Evidence-based medicine in exotic-animal practice (Proceedings)

Treatments based on evidence that they will actually have a significant chance to improve the patients' condition without causing excessive detrimental effects are the gold standard in human medicine. In veterinary medicine we tend to look towards these standards to improve our practice and ultimately to provide the best possible care for our patients. While this approach is laudable, very often shortcuts are taken in veterinary medicine due to financial limitations, insufficient access to diagnostic modalities, or a lack of clear treatment standards. These considerations are, however, not sufficient justification to provide substandard care or to not think critically about every case as it is presented.

The identification of a specific clinical problem often occurs on multiple cognitive levels. Once confronted with a case, the clinician makes an initial, intuitive assessment. This is often described as a "gut feeling," and is often based on unsystematically recorded past experiences and individual biases. Intuitive decision-making is difficult for the novice clinician, but can become very effective with experience. The process involves rapid exploration of the problem and an initial quick fix. While this method follows similar patterns to an explicit decision analysis in which a more extensive & systematic assessment of the problem is applied, the algorithms are employed in minutes rather than many hours to weeks. Both approaches have their place and validity in veterinary medicine. In the everyday clinical situation, an initial review and assessment of a case very often must proceed rapidly in order to assist a patient before the problems worsen. However, in order to proceed appropriately in a rapid fashion, a solid basis for decision-making anchored in a thorough understanding of the published literature is necessary. Keeping up with new publications requires periodic literature searching and appraisal, which can be recorded as a Critically Appraised Topic that is kept on hand for quick reference.

Problem-oriented veterinary medicine involves a series of defined steps. Initially objective case information needs to be collected, e.g., vital signs and results of initial bloodwork, which is then paired with subjective data including history, signalment, and a descriptive physical exam. A list of problems is identified from this information, and differential diagnoses are proposed for each problem using the "DAMNIT" mnemonic device as a guide. These differential diagnoses are ranked according to probability and then plans are made for refining the diagnosis, providing initial treatment, and educating the clients. After an initial diagnosis is formed, new questions can be identified, and the case management proceeds during follow-up evaluations through the process of again collecting information and evaluating the effectiveness of previous plans, revising the problem list by working toward more refined diagnoses, and revising the plans accordingly. The quality of a diagnosis is based on how we select and interpret diagnostic tests, clinical signs, and the history. Basing our case management on evidence provided by diagnostic testing and response to treatment can be the first step in overcoming the lack of normal data for many different species, which is a commonly encountered hurdle in exotic pet medicine. This article describes how practical problem-solving methodology was applied to manage a case of chronic weight loss in a guinea pig.

Initial problem-solving process

The example case is a 4-year old, female guinea pig that was presented for chronic weight loss. The initial physical exam did not reveal any other significant clinical abnormalities, the bodyweight was 870 gr. (previous bodyweight was 1000 gr.), a blood sample was analyzed as part of the minimum database. The initial diagnostic plan for this guinea pig consisted of an abdominal ultrasound. The selection of this test was based on 1) knowledge of the literature documenting that a large proportion of intact female guinea pigs develop ovarian cysts1 and 2) the author's previous experience with other cases of ovarian cysts where a variety of clinical signs including weight loss were seen. At this initial step of the decision making process, a very common disease syndrome of an old intact female guinea pig and the clinician's experience were used to immediately narrow and rank the differential diagnoses without explicitly listing them. This process was directed toward efficiently ruling in the most likely diagnosis.

The ultrasound exam revealed bilateral ovarian cysts and a thickened uterine body and unremarkable liver architecture. The plasma biochemistry, however, revealed elevated GGT activity of 28 IU/L (normal < 12 IU/L2). Based on these diagnostic findings, ovariohysterectomy and liver biopsy were performed. The surgery was uneventful and the histopathological examination of the liver biopsy revealed "severe, multifocal, chronic bridging portal fibrosis and bile duct hyperplasia with periportal hepatocellular fatty change, hepatocyte loss and acute hemorrhage." The pathologist went on to comment, "There is no evidence of granulocytic or plasmacytic inflammation or lymphoid follicle formation to suggest a bacterial etiology such as cholangitis. A toxic etiology should be considered."

Initial follow-up

Three weeks after surgery the animal had gained 135 g (bodyweight 995 gr) and the owners reported it to be 100% back to its normal attitude; so further diagnostic testing and treatment plans were not pursued. A very good prognosis for long-term resolution of the problem was based on the experience of the clinician.

