dose. Heterogeneity was moderate to high in the meta-analyses, but at sensitivity analysis this estimate was not affected by study design or anaphylaxis definition. Conclusion Around 1 in 10 anaphylaxis reactions are treated with more than 1 dose of epinephrine.
32 citations
TL;DR: In this article, the main well-established signaling modalities used by cardiac autonomic GPCRs, including receptors for salient NANC mediators, and also highlight the latest developments pertaining to cardiac cell type-specific signal transduction, resulting in cell type specific cardiac effects of each of these autonomic receptors.
Abstract: The two branches of the autonomic nervous system (ANS), adrenergic and cholinergic, exert a multitude of effects on the human myocardium thanks to the activation of distinct G protein-coupled receptors (GPCRs) expressed on the plasma membranes of cardiac myocytes, cardiac fibroblasts, and coronary vascular endothelial cells. Norepinephrine (NE)/epinephrine (Epi) and acetylcholine (ACh) are released from cardiac ANS terminals and mediate the biological actions of the ANS on the heart via stimulation of cardiac adrenergic or muscarinic receptors, respectively. In addition, several other neurotransmitters/hormones act as facilitators of ANS neurotransmission in the heart, taking part in the so-called nonadrenergic noncholinergic (NANC) part of the ANS's control of cardiac function. These NANC mediators also use several different cell membrane-residing GPCRs to exert their effects in the myocardium. Cardiac ANS dysfunction and an imbalance between the activities of its two branches underlie a variety of cardiovascular diseases, from heart failure and hypertension to coronary artery disease, myocardial ischemia, and arrhythmias. In this review, we present the main well-established signaling modalities used by cardiac autonomic GPCRs, including receptors for salient NANC mediators, and we also highlight the latest developments pertaining to cardiac cell type-specific signal transduction, resulting in cell type-specific cardiac effects of each of these autonomic receptors.
25 citations
TL;DR: Intramuscular injection with epinephrine had limited impact in reversing the decrease in stroke volume caused by peanut-induced anaphylaxis and the need for guidelines to incorporate effective adjuvant treatments in addition to intramuscles in the management of refractory anaphlyaxis is supported.
16 citations
15 citations
TL;DR: Intramuscular injection with higher doses of epinephrine appears to lead to a higher C max and there is a dose dependent increase in plasma concentration and AUC 0-20 .
Abstract: For a century, epinephrine has been the drug of choice for acute treatment of systemic allergic reactions/anaphylaxis. For 40 years, autoinjectors have been used for the treatment of anaphylaxis. Over the last 20 years, intramuscular epinephrine injected into the thigh has been recommended for optimal effect. To review the literature on pharmacokinetics of epinephrine autoinjectors. Six studies assessing epinephrine autoinjector pharmacokinetics were identified. The studies, all on healthy volunteers, were completed by Simons, Edwards, Duvauchelle, Worm and Turner over the span of 2 decades. Simons et al. published two small studies that suggested that intramuscular injection was superior to subcutaneous injection. These findings were partially supported by Duvauchelle. Duvauchelle showed a proportional increase in Cmax and AUC0-20 when increasing the dose from 0.3 to 0.5 mg epinephrine intramuscularly. Turner confirmed these findings. Simons, Edwards and Duvauchelle documented the impact of epinephrine on heart rate and blood pressure. Turner confirmed a dose-dependent increase in heart rate, cardiac output and stroke volume. Based on limited data, confirmed intramuscular injections appeared to lead to faster Cmax. Two discernable Cmax’s were identified in most of the studies. We identified similarities and discrepancies in a number of variables in the aforementioned studies. Intramuscular injection with higher doses of epinephrine appears to lead to a higher Cmax. There is a dose dependent increase in plasma concentration and AUC0-20. Most investigators found two Cmax’s with Tmax 5–10 min and 30–50 min, respectively. There is a need for conclusive trials to evaluate the differences between intramuscular and subcutaneous injections with the epinephrine delivery site confirmed with ultrasound.
10 citations
TL;DR: In this paper, the authors investigated the current standard of care in the treatment of anaphylaxis, barriers to IM epinephrine use, and alternative therapies under investigation for administration in anophylaxis.
Abstract: Anaphylaxis is a severe, life-threatening, systemic allergic reaction that should be recognized and treated promptly. Intramuscular (IM) epinephrine is the first-line treatment for anaphylaxis and there are no absolute contraindications to its use. Despite its established track record of efficacy and safety, physicians and patients face barriers in the recognition and treatment of anaphylaxis, including the maintenance and appropriate use of epinephrine auto-injectors. This has led to investigation into potential alternatives to IM epinephrine administration in anaphylaxis. This review investigates the current standard of care in the treatment of anaphylaxis, barriers to IM epinephrine use, and alternative therapies under investigation for administration in anaphylaxis. Alternative routes under investigation include intranasal, sublingual, inhaled, and needle-free intramuscular administration of epinephrine. There are currently numerous investigational alternatives to IM epinephrine therapy which could hold promise as future effective treatments in the emergent management of anaphylaxis.
