Showing papers on "Epinephrine published in 2000"

New insights into sympathetic regulation of glucose and fat metabolism.

Abstract: The autonomic nervous system modulates glucose and fat metabolism through both direct neural effects and hormonal effects. This review presents recent concepts on the sympathetic regulation of glucose and fat metabolism. Focally released norepinephrine from sympathetic nerves is likely to increase glucose uptake in skeletal muscle and adipose tissues independent of insulin but norepinephrine does not contribute so much as epinephrine to hepatic glucose production. Epinephrine increases hepatic glucose production and inhibits insulin secretion and the glucose uptake by tissues that is induced by insulin. Additionally, catecholamines can increase thermogenesis and lipolysis, leading to increased energy expenditure and decreased fat stores. It is likely that beta-(beta3)-adrenergic receptors mediate these responses. Alterations of central neurotransmission and environmental factors can change the relative contribution of sympathetic outflow to the pancreas, liver, adrenal medulla and adipose tissues, leading to the modulation of glucose and fat metabolism. Recent studies have proposed that leptin, an adipocyte hormone, affects the central nervous system to increase sympathetic outflow independent of feeding. The effects of leptin on glucose and fat metabolism could be in part mediated by the sympathetic nervous system. Studies using mice with a genetic disruption of serotonin 5-HT2c receptor indicate that central neural mechanisms in the regulation of sympathetic outflow and satiety could be dissociated. Abnormalities of sympathetic effects, including disturbances of leptin and beta3-adrenergic receptor signalling, are likely to cause obesity and impaired glucose tolerance in rodents and humans. These findings indicate that dysfunction of the sympathetic nervous system could predispose to obesity and Type II (non-insulin-dependent) diabetes mellitus.

Human ageing and the sympathoadrenal system.

Abstract: Over the past three decades the changes in sympathoadrenal function that occur with age in healthy adult humans have been systematically studied using a combination of neurochemical, neurophysiological and haemodynamic experimental approaches. The available experimental evidence indicates that tonic whole-body sympathetic nervous system (SNS) activity increases with age. The elevations in SNS activity appear to be region specific, targeting skeletal muscle and the gut, but not obviously the kidney. The SNS tone of the heart is increased, although this appears to be due in part to reduced neuronal reuptake of noradrenaline (norepinephrine). In contrast to SNS activity, tonic adrenaline (epinephrine) secretion from the adrenal medulla is markedly reduced with age. This is not reflected in plasma adrenaline concentrations because of reduced plasma clearance. Despite widely held beliefs to the contrary, sympathoadrenal responsiveness to acute stress is not exaggerated with age in healthy adults. Indeed, adrenaline release in response to acute stress is substantially attenuated in older men. The mechanisms underlying the age-associated increases in SNS activity have not been established, but our preliminary data are consistent with increased subcortical central nervous system (CNS) sympathetic drive. These changes in sympathoadrenal function with advancing age may have a number of important physiological and pathophysiological consequences for human health and disease.

Increased Sympathetic Nervous Activity in Patients With Nontraumatic Subarachnoid Hemorrhage

Abstract: Background and Purpose —Activation of the sympathetic nervous system, which leads to elevation of circulating catecholamines, is implicated in the genesis of cerebral vasospasm and cardiac aberrations after subarachnoid hemorrhage. To this juncture, sympathetic nervous testing has relied on indirect methods only. Methods —We used an isotope dilution technique to estimate the magnitude and time course of sympathoadrenal activation in 18 subarachnoid patients. Results —Compared with 2 different control groups, the patients with subarachnoid hemorrhage exhibited an approximately 3-fold increase in total-body norepinephrine spillover into plasma within 48 hours after insult (3.2±0.3 and 4.2±0.7 versus 10.2±1.4 nmol/L; P <0.05 versus both). This sympathetic activation persisted throughout the 7- to 10-day examination period and was normalized at the 6-month follow-up visit. Conclusions —The present study has established that massive sympathetic nervous activation occurs in patients after subarachnoid hemorrhage. This overactivation may relate to the well-known cardiac complications described in subarachnoid hemorrhage.

