The Case: 5-Fluorouracil Toxicity

Presentation/History

A 10-month-old, intact female Jack Russell terrier was presented about 12 to 13 hours after ingesting approximately one fifth of a tube of 5-fluorouracil cream (Efudex®Topical Solution 5%). She had vomited profusely after ingestion.  When vomiting had resolved, she slept for 8 to 9 hours following the incident. When the dog awoke, she resumed vomiting and was inappetent and uninterested in water throughout the day. A history of a “loud murmur” was noted in her medical record.

Physical Examination

• Weight/Body Condition Score: 18.5 lb (8.4 kg)/5 of 9

• Temperature: 96.4⁰F

• General Appearance: hindlimb weakness, more pronounced in the left pelvic limb than the right

• Cardiovascular Status: 

  • Mucous membranes: pink and moist

  • Capillary refill time: < 2 sec

  • Heart rate: 80 bpm

  • Grade V/VI murmur. No arrhythmia auscultated; femoral pulses strong and synchronous

• Neurologic Status:

  • Appropriate mentation

  • Positive menace and palpebral responses OU

  • Intact pupillary light reflex––direct and consensual OU

  • No ataxia noticed on walk

  • Intact conscious proprioception in all four limbs

• Urogenital Status:

  • Intact female

  • Bilaterally enlarged mammary chain

  • No vaginal discharge

Otherwise unremarkable examination.

Contacted Poison Control and instituted recommendations: baseline complete blood count, serum chemistry/electrolytes with repeat blood analysis in 24 hours. CBC rechecked every 24 to 72 hours for 2 weeks to monitor for myelosuppression. If patient survived, radiographs to determine passage of aluminum portion of the medication tube.

Diagnostics

• Complete blood count:

  • Hemoglobin: 19.5 g/dL (range, 12–18)

  • Mean corpuscular hemoglobin: 31.5 pg (range, 18.5–30)

  • Eosinophils: 0.04 × 10³/μL (range, 0.10–1.49).

  • Platelets: 160 × 10³/mL (range, 175–500)

• Serum Chemistry:

  • Glucose: 250 mg/dL (range, 74–143)

  • Blood urea nitrogen: 36 mg/dL (range, 7–27)

  • Creatinine: 2.1 mg/dL (range, 0.5–1.8)

  • Phosphorus: 7.5 mg/dL (range, 2.5–6.8)

  • Alanine aminotransferase: 111 IU/L (range, 10–100)

  • Sodium: 165 mg/dL (range, 144–160)

  • Packed cell volume/total protein: 63% (range, 35%–45%)/ 8.8 g/dL (range, 6.5–8.0)

• Clotting times:

  • Activated partial thromboplastin time: 120 sec (range, 71–102)

  • Prothrombin time: 21 sec (range, 12–17)

Treatment

Poison Control recommended: symptomatic/supportive care; anti-emetic therapy; fluid diuresis for decontamination; gastroprotectants (sucralfate and omeprazole or famotidine); management of potential seizures with diazepam and barbiturates; bulk diet for decontamination of metal tube ingestion; control of potential pain with butorphanol; thermoregulation. Metronidazole and metoclopromide are contraindicated.

Patient was hospitalized and heat-supported with a Bair Hugger.

• Intravenous fluid: 50 mL/hr; lowered to 30 mL/hr after 2 hours

• Maropitant: 1 mg/kg q24h IV

• Sucralfate: 60 mg/kg q8h PO

• Famotidine: 0.5 mg/kg q24h IV

At 2.5 hours after presentation:

The patient had 3 seizures, which were subsequently controlled with 0.5 mg/kg IV diazepam in a single dose. Oxygen was instituted and heat support continued in response to low oxygen saturation via pulse oximetry (SpO₂) and persistent hypothermia. When seizures continued and worsened, a propofol CRI was started at 5 mg/kg/hr.

At 3 hours:

Seizure activity increased; an additional 0.5 mg/kg IV diazepam was administered.

At 5 hours:

Seizures worsened and increased in frequency. Propofol CRI was increased to 6 mg/kg/hr and an additional 0.5 mg/kg IV diazepam was administered, with no response. An intravenous bolus of both 8 mg/kg phenobarbital and 2.5 mg/kg propofol IV was administered, which provided control of predominant seizure activity. Breakthrough seizures still occurred.

