Showing papers on "Epinephrine published in 2013"

Anaphylaxis: clinical patterns, mediator release, and severity.

Abstract: Background Prospective human studies of anaphylaxis and its mechanisms have been limited, with few severe cases or examining only 1 or 2 mediators. Objectives We wanted to define the clinical patterns of anaphylaxis and relationships between mediators and severity. Methods Data were collected during treatment and before discharge. Serial blood samples were taken for assays of mast cell tryptase, histamine, anaphylatoxins (C3a, C4a, C5a), cytokines (IL-2, IL-6, IL-10), soluble tumor necrosis factor receptor I, and platelet activating factor acetyl hydrolase. Principal component analysis defined mediator patterns, and logistic regression identified risk factors and mediator patterns associated with reaction severity and delayed reactions. Results Of 412 reactions in 402 people, 315 met the definition for anaphylaxis by the National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network. Of 97 severe reactions 45 (46%) were hypotensive, 23 (24%) were hypoxemic, and 29 (30%) were mixed. One patient died. Severe reactions were associated with older age, pre-existing lung disease, and drug causation. Delayed deteriorations treated with epinephrine occurred in 29 of 315 anaphylaxis cases (9.2%) and were more common after hypotensive reactions and with pre-existing lung disease. Twenty-two of the 29 delayed deteriorations (76%) occurred within 4 hours of initial epinephrine treatment. Of the remaining 7 cases, 2 were severe and occurred after initially severe reactions, within 10 hours. All mediators were associated with severity, and 1 group (mast cell tryptase, histamine, IL-6, IL-10, and tumor necrosis factor receptor I) was also associated with delayed deteriorations. Low platelet activating factor acetyl hydrolase activity was associated with severe reactions. Conclusion The results suggest that multiple inflammatory pathways drive reaction severity and support recommendations for safe observation periods after initial treatment.

Anaphylaxis in dogs and cats.

Abstract: Objective To review and summarize current information regarding the pathophysiology and clinical manifestations associated with anaphylaxis in dogs and cats. The etiology, diagnosis, treatment, and prognosis is discussed. Etiology Anaphylaxis is a systemic, type I hypersensitivity reaction that often has fatal consequences. Many of the principal clinical manifestations involve organs where mast cell concentrations are highest: the skin, the lungs, and the gastrointestinal tract. Histamine and other deleterious inflammatory mediators promote vascular permeability and smooth muscle contraction; they are readily released from sensitized mast cells and basophils challenged with antigen. Anaphylaxis may be triggered by a variety of antigens including insect and reptile venom, a variety of drugs, vaccines, and food. Diagnosis Anaphylaxis is a clinical diagnosis made from a collection of signs and symptoms. It is most commonly based on pattern recognition. Differential diagnoses include severe asthma, pheocromocytoma, and mastocytosis. Therapy Epinephrine is considered the drug of choice for the treatment of anaphylaxis. It acts primarily as a vasopressor in improving hemodynamic recovery. Adjunctive treatments include fluid therapy, H1 and H2 antihistamines, corticosteroids, and bronchodilators; however, these do not substitute for epinephrine. Prognosis Prognosis depends on the severity of the clinical signs. The clinical signs will vary among species and route of exposure. The most severe clinical reactions are associated when the antigen is administered parenterally.

Epinephrine for cardiac arrest.

Abstract: Purpose of reviewEpinephrine is the primary drug administered during cardiopulmonary resuscitation (CPR) to reverse cardiac arrest. Epinephrine increases arterial blood pressure and coronary perfusion during CPR via alpha-1-adrenoceptor agonist effects. However, the dose, timing and indications for

