September 2007

Gastroenterology

Todd R. Tams, DVM, Dipl. AVCIM
VCA West Los Angeles Animal Hospital




Diagnosis and Management of Acute and Chronic
Vomiting in Dogs and Cats

Vomiting is among the most common reasons that dogs and cats are presented for evaluation. Because there are a multitude of causes of vomiting, ranging from simple to complex, this can be a challenging problem for clinicians to accurately diagnose and manage. The problem also causes significant concern for pet owners, especially when there is an onset of frequent severe vomiting or when the occurrence becomes more chronic and intermittent without adequate control. However, by following a systematic approach beginning with an accurate history, a thorough physical exam, and appropriate baseline testing (Stage 1), then performing tests more specific for certain conditions or organ systems (e.g., bile acids assay, leptospirosis serology, ACTH stimulation, ultrasonography) (Stage 2), and finally where indicated performing advanced procedures for more thorough examination and biopsy or definitive therapy (endoscopy, exploratory laparotomy), most cases can be diagnosed successfully and managed judiciously. Vomiting does not constitute a diagnosis in itself. It is emphasized that vomiting is simply a clinical sign of any of a number of disorders that can involve any organ system in the body. In fact, one diagnostic registry service listed over 400 potential causes of vomiting in dogs! These notes summarize diagnostic approach and various treatment options for managing dogs and cats with vomiting.

Vomiting refers to a forceful ejection of gastric and occasionally proximal small intestinal contents through the mouth. The vomiting act involves three stages: nausea, retching, and vomiting. Serious consequences of vomiting include volume and electrolyte depletion, acid-base imbalance, and aspiration pneumonia.

It is essential that the clinician make a clear differentiation between regurgitation and vomiting at the outset. Regurgitation is defined as passive, retrograde movement of ingested material, usually before it has reached the stomach. Failure to recognize the difference between regurgitation and vomiting often leads to misdiagnosis. Regurgitation may occur immediately after uptake of food or fluids or may be delayed for several hours or more.

Clinical Features Of Vomiting


Because of the wide variety of disorders and stimuli that can cause it, vomiting may present the clinician with a major diagnostic challenge. A complete historical review with emphasis on all body systems is essential for determining a realistic and effective initial work-up plan and treatment protocol. All too often concentration on only the gastrointestinal tract leads to an incorrect diagnosis and inappropriate treatment. Consideration of the following features is useful in assessing and diagnosing a patient with vomiting:
  1. duration of signs
  2. signalment and past pertinent history
  3. environment and diet
  4. systems review (e.g., history of PU/PD, coughing and sneezing, dysuria or dyschezia, etc.)
  5. time relation to eating (vomiting of undigested or partially digested food more than 8-10 hours after eating often indicates a gastric motility disorder [more common] or gastric outlet obstruction [less common])
  6. content of the vomitus (food, clear fluid, bile, blood, material with fecal odor), and
  7. type and frequency of vomiting (projectile?, chronic intermittent?, cyclic?, morning vomiting only?).
Most Common Causes of Acute or Chronic Vomiting in Dogs

First need to Rule-Out:
  • Dietary problem
    • Indiscretion (e.g., table scraps, garbage ingestion; foreign body)
    • Food adverse reaction (dietary sensitivity)
    • True food allergy
    • Parasites
    • Intestinal (including Giardia)
    • Gastric (Physaloptera)
  • Drug related problems
    • NSAIDS must always be considered
    • Other drugs (e.g., cardiac glycosides, antibiotics, chemotherapeutic agents)
  • Metabolic disorders
    • Renal disease
    • Liver disease
    • Electrolyte abnormalities
Rule-Outs for Chronic Vomiting, Once the Causes Listed Above are Ruled Out (Main Categories):
  • Motility Disorders
    • Gastric hypomotility
  • Inflammatory Disorders
    • Chronic gastritis (with or without Helicobacter)
    • Inflammatory bowel disease
  • Obstructive Disorders
    • Foreign body
    • Hypertrophic gastropathy (uncommon)
  • Neoplasia
Most Common Causes of Chronic Vomiting in Cats
  • Dietary problem
    • Food adverse reaction (dietary sensitivity)
  • IBD
  • Hyperthyroidism
  • Liver disease
  • Renal disease
  • GI lymphoma (intestinal is more common)
  • Chronic pancreatitis
  • Heartworm disease
Intermittent Chronic Vomiting

Chronic intermittent vomiting is a common presenting complaint in veterinary medicine. Often there is no specific time relation to eating, the content of the vomitus varies, and the occurrence of vomiting may be very cyclic in nature. Depending on the disorder, other signs such as diarrhea, lethargy, inappetence, and salivation (nausea) may occur as well. When presented with this pattern of clinical signs, the clinician should strongly consider chronic gastritis, inflammatory bowel disease, irritable bowel syndrome, and gastric motility disorders as leading differential diagnoses. A detailed work-up including gastric and intestinal biopsies is often required for definitive diagnosis in these cases. It is important to note that chronic intermittent vomiting is a common clinical sign of inflammatory bowel disease in both dogs and cats.

Vomiting from systemic or metabolic causes may be an acute or chronic sign and generally there is no direct correlation with eating and no predictable vomitus content.

Diagnostic Plan


If reasonable concern is established based on the history (e.g., patient is inappetent, ingested a toxin, is vomiting frequently) or physical assessment (e.g., patient is listless, dehydrated, in pain), then a minimum data base of CBC, complete biochemical profile (or specific tests for evaluation of liver, kidney, pancreas, electrolytes), complete urinalysis (pre-treatment urine specific gravity extremely important for diagnosis of renal failure), and fecal examination is essential. T4 and both a heartworm antibody test and heartworm antigen test are considered routine baseline tests for vomiting cats (approximately 40% of vomiting cats will have vomiting as a clinical manifestation of the disease). Survey abdominal radiographs are indicated if thorough abdominal palpation is not possible or suggests an abnormality (e.g. foreign body, pancreatitis, pyometra). Unfortunately these tests are often not done early enough. Even if baseline results are unremarkable they are more than justified because they help to rule out serious problems at the outset (e.g., vomiting due to renal failure, diabetes mellitus, liver disease). Alternatively, any abnormalities provide direction for initial treatment and further diagnostics.

The decision for performing more in-depth diagnostic tests is based on ongoing clinical signs, response to therapy, and initial test results. These tests include ACTH stimulation to confirm hypoadrenocorticism in a patient with an abnormal Na:K ratio or to investigate for this disorder if electrolytes are normal, complete barium series or BIPS study (for gastric or intestinal foreign body, gastric hypomotility, gastric outflow obstruction, partial or complete intestinal obstruction), cPLI* or fPLI*(canine and feline lipase immunoreactivity, respectively, for diagnosis of pancreatitis in dogs and cats), and serum bile acids assay (to assess for significant hepatic disease). Barium swallow with fluoroscopy is often necessary for diagnosis of hiatal hernia disorders and gastroesophageal reflux disease. Serum gastrin levels are run if a gastrinoma (Zollinger-Ellison Syndrome) is suspected.

Pancreatitis: Pancreatitis continues to be a challenging disorder to accurately diagnose, short of thorough direct examination and biopsy. Assays for amylase and lipase are of very limited value, especially in cats. In general, the following can be stated regarding the various diagnostic tests for pancreatitis:

Value of the Various Diagnostic Tests for Pancreatitis
  • Amylase/Lipase
    • of value as a screening test in dogs only
    • need to be 3x or > above normal reference range in order to suggest pancreatitis
    • normal does not rule-out pancreatitis
  • Abdominal Ultrasound
    • highly specific, but not very sensitive, especially in cats
  • Serum PLI
    • highly sensitive for pancreatitis
  • Pancreatic Lipase Immunoreactivity (cPLI and fPLI)
    • Exocrine Pancreatic Insufficiency (EPI)
      • cPLI is reliably significantly decreased
      • cPLI is specific for EPI
    • Chronic Renal Failure
      • Increased, but usually still within reference range
    • Dogs with Biopsy Proven Pancreatitis
      • cPLI sensitivity is > 80%
      • currently recommended cutoff value for dogs is >200 ug/L
      • preliminary results are also promising for cats
BIPS are barium impregnated polyethylene spheres. Traditionally, veterinarians have relied on barium liquid as the contrast agent of choice for gastrointestinal studies. However, recognized limitations of barium liquid have led to the development of barium-impregnated solid radiopaque markers for the diagnosis of motility disorders and bowel obstructions. Barium liquid contrast studies are of limited value in detecting hypomotility. Radiopaque markers can be used to investigate a number of common gastroenteric problems. These spheres have been specifically validated for use in dogs and cats and are the only radiopaque markers with which there is extensive clinical experience in veterinary medicine. BIPS are manufactured in New Zealand and are now available in many countries. Information on availability of this product, including instructions on use and interpretation of radiographic studies, can be found at (www.medid.com; 800-262-2399).

One of the most reliable and cost efficient diagnostic tools currently available for evaluation of vomiting is flexible GI endoscopy. Endoscopy allows for direct gastric and duodenal examination, mucosal biopsy from these areas, and in many cases gastric foreign body retrieval. Endoscopy is considerably more reliable than barium series for diagnosis of gastric erosions, chronic gastritis, gastric neoplasia, and inflammatory bowel disease (a common cause of chronic intermittent vomiting in dogs and cats). It is stressed that biopsy samples should always be obtained from stomach and whenever possible small intestine regardless of gross mucosal appearance. Normal gastric biopsies may support gastric motility abnormalities, psychogenic vomiting, irritable bowel syndrome, or may be noncontributory (i.e., look elsewhere for diagnosis). Many dogs with vomiting due to inflammatory bowel disease have no abnormalities on gastric examination or biopsy. If only gastric biopsies are obtained, the diagnosis may be missed.

Ultrasonography can be useful in the diagnostic work-up of a number of disorders that can cause vomiting. Among the problems that may be detected with ultrasonography are certain disorders of the liver (e.g., inflammatory disease, abscessation, cirrhosis, neoplasia, vascular problems), gall bladder (cholecystitis, choleliths, gallbladder mucocele), GI foreign bodies, intestinal and gastric wall thickening, intestinal masses, intussusception, kidney disorders, and others. Needle aspirations and/or biopsies can be done at many sites under ultrasound guidance.

Abdominal exploratory is indicated for a variety of problems including foreign body removal, intussusception, gastric mucosal hypertrophy syndromes, procurement of biopsies, and for resection of neoplasia.

*fPLI is only available at Texas A&M University. Serum samples can either be sent directly to the GI Laboratory at Texas A&M University, or they can be forwarded to Texas A&M by a commercial laboratory.

The address is:
GI Lab at Texas A&M University
College of Veterinary Medicine
TAMU 4474
College Station, TX 77843-4474
979-862-2861
www.cvm.tamu.edu/gilab


Diagnosis of Vomiting


Stage 1-Baseline Assessment
  • History and physical examination
  • Conservative vs. more aggressive diagnostic plan based on patient's condition and clinician's concern
Conservative Approach
Fecal examinationa
Selected diagnostics
Specific/symptomatic therapy
Fecal examinationa
Parvovirus test if indicated
Survey radiographs
Appropriate specific/supportive therapy
Serious or Systemic Clinical Signs
Complete blood count
Complete biochemical profile
Urinalysis

T4 (cats)
Heartworm antibody test (cats)


Stage 2-Further assessment (if vomiting persists or initial tests indicate further investigation should be performed promptly):
  • Special Blood Tests
    • Corticotropin stimulation
    • cPLI or fPLI (pancreatitis)
    • Leptospirosis serology
    • Bile acids assay (to asses liver function)
    • Coagulation tests (consider in patients with hematemesis/melena)
  • Contrast Radiography
    • Barium contrast
    • Air contrast gastrogram (to further assess for gastric foreign body)
    • BIPS (barium-impregnated polyethylene spheres; with food to assess GI motility)
  • Ultrasonography
    • Evidence of GI or non-GI disease
    • Aspirates or biopsy
    • Abdominocentesis
  • Nuclear Scintigraphy
    • Transcolonic portal angiography for detection of portosystemic anomaly
    • GI motility study
Stage 3-Invasive Procedures
  • Flexible GI endoscopyb (minimally invasive)
    • Examination, biopsy, foreign body retrieval
  • Laparoscopy
    • Biopsies (e.g., liver, pancreas)
    • Aspirates (e.g., gall bladder, lymph nodes, mass lesion)
    • Intestinal biopsy
  • Surgical intervention
    • Therapeutic or exploratory with multiple biopsies
*GI parasites, including Giardia, should always be considered in dogs with acute or intermittent vomiting. Best baseline testing on a single fecal sample includes centrifugal flotation and Giardia antigen test.

bEndoscopy is a diagnostic or therapeutic tool that can be used in Stage 1, Stage 2, or Stage 3, depending on the clinical situation.

References
  1. DeNovo RC: Diseases of the stomach. In Tams TR, ed: Handbook of small animal gastroenterology, ed 2, Philadelphia, 2003, WB Saunders.
  2. Richards JR, Dillon R, Nelson T, Snyder, P: Heartworm-associated respiratory disease in cats - a roundtable discussion. Veterinary Medicine June 2007.
  3. Tams TR: Gastrointestinal symptoms. In Tams TR, ed: Handbook of small animal gastroenterology, ed 2, Philadelphia, 2003, WB Saunders.
  4. Tams TR: Chronic diseases of the small intestine. In Tams TR, ed: Handbook of small animal gastroenterology, ed 2, Philadelphia, 2003, WB Saunders.



Pharmacologic Control of Vomiting

PHYSIOLOGY OF EMESIS

Vomiting is under the control of a complex set of mechanisms. Essential components of the emetic reflex include an emetic center in the medulla oblongata of the brain, the chemoreceptor trigger zone (CTZ; located in the floor of the fourth ventricle, astride the opening of the spinal canal), visceral receptors, and afferent vagal, sympathetic, vestibular, glossopharyngeal, and cerebrocortical pathways. Vomiting occurs either through activation of the CTZ (humoral/peripheral pathway) or through activation of the emetic center (neural/central pathway). The essential component of the humeral pathway is the CTZ, which is sensitive to blood-borne substances (e.g., uremic toxins, hepatoencephalopathic toxins, such drugs as cardiac glycosides and apomorphine, bacterial toxins), metabolic derangements, acid-base and electrolyte disorders, and osmolar disorders. The emetic center is activated by a number of neural stimuli, including afferent vagal, sympathetic, vestibular, glossopharyngeal, and cerebrocortical pathways. These neural pathways can be stimulated via activation of receptors found throughout the body, including the abdominal viscera. Vomiting associated with many of the primary disorders of the gastrointestinal (GI) tract, which are frequently characterized by inflammation, infection, toxicity, or malignancy, is often due to activation of the neural pathway. Examples include pancreatitis, gastritis, inflammatory bowel disease, and inflammatory diseases of the liver. Central nervous system disease may also directly stimulate the emetic center. In cases of motion sickness or vestibular disease, the vestibular apparatus is responsible for vomiting.

The emetic center can also be activated indirectly through humoral pathway activation of the CTZ. Common diseases that induce vomiting via this pathway include renal failure (effect of blood-borne uremic toxins on the CTZ), diabetes mellitus with ketoacidosis or electrolyte imbalances, and hepatic encephalopathy. Many drugs, chemicals, and bacterial toxins can also stimulate the CTZ to cause vomiting.

In some clinical cases, vomiting is activated through both the neural and humoral pathways. Examples include such systemic diseases as parvovirus enteritis, leptospirosis, and canine distemper. Adrenocortical insufficiency is often associated with vomiting and may be accompanied by regurgitation and diarrhea as well; in these patients, vomiting may result from activation of both the humoral (effects of electrolyte abnormalities and potential acid-base imbalance) and neural (e.g., associated gastritis) pathways.

