Journal of Veterinary Emergency and Critical Care 25(5) 2015, pp 667–671 doi: 10.1111/vec.12371
Case Series
Intravenous lipid emulsion therapy in 20 cats accidentally overdosed with ivermectin Geraldine Jourdan, DMV, MSc, PhD; Guillaume Boyer, DMV; Isabelle Raymond-Letron, DMV, MSc, PhD; Emilie Bouhsira, DMV, MSc, PhD; Benjamin Bedel, DMV and Patrick Verwaerde, DMV, MSc, PhD
Abstract
Objective – To describe the outcome of 20 cats treated with intravenous lipid emulsion (IVLE) after an accidental parenteral ivermectin overdose. Case Series Summary – Twenty adult cats presented after receiving a 4 mg/kg accidental subcutaneous overdose of ivermectin. After admission, two IVLE treatments were initiated in asymptomatic cats: a single bolus (1.5 mL/kg; n = 16) versus a bolus followed by a 30-minute constant rate infusion (0.25 mL/kg/min; n = 4). Six out of the 16 cats that received only the single bolus developed clinical signs of ivermectin intoxication. Based on the severity of the clinical signs and their duration (approximately 48 hours), these 6 cats were retrospectively considered either moderately (n = 3) or severely (n = 3) intoxicated by ivermectin. Cats with a low body condition score (BCS) had more severe signs of ivermectin toxicity. Additional IVLE was administered until clinical resolution was complete. Median (min to max) cumulative dose of IVLE per cat was 4.5 (3.0–4.5) mL/kg for 36 (12–36) hours and 19.5 (7.5–37.5) mL/kg for 96 (72–168) hours for moderately and severely intoxicated cats, respectively. New or Unique Information Provided – Our series describes the treatment of accidental ivermectin parenteral overdose in 20 cats with early initiation of IVLE therapy. An early bolus followed by a 30-minute constant rate infusion of IVLE appeared to mitigate the signs of ivermectin toxicosis in cats compared to a single treatment bolus. Our observations also suggest that cats with a low BCS given only a bolus of IVLE treatment were more likely to develop signs of ivermectin intoxication and require a greater amount of IVLE for the resolution of clinical signs. Based on our observations, BCS appears to influence the severity of ivermectin toxicity with a low BCS being associated with more severe signs of ivermectin toxicity. (J Vet Emerg Crit Care 2015; 25(5): 667–671) doi: 10.1111/vec.12371 Keywords: avermectins, intralipid, toxicosis, treatment
Introduction Abbreviations
BCS body condition score CRI constant rate infusion IVLE intravenous lipid emulsion
From the Critical and Intensive Care, Anesthesia Unit (Jourdan, Boyer, Verwaerde), the Parasitology-Dermatology Unit (Bouhsira), the Anatomy, Pathology Unit (Raymond-Letron), Toulouse National Veterinary School, Toulouse, France; and the Emergency, Critical and Intensive Care Unit, Alfort National Veterinary School, Maisons-Alfort, France (Bedel, Verwaerde). The authors declare no conflict of interest. Presented in part at the 13th EVECCS Congress, Prague, Czech Republic, June 2014. Address correspondence and reprint requests to Dr. Geraldine Jourdan, Critical and Intensive Care, Anesthesia Unit, Toulouse National Veterinary School, 23 Chemin des Capelles, Toulouse, France. Email:
[email protected] Submitted August 01, 2014; Accepted July 26, 2015.
