Important Advice On Anticoagulant Rodenticide Toxicity

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Key Points

  • Anticoagulant rodenticides are among the few toxins for which there is a reliable antidote.
  • The clinician must identify the type of rodenticide consumed.
  • Patients who ingested the anticoagulant rodenticide within 3 days of presentation will not yet be bleeding, and can either be started on vitamin K or their coagulation status monitored with serial PT checks.
  • Patients with bleeding are treated with plasma transfusion and vitamin K.
  • Bleeding most commonly occurs in the body cavities (such as the pleural space), and the pulmonary parenchyma.
  • Treated correctly, prognosis is excellent.

Introduction

Anticoagulant rodenticide ingestion is a common toxicity in dogs. That the clinical signs are delayed and an antidote is readily available makes this a unique toxicity in regards to diagnosis and treatment. The following is a recommendation for a clinical approach to rodenticide toxicity based on the way rodenticides interact with the coagulation system and the timeline of events that occur following ingestion of a toxic dose. .

Background

Worldwide, there are five groups of commonly used rodenticides:

  1. Coumarin and indandione derivatives, which antagonise the coagulation system to cause haemorrhage
  2. Bromethalin, which causes arrest of oxidative phosphorylation in the CNS
  3. Cholecalciferol, which causes hypercalcaemia
  4. Zinc phosphide, causes the release of phosphine gas and free radicals following contact with gastric acid. Mechanism of toxicity unknown.
  5. Strychnine, causes disinhibition of cells within the central nervous system

To the author’s knowledge, there are no bromethalin or strychnine-based rodenticides registered for use in Australia. The anticoagulant products are by far the most commonly ingested by pets. Exposure occurs primarily in the family home or yard. The coumarin-based product pindone is used in Australian national parks as a rabbit bait.

It is unclear if secondary exposure – that is ingestion of poisoned rodents – is a viable route to toxicity. The LD50 (toxic dose) is thought to be much lower in rodents than dogs and cats, meaning the rodent will have needed to ingest many times their fatal dose in order to pass on a clinically relevant dose to the dog or cat, which also have much higher body weights.

Anticoagulant rodenticides are marketed as pellets (which can be green or blue), wax blocks, and pastes. The Australian government public chemical registration lists 59 registered products, many of which are available for household use (see table 1).1  These products have a very long shelf life and many clients will forget having placed them around the house.

Tip 1: If you have a strong suspicion of rodenticide toxicity, do not let a client convince you that it is impossible. Due to the long half-lives of these products, many clients are unable to recall placing baits, or the rodenticide was placed by previous tenants/property owners, or the client thinks their product is “pet-friendly”.

Pathophysiology

Ingestion of a toxic dose of anticoagulant rodenticides leads to coagulopathy via disruption of vitamin K recycling. Vitamin K is a fat-soluble vitamin that is necessary to turn “spent” procoagulant factors II, VII, IX, and X back into their active forms via carboxylation (Figure 1).  Anticoagulant rodenticides antagonise the enzyme Vitamin K epoxide reductase, which converts inactive, oxidised vitamin K into active, reduced Vitamin K. Only active vitamin K can perform carboxylation.

Figure 1: Mechanism of action of anticoagulant rodenticides

In the absence of active vitamin K, the plasma concentrations of functional factors II, VII, IX, and X are depleted, leading to spontaneous bleeding.  The timing of factor depletion and bleeding takes a predictable course that can be monitored via the measurement of the prothrombin time (PT). The factor with the shortest half-life is factor VII, at 6.2 hours.2

In the traditional model of coagulation, factor VII is considered an extrinsic factor, which is evaluated by the PT (Figure 2). Depletion of factor VII will cause the PT to become elevated approximately 24 - 36 hours after ingestion of toxic amount of rodenticide, before elevation of the PTT, and importantly, before onset of bleeding, which is linked primarily to the depletion of Factor II, and takes about 3.5 days in adults.2 Young animals will bleed sooner as they have smaller stores of clotting factors.

