Adrenergic Therapy Research Articles

Gabapentin add-on therapy for patients with spinal cord injury associated neurogenic overactive detrusors that are unresponsive to combined anticholinergic and beta-3 adrenergic therapy.

IntroductionSpinal cord injury is a major cause of lifelong morbidity and functional micturition problems. Some patients are refractory to the available therapeutics, even when used in combination. In this paper we report our results of using gabapentin as an add-on treatment in refractory overactive detrusor cases secondary to spinal cord injury.Material and methodsA total of 27 patients who had a spinal cord injury between the levels of the second thoracic and fourth lumbar vertebrae and had an overactive detrusor in urodynamic studies were included in this retrospective study. The patients were selected due to the fact that they also had not responded to a combination of an anticholinergic and mirabegron and had neuropathic pain. Gabapentin treatment was added to the previous therapy. Demographics, previous treatments, chronic conditions, urodynamic findings, clinical and urodynamic responses are reported in this paper.ResultsWe observed a response to treatment in the urodynamic studies of 11 patients (40.17%), in terms of decreased detrusor contractions, maximal detrusor pressure, and the number of incontinence episodes. Sixteen patients did not respond to the gabapentin add-on therapy and were referred for Botulinum toxin injections to the bladder.ConclusionsGabapentin add-on therapy can be considered as a third or further option, before Botulinum toxin injection, for patients with neurogenic overactive detrusor who did not respond to the combination of anticholinergics and mirabegron. The approved usage of gabapentin for neurogenic pain justifies its usage in this area. In our selected patient group, who had not responded to the combination therapy, we observed a clinical benefit in one-third of the patients.

Non-invasive characterization of hemodynamics in adult out-of-hospital cardiac arrest patients soon after return of spontaneous circulation

BackgroundLittle is known about hemodynamics in adult, out-of-hospital (OHCA) patients following return of spontaneous circulation (ROSC). A 1994 study when “high-dose epinephrine” use was common showed consistently elevated systemic vascular resistance (SVR) lasting ≥6 h in 49 adult patients after return of spontaneous circulation (ROSC). Study aimTo characterize hemodynamic abnormalities in adult OHCA patients soon after ROSC. Our hypothesis was that, unlike the consistently high SVR values reported when “high-dose” epinephrine was in common use, there would be a more heterogenous distribution of SVR values using current adrenergic therapy. MethodsWe included adult, OHCA patients transported by paramedics to the Emergency Department (ED) post-ROSC. Children, prisoners, pregnant women, and those with ongoing CPR or arrest due to traumatic injury were excluded. Hemodynamics were recorded non-invasively as soon as feasible after ED arrival but were not used to influence therapy, which was guided by clinical judgment of treating ED physicians. ResultsHemodynamics were recorded on 30 patients 20 [16,25] minutes after ED arrival: 50% had a normal SVR, 30% had a high SVR, and 20% had a low SVR. There was no difference in survival to admission among groups, although there was a difference among groups in survival to discharge. Comparing the low SVR group vs the combined normal and high group revealed a trend for fewer 0/6 (0%) low vs. 10/24 (42%) normal or high SVR patients surviving to hospital discharge (p = .053). ConclusionA heterogeneous range of hemodynamic states exist post-ROSC rather than consistent vasoconstriction. Adequately powered, randomized clinical trials will be needed to determine whether noninvasively-derived, hemodynamic-directed therapy can play a role in improving neurologically-intact survival following OHCA in adults.

α1A‐Subtype Adrenergic Therapy is Beneficial for Failing Right Ventricle (RV)

