Safety and efficacy of intravenous administration for tranexamic acid-inducedemesis in dogs with accidental ingestion of foreign substances
Abstract
Dogs are frequently exposed to various toxic materials, including chocolate, pharmaceuticals,tobacco, nuts, onions, and xylitol [13]. For thetreatment of accidental ingestion of these materials, emetics are helpful to remove them fromthe gastrointestine and to prevent further absorption in some situation. Intravenous injectionand ocular conjunctival administration of apomorphine and oral administration of 3% hydrogenperoxide are the most common methods used to induce vomiting [12, 13, 20]. Apomorphine induces emesis by directly stimulating dopamine 2 receptors in themedullary chemoreceptor zone [13, 17], whereas 3% hydrogen peroxide induces emesis through a vomiting reflexby direct stimulation of the oropharynx and stomach lining [13, 20]. Adverse effects of these emetics aregenerally mild and limited [13, 16]. Tranexamic acid has antifibrinolytic properties and is widely used tocontrol bleeding in trauma patients in both veterinary and human medicine [3, 6, 11]. Nausea and vomiting are recognized as adverse effectsfor tranexamic acid in humans [4, 5, 22]. Moreover, a higher-than-usualdose of tranexamic acid may induce emesis after IV administration in humans [5]. Recently, our research group found that a vomitingmechanism of tranexamic acid differs qualitatively from that of apomorphine or hydrogenperoxide. Tranexamic acid induces emesis by stimulating a pathway involving tachykininneurokinin 1 receptors, as opposed to stimulation of dopamine 2 receptors or directstimulation of the stomach lining by apomorphine and hydrogen peroxide, respectively [9]. We also found that IV tranexamic acid induced emesis ina dose-dependent manner in both single-dose and dose-escalating administration in dogs [10]. The antifibrinolytic effect of tranexamic acid, whichis its main medical application, decreased steeply and resolved completely within 24 hr indogs [10]. Tranexamic acid-induced emesis has beenapplied empirically to canine patients that ingested toxic materials in Japan; however, theveterinary clinical profile of tranexamic acid as an emetic thus far, has not beensystematically investigated. In the present study, the safety and emetic profiles of IVadministration of tranexamic acid have been revealed in a canine clinical medicinesetting.
MATERIALS AND METHODS
Animals
Medical records from the Tokyo Jonan Regional Veterinary Medicine Promotional AssociationAnimal Medical Center, a night-time veterinary hospital in Japan were searched for dogsaccidentally ingested the materials. When owners suspected or witnessed that their dog hadingested inappropriate materials, they brought their dog to the hospital. Veterinariansused tranexamic acid for the treatment of accidental ingestion when the dog was exposed toa material with a potential risk of causing a severe clinical reaction based on theestimated amount ingested. When dogs were suspected to ingesting sharp-pointed objects,such as wire or a bamboo skewer, or large objects with a risk of occluding gastric cardia,veterinarians did not use tranexamic acid, because vomiting would induce perforation of astomach ulcer or gastrointestinal injury. Veterinarians did not administer tranexamic acidto dogs that have already vomited several times. A depressed consciousness and underlyingdisorder, such as depression of laryngeal reflex, seizure, and megaesophagus werecontraindications to emetic treatment. If dogs ingested epileptic agents, organicchemicals, such as kerosene and volatile agents, detergents, or strong acid and alkalinematerials, tranexamic acid were not used. If such contraindications to inducing emesisexisted, veterinarians used a different treatment, such as endoscopic examination orabdominal operation. Tranexamic acid was administered intravenously according to thefollowing medical protocol: Veterinarians typically fed the dog a small meal, such ascanned or paste dog food, unless the dog had eaten during the 2 hr prior to emeticadministration. Veterinarians administered tranexamic acid IV to dogs through anindwelling catheter. The first dose was 50 mg/kg of 10% tranexamic acid (Daiichi-SankyoCo., Ltd., Tokyo, Japan). When the first dose failed to induce vomiting, a second andthird dose (20–50 and 25–50 mg/kg, respectively) were administered 5 to 10 min apart ifthe previous dose did not induce emesis. If dogs just had retching, which is called “dryvomiting”, we considered that the material ingested would have already moved to intestine.Thus, veterinarians did not administer another dose and recorded it as “a dog with novomit”. If a dog did not exhibit vomiting behavior at all after administration oftranexamic acid, veterinarians judged that another emetic would induce emesis moreeffectively than an additional dose of tranexamic acid. Then, a 3% hydrogen peroxidesolution was administered.
