Difficult vomiting disorders (Proceedings)

I. History Taking

A complete and detailed history is the first step in establishing a correct diagnosis of a vomiting disorder. The patient's signalment will usually establish some level of probability for many of the differential diagnoses. For example, adrenocortical insufficiency would be an important differential diagnosis for a two year old dog presented with an acute history of vomiting and muscular weakness, with or without diarrhea. Similarly, the acute onset of vomiting in an unvaccinated puppy should alert the veterinarian to the possibility of an infectious disease, for example, parvoviral or distemper viral gastroenteritis. Chronic vomiting in an eleven year old dog, on the other hand, would elicit a different set of differential diagnoses.

Following consideration of the patient's signalment, the history taking should ascertain vaccination status, travel history, and any recent dietary changes. Previous medical problems, medication history, and the possible ingestion of toxic substances or foreign bodies should also be ascertained. These pieces of information can be quite useful in formulating a list of differential diagnoses. Next, the veterinarian should be convinced that the pet owner is describing vomiting, and not some other sign. For example, the coughing associated with inflammatory disorders of the upper airway will often be described as vomiting by many pet owners. Gagging is also occasionally confused with vomiting. A careful history taking will usually discriminate coughing and gagging from vomiting. Pet owners will also often confuse regurgitation and dysphagia with vomiting. Regurgitation is the passive evacuation of ingested food from the pharynx and/or esophagus; the premonitory signs of retching and abdominal contractions seen with vomiting are not observed with regurgitation. The description of regurgitation by a pet owner would suggest a more proximal disorder of the pharynx or esophagus. Dysphagia or difficulty in swallowing would also suggest a more proximal disorder of the pharynx.

The history taking should then elicit the duration, frequency, and time of vomiting episodes, as well as the relationship of vomiting to food and water consumption. Disorders of vomiting that are of short duration are usually self-limiting and not worthy of extensive investigation; chronic vomiting histories, on the other hand, are more serious and certainly require a more detailed investigation. Frequent vomiting usually occurs as result of systemic, metabolic, or endocrine disorders or severe inflammatory disorders of the primary gastrointestinal tract. Vomiting that occurs in the immediate post-prandial period is usually suggestive of overeating, excitement, or disorders of the esophageal body or esophageal hiatus (e.g. hiatal hernia). Conversely, vomiting of undigested or partially digested food 8 or more hours post-prandially would suggest a distal gastric (corpus, antrum, and pylorus) motility disorder or obstruction. Vomiting of water would be more suggestive of a proximal gastric (cardia, fundus) motility disorder. Vomiting during the early morning hours often may result from gastroesophageal reflux.

Finally, the physical characteristics of the vomitus, including the color, amount, odor, consistency, and the presence or absence of blood or bile should be ascertained. Undigested food in the vomitus implies a gastric etiology, while digested food (chyme) implies an intestinal etiology for the vomiting. The presence of blood in the vomitus implies disruption of the gastrointestinal mucosa; blood may appear as frank red clots or as a dark brown "coffee-grounds" material resulting from acid proteolysis. Bile in the vomitus usually suggests only that the pylorus has permitted bile reflux. However, bile salts are known to increase the permeability of the gastric mucosal barrier resulting in a syndrome of bile reflux gastritis. Bilious vomiting, therefore, might provide a clue to the pathogenesis of the disorder. A fecal odor has been described with lower intestinal (jejuno-ileal) obstruction.

II. Physical Examination

Examination of the mouth and pharyngeal structures often provide important clues to the pathogenesis of vomiting, e.g. uremic breath or ulcers, icteric mucous membranes, severe pharyngitis or pharyngeal string foreign bodies. The physical examination finding of generalized lymphadenopathy would suggest neoplasia or a systemic inflammatory disease as the pathogenesis of the vomiting. Hence, all lymph nodes should be carefully palpated to determine if they are enlarged and/or painful. The presence of fever on physical examination would likewise suggest an inflammatory pathogenesis for the vomiting disorder. Extreme bradycardia or other rhythm disturbance detected upon cardiac auscultation might be an important sign of a metabolic disturbance such as adrenocortical insufficiency or septic shock. The abdomen should then be carefully palpated for effusion (e.g. peritonitis), masses (e.g. carcinomatosis or other malignancy), pain (e.g. peritonitis, pancreatitis, or nephritis), gaseous or fluid distension of the intestine (e.g. obstruction), kidney size and shape (e.g. end-stage fibrotic kidneys or nephritis), liver size (e.g. hepatitis), uterine distension (e.g. pyometra), and urinary bladder size (e.g. bladder obstruction). Rectal examination might also provide some evidence of pain or hematochezia (e.g. colitis), worms (e.g. hook or whipworms), or painful prostatomegaly (e.g. prostatitis or prostatic neoplasia). Finally, examination of the central nervous system should be considered, especially in the animal in which the cause of vomiting is not so obvious. Some animals with intervertebral disc disease will vomit because of pain.