Stress-Triggered Changes in Peripheral Catecholaminergic Systems

Abstract: The sympathetic nervous system not only regulates cardiovascular and metabolic responses to stress but also is altered by stress. The sympathoneural and sympathoadrenomedullary systems are modified by different metabolic pathways and have different responses to short- and to long-term stressors. Stress also induces nonneuronal catecholamine enzymes, primarily through corticosteroids. Catecholamine synthetic enzymes are induced by different pathways in response to short- and long-term acting stressors, like cold exposure or immobilization, and differently in the sympathetic ganglia and the adrenal medulla. However, a long-term exposure to one stressor can increase the response to a second, different stressor. Tyrosine hydroxylase gene transcription increases after only 5min of immobilization through phosphorylation of CREB, but this response is short lived. However, repeated stress gives a longer-lived response utilizing transcription factors such as Egr-1 and Fra-2. Glucocorticoids and ACTH also induce sympathoneural enzymes leading to distinct patterns of short-term and long-lived activation of the sympathetic nervous system. Nonneuronal phenylethanolamine N-methyltransferase (PNMT) develops early in the heart and then diminishes. However, intrinsic cardiac adrenergic cells remain and nonneuronal PNMT is present in many cells of the adult organism and increases in response to glucocorticoids. Both stress-induced and administered glucocorticoids induce fetal PNMT and hypertension. Human stressors such as caring for an ill spouse or sleep apnea cause a persistent increase in blood norepinephrine, increased blood pressure, and downregulated catecholamine receptors. Hypertension is associated with a loss of slow-wave sleep, when sympathetic nerve activity is lowest. These findings indicate that stress-induced alteration of the sympathetic nervous system occurs in man as in experimental animals.

β2-Adrenoceptor Agonists Are Required for Development of the Asthma Phenotype in a Murine Model

Abstract: β2-Adrenoceptor (β2AR) agonists are the most effective class of bronchodilators and a mainstay of asthma management. The first potent β2AR agonist discovered and widely used in reversing the airway constriction associated with asthma exacerbation was the endogenous activator of the β2AR, epinephrine. In this study, we demonstrate that activation of the β2AR by epinephrine is paradoxically required for development of the asthma phenotype. In an antigen-driven model, mice sensitized and challenged with ovalbumin showed marked elevations in three cardinal features of the asthma phenotype: inflammatory cells in their bronchoalveolar lavage fluid, mucin over production, and airway hyperresponsiveness. However, genetic depletion of epinephrine using mice lacking the enzyme to synthesize epinephrine, phenylethanolamine N-methyltransferase, or mice that had undergone pharmacological sympathectomy with reserpine to deplete epinephrine, had complete attenuation of these three cardinal features of the asthma phenotype. Furthermore, administration of the long-acting β2AR agonist, formoterol, a drug currently used in asthma treatment, to phenylethanolamine N-methyltransferase–null mice restored the asthma phenotype. We conclude that β2AR agonist–induced activation is needed for pathogenesis of the asthma phenotype. These findings also rule out constitutive signaling by the β2AR as sufficient to drive the asthma phenotype, and may help explain why chronic administration of β2AR agonists, such as formoterol, have been associated with adverse outcomes in asthma. These data further support the hypothesis that chronic asthma management may be better served by treatment with certain “β-blockers.”

Safety of epinephrine for anaphylaxis in the emergency setting.

Abstract: Background While epinephrine is the recommended first-line therapy for the reversal of anaphylaxis symptoms, inappropriate use persists because of misunderstandings about proper dosing and administration or misconceptions about its safety. The objective of this review was to evaluate the safety of epinephrine for patients with anaphylaxis, including other emergent conditions, treated in emergency care settings. Methods A MEDLINE search using PubMed was conducted to identify articles that discuss the dosing, administration, and safety of epinephrine in the emergency setting for anaphylaxis and other conditions. Results Epinephrine is safe for anaphylaxis when given at the correct dose by intramuscular injection. The majority of dosing errors and cardiovascular adverse reactions occur when epinephrine is given intravenously or incorrectly dosed. Conclusion Epinephrine by intramuscular injection is a safe therapy for anaphylaxis but training may still be necessary in emergency care settings to minimize drug dosing and administration errors and to allay concerns about its safety.

Predictors of epinephrine autoinjector needle length inadequacy

Abstract: Background Self-administered epinephrine is the primary out-of-hospital treatment of anaphylaxis. Intramuscular injection of epinephrine results in higher peak plasma concentration than subcutaneous injection. With the prevalence of obesity, autoinjectors may not have an adequate needle length for intramuscular injection. Objectives To measure muscle depth and evaluate predictors of autoinjector needle length inadequacy. Methods We performed a prospective cross-sectional study of a convenience sample of low acuity emergency department patients aged 18 to 55 years. We recorded demographic data, measured thigh circumference, and calculated body mass index (BMI). Using ultrasound, we took depth-to-muscle measurements of the vastus lateralus in a standing position, with and without gentle pressure to simulate muscle compression that occurs with correct autoinjector use. We conducted univariate analyses using χ 2 and t tests with P ≤ .05 and 95% confidence intervals. We considered the patient a potential "failure" risk if his/her muscle depth exceeded 15.9 mm (longest available epinephrine autoinjectors needle). Results We enrolled 120 subjects with a mean BMI of 29.2 kg/m 2 . Thirty-one percent (31%) of our sample were found to be failure risks (36/116; confidence interval, 22.6%-39.5%). Women were 6.4 times more likely than men to be a failure risk (54.4% vs 5% for men failure rate; P P Conclusion The current epinephrine autoinjector needle length is inadequate for intramuscular injection, especially among women.