10 citations
TL;DR: In this paper, the authors evaluated the effect of 1-mL and 2.5-mL flush volumes after UVC epinephrine administration on the incidence and time to achieve return of spontaneous circulation (ROSC) in a near-term ovine model of perinatal asphyxia induced cardiac arrest.
Abstract: The 7th edition of the Textbook of Neonatal Resuscitation recommends administration of epinephrine via an umbilical venous catheter (UVC) inserted 2-4 cm below the skin, followed by a 0.5-mL to 1-mL flush for severe bradycardia despite effective ventilation and chest compressions (CC). This volume of flush may not be adequate to push epinephrine to the right atrium in the absence of intrinsic cardiac activity during CC. The objective of our study was to evaluate the effect of 1-mL and 2.5-mL flush volumes after UVC epinephrine administration on the incidence and time to achieve return of spontaneous circulation (ROSC) in a near-term ovine model of perinatal asphyxia induced cardiac arrest. After 5 min of asystole, lambs were resuscitated per Neonatal Resuscitation Program (NRP) guidelines. During resuscitation, lambs received epinephrine through a UVC followed by 1-mL or 2.5-mL normal saline flush. Hemodynamics and plasma epinephrine concentrations were monitored. Three out of seven (43%) and 12/15 (80%) lambs achieved ROSC after the first dose of epinephrine with 1-mL and 2.5-mL flush respectively (p = 0.08). Median time to ROSC and cumulative epinephrine dose required were not different. Plasma epinephrine concentrations at 1 min after epinephrine administration were not different. From our pilot study, higher flush volume after first dose of epinephrine may be of benefit during neonatal resuscitation. More translational and clinical trials are needed.
9 citations
TL;DR: In this article, the authors compared the effects of endovascular balloon occlusion of the aorta (REBOA) and epinephrine administration on return of spontaneous circulation and cerebral hemodynamics during cardiopulmonary resuscitation (CPR) in a swine model of non-traumatic cardiac arrest.
Abstract: The administration of epinephrine in the management of non-traumatic cardiac arrest remains recommended despite controversial effects on neurologic outcome. The use of resuscitative endovascular balloon occlusion of the aorta (REBOA) could be an interesting alternative. The aim of this study was to compare the effects of these 2 strategies on return of spontaneous circulation (ROSC) and cerebral hemodynamics during cardiopulmonary resuscitation (CPR) in a swine model of non-traumatic cardiac arrest. Anesthetized pigs were instrumented and submitted to ventricular fibrillation. After 4 min of no-flow and 18 min of basic life support (BLS) using a mechanical CPR device, animals were randomly submitted to either REBOA or epinephrine administration before defibrillation attempts. Six animals were included in each experimental group (Epinephrine or REBOA). Hemodynamic parameters were similar in both groups during BLS, i.e., before randomization. After epinephrine administration or REBOA, mean arterial pressure, coronary and cerebral perfusion pressures similarly increased in both groups. However, carotid blood flow (CBF) and cerebral regional oxygenation saturation were significantly higher with REBOA as compared to epinephrine administration (+ 125% and + 40%, respectively). ROSC was obtained in 5 animals in both groups. After resuscitation, CBF remained lower in the epinephrine group as compared to REBOA, but it did not achieve statistical significance. During CPR, REBOA is as efficient as epinephrine to facilitate ROSC. Unlike epinephrine, REBOA transitorily increases cerebral blood flow and could avoid its cerebral detrimental effects during CPR. These experimental findings suggest that the use of REBOA could be beneficial in the treatment of non-traumatic cardiac arrest.
TL;DR: In this paper, the effect of acute heat stress on the protein profile and histone modification in the adrenal gland of layer-type country chickens was investigated, and a total of 192 roosters were subject to thermal stress and thereafter classified into a resistant or susceptible group according to body temperature change.
