Showing papers on "Epinephrine published in 2009"

Sympathetic Overstimulation During Critical Illness: Adverse Effects of Adrenergic Stress:

Abstract: The term ''adrenergic'' originates from ''adrenaline'' and describes hormones or drugs whose effects are similar to those of epinephrine. Adrenergic stress is mediated by stimulation of adrenergic receptors and activation of post-receptor pathways. Critical illness is a potent stimulus of the sympathetic nervous system. It is undisputable that the adrenergic-driven ''fight-flight response'' is a physiologically meaningful reaction allowing humans to survive during evolution. However, in critical illness an overshooting stimulation of the sympathetic nervous system may well exceed in time and scope its beneficial effects. Comparable to the overwhelming immune response during sepsis, adrenergic stress in critical illness may get out of control and cause adverse effects. Several organ systems may be affected. The heart seems to be most susceptible to sympathetic overstimulation. Detrimental effects include impaired diastolic function, tachycardia and tachyarrhythmia, myocardial ischemia, stunning, apoptosis and necrosis. Adverse catecholamine effects have been observed in other organs such as the lungs (pulmonary edema, elevated pulmonary arterial pressures), the coagulation (hypercoagulability, thrombus formation), gastrointestinal (hypoperfusion, inhibition of peristalsis), endocrinologic (decreased prolactin, thyroid and growth hormone secretion) and immune systems (immunomodulation, stimulation of bacterial growth), and metabolism (increase in cell energy expenditure, hyperglycemia, catabolism, lipolysis, hyperlactatemia, electrolyte changes), bone marrow (anemia), and skeletal muscles (apoptosis). Potential therapeutic options to reduce excessive adrenergic stress comprise temperature and heart rate control, adequate use of sedative/analgesic drugs, and aiming for reasonable cardiovascular targets, adequate fluid therapy, use of levosimendan, hydrocortisone or supplementary arginine vasopressin.

Epinephrine reduces cerebral perfusion during cardiopulmonary resuscitation.

Abstract: Objective:Epinephrine has been the primary drug for cardiopulmonary resuscitation (CPR) for more than a century. The therapeutic rationale was to restore threshold levels of myocardial and cerebral blood flows by its alpha1 (α1) and alpha2 (α2)-adrenergic agonist vasopressor actions. On the basis of

Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest.

Abstract: Background Animal data on cardiac arrest showed improved long-term survival with combined vasopressin-epinephrine. In cardiac arrest, cortisol levels are relatively low during and after cardiopulmonary resuscitation. We hypothesized that combined vasopressin-epinephrine and corticosteroid supplementation during and after resuscitation may improve survival in refractory in-hospital cardiac arrest. Methods We conducted a single-center, prospective, randomized, double-blind, placebo-controlled, parallel-group trial. We enrolled 100 consecutive patients with cardiac arrest requiring epinephrine according to current resuscitation guidelines. Patients received either vasopressin (20 IU per cardiopulmonary resuscitation cycle) plus epinephrine (1 mg per resuscitation cycle) (study group; n = 48) or isotonic sodium chloride solution placebo plus epinephrine (1 mg per resuscitation cycle) (control group; n = 52) for the first 5 resuscitation cycles after randomization, followed by additional epinephrine if needed. On the first resuscitation cycle, study group patients received methylprednisolone sodium succinate (40 mg) and controls received saline placebo. Postresuscitation shock was treated with stress-dose hydrocortisone sodium succinate (300 mg daily for 7 days maximum, with gradual taper) (27 patients in the study group) or saline placebo (15 patients in the control group). Primary end points were return of spontaneous circulation for 15 minutes or longer and survival to hospital discharge. Results Study group patients vs controls had more frequent return of spontaneous circulation (39 of 48 patients [81%] vs 27 of 52 [52%]; P = .003) and improved survival to hospital discharge (9 [19%] vs 2 [4%]; P = .02). Study group patients with postresuscitation shock vs corresponding controls had improved survival to hospital discharge (8 of 27 patients [30%] vs 0 of 15 [0%]; P = .02), improved hemodynamics and central venous oxygen saturation, and more organ failure–free days. Adverse events were similar in the 2 groups. Conclusion In this single-center trial, combined vasopressin-epinephrine and methylprednisolone during resuscitation and stress-dose hydrocortisone in postresuscitation shock improved survival in refractory in-hospital cardiac arrest. Trial Registration clinicaltrials.gov Identifier:NCT00411879

Catecholamines in plasma and urine in patients with essential hypertension determined by double-isotope derivative techniques.