When selecting specific therapy to control vomiting, clinicians must consider the causal mechanisms. Some drugs have a mechanism of action that affects only certain pathways in the vomiting reflex. The ideal drugs for prompt and effective symptomatic control of vomiting are those with a more broad-spectrum effect that work on both the neural and humoral pathways.

Pharmacologic Control of Acute Vomiting


Initial nonspecific management of vomiting includes NPO (in minor cases a 6-12 hour period of nothing per os may be all that is required), fluid support, and antiemetics. Drugs used to control vomiting will be discussed here.

The most effective antiemetics are those that act at both the vomiting center and the chemoreceptor trigger zone. Vomiting is a protective reflex and when it occurs only occasionally treatment is not generally required. However, patients that continue to vomit should be given antiemetics to help reduce fluid loss, pain and discomfort.

I strongly favor chlorpromazine (Thorazine), a phenothiazine drug, as the first choice for pharmacologic control of vomiting in most cases. Phenothiazine antiemetics (chlorpromazine, prochlorperazine) have a broad spectrum effect and are effective in controlling vomiting due to a variety of causes. Chlorpromazine acts on the emetic center, chemoreceptor trigger zone, and on peripheral receptors. It is also thought to function as a calcium channel antagonist. This effect decreases cyclic AMP concentrations in intestinal epithelial cells which leads to decreased intestinal epithelial cell secretion. Further, chlorpromazine has minimal anticholinergic effects. The recommended dose is 0.1 to 0.25 mg/lb IM or SC SID - TID as needed to control vomiting. At this dose there is a minimal sedative effect. Any sedation resulting from use of chlorpromazine, unless pronounced, is not considered a deleterious side effect, and in fact this is often considered a beneficial effect through decreasing the discomfort and distress that can be associated with nausea. Chlorpromazine is an excellent choice for control of nausea. Patient comfort should always be a priority.

A potential side effect of phenothiazine drugs is hypotension, which can result from an alpha-adrenergic blocking action, causing arteriolar vasodilation. This is of minimal concern in well-hydrated patients, and in dehydrated patients it is readily controlled with intravenous fluid support. For patients with vomiting due to renal or liver disease that are already depressed, the dosage of chlorpromazine is often reduced to 0.1-0.15 mb/lb SID-BID. This lower dose is often effective for controlling vomiting and is not likely to cause significantly more sedation.

If chlorpromazine is ineffective as an antiemetic, metoclopramide (Reglan), a gastric promotility drug that also has central antiemetic effect, can be used. Metoclopramide increases gastric and proximal small intestinal motility and emptying without causing acid secretion, decreases enterogastric reflux, and provides inhibition of the chemoreceptor trigger zone. The central antiemetic effect is mediated through antagonism of dopaminergic D2 receptors in the chemoreceptor trigger zone of the medulla to inhibit vomiting induced by drugs, toxins, metabolic disease, and acid-base imbalances. Metoclopramide is a less effective central antiemetic drug in cats than in dogs because serotonin receptors, rather than dopaminergic receptors, predominate in the CTZ of cats. For vomiting in cats, I generally usually use metoclopramide only if a promotility effect is desired.

Parvovirus can cause gastric hypomotility and therefore the promotility effects of metoclopramide may prove beneficial.

The recommended injectable dose is 0.1 to 0.25 mg/lb IM or SC given TID to QID as needed. Metoclopramide can also be given IV as a constant rate infusion (0.5 - 1.0 mg/lb over 24 hours). Metoclopramide should not be used if gastric outlet obstruction or GO perforation is suspected, or in patients with a seizure disorder. Chlorpromazine and metoclopramide are occasionally used together in dogs in which neither drug is effective in significantly reducing the frequency of vomiting when used alone. It is possible, however, that the combination may potentiate side effects that may result from use of either drug individually. Animals that are treated with a combination of chlorpromazine and metoclopramide are observed carefully for nervous-type behavior or significant depression. My preference at this time, if both chlorpromazine and metoclopramide are ineffective when given individually, or if there is severe vomiting that does not respond to whichever of these drugs is used first, is to institute dolasetron (Anzemet) or ondansetron (Zofran) therapy (see later discussion).

Metoclopramide - Clinical Applications for Chronic Vomiting


Several clinical applications for use of metoclopramide in dogs with chronic vomiting have been identified. These include gastric motility disorders, gastroesophageal reflux disease (GERD), primary or adjunctive therapy for antral and pyloric mucosal hypertrophy, and as treatment for nausea and vomiting caused by various other disorders.

Gastric motility disorders have been recognized with increased frequency in veterinary medicine, but are still overlooked. Gastric stasis, characterized by abdominal discomfort, periodic bloating, borborhygmus, nausea and vomiting may be associated with a number of clinical states that include inflammatory disorders (e.g., chronic gastritis), gastric ulcers, gastroesophageal reflux, infiltrative lesions (e.g., neoplasia), and chronic gastric dilatation. Metabolic disturbances that may cause gastric stasis include hypokalemia, hypercalcemia, acidosis, anemia, and hepatic encephalopathy. Short-term continued vomiting that is observed in some cases after apparent recovery from viral enteritis may be due to abnormal gastric motility. Transient (3 to 14 days) gastric hypomotility may also occur after gastric or abdominal surgery. Motility disorders with no organic cause may be best classified as idiopathic. For any of the disorders listed, the primary cause should be treated, and metoclopramide may be a valuable short-term adjunct to therapy in these cases, along with feeding low fat foods in divided amounts. Metoclopramide alternatively may be used as the primary treatment on a long-term basis for idiopathic hypomotility disorders. Metoclopramide has also been useful in treatment of dogs that have chronic vomiting characterized by episodes occurring routinely in the early morning and containing bilious fluid. In addition, metoclopramide's antiemetic action has proven quite effective in management of chemotherapy induced vomiting.

In general, patients less than 10 pounds receive 2.5 mg per dose, 11-40 pounds 5 mg per dose, and greater than 40 pounds 10 mg per dose. Metoclopramide is given 30 to 45 minutes before meals and again at bedtime. Animals that require chronic medication may need only 1 to 2 doses daily. Because of its short half-life, the drug is not effective when given by intravenous or intramuscular bolus injection for purposes other than when only one treatment would be administered (i.e., to aid in evacuating the stomach if an anesthetic procedure in a non-fasted patient becomes necessary, pre-radiologic contrast study). Subcutaneous administration into fat may be of benefit when oral therapy is contraindicated and an intravenous line is not available.

Metoclopramide is less effective as a promotility drug than cisapride (see later discussion). While many animals with gastric hypomotility respond well to metoclopramide, some have a less than desired response. If a patient with a suspected gastric hypomotility disorder has an inadequate response to metoclopramide, cisapride should be tried next.

Metoclopramide is supplied as 5 and 10 mg tablets and as a cherry flavored liquid containing 5 mg/ml. Injectable metoclopramide is available in 2 ml single dose vials and in 10 ml multiple dose vials (5 mg/ml).

Side Effects


Some adverse effects may occur if metoclopramide is given in the usual therapeutic doses. Clients should be apprised of these before the medication is prescribed. These effects are uncommon in animals, and somewhat more common in humans.

Motor restlessness and hyperactivity may occur; and when observed, these signs usually begin 20 to 30 minutes after a dose and last 4 to 5 hours. The reaction can range from mild to quite dramatic. Alternatively, drowsiness and depression occasionally occur. Side effects are infrequent in cats, but clients have reported disorientation, frenzied behavior, and hiding tendencies associated with the medication. Hospitalized animals may chew excessively at catheter sites or be more aggressive toward hospital staff. Sometimes these effects are subtle and house staff need to be observant. Humans describe metoclopramide side effects as quite bothersome and some individuals have said they "felt like they were going to jump out of their skin." These side effects are reversible (diphenhydramine [Benadryl 1 mg/lb IV or discontinuing the drug) but generally do not subside when lower doses are given. Unless side effects are infrequent, the use of metoclopramide should be discontinued if adverse reactions are seen. Cisapride does NOT cause these same type of adverse reactions. Metoclopramide crosses the blood brain barrier, cisapride does not.

In general, metoclopramide should not be given to epileptic patients. Other contraindications include evidence of significant mechanical obstruction, simultaneous use of anticholinergic agents (antagonism of metoclopramide's effects), and pheochromocytoma.

Ondansetron - Clinical Applications for Acute Vomiting


Ondansetron (Zofran, Glaxo Pharmaceuticals) is a potent antiemetic drug that has proven to be very effective in both humans and animals for control of severe vomiting. It has been used in human cancer patients undergoing cisplatin therapy, a drug that frequently causes nausea and severe vomiting, with dramatic results. Ondansetron acts as a selective antagonist of serotonin S3 receptors (a principal mediator of the emetic reflex). S3 receptors are found primarily in the CTZ, on vagal nerve terminals, and in the gut in enteric neurons. The principal site of action of ondansetron is in the area postrema, but it also has some peripheral gastric prokinetic activity.

In my experience, ondansetron has produced dramatic results in either controlling or at least significantly decreasing the frequency of vomiting in dogs and cats with frequent or severe vomiting, including in dogs with severe parvovirus enteritis, in pancreatitis patients, and cats with hepatic lipidosis. The recommended dose is 0.05 to 0.08 mg/lb IV given as a slow push every 6 to 12 hours (based on patient response). Frequently dogs that appear quite distressed due to nausea and vomiting look much more relaxed and comfortable within 15 minutes of receiving ondansetron. There are no reports of any significant side effects such as diarrhea, sedation, or extrapyramidal signs in human and animal trials. Previously, the primary limitation for ondansetron was expense. However, a generic preparation is now available and is the drug is much more affordable. Oftentimes early use of more aggressive therapy in controlling severe vomiting, in conjunction with other therapy, will hasten an earlier positive response and a shorter hospital stay, with a lower hospital bill than if the patient is allowed to linger too long while it receives less than effective therapy.

Dolasetron


Dolasetron (Anzemet) is also a 5-HT3 receptor antagonist antiemetic drug, with action similar to ondansetron. It is a less expensive alternative to ondansetron and only needs to be administered once daily. Indications are the same as for ondansetron, namely, for control of frequent vomiting that is poorly responsive to lesser expensive front-line antiemetic drugs. The dose is 0.25-0.3 mg/lb IV once daily. Dolasetron is generally well tolerated in animals. In humans, it has been associated with dose-related ECG interval prolongation (PR, QT, and QRS widening. Headache and dizziness also sometimes occur in humans.

It is strongly recommended that all animal hospitals maintain either Anzemet or Zofran in stock, along with other antiemetic drugs, for most effective control of vomiting from a variety of causes.

A NEW ANTIEMETIC DRUG FOR DOGS


Most drugs used to control vomiting in animals have been developed for use in humans. There has been a need for a broad-spectrum antiemetic drug for use in animals that is effective in a variety of situations, has a rapid onset of action, is safe and affordable, and is available in both injectable and oral preparations. Maropitant citrate (Cerenia) is a new broad-spectrum antiemetic drug that is indicated for the treatment of acute vomiting in dogs. Maropitant is a neurokinin receptor antagonist that blocks the pharmacologic action of the neuropeptide substance P in the central nervous system. Substance P is found in significant concentrations in the nuclei comprising the emetic center and is considered a key neurotransmitter involved in emesis. By inhibiting the binding of substance P within the emetic center, maropitant provides broad-spectrum effectiveness against both neural and humoral causes of vomiting. Clinical trials have shown maropitant to be very effective for control of a variety of causes of acute vomiting in dogs. It is administered as a once-daily injection, which is a significant advantage over many other antiemetic drugs, and has a rapid onset of action. Maropitant is also available in tablet form for outpatient use, which makes it a very attractive choice for use in small animal practice.

Cisapride


Cisapride is a potent GI promotility drug. It is no longer on the market for use in humans because of an association with fatal arrhythmias. There are no reports of similar complications existing in dogs and cats, and cisapride continues to be readily available to veterinarians through compounding pharmacies.

Cisapride has broader promotility effects than metoclopramide (e.g., cisapride has demonstrated excellent efficacy in management of colonic inertia). Cisapride is unique among prokinetic agents in that it does not have antidopaminergic properties. Whereas metoclopramide antagonizes the inhibitory effects of dopamine and can cross the blood-brain barrier, cisapride has no effect on the central nervous system. Cisapride is a benzamide derivative that promotes GI motility by increasing the physiologic release of acetylcholine from post ganglionic nerve endings of the myenteric plexus, leading to improved motor activity of the esophagus, stomach, small bowel, and large bowel. In contrast to metoclopramide, which has central effect at the CRTZ in addition to its peripheral effects, cisapride has no known direct antiemetic properties. The onset of pharmacologic action of cisapride is approximately 30 to 60 minutes after oral administration.

Cisapride increases lower esophageal pressure and lower esophageal peristalsis compared to placebo and/or metoclopramide. It significantly accelerates gastric emptying of liquids and solids. Small intestinal and colonic motor activity are also significantly enhanced. Cisapride had been approved for treating gastroesophageal reflux disease in humans, but it also had been shown to be effective in treating a variety of other conditions (e.g., gastroparesis, bile reflux gastritis, nonulcer dyspepsia, intestinal manifestations of systemic disorders, postoperative ileus, constipation, irritable bowel syndrome, and in diagnostic studies [radiographic studies, aid in duodenal intubation of motility and suction catheters]).

The most relevant uses of cisapride in animal patients include treatment of gastroparesis, especially in patients that experience significant side effects from metoclopramide (e.g., hyperactivity and other dystonic reactions), idiopathic constipation, gastroesophageal reflux disease (if H2-receptor antagonists or proton pump inhibitors and dietary management alone are not effective), and postoperative ileus.

Cisapride is extremely well tolerated by animal patients. I have used cisapride in dogs and cats that have experienced neurologic side effects from metoclopramide. I have observed no adverse reactions to cisapride in any of these patients, even in those whose side effects to metoclopramide included very bizarre behavior changes.

The suggested dose of cisapride is similar to what has been recommended for metoclopramide (0.1 - 0.25 mg/lb orally SID-TID depending on the clinical situation). In general, animals weighing 10 pounds or less receive 2.5 mg per dose, 11-14 pounds 5 mg per dose, and those over 40 pounds 10 mg per dose. The dose can be gradually increased if necessary. As is recommended for metoclopramide, cisapride should be administered no closer than 30 minutes before feeding.

References
  1. DeNovo RC: Diseases of the stomach. In Tams TR, ed: Handbook of small animal gastroenterology, ed 2, Philadelphia, 2003, WB Saunders.
  2. Tams TR: Gastrointestinal symptoms. In Tams TR, ed: Handbook of small animal gastroenterology, ed 2, Philadelphia, 2003, WB Saunders.
  3. Tams TR: Chronic diseases of the small intestine. In Tams TR, ed: Handbook of small animal gastroenterology, ed 2, Philadelphia, 2003, WB Saunders.



Giardiasis, Clostridium perfringens Enterotoxicosis, Tritrichomonas foetus, and Cryptosporidiosis

Introduction

Giardia, Clostridium perfringens enterotoxin, and Cryptosporidium are important causes of diarrhea in dogs and cats. Tritrichomonas foetus is an important problem in cats. These disorders should be investigated early in the course of diarrhea, whether it is persistent or intermittent, along with evaluation for dietary causes of GI signs, nematode parasites, bacterial and viral causes, and acute idiopathic colitis. This group of disorders constitutes a thorough differential list for animals with acute and intermittent diarrhea (Table 1).

