Showing papers on "Epinephrine published in 2012"

High Levels of Circulating Epinephrine Trigger Apical Cardiodepression in a β2-Adrenergic Receptor/Gi–Dependent Manner A New Model of Takotsubo Cardiomyopathy

Abstract: Background—Takotsubo cardiomyopathy is an acute heart failure syndrome characterized by myocardial hypocontractility from the mid left ventricle to the apex. It is precipitated by extreme stress and can be triggered by intravenous catecholamine administration, particularly epinephrine. Despite its grave presentation, Takotsubo cardiomyopathy is rapidly reversible, with generally good prognosis. We hypothesized that this represents switching of epinephrine signaling through the pleiotropic β2-adrenergic receptor (β2AR) from canonical stimulatory G-protein–activated cardiostimulant to inhibitory G-protein–activated cardiodepressant pathways. Methods and Results—We describe an in vivo rat model in which a high intravenous epinephrine, but not norepinephrine, bolus produces the characteristic reversible apical depression of myocardial contraction coupled with basal hypercontractility. The effect is prevented via Gi inactivation by pertussis toxin pretreatment. β2AR number and functional responses were greater...

Renalase Lowers Ambulatory Blood Pressure by Metabolizing Circulating Adrenaline

Abstract: Background Blood pressure is acutely regulated by the sympathetic nervous system through the action of vasoactive hormones such as epinephrine, norepinephrine, and dopamine. Renalase, a recently described, secreted flavoprotein, acutely decreases systemic pressure when administered in vivo. Single‐nucleotide polymorphisms present in the gene are associated with hypertension, cardiac disease, and diabetes. Although renalase's crystal structure was recently solved, its natural substrate(s) remains undefined. Methods and Results Using in vitro enzymatic assays and in vivo administration of recombinant renalase, we show that the protein functions as a flavin adenine dinucleotide– and nicotinamide adenine dinucleotide–dependent oxidase that lowers blood pressure by degrading plasma epinephrine. The enzyme also metabolizes the dopamine precursor L‐3,4‐dihydroxyphenylalanine but has low activity against dopamine and does not metabolize norepinephrine. To test if epinephrine and L‐3,4‐dihydroxyphenylalanine were renalase's only substrates, 17 246 unique small molecules were screened. Although the search revealed no additional, naturally occurring compounds, it identified dobutamine, isoproterenol, and α‐methyldopa as substrates of renalase. Mutational analysis was used to test if renalase's hypotensive effect correlated with its enzymatic activity. Single–amino acid mutations that decrease its enzymatic activity to varying degrees comparably reduce its hypotensive effect. Conclusions Renalase metabolizes circulating epinephrine and L‐3,4‐dihydroxyphenylalanine, and its capacity to decrease blood pressure is directly correlated to its enzymatic activity. These findings highlight a previously unrecognized mechanism for epinephrine metabolism and blood pressure regulation, expand our understanding of the sympathetic nervous system, and could lead to the development of novel therapeutic modalities for the treatment of hypertension. ( J Am Heart Assoc . 2012;1:e002634 doi: 10.1161/JAHA.112.002634.)

Impact of Early Intravenous Epinephrine Administration on Outcomes Following Out-of-Hospital Cardiac Arrest

Abstract: Background: The effectiveness of epinephrine administration for cardiac arrests has been shown in animal models, but the clinical effect is still controversial. Methods and Results: A prospective, population-based, observational study in Osaka involved consecutive outof-hospital cardiac arrest (OHCA) patients from January 2007 through December 2009. We evaluated the outcomes among adult non-traumatic bystander-witnessed OHCA patients for whom the local protocol directed the emergency medical service personnel to administer epinephrine. After stratifying by first documented cardiac rhythm, outcomes were compared among the following groups: non-administration, ≤10, 11–20 and ≥21 min as the time from emergency call to epinephrine administration. A total of 3,161 patients were eligible for our analyses, among whom 1,013 (32.0%) actually received epinephrine. The epinephrine group had a significantly lower rate of neurologically intact 1-month survival than the non-epinephrine group (4.1% vs. 6.1%, P=0.028). In cases of ventricular fibrillation (VF) arrest, patients in the early epinephrine group who received epinephrine administration within 10 min had a significantly higher rate of neurologically intact 1-month survival compared with the non-epinephrine group (66.7% vs. 24.9%), though other epinephrine groups did not. In cases of non-VF arrest, the rate of neurologically intact 1month survival was low, irrespective of epinephrine administration. Conclusions: The effectiveness of epinephrine after OHCA depends on the time of administration. When epinephrine is administered in the early phase, there is an improvement in neurological outcome from OHCA with VF. (Circ J 2012; 76: 1639 – 1645)

Epinephrine: a short- and long-term regulator of stress and development of illness : a potential new role for epinephrine in stress.

