Managing vomiting: Examining the physiology, common causes, and control in dogs (Sponsored by Pfizer Animal Health)

Sponsor's note: The objective of this roundtable discussion is to share the current clinical, medical, and scientific understanding of vomiting and its physiology, cause, and control in companion animal medicine. Due to the paucity of FDA-approved products, the discussion includes the extra-label use of human pharmaceuticals.

Topics discussed:

• The pathophysiology of vomiting

• The importance of the central and peripheral pathways

• Common causes and conditions that induce vomiting

• The role of the chemoreceptor trigger zone

• The diagnostic workup of a vomiting patient

• Treatment for vomiting patients

• Use of antiemetic therapy

• Changes in nutrition and diet

Physiology and causes of vomiting

Dr. Michael Leib: Let's start by discussing the physiology of vomiting, including the role and importance of the central and peripheral pathways.

Dr. Albert E. Jergens: Simplistically, we can subdivide the pathophysiology of vomiting by cause:

1. Blood-borne toxins or metabolites that stimulate the chemoreceptor trigger zone

2. Input from the central nervous system

3. Stimuli that trigger responses from the vestibular system

4. Visceral vagal nerves, "which send afferent signals from abdominal parenchyma in response to distention, irritation, or inflammation.

The spectrum of clinical cases I see includes vomiting from dietary causes, pancreatitis, inflammatory bowel disease, and liver disease in dogs and cats. I also see chemoreceptor trigger zone-induced vomiting from drugs, blood-borne toxins, or problems secondary to metabolic disturbances (e.g., uremia or hyperbilirubinemia). In my experience, vestibular-induced causes and central nervous system disturbances that cause vomiting are infrequent. Many causes for acute vomiting are self-limiting and will not require specific therapy.

Dr. David Twedt: A lot of veterinarians associate vomiting with the gastrointestinal tract, but receptors also exist in the peritoneum, kidneys, urinary bladder, and thoracic cavity. Anything in those cavities could cause vomiting.

Leib: With gastrointestinal visceral disease, the duodenum is extremely important. Sometimes the cause of the vomiting may be the duodenum or the rest of the small bowel—not the stomach.

Dr. Kenneth Simpson: One of the more common causes of vomiting, apart from uremia, is the rapid administration of intravenous drugs.

Leib: Does anyone think that with disorders such as gastritis, enteritis, or gallbladder disease, the vomiting center may receive input from both visceral afferent nerves and the chemoreceptor trigger zone?

Jergens: I've performed gastrointestinal endoscopy in a handful of vomiting, uremic animals with gastric erosions or obvious mucosal abnormalities. When uremic toxins stimulate the chemoreceptor trigger zone with concurrent gastric mucosal disruption, both conditions may stimulate vomiting. The same is true for acute pancreatitis where mucosal inflammation and metabolic disturbances may contribute to vomiting episodes. Many common diseases have multiple modalities.

Dr. David Williams: We often don't know if the cause is a gastric, pancreatic, or small intestinal modality. When patients have abnormalities in two or three locations, it's sometimes hard to determine a single cause for the vomiting.

Twedt: Inflammatory bowel disease or Helicobacter gastritis cases are probably just peripheral in nature. But in animals with acute gastroenteritis, they ingest something, are affected locally, and may absorb something that causes problems centrally. It's hard to predict.

Vomiting mechanisms

Leib: Let's look at Figure 1. What causes vomiting?

Figure 1. Causes of vomiting

Williams: I don't think you usually know. It is often a local visceral response, but the animal may have ingested something that is absorbed and acts centrally.

Leib: You're referring to the potential for toxins to affect the chemoreceptor trigger zone also.

Twedt: I agree. Often we don't know whether it's foreign material causing gastric irritation or absorption of toxic substances. In evolutionary terms, vomiting is the defense mechanism for getting rid of rancid food or toxic substances once these substances stimulate the chemoreceptor trigger zone.

Kenneth Simpson

Simpson: Often, the cases we have the most problems with are the ones involving, for example, a post-barbecue binge, where you try to discriminate acute gastroenteritis from acute pancreatitis.

Leib: What about motion sickness?

Williams: I think it is under-diagnosed in veterinary practice. Owners are far more aware of the problem than their veterinarians.

Simpson: The mechanism would be vestibular input and is different in cats than dogs in terms of where it feeds into the vomiting pathway. I rarely deal with motion sickness.

Leib: But it's very common in general practice and has a profound impact on family automobile travel.

Williams: While owners are aware of motion sickness in their pets, most don't seek veterinary advice for its management.

Albert E. Jergens

Simpson: Offering advice on premedicating animals for travel is a challenge. Is the owner going to leave the pet alone? How anxious will the pet get? Is it at risk for overheating? Do we use sedatives vs. antiemetics? Motion sickness is difficult to medicate effectively.

Twedt: The trend has been to tranquilize, but that may not be the best approach.

Leib: Dr. Simpson, you mentioned intravenous drug treatment in the intensive care unit and frequent vomiting. Could you make some general comments on the mechanisms that cause vomiting?

Simpson: I presume it's through the chemoreceptor trigger zone. I consider it a potential cause when the animal's vomiting corresponds with the administration of an intravenous medication, especially if the intravenous medication is administered rapidly.

Leib: So slowing down the rate of administration will decrease the vomiting frequency?

Simpson: Yes.

Jergens: We also see numerous medication-induced vomiting cases in my practice. We have a lot of oncology cases, and vomiting may be attributable to the use of cancer chemotherapeutic drugs. And I also have observed rapid infusions of intravenous antibiotics stimulating vomiting.

Leib: Do certain antibiotics cause vomiting more frequently?

Twedt: Penicillins and cephalosporins given intravenously and erythromycin orally.