The challenge to veterinarians is in making an accurate diagnosis, so that the best therapy can be instituted as early as possible. This will then lead to the best opportunity for successful control of the medical disorder. It is also important to recognize that some animals will have several disorders at the same time, so a thorough diagnostic approach is recommended. This is why it is often best to run tests for these disorders at the same time, through use of a "fecal diagnostics panel" that is now available at many commercial laboratories. A single fecal sample is submitted to the lab, and tests for each of these disorders is done at the same time. This provides a prompt and thorough analysis for important clinical disorders of the GI tract. The clinician then has more clear direction on how to proceed with treatment, or other diagnostic tests in the event that none of these disorders is identified.

Table 1: Common Causes of Acute Diarrhea in Dogs and Cats

Young Animals

Dietary problems
Parasites

- nematodes
- protozoa (Giardia, Trichomonads)
- coccidia (including Cryptosporidium)
Viral and bacterial

Clostridium perfringens enterotoxin
(CPE)
Older Animals

Dietary problems
Parasites less common but always possible
- nematodes
- protozoa (Giardia, Trichomonads)
- coccidia (including Cryptosporidium)
Viral causes uncommon in older animals
CPE (common in older animals)
Acute colitis (fairly common cause of diarrhea in older animals)


Giardia is an important cause of diarrhea, and for some patients other GI signs as well. It is an important pathogen in dogs and cats, as well as humans and other species. Historically, accurate diagnosis of Giardia has posed a significant challenge to veterinary practitioners, but there are now much more sensitive tests readily available for veterinarians to use on a routine basis. Because of the impact that this organism can have on animals, and also humans because of its zoonotic potential, it is important that veterinarians perform accurate diagnostic testing on animals to determine whether or not an animal is infected with Giardia. These notes will emphasize steps for accurate diagnosis, and also management of giardiasis.

Clostridium perfringens enterotoxicosis is a common cause of intermittent diarrhea in dogs and cats. Veterinary practitioners should test for the enterotoxin whenever faced with a patient that has unexplained diarrhea.

Cryptosporidiosis is now recognized to be a more common disorder in dogs and cats than was previously thought. It can cause significant abnormalities, and it has zoonotic potential. Cryptosporidiosis can be fatal in people that also are immunosuppressed (e.g., on chemotherapy or corticosteroids, carriers of HIV). Therefore, it is incumbent on veterinarians to test for this disorder, as there are important implications to both the patient as well as to humans who may come in contact with an infected animal.

Diagnosis and Management of Giardia


Diagnosis


Standard diagnostic tests used in any practice setting should include fresh saline fecal smears and zinc sulfate flotation with centrifugation. Zinc sulfate flotation with centrifugation, rather than gravity flotation alone, is a somewhat more sensitve means of testing for Giardia and other parasites. Trophozoites are more likely to be found in loose stools, while cysts are more often found in semi-formed or formed stools. Performing both zinc sulfate concentration with centrifugation and a Giardia antigen test together constitutes the most accurate means of evaluating a patient for the presence of Giardia. This has been recognized as the "gold standard" in human medicine, and is true also in veterinary medicine.

Direct Saline Smear


Direct smears should be performed on fresh fecal samples as soon as possible after being passed, but definitely within 1 hour. A fresh saline smear is made by mixing a drop of feces with a drop of saline on a glass slide. A coverslip is applied and the preparation is examined immediately under 40x magnification. Trophozoites are pear-shaped and have a characteristic concave ventral disk. They demonstrate rolling/wobbling motion (e.g., like a falling leaf). Adding a drop of Lugol's solution of iodine on the edge of the coverslip can be done as an optional procedure and this will enhance the morphologic features of the organisms and make them easier to find. The iodine kills the parasite, so motion will no longer be seen if this procedure is used. Differentiation of trichomonads from Giardia is based on a different motion pattern (more forward motion with trichomonads versus rolling motion with Giardia), the absence of a concave disk, a single nucleus, and the presence of an undulating membrane. Identification of Giardia trophozoites is diagnostic, while their absence in fecal samples does not rule out presence of infection.

Zinc Sulfate Concentration with Centrifugation


Many studies have now shown that zinc sulfate concentration with centrifugation is the most reliable test available for demonstration of Giardia cysts in fecal samples. The test can be done in any practice setting, and the technique is described below. Alternatively, because the best accuracy in detection of Giardia is achieved through well trained and experienced lab personnel consistently setting up the assay and studying the microscopic specimens on time, many practices now submit fecal samples for centrifugation assays to a commercial laboratory.

Zinc sulfate centrifugation is also a very effective method for identifying nematode eggs in feces. It is therefore now used as the standard test for screening for intestinal parasites in most academic and many private practices. Studies have shown that approximately 70-75 percent of Giardia positive dogs can be identified on a single zinc sulfate centrifugation test (as opposed to approximately 40 percent of dogs after 3 separate saline smear preparations). Slides should be examined within 10 minutes of preparation because the cysts may begin to shrink. Since animals shed Giardia on an intermittent basis it is recommended that a series of zinc sulfate concentration tests be run over a 3 to 5 day period in order to maximize chances of accurately diagnosing or ruling out Giardia in animals with chronic diarrhea (or, alternatively, an antigen test can be run at the same time to help increase diagnostic efficiency and accuracy - this is what I recommend now as a standard practice). Diagnostic efficiency increases to 95 percent when 3 zinc sulfate examinations are conducted over a 3 to 5 day period. A positive result on any of the tests warrants treatment for Giardia.

Caution: It is not uncommon for plant spores, yeast bodies, and other amorphous debris to be mistaken for Giardia cysts. In fact, Giardia is frequently misdiagnosed - either it is being diagnosed incorrectly, or the wrong tests are being run and animals with Giardia are being missed. Giardia cysts are 11-13 u in size, and the subtle characteristics of the nuclei, axostyles, and median bodies are often more easily observed under 100X oil immersion magnification. Sometimes there are crescent shaped indentations of the cyst wall. Yeast bodies are similar to Giardia in size, shape, and color. Yeast bodies appear to be far more common than Giardia.

Zinc Sulfate Concentration - Summary
  • Zinc sulfate is the flotation solution of choice in small animal practices (excellent for detection of Giardia as well as nematodes)
  • Zinc sulfate concentration with centrifugation is the best test for identification of Giardia cysts
  • Causes less distortion of Giardia cysts than standard salt solution
Zinc Sulfate Centrifugation Flotation Technique
  1. Thoroughly mix approximately 2 grams of feces with approximately 15 milliliters of 33% zinc sulfate solution (33 grams zinc sulfate made up to 100 milliliters with distilled water; specific gravity 1.18).
  2. Strain the solution through cheesecloth or a tea strainer.
  3. Pour the strained suspension into a 15-milliliter centrifuge tube; polypropylene tubes are preferable to polystyrene tubes.
  4. Place the tube in a centrifuge (a standard bench-top centrifuge can be used). If the tubes hang vertically in the centrifuge, flotation solution can be added until a reverse meniscus forms. A coverslip is added and spun in place on top of the tube. If the tubes are placed in the centrifuge at an angle, the surface layer is harvested after spinning.
  5. Spin the tube at approximately 1500 rpm for three to five minutes.
  6. Remove the coverslip and the adhering drop of fluid and place them on a microscope slide. When a coverslip is not used, collect the surface layer of fluid by touching a glass rod (a 3-milliliter blood collection tube makes a convenient substitute) or bacteriologic loop to the surface of the centrifuge tube. As previously described, however, use of a coverslip is preferred. Deposit the collected fluid on a slide, add a coverslip (if not already used) and examine. Lugol's iodine may be added, if desired, to stain organisms.
Initially mixing the sample with water and centrifuging it can remove some of the debris in the fecal sample. Resultant supernatant is discarded, and zinc sulfate solution is added to the pellet and centrifuged as described above. This initial water wash is not necessary on a routine basis. When steatorrhea is present, large amounts of fat float with the Giardia cysts and may complicate reading of the slide. In these situations, an ethyl acetate sedimentation technique can be used: the sample is mixed with water, filtered, and placed in a centrifuge tube with two to three milliliters of ethyl acetate or ether. After centrifuging, the supernatant, including a distinct layer containing the organic solvent and fat, is discarded. The pellet is then resuspended, and a drop is stained with Lugol's iodine and examined.

Reference


Zajac, AM: Giardiasis. Compendium on Continuing Education for the Practicing Veterinarian 14(5):606, 1992.

Differentiation of Cyst Structures
  • Giardia
    1. Floats in 33% zinc sulfate solution under centrifugal flotation. Doesn't float readily in other flotation solutions.
    2. Size 12-15 microns in length, usually very consistent in size, usually egg-shaped, and refractile green in color.
    3. Contains axoneme/nuclei/median bodies, however, these structures are not always visible. The use of oil immersion (100X) objective is helpful in seeing these structures when one is having difficulty at a lower magnification. Usually the median bodies are the most visible of the three structures.
    4. Some cysts have a crescent-shaped indentation caused by high salt concentration.
    5. Cysts appear to float in their own fecal plane just beneath the cover glass.
    6. When scanning the slide, use 10X objective magnification with a moderate amount of light and a reduced diaphragm aperture for high light contrast.
  • Yeast Bodies
    1. Float in all commonly used flotation solutions. Float in both simple and centrifugal flotation procedures.
    2. Similar to Giardia in size, shape, and color. Yeast bodies appear to be far more common than Giardia.
    3. Contains circular vacuoles, but no structures resembling axonemes, nuclei, or median bodies.
    4. Cytoplasm doesn't indent in flotation solutions.
    5. If yeasts are actively growing, buds can form on the yeast bodies.
    6. The yeast Saccharomycopsis is seen occasionally in dogs. The yeast is much larger than Giardia and has the shape of a gelatin capsule. Not a proven pathogen, but it is often found in dogs suffering from GI distress.
  • Sarcocystis sp. and Cryptosporidium sp.
    1. Sarcocystis sp. sporocysts are about the same size as Giardia cysts. They float in all commonly used flotation solutions. Their internal structure consists of four banana-shaped sporozoites and a clump of material called a residium. Because of its relatively thicker cyst wall, Sarcoystis is more easily seen than Giardia.
    2. Cryptosporidium sp. is spherical and measures 3 to 5 microns in diameter. They are so small that they are often missed during fecal examination.
Giardia Antigen Testing

Other diagnostic tests for Giardia include an enzyme-linked immunosorbent assay (ELISA) test for Giardia antigen in feces, a direct immunofluorescent assay, duodenal aspiration under endoscopic guidance, and the peroral string test. The latter two tests are impractical for routine use in small animal practice, especially when the effectiveness of today's fecal tests is recognized.

The fecal ELISA test detects Giardia antigen that is produced by dividing trophozoites. The test is very sensitive in humans and reportedly detects 30 percent more cases of Giardia than does zinc sulfate. Studies have now confirmed that this is also an excellent test for use in animals. One advantage of the ELISA test is that, since it detects Giardia specific antigen in the feces, it avoids the problem of intermittent cyst excretion in the feces. This test can be a significant aid in accurate diagnosis of Giardia in any private practice setting, and I highly recommend that veterinarians utilize this test in order to more consistently make an accurate diagnosis of giardiasis in their small animal patients.

Indications for Running Giardia Antigen Test:
  • Cases of acute or chronic diarrhea in which zinc sulfate centrifugation tests are negative for parasites
    *Including young dogs with suspected viral or bacterial enteritis - Giardia and other parasitic infections can significantly compromise animals with these conditions. I recommend that all puppies with parvoviral enteritis be screened early for parasites with a combination of zinc sulfate with centrifugation and a Giardia antigen test (both tests day one or two on a single fecal sample)
  • Cases in which it is unclear whether Giardia cysts are being seen on flotation tests (e.g., vs. plant spores)
  • For evaluation of animals with unexplained weight loss, unthriftiness, abdominal pain
  • Acute or chronic vomiting **(some animals with disease related to Giardia have only vomiting as a clinical sign)
Treatment of Giardia

For many years the primary treatment for Giardia in dogs and cats has involved metronidazole. For dogs in which metronidazole proved ineffective, quinacrine was often used in the past. However, although quinacrine has been shown to be more effective than metronidazole, it frequently causes side effects, including lethargy, anorexia, and vomiting. It was also used in cats. Quinacrine is no longer available, however. More recently it was shown that albendazole (Valbazen) is highly effective in controlling Giardia. I recommended albendazole as an effective treatment for Giardia from 1993-1997, but experience with albendazole in dogs and cats has shown that it can cause bothersome side effects; including leukopenia, lethargy, and inappetence. Therefore, I no longer recommend albendazole for treatment for giardiasis in dogs and cats.

Fenbendazole (Panacur), well known for its effectiveness against a variety of intestinal parasites, also appears to be very effective against Giardia. In a controlled trial at Cornell University 6/6 dogs were effectively treated in an initial study. The same dose that is used to treat roundworms, hookworms, whipworms, and the tapeworm Taenia pisiformis (50 mg/kg orally once daily for 3 consecutive days) is used to treat Giardia. If the infection is not cleared on this regimen, a longer course of therapy is used (5 to 7 days). Fenbendazole has a proven track record for being very safe and is thought to not have any teratogenic effects. Fenbendazole is therefore the drug of choice for treatment of Giardia in pregnant animals. This is now also the preferred treatment for Giardia in cats.

Drontal Plus (Bayer Animal Health) is also an excellent choice for treatment of Giardia. This product includes febantel in addition to praziquantel and pyrantel pamoate. Febantel is the drug component that treats Giardia. Febantel is metabolized into fenbendazole and oxyfenbendazole after oral administration. Drontal Plus is administered once daily for 3 to 5 consecutive days for treatment of Giardia. Drontal Plus has been approved for use in dogs. Drontal Plus has been administered to cats empirically at a dosage of two small dog tablets per cat (about 50 mg/kg febantel) orally for 5 days with subsequent demonstration of decreased shedding of cysts (Scorza, Radecki, and Lappin).

Metronidazole is still a useful drug for treating Giardia, and it has the added advantage of having antibacterial as well as antiinflammatory properties. In situations in which it is unclear whether diarrhea is due to giardiasis, bacterial overgrowth, or mild inflammatory bowel disease, metronidazole is an excellent choice, especially when a client requests empirical therapy rather than definitive diagnostic testing. Metronidazole is only 67-74 percent effective in eliminating Giardia from dogs, however, and if a positive diagnosis is made fenbendazole or febantel would also be a reasonable choice. Potential side effects of metronidazole include anorexia, vomiting, and neurologic problems (ataxia, vestibular problems, seizures). In my experience these side effects are not common. They are more likely to occur when the anti-Giardia dose is used (25 to 30 mg/kg orally every 12 hours for 5 to 7 days). The total dose of metronidazole should not exceed 65 mg/kg per day (30 mg/lb per day). A lower dose (10 to 20 mg/kg every 12 hours) is used in treatment of intestinal bacterial overgrowth and inflammatory bowel disease. Side effects are infrequent at this dose. In the past, if a 5 to 7 day course of metronidazole failed to eliminate Giardia, a longer follow-up course (10 to 14 days) was often used. With the availability of fenbendazole and Drontal Plus it is recommended that one of these drugs be used instead in this situation.

In addition to use of pharmacotherapy to eradicate Giardia, it is important to consider environmental control so as to minimize chances of reinfection, especially in kennel or cattery situations. Cysts present in a cool environment can remain infective for a long period of time. Cages and runs should be thoroughly cleaned of all solid fecal material. Steam cleaning, or treatment with a quaternary ammonium compound are both very effective measures for killing cysts. Allowing time for thorough drying is important, to desiccate any remaining cysts.

