Further information

The purpose of seeking additional information about the poison in question is to ascertain if possible the severity of exposure that has or may have occurred (see Box 30.2).

A number of sources of information are available with respect to veterinary toxicology that includes:

Some information that may be useful when calculating exposure dosages is presented in Box 30.3.

Home management

If the decision is made for the animal to be monitored at home, the owner must be thoroughly briefed both on what signs to observe the animal for and the typical time frame for their onset and progression. In general, if there is any doubt as to the animal’s condition, veterinary examination should be recommended. Owners should be advised on appropriate measures to implement during transportation (e.g. keeping unconscious animals warm or keeping seizuring animals cool and protected from injury).

Inducing emesis at home

In some cases in which poison ingestion has occurred within a suitable period of time, it may be appropriate for the owner to induce emesis at home, for example if financial concerns or practical constraints preclude presentation to the practice. In addition, if a considerable delay is anticipated prior to presentation, and the owner has ready access to an appropriate emetic, inducing emesis prior to departure from home may be advisable to minimize further absorption of the poison in transit. The owner must be questioned carefully to ensure that contraindications to inducing emesis do not exist; these are summarized in Box 30.4.

BOX 30.4 Contraindications to induction of emesis

• Significantly altered mentation due to increased risk of aspiration of vomitus; in particular in depressed animals in whom there may be dysfunction of the gag reflex

• Respiratory distress and pre-existing conditions (e.g. laryngeal paralysis) that may predispose the animal to aspiration

• Animals that are already vomiting

• Ingestion of a caustic or corrosive agent (e.g. acids or alkalis) – emesis will potentially expose the oropharyngeal and oesophageal mucosa to further injury. Consumption of milk or water should be encouraged if not contraindicated

Agents that may be used to induce emesis at home are shown in Table 30.1.

Table 30.1 Agents for inducing emesis at home

Agent	Dose	Comments
Soda crystals (washing soda)	1 crystal	Place on tongue at back of mouth Emesis usually within 10 minutes Can be repeated NB. Not caustic soda (sodium hydroxide)
Syrup of ipecacuanha (7%)	D: 1–2 ml/kg p.o. C: 3.3 ml/kg p.o.	Emesis usually within 30 minutes Can be repeated once Bitter taste therefore poor compliance
Hydrogen peroxide (3%)	D, C: 1–3 ml/kg	Emesis usually within 10 minutes Can be repeated once Care to avoid aspiration
Table salt (sodium chloride)	Not recommended	Unreliable May induce or exacerbate hypernatraemia with potentially severe consequences Ad lib access to water imperative if used

C, cats; D, dogs.

Clinical Tip

• It is very important to make sure that soda crystals (washing soda) are used for emesis, as owners have inadvertently administered caustic soda (sodium hydroxide) instead. This is very harmful following ingestion, causing severe injury to the oropharyngeal and oesophageal mucosa with potentially fatal consequences (Figure 30.1).

Figure 30.1 Severe oral cavity injury in a dog inadvertently given caustic soda by her owners for emesis. Severe mucosal injury extended all the way down the oesophagus.

(Photograph courtesy of Tammy Ford)

History

All the information in Boxes 30.1 and 30.2 should be obtained at the appropriate time. In some emergency patients, clinical signs and progression are compatible with possible intoxication without an immediately suggestive history. In such cases, the owner must be carefully and thoroughly questioned to establish whether a potential source of poison exists that the owner has not considered.

Initial management of ingested poisons

As for all emergency patients, a major body system (cardiovascular, respiratory, neurological) examination (see Ch. 1), including measurement of rectal temperature, should be performed and immediate measures taken to correct potentially life-threatening problems. Intravenous fluid therapy (see Ch. 4) may be required to correct hypovolaemia and/or dehydration. Fluid therapy is also indicated in the management of poisons that are nephrotoxic (e.g. nonsteroidal antiinflammatory agents) and those that are largely dependent on renal excretion. Oxygen supplementation is indicated in patients with respiratory compromise, for example from aspiration following vomiting, and in the context of certain poisons such as carbon monoxide.

Topical poisoning

Washing the patient is recommended to minimize irritation of and absorption via the skin; this should also minimize absorption through ingestion following grooming. Washing is usually done using mild soap or detergent, followed by copious rinsing with water and then drying the animal as thoroughly as possible. Powdered toxins may be vacuumed off before washing. All individuals involved in handling the animal should take care to wear gloves and preferably an apron so as to avoid self-contamination. In some cases it may be appropriate for the owner to wash the animal at home. However, in compromised or noncompliant animals, veterinary care is recommended.

Clipping the coat of long-haired patients may help to maximize decontamination. Chemical restraint may be preferable during washing to allow protection of the eyes and in some cases general anaesthesia with endotracheal intubation is safest to minimize the risk of aspiration. Vital parameters including rectal temperature should be monitored closely throughout.

Oily substances may be more successfully removed using commercial hand-cleaning degreaser formulations (e.g. Swarfega Hand Cleaner^® products) but it is important to ensure that such preparations are thoroughly washed off the animal subsequently.