Jergens: I might argue that I see it more with oral antimicrobials than the intravenous medications. Tetracyclines come readily to mind.

Leib: Do you see vomiting after plasma transfusions as well?

Twedt: Yes, I have seen animals vomit when given blood or plasma too quickly. Slowing down the infusion rate solves the problem. As far as chemotherapy-associated vomiting, we tend to see two types: an immediate response, which is probably through the chemoreceptor trigger zone, and a more delayed effect four or five days after chemotherapy. The best example is cisplatin. Some of those dogs will have delayed vomiting that may have more of a peripherial afferent input.

Leib: Let's look at diabetes mellitus and central vomiting mechanisms.

Twedt: With ketosis, acidosis, and electrolyte abnormalities, we're looking at the chemoreceptor trigger zone. So it's centrally acting.

Simpson: Dogs with diabetic ketoacidosis usually have other complications, such as pancreatitis, that may be associated with vomiting. If you look at the University of Pennsylvania studies, pancreatitis was diagnosed in about 40% of dogs with diabetic ketoacidosis.1

Twedt: So it could also be peripheral associated with pancreatitis.

Jergens: Over the past year, I've treated several schnauzers with diabetes mellitus and concurrent Cushing's disease. They may have pancreatitis as well. So you have these animals with multiple endocrinopathies that are vomiting, and sometimes it's tough to pinpoint the trigger.

Twedt: Many of those schnauzers are hyperlipidemic. That may even play a role in gastrointestinal tract ischemia.

Leib: What about parvovirus— are the mechanisms of vomiting straightforward?

Twedt: Parvovirus isn't all that straightforward. As we know, vomiting is a common complication of parvovirus infection, and it is one of the big problems we deal with at our hospital. I certainly think the gastrointestinal inflammation and ulceration provide peripheral input for vomiting, but there may be some central effects too, such as bacteremia, septicemia, and endotoxemia. Treating these patients with antiemetics that only work centrally is not completely effective. I think it is a multifactorial mechanism of vomiting.

Leib: Do the same dual mechanisms occur with hemorrhagic gastroenteritis?

Twedt: It's a different etiology, but it's probably similar in mechanism to parvovirus.

Jergens: They share the common theme of mucosal breakdown and impaired barrier functions.

Leib: Can we discuss gallbladder disease, maybe using mucocele or cholecystitis as examples? Why do these patients vomit?

Twedt: There are a lot of sympathetic receptors in the biliary system and the liver. With inflammation, peripheral input stimulates vomiting. Certainly with mucoceles, many have secondary infections, so there may also be systemic effects.

Leib: Do you think there are central effects of biliary obstruction due to hyperbiliru-binemia or other substances in the blood?

Williams: It is my understanding that bilirubin levels can be very high experimentally and the dog will be just fine.

Simpson: Some of the highest bilirubins we see are in dogs with immune-mediated hemolytic anemia. These dogs do not usually vomit, so maybe bilirubin itself doesn't do it.

Jergens: With decreased liver function there are other factors as well. Again, portal toxins, altered bile acid pools, and other microbial-derived substances should be metabolized by the liver, and they certainly could affect the animal centrally. If you think about portosystemic shunts, the most common clinical presentations are gastrointestinal signs, including vomiting. That may not be from the inflammation of the liver but rather from the diverse metabolic substances described above.

Leib: What disorders have we not discussed yet?

Williams: Simple mechanical obstruction of the gastrointestinal tract. Sometimes dogs vomit just because there is a blockage.

Leib: Local bowel distention stimulates afferent receptors?

Williams: Or just because of the mechanical blockage.

Leib: Again, it's multifactorial.

Diagnostic plan

Leib: Let's discuss the typical diagnostic workup for vomiting patients with mild to moderate clinical signs.

Jergens: I try to distinguish between a benign process and a more serious disease process. A history and physical examination are important in those animals. We need to learn the severity, progressive nature, and magnitude of the vomiting episodes.

A lot relies on physical examination. We look for significant dehydration, the presence or absence of overt abdominal pain, and obvious cardiovascular abnormalities (e.g., weak or rapid pulse). We'll also look at capillary refill time, mucous membrane pallor, or icterus.

So there are some easy things we can do to help determine if an animal has a benign, self-limiting cause for vomiting or a more serious disease requiring hospitalization and a diagnostic workup.

Leib: So based on your history and physical exam, if you think it is a more benign and self-limiting problem, you're not recommending an extensive diagnostic workup.

Jergens: As far as an extensive diagnostic workup, no. It also may be dictated by client finances. We may however, run some baseline laboratory work, including a packed cell volume and total plasma protein. If it is an older animal, we may evaluate serum glucose, alanine transaminase, and creatinine and observe the pet throughout the day. It's also important to determine if there has been any change in medications or diet and if the pet is current on vaccines.

Twedt: Make sure the animal truly is vomiting and not regurgitating, gagging, or coughing, which would take your workup in a different direction.

David Williams

As for the physical exam and history, I always ask about polydipsia and polyuria and the character of the stools. Does the animal have mucousy stools, which might reflect an animal that is vomiting from colitis? Most veterinarians probably see the animals with acute mild self-limiting disease, but you have to make sure you don't miss more complex or critical disorders.

Simpson: Try to determine if it is a happy, healthy vomiter with no alarm bells or warning signs. These cases are treated symptomatically and require a minimal workup ( parasite check). If they are not happy and healthy or if there are alarm bells, then they need a more comprehensive workup.

Williams: A lot of this is classical conventional veterinary medicine: the signalment, the history, the physical examination, getting a feel for whether it's self-limiting or whether the patient requires additional workup at this stage.

Leib: What are the most com mon causes of the vomiting in that type of patient?