Abstract: Employing double-isotope derivative techniques, noradrenaline and adrenaline have been determined in plasma and in urine and dopamine in urine in 21 patients with essential hypertension as well as in 32 controls. Plasma noradrenaline rose with age in both groups of subjects. No differences were observed in plasma noradrenaline and plasma adrenaline in the resting supine position and in urinary excretion of noradrenaline and dopamine in hypertensive patients as compared to control subjects. Urinary excretion of adrenaline was somewhat lower in the hypertensives than in the controls. Treatment with alprenolol, a beta-adrenergic blocking agent, did not influence noradrenaline and adrenaline in plasma in the basal state or the urinary excretion of the three catecholamines. The combined treatment with alprenolol and hydralazine was followed by a significant rise in plasma noradrenaline. It is concluded that the adrenergic activity evaluated by circulating catecholamines is normal in most patients with essential hypertension.

Epinephrine impairs lipid resuscitation from bupivacaine overdose: a threshold effect.

Abstract: Background: Lipid emulsion infusion reverses local anesthetic-induced cardiac toxicity, but the effect of adding epinephrine has not been studied. We compared escalating doses of epinephrine on recovery with lipid infusion in a rat model of bupivacaine overdose. Methods: Rats anesthetized with isoflurane received an IV bolus of 20 mg/kg bupivacaine, producing asystole (zero time) in all animals. Ventilation (100% oxygen) and chest compressions were started immediately, and at 3 min the rats received one of six IV treatments (n = 5 for all groups): 5 ml/kg saline followed by infusion for 2 min at 1.0 ml · kg -1 · min -1 , and a second 5 ml/kg bolus at 5 min; or the same bolus and infusion treatment using 30% lipid emulsion plus a single injection of epinephrine at one of five doses: 0 (lipid control), 1, 2.5, 10, or 25 mcg/kg. An electrocardiogram and arterial pressure were monitored continuously, and arterial blood gas was measured at 7.5 and 15 min. Results: Epinephrine improved initial return of spontaneous circulation (rate-pressure product > 30% baseline) but only 3 of 5 rats at 10 mcg/kg and 1 of 5 rats at 25 mcg/kg sustained return of spontaneous circulation by 15 min. Lipid alone resulted in slower but more sustained recovery. Epinephrine doses above a threshold near 10 mcg/kg increased lactate, worsened acidosis, and resulted in poor recovery at 15 min, as compared with lipid controls. There was tight correlation of epinephrine dose to serum lactate at 15 min. Conclusions: Epinephrine over a threshold dose near 10 mcg/kg impairs lipid resuscitation from bupivacaine overdose, possibly by inducing hyperlactatemia.

Anaphylaxis in the community: Learning from the survivors

Abstract: Background Most studies of anaphylaxis in the community focus on persons at risk who might, or might not, have experienced anaphylaxis. Objective We sought to focus on survivors of anaphylaxis in the community and their experiences in using, or not using, an epinephrine autoinjector for first-aid treatment. Methods An e-mail survey was conducted. Responses were anonymous and could not be traced to any person or location. Anaphylaxis was defined as the most severe sudden-onset allergic reaction ever experienced by the participants or a person for whom they were responsible (eg, a child). There were 17 core multiple-choice questions for all participants, with 16 additional questions for users who injected epinephrine either into themselves or someone else, and 1 additional question for nonusers. Results Of the 1885 participants, 500 (27%) were epinephrine users, and 1385 (73%) were nonusers. The groups were similar with regard to multisystem organ involvement (82% vs 78%, P = .07) and many other aspects of anaphylaxis; however, epinephrine users were more likely (all P Conclusions In a unique population composed of 1885 survivors of anaphylaxis in the community, users of epinephrine autoinjectors for first-aid treatment were outnumbered by nonusers. The insights reported by epinephrine users and the reasons why nonusers did not inject epinephrine are documented.

