Assessing the Efficacy of Maropitant Versus Ondansetron in the Treatment of Dogs with Parvoviral Enteritis
ABSTRACT
Antiemetics are commonly prescribed during the treatment of canine parvoviral enteritis. This blinded, randomized prospective study compared the quality of clinical recovery and duration of hospitalization in canine parvoviral dogs receiving either maropitant (1 mg/kg [0.45 mg/lb] IV q 24 hr, n = 11) or ondansetron (0.5 mg/kg [0.23 mg/lb] IV q 8 hr, n = 11). All dogs were treated with IV fluids, cefoxitin, and enteral nutrition. Frequency of vomiting and pain scoring were recorded twice daily. Rescue analgesics and antiemetics were administered as dictated by specific pain and vomiting criteria. Clinical severity scoring, body weight, and caloric intake were monitored daily. When comparing dogs receiving maropitant versus ondansetron, respectively, there were no differences in duration of hospitalization (3.36 ± 0.56 versus 2.73 ± 0.38 days, P = .36), requirement of rescue antiemetic (3/11 versus 5/11 dogs, P = .66), duration of vomiting (5 versus 4 days, P = .65), or days to voluntary food intake (2 versus 1.5 days, P = 1.0). Results of this study suggest that maropitant and ondansetron are equally effective in controlling clinical signs associated with parvoviral enteritis.
Introduction
Parvoviral enteritis is an important cause of illness in unvaccinated dogs, with mortality approaching 90% without medical intervention.1 Mortality can be substantially decreased to <10% with prompt veterinary attention.2 Given the potentially high risk of death, as well as significant costs associated with veterinary care, clients may elect relinquishment or euthanasia. Implementing canine parvoviral (CPV) treatment protocols that optimize care and limit hospitalization and financial expense may help prevent these negative outcomes in dogs with CPV.
Currently accepted treatment protocols include reestablishment of intravascular volume and hydration status, nutritional support, antimicrobials, and antiemetic therapy. Because vomiting can be present and result in life-threatening dehydration and electrolyte abnormalities, parenteral antiemetics are commonly used in CPV dogs.2 Opioid analgesics may also be required to control visceral pain but can exert negative effects on gastrointestinal motility and worsening nausea.3 Alternatively, untreated abdominal pain may further complicate the disease and increase the risk for severe infection and death.4 Proper management of both nausea and abdominal pain often present a therapeutic challenge to practitioners when treating this disease.
Ondansetron is a parenteral antiemetic commonly used off-label to treat nausea and vomiting, exerting its effects through antagonism of the serotonin type 3 on the vagal nerve terminals and centrally within the chemoreceptor trigger zone.5 Maropitant, alternatively, is approved for use in dogs and exhibits potent antiemetic effects through antagonism of neurokinin-1 (NK-1) receptors both peripherally and within the vomiting center.6 A potential added benefit of maropitant is modulation of visceral analgesia via NK-1 receptor antagonism, which has been previously demonstrated in dogs undergoing abdominal surgery.7,8 Other potential advantages of maropitant include once-daily dosing, as well as administration via a subcutaneous or IV route. Maropitant lacks undesirable side effects at published doses and also demonstrates a large margin of safety.9 The comparative efficacy of maropitant and ondansetron has been experimentally studied in dogs, with maropitant demonstrating superior efficacy in preventing centrally induced emesis.10 With recent label changes allowing the use of maropitant in puppies as young as 8 wk of age, the role of maropitant as a primary antiemetic in the treatment of parvoviral enteritis has yet to be clinically evaluated.
This prospective study compared the effects of maropitant versus ondansetron on the clinical recovery of dogs with parvoviral enteritis. The hypothesis was that maropitant would result in an improved clinical recovery, as defined by the study objectives, when administered to dogs with CPV. The primary objective was to compare frequency and duration of vomiting in dogs receiving maropitant versus those receiving ondansetron during treatment for CPV. Secondary objectives included comparison of pain scores during hospitalization, changes in body weight (BW) during hospitalization, days until return to voluntary food intake, and duration of hospitalization.
Materials and Methods
Dogs
Client-owned dogs were admitted to the Veterinary Teaching Hospital at Colorado State University for hospitalized treatment of parvoviral enteritis. Inclusion criteria were clinical signs consistent with active parvoviral infection (e.g., vomiting, diarrhea, anorexia, and/or lethargy), a positive snap enzyme-linked immunosorbent assay parvoviral test, and informed written owner consent. Dogs were excluded if vaccination was known to have occurred ≤14 days prior to admission, if treatment had been instituted prior to arrival at the Veterinary Teaching Hospital at Colorado State University, or if comorbidities capable of affecting outcome or length of hospitalization (e.g., intestinal intussusception, concurrent systemic disease) were identified (Figure 1). This study was approved by the Institutional Animal Care and Use Committee.