Compared to non‐failing RV, we reported that failing RV had an increased inotropic response to stimulation of α1‐adrenergic receptors (α1‐ARs). Recently, we found that a single subtype (α1A) was responsible. We hypothesized that increased α1A‐subtype signaling is beneficial in RV failure and a potential therapeutic target. Studies in several laboratories suggest that chronic α1A‐subtype stimulation has a beneficial effect on LV function in multiple heart failure models. However, no studies have investigated chronic α1A‐subtype stimulation in the setting of RV failure.GoalDetermine if α1A‐subtype adrenergic therapy is beneficial for failing RV.MethodsWe used tracheal instillation of the fibrogenic antibiotic bleomycin in mice to induce pulmonary fibrosis, pulmonary hypertension, and RV failure within 2 wk. Mice were treated concurrently using osmotic mini‐pump infusion with either a low dose of the α1A‐subtype agonist A61603 (10ng/kg/day) or saline (vehicle controls). We assessed multiple readouts of cell injury in failing RV and determined if these were improved by A61603 therapy.ResultsMultiple readouts of cell injury in failing RV myocardium were markedly attenuated by A61603 therapy. Specifically, the Table summarizes that the level of serum troponin I (TnI) was significantly increased in the bleomycin RV failure model and this increase was prevented by A61603 therapy. Myofilament force development was significantly reduced in failing RV, and this decrease was prevented by A61603 therapy. Two isoforms of matrixmetalloproteinase‐2 (MMP‐2), which are associated with cell injury, were increased in failing RV, and these increases were prevented by A61603 therapy. Finally, bleomycin‐induced pulmonary fibrosis was associated with markedly increased lung weight, and this increase was not abolished by A61603 therapy, suggesting that the beneficial effect of A61603 therapy on the RV did not occur via a beneficial effect on the bleomycin model of lung injury. Preliminary studies suggest that the beneficial effect of A61603 therapy involves a reduction in the level of oxidative stress.ConclusionChronic therapy with the α1A‐subtype‐specific agonist A61603 resulted in decreased cellular injury in a model of RV failure. The α1A‐subtype is a potential therapeutic target to treat RV failure.Support or Funding InformationSupported by Department of Veterans Affairs Merit Review Awards I01BX000740 (AJB), I01BX000593 (DHL), National Heart, Lung and Blood Institute Grant HL31113 (PCS) and an American Heart Association Grant‐in‐Aid (AJB). A61603 Treatment Reduced Markers of Cell Injury in Bleomycin‐Induced RV Failure Non‐failing Bleomycin Bleomycin +A61603 Serum Tnl (ng/ml) 5.6 ± 0.8 11.7 ± 0.6*** 6.7 ± 0.7 Fmax (nN/mm2) 88 ± 3 64 ± 2*** 79 ± 2 FL‐MMP‐2 1 9.8 ± 1.8* 3.9 ± 0.8 NTT‐MMP‐2 1 6.2 ± 1* 2.2 ± 1 Lung wt. /body wt. (mg/g) 7.2 ± 0.2 13 ± 0.3*** 12.9 ± 0.4*** Significant differences compared to non‐failing: P < 0.001; P < 0.05.

Norepinephrine versus dopamine pretreatment of potential heart donors – impact on long-term outcome

Current guidelines advocate administration of inotropic agents to stabilize potential deceased heart-beating donors. A consensus on the specific agent or combination therapy is lacking. We thus initiated a retrospective analysis of patients being transplanted at our center in a matched-pair study design focusing on survival after donor pre-treatment either with norepinephrine or dopamine. 936 patients (759 male; 177 female; mean age: 47.5 ± 15.4 years) were transplanted at our center between 8/1981 and 12/2010. An overall of 22 patient pairs (all male; mean age 55.4 ± 7.5 years; range 23-67 years) were matched according to our strict criteria. During follow-up (5037 ± 1791 days) 11 deaths occurred. Overall survival in both groups was not different (p=0.1438). In a sub-population analysis of all patient-pairs that completed 5-year follow-up (n=19), Kaplan-Meier analysis revealed significant superior survival of recipients that received hearts pre-treated with norepinephrine vs. dopamine pre-treatment (p=0.0368). Neither norepinephrine nor dopamine pre-treatment of potential heart donors showed superior overall survival. In a sub-population of long-term survivors norepinephrine pre-treatment was associated with better survival in a rather small cohort of heart transplant recipients. These findings underscore the urgent need of further prospective multicenter randomized trials to recommend a preferable adrenergic therapy.

Drug Interaction or Drug Overdose? Supercaine Revisited

To the Editor: We read with great interest the article of Marcucci et al. (1) illustrating the contribution of drug–drug interactions to a case of intraoperative cardiac arrest. They attribute the event to an exaggerated effect of metoprolol. We believe local anesthetic toxicity is often overlooked (2) and were disappointed that the authors did not consider the interaction of tetracaine and mepivacaine in the differential diagnosis of a patient who experienced asystole and contractile depression after a brachial plexus block. Moore et al. (3) confirmed the safety of this popular combination when the total mepivacaine dose was limited to 500 mg. However, the reported patient received 675 mg mepivacaine plus 50 mg tetracaine which, in view of their additive toxicities, might have contributed to the patient’s cardiovascular symptoms. Furthermore, the patient’s weight was not reported, and we think it is very important, particularly when combining local anesthetics, to be mindful of the total dose of drug per kilogram of lean body mass. This is especially appropriate when, as the authors postulate, the patient’s genetic, metabolic, dietary, and medical milieu lowered the threshold for toxicity of such agents. The patient received ephedrine, epinephrine, dopamine, phenylephrine, and norepinephrine during his resuscitation. Aggressive adrenergic therapy is associated with adverse outcomes in several models and studies of cardiac arrest (4,5). A recent survey by Corcoran et al. (6) indicates that there is a lack of consensus among anesthesiologists regarding proper treatment of severe local anesthetic toxicity. In light of two recent case reports (7,8), we recommend considering lipid infusion (9,10) as an adjunct to other modes of therapy in cases of local anesthetic toxicity. Guy Weinberg, MD Department of Anesthesiology University of Illinois College of Medicine Chicago, IL [email protected] Timothy VadeBoncouer, MD Jesse Brown VA Medical Center Chicago, IL We did not obtain a response from Marcucci et al.