Chronic exposure to stress hormones promotes transformation and tumorigenicity of 3T3 mouse fibroblasts

Abstract: Epinephrine and norepinephrine are produced during psychological stress and can directly bind to cells to induce DNA damage. These effects may have more long-lasting consequences such as DNA mutations resulting in an increased potential for cellular transformation and/or tumor progression. This study examined the molecular effects of a chronic (24 h) in vitro exposure to these stress hormones on murine 3T3 cells. Long exposures (24 h) in dose-response experiments with norepinephrine or epinephrine induced significant increases in DNA damage in treated cells compared to that of untreated controls as measured by the alkaline comet assay. Pre-treatment with a blocking agent (the β-adrenergic receptor antagonist propranolol) eliminated this increase in damage. In addition, both norepinephrine and epinephrine increased cellular transformation, as assessed by growth in soft agar, and 3T3 cells pre-treated with either norepinephrine or epinephrine induced a more rapid onset of tumors and more aggressive tumor growth in nude mice. In summary, incubation of 3T3 cells with catecholamines results in long-term DNA damage as measured by increased transformed phenotypes and tumor progression, indicating that they are important mediators of stress effects on genomic instability and vulnerability to tumor formation.

Reverse Takotsubo cardiomyopathy in the setting of anaphylaxis treated with high-dose intravenous epinephrine.

Abstract: Background Takotsubo cardiomyopathy is seen, though rarely, in anaphylaxis treated with epinephrine. Stress cardiomyopathy is most likely to occur in middle-aged women. The underlying etiology is believed to be related to catecholamine release in periods of intense stress. Catecholamines administered exogenously, and those secreted by neuroendocrine tumors (e.g., pheochromocytoma) or during anaphylaxis have been reported to cause apical ballooning syndrome, or takotsubo syndrome. However, reverse takotsubo stress cardiomyopathy is rarely seen or reported in anaphylaxis treated with epinephrine. Objectives To report a case illustrating that high-dose intravenous epinephrine can trigger stress cardiomyopathy, and that the risk is heightened with inappropriate dosing in the treatment of anaphylaxis. Case Report We report a rare case of iatrogenic reverse takotsubo syndrome in a young woman who was inappropriately treated with high-dose intravenous epinephrine for mild anaphylaxis. Conclusion Inappropriately high doses of intravenous epinephrine can trigger stress cardiomyopathy. Emergency physicians should be familiar with the diagnosis, grading, and appropriate treatments of anaphylaxis to avoid this unnecessary complication.

Methylene blue and epinephrine: a synergetic association for anaphylactic shock treatment.

Abstract: Background:Severe hypotension resulting from anaphylactic shock may be refractory to epinephrine and impair cerebral oxygenation and metabolism contributing to anaphylactic shock morbidity and mortality. Refractoriness to epinephrine could be corrected by nitric oxide pathway inhibitors such as meth

Interaction between AT1 receptor and NF-κB in hypothalamic paraventricular nucleus contributes to oxidative stress and sympathoexcitation by modulating neurotransmitters in heart failure.