The use of activated charcoal is generally recommended following topical poisoning. This is to minimize gastrointestinal absorption that may occur following ingestion from grooming. In addition, some poisons undergo enterohepatic circulation following absorption from the skin and thereby become available in the gastrointestinal tract.

In cases in which the skin has come into contact with an acidic or caustic substance, the affected area should be lavaged very thoroughly (’the solution to pollution is dilution’) using normal saline or indeed warm water. The same is true in cases of ocular contamination and in both cases the animal should be given appropriate analgesia and chemically restrained to allow comprehensive lavage to be performed. Damaged skin is highly susceptible to mechanical injury and gentle lavage is therefore mandatory.

Diuresis

Diuresis is most indicated in the treatment of poisoning by agents for which renal excretion of either the primary intoxicant or its metabolites is a significant feature (e.g. phenobarbital, salicylates). Standard intravenous isotonic crystalloid therapy is employed to promote renal excretion with or without additional diuretic administration. Isotonic crystalloid therapy is administered at a rate of 1–4 ml/kg/hr above calculated fluid requirements and the patient must be monitored closely to ensure that adequate urine production occurs. In cases of aggressive diuresis, close monitoring of hydration status and electrolyte concentrations is indicated.

Antidotes

In a significant proportion of canine and feline patients a diagnosis of poisoning is made presumptively with the poison in question remaining unknown. Furthermore, specific antidotes or antagonists do not exist for the majority of potentially poisonous substances to which dogs and cats may be exposed. That said, the majority of clinical cases reported are due to a relatively small number of poisons for which, in some cases, specific treatments are available. These will be alluded to in the discussion of specific poisons that follows.

Theory refresher

Pyrethrins are naturally occurring insecticidal esters of chrysanthemic acid and pyrethric acid extracted from the Chrysanthemum cinerariaefolium plant; pyrethroids (e.g. permethrin) are synthetic pyrethrins. Many topical and household insecticidal preparations containing these compounds are marketed for the control of flea and lice infestations amongst others in dogs and cats. These preparations are widely available from a variety of outlets.

Case management

Diazepam (5 mg) was administered per rectum to facilitate intravenous catheter placement and blood was obtained via the catheter for an emergency database to be performed; this was found to be unremarkable. Major body system examination was unremarkable except for the muscle tremors that were less severe but still marked.

Intravenous fluid therapy was commenced and anaesthesia was induced using propofol and maintained using isoflurane. The cat was washed thoroughly in a mild detergent and dried before being recovered with an Elizabethan collar in place. Muscle tremors were apparent in recovery but of lesser severity and a single intravenous bolus of midazolam (0.2 mg/kg) was administered.

Tremors resolved fully over the next 24 hours, during which time vital parameters, in particular temperature, were monitored closely and appropriate supportive and nursing measures instituted.

Permethrin dosage in this case was approximately 150 mg/kg.

Theory refresher

Metaldehyde is a cyclic tetramer of acetaldehyde that is commonly used as a pesticide against slugs and snails (molluscicide). Commercial pellet preparations usually contain 1.5–8% metaldehyde w/w (see Box 30.3) in a cereal base. The pellets are often blue or green in colour and the cereals and other additives make slug/snail baits palatable to dogs. Cats as usual are more discerning and metaldehyde poisoning has only been reported in a few cases. Liquid preparations containing higher concentrations of metaldehyde are also available, as are granular and powdered preparations. Metaldehyde baits sometimes contain additional herbicides and pesticides, most commonly carbamate insecticides.

Case management

After checking the dog’s temperature, diazepam (1 mg/kg) was administered per rectum and an intravenous catheter subsequently placed. A further intravenous bolus of diazepam (0.5 mg/kg) was administered and a major body system examination performed. Anaesthesia was then induced using propofol and maintained using isoflurane following endotracheal intubation. Thorough gastric lavage was performed and revealed blue-green coloured material. Activated charcoal was then administered into the stomach. Colorectal lavage was also done and an activated charcoal enema administered.

The dog was maintained on a propofol infusion for the next 12 hours, during which phenobarbital loading was performed (3 mg/kg i.v. q 1 hr for six doses); thereafter the dog was gradually weaned off propofol (over 4 hours). External stimulation was kept to a minimum (e.g. cotton wool balls/swabs in the ears, dim lighting, minimal noise and passage of personnel). The dog remained markedly depressed for the following 24 hours but gradually became ambulatory and although ataxic initially went on to make a full recovery over the following 3 days. Fluid therapy and appropriate nursing measures were instituted throughout. Phenobarbital (3 mg/kg i.v. then p.o. q 12 hr) therapy was discontinued at discharge.

The slug bait container contained 1 kg of blue pellets with a metaldehyde composition of 4% w/w. Assuming the dog had ingested all 1 kg of bait, this was equal to 40 mg (i.e. 4% × 1000 mg) of metaldehyde and a maximum dosage of only 1.3 mg/kg.

Toxic dose

The minimum lethal dose of undiluted EG is reported to be 4.4–6.6 ml/kg in dogs and 1.5 ml/kg in cats.