Data collection
Data included the following when available: signalment (breed, age, gender, body weight,anamnesis and clinical signs); information regarding materials ingested (name or type,time of ingestion); estimated amount and location of the material ingested according to anX-ray examination; what food veterinarians gave before inducing emesis; dose of tranexamicacid; number of times tranexamic acid was administered [once, twice, or thrice]; emeticprofiles (time to onset of emesis episodes after IV administration of tranexamic acid[sec], duration of emesis [sec], number of emetic episodes per dog); and whether anyadverse effects were observed.
Classification of materials ingested
Materials ingested were classified based on the veterinarian’s interpretation of witnessaccounts, X-ray examinations, and findings in the vomited materials. The classificationincluded the following: foreign substances, chocolate, other food, pharmaceuticals,tobacco, nuts, onions, grapes, refrigerant, xylitol, unknown, and rodenticide. Theclassification “foreign substances” included non-food items and most commonly includedhousehold items, such as sponges, cling film, buttons, gum elastic, aluminium foil,plastic goods, sanitary goods, and cosmetics. Most of the cases in the “Other food”category involved consumption of human food, such as bread, cookies, curry, sweet potato,prune, and meal. The “Clothing” category included clothing, such as cloth, stuffed toys,socks, and stockings. When a dog was suspected of ingesting an unidentified material, itscase was included in the classification “Unknown”.
Statistical analysis
Data were expressed as mean ± SEM, median and range according to the number of timestranexamic acid was administered [once, twice, or thrice]. Differences in age and bodyweight between the success and failure groups for tranexamic acid-induced emesis wereanalysed using Mann-Whitney’s U test.
RESULTS
Clinical data of canine patients administered tranexamic acid for vomiting were collectedin 137 dogs from 27 January 2013 to 30 October 2014. The kinds of breed and numbers of dogswere as follows: 30 Poodles (Toy); 28 Dachshunds (Miniature); 12 hybrids; 7 Chihuahuas; 6Yorkshire Terriers; 5 Retrievers (Golden, Labrador); 4 each of Italian Greyhounds,Papillons, Border Collies, and Miniature Pinschers; 3 each of Cavalier King Charles Spanielsand Pomeranians; 2 each of Welsh Terriers, Shih Tzus, Norfolk Terriers, Pugs, Beagles,Bichon Frises, Malteses, Miniature Schnauzers, Lakeland Terriers, Japanese Shiba Inus, andFrench Bulldogs; and 1 each of Spaniel (American Cocker), West Highland White Terrier, WelshCorgi, Parson Russell Terrier, and Boston Terrier.
Emetic profile of IV administration of tranexamic acid
After administration of the first dose of tranexamic acid, 116 of 137 (84.7%) dogsvomited within 370 sec. When a second dose was administered IV to 17 of the 21 dogs thatdid not vomit after the first administration, 11 of the 17 (64.7%) dogs vomited within 440sec. When a third dose was administered IV to 3 of 6 the dogs that did not vomit after thesecond administration, 2 of the 3 (66.7%) dogs vomited at 50 and 640 sec. Results oftreatment with tranexamic acid, the time to onset of vomiting, duration of emesis, andnumber of episodes of vomiting are summarized in Table 1
| Variable | Administration | |||
|---|---|---|---|---|
| 1st | 2nd | 3rd | ||
| Dose of tranexamic acid (mg/kg, IV) | ||||
| Mean ± SEM | 50 ± 0 | 39 ± 3 | 42 ± 8 | |
| Median (range) | 50 (50) | 50 (20–50) | 50 (25–50) | |
| No. of dogs that vomited/total No. of dogsthat received tranexamic acid | 116/137 | 11/17 | 2/3 | |
| No. of dogs in which materials ingested wererecovered/No. of dogs that vomited | 78/116 | 8/11 | 1/2 | |
| Duration of emesis (sec) | ||||
| Mean ± SEM | 166 ± 8 | 249 ± 104 | 480 ± 240 | |
| Median (range) | 152 (30–780) | 131 (50–1,260) | 480 (240–720) | |
| No. of vomiting episodes per dog | ||||
| Mean ± SEM | 2.1 ± 0.1 | 1.9 ± 0.3 | 1.7 ± 0.7 | |
| Median (range) | 2 (1–8) | 2 (1–4) | 1 (1–3) | |
| Time to onset of first episode of vomiting(sec) | ||||
| Mean ± SEM | 124 ± 5 | 150 ± 38 | 345 ± 295 | |