Abstract: Angiotensin II type 1 receptor (AT1-R) and nuclear factor-kappaB (NF-κB) in the paraventricular nucleus (PVN) play important roles in heart failure (HF); however, the central mechanisms by which AT1-R and NF-κB contribute to sympathoexcitation in HF are yet unclear. In this study, we determined whether interaction between AT1-R and NF-κB in the PVN modulates neurotransmitters and contributes to NAD(P)H oxidase-dependent oxidative stress and sympathoexcitation in HF. Rats were implanted with bilateral PVN cannulae and subjected to coronary artery ligation or sham surgery (SHAM). Subsequently, animals were treated for 4 weeks through bilateral PVN infusion with either vehicle or losartan (LOS, 10 μg/h), an AT1-R antagonist; or pyrrolidine dithiocarbamate (PDTC, 5 μg/h), a NF-κB inhibitor via osmotic minipump. Myocardial infarction (MI) rats had higher levels of glutamate (Glu), norepinephrine (NE) and NF-κB p65 activity, lower levels of gamma-aminobutyric acid (GABA), and more positive neurons for phosphorylated IKKβ and gp91phox (a subunit of NAD(P)H oxidase) in the PVN when compared to SHAM rats. MI rats also had higher levels of renal sympathetic nerve activity (RSNA) and plasma proinflammatory cytokines (PICs), NE and epinephrine. PVN infusions of LOS or PDTC attenuated the decreases in GABA and the increases in gp91phox, NF-κB activity, Glu and NE, in the PVN of HF rats. PVN infusions of LOS or PDTC also attenuated the increases in RSNA and plasma PICs, NE and epinephrine in MI rats. These findings suggest that interaction between AT1 receptor and NF-κB in the PVN contributes to oxidative stress and sympathoexcitation by modulating neurotransmitters in heart failure.

Combination of Epinephrine with Esmolol Attenuates Post-Resuscitation Myocardial Dysfunction in a Porcine Model of Cardiac Arrest

Abstract: Background Recent experimental and clinical studies have indicated that the β-adrenergic effect of epinephrine significantly increases the severity of post resuscitation myocardial dysfunction. The aim of the study was to investigate whether the short-acting β1-selective adrenergic blocking agent, esmolol, would attenuate post resuscitation myocardial dysfunction in a porcine model of cardiac arrest. Methods and Results After 8 min of untreated ventricular fibrillation and 2 min of basic life support, 24 pigs were randomized to three groups (n = 8 per group), which received central venous injection of either epinephrine combined with esmolol (EE group), epinephrine (EP group), or saline (SA group). Hemodynamic status and blood samples were obtained at 0, 30, 60, 120, 240 and 360 min after return of spontaneous circulation (ROSC). Surviving pigs were euthanatized at 24 h after ROSC, and the hearts were removed for analysis by electron microscopy, Western blotting, quantitative real-time polymerase chain reaction, and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) assay. Compared with the EP and SA groups, EE group had a better outcome in hemodynamic function, (improved dp/dt maxima and minima and cardiac output) (P<0.05), and improved oxygen metabolism (oxygen delivery and oxygen consumption) (P<0.05), which suggesting that EE can protect myocardial tissue from injury and improve post-resuscitation myocardial dysfunction. The protective effect of EE also correlated with reducing cardiomyocyte apoptosis, evidenced by reducing TUNEL-positive cells, increasing anti-apoptotic Bcl-2/Bax ratio and suppression of caspase-3 activity in myocardium. Conclusions Esmolol, a short-acting β1-selective adrenergic blocking agent, given during CPR has significant effects on attenuating post resuscitation myocardial dysfunction. The current study provides a potential pharmacologic target for post resuscitation myocardial dysfunction.

Customizing anaphylaxis guidelines for emergency medicine.

Abstract: Background Most episodes of anaphylaxis are managed in emergency medical settings, where the cardinal signs and symptoms often differ from those observed in the allergy clinic. Data suggest that low recognition of anaphylaxis in the emergency setting may relate to inaccurate coding and lack of a standard, practical definition. Objective Develop a simple, consistent definition of anaphylaxis for emergency medicine providers, supported by clinically relevant consensus statements. Discussion Definitions of anaphylaxis and criteria for diagnosis from current anaphylaxis guidelines were reviewed with regard to their utilization in emergency medical settings. The agreed-upon working definition is: Anaphylaxis is a serious reaction causing a combination of characteristic findings, and which is rapid in onset and may cause death. It is usually due to an allergic reaction but can be non-allergic. The definition is supported by Consensus Statements, each with referenced discussion. For a positive outcome, quick diagnosis and treatment of anaphylaxis are critical. However, even in the emergency setting, the patient may not present with life-threatening symptoms. Because mild initial symptoms can quickly progress to a severe, even fatal, reaction, the first-line treatment for any anaphylaxis episode—regardless of severity—is intramuscular injection of epinephrine into the anterolateral thigh; delaying its administration increases the potential for morbidity and mortality. When a reaction appears as “possible anaphylaxis,” it is generally better to err on the side of caution and administer epinephrine. Conclusion We believe that this working definition and the supporting Consensus Statements are a first step to better management of anaphylaxis in the emergency medical setting.

