Paradoxical Reactions to Benzodiazepines in Intravenous Sedation

In: Main

13 Dec 2009


Since the discovery of the anesthetic properties of nitrous oxide by Horace Wells in 1844, the availability of anesthetic agents has considerably increased. The newer synthesized drugs have proved advantageous over the older agents. Benzodiazepines are used for their sedative, anxiolytic, amnesic, *anticonvulsant drug, and muscle relaxant properties; however, they are associated with rare adverse effects.

Benzodiazepines stimulate the effect of gamma-aminobutyric acid (GABA) in the ascending reticular activating system. GABA receptors are found in different parts of the brain. Activation of the GABA receptor by the benzodiazepines increases inhibition of the cortical and limbic arousal states. The benzodiazepines depress the electrical after-discharge in the septum, amygdala, and hippocampus. These structures are involved in the regulation of emotions. The sedative effects of the benzodiazepines are mediated by the brainstem GABA receptors that inhibit the ascending pathways that activate the brain cortex. The ataxia and memory impairment are mediated by GABA receptors in the cerebellar, hippocampal, and forebrain areas. Benzodiazepines also decrease the catecholamine uptake in certain areas of the brain, reduce the metabolism of 5-hydroxytrypta-mine in the cortex, and alter the availability of acetylcholine in the brain.  canadian antibiotics

Benzodiazepines are associated with a rare and puzzling paradoxical reaction. A paradoxical reaction is an unanticipated restlessness and agitated episode. Aggression, hostility, and rage may also be seen but rarely. The patient shows an increased state of anxiety. Typically, the patient is an apprehensive young woman who lapses into a fuguelike state with eyes tightly closed and is crying. She does not respond to requests to open her eyes or to give rational responses to questions. The episode is lost to recall. DiMascio and Shader proposed a definition of behavioral toxicity. “The pharmacological reactions of a drug that when administered within the dose range in which it has been found to possess clinical utility produce—through mechanisms not immediately specifiable—alterations in perceptual and cognitive reactions, psychomotor performance, motivation, mood, interpersonal relationships or intrapsychic processes of an individual to the degree that they interfere with, or limit the capacity of an individual to function within his/her setting.” Hall and Zisook described the reactions as uncharacteristic, rare and most often idiosyncratic, and consequently extremely difficult to predict. They divided the reactions into 3 major types: (a) depression, (b) gross behavioral disturbances, and (c) hostility, aggression, and rage. These types of reactions can range from an unrecognized episode of unpleasantness during a procedure to a dangerous life-threatening incident to both patient and caregiver.

The first benzodiazepine synthesized was chlordiaz-epoxide (in 1955). Ingram and Timbury were the first to report paradoxical reactions with the administration of chlordiazepoxide. In 1980, Litchfield reported a review of 16,000 cases of intravenous use of diazepam in dental practices. He concluded that 29% of patients had minor adverse reactions. These were talkativeness, crying, loss of inhibitions, excitement, and rage. The incidence of these reactions was more frequent with higher dosage and in younger patients (3- to 19-years old). Pena and Krauss reported 7 cases of paradoxical reactions and other adverse effects in a series of 1180 patients on whom diverse agents were used for pediatric emergency procedures. All 7 cases were associated with the administration of intravenous midazolam. Massanari et al reviewed a sample of 2617 children who underwent endoscopic procedures under sedation with meperidine and midazolam and reported a 1.4% incidence of paradoxical reactions. They also recommended flu-mazenil to reduce the duration of the reactions. Rodri-go was the first to recommend the use of flumazenil. He reported the case of a female sedated with midazolam who developed severe aggressive behavior during an oral surgery procedure, which increased with further use of midazolam. The paradoxical reaction was terminated by the administration of flumazenil. This article describes 2 cases of paradoxical reactions. 

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