Effects of sympathetic activation by adrenergic infusions on hemostasis in vivo

Abstract: Overactivity of the sympathetic nervous system (SNS) has been related to increased cardiovascular morbidity. Historical reports suggest hastening of blood coagulation following intravenous administration of epinephrine. Given the important role of the hemostatic system in atherosclerosis and thrombosis, it is surprising that short-term adrenergic effects on blood coagulation, fibrinolysis and platelet activity have not been scrutinized closely. To elucidate such effects in vivo, this paper reviews human studies in which alpha- and beta-sympathomimetic agents had been infused. The literature suggests a dose-dependent stimulation of factor VIII clotting activity, von Willebrand factor antigen, tissue-type plasminogen activator, and platelets within a 15- to 40-min infusion of epinephrine. Precise mechanisms underlying hemostatic changes with sympathetic activation remain to some extent speculative. However, there is evidence from adrenoreceptor blockade studies that coagulation and fibrinolysis molecules are released into circulation by stimulation of vascular endothelial beta-adrenoreceptors (most likely beta2-receptors). Combined alpha2- and beta2-adrenoreceptor-related mechanism(s) are responsible for platelet activation. Short-term activation of the SNS effects regular hemostatic activity. While in healthy individuals the hemostatic balance between coagulation and fibrinolysis may be preserved, catecholamine surge may trigger a hypercoagulable state and enhance the odds of overt thrombosis in patients with atherosclerotic disease.

Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency.

Abstract: Background Glucocorticoids are essential for the normal development and functioning of the adrenal medulla. Whether adrenomedullary structure and function are normal in patients with congenital adrenal hyperplasia is not known. Methods We measured plasma and urinary catecholamines and plasma metanephrines in 38 children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (25 children with the salt-wasting form and 13 with the simple virilizing form), 39 age-matched normal subjects, and 20 patients who had undergone bilateral adrenalectomy. Adrenal specimens obtained from three other patients with 21-hydroxylase deficiency who had undergone bilateral adrenalectomy and specimens obtained at autopsy from eight other patients were examined histologically. Results Plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were 40 to 80 percent lower in the patients with congenital adrenal hyperplasia than in the normal subjects (P< 0.05), and the values were lowest in...

Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock.

Abstract: A major feature of septic shock is the development of a vascular crisis characterized by nonresponsiveness to sympathetic vasoconstrictor agents and the subsequent irreversible fall in blood pressure. In addition, sepsis, like other inflammatory conditions, results in a large increase in the production of free radicals, including superoxide anions (O2⨪) within the body. Here we show that O2⨪ reacts with catecholamines deactivating them in vitro. Moreover, this deactivation would appear to account for the hyporeactivity to exogenous catecholamines observed in sepsis, because administration of a superoxide dismutase (SOD) mimetic to a rat model of septic shock to remove excess O2⨪ restored the vasopressor responses to norepinephrine. This treatment with the SOD mimetic also reversed the hypotension in these animals; suggesting that deactivation of endogenous norepinephrine by O2⨪ contributes significantly to this aspect of the vascular crisis. Indeed, the plasma concentrations of both norepinephrine and epinephrine in septic rats treated with the SOD mimetic were significantly higher than in untreated rats. Interestingly, the plasma concentrations for norepinephrine and epinephrine were inversely related to the plasma concentrations of adrenochromes, the product of the autoxidation of catecholamines initiated by O2⨪. We propose, therefore, that the use of a SOD mimetic represents a new paradigm for the treatment of septic shock. By removing O2⨪, exogenous and endogenous catecholamines are protected from autoxidation. As a result, both hyporeactivity and hypotension are reversed, generation of potentially toxic adrenochromes is reduced, and survival rate is improved.

Different adrenal sympathetic preganglionic neurons regulate epinephrine and norepinephrine secretion

Abstract: Brain stimulation or activation of certain reflexes can result in differential activation of the two populations of adrenal medullary chromaffin cells: those secreting either epinephrine or norepinephrine, suggesting that they are controlled by different central sympathetic networks. In urethan-chloralose-anesthetized rats, we found that antidromically identified adrenal sympathetic preganglionic neurons (SPNs) were excited by stimulation of the rostral ventrolateral medulla (RVLM) with either a short (mean: 29 ms) or a long (mean: 129 ms) latency. The latter group of adrenal SPNs were remarkably insensitive to baroreceptor reflex activation but strongly activated by the glucopenic agent 2-deoxyglucose (2-DG), indicating their role in regulation of adrenal epinephrine release. In contrast, adrenal SPNs activated by RVLM stimulation at a short latency were completely inhibited by increases in arterial pressure or stimulation of the aortic depressor nerve, were unaffected by 2-DG administration, and are presumed to govern the discharge of adrenal norepinephrine-secreting chromaffin cells. These findings of a functionally distinct preganglionic innervation of epinephrine- and norepinephrine-releasing adrenal chromaffin cells provide a foundation for identifying the different sympathetic networks underlying the differential regulation of epinephrine and norepinephrine secretion from the adrenal medulla in response to physiological challenges and experimental stimuli.

Comparison of epinephrine and vasopressin in a pediatric porcine model of asphyxial cardiac arrest.

Abstract: ObjectiveThis study was designed to compare the effects of vasopressin vs. epinephrine vs. the combination of epinephrine with vasopressin on vital organ blood flow and return of spontaneous circulation in a pediatric porcine model of asphyxial arrest.DesignProspective, randomized laboratory investi

Anaphylactic reactions during induction of anaesthesia using rocuronium for muscle relaxation: a report including 3 cases.