Abstract: The adrenal gland responds to heat stress by epinephrine and glucocorticoid release to alleviate the adverse effects. This study investigated the effect of acute heat stress on the protein profile and histone modification in the adrenal gland of layer-type country chickens. A total of 192 roosters were subject to acute heat stress and thereafter classified into a resistant or susceptible group according to body temperature change. The iTRAQ analysis identified 80 differentially expressed proteins, in which the resistant group had a higher level of somatostatin and hydroxy-δ-5-steroid dehydrogenase but a lower parathymosin expression in accordance with the change of serum glucocorticoid levels. Histone modification analysis identified 115 histone markers. The susceptible group had a higher level of tri-methylation of histone H3 lysine 27 (H3K27me3) and showed a positive crosstalk with K36me and K37me in the H3 tails. The differential changes of body temperature projected in physiological regulation at the hypothalamus-pituitary-adrenal axis suggest the genetic heterogeneity in basic metabolic rate and efficiency for heat dissipation to acclimate to thermal stress and maintain body temperature homeostasis. The alteration of adrenal H3K27me3 level was associated with the endocrine function of adrenal gland and may contribute to the thermotolerance of chickens.
TL;DR: A randomized, placebo-controlled, crossover study in 28 healthy men and women to determine the effect of PA (1500 mg calcium propionate) on these factors was performed in this paper.
Abstract: Introduction Propionic acid (PA) is a common food preservative generally recognized as safe by the US Food and Drug Administration; however, exogenous PA has effects on glucose metabolism that are not fully understood. Our preclinical studies demonstrated exogenous PA increases glucagon, norepinephrine, and endogenous glucose production (EGP). Research design and methods We performed a randomized, placebo-controlled, crossover study in 28 healthy men and women to determine the effect of PA (1500 mg calcium propionate) on these factors. Subjects had two study visits, each preceded by a 1 week, PA-free diet. During each visit, glucose, insulin, glucagon, norepinephrine, epinephrine, and EGP were assessed for 2 hours after oral administration of PA/placebo under resting conditions (protocol 1) and during either a euglycemic (~85–90 mg/dL) or hypoglycemic (~65–70 mg/dL) hyperinsulinemic clamp (protocol 2). Results PA, as compared with placebo, significantly increased: (1) glucagon and norepinephrine during protocol 1; (2) glucagon, norepinephrine, and epinephrine under euglycemic conditions in protocol 2; and (3) norepinephrine, epinephrine, and EGP under hypoglycemic conditions in protocol 2. Conclusion Oral consumption of PA leads to inappropriate activation of the insulin counterregulatory hormonal network. This inappropriate stimulation highlights PA as a potential metabolic disruptor.
TL;DR: In this article, the impact of epinephrine on the outcome in venoarterial (VA) extracorporeal membrane oxygenation (ECMO) patients is limited, and existing data are conflicting.
Abstract: AIMS Knowledge about the impact of epinephrine on the outcome in venoarterial (VA) extracorporeal membrane oxygenation (ECMO) patients is limited, and existing data are conflicting. METHODS AND RESULTS We conducted a retrospective cohort study in a 1500 bed tertiary university hospital. Five hundred and eighty-nine VA-ECMO patients were analysed. The median age was 57 years [47-65], 68% of male. The major indications for ECMO were post-cardiotomy cardiogenic shock (CS) (38%) and medical CS (36%). Two hundred and sixty-two (44.5%) patients received epinephrine alone or associated with another catecholamine while on ECMO. Baseline factors significantly associated with epinephrine administration were younger age, higher sequential organ failure assessment score, cardiac arrest at implantation, and intra-aortic balloon pump support at implantation, whereas medical CS and dobutamine administration were significantly associated with a lower risk of epinephrine administration. Epinephrine administration was independently associated with death [hazard ratio = 1.68 (1.44-2.23); P < 0.01]. A sensitivity analysis with propensity score inverse probability weighting in complete cases confirmed a significant association of epinephrine administration with death [hazard ratio = 1.69 (1.43-2.00); P < 0.001]. CONCLUSIONS Among patients who required VA-ECMO, epinephrine administration was associated with an increased risk for death.
TL;DR: In this article, a review of the molecular mechanisms behind catecholamine-induced cardiotoxicity including Ca2+ overload, oxidative stress, apoptosis, cardiac hypertrophy, interstitial fibrosis, and inflammation is presented.
TL;DR: There is discordance among pediatricians of when allergic reaction is considered anaphylaxis, as well as a discordance of when epinephrine is warranted, which highlights the need for continued improvement of the definition of anphylaxis.