| Median (range) | 116.5 (26–370) | 100 (50–440) | 345 (50–640) | |
| No. of dogs that vomited twice | 65 | 7 | 1 | |
| Time to onset of second episode of vomiting(sec) | ||||
| Mean ± SEM | 142 ± 12 | 198 ± 61 | 120 | |
| Median (range) | 130 (35–780) | 110 (70–493) | 120 (120) | |
| No. of dogs that vomited 3 times | 39 | 2 | 1 | |
| Time to onset of third episode of vomiting(sec) | ||||
| Mean ± SEM | 149 ± 8 | 532 ± 292 | 240 | |
| Median (range) | 153 (40–280) | 531.5 (240–823) | 240 (240) | |
| No. of dogs that vomited 4 times | 15 | 1 | — | |
| Time to onset of fourth episode of vomiting(sec) | ||||
| Mean ± SEM | 152 ± 18 | 1,260 | — | |
| Median (range) | 130 (45–338) | 1,260 (1,260) | — | |
| No. of dogs that vomited 5 times and over | 5 | — | — | |
Veterinarians did not administer additional doses of tranexamic acid to 4 dogs that didnot vomit after the first administration, because 3 of the 4 dogs exhibited only retchingand the other dog seemed to have almost no residual contents in its stomach because theelapsed time from ingestion to administration of tranexamic acid was over 2 hr. Inaddition, the veterinarians did not administer further doses to 3 dogs that did not vomitafter both first and second administrations. Instead, 3% hydrogen peroxide solution (0.5ml/kg, PO) was administered to 1 of the 3 dogs, and the other dogsreceived no further treatment as their condition was stable.
Adverse effects with IV administration of tranexamic acid
Adverse effects were observed in 2 of 137 (1.5%) dogs after the first administration oftranexamic acid. One dog (Bichon Frise, male, 11 years old, 9 kg) had a tonic-clonicconvulsion. The dog received an injection of diazepam for relieving anxiety and relaxingmuscles, and subsequently recovered. The other dog (Papillon, female, 8 years old, 3.26kg) developed bleeding just after withdrew the IV catheter, and the veterinarian was ableto stop the bleeding from the injection site with tape.
Differences in vomiting and non-vomiting groups
No significant differences in body weight or age were found between dogs that vomitedafter either the first, second, or third administration of tranexamic acid and those thatdid not. Data including dose, age, and body weight in vomiting and non-vomiting groups peradministration of tranexamic acid are summarized in Table 2
| Variable | Administration | ||||||
|---|---|---|---|---|---|---|---|
| 1st | 2nd | 3rd | |||||
| Vomiting | Non-vomiting | Vomiting | Non-vomiting | Vomiting | Non-vomiting | ||
| No. of dogs | 116 | 21 | 11 | 6 | 2 | 1 | |
| Dose of tranexamic acid (mg/kg, IV) | |||||||
| Mean ± SEM | 50 ± 0 | 50 ± 0 | 42 ± 4 | 35 ± 6 | 50 ± 0 | 25 | |
| Median (range) | 50 (50) | 50 (50) | 50 (25–50) | 32.5 (20–50) | 50 (50) | 25 (25) | |
| Efficacy (%) | 84.7 | — | 64.7 | — | 66.7 | — | |
| Age (year) | |||||||
| Mean ± SEM | 3.6 ± 0.3 | 4.6 ± 1.0 | 2.6 ± 1.2 | 7.2 ± 1.9 | 11.5 ± 2.5 | 10 | |
| Median (range) | 3 (0–12) | 3 (0–14) | 0 (0–10) | 7 (1–14) | 11.5 (9–14) | 10 (10) | |
| Body weight (kg) | |||||||
| Mean ± SEM | 5.8 ± 0.4 | 6.1 ± 0.6 | 6.9 ± 0.9 | 5.2 ± 0.7 | 4.7 ± 0.3 | 3.1 | |
| Median (range) | 4.5 (1.8–32.8) | 5.8 (1.3–11.3) | 6.2 (2.7–11.3) | 5 (3.1–7.3) | 4.7 (4.4–5) | 3.1 | |
Materials ingested and rates of successful induction of emesis
A single-dose of tranexamic acid successfully induced emesis in all categories ofingested material. The success rate of emesis induction for each administration percategory group is summarized in Table3
| Material ingested | Administration | |||
|---|---|---|---|---|
| 1st (%) | 2nd (%) | 3rd (%) | Total (%) | |
| Foreign substances | 35/45 (77.8) | 7/8 (87.5) | 1/1 (100) | 43/45 (95.6) |
| Chocolate | 32/36 (88.9) | 1/3 (33.3) | — | 33/36 (91.7) |
| Other food | 14/17 (82.4) | 1/2 (50) | — | 15/17 (88.2) |
| Clothing | 12/12 (100) | — | — | 12/12 (100) |
| Pharmaceuticals | 7/9 (77.8) | 1/2 (50) | 1/1 (100) | 9/9 (100) |
| Tobacco | 8/8 (100) | — | — | 8/8 (100) |
| Nuts | 7/8 (87.5) | 0/1 (0) | — | 7/8 (87.5) |
| Onions | 5/6 (83.3) | 0/1 (0) | 0/1 (0) | 5/6 (83.3) |
| Grapes | 4/5 (80) | 1/1 (100) | — | 5/5 (100) |
| Refrigerant | 3/3 (100) | — | — | 3/3 (100) |