Spleen volume changes during adrenergic stimulation with low doses of epinephrine.

Abstract: It is generally accepted that the spleen contraction is a consequence of humoral stimulation but recent data suggest a role of neural mechanisms. This study tested the hypothesis that the reduction in spleen size in response to low dose epinephrine infusion is a consequence of neurally mediated unloading of baroreceptors. Continuous ultrasonic measurements of spleen volume in response to intravenous infusion of low doses of epinephrine (0.06 μg/kg/min for 6 minutes, followed 0.12 μg/kg/min for 3 minutes) were performed with simultaneous continuous noninvasive measurements of cardiovascular parameters in thirteen subjects. In subgroup of six subjects we also continuously measured muscle sympathetic nerve activity (MSNA) as an index of peripheral sympathetic activation. Significant spleen contraction (≈30%, p=0.008) was observed early after the onset of epinephrine infusion and was preceded by a decrease in total peripheral resistance (41%, p=0.001) and mean arterial pressure (6.2%, p=0.02) and an increase in heart rate (27%, p=0.001) and total MSNA (120%, p=0.02). Our results demonstrate rapid spleen contraction induced by low-dose epinephrine infusion in conditions of decreased blood pressure and increased MSNA suggesting that the spleen may represent a constitutive part of the sympathetic nervous system under stressful situations.

Clinical evaluation of pediatric anaphylaxis and the necessity for multiple doses of epinephrine

Abstract: BACKGROUND Epinephrine administered intramuscularly is the treatment of choice for anaphylaxis, and more than 1 dose is occasionally required. OBJECTIVE To determine clinical background of anaphylaxis for improving the treatment, management, and prognosis of anaphylaxis. METHODS Children who had satisfied the diagnostic criteria for anaphylaxis according to the National Institute of Allergy and Infectious Disease Food Allergy and Anaphylaxis Network were selected from our hospital from April 1, 2009 to March 31, 2012. RESULTS We analyzed 61 patients from the ages of 2 months to 14 years who satisfied the diagnostic criteria for anaphylaxis. Parents of 32 children (52.5%) reported that they had been administered single dose of epinephrine, and 3 children (4.9%) reported receiving multiple doses of epinephrine. The latter group experienced syncope more often (p = 0.049) than the former and suffered more often from comorbid allergic diseases (p = 0.043) that included either bronchial asthma, allergic rhinitis, or atopic dermatitis. Two (3.3%) children experienced biphasic reactions. Patients who experienced a biphasic reaction were more likely to have experienced syncope (p = 0.033), vomiting (p = 0.02), and administration of multiple doses of epinephrine (p = 0.0016). CONCLUSION Our findings lead us to recommend that children receiving more than 1 injection of epinephrine should be observed for 24 hours, because it seems that children with requiring more than 1 injection of epinephrine might be have biphasic reactions.

Methylene blue for the treatment of refractory anaphylaxis without hypotension

Abstract: Anaphylaxis is a life-threatening reaction treated primarily with epinephrine. Methylene blue, a competitive inhibitor of guanylate cyclase, interferes with the vasodilatory actions of nitric oxide. It has recently been proposed by the Joint Taskforce on Practice Parameters as an alternative treatment for anaphylaxis with hypotension that is not responsive to classical therapy. Little evidence supports its use in normotensive patients with refractory anaphylaxis. We present the case of a 43-year-old woman with severe anaphylaxis unresponsive to epinephrine. Physical examination revealed marked respiratory distress, raised oral lesions, and altered mental status but lacked hypotension. After infusion of methylene blue, symptom resolution occurred almost immediately, and intubation was spared. Side effects were minimal. We propose methylene blue as a safe treatment option for refractory anaphylaxis, whether with or without hypotension.

Impaired conditioned fear response and startle reactivity in epinephrine-deficient mice.