Stress-Mediated Increases in Systemic and Local Epinephrine Impair Skin Wound Healing: Potential New Indication for Beta Blockers

Abstract: Author(s): Sivamani, Raja K; Pullar, Christine E; Manabat-Hidalgo, Catherine G; Rocke, David M; Carlsen, Richard C; Greenhalgh, David G; Isseroff, R Rivkah | Abstract: BackgroundStress, both acute and chronic, can impair cutaneous wound repair, which has previously been mechanistically ascribed to stress-induced elevations of cortisol. Here we aimed to examine an alternate explanation that the stress-induced hormone epinephrine directly impairs keratinocyte motility and wound re-epithelialization. Burn wounds are examined as a prototype of a high-stress, high-epinephrine, wound environment. Because keratinocytes express the beta2-adrenergic receptor (beta2AR), another study objective was to determine whether beta2AR antagonists could block epinephrine effects on healing and improve wound repair.Methods and findingsMigratory rates of normal human keratinocytes exposed to physiologically relevant levels of epinephrine were measured. To determine the role of the receptor, keratinocytes derived from animals in which the beta2AR had been genetically deleted were similarly examined. The rate of healing of burn wounds generated in excised human skin in high and low epinephrine environments was measured. We utilized an in vivo burn wound model in animals with implanted pumps to deliver beta2AR active drugs to study how these alter healing in vivo. Immunocytochemistry and immunoblotting were used to examine the up-regulation of catecholamine synthetic enzymes in burned tissue, and immunoassay for epinephrine determined the levels of this catecholamine in affected tissue and in the circulation. When epinephrine levels in the culture medium are elevated to the range found in burn-stressed animals, the migratory rate of both cultured human and murine keratinocytes is impaired (reduced by 76%, 95% confidence interval [CI] 56%-95% in humans, p l 0.001, and by 36%, 95% CI 24%-49% in mice, p = 0.001), and wound re-epithelialization in explanted burned human skin is delayed (by 23%, 95% CI 10%-36%, p = 0.001), as compared to cells or tissues incubated in medium without added epinephrine. This impairment is reversed by beta2AR antagonists, is absent in murine keratinocytes that are genetically depleted of the beta2AR, and is reproduced by incubation of keratinocytes with other beta2AR-specific agonists. Activation of the beta2AR in cultured keratinocytes signals the down-regulation of the AKT pathway, accompanied by a stabilization of the actin cytoskeleton and an increase in focal adhesion formation, resulting in a nonmigratory phenotype. Burn wound injury in excised human skin also rapidly up-regulates the intra-epithelial expression of the epinephrine synthesizing enzyme phenylethanolamine-N-methyltransferase, and tissue levels of epinephrine rise dramatically (15-fold) in the burn wounded tissue (values of epinephrine expressed as pg/ug protein +/- standard error of the mean: unburned control, 0.6 +/- 0.36; immediately postburn, 9.6 +/- 1.58; 2 h postburn, 3.1 +/- 1.08; 24 h post-burn, 6.7 +/- 0.94). Finally, using an animal burn wound model (20% body surface in mice), we found that systemic treatment with betaAR antagonists results in a significant increase (44%, 95% CI 27%-61%, p l 0.00000001) in the rate of burn wound re-epithelialization.ConclusionsThis work demonstrates an alternate pathway by which stress can impair healing: by stress-induced elevation of epinephrine levels resulting in activation of the keratinocyte beta2AR and the impairment of cell motility and wound re-epithelialization. Furthermore, since the burn wound locally generates epinephrine in response to wounding, epinephrine levels are locally, as well as systemically, elevated, and wound healing is impacted by these dual mechanisms. Treatment with beta adrenergic antagonists significantly improves the rate of burn wound re-epithelialization. This work suggests that specific beta2AR antagonists may be apt, near-term translational therapeutic targets for enhancing burn wound healing, and may provide a novel, low-cost, safe approach to improving skin wound repair in the stressed individual.

