A number of clinical studies recently performed at the RVC have been published, but the evidence base for the management of animals with a congenital portosystemic shunt (CPSS), particularly cats, remains weak (M. Tivers & Lipscomb, 2011a, 2011b; M. S. Tivers, Upjohn, House, Brockman, & Lipscomb, 2012). There is no overall consensus as to the optimum therapy, although the probability of survival is lower in dogs that are not treated surgically (Greenhalgh et al., 2014).

There is a sparse evidence base and no consensus upon which to choose which medical therapies are most beneficial, or when and how they should be given, and successful treatment can be challenging. Rather than relying on a single specialist to find the best tailored treatment for each patient at the RVC we work hard to bring in expertise from related disciplines right from the start with the aim of bringing about improved outcomes for the animals. Listen in to the daily discussions that they regularly debate together when faced with these complex CPSS cases:

Key Questions on stabilisation of CPSS patients prior to surgery

1 What is your general approach to the initial medical management of a dog or cat diagnosed with a CPSS, including your opinion on which therapies are most important and how long you treat them prior to surgery?

RJ: For dogs and cats with CPSS of any age, presenting in a stable clinical state, I normally recommend a period of 3-4 weeks of medical therapy comprising dietary management, oral lactulose and antibiotics, with the first two being the most important components. Until a few years ago, my dietary option of choice for dogs was a hepatic support diet. However, particularly for dogs diagnosed with CPSS at a young age, in poor body condition and/or with evidence of hypoproteinaemia, I now use a soy based gastrointestinal diet as true hepatic diets are very protein restricted and current thoughts are that stringent protein restriction is not beneficial. Dietary management in cats can be challenging due to their higher protein requirements, particularly in young growing cats, and their tendency to be fussy with food! Again soy-based gastrointestinal diets that are highly digestible are my first choice although I have also used feline hepatic diets.

OG: Medical therapy for CPSS has not changed significantly in the past 30 years, reflecting, until recently, stagnation of research in this space. The excellent work undertaken by Drs Lipscomb and Tivers has made significant advances in this area, with translational ramifications for the future.

2 How should we relate the possible need for short or long-term antibiotic therapy in these patients with the need to prescribe antibiotics responsibly?

RJ: Most texts describe that antibiotics should be administered as part of routine therapy for patients with CPSS prior to surgery but the evidence base for antibiotic therapy in dogs with CPSS in the pre-surgical period or for long-term management where surgery is not possible is sparse. Much of the human literature evaluating antibiotic usage relates to patients that develop HE as a consequence of cirrhotic liver disease, which is not necessarily an appropriate model to be extrapolated to our CPSS patients. In the age of appropriate antibiotic stewardship I think we certainly need to avoid using broad-spectrum antimicrobial agents because of their convenience, e.g. clavulanate potentiated amoxicillin, and ensure that, when needed, we use narrow spectrum antibiotics. Ampicillin is my antibiotic of choice if I feel antibiotics are required for pre-operative management. However, I would pose the question whether we have evidence to say that all dogs with a CPSS need antibiotics as part of their short or long-term management.

OG: While I might reach for ampicillin as a first-line drug, I am personally equally comfortable administering metronidazole in this context. Given the overwhelming predominance of anaerobic bacteria in both the small and large intestine of dogs and cats, and the known urease activity of many of these anaerobic species, I believe there is sound rationale for using this drug as an alternative. Much work remains to be done in this area: the impact of the intestinal microbiome is undoubtedly the ‘missing link’ and is likely to be intricately involved in the pathogenesis of this potentially devastating disease, as well as many others – for example, immune-mediated diseases involving remote tissues.

DC: I certainly agree with all of the recommendations made by colleagues. However, remembering we are working in the context of no controlled clinical studies, if we are going to use antibiosis, it is worth bearing in mind what we are trying to achieve and what we do know in deciding on the antibiotic of choice. The justification is principally, if not entirely, to reduce the production of ammonia from the gut; not to potentially manage a possible unspecified nor documented inflammatory process somewhere in the body. The potential advantage of ampicillin in this setting is, because of its poor bioavailability when administered with food, we can limit any systemic effect it might have. It also will not be as effective as metronidazole in the breadth of its anaerobic spectrum of action and while it will have added coliform activity (which of course can also be urease producing and thus contribute to the ammonium load) again this will not be as extensive as other potential choices such as amoxicillin-clavulanate.