Abstract: Epinephrine (Epi), which initiates short-term responses to cope with stress, is, in part, stress-regulated via genetic control of its biosynthetic enzyme, phenylethanolamine N-methyltransferase (PNMT). In rats, immobilization (IMMO) stress activates the PNMT gene in the adrenal medulla via Egr-1 and Sp1 induction. Yet, elevated Epi induced by acute and chronic stress is associated with stress induced, chronic illnesses of cardiovascular, immune, cancerous, and behavioral etiologies. Major sources of Epi include the adrenal medulla and brainstem. Although catecholamines do not cross the blood-brain barrier, circulating Epi from the adrenal medulla may communicate with the central nervous system and stress circuitry by activating vagal nerve β-adrenergic receptors to release norepinephrine, which could then stimulate release of the same from the nucleus tractus solitarius and locus coeruleus. In turn, the basal lateral amygdala (BLA) may activate to stimulate afferents to the hypothalamus, neocortex, hippocampus, caudate nucleus, and other brain regions sequentially. Recently, we have shown that repeated IMMO or force swim stress may evoke stress resiliency, as suggested by changes in expression and extinction of fear memory in the fear-potentiated startle paradigm. However, concomitant adrenergic changes seem stressor dependent. Present studies aim to identify stressful conditions that elicit stress resiliency versus stress sensitivity, with the goal of developing a model to investigate the potential role of Epi in stress-associated illness. If chronic Epi over expression does elicit illness, possibilities for alternative therapeutics exist through regulating stress-induced Epi expression, adrenergic receptor function and/or corticosteroid effects on Epi, adrenergic receptors and the stress axis.

Intravenous Epinephrine Infusion Test in Diagnosis of Catecholaminergic Polymorphic Ventricular Tachycardia

Abstract: Epinephrine Infusion in Diagnosis of CPVT. Introduction: A test involving intravenous infusion of epinephrine has been proposed as a method alternative to exercise stress test in diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT). We aimed at estimating the predictive value of intravenous epinephrine administration in CPVT patients with frequent exercise-induced ventricular ectopy. Methods and Results: We recruited 81 subjects, including 25 CPVT-linked ryanodine receptor 2 (RYR2) mutation carriers, 11 genetically undefined CPVT patients, and 45 unaffected family members. All subjects underwent a maximal exercise stress test and an intravenous epinephrine infusion test. Exercise stress test was positive in 25 (31%) patients including 14 of 25 (56%) established RYR2-mutation carriers and all 11 (100%) genetically undefined CPVT patients. Epinephrine infusion induced arrhythmias in 3 (12%) RYR2-mutation carriers, 4 (36%) genetically undefined CPVT patients, and 1 (2%) unaffected family member. A total of 18 exercise stress test positive patients did not respond to intravenous epinephrine administration, whereas only 1 epinephrine test responder had a normal exercise stress test. Thus, if exercise stress test is used as a standard, the sensitivity of the epinephrine infusion test is 28% and specificity is 98%. Conclusions: Intravenous epinephrine infusion has low sensitivity and may not be considered as an alternative method for a maximal exercise stress test in diagnosis of CPVT. (J Cardiovasc Electrophysiol, Vol. 23, pp. 194-199, February 2012)

Epinephrine and the metabolic syndrome.

Abstract: Epinephrine is the prototypical stress hormone. Its stimulation of all α and β adrenergic receptors elicits short-term systolic hypertension, hyperglycemia, and other aspects of the metabolic syndrome. Acute epinephrine infusion increases cardiac output and induces insulin resistance, but removal of the adrenal medulla has no consistent effect on blood pressure. Epinephrine is the most effective endogenous agonist at the β2 receptor. Transgenic mice that cannot make epinephrine and mice that lack the β2 receptor become hypertensive during exercise, presumably owing to the absence of β2-mediated vasodilatation. Epinephrine-deficient mice also have cardiac remodeling and poor cardiac responses to stress, but do not develop resting hypertension. Mice that cannot make epinephrine have a normal metabolism on a regular 14% fat diet but become hyperglycemic and insulin resistant when they eat a high fat diet. Vigorous exercise prevents diabetes in young mice and humans that overeat. However, exercise is a less effective treatment in older type 2 human diabetics and had no effect on glucose or insulin responses in older, diabetic mice. Sensitivity of the β2 receptor falls sharply with advancing age, and adrenal epinephrine release also decreases. However, treatment of older diabetic mice with a β2 adrenergic agonist improved insulin sensitivity, indicating that β2 subsensitivity can be overcome pharmacologically. Recent studies show that over the long term, epinephrine prevents hypertension during stress and improves glucose tolerance. The hyperglycemic influence of epinephrine is short-lived. Chronic administration of epinephrine and other β2 agonists improves cellular glucose uptake and metabolism. Overall, epinephrine counteracts the metabolic syndrome.