Abstract: Background Anaphylaxis remains difficult to diagnose and epinephrine underused. Objective To better understand the thoughts of pediatricians regarding when acute allergic reactions constitute anaphylaxis and when epinephrine should be given by conducting an anonymous online survey. Methods The survey consisted of 8 case-based scenarios of allergic reactions with the following 2 questions on each case: (1) does this case represent anaphylaxis? and (2) if this patient immediately presented to you, would you treat the patient with epinephrine during the reaction? Results A total of 1001 responses were analyzed. When assessing all cases combined, there was discordance in whether a case represented anaphylaxis and administration of epinephrine was warranted in 8% of the cases. An average of 5% of all the respondents suggested that the case represented anaphylaxis but would not warrant epinephrine, whereas an average of 3% suggested that the case did not represent anaphylaxis but that epinephrine was warranted. Conclusion The results of this survey reveal that there is discordance among pediatricians on when an allergic reaction is considered anaphylaxis and when epinephrine is warranted. These data highlight the need for continued improvement of the definition of anaphylaxis and continued need for education regarding the diagnosis and management of anaphylaxis.
TL;DR: In this paper, the alpha-2-adrenergic receptors (B2AR) were found to increase the rate of cell migration and wound epithelialization in the presence of low concentrations of epinephrine.
Abstract: Keratinocyte migration into skin wounds is the step of the healing process that correlates with the wound closure rate. Keratinocyte migration, and wound epithelialization are decreased when beta 2-adrenergic receptors (B2AR) are activated by 1 μM epinephrine/adrenaline, resulting in delayed wound healing in human and mouse skin. In the present study, we found paradoxically, that in a subset of keratinocyte strains exposure to low concentrations of epinephrine (0.1 nM) increased, rather than decreased, their migratory rate. We find that both the alpha- and the beta-adrenergic receptors are expressed in human keratinocytes, and expression of alpha-2 AR subtypes demonstrated for the first time. Therefore, we tested if the alpha-AR could be modulating the increased migratory response observed in these cell strains. By using specific inhibitors to alpha-AR, we demonstrated that blocking A2B-AR could reverse the rapid cell migration induced by the 0.1 nM epinephrine. Phosphorylation of ERK was elevated after 1-10 minutes of the low epinephrine treatment and the A2B-AR inhibitor blocked the ERK phosphorylation. The results suggest that both the A2B-AR and B2AR mediate keratinocyte migration, in which with a low level of epinephrine treatment, A2B-AR could alter the B2AR signals and regulate the migration rate.
TL;DR: Smoking may accelerate atrioventricular nodal conduction via increased dopamine production and elevated urinary dopamine and norepinephrine and the relationship between cotinine and PR segment was tested.
Abstract: Smoking is associated with cardiac arrhythmia, stroke, heart failure, and sudden cardiac arrest, all of which may derive from increased sympathetic influence on cardiac conduction system and altered ventricular repolarization. However, knowledge of the effects of smoking on supraventricular conduction, and the role of the sympathetic nervous system in them, remains incomplete. Participants with intermediate-high cardiovascular disease risk were measured for urinary catecholamines and cotinine, and 12-lead electrocardiograms (ECGs) were measured for atrial and atrioventricular conduction times, including P duration, PR interval, and PR segment (lead II), which were analyzed for associations with cotinine by generalized linear models. Statistical mediation analyses were then used to test whether any significant associations between cotinine and atrioventricular conduction were mediated by catecholamines. ECG endpoints and urinary metabolites were included from a total of 136 participants in sinus rhythm. Atrial and atrioventricular conduction did not significantly differ between smokers (n = 53) and non-smokers (n = 83). Unadjusted and model-adjusted linear regressions revealed cotinine significantly and inversely associated with PR interval and PR segment, but not P duration. Dopamine, norepinephrine, and epinephrine all inversely associated with PR interval, whereas only dopamine was also inversely associated with PR segment (p < 0.05). Dopamine and norepinephrine (but not epinephrine) also associated positively with cotinine. Dopamine mediated the relationship between cotinine and PR interval, as well as the relationship between cotinine and PR segment. Smoking is associated with accelerated atrioventricular conduction and elevated urinary dopamine and norepinephrine. Smoking may accelerate atrioventricular nodal conduction via increased dopamine production.
TL;DR: In this paper, animal studies of cardiac arrest suggest that shorter epinephrine dosing intervals than currently recommended (every 3-5 min) may be beneficial in select circumstances, such as cardiac arrhythmia.
Abstract: Rationale: Animal studies of cardiac arrest suggest that shorter epinephrine dosing intervals than currently recommended (every 3–5 min) may be beneficial in select circumstances. Objectives: To ev...
TL;DR: In this article, the authors reveal that deficiency of HIF (hypoxia inducible factors) prolyl hydroxylase domain protein-2 (PHD2) in the adrenal medulla of mice results in HIF2α-mediated reduction in phenylethanolamine N-methyltransferase (PNMT) expression, and consequent reduction in epinephrine synthesis.
