Treatment of severe parvoviral enteritis (Proceedings)

Without treatment, canine parvovirus (CPV) infection is often a fatal disease ending in severe dehydration, endotoxic or septic shock, and multiple organ failure. With aggressive therapy and supportive care, however, a survival rate of 85-95% has been achieved at our hospital. Following are recommendations which should be considered in the treatment of all dogs infected with CPV.

Fluid Therapy

Fluid replacement for losses incurred through vomiting and diarrhea is the cornerstone of treatment for dogs with CPV enteritis and should be continued until oral intake is resumed.

The initial fluid of choice is a balanced electrolyte solution. The route and rate of initial fluid therapy varies with the patient. If CPV infection has resulted in hypovolemic shock, a rapid intravenous fluid bolus of up to 90 ml/kg/hr may be necessary to restore perfusion. If circulatory collapse prevents venous access, fluids can be administered initially via a 20 g 1½" spinal needle placed in the intraosseous space in the shaft of the femur. Once circulation has improved with intraosseous fluids, an intravenous catheter can be placed for continued fluid therapy. It is important to note that subcutaneous fluids will not be absorbed by animals with severe dehydration or circulatory collapse because of peripheral vasoconstriction. In addition, hypertonic solutions should be avoided in dehydrated patients.

Animals that are dehydrated but not in shock should be rehydrated over 4 hours. The amount of fluid given is estimated by the following formula: % dehydration x body weight (kg) = # liters to replace deficit. Maintenance requirements (2-3 ml/kg/h), as well as continuing losses from vomiting and diarrhea, must also be taken into consideration during initial fluid therapy.

Once perfusion has been restored, the fluid rate can be decreased to 4 - 6 ml/kg/h in most patients. Urine output should approximate 1 - 2 ml/kg/h and urine specific gravity should range from 1.015 - 1.020. Fluid therapy must be adjusted to replace continuing losses through vomiting and diarrhea. As fluid losses subside, the fluid rate is gradually tapered.

Many puppies, particularly toy breeds or septic animals, are prone to hypoglycemia with CPV enteritis. Following rehydration, 2.5 - 5% dextrose can be added to the balanced electrolyte solution (100 ml of 50% dextrose added to 1 liter will make a 5% solution).

Puppies with anorexia, vomiting, and diarrhea are also prone to hypokalemia which can result in muscle weakness, gastrointestinal ileus, polyuria, cardiac arrhythmias, and general malaise. Serum potassium should be monitored daily in these patients. If it is low, potassium chloride should be added to the fluids according to recommendations in medical texts. If potassium is in the normal range, 14-20 mEq KCl should be added to each liter to prevent the levels from dropping.

Puppies with CPV enteritis often experience severe protein losing enteropathy because of destruction of the intestinal villi. If the albumin decreases below 1.5 g/dl, the total protein decreases below 3.5 g/dl, or the animal develops evidence of pitting edema, administration of a colloid fluid is indicated to maintain intravascular oncotic pressure. If the puppy is anemic through parasitism or gastrointestinal blood loss, a transfusion of whole blood (preferably from a recovered animal with a high CPV antibody titer) is indicated. A dosage of 10 - 20 ml/kg can safely be administered to most puppies over a 4 hour period. If the puppy is not anemic but is hypoproteinemic, a plasma transfusion (10 - 20 ml/kg IV) should be administered through an in-line filter over 2 - 4 hours. In addition to providing oncotic components, both whole blood and plasma contain antibodies and serum protease inhibitors which may be beneficial in neutralizing circulating virus and controlling the systemic inflammatory response associated with the disease. Plasma and blood products are available though commercial blood banks.

If natural colloids are not available, puppies with decreased total protein and edema should receive a synthetic colloid, such as hetastarch or dextran 70. To avoid potential volume overload, the dosage of 20 ml/kg/day should not be exceeded, but colloid infusions can be repeated after 24 hours if needed. Colloids can be given rapidly to patients in shock or as a continuous infusion over 24 hours to more stable patients. General guidelines are to supply one third of fluid needs as a colloid and two thirds as a crystalloid solution.

