key: cord-0739039-0x73yqcg authors: Elwood, C.; Devauchelle, P.; Elliott, J.; Freiche, V.; German, A. J.; Gualtieri, M.; Hall, E.; den Hertog, E.; Neiger, R.; Peeters, D.; Roura, X.; Savary‐Bataille, K. title: Emesis in dogs: a review date: 2009-12-24 journal: J Small Anim Pract DOI: 10.1111/j.1748-5827.2009.00820.x sha: 6d8ba53596b6fb3b480fa07a630cb4e885c2b34c doc_id: 739039 cord_uid: 0x73yqcg Emesis is a common presenting sign in small animal practice. It requires a rational approach to management that is based upon a sound understanding of pathophysiology combined with logical decision making. This review, which assesses the weight of available evidence, outlines the physiology of the vomiting reflex, causes of emesis, the consequences of emesis and the approach to clinical management of the vomiting dog. The applicability of diagnostic testing modalities and the merit of traditional approaches to management, such as dietary changes, are discussed. The role and usefulness of both traditional and novel anti‐emetic drugs is examined, including in specific circumstances such as following cytotoxic drug treatment. The review also examines areas in which common clinical practice is not necessarily supported by objective evidence and, as such, highlights questions worthy of further clinical research. In October 2006, after a series of meetings, the authors published 'Approach to the Management of Emesis in Dogs' (Devauchelle and others 2006), intended as a clinical guide to 'best practice' in the management of canine emesis. Statements in these guidelines were developed from published papers, consensus opinion and, where necessary, the authors' own expert opinions. This review details the evidence and emphasises the opinion from which the guidelines were developed and, by doing so, highlights where evidence is lacking or contradictory. A systematic search of the literature was performed on the sites Google Scholar, Web of Science and PubMed, using the terms 'vomit*' or 'emesis' AND 'dog' or 'canine' to identify relevant references. Where primary sources were available (papers published in peer reviewed journals) these are referenced. Where relevant information did not fi t the above search terms (e.g. secondary effects of drugs), references were identifi ed in a standard manner. To further quantify the strength of evidence available to support the information provided, individual references used to support statements were classifi ed according the scheme shown in Table 1a and assigned an evidence level (EL). As appropriate to support the text an overall evidence grade (OEG) was given according to the scheme in Table 1b . Where multiple references were available, we attempted to ensure those with the highest evidence level were cited. Where peer-reviewed sources were lacking, statements should be considered the opinion of the authors. Emesis is facilitated by a sequence of programmed overlapping and coordinated events which reduce the risks of adverse consequences (such as aspiration of acid stomach contents) whilst achieving elimination. The refl ex is controlled within the brainstem by a central pattern generator, Emesis is a common presenting sign in small animal practice. It requires a rational approach to management that is based upon a sound understanding of pathophysiology combined with logical decision making. This review, which assesses the weight Experimental studies show that many peripheral stimuli of abdominal structures will initiate emesis in dogs (Lang and Marvig 1989 [2b] , Xu and Chen 2008 [2b] ). Release of 5-hydroxytryptamine/ serotonin (5-HT) from enterochromaffi n cells, which have been demonstrated in canine gastric and duodenal mucosa, stimulates vagal afferents via 5-HT 3 receptors (Fukui and others 1992 [2b], Fukui and others 1993a [2b] ). It seems that other pathways and local modulatory signals are also important (Lang and others 1988 [2b], Sanger and Andrews 2006 [3a] ). Peripheral emetogenic triggers may be abrogated by bilateral vagotomy, effects which are enhanced when combined with ablation of the greater splanchnic nerves, suggesting more than one signal pathway (Fukui and others 1993b [2b] The 'chemoreceptor trigger zone' of the brainstem has been identifi ed as the area postrema which is located on the dorsal surface of the medulla oblongata adjacent to the caudal end of the fourth ventricle (Chernicky and others 1980 [2b] ). This region, lacking a blood-brain barrier, is responsive to circulating emetogens. As well as inputs from peripheral, vestibular and area postrema triggers, stimulation from higher centres has been proposed, presumably co-ordinated in the nucleus tractus solitarius. Clinical diseases associated with emesis in dogs are summarised (Tables 2-5 ). In many of these diseases emesis is triggered peripherally and co-ordinated centrally, although there may be concomitant activation of the chemoreceptor trigger zone in some conditions e.g. uraemia. Whilst generally considered a mechanism of protection, vomition of