Citation: Journal of the American Animal Hospital Association 54, 6; 10.5326/JAAHA-MS-6650
Historical information collected upon admission included age, breed, sex, duration, and severity of clinical signs, as well as any previous vaccination or deworming. Prior to therapeutic intervention, baseline parameters (physical examination findings, body weight, clinical severity score [Table 1], and pain score [Figure 2]) were recorded. Each dog had a fecal flotation performed to identify coinfection with internal parasites. Venous blood was obtained for a baseline packed cell volume, total solids concentration (TS), blood gas and electrolyte panel, and complete blood count.
Citation: Journal of the American Animal Hospital Association 54, 6; 10.5326/JAAHA-MS-6650
Treatment Protocol
All dogs were hospitalized within the small animal isolation unit. Vascular access was immediately established using the cephalic or jugular vein. Dogs displaying poor perfusion parameters received rapid fluid resuscitation with IV crystalloidsa and/or colloidsb. Intravascular volume resuscitation was performed at the discretion of the primary clinician (L.S.), and dogs were resuscitated until perfusion parameters normalized. Following cardiovascular stabilization, all dogs received maintenance IV fluid therapy using a buffered isotonic solutiona at a rate of 120 mL/kg/day (55 mL/lb/day). Dextrosec and potassium chlorided supplementation were provided within the base fluid using daily blood glucose and electrolyte results as a guide. Ongoing fluid loss from vomiting or diarrhea was visually estimated and immediately replaced using 0.9% NaCle. Colloidal therapyb was provided at 0.8 mL/kg/hr (0.36 mL/lb/hr) if clinically required to maintain cardiovascular stability, or if TS < 3.0 mg/dL.
At hospital admission, dogs were randomized using a computer-generated spreadsheetf to receive either maropitantg (1 mg/kg [0.45 mg/lb] IV q 24 hr) or ondansetronh (0.5 mg/kg [0.23 mg/lb] IV q 8 h) as their primary antiemetic. The maropitant and ondansetron doses used during the study are the antiemetic doses recommended by the pharmaceutical company. One study author (L.S.), not associated with the team performing blinded clinical scoring, was responsible for administration of all antiemetics and analgesics. Using specific pain and nausea criteria, rescue medications were administered by the nursing team as required. If the dog vomited three or more times within a 6 hr period while receiving its primary antiemetic, the other antiemetic (either maropitant 1 mg/kg [0.45 mg/lb] IV or ondansetron 0.5 mg/kg IV [0.23 mg/lb]) was administered as a rescue antiemetic during that time. Rescue analgesia was provided as a single dose using buprenorphinei (0.02 mg/kg [0.01 mg/lb] IV) if a dog had a pain score ≥2/4.
Additional treatments consisted of antimicrobial therapy (cefoxitinj 22 mg/kg [10 mg/lb] IV q 8 hr) and enteral nutrition q 8 hr. If dogs did not demonstrate a voluntary interest in food, they were syringe fed 1 mL/kg (0.45 mL/lb) of a critical-care formulak. The presence and/or absence of voluntary appetite, type of food administered, and kilocalories ingested were quantified at each feeding. Percentage of resting energy requirement (RER) consumed per day was recorded for each dog. If intestinal parasites were identified on fecal flotation, appropriate deworming treatments were administered. The perineal area was evaluated q 12 hr for redness, irritation, or scalding. If present, a zinc oxide emollientl was applied q 8–12 hr. Any other medications deemed necessary during hospitalization were also recorded.
Clinical Scoring
A previously described scoring system for parvoviral enteritis was used to semiquantify clinical disease severity.11 General attitude, appetite, vomiting, and diarrhea were awarded numerical values based on severity. A daily composite clinical score was calculated as the sum of the above scores and recorded for each dog (Table 1). Clinical severity scores and body weight were obtained upon hospital admission and subsequently every 24 hr for each dog. Percent change in body weight was calculated based upon initial and final body weight during hospitalization ([final BWkg – initial BWkg / initial BWkg]).
Every 12 hr, an individual blinded to treatment group assignment performed pain and nausea scoring for each dog. The pain scoring system used was an acute pain scale developed at Colorado State University, which uses a combination of behavioral pictures and descriptions. This scale asks the evaluator to assign the dog a number between 0 and 4, with 0 indicating no pain and 4 corresponding to the worst pain (Figure 2). Pain score could be assessed more frequently than q 12 hr, based upon clinical indication. Additional information recorded for each dog included the highest clinical severity score during hospitalization, duration of clinical signs (defined as a clinical severity score ≥2), and average daily pain score.