Abstract: Anaphylaxis during induction of anaesthesia is a dreaded complication with a mortality rate of 3-6%, most frequently associated with the use of muscle relaxants. Current knowledge on this matter is reviewed in relation to the presentation of 3 cases of anaphylaxis and bronchospasm associated with the use of the recently released nondepolarizing muscle relaxant rocuronium. Bronchospasm may be the sole sign of a serious drug reaction, triggered by precipitation of insoluble thiopental crystals when mixed with a muscle relaxant in the intravenous (iv) line. It is recommended that these drugs are administered via different injection ports. The hypotension requires immediate treatment with oxygen, epinephrine and large amounts of iv fluids. Epinephrine infusion may be needed for hours. It is recommended that serum tryptase is measured approximately 2 h after debut of the serious drug reaction. Allergy testing should be performed for all the drugs the patient was exposed to, 4-8 weeks after the incident, and due to cross-reactivity, including all available muscle relaxants. Doctors are urged to inform their patients, and systematically register adverse drug reactions.

Measurement of sympathetic nervous system activity in heart failure: the role of norepinephrine kinetics.

Abstract: Recent demonstration that the level of sympathetic nervous drive to the failing heart in patients with severe heart failure is a major determinant of prognosis, and that mortality in heart failure is reduced by beta-adrenergic blockade, indicate the clinical relevance of heart failure neuroscience research. The cardiac sympathetic nerves are preferentially stimulated in severe heart failure, with the application of isotope dilution methods for measuring cardiac norepinephrine release to plasma indicating that in untreated patients cardiac norepinephrine spillover is increased as much as 50-fold, similar to levels of release seen in the healthy heart during near maximal exercise. This preferential activation of the cardiac sympathetic outflow contributes to arrhythmia development and to progressive deterioration of the myocardium, and has been linked to mortality in both mild and severe cardiac failure. Although the central nervous system mechanisms involved in the sympathetic nervous activation at present remain uncertain, increased intracardiac diastolic pressure seems to be one peripheral reflex stimulus, and increased forebrain norepinephrine turnover an important central mechanism.Additional neurophysiological abnormalities present in the failing human heart include release of the sympathetic cotransmitters, epinephrine and neuropeptide Y, at high levels more typical of their release during exercise in healthy subjects, and the possible presynaptic augmentation of norepinephrine release from the cardiac sympathetic nerves by the regionally released epinephrine. Following on the demonstrable benefit of beta-adrenergic blockade in heart failure, additional antiadrenergic measures (central suppression of sympathetic outflow with imidazoline binding agents such as clonidine, blocking of norepinephrine synthesis by dopamine-beta-hydroxylase inhibition, antagonism of neuropeptide Y) are now under active investigation.

Can epinephrine inhalations be substituted for epinephrine injection in children at risk for systemic anaphylaxis

Abstract: Background. For out-of-hospital treatment of anaphylaxis, inhalation of epinephrine from a pressurized metered-dose inhaler is sometimes recommended as a noninvasive, user-friendly alternative to an epinephrine injection. Objective. To determine the feasibility of administering an adequate epinephrine dose from a metered-dose inhaler in children at risk for anaphylaxis by assessing the rate and extent of epinephrine absorption after inhalation. Methods. We performed a prospective, randomized, observer-blind, placebo-controlled, parallel-group study in 19 asymptomatic children with a history of anaphylaxis. Based on the child9s weight, 10, 15, or 20 carefully supervised epinephrine or placebo inhalations were attempted. Before dosing, and at intervals from 5 to 180 minutes after dosing, we monitored plasma epinephrine concentrations, blood glucose, heart rate, blood pressure, and adverse effects. Results. Eleven children (mean ± standard error of the mean: 9 ± 1 years and 33 ± 3 kg) in the epinephrine group were able to inhale 11 ± 2 (range: 3–20) puffs, equivalent to 74% ± 7% of the precalculated dose or 0.078 ± 0.009 mg/kg. They achieved a mean peak plasma epinephrine concentration of 1822 ± 413 (range: 230-4518) pg/mL at 32.7 ± 6.2 minutes. Eight children (10 ± 1 years of age and 33 ± 5 kg) in the placebo group were able to inhale 12 ± 2 (range: 8–20) puffs, 89% ± 3% of the precalculated dose, and had a peak endogenous plasma epinephrine concentration of 1316 ± 247 (range: 522-2687) pg/mL at 44.4 ± 16.7 minutes. In the children receiving epinephrine compared with those receiving placebo, mean plasma epinephrine concentrations were not significantly higher at any time, mean blood glucose concentrations were significantly higher from 10 to 30 minutes, mean heart rate was not significantly different at any time, and mean systolic and diastolic blood pressures were not significantly increased at most times. After the inhalations of epinephrine or placebo, the children complained of bad taste and many experienced cough or dizziness. After inhaling epinephrine, 1 child developed nausea, pallor, and muscle twitching. Conclusions. Despite expert coaching, because of the number of epinephrine inhalations required and the bad taste of the inhalations, most children were unable to inhale sufficient epinephrine to increase their plasma epinephrine concentrations promptly and significantly. Therefore, we urge caution in recommending epinephrine inhalation as a substitute for epinephrine injection for out-of-hospital treatment of anaphylaxis symptoms in children.