At 7 hours:

Seizures again worsened and increased in frequency. Propofol CRI was increased to 8 mg/kg/hr and 0.5 mg/kg IV diazepam with a 3.5 mg/kg bolus of propofol IV were administered. Predominant seizure activity was controlled but breakthrough tremors persisted.

Clinical Outcome

At 8 hours after presentation (~ 20 hours after ingestion), the patient experienced sudden cardiopulmonary arrest.

The Specialist’s Opinion

Ahna G. Brutlag, DVM, MS, DABT, DABVT

Due to the extreme toxicity of 5-fluorouracil (5-FU), the outcome of this case is, unfortunately, relatively unsurprising—published mortality rates are approximately 60%, with most patients dying within 24 hours of ingestion.¹ That said, the next most likely contributing factor to this dog’s death was the delayed onset of treatment. 5-FU is a potent toxicant and, in spite of additional treatments and diagnostics that may have been helpful, the ultimate outcome closely mirrors the majority of intoxications.

Toxicity

5-fluorouracil is an antineoplastic agent used topically in human medicine for treatment of actinic keratosis and superficial basal cell carcinomas. It is also used parenterally in both human and veterinary medicine. Dogs chewing into tubes of the topical product represent the vast majority of current canine intoxications.

The minimum canine toxic dose is approximately 5 mg/kg (PO or IV). Experimentally, the minimum lethal dose is approximately 20 mg/kg with 40 mg/kg considered uniformly fatal.¹ Notable exceptions include dogs surviving 43, 46, and, shockingly, 330 mg/kg dosages.^1-4 To calculate this dog’s dose and help contextualize the case, it would have been helpful to know the size of the Efudex® tube the dog chewed on.

Signs of Poisoning

The onset of clinical signs is rapid, often 45 to 60 minutes after ingestion. Death occurs in less than 24 hours. The most common initial signs on presentation include vomiting, grand mal seizures, tremors, dyspnea, and cyanosis. Seizures are often refractory to diazepam. Additional acute signs include ataxia, depression, hypersalivation, and diarrhea. Death occurring in the first 24 hours is usually a result of poorly controlled seizures leading to non-cardiogenic pulmonary edema with subsequent cardiopulmonary arrest. If the patient survives the initial phase of intoxication, then cytotoxic effects such as bone marrow suppression and GI toxicity due to the loss of intestinal crypt cells may occur. Given the patient’s history of a heart murmur, this dog may have been at greater risk for complications.

Considerations Regarding Treatment, Monitoring, & Diagnostics

Treatment for 5-FU intoxication is primarily supportive as the antidote currently used in human medicine does not appear to be effective in dogs. The initial approach and treatment in this case were appropriate, including consultation with an animal poison center, the administration of IV fluids, anti-emetics, warming measures, and when warranted, oxygen supplementation. The difficulty controlling the dog’s seizures is typical of 5-FU intoxications and highlights the need for multimodal therapies. Additionally, there is some evidence to suggest that agents that act on the GABA_A  receptor, such as diazepam and phenobarbital, are less effective than other anti-seizure agents in 5-FU toxicity. Propofol or general anesthesia is also an appropriate choice. In a dog exposed to 330 mg/kg of 5-FU, levetiracetam was used successfully after traditional anti-seizure agents had failed to stop breakthrough seizures. This agent could be considered as part of the multi-modal suite of anti-seizure therapies.  

Due to the critical nature of 5-FU intoxications, treatment in an ICU setting is always advised so that the patient may be closely monitored. In this case, ongoing monitoring of the patient’s blood pressure, ECG, and oxygen saturation would have been helpful given the risk for cardiopulmonary complications and the dog’s underlying cardiac condition. As the patient was also at risk for increased intracranial pressure, such monitoring would have allowed for the observation of the Cushing reflex—a triad of signs including an increase in blood pressure, drop in heart rate, and irregular breathing or apnea—consistent with increased intracranial pressure/decreased cranial perfusion. If this were to occur, mannitol or other agents to decrease intracranial pressure should be immediately administered. Additional desired diagnostics include blood gas analysis, especially as lactic acidosis is common in these poisonings, and thoracic radiographs which may have helped detect the reason for the patient’s poor oxygenation (e.g., pulmonary edema or aspiration). Finally, if available, mechanical ventilation should have been considered.