Bathing: Steps to prevent reinfection play an important role in resolution of giardiasis in dogs. Dogs may be reinfected with cysts from the hair or the environment, and bathing at the time that drug therapy is concluded, thereby removing cysts that could be licked from the hair coat by the animal, may be a very helpful additional step in decreasing the chances of reinfection. Changing the environment, if possible, can also be beneficial.

Zoonotic Potential: Current information indicates that zoonotic potential definitely exists with Giardia. When both animals and humans living in the same environment become infected, a common source of infection rather than direct transmission must also be considered.

The question whether animals that are asymptomatic carriers of Giardia should be treated is often asked. Giardia cysts have been found in many animals with well-formed feces. Giardia is clearly not pathogenic in some animals, while in others it causes significant enteritis. Because the public health considerations must still be considered, it is recommended that all animals with fecal samples that contain Giardia be treated.

Preventing Infection/Premises Control


In controlled environments, the following methods should be used to keep the area as decontaminated as possible:
  1. Decontaminate the environment
  2. Treat all animals in the environment
  3. Bathe at the conclusion of drug therapy to remove cysts from haircoats
  4. Prevent reintroduction of infection
In hospital and kennel/cattery situations (controlled environments) moving animals away from contaminated areas so they can be cleaned and decontaminated is very important. Steam cleaning after all fecal material has been removed is very effective.

Chemical disinfection can be effectively accomplished using quaternary ammonium (QUAT) - containing disinfectants (e.g. Roccal, Totil), which will inactivate cysts in one minute at room temperature. The area should be allowed to dry completely and if possible left open for a few days. Animals should be bathed with a general cleansing shampoo before being returned. In some situations, e.g., shelters, research facilities, it may also be advisable to bathe the animals a second time, especially around the perianal area, using a quaternary ammonium compound. These can be safely left on the coat for 3 to 5 minutes, before being thoroughly rinsed off (longer exposure can cause irritation). Allow the coat to dry thoroughly before returning the animal to the clean area, and then administer one more course of anti-Giardia therapy, preferably using a different drug than was used during the initial course. Subsequently, any new animals introduced to the kennel or cattery should be tested as a matter of routine, but also bathed and treated as well,m regardless of whether the fecal tests are positive or negative for Giardia.

Vaccination: Giardia Vaccine (GiardiaVax)


In 1999 a new vaccine was released by Ft. Dodge for control of Giardia. The vaccine is a killed product containing chemically inactivated trophozoites. Efficacy studies showed that vaccinated dogs were less severely affected clinically and shed cysts for a shorter time following challenge with infective cysts, compared with nonvaccinated dogs. In addition, chronic giardiasis resolved after dogs were vaccinated with this product. In these studies clinical signs of infection were less severe by 21 to 35 days after vaccination, and cysts were no longer detected in the feces by 21 to 70 days. However, subsequent studies have not demonstrated significant reduction in incidence of giardiasis, so the effectiveness of the vaccine remains in question. This is not a "core" vaccine (i.e., recommended for annual vaccination of all dogs and cats), but there may still be a place for it in our armamentarium. The vaccine has been approved for use in both dogs and cats.

Which Dogs Should Be Considered Candidates for Vaccination?


Pets considered at higher risk of exposure to Giardia (and therefore candidates for vaccination) include dogs that frequently visit parks or play areas frequented by other dogs, dogs in multi-pet households, dogs living in endemic areas, hunting dogs, dogs that travel to pet shows, farm dogs, dogs that board at training kennels, dogs that board frequently at boarding kennels, and dogs that have chronic giardiasis with poor response to therapy.

One ml of vaccine is administered subcutaneously and repeated 2-4 weeks later. Annual vaccination is recommended at this time.

Reference


Payne, PA, Ridley, RK, Dryden, MD, et al: Efficacy of a combination febantel-praziquantel-pyrantel product, with or without vaccination with a commercial Giardia vaccine, for treatment of dogs with naturally occurring giardiasis. Journal of the American Veterinary Medical Association, Vol 220, No. 3, February 1, 2002.

Tritrichomonas foetus


Tritrichomonas foetus is a recently identified enteric protozoan of cats. It causes chronic large bowel diarrhea (loose stools, presence of blood and mucus, straining to defecate), and is most commonly seen in young cats that have resided in densely populated housing such as catteries and shelters. The diarrhea may be intermittent or persistent. Loose stool may dribble out (lack of control) and the anal area may become edematous. The organism is present in the ileum, cecum, and colon as a trophozoite. The organism does not encyst, so trophozoites are the only recognized stage. Infection in feral cats and healthy cats appears to be uncommon.

Until 2005 no effective treatment had been identified. The diarrhea eventually resolves over a period of time (months up to one to two years), but currently ronidazole is the recommended therapy, and tinidazole may be effective in some cases. It is important that an accurate diagnosis be made so that clients can be counseled appropriately, i.e., they should expect that their cat(s) will continue to have abnormal stools for some period of time. Also, it is not uncommon for cats to be co-infected with Giardia, so a thorough evaluation for parasites is important (run a minimum of one zinc sulfate with centrifugation and a Giardia antigen test).

Tritrichomonas foetus is commonly mistaken for Giardia trophozoites on direct smear exam. All trichomonads posses three to five anterior flagella, an undulating membrane, and a recurrent flagellum attached to the edge of the undulating membrane. All flagella originate from an anterior basal body. An axostyle extends the length of the trichomonad and extends posteriorly. A cyst stage is not known for this genus. Video clips showing both Giardia and Tritrichomonas trophozoites are available on the North Carolina State University website cited in the reference list below.

Definitive diagnosis can be made in some cases by direct smear of fresh feces in saline and examined at 200 to 400x magnification. Sensitivity is low, however, for diagnosis by direct smear (only 14% in one study), so results can often be false negative. To increase the chance of finding Tritrichomonas trophozoites on direct smear, it is recommended that multiple direct smears be done on the same day. Whenever possible, a cat with suggestive signs should be hospitalized for part or all of a day so that each fecal sample that is passed can be examined quickly via direct saline smear.

Tritrichomonas foetus can also be grown from feces via incubation at 37 degrees C in Diamond's medium. A commercially available culture system is also available and is recommended for use in clinical practice (InPouch TF, Biomed Diagnostics Inc., San Jose, CA). The medium in InPouch does not support the growth of Giardia species or Pentatrichomonas hominis so presence of organisms is consistent with T. foetus. PCR is the most sensitive means for confirming a diagnosis. In one study of 36 cats with T. foetus infection, 20/36 were positive on the InPoch TF test and 34/36 were positive on PCR. Details on the PCR assay can be reviewed on the North Carolina State website.

Recent studies at North Carolina State University showed that ronidazole is effective (30 mg/kg BID for 14 days). Ronidazole is a nitroimidazole antimicrobial that is not licensed for any use in the U.S. The medication is not readily available in the United States, but several compounding pharmacies are preparing to make the drug available. The drug has mutagenic properties, so it must be compounded the same way as chemotherapy drugs. Several sources for ronidazole include WestLab Pharmacy in Gainesville, FL and Diamondback Drugs in Scottsdale, AZ (www.diamondbackdrugs.com). We have had several cats experience mild neurological side effects to ronidazole, similar to what can be seen with metronidazole. These resolved upon discontinuation of the drug. The dose of 30 mg/kg should not be exceeded. It is important that an accurate diagnosis be made so that clients can be counseled appropriately, i.e., they should expect that their cat(s) will continue to have abnormal stools for some period of time until definitive treatment can be administered.

An alternative drug which can be tried is tinidazole. This is also a nitroimidazole antimicrobial. A dose of 15-30 mg/kg SID can be tried. It should be safe and may or may not be effective. Studies are ongoing.

References
  1. Gookin JL, Foster DM, Poore MF, et al: Use of a commercially available culture system for diagnosis of Tritrichomonas foetus infection in cats. J AM Vet Med Assoc, 222 (10), 2003.
  2. Website for periodic updates and video clips of motile trophozoites:
    www.cvm.ncsu.edu/mbs/gookin_jody.htm
Clostridium Perfringens Enterotoxicosis

Over the last 12 years Clostridium perfringens enterotoxicosis (CPE) has emerged as a frequently recognized cause of chronic intermittent diarrhea in dogs. Although it is likely a less common cause of diarrhea in cats it is still diagnosed frequently enough that it should be considered in the diagnosis of diarrhea in cats as well. This is not a new disease. Frequent use of the definitive test (enterotoxin assay performed on feces) for this disorder has revealed that CPE is seen relatively commonly in clinical practice and that CPE is a disorder that should be considered in any dog or cat with intermittent or chronic persistent diarrhea.

C. perfringens is a normal vegetative enteric organism. Simply identifying C. perfringens on a fecal culture is meaningless. The pathogenesis of CPE is through an enterotoxin that is produced after certain strains of C. perfringens sporulate. The toxin damages epithelial cells of the distal ileum and colon. Inciting factors that promote sporulation are not clearly understood but may include stress, diet changes, concurrent disease, or inherent immune status.

The most common clinical signs are chronic intermittent or persistent diarrhea. In some animals acute diarrhea is the primary sign. In fact, some of the cases of hemorrhagic gastroenteritis (HGE syndrome), characterized by acute bloody diarrhea and an increased packed cell volume that most practitioners have seen over the years, may have been due to CPE. Many animals exhibit signs of large bowel diarrhea, but small bowel signs may be seen as well. In some cases signs may be seen for only a day or two at a time, with persistent recurrences on a weekly, monthly, or on a less frequent basis. Stressful events or diet changes may incite flare-ups of clinical signs. In other cases C. perfringens enterotoxicosis is one of several problems that an animal may have concurrently and diarrhea may be persistent.

Diagnosis


CPE must be considered whenever more than one animal in the environment has diarrhea (e.g., household, kennel, cattery). Transmission from animal to animal can occur. A presumptive diagnosis may be suggested on fecal cytology in which more than 3-4 spores per high power oil immersion field are observed (the spores have a safety pin appearance and are larger than most bacteria). However, definitive diagnosis is by identification of enterotoxin which is currently done via a fecal assay. Clinicians should be aware that simply seeing spores on fecal cytology does not establish a definitive diagnosis (see JAVMA February 1, 1999). Stool is submitted to the lab for enterotoxin analysis. Fecal samples that will be shipped off from the hospital directly to a laboratory should be sent on ice via overnight express. If a courier service will be picking up samples for transport to the laboratory it is sufficient to keep the sample refrigerated until pick-up. The courier service will keep the sample properly chilled during transport. The minimum amount of stool that should be submitted is the size of a pea. Typically I submit samples in a red top tube, without serum separator. In animals with intermittent diarrhea the chances of a positive toxin finding are greater when abnormal rather than a normal stool is examined. A negative result does not definitively rule-out CPE.

Treatment


Several antibacterial drugs are effective in controlling CPE. Acute cases often respond well to amoxicillin (22 mg/kg BID) or metronidazole (10-20 mg/kg BID) for 7-28 days. Many clinicians have likely treated CPE with these medications empirically without knowing what they were treating. Chronic cases tend to respond best to tylosin powder. The recommended dose is: Animals greater than 23 kg tsp BID, 12 to 23 kg 1/8 tsp BID, 5 to 12 kg 1/12 tsp BID, and less than 4.5 kg 1/16 tsp BID (a "pinch"). Cats definitely do not accept the powder well at all, even when it is mixed in very tasty foods. It is best to have the powder reconstituted to capsule form for administration to cats. The medication is very safe. Some animals require treatment for several to many months (3 to12 months or more). Over time the dose may in some cases be successfully reduced to SID and then every other day dosage (after several months or more on a BID schedule).

Dietary fiber supplementation may also help control CPE. Probable mechanisms include decreased C. perfringens fecal concentration, lower colonic pH, which prevents sporulation, and increased concentrations of SCFA. Some patients may respond well to dietary fiber supplementation alone.

Follow-up testing at 3-6 months can be done to determine if toxin persists. Once daily to every other day tylosin in conjunction with dietary fiber supplementation are used in chronic cases.

Cryptosporidiosis


Infection with Cryptosporidium is much more common than most small animal practitioners recognize. Currently it is recommended that all dogs and cats with diarrhea, whether acute or chronic, be screened for Cryptosporidium in addition to testing for nematode and protozoan parasites. In 2004 the American Association of Feline Practitioners adopted a position statement recommending that all kittens and adult cats with diarrhea be screened for Cryptosporidium. It is recommended that the same policy be followed with dogs (given that the cause is not simple diarrhea related to an acute upset due to sudden change in diet or dietary sensitivity).

Cryptosporidium spp. are coccidians that reside in the gastrointestinal tract. Infection can be associated with diarrhea in both immunocompetent and immunodeficient hosts. In the past, most of the cases of mammalian cryptosporidiosis were attributed to C. parvum. However, molecular studies have demonstrated that cats are usually infected with the host-specific C. felis, dogs are infected with C. canis, and people are infected with C. parvum or C. hominus (Scorza and Lappin). In a recent study at Colorado State University, they documented the presence of Cryptosporidium spp. DNA in diarrhea from 24.3% of the 292 animals tested (180 cats, 112 dogs) (Scorza and Lappin). This highlights the importance of testing dogs and cats for cryptosporidiosis. PCR is much more sensitive than the tests that are used most commonly at this time (acid fast staining of fecal smears or IFA). In this same series with 24.3% positive on PCR, only 2.7% were positive on IFA.

All dogs and cats infected with Giardia or Cryptosporidium species should be considered potentially zoonotic, even though the number of cases in which humans are infected through contact with pets is probably not high. Infection in humans is sometimes fatal in the presence of severe immunosuppression. Acute symptoms may include diarrhea, abdominal pain, vomiting, fever, and listless behavior. Infection can also be subclinical in dogs and cats. Chronic unresponsive diarrhea has been associated with cryptosporidiosis in cats with serious underlying disease as well as in dogs.

Because Cryptosporidia oocysts are quite small (as little as one-tenth the size of common Isospora oocysts) and are usually present in the feces in small numbers, they are very difficult to detect on routine fecal flotation and microscopy. The best tests currently available for routine testing for Cryptosporidium are fecal IFA and acid fast staining of fecal smears; however, they lack sensitivity. These tests are readily available at commercial laboratories (acid fast staining can also be done in house). PCR is a much more sensitive test but is labor intensive, expensive and is only available at a limited number of laboratories. Antigen tests for detecting C. parvum in human species are not sensitive for use in dogs and cats. In time there will be more sensitive tests readily available.

Treatment


The following treatment regimens may be used for cryptosporidiosis:

Canine Feline
Azithromycin 5-10 mg/kg, BID orally, for 14 days Azithromycin 7-15 mg/kg, BID orally, for 14 days
Paromomycin 150 mg/kg, SID orally, for 5 days Paromomycin 150 mg/kg, SID orally, for 5 days
Tylosin 15 mg/kg, BID orally, for 21-28 days Tylosin 15 mg/kg, BID orally, for 21-28 days


References
  1. Barr SC. Giradiasis. In Greene CE 3rd ed., Infectious Diseases of the Dog and Cat
    Philadelphia: Elsevier, 2006; 736-742.
  2. Blagburn BL and Butler JM. Optimize intestinal parasite detection with centrifugal fecal flotation. Veterinary Medicine 2006; 101: 455-464.
  3. Brown RR, Elston TH, Evans L, et al. American Association of Feline Practitioners 2003 Report on Feline Zoonoses. Comp Cont Ed Pract Vet 2003;25:936-965.
    Dryden MW, Payne PA, Ridley RK, Smith VE. Gastrointestinal parasites: The practice guide to accurate diagnosis and treatment. Suppl Compend Contin Educ Vet, July 2006; Vol. 28, No. 7(A)
  4. Gookin JL, Foster DM, Poore MF, et al: Use of a commercially available culture system for diagnosis of Tritrichomonas foetus infection in cats. J AM Vet Med Assoc, 222 (10), 2003.
  5. Scorza AV and Lappin MR. An update on three important protozoan parasitic infections of cats: cryptosporidiosis, giardiasis, and tritrichomoniasis. Supplement to Veterinary Medicine, March 2006; 18-32.
  6. Scorza AV, Radecki SV, and Lappin MR. Efficacy of a combination of febantel, pyrantel, and praziquantel for the treatment of kittens experimentally infected with Giardia species. J Fel Med Surg 2006; 8:7-13.
  7. Scorza AV, Lappin MR. Detection of Cryptosporidium spp. in feces of cats and dogs in the United States by PCR assay and IFA. J Vet Int Med 2005;19:437.
  8. Stockdale HD, Spencer JA, Dykstra CC, Blagburn BL, et al. Feline trichomoniasis: an emerging disease? Compend Contin Educ Vet, June 2006; 463-471.