Abstract: The adrenal gland and its hormones regulate numerous fundamental biological processes; however, the impact of hypoxia signaling on adrenal function remains poorly understood. Here, we reveal that deficiency of HIF (hypoxia inducible factors) prolyl hydroxylase domain protein-2 (PHD2) in the adrenal medulla of mice results in HIF2α-mediated reduction in phenylethanolamine N-methyltransferase (PNMT) expression, and consequent reduction in epinephrine synthesis. Simultaneous loss of PHD2 in renal erythropoietin (EPO)-producing cells (REPCs) stimulated HIF2α-driven EPO overproduction, excessive RBC formation (erythrocytosis), and systemic hypoglycemia, which is necessary and sufficient to enhance exocytosis of epinephrine from the adrenal medulla. Based on these results, we propose that the PHD2-HIF2α axis in the adrenal medulla regulates the synthesis of epinephrine, whereas in REPCs, it indirectly induces the release of this hormone. Our findings are also highly relevant to the testing of small molecule PHD inhibitors in phase III clinical trials for patients with renal anemia. KEY MESSAGES: HIF2α and not HIF1α modulates PNMT during epinephrine synthesis in chromaffin cells. The PHD2-HIF2α-EPO axis induces erythrocytosis and hypoglycemia. Reduced systemic glucose facilitates exocytosis of epinephrine from adrenal gland.
TL;DR: The first-line therapy for anaphylaxis is given in doses of 0.01 mg/kg (up to 0.5 mg in adults) intramuscularly (IM) in the anterolateral thigh as discussed by the authors.
Abstract: Introduction Anaphylaxis is a potentially deadly condition that requires emergent therapy. While frequently treated in the emergency department (ED), recent evidence updates may improve the diagnosis and management of this condition. Objective This paper evaluates key evidence-based updates concerning the diagnosis and management of anaphylaxis for the emergency clinician. Discussion The presentation of anaphylaxis can vary. Current diagnostic criteria can be helpful when evaluating patients for anaphylaxis, though multiple criteria exist. While the most common causes of anaphylaxis include medications, insect venom, and foods, recent literature has identified an IgE antibody response to mammalian galactose alpha-1,3-galactose, known as alpha-gal anaphylaxis. Epinephrine is the first-line therapy and is given in doses of 0.01 mg/kg (up to 0.5 mg in adults) intramuscularly (IM) in the anterolateral thigh. Intravenous (IV) epinephrine administration is recommended in patients refractory to IM epinephrine and IV fluids, or those with cardiovascular collapse. Antihistamines and glucocorticoids should not delay administration of epinephrine and do not demonstrate a significant reduction in risk of biphasic reactions. Biphasic reactions may affect 1–7% of patients with anaphylaxis. Risk factors for biphasic reaction include severe initial presentation and repeated doses of epinephrine. Disposition of patients with anaphylaxis requires consideration of several factors. Conclusions Emergency clinicians must be aware of current updates in the evaluation and management of this disease.
TL;DR: In this article, the authors compared intraosseous with intravenous epinephrine administration during resuscitation of severely asphyxiated lambs at birth, and found that the results supported the inclusion of intra-seous access as a route for epineeline administration in current guidelines.
Abstract: Objective Intraosseous access is recommended as a reasonable alternative for vascular access during newborn resuscitation if umbilical access is unavailable, but there are minimal reported data in newborns. We compared intraosseous with intravenous epinephrine administration during resuscitation of severely asphyxiated lambs at birth. Methods Near-term lambs (139 days’ gestation) were instrumented antenatally for measurement of carotid and pulmonary blood flow and systemic blood pressure. Intrapartum asphyxia was induced by umbilical cord clamping until asystole. Resuscitation commenced with positive pressure ventilation followed by chest compressions and the lambs received either intraosseous or central intravenous epinephrine (10 μg/kg); epinephrine administration was repeated every 3 min until return of spontaneous circulation (ROSC). The lambs were maintained for 30 min after ROSC. Plasma epinephrine levels were measured before cord clamping, at end asphyxia, and at 3 and 15 min post-ROSC. Results ROSC was successful in 7 of 9 intraosseous epinephrine lambs and in 10 of 12 intravenous epinephrine lambs. The time and number of epinephrine doses required to achieve ROSC were similar between the groups, as were the achieved plasma epinephrine levels. Lambs in both groups displayed a similar marked overshoot in systemic blood pressure and carotid blood flow after ROSC. Blood gas parameters improved more quickly in the intraosseous lambs in the first 3 min, but were otherwise similar over the 30 min after ROSC. Conclusions Intraosseous epinephrine administration results in similar outcomes to intravenous epinephrine during resuscitation of asphyxiated newborn lambs. These findings support the inclusion of intraosseous access as a route for epinephrine administration in current guidelines.