Figure 2: Classical pathway of coagulation

Supplemental vitamin K is the antidote to anticoagulant rodenticide and is available in oral and injectable forms. It is the “active” form of vitamin K, and thus is available to the coagulation system for carboxylation of inactive clotting factors. The required duration of Vitamin K treatment varies depending on the “generation” of rodenticide ingested. Older rodenticides are termed “first generation” and exert their anticoagulant effect for approximately one week. Newer products are “second generation” and last up to 8 weeks.

Case Management

Almost all rodenticide patients present to the hospital in one of two ways; either following known ingestion, or for spontaneous haemorrhage. A third group of patients will present with bleeding following provocation to the coagulation system such as a blood draw or surgery. These patients likely ingested the rodenticide between 1 and 4 days prior, which is long enough to cause depletion of active clotting factors, but not long enough to experience spontaneous haemorrhage.

  • Known ingestions

History

It is important to clarify which group of rodenticide has been eaten, and in the case of the anticoagulants, which generation.  Shape and colour cannot be relied upon as there is overlap between products. A list of the lethal dose of the more popular products is provided for completeness (see table 2) however attempting to calculate the ingested dose is impractical as clients can rarely recall how much bait was laid so the author usually skips this step.

Note: The majority of these cases will present long before PT elevation, hence performing coagulation testing is not required.

Treatment

Step 1: Gastrointestinal decontamination

If the patient presents within six hours of ingestion and there are no contraindications, (see table 3), emesis should be induced.

Tip 2: The fastest and most reliable way to induce emesis is with apomorphine administered IV at a dose of 0.03mg/kg. An anti-emetic is generally not required. If you are worried about excessive vomiting, metoclopramide administered SQ is the best choice as it is a direct antagonist of apomorphine (via dopamine receptors in the chemoreceptor trigger zone). If an injectable preparation of apomorphine is not available, the next best choice is a crushed tablet administered subconjunctivally. Administration of a crushed tablet via injection of any route, is not recommended.

This can be followed by one dose of activated charcoal; either the plain formulation or with the cathartic sorbitol, which works to hasten intestinal emptying.

Tip 3: While recommended in most toxicity books, it is the author’s experience that activated charcoal is not essential in cases of rodenticide toxicity as long as the rest of the steps are followed. Skip the charcoal if your patient is fighting you.

More aggressive decontamination procedures such as gastric lavage are not necessary mostly for the reason that there is an antidote for this toxicity therefore the risks inherent to these procedures far outweigh the benefits. It is also important to consider that studies in human medicine have shown very poor toxin recovery with emesis and gastric lavage if they are performed beyond one hour post-ingestion which is when most veterinary patients are presented to the veterinarian.3 Similar controversy exists as to whether activated charcoal is useful beyond one hour.3  Timing must be taken into consideration when weighing up the pros/cons of decontamination in all toxicities.

Step 2: Vitamin K v Surveillance

Following decontamination, there are two options for ongoing care:

  1. Vitamin K

Start vitamin K at a 2.5mg/kg PO BID for 4 weeks. Recheck PT 48 hours following cessation of therapy. If the PT is prolonged, extend the course of Vitamin K by one to two weeks.

Tip 4: If PT testing is not available in your hospital, send it to an external lab. If the turn-around time is long enough to put your patient at risk of bleeding (for example, beyond 3.5 days of initial ingestion or the last dose of Vitamin K), it is safest to administer vitamin K in the mean time, then stop if the PT results are normal.

 The activated clotting time is too subjective and yields unreliable results, so is not a suitable alternative for PT in this situation.

  1. Monitor Coagulation

Have patient return for a PT 36 – 48 hours after estimated ingestion time. If the PT is prolonged, this indicates the patient ingested a clinically relevant dose of rodenticide and they must be started on Vitamin K. If the PT is high-normal, repeat in 24 hours.

The author’s preferred approach is option #2. It has been evaluated in a large retrospective study and found to be safe.4 In the author’s experience, almost all patients will have a normal PT on their recheck, and remain asymptomatic.  In large dogs, it can also be the less expensive approach due to the high cost of Vitamin K.

It is important to not make the mistake of administering a single dose of vitamin K “just in case”.  Not only does this confound PT results, but it is inadequate in treating cases of actual toxicity.

