Epinephrine Toxicity Research Articles

Intra-rectal use of epinephrine in radiotherapy of prostate cancer.

Purpose: The aim of the study was to evaluate the feasibility and toxicity of intra-rectal epinephrine during prostatic radiotherapy.Materials and methods: A total of 34 patients with prostate cancer were randomized to receive daily intra-rectal epinephrine (4 mg in 40 mL, n=16) or placebo (40 mL normal saline, n=18) 5 min before daily radiotherapy. Physical examination including systolic blood pressure (SBP) and heart rate (HR) was performed before, 5 min after, and 20 min after intra-rectal use. Toxicities were graded using the Radiation Therapy Oncology Group standard. A two-sided Fisher's exact test was used to compare proportions between groups. A mixed-effects model was used to analyze multiple measurements of SBP and HR. Survival curves were calculated using the Kaplan–Meier method and compared between groups using the log-rank test.Results: All patients completed the protocol treatment and reported no cardiovascular symptoms after intra-rectal administration. There were no differences in SBP and HR between these two groups at any time point (before, 5 min after, and 20 min after epinephrine). At 5 weeks after the start of radiotherapy, the incidence of rectal toxicity≥grade 2 was 27.8% (5/18) for the control group versus 12.5% (2/16) for the epinephrine group, but was not statistically significant (p=0.4). There was no rectal toxicity≥grade 2 in these two groups beyond 2-year follow-up. The 5-year biochemical relapse-free survival was 75.0% and 72.2% for the epinephrine and control group, respectively.Conclusion: Results of this pilot randomized trial have demonstrated that intra-rectal administration of epinephrine is feasible and safe in prostatic radiotherapy. Its radio-protective effect warrants further investigation.

Identifying Risk for Acute Kidney Injury in Infants and Children Following Cardiac Arrest.

Our goal was to identify risk factors for acute kidney injury in children surviving cardiac arrest. Retrospective analysis of a public access dataset. Fifteen children's hospitals associated with the Pediatric Emergency Care Applied Research Network. Two hundred ninety-six subjects between 1 day and 18 years old who experienced in-hospital or out-of-hospital cardiac arrest between July 1, 2003, and December 31, 2004. None. Our primary outcome was development of acute kidney injury as defined by the Acute Kidney Injury Network criteria. An ordinal probit model was developed. We found six critical explanatory variables, including total number of epinephrine doses, postcardiac arrest blood pressure, arrest location, presence of a chronic lung condition, pH, and presence of an abnormal baseline creatinine. Total number of epinephrine doses received as well as rate of epinephrine dosing impacted acute kidney injury risk and severity of acute kidney injury. This study is the first to identify risk factors for acute kidney injury in children after cardiac arrest. Our findings regarding the impact of epinephrine dosing are of particular interest and suggest potential for epinephrine toxicity with regard to acute kidney injury. The ability to identify and potentially modify risk factors for acute kidney injury after cardiac arrest may lead to improved morbidity and mortality in this population.

Cardiac failure following inadvertent administration of high-dose epinephrine subcutaneously.

Our aim is to report the consequences of epinephrine toxicity leading to cardiac failure in a child and the successful management with dopamine and milrinone. A previously healthy 13-year-old girl undergoing a left tympanomastoidectomy was inadvertently administered 10 mL of 1:1000 epinephrine subcutaneously (0.175 mg/kg) on the left post auricular region in lieu of lidocaine. She developed sudden supraventricular tachycardia, hypertension and flash pulmonary edema. She was initially treated with propofol, nitrogycerin and increased peak end-expiratory pressure. Within 4 h, she remained tachycardic, but was hypotensive with an increased central venous pressure. Electrocardiogram and echocardiogram investigations showed ST changes indicative of myocardial ischemia and globally reduced function, respectively. Dopamine infusion was administered, together with milrinone, resulting in a gradual improvement of cardiac function within 3 days. She was transitioned to enalapril and discharged home. This case highlights the clinical features of high dose epinephrine toxicity secondary to iatrogenic subcutaneous overdose followed by hypotension and pulmonary edema as a possible late effect of epinephrine and the successful management of secondary cardiac failure with administration of dopamine, milrinone and enalapril.