C Veterinary Emergency and Critical Care Society 2015
In veterinary practice, avermectins (eg, abamectin, ivermectin, eprinomectin, doramectin, and selamectin) are widely used for their endectocidal properties.1 In mammals, these drugs have a wide margin of safety when the blood-brain barrier is intact or an appropriate dose is used.2 Nevertheless, ivermectin toxicity can occur when excessive doses are administered (above 500 g/kg in cats).3,4 While ivermectin intoxication is quite well documented in dogs,5 only a few reports of intoxication in cats have been described. To the best of our knowledge, only 6 case reports corresponding to a total of 13 clinical cases (9 kittens and 4 adult cats) have described ivermectin intoxication in cats.6–12 Symptoms of ivermectin toxicosis are mainly neurological and include mydriasis, blindness, ataxia, tremors, disorientation, and mentation changes ranging from depression to coma.4
667
G. Jourdan et al.
Due to the lack of a specific antidote, symptomatic treatment and fluid therapy are usually the sole recommendation for the management of ivermectin toxicosis.4,6–12 Intravenous lipid emulsion (IVLE) should now be considered in the management of ivermectin toxicosis. Indeed, in the last decade, there has been an increasing amount of evidence supporting its use in the management of lipophilic drugs intoxication. In veterinary medicine, 3 recent reviews13–15 and case reports have described the use of IVLE for the management of toxicity due to various lipophilic drugs: ivermectin,16–19 moxidectin,16,20 diltiazem,21 and baclofen16 in dogs; ivermectin,7,10 lidocaine,22 baclofen,23 and permethrin24–27 in cats. The case series presented herein describes the clinical consequence of an accidental parenteral overdose of ivermectin in 20 adult cats treated with 2 different early IVLE therapy regimens. Case series presentation A cat breeder used a parenteral ivermectin product off-label to treat an ear mite infestation in his cats. Twenty cats received a 4 mg/kg subcutaneous dose of ivermectina used for cattle, corresponding to a 20-fold overdose compared to veterinary recommended extralabel dose (0.2–0.3 mg/kg).3 The breeder immediately realized the mistake and all the cats were presented 2 hours later to the Toulouse National Veterinary School, France. All cats were initially healthy apart from ear mite infestation, with no previous medical treatment and were no receiving any other medication. Four of the cats were Sphinx cats (2 males and 2 females, aged (median [min to max]) 3 [1.4–3.6] years, weighing 3.3 [2.6–4.1] kg, body condition score [BCS] 3/9 [2/9–4/9]). The others were Domestic Shorthair cats (10 males and 6 females, aged 6.7 [2.0–12.4] years, weighing 4.0 [2.8–8.2] kg, BCS 6/9 [3/9–8/9]). The BCS was evaluated with a 1–9 scale by the same veterinarian (PV).28 Upon admission, 2 hours after the administration of the overdose of ivermectin, cats did not display any clinical signs of intoxication. However, in agreement with a French toxicology center (CNITV – Vetagrosup Lyon France) and a putative good risk to benefit ratio, cats were treated with an IVLE in order to prevent the occurrence of ivermectin-induced clinical signs. Following treatment, the cats were hospitalized and observed to detect onset of ivermectin intoxication and potential clinical adverse effects of IVLE therapy (4 clinical examinations per day, at 08:00 AM, 12:00, 18:00, and 00:00). Signs of toxicity began to develop in 6 of the 20 cats. Affected cats were aged (median [min to max]) 6.7 [6.7– 11.4] years, weighing 3.5 [2.8–5.9] kg, and had a BCS
668
4.5/9 [3/9–7/9]). Clinical signs were noted at 14 hours (n = 1/6), 22 hours (n = 4/6), and 48 hours (n = 1/6) after the administration of the ivermectin overdose. In 3 of the 6 symptomatic cats, the main clinical signs observed were abnormal gait, slight weakness, and mydriasis with intact direct pupillary light reflexes. Clinical signs began to resolve between 12 and 36 hours. Based on the nature and the duration of clinical signs (48 hours), these cats were considered to be severely intoxicated by ivermectin (Table 1). It is noteworthy that mydriasis was present in all the symptomatic cats, and that it was the first clinical sign to occur and the last to resolve. Upon admission, all the cats received a slow bolus of 1.5 mL/kg of IVLE. With the owner’s consent, the 4 Sphynx cats were also treated with a 30-minute constant rate infusion (CRI) of IVLE (0.25 mL/kg/min) after the initial IV bolus (1.5 mL/kg). A decision was made to treat the cats with additional IVLE (bolus followed or not by a CRI of IVLE) if clinical signs occurred during hospitalization and if required, with other symptomatic treatments (eg, iv fluids). The moderately intoxicated cats received 1–2 additional boluses (Table 2). Median (min to max) cumulative dose of IVLE per cat was 4.5 (3.0–4.5) mL/kg for 36 (12–36) hours. The severely intoxicated cats also received additional boluses and 2 of these cats were treated with a 30-minute CRI for 1 and 2 days, respectively (Table 2). Median (min to max) cumulative dose of IVLE per cat was 19.5 (7.5–37.5) mL/kg for 96 (72–168) hours. These symptomatic cats only received additional IVLE therapy during hospitalization since the treatment criterion was the appearance or the observation of at least 1 clinical sign of intoxication during a clinical exam. It is worth noting that IVLE administration failed to induce immediate effects on clinical signs.