Intensive Care Management for Dogs with Severe Viral Enteritis

Puppies and Young Dogs - Parvovirus Enteritis

Disease caused by parvovirus in dogs (destruction of intestinal crypt epithelium, lymphocyte depletion, neutropenia) is generally more severe than that caused by coronavirus (destruction of intestinal villi). Coronavirus enteritis is often characterized by mild and self-limiting clinical signs. Intestinal mucosal injury due to parvovirus is more extensive, involving both crypt and villous epithelium. A combination of secretory and malabsorptive diarrhea results. Sepsis occurs commonly in dogs with parvovirus due to absorption of preformed bacterial toxins and intact bacteria across the damaged intestinal epithelium. Bacteremia is more likely to occur in severely leukopenic animals. Sepsis occurs infrequently in dogs with coronavirus enteritis.

Treatment of Acute Infectious Diarrhea in Dogs (e.g., Parvovirus Enteritis)


Fluid Therapy


Fluid replacement is one of the most important treatments for patients suffering from vomiting and diarrhea. Rate and route varies with each patient, but patients with hemorrhagic gastroenteropathy are often dehydrated at presentation and strong consideration must be given to intravenous fluid therapy. Restoration of an effective circulating blood volume is of primary importance in the management of hypovolemic and septic shock. Subcutaneous fluid administration provides slow, unreliable volume replacement, may induce hypothermia, and occasionally results in the formation of subcutaneous abscesses.

Initially, a buffered crystalloid solution such as lactated Ringer's or Normosol-R should be given, followed by fluids with glucose added (lactated Ringer's or Normosol-R with 5% dextrose) when dehydration becomes less severe (5-6%). Both lactated Ringer's and Normosol-R are mildly alkalinizing and may be beneficial in patients with metabolic acidosis, especially in animals with severe diarrhea. The buffer sources in Normosol-R are acetate and gluconate. An advantage of acetate and gluconate is that they do not require hepatic metabolism and they do not contribute to lactate levels.

The calculation of fluid requirements should be the sum total of: 1)daily maintenance requirements, 2)deficits due to dehydration, and 3)continued (contemporary) losses (vomiting and diarrhea). Generally, the average adult dog requires a maintenance volume of approximately 60 ml/kg body weight per day. Estimation of dehydration is at best crude, but is derived from an accurate history, physical examination, and laboratory data. Once calculated only 75-80% of this volume is replaced the first twenty-four hours with the remainder given the second day. Below is an example of typical fluid calculations.

Case Example:


A 20 kg dog with vomiting and diarrhea is estimated to be 10% dehydrated. The calculated 24 hour fluid requirement would be 2,850 ml
  1. Maintenance: 60 ml/kg x 20 kg = 1,200 ml
  2. Dehydration: 10% x 20 kg = 2.0 kg
    2.0 kg x 1,100 mg/kg (clinical approximation) = 2,200 ml
    2,200 ml x 75% replacement the first 24 hours = 1,665 ml
    1,200 ml maintenance + 1,650 ml dehydration = 2,850 ml
  3. Ongoing losses: if vomiting or diarrhea continues during fluid therapy the volume lost is estimated and added to the original 2,850 ml calculated requirements. Too often dogs with severe viral enteritis are not adequately hydrated in clinical practice. One of the major reasons for this is that the importance of determining and replacing ongoing losses is not recognized. Inadequate volume replacement is one of the causes of a poor response to therapy.
If the animal is in critical condition, a "shock dose" of fluids is often given the first hour and is roughly up to 90 ml/kg (in the first one to two hours).

Antibiotic Therapy


Most cases of simple vomiting and diarrhea do not warrant any antibiotic therapy. However, patients with hemorrhagic gastroenteropathies should be given antibiotics because the severe intestinal mucosal inflammatory changes which occur allow the normal intestinal microflora to invade the intestinal mucosa and lead to septicemia. Antibiotics are specifically given to eliminate microflora invading the mucosa, to eliminate microflora causing septicemia, and to eliminate pathogens that have invaded.

Bacteria invading the mucosa to produce bacteremia are members of the normal intestinal microflora. Antibiotic treatment is directed against both groups of bacteria, the aerobes (especially Escherichia coli) and anaerobes (especially Bacteroides and Clostridium of bowel origin). The important source of the bacteremia is the anaerobes (outnumber the aerobes in the colon by 1,000 to 1). Penicillin is the most effective antibiotic against anaerobes invading from the colon.

If patients with hemorrhagic gastroenteropathy are only mildly ill, and have an adequate number of white blood cells, penicillins are a good initial choice. Amoxicillin (22 mg/kg IM or SC every 12 hours) or ampicillin provide adequate coverage. Cephalosporins also provide good coverage for both aerobic and anaerobic bacteria (22 mg/kg IV every 8 hours). Antibiotics should not be administered subcutaneously in dehydrated animals because the rate of absorption will be delayed.

In more severe cases, a combination of penicillins and an aminoglycoside; or, a second generation cephalosporin and aminoglycoside can be used. Aminoglycosides can cause acute renal tubular necrosis. Maintenance of normal blood volume is essential when using aminoglycoside antibiotics.

Cefoxitin (Mefoxin) is a second generation cephalosporin. It has greater activity against many gram-negative bacteria (e.g., resistant E.coli, Proteus, Klebsiella) that are resistant to the first generation cephalosporins. It has activity against anaerobes. The dose is 10-15 mg/lb IV q 6 - 8 hrs.

Antiviral Therapy - Oseltamivir (TAMIFLU, Roche Laboratories) for Parvovirus Enteritis


Tamiflu is an antiviral drug used most commonly in humans with Influenza A and B. Tamiflu is a neuraminidase inhibitor. NA is an enzyme that is necessary for viral replication and penetration through mucus and respiratory secretions. In people, it prevents the secondary bacterial complications that occur with influenza (such as pneumococcal pneumonia) and also decreases viral replication resulting in a milder course of disease. We think it does the same thing in parvovirus, preventing the penetration of the virus into the gut and the resultant bacterial effects such as endotoxemia and shock, which are leading causes of death in parvovirus enteritis patients.

How did experience with this drug initially come about in dogs with parvo? A veterinarian named Dr. Jack Broadhurst first tried it on shelter puppies in North Carolina where funds for major care are limited. Pups that did not respond to basic care (subcutaneous fluids, oral rehydration products, and antibiotics) either died or were euthanized. Naturally, this lead to frustration caused by losing too many parvo puppies, and Dr. Broadhurst decided to try the human antiviral drug Tamiflu, adding it on to the standard basic care package to see if it made any difference. The first 10 puppies he tried it on all survived. Good start! After he had 10 cases get better with no change in treatment other than adding Tamiflu, he posted a message on VIN and asked others to try it. He also did further research into Tamiflu.

Conversations that I have had in recent months with Dr. Dougie Macintire, an internist and critical care specialist at Auburn University who has done a lot of work on the parvovirus enteritis syndrome, have been very positive. Dr. Macintire feels that there is truly very good potential for Tamiflu to become an accepted and recommended part of our treatment guidelines for parvovirus enteritis.

Dr. Macintire and her residents at Auburn have been working on a study to document the effectiveness of Tamiflu in parvo dogs. It appears that EARLY use of Tamiflu in parvo puppies really shortens hospitalization time, and if you have a litter infected and give it early to the ones that aren't sick yet, they never get sick. It's pretty amazing so far, but we are still in the early stages of looking at it and need more cases."

Recommended dose schedule: 1 mg/lb PO bid for 5 days. It is available as a liquid (12 mg/ml when reconstituted). It is also available in 75 mg capsules, but in most cases we will be using the liquid.

To better insure that a vomiting patient will keep the Tamiflu down, I recommend administering it 30 minutes after an injection of an antiemetic drug. Patients that are on metoclopramide CRI for control of emesis may also be able to keep the drug down without need for readministration.

Glucose


It is not uncommon for hemorrhagic gastroenteropathy patients to be hypoglycemic at or shortly after the time of presentation. Glucose is required in adequate levels for normal white blood cell migration and phagocytosis and for treatment and prevention of hypoglycemia occurring with septic or endotoxic shock. A bolus of glucose (1 to 2 gms/5 kg, or approximately 1 ml 50% dextrose per 2 kg), is given slowly IV at the start of therapy and then added to the fluids as a 5% solution as dehydration nears resolution. A bolus of 25% dextrose is preferred over a 50% concentration because the latter is quite hypertonic and may induce vomiting.

Antiemetics


The most effective antiemetic drugs for viral enteritis patients are the phenothiazine drug chlorpromazine or the promotility drug metoclopramide. Ondansetron or dolasetron are used in animals with intractable vomiting. Use of anticholinergic drugs (e.g., aminopentamide [Centrine], atropine) must be avoided.

I strongly favor chlorpromazine (Thorazine), a phenothiazine drug, as the first choice for pharmacologic control of vomiting in most cases. Phenothiazine antiemetics have a broad spectrum effect and are effective in controlling vomiting due to a variety of causes. Chlorpromazine acts on the emetic center, chemoreceptor trigger zone, and on peripheral receptors. It is also thought to function as a calcium channel antagonist. This effect decreases cyclic AMP concentrations in intestinal epithelial cells which leads to decreased intestinal epithelial cell secretion. Further, chlorpromazine has minimal anticholinergic effects. The recommended dose is 0.1 to 0.25 mg/lb IM or SC SID - TID as needed to control vomiting. At this dose there is a minimal sedative effect. Any sedation resulting from use of chlorpromazine, unless pronounced, is not considered a deleterious side effect. Patient comfort should always be a priority. Chlorpromazine is an excellent choice for control of nausea.

A potential side effect of phenothiazine drugs is hypotension which can result from an alpha-adrenergic blocking action, causing arteriolar vasodilation. This is a minor problem and it is readily controlled with intravenous fluid support.

If chlorpromazine is ineffective as an antiemetic, metoclopramide (Reglan), a gastric promotility drug that also has central antiemetic effect, can be used. Metoclopramide increases gastric and proximal small intestinal motility and emptying without causing acid secretion and provides inhibition of the chemoreceptor trigger zone. Parvovirus can cause gastric hypomotility and therefore the promotility effects of metoclopramide may prove beneficial. The recommended injectable dose is 0.1 to 0.2 mg/lb IM or SC given TID to QID as needed. Metoclopramide can also be given IV as a constant rate infusion (0.5 - 1.0 mg/lb over 24 hours). Chlorpromazine and metoclopramide are occasionally used together in dogs in which neither drug is effective in significantly reducing the frequency of vomiting when used alone. It is possible, however, that the combination may potentiate side effects that may result from use of either drug individually. Animals that are treated with a combination of chlorpromazine and metoclopramide are observed carefully for nervous-type behavior or significant depression. My preference at this time, if both chlorpromazine and metoclopramide are ineffective when given individually, or if there is severe vomiting that does not respond to whichever of these drugs is used first, is to institute dolasetron (Anzemet) or ondansetron (Zofran) therapy (see later discussion).

Some adverse effects may occur if metoclopramide is given in the usual therapeutic doses. Clients should be apprised of these before the medication is prescribed. These effects are uncommon.

Motor restlessness and hyperactivity may occur; and when observed, these signs usually begin 20 to 30 minutes after a dose and last 4 to 5 hours. Alternatively, drowsiness and depression occasionally occur. Side effects are infrequent in cats, but clients have reported disorientation, frenzied behavior, and hiding tendencies associated with the medication. These side effects are reversible (Benadryl 1 mg/lb IV or discontinuing the drug) but generally do not subside when lower doses are given. Unless side effects are infrequent, the use of metoclopramide should be discontinued if adverse reactions are seen.

In general, metoclopramide should not be given to epileptic patients. Other contraindications include evidence of significant mechanical obstruction, simultaneous use of anticholinergic agents (antagonism of metoclopramide's effects), and pheochromocytoma.

Ondansetron


Ondansetron (Zofran, Glaxo Pharmaceuticals) is a potent antiemetic drug that has proven to be very effective in both humans and animals for control of severe vomiting. It has been used in human cancer patients undergoing cisplatin therapy, a drug that frequently causes nausea and severe vomiting, with dramatic results. Ondansetron acts as a selective antagonist of serotonin S3 receptors (a principal mediator of the emetic reflex). S3 receptors are found primarily in the CTZ, on vagal nerve terminals, and in the gut in enteric neurons. The principal site of action of ondansetron is in the area postrema, but it also has some peripheral gastric prokinetic activity.

In my experience, ondansetron has produced dramatic results in either controlling or at least significantly decreasing the frequency of vomiting in dogs and cats with frequent or severe vomiting, including in dogs with severe parvovirus enteritis, in pancreatitis patients, and cats with hepatic lipidosis. The recommended dose is 0.05 to 0.08 mg/lb IV given as a slow push every 6 to 12 hours (based on patient response). Frequently dogs that appear quite distressed due to nausea and vomiting look much more relaxed and comfortable within 15 minutes of receiving ondansetron. There are no reports of any significant side effects such as diarrhea, sedation, or extrapyramidal signs in human and animal trials. A previous limitation was the expense of Zofran, however, a generic preparation is now available and is much less expensive. Oftentimes early use of more aggressive therapy in controlling severe vomiting, in conjunction with other therapy, will hasten an earlier positive response and a shorter hospital stay, with a lower hospital bill than if the patient is allowed to linger too long while it receives less than effective therapy.

Dolasetron


Dolasetron (Anzemet) is also a 5-HT3 receptor antagonist antiemetic drug, with action similar to ondansetron. It is a less expensive alternative to ondansetron and only needs to be administered once daily. Indications are the same as for ondansetron, namely, for control of frequent vomiting that is poorly responsive to lesser expensive front-line antiemetic drugs. The dose is 0.25-0.3 mg/lb IV once daily. Dolasetron is generally well tolerated in animals. In humans, it has been associated with dose-related ECG interval prolongation (PR, QT, and QRS widening. Headache and dizziness also sometimes occur in humans.

It is strongly recommended that all animal hospitals maintain either Anzemet or Zofran in stock, along with other antiemetic drugs, for most effective control of vomiting from a variety of causes.

Corticosteroids


Pharmacologic doses of glucocorticoids have been shown to have antishock effects in all forms of shock, especially septic. There is still no definitive evidence, however, to show that these agents improve overall survival. Beneficial effects include improved tissue perfusion, decreased leukocyte margination and perivascular leukocyte degeneration, and reduced absorption of endotoxins. It seems advisable at this time that corticosteroids should be administered as early as possible in a septic shock state. Dexamethasone sodium phosphate is administered at 2 to 4 mg/kg IV after an initial bolus of IV fluids is delivered. It may be necessary to repeat the dose at 8 to 12 hour intervals for 2 to 3 total treatments (decision based on patient response).