Vasopressin improves survival after cardiac arrest in hypovolemic shock.

Abstract: UNLABELLED: Survival after hypovolemic shock and cardiac arrest is dismal with current therapies. We evaluated the potential benefits of vasopressin versus large-dose epinephrine in hemorrhagic shock and cardiac arrest on vital organ perfusion, and the likelihood of resuscitation. In 18 pigs, 35% of the estimated blood volume was withdrawn over 15 min and ventricular fibrillation was induced 5 min later. After 4 min of cardiac arrest and 4 min of standard cardiopulmonary resuscitation, a bolus dose of either 200 microg/kg epinephrine (n = 7), 0.8 unit/kg vasopressin (n = 7), or saline placebo (n = 4) was administered in a blinded, randomized manner. Defibrillation was attempted 2.5 min after drug administration, and all animals were subsequently observed for 1 h without further intervention. Spontaneous circulation was restored in 7 of 7 vasopressin animals, in 6 of 7 epinephrine pigs, and in 0 of 4 placebo swine. At 5 and 30 min after return of spontaneous circulation, median (minimum and maximum) renal blood flow after epinephrine was 2 (0-31), and 2 (0-48) mL. 100 g(-1). min(-1), respectively; and after vasopressin 96 (12-161), and 44 (16-105) mL. 100 g(-1). min(-1), respectively (P: or =55 min (P: < 0. 01). In conclusion, treatment of hypovolemic cardiac arrest with vasopressin, but not with large-dose epinephrine or saline placebo, resulted in sustained vital organ perfusion, less metabolic acidosis, and prolonged survival. Based on these findings, clinical evaluation of vasopressin during hypovolemic cardiac arrest may be warranted. IMPLICATIONS: The chances of surviving cardiac arrest in hemorrhagic shock are considered dismal without adequate fluid replacement. However, treatment of hypovolemic cardiac arrest with vasopressin, but not with large-dose epinephrine or saline placebo, resulted in sustained vital organ perfusion and prolonged survival in an animal model of suspended infusion therapy.

Impaired basal and restraint-induced epinephrine secretion in corticotropin-releasing hormone-deficient mice.

Abstract: CRH is thought to play a role in responses of the adrenocortical and adrenomedullary systems during stress. To investigate the role of CRH in stress-induced secretions of corticosterone and epinephrine, we subjected wild-type (WT) and CRH-deficient (knockout, KO) mice to restraint, and analyzed plasma corticosterone, plasma catecholamines, and adrenal phenylethanolamine N-methyltransferase (PNMT) gene expression and activity before and during 3 h of restraint. Plasma corticosterone increased over 40-fold in WT mice, but minimally in CRH KO mice. Adrenal corticosterone content tended to increase in CRH KO mice, although to levels 5-fold lower than that in WT mice. CRH KO mice had significantly lower plasma epinephrine and higher norepinephrine than WT mice at baseline, and delayed epinephrine secretion during restraint. Adrenal PNMT messenger RNA content in CRH KO mice tended to be lower than that in WT mice, though the degree of induction was similar in both genotypes. PNMT enzyme activity was significant...

Carvedilol prevents epinephrine-induced apoptosis in human coronary artery endothelial cells: modulation of Fas/Fas ligand and caspase-3 pathway.