C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12371
IVLE therapy after ivermectin overdose in cats
Table 1: Signalment and occurrence of clinical signs in 20 cats after accidental ivermectin overdose (4 mg/kg subcutanously) and initial management with intravenous lipid emulsion therapy
Bolus + 30 minute CRI (n = 4)
Initial management of ivermectin intoxication with IVLE Clinical signs Onset of first clinical signs (hours) Sex ratio (female/male) Age (months) Body weight (kg) Body condition score (out of 9)
Single bolus (n = 16)
None (n = 4)
None (n = 10)
Moderate (n = 3)
Severe (n = 3)
–
–
2/2 3 (1.4–3.6) 3.3 (2.6–4.1) 3.0 (2.0–4.0)
7/3 6.7 (2–12.4) 4.4 (3.1–8.2) 6.0 (4.0–8.0)
22 (22–48) 0/3 6.7 (6.7–11.4) 5.6 (3.8–5.9) 6.0 (6.0–7.0)
22 (14–22) 3/0 6.7 (6.7–7.4) 2.9 (2.8–3.1) 3.0 (3.0–3.0)
Results are presented as median (min to max). IVLE, intravenous lipid emulsion; CRI, continuous rate infusion.
Table 2: Initial and additional intravenous lipid emulsion therapy in 20 cats with clinical signs after ivermectin overdose (4 mg/kg subcutaneously; n = 6)
Day 1 upon admission Moderately intoxicated Cat no. 1 Cat no. 2 Cat no. 3 Severely intoxicated Cat no. 4 Cat no. 5 Cat no. 6
Day 2
Day 3
Bolus Bolus Bolus
Bolus Bolus
Bolus Bolus Bolus
2 Boluses
3 Boluses
Bolus Bolus
2 Boluses 3 Boluses
2 Boluses + 1 CRI Bolus Bolus + CRI
Day 4
Day 5
Day 6
Day 7
Day 8
Cumulative dose of IVLE (mL/kg) 4.5 4.5 3.0
Bolus + CRI
2 Boluses
Bolus Bolus
2 Boluses
2 Boluses
2 Boluses
Bolus
37.5 7.5 19.5
IVLE, intravenous lipid emulsion; CRI, continuous rate infusion. Bolus: 1.5 mL/kg iv; CRI: 30-minute CRI of IVLE (0.25 mL/kg/min).
Outcome All the cats were discharged to the owner 10 days after ivermectin overdose without discernible clinical sequelae.