Comparison of equipressor doses of norepinephrine, epinephrine, and phenylephrine on septic myocardial dysfunction.

Abstract: Background Myocardial depression is a frequent event during septic shock and may mimic a cardiogenic shock state with decreased cardiac output. Nevertheless, data are scarce regarding the myocardial effects of vasopressors used to treat hypotension. In this study, the authors compared the effects of three commonly used vasopressors acting on different adrenergic receptors on myocardial function in a rodent model of septic shock, as explored with conductance catheter and positron emission tomography. Methods Septic shock was induced in rats by peritonitis. Eighteen hours after septic insult, vasopressors were titrated to increase mean arterial pressure by 20% compared with baseline values. Results We observed that peritonitis was associated with arterial hypotension and systolodiastolic dysfunction. Norepinephrine and epinephrine improved mean arterial pressure, cardiac output, and preload recruitable stroke work, a load-independent measure of systolic function, as well as diastolic function and ventriculoarterial coupling. Heart rate, myocardial oxygen consumption, and arrhythmia incidence were furthermore increased in the epinephrine group. Conversely, phenylephrine, a peripheral α-agonist, exhibited deleterious effects on systolodiastolic function and ventriculoarterial coupling. Conductance catheter and positron emission tomography yielded identical results with regard to myocardial function evolution under vasopressor treatment. Conclusions Phenylephrine, a drug without β-1 effects, was associated with decreased ventricular performance and ventriculoarterial uncoupling, whereas epinephrine and norepinephrine improved global hemodynamics and myocardial function in severely hypokinetic and hypotensive experimental septic shock. Nevertheless, epinephrine was associated with increased myocardial oxygen consumption. Thus, norepinephrine appears to be a more reliable and safer strategy as a first-line therapy in this particular setting.

Epinephrine infusion in the evaluation of unexplained cardiac arrest and familial sudden death: from the cardiac arrest survivors with preserved Ejection Fraction Registry.

Abstract: Background— Epinephrine infusion may unmask latent genetic conditions associated with cardiac arrest, including long-QT syndrome and catecholaminergic polymorphic ventricular tachycardia (VT). Methods and Results— Patients with unexplained cardiac arrest (normal left ventricular function and QT interval) and selected family members from the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry (CASPER) registry underwent epinephrine challenge at doses of 0.05, 0.10, and 0.20 μg/kg per minute. A test was considered positive for long-QT syndrome if the absolute QT interval prolonged by ≥30 ms at 0.10 μg/kg per minute and borderline if QT prolongation was 1 to 29 ms. Catecholaminergic polymorphic VT was diagnosed if epinephrine provoked ≥3 beats of polymorphic or bidirectional VT and borderline if polymorphic couplets, premature ventricular contractions, or nonsustained monomorphic VT was induced. Epinephrine infusion was performed in 170 patients (age, 42±16 years; 49% men), including 98 patients with unexplained cardiac arrest. Testing was positive for long-QT syndrome in 31 patients (18%) and borderline in 24 patients (14%). Exercise testing provoked an abnormal QT response in 42% of tested patients with a positive epinephrine response. Testing for catecholaminergic polymorphic VT was positive in 7% and borderline in 5%. Targeted genetic testing of abnormal patients was positive in 17% of long-QT syndrome patients and 13% of catecholaminergic polymorphic VT patients. Conclusions— Epinephrine challenge provoked abnormalities in a substantial proportion of patients, most commonly a prolonged QT interval. Exercise and genetic testing replicated the diagnosis suggested by the epinephrine response in a small proportion of patients. Epinephrine infusion combined with exercise testing and targeted genetic testing is recommended in the workup of suspected familial sudden death syndromes. Clinical Trial Registration— URL: . Unique identifier: [NCT00292032][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00292032&atom=%2Fcircae%2F5%2F5%2F933.atom

Hypnotic hypersensitivity to volatile anesthetics and dexmedetomidine in dopamine β-hydroxylase knockout mice.