Epinephrine toxicity : An avoidable fatal complication due to iatrogenic overdose

The Sri Lankan Journal of Anaesthesiology is the official journal of the College of Anaesthesiologists of Sri Lanka. It publishes clinical investigations, research articles, audits, case reports, review articles and CME articles relating to anaesthesiology, critical care and pain. It is published bi annually in January and June. Sri Lankan Journal of Anaesthesiology is included on DOAJ and Scopus.

Apparent Epinephrine Toxicity in the Treatment of Anaphylaxis: A Patient Case of Prolonged Hypotension

Background The emergent nature of anaphylaxis creates an environment of heightened risk for epinephrine medication misadventures that may occur in any health care setting. Literature to date has focused on the immediate adverse outcomes associated with epinephrine dosing and administration errors, with a lack of data available on prolonged consequences. Objective We present a unique case of refractory hypotension associated with the administration of high-dose epinephrine for the treatment of anaphylaxis that prompted a comprehensive safety evaluation and implementation of a process improvement plan for all patients experiencing an anaphylactic reaction in our institution. Case Report A 29-year-old female presented to an immediate care facility for treatment of anaphylaxis including 2 doses of epinephrine 1 mg (1:1000) intramuscularly. The patient was subsequently transported to our adult emergency department and developed isolated hypotension refractory to fluid resuscitation. The patient was then admitted to the medical intensive care unit with a diagnosis of epinephrine toxicity. The prolonged hypotensive response seen in this patient is believed to be a result of residual stimulation of the more sensitive beta receptors by high doses of epinephrine administered to the patient, resulting in a prolonged vasodilatory response. Conclusion Epinephrine is a high-alert medication used for the treatment of anaphylaxis. Proactive evaluation of current processes among institutions is recommended in order to minimize dosing and administration errors with epinephrine as these errors can lead to substantial harm to patients.

Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome.

The author's goal was to develop a pathophysiological model for neuroleptic malignant syndrome with greater explanatory power than the alternative hypotheses of hypothalamic dopamine antagonism (elevated set point) and direct myotoxicity (malignant hyperthermia variant). Published clinical findings on neuroleptic malignant syndrome were integrated with data from human and animal studies of muscle physiology, thermoregulation, and autonomic nervous system function. The data show that the sympathetic nervous system's latent capacity for autonomous activity is expressed when tonic inhibitory inputs from higher central nervous system centers are disrupted. These tonic inhibitory inputs are relayed to preganglionic sympathetic neurons by way of dopaminergic hypothalamospinal tracts. The sympathetic nervous system mediates hypothalamic coordination of thermoregulatory activity and is a primary regulator of muscle tone and thermogenesis, augmenting both of these when stimulated. In addition, the sympathetic nervous system modulates all of the other end-organs that function abnormally in neuroleptic malignant syndrome. There is substantial evidence to support the hypothesis that dysregulated sympathetic nervous system hyperactivity is responsible for most, if not all, features of neuroleptic malignant syndrome. A predisposition to more extreme sympathetic nervous system activation and/or dysfunction in response to emotional or psychological stress may constitute a trait vulnerability for neuroleptic malignant syndrome, which, when coupled with state variables such as acute psychic distress or dopamine receptor antagonism, produces the clinical syndrome of neuroleptic malignant syndrome. This hypothesis provides a more comprehensive explanation for existing clinical data than do the current alternatives.

Lidocaine and epinephrine levels in tumescent technique liposuction.

The safety of lidocaine dosing in the tumescent technique has been well documented, but there is little evidence regarding the safety of combining tumescent lidocaine infiltration with subcutaneous lidocaine infiltration required in other aesthetic surgery. The safety of lidocaine and epinephrine dosing was investigated in 10 patients undergoing tumescent technique liposuction alone and in 10 patients undergoing tumescent liposuction with concurrent facial and aesthetic breast surgery by determining serum lidocaine and epinephrine levels at 3, 12, and 23 hours following infiltration of the tumescent solution and the subcutaneous lidocaine. The mean lidocaine dose of all patients was 22.3 mg/kg. All patients demonstrated safe lidocaine levels at all intervals, with the highest levels occurring in patients who received intravenous lidocaine at the induction of anesthesia. The peak epinephrine levels occurred at the 3-hour blood draw and were approximately four times physiologic. No patient demonstrated any subjective or objective signs of lidocaine or epinephrine toxicity.