Lipid Emulsion Combined with Epinephrine and Vasopressin Does Not Improve Survival in a Swine Model of Bupivacaine-induced Cardiac Arrest

Abstract: Background:This study sought to evaluate the efficacy of lipid emulsion in reversing bupivacaine-induced cardiovascular collapse when added to a resuscitation protocol that included the use of epinephrine and vasopressin. Methods:After induction of general anesthesia and instrumentation, 19 mixed-breed domestic swine had cardiovascular collapse induced by an intravenous bolus of 10 mg/kg bupivacaine. After 5 min of resuscitation including chest compressions, epinephrine (100 !g/kg) and vasopressin (1.5 U/kg), animals were randomized to receive either a bolus of 20% lipid emulsion (4 ml/kg) followed by a continuous infusion (0.5 ml · kg "1 · min "1 ) or an equal volume of saline. Investigators were blinded to the treatment assignment. The primary endpoint was return of spontaneous circulation (mean arterial pressure of at least 60 mmHg for at least 1 min). Results:Treatment groups were similar with respect to baseline measurements of weight, sex, and hemodynamic and metabolic variables. The rates of return of spontaneous circulation were similar between groups: (3 of 10) in the lipid group and 4 of 9 in the saline group (P#0.65). Total serum bupivacaine concentrations were higher in the lipid group at the 10-min timepoint (mean$SEM: 23.13$5.37 ng/mlvs.15.33$4.04 ng/ml,P#0.004). More norepinephrine was required in the lipid group compared to the saline group to maintain a mean arterial pressure above 60 mmHg during the 60-min survival period (mean$SEM: 738.6$94.4vs.. 487.3$171.0 !g). Conclusions:In this swine model, lipid emulsion did not improve rates of return of spontaneous circulation after bupivacaine-induced cardiovascular collapse. SYSTEMIC toxicity from local anesthetic overdose can occur from accidental intravascular injection, drug overdose, or rapid absorption from the administration site. The risk of toxicity is low when appropriate dosing and injection are used; the incidence is estimated at 7.5 to 20 events per 100,000 in adults. 1 Toxicity manifests in the central nervous system as confusion, seizure, and coma and in the cardiovascular system as dysrhythmia and eventually cardiac arrest. Treatment of cardiovascular collapse caused by local anesthetic overdose in humans is notoriously difficult to treat. 2‐4 There are conflicting reports in the literature regarding the efficacy of lipid emulsion in the treatment of cardiac arrest caused by local anesthetic toxicity. Rodent and canine models in which cardiac arrest was induced with a rapid bolus of intravenous bupivacaine report 100% survival with the administration of lipid emulsion and 100% mortality without lipid emulsion; no vasopressors were used in either group. 5‐8 These results contrast with the findings in a swine model used by Mayret al. 9,10 in which 100% of swine were resuscitated from a cardiac arrest induced by an intravenous bolus of 5 mg/kg bupivacaine after treatment with chest compressions and vasopressors. When these authors 9 examined the use of lipid emulsion without the use of vasopressors in their model, they found that none of the animals could be resuscitated.

Epinephrine auto-injectors: is needle length adequate for delivery of epinephrine intramuscularly?

Abstract: Objective Studies show that intramuscular epinephrine results in peak plasma concentrations of epinephrine faster than the subcutaneous route, and therefore, epinephrine is recommended to be administered intramuscularly. The objective of this study was to determine if the needle length on epinephrine auto-injectors is adequate to deliver epinephrine intramuscularly in children. Methods Patients between the ages of 1 and 12 years who presented to a children's hospital were enrolled in the study. Ultrasound was used to determine the depth from the skin to the vastus lateralis muscle. The patient's body mass index was recorded. The data were analyzed using simple descriptive statistics, and logistic regression was used to identify variables that might predict whether or not the needle length was exceeded. Results A total of 256 children were enrolled. Of these, 158 children weighed less than 30 kilograms and would be prescribed the 0.15 mg epinephrine auto-injector. Nineteen of these children (12%) had a skin to muscle surface distance of >(1/2)'' and would not receive epinephrine intramuscularly from current auto-injectors. There were 98 children weighing >or=30 kilograms who would receive the 0.3 mg epinephrine auto-injector. Of these 98 children, a total of 29 (30%) had a skin to muscle surface distance of >(5/8)'' and would not receive epinephrine intramuscularly. Conclusion The needle on epinephrine auto-injectors is not long enough to reach the muscle in a significant number of children. Increasing the needle length on the auto-injectors would increase the likelihood that more children receive epinephrine by the recommended intramuscular route.