Jergens: I emphasize three big categories: dietary indiscretion, parasites, and infectious disease. From an infectious disease standpoint, I don't have a feeling for what the prevalence of acute viral enteropathies or gastropathies are in the dog or cat. Furthermore, we can rule those out quickly with a client interview, a vaccine history, dietary trial, and routine anthelmintic therapy.

Leib: Let's move on to that acute patient that, as Dr. Simpson says, "presents alarm bells." Perhaps that animal has a greater degree of dehydration, abdominal pain, or concurrent diarrhea. Maybe there isn't a clear history of dietary indiscretion. What is our diagnostic workup in those patients?

Williams: A classic minimum database: a complete blood count, serum chemistry panel, urinalysis, and fecal examination.

Twedt: Your clinical findings would direct you into further diagnostics. For example, if you suspect that the patient may have a gastrointestinal foreign body, abdominal radiographs would be the next step. If you suspect pancreatitis, then you might evaluate the patient with other diagnostics, such as a pancreatic lipase immuno-reactivity test and ultrasonography.

Simpson: I agree that a minimum database is really important. Systemic illness and vomiting associated with acute renal failure and leptospirosis is reasonably common in our practice. In these patients, measuring urine specific gravity and serum creatinine up front helps rule out renal involvement and helps us determine whether to pursue other causes of vomiting.

Treatment

Leib: Let's start with ani that have a mild, self-limiting case of vomiting. How should we manage these patients?

Jergens: If the deworming history is vague or nonexistent, I might deworm that patient with a broad-spectrum anthelmintic. Recently I've had several young animals in which I suspected an adverse food reaction. I don't know whether it is intolerance or dietary sensitivity, but I try to find an appropriate elimination diet that meets the patient's nutritional requirements. If they are on a general commercial diet, I move them to a commercial diet that's suitable for gastrointestinal disorders.

Twedt: Yes, I agree. When prescribing a diet, it is usually a commercial formulation. A premade preparation is easier for the client than cooking diets, such as rice and boiled chicken.

Leib: So these diets are the moderately fatrestricted, low-fiber, highly digestible diets that the nutritional companies market as their classic gastrointestinal diet.

What about witholding food from a vomiting animal?

Williams: How the food is introduced is probably more important than what the patient eats. I withhold food for approximately 24 hours, reintroduce it by test feeding small amounts, and gradually return to normal meal portions.

Twedt: Most animals with acute self-limiting vomiting due to dietary indiscretion are better within 24 hours, so that is a good time to reintroduce a diet. If they continue to vomit, it signals something more serious, and I start to investigate other potential causes.

Leib: What about fluid therapy in these patients? I assume they are minimally dehydrated, based on your assessment.

Jergens: I haven't seen many cases where hydration status is an issue. We may give some subcutaneous fluids in the hospital before they leave, but beyond that I don't see significant dehydration.

Twedt: I agree; I'll probably give them some subcutaneous fluids.

Leib: Then the last thing we should address is the routine use of antiemetics.

Williams: I don't use them unless the vomiting is severe and the patient looks uncomfortable.

Jergens: I agree with Dr. Williams. Furthermore, indiscriminate use of antiemetics may mask the presence of more serious diseases.

Leib: That is an important point. We are assessing these animals at a specific point in time, and they often will leave the hospital. Then we rely on the owner to monitor progress at home and decide whether they need further evaluation and treatment. If we stop the vomiting, which is the most obvious clinical sign visible to owners, then the underlying condition can worsen and we lose valuable time before the animal is returned.

Let's shift to treatment for moderate to severe clinical signs, including dehydration, diarrhea, and abdominal pain. How will therapy be different?

Simpson: The first step is trying to identify the cause: Does the patient have pancreatitis? Does it have renal failure? Is it an Addison's case? Often you have to start symptomatic therapy, such as intravenous fluids, if the animal is dehydrated or start colloids if it is hypoproteinemic before making a definitive diagnosis.

If the patient has been vomiting or is dehydrated and is hospitalized, we start intravenous fluid therapy. Then I monitor the frequency of vomiting. Is there hematemesis? Are there severe electrolyte disturbances that require us to stop the vomiting? We monitor the frequency of vomiting so we can decide whether to use an antiemetic. When we're dealing with a foreign body, we might not want to use metoclopramide. If the animal is dehydrated, we might not want to use a pheno-thiazine until we have rehydrated it. So there are contraindications for some antiemetics—although these may not apply to the newer generation medications.

Leib: If we were looking at either private practice or community-based university practices, what percentage of patients hospitalized with acute vomiting would receive an antiemetic?

Twedt: I did a survey of our intensive care unit patients that were getting intravenous fluids and were vomiting. Virtually every patient was given an antiemetic.

Leib: I agree that if we review the vomiting patients in our intensive care unit, close to 100% receive antiemetics. If they weren't vomiting frequently, they might not even be in the intensive care unit.

Williams: If the animal is sick enough to be hospitalized for acute vomiting, it is probably going to be given an antiemetic.

Twedt: In those patients, we need to be aggressive about determining the etiology of the vomiting. An antiemetic can be effective for the nausea and for preventing fluid and electrolyte loss that occurs with vomiting. If this occurs, the patient will be more comfortable. But antiemetics should not replace a good diagnostic evaluation.

Williams: In a general practice setting, mechanical obstruction or foreign bodies in the younger animal should be ruled out as soon as possible. We would treat that very differently.

Leib: I think that gets back to abdominal radiographs that might reveal small bowel obstructive disease or foreign objects.

Simpson: It's a two-step approach: We do an initial evaluation and hold off on antiemetics until we have our working diagnosis. Then most of those animals are put in an intensive care unit and given an antiemetic or other appropriate medication. So often there is a holding period where the animal is being worked up, and the patient is getting fluids but little else.