Abstract: Background: Several studies have shown that carvedilol, a multiple action neurohumoral antagonist, reduces mortality in patients with congestive heart failure (CHF). In addition to being a β-adrenoceptor antagonist, carvedilol is a potent antioxidant. Since there is evidence for elevation of catecholamine levels in plasma and coronary artery endothelial cell injury in CHF, the present study was designed to test the hypothesis that carvedilol inhibits epinephrine-induced apoptosis, and the inhibitory effect is mediated by modulation of Fas, Fas ligand (FasL) and caspase-3 pathway, in cultured human coronary artery endothelial cells (HCAECs). Methods and results: HCAECs were exposed to epinephrine alone, carvedilol+epinephrine, or atenolol+epinephrine for 24 h. Epinephrine increased the number of apoptotic cells, measured by in situ nick end-labeling staining (from 4.2±1.3% to 28.6±6.0%, P <0.01, n =6) and by DNA laddering on agarose gel electrophoresis. Epinephrine also increased Fas and FasL protein expression ( P <0.01 vs. control, n =6), and activated intracellular protease caspase-3 ( P <0.01 vs. control, n =6). These effects of epinephrine were completely inhibited by carvedilol. Atenolol in equimolar concentration also attenuated epinephrine-mediated effects, but the effects of atenolol were less marked than those of carvedilol ( P <0.01). To explore the basis of differential effects of carvedilol and atenolol, effects of these agents on epinephrine-induced lipid peroxidation was measured. Lipid peroxidation was completely blocked by carvedilol, whereas equimolar concentration of atenolol had much less ( P <0.05) effect. Conclusion: Epinephrine induces apoptosis in HCAECs, and this effect is associated with activation of Fas–FasL and caspase-3 signal transduction pathway. Carvedilol can, more effectively than atenolol, inhibit these effects of epinephrine. The potent antioxidant effect of carvedilol is probably responsible for the superior effect.

Cardiopulmonary resuscitation during severe hypothermia in pigs: does epinephrine or vasopressin increase coronary perfusion pressure?

Abstract: UNLABELLED The American Heart Association does not recommend epinephrine for management of hypothermic cardiac arrest if body core temperature is below 30 degrees C. Furthermore, the effects of vasopressin administration during hypothermic cardiac arrest are totally unknown. This study was designed to assess the effects of vasopressin and epinephrine on coronary perfusion pressure in a porcine model during hypothermic cardiac arrest cardiopulmonary resuscitation (CPR). Pigs were surface-cooled until their body core temperature was 26 degrees C. After 30 min of untreated cardiac arrest, followed by 3 min of basic life support CPR, 15 animals were randomly assigned to receive, at 5-min intervals, either vasopressin (0.4, 0.4, and 0.8 U/kg; n = 5), epinephrine (45, 45, and 200 microg/kg; n = 5), or saline placebo (n = 5). Compared with epinephrine, mean +/- SEM coronary perfusion pressure was significantly higher (P < 0.05) 90 s and 5 min after the first (35+/-4 vs 22+/-3 mm Hg and 37+/-2 vs 16+/-2 mm Hg) and the second vasopressin administration (40+/-5 vs 26+/-5 mm Hg and 36+/-5 vs 18+/-2 mm Hg, respectively). After the third drug administration, coronary perfusion pressure in the epinephrine group increased dramatically and was comparable to vasopressin. In the saline placebo group, coronary perfusion pressure was significantly lower (P < 0.05) than in the vasopressin and epinephrine groups. Six animals treated with epinephrine or vasopressin had transient return of spontaneous circulation, whereas all placebo animals died (P < 0.05). During CPR in severe hypothermia, administration of both vasopressin and epinephrine resulted in significant increases in coronary perfusion pressure when compared with placebo. IMPLICATIONS Our study was designed to assess the effects of vasopressin and epinephrine in a porcine model simulating cardiac arrest during severe hypothermia. This study demonstrates that the administration of both emergency drugs results in an increased perfusion pressure in the heart.

Effects of dopamine and epinephrine infusions on renal hemodynamics in severe malaria and severe sepsis.

Abstract: OBJECTIVE: To describe and compare the effects of dopamine and epinephrine in various doses on renal hemodynamics and oxygen transport in patients with severe malaria and severe sepsis. DESIGN: Prospective, controlled, crossover trial. SETTING: The intensive care unit of an infectious diseases hospital in Viet Nam. PATIENTS: Fourteen patients with severe falciparum malaria and five with severe sepsis. INTERVENTIONS: In an open, crossover design, we observed the effects on renal and systemic hemodynamics and oxygen transport of separate stepped infusions of epinephrine and dopamine. We measured renal blood flow (RBF) and cardiac output by the thermodilution method using fluoroscopically guided catheters. Creatinine clearance at each time point was calculated from the renal plasma flow and the renal arteriovenous difference in plasma creatinine. MEASUREMENTS AND MAIN RESULTS: Dopamine at a "renal" dose (2.5 microg/kg/min) was associated with a mean (95% confidence interval) fractional increase in the absolute renal blood flow index (RBFI) of 37% (13% to 61%) and in RBF as a fraction of cardiac output (RBF/CO) of 35% (10% to 59%; p = .007 and p = .014, respectively). The consequent 39% (14% to 64%) increase in renal oxygen supply (p = .002) was accompanied by a 32% (20% to 44%) decrease in the renal oxygen extraction ratio (p = .0003), leading to no net change in renal oxygen consumption. At higher doses (10 microg/kg/min), both RBF and RBF/CO were not significantly different from baseline values and decreased further as the dose was reduced again. There was no obvious explanation for this hysteresis. There was no change in renal oxygen consumption throughout the study. Because lactic acidosis developed, epinephrine was only given to eight of the 19 patients, and the full stepped epinephrine infusion was given to four patients. Epinephrine infusion was associated, both in absolute terms and when compared with dopamine, with a significant increase in renal vascular resistance (p = .0008 and .0005, respectively), a decrease in RBF/CO (p = .002 and .03), and a compensatory increase in the renal oxygen extraction ratio (p = .005 and .0001). RBFI and renal oxygen consumption remained constant throughout the epinephrine infusion profile. Neither epinephrine nor dopamine significantly affected creatinine clearance or urine output. Twelve patients (63%) were in established renal failure (plasma creatinine, >3 mg/dL) at the time of the study, although the presence or absence of renal failure did not significantly influence the effects of the study drugs. However, overall, the presence of renal failure was associated with a lower mean renal oxygen consumption, a lower mean renal oxygen consumption as a fraction of systemic oxygen consumption, and a higher mean renal vascular resistance. CONCLUSION: Although dopamine increased and epinephrine decreased fractional renal blood flow, there was no evidence that either drug produced either a beneficial or a deleterious effect on renal oxygen metabolism or function at any of the doses investigated.

