Nausea is described as the unpleasant sensation of needing to vomit, while vomiting or emesis is the forceful oral expulsion of gastrointestinal (GI) contents. While vomiting may have a protective mechanism by removing potential harmful substances, nausea can result in significant debilitation and impact patient welfare. The possibility of nausea in an owner's cat or dog can result in owner distress and most owners are willing to pay for additional treatment for the clinical signs of nausea (Hay Kraus and Cazlan, 2019).
Nausea does not always result in vomiting, and is believed to be more challenging to manage than the act of vomiting (Morrow et al, 2002; Topal et al, 2005). There are numerous causes of nausea such as postoperative and anaesthesia-associated drugs including opioids and chemotherapeutics, and conditions affecting the brain, vestibular system and abdominal viscera. However, nausea is a subjective individual event and, while it is associated with numerous clinical signs, it may be difficult to truly interpret its full impact on a particular patient. Vomiting should not be misinterpreted as regurgitation, and therefore regurgitation will also be discussed. Registered veterinary nurses play a key role in identifying nauseous patients, administering antiemetics and providing additional supportive measures to decrease nausea in hospitalised patients.
Nausea and vomiting physiology
Nausea is believed to be caused by the activation of multiple cortical (forebrain) areas, while vomiting is initiated through activation of the vomiting centre in the medulla oblongata (brain stem) (Kenward et al, 2015). There are multiple sensory inputs, which can stimulate nausea and vomiting, and the mechanism of vomiting is better understood than that of nausea. Inputs into the vomiting centre include motor pathways (vagal afferents), the vestibular system, chemoreceptors within the chemoreceptor trigger zone of the vomiting centre, and physiological/forebrain signals. When activated, motor pathways that travel within the cranial nerves (glossopharyngeal and vagal) to the upper GI tract, trigger nausea and vomiting. Several principal receptors are involved in this physiological process including histamine (H1), acetylcholine (M1), serotonin (5-HT3), dopamine (DA2), neurokinin (NK1), substance P and mu/kappa opioids (Figure 1).
There is a period of reverse peristalsis prior to vomiting where GI contractions move contents orally instead of down (aborally). Within a few minutes, these antiperistaltic contractions move intestinal contents into the duodenum and stomach. As the upper GI tract becomes distended, nerve impulses are sent to the vomiting centre. Further intrinsic contractions in the duodenum and stomach result in relaxation of the lower oesophageal sphincter, allowing the stomach contents to move into the oesophagus. This is followed by contraction of the thoracic and abdominal muscles, which expel the vomitus into the mouth.
Studies have tried to detect biomarkers that would help to identify individuals affected by nausea and their response to anti-nausea medication. Plasma arginine vasopressin (AVP) and cortisol are increased in dogs during cisplatin-induced nausea (Kenward et al, 2017). While these biomarkers correlate with the nausea-like behavioural response, they require further evaluation and interrogation using different drug doses to make them more clinically applicable, particularly as both hormones are affected by multiple other physiological states.
While vomiting can be a protective mechanism, it has many potential detrimental consequences including aspiration pneumonia, reflux oesophagitis, abdominal pain, fluid sequestration and inadequate nutritional intake.
Clinical signs of nausea
Nausea and vomiting are thought to co-exist. However, it is possible for a patient to experience severe nausea without vomiting — hence the importance of observing signs to identify a nauseous patient. It is recognised that each person has a threshold for nausea, which depends on inherent factors and the individual's psychological state; this likely explains the inter and intra-individual variability. There is currently no validated scale for nausea in animals; however, both numerical rating scales and visual analogue scales have been used in veterinary studies to score patients for nausea based on behavioural observation (Hay Kraus, 2014; Johnson et al, 2017; St James et al, 2019). Typical nausea behaviours include hypersalivation (Figure 2), lip smacking, exaggerated swallowing movements, lethargy or restlessness, and avoidance of food sources (Hay Kraus, 2014; Kenward et al, 2015). If measured, heart rate is often increased (Goineau and Castagné, 2016). The Veterinary Cooperative Oncology Group (VCOG) (2016) monitors chemotherapy-associated nausea using the VCOG-CTCAE scoring system:
- 1. Loss of appetite without alteration in eating habits
- 2. Salivation or smacking of lips <3 days and altered oral intake (≤3 days) without significant weight loss; oral nutritional supplements/appetite stimulants may be indicated
- 3. Salivation or smacking of lips >3–5 days with anorexia >3 days' duration; associated with significant weight loss (≥10%) or malnutrition; intravenous (IV) fluids, tube feeding or force feeding may be indicated
- 4. Salivation or smacking of lips >3–5 days with anorexia >5 days' duration with life-threatening consequences; total parenteral nutrition (TPN) indicated.