III. Differential Diagnosis

After identifying problems from the history and physical examination, a reasonable list of differential diagnoses may then be considered based upon pathogenetic mechanism: abdominal alimentary, abdominal extra-alimentary, systemic-metabolic-endocrine, drug-induced, toxicity, diet-related, and neurologic disorders.

IV. Diagnostic Workup

If a definitive diagnosis is not established from the history and physical examination, then the following "initial tests" are warranted: complete blood count, serum chemistry, urinalysis, fecal parasitologic examination, and abdominal radiographs.

Peripheral eosinophilia in a complete blood count would suggest the possibilities of systemic mast cell disease, intestinal parasitism, or adrenocortical insufficiency. Leukopenia and neutropenia might be observed in the acute phase of a viral gastroenteritis. Leukocytosis, on the other hand, might suggest an inflammatory disorder like acute pancreatitis. The serum chemistry will often help identify systemic, metabolic, and endocrine causes of vomiting. For example: 1) azotemia and hyperphosphatemia suggest that the vomiting has resulted from chronic renal failure; 2) hyperglycemia, acidosis, glucosuria, and ketonuria suggest diabetic ketoacidosis as the cause of vomiting; 3) hyponatremia and hyperkalemia suggest adrenocortical insufficiency; 4) amylasemia and lipasemia suggest acute pancreatitis; 5) increases in serum liver enzyme activities (ALT, AST, ALP) suggest primary liver disease; and, 6) hypercalcemia suggests parathyroid or other malignancy. Urinalysis will be useful in differentiating pre-renal and primary renal azotemia, while fecal examination may provide evidence of intestinal helminth infestation.

Survey radiographs of the abdomen are certainly indicated in the initial workup of a vomiting disorder. The abdominal radiographs will provide useful information about the abdominal alimentary and extra-alimentary structures. The decision to perform additional tests is based on response to empirical therapies and initial test results. Further tests might include: thoracic radiography, abdominal ultrasonography, contrast radiography, ACTH stimulation, liver function tests, gastrointestinal endoscopy, and laparotomy.

V. Anti-Emetic Therapy

Physiology of Emesis: The essential components of the emetic reflex are visceral receptors, vagal and sympathetic afferent neurons, a chemoreceptor trigger zone (CRTZ) located within the area postrema that is sensitive to blood-borne substances, and an emetic center within the reticular formation of the medulla oblongata receiving input from vagal and sympathetic neurons, CRTZ, vestibular apparatus, and cerebral cortex. An important concept dating from the early 1950's is that vomiting occurs either through activation of the CRTZ by blood-borne substances (humoral pathway), or through activation of the emetic center by vago-sympathetic, CRTZ, vestibular, or cerebrocortical neurons (neural pathway). Thus, activation of the CRTZ by a variety of humoral emetogenic substances (e.g. uremic toxins, cardiac glycosides, and apomorphine) is abolished by surgical ablation of the area postrema, but not by vagotomy or sympathectomy. In contrast, neural activation of the emetic center by gastric disease (e.g. gastritis) is abolished by vagotomy or sympathectomy, but not by ablation of the area postrema. Many experimental data have been readily explained by this two-component model. Despite contemporary reexamination, there is still good agreement on the two general patterns of emesis, one humoral and one neural. Current therapy is largely based on these assumptions.