TL;DR: The data indicate that the current cut-off to define normal HPA axis response in children after insulin-induced hypoglycemia warrants reevaluation to avoid over-diagnosis of adrenal insufficiency and suggest that peak cortisol levels in children undergoing ITT might represent a normal cortisol response to stress, regardless of age, BMI or GH secretory capacity.
Abstract: To evaluate factors that could potentially affect the hypothalamic-pituitary adrenal (HPA) axis response to insulin-induced hypoglycemia in children without history or symptoms of adrenal insufficiency and to propose a cut-off value to define a normal response in this population. Exploratory single-center study involving 78 children that prospectively underwent insulin tolerance test (ITT) for suspected growth hormone (GH) deficiency. Glucose, cortisol, GH, adrenocorticotrophic hormone (ACTH), epinephrine and norepinephrine levels were measured at baseline and after insulin-induced hypoglycemia. Serum cortisol was measured using Access automated immunoassay. Mean (range) basal morning serum cortisol of 8 (2.2–19.5) µg/dL/222 (61–542) nmol/L increased after hypoglycemia to 20.5 (14.6–29.5) µg/dL/570 nmol/L (405–819) nmol/L. Peak serum cortisol levels of 14.6 µg/dL (405 nmol/L) and 15.4 µg/dL (428 nmol/L) corresponded to the 2.5th and 5th percentiles, respectively. Peak serum cortisol correlated with peak plasma epinephrine (r = 0.367; P = 0.0014) but did not correlate with age, BMI-SD or peak serum GH. Children with intact and abnormal GH responses presented similar mean peak serum cortisol levels (20.0 vs. 20.6 µg/dL/555 vs. 572 nmol/L; P = 0.21). Our data indicate that the current cut-off to define normal HPA axis response in children after insulin-induced hypoglycemia warrants reevaluation to avoid over-diagnosis of adrenal insufficiency. Our results suggest that peak serum cortisol levels ≥ 15.4 µg/dL (428 nmol/L) in children undergoing ITT might represent a normal cortisol response to stress, regardless of age, BMI or GH secretory capacity.
TL;DR: In this paper, the long-term effect of epinephrine when used in a cohort of patients that underwent cardiac arrest during cardiopulmonary resuscitation was analyzed by univariate analysis and multivariate logistic regression.
Abstract: Introduction. Although epinephrine is universally acknowledged to increase return of spontaneous circulation (ROSC) after cardiac arrest, its balanced effects on later outcomes remain uncertain, causing potential harm during post-resuscitation phase. Recent studies have questioned the efficacy and potential deleterious effects of epinephrine on long-term survival and neurological outcomes, despite that the adverse relationship between epinephrine dose and outcome can be partially biased by longer CPR duration and underlying comorbidities. This study explored the long-term effect of epinephrine when used in a cohort of patients that underwent cardiac arrest during cardiopulmonary resuscitation. Methods. The data were originally collected from a retrospective institutional database from January 2007 to December 2015 and are now available on Dryad (via: https://doi.org/10.5061/dryad.qv6fp83). Use of epinephrine was coded by dose ( <2mg, 2 mg, 3 to 4 mg, ≥5 mg). A favorable neurological outcome was defined using a Cerebral Performance Category (CPC) 1 or 2. The association between epinephrine dosing and 3-month neurological outcome was analyzed by univariate analysis and multivariate logistic regression. Results. Univariate and multivariate analysis demonstrated a negative association between total epinephrine dose and neurological outcome. Of the 373 eligible patients, 92 received less than 2 mg of epinephrine, 60 received 2 mg, 97 received 3 to 4 mg and 124 received more than 5 mg. Compared to patients who received less than 2 mg of epinephrine, the adjusted odds ratio (OR) of a favorable neurological outcome was 0.8 (95% confidence interval [CI]: 0.38 to 1.68) for 2 mg of epinephrine, 0.43 (95% confidence interval [CI]: 0.21 to 0.89) for 3 to 4 mg of epinephrine and 0.40 (95% confidence interval [CI]: 0.17 to 0.96) for more than 5 mg of epinephrine. Conclusions. In this cohort of patients who achieved ROSC, total epinephrine dosing during resuscitation was associated with a worse neurological outcome three months after cardiac arrest, after adjusting other confounding factors. Further researches are needed to investigate the long-term effect of epinephrine on cardiac arrest patients.