| Xylitol | 3/3 (100) | — | — | 3/3 (100) |
| Unknown | 2/2 (100) | — | — | 2/2 (100) |
| Rodenticide | 1/1 (100) | — | — | 1/1 (100) |
| All groups | 116/137 (84.7) | 11/17 (64.7) | 2/3 (66.7) | 129/137 (94.2) |
DISCUSSION
The results of the present study indicate that tranexamic acid effectively induces emesisin dogs in a clinical setting. A single-dose of tranexamic acid successfully induced emesiswith a high probability. For dogs that withstood the first dose, a second and thirdadministration induced emesis. After the first administration of tranexamic acid, emesis wasinduced promptly, and the duration of action was short. Generally, emesis should be inducedas soon as possible to remove a large portion of the stomach contents, as gastric transittime is approximately 2 hr [7, 19]. Therefore, induction of emesis may not be effective 2 to 3 hr afteringestion of a poison [1]. Once dogs regurgitate theirstomach contents, further episodes of vomiting are not necessary. Taken together, the promptand short-acting properties of tranexamic acid make it a good choice as an emetic.
Intravenous and ocular conjunctival administration of apomorphine and oral administrationof 3% hydrogen peroxide have yielded high success rates of 94 and 90%, respectively [12]. The median time from IV and ocular conjunctivaladministration of apomorphine to onset of vomiting was 1 min and 6 min, respectively [2]. The median time from oral administration of 3%hydrogen peroxide to onset of vomiting was 10 min [12]. Therefore, tranexamic acid induces emesis in dogs as promptly as IVadministration of apomorphine, and more promptly than ocular administration of apomorphineand oral administration 3% hydrogen peroxide.
We demonstrate that a second and third administration of tranexamic acid induced emesis indogs that did not vomit after the first and second administration, suggesting that anadditional dosing approach may be an effective way to recover the ingested material from thestomach. It is noted, however, the success rates of inducing emesis with a second and thirdadministration were less than the success rates with the first administration.
There were no differences in age and body weight between dogs in which tranexamic acidinduced emesis and those in which it did not induce emesis. In addition, the success rate toinduce emesis was very high in all categories of material ingested. Therefore, tranexamicacid may induce emesis in dogs with a high probability regardless of age, body weight, andkinds of material ingested. Further studies are warranted to investigate the effects ofthese factors on tranexamic acid-induced emesis.
In the present study, one dog developed a hemostatic disorder at the injection site.Fletcher et al. found that dogs are physiologically more hyperfibrinolyticthan humans, which could explain the observed effect [6].
One dog that had ingested some amount of cocoa powder had a tonic-clonic convulsion afterthe first administration. High-dose administration of tranexamic acid increases the risk ofpostoperative seizures in humans [18]. Tranexamicacid postsynaptically antagonizes γ-aminobutyric acid receptors type A and glycinereceptors, both of which are major central inhibitory neurotransmitters, and lead to anincreased neuronal excitation ex vivo in mice [14, 15]. In addition, a xanthinederivative “theobromine”, a main component of cocoa powder, may induce an acute seizure byitself [8, 21].These excitatory mechanisms may be involved in the incidence of seizure in dogs treated withtranexamic acid. Further studies are warranted to investigate the proconvulsant effect oftranexamic acid in dogs.
Limitations of the present study included that the amount of the potentially toxic materialrecovered in the vomitus was not calculated, although veterinarians judged whether recoveryof the material ingested was successful by visually comparing the amount recovered to theestimated amount ingested.
In conclusion, tranexamic acid promptly induces emesis with a high probability followingsingle-dose administration. A dose-escalation approach also effectively induces emesis.Adverse effects of tranexamic acid are considered low and self-limiting.