  • Spontaneous haemorrhage

History/Physical Exam

Depletion of clotting factors tends to cause large cavity bleeding however bleeding at any site is possible. The most commonly affected sites are the pleural and peritoneal spaces, lungs, brain, pericardial space, and along the gingival margin. Gastrointestinal bleeding, and mucocutaneous bleeding (petechiae/ecchymoses) are uncommon.

As the bleeding is usually internal and thus imperceptible to the owner, patients rarely present for “bleeding”, rather for clinical signs associated with bleeding. Depending on the volume of blood loss, the rate, and the location, these can either be generalised signs caused by anaemia/hypovolaemia such as weakness or collapse, or signs related to dysfunction of the organ that is bleeding such as coughing in cases of pulmonary haemorrhage, or seizures with intracranial involvement (Figure 3).

Figure 3: Dorsoventral view of the thorax of a dog with rodentidicide toxicity. Note the consolidation of the right caudal lung lobe.

Diagnosis

The diagnosis of rodenticide toxicity can be made with a PT above the upper level of detection. In almost all cases it will be “out of range” high.

There are few other clinical situations in which a PT will be very high (and rarely out of range). These include liver failure, and DIC due to severe inflammatory conditions or neoplasia. It is fairly easy to distinguish these cases from rodenticide toxicity for they typically present to the veterinarian for signs related to their primary condition such as vomiting, and jaundice, rather than for bleeding. Inherited coagulopathies such as haemophilia usually do not cause prolongation of the PT.

Definitive diagnosis of anticoagulant rodenticide toxicity is possible by measuring serum levels of rodenticide with spectrophotometry, however it is unclear if this test is available in Australia. PIVKA (proteins induced by vitamin K antagonism) serum levels were previously thought to be useful in distinguishing rodenticide toxicity from other causes of coagulopathy, however in a 1999 study in dogs5 it was found that PIVKA can be elevated in a range of conditions, so this test cannot be recommended.

Tip 5: There are really only two causes of spontaneous (not trauma-related causes) haemorrhage into the peritoneal and pleural spaces – rodenticide toxicity and neoplasia. If you suspect your patient has blood in either of these locations it is important to check a PT before confirming your suspicion with a centesis, particularly if your patient is unlikely to have neoplasia (such as a puppy).

Treatment

  1. Plasma Transfusion

Plasma transfusion is indicated in all patients who are actively bleeding. Plasma provides clotting factors immediately and is the fastest way to reduce the risk a patient will experience life-threatening hemorrhage into a critical organ such as the lungs or brain. Fresh frozen plasma (FFP) or fresh whole blood (FWB), which contains both plasma and red blood cells, can be used. A dose of 10 – 20ml/kg of plasma administered over 4 hours is usually adequate, but can be given faster if the patient is bleeding heavily. If using FWB, remember that approximately half the total volume of the unit is plasma and be mindful of fluid overload although this is less of a concern in hypovolaemic patients.

  1. Antidote: Vitamin K

Vitamin K should also be started as soon as possible either orally, or if the patient cannot take oral medication, via subcutaneous injection through a small gauge needle. The author usually waits until the patient has received at least ¼ of their transfusion before giving an injection. Vitamin K should never be administered intraveneously due to high risk of anaphylaxis. Initial dose of Vitamin K (either route) is 5mg/kg followed by at least 4 weeks of oral therapy at 2.5mg/kg q12h.

A PT should be checked a few hours after transfusion, and the following day to ensure the vitamin K is being effective. As with all patients prescribed a course of Vitamin K, the PT should also be checked 48 hours after completion to check if a longer course is necessary.  Further follow-up is not necessary however patients are not immune to future toxicity so clients should be encouraged to find the rodenticide and remove it or secure it.

If the client cannot afford a plasma transfusion, it is worth trying Vitamin K alone, however it will be at least 6 hours before active clotting factors are produced, perhaps much longer.

Tip 6: Oral Vitamin K has a faster onset of action than injectable, particularly if administered with a fatty meal, so is the desirable route if possible.

  1. Ancillary Therapies

Some patients – particularly those with rapid, large volume haemorrhage - will require red cell transfusion, in the form of FWB or packed red blood cells (pRBC). For patients in hypovolaemic shock it can be difficult to decide whether to administer plasma or red cells first. Ideally, FWB would be given in these situations so the patient receives clotting factors and red cells at the same time. Alternatively, FFP and pRBC can be administered simultaneously. This is safe, even through the same intravenous catheter.