Statistical Analysis
Data was analyzed to compare dogs receiving maropitant versus ondansetron using computerized softwarem. A power calculation was performed using data from a previous study that compared maropitant and ondansetron (among other antiemetics) in preventing emesis induced by centrally or peripherally acting emetogens in dogs, which determined that a minimum of 10 dogs per group would be needed to statistically evaluate the current study objectives.10 The mean duration of hospitalization (days) and mean change in body weight during hospitalization (kilograms) were compared between groups using a two-tailed t test. Median days to voluntary food intake, maximum clinical severity score, duration of clinical signs (days), duration of vomiting (days), and maximum number of vomiting episodes per day were compared using a Wilcoxon’s rank sum test. A Fisher exact test was used to compare the percentage of dogs who required a rescue antiemetic during hospitalization. Serial evaluation of packed cell volume/TS, RER intake, and pain score were evaluated using repeated analysis of covariance measures.
Results
Twenty-two dogs were enrolled in the study, of whom 15 were female (2 sexually intact and 13 spayed) and 7 were male (all sexually intact). Median age was 6 mo (range 9 wk to 1.6 yr). Breeds represented included mixed-breed (n = 11), Labrador retriever (n = 3), Pekingese (n = 2), Staffordshire bull terrier (n = 1), golden retriever (n = 1), boxer (n = 1), miniature poodle (n = 1), Chihuahua (n = 1), and shih tzu (n = 1). Fecal flotation diagnosed two dogs with Isospora, one dog with Ancyclostoma, and one dog with Taenia. All the dogs requiring treatment for internal parasites had been randomized to receive maropitant as a primary antiemetic.
There was no difference between groups in baseline clinical severity score (maropitant group 6, range 5–9; ondansetron group 7, range 5–10; P = .6). There was also no difference (P = .36) in mean duration of hospitalization when comparing dogs treated with maropitant (3.36 ± 0.56 days) with those treated with ondansetron (2.73 ± 0.38 days). Median duration of clinical signs during hospitalization was 3 days for both groups (range 2–6 days for maropitant group, 2–7 days for ondansetron group, P = .92). Both groups had a maximum clinical severity score of 8 during hospitalization (range 5–9 for maropitant group, 5–10 for ondansetron group, P = .6). All dogs in both groups survived to hospital discharge.
There was no difference in median duration of vomiting (maropitant group 5 days, range 0–6 days; ondansetron group 4 days, range 1–5 days; P = .65), maximum number of vomiting episodes per day (maropitant group 1 episode, range 1–7 episodes; ondansetron group 3 episodes, range 1–11 episodes; P = .12), or days from hospital admission to voluntary food intake (maropitant group 2 days, range 0–4 days; ondansetron group 1.5 days, range 1–6 days; P = 1.0). There was also no difference in mean percentage of calculated daily RER percent consumed between groups (25.5 ± 13% in the maropitant group versus 34.55 ± 9.64% in the ondansetron group, P = .11). There was no difference in body weight between groups at admission or change in body weight (0.003 ± 0.45 kg in the maropitant group versus 0.06 ± 0.66 kg in the ondansetron group, P = .06) during hospitalization.
Data regarding pain scoring across groups was mostly collected on the first 4 days of hospitalization; therefore, only these days were included in statistical analysis. There was no difference when comparing mean pain score (1.25 ± 0.18 versus 1.10 ± 0.16, P = .87) in dogs receiving maropitant versus ondansetron, respectively. No dogs required rescue analgesia during hospitalization due to pain.
Of dogs receiving maropitant, 3/11 (27.3%) were provided a rescue antiemetic during hospitalization, versus 5/11 (45.5%) of dogs receiving ondansetron (P = .66). Additional treatments administered included fenbendazolen 50 mg/kg (22.7 mg/lb) per os (PO) q 24 hr for one dog, praziquantelo 5 mg/kg (2.3 mg/lb) PO once for one dog, and sulfadimethoxinep 55 mg/kg (25 mg/lb) PO once followed by 25 mg/kg (11.4 mg/lb) PO q 24 hr in two dogs for intestinal parasites. Four dogs (one dog receiving maropitant, three dogs receiving ondansetron) had hematemesis during hospitalization and concurrently received famotidineq 0.5 mg/kg (0.23 mg/lb) IV q 12 hr.
Discussion
Results of this study suggest that maropitant and ondansetron are equally effective when controlling emesis associated with parvoviral enteritis in dogs. The decreased frequency of administration required with maropitant, as well as various routes of administration (subcutaneously, IV), make it an attractive antiemetic for use in the clinical setting. This study administered maropitant via an IV route for daily administration, with no noted adverse effects. As related to their antiemetic properties, this study did not identify any differences between maropitant and ondansetron when evaluating duration of vomiting, maximum number of vomiting episodes per day, days to voluntary food intake, or requirement of a rescue antiemetic.