Systemic Antibiotics

Hemorrhagic diarrhea and mucosal sloughing are commonly seen in dogs with CPV enteritis, and indicate breakdown of the GI mucosal barrier which can lead to bacterial translocation, endotoxemia, and sepsis. Severe neutropenia often coincides with the severe enteritis contributing to the risk of systemic sepsis. For these reasons, intravenous broad-spectrum, bacteriocidal antibiotics are indicated in severely affected puppies. A combination of an aminoglycoside (gentamicin 2.2 mg/kg q 8 h or amikacin 10 mg/kg q 8 h) with a beta lactam antibiotic (ampicillin 22 mg/kg q 8 h or cefazolin 22 mg/kg q 8 h) provides excellent coverage against gram negative and anaerobic bacteria which may originate from the gut. Aminoglycosides can cause acute renal failure and should only be administered after rehydration has been accomplished. Once daily dosing of aminoglycosides (6.6 mg/kg gentamicin or 30 mg/kg amikacin q 24) may minimize renal damage while maximizing bacterial kill because of high peak and low trough antibiotic concentrations, but the high dose should never be given to dehydrated patients. Urine sediment should be monitored for the appearance of proteinuria or renal tubular casts, which would warrant discontinuation of aminoglycoside therapy. Enrofloxacin (5 mg/kg q 12 h) is an alternative choice to the aminoglycosides. It has an excellent gram negative spectrum, but is not approved for intravenous use and may cause cartilage abnormalities in young growing animals. The author has not encountered any problems with enrofloxacin when it is diluted 1:1 with saline and administered slowly IV for a relatively short term (usually 3 - 5 days) in puppies with CPV enteritis. Rapid administration may cause vomiting. The drug can be discontinued when leukopenia resolves.

Mildly affected dogs with an adequate white blood cell count generally do not require combination antibiotic therapy. Appropriate antibiotic choices include ampicillin, cephalosporins, or trimethoprim-sulfa in these patients.

Anti-Emetics

Vomiting often decreases when oral intake of food and fluid is discontinued, but in some patients the problem persists and must be treated to reduce fluid losses and increase patient comfort.

The two antiemetics most commonly used in dogs with CPV enteritis are metoclopramide and chlorpromazine. Metoclopramide is a gastric promotility drug which can reduce vomiting by stimulating gastric emptying and inhibiting the chemoreceptor trigger zone. The promotility effect may prevent gastric atony and ileus from occurring in dogs with CPV. Metoclopramide can be added to the intravenous fluids or administered in a separate drip at a dosage of 1.0 - 2.0 mg/kg/24 hours and given as a constant rate infusion.

If metoclopramide is ineffective in controlling vomiting, a more effective antiemetic is chlorpromazine. This drug is a phenothiazine derivative and acts on the emetic center, the chemoreceptor trigger zone, and peripheral receptors to reduce the vomiting reflex. The recommended dosage is 0.1 mg/kg IV q 4-6 h or 0.2 - 0.5 mg/kg IM q 6 - 8 h as needed. Phenothiazine derivatives can cause hypotension and systemic vasodilation via their alpha adrenergic blocking effect and should only be given after the patient is well hydrated.

In dogs with intractable vomiting, metoclopramide and chlorpromazine may be used together, but only with caution because the potential for side effects may increase. Dogs should be monitored for restlessness, hyperactivity, bizarre behavior, or extreme drowsiness and if any of these signs occur anti-emetic therapy should be discontinued. Intractable vomiting may respond to treatment with the serotonin antagonist odansetron (Zofran, Cerenex Pharmaceuticals, Research Triangle Park, NC; 0.1 - 0.15 mg/kg IV q 6 - 12 h). Although the drug is highly effective and safe, it is also very expensive. Anticholinergic drugs should not be administered to dogs with CPV enteritis, as they increase the potential for gastric atony, ileus, and intussusception of an irritated bowel segment. Dogs with intractable vomiting should always be evaluated for foreign body obstruction or intussusception. Other causes of continued vomiting include reflux esophagitis and acute pancreatitis. Reflux esophagitis may be manifested by signs of drooling, nausea, and exaggerated swallowing motions. Treatment involves administration of a systemic antacid (famotidine 0.5 mg/kg IV or ranitidine 2 mg/kg IV q 12 h) and an oral suspension of sucralfate (1 gram dissolved in 10 ml warm water q 8 h). Ideally, the antacid should be administered 1 - 2 hours after sucralfate. The new antiemetic maripotan (Cerenia, Pfizer, Inc) is not approved for puppies less than 16 weeks, but it has been used off-label by many veterinarians to treat puppies with CPV. The drug inhibits the vomiting center and the chemo-receptor trigger zone, and is less expensive than the serotonin antagonists. The dose is 1 mg/kg SC q 24 h. It can also be diluted with saline and given IV. It has been very effective in the author's hands, and has not been associated with any signs of toxicity.