Secondary follow-up

Secondary Information Gathering

Eighteen months later the client presented the same guinea pig again with weight loss over the course of many weeks. In addition, this time the client also reported "hyperactive behavior" and intermittent soft stool. The animal now weighed 710 g and the owner reported weight loss of 265 g over the last 4 months in spite of a ravenous appetite. The owner had been syringe feeding a liquid nutritional support mixture (Herbivore Critical Care, Oxbow Hay, Omaha, NB) and reported that the animal would eat up to 200 ml of the slurry within a 24-hour period, eating roughly every 4 hours by syringe feeding while also nibbling on hay and other food items in between. A repeat ultrasound exam and a recheck of the liver enzymes were performed as initial diagnostic testing in light of the patient's history. Results of both were unremarkable and within published reference ranges2. Fecal and dental exams did not reveal any abnormal findings.

Secondary Assessment

At this point in the case a diagnostic algorithm was created in order to assess potential causes for the chronic weight loss in the face of a ravenous appetite and hyperactive behavior in an otherwise apparently normal animal (Fig. 1). The search included printed publication such as the Veterinary Clinics of North America (Exotic Practice), The Journal of Exotic Pet Medicine, Laboratory Animal Medicine (2nd ed.) and Ferrets, Rabbits and Rodents: Clinical Medicine and Surgery. None of the above mentioned publications did offer an explanation for the observed case. In addition, online database and discussion forums were searched for any published data on the clinical observation of having an animal with a good appetite, which is still losing weight. It was noticed that many clinicians expressed concerns on the VIN discussion forum about having a Guinea pig as a patient, which displays typical signs of hyperthyroidism with some of the animals appeared to have relative high thyroid hormone levels. A German publication was also included in the literature search and revealed that hyperthyroidism is a relatively common clinical presentation in Germany according to the publication.

Secondary Diagnostic Plan

Due to the phenomenon that hyperthyroidism has been noted multiple times in Guinea pig in Germany, thyroid levels were tested after using this algorithm to rule out other potential causes for the primary problem. In order to work through the work up of hyperthyroidism correctly another algorithm was established in order to make sure all tests and treatment are offered and done in a logical sequence

Even though, no confirmed case of hyperthyroidism could be found in the searchable English language literature, the clinical history and the clinical signs strongly suggested inclusion of this disease in the differential diagnosis. However, blood test results were inconclusive as only the free T4 value was elevated. In exotic species it might be very difficult to obtain enough blood or blood at all to run a multitude of tests. Even if the resource blood is readily available, interpreting T4 values in species for which the specific assay has not been validated poses significant problems to the clinician regarding the validity of the results and the conclusion drawn from the results. Interpretation of the values can be even considered to be difficult in species for which the test has been validated. It is interesting to note that this inconclusive test is nothing odd as it has been well known that in cats with early or mild forms of hyperthyroidism the levels might fall well within described normal references values. In addition the presence of a concurrent secondary problem might lower the T4 value back into the reference value in a true hyperthyroid patient4. Due to these common problems it has been suggested to perform a 'free' T4 test as this essay is considered more sensitive for the diagnosis of early stages of hyperthyroidism.

Because thyroid testing was inconclusive, a nuclear scintigraphy scan was scheduled in order to visualize the functioning of the thyroid gland and to assess for any asymmetry. The scintigraphy was chosen as it is a test of the thyroid function and due to the low expense to the owner (about $200). The animal was anesthetized with sevoflurane (Sevoflo, Abbott Laboratories. Abbott Park, Illinois, U.S.A.)) and a dose of 1.2 mCi of Technetium (pertechnetate) (Tc-99m) was given as an intravenous bolus via the cephalic vein. The animals were recovered immediately after the nucleotide was given as an i.v. bolus and flushed with 2 ml of heparinized saline. The animals were placed on a gamma camera (IS2 Research Corp. Ottowa, Canada) using a HRGP (High Resolution General Purpose) collimator for the initial reading about 15 minutes post injection. The interpretation of the initial scan revealed the expected uptake of the imaging agent in the salivary gland and the thyroid. All images were acquired for 100,000 counts. The images were analyzed using specific Software (Segami Corp. Columbia, MD). The initial images obtained between 15-25 minutes post injection did show a mild difference in the pattern of the nucleotide uptake of the thyroids between a healthy and the diseased animal. In order to get a better image of the thyroid as to avoid the superimposition of the salivary gland with the thyroid, a second series of images were obtained 60-80 minutes post injection and clearly showed a significant difference of the uptake of radioactive material by the two thyroids of the diseased animal indicating a unilaterally affect thyroid gland.

Results show a significantly abnormal distribution within the thyroid gland indicating a pathological process. The animal was anesthetized for the scanning procedure as movement of the animal would render the image useless for analysis

The animal was hospitalized for 24 hours in order to avoid any environmental contamination with the radioactive material, which the animal secretes in bodily waste products. As soon as the animal was measured to emit less than 2.0 mR/hr of radioactivity at the skin surface it was cleared to be released.

The results of this imaging study, in combination with the history and clinical signs, supported a working diagnosis of hyperthyroidism despite the fact that this condition had not been previously reported in the English-speaking literature. A further search showed that it had however been described in the European literature where it is reported to be a very common problem in Guinea pigs in Germany.