Discussion As reported in the veterinary literature, the recommended dose of ivermectin to treat ectoparasites is approximately 0.2–0.3 mg/kg in cats.3 Thus, with 4 mg/kg, all cats of our series received a dose 20-fold higher than the recommended dose, a potentially lethal dose of ivermectin for cats.4 Although ivermectin overdose is rarely reported in cats, it can lead to coma and ultimately death, especially in kittens.4,6,8,9,11 To date, only 6 case reports (13 clinical cases: 9 kittens and 4 adults) have described ivermectin intoxication in cats.6–12 Our case series describes the early treatment with IVLE and outcome for 20 cats following an accidental ivermectin parenteral overdose. In the present series, only 6 of the 20 C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12371
cats (30%) developed clinical signs, including mydriasis, blindness, weakness, depressed mentation, tremor, hyperesthesia, abnormal gait, dysorexia, and anorexia, as previously reported in veterinary literature.4,6,8,9,11 Mydriasis, which has been historically reported in 25% of intoxicated cats,4 was observed in all clinically intoxicated cats in our series. Interestingly, mydriasis was the most frequent clinical sign observed in our study but is seldom reported in dogs with ivermectin intoxication.16,18 Hypermetric ataxia and blindness were only observed in severely intoxicated cats. Neither coma state nor death was observed in this series of cats. Due to its highly lipophilic nature, ivermectin is known to be extensively distributed with broad volumes of distribution in all species and tends to accumulate in fat tissue, which acts as a drug reservoir.29 Pharmacokinetics of subcutaneous ivermectin administration have been recently established in cats.30 Chittrakarn et al showed that ivermectin subcutaneously injected is rapidly absorbed (ie, within 6.48 ± 6 hours) and has a 669
G. Jourdan et al.
larger volume of distribution (Vd = 9.87 ± 5.41 L/kg) in cats than in other domestic species. This suggests a large distribution of ivermectin in adipose tissue in cats.30 Onset and duration of clinical signs observed in our cats are in agreement with previously published data. Moreover, this pharmacokinetic study supports our original observation about the influence of the BCS in ivermectin feline intoxication. Cats with clinical signs had a lower BCS compared to those without intoxication signs and the most severe and lasting clinical signs were observed in cats with the lowest BCS. It could be hypothesized that cats with low BCS will suffer more serious clinical signs of ivermectin intoxication because of poor body fat deposition leading to a high free plasma concentration of ivermectin, thereby exposing their brain to high xenobiotic concentrations. In the last decade, there has been an increasing amount of evidence supporting the use of IVLE in the management of intoxication from various lipophilic drugs in people and animals. Even though the mechanism of action of IVLE remains incompletely elucidated,13,14 several mechanisms have been proposed. According to the “lipid sink” theory, lipid emulsion would be able to reduce free plasma concentrations of lipophilic drugs through a “plasma drug sequestration,” decreasing their tissue availability, limiting their brain distribution, and thus the development of neurological events. This is suggested by the study performed by Clarke et al showing a rise in serum ivermectin concentration immediately after each administration of IVLE in dogs.17 In veterinary medicine, few case reports have recently described the successful management of ivermectin toxicity with IVLE in dogs16,17,19 and cats.7,10 Two cats were successfully treated with a bolus (1.5 or 4 mL/kg) followed by a CRI (0.25 or 0.05 mL/kg/min) of IVLE, several hours after the occurrence of signs of toxicosis.7,10 All the cats of our series received an initial bolus of IVLE, even though they were asymptomatic. Administration of IVLE was initiated early in the course of the management of intoxication. This differs from the approach undertaken in the 2 case reports in cats as well as in human and veterinary medicine until now, where IVLE has been initiated in symptomatic patients or when conventional therapies have failed to reduce toxicosis symptoms. Our report shows a putative influence of the initial IVLE therapy regimens on the incidence of development of signs of ivermectin toxicosis. Thirtyeight percent (n = 6/16) of the cats that had been only treated with an initial single IVLE bolus (1.5 mL/kg) developed clinical signs, whereas all (n = 4/4) of the cats that had been treated with a bolus followed by a 30-minute CRI (for a cumulative dose of 9 mL/kg) remained asymptomatic, even if cats had a low BCS. Additionally, in symptomatic cats (n = 6), the 670