Abstract: Norepinephrine and epinephrine signaling is thought to facilitate cognitive processes related to emotional events and heightened arousal, however, the specific role of epinephrine in these processes is less known. To investigate the selective impact of epinephrine on arousal and fear-related memory retrieval, mice unable to synthesize epinephrine (phenylethanolamine N-methyltransferase knockout, PNMT-KO) were tested in context and cued fear conditioning. To assess the role of epinephrine in other cognitive and arousal-based behaviors these mice were also tested for acoustic startle, prepulse inhibition, novel object recognition and open field activity. Our results show that compared to wild-type (WT) mice, PNMT-KO mice displayed reduced context fear but normal cued fear. Mice exhibited normal memory performance in the short-term version of the novel object recognition task suggesting PNMT mice exhibit more selective memory effects on highly emotional and/or long term memories. Similarly, open field activity was unaffected by epinephrine deficiency, suggesting differences in freezing are not related to changes in overall anxiety or exploratory drive. Startle reactivity to acoustic pulses was reduced in PNMT-KO mice while prepulse inhibition was increased. These findings provide further evidence for a selective role of epinephrine in contextual fear learning, and support its potential role in acoustic startle.

Glucocorticosteroids for the treatment and prevention of anaphylaxis

Abstract: Purpose of review To review recent evidence on the effectiveness of glucocorticosteroids in the treatment and prevention of anaphylaxis. Recent findings Glucocorticosteroids are often used in the management of anaphylaxis in an attempt to reduce the severity of the acute reaction and decrease the risk of biphasic/protracted reactions. A recent Cochrane systematic review failed to identify any randomized controlled or quasi-randomized trials investigating the effectiveness of glucocorticosteroids in the emergency management of anaphylaxis. In contrast, randomized controlled trials have been undertaken of glucocorticosteroids, given individually or in combination with other drugs, in preventing anaphylaxis. Systematic reviews of these prophylactic approaches undertaken in patients being investigated with iodinated contrast media and treated with snake anti-venom therapy have found routine prophylaxis to be of questionable value. Trials of a combination of glucocorticosteroids and H1/H2-antihistamine premedication for preventing allergen immunotherapy-triggered anaphylaxis have yielded mixed results. Summary Glucocorticosteroids should be regarded, at best, as a second-line agent in the emergency management of anaphylaxis, and administration of epinephrine should therefore not be delayed whilst glucocorticosteroids are drawn up and administered. Routine premedication with glucocorticosteroids in patients receiving iodinated contrast media, snake anti-venom therapy or allergen immunotherapy is unlikely to confer clinical benefit.

Clinical management of the cardiovascular failure in sepsis.

Abstract: Cardiovascular failure in sepsis involves a combination of hypovolemia, decreased vascular tone, myocardial depression and microcirculatory alterations. Fluids represent the first line therapeutic intervention, with controversy regarding the type of fluid. Recent data indicate that albumin is safe and might even be beneficial in specific subgroups. Starches may be an alternative, although concerns exist on potential detrimental effects on renal function of old generation starches. Trials testing new generation starches are ongoing. When fluids fail to correct hypotension, vasopressor agents are used. Various adrenergic agents increase blood pressure, especially dopamine, noradrenaline and adrenaline, by stimulating alpha-adrenergic receptors. They also variably stimulate beta-adrenergic receptors, increasing cardiac contractility, heart rate, and splanchnic perfusion, but with increased risk of arrhythmias, immunomodulation and increased metabolism. Furthermore, dopamine stimulates dopaminergic receptors, resulting in doubtful effects on splanchnic and renal perfusion, but also in endocrine alterations. Do these pharmacologic differences among the various alpha-adrenergic agents translate into clinical differences? Several randomized trials tested the effects of these agents on outcome. Epinephrine produces more undesired effects than norepinephrine, but no clear cut differences on outcome were observed in underpowered trials. Norepinephrine should be preferred over dopamine, as suggested in one large trial and confirmed in a meta-analysis. Vasopressin may be considered as an alternative or in addition to adrenergic agents. In one large trial, no significant difference in outcome was observed, and the exact role of vasopressin still needs clarification. Finally, various inotropic agents can counteract septic myocardial depression. So far, no study supports their routine use, but these may be justified on an individual basis.

Sympathetic cardiac hyperinnervation and atrial autonomic imbalance in diet-induced obesity promote cardiac arrhythmias.