Factors associated with repeated use of epinephrine for the treatment of anaphylaxis

Abstract: Background Studies looking at the use of repeated doses of epinephrine in patients experiencing anaphylaxis are limited. Objective To determine which patients are most likely to receive repeated doses of epinephrine during anaphylaxis management. Methods A population-based study with medical record review was conducted. All patients seen during the study period who met the criteria for the diagnosis of anaphylaxis were included. Results The cohort included 208 patients (55.8% female). Anaphylaxis treatment included epinephrine in 104 patients (50.0%). Repeated doses were used in 27 patients (13.0%), 13 (48.1%) of them female. The median age of those who received repeated doses was 18.9 (interquartile range, 10–34) years vs 31.1 (interquartile range, 15–41) years for those who did not receive repeated doses ( P = .06). The inciting agents were food (29.6%), insects (11.1%), medications (22.2%), others (7.4%), and unknown (29.6%). Patients who received repeated doses were more likely to have wheezing ( P = .03), cyanosis ( P = .001), hypotension and shock ( P = .03), stridor and laryngeal edema ( P = .007), nausea and emesis ( P = .04), arrhythmias ( P P = .04) and less likely to have urticaria ( P =.049). They were more likely to be admitted to the hospital than patients who did not receive repeated doses (48.2% vs 15.6%; P P = .17). Conclusions Of the patients, 13.0% received repeated epinephrine doses. Patients were younger and were likely to present with wheezing, cyanosis, arrhythmias, hypotension and shock, stridor, laryngeal edema, cough, nausea, and emesis and less likely to have urticaria. A history of asthma did not predict use of repeated doses of epinephrine. Our results help identify high-risk patients who may benefit from carrying more than 1 dose of epinephrine.

Adrenaline but not noradrenaline is a determinant of exercise-induced lipid mobilization in human subcutaneous adipose tissue

Abstract: The relative contribution of noradrenaline (norepinephrine) and adrenaline (epinephrine) in the control of lipid mobilization in subcutaneous adipose tissue (SCAT) during exercise was evaluated in men treated with a somatostatin analogue, octreotide. Eight lean and eight obese young men matched for age and physical fitness performed 60 min exercise bouts at 50% of their maximal oxygen consumption on two occasions: (1) during i.v. infusion of octreotide, and (2) during placebo infusion. Lipolysis and local blood flow changes in SCAT were evaluated using in situ microdialysis. Infusion of octreotide suppressed plasma insulin and growth hormone levels at rest and during exercise. It blocked the exercise-induced increase in plasma adrenaline while that of noradrenaline was unchanged. Plasma natriuretic peptides (NPs) level was higher at rest and during exercise under octreotide infusion in lean men. Under placebo, no difference was found in the exercise-induced increase in glycerol between the probe perfused with Ringer solution alone and that with phentolamine (an alpha-adrenergic receptor antagonist) in lean subjects while a greater increase in glycerol was observed in the obese subjects. Under placebo, propranolol infusion in the probe containing phentolamine reduced by about 45% exercise-induced glycerol release; this effect was fully suppressed under octreotide infusion while noradrenaline was still elevated and exercise-induced lipid mobilization maintained in both lean and obese individuals. In conclusion, blockade of beta-adrenergic receptors during exercise performed during infusion of octreotide (blocking the exercise-induced rise in adrenaline but not that of noradrenaline) does not alter the exercise-induced lipolysis. This suggests that adrenaline is the main adrenergic agent contributing to exercise-induced lipolysis in SCAT. Moreover, it is the combined action of insulin suppression and NPs release which explains the lipolytic response which remains under octreotide after full local blockade of fat cell adrenergic receptors. For the moment, it is unknown if results apply specifically to SCAT and exercise only or if conclusions could be extended to all forms of lipolysis in humans.