food by bitches is believed to be part of the normal rearing process (Korda 1972 [3b]) [OEG C]. Initial assessment of dogs with emesis should evaluate their general health condition (determination of the severity of the disease process) which will differentiate those in which no treatment is necessary, those which need to be treated symptomatically and those which need further examination or specifi c treatment. In addition the initial assessment may give clear indications of the underlying cause of the vomiting. The initial assessment starts with the age, breed and gender of the dog. The age is important because some diseases are more common in young dogs, e.g. ingestion of foreign bodies, foreign body induced ileus ( . There are many more breed predilections that can be mentioned. Some diseases also have a gender predilection e.g. hypoadrenocorticism is more commonly seen in female dogs (Kintzer and Peterson 1997 [3a] ) and some diseases exclusively affect one gender (e.g. pyometra, prostatitis). A full and complete history is essential for evaluation of a vomiting dog. Information which should be obtained is listed ( Table 6 ). The most important distinction is that between vomiting and regurgitation, because their aetiologies are very different and this will direct specifi c diagnostic testing. Regurgitation is passive, with undigested food or saliva returned under gravity, whereas vomiting is a refl ex, accompanied by signs of nausea, hypersalivation and activity of the abdominal musculature. A thorough physical examination is required and should include assessment of features shown (Table 7) . From the signalment, history and physical examination, the clinician should be able to identify criteria for concern which might indicate a need for immediate diagnostics investigation and/or therapy ( The misnomer 'acute gastritis' is commonly used to describe a syndrome of acute and self limiting emesis. In almost all of these cases, however, gastric infl ammation is not proven by histopathology. Gastritis is a frequently cited yet rarely confi rmed diagnosis in cases of canine anorexia and emesis. Dogs with simple, mild, acute self limiting emesis do not need further workup, and can be treated symptomatically. Many of these animals are not seriously ill, and may need no treatment. A recent study suggests 95% of dogs with emesis do not present to the veterinary surgeon (Hubbard and others 2007 [4a]). Even in those that present to a veterinary surgeon, in most cases of acute self limiting emesis, the aetiology is never determined: dietrelated factors (dietary indiscretion), infectious agents and toxins are considered the most important causes. If the signs resolve after 1 to 2 days, with or without symptomatic and supportive therapy, the tentative diagnosis of acute self limiting emesis is considered correct. In those cases where further investigation is considered necessary a variety of diagnostic tests may be indicated ( Table 9) . TREATMENT A number of potential adverse effects of persistent emesis have already been detailed. Treatment of persistent emesis reduces suffering and prevents complications whilst a thorough investigation is undertaken to identify and, where possible, treat the underlying cause. The decision to treat emesis or to wait and see if the problem resolves will depend on the circumstances in each individual case where the risk-benefi t analysis of using a drug to prevent further emesis ). These authors showed that in 89% of dogs with signs of vomiting, signs resolved in less than two days. The clinician should judge the need for further investigation and treatment; a suggested approach is summarized in the algorithm ( Figure 2 ). Emesis may be a desirable outcome following toxic ingestion, and antiemetics, especially where there is also a pro-kinetic effect, are not indicated where there is gastrointestinal obstruction. To minimise the risk of anti-emetics masking signifi cant clinical signs it is important to initially identify those cases requiring further investigation and to ensure effective follow-up examinations are planned to reassess the progress of cases that are treated symptomatically. A risk benefi t assessment should be made of the likely success of a particular drug in preventing and treating emesis versus the likelihood of the drug inducing adverse effects. If the veterinarian considers initial treat ment unnecessary or institutes nonspecifi c, symptomatic management for suspected acute self-limiting vomiting, pet owners should be advised that, following initial assessment, there is no immediate need for a more specifi c diagnosis or treatment and that non-specifi c therapy is suffi cient in many cases (Hubbard and others 2007 [4a]). They should be advised of the benefi ts and effects of therapy and of what outcome measures to monitor (see 'Monitoring' below). The use of an antiemetic drug should not delay any necessary investigation or treatment if deemed necessary by the clinician. Supportive care of the patient with emesis may