Abstract: Obesity increases the risk of arrhythmias and sudden cardiac death, but the mechanisms are unknown. This study tested the hypothesis that obesity-induced cardiac sympathetic outgrowth and hyperinnervation promotes the development of arrhythmic events. Male Sprague-Dawley rats (250–275 g), fed a high-fat diet (33% kcal/fat), diverged into obesity-resistant (OR) and obesity-prone (OP) groups and were compared with rats fed normal chow (13% kcal/fat; CON). In vitro experiments showed that both OR and OP rats exhibited hyperinnervation of the heart and high sympathetic outgrowth compared with CON rats, even though OR rats are not obese. Despite the hyperinnervation and outgrowth, we showed that, in vivo, OR rats were less susceptible to arrhythmic events after an intravenous epinephrine challenge compared with OP rats. On examining total and stimulus-evoked neurotransmitter levels in an ex vivo system, we demonstrate that atrial acetylcholine content and release were attenuated in OP compared with OR and CON groups. OP rats also expressed elevated atrial norepinephrine content, while norepinephrine release was suppressed. These findings suggest that the consumption of a high-fat diet, even in the absence of overt obesity, stimulates sympathetic outgrowth and hyperinnervation of the heart. However, normalized cardiac parasympathetic nervous system control may protect the heart from arrhythmic events.

Endocrine Disruption in the European Eel, Anguilla anguilla, Exposed to an Environmental Cocaine Concentration

Abstract: The aim of the present study was to verify if cocaine, at environmental concentrations, influences the endocrine system of the European eel. Silver eels (a stage of the eel life cycle preparing the fish for the oceanic reproductive migration) were exposed to a nominal cocaine concentration of 20 ng/l during 30 days; at the same time, control, carrier, and postexposure recovery groups were made. The effects of cocaine were observed in (1) brain dopamine content, (2) plasma catecholamine levels (dopamine, norepinephrine, and epinephrine), (3) pituitary–adrenal axis activity [plasma adrenocorticotropic hormone (ACTH), corticosterone, cortisol, and aldosterone levels], and (4) pituitary–thyroid axis activity [plasma thyroid-stimulating hormone (TSH), triiodothyronine, and thyroxine levels]. In the treated group, brain dopamine, plasma catecholamines, cortisol, and TSH levels were higher, whereas ACTH, corticosterone, and triiodothyronine levels were lower than controls. In the postexposure recovery group, brain dopamine, plasma dopamine and epinephrine, and thyroxine levels further increased, whereas plasma norepinephrine, cortisol, and corticosterone levels were similar to treated values. Finally, ACTH and TSH were similar, whereas triiodothyronine levels were lower than controls. Aldosterone levels were unaffected by cocaine exposure. The results of the present study show that cocaine, at environmental concentrations, behaves like an endocrine disruptor changing brain dopamine and plasma catecholamine levels and the activity of pituitary–adrenal/thyroid axes. Since the endocrine system plays a key role in the metabolic and reproductive processes of the eel, our results suggest that environmental cocaine could be considered another cause for the decline in the European eel.

Antivenom for snake bite in Korea

Abstract: In Korea, there are four types of snakes, Glyoidius brevicaudus, G. intermedius (formerly named, saxatilis), G. ussuriensis, Rhabdophis tigrinus. The case-fatality rate in snake bite envenomation is very low. Snake venom is a heterogeneous mixture of pharmacologically active enzymatic, non-enzymatic protein, peptide toxins, other organic and inorganic substances. The pathophysiology evokes a complex series of events that depend on the combined and synergistic action of toxic and non-toxic components. The manifestation includes local and systemic effects. Local tissue effects includes of tissue pain, redness, swelling, tenderness, bullae formation, and necrosis. The major systemic manifestations of snake bite include neurotoxicity, myotoxicity, cytotoxicity, hemolytic, procoagulant, hemorrhagic, and hypotensive effects and interfere in platelet function. General care includes parenteral analgesia, antivenom administration, and serial assessments of limb swelling and laboratory tests. Despite the presence of soft tissue inflammation, prophylactic antibiotics are rarely required, and most patients achieve good outcomes with supportive care and antivenom alone. In the case of mild poisoning do not need to be treated with antivenom. In moderate to severe envenomation, antivenom should be administered. When administered antivenom, adverse reactions are monitored closely and treated early with epinephrine and anti-histamine. In future, we should establish algorithm provides guidance about clinical and laboratory observations, indications for and dosing of antivenom, adjunctive therapies, post-stabilization care, and management of complications from envenomation and therapy.