Commonly used antiemetics

Leib: Next, we will discuss the most commonly used antiemetics—their class and their advantages and disadvantages. Does anyone want to start with metoclopramide?

Twedt: Up until recently at Colorado State, vomiting dogs on intravenous fluids would usually be placed on metoclopramide as the first antiemetic. This works specifically at the chemoreceptor trigger zone, blocking dopamine receptors. So it blocks the central input of factors in the blood that stimulate the chemoreceptor trigger zone. One question is its effects peripherally on gastrointestinal motility. Though it does have some prokinetic effects, in my opinion, metoclopramide is not a very good prokinetic agent compared with other prokinetic drugs. And there are side effects. It can cause central nervous system-related behavior, such as agitation, anxiety, and restlessness. It also may precipitate seizures.

Leib: Any contraindications?

Twedt: It's contraindicated in animals that have a gastrointestinal obstruction or seizure disorder, and it may interact with certain other drugs. The other problem with metoclopramide is that it has to be administered continuously to be most effective. So this requires an infusion pump. If you are giving it subcutaneously or intramuscularly, it is rapidly absorbed and removed, so it doesn't have a prolonged effect. For a general practice, unless you have an infusion pump, it is not ideal.

Simpson: In dogs, we almost always start with a continuous rate infusion of metoclopramide for our antiemetic.

Williams: Some experts say you should not give metoclopramide to patients with pancreatitis because dopamine may decrease the severity of pancreatitis. They say if you give metoclopramide, you could block that sparing effect and make things worse.

Having said that, many people have given metoclopramide to pancreatitis patients without apparent adverse effects. Nonetheless, it is certainly a theoretical concern that drugs that block dopamine receptors may be contraindicated. Apparently there is a lot of dopamine in the exocrine pancreas, and this endogenous dopamine may actually help preserve pancreatic blood flow in some cases of pancreatitis.

Simpson: Practitioners should also take care with uremic cases, where they may use dopamine and furosemide and the animal is vomiting. The last time I checked with a nephrologist, he indicated it was best to avoid metoclopramide if the patient was heading toward renal shutdown.

Leib: Any parting comments on metoclopramide? It has certainly stood the test of time in veterinary medicine.

Jergens: It's inexpensive, and it's been a standard.

Leib: How about phenothiazines?

Williams: I've used chlorproma-zine when metoclopramide doesn't seem to be working, once the patient is hydrated. Hydration is important because phenothiazines may cause vasodilation and hypotension.

Leib: So we have to rehydrate the patient before we can start phenothiazines?

Jergens: I thought phenothiazines had a direct effect on the vomiting center. I also thought they had some anticholinergic activity.

Twedt: There are alpha2 adrenergic receptors in the emetic center and in the chemoreceptor trigger zone. I think that is where the phenothiazine derivative tranquilizers work. The downside of the phenothiazine derivative tranquilizers is the peripheral vasodilatation. It can make hypotensive animals more hypotensive. Plus there are some tranquilization effects, which may be disadvantageous.

Leib: If you're evaluating a patient and looking for signs of discomfort, monitoring mental status becomes an important tool. If you tranquilize the pet, you lose that monitoring tool. And if they vomit, then they might aspirate.

Phenothiazines also have some histamine blocking effects. Phenothiazines represent a class of antiemetics with a broad spectrum that are very inexpensive and readily available. I know some drugs used in humans are also available as suppositories, which can have benefits for outpatient administration.

Twedt: My other fear is that because the effective antiemetic dose is low and below the tranquilization dose, there may be a tendency for people to overdose these patients, tranqulizing them.

Leib: When we use them, we try to stay just below the dose that causes tranquilization. Often, that is difficult to do because it is a very low dose.

The next important class is serotonin antagonists. A classic example would be ondansetron.

Twedt: One of the major indications for ondansetron in human medicine is chemotherapy.

Simpson: If metoclopramide fails, ondansetron is the next drug that our residents usually reach for. I haven't seen good studies on ondansetron in nonchemotherapeutic patients, but clinicians seem to be happy with it in terms of puppies with parvovirus and some pancreatitis cases.

Jergens: I agree that when animals fail to respond adequately to metoclopramide, they get ondansetron. I don't use it that often outside the realm of the chemotherapeutic patients. But the doctors in the residency training programs seem to make that a first or second choice in many nonchemotherapeutic vomiting patients.

Simpson: I understand that it is the 5-hydroxytryptamine (5-HT) receptors in the peripheral vagal afferent nerves that are the main ones where it exerts its antiemetic effect, but there are some central 5-HT3 receptors as well. I think there is also a dog-cat difference in the distribution of 5-HT3 receptors with dogs having confirmed peripheral receptors.

Leib: So we're getting some peripheral effects by blocking afferent transmission as well as central effects through the chemoreceptor trigger zone?

Simpson: Yes, likely through the peripheral vagal 5-HT3 receptors that are being blocked.

Twedt: Yes, there are 5-HT, receptors on peripheral afferent nerves as well as the chemoreceptor trigger zone. So this class of antiemetics has an effect centrally and peripherally. It has become less expensive because there are generic forms now, but the oral product is still price prohibitive.

Leib: In our clinic, the practical limitation has been expense. We use ondansetron when everything else fails. Our decision to utilize ondansetron is somewhat related to the size of the animal. If we are treating a cocker spaniel, an owner can usually afford to use the drug. If it is a German shepherd or Great Dane, the answer is usually no.

Williams: Granisetron is used more widely now in veterinary medicine than ondansetron for that reason. Granisetron is used as a second-choice agent when metoclopramide isn't working.