The ‘adrenaline hypothesis’ of hypertension revisited: evidence for adrenaline release from the heart of patients with essential hypertension

Abstract: OBJECTIVE: Whether adrenaline acts as a sympathetic nervous cotransmitter in humans and stimulates beta2-adrenoceptors to augment neuronal noradrenaline release remains a subject of considerable dispute. The aim of this study was to test if adrenaline is released from regional sympathetic nerves (in the heart) in patients with essential hypertension, and to investigate whether locally released adrenaline might enhance cardiac noradrenaline release. METHODS: Using dual isotope dilution methodology, adrenaline and noradrenaline plasma kinetics was measured for the whole body and in the heart in 13 untreated patients with essential hypertension and 27 healthy volunteers. All research participants underwent cardiac catheterization under resting conditions. RESULTS: At rest, there was negligible adrenaline release from the sympathetic nerves of the heart in healthy subjects, 0.27 +/- 1.62 ng/min. In contrast, in patients with essential hypertension, adrenaline was released from the heart at a rate of 1.46 +/- 1.73 ng/min, equivalent on a molar basis to approximately 5% of the associated cardiac noradrenaline spillover value. Cardiac noradrenaline spillover was higher in hypertensive patients, 24.9 +/- 17.0 ng/min compared to 15.4 +/- 11.7 ng/min in healthy volunteers (P< 0.05). Among patients, rates of cardiac adrenaline and noradrenaline spillover correlated directly (r= 0.59, P< 0.05). CONCLUSIONS: This study, in demonstrating release of adrenaline from the heart in patients with essential hypertension, and in disclosing a proportionality between rates of cardiac adrenaline and noradrenaline release, provides perhaps the most direct evidence to date in support of the 'adrenaline hypothesis' of essential hypertension.

The effects of repeated doses of vasopressin or epinephrine on ventricular fibrillation in a porcine model of prolonged cardiopulmonary resuscitation.

Abstract: This study evaluated ventricular fibrillation mean frequency and amplitude to predict defibrillation success in a porcine cardiopulmonary resuscitation (CPR) model using repeated administration of vasopressin or epinephrine. After 4 min of cardiac arrest and 3 min of CPR, 10 pigs were randomly assigned to receive either vasopressin (early vasopressin: 0.4, 0.4, and 0.8 units/kg, respectively, n 5 5) or epinephrine (early epinephrine: 45, 45, and 200 mg/kg, respectively, n 5 5). Another 11 animals were randomly allocated after 4 min of cardiac arrest and 8 min of CPR to receive every 5 min either vasopressin (late vasopressin: 0.4 and 0.8 units/kg, respectively, n 5 5) or epinephrine (late epinephrine: 45 and 200 mg/kg, n 5 6). Ventricular fibrillation mean frequency and amplitude on defibrillation were significantly higher in the vasopressin groups than in the epinephrine groups, respectively. In vasopressin versus epinephrine animals, mean frequency immediately before defibrillation was 9.6 6 1.5 Hz vs 7.0 6 0.7 Hz (P , 0.001), mean amplitude was 0.65 6 0.26 mV vs 0.21 6 0.14 mV (P , 0.001, and coronary perfusion pressure was 27 6 9m m Hg vs 86 4m m Hg (P , 0.00001), respectively. In contrast to no epinephrine animals, all vasopressin animals were successfully defibrillated and survive d1h( P , 0.05). Mean fibrillation frequency and amplitude predicted successful defibrillation and may serve as noninvasive markers to monitor continuing CPR efforts. Furthermore, vasopressin was superior to epinephrine in maintaining these variables above a threshold necessary for successful defibrillation. (Anesth Analg 2000;90:1067‐75)

Racemic ketamine decreases muscle sympathetic activity but maintains the neural response to hypotensive challenges in humans.