Toxicokinetics

EG is rapidly absorbed from the gastrointestinal tract and distributed systemically. Its plasma half-life is approximately 3 hours and a variable proportion is excreted unchanged in urine. The remainder is metabolized predominantly in the liver. The first step in this metabolism is oxidation of EG to glycoaldehyde by alcohol dehydrogenase (ADH), a conversion that can be saturated. Glycoaldehdye is then converted to glycolic acid, glyoxylic acid and finally to oxalic acid. EG metabolic pathways may vary between species.

Calcium binds to oxalic acid, resulting in the formation of calcium oxalate crystals that are deposited widely but especially in the renal tubules, and calcium oxalate crystalluria is a common finding.

Mechanism of toxicity

Metabolism of EG generates free oxygen radicals that are potentially cytotoxic to a variety of tissues. In addition, the organic acid metabolites produced interfere with normal cellular processes. Central nervous system (CNS) dysfunction is thought to be predominantly due to the effects of glycoaldehyde along with calcium oxalate deposition in nervous tissue. Both hypocalcaemia secondary to binding of calcium to oxalic acid and metabolic acidosis may contribute further to CNS signs. Metabolic acidosis may be severe and is due to the accumulation of acid metabolites, most notably glycolic acid.

Clinical signs

Clinical signs of EG poisoning are dose-dependent and in companion animals occur in two phases. The first is predominantly associated with EG itself prior to metabolism. Signs develop within an hour of ingestion and may persist for 12 hours. They include CNS depression, somnolence, ataxia, impairment of conscious proprioception, nausea, vomiting, and osmotic diuresis with consequent polyuria/polydipsia. In severe cases seizures, coma and death may occur. In dogs these signs may seemingly resolve with apparent recovery although they may occur earlier and be more persistent in cats.

The second phase of clinical signs is associated with the highly toxic metabolites of EG and is predominantly related to acute renal failure. Signs usually develop within 24–72 hours of ingestion in dogs, often earlier in cats, and may include reduced mentation from depression through to coma, seizures, anorexia, vomiting, and oliguria with low urine specific gravity or isosthenuria. Anuria may develop 3–4 days post-ingestion.

An intermediate phase between the two phases already described consists of cardiopulmonary manifestations (tachycardia, tachypnoea, pulmonary oedema) but this is recognized much less commonly in dogs and cats than in people.

Laboratory tests

Urinalysis

Osmotic diuresis and polydipsia (due to increased serum osmolality) result in reduced urine specific gravity, typically within 3 hours of EG ingestion. Dogs are usually isosthenuric (urine specific gravity 1.007–1.015) but urine specific gravity may be higher than this and often is in cats. Urine specific gravity remains low as renal insufficiency and impaired ability to concentrate urine develop in the later stages. Glucosuria with concurrent normoglycaemia may be detected in dogs as a result of proximal renal tubular damage.

Calcium oxalate crystals may be identified in urine 3–6 hours after EG ingestion. Calcium oxalate monohydrate crystals (clear six-sided prisms or dumbbell-shaped (Figure 30.2) crystals) are more common than the dihydrate form (envelopes or Maltese cross-shaped). Aciduria, haematuria, renal epithelial cells and casts are other common urinalysis findings.

Figure 30.2 Dumbbell-shaped calcium oxalate monohydrate crystals in urine.

(Photograph courtesy of Kate English)

Treatment

Treatment of suspected EG poisoning should be instituted as early as possible because it is metabolized rapidly into highly toxic metabolites. Treatment consists of the following components:

Prognosis

Prognosis depends on the dosage of EG ingested, rate of absorption and, most importantly, the time to institution of specific therapy. The prognosis for dogs treated with fomepizole within 5 hours of ingestion is good, and most will recover if treatment is administered within 8 hours of ingestion. The prognosis is reasonable for cats receiving therapy within 3 hours of ingestion.

However, a grave prognosis for survival is heralded by the onset of oliguric renal failure in both species and unfortunately most animals present at this late stage.

Theory refresher

Grape/raisin poisoning in dogs has been recognized since the late 1990s. No confirmed cases have been reported in cats at the time of writing but susceptibility is suspected. A similar syndrome has not been reported in people.

Major body system examination

Physical examination revealed the dog to be very depressed and moderately dehydrated but was otherwise unremarkable.

Emergency database

An intravenous catheter was placed in a cephalic vein and blood obtained via the catheter for an emergency database. This revealed severe azotaemia (blood urea nitrogen 45 mmol/l, reference range 3–9.10 mmol/l; creatinine 1250 µmol/l, reference range 98–163 µmol/l) and moderate hyperkalaemia (6.0 mmol/l, reference range 4.1–5.3 mmol/l). Dehydration was confirmed (manual packed cell volume 55%, reference range 37–55%; plasma total solids 75 g/l, reference range 49–71 g/l). The severity of azotaemia was consistent with a primary renal or postrenal cause but some prerenal contribution due to dehydration was also likely.