Other treatments may be necessary, such as supplemental oxygen in cases of pulmonary haemorrhage, or additional intravenous fluid therapy.

Free blood in the peritoneal cavity should be left in place to be resorbed by the patient. Thoracocentesis or pericardiocentesis can be considered in patients who are clinical for their effusions, otherwise also left in place for resorption. Ideally this would occur after the patient has received some plasma due to the high risk of bleeding, but sometimes is required earlier as a life-saving intervention.

Conclusion

Anticoagulant rodenticide toxicity is a common cause of spontaneous bleeding, particularly in dogs. Understanding the unique pathophysiology of the toxin is key to formulating a logical approach to work-up and treatment. Done correctly, most patients will survive and have normal quality of life.

Author
Dr Erin Mooney BVSc DACVECC
Registered specialist in veterinary emergency and critical care

Erin graduated from the University of Sydney in 2007. Following graduation she undertook an internship in small animal medicine and surgery at a referral hospital in Connecticut, USA. This was followed by a residency in small animal emergency and critical care (E/CC) at Tufts University in Massachusetts, a world-leading centre for E/CC training and clinical research. Erin became a Diplomate of the American College of Veterinary Emergency and Critical Care in 2012.

Following her residency, Erin returned to Australia to work as a specialist clinician and lecturer at the University of Melbourne, a role which fostered her passion for teaching and research. Erin returned to her home town of Sydney in April 2014 to join the team at the Small Animal  Specialist Hospital (SASH), and was the first full-time criticalist in NSW.

References

  1. Australian Pesticides and Veterinary Medicines Authority PubCRIS Database. Retrieved from: http://apvma.gov.au
  2. Hellemans J, Vorlat M, Verstraete M. Survival time of prothrombin and factors VII, IX and X after completely synthesis blocking dose of coumarin derivatives. British Journal of Haematology 1963; 9:506–512.
  3. Position papers. American Academy of Clinical Toxicology. Retrieved from: http://www.nacct.org/positionstatements.cfm
  4. Pachtinger GE, Otto CM, Syring RS. Incidence of prolonged prothrombin time following gastrointestinal decontamination for acute anticoagulant rodenticide ingestion. Journal of Veterinary Emergency and Critical Care 2008; 18(3):285 – 291.
  5. Rozanski EA, Drobatz KJ, Hughes D et al. Thrombotest (PIVKA) test results in 25 dogs with acquired and hereditary coagulopathies. Journal of Veterinary Emergency and Critical Care 1999; 9(2):73-78

 

Tables

Table 1: Anticoagulant Rodenticides in Australia

Class Active Ingredient Brand name
Coumarin Warfarin Rattex®

 

Pindone

 

 

Surefire®

Aldi Bunnybait®

 

Brodifacoum Pest Defence®

Ratshot®

Ratsak®

Defence-Us®

Brigand®

Rodenthor®

Mortein Rat Kill®

Surefire®

X-Verminator®

Talon®

Ditrac®

Difenacoum Ratsak®

All Weather®

Surefire®

Roban®

Atlas®

Effect®

Ratshot®

The Big Cheese®

Time’s Up®

Cougar®

Roban®

Sorexa®

Ramik®

 

Flocoumafen Stratagem®
Indandione Diphacinone Ramik®
Bromadiolone Rodemise®

Surefire®

Rentokil®

Difethialone Generation®

Rodilon®

 

Table 2: Toxic dose and generation of common anticoagulant rodenticides

Lethal Dose (mg/kg)
Active Ingredient Generation Dogs Cat
Warfarin First 20 - 300 5 - 30
Brodifacoum Second 0.2 - 4 25
Bromadiolone Second 11 - 15 >25
Diphacinone First 0.9 - 8 15

 

Table 3: Contraindications to Induction of Emesis

Contraindications to Induction of Emesis
Altered mentation

-       obtundation/semi-coma/coma

-       seizures

Oesophageal disorders
Laryngeal dysfunction
Ingestion of corrosive substances

-       petroleum distillates

-       acids

-       alkaline substances

Recent abdominal surgery

 

 

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