Simpson: Granisetron might work better peripherally, especially with some of our puppies with parvovirus. It has become standard for parvoviral-related vomiting. Some studies indicate that granisetron may bind irreversibly to peripheral 5-HT receptors, and this may account for its efficacy.

Leib: There are four approved serotonin antagonists available for use in humans. Is anybody aware of the different efficacies or mechanisms of the other drugs in this class?

Williams: I believe they are equally effective.

Leib: How about contraindications for ondansetron?

Jergens: I am unaware of major contraindications.

Leib: So it really would be a financial decision more than anything. Are there any other commonly used antiemetics that we haven't commented on?

Simpson: Opioids, such as buprenorphine, are supposed to offer some antiemetic effects.

Leib: Working through opioid receptors in the vomiting center?

Simpson: Yes, I think so. They were used to ameliorate chemotherapy induced vomiting prior to 5-HT3 receptor antagonists.

Michael Leib

Jergens: The best example might be acute pancreatitis. Many times you just put patients on pain medications to treat their discomfort and vomiting markedly decreases.

Leib: I believe butorphanol also has been used in some chemotherapy protocols as an antiemetic.

Simpson: It would be similar to buprenorphine?

Williams: Aminopentamide, under the trade name Centrine, was once widely used in general practice but was rarely used in academic institutions.

Leib: So we are talking about the anticholinergic compounds. Does anybody want to comment on their proposed antiemetic actions?

Twedt: There are receptors in the chemoreceptor trigger zone, so they may have some effects there. Some effects may exist peripherally with efferent receptors in the smooth muscle and glands of the gastrointestinal tract. And the receptors may have some effect in decreasing gastrointestinal secretions but also decrease gastrointestinal motility.

Williams: Which is probably why the receptors may help in the symptomatic control of diarrhea, for example.

Leib: They relieve smooth muscle spasms that may be producing pain. The majority of acute, self-limiting vomiting dogs managed as outpatients are going to get better. So over time, clinicians may associate the result with treatment, and that treatment might have no effect. Practitioners will say they have been using a treatment for years because it works, despite the negative physiologic effects of that drug class.

Twedt: In fact, as far as contraindications, the anticholinergics are probably more contraindicated with an obstruction than metoclo-pramide. I think they are definitely contraindicated because they cause decreased gastrointestinal motility.

Leib: So if we use anticholinergics to treat a vomiting animal with abnormal gastrointestinal motility, we are promoting ileus and potentially worsening the vomiting.

Jergens: Yes. Anticholinergics aggravate vomiting patients by their negative effects on gut motility.

Twedt: And give them a dry mouth.

Leib: So why are these drugs so ingrained in veterinary practice? I guess they have been utilized for a long time.

Jergens: I think certain practitioners grew up with these medications and are more familiar with them. The vomiting probably resolves spontaneously, and the veterinarians attribute it to the medication.

Leib: Pfizer has just released a new antiemetic: maropitant citrate (Cerenia). It has a novel mechanism of action that is different from any of the other drugs we have mentioned.

Twedt: Yes, Cerenia is an antagonist for neurokinin1 receptors, which are found in peripheral afferent neurons. They are also found in the chemoreceptor trigger zone, and there are apparently high numbers of those receptors in the vomiting center as well. They are stimulated by substance P, a neurotransmitter found throughout the body. Cerenia blocks those neurokinin1 receptors, so it works both peripherally and centrally.

Leib: We've all used this new product in our clinics. Are there contraindications, side effects, or administration problems that we should be aware of?

Williams: We have not seen any side effects. It appears to be safe and effective. (Sponsor's note: In clinical studies, diarrhea, bloody stools, inappetence, lethargy, hypersalivation, vomiting, muscle tremors, and death have been observed with the use of Cerenia.)

Twedt: Our hospital uses it extensively now for vomiting dogs. In fact, it's replaced the other antiemetics for our critical care cases and chemotherapeutic patients. I've followed up on a number of these cases, and I have not identified any side effects. And the once-a-day administration is very user friendly.

Jergens: I would also add that Reto Niger from the European College of Veterinary Internal Medicine did an overview of antiemetics at the 2007 ECVIM Congress. In this lecture, he reported that the European experience with Cerenia has been uniformly positive. He reported no adverse effects with the use of the drug and the clinical data presented were very promising.

Simpson: We have been impressed. A dog whose vomiting was not controlled with metoclo-pramide or ondansetron comes to mind. The dog had severe neutrophilic enteropathy and Cerenia was the only drug that controlled the vomiting.

Leib: The drug is approved for both the prevention of motion sickness and treatment and prevention of acute vomiting. Can someone comment on its labeling for puppies greater than 16 weeks of age?

Twedt: In Pfizer's initial study researchers studied dogs as young as 8 weeks old.2 Some of these puppies were not healthy and had problems such as parasitim or gastroenteritis. They were given either a placebo or Cerenia. Following the treatment period, bone marrow hypoplasia was identified in some of the Cerenia-treated dogs and some of the placebo-treated dogs. Many of these dogs were stressed and not acclimated when entering the study which could explain the bone marrow changes. Pfizer is reevaluating the drug in young, healthy dogs. In our hospital, puppies with parvovirus are the prime cases for Cerenia use, and we have treated many cases without identifying adverse effects. (Sponsor's note: Cerenia is recommended for use in dogs 16 weeks or older.)

Simpson: We have some potential questions—one is how hypoproteinemia might affect the kinetics of the drug because it is heavily protein bound. Then in extremely azotemic animals, do we have to adjust the dose based on the decreased glomerular filtration rate. The other issue is administration with other antiemetics, such as ondansetron or metoclopramide. Are there any interactions with other antiemetics if Cerenia is used in combination? (Sponsor's note: The concurrent use of Cerenia with other antiemetics has not been evaluated.)