Case management

A soft indwelling Foley urethral catheter was placed with ease, thereby excluding urethral obstruction, and an emergency abdominal ultrasound revealed no free peritoneal fluid, thus excluding uroperitoneum; both kidneys had grossly normal architecture. Urinalysis on a sample collected via the urethral catheter revealed a specific gravity of 1.020 and mild proteinuria, glucosuria and haematuria. The azotaemia was diagnosed as renal in origin (with the caveat that the ureters had not been imaged to exclude completely a postrenal cause or component). A presumptive diagnosis of acute renal failure due to raisin poisoning was therefore made.

The dog was not felt to be hypovolaemic but moderate dehydration (7%) was suspected, and he was started on 0.9% sodium chloride (normal, physiological saline) at 10 ml/kg/hr to provide rehydration and maintenance requirements over approximately 8 hours. The bladder was emptied via the urethral catheter at the outset. After 10 hours of fluid therapy, urine output was calculated and the dog was found to have produced only 0.5 ml/kg/hr of urine. A diagnosis of oliguric acute renal failure was therefore made. The decision was made at this point to refer the dog.

Despite aggressive diuretic therapy at the referral centre, using furosemide and mannitol, oliguria persisted and the dog became overhydrated, showing chemosis, diffuse subcutaneous oedema and mild peritoneal and pleural effusion. Peritoneal dialysis was considered appropriate in this case (young previously healthy dog with potentially curable disease) and was performed successfully. Four months following discharge from the referral hospital mild persistent azotaemia was present (blood urea nitrogen 13 mmol/l, creatinine 190 µmol/l) but the dog was clinically well. Appropriate dietary management and on-going monitoring were recommended.

Toxic dose, toxicokinetics, mechanism of toxicity

Even very small amounts of plant ingest may be poisonous to cats and rapid absorption from the gastrointestinal tract is suspected as some cats still develop renal insufficiency despite early gastrointestinal decontamination. The toxin or toxins involved have yet to be identified and the metabolism is unknown. The precise mechanism of toxicity is unknown but renal tubular epithelial necrosis and subsequent acute renal failure are known to occur.

Pancreatitis and pancreatic degeneration have also been reported in cats with lily poisoning, as have seizures of unconfirmed pathogenesis.

Clinical signs

Clinical signs may develop in as little as 5–10 minutes following ingestion. Within 1–3 hours vomiting, salivation, depression, lethargy and anorexia may be apparent. Polyuria and consequent dehydration occur 12–30 hours following ingestion and this is followed by anuria.

Anuria typically occurs 24–48 hr following ingestion and death may occur within 7 days of exposure. Renomegaly and abdominal pain may be detected in some cats.

Laboratory tests

Depending on the time elapsed since ingestion, clinicopathological findings are likely to reflect acute renal failure with azotaemia, hyperphosphataemia and possible hyperkalaemia. These abnormalities are usually evident within 24–72 hours of ingestion. Urinalysis may reveal isosthenuria, tubular casts (Figure 30.3), proteinuria and glucosuria.

Figure 30.3 Tubular cast in urine (×200).

(Photograph courtesy of Kate English)

Treatment

Depending on the time elapsed since ingestion, routine GID may be indicated to minimize absorption. Fluid diuresis should be implemented for 24–72 hours, with regular monitoring of serum biochemistry and urinalysis. Diuretic therapy (furosemide, mannitol) may be beneficial in cats with oliguric renal failure but is unlikely to induce urine production in anuric cats for which referral for dialysis may be the only treatment option if available and affordable. Mannitol should not be used in anuric animals.

Prognosis

Prognosis depends in large part on the time between ingestion and presentation for treatment. Early presentation with GID and fluid diuresis carries a good prognosis for clinical recovery although some chronic renal dysfunction may persist. The prognosis is grave with standard medical therapy following the onset of anuria. The prognosis for anuric animals receiving dialysis may be favourable but remains to be elucidated.

Toxic dose

The pharmacokinetics of NSAIAs show differences between species and doses used in people should not be extrapolated to dogs and cats.

Toxicokinetics, mechanism of toxicity

NSAIAs are direct inhibitors of cyclooxygenase (COX) and cause reduced production of prostaglandins and thromboxane. Some NSAIAs are reported to be more COX-2 selective; COX-2 is induced during tissue injury and inflammation. However, it is important to remember that at excessive dosages both COX-1 (constitutive/housekeeping form responsible for physiological functions) and COX-2 inhibition is likely.

NSAIAs are generally readily absorbed following oral exposure. Metabolism is usually hepatic. In dogs, a number of NSAIAs undergo enterohepatic circulation. Adverse effects of NSAIAs have been reported to involve predominantly the gastrointestinal tract, the kidneys, coagulation, and the liver.

Clinical signs

Early clinical signs of NSAIA intoxication in dogs are likely to reflect gastrointestinal complications and include vomiting, with or without haematemesis, and diarrhoea, with or without melaena (or haematochezia); inappetence, lethargy, depression, weakness and possible abdominal pain may occur. Dehydration and potentially hypovolaemia may be present. Cats may show gastrointestinal signs less frequently but tachypnoea may be more common than in dogs. In severe cases gastrointestinal perforation may occur with subsequent peritonitis that may be accompanied by abdominal pain and severe cardiovascular compromise.