Potassium


Hypokalemia is a frequent occurrence in patients with anorexia, vomiting and diarrhea. Significant potassium losses also occur through the kidneys. As a result, potassium supplementation is a very important part of therapy for animals with hemorrhagic gastroenteropathies.

Early potassium supplementation is extremely important for successful management of dogs with severe parvovirus enteritis. Supplementation should be instituted before hypokalemia is detected because serum potassium concentration represents only a small fraction of total body potassium stores. Most patients receive 20 to 30 mEq per liter of fluids administered. Some dogs require supplementation at 40 mEq per liter.

Flunixin Meglumine


Flunixin meglumine is a potent nonsteroidal antiinflammatory, analgesic agent that has antidiarrheal and antipyretic effects. It is believed to act by reducing the excessive production of prostaglandin synthetase. With regard to diarrhea, flunixin meglumine acts at the intestinal cellular level to decrease fluid production, gut fluid secretion, and mucus secretion. Flunixin meglumine also helps to reverse the severe intestinal inflammatory changes that occur with viral and bacterial enteritis, and is circulatory supportive in an endotoxic shock state. Effectiveness is improved if administered along with fluids, antibiotics, and corticosteroids. Flunixin is dosed at 1 mg/kg IV in dogs. Antiprostaglandin drugs such as flunixin meglumine have some potentially deleterious side effects. The most common appears to be GI ulceration and hemorrhage. Flunixin meglumine should not be administered more than once in a patient that has received corticosteroids.

Treatment Of Pronounced Hypoproteinemia


Hypoproteinemia often develops rapidly in animals with severe diarrhea and small intestinal injury. Replacement of lost proteins by administration of fresh-frozen plasma may prove beneficial, especially when the total protein level drops below 3.5 g/dl. A plasma transfusion serves to both help in restoration of plasma oncotic pressure and to provide a source of immunoglobulins. Administration of fresh-frozen plasma from regularly immunized donor animals is a means of providing antibodies against circulating parvovirus. This is an effective means of neutralizing the virus in clinical patients. Use of fresh-frozen plasma may help reduce mortality in severely ill parvovirus enteritis patients.
A dose of 6 to 10 ml/kg of plasma is usually administered. This volume can be administered up to 2 times per 24 hours. An in-line filter is used to remove particulate material during plasma infusion. Plasma should be administered slowly for the first 10 to 30 minutes to monitor for signs of adverse reaction.

Intestinal Parasite Control


In addition to providing primary care for the sequelae of viral enteritis, it is important that any concurrent intestinal parasite problems be controlled as well. Intestinal parasitism, especially in puppies, can add significantly to the debilitation that viral or bacterial enteritis can cause. Fecal samples should be evaluated as early as possible for evidence of parasites. This should include using a Giardia antigen test to help improve diagnostic sensitivity for Giardia.

Anthelmintic drugs most commonly used include pyrantel pamoate (roundworms, hookworms) or fenbendazole (roundworms, hookworms, whipworms, and Giardia) at 50 mg/kg once daily for 5 consecutive days. For animals that are vomiting I prefer to use fenbendazole since it requires only one dose per day and has such a broad spectrum of activity (including Giardia).

Reflux Esophagitis


Significant reflux esophagitis probably occurs in animals with persistent vomiting much more commonly than we recognize. Dogs with parvovirus enteritis that are debilitated and recumbent are especially at risk. Vomited fluid that is retained in the esophagus is not cleared adequately in weak and recumbent animals. As a result, the esophageal mucosa is bathed with gastric acid and activated enzymes that will cause mucosal injury. Because significant discomfort can result from esophagitis it is important that it be recognized and treated in a timely manner.

Treatment of esophagitis in animals with persistent vomiting includes use of an injectable histamine H2-receptor antagonist (e.g., cimetidine, famotidine), and a cytoprotective drug in suspension form (sucralfate). Metoclopramide is also beneficial because of its promotility (gastric emptying) effect and because it increases lower esophageal sphincter tone. H2-receptor antagonists are used to decrease gastric acid production, thereby decreasing acid volume available for reflux. H2-blockers also reduce the volume of gastric juice that is produced. I most often use famotidine at a dose of 0.5 mg/kg IV every 12 hours, if I am concerned about esophagitis being present.

Pain Management for Patients with Parvovirus Enteritis


Dogs with parvovirus enteritis, or any other cause of severe viral enteritis, can experience significant abdominal pain. Causes of pain include diffuse intestinal injury, cramping, and reflux esophagitis (described above).

Butorphanol will help provide relief in patients with mild pain and it also has some level of antiemetic activity. It can be used in conjunction with chlorpromazine or metoclopramide. Transdermal Fentanyl (Fentanyl patch) or injectable morphine (0.1-0.5 mg/lb every 6 hours SC or IM) or hydromorphone (0.05-0.2 mg/lb every 6 hours SC or IM) can be used in parvovirus enteritis patients that are experiencing moderate to severe abdominal pain. Notable changes in patient behavior that can be indicative of good pain relief often include more frequent assumption of a position of relief or comfort (less curling up, more laying out in a more extended or "sprawling" form), more effective antiemetic drug effects, and an earlier return of appetite. Butorphanol should not be given in conjunction with other opioids, including fentanyl, morphine, or hydromorphone, since it is a partial antagonist. It must be noted that both human and animal patients that receive the benefit of effective analgesia often have lower morbidity and mortality.

When a fentanyl patch is placed on a patient that is already in significant pain, morphine or hydromorphone are administered every 6 hours for 24-36 hours, so that the patient receives adequate analgesia while awaiting achievement of effective blood levels of fentanyl from the patch.

Flunixin meglumine (Banamine) is also useful for visceral pain and can be used in combination with opioid analgesia in dogs with viral enteritis (see earlier discussion). If steroids have also been administered for some reason, use of flunixin meglumine should be limited to one dose during the course of hospitalization.

Summary


Successful management of dogs with severe parvovirus enteritis requires a multifaceted treatment approach, a hospital staff that is dedicated to high detail patient care, and a committed pet owner. The success rate is very high when all of these factors are present.



Inflammatory Bowel Disease in Dogs

Management of Inflammatory Bowel Disease in Dogs

It is important that the clinician formulate a treatment protocol based on a correlation of clinical course, laboratory and gross findings, and histologic findings rather than relying on histologic changes alone. Although treatment principles for cats and dogs with IBD are similar, drug selection and dosage regimens vary between these two species in some situations.

Specific treatment recommendations for dogs with inflammatory bowel disease (IBD) are as follows. Corticosteroids are the initial treatment of choice for lymphocytic-plasmacytic and eosinophilic enteritis in most cases. Mild to moderate cases (as determined by clinical signs, normal protein levels, and degree of inflammatory cell infiltrate on biopsy) often respond to prednisone at a dose of 0.25 to 0.75 mg/lb divided twice daily for two to four weeks followed by a gradual decrease in 50% increments at two-week intervals. Alternate day or every third day treatment can often be reached by two to three months. Occasionally treatment can be discontinued altogether by three to six months.

Moderate to severe cases and any case in which the total protein is less than 5.5 g/dl should be treated more aggressively using an initial prednisone dose of 1 mg/lb per day for two to four weeks before an attempt is made to decrease the dose. Dogs in this category often require long-term therapy (months to years) on an every other day or every third day basis to maintain remission. Use of combination drug therapy (prednisone and metronidazole) in these cases at the outset is recommended in order to improve chances of controlling clinical signs more quickly and to prevent progression of the disease.

If significantly bothersome side effects are caused by prednisone (e.g., severe polyuria/polydipsia, panting, lethargy, etc.), oral dexamethasone can be used instead. In some dogs dexamethasone is much better tolerated and side effects are minimal or nonexistent. If prednisone side effects are judged to be severe it is generally discontinued for 12 to 36 hours in order to allow for adequate metabolism and clearance. Prednisone may then be reintroduced at 25 to 50 percent of the previous dose or alternatively dexamethasone can be instituted at a conservative level (0.005 to 0.01 mg/lb/day orally).

When a patient is either poorly responsive to corticosteroids when used as outlined above, or if there is poor tolerance, the next best options are to try either budesonide or cyclosporine. Cyclosporine is described further below. Budesonide is a newer corticosteroid for use in humans. Budesonide is a glucocorticoid that also represents a new alternative for management of IBD in dogs and cats, especially in severe cases that have proven to be refractory to prednisolone, metronidazole, azathioprine, and dietary management; or that are intolerant of the corticosteroids discussed above. It is one of a group of novel corticosteroids that have been in development for use in humans in an attempt to make available alternative preparations that will help limit toxicity associated with corticosteroid use. Others include fluticasone propionate, tixocortol pivalate, and beclomethasone dipropionate.

Budesonide undergoes high first pass metabolism in the liver and 90% is converted into metabolites with low corticosteroid activity. It has minimal systemic availability. The potential for typical corticosteroid side effects is significantly reduced as a result of decreased bioavailability and the resulting limited systemic exposure, which makes this a particularly attractive drug for use in humans and animals that are poorly tolerant of other corticosteroids. Budesonide also has a high receptor-binding affinity in the mucosa. It has been referred to as a "locally acting" corticosteroid.

Therapeutic results with budesonide have been promising in humans with Crohn's disease, collagenous colitis and lymphocytic colitis, ulcerative colitis, either when administered as a retention enema or in oral form, and primary biliary cirrhosis. Budesonide has been used by some veterinary clinicians in recent years to treat IBD in dogs and cats. Dose recommendations vary. In humans, a range of 6 mg to 9 mg per day has been used during initial therapy. The following general recommendations have been made for dogs. In general, budesonide is administered to small dogs at 1 mg administered once per day. It has been used at higher doses (3 mg per small dog per day), but the lower dose is frequently effective. Large dogs receive 3 mg twice daily initially, and the dose is later tapered to 3 mg once daily, and then to alternate day administration for longer term use.

Budesonide can be used in combination with other drugs. Potential adverse effects include PU/PD, when budesonide is used at the high end of the dose range, and GI ulceration. These reactions have been observed in some human patients. These problems would be more likely to occur in dogs than in cats. It appears to be very safe when used at the levels listed above.

Metronidazole has both an antibacterial and antiinflammatory effect. It is useful in treatment of IBD in dogs as well as in cats. Metronidazole's mechanism of action includes an antiprotozoal effect, inhibition of cell-mediated responses, and anaerobic antibacterial activity. Metronidazole is administered at 5 to 10 mg/lb two times daily. A major advantage of using combination therapy is that the corticosteroid dose can usually be decreased from the high initial dose in a timely manner, thus decreasing the likelihood of significant corticosteroid-related side effects. Also, I have successfully managed on a long-term basis canine patients with mild to moderate lymphocytic-plasmacytic enteritis that were intolerant to corticosteroids or metronidazole alone.

When prednisone and metronidazole are used in combination the dosage level of each drug is generally gradually decreased as the animal's condition improves and laboratory parameters (especially protein levels and white blood cell count) return to normal. Corticosteroids are decreased gradually for several months before any reduction is made on the metronidazole dose. If there has been an excellent response it is possible that metronidazole can be discontinued after several months. Alternatively, if chronic therapy is required, metronidazole can often be administered on a once daily and eventually on an every other day basis. If it is not possible to discontinue medication altogether due to recurrence of symptoms when no medication is given control can be maintained with prednisone and/or metronidazole given on an alternate day basis. If both drugs are used, I often recommend giving prednisone on one day and metronidazole on the alternate day. Occasionally in dogs with moderate to severe IBD or in a case where both IBD and chronic bacterial overgrowth are present it is necessary to continue metronidazole on a long-term (months to years) basis (5 to 10 mg/lb twice daily). I have observed no instances of significant complications when this protocol has been used.

Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic oral administration in mice and rats. There are reports of humans with Crohn's disease who have been treated with high doses of metronidazole for prolonged periods of time and who subsequently developed breast or oral cancer. A cause and effect relationship has not been established. To date I am aware of no cases of GI or mammary cancer that have occurred in dogs or cats in conjunction with metronidazole use. I consider it to be a safe drug for prolonged use (months to years) in patients with chronic disorders for which long-term therapy is required.

Dogs with marked hypoproteinemia (total protein less than 4.5 g/dl) caused by lymphocytic-plasmacytic enteritis often respond well when an aggressive therapeutic course is undertaken (prednisone, metronidazole, and azathioprine used in combination). This aggressive approach has led to control of clinical signs and return to a total protein level of greater than 6.0 g/dl (by 2 to 4 months) in a number of cases. One exception to this approach, in my experience, is that animals with hypoproteinemia resulting from eosinophilic enteritis often respond well to corticosteroids alone.

Combination drug therapy is used early in severe cases or if a side effect to one drug requires that it be used at a lower dose. If corticosteroids are poorly tolerated (e.g., excessive polyuria/polydipsia, listlessness, panting, inappetence associated with steroid hepatopathy) or if corticosteroids and metronidazole are unable to achieve remission, then azathioprine should be added to the regimen. Azathioprine is started early in the course for cases of lymphocytic-plasmacytic enteritis that cause a protein-losing enteropathy with a total protein level less than 4.5 g/dl. The canine dose is 1 to 1.25 mg/lb once daily (note significant difference in dose between cats [0.15 mg/lb once every other day] and dogs). If azathioprine is used at the outset, the prednisone dose is decreased by 50% from 1mg/lb per day after three to four weeks or based on clinical improvement (i.e., remission of signs and increase in protein levels) and degree of tolerance of this dose of prednisone. Subsequent decreases in the prednisone dose can usually be made at monthly intervals until an alternate day schedule is reached.

If azathioprine is started in any type of IBD case because of significant corticosteroid side effects, the prednisone is initially decreased by 50% to 75% but is not stopped completely unless absolutely necessary because loss of remission might result. Azathioprine is generally used for three to nine months in dogs. Once adequate control is achieved, the daily dose is decreased by 50%, and subsequently alternate day therapy is used. Side effects are uncommon in dogs but may include anorexia, jaundice (hepatic damage), poor hair growth, and bone marrow suppression. In addition, it is suspected that azathioprine has the potential to induce pancreatitis. This is an uncommon occurrence, however, in my experience. A complete blood count should be run to monitor for evidence of anemia or leukopenia at three week intervals for the first two months and then once every several months. Routine monitoring also includes periodic (once every 4 to 6 weeks initially) evaluation of hepatic enzyme levels (increases may be due to corticosteroids and occasionally azathioprine) and protein levels.

Cyclosporine: Cyclosporine A (cyA) has been shown to be effective in steroid-resistant IBD in humans and also perianal fistula management in both humans and dogs. Other uses in dogs have included management of atopic dermatitis and sebaceous adenitis. A study was undertaken to evaluate the pharmacokinetics and clinical efficacy of oral cyA treatment in 14 dogs with steroid-refractory IBD (Allenspach K, et al, JVIM 2006). Patient assessment included determination of a clinical activity score to assess severity of clinical signs before and after treatment. The total number of infiltrating lymphocytes and T cells in duodenal biopsies obtained via endoscopy were also assessed before and after treatment. Improvement was noted in 12/14 dogs. There was a significant improvement in clinical activity score and a decrease in T cell numbers, implying that T cell lysis is a possible mechanism of action. Results from this study suggest that cyA is an effective option for managing some dogs with steroid refractory IBD.

The anti-inflammatory effect of cyA in human IBD is believed to be due to suppression of activated T cells infiltrating the mucosa, thereby decreasing the amount of proinflammatory cytokines, and ultimately, the clinical signs of disease. The cyA dose used in the study of 14 dogs was 5 mg/kg (2.3 mg/lb) SID. The sole therapy was cyA. Previous therapy had included immunosupporessive doses of steroids in all dogs (starting dose of prednisolone was 1 mg/lb/day, administered for a range of 6 to 14 weeks before the dose was decreased). Other drugs tried in most of the dogs included metronidazole (range of 2 to 38 weeks).

