DRUGS AND ANESTHESIA Review of Fatalities and Adverse Reactions After Administration of ␣-2 Adrenergic Agonist Reversal Agents in the Horse David B. Scofield, DVM; Dana L. Alexander, BS; Robert P. Franklin, DVM, Diplomate ACVIM; and Joseph J. Bertone, DVM, MS, Diplomate ACVIM Elective reversal of ␣-2 adrenergic receptor agonist sedation with either tolazoline or yohimbine is not without serious risk of idiosyncratic and potentially fatal consequences in the horse; as evidenced by clinical reports of drug reaction and possible death resulting from administration of tolazoline or yohimbine to reverse the effects of ␣-2 agonist sedation for veterinary procedures in the horse. Au- thors’ addresses: Equine Reproduction Laboratory, Colorado State University, Fort Collins, Colo- rado 80523 (Scofield); Weatherford Equine Medical Center, Weatherford, Texas 76088 (Franklin); and Western College of Veterinary Medicine, Pomona, California 91766 (Alexander and Bertone); e-mail: scofi[email protected]. © 2010 AAEP. 1. Introduction antagonize the effects of ␣-2 agonist sedatives. Selective ␣-2 adrenergic agonist drugs, such as xy- Therapeutic doses in horses may cause peripheral lazine HCl,a detomidine,b and romifidine,c represent vasodilation, which clinically leads to a transient commonly used sedatives and pre-anesthetics in increase in heart rate.2 Toxicity studies report dos- equine practice. These drugs are sometimes re- ages of five times the labeled dose in the horse may versed with ␣-2 adrenergic antagonists such as yo- cause increased gastric secretions, hyperperistalsis, himbine,d atipamezole,e and tolazoline.f Tolazoline flatulence, mild colic, or transient diarrhea.3 These is the only labeled product for the equid; therefore, same overdoses could lead to ventricular arrhyth- use of either yohimbine or atipamezole constitutes mias with prolonged QRS complexes and resultant as extra-label drug use. These reversal agents are death.3 ␣-2 Antagonists have been recommended deemed as safe pharmacologic products. Anecdotal as prokinetics because of their ability to counteract information, however, suggests that these products sympathetic outflow related to endotoxin and noci- can have significant adverse side effects in some cases. ceptive stimuli.4 Tolazoline produces strong peripheral vasodila- Anecdotal reports of deaths associated with tola- tion with sympathetic blocking and histamine- zoline reversal have created concern regarding the like actions.1 The drug competitively binds to ␣-1 safety of this drug.5 Sinus bradycardia, second-de- and ␣-2 adrenergic receptors, allowing the drug to gree atrioventricular block, and brief periods of si- NOTES 44 2010 ր Vol. 56 ր AAEP PROCEEDINGS DRUGS AND ANESTHESIA nus arrest occurred after rapid IV administration of Table 1. Summary of 18 Respondent Case Outcomes in Terms of Drug tolazoline (1 mg/kg) in five of six xylazine-sedated Use and Outcome 6 calves. A case of suspected idiosyncratic tolazo- Number of Compounded line reaction in a llama has been reported in which Respondents Outcome Products the patient exhibited generalized weakness, sei- zures, dyspnea, severe hypotension, tachycardia, Tolazoline 7 4 deaths None and diarrhea after receiving tolazoline.7 Both tola- Yohimbine 11 9 deaths 6 compounded products; zoline and yohimbine, when administered IV, will ϳ 3 labeled canine increase ventricular heart rate for 30 min after products; 8 injection. 2 undetermined In dogs, yohimbine blocks central ␣-2 adrenergic products receptors and can cause tachycardia, elevated blood pressure, and stimulation to the central nervous system (CNS).9 Yohimbine also blocks peripheral ␣-2 receptors found in the cardiovascular system, from hand walking to the administration of epineph- genitourinary system, gastrointestinal tract, adi- rine via IM injection, dexamethasone IV, and pred- pose tissue, and platelets, which can manifest clin- nisolone sodium succinate IV. Although these ically as muscle tremors, tachypnea, and hyperemic resuscitation efforts and pharmacologic interven- mucous membranes.9 tions were attempted, none clearly altered the out- Administration of ␣-2 adrenergic antagonists to come for the patient. reverse sedation has resulted in reported idiosyn- Nine of 18 patients were sedated with ␣-2 adren- cratic reactions in non-equid species. Animals ergic agonists for dental procedures. Other proce- have died after receiving rapid IV overdoses of yo- dures performed requiring sedation included IV himbine, atipamezole, or tolazoline.10 A 1-yr-old catheter placement, foot trimming, trailer loading, female polar bear (Ursus maritimus) immobilized laceration repair, and endoscopy. Three respon- with medetomidine-zolazepam-tiletamine died shortly dents did not report a specific procedure during