Animals may also present with oliguric or polyuric acute renal failure.

Laboratory and other tests

Depending on the time elapsed since ingestion, clinicopathological findings may reflect gastrointestinal blood loss, with anaemia and possible panhypoproteinaemia. Anaemia may be preregenerative or regenerative (see Ch. 3). Prerenal azotaemia may be identified and urea may be disproportionately elevated compared to creatinine due to gastrointestinal haemorrhage. Renal insufficiency will likely manifest as azotaemia, hyperphosphataemia, possible hypercalcaemia and isosthenuria. Proteinuria may also be detected.

If gastrointestinal perforation and peritonitis are suspected, additional testing is mandatory. Abdominal radiography may show loss of serosal detail due to free peritoneal fluid, and free peritoneal gas. Abdominal ultrasonography may reveal free peritoneal fluid and may be used to guide abdominocentesis (see p. 293). Alternatively, blind abdominocentesis may be performed. Any fluid obtained should be examined cytologically and will typically be consistent with a purulent exudate if perforation has occurred.

Treatment

Depending on the time elapsed since ingestion, routine GID including the use of activated charcoal may be indicated to minimize further drug absorption. Intravenous fluid therapy using an isotonic crystalloid solution is indicated to correct hypovolaemia or dehydration and recurrence must be prevented to minimize the risk of nephrotoxicity.

Medical therapy designed to minimize further gastrointestinal compromise and to promote ulcer healing should be provided (Table 30.3). Routine use of anti-emetics may be required.

Table 30.3 Medical therapy for nonsteroidal antiinflammatory agent (NSAIA) intoxication

C, cats; D, dogs; i.v., intravenous; p.o., per os.

Surgical intervention is required in animals with gastrointestinal perforation and standard management of acute renal failure (see Ch. 36) is indicated in appropriate cases. NSAIA-mediated acute renal insufficiency is often reversible with adequate supportive care.

Toxic dose

In dogs, aspirin administration at 50 mg/kg q 12 hr has been reported to cause vomiting, and haematemesis and gastric ulcer perforation have been reported at 100–300 mg/kg/day for 1–4 weeks. Due to deficiencies in aspirin metabolism, cats are more susceptible and the toxic dose is lower than for dogs.

Toxicokinetics, mechanism of toxicity, clinical signs

Aspirin (acetylsalicylic acid) is a synthetic NSAIA. Following ingestion, aspirin is readily absorbed and is then metabolized in the liver to salicylic acid. Some local hydrolysis to salicylic acid also occurs in the gastrointestinal tract. Salicylic acid is the active form and the form that is absorbed into the circulation. Elimination from the circulation depends on conjugation with glucuronic acid. At high dosages this conjugation becomes overwhelmed, resulting in delayed clearance and accumulation of the active drug. Cats have a defective glucuronic acid conjugation system that results in prolonged drug elimination compared to dogs and an increased susceptibility to aspirin poisoning.

Gastrointestinal irritation and injury are the most common adverse effects of aspirin ingestion and nephrotoxicity is also reported. Metabolic acidosis is responsible for the majority of clinical signs. The metabolic acidosis in salicylate poisoning is a high anion gap acidosis. Severe and fatal acidaemia may occur within a few hours of aspirin ingestion.

Salicylates also have toxic effects in the CNS although the exact mechanism of toxicity is not known. Seizures have been reported in both dogs and cats secondary to salicylate toxicity. Noncardiogenic pulmonary oedema is the most common cause of major morbidity in people and might be related to a salicylate-induced increase in the permeability of the pulmonary vasculature. Salicylates inhibit vitamin K-dependent synthesis of coagulation factors (II, VII, IX and X), leading to a prolonged prothrombin time, and also inhibit prostaglandin-dependent platelet aggregation. Aspirin-induced hepatitis has been reported in cats following excessive exposure.

Treatment

Treatment of aspirin poisoning is the same as described for other NSAIAs earlier in this chapter.

Theory refresher

Paracetamol (acetaminophen in the USA) is used extensively by people and is widely available over the counter. It is contained in a variety of preparations, either solely or in conjunction with other drugs, including aspirin and opioids. It is an antipyretic and analgesic agent. Paracetamol has been used therapeutically in dogs but should not be administered to cats.

Major body system examination

On presentation the dog was ambulatory but depressed. Tachycardia (heart rate 130 beats per minute) and brown mucous membranes were identified but the rest of the examination was unremarkable.

Emergency database

An intravenous catheter was placed in a cephalic vein and blood obtained via the catheter for an emergency database that was found to be unremarkable.

Case management

Additional venepuncture was performed and the dog’s blood was confirmed to be dark brown in colour, suggestive of methaemoglobinaemia (Figure 30.4). An in-house coagulation analyser was available and prothrombin time (PT) and activated partial thromboplastin time (APTT) were found to be within normal limits.