NO production and eNOS phosphorylation induced by epinephrine through the activation of β-adrenoceptors

Abstract: Epinephrine plays a key role in the control of vasomotor tone; however, the participation of the NO/cGMP pathway in response to β-adrenoceptor activation remains controversial. To evaluate the invo...

Influence of Acute Epinephrine Infusion on Endotoxin Induced Parameters of Heart Rate Variability: A Randomized Controlled Trial

Abstract: Objective To determine whether the acute anti-inflammatory influence of epinephrine (EPI) extends to changes in heart rate variability (HRV) induced by the prototypical inflammatory stimulus, endotoxin (LPS).

Brain death effects on catecholamine levels and subsequent cardiac damage assessed in organ donors.

Abstract: Background Brain death (BD) causes hemodynamic and neuroendocrine alterations including a catecholamine surge, which in turn causes histologic lesions in cardiac muscle such as contraction bands, focal mononuclear cell infiltrates and cardiomyocyte necrosis. These changes are likely to compromise heart function and could therefore also affect the graft response after heart transplantation. This study was designed to examine the catecholamine surge, the catecholamine release pattern and the histologic lesions traditionally described as characteristic of BD in hearts procured from BD donors. Methods After BD diagnosis, specimens were taken from the left ventricle (n = 50) for histologic examination. Arterial blood samples were collected from 40 of the donors at different time-points (1 hour before BD; on BD diagnosis; and 1, 2, 3 and 4 hours after BD) to determine catecholamine levels by high-performance liquid chromatography (HPLC). Results The three hormones examined showed above-normal levels (epinephrine 2.36-fold, norepinephrine 8.56-fold, dopamine 54.76-fold). Release patterns included epinephrine and dopamine peaks at the time of BD and a norepinephrine peak 1 hour later. Fifty percent of the BD donors showed contraction bands and 62% displayed cardiomyocyte necrosis, which was associated with focal mononuclear cell infiltrates in 18% of cases. In 40% of donors, colocalized apoptotic and necrotic damage was observed. Conclusions Differing extents of BD-associated cardiac lesions were observed in the donors, and >50% also showed apoptotic damage. The expected catecholamine peak at the time of BD was only detected for epinephrine and dopamine. Hormone increases were below those described in the literature, except for dopamine.

Catecholamine alterations in pediatric obstructive sleep apnea: effect of obesity.

Abstract: Study Objectives Obstructive sleep apnea (OSA) elicits increased sympathetic activity in adults and increased urinary catecholamines. Moreover, urinary catecholamine excretion is altered in obese patients. We hypothesized that morning urine catecholamine levels would be correlated with the severity of obstructive sleep apnea and degree of obesity in children. Methods Children referred to the pediatric sleep center for habitual snoring underwent overnight polysomnography, and the first morning voided urine sample was collected. Urinary concentrations of norepinephrine, epinephrine and dopamine were measured and corrected for creatinine levels. In a subset of children, blood samples were drawn and gene expression of catecholamine-relevant genes analyzed by quantitative real-time PCR. Results One hundred fifty-nine children were recruited and completed the protocol. Children with OSA had significantly higher urinary norepinephrine and epinephrine levels, but not dopamine, compared to habitual snorers (norepinephrine: 40.1 ± 24.7 ng/mg creatinine vs. 31.6 ± 16.2 ng/mg creatinine, P < 0.01; epinephrine: 6.4 ± 10.5 ng/mg vs. 4.5 ± 0.5 ng/mg, P < 0.01). There was a positive correlation between norepinephrine and epinephrine values and polysomnographic indices, but no effect of obesity on catecholamine levels. In addition, expression of several of the major genes involved in synthesis and transport of catecholamines, as well as in selected receptors were compatible with increased bioavailability of catecholamines. Conclusions In children with OSA, morning urinary norepinephrine and epinephrine levels are significantly higher than those without OSA, and correlate with the severity of the disease. Gene expression patterns are in agreement with such findings. Urine catecholamine levels do not appear to be influenced by the presence of obesity. Thus, altered sympathetic activity in OSA patients appears to occur independently of the presence of obesity. Pediatr Pulmonol. 2009; 44:559–567. © 2009 Wiley-Liss, Inc.

