DRUGS AND ANESTHESIA

Review of Fatalities and Adverse Reactions After Administration of ␣-2 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 agonist sedation with either tolazoline or 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 drugs, such as xy- Therapeutic doses in horses may cause peripheral lazine HCl,a ,b and romifidine,c represent , 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 ,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 -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 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 -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.

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Table 2. Summary of All Respondent Data With All Provided Information RG N ANESTHESIA AND DRUGS

ր Nature of ␣ ␣ o.56 Vol. 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;

APPROCEEDINGS AAEP 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 Pulmonary Compounded product gelding Yohimbine respiratory edema distress, found on tachycardia, postmortem. with bloody/ Classified as frothy nasal death due discharge. to drug reaction. 24-yr-old Arabian Unknown Unknown Unknown 800 mg IV Signs of distress, None Recovery N/A N/A mare Tolazoline Tachycardia, without Tachypnea, and intervention collapse 2-yr-old Quarter Tracheotomy Severe Streptococcus Xylazine 100 mg and 1000 mg IV Mare became None Died No gross Labeled product; Horse mare and guttural equi sub. equi Butorphanol 5 mg Tolazoline agitated, then pathology Differentials for pouch Infection; IV slowly agonal. noted death were severe endoscopy azotemia; idiosyncratic drug tracheotomy reaction, embolism, patent and or septic shock completed 10-yr-old Quarter Unknown No known medical , Tolazoline IV Extreme None Recovery N/A N/A Horse mare conditions Detomidine, and excitement and Xylazine aggitation 15-yr-old Quarter Routine dental No known medical Xylazine 600 mg IV 25 mg IV Lateral Epinephrine IM, Died N/A Compounded product Horse Bay procedure conditions and Detomidine 5 Yohimbine recumbency Dexamethasone gelding mg IV and expired 40 mg IV within 4 minutes. Unknown Routine dental No known medical Xylazine and Yohimbine Horse unstable on None Died N/A Pending litigation procedure conditions Detomidine mix (unknown dose) feet, fell lateral, with unknown convulsed, and dosage died Table 2. (continued)

Nature of Signalment Procedure Medical Problems ␣ Agonist ␣ Antagonist Reaction Intervention Outcome Postmortem Notes

4-mo-old Quarter Facial No known medical 2.5 mg Detomidine Tolazoline N/A None Died N/A Approved product Horse filly laceration conditions (unknown dose) repair 5 mg Butorphanol IV 1-yr-old Quarter Foot trim No known medical 100 mg Xylazine IV Yohimbine N/A None Died N/A Labeled product for Horse gelding conditions (unknown dose) canines 18-yr-old Paint Foreleg No known medical 7.5 mg Detomidine Tolazoline N/A None Died N/A Approved product gelding laceration conditions 10 mg Butorphanol (unknown dose) IV 24-yr-old Routine dental No known medical 10 mg Detomidine IV Yohimbine N/A None Died N/A Labeled product for Appaloosa procedure conditions (unknown dose) canines gelding 1.5-yr-old Trailer loading No known medical 100 mg Xylazine IV Tolazoline N/A None Died N/A Approved product Thoroughbred conditions (unknown dose) filly 8-yr-old Routine dental No known medical 5 mg IV Detomidine Yohimbine N/A None Died N/A Labeled product for Warmblood procedure conditions 10 mg IV (unknown dose) canines gelding Butorphanol 7-yr-old Tennessee Routine dental No known medical 10 mg Detomidine IV 30 mg IV Respiratory 10 ml epinephrine Died N/A Compounded product Walking cross procedure conditions Yohimbine; 5 distress, ataxia, (1:1000) IV; 500 gelding mg IV and collapse to mg prednisolone Yohimbine at lateral sodium APPROCEEDINGS AAEP 30 min. recumbency succinate (solu- delta cortef) ANESTHESIA AND DRUGS 9-yr-old Quarter Routine dental No known medical Xylazine and Yohimbine IV Gelding unstable Dexamethasone IV Died N/A Compounded product Horse gelding procedure conditions detomidine (unknown dose) and collapsed and epinephrine (unknown dosages) in stocks IM (unknown dosages)