Abstract: Background Multiple lines of evidence suggest that the adrenergic system can modulate sensitivity to anesthetic-induced immobility and anesthetic-induced hypnosis as well. However, several considerations prevent the conclusion that the endogenous adrenergic ligands norepinephrine and epinephrine alter anesthetic sensitivity. Methods Using dopamine β-hydroxylase knockout (Dbh) mice genetically engineered to lack the adrenergic ligands and their siblings with normal adrenergic levels, we test the contribution of the adrenergic ligands upon volatile anesthetic induction and emergence. Moreover, we investigate the effects of intravenous dexmedetomidine in adrenergic-deficient mice and their siblings using both righting reflex and processed electroencephalographic measures of anesthetic hypnosis. Results We demonstrate that the loss of norepinephrine and epinephrine and not other neuromodulators co-packaged in adrenergic neurons is sufficient to cause hypersensitivity to induction of volatile anesthesia. However, the most profound effect of adrenergic deficiency is retarding emergence from anesthesia, which takes two to three times as long in Dbh mice for sevoflurane, isoflurane, and halothane. Having shown that Dbh mice are hypersensitive to volatile anesthetics, we further demonstrate that their hypnotic hypersensitivity persists at multiple doses of dexmedetomidine. Dbh mice exhibit up to 67% shorter latencies to loss of righting reflex and up to 545% longer durations of dexmedetomidine-induced general anesthesia. Central rescue of adrenergic signaling restores control-like dexmedetomidine sensitivity. A novel continuous electroencephalographic analysis illustrates that the longer duration of dexmedetomidine-induced hypnosis is not due to a motor confound, but occurs because of impaired anesthetic emergence. Conclusions Adrenergic signaling is essential for normal emergence from general anesthesia. Dexmedetomidine-induced general anesthesia does not depend on inhibition of adrenergic neurotransmission.

Effect of epinephrine on platelet-activating factor–stimulated human vascular smooth muscle cells

Abstract: Background Animal and human data show that platelet-activating factor (PAF) mediates the life-threatening manifestations of anaphylaxis. Although administration of epinephrine is the mainstay of therapy of acute anaphylaxis, the interaction between epinephrine and PAF has not been studied. In particular, the effect of the timing of epinephrine administration on the action of PAF has not been examined. Objective Using human vascular smooth muscle cells (HVSMCs), we examined the effect of timing of epinephrine addition on the action of PAF. Methods The effect of epinephrine on PAF-mediated prostaglandin E 2 (PGE 2 ) release from human aortic smooth muscle cells was examined. Epinephrine was added at various times before and after PAF stimulation. Results HVSMCs stimulated with PAF released PGE 2 in a concentration- and time-dependent manner. Whereas preincubation of HVSMCs with epinephrine before the addition of PAF suppressed PGE 2 release, treatment with epinephrine after PAF stimulation was less effective with time after PAF stimulation. PGE 2 release was suppressed by means of preincubation with 8-bromo–cyclic AMP and forskolin. Conclusions PAF induced PGE 2 release from HVSMCs in a concentration- and time-dependent manner, and early addition of epinephrine was essential for the control of PAF-induced PGE 2 release. Epinephrine was most effective when administered before stimulation with PAF but was progressively less effective with time after PAF stimulation.

The role of catecholamines in the pathogenesis of neurogenic pulmonary edema associated with subarachnoid hemorrhage

Abstract: Neurogenic pulmonary edema (NPE) occurs frequently after aneurysmal subarachnoid hemorrhage (SAH), and excessive release of catecholamines (epinephrine/norepinephrine) has been suggested as its principal cause. The objective of this retrospective study is to evaluate the relative contribution of each catecholamine in the pathogenesis of NPE associated with SAH. Records of 63 SAH patients (20 men/43 women) whose plasma catecholamine levels were measured within 48 h of SAH onset were reviewed, and the clinical characteristics and laboratory data of those who developed early-onset NPE were analyzed thoroughly. Seven patients (11 %) were diagnosed with NPE on admission. Demographic comparison revealed that the NPE+ group sustained more severe SAH than the NPE− group. Cardiac dysfunction was also significantly more profound in the former, and the great majority of the NPE+ group sustained concomitant cardiac wall motion abnormality. There was no significant difference in the plasma epinephrine levels between NPE+ and NPE− group (324.6 ± 172.8 vs 163.1 ± 257.2 pg/ml, p = 0.11). By contrast, plasma norepinephrine levels were significantly higher in the NPE+ group (2977.6 ± 2034.5 vs 847.9 ± 535.6 pg/ml, p < 0.001). Multivariate regression analysis revealed that increased norepinephrine levels were associated with NPE (OR, 1.003; 95 % CI, 1.002–1.007). Plasma epinephrine and norepinephrine levels were positively correlated (R = 0.48, p < 0.001). According to receiver operating characteristic curve analysis, the threshold value for plasma norepinephrine predictive of NPE was 2,000 pg/ml, with an area under the curve value of 0.85. Elevated plasma norepinephrine may have more active role in the pathogenesis of SAH-induced NPE compared with epinephrine, although both catecholamines may be involved via multiple signaling pathways.