Pharmacokinetics of epinephrine in patients with septic shock: modelization and interaction with endogenous neurohormonal status.

Abstract: In septic patients, an unpredictable response to epinephrine may be due to pharmacodynamic factors or to non-linear pharmacokinetics. The purpose of this study was to investigate the pharmacokinetics of epinephrine and its determinants in patients with septic shock. Thirty-eight consecutive adult patients with septic shock were prospectively recruited immediately before epinephrine infusion. A baseline blood sample (C0) was taken to assess endogenous epinephrine, norepinephrine, renin, aldosterone, and plasma cortisol levels before epinephrine infusion. At a fixed cumulative epinephrine dose adjusted to body weight and under steady-state infusion, a second blood sample (C1) was taken to assess epinephrine and norepinephrine concentrations. Data were analyzed using the nonlinear mixed effect modeling software program NONMEM. Plasma epinephrine concentrations ranged from 4.4 to 540 nmol/L at steady-state infusion (range 0.1 to 7 mg/hr; 0.026 to 1.67 μg/kg/min). A one-compartment model adequately described the data. Only body weight (BW) and New Simplified Acute Physiologic Score (SAPSII) at intensive care unit admission significantly influenced epinephrine clearance: CL (L/hr) = 127 × (BW/70)0.60 × (SAPS II/50)-0.67. The corresponding half-life was 3.5 minutes. Endogenous norepinephrine plasma concentration significantly decreased during epinephrine infusion (median (range) 8.8 (1 – 56.7) at C0 vs. 4.5 (0.3 – 38.9) nmol/L at C1, P < 0.001). Epinephrine pharmacokinetics is linear in septic shock patients, without any saturation at high doses. Basal neurohormonal status does not influence epinephrine pharmacokinetics. Exogenous epinephrine may alter the endogenous norepinephrine metabolism in septic patients.

Blood-brain barrier to albumin in awake rats in acute hypertension induced by adrenaline, noradrenaline or angiotensin

Abstract: Acute hypertension was induced by adrenaline, noradrenaline or angiotensin in awake unrestrained rats with chronic indwelling catheters in a jugular vein and in the aorta. The leakage of 125IHSA (human serum albumin) into the brains from rats given adrenaline was significantly larger than in the brains from rats given noradrenaline or angiotensin. It is likely that the enhanced vulnerability of the blood-brain barrier to an adrenaline-induced increase in blood pressure is due to the beta-adrenergic stimulating effect of adrenaline.

Impaired counter regulation of hypoglycemia in a group of insulin-dependent diabetics with recurrent episodes of severe hypoglycemia.

Abstract: The counterregulatory response to insulin-induced hypoglycemia was investigated in 22 insulin-dependent diabetics (IDD) with recurrent hypoglycemia and in 6 healthy volunteers. Hypoglycemia was induced by a constant rate infusion of insulin (2.4 U/h) up to four hours. Conventional insulin therapy was changed to an i.v. infusion of regular insulin 24 hours prior to the experiment. The presence of diabetic autonomic neuropathy was evaluated by respiratory sinus arrhythmia and Valsalva maneuver. In healthy subjects, blood glucose was decreased to 2.5 mmol, here reaching steady state level and giving rise to marked glucagon and growth hormone (GH) responses. The majority of IDD (group A) reached a slightly lower steady state glucose level and exhibited similar glucagon and GH responses while the epinephrine response was augmented. Six IDD (group B) showed a continuous decrease in blood glucose to 1.2 +/- 0.1 mmol/l at which level the infusion of insulin was discontinued due to neuroglucopenic symptoms. These subjects had no glucagon and epinephrine responses while their GH and cortisol responses were normal. A comparison of the diabetic groups revealed a longer duration of diabetes and a more impaired autonomic nervous function in group B while glycosylated hemoglobin was similar. It is concluded that most IDD have normal hormonal responses (epinephrine, glucagon, GH, cortisol) and normal counterregulartory capacity to hypoglycemia induced by a prolonged infusion of a moderate dose of insulin. Some patients with long-term diabetes and impaired capacity to counteract hypoglycemia exhibit deficient glucagon and epinephrine responses to hypoglycemia.