Twedt: It is also metabolized by the liver. So the other concern would be liver failure cases. Does the dose need to be adjusted in those cases? We typically adjust dosages of drugs that are metabolized by the liver in liver failure patients. I think you probably need to make educated judgments based on the hepatic function of each patient and decrease the dose or frequency of administration accordingly. The same is true with a severely hypoproteinemic animal, which actually might make more of the active drug available due to decreased binding, though this is probably not that important in most cases. (Sponsor's note: Cerenia should be used with caution in dogs with hepatic dysfunction.)

Leib: There have also been concerns about benign electrocardiogram changes. Can anyone comment on those?

Williams: I understand that slight prolongation of the QT interval was observed in some dogs.2 Apparently because of innate electrophysiologic differences between the myocardium of people and dogs, such relatively minor prolongations of the QT interval may predispose people to life-threatening arrhythmias but are of no consequence in dogs.

Leib: I am pleased that we have a new product that is preceded by at least three peer-reviewed, published articles in the veterinary literature.3-5 It certainly gives us a lot more confidence to use a new drug. Those articles cover several causes of acute vomiting, including chemotherapy-induced vomiting. These publications are commendable because there are few publications concerning efficacy in clinical patients for most of the other drugs we've discussed today.

Twedt: Our hospital uses it extensively now for vomiting dogs. In fact, it's replaced the other antiemetics for our critical care cases and chemotherapeutic patients. I've followed up on a number of these cases, and I have not identified any side effects. And the once-a-day administration is very user friendly.

Jergens: I would also add that Reto Niger from the European College of Veterinary Internal Medicine did an overview of antiemetics at the 2007 ECVIM Congress. In this lecture, he reported that the European experience with Cerenia has been uniformly positive. He reported no adverse effects with the use of the drug and the clinical data presented were very promising.

Simpson: We have been impressed. A dog whose vomiting was not controlled with metoclo-pramide or ondansetron comes to mind. The dog had severe neutrophilic enteropathy and Cerenia was the only drug that controlled the vomiting.

Leib: The drug is approved for both the prevention of motion sickness and treatment and prevention of acute vomiting. Can someone comment on its labeling for puppies greater than 16 weeks of age?

Twedt: In Pfizer's initial study researchers studied dogs as young as 8 weeks old.2 Some of these puppies were not healthy and had problems such as parasitim or gastroenteritis. They were given either a placebo or Cerenia. Following the treatment period, bone marrow hypoplasia was identified in some of the Cerenia-treated dogs and some of the placebo-treated dogs. Many of these dogs were stressed and not acclimated when entering the study which could explain the bone marrow changes. Pfizer is reevaluating the drug in young, healthy dogs. In our hospital, puppies with parvovirus are the prime cases for Cerenia use, and we have treated many cases without identifying adverse effects. (Sponsor's note: Cerenia is recommended for use in dogs 16 weeks or older.)

Simpson: We have some potential questions—one is how hypoproteinemia might affect the kinetics of the drug because it is heavily protein bound. Then in extremely azotemic animals, do we have to adjust the dose based on the decreased glomerular filtration rate. The other issue is administration with other antiemetics, such as ondansetron or metoclopramide. Are there any interactions with other antiemetics if Cerenia is used in combination? (Sponsor's note: The concurrent use of Cerenia with other antiemetics has not been evaluated.)

Twedt: It is also metabolized by the liver. So the other concern would be liver failure cases. Does the dose need to be adjusted in those cases? We typically adjust dosages of drugs that are metabolized by the liver in liver failure patients. I think you probably need to make educated judgments based on the hepatic function of each patient and decrease the dose or frequency of administration accordingly. The same is true with a severely hypoproteinemic animal, which actually might make more of the active drug available due to decreased binding, though this is probably not that important in most cases. (Sponsor's note: Cerenia should be used with caution in dogs with hepatic dysfunction.)

Leib: There have also been concerns about benign electrocardiogram changes. Can anyone comment on those?

Williams: I understand that slight prolongation of the QT interval was observed in some dogs.2 Apparently because of innate electrophysiologic differences between the myocardium of people and dogs, such relatively minor prolongations of the QT interval may predispose people to life-threatening arrhythmias but are of no consequence in dogs.

Leib: I am pleased that we have a new product that is preceded by at least three peer-reviewed, published articles in the veterinary literature.3-5 It certainly gives us a lot more confidence to use a new drug. Those articles cover several causes of acute vomiting, including chemotherapy-induced vomiting. These publications are commendable because there are few publications concerning efficacy in clinical patients for most of the other drugs we've discussed today.

David Twedt

Williams: The comparisons with the antiemetics that we formerly used are impressive.

Twedt: I've been fortunate to to use maropitant for about five months and three months before the drug launched. And it is our number one antiemetic now because of clinician experience. I recently reviewed the first 50 cases in which we used it. Out of those cases, which included chemotherapy, parvovirus infection, renal failure, and pancreatitis, there were no clinically apparent adverse effects other than minor stinging at the injection site in a few cases. There was a positive response in 49 out of 50 cases. The animal that didn't respond had gastrointestinal neoplasia.

Leib: How did you define positive response? Just a reduction in vomiting frequency?

Twedt: A reduction or stopping of the vomiting. It was the clinician's impression. We didn't have any specific criteria or scoring system. But those impressions have carried over into our clinicians' continued use of the product. We rarely use metoclopramide anymore in our critical care unit cases.

Jergens: Our experience is similar. There was a tremendous acceptance of the drug by our group of clinicians. We initially ran out and the pharmacy couldn't get it. My phone started ringing. They were saying, "Where is it? We want it. We need it." It was a very positive response.

Leib: That's great. Other com ments on maropitant before we move on?