Aggressive Adjunctive Treatments

Bacterial endotoxemia is believed to be an important factor in the terminal acute shock which occurs in severe cases of CPV. A polyvalent equine origin antiserum against LPS endotoxin is available for use in small animals (SEPTI-serum, Immvac, Inc., Columbia MO 75201). It is recommended that the product be administered over 30 - 60 minutes at the dosage of 4.4 ml/kg and diluted 1:1 with intravenous crystalloid fluids. Antiendotoxin should be most effective if it is administered before antibiotic therapy because circulating plasma LPS concentrations can increase dramatically following antibiotic kill-off of gram negative bacteria. Patients receiving equine origin antiserum must be observed closely during administration for signs of anaphylaxis. If a second administration of antiserum is deemed necessary, it should be given within 5 - 7 days following the initial treatment. After that time, a severe immunologic reaction is more likely to occur.

In one report, the use of recombinant granulocyte colony stimulating factor (rG-CSF) in dogs with leukopenia secondary to CPV enteritis was described. The recommended dosage was 5 - 10 ug/kg per day SC. Animals that responded generally showed an increase in white blood cell count within 24 hours. Unfortunately, there was no increase in survivability with use of this product, and it is very expensive (approximately $130 - $150 to treat a puppy).

Anecdotal reports describe the use of convalescent serum (1.1 - 2.2 ml/kg IV or SC) collected from CPV-recovered dogs in an effort to provide passive immunity to exposed or infected dogs. Research is needed to determine the efficacy and safety of this practice.

The most recent adjunctive therapy to be recommended is oseltamivir (Tamitlo). This product is a neurominidase inhibitor that has anecdotally been reported to reduce the severity of disease in puppies with CPV. Neurominidase is necessary for bacteria to adhere to the intestinal endothelium and penetrate mucin layers. By inhibiting neurominidase, Tamiflu may reduce bacterial translocation, sepsis, and endotoxemia in dogs with CPV. In a study done at Auburn University, dogs with CPV that were treated with Tamiflu had increased weight gain and 100% survival rate compared to dogs that received a placebo (weight loss and 81% survival). The dosage of Tamiflu is 1 mg/lb PO q 12 h. The incidence of vomiting is reduced if the drug is diluted 50:50 with water or chicken broth immediately prior to administration.

Eradication of Intestinal Parasites

The presence of intestinal parasites has been identified as a factor which can exacerbate CPV infection by enhancing intestinal cell turnover and subsequent viral replication. Fecal samples should be evaluated to identify coccidia, Giardia sp, hookworms, roundworms, or whipworms. Appropriate oral therapy can be initiated as soon as vomiting ceases, or ivermectin (250 ug/kg SC) can be given to non-Collie mix dogs.

Nutrition

Dogs with severe CPV enteritis may have a prolonged course of hospitalization and may require nutritional support to prevent catabolism and immune dysfunction associated with negative nitrogen balance.

Partial parenteral nutrition (PPN) does not supply all of the patient's nutrient needs but can provide short term support for animals that are expected to recover soon. The advantage of PPN solutions is that they can be delivered through a peripheral vein rather than through a large central vein. PPN solutions are usually given at a maintenance dose (60 ml/kg/day) and additional fluid needs are met with crystalloid solutions as described earlier. Procalamine (McGaw, Inc.) is a commercial product which contains 3% amino acids, 3% glycerol, and electrolytes. A "homemade" PPN solution can be made by adding 300 ml of 8.5% amino acid solution (Travenol, Baxter, Inc.) to 700 ml lactated Ringer's solution with 5% dextrose. The addition of lipid emulsions is controversial. Although lipids are rich in caloric content, they have been associated with immunosuppression through impairment of reticuloendothelial function and reduction in white blood cell phagocytosis.

A common complication of PPN solutions is catheter phlebitis because the solutions are hypertonic. Catheters must be placed aseptically and the site monitored carefully for redness, swelling or pain. Solutions containing dextrose should be tapered off gradually to prevent rebound hypoglycemia.

Most practitioners offer water after vomiting has been absent for 12 - 24 hours. Early enteral nutrition is important to promote intestinal regeneration. A liquid diet (Clinicare) can be offered initially, or a gruel can be made with an easily digestible high carbohydrate, low fat diet. The addition of glutamine powder (0.5 g/kg divided q 12 hours) to drinking water may promote GI healing in dogs recovering from CPV enteritis. Various veterinary recovery diets are available for post hospital care. The puppy may have temporary intestinal malabsorption and protein-losing enteropathy until intestinal villi are repaired. Initial feeding should consist of small amounts of an easily digestible low fat diet fed frequently. The normal diet is gradually re-introduced after appetite and stool have returned to normal. Following recovery, immunity to parvo virus infection lasts at least 2 years, and may even be lifelong.