cumulative dose of IVLE was higher in severely intoxicated cats compared to the moderately intoxicated ones. This observation suggests that cats with low BCS that were more likely to have severe intoxication after the same ivermectin overdose and required more lipids prior to resolution of clinical signs. In our case series, there were no untreated animals; as a consequence, it still remains unclear how IVLE therapies affect the clinical course and duration of ivermectin toxicosis in cats. However, a previously published study reported 10% feline mortality and 25% incidence of coma after ivermectin overdose.4 In our series of cats subjected early to IVLE, neither coma state nor death was observed. It could be hypothesized that incidence and severity of ivermectin toxicosis would have been probably higher than those observed if IVLE was administered later or not at all. Nevertheless, the duration of ivermectin toxicosis observed in severely intoxicated cats is in agreement with the elimination of half-life of ivermectin based on the Chittrakarn study (2.53 ± 2.24 days).30 Thus, our observations suggest that IVLE therapies may have no effect on duration of ivermectin toxicosis in severely intoxicated cats. The influence of IVLE therapies on ivermectin plasma levels rather than ivermectin elimination should be evaluated in a pharmacokinetic approach in cats. This series provides further evidence of clinical benefit of IVLE as a nonspecific therapy for ivermectin intoxication in cats. We could hypothesize that IVLE when administered early and continuously to asymptomatic animals is able to significantly reduce free plasma concentrations of ivermectin due to a lack of fat reservoir, supporting the “lipid sink” theory. Thus, our findings suggest that an early IVLE therapy (bolus + 30-minute CRI) should be the part of the initial management of ivermectin intoxication in cats, particularly in those with a low BCS who appear to be more at risk of toxicity. Further studies are warranted to determine the effect of IVLE administered early prior to the development of signs compared to IVLE administration later in the course of intoxication.b
Acknowledgments The authors wish to acknowledge the contributions of Professor Michel Franc, Mrs. S´everine Dumond, Sonia Gounaud, Martine Roques, and Solange Vermot for their technical and nursing assistance.
Footnotes a b
Ivomec Bovin, Merial-Aventis, Lyon, France. Intralipide 20%, Fresenius Kabi, S´evres, France.
References 1. Ghubash R. Parasitic miticidal therapy. Clin Tech Small Anim Pract 2006; 21(3):135–144. C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12371
IVLE therapy after ivermectin overdose in cats 2. Merola VM, Eubig PA. Toxicology of avermectins and milbemycins (macrocyclic lactones) and the role of P-glycoprotein in dogs and cats. Vet Clin Small Anim 2012; 42(2):313–333. 3. Burrows A. Avermectins in dermatology. In: Kirk RW. ed. Kirk’s Current Veterinary Therapy XIV. St. Louis: Saunders Elsevier; 2009, pp. 390–394. 4. Lovell R. Ivermectin and piperazine toxicoses in dogs and cats. Vet Clin North Am Small Anim Pract 1990; 20(2):453–468. 5. Merola V, Khan S, Gwaltney-Brant S. Ivermectin toxicosis in dogs: a retrospective study. J Am Anim Hosp Assoc 2009; 45(3):106–111. 6. Frischke H, Hunt L. Alberta. Suspected ivermectin toxicity in kittens. Can Vet J 1991; 32(4):245. 7. Kidwell JH, Buckley GJ, Allen AE, Bandt C. Use of IV lipid emulsion for treatment of ivermectin toxicosis in a cat. J Am Anim Hosp Assoc 2014; 50(1):59–61. 8. Lewis DT, Merchant SR, Neer TM. Ivermectin toxicosis in a kitten. J Am Vet Med Assoc 1994; 205(4):584–586. 9. Muhammad G, Abdul J, Khan MZ, Saqib M. Use of neostigmine in massive ivermectin toxicity in cats. Vet Hum Toxicol 2004; 46(1):28– 29. 10. Pritchard J. Treating ivermectin toxicity in cats. Vet Rec 2010; 166(24):766. 11. Rowley J. Ivermectin toxicity in two kittens. Companion Anim Pract 1988; 2(9):31–32. 12. Houston DM. Extra-label use of drugs. J Am Vet Med Assoc 1985; 187(7):671. 13. Fernandez AL, Lee JA, Rahilly L, et al. The use of intravenous lipid emulsion as an antidote in veterinary toxicology. J Vet Emerg Crit Care 2011; 21(4):309–320. 14. Gwaltney-Brant S, Meadows I. Use of intravenous lipid emulsions for treating certain poisoning cases in small animals. Vet Clin Small Anim 2012; 42(2):251–262. 15. Kaplan A, Whelan M. The use of IV lipid emulsion for lipophilic drug toxicities. J Am Anim Hosp Assoc 2012; 48(4):221–227. 16. Bates N, Chatterton J, Robbins C. Lipid infusion in the management of poisoning: a report of 6 canine cases. Vet Record 2013; 172(13): 339. 17. Clarke DL, Lee JA, Murphy LA., Reineke EL. Use of intravenous lipid emulsion to treat ivermectin toxicosis in a Border Collie. J Am Vet Med Assoc 2011; 239(10):1328–1133.