include fl uid and electrolyte therapy to correct or prevent dehydration and/or electrolyte and acid-base therapy. Though treating the symptom itself will often improve patient demeanour and comfort, it is no replacement for making a correct diagnosis. [OEG D]. The ideal antiemetic Antiemetics are used symptomatically to manage a clinical manifestation of a wide spectrum of different diseases. In many clinical situations e.g. uraemia, emesis may occur because of a combination of stimuli (central and peripheral). The relative importance of the different pathways may or may not be apparent from the clinical presentation or diagnosis. The ideal drug will, therefore, prevent both central and peripheral stimuli of the 'vomiting centre' (see section 'Causes of vomiting'). In addition, because persistent and/or severe emesis can result in signifi cant fl uid loss and electrolyte disturbances, the ideal antiemetic drug should be without effect on the cardiovascular system since actions here can upset the delicate haemodynamic balance in a dehydrated patient. Furthermore, a drug with a very wide therapeutic index would be desirable, particularly as emesis can be associated with kidney and liver disease, two major organ systems involved in the clearance of drugs from the body. Drugs with narrow therapeutic indices would be unsafe to administer to dogs with signifi cant kidney or liver dysfunction. In addition central nervous system side-effects, such as sedation, might be undesirable in drugs used treat emesis because changes in central nervous system (CNS) function may make diagnosis of the underlying cause of the emesis or assessment of the progression of the dog's condition diffi cult and, potentially, predispose to adverse events such as aspiration. Finally, a lack of direct effects of an antiemetic on GI motility would be desirable in most cases, although a prokinetic effect may be benefi cial in some conditions such as chronic gastritis. It should be recognised that, because of the multiple inputs into the vomiting centre, the involvement of co-transmitters within a given pathway and the facilitatory actions of a number of neurotransmitters on each pathway, the holy grail of identifying one drug that inhibits all causes of emesis and nausea is never likely to be achieved. Figure 3 outlines the antiemetic drug target receptor distribution in relation to different arms of the vomiting refl ex and Table 10 summarizes the properties of currently available antiemetic drug classes in veterinary medicine and the evidence for their usefulness in dogs, helping the clinician to select the drug whose profi le best suits the individual patient. Most of the studies used to provide evidence for the statements made in There are limited data to advise small animal clinicians on the optimal feeding strategy for vomiting patients. Two main scenarios should be considered, and will be approached separately. The fi rst is a severely affected vomiting patient where hospitalisation is required; the second is a patient where vomiting is less severe and can be handled as an out-patient. In humans, there is a wealth of information supporting the use of enteral methods of feeding over parenteral nutrition. In a critical review by Zaloga (2006 [1b] ), compared with parenteral nutrition (PN), the use of enteral nutrition (EN) improved survival, decreased infection rate, decreased bacterial translocation, enabled earlier discharge from hospital, and was more cost effective. However, a metaanalysis examining the benefi ts of either enteral nutrition or volitional nutritional support over nil per os strategies is more controversial, suggesting that, asides from using volitional nutritional support in ger- Clinical studies in dogs One randomised, unblinded, clinical study has compared the effect of early enteral nutrition (EEN), versus food withholding, in cases with parvoviral enteritis whose signs included emesis (Mohr and others 2003 [2b] ). The EEN group were fed with a standard critical care diet, via naso-oesophageal tube, commencing after 12 hours of hospitalisation; in contrast, food was withheld in the 'nil per os' (NPO) group until emesis had ceased. There was a trend towards improved survival in the EEN group, given that all EEN dogs survived whilst 13/15 NPO did. The EEN group also showed earlier clinical improvement, with more rapid (by 1 day) improvement in demeanour, appetite, vomiting and diarrhoea. Further, signifi cant weight gain occurred in this group, but did not in the NPO group, whilst improved intestinal barrier function was seen. A similar clinical study has assessed the benefi ts of combined parenteral and oral nutrition compared with parenteral nutrition alone, in young dogs with haemorrhagic gastroenteritis (Will and others 2005 [2b] ). Dogs were alternately allocated to each group, and treated for at least 4 days. In the enteral nutrition group, a 'hydrolysed' cottage cheese based diet, pre-incubated with pancreatic enzymes, was administered by syringe from day 2 