There were transient adverse effects observed in 5 dogs, most of which occurred in the first 1-2 weeks of therapy, after which time they abated. Adverse reactions included vomiting and inappetence (4/14 dogs), and gingival ulceration and alopecia followed by hypertrichosis in 1 dog. A lag phase of 7 to 10 days has been seen in humans before there are obvious signs of clinical improvement, and a similar finding was observed in the dogs in the study reported here.

The clinical efficacy study showed that cyA was effective in 11/14 of the dogs (78%). Nine dogs were considered complete responders after 10 weeks of treatment, 3 were partial responders, and 2 were nonresponders that had to be euthanized during the study because no clinical improvement was observed. Eight out of the 9 dogs that responded well initially were still doing well after 6 months to 2 years follow-up. One dog responded well for 14 weeks but then relapsed and declined with severe vomiting and was euthanized. Eight dolgs were discontinued from cyA after 10 weeks of therapy. Three dogs were kept on therapy for 4, 6, and 36 months. These dogs had all shown significant improvement in clinical score but the owners elected to keep their dogs on therapy.

Further clinical experience is needed with cyA in dogs with IBD, but the results from the study as well as some anecdotal reports of positive responses indicate that cyA can be an effective form of therapy in dogs with steroid refractory IBD.

Dietary Management of IBD


In some animals with mild lymphocytic-plasmacytic enteritis or eosinophilic enteritis dietary modification may lead to partial or complete resolution of clinical signs and even improvement in histologic lesions. In others dietary therapy may be an important adjunct to pharmacotherapy in the control of clinical signs related to chronic IBD. It is also possible that dietary management used on a long-term basis will effectively help maintain control once drug therapy is discontinued. Potential benefits of dietary therapy include reduction of hypersensitivity reactions to dietary antigens, alteration of bowel motility, and effects on composition of the bowel flora and mucosal morphology and function.

Dietary therapy for IBD may involve use of a strict elimination diet or a balanced commercial diet that contains minimal additives. In most cases, diets that are highly digestible and low-residue work best for small intestinal disease. If a decision is made to initially manage an animal with dietary therapy alone the dietary trial should be conducted for a minimum of three to four weeks. Some animals require six weeks or more before clinical improvement occurs. If biopsies reveal moderate to severe IBD and/or if there is any degree of patient compromise pharmacotherapy should be included in the treatment regimen along with dietary management. In my experience, animals with this degree of disease rarely respond to dietary manipulation alone.

Diets that often work well include those that supply a single source of protein to which the animal has not previously been exposed (i.e., "novel" proteins). These may include lamb, rabbit, venison, duck, or low-fat cottage cheese. A single digestible carbohydrate such as boiled rice should be added to home prepared diets. Many of the premium commercial diets now include optimum levels of omega-6 and omega-3 fatty acids. These agents may be useful in reducing inflammation in the intestine. Baby food or boiled chicken are often well tolerated in cats that will not eat commercial foods. Dividing feedings into two to three meals per day will help maximize dietary assimilation.

Summary


IBD that is initially graded as moderate to severe usually can be managed quite successfully and can be maintained in remission but not often cured. Sometimes follow-up biopsies in severe cases reveal only slight to moderate histologic resolution of inflammatory infiltrates despite excellent clinical control even on lower drug doses. Alternatively, dramatic histologic resolution has been noted in other cases. Treatment decisions (e.g., can treatment be discontinued completely?) ideally are based on a thorough review of clinical response to date (control of clinical signs, levels of medication required, and resolution of hypoproteinemia if it was initially present) and follow-up endoscopic biopsy information. As a general clinical rule of thumb an attempt can be made to discontinue therapy after two to three months of successful control on twice weekly medication. If signs recur then medication is resumed on a daily basis for 7 to 14 days before a gradual reduction program is started. In some dogs with severe lymphocytic-plasmacytic enteropathy and marked hypoproteinemia, therapy can be successfully discontinued as early as six months to one year. In others, lifelong treatment is required.

German Shepherd Dog Enteropathy


German shepherd dogs appear to be predisposed to an increased incidence of GI diseases such as IBD and SIBO. Practitioners who see German shepherds with any frequency no doubt recognize that these dogs have an increased incidence of diarrhea and sometimes weight loss and other symptoms. It is not known for sure why German shepherds are predisposed to IBD and SIBO, but there are several theories, and perhaps there are at least several factors involved concurrently.

Possible factors include:
  • Genetic susceptibility, as a result of major histocompatibility complex class II antigens
  • A breakdown in immunological tolerance to endogenous bacterial components
  • Mucosal permeability and brush border enzyme defects, which may allow increased antigen exposure to the mucosal immune system
  • Underlying selective IgA deficiency. German shepherd dogs with small intestinal disease have been shown to have a relative deficiency of IgA secretion from the small intestinal mucosa.
  • IBD in German shepherd dogs is accompanied by marked disturbances in inflammatory cell populations and the cytokine profile
It is possible that IBD and SIBO in German shepherds are part of a single disease syndrome. It is also possible that, given that SIBO is more common in young animals and IBD is more common in older dogs, that SIBO can predispose to IBD. There is currently no substantiation of this hypothesis, but studies are ongoing.

Clinical signs in German shepherds are variable. The most common signs of SIBO are diarrhea and weight loss or failure to thrive. Signs of IBD are more variable and in addition to diarrhea and weight loss may include vomiting, flatulence, decreased appetite, and other signs. German shepherd dogs with GI signs should be investigated in the same manner as has been described for intestinal disease earlier in this chapter. Problems other than SIBO and/or IBD may be present, so a thorough diagnostic work-up should be recommended. In addition to a baseline of a CBC, biochemical profile, and urinalysis, other tests should include fecal tests for nematode parasites, Giardia, Cryptosporidium, and Clostridium perfringens enterotoxin, TLI if exocrine pancreatic insufficiency has not already been ruled out, serum cobalamin, folate, and SUCA or other currently recommended indirect test for SIBO, and upper and lower GI endoscopy for procurement of intestinal biopsies. Alternatively, if there are minimal signs and the dog's condition remains good overall, a trial with antibiotics (see treatment section below) for 4 to 6 weeks may be tried. A positive response would be suggestive of SIBO. It will then need to be determined if antibiotics need to be continued long-term or on an intermittent basis.

Treatment


If it is thought that the problem is limited to SIBO and/or IBD, it is generally recommended that antibiotics alone be used initially, unless there is a moderate or of course severe degree of IBD present, in which case immunosuppressive therapy is also indicated. Antibiotics may include oxytetracycline, metronidazole, or tylosin. Initially a course of 4 to 6 weeks in prescribed, and then if there has been a good response the medication can be discontinued. The dog is then observed for relapse, and if this occurs the antibiotic therapy should be reinstituted. Again, it is important that other causes of diarrhea be ruled out, if they have not been already, and an effort to look for evidence of Clostridium perfringens enterotoxicosis (CPE) must be made. CPE sometimes responds to metronidazole, and more consistently, especially in chronic cases, to tylosin. Fiber supplementation is also very beneficial in management of CPE. For SIBO and IBD, a highly digestible low residue diet is generally preferred, so dietary trials may be necessary, along with a thorough diagnostic effort, to determine which type of diet is most indicated. If there is an excellent response to antibiotics and the diarrhea recurs when they are discontinued, antibiotics can be used either continuously on a low dose basis (I prefer to use tylosin in this situation as a first choice, and metronidazole as a second choice) or pulse therapy may be used, in which case antibiotics are administered once daily two to three times a week. In some dogs this is sufficient to maintain control.

If IBD is present and not responsive to antibiotics and dietary management, immunosuppressive drugs are used following the guidelines described earlier in this chapter. In general, I rarely find it necessary to use a prednisone dose greater than 0.5 mg/lb per day in German shepherd dogs.

Pythiosis


Pythiosis is a severe and often fatal cause of chronic GI or cutaneous disease in dogs living mostly in tropical or subtropical climates. In the United States, most cases are seen in the Gulf Coast states region, but it has been seen as far north as southern Indiana, Missouri, Kentucky, and North Carolina. There are also rare cases in cats that involve mostly invasive subcutaneous lesions. Pythiosis is caused by the aquatic oomycete Pythium insidiosum. The infective stage of Pythium insidiosum is thought to be the zoospore, which is released into warm water environments. Infection is caused either through encystment in the skin or through ingestion. GI pythiosis causes severe segmental transmural thickening of the GI tract with variable mucosal ulceration and mesenteric lymphadenopathy.
There are other fungal agents of the class Zygomycetes that can cause severe intestinal and skin disease. It is difficult to differentiate some of the agents, however, and so the general term zygomycosis is often used. Dogs with zygomycosis oftentimes are undifferentiated from those cases with pythiosis. These infections were formerly misnamed phycomycosis (outdated name that should no longer be used).

Historically definitive diagnosis of pythiosis and zygomycosis has been difficult because of the challenges inherent in obtaining a culture-based confirmation of these organisms. Therefore, a presumptive diagnosis has often been made, i.e., "suspected pythiosis," based on histopathologic findings. Newer tests are now available which are making specific diagnosis somewhat easier.

Clinical signs include chronic intractable diarrhea and vomiting, loss of appetite, depression, and chronic weight loss. The diarrhea may become bloody due to intestinal necrosis and ulceration. Extensive granulomatous reaction may cause palpable enteromesenteric masses to develop. There may eventually be spread to other abdominal viscera.

Baseline laboratory tests may reveal mild to moderate nonregenerative anemia, neutrophilic leukocytosis, and panhypoproteinemia. Survey abdominal radiography may reveal a mass effect and barium contrast radiography may identify an area of obstruction. Abdominal ultrasonography can identify intestinal thickening and lymphadenopathy. Rectal scraping cytology may reveal organisms as may a fecal culture. Historically diagnosis has been dependent on histologic identification of characteristic hyphae in biopsy samples of stomach, intestine, or abdominal lymph nodes. Diagnostic tissue samples are best obtained surgically, as endoscopic biopsy techniques do not reliably harvest adequate tissue in all cases for diagnosis of pythiosis. Extensive tissue reaction may be evident at laparotomy, and this should not be mistaken for neoplasia. It is best to obtain tissues and await a histologic diagnosis rather than making assumptions based on visual inspection alone.

The clinical faculty at Louisiana State University has extensive experience in diagnosis and management of pythiosis and zygomycosis, and some promising new tests have recently been developed in their laboratory. These include PCR-based assays and serology. There is now a PCR test available for identification of P. insidiosum. This assay can be applied to DNA extracted either from cultured isolates or from appropriately preserved infected tissue samples. The test will reliably differentiate P. insidiosum from other Pythium species. A new highly specific and sensitive mycelial antigen-based ELISA assay for the detection of anti-P insidiosum antibodies is also now available for use on samples from both dogs and cats. This test provides an excellent means for making an early, non-invasive diagnosis, and also provides an excellent means for monitoring response to therapy. This is especially important with regard to the GI form of the disease because, unlike with skin lesions, the owner cannot visually monitor the lesions.

Treatment


The treatment of choice for pythiosis is aggressive surgical removal of lesions. Complete resection provides the best chance for long term cure. For intestinal lesions, the goal is to resect infected tissues with 4 to 6 cm margins. Post-operative medical management is also necessary, as there is always a chance for local recurrence. Medical management utilizing either itraconazole with or without terbinafine is recommended for a period of 2 to 4 months after surgery. Drug cost is a significant concern for some owners. If medical management cannot be afforded, then ELISA serology is recommended at several month intervals for up to a year after surgery to monitor for evidence of recurrence.

Medical management alone is often unrewarding, but this is the only choice in patients that have diffuse nonresectable disease. The internal medicine service at Louisiana State University has reported that in recent years about 15% of their cases of pythiosis in dogs have responded to either itraconazole at 5 mg/lb every 24 hours for 3 to 6 months or amphotericin B lipid complex (Albecet) 1 to 1.5 mg/lb administered IV over several hours, every other day to a cumulative dose of 11 to 12.5 mg/lb. The drugs can also be used in combination, or alternatively, itraconazole and terbinafine (2.5 to 5 mg/lb per 24 hours) can be used in combination. Combination has been shown to achieve a better response overall, although the prognosis still remains very guarded.

References
  1. Allenspach K, Rufenacht S, Sauter S, Grone A, et al. Pharmacokinetics and clinical efficacy of cyclosporine treatment of dogs with steroid-refractory inflammatory bowel disease. J Vet Intern Med 2006; 20:239-244.
  2. Grooters AM, Leise BS, Lopez MK, et al. Development and evaluation of an enzyme-linked immunosorbent assay for the serodiagnosis of pythiosis in dogs. J Vet Intern Med 2002; 16:142-146.
  3. Grooters AM. Phycomycosis revisited: new developments in canine pythiosis. ACVIM Annual Forum Proceedings 2002; 479-481.
  4. House AK, Guitian J, Gregory SP, Hardie RJ. Evaluation of the effect of two dose rates of cyclosporine on the severity of perianal fistulae lesions and associated clinical signs in dogs. Vet Surg 2006; 35:543-549.
  5. Tams TR. Chronic diseases of the small intestine. In Tams TR, ed, Handbook of Small Animal Gastroenterology. Elsevier, Philadelphia, 2003, p. 211-250.


Inflammatory Bowel Disease and Intestinal Lymphoma in Cats

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) currently is recognized as a common and important medical problem in cats. Three general types of clinical presentations have been identified in cats with idiopathic IBD: (1) a clinical course characterized primarily by vomiting, (2) a clinical course characterized primarily by diarrhea, and (3) a clinical course that includes both vomiting and diarrhea as primary signs. Associated clinical signs can include change in appetite (anorexia, inappetence, or ravenousness), weight loss, and lethargy. In some cats, the clinical signs are cyclic; they seem to flare up and then abate in a predictable pattern.

Vomiting, one of the most frequent clinical signs of IBD in cats, is most often recognized as an intermittent occurrence for weeks, months, or years. Affected cats are frequently misdiagnosed as having hairballs as the primary problem. As the disorder progresses, an increased frequency of vomiting often leads the owner to seek veterinary attention. In addition to vomiting, diarrhea is a common sign observed in feline IBD and most likely is due to derangement of normal mechanisms of absorption and motility caused by mucosal inflammation. In most cases, diarrhea is intermittent early in the course of the disorder, and there may be a transient response (weeks to several months) to dietary manipulation or any of a variety of medications. Later, the diarrhea becomes persistent and usually responds only to specific treatment, which is determined after a definitive diagnosis is made. Signs of small bowel diarrhea predominate, but signs of large bowel diarrhea may be evident as well if there is generalized intestinal tract involvement.

Appetite changes in cats with idiopathic IBD vary from decreased appetite to complete anorexia to ravenousness. Inappetence seems to occur more commonly in cats that have vomiting as the primary clinical sign and usually occurs during exacerbation of clinical signs, and vomiting or diarrhea is not observed until later or not at all. The three leading differential diagnoses for a cat with a ravenous appetite, diarrhea, and weight loss are IBD, hyperthyroidism, and exocrine pancreatic insufficiency (uncommon).

A definitive diagnosis of IBD can be made based only on intestinal biopsy. Further tests are run to evaluate the overall health status of the patient and to rule out other disorders. Recommended baseline tests include a complete blood count, biochemical profile, urinalysis, fecal exams for parasites, serum thyroxine test, and a feline leukemia virus test. Testing for feline immunodeficiency virus should be considered in cats with chronic wasting disease.