se- after reversal from anesthesia with atipamezole ad- dation. Seven respondents reported injections of ministered IV.11 antagonists at or below the recommended dosages, The intent of this paper is to document adverse whereas 11 respondents did not provide dosage reactions and serious complications encountered information. when using the ␣-2 adrenergic antagonists tolazo- line and yohimbine to reverse common ␣-2 adrener- 4. Discussion gic agonists xylazine, detomidine, and romfidine in A high number of respondents (13/18) reported ulti- the horse. mate death of the animal in the immediate time frame of administering the reversal agent. All 2. Materials and Methods deaths attributed to tolazoline administration were Case reports of adverse reactions to administration with the product labeled for equine use. Although of either tolazoline or yohimbine for ␣-2 agonist re- five yohimbine reactions occurred with compounded versal were solicited from the AAEP List Serve and products, a Food and Drug Administration-approved Equine Clinician’s List Serve in early 2010. Respon- canine product (used off-label) was used in three dents were asked for patient signalment, medical cases. Compounding pharmacies have the ability problems, all pharmacologic agents administered, to alter certain characteristics of the drug such as nature of reaction, interventions attempted, out- concentration, delivery vehicles, pH, and storage re- come of situation, and any postmortem findings if quirements. In turn, each compounded product applicable. All data points were not obtained in all may, in fact, have different components that could cases in the series because of lack of available lead to reactions. Differences in pH, shelf life, sol- records in several instances. ubility, or preservatives from an approved product Additional information regarding the type of drug may alter the actions of the drug in vivo and in turn used, compounded or labeled product, was incor- potentiate adverse side effects. Compounded prod- porated as available. Data were compiled and are uct drug concentrations were examined post hoc in presented in Tables 1 and 2. two cases. Results supported an appropriate con- centration of yohimbine in compounded products, 3. Results although this does not exclude a reaction to the Briefly, 18 total responses were returned to the au- vehicle itself. thors. Of the 18 cases reported via email, mail, and The cause of negative reaction or death in this telephone conversations, there were 16 horses com- case series cannot be definitively attributed to the prised of various breeds, 4 mo to 24 yr of age, 1 administration of tolazoline or yohimbine. Circum- miniature Donkey, and 1 adult horse of unknown stantial evidence does support an adverse drug re- age. Of the 18 responses, 13 animals died despite action. Other possible causes include intracarotid intervention and resuscitation efforts (Table 2). injection, anaphylaxis, overdosage, confounding Five animals recovered with interventions varying medical issues, or unrelated cardiovascular event. AAEP PROCEEDINGS ր Vol. 56 ր 2010 45 46 2010 Table 2. Summary of All Respondent Data With All Provided Information DRUGS AND ANESTHESIA ր Nature of ␣ ␣ Vol. 56 Signalment Procedure Medical Problems Agonist Antagonist Reaction Intervention Outcome Postmortem Notes Male intact 3-yr- IV catheter ϳ7-day history of 10 mg IM Detomidine 100 mg Tolazoline Reaction occurred 250 mg IV flunixin Rose to feet N/A Continued treatment old miniature placement for broncho- (12 hours prior to IV slowly within 15 meglumine and within 20 for ր donkey; ϳ250 kg treatment of pneumonia reaction); and minutes. 500 mg solu- minutes, no bronchopneumonia; AAEP PROCEEDINGS broncho- evening dose of Tachycardia, delta cortef; 5 l significant tolazoline was pneumonia ceftiofur tachypneia, IV fluids post reaction given IV slowly blanched abnormalities over 30 seconds. mucus membranes, and sweating were observed. 6-yr-old Quarter Routine dental No known problems 5 mg IV Detomidine Yohimbine Gelding unstable Attempted Died N/A Quality control Horse Bay procedure (unknown dose) on feet. dexamethasone concentration of gelding and epinephrine yohimbine correct; administration Compounded product 16-yr-old Routine dental No known problems 5 mg Detomidine IV Yohimbine Mild ataxia 3 to 5 Stabilized within 5 Uneventful N/A Quality control found Warmblood procedure (unknown dose) minutes post min concentration of mare reversal yohimbine correct; Compounded product 5-yr-old Quarter Routine dental No known problems 250 mg Xylazine IV Yohimbine Tachypnea and Handwalked for 20 Uneventful N/A N/A Horse Bay procedure (unknown dose) injected mucus min and stable gelding membranes 6-yr-old Morgan Unknown Unknown Unknown 30 mg IV Immediate None Died