A Protocol for the Emergency Treatment of Alpha-2 Agonist Overdose using Atipamezole, a Selective Alpha-2 Antagonist

摘要

Highly concentrated alpha-2 agonists such as medetomidine commonly used in veterinary anesthesia, can potentially cause signific-ant harm or death if accidentally exposed to a human. Current treatments for alpha-2 agonist overdose in humans are nonspecific and unreliable. Atipamezole, a drug which is not FDA approved for human use, is a potent alpha-2 specific antagonist, which could be used as lifesaving therapy to reverse the adverse effects of an accidental alpha-2 agonist overdose. To develop a resuscitation algorithm using atipamezole for alpha-2 agonist overdose, we performed a literature review of atipamezole use in humans from 1970 to the present. We compared this to the data from atipamezole use in non-human primates and other wild animals. The results show that when compared to animals, humans require approximately 10 times less alpha-2 agonists for deep sedation, but 10 times more atipamezole for adequate reversal. Using this evidence based information, a resuscitation protocol, which includes the potential use of atipamezole in the field for emergency overdose is presented. When intensive care treatment is not available, atipamezole should be made available for intravenous or intramuscular administration in humans for life-threatening alpha 2-agonist overdose. The use of atipamezole in this circumstance could be lifesaving. Introduction: Accidental overdose (OD) with an alpha-2 agonist (a2a), such as dexmedetomidine (DEX) medetomidine (MED), or clonidine can potentially be life-threatening.1-5 When using MED for large animal immobilizations, accidental overdose due to MED availability in high concentration, is especially worrisome for veterinarians and their staff. Life- threatening accidents with veterinary a2a’s have been described in the literature.1,6 The current management of accidental OD of a2a is primarily supportive care including; activated charcoal, tracheal intubation, mechanical ventilation, and administration of fluids and inotropes. Nonspecific alpha-2 antagonists (a2ANT) such as tolazoline, and naloxone an opioid antagonist, have also been tried with limited but unpredictable success.7When using highly concentrated a2a’s for anesthetizing wildlife in the field, the potential for fatal accidents in humans is concerning because there is no antidote. With MED supplied in a concentration up to 40 mg/ml (Wildlife Pharmaceuticals, Inc, Windsor, CO 80550 USA), an accidental dose of one milliliter is potentially 200 times an intravenous dose known to cause cardiac arrest in humans.8 Atipamezole (AT) is a selective a2ANT, which competitively inhibits alpha-2 adrenergic receptors. AT is routinely used in animals anesthetized with a2a for the rapid reversal of sedation and analgesia.9 AT has been studied in both unanesthetized and DEX sedated humans, and has been shown to be both safe and effective.10-12 Review of the literature reveals that, compared to animals (including primates13-15), humans appear to be 10 times more sensitive to DEX, and approximately 10 times less sensitive to AT.Using a literature review of the use of AT in humans and personal experience with its use in animals, we provide a scientific basis for the use of AT to reverse the adverse effects associated with an accidental human a2a overdose. We also provide an algorithm and recommended dosage for using atipamezole as a potential antidote for life-threating human a2a OD in the field or emergency department. Materials and Methods: We performed a PubMed search from 1970 to 2017 for all information related to AT use in humans. We then compared the experimental AT dosing information obtained in human subjects with its clinical use in non-human primates and other animals. Using this information, we present a dosing range for human use as well as an algorithm for the emergent management of a2a OD. Results: Human ResearchHuman research of AT use in healthy non-sedated and DEX sedated volunteers has been conducted. In 1990, Karhuvaara et al. studi