The Case: Suspected Bordetella Vaccine-Induced Acute Hepatic Disease

Presentation

An 8-week-old, 4.5 kilogram, male collie was presented for vomiting and lethargy 11 hours after vaccinations—DA₂PP (distemper, adenovirus type2, parainfluenza, parvovirus) and Bordetella bronchiseptica. The medical record suggests intranasal Bordetella vaccine may have been given subcutaneously.

Physical Examination

• General: Laterally recumbent, dull

• Hydration: estimated 6% dehydrated

• Cardiopulmonary: No murmurs, arrhythmias, or abnormal lung sounds

• Hemodynamic: mucous membranes pale/tacky, prolonged capillary refill time

• Musculoskeletal: Non-ambulatory

Diagnostic Procedures

• Systolic blood pressure (Doppler): 74 mmHg (range, 110-150 mmHg)

• Glucose: 34 mg/dL (range, 77-150)

• Sodium: 137.3 mEq/L (range, 145-157)

• Globulin: 2.0 g/dL (range, 2.3-3.8)

• Total bilirubin: 1.4 mg/dL (range, 0.0-0.8)

• Alanine transferase: 6302 IU/L (range, 8-75)

• Alkaline phosphatase: 1169 IU/L (range, 46-337)

• Prothrombin time (PT)/Partial thromboplastin time (PTT): 52 sec (range, 5.4-8.8)/150 sec (range, 9.1-15.6) 

• Abdominal ultrasound: diffusely hyperechoic liver

Therapeutic Procedures

Acute liver disease from possible inappropriate administration of Bordetella vaccine was suspected.

The patient was admitted for intensive supportive care:

Fluids: 

• Plasmalyte*: 5.0 mL/kg/hr

  • Hydroxyethyl starch 6%: 7.0 mL/kg bolus x 2 doses within the first 4 hours

  • Fresh frozen plasma: 20 mL/kg over 12 hours daily for 3 days

• Dolasetron: 0.6 mg/kg SC q24h

• Ampicillin/sulbactam: 30 mg/kg IV q8h

• Vitamin K₁ (phytonadione): 2 mg/kg SC distributed in multiple sites q24h

• Famotidine: 0.5 mg/kg IV q12h

• Pantoprazole: 0.8 mg/kg IV q24h

• Maropitant: 1.0 mg/kg SC q24h

• S-adenosylmethionine (SAMe)/silybin: 90 mg tablets, 1 tablet PO q24h

• N-acetylcysteine: 140 mg/kg IV once; then 70 mg/kg IV q6h X 9 treatments

After 6 days of treatment the patient was doing well and was discharged. The following medications were dispensed:

• Vitamin K₁ (phytonadione): 25 mg tablets, ¼ to ½ tablet (~2 mg/kg) PO q24h with fatty food

• Omeprazole: 10 mg tablets, ½ tablet (~1 mg/kg) PO q24h

• S-adenosylmethionine (SAMe)/silybin: 90 mg tablets, 1 tablet PO q24h

• Amoxicillin/clavulanic acid: 62.5 mg tablets, 1 tablet (13.75 mg/kg) PO q12h

Follow-up

The patient’s liver values were monitored after discharge and decreased gradually. Blood work performed 5 days after discharge: 

• Alkaline phosphatase: 307 IU/L (range, 46-337)

• Alanine transferase: 31 IU/L (range, 8-75)

• Aspartate aminotransferase: 36 IU/L (range, 0-50)

• Albumin: 3.0 g/dL (range, 2.1-3.6)

• Blood urea nitrogen: 19 mg/dL (range, 7-29)

• Gamma-glutamyl transferase: 3 IU/L (range, 0-2)

• Total bilirubin: 0.1 mg/dL (range, 0.0-0.8)

• Bile acids testing: preprandial–2 μmol/L (range, <25 μmol/L), postprandial–10 μmol/L (range, <25 μmol/L)

Outcome

The puppy was clinically normal upon and after discharge. Any long-term effects on the liver are unknown at this time.

The Specialist’s Opinion

Gretchen Statz, DVM, DACVECC

Medical errors are a common problem in both human and veterinary medicine and can lead to increased morbidity and mortality. Anyone can make a mistake but inexperienced staff or people who are rushed or tired are particularly prone to error. Many veterinary technicians are trained on the job and most veterinary practices are fast-paced, busy places that can create high stress and fatigue. This case is an example of a medical error causing severe consequences to the patient. No predisposing cause to account for the error was mentioned.

Intranasal Bordetella Vaccine

The intranasal (IN) Bordetella vaccine is made up of live bacteria that are not intended to be given subcutaneously (SC). The main complications when an IN Bordetella vaccine is given SC are local inflammation, infection, abscessation, and skin sloughing. Antibiotics should be given to help prevent infection at the injection site. Another less common but more severe complication of inappropriate SC administration is hepatic necrosis. One such case is reported in the literature.¹

Hepatic Necrosis

Hepatic necrosis can progress rapidly after a damaging insult (toxic or hypoxic) to the liver. As hepatic cells are damaged, the hepatic enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), abruptly rise and an inflammatory cascade begins. If enough of the liver is damaged, hepatic failure can then occur. The puppy in this case presented within 12 hours of the administration. Blood analysis changes were suggestive of severe cellular damage (ALT 6302 IU/L) and hepatic failure (increased clotting times, hypoglycemia, elevated total bilirubin). The dog in the previously published case report was first treated for fever, pain, and swelling over the injection site. Clinical signs started within 4 hours of administration; however, it is unclear whether the acute signs were due to the hepatic complications or the injection site complications. Blood work was not performed until day 4 after administration, at which time the hepatic changes were discovered.¹

Treatment for Acute Hepatic Necrosis

The treatment in this case was appropriate. Much of it was directed at general supportive care and correcting complications such as coagulopathies. As the puppy was hypotensive and dehydrated (estimated at 6%) on presentation, he was treated with an initial bolus of a colloid, presumably for the hypotension, followed by a crystalloid to treat dehydration and for maintenance. Plasma and vitamin K₁ were given to help correct the coagulopathy associated with hepatic failure. Other treatments were directed at hepatic cellular repair: S-adenosylmethionine (SAMe) and N-acetylcysteine provide hepatic support.