Marked resistance of femoral adipose tissue blood flow and lipolysis to adrenaline in vivo

Abstract: Fatty acid entrapment in femoral adipose tissue has been proposed to prevent ectopic fat deposition and visceral fat accumulation, resulting in protection from insulin resistance. Our objective was to test the hypothesis of femoral, compared with abdominal, adipose tissue resistance to adrenergic stimulation in vivo as a possible mechanism. Regional fatty acid trafficking, along with the measurement of adipose tissue blood flow (ATBF) with 133Xe washout, was studied with the arteriovenous difference technique and stable isotope tracers in healthy volunteers. Adrenergic agonists (isoprenaline, adrenaline [epinephrine]) were infused either locally by microinfusion or systemically. Local microinfusion of adrenoceptor antagonists (propranolol, phentolamine) was used to characterise specific adrenoceptor subtype effects in vivo. Femoral adipose tissue NEFA release and ATBF were lower during adrenaline stimulation than in abdominal tissue (p < 0.001). Mechanistically, femoral adipose tissue displayed a dominant α-adrenergic response during adrenaline stimulation. The α-adrenoceptor blocker, phentolamine, resulted in the ‘disinhibition’ of the femoral ATBF response to adrenaline (p < 0.001). Fatty acids, once stored in femoral adipose tissue, are not readily released upon adrenergic stimulation. Femoral adipose tissue resistance to adrenaline may contribute to the prevention of ectopic fatty acid deposition.

Epinephrine Induces Rapid Deterioration in Pulmonary Oxygen Exchange in Intact, Anesthetized Rats A Flow and Pulmonary Capillary Pressure-dependent Phenomenon

Abstract: Background Previous studies indicate epinephrine adversely affects arterial oxygenation when administered in a rat model of local anesthetic overdose. The authors tested whether epinephrine alone exerts similar effects in the intact animal. Methods Anesthetized rats received a single intravenous injection of epinephrine (25, 50, or 100 mcg/kg); matched cohorts were pretreated with phentolamine (100 mcg/kg); n = 5 for each of the six treatment groups. Arterial pressure and blood gases were measured at baseline, 1 and 10 min after epinephrine administration. Pulmonary capillary pressures during epinephrine infusion with normal and increased flows were measured in an isolated lung preparation. Results Epinephrine injection in the intact animal caused hypoxemia, hypercapnia, and acidosis at all doses. Arterial oxygen tension was reduced within 1 min of injection. Hyperlactatemia occurred by 10 min after 50 and 100 mcg/kg. Rate pressure product was decreased by 10 min after 100 mcg/kg epinephrine. Pretreatment with phentolamine attenuated these effects except at 100 mcg/kg epinephrine. In the isolated lung preparation, epinephrine in combination with increased pulmonary flow increased pulmonary capillary pressure and lung water. Conclusions Bolus injection of epinephrine in the intact, anesthetized rat impairs pulmonary oxygen exchange within 1 min of treatment. Effects were blunted by α-adrenergic receptor blockade. Edema occurred in the isolated lung above a threshold pulmonary capillary pressure when epinephrine treatment was coupled with an increase in pulmonary flow. These results potentially argue against using traditional doses of epinephrine for resuscitation, particularly in the anesthetized patient.

Resuscitation strategies from bupivacaine-induced cardiac arrest.

Abstract: Objectives: Local anesthetic (LA) intoxication with cardiovascular arrest is a potential fatal complication of regional anesthesia. Lipid resuscitation has been recommended for the treatment of LA-induced cardiac arrest. Aim of the study was to compare four different rescue regimens using epinephrine and/or lipid emulsion and vasopressin to treat cardiac arrest caused by bupivacaine intoxication. Methods: Twenty-eight piglets were randomized into four groups (4 × 7), anesthetized with sevoflurane, intubated, and ventilated. Bupivacaine was infused with a syringe driver via central venous catheter at a rate of 1 mg·kg(-1) ·min(-1) until circulatory arrest. Bupivacaine infusion and sevoflurane were then stopped, chest compression was started, and the pigs were ventilated with 100% oxygen. After 1 min, epinephrine 10 μg·kg(-1) (group 1), Intralipid(®) 20% 4 ml·kg(-1) (group 2), epinephrine 10 μg·kg(-1) + Intralipid(®) 4 ml·kg(-1) (group 3) or 2 IU vasopressin + Intralipid(®) 4 ml·kg(-1) (group 4) were administered. Secondary epinephrine doses were given after 5 min if required. Results: Survival was 71%, 29%, 86%, and 57% in groups 1, 2, 3, and 4. Return of spontaneous circulation was regained only by initial administration of epinephrine alone or in combination with Intralipid(®) . Piglets receiving the combination therapy survived without further epinephrine support. In contrast, in groups 2 and 4, return of spontaneous circulation was only achieved after secondary epinephrine rescue. Conclusions: In cardiac arrest caused by bupivacaine intoxication, first-line rescue with epinephrine and epinephrine + Intralipid(®) was more effective with regard to survival than Intralipid(®) alone and vasopressin + Intralipid(®) in this pig model. © 2011 Blackwell Publishing Ltd.