Effects of metoprolol on the counter-regulation and recognition of prolonged hypoglycemia in insulin-dependent diabetics

Abstract: The effect of metoprolol on the counter-regulation of prolonged hypoglycemia was studied in eight insulin-dependent diabetics Insulin was given as an iv infusion of 24 U/h over 180 min alone, or together with metoprolol (30 mg iv bolus followed by an iv infusion of 48 mg/h) in random order Blood glucose, counter-regulatory hormones, hypoglycemic symptoms and the cardiovascular responses were assayed over 240 min Metoprolol did not significantly modify the blood glucose levels The plasma levels of free insulin, however, were elevated by approximately 20% (p less than 001) by metoprolol during hypoglycemia and the plasma concentrations of epinephrine, norepinephrine, growth hormone and cortisol were enhanced by the drug Sweating was increased by metoprolol, while other symptoms were unaltered We conclude that metoprolol administered acutely does not aggravate prolonged hypoglycemia in diabetics with blunted response of glucagon Moreover, exaggerated responses of counter-regulatory hormones, provoked by metoprolol, may compensate for the inhibitory effect of this drug on insulin clearance

Greater systemic lipolysis in women compared with men during moderate-dose infusion of epinephrine and/or norepinephrine.

Abstract: Women have lower circulating catecholamine levels during metabolic perturbations, such as exercise or hypoglycemia, but similar rates of systemic lipolysis. This suggests women may be more sensitiv...

The Hemostatic and Hemodynamic Effects of Epinephrine During Endoscopic Sinus Surgery: A Randomized Clinical Trial

Abstract: Objective To assess the hemodynamic and hemostatic effects of 2 different concentrations of epinephrine in local anesthetic used during functional endoscopic sinus surgery (FESS). Injection of local anesthetic containing epinephrine during endoscopic sinus surgery, while providing hemostasis, has been associated with cardiac adverse effects such as tachycardia, hypertension, as well as arrhythmias. Design Double-blind, randomized clinical trial. Setting Tertiary referral center. Patients A total of 140 patients undergoing FESS randomly divided into 2 groups, with group 1 receiving lidocaine hydrochloride, 2%, with 1:100 000 epinephrine and group 2, lidocaine, 2%, with 1:200 000 epinephrine. Main Outcome Measures Baseline and postinjection hemodynamic parameters were recorded at 1-minute intervals for 5 minutes. Patient demographics, the extent of surgery, and the presence of polyps were recorded in both groups. Hemodynamic and hemostatic parameters and intraoperative blood loss were compared. Results Significant hemodynamic fluctuations were noted following injection of lidocaine, 2%, with 1:100 000 epinephrine (group 1). Increases in heart rate and systolic, diastolic, and mean arterial blood pressure were noted in group 1 patients. The increase was found to be significant ( P P > .05). Conclusion Submucosal injection of lidocaine, 2%, with 1:200 000 epinephrine during FESS does not lead to hemodynamic fluctuations or increased intraoperative bleeding compared with lidocaine, 2%, with 1:100 000 epinephrine. Trial Registration clinicaltrials.gov Identifier:NCT00852410

Antagonism between glucose and epinephrine regarding insulin secretion. A dose-response study in man.

Abstract: . A dose-response study of the inhibitory effect of epinephrine on glucose-induced insulin secretion in man has been performed. The results demonstrate the exquisite sensitivity of the pancreatic β-cells to epinephrine, as small a dose as 3 mμg/kg/min inducing a 50% inhibition. These studies emphasize the physiological significance of epinephrine for the regulation of insulin secretion. They also show that in previous studies in man and animals supramaximal amounts of epinephrine have been employed. Our results also suggest that the actions of epinephrine and glucose on insulin secretion are competitive. Infusion of aminophylline had only a minor inhibitory effect on the action of epinephrine. Therefore, our data do not permit the conclusion that epinephrine suppresses insulin release exclusively by diminishing the rate of synthesis of cyclic AMP. Other possible mechanisms are discussed.