The prognosis with acute hepatic necrosis is variable. It is difficult to predict which patients will recover and whether they will have long-term hepatic damage. The liver has a remarkable ability to heal and regenerate; however, if severe damage occurs, hepatic fibrosis and cirrhosis can occur over time. Hepatic biopsy can help to confirm hepatic necrosis and determine the extent of the damage. The bile acids and blood work in this case were normal on day 11 and the puppy may avoid any long-term hepatic dysfunction from this insult. The dog in the previous case report still had hepatic dysfunction (based on elevated bile acids) with small hepatic size two months after the initial insult, which could indicate end-stage, chronic disease.¹

Preventing Mistakes

Because Bordetella comes in both intranasal and subcutaneous forms, it is understandable that there could be confusion surrounding route of administration. Some of the intranasal vaccines need to be drawn into a syringe prior to administration while others employ a plastic vial without a needle. To avoid this complication in the future, it may be prudent to use vaccines with a plastic vial instead of a needle and syringe. All staff handling vaccines should be trained on the vaccine protocols of the clinic and proper vaccine administration. Whenever handling any medication, especially for the first time, staff should double-check the concentration, dose, and route prior to administration.

Reporting Adverse Events

A severe adverse event such as this case should be reported to the vaccine company so they can use the information if this same mistake happens in the future and to gather any new or useful information they may have to help treat an adverse event. Adverse events should also be reported to the United States Department of Agriculture - Animal Health and Plant Inspection Service by going to their Veterinary Biologics website and clicking on adverse event reporting.

Client Communication & Medical Errors

It is important to discuss medical errors quickly and openly with clients when they occur despite how difficult it may be. Notifying them of what measures will be taken to correct the error for their pet is essential. Additional steps that can be taken to ensure that the situation is resolved with a minimum of negative impact on the operation of the clinic include:

• Practicing active listening

• Not becoming defensive

• Allowing time for client questions

• Informing the client that steps will be taken to prevent future medical errors from occurring

Conclusion 

This case was handled appropriately and luckily the dog survived and will likely do well. It is an excellent example of a complication secondary to a medical error.

The Generalist’s Opinion

Barak Benaryeh, DVM, DABVP

It is difficult to find precise data as to just how often intranasal Bordetella vaccine is erroneously administered subcutaneously, as likely many cases go unreported. However, the number of such reports to manufacturers and to online veterinary websites indicates this mistake is common. Many intranasal Bordetella vaccines need to be drawn from a vial using a syringe with needle attached. If someone does not replace the needle with the applicator tip, the preparation could easily be confused with an injectable. This error will undoubtedly continue to occur if veterinary professionals are not proactive in averting it.

Prevention is the Best Medicine

Educating the staff is vital; and everyone should understand the seriousness of this mistake. There are brands of intranasal Bordetella vaccine available with a needle-free system, eliminating confusion with an injectable formulation. Alternatively, one can choose to carry only one type of vaccine, either oral, injectable, or intranasal, to reduce the chance for confusion. There is significant debate and several studies^1,2,3 that examine which delivery route is most efficacious and/or easiest to administer.

Immediate & Continued Care

Two main concerns connected with accidental injection of intranasal Bordetella vaccine are developing either a local reaction/infection and/or a systemic reaction such as outlined in this case. The local reaction is caused by the introduction of live bacteria into the subcutaneous space, which carries a significant risk of a local inflammatory response or an abscess. The antibiotics of choice for such a reaction are doxycycline or azithromycin, as these are considered most effective against Bordetella. In this case the clinicians initially used ampicillin-sulbactam followed by amoxicillin/clavulanic acid. These antibiotics have coverage against Bordetella and were clearly effective despite not being the drugs of choice.

The systemic reaction of concern is hepatocellular necrosis⁴; erythema multiforme has also been reported.⁵ The recommended treatment in cases of liver damage is supportive care and liver protectants. The doctors in this case did an excellent job of treating and monitoring the acute liver inflammation. They followed up with diagnostic testing to ensure there was no continued liver damage. The only point that was not pursued was the elevation in clotting times. The dog was given vitamin K₁ but ideally a follow-up prothrombin (PT) and partial thromboplastin (PTT) would have been appropriate as a decision point regarding continued treatment with vitamin K₁. While the dog apparently made a complete recovery, it should have its hepatic values checked regularly in the future.

In Case of a Mistake

No one is immune to making mistakes. The best we can do is practice carefully and put systems in place within our respective practices to minimize errors. Should we recognize a mistake, it is important to be proactive. Report any adverse events to the manufacturer (even if due to error), which allows the company to recognize and correct weaknesses in their products. In addition, manufacturers have veterinarians on staff to advise you how to proceed medically. It is also a good idea to call your malpractice insurance provider to secure advice as to the extent of your legal exposure. As clinicians, admitting and owning our mistakes to clients is difficult, and sometimes costly. Honesty keeps us human and maintains the integrity of our great profession.