The yin and yang of increased β-adrenergic signaling: β1-adrenergic genetic polymorphism and protection against acute myocardial ischemic injury

significant improvements in the treatment and prevention of cardiac diseases have led to declining morbidity and mortality over the past three decades ([2][1]), and drugs targeting adrenergic signaling have played a key role in the beneficial effects recently afforded to these patients. However,

Adrenergic Drugs Alter Both the Fluid Kinetics and the Hemodynamic Responses to Volume Expansion in Sheep

Plasma volume expansion is often performed during adrenergic therapy in the intensive care unit, but little is known about their combined effects. The influence of three adrenergic drugs (50 microg/kg/min of dopamine, 0.1 microg/kg/min of isoprenaline, or 3 microg/kg/min of phenylephrine) on the relationship between plasma dilution (an index of volume expansion) and the central hemodynamic responses to volume loading with 24 ml/kg of 0.9% saline were evaluated in 6 adult sheep. Kinetic analysis was also applied to the data on plasma dilution and the urinary excretion measured during and after volume loading. The adrenergic agents markedly changed the baseline values for all hemodynamic parameters. The kinetic analysis showed that phenylephrine, which is an alpha-adrenergic receptor agonist, promoted renal excretion of infused fluid at the expense of fluid distribution to the periphery (P < 0.05 versus controls). Isoprenaline, which stimulates adrenergic beta-receptors, had the opposite effect. During volume expansion, cardiac atrial pressures increased by 25 to 90%, cardiac output by 13-80% and the arterial pressures by 2 to 22%. Plasma dilution during and after volume loading correlated, in a linear fashion, with these hemodynamic responses. The correlations were strong (r > 0.80) in the control and phenylephrine groups, but weaker in the dopamine and isoprenaline groups. Dopamine was associated with the most variable hemodynamic responses overall. Adrenergic drugs altered the hemodynamics at baseline (direct effects), changed the distribution and elimination of infused 0.9% saline (indirect effects) and, finally, modified most hemodynamic responses to plasma dilution (interaction effects).

Persistent nonallergic rhinosinusitis

Nonallergic rhinitis is a complex of syndromes that are united by the absence of atopic, T(H)2 lymphocyte, immunoglobulin E (IgE)-mediated mechanisms. We propose a classification system based on the presence or absence of inflammatory granulocytes. Eosinophilic nonallergic rhinosinusitis may also be called chronic eosinophilic sinusitis syndromes (CESS) to help classify these disorders in which diverse mechanisms of eosinophil chemoattraction and survival predominate. Allergic fungal sinusitis, eosinophilic nasal polyps, aspirin sensitivity, and related disorders would fit in this category. Accumulation of neutrophils occurs in chronic infectious rhinosinusitis, foreign body reactions, and immunodeficiencies. More complex and variable combinations of leukocytes are found in Wegner's granulomatosis and related syndromes, and during the evolution of viral infections. The noninflammatory disorders can be divided by mechanism into hormonal; sympathetic dysfunction (including antihypertensive adrenergic drug therapy); cholinergic rhinitis; and nociceptive syndromes with hyperalgesia and other features (eg, the nonallergic rhinitis of chronic fatigue syndrome). Therapy based on the most likely pathophysiologic mechanism is anticipated to have the most success, but requires acceptance of the wide differential diagnosis of nonallergic rhinitis and rejection of the obsolete term of "vasomotor rhinitis."

Asthma Update

Asthma Update

Role of beta blockers in congestive heart failure.