Acknowledgments
The authors would like to thank the staff at the Tokyo Jonan RegionalVeterinary Medicine Promotional Association Animal Medical Center for their technicalassistance. This research was supported by a research grant from Anicom Holdings, Inc. and aresearch project grant awarded by Azabu University.
References
- 1. 1959. Evaluation of the efficacy of lavage andinduced emesis in treatment of salicylate poisoning.Pediatrics23:286–301. [PubMed][Google Scholar]
- 2. 2008. Safety and efficacy of an ocular insertfor apomorphine-induced emesis in dogs. Am. J. Vet.Res.69: 1360–1365.doi: [PubMed][Google Scholar]
- 3. CRASH-2 trial collaborators.2010Effects of tranexamic acid on death, vascularocclusive events, and blood transfusion in trauma patients with significant haemorrhage(CRASH-2): a randomised, placebo-controlledtrial.Lancet376:23–32.[PubMed][Google Scholar]
- 4. 1999. Tranexamic acid: a review of its use insurgery and other indications.Drugs57:1005–1032. doi: [PubMed][Google Scholar]
- 5. 2009. Anti-fibrinolytic agents in post partumhaemorrhage: a systematic review. BMC PregnancyChildbirth9: 29. doi: [PubMed][Google Scholar]
- 6. 2014. Evaluation of tranexamic acid andε-aminocaproic acid concentrations required to inhibit fibrinolysis in plasma of dogsand humans. Am. J. Vet.Res.75: 731–738. doi:[PubMed][Google Scholar]
- 7. 2000. Emergency approach tointoxications. Clin. Tech. Small Anim.Pract.15: 82–87. doi:[PubMed][Google Scholar]
- 8. 2011. Effect of prolonged status epilepticus asa result of intoxication on epileptogenesis in a U.K. canine population.Vet. Rec.169: 361.doi: [PubMed][Google Scholar]
- 9. 2014. Tranexamic acid induces kaolin intakestimulating a pathway involving tachykinin neurokinin 1 receptors inrats. Eur. J.Pharmacol.723: 1–6.doi: [PubMed][Google Scholar]
- 10. 2014. Efficacy and safety of tranexamic acid asan emetic in dogs. Am. J. Vet.Res.75: 1099–1103. doi:[PubMed][Google Scholar]
- 11. 2015. Effects of intravenous administration oftranexamic acid on hematological, hemostatic, and thromboelastographic analytes inhealthy adult dogs. J. Vet. Emerg. Crit. Care. (SanAntonio)25: 495–501.doi: [PubMed][Google Scholar]
- 12. 2012. Effectiveness and adverse effects of theuse of apomorphine and 3% hydrogen peroxide solution to induce emesis indogs. J. Am. Vet. Med.Assoc.241: 1179–1184.doi: [PubMed][Google Scholar]
- 13. 2009. Some food toxic for pets.Interdiscip. Toxicol.2:169–176. doi: [PubMed][Google Scholar]
- 14. 2014. Tranexamic acid impairs γ-aminobutyricacid receptor type A-mediated synaptic transmission in the murine amygdala: a potentialmechanism for drug-inducedseizures?Anesthesiology120:639–649. doi: [PubMed][Google Scholar]
- 15. 2012. Tranexamic acid concentrations associatedwith human seizures inhibit glycine receptors. J. Clin.Invest.122:4654–4666. doi: [PubMed][Google Scholar]
- 16. 1980. Emesis and lavage.Vet. Hum. Toxicol.22:225–234. [PubMed][Google Scholar]
- 17. 1992. Pharmacological agents affecting emesis.A review (Part I).Drugs43:295–315. doi: [PubMed][Google Scholar]
- 18. 2010. High-dose tranexamic Acid is associatedwith nonischemic clinical seizures in cardiac surgical patients.Anesth. Analg.110:350–353. doi: [PubMed][Google Scholar]
- 19. 2013. Effect of Gongronema latifolium ongastric emptying in healthy dogs. World J.Gastroenterol.19:897–902. doi: [PubMed][Google Scholar]
- 20. 2011. Veterinary Drug Handbook. 7th ed., Wiley-Blackwell,Ames.
- 21. 1994. Theobromine poisoning indogs. Vet. Rec.134:284. doi: [PubMed][Google Scholar]
- 22. 2003. Tranexamic acid: a review of its use inthe management of menorrhagia.Drugs63:1417–1433. doi: [PubMed][Google Scholar]