Figure 30.4 Dark brown blood from a dog with paracetamol intoxication.

Emesis was induced using apomorphine (0.02 mg/kg s.c.) and the vomitus contained a minimum of 30 paracetamol tablets (500 mg per tablet). The dog’s body weight was 20 kg and an exposure of 750 mg/kg was therefore possible, although it was not clear exactly how many more tablets, if any, the dog had ingested. In addition, the degree of absorption prior to emesis could not be known.

Initial therapy consisted of intravenous N-acetylcysteine (initial loading dose of 140 mg/kg i.v.; further five doses of 70 mg/kg i.v. q 6 hr) and oral ascorbic acid (vitamin C) (30 mg/kg p.o. in drinking water q 6 hr for five doses). Isotonic crystalloid intravenous fluid therapy was provided using compound sodium lactate at 4 ml/kg/hr and oxygen supplemented via an oxygen cage.

Twenty-four hours following presentation clotting tests were prolonged and moderate elevations in serum alanine aminotransferase (ALT) and bilirubin were detected. Mild anaemia was also identified (manual packed cell volume 30%, reference range 37–55%). A type-specific fresh whole blood transfusion (15 ml/kg over 4 hr) (see Ch. 40) was administered for the coagulopathy and anaemia, and additional therapy with S-adenosylmethionine (40 mg/kg p.o.) was commenced.

The dog continued to deteriorate, however, with evidence of haemolysis in the form of severe haemoglobinaemia and haemoglobinuria, with worsening anaemia despite blood transfusion, and with progressive severe dyspnoea. A haemoglobin-based oxygen-carrying solution (Oxyglobin^®, Biopure Corporation; see Ch. 4) was administered (6 ml/kg i.v. over 1 hr) with no obvious clinical effect and the dog was euthanased approximately 36 hours after ingestion of the paracetamol tablets. A presumptive diagnosis of fulminant acute hepatic failure and severe haemolysis due to paracetamol poisoning was made.

Toxic dose

Given the large number of anticoagulant rodenticide substances in use it is beyond the scope of this chapter to detail toxic doses for each individual substance and the reader is recommended to consult other texts or a veterinary poisons database.

Toxicokinetics

Anticoagulant rodenticides are generally absorbed slowly but substantially from the gastrointestinal tract. A long plasma half-life potentially of a number of days is typical, and the duration of action can be very prolonged – even up to several weeks in some cases. These compounds undergo slow metabolism by hepatic microsomal mixed-function oxidases to form inactive metabolites that are excreted in urine or bile.

Mechanism of toxicity

Vitamin K₁ hydroquinone is required for the conversion of inactive precursor coagulation factors to their active forms. During this conversion vitamin K₁ hydroquinone is oxidized to vitamin K₁ epoxide. Following absorption, anticoagulant rodenticides inhibit hepatic vitamin K₁ epoxide-reductase which is responsible for the conversion of vitamin K₁ epoxide back to vitamin K₁ hydroquinone. Anticoagulant rodenticides therefore impair vitamin K₁ ‘recycling’ by the liver, leading to its depletion as existing stores are exhausted; they thereby prevent conversion of several inactive coagulation factors to their active forms. The vitamin K₁-dependent coagulation factors are factors II (prothrombin), VII, IX and X.

A delay in the onset of clinical signs following anticoagulant rodenticide ingestion is usually seen. This is due to the presence of circulating active vitamin K-dependent coagulation factors that must be exhausted for clinical signs to become apparent. Of the vitamin K-dependent factors, factor VII has the shortest plasma half-life. This factor is traditionally classified as part of the extrinsic coagulation pathway that is evaluated using the prothrombin time (PT). This explains the early clinical usefulness of measuring PT in cases of suspected anticoagulant rodenticide poisoning. Activated partial thromboplastin time (APTT) and activated clotting time (ACT) are used to evaluate the intrinsic (includes factors II, IX and X) coagulation pathway and are expected to become prolonged subsequently also.

Clinical signs

Clinical signs usually develop from 3–5 days after exposure and may persist for more than 2 weeks without intervention. Clinical signs reflect bleeding tendency as described above and may be accompanied by a variety of nonspecific signs such as lethargy, depression and reduced appetite. Anticoagulant rodenticide poisoning may manifest with signs of respiratory distress, most commonly due to haemothorax but also secondary to pulmonary haemorrhage, and coughing (including haemoptysis) is reported. Bleeding into the peritoneal cavity and mediastinum is also reported. There may be evidence of external bleeding (e.g. nasal or gingival) and gastrointestinal haemorrhage may manifest as melaena, haematemesis and abdominal pain. Petechiae, ecchymoses and excessive bleeding at venepuncture sites may be identified. Bleeding in other sites will manifest with expected clinical signs (e.g. lameness secondary to bleeding into joints or neurological signs secondary to CNS haemorrhage).

In animals that have become anaemic secondary to blood loss, anticipated physical examination findings such as pale mucous membranes, tachycardia and hyperdynamic pulse quality will be present. If blood loss is considerable and rapid, evidence of hypoperfusion secondary to hypovolaemic shock may be identified.