Causes of death during acute asthma in children.

The medical records of children who had died of asthma, asthmatic bronchitis, and bronchiolitis at Charity Hospital of Louisiana at New Orleans during 1943 through 1973, excluding 1945 through 1949, were examined. Medical records suggested that death had occurred during acute asthmatic attacks in eight patients, and this was confirmed by a review of their postmortem examinations and histologic slide findings. Factors in these eight deaths included infection in four, sedation in three, aminophylline toxicity in one, epinephrine toxicity in one, and failure to initiate appropriate therapy early in five. Death reportedly occurred very suddenly in one child who died before reaching the hospital, and three others died within 3½ hours after reaching the hospital. Death from asthma in children is usually preventable by early initiation of appropriate therapy.

Changes in Pupil Diameter and Effects on Corneal Tissue Cultures from Topically Administered N-Butyl Gallate (COMT Inhibitor) and Epinephrine

Pupillometry and tissue culture methods were employed to study the changes in pupil diameter and effects on corneal epithelium Pigment deposits from topical N-butyl gallate (catechol-o-methyl-transferase inhibitor, COMT) and epinephrine therapy. The combined therapy with both drugs prolongs significantly the effect of epinephrine. Moreover, this combination also has a protective effect against epinephrine toxicity on epithelial cells. The evolution of epinephrine-induced pigment deposits in corneal epithelial cells and extracellularly was not affected by the N-butyl gallate.

Effect of temperature on toxicity and cardiac chronotropic action of sympathicotropic drugs

The effect of increased temperature on the i.v. toxicity of adrenergic stimulating or blocking agents was studied in mice. The toxicity of epinephrine increased 14.4 times when the environmental temperature was raised from 23° to 35°C; the Q' 10 = [1/ Q 10] being 9.2. Norepinephrine became 2.3 times more toxic, [ Q' 10=2.4]. This appears to be the greatest quantitative difference in activity reported between these two amines. The alpha-stimulators phenylephrine and methoxamine also showed marked increases in toxicity and high Q' 10 values of 6.6 and 1.86, respectively, but not tyramine, the beta-stimulator isoproterenol, or the adrenergic blocking agents dichlorisoproterenol, phenoxybenzamine and propranolol. Effects of these drugs on the contraction rate of isolated guinea-pig atria was determined at temperature intervals of 2°C, between 32°–42°C. All beta-stimulating compounds caused rate increases composed of temperature and drug effects, but only epinephrine at 1.17 × 10 −4 mM concentration changed the slope of the dose-effect curve. Phenylephrine, phenoxybenzamine and propranolol failed to influence the rate at any temperature studied.

A histochemical and electron microscopic study of of epinephrine-induced myocardial necrosis

A histochemical and electron microscopic study was made of the effects of large doses of epinephrine on the rat heart. Diffuse changes observed in the initial phases of epinephrine toxicity consisted of the deposition of lipid droplets in the myocardial fibres, an increase in the activity of oxidative enzymes, and a rapid fall in myocardial glycogen. These alterations gradually subsided except in certain areas, mostly in the subendocardium, in which foci of myocardial necrosis developed with marked fatty degeneration and total loss of oxidative enzyme activity. Electron microscopy revealed swelling of the sarcoplasmic reticulum, the T-system, and the mitochondria. The mitochondrial cristae often developed angulations in their ordinarily straight, parallel surfaces. These changes appeared to be largely reversible. Alterations of the contractile elements were found only in association with myocardial necrosis and were characterized by hyalinization and loss of the striations.