Questioning the Use of Epinephrine to Treat Cardiac Arrest

Abstract: THE MOST EXCITING SCIENTIFIC PROGRESS OCCURS WHEN new research challenges conventional wisdom. Even when a medical practice is founded on less-thanperfect scientific data, testing of an established therapy is nearly impossible to justify unless compelling new data lead to questioning of standard care. One example is the use of epinephrine, which has been a cornerstone of cardiac resuscitation and advanced cardiac life support since the 1960s. In this issue of JAMA, the report by Hagihara et al, based on one of the largest observational databases of cardiopulmonary resuscitation (CPR) ever assembled, challenges the role of epinephrine drug therapy during cardiac arrest. These new data suggest that epinephrine use may be associated with lower survival and worse neurological outcomes after cardiac arrest. The original rationale for the use of epinephrine was that this drug increases aortic blood pressure and, thus, coronary perfusion pressure during chest compressions in animals. When CPR does not generate coronary perfusion pressure greater than 15 to 20 mm Hg, return of cardiac mechanical activity rarely or never occurs. The ability of epinephrine to increase coronary perfusion pressure during CPR has been confirmed in humans. Thus, administering epinephrine during CPR increases the probability of restoring cardiac activity with pulses, which is an essential intermediate step toward long-term survival. The original studies in the 1960s in dogs defined the standard 1-mg dose of epinephrine that has been used with no weight adjustment or interspecies comparison for adult patients ever since. Restoring pulses after cardiac arrest appears to be an immediate step toward recovery but does not guarantee good patient outcomes. During the last decade, induced hypothermia and integrated plans of care have increased the proportion of patients hospitalized after CPR who survive to hospital discharge. These experiences have raised expectations that resuscitation therapies should improve not just short-term outcomes such as return of pulses but also longerterm and patient-centered outcomes such as functional status and quality of life. The study by Hagihara et al surpasses many prior reports by having complete 1-month survival and functional status data, measured by Cerebral Performance Category (CPC) and Outcome Performance Category (OPC). The CPC and OPC ordinal scales describe the global functioning of patients. Patients with CPC or OPC scores of 1 or 2 can return to their lives and families, whereas patients with CPC or OPC scores of 3 or higher require long-term care and may not even be conscious. Even the raw numbers in this report show that prehospital administration of epinephrine, despite increasing the rates of return of pulses (18% vs 5%), is associated with a more modest increase in the number of patients alive after 1 month (5.4% vs 4.7%) and lower rates of good functional status, defined as a CPC of 1 to 2 (1.4% vs 2.2%). When adjusted for important covariates or when using propensitymatched cases, the odds of both 1-month survival and better functional status were markedly lower in epinephrinetreated patients (odds ratios, 0.21-0.71). These findings were confirmed in various sensitivity analyses that accounted for in-hospital epinephrine use and CPR duration. Therefore, the association of prehospital epinephrine with worse meaningful outcomes appears to be real and robust. If these observations are true, prehospital epinephrine use must increase morbidity and mortality after restoration of pulses to a degree that more than offsets its short-term benefits. This paradoxical effect may be related to its mechanism of action. Epinephrine increases CPR-generated aortic pressures via -adrenergic–mediated vasoconstriction. Thus, epinephrine increases coronary perfusion pressure by decreasing blood flow to all other organs, an effect that may persist after restoration of pulses. Epinephrine impairs cerebral microcirculation during and after CPR in the laboratory. Likewise, the total dose of epinephrine is associated with impaired tissue oxygen utilization and impaired lactate clearance for hours after CPR in humans. These data suggest that epinephrine provides a short-term gain for the heart by incurring a metabolic debt from the body and brain. This debt may be too great for many patients. Additional post-CPR adverse effects of epinephrine may include -adrenergic stimulation, which promotes dys-

Disorders of Blood Pressure Regulation—Role of Catecholamine Biosynthesis, Release, and Metabolism

Abstract: Catecholamines (epinephrine and norepinephrine) are synthesised and produced by the adrenal medulla and postganglionic nerve fibres of the sympathetic nervous system. It is known that essential hypertension has a significant neurogenic component, with the rise in blood pressure mediated at least in part by overactivity of the sympathetic nervous system. Moreover, novel therapeutic strategies aimed at reducing sympathetic activity show promise in the treatment of hypertension. This article reviews recent advances within this rapidly changing field, particularly focusing on the role of genetic polymorphisms within key catecholamine biosynthetic enzymes, cofactors, and storage molecules. In addition, mechanisms linking the sympathetic nervous system and other adverse cardiovascular states (obesity, insulin resistance, dyslipidaemia) are discussed, along with speculation as to how recent scientific advances may lead to the emergence of novel antihypertensive treatments.