Many of the spontaneous vomiting disorders of cats and dogs, particularly those of the primary gastrointestinal tract, are believed to result from activation of the neural pathway. Vomiting associated with primary gastrointestinal tract disease (e.g., inflammation, infection, malignancy, toxicity) results from activation of visceral receptors, afferent neurons, and the emetic center. Efferent information transmitted back to the gastrointestinal tract stimulates the motor correlates of vomiting (retrograde duodenal and gastric contractions, relaxation of the caudal esophageal sphincter, gastroesophageal reflux, opening of the proximal esophageal sphincter, and evacuation of gastrointestinal contents). A neural pathway can also be involved in vomiting associated with motion sickness. Motion within the semicircular canals is transduced to vestibulo-cochlear neurons that ultimately synapse in the CRTZ or emetic center. Cats and dogs experience motion sickness, although the neuroanatomy and pharmacology appear to be somewhat different between the two species. Histaminergic neurons and the CRTZ are involved in motion sickness in the dog, whereas neither are involved in motion sickness in the cat. A neural pathway involving cerebrocortical neurons may be involved in vomiting disorders associated with anxiety or anticipation, but these are probably more important in human beings.

The essential component of the humoral pathway is the chemoreceptor trigger zone (CRTZ) located within the area postrema that is sensitive to blood-borne substances. Receptors within the CRTZ may be activated by many endogenous (e.g., uremic-, hepatoencephalopoathic-, or endo-toxins) and exogenous (e.g., digitalis glycosides, apomorphine) blood-borne substances. Most pharmacological approaches to anti-emetic therapy have been based on neurotransmitter-receptor interactions at the CRTZ, emphasizing the humoral pathway of emesis. The neural pathway has received much less emphasis even though it is a much more important pathway.

Pharmacology of Emesis: Vomiting is initiated through activation of one or more neurons in the CRTZ or emetic center.

Anti-Emetic Classifications

A number of anti-emetic drugs have been formulated based on the aforementioned neurotransmitter-receptor systems. These drugs may be classified as: α2 adrenergic antagonists, D2 dopaminergic antagonists, H1 and H2 histaminergic antagonists, M1 muscarinic cholinergic antagonists, ENK enkephalinergic mixed agonists/antagonists, and 5-HT3 serotonergic antagonists. The 5-HT4 serotonergic agonists are not direct anti-emetic drugs per se, but may have an indirect anti-emetic effect by promoting gastrointestinal motility.

Rational use of Anti-Emetic Agents in the Diagnosed Patient

1. Motion Sickness - Motion sickness is believed to arise from stimulation of labyrinthine structures in the inner ear. The chemoreceptor trigger zone and H1 histaminergic receptors are involved in this pathway in the dog, but apparently they are less importantly involved in the cat. Motion sickness in the cat is probably best treated with an α-adrenergic antagonist, e.g., chlorpromazine, instead of a pure H1 histaminergic antagonist.

2. Uremia – Vomiting associated with uremia has both central and peripheral components. The central component of uremic vomiting is associated with activation of CRTZ D2 dopaminergic receptors by circulating uremic toxins. The central component is best treated with a D2 dopaminergic antagonist, e.g. metoclopramide. The peripheral component of uremic vomiting is associated with uremic gastritis and is best treated with acid secretory inhibitors (e.g. ranitidine 1-2 mg/kg q 12 h IV; omeprazole 0.7 mg/kg q 12 h PO) to diminish gastric parietal cell H+ ion secretion, and with chemical barrier diffusion barriers (e.g., sucralfate 0.25-0.5 grams q 8-12 h PO) to provide a barrier to H+ ion back diffusion. The 5-HT3 antagonists may be more effective in cats.

3. Cancer Chemotherapy – Certain cancer chemotherapies (e.g. cisplatinum, cyclophosphamide) are associated with a high incidence of vomiting. Chemotherapy-induced emesis is mediated by 5-HT3 serotonergic receptors, either in the CRTZ or in vagal afferent neurons. Antagonists of the 5-HT3 serotonergic receptor (e.g. ondansetron, granisetron, tropisetron) abolish the vomiting associated with cisplatinum administration in the cat.

4. Delayed Gastric Emptying Orders – Disorders of delayed gastric emptying (e.g. gastritis, metabolic derangements, post-operative gastric dilatation and volvulus) may cause an animal to experience nausea and vomiting. Treatment of these disorders with cholinomimetic agents has been associated with untoward side effects. Contemporary therapy consists of 5-HT3 serotonergic agonists (e.g., cisapride, metoclopramide), cholinesterase inhibitors (e.g., ranitidine or nizatidine), and motilin agonists (e.g., low dose erythromycin – dog only). Cisapride is superior to metoclopramide in the treatment of gastric emptying disorders in cats and dogs. Ranitidine and nizatidine inhibit acetylcholinesterase activity in addition to their effects on histamine H2 receptors in the gastric mucosa. Both drugs (ranitidine and nizatidine) stimulate gastric emptying in the cat and dog.