onwards. Most dogs in the enteral nutrition group vomited within half an hour of starting feeding on the second day, but were able to tolerate food better on subsequent days. There was no signifi cant difference in general health status and clinicopathological parameters between groups. However, all 10 dogs in the early enteral nutrition group survived, compared with 7 out of 9 of those in the parenteral nutrition group. Although the study is small, this latter fi nding in conjunction with the survival data from Mohr and others (2003 [2b] ), may suggest a benefi t of early enteral feeding in patients with severe gastrointestinal disease. More work would, however, be required to support such an approach. The remaining publications are either review articles or pertain to single case reports or small case series where nutritional support is employed as a component of therapy for patients with severe gastrointestinal signs ( Vomiting patients handled as out-patients In dogs with acute emesis that are systemically well, the most common approach is to withhold food for a period (usually ~24 hours). In contrast, the trend in human gastroenterology is to continue to feed in the face of gastrointestinal signs, and there is now clear evidence that continuation of feeding during gastroenteritis has advantages (Sandhu 2001 [2b] ). There are no equivalent published studies assessing the relative merits of food withholding and early feeding in veterinary medicine. Given that the majority of dogs with acute gastrointestinal signs are likely to have self-limiting disease, it is unlikely that there would be a dramatic benefi t or detriment for either method. Finally, published data examining what dietary characteristics are most appropriate for acutely vomiting dogs are lacking. In the absence of such information, a highlydigestible diet seems most appropriate. [OEG D]. When symptomatic management is instituted, only the prescribed medications and diet recommended by veterinarian should be administered and an initial limit of 24 hours of any anti-emetic treatment is suggested. Owners should be made aware of the potential of any antiemetic therapy to mask emesis and should be advised to observe the pet closely and to contact the veterinary surgeon as soon as possible if there are any signs of deterioration and/or the patient is getting worse, with a view to arranging a re-examination. They should be advised to re-present the patient after a maximum of 48 hours if there is continued emesis or if there is no improvement in other outcome measures. Alternative outcome measures include appetite (which may refl ect associated nausea), general demeanour, and other associated clinical signs e.g. diarrhoea. It should be stressed that the owners should return more quickly if they are concerned. At reassessment, the clinician should repeat the initial consultation and re-consider criteria for further treatment and/or investigation as above. [OEG D]. Nausea and vomiting are among the most feared complications of chemotherapy and the owner of an animal with cancer is often more concerned about the well-being of the patient than about the success of a treatment. Nausea and vomiting in an animal with cancer can be explained by three main mechanisms: i. Here, we will only discuss nausea and vomiting originating from chemotherapy in dogs. Treatment has changed over time because of better understanding of the pathophysiology, more insight in the relationship between the different drugs used in cancer chemotherapy and, fi nally, the development of new drugs. [OEG C]. Pathophysiology and origin of vomiting Three types of vomiting due to cancer chemotherapy can be distinguished: i. Anticipated vomiting, which is frequently seen in human medicine but is very rare in our domestic animals. It corresponds to a Pavlov-like type of refl ex and is dependent on the memory (e.g. visual stimuli, stimuli by odour related to the clinic, the hospitalisation or personnel). In this type of vomiting it is important to treat with an antiemetic before chemotherapy to avoid activation of the refl ex. Whilst there is evidence of nausea and emesis as a conditioned response in humans receiving chemotherapy, there is no published evidence for these mechanisms in dogs. ii. Acute vomiting, which can manifest during the fi rst 24 hours after chemotherapy and can caused by either central (chemoreceptor trigger zone) or peripheral stimulation. This is the predominant mode of action of cytotoxic drugs. iii. Delayed vomiting which starts between 1 and 5 days after treatment (Fukui and Yamamoto 1999 [1b] ). Its mechanism is complex and multi-factorial. It may be attributed to a reduction in intestinal motility or to alteration of the intestinal mucosa and its release of hormones (serotonin, norepinephrine) or to a reduction of urinary cortisol excretion. It can also be the result of accumulation of metabolites of cytotoxic agents (especially those derived from platinum). [OEG C]. 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