DJB: As you see above, there is a real lack of clarity in terms of what we are aiming to achieve with the antibiotic therapy. The “ideal” antibiotic, therefore, would be: active against but not devastating towards urease positive gut flora (Gram +ve and –ve), not be absorbed into the systemic circulation, be non-toxic to the patient, and not be a potent creator of, or trigger for, antibiotic resistance. This antibiotic does not exist. Administration of an antibacterial that is absorbed, even in small amounts, exposes the bacterial flora in the entire body to that agent, which especially in the case of beta-lactam ring molecules, can initiate, embed and transfer resistance to many other antibiotics within the normal bacterial flora. My preference, given what we are trying to achieve, would be to only use antibiotics in animals that are severely affected at the outset or are difficult to control.

3 How do you deal with the CPSS patient presenting in a coma from HE?

RJ: Baseline assessment of clinical and neurological status, glucose, electrolyte and acid base derangements is really important. My initial management will be aimed at providing fluid therapy to correct volume and hydration status, correcting hypokalaemia (potassium supplementation of intravenous fluid therapy), hypoglycaemia and metabolic acidosis where present. The latter often improves with fluid therapy alone although if sufficiently severe might require direct management e.g. sodium bicarbonate. If patients are hypoglycaemic then I’ll provide dextrose supplementation. For patients in a coma then oral lactulose is not an option and so I will initiate lactulose retention enemas which can be repeated if necessary. In these patients I will also start antibiotic therapy intravenously. I don’t normally provide any anti-epileptic therapy to these patients unless they show signs of seizure activity. However, these patients do require careful monitoring and nursing care.

OG: I also consider betadine enemas in the dog (not cat) and the use of intravenous mannitol if I believe that increased intracranial pressure may be playing a role in the coma of the patient. The pathogenesis of increased intracranial pressure in this disorder remains unclear, but ammonia is thought to be necessary and sufficient to induce astrocyte swelling, brain oedema and intracranial hypertension. The detoxification of ammonia to glutamine in the astrocytes via glutamine synthetase is thought to perturb the osmotic equilibrium of these cells: glutamine is an osmotically active amino acid, whose accumulation in astrocytes is thought to lead to their swelling. Changes in cerebral blood flow also probably contribute to intracranial hypertension. As knowledge in this area progresses, new therapeutic targets are likely to emerge for our patients. Drugs such as flumazenil, while fashionable for a while, are now thought to be of doubtful clinical efficacy.

4 What is your opinion on the need for prophylactic peri-operative anti-epileptic treatment in all CPSS patients undergoing surgery and which protocol do you recommend?

RJ: I don’t use anti-epileptic drug therapy during the period of medical stabilisation if the dog has not demonstrated any seizure activity. The optimal prophylactic peri-operative anti-epileptic treatment is still controversial. When the publication by Fryer and colleagues regarding pre-operative leviteracetam was first published I started prescribing leviteracetam to be administered for seven days immediately prior to them being re-admitted for surgery. However, the range of days that dogs received levetiracetam in that study was very wide and now, given rapid onset of action of this drug, they receive it just for 24 hours before surgery after admission to the hospital.

HV: There is evidence in the literature that levetiracetam could be the current drug of choice for patients undergoing surgical correction for a portosystemic shunt. Levetiracetam has minimal protein binding, undergoes minimal hepatic metabolisation and is mainly renally excreted. I agree with Rosanne that there is no need to give levetiracetam chronically prior surgery. I would advocate if you consider giving the drug prior to surgery then the first dose should be between 40-60 mg/kg followed by 20mg/kg q 8hrs. This treatment protocol has been successfully used in dogs with status epilepticus and for cluster seizures (Hardy, Patterson, Cloyd, Hardy, & Leppik, 2012). However, we have no evidence showing that dogs treated post-surgery for acute seizures do worse than dogs that have been treated prophylactically. We recently followed-up all dogs which presented in status epilepticus secondary to an intoxication (Jull, Risio, Horton, & Volk, 2011). None of the discharged dogs developed epilepsy (had recurrent epileptic seizures). If a patient presents with reactive seizures due to a portosystemic shunt then levetiracetam (20mg/kg TID) remains my first choice anti-epileptic, because of its pharmacokinetic properties and despite a recent study showing that levetiracetam could be of limited value for first-line treatment of idiopathic epilepsy (Fredsø, Sabers, Toft, Møller, & Berendt, 2016).

Conclusion

Medical stabilisation of animals with a CPSS has certainly been an interesting topic to debate within our transdisciplinary team, and only a fraction of the full conversations could be printed here. The results of our discussions in these patients have been the stimulus for us to set up a number of prospective clinical studies, including evaluating the need for antibiotics as part of medical stabilisation and the need for a prophylactic anti-epileptic as part of the peri-operative protocol.

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