Williams: A European study showed similar effectiveness and safety in cases of spontaneous vomiting due to a variety of causes.

Other drugs used for vomiting

Leib: Other drugs are used to treat vomiting. These drugs are not necessarily antiemetics, but they have pronounced gastrointestinal effects.

Let's start with the histamine-2 receptor blockers that are commonly used in the vomiting patient. Dr. Williams, do you use famotidine and other histamine blockers?

Williams: Some clinicians may think that there is a high prevalence of gastritis because the animals are stressed or sick and reducing stress-induced gastritis may reduce vomiting. True or not, famotidine is a very safe drug.

Leib: If it were rational, would decreasing acid secretion potentially benefit some patients with gastritis and erosive disease?

Williams: If they have gastritis and erosive disease, yes. But in most cases, it is pure speculation. I suspect famotidine probably doesn't do a whole lot to reduce vomiting in many patients, but has become standard practice for some people to use.

Twedt: Veterinarians carry those medications in their practice. They are easy to dispense. Clients can get many histamine blockers over the counter now. That's probably why they're so widely used.

Simpson: If you review the human literature on gastric acid and pH in the stomach of people with renal failure, gastric acidity was actually reduced in most patients. I am usually happier if these patients get sucralfate rather than a histamine antagonist because sucralfate is less specific in its mode of action.

Jergens: Dr. Simpson, one of the problems using sucralfate is that it is an oral medication. Often these patients are being held NPO. You are contradicting one of your basic tenants of therapy if you use it.

Simpson: We are starting to feed patients much earlier. At least we're feeding through vomiting. After 12 to 24 hours of dietary rest, they need some nutrition. We are more concerned about trying to preserve some gastrointestinal barrier function early on rather than waiting to feed as the gut deteriorates.

Leib: So let's say you have a patient in the hospital that has moderate to severe vomiting and you may or may not have a diagnosis. You are treating it with an antiemetic that seems to be working appropriately. Should these animals be receiving a histamine-2 blocker or sucralfate?

Jergens: I tend not to be a poly-pharmaceutical clinician, and I direct my drug therapy as specifically as I can. So, if I am able to control it with an antiemetic and I have no concern about disrupted gastric or intestinal barrier integrity, then I won't use a histamine-2 blocker.

Twedt: I agree. It's uncommon to see gastric ulcers in our patients. We do see some animals that have erosions and possibly hematemesis. In those cases, I would use an acid-blocking drug. But I don't routinely use them. For example, I wouldn't routinely put a parvovirus patient on a histamine blocker.

Simpson: In general, I tend to avoid nonspecific antisecretory therapy unless I have a specific indication. Maybe there's a case for combined use of histamine blockers and an antiemetic in prophylactically treating esophagitis and animals at high risk for aspiration.

Leib: Does the same philosophy exist with proton pump inhibitors even though they are more potent acid suppressors?

Twedt: In those acute cases it takes a while for them to work.

Williams: I recommend proton pump inhibitors in chronic vomiting cases with underlying chronic gastritis.

Leib: What about specific pro-kinetic therapies like cisapride?

Simpson: I would almost always reserve cisapride for suspected motility problems rather than vomiting (e.g., a patient with delayed gastric emptying associated with vomiting and bloating).

Leib: Are there other adjunctive drugs? What about using ranitidine as a pro-motility agent? Are people prescribing it for small intestinal and colonic motility disorders? Maybe in some cats with megacolon?

Williams: There is evidence that available alternative promotility drugs are more effective.

Simpson: My impression is ranitidine is not as effective as cisapride or erythromycin.

Twedt: I agree. I also believe metoclopramide is a potent prokinetic agent. So cisapride or erythromycin would be my choices as a prokinetic agent. I probably use cisapride more than any other, especially in cats with megacolon

Leib: But, once again, we wouldn't use a prokinetic agent in an animal with nonspecific acute vomiting that doesn't have signs of delayed gastric emptying.

Williams: On what basis does the group diagnose the delayed gastric emptying? I don't think it is that common, and I would diagnose it primarily when I do an endoscopic examination and the stomach is full of food after what I know is an overnight fast. Do you make that diagnosis frequently?

Twedt: I sometimes see it secondary to inflammatory bowel disease. Occasionally we see animals that have altered gastrointestinal motility, but we have first ruled out inflammatory and infectious etiologies. In those patients, I try a prokinetic agent. Another example is the gastric dilatation volvulus case that had a surgical gastropexy but postoperatively still had a huge stomach with delayed gastric emptying.

Simpson: That's the group I see.

Twedt: Those animals definitely benefit from prokinetics and not antiemetics.

Leib: I think abnormal motility in some cases is a component of gastritis with or without inflammatory bowel disease, and I'm not sure whether it needs to be treated specifically.

Nutrition and diet

Leib: Let's talk about nutrition and diet in the vomiting pet. If we have trouble controlling the vomiting and the animal is being held NPO, how long do we withhold food and what parameters do we evaluate? What options do we have to provide nutrition in those patients?

Twedt: When I get an acute vomiting patient that hasn't eaten for three days, I get concerned about its nutritional status.

Leib: Are you talking about a young animal or an adult animal?

Twedt: Either. Our philosophies are changing on this topic. We are trying harder to provide nutrition to acute vomiting cases, such as animals with pancreatitis or parvovirus. Sometimes effective antiemetic and fluid therapy helps these animals eat sooner, which is important. Our critical care clinicians think that now that we have started using maropitant, our parvovirus patients spend about a day less in the hospital because they begin eating sooner.

Leib: Dr. Simpson, you commented on initiating feeding sooner. Are you feeding although vomiting continues?