When data were unavailable, N/A or unknown was substituted in table. ր o.56 Vol. ր 0047 2010 DRUGS AND ANESTHESIA Physiologic responses to the administration of tola- 1. IM administration: the reversal agent may zoline and yohimbine may include varying degrees be given IM, and this is preferred in all but of anxiety, respiratory distress, and cardiovascular emergency situations because it decreases the compromise.3,9 Both drugs, because of their ability risk for CNS excitement or cardiovascular to block ␣-2 adrenergic receptors centrally, periph- complications.15 erally in the distal airway smooth muscle, and in the 2. Intravascular administration: administer three peripheral vasculature, can cause vasodilation and separate aliquots equal to one third total IV airway constriction, which may manifest as tachy- dose over a 30-min window to prevent sudden pnea, tachycardia, and anxiety. Although death cardiopulmonary changes seen with sudden ␣-2 was not noted in all circumstances, a temporal re- antagonism.12 action to a medication may result in owner distress and possibly litigation or further medical issues if 5. Conclusion damages to the horse, personnel, or property occur It is understood that no pharmacologic therapy is during these reactions. without risk. However, these cases illustrate that Atipamezole was not included in this case series ␣-2 antagonists have the potential for serious and but has been successfully administered to a pony unpredictable reactions in our equine patients. overdosed with detomidine during a routine castra- Veterinarians should be aware of the potential life- tion.12 Although used in the reported case, atipa- threatening side effects to the use of these drugs and mezole carries no label claim for the equid and may weigh the benefits of their use for non-emergency prove to be cost prohibitive. Furthermore, tolazo- situations. If one should use tolazoline or yohim- line was shown to antagonize detomidine sedation bine clinically, they should also be prepared for any more effectively than atipamezole in the horse.13 reactions to administration and treat them accord- In ponies that were not experiencing any pain, how- ing to clinical presentation. Although there are no ever, ␣-2 antagonism with tolazoline induced hor- firm guidelines for treatment of idiosyncratic reac- monal and metabolic stress responses.14 Therefore, tions to ␣-2 antagonists, it may be recommended atipamezole may prove to be a promising agent for use that cardiovascular support with IV fluid therapy in the horse in the future. and vasoactive drugs such as , based on ␣-2 Agonists are commonly used in equine prac- data procured from the human literature or phenyl- tice. Overdoses and cardio-depressant events may ephrine from the veterinary literature, be used in 3,7 occur with their administration, necessitating ␣-2 emergent situations. For the clinical use of these adrenergic antagonism. Based on this case series, drugs, we advise following the dosage time frame appropriate case selection for ␣-2 antagonism should and routes of administration proposed in the results be reviewed carefully. Clients should be informed of section above. the possibility of idiosyncratic and potentially fatal reactions from their use. There does not seem to be a Acknowledgments predisposing factor to these reactions based on the We thank our respondents from the Equine Clini- limited number of cases in this series. A clear mech- cian’s Network and AAEP Listserve for their candid anism for the adverse reactions from the use of tola- answers to our queries and for their help during our zoline or yohimbine has not been identified but likely investigation of these reactions. is caused by cardiopulmonary and CNS events. In a reported overdose of tolazoline in a llama, References and Footnotes resuscitation efforts consisted of IV fluids, oxygen 1. Thurmon JC, Sarr R, Denhart JW. Xylazine sedation an- 7 therapy, diazepam IV, and IV. tagonized with tolazoline. Compend Food Anim 1999;21: Treatment was successful, and these efforts should 1–9. be considered for the treatment of an acute reaction 2. Hoffman BB, Lefkowitz RJ. Adrenergic receptor antago- ␣ nists. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. to -2 antagonism. Of note, treatment with either Goodman and Gilman’s the pharmacological basis of thera- or epinephrine after tolazoline ad- peutics. New York: Pergamon Press, 1990;221–243. ministration will produce a paradoxical decrease in 3. Plumb DP. Veterinary drug handbook, 5th ed. Ames, IA: blood pressure, followed by increased blood pres- Blackwell Publishing, 2005. 3 4. Lester GD. Gastrointestinal ileus. In: Smith BP, ed. sure. In humans, ephedrine is the recommended Large animal internal medicine, 3rd ed. St. Louis: Mosby, agent to counteract hypotension after tolazoline ad- 2002;674–678. ministration.3 Attempts to prevent injury to the 5. Abrahamsen EJ. Chemical restraint, anesthesia, and anal- animal with soft footing, open spaces, and a lack of gesia for camelids. Vet Clin North Am [Food Anim Pract] 2009;25:455–494. noxious stimuli should also be attempted. 6. Lewis CA, Constable PD, Huhn JC, et al. Sedation with The recommended dosages for ␣-2 antagonists in xylazine and lumbosacral epidural administration of lido- the horse are as follows: tolazoline, 4 mg/kg, IV, caine and xylazine for umbilical surgery in calves. JAmVet slowly at a rate of 1 ml/s3; yohimbine, 0.075 mg/kg, Med Assoc 1999;214:89–95. 4 ␣ 7. Reed MR, Duke T, Toews AR. Suspected tolazoline toxicosis IV (off-label use). To increase the safety of -2 in llama. J Am Vet Med Assoc 2000;216:227–229. adrenergic antagonists, the following guidelines 8. Kollias-Baker CA, Court MH, Williams LL. Influence of yo- should be observed. himbine and tolazoline on the cardiovascular, respiratory,

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and sedative effects of xylazine in the horse. J Vet Pharma- 14. Carroll GL, Matthews NS, Hartsfield SM, et al. The effects col Ther 1993;16:350–358. of detomidine and its antagonism with tolazoline on stress- 9. Plumb DP. Veterinary drug handbook, 5th ed. Ames, IA: related hormones, metabolites, physiologic responses, and Blackwell Publishing, 2005;1160–1162. behavior in awake ponies. Vet Surg 1997;26:69–77. 10. Hsu WH, Schaffer DD, Hanson CE. Effects of tolazoline and 15. Abrahamsen EJ. Ruminant field anesthesia. Vet Clin yohimbine on xylazine-induced central nervous system de- North Am [Food Anim Pract] 2008;24:429–441. pression, bradycardia, and tachypnea in sheep. JAmVet Med Assoc 1987;190:423–426. 11. Cattet MR, Caulkett NA, Pollschuk SC, et al. Reversible immobilization of free-ranging polar bears with medetomi-

dine-zolazepam-tiletamine and atipamezole. J Wildl Dis a 1997;33.3:611–617. TranquiVed, Vedco, St. Joseph, MO 64507. b 12. Di Concetto S, Archer MR, Sigurdsson SF, et al. Atipam- Dormosedan, Pfizer, Orion, Exton, PA 19341. c ezole in the management of detomidine overdose in a pony. Sedivet, Boehringer Ingleheim Vetmedica, St. Joseph, MO Vet Anaesth Analg 2007;34:67–69. 64506. 13. Hubbell JA, Muir WW. Antagonism of detomidine sedation dYobine, Lloyd, Ben Venue Labs, Bedford, OH 44146. in the horse using intravenous tolazoline or atipamezole. eAntiseden, Pfizer, Orion, Exton, PA 19341. Equine Vet J 2006;38.3:238–241. fTolazine, Lloyd, Akorn Manufacturing, Decatur, IL 62525.

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