Reversal of a Paradoxical Reaction to Midazolam with Flumazenil

Abstract

Paradoxical excitement occurs in less than 1% of all patients receiving midazolam [1]. In the past, midazolam-induced excitatory reactions have been controlled by increasing the level of sedation (preferably with a nonbenzodiazepine), inducing general anesthesia, or waiting for the reaction to subside. In this report, we describe a patient who developed a paradoxical reaction to midazolam that was reversed with a small dose of flumazenil. Case Report A healthy, 27-yr-old male underwent cystoscopy and laser ablation of a meatal condyloma under spinal anesthesia with hyperbaric lidocaine. The patient reported no history of psychiatric illness, denied use of illicit drugs, and only occasionally drank alcohol. The patient was initially given 2 mg of midazolam intravenously (IV), followed by placement of the spinal anesthetic. Several minutes after starting the surgical procedure, the patient became agitated, anxious, and restless, but reported no pain. His vital signs and temperature were normal, and oxygen saturation was 100%. An additional 5 mg of midazolam was administered IV in divided doses over the next 10 min with no improvement in the patient's symptoms. Despite poor cooperation from the patient, the surgical procedure was completed. On arrival in the postanesthesia care unit, he continued to be restless and agitated but still denied having any pain. His oxygen saturation was 100%, and his vital signs and temperature remained stable. Lorazepam 4 mg was administered in divided doses with no change in the patient's symptoms. Approximately 3 min after giving the last dose of lorazepam, flumazenil 0.1 mg was administered, followed by an additional 0.2 mg 2 min later. About 4 min after giving the initial dose of flumazenil, the patient's agitation abated completely and he fell asleep. The patient was still easily aroused and answered questions appropriately when awakened. On questioning several weeks later, the patient had no recollection of any of the events after the spinal anesthetic had been placed. Discussion Flumazenil is a benzodiazepine antagonist that can effectively reverse benzodiazepine-induced sedation, hypnosis, and respiratory depression [2]. Curran and Birch [3] suggested that flumazenil is only partially effective in reversing the amnestic properties of benzodiazepines. Patients treated with midazolam rarely develop paradoxical reactions characterized by restlessness, agitation, anxiety, and sometimes aggressive behavior [1]. Several previous reports have demonstrated successful treatment of benzodiazepine-induced paradoxical reactions with flumazenil [4-6]. As in our patient, these authors reported that only small doses of flumazenil were required to antagonize the paradoxical reaction. The case described here is unusual in that the sedative effects of midazolam clearly persisted despite complete reversal of the paradoxical reaction. In conclusion, this case report demonstrates that paradoxical reactions to midazolam can be treated with small doses of flumazenil without reversing the amnestic and sedative effects of the benzodiazepine. The antagonism of a paradoxical reaction by flumazenil without ablating the sedative or amnestic effects of midazolam suggests that paradoxical reactions are mediated at a site that is different from that for sedative or amnestic responses. Considering our own experience and the reports of others, we recommend treating excitatory reactions to benzodiazepines with small doses (0.1-0.4 mg) of IV flumazenil.