TL;DR: In this article, a 78-year-old woman with mycosis in the maxillary sinus was scheduled to undergo endoscopic sinus surgery, and after the submucosal injection of 3 mL of local anesthetic (lidocaine, 0.5%; epinephrine, 1: 200 000) immediately before the incision, her heart rate and blood pressure reached 135 beats per min and 254/185 mmHg, respectively, inducing ventricular tachycardia.
Abstract: BACKGROUND Takotsubo cardiomyopathy is a reversible left ventricular dysfunction triggered by emotional or physical stress. Perioperatively, takotsubo cardiomyopathy is sometimes induced by various psychological factors, such as stress from surgery, and non-psychological factors, such as epinephrine misinjection. This report describes a case of takotsubo cardiomyopathy induced by the administration of very low-dose epinephrine contained in a local anesthetic. CASE REPORT A 78-year-old woman with mycosis in the maxillary sinus was scheduled to undergo endoscopic sinus surgery. After the submucosal injection of 3 mL of local anesthetic (lidocaine, 0.5%; epinephrine, 1: 200 000) immediately before the incision, her heart rate and blood pressure reached 135 beats per min and 254/185 mmHg, respectively, inducing ventricular tachycardia. After receiving 50 mg of lidocaine, her cardiac rhythm resumed a normal sinus rhythm, without cardioversion. As her hemodynamics stabilized, the surgical procedure began as planned. Postoperative electrocardiography, echocardiography, and coronary arteriography demonstrated takotsubo cardiomyopathy. Subsequently, her cardiac movement gradually improved, and she was discharged from the hospital on postoperative day 9. CONCLUSIONS To the best of our knowledge, this is the first reported case in which a very small amount of epinephrine (0.015 mg) induced takotsubo cardiomyopathy. Therefore, epinephrine should be used cautiously, especially in the nasal mucosa, vaginal mucosa, and uterus, where blood flow is relatively high. If unexpected hemodynamic alterations and ST-segment abnormalities occur after epinephrine administration, asymptomatic takotsubo cardiomyopathy should be considered.
TL;DR: In this article, the authors determined the utility of AV epinephrine levels in assessing successful AV cannulation, defined by an AV/IVC cortisol ratio selectivity index (SI) ≥ 3:1.
TL;DR: In this article, the authors compared the efficacy and safety of push-dose phenylephrine (PDP-PE) and epinephrine injection in the emergency department (ED).
Abstract: Background There is limited evidence to support the efficacy and safety of push-dose vasopressor (PDP) use outside of the operating room (OR). Specifically, there are few head-to-head comparisons of different PDP in these settings. The purpose of this study was to compare the efficacy and safety of push-dose phenylephrine (PDP-PE) and epinephrine (PDP-E) in the Emergency Department (ED). Methods This retrospective, single-center study evaluated adults given PDP-PE or PDP-E in the ED from May 2017 to November 2020. The primary outcome was a change in heart rate (HR). Secondary outcomes included changes in blood pressure, adverse effects, dosing errors, fluid and vasopressor requirements, ICU and hospital lengths of stay (LOS), and in-hospital mortality. Results Ninety-six patients were included in the PDP-PE group and 39 patients in the PDP-E group. Median changes in HR were 0 [−7, 6] and − 2 [−15, 5] beats per minute (BPM) for PDP-PE and PDP-E, respectively (p = 0.138). PDP-E patients had a greater median increase in systolic blood pressure (SBP) (33 [24, 53] vs. 26 [8, 51] mmHg; p = 0.049). Dosing errors occurred more frequently in patients that received PDP-E (5/39 [12.8%] vs. 2/96 [2.1%]; p = 0.021). PDP-E patients more frequently received continuous epinephrine infusions before and after receiving PDP-E. There were no differences in adverse effects, fluid requirements, LOS, or mortality. Conclusion PDP-E provided a greater increase in SBP compared to PDP-PE. However, dosing errors occurred more frequently in those receiving PDP-E. Larger head-to-head studies are necessary to further evaluate the efficacy and safety of PDP-E and PDP-PE.
TL;DR: In this paper, a single-center, randomized clinical trial aimed to investigate the efficacy and safety of dopamine versus norepinephrine in postcardiotomy circulatory shock, and the results showed that dopamine as a first-line vasopressor was associated with higher tachyarrhythmic events and greater need for additional VIAs.