Simpson: I have been trying to promote it, but some people are reluctant. I think that if you have an effective antiemetic and pain control, then attempting to feed even in the face of vomiting is worth a try. That is what the Mohr study6 shows; puppies with parvovirus receiving enteral nutritional support gained weight, had decreased barrier damage, and tended to leave the hospital a day earlier. So it seems to be doing no harm and may, in fact, be beneficial. I also started feeding our pancreatitis dogs soups and broths early on and try to feed them through their vomiting. I don't have any evidence that it's going to make the pancreatitis worse.

Twedt: I agree with that philosophy. Still, if the animal is improving and doing well and then vomits, my residents and other clinicians want to continue the NPO period for another 24 hours. I think that if the pets are interested in eating, and we have ruled out obstruction, providing some nutrition is not contraindicated.

Leib: Is the emphasis on enteral nutrition to promote barrier function vs. starting parenteral nutrition and maintaining the NPO status?

Jergens: It is all about enteral nutrition. The population of patients that we have on total parenteral nutrition or even partial parenteral nutrition is markedly reduced from what it was three to five years ago. There is a greater appreciation for supplementing through nasoesophageal or esophagostomy tubes. Even with some surgery cases, the surgeon is working with the internist to put in jejunostomy feeding tubes. There is an increased awareness of the benefits of enteral nutrition in a whole spectrum of cases.

Simpson: Another study of parenteral nutrition in dogs and cats6 found that dogs receiving supplemental enteral nutrition in combination with parenteral nutrition survived more often than those receiving parenteral nutrition exclusively.7

Williams: So, as long as they are keeping down a substantial proportion of what you feed them, you should continue to do that.

Simpson: And I think we tend to overestimate how much food an animal is vomiting. If the animal is vomiting bile, it has likely kept down the food you fed it. There is a disconnect sometimes. We think it has vomited everything. That's where the Mohr study6 was really interesting. They were feeding puppies with parvovirus—our poster children for severe vomiting and diarrhea—through an esophagostomy tube. Those puppies gained weight and experienced no adverse effects.

Twedt: I think the big contraindication would be if there was any fear of aspiration pneumonia. You may not want to feed a semicomatose animal with a nasogastric tube if the animal is going to vomit and aspirate.

Leib: My comment on the parvovirus study was that they didn't describe the difference in nursing manpower for puppies receiving continuous nasoesophageal feeding. Looking at the difficulties in keeping intravenous lines clean and untangled, adding an Elizabethan collar and nasoesophageal tube requires a great deal of nursing support. Even in veterinary teaching hospitals, manpower in an intensive care unit is often challenged with traditional therapy for parvovirus.

Williams: Bringing this back to antiemetics, should we give a potent antiemetic when we are tube feeding an anorectic patient and there is vomiting? An antiemetic might not only ameliorate vomiting, but it may help reduce nausea and diminish the anorexia.

Twedt: We had an anorectic dog in chronic renal failure with serial serum creatinine levels of 5 mg/dl. Even with fluid therapy, the dog would not eat and was very nauseated with salvation but did not vomit. We decided to use maropitant, and the dog started eating. So there may be some benefits just for nausea, particularly with the chronic cases. (Sponsor's note: Cerenia has not been approved for use to treat/control nausea in dogs.)

Jergens: If we move toward early feeding, then I think we need to be more aggressive with antiemetics, not only so the patient will eat on its own but also to reduce the potential for aspiration after vomiting.

Williams: I wonder if we are overemphasizing the risk of administering symptomatic, antiemetic and antinausea therapy. Earlier we discussed being concerned about masking the signs of an obstructive lesion, but if your workup is appropriate, then you probably would detect it. Maybe we risk denying a positive effect in many of our patients because we are overly concerned about masking signs in a small minority.

Twedt: Some cases will be missed. We just have to do our best to rule out obstructive disease or foreign bodies. Certainly you don't want to treat a dog that has Addison's disease with an antiemetic. You treat the Addison's disease.

Williams: We are much more aggressive at treating perceived pain now, and we should be more aggressive at treating perceived nausea as well. Our patients may do better as a result.

Simpson: So we look for hyper-salivation, restlessness, and food aversion, rather than emesis. It is a prodromal sign.

Lieb: In conclusion, maropitant is making life easier for practitioners— and better for their patients.

References

1. Hume DZ, Drobatz KJ, Hess RS. Outcome of dogs with diabetic keto-acidosis: 127 dogs. / Vet Intern Med 2006;20:547-55.

2. Cerenia (maropitant citrate) tablets. Pfizer Animal Health, New York, NY. Product label, Nov 2006.

3. de la Puente-Redondo V, Siedek E,

Benchaoui H, et al. The antiemetic efficacy of maropitant (Cerenia) in the treatment of ongoing emesis caused by a wide range of underlying clinical aetiologies in canine patients in Europe. / Small Anim Pract 2007:48:93-98.

4. Vail D, Rodabaugh H, Conder G, et al. Efficacy of injectable maropitant (Cerenia) in a randomized clinical trial for prevention and treatment of cisplatin-induced emesis in dogs presented as veterinary patients. Vet Comp Oncol 2007;5:38-46.

5. de la Puente-Redondo V, Tilt N, Rowan

TG, et al. Efficacy of maropitant for treatment and prevention of emesis caused by intravenous infusion of cisplatin in dogs. Am J Vet Res 2007;68:48-56.

6. Mohr AJ, Leisewitz AL, Jacobson LS, et al. Effect of early enteral nutrition on intestinal permeability, intestinal protein loss, and outcome in dogs with severe parvoviral enteritis. JVet Intern Med 2003;17:791-798.

7. Chan DL, Freeman LM, Labato MA, et al. Retrospective evaluation of partial parenteral nutrition in dogs and cats. / Vet Intern Med 2002;16:440-445.