The comparative effects of lipid, epinephrine, and their combination in the reversal of bupivacaine-induced asystole in the isolated rat heart.

Abstract: BACKGROUND:It remains unclear whether lipid combined with epinephrine is superior or inferior to either drug alone in treating bupivacaine cardiotoxicity. We compared the effects of lipid, epinephrine, and the combination of the two in reversing bupivacaine-induced asystole in the isolated rat heart

Chapter 24: Anaphylaxis.

Abstract: Anaphylaxis is a sudden-onset, immediate reaction that implies a risk of death. Think of a "rule of 2's" for anaphylaxis implying that reactions usually begin within 2 minutes to 2 hours after injection, infusion, ingestion, contact, or inhalation. Fatalities can be from asphyxiation from laryngeal or oropharyngeal swelling, collapse from hypotensive shock, cardiac arrest, or acute severe bronchoconstriction causing respiratory failure and arrest. When there is activation of mast cells and basophils in anaphylaxis, chemical mediators are detectable. The preformed mediators from mast cells include histamine, tryptase, carboxypeptidase A, and proteoglycans (heparin and chondroitin sulfates). Newly synthesized mediators include prostaglandin D(2), leukotriene D(4), and platelet-activating factor. Crucial actions of the mediators include an abrupt increase in vascular permeability, vascular smooth muscle relaxation, and bronchial smooth muscle contraction. Anaphylaxis can be classified into immunologic, nonimmunologic, or idiopathic based on the associated mechanism. For example, immunologic causes of anaphylaxis are those mediated by IgE antibodies acting through the FceR I (foods, insect venom, and beta-lactam antibiotics) whereas non-IgE immunologic anaphylaxis is mediated without presence of antiallergen IgE antibodies or via FceRI activation (radiographic contrast material). Nonimmunologic anaphylaxis involves mast cell mediator release such as occurs with exercise, cold temperature exposure, or from medications such as opioids or vancomycin. Idiopathic anaphylaxis involves mast cell activation (acutely elevated urine histamine or serum tryptase) and activated lymphocytes. Because anaphylaxis is a medical emergency, the drug of choice is epinephrine, not H(1)-receptor antagonists.

Endocrine-disrupting effects of nonylphenol in the newt, Triturus carnifex (Amphibia, Urodela)

Abstract: The aim of our study was to verify whether environmental concentrations of nonylphenol influenced the adrenal gland of Triturus carnifex. Newts were exposed to 19 μg/L nominal concentration of nonylphenol throughout the periods of December-January and March-April, corresponding to different stages of the chromaffin cell functional cycle. The morphological features of the steroidogenic and chromaffin tissues, and the serum levels of ACTH, aldosterone, corticosterone, norepinephrine and epinephrine were evaluated. Nonylphenol did not influence ACTH serum levels. During the two periods examined, the steroidogenic tissue had the same reaction: the quantity of cytoplasmic lipids, and the corticosteroid serum levels, decreased, suggesting the inhibition of synthesis and release of corticosteroids. During the two periods examined, the chromaffin tissue reacted differently to nonylphenol. During December-January, the numeric ratio of norepinephrine granules to epinephrine granules, and the epinephrine serum levels, increased, suggesting the stimulation of epinephrine release. During March-April, the numeric ratio of norepinephrine granules to epinephrine granules did not change, and the norepinephrine serum levels decreased, suggesting the inhibition of norepinephrine release. Our results show that nonylphenol influences the activity of the newt adrenal gland; considering the physiological role of this gland, our results suggest that nonylphenol may contribute to amphibian decline.

Norepinephrine supplemented with dobutamine or epinephrine for the cardiovascular support of patients with septic shock

Abstract: Background and Aims: Sepsis management remains a great challenge for intensive care medicine. The aim of this study was to evaluate the effect of adding dobutamine versus epinephrine to norepinephrine in treating septic shock patients refractory to fluid therapy. Materials and Methods: Sixty adult patients with the diagnosis of septic shock were included in this study. Norepinephrine infusion was started at a dose of 0.05 μg/kg/min, and increased gradually up to 0.1 μg/kg/min. Upon reaching this dose, patients with mean arterial pressure Results: Group II patients developed significantly better cardiovascular parameters, lower arterial pH and higher serum lactate and urine output; however, the 28-day mortality and major adverse effects were comparable in both groups. Conclusions: The addition of epinephrine to norepinephrine has positive effects on the cardiovascular parameters but negative results on the serum lactate concentration and systemic pH compared with the addition of dobutamine to norepinephrine.