Abstract: BACKGROUND: Cardiovascular stimulation and increased catecholamine plasma concentrations during ketamine anesthesia have been attributed to increased central sympathetic activity as well as catecholamine reuptake inhibition in various experimental models. However, direct recordings of efferent sympathetic nerve activity have not been performed in humans. The authors tested the hypothesis that racemic ketamine increases efferent muscle sympathetic activity (MSA) and maintains the muscle sympathetic response to hypotensive challenges. METHODS: Muscle sympathetic activity was recorded by microneurography in the peroneal nerve of six healthy subjects before and during anesthesia with racemic ketamine (2 mg/kg intravenously plus 30 microg x kg(-1) x min(-1)). Catecholamine plasma concentrations, heart rate, and blood pressure were also determined. Muscle sympathetic neural responses to a hypotensive challenge were assessed by injection of sodium nitroprusside (2-10 microg/kg) before and during ketamine anesthesia. In the final step, increased arterial pressure observed during ketamine anesthesia was adjusted to preanesthetic baseline by sodium nitroprusside infusion (1-6 microg x kg(-1) x min(-1)). RESULTS: Ketamine significantly decreased MSA burst frequency (mean +/- SD, 18 +/- 9 bursts/min to 9 +/- 8 bursts/min) and burst incidence (26 +/- 11 bursts/100 heart beats to 9 +/- 6 bursts/100 heart beats). However, when increased mean arterial pressure (85 +/- 8 mmHg to 121 +/- 20 mmHg) was normalized to the awake baseline by sodium nitroprusside, MSA recovered (25 +/- 18 bursts/min; 23 +/- 14 bursts/100 heart beats). During ketamine anesthesia, both epinephrine (15 +/- 10 pg/ml to 256 +/- 193 pg/ml) and norepinephrine (250 +/- 105 pg/ml to 570 +/- 270 pg/ml) plasma concentrations significantly increased, as did heart rate (67 +/- 13 beats/min to 113 +/- 15 beats/min). Hypotensive challenges similarly increased MSA both in the awake state and during ketamine anesthesia. CONCLUSIONS: During increased arterial blood pressure associated with ketamine, sympathetic discharge to muscle blood vessels decreases at the same time that plasma concentrations of norepinephrine increase. When this increase in arterial blood pressure is reversed, MSA during ketamine is not changed from preketamine baseline recordings. Finally, hypotensive challenges still evoke an unchanged sympathetic reflex response. Thus, our results do not support the assumption that ketamine anesthesia increases sympathetic nerve activity in a generalized fashion

Adverse effects of high-dose epinephrine on cerebral blood flow during experimental cardiopulmonary resuscitation.

Abstract: Objective:To study the effects of high-dose epinephrine, compared with standard-dose epinephrine, on the dynamics of superficial cortical cerebral blood flow as well as global cerebral oxygenation during experimental cardiopulmonary resuscitation. We hypothesized that high-dose epinephrine might be

Absorption and hemodynamic effects of airway administration of adrenaline in patients with severe cardiac disease.

Abstract: This prospective study demonstrates that administration of adrenaline into the airways is hemodynamically effective and increases adrenaline plasma levels in adults with severe cardiac disease.

Hyperinnervation during adrenal regeneration influences the rate of functional recovery.

Abstract: The rat adrenal cortex has the uncommon ability to demonstrate morphological and functional regeneration after injury-induced loss of cortical tissue. Peripheral nerves are involved in tissue regeneration and healing after injury, implying that nerves may also be involved in modulating the regeneration of the adrenal cortex. Studies were initiated to assess changes in adrenal innervation during cortical tissue regeneration subsequent to adrenal enucleation. Innervation of regenerating adrenals was assessed from 3 to 62 days postenucleation by immunohistofluorescent detection of neuronal markers for primary afferent, preganglionic sympathetic, and postganglionic sympathetic fibers. The regenerating adrenal contained few nerves at 3 days postenucleation, but became differentially innervated, with extensive innervation by nerve fibers positive for calcitonin gene-related peptide (CGRP), tyrosine hydroxylase (TH), neuropeptide Y (NPY), and neuronal nitric oxide synthase (nNOS). In contrast, there was only minimal innervation by nerve fibers positive for vasoactive intestinal peptide. By 14 days postenucleation, the CGRP-, TH-, and NPY-positive innervation included areas of hyperinnervation in the capsule, cortex, and central inflammatory site of the regenerating gland. In addition, many chromaffin cells were present at all time points postenucleation. Quantification of the regenerating gland content of CGRP, norepinephrine, epinephrine, and nNOS verified the immunohistofluorescent observations. The period of extensive innervation correlated temporally with the time (3-30 days) during which the regenerating glands recovered steroidogenic function. Moreover, splanchnic nerve transection at the time of adrenal enucleation decreased the innervation by CGRP-positive and vesicular acetylcholine transporter-positive fibers and delayed regeneration. These results support the hypothesis that adrenal innervation modulates tissue regeneration and functional recovery of the enucleated adrenal gland.