An important clinical limitation during this study was an inability to differentiate vomiting from regurgitation. Many vomiting episodes were unwitnessed and could not be confirmed by the technical staff. As neither maropitant nor ondansetron would decrease regurgitation in CPV cases, this might provide further explanation as to a lack of difference between the two groups. A final explanation for lack of difference between groups would be a lack of statistical power; the wide range and non-Gaussian distribution of vomiting frequency within the groups precluded the authors’ ability to identify a significant difference in vomiting when comparing maropitant and ondansetron.
This study did not use a control group (i.e., no antiemetic) when evaluating overall effect of antiemetic on outcome. A previous study found that many dogs with CPV-associated enteritis had persistent vomiting despite antiemetic administration, and that dogs receiving an antiemetic had a longer duration of hospitalization.2 This study did not evaluate maropitant or ondansetron specifically regarding overall outcome or emesis control. Although the apparent difference in antiemetic-treated dogs and other dogs likely reflects disease severity, antiemetic adverse events cannot be completely ruled out. For this study, the authors felt that including an antiemetic in the treatment of CPV would be standard-of-care, although this recommendation has not received scientific validation. Additional studies evaluating the effect of an antiemetic on survival and secondary outcomes (i.e., duration of hospitalization, hydration status, return of voluntary appetite) would be needed to further address the larger role of antiemetics in the treatment of CPV. Trending colloid osmotic pressure or serum albumin concentration could also be helpful in assessing nutritional goals and other treatment interventions, including colloidal support.
A previous study identified the value of early enteral nutrition on the clinical recovery from CPV.11 It is possible that improved emesis control may facilitate tolerance of enteral nutrition, although that was not an objective of the current study. Ideally, caloric intake would have been optimized through use of a nasoesophageal feeding tube. The method used in the current study (syringe feeding) may lead to additional adverse events including ineffective caloric intake, food aversion, and aspiration pneumonia. Larger studies would be needed to confirm the effects of antiemetics alongside more aggressive nutritional support on severity of vomiting and clinical outcome in dogs with CPV.
Previous studies have shown that maropitant provides analgesia because of its action on the NK-1 receptors, and more specifically, maropitant may be used to help manage visceral pain in dogs during the operative period.7,8 It is unknown whether maropitant may help alleviate the visceral pain associated with CPV. Given the inherent subjectivity associated with pain evaluation in animals, an attempt was made to standardize pain assessment using a scoring system that uses both pictorial and descriptive terms to quantify pain. With this method, we were unable to detect a difference between dogs receiving maropitant and ondansetron when comparing mean pain scores. This may have been because of a lack of scoring system sensitivity, a high degree of interobserver variability when using the scoring system, an inability of the analgesic properties of maropitant to overcome the abdominal pain associated with parvovirus, or insufficient power to detect a difference between antiemetics.
One reported concern regarding the use of maropitant in puppies is the observation of bone marrow hypocellularity when the drug was administered at high doses. Drug labeling was subsequently changed to a minimum age of 8 wk in dogs. More recent drug summaries support an adequate safety profile for maropitant when administered at 1 mg/kg by subcutaneous injection once daily, in puppies as young as 8 wk of age, for up to 5 consecutive days.12 Although leukopenia is commonly observed in young dogs with CPV, this study did not compare complete blood count findings between maropitant and ondansetron groups. All dogs receiving maropitant appeared to have a normal and orderly return of white blood cells during their CPV recovery. Additional follow-up was not obtained to determine the long-term effects of CPV and/or maropitant administration on bone marrow cellularity.
Conclusion
Maropitant appears to be equally as effective in controlling clinical signs of parvovirus when compared with ondansetron. Additionally, this study found that maropitant can be administered intravenously in puppies as young as 8 wk of age, and for up to 6 consecutive days, with no noted adverse effects. The high survival rate observed in this study supports previous findings that parvoviral enteritis can be successfully managed with aggressive supportive care that includes parenteral antiemetics, antimicrobials, and appropriate fluid therapy based upon close monitoring of blood electrolytes. Additional studies would be required to further delineate the effects of individual treatment components on overall outcome in CPV dogs.
Flow diagram illustrating the study population enrolled to examine the effects of maropitant versus ondansetron on clinical recovery from CPV. CPV, canine parvoviral; ELISA, enzyme-linked immunosorbent assay.
Pictorial and descriptive pain scale used at the CSU-VTH. CSU-VTH, Veterinary Teaching Hospital at Colorado State University.
Contributor Notes