Comparison of the effects of some drugs on guinea pigs at high altitudes and at sea level

A comparative study of the effects of several drugs has been carried out in guinea pigs born and raised at sea level and in guinea pigs born and raised at altitudes over 4000 m. No differences were found in the toxicity of potassium cyanide, strychnine, metrazol, epinephrine, histamine or ethanol. Animals from high altitudes were more sensitive to the hypnotic and lethal effects of pentobarbital and needed a shorter time to recover from the experimental asthmatic attack produced by histamine.

A clinical evaluation of local anaesthetic solutions containing graded epinephrine concentrations

A double-blind study using five local anaesthetic solutions and 542 patients was conducted by a group of dentists. The following properties of the anaesthetic solutions were evaluated: (1) speed of onset of anaesthesia, (2) efficacy of anaesthesia, (3) duration of soft tissue anaesthesia, (4) degree of haemostasis, (5) toxic symptoms. In comparing the anaesthetic solutions tested, it was found that solutions with 1 300,000 epinephrine were as satisfactory as solutions with 1 100,000 epinephrine, whether the local anaesthetic was lidocaine or propitocaine. Propitocaine without epinephrine compared favourably with any of the solutions with epinephrine when used in mandibular blocks, and in operative dentistry. A less favourable anaesthetic efficacy was obtained for propitocaine without epinephrine when used in infiltration anaesthesia and in surgery. The experiments support the idea that solutions with lower epinephrine concentrations can be used for effective dental anaesthesia, thus reducing the danger of epinephrine toxicity due to intravascular injection.

Phosgene Poisoning as an Example of Neuroparalytic Acute Pulmonary Edema: The Sympathetic Vasomotor Reflex Involved

SUMMARY Conditions of acute pulmonary edema are classified into two great groups, according to certain empirically useful anatomic, physiologic, pharmacologic, clinical and radiologic criteria. The hyperactive-sympathetic group is characterized by diffuse lung hyperemia, pulmonary hypertension, amelioration by sympatholytic agents, systemic hypertension and uniformly dense lung fields; it includes epinephrine toxicity and brainstem irritation. The hypoactive-sympathetic or neuroparalytic group is characterized by patchy lung hyperemia, pulmonary normo- or hypotension, non-amelioration by sympatholytic agents, systemic normo- or hypotension and generalized reticulogranular images in the lung fields; it includes vagal section, so-called high altitude pneumonia, hyaline membrane disease, explosive recompression, probably paroxysmal nocturnal dyspnea, and phosgene poisoning. The basic assumption of this classification, specifically in relation to the neuroparalytic group, is tested by direct assay of total electrical activity of the right cervical sympathetic nerve in the rabbit before and after a lethal dose of phosgene. An immediate abrupt marked drop in systemic sympathetic outflow which precedes the lung changes occurs upon phosgene poisoning in the rabbit. Other data are marshalled to establish that the sympathetic neuroparalysis of phosgene poisoning is reflex in nature and associated with vasoconstriction of the lung vascular bed, such pulmonary shutdown being essentially a post-capillary phenomenon. The autonomic sensorimotor negative feedback reflex thus identified as controlling the vascular dynamics of the lung is presented as coursing afferently with the vagus, synapsing at the bulbar reticular formation, and coursing efferently with the upper thoracic sympathetics.

Potentiation of epinephrine and norepinephrine by iproniazid.

The effects of pretreatment with iproniazid on the toxicity and cataract-producing ability of epinephrine and norepinephrine were studied. The epinephrine and norepinephrine were administered in such a way that a slow, prolonged rate of absorption was achieved. Under these conditions, the lethality and cataract-producing ability of these amines were shown to be significantly enhanced by the action of iproniazid.

An Evaluation of the Pharmacologic Activity of a New Series of Chalcone Derivatives

A series of fourteen new chalcone derivatives, synthesized as potential antagonists of norepinephrine biogenesis, were evaluated with regard to their hypotensive potency in the normotensive dog. The compound 2-(2-dimethylammoethoxy) chalcone citrate, selected as the most active member of this group, was subjected to further study including determination of depressor effect in the hypertensive rat, acute toxicity, influence on epinephrine toxicity, and modification of barbiturate induced “sleeping time.” This series of chalcones was also screened for antihistaminic and antispasmodic activity on isolated guinea pig ileum, and the three most effective compounds in this respect were examined for their ability to inhibit the histamine depressor response in the cat. The chalcones investigated in this study compared unfavorably with available therapeutic agents in regard to specificity, potency, and duration of action. Recommendation is made for synthesis of additional chalcones with consideration given to the activities reported.