Laboratory and other tests

In any animal presenting following suspected anticoagulant rodenticide ingestion a baseline minimum database should be established. This should include manual packed cell volume, plasma total solids, peripheral blood smear, and coagulation profile (in particular PT) taken before initiation of therapy (see below). PT is prolonged first in poisoned patients as factor VII becomes depleted earliest but prolongation of APTT and ACT usually also occurs before the onset of clinical signs.

A peripheral blood smear should be evaluated for platelet count and, where anaemia is identified, for evidence of regeneration. Mild to moderate thrombocytopenia is a common finding. Lack of a regenerative red blood cell response may represent preregenerative (as opposed to nonregenerative) anaemia (see Ch. 3). Blood typing may also be appropriate. Low serum total solids are expected in anaemia secondary to blood loss.

Thoracic and abdominal diagnostic imaging may identify major sites of haemorrhage, with the thoracic cavity being the most common site of bleeding. Thoracocentesis and abdominocentesis will likely reveal a nonclotting sanguineous effusion with packed cell volume similar to that of the patient’s peripheral blood.

Treatment

Treatment of anticoagulant rodenticide poisoning is dependent largely on whether the patient is showing evidence of bleeding at the time of presentation. Routine GID, including the use of activated charcoal, is indicated in asymptomatic patients presenting within an appropriate timeframe. PT should be measured and no additional therapy is required if PT is within normal limits. Repeat testing of PT should be performed within 2–3 days. If a significant delay in obtaining the results of this test is unavoidable, it may be appropriate in individual cases to commence antidotal therapy with synthetic vitamin K₁ (phytomenadione) once blood sampling has been performed and to discontinue therapy if normal results are subsequently obtained. Guidelines for vitamin K₁ therapy in anticoagulant rodenticide intoxication are summarized in Box 30.8.

If vitamin K₁ therapy is commenced a significant period of time prior to sampling for testing of PT, subsequent results may be affected and a definitive diagnosis of coagulopathy secondary to rodenticide poisoning cannot be established. Subsequent vitamin K₁ therapy in these cases should then be managed as recommended for animals presenting with clinical signs of haemorrhage or with prolongation of PT.

Replacement of clotting factors may be performed in symptomatic patients by administering appropriate blood products. This is typically achieved through the use of fresh frozen plasma but fresh whole blood may be used to treat severe anaemia as well as coagulopathy in appropriate cases. Alternatively, a combination of fresh frozen plasma and packed red blood cells may be employed in these cases (see Ch. 40).

Prognosis

Prognosis is generally good with adequate and timely treatment but is partly dependent on site and severity of haemorrhage at the time of presentation.

Rodenticides containing vitamin D

Some rodenticide preparations contain calciferol (vitamin D₂) or cholecalciferol (vitamin D₃), either alone or together with anticoagulant agents. Calciferol/cholecalciferol is metabolized to calcitriol (1,25-dihydroxycholecalciferol) which induces hypercalcaemia via increased intestinal absorption, increased renal reabsorption and enhanced bone resorption. Hyperphosphataemia is also consistently present.

Clinical signs of hypercalcaemia are most commonly associated with the neurological, cardiovascular and gastrointestinal systems and with the kidneys. Depending on the preparation consumed, signs may be seen 8–48 hours post-ingestion. Treatment of hypercalcaemia involves: promoting calciuresis using intravenous 0.9% sodium chloride (normal saline) and furosemide; corticosteroid therapy to suppress bone resorption, reduce intestinal calcium absorption and promote calciuresis; possible additional use of salmon calcitonin; and, more recently, treatment with a bisphosphonate drug. Animals poisoned with anticoagulant rodenticides containing vitamin D may have severe morbidity.

Toxic dose

Fatal doses of theobromine are reported to be in the range of 90–250 mg/kg in dogs and 80–150 mg/kg in cats.

Toxicokinetics

Absorption of theobromine from the gastrointestinal tract is relatively slower in dogs compared to people, with complete absorption potentially taking up to 10 hours. Metabolism is primarily hepatic and enterohepatic circulation occurs. Excretion is considerably slower than in people.

Mechanism of toxicity

Methylxanthines inhibit cyclic nucleotide phosphodiesterases and also act as adenosine receptor antagonists. As with other methylxanthines, theobromine (and caffeine) causes CNS stimulation with consequent cardiac and respiratory effects. It directly stimulates the myocardium and skeletal muscle causing increased contractility and competitively inhibits cerebral benzodiazepine receptors. Theobromine also causes smooth muscle relaxation, especially of the bronchi, and renal diuresis.

Clinical signs

Clinical signs usually develop within 24 hours of ingestion and typically much sooner. Signs may persist for 48–72 hours in some cases. Commonly reported clinical signs include vomiting, abdominal discomfort, restlessness, excitability and hyperactivity, ataxia, tachycardia, and tachypnoea or panting. In more severe cases muscle rigidity, muscle tremors, hyperthermia, seizures and dysrhythmias have been reported. Urinary incontinence, polyuria and polydipsia may also occur. Severe seizures and/or cardiovascular compromise are typically reported in fatal cases.