Epinephrine application via an endotracheal airway and via the Combitube in esophageal position.

Abstract: OBJECTIVE: To compare plasma concentrations and cardiovascular effects of epinephrine after application via a conventional endotracheal airway and via the esophageal lumen of a new emergency airway, the esophageal tracheal Combitube. DESIGN: Prospective, randomized study. SETTING: Center for Biomedical Research, University of Vienna. SUBJECTS: Fourteen juvenile swine received either an endotracheal tube (Group A) or a Combitube in esophageal position (Group B). INTERVENTIONS: In Part I of the study, epinephrine was administered during spontaneous beating of the heart; in Part II, epinephrine was administered during cardiopulmonary resuscitation, using a ten-fold higher dosage in Group B, respectively. MEASUREMENTS: Plasma epinephrine levels were measured 1, 2, 3, 5, 7, 10, 15, and 30 mins after application. Systolic arterial blood pressure and cardiac output in Part I, and end-tidal CO2 and coronary perfusion pressure in Part II were recorded. MAIN RESULTS: In Part I, increased levels of plasma epinephrine and systolic arterial pressure were maintained significantly longer in Group B when compared with Group A. In Part II, no significant differences between the groups were found with regard to plasma epinephrine levels and hemodynamic variables. CONCLUSION: Epinephrine applied via the esophageal lumen of the Combitube in a ten-fold higher dosage has similar effects on plasma epinephrine levels and hemodynamic variables compared to endotracheal administration.

Control of fetal insulin secretion.

Abstract: In this study, we investigated the way in which fetal insulin secretion is influenced by interrelated changes in blood glucose and sympathoadrenal activity. Experiments were conducted in late gestation sheep fetuses prepared with chronic peripheral and adrenal catheters. The fetus mounted a brisk insulin response to hyperglycemia but with only a minimal change in the glucose-to-insulin ratio, indicating a tight coupling between insulin secretion and plasma glucose. In well-oxygenated fetuses, alpha(2)-adrenergic blockade by idazoxan effected no change in fetal insulin concentration, indicating the absence of a resting sympathetic inhibitory tone for insulin secretion. With hypoxia, fetal norepinephrine (NE) and epinephrine secretion and plasma NE increased markedly; fetal insulin secretion decreased strikingly with the degree of change related to extant plasma glucose concentration. Idazoxan blocked this effect showing the hypoxic inhibition of insulin secretion to be mediated by a specific alpha(2)-adrenergic mechanism. alpha(2)-Blockade in the presence of sympathetic activation secondary to hypoxic stress also revealed the presence of a potent beta-adrenergic stimulatory effect for insulin secretion. However, based on an analysis of data at the completion of the study, this beta-stimulatory mechanism was seen to be absent in all six fetuses that had been subjected to a prior experimentally induced hypoxic stress but in only one of nine fetuses not subjected to this perturbation. We speculate that severe hypoxic stress in the fetus may, at least in the short term, have a residual effect in suppressing the beta-adrenergic stimulatory mechanism for insulin secretion.

Biphasic response after brain death induction: prominent part of catecholamines release in this phenomenon.

Abstract: Background: The physiopathology of hemodynamic instability that occurs after brain death remains unknown. The aim of this study was to examine the initial response to brain death induction. Methods After anesthesia and monitoring, 16 pigs were randomized into a control group (C, n = 8) and a brain death group (BD, n = 8). We inflated a subdural catheter balloon to induce brain death. We analyzed hemodynamic and plasmatic biochemical data for 180 minutes after brain death induction. Energetic compounds were measured. We expressed the results in comparison with the C group. Results The C group remained stable. One minute after brain death, the Cushing reflex appeared, with a hyperdynamic response to plasma catecholamines levels increasing (norepinephrine and epinephrine, 3.1-fold, p = 0.02, and 3.8-fold, p = 0.07, respectively). After a return to baseline, we recorded a second hyperdynamic profile 120 minutes later. At this time, a second peak of catecholamines appeared (6.3-fold, p = 0.04, and 9.1-fold, p = 0.02, concerning norepinephrine and epinephrine). At the same time, we observed brief myocardial lactate production (+175%, p p = 0.03). The energetic index was similar in both groups: 0.85 (±0.02) in the C group vs 0.87 (±0.02) in the BD group. Conclusions In this model, biphasic plasmatic catecholamine release appears to primarily explain the physiopathology of the hemodynamic response to brain death induction.