Abstract: BACKGROUND AND AIM OF THE STUDY Although dopamine and norepinephrine are recommended as first-line agents in the treatment of shock, it is unclear which is the optimal vasoactive inotropic agent (VIA) to manage postcardiotomy circulatory shock. This single-center, randomized clinical trial aimed to investigate the efficacy and safety of dopamine versus norepinephrine in postcardiotomy circulatory shock. METHODS We randomly assigned the patients with postcardiotomy circulatory shock to receive either dopamine or norepinephrine. When shock persisted despite the dose of 20 μg/kg/min of dopamine or the dose of 0.2 μg/kg/min of norepinephrine, epinephrine or vasopressin could be added. The primary endpoint was new-onset tachyarrhythmic event during drug infusion. Secondary endpoints included requirement of additional VIAs, postoperative complications, and all-cause mortality within 30 days of drug initiation. RESULTS At the planned interim analysis of 100 patients, the boundary for the benefit of norepinephrine has been crossed, and the study was stopped early. Excluding two patients withdrawing a consent, 48 patients were assigned to dopamine and 50 patients to norepinephrine. New-onset tachyarrhythmic event occurred in 12 (25%) patients in the dopamine and one (2%) patient in the norepinephrine group (p = .009). The requirement for additional VIAs was more common in the dopamine group (p < .001). Other secondary endpoints were similar between groups. CONCLUSIONS Despite the limited study subjects with early determination, in patients with postcardiotomy circulatory shock, dopamine as a first-line vasopressor was associated with higher tachyarrhythmic events and greater need for additional VIAs compared with norepinephrine.
TL;DR: In this article, the impact of ginseng extract on epinephrine-induced myocardial infarction (MI) and its renal complication was assessed; however, the authors did not consider the effect of the drug on the renal function.
Abstract: The expression of angiotensin II type 1 receptor (AT1 receptor)/protein kinase C (PKC) in heart tissues has a vital role in myocardial infarction (MI). The current work aimed to clarify the renal complication enhanced by MI following epinephrine injection via AT1 receptor/ PKC expression; in addition, the impact of ginseng extract on epinephrine-induced MI and its renal complication was assessed. Adult male albino Wistar rats were pretreated orally with ginseng extract (200 & 400 mg/kg/day) for 14 days, then two successive doses of epinephrine injection (100 mg/kg, i.p.). Epinephrine evoked electrocardiographic (ECG) and renal changes accompanied with a significant increase in heart and kidney contents of malodialdehyde (MDA), nitric oxide (NO), protein kinase C (PKC), heart contents of nuclear factor-kabba B (NF-κB) and angiotensin 1receptor (AT1R), as well as a decrease in heart and kidney reduced glutathione (GSH) and nuclear factor-erythroid-related factor 2 (Nrf2) contents. In histopathological investigations epinephrine exhibited deleterious heart changes in the form of acute MI with the presence of necrosis of cardiomyocytes with iNOS expression and produced glomerulus and renal tubules degeneration. Pretreatment of rats with ginseng extract in both doses significantly corrected epinephrine-induced heart and renal changes. The current work revealed that epinephrine-induced MI associated with aggravated renal complication and ginseng extract has cardio and reno protective role against this as it reduces infarct size, preserves cardiac and renal tissues and functions through activating Nrf2 and down-regulating NF-κB, PKC, AT1R and iNOS.
TL;DR: In this article, the authors examined the clinical significance of epinephrine deficiency in the first year of life in infants with classical congenital adrenal hyperplasia (CAH).
Abstract: Context Youth with classical congenital adrenal hyperplasia (CAH) exhibit abnormal adrenomedullary function with decreased epinephrine levels noted in newborns and young infants. Little is known about how this relates to morbidity during the first year of life. Objective To study plasma epinephrine levels in infants with classical CAH and examine the clinical significance of epinephrine deficiency in the first year of life. Design Prospective cohort study. Setting Study participants were recruited from a pediatric tertiary care center. Patients or other participants 36 infants with classical CAH due to 21-hydroxylase deficiency and 27 age-matched unaffected controls with congenital hypothyroidism. Main outcome measures Plasma epinephrine levels (N=27), CYP21A2 genotype (N=15), and incidence of acute illnesses from birth to 1 year of age (N=28). Results Epinephrine levels in CAH infants independently predicted illness incidence in the first year of life (β=-0.018, R=-0.45, P=0.02) and were negatively correlated with 17-hydroxyprogesterone at diagnosis (R=-0.51, P=0.007). Infants with salt-wasting CAH exhibited lower epinephrine levels as newborns than simple-virilizing infants (P=0.02). CAH patients had lower epinephrine as newborns than controls (P=0.007) and showed decreases in epinephrine from birth to 1 year of age (P=0.04). Null genotype was associated with lower newborn epinephrine and more illness in the first year of life, compared to less severe mutation categories. Conclusions Lower epinephrine levels are associated with increased risk of illness among CAH infants. While not currently part of clinical standard of care, measuring epinephrine levels and assessing genotype may help predict acute illness in the first year of life.