Hyperreactive platelet phenotypes: Relationship to altered serotonin transporter number, transport kinetics and intrinsic response to adrenergic co-stimulation

Abstract: The mechanism underlying a hyperreactive platelet phenotype remains unknown. Since serotonin has been shown to influence platelet biology and atherothrombosis, we sought to investigate the association of platelet serotonin transporter number, binding affinity, and uptake kinetics with platelet aggregation. A total of 542 healthy volunteers had light transmittance platelet aggregometry measured in response to varying concentrations of epinephrine, serotonin, epinephrine plus serotonin, ADP and collagen. Transporter-dependent serotonin uptake rate was determined (Vmax), as were serotonin transporter number (Bmax) and binding affinity (Kd) using 3H paroxetine binding in a homologous displacement assay, nonlinear regression and validated algorithms for kinetic modelling. Stimulation with submaximal (2μM) epinephrine concentration elicited a distinct, bimodal pattern of platelet aggregation in this population. In contrast, subjects exhibited minimal aggregation in response to serotonin alone. Co-stimulation with submaximal epinephrine and serotonin induced platelet aggregation to a level beyond that observed with either agonist alone and maintained a bimodal response distribution. Subjects with heightened (>60%) platelet aggregation to both epinephrine alone and epinephrine plus serotonin exhibited increased platelet serotonin uptake, and transporter number and affinity. In a population of healthy subjects, co-stimulation with submaximal concentrations of epinephrine and serotonin identifies a subset of individuals with a hyperreactive platelet aggregation profile that is associated with changes in platelet serotonin function.

A survey study of index food‐related allergic reactions and anaphylaxis management

Abstract: Background: Initial food-allergic reactions are often poorly recognized and undertreated. Methods: Parents of food-allergic children were invited to complete an online questionnaire, designed with Kids with Food Allergies Foundation, about their children’s first food-allergic reactions resulting in urgent medical evaluation. Results: Among 1361 reactions, 76% (95% CI 74–79%) were highly likely to represent anaphylaxis based on NIAID/FAAN criteria. Only 34% (95% CI 31–37%) of these were administered epinephrine. In 56% of these, epinephrine was administered by emergency departments; 20% by parents; 9% by paramedics; 8% by primary care physicians; and 6% by urgent care centers. In 26% of these, epinephrine was given within 15 min of the onset of symptoms; 54% within 30 min; 82% within 1 h; and 93% within 2 h. Factors associated with a decreased likelihood of receiving epinephrine for anaphylaxis included age <12 months, milk and egg triggers, and symptoms of abdominal pain and/or diarrhea. Epinephrine was more likely to be given to asthmatic children and children with peanut or tree nut ingestion prior to event. Post-treatment, 42% of reactions likely to represent anaphylaxis were referred to allergists, 34% prescribed and/or given epinephrine auto-injectors, 17% trained to use epinephrine auto-injectors, and 19% given emergency action plans. Of patients treated with epinephrine, only half (47%) were prescribed epinephrine auto

Plasma norepinephrine in hypertensive rats reflects α2-adrenoceptor release control only when re-uptake is inhibited

Abstract: α2 adrenoceptors (AR) lower central sympathetic output and peripheral catecholamine release, thereby protecting against sympathetic hyperactivity and hypertension. Norepinephrine re-uptake transporter effectively (NET) removes norepinephrine from the synapse. Overflow to plasma will therefore not reflect release. Here we tested if inhibition of re-uptake allowed presynaptic α2AR release-control to be reflected as differences in norepinephrine overflow in anesthetized hypertensive (SHR) and normotensive (WKY) rats. We also tested if α2AR modulated the experiment-induced epinephrine secretion, and a phenylephrine-induced, α1-adrenergic vasoconstriction. Blood pressure was recorded through a femoral artery catheter, and cardiac output by ascending aorta flow. After pre-treatment with NET inhibitor (desipramine), and/or α2AR antagonist (yohimbine, L-659,066) or agonist (clonidine, ST-91), we injected phenylephrine. Arterial blood was sampled 15 min later. Plasma catecholamine concentrations were not influenced by phenylephrine, and therefore reflected effects of pre-treatment. Desipramine and α2AR antagonist separately had little effect on norepinephrine overflow. Combined, they increased norepinephrine overflow, particularly in SHR. Clonidine, but not ST-91, reduced, and pertussis toxin increased norepinephrine overflow in SHR and epinephrine secretion in both strains. L-659,066+clonidine (central α2AR-stimulation) normalized the high blood pressure, heart rate and vascular tension in SHR. α2AR antagonists reduced phenylephrine induced vasoconstriction equally in WKY and SHR. Conclusions: α2AAR inhibition increased norepinephrine overflow only when re-uptake was blocked, and then with particular efficacy in SHR, possibly due to their high sympathetic tone. α2AAR inhibited epinephrine secretion, particularly in SHR. α2AAR supported α1AR-induced vasoconstriction equally in the two strains. α2AR malfunctions were therefore not detected in SHR under this basal condition.