Prolonged activation of the adrenergic nervous system has adverse consequences on the cardiovascular system in patients with congestive heart failure. Beta adrenergic receptor-blocker therapy modifies these deleterious effects. Beta blockers have been shown to improve myocardial function and survival when used in conjunction with conventional treatment with diuretics, angiotensin-converting enzyme inhibitors, and digoxin. Beta blocker therapy in mild-to-moderate heart failure should not be delayed because it causes some reversal of both neurohormonal compensatory mechanisms and the deleterious myocardial remodeling process. This paper reviews the beneficial effects of beta adrenergic receptor-blocker therapy on the pathophysiology, symptoms, left ventricular function, morbidity, and mortality in patients with congestive heart failure. (c)2000 by CHF, Inc.

The Relation Between Cardiac Index and Oxygen Extraction in Acutely III Patients

The relation between cardiac index and oxygen extraction (O2ER) can represent a useful basis for the interpretation of hemodynamic parameters in the acutely ill patient. We prospectively collected cardiac index and paired arterial and mixed venous blood gas values in 79 acutely ill patients who were successively monitored invasively during their ICU course. For each patient, the degree of cardiac failure score and sepsis was scored at time of each measurement. A total of 122 observations were reported on a cardiac index/O2ER diagram, on which, based on physiologic data obtained during physical exercise, a line of reference was included representing equal increases in cardiac index and O2ER from normal values at rest. Patients with established heart failure fell below the line of reference. However, patients without cardiac failure or with compensated cardiac failure during adrenergic therapy fell close to the line of reference. Sepsis was associated with elevated oxygen delivery (Do2) and oxygen consumption (Vo2). Although O2ER was lower in the presence than in the absence of septic shock, patients with sepsis fell close to the line of reference. Among these patients with sepsis, O2ER was greater in patients with established heart failure than without heart failure (37.6 +/- 11.7 percent vs 21.5 +/- 4.4 percent, p < 0.01). The relationship between cardiac index and O2ER is much simpler than the relationship between Vo2 and Do2 and it avoids problems of mathematical coupling. It also allows us to refer to physiologic adaptation to changes in oxygen demand. This diagram may be useful at the bedside to facilitate the interpretation of cardiac index and to guide therapy.

Use of adrenergic agonists during CPR in adults

Adrenergic therapy is indicated during CPR to increase the coronary and cerebral perfusion pressure. Epinephrine hydrochloride at a dosage of 1.0 mg has been the most commonly used adrenergic agonist for resuscitation of adults, but there has been considerable controversy over whether higher doses should be given. At the 1992 National Conference on Emergency Cardiac Care and CPR, preliminary data were presented from three large, prospective, blinded, unpublished clinical trials that included a comparison of standard-dose (0.02 mg/kg or approximately 1.0 mg) and high-dose (approximately 0.1-0.2 mg/kg) epinephrine in 2,415 adults. Although the studies differed from each other somewhat in design, the results were remarkably consistent across all three studies: there was no difference in survival between the standard- and high-dose epinephrine regimens. There were no consistent adverse effects associated with the use of higher-than-standard doses of epinephrine. The consensus of the Adrenergic Agonist Panel was that: 1) epinephrine by i.v. bolus should remain the drug of choice for use during resuscitation in adults; 2) data presented from the clinical trials in adults do not support an increase in the recommended dose of epinephrine; 3) because there was no evidence of significant harm from the use of high-dose epinephrine, it was felt that use of such dosages should receive a II-b recommendation pending the results of further ongoing clinical trials; 4) the standard i.v. bolus dosage of epinephrine should be simplified to 1.0 mg every three to five minutes; and 5) the endotracheal dosage of epinephrine should be at least 2 to 2.5 times larger than the peripheral i.v. dosage.

Acute life-threatening asthma

Although adrenergic therapy may be lifesaving in patients with severe acute asthma, attention must also be directed toward reversing underlying inflammation with corticosteroids. Other therapy for acute severe bronchospasm is controversial, although inhalant anticholinergic therapy may have adjunctive benefit. Aminophylline or magnesium sulfate may be indicated in those patients with life-threatening asthma who do not respond to conventional therapy. Chest radiographs are needed in patients who (1) present in extreme distress, (2) need to be hospitalized, or (3) have clinical manifestations of pneumonia or pneumothorax. Antibiotics are not used for acute asthma in the absence of pneumonia.

The Use of Anticholinergic Agents in the Treatment of Airways Disease

Anticholinergic agents are useful bronchodilators, the use of which should not be overlooked in patients with airways diseases. In patients with stable asthma, they are not first-line therapy but may be valuable as adjunctive therapy. In status asthmaticus they add to the bronchodilatation achieved by adrenergic therapy. Their principal role is in the maintenance therapy of chronic obstructive pulmonary disease. The newer synthetic forms, such as ipratropium bromide, are free of atropine-like side effects and have a wide therapeutic margin.