Laboratory and other tests

An emergency database including electrocardiogram is recommended.

Treatment

Routine GID is indicated in appropriate cases. As theobromine is absorbed slowly in dogs, induction of emesis may be appropriate even after a significant delay; however, it may be best avoided in animals that are very hyperactive. Theobromine undergoes enterohepatic circulation so repeated use of charcoal may enhance elimination. There is no specific antidote for theobromine poisoning and therapy is otherwise symptomatic. This may include intravenous fluid therapy, antiemetic administration, sedation if excitability is excessive, and routine treatment of seizures. Antidysrhythmic therapy may also be indicated in some cases.

Prognosis

Prognosis is generally good with appropriate treatment but may be worse for animals showing marked cardiovascular or neurological signs at presentation.

Toxic dose

Hypoglycaemia has been reported to occur in dogs at dosages greater than 0.15 g/kg and a dosage of 0.5 g/kg has been associated with hepatic failure. However, it remains unclear whether the hepatotoxic effect of xylitol is dose-related or idiosyncratic, and the possibility of hepatic injury at doses less than 0.5 g/kg cannot therefore be excluded.

Toxicokinetics

Xylitol is a normal intermediate product in the glucuronic acid cycle but excessive exposure occurs through ingestion. Subsequent absorption varies between species but is rapid and almost complete in dogs. Slow release from ingested foodstuffs may delay absorption and explain the potentially sustained hypoglycaemia seen in dogs. Metabolism is predominantly hepatic and occurs rapidly. Virtually no urinary excretion occurs.

Mechanism of toxicity

In dogs xylitol acts as a potent and dose-dependent stimulator of pancreatic insulin release (this effect is negligible or only mild in people). It also causes hepatic injury and probable acute hepatic necrosis by a currently unknown mechanism. Hypoglycaemia may occur as a result of the insulin release and may be both severe and sustained. Hypokalaemia may also result from insulin release. Clinically significant coagulopathy is one potential consequence of hepatic injury and consequent dysfunction. Hepatic failure may also contribute to hypoglycaemia and is thought to be responsible for this finding in dogs that do not show earlier evidence of hypoglycaemia attributable to insulin release.

Clinical signs

Clinical signs associated with hypoglycaemia often develop within an hour of exposure but may be delayed. Signs include lethargy, weakness, vomiting, ataxia, altered mentation from depression through to coma, and seizures. Signs associated with liver failure are more delayed in onset (up to 72 hours after exposure) and may occur with or without earlier signs of hypoglycaemia. Coagulopathy may manifest as petechiae/ecchymoses, haemorrhagic faeces, and excessive bleeding from venepuncture sites.

Laboratory tests

Blood glucose should be evaluated as part of the emergency database and may be normal or mildly to severely reduced. Occasionally dogs will present with hyperglycaemia that then progresses to hypoglycaemia. Regular monitoring is recommended even in dogs that are normoglycaemic at presentation. Electrolyte screening may reveal hypokalaemia that is usually mild or perhaps moderate.

If hepatic injury has occurred, a serum biochemistry profile may reveal a marked increase in serum alanine transaminase (ALT) activity, a mild to moderate increase in serum alkaline phosphatase (ALP) activity, and hyperbilirubinaemia. Prolongation of PT and APTT may be detected in coagulopathic animals, and mild to moderate thrombocytopenia is commonly reported. Regular monitoring of these parameters is recommended for 3–4 days following exposure to a toxic dosage, including in dogs that are normoglycaemic at presentation.

Treatment

Routine GID is indicated in appropriate cases. Emesis should not be induced in dogs with marked neurological compromise secondary to hypoglycaemia. Activated charcoal should be administered empirically but may have limited benefit due to low binding of xylitol (demonstrated in an in vitro study).

Hypoglycaemia is treated using standard parenteral and possibly oral glucose supplementation therapy that may need to be both aggressive and prolonged. Regular small meals and possible oral sugar supplementation may be sensible in asymptomatic dogs. Coagulopathy secondary to hepatic dysfunction may necessitate fresh frozen plasma (FFP) administration (see Ch. 40) and vitamin K₁ should be administered. As with any severe coagulopathy, animals should be handled gently, subjected to minimum stress and undergo exercise restriction. Venepuncture should only be performed using peripheral veins and with the smallest needle possible; adequate prolonged pressure should be applied to the site following sampling.

Empirical use of antioxidant hepatoprotectants such as SAMe, N-acetylcysteine and silymarin is reasonable. In cases of severe hepatic failure, treatment for possible hepatic encephalopathy may need to be instituted. Therapy is otherwise supportive and symptomatic.

Prognosis

The prognosis associated with hypoglycaemia alone from xylitol poisoning is good with timely and appropriate management. The prognosis for animals with evidence of hepatic dysfunction is guarded to poor, and grave for acute hepatic failure. Survival from xylitol poisoning may not be correlated with exposure dosage.