C Veterinary Emergency and Critical Care Society 2015, doi: 10.1111/vec.12371
18. Epstein SE, Hollingsworth SR. Ivermectin-induced blindness treated with intravenous lipid therapy in a dog. J Vet Emerg Crit Care 2013; 23(1):58–62. 19. Wright HM, Chen AV, Talcott PA, Poppenga RH, Mealey KL. Intravenous fat emulsion as treatment for ivermectin toxicosis in three dogs homozygous for the ABCB1-1 gene mutation. J Vet Emerg Crit Care 2011; 21(6):666–672. 20. Crandell DE, Guy L. Moxidectin toxicosis in a puppy successfully treated with intravenous lipids. J Vet Emerg Crit Care 2009; 19(2):181–186. 21. Maton BL, Simmonds EE, Lee JA, Alwood AJ. The use of highdose insulin therapy and intravenous lipid emulsion to treat severe, refractory diltiazem toxicosis in a dog. J Vet Emerg Crit Care 2013; 23(3):321–327. 22. O’Brien TQ, Clark-Price SC, Evans EE, Di Fazio R, McMichael M. Infusion of a lipid emulsion to treat lidoca¨ıne intoxication in a cat. J Am Vet Med Assoc 2010; 237(12):1455–1458. 23. Edwards P, Shihab N, Scott HW. Treatment of a case of feline baclofen toxicosis with intravenous lipid therapy. Vet Rec Case Rep 2014; 2(1):e000059. 24. Haworth MD, Smart L. Use of intravenous lipid therapy in three cases of feline permethrin toxicosis. J Vet Emerg Crit Care 2012; 22(6):697–702. ¨ 25. Bruckner M, Schwedes CS. Successful treatment of permethrin toxicosis in two cats with an intravenous lipid administration. Tier¨arztl Prax 2012; 40(K):129–134. 26. DeGroot WD. Intravenous lipid emulsion for treating permethrin toxicosis in a cat. Can Vet J 2014; 55(1):1253–1254. Erratum in: Can Vet J 2014; 55(2):106. 27. Muentener CR, Spicher C, Page SW. Treating permethrin poisoning in cats. Vet Rec 2013; 172(24):643. 28. http://www.purina.co.uk/content/your-cat/helping-to-keepyour-cat-healthy/managing-your-cat%27s-weight/purina-bodycondition-tool 29. Gonzalez Canga A, Sahagun Prieto AM, Diez Liebana MJ, et al. The pharmacokinetics and metabolism of ivermectin in domestic species. Vet J 2009; 179(1):25–37. 30. Chittrakarn S, Janchawee B, Ruangrut P, et al. Pharmacokinetics of ivermectin in cats receiving a single subcutaneous dose. Res Vet Sci 2009; 86(3):503–507.
671