Secondary Client Education Plan

As a case progresses and more evidence is gathered to support either a working or a definitive diagnosis, the owner needs to be educated regarding the prognosis. This is often complicated by a lack of information in the literature regarding treatment outcomes for various diseases in exotic species. The absence of good data is important to communicate to the owner in order to avoid misunderstandings or disappointments. The key here is to describe the possible outcomes with or without various treatments. Often we look towards results of studies performed on domestic small animal species if these exist in the literature, however in the author's experience this is often of limited value for most problems in exotics. An educated guess might be possible after data from other species has been reviewed, but often the long-term outcome varies substantially, especially in the field of oncology. The prognosis for many of the metabolic diseases is often based on personal experience or on anecdotal evidence, however in our guinea pig case with a working diagnosis of hyperthyroidism, it was useful to look to the feline literature for information regarding the long term prognosis for treatment with either medication or surgery because of the high prevalence of this disease in the feline species.

Secondary Treatment Plan

While designing a specific treatment plan, one of the key goals is the selection of a treatment plan that does more good than harm. This is especially important in the patient presented with cancer, where quality of life issues need to be balanced with treatment objectives. For the guinea pig with the working diagnosis of hyperthyroidism, the owner was offered several treatments options. The advantages and disadvantages of each treatment were discussed in order to allow them to make an educated decision. In the authors opinion it is important to discuss all available treatment options and let the owner decide what course of action they would prefer considering the costs, and the risks and benefits associated with the treatment, including the associated side effects, and the long term prognosis. The treatment options for this case included: 1) medical management with methimazole given orally on a daily basis; 2) surgical removal of the hyperactive thyroid gland; 3) treatment with radioactive iodine.

The owner initially elected to start with medical management and to monitor the animal's response to treatment. The animal was started on oral methimazole (Tapazole® Lilly, Indianapolis, USA) at 1 mg/animal PO BID.

Tertiary follow-up

The animal responded very well initially and gained approximately 60 g (8% of initial bodyweight) in the first week after medication was started. After 1 month the animal was presented once again and had gained approximately 180 g (25% of initial bodyweight). The animal still displayed an increased interest in food and the owner continued to syringe feed the liquid nutritional support mixture on a daily basis.

In this case the owner was initially reluctant to have the animal undergo a surgical procedure although it might have been curative, and elected to continue with non-invasive, medical management. Once the owner saw a significant improvement in the animal in response to the oral medication and was convinced that the condition was truly caused by thyroid pathology, consent was given for radioactive iodine treatment. In order for this treatment to be successful, the oral medication needed to be stopped for at least 5 days prior to the administration of the radioactive component, so 30 days after the oral medication had been started, it was discontinued for 4 days. Unfortunately, the animal died on the 4th day and was not presented for a necropsy.

Conclusions

In summary, while it can be challenging in exotic small mammal medicine to practice good, sound, evidence based medicine (EBM), a few easy steps when working up a case can result in a satisfying solution for the clinician, the owner, and the patient. This outcome is most readily achieved through integration of the best research evidence, the perceived value of the pet, and the expertise of the clinician. The lack of peer reviewed literature and the inability to perform certain diagnostic tests or treatment modalities should not be a cause for resignation but only act as motivators to increase the quality of medicine and therefore help the community. Following the basic tenants of problem-oriented medicine and keeping all three aspects of evidence-based medicine in mind is a rewarding way to apply good medicine to the daily workload with exotic mammals.

References

Keller LS, Griffith JW, Lang CM. Reproductive failure associated with cystic rete ovarii in guinea pigs.Vet Pathol. 1987 Jul;24(4):335-9.

Ewringmann A., Glöckner B. 2005 Leitsymptome bei Meerschweinchen, Chinchilla und Degu. Diagnostischer Leitfaden und Therapie. Enke publishing, Stuttgart/Germay; 1st edition (October 2005)

Castro, M. I., S. Alex, et al. (1986). "Total and free serum thyroid hormone concentrations in fetal and adult pregnant and nonpregnant guinea pigs." Endocrinology 118(2): 533-7.

Peterson, M. E. and D. A. Gamble (1990). "Effect of nonthyroidal illness on serum thyroxine concentrations in cats: 494 cases (1988)." J Am Vet Med Assoc 197(9): 1203-8.

Peterson, M. E., C. Melian, et al. (2001). "Measurement of serum concentrations of free thyroxine, total thyroxine, and total triiodothyronine in cats with hyperthyroidism and cats with nonthyroidal disease." J Am Vet Med Assoc 218(4): 529-36.

This text has been reprinted with permission from Elsevier. The original text was published as: Mayer J. Evidence-based Medicine in Small Mammals. Journal of Exotic Pet Medicine. Volume 18 issue 3 Pages 213-219 1 July 2009