Catecholamine dosing and survival in adult intensive care unit patients.

Abstract: Volume management and vasopressor support remain the gold standard of critical care for patients with shock. However, prolonged therapy with catecholamines in high doses is associated with a negative patient outcome. The aim of the present study was to analyze the administered levels of catecholamines over time with respect to survival, and to identify a cut-off to allow a prediction of survival. Consecutively, 9,108 adult patients during 22 months were evaluated. This group included 1,543 patients treated with epinephrine and/or norepinephrine with any dose at any time. Time and dosages of the applied drugs, the sequential organ failure assessment and acute and chronic health evalutation II scores on admission and daily, the length of intensive care unit stay, and the outcomes were recorded. The non-survivors received higher doses of norepinephrine and epinephrine than the survivors (p < 0.001). The receiver operator characteristic curve for the area under the curve with non-survival as the classifier revealed a cut-off level of 294.33 μg/kg for norepinephrine with a sensitivity of 74.73 % and a specificity of 70.48 % and a cut-off for epinephrine of 70.36 μg/kg with a sensitivity of 83.87 % and a specificity of 72.79 %. Dose-dependent time curves using these cut-off values were calculated. Survival of patients with prolonged therapy with norepinephrine and epinephrine above the evaluated thresholds is poor, whereas short-term application of high-dose catecholamines is not associated with poor outcome. Therefore, it remains for the individual clinician, patients, and their surrogates to decide whether the use of high doses of vasopressors is appropriate in view of the low probability of survival.

Epinephrine nanoparticles, methods of fabrication thereof, and methods for use thereof for treatment of conditions responsive to epinephrine

Abstract: The invention provides compositions including epinephrine nanoparticles and methods for therapeutic use of the compositions in the treatment of conditions responsive to epinephrine such as a cardiac event or an allergic reaction, particularly anaphylaxis. The epinephrine nanoparticles can be incorporated into orally-disintegrating and fast-disintegrating tablet pharmaceutical formulations and can significantly increase the sublingual bioavailability of epinephrine, and thereby reduce the epinephrine dose required. Additionally, the invention provides methods for fabrication of stabilized epinephrine nanoparticles for use in the described compositions.

Epinephrine-induced myocardial infarction in severe anaphylaxis: is nonselective β-blockade a contributory factor?

Abstract: Epinephrine-induced myocardial ischemia in the setting of anaphylaxis is a rare event and is postulated to be due to coronary artery spasm. We report the case of a 43-year-old woman who presented to the emergency department with an anaphylactic reaction triggered by flucloxacillin. She was treated with intramuscular epinephrine, following which she developed ischemic chest pain and electrocardiographic changes, associated with troponin elevation. Subsequent coronary angiography demonstrated normal coronary arteries. In this case report, we discuss the potential role of prior nonselective β-blockade with propranolol in predisposing such patients to ischemic cardiac events following treatment with epinephrine.

Effects of Shen-Fu Injection on the Expression of T-Cell-Specific Transcription Factors T-bet/Gata-3 in Porcine Postresuscitation Lung Injury

Abstract: Shen-Fu injection (SFI) derived from the ancient traditional Chinese medicine. In this study, the effects of SFI on the expression of T-bet/GATA-3 and its potential mechanisms causing the shift of T cells from Th2 to Th1 on postresuscitation lung injury were examined in a porcine model of cardiac arrest. 30 pigs were randomly divided into SHAM () and three return of spontaneous circulation (ROSC) groups ( per group); 24 pigs were subjected to 8 min of electrically induced cardiac arrest and 2 min of basic life support, which received central venous injection of Shen-Fu (SFI), epinephrine (EP) or saline (SA). After successful ROSC, 18 surviving pigs were sacrificed at 24 h after ROSC ( per group). The levels of serum and lung tissue interleukin (IL)-4 and interferon (IFN)-γ were measured by ELISA, and the protein and mRNA levels of GATA-3 and T-bet in the lung tissue were determined by western blotting and quantitative real-time polymerase chain reaction, respectively. Compared with the EP and SA groups, SFI treatment reduced the levels of IL-4 (), increased levels of IFN-γ (), and induced T-bet mRNA upregulation and GATA-3 mRNA downregulation (). SFI attenuated lung injury and regulated lung immune disorders. Therefore, SFI could protect postresuscitation lung injury by modulating a Th1/Th2 imbalance.