Treatment


It is important that the clinician formulate a treatment protocol based on a correlation of clinical course, laboratory and gross findings, and histologic findings rather than relying on histologic changes alone. Corticosteroids are the cornerstone of treatment for idiopathic inflammatory bowel disorders. Mild to moderate cases often respond to prednisone or prednisolone at a starting dose of 0.5 to 1 mg/lb divided twice daily for two to four weeks followed by a gradual decline in 50% increments at two week intervals. Cats with inflammatory changes graded as mild usually respond quite well to the lower dose and alternate day or every third day treatment can often be achieved by two to three months. Occasionally treatment can be discontinued altogether by three to six months.

If biopsies reveal disease that is moderate to severe a prednisolone dose of 1 to 2 mg/lb divided twice daily is used for the first 2 to 8 weeks or until clinical signs resolve. I do prefer to use prednisolone over prednisone in cats with inflammatory disorders of a moderate to severe nature, as there may be improved bioavailability in some cats with prednisolone. This dose of corticosteroid is usually well tolerated in cats. In these cases a dose of 0.5 to 1 mg/lb per day may be necessary long term (months to years) to maintain clinical remission. Use of combination drug therapy may also be required at the outset to control clinical signs and prevent progression of the disease. Cats with hypoproteinemia and histologic changes graded as severe often respond quite well when an aggressive therapeutic course is undertaken.

Budesonide is a glucocorticoid that represents a new alternative for management of IBD in dogs and cats, especially in severe cases that have proven to be refractory to prednisolone, metronidazole, azathioprine, and dietary management; or that are intolerant of the corticosteroids discussed above. Budesonide is a new and recently approved corticosteroid for use in humans. It is one of a group of novel corticosteroids that have been in development for use in humans in an attempt to make available alternative preparations that will help limit toxicity associated with corticosteroid use. Others include fluticasone propionate, tixocortol pivalate, and beclomethasone dipropionate.

Budesonide undergoes high first pass metabolism in the liver and 90% is converted into metabolites with low corticosteroid activity. It has minimal systemic availability. The potential for typical corticosteroid side effects is significantly reduced as a result of decreased bioavailability and the resulting limited systemic exposure, which makes this a particularly attractive drug for use in humans and animals that are poorly tolerant of other corticosteroids. Budesonide also has a high receptor-binding affinity in the mucosa. It has been referred to as a "locally acting" corticosteroid.

Therapeutic results with budesonide have been promising in humans with Crohn's disease, collagenous colitis and lymphocytic colitis, ulcerative colitis, either when administered as a retention enema or in oral form, and primary biliary cirrhosis.

Budesonide has been used by some veterinary clinicians in recent years to treat IBD in dogs and cats. Dose recommendations vary. In humans, a range of 6 mg to 9 mg per day has been used during initial therapy. In general, budesonide is administered to cats at 1 mg administered once per day. It is available as a 3 mg capsule preparation (Entocort, AstraZeneca). The 1 mg formulation for cats is obtained through a compounding pharmacy.

Budesonide can be used in combination with other drugs. Since cats tolerate corticosteroids very well, there is little indication to use budesonide as initial therapy for IBD. However, this may be a very attractive option for use in diabetic cats that also have IBD, or in patients where conventional therapies have not been sufficiently effective.

Potential adverse effects include PU/PD, when budesonide is used at the high end of the dose range, and GI ulceration. These reactions have been observed in some human patients. These problems would be more likely to occur in dogs than in cats. It appears to be very safe when used at the levels listed above.

When combination therapy is indicated metronidazole (Flagyl) is usually the first choice to be used in conjunction with prednisone. Metronidazole's mechanism of action includes an antiprotozoal effect, inhibition of cell-mediated immune responses, and anaerobic antibacterial activity. A dosage of 5 to 10 mg/lb two times daily is used for IBD. Ideally, at least several months of metronidazole therapy is given once it is started. In some cats with severe disease long term consecutive use or one to two month cycles of treatment may be required. Side effects to metronidazole at this low dose are uncommon in cats. Occasionally nausea or vomiting may be seen.

Methylprednisolone acetate (Depo-Medrol, Upjohn) can be used as sole treatment for cats with mild to moderate IBD or as adjunctive therapy when oral prednisone and/or metronidazole are used as the primary treatment and flare-ups of clinical signs occur. Consistent control of clinical signs in cats with moderate to severe IBD is more difficult to maintain when methylprednisolone acetate is used alone, however. It is recommended that sole use of methylprednisolone acetate be reserved for situations in which the owner is unable to consistently administer tablet or liquid prednisolone preparations. Initially 20 mg is given subcutaneously or intramuscularly and is repeated at 2-week intervals for 2 to 3 doses. Injections are then given every 2 to 4 weeks or as needed for control.

If remission cannot be maintained with use of corticosteroids and metronidazole then azathioprine (Imuran) should be used. Azathioprine is an immunosuppressive drug with a nonspecific effect. Replication of rapidly dividing cells, including immunoblasts, is inhibited. Azathioprine is usually used in cats only when the previously discussed therapeutic measures fail to control the disease. The most important side effect of azathioprine in cats is bone marrow suppression. I use a maximum starting dose in cats of 0.15 mg/lb once every other day. At this low dose side effects are extremely uncommon. Alternatively if clinical signs of IBD do not resolve on the initial azathioprine dose the dose can be increased slightly if there is no evidence of bone marrow suppression. Because of a lag effect, beneficial therapeutic results from azathioprine often are not apparent until 2 to 3 weeks after treatment is started. Azathioprine is generally used for 3 to 9 months in cats. A majority of cats with IBD do not require azathioprine treatment.

A complete blood count should be run to monitor for anemia and leukopenia at 3 to 4 week intervals for the first 2 months and then once monthly. Significant side effects are most often identified during the first 3 to 6 weeks of treatment with azathioprine. There is usually no physical evidence of early azathioprine toxicity in cats. Mild leukopenia (e.g., 3000 - 4000 cells/mm) is usually the first abnormality that is identified. Azathioprine is currently only available as 50 mg tablets. The low dosage used in cats requires that the tablet be broken into small fragments (i.e., 1/30 - 1/50 tablet depending on body weight). Since this is a very inaccurate and potentially dangerous way of administering azathioprine to cats, this drug must be administered in suspension form.

A suspension preparation can be made by a compounding pharmacy service. A major advantage of administering azathioprine in this manner is that any required increase in dosage can be done very accurately. If azathioprine is well tolerated and there has been inadequate clinical improvement the dosage can be increased form 0.15 mg/lb to 0.2 to 0.25 mg/lb once every 48 hours.

Another immunosuppressive drug that is used in some cats with severe IBD is chlorambucil (Leukeran). Some clinicians use chlorambucil as an alternative to azathioprine (they are not used in conjunction). Chlorambucil is an alkylating agent. Alkylating agents alter DNA synthesis and inhibit rapidly proliferating cells. Chlorambucil is administered initially at 0.05 to 0.1 mg/lb/day in conjunction with prednisolone at 1 mg/lb/day. The small pill size of chlorambucil (2 mg) allows for easy dosing. Most cats receive one-half tablet (1 mg) per day. Various dosage schedules for cats have been published. An alternate schedule is 0.07 to 0.15 mg/lb every 72 hours. Toxicities are uncommon in cats but may include anorexia, vomiting, and diarrhea, but these problems generally resolve rapidly when chlorambucil is reduced from daily to every other day administration. Bone marrow suppression is possible but uncommon, and is mild and rapidly reversible when it does occur. Once the desired clinical response is achieved, chlorambucil is gradually tapered over several months while prednisolone is continued as the primary maintenance drug.

Cobalamin therapy in cats: Significant tissue level cobalamin deficiency is present in some animals with GI disease. This is usually secondary to reduced cobalamin absorptive capacity. Therapy involves administering injectable cobalamin at the following schedule for cats: 250 ug subcutaneously once a week for 6 weeks, then every 2 weeks for the next 6 doses, then dose monthly. Most generic cobalamin preparations contain 1 mg/ml (1000 ug/ml). It is important to note that multi-vitamin and B-complex injectable formulations contain significantly lower concentrations of cobalamin and they also cause pain when injected. Therefore, it is recommended that these preparations not be used for cobalamin supplementation. Unless the intestinal disease is totally resolved, long-term and perhaps lifelong supplementation with cobalamin may be necessary. The frequency of injections on a long-term basis is determined by regular measurement of serum cobalamin concentration.

Because dietary allergens may play a role in the cause if IBD, specific dietary therapy may be beneficial. Often, moderate to severe degrees of IBD are either temporarily responsive or only minimally responsive to careful dietary manipulations. However, long term control of IBD with as minimal a drug administration schedule as possible may be aided by specific dietary management. This should be started as soon as a diagnosis is made and continued as drug therapy is decreased later. Chicken, duck, lamb, or venison based diets are often tried initially. A gradual change to commercial diets that are low in additives and that are formulated with chicken or lamb as their primary ingredient is then attempted. Diets such as IVD Select Care Neutral or IVD Limited Ingredient Diets, Iams Feline, Hill's Prescription Diet c/d or w/d, or Waltham select protein diets are generally recommended.

Poor responses to treatment of cats with IBD usually result from:
  1. Inadequate initial or long-term maintenance corticosteroid dosage (and consider using prednisolone rather than prednisone).
  2. Failure to use ancillary medications (metronidazole, azathioprine, chlorambucil) in cases where disease is moderate to severe.
  3. Failure to recognize and treat a concurrent condition (e.g., gastric hypomotility disorder that may either be secondary to IBD or idiopathic in nature, hyperthyroidism, parasitism [e.g., Giardia, Cryptosporidium], Clostridium perfringens enterotoxicosis).
  4. Treatment for only small intestinal inflammatory disease when colitis is present as well. Some cats with concurrent IBD and colitis may show minimal or no clinical signs of colitis.
  5. Failure to recognize and treat low body cobalamin levels (measure serum cobalamin).
  6. Failure to identify an effective diet.
  7. Poor client compliance
Treatment of Intestinal Lymphoma in Cats

Lymphoma is the most common feline neoplasm. It is also the most common form of gastrointestinal neoplasia in cats. Gastrointestinal lymphoma is often referred to as either well differentiated (low grade or lymphocytic), poorly differentiated (high grade, lymphoblastic, or immunoblastic), and intermediate (or mixed). Endoscopy has been shown to be a very useful modality for diagnosis of intestinal lymphoma in cats, especially when multiple biopsies are obtained using proper technique and instruments that can procure adequate size tissue samples. Full thickness intestinal biopsies may be required in a very limited number of cases in order to establish the correct diagnosis.

Many cats respond favorably to treatment for intestinal lymphoma, especially with the low grade or chronic lymphocytic type. Clinical signs can be very similar to cats with IBD. Therefore, it is strongly recommended that cats with chronic GI signs undergo a biopsy procedure as early as possible, so that the correct diagnosis can be established and the best course of therapy be made available for each individual cat.

Multi-agent chemotherapy is recommended for all cats with GI lymphoma. Surgery is done only if there is an isolated mass that is causing some degree of luminal obstruction. Survival times in excess of 12 to 18 months are not unusual. In some cats the response is somewhat shorter (three to six months). The prognosis for longer survival time is much better if the diagnosis is made before clinical signs become chronic and debilitation results.

One study has reported excellent results in cats with chronic lymphocytic lymphoma using a protocol of prednisone (10 mg PO per cat per day) and chlorambucil (Leukeran) at a dosage of 15 mg/m2 PO, once every day for 4 days, repeated every 3 weeks. Sixty-nine percent of the cats with lymphocytic lymphoma treated with this regimen achieved a complete remission. The median disease free interval for cats that achieved complete remission was 20.5 months (range, 5.8-49 months). The median survival for all cats with lymphocytic lymphoma treated with chemotherapy was 17 months (range, 0.33-50 months). Cyclophosphamide (Cytoxan) was used for rescue in some of the cats that were entered in this protocol (225 mg/m2, PO, every 3 weeks). For further reference on this protocol, see Richter,K: Feline gastrointestinal lymphoma, ACVIM Proceedings 2001, p. 547-549.

The protocol that I have used most often was originally published by Cotter in 1983. Dosage levels have been modified slightly since that time. This protocol utilizes cyclophosphamide, oncovin, and prednisone or prednisolone (COP). This protocol can be easily managed in any practice setting. Vincristine is administered intravenously at a dose of 0.5-0.75 mg/m2 once weekly for 4 consecutive weeks and then once every 3 weeks. The initial doses are often decreased by approximately 25 percent for cats that are inappetent or debilitated. If well tolerated the dose can then be gradually increased. Care is taken to ensure that none of the vincristine is given extravascularly. The average volume that is administered is quite low (0.1 to 0.15 ml for many cats, using a vincristine concentration of 1 mg/ml). Cyclophosphamide is given orally at a single dose of 225 mg/m2 every 3 weeks (50 mg tablets are used with dosage adjusted to the nearest 25 mg on the low side of the calculated dose). Prednisone or prednisolone (preferred) is given orally at 10 mg per cat per day. Although cyclophosphamide and vincristine can be given on the same day I often prefer to have the owner administer the cyclophosphamide 2 to 3 days after the oncovin. A CBC is done several times during the first month and then every 3 weeks to be sure that adequate granulocytes are present before treatment. At least 3,000 granulocytes/ul must be present before cyclophosphamide is given. If the granulocyte count drops to less than 1,000/ul 5 to 7 days after cyclophosphamide, the dose for subsequent treatments is reduced by 25 percent. The highest non-toxic dose is most likely to result in the greatest tumor cell kill.

The COP protocol is generally well tolerated, although side effects may occur and dosage or interval adjustments may be necessary. Side effects of COP in cats may include anorexia, vomiting, lethargy, and severe tissue irritation if any vincristine is given extravascularly. Also, the haircoat may become thinner, but complete hair loss does not occur. Cats do tend to lose whiskers. Cats should be carefully observed for sepsis especially during the induction phase. Prophylactic antibiotics are not indicated, but any infections that occur should be treated aggressively. Advantages of this protocol include hospital visits at only 3 week intervals after the first 4 weeks, lower cost to the owner, and a treatment interval that allows recovery of normal cells between treatments. I would like to emphasize that with careful monitoring and use of a dosage schedule that is tailored to each individual cat few problems are encountered It is my general practice to encourage owners of most cats with GI lymphoma to pursue treatment that includes chemotherapy.

Nutritional and metabolic support are also important. If inappetence is a problem cyproheptadine can be administered as an appetite stimulant (1 to 2 mg PO every 12 to 24 hours) on an as needed basis (long-term if necessary). If there is concurrent renal disease with azotemia or if dehydration is a problem owners are taught how to administer subcutaneous fluids at home (e.g., lactated Ringer's 100 to 150 ml every 24 hours to 48 hours, based on each individual cat's needs). Injections of B complex vitamins are sometimes helpful as well.

Rarely chemotherapy can be discontinued after one year. This is done only if follow-up endoscopic intestinal biopsies indicate that there is no remaining lymphoma. Most cats remain on treatment for the remainder of their lives. If chemotherapy is poorly tolerated and reduced dosages and increased intervals between treatment times are unsuccessful in adequately decreasing side effects chemotherapy should be suspended. Prednisone should be continued however because it may help maintain remission for a period of time. L-asparaginase can also be used if cyclophosphamide and vincristine are poorly tolerated. Doxorubicin (Adriamycin) can also be used in cats.

For clinicians who are inexperienced in administering chemotherapy, nor who have not treated many cats with intestinal lymphoma, it is recommended that a veterinary oncologist or internist be consulted for guidance on protocol selection and ongoing management. Many cats with intestinal lymphoma can be managed successfully for some period of time!



© 2007 - Todd R. Tams, DVM, Dipl. AVCIM - All rights reserved