The use of the intravenous anesthetic etomidate for prolonged sedation has been associated with low levels of plasma cortisol and increased mortality. We measured the cortisol and aldosterone responses to ACTH stimulation in five patients receiving etomidate, and we also studied the direct effects of etomidate on enzymes in the rat steroidogenic pathway. One patient who was receiving a 20-hour infusion of etomidate (1.3 to 1.5 mg per kilogram of body weight per hour) had marked adrenocortical suppression that was still evident four days after etomidate was discontinued. Four surgical patients receiving etomidate during their operations were all found to have adrenal suppression four hours after the operation; mean (+/- S.D.) increases in cortisol and aldosterone after ACTH stimulation were only 1.8 +/- 0.5 micrograms per deciliter and 0.5 +/- 1.1 ng per deciliter, respectively. In rat adrenal cells, etomidate produced a concentration-dependent blockade of the two mitochondrial cytochrome P-450-dependent enzymes, cholesterol-side-chain cleavage enzyme, and 11 beta-hydroxylase, without evident inhibition of the microsomal enzymes in the glucocorticoid pathway. Physicians should be aware that etomidate inhibits adrenal steroidogenesis, and they should consider treating selected patients with corticosteroids if etomidate is used.

Inhibition of Adrenal Steroidogenesis by the Anesthetic Etomidate

Drug response triggered by receptor activation arises from a chain of events that are regulated by many factors. Molecular changes associated with drug sensitization or tolerance are currently being elucidated on the molecular level, e.g. for adenylate cyclase coupled systems. Despite the complexity of the drug-response mechanism, simple empirical pharmaco-dynamic models on the basis of the law of mass action are widely applicable to describe drug-effect relationships. In combination with a pharmacokinetic model and suitable delay functions, such models are capable of simulating the complete time course of drug action in vivo. The predictive potential of the pharmacokinetic-pharmacodynamic models should prove useful in evaluating pharmaceutical formulations with controlled drug delivery.

Directed Drug Delivery

Several preparations of Cremophor El®, several of other non-ionic detergents and several components of Cremophor El were tested for their histamine-releasing capacity in dogs. Lutensol AP 10 and a derivative of 1,2-propylenglycol were ineffective, but showed excellent properties as detergents. Thus the histamine-releasing capacity was not necessarily combined with the tenside effect of the surfactants. Oleic acid found in Tween 80 as well as in Cremophor El seems to be the most effective constituent, but the alcohol seems also to be important for the histamine-releasing capacity. The development of a non-toxic solubilizer for lipophilic drugs seems of considerable clinical interest.

Histamine release in dogs by Cremophor E1 and its derivatives: oxethylated oleic acid is the most effective constituent.

Currently, there is no one drug that is the agent of choice for induction in rapid sequence intubation in the emergency department (ED). All agents currently used as induction agents in the ED offer distinct advantages for various clinical conditions, but each has a significant side effect profile and specific contraindications that limit its use in many common clinical settings. A review of the data available from the anesthesia literature suggests that etomidate possesses many properties that may make it the agent of choice for rapid sequence intubations in the ED. These advantages include excellent pharmacodynamics, protection from myocardial and cerebral ischemia, minimal histamine release, and a hemodynamic profile that is uniquely stable. Disadvantages include a lack of blunting of sympathetic response to intubation, a high incidence of myoclonus, prominent nausea and vomiting, potential activation of seizures in patients with epileptogenic foci, and impaired glucocorticoid response to stress. Further studies are needed to evaluate the advantages and disadvantages of the use of etomidate for rapid sequence intubation in the ED.

A review of etomidate for rapid sequence intubation in the emergency department

In 2 clinical studies in 40 conscious human volunteers and 164 orthopedic patients histamine-release responses were diagnosed, defined and classified. Polygeline (Haemaccel) in its now outdated formulation [40] was chosen as a clinical histamine releaser. The main interest was not concentrated on the extreme, the “classical” anaphylactic response, but on theaverage histamine-release response found in clinical experiments with so many drugs in the last 10 years. In human volunteers 600 ng/kg histamine was i. v. injected. Indicants for a systemic anaphylactoid reaction with the highest incidence ratio were tachycardia, plasma histamine levels >1 ng/ml, “metallic taste”, flush, congestion of head, “wet eyes” and tears, hypertension and headache. Following polygeline none of these subjects developed a life-threatening reaction, but 12 showed a systemic response, 11 a cutaneous reaction and 17 were non-responders. Indicants for a systemic anaphylactoid reaction with the highest incidence ratio were plasma histamine levels >1 ng/ml, tachycardia, wheals, sensation of heat, narrowness of throat, hypertension, headache and wet eyes or tears. In a prolective, cohort study in the orthopedic patients 3 subjects with life-threatening reactions, 27 with systemic response, 96 with cutaneous reaction and 38 non-responders were included. Indicants with the highest incidence ratio were tachycardia, plasma histamine levels >1 ng/ml, erythema and wheals, cough, flush, stuffy nose and facial oedema. With this trial the indicants for diagnosing a systemic histamine release response in volunteers were validated in patients to a large extent. Thus the average histamine-release response was defined by clinical signs such as tachycardia and mild hypertension, scattered hives such as spots of erythema and wheals, respiratory symptoms in the laryngeal and nasal region, such as cough, narrowness in the throat, stuffy nose and sneezingand by pathological plasma histamine levels (>1 ng/ml). In addition histamine-release responses were differentiated as cutaneous responses, systemic responses and life-threatening responses by clinical and operational criteria and by plasma histamine levels. Using clinical trials and medical decision making procedures the incidence of systemic histamine-release responses in patients higher by two orders of magnitude than in other studies reported hitherto.

/pdf/definition-and-classification-of-the-histamine-release-5dyv2reifp.pdf

Definition and Classification of the Histamine-Release Response to Drugs in Anaesthesia and Surgery: Studies in the Conscious Human Subject* **

The subject of histamine release was investigated in 16 volunteers by means of plasma histamine determination after the administration of etornidate, Althesin, propanidid, and Cremophor EL. Althesin and propanidid caused release of histamine in various degrees of frequency. Blood pressure changes were rather pronounced with both anaesthetic agents; tachycardia reached its maximum in the first and second minute, which seems to be an argument against histamine release as the underlying cause of this reaction. Histamine was, indeed, only released to such an extent (with the exception of one borderline case) that no clinical symptoms other than secretion of gastric juice and erythema were to be expected. After the application of etomidate and Cremophor EL an increase in plasma histamine was not detectable. Changes in the differential blood picture in terms of a decrease in basophils only occurred after Althesin and propanidid; not, however, after etomidate and Cremophor EL. Etomidate is, therefore, the first hypnotic drug for intravenous application which is unlikely to cause chemical histamine release.

https://epub.uni-regensburg.de/21884/1/lorenz70.pdf

G. Uhlig

Papers

HISTAMINE RELEASE AFTER INTRAVENOUS APPLICATION OF SHORT-ACTING HYPNOTICS: A Comparison of Etomidate, Aithesin (CT1341) and Propanidid*

Histamine release after intravenous application of short-acting hypnotics