Potentiation of urethan anesthesia by epinephrine.

Three strains of mice (CAF1, C3H and C57 Black) were treated with various dose combinations of urethan and epinephrine. Duration of anesthesia, lethal toxicity and survival time were observed, with the following findings: 1. Epinephrine lethal toxicity was greatest in C57 Black mice and lowest in the CAF1 strain. 2. In all strains, urethan anesthetic time was greatly prolonged; this effect increased with dose of epinephrine. 3. Urethan reduced lethal toxicity of epinephrine; with increase of dose of epinephrine, reduction of toxicity was less. 4. Urethan anesthetic time was also potentiated by nor-epinephrine; its lethal toxicity was somewhat reduced by urethan. 5. Anesthetic time of phenobarbital sodium and of pentobarbital sodium was slightly potentiated by epinephrine. These agents did not reduce the lethal toxicity of epinephrine.

Effect of Various Drugs on Epinephrine-Induced Pulmonary Edema in Rabbits.

Summary1. Pulmonary edema and mortality induced in rabbits by intravenous injections of epinephrine were completely prevented by comparatively small doses of adrenergic blocking drugs, N-(2-bromoethyl)-N-ethyl-1-naph-thalenemethylamine. HBr (SY-28) and N-(2-chloroethyl) - N-ethylbenzhydrylamine. HCl (SY-2).2. It would appear unlikely that epinephrine toxicity and the pulmonary edema involved are importantly related to histamine release from tissues since the antihistaminics, Pyranisamine (Neoantergan maleate) and Phenergan (3277 RP), failed to prevent edema although large subcutaneous doses of Phenergan reduced mortality.3. The barbiturates, pentobarbital sodium and phenobarbital sodium did not decrease mortality or edema.4. The available evidence indicates that epinephrine toxicity is most readily reduced by vasodilator drugs which represent physiological antagonists, and by adrenergic blocking drugs which are pharmacological antagonists of epinephrine.

Ulceration of Wedding-ring into Phalanx

The relative toxicity of epinephrine and norepinephrine and their effects on brain excitability were determined in mice. In addition, the effects of these agents on blood pH and acid-base balance were studied. Epinephrine appears to be 4 to 8 times more toxic than norepinephrine. Both drugs exerted a non-monotonic effect on pentylenetetrazol seizure threshold (PST). Small nontoxic doses of both catecholamines elevated PST and large toxic doses lowered this threshold. Epinephrine had a similar non-monotonic effect on electroshock seizure threshold (EST). On the other hand, small nontoxic doses of norepinephrine had no significant effect on EST, whereas large toxic doses lowered EST. Within 30 seconds after their intravenous injection, both catecholamines decreased blood pH and induced a metabolic acidosis accompanied by some respiratory acidosis; but these metabolic alterations were causally unrelated to changes in brain excitability. It is suggested that epinephrine and norepinephrine act directly on the CNS to alter brain excitability.

A pharmacologic study of epinephrine suspensions in oil

1. 1. It has been shown that the toxicity of epinephrine in oil suspension by intramuscular injection in rats is about equal to that of a freshly prepared epinephrine hydrochloride aqueous solution. Ordinary commercial epinephrine solutions containing sodium bisulfite have a considerably higher toxicity. 2. 2. While the onset of toxic symptoms and the occurrence of deaths with the oil suspension were, as a rule, delayed as compared with aqueous solutions, there was still a significant number of instances in which symptoms of poisoning and deaths occurred as quickly as with the aqueous solutions, thus indicating difficulty in controlling the absorption of suspensions of epinephrine. 3. 3. We were unable to demonstrate a more prolonged action of the oil suspension by following the blood sugar curve in dogs and rabbits or the pupillary dilation in rabbits. 4. 4. It has been shown that finer particle sizes result in a less toxic and probably less potent preparation, which is also less stable than one made up of somewhat coarser particles.