Conclusion

Topical preparations of 5-FU are highly toxic and the risk to pets is not on the “radar” of most prescribing physicians or dispensing pharmacists. Likewise, many veterinary professionals or frontline hospital staff may not be aware of the risk posed by this agent, especially as most topical products are relatively low-risk. In this case, as with many potential poisoning cases, consultation with an animal poison control center is highly recommended. Such expert advice can be provided immediately and tailored to the individual patient. If unexpected or concerning clinical signs arise following the original consultation, the clinician is encouraged to call back so that additional therapies or diagnostics can be discussed.

Ahna Brutlag, DVM, MS, DABT, DABVT, is Associate Director of Veterinary Services at Pet Poison Helpline and holds an adjunct assistant professor appointment at the University of Minnesota’s (UMN) College of Veterinary Medicine.  She graduated from UMN and practiced small animal medicine in the Minneapolis area before pursuing post-doctoral training in veterinary toxicology. She completed a Master’s of Science in toxicology at UMN and a professional externship at the California Animal Health and Food Safety Laboratory at the University of California—Davis, School of Veterinary Medicine.  Her primary interest is in small animal clinical toxicology and she is a diplomate of both the American Board of Toxicology and the American Board of Veterinary Toxicology.

The Generalist’s Opinion

Barak Benaryeh, DVM, DABVP

This is a truly sad case. It’s hard to find fault with anything that was done clinically. Ingestion of toxic substances is something that every veterinary practitioner deals with on a regular basis. We can look at the learning points of the case as both a discussion of this particular toxin as well as toxicity in general.

5-fluorouracil

5-fluorouracil (5-FU) is a general antineoplastic agent and is used topically in people to treat certain skin disorders. It is unfortunately highly toxic to dogs starting at approximately 5 mg/kg.¹ The prognosis is very poor and any dose over 40 mg/kg is considered fatal, regardless of treatment.^1,2 We are not told if a calculation was done to estimate the dose consumed. From some minimal research, it is evident that Efudex® cream generally comes in a 40-gm tube.  The report is that this dog ate approximately a fifth of the tube (8 gm). Based on a 5% solution, the dog ingested 400 mg of drug, translating to 47.6 mg/kg, which would be well above a fatal dose.

It’s likely that given the time from ingestion to treatment in this case, no intervention would have saved this dog. The medical steps that were taken were appropriate. What we do not know is how the owners were prepared for what was likely an inevitable outcome. The hope is that this was communicated in a gentle and truthful manner.

We can always hope for the miracle case, and from time to time in a career one may happen. We generally do not win the medical lottery, however, so it’s important that we communicate realistic expectations to clients. Our job is not to shatter hope, but we do our clients a disservice if we don’t prepare them. Discussions of outcome are extraordinarily important and can make a vast difference in how people perceive a traumatic experience. Be sure always to evaluate how you and your staff speak to clients in distress and how discussions such as these are managed.

General Guidelines for Toxicity Cases

Often clients expect that we know the answer to every toxicity question. If you do not have the number for an animal poison control hotline or helpline prominently displayed and posted on your hospital website, you should. If you are busy, a veterinary technician can make the all-important call to the hotline for treatment information. The staff should be trained to explain to clients that this phone call is a consult with a veterinary toxicologist, and the veterinary invoice  should reflect that the charge is for expert consultation.

Always err on the side of over-treating when it comes to ingestion of toxic substances. Precise calculations are sometimes impossible. Very frequently, if we wait to monitor for effects of a toxin, it can be too late as the damage has already been done. If someone declines treatment, you are at least protected should things turn out badly. Be sure the staff is appropriately trained to field phone calls about incidents of inadvertent possibly toxic ingestions and treat them as emergencies. Incorrect telephone advice can have serious consequences.

Barak Benaryeh, DVM, DABVP, is the owner of Spicewood Springs Animal Hospital. He graduated from University of California–Davis School of Veterinary Medicine in 1997 and completed an internship in Small Animal Medicine, Surgery, and Emergency at University of Pennsylvania. Dr. Benaryeh has also taught practical coursework to first-year veterinary students and was a primary veterinary surgeon for the Helping Hands Program, which trains assistance monkeys for quadriplegic people. Dr. Benaryeh is certified by the American Board of Veterinary Practitioners in Canine and Feline Practice.