Adrenergic therapy of bronchial asthma

Beta-adrenergic therapy of bronchial asthma began with the introduction of injected epinephrine by Bullowa and Kaplan’ in 1903 and oral ephedrine by Chen and Schmidt* in 1924. Agents that cause relaxation of bronchial smooth muscle by interaction with P-adrenergic receptors share certain common structural features. The basic structure is that of a phenylethylamine, and all drugs possessing bronchodilator properties have in addition a hydroxyl group on the beta carbon of the side chain.3 This basic structure with only the addition of a methyl group on the alpha carbon of the side chain yields ephedrine, a weak bronchodilator but one that is active on oral administration. Addition of hydroxyl groups on the third and fourth carbons of the benzene ring produces the catecholamines that are more potent but also susceptible to conjugation in the gut and liver and inactivation by the enzyme COMT that methylates

Decreased beta-adrenergic receptors on polymorphonuclear leukocytes after adrenergic therapy.

β-ADRENERGIC catecholamines, which modulate function of a variety of tissues, are assumed to act by initially binding to receptors on target-cell plasma membranes, thereby activating adenylate cyclase and stimulating generation of adenosine 3′:5′-monophosphate (cyclic AMP). In addition to activating adenylate cyclase, β-adrenergic agonists commonly have a second action — regulation of responsiveness of the target cells. Thus, continued treatment with such agonists often results in decreased cellular response. This self-regulation of target-cell responsiveness, variously termed refractoriness, desensitization and down-regulation, has been observed with catecholamines, as well as with a number of other hormonal agonists.1 2 3 For catecholamines, studies in several experimental . . .

Controlled Assessment of Beta2 Adrenergic Therapy for Childhood Asthma

Single-entity sympathomimetic bronchodilators are often the primary therapeutic modality for asthma in children, especially when avoidance of the systemic adverse effects of the methylxanthines and the corticosteroids is of major concern. Metaproterenol, a recognized beta2 adrenergic agonist resistant to deactivation by catechol-o-methyl-transferase, was the object of two double-blind studies in Denver, among children 6 to 16 years of age, with a confirmed diagnosis of variable obstructive airways disease.

Symposium on Ocular Therapy,

This monograph contains the papers presented at the drug symposium held by the American Academy of Ophthalmology and Otolaryngology together with the Association for Research in Vision and Ophthalmology in Dallas, 1974. All ten papers are of interest to the practicing ophthalmologist. Some of the papers summarize in an excellent and concise form the present state of the arts and certain aspects of ocular therapeutics. In this category fall the papers on local anesthetics by P. P. Ellis, treatment of viral infections by H. Kaufman, and management of bacterial corneal ulcers by T. Pettit. Other papers summarize modern aspects of ocular therapy in a scientific and most sophisticated manner, such as the review on adrenergic therapy of open angle glaucoma by Marvin Sears. A few of the papers report on new findings or the results of new and unusual treatments, such as the contribution on immunosuppressive therapy by Robert Burns

Effect of adrenergic blockade and specific antithyroid therapy on electrocardiographic changes in hyperthyroidism.

Abstract:Considerable controversy still exists whether the cardiovascular manifestations of hyperthyroidism are due to the direct action of an increased amount of thyroid hormones on the heart or due to increased adrenergic activity of catecholamines. In this study, electrocardiograms (ECG) were rec

Adrenergic beta-receptor blockade in neurocirculatory asthenia

Twenty patients with neurocirculatory asthenia (NCA) have been investigated. They suffered from at least three out of seven defined symptoms and the severity of the symptoms prevented an ordinary daily activity. The patients were classified according to physiological variables and psychiatric (interview) criteria. They were treated with Aptin®, an adrenergic beta-blocking agent, and placebo in a double-blind cross-over design. From objective and subjective assessment of symptomatic improvement and drug preference, eight patients were classified as Aptin-responders and eleven as placebo responders. Physiological characteristics of hyperkinetic circulation due to increased activity of the sympathetic nerves was found in seven Aptin-responders but only in four placebo-responders. Six Aptin-responders were classified as anxiety states but only four placebo-responders. — The trial illustrates how therapy with a specific drug can reveal differences of probably etiological character in patients constituting a symptomatic entity. Adrenergic beta-blocking therapy in NCA seems to be of value predominately in patients with signs of hyperkinetic circulation and/or anxiety states.