Alternative scoring systems have been used, which compute the sum of clinical signs, their severity and frequency, and use this as a baseline to determine if an intervention has subjectively altered nausea scores (St James et al, 2019).
Regurgitation
Regurgitation is the passive ejection of food or fluid from the pharynx or oesophagus contents into the mouth. The length of the dog's oesophagus is striated muscle; while in cats, the proximal one-third of the oesophagus is striated muscle and the remainder is smooth muscle. Regurgitation of gastric contents follows a sequalae of events where the lower oesophageal sphincter relaxes and the oesophageal muscular activity is altered, leading to the passive process of gastric contents passing into the mouth. In some cases, the gastric contents may be regurgitated silently into the mouth and swallowed back down. In other cases, the contents may come out of either the mouth or nose, and be observed by the veterinary team. There are several causes of regurgitation which may be linked to a primary underlying condition contributing to either hypomotility, inflammation or an obstruction to the oesophagus. It is often not associated with any preceding signs and typically occurs after eating or drinking, but not always. Regurgitant material often contains undigested food and no bile. In the critically ill patient, a common complication of regurgitation is aspiration pneumonia.
Ileus
Ileus is defined as a temporary lack or abnormal pattern of GI muscular contractions. It typically results in the accumulation of fluid or gas in the gut lumen, increasing the risk of regurgitation and may cause nausea. Gastric emptying and functional peristalsis rely on coordinated gastric and small intestinal muscular contraction and relaxation to move ingesta from the stomach though the intestines. Delayed gastric emptying and ileus can result from a primary GI or secondary disorder in the hospitalised patient.
Pharmacological support
Understanding the physiology of nausea, vomiting, regurgitation and ileus helps to guide the rationale for drug choice. Knowing that vomiting and nausea are triggered by the visceral, vestibular, chemoreceptor trigger zone or the GI tract, and understanding the likely underlying cause in the individual patient, may alter drug selection. Most antiemetic and anti-nausea drugs work by inhibiting the emetic pathway and preventing the vomiting reflex. Currently available common drug choices are based on drugs that affect the receptors in each trigger zone. They can be split into the following groups: serotonin (5-HT3), dopamine (DA2), neurokinin (NK1) receptor antagonists and antihistamines. The drugs used to treat GI dysmotility and ileus have prokinetic effects, which affect the receptors within the GI tract. While some medications or preparations are licensed and preferred under the veterinary cascade, they may not be the most appropriate choice for an individual patient. In human medicine, nausea is treated often via a multimodal approach — something that should be considered in the veterinary patient population.
Veterinary nurses should have an understanding of the medications they are administering to their patients, in particular, mechanism of action, anticipated effects and side effects, potential drug interactions and how to prepare and administer the medication. The route of administration must also be considered, with some medications having poor oral bioavailability (not well absorbed or large individual variability of absorption via the GI tract), the patient condition may alter medication absorption (i.e. if a patient has ileus or severe malabsorptive disease, the oral route may result in poor drug absorption), and the actively vomiting patient may benefit from an IV (rather than oral) administration. If the medication can only be administered orally, it may be that there is an alternative formulation to allow the medication to be administered via an alternative route (i.e. transdermal) or that there is an alternative medication that can be administered intravenously. Compounding pharmacies offer alternative preparations of some medications making them more suitable and available for veterinary patients.
Maropitant
- Maropitant is an NK1 receptor antagonist which acts directly on the vomiting centre (centrally) by inhibiting substance P and reduces peripherally and centrally mediated vomiting
- Indications and rationale: the main indication for maropitant is vomiting. It does not affect gastric emptying times or GI transit times, and is therefore of limited benefit for ileus. It is not clear whether it alleviates the feeling of nausea (Rau et al, 2010; Claude et al, 2014; Hay Kraus, 2014; Koh et al, 2014; Ramsey et al, 2014; Lorenzutti et al, 2017)
- Contraindications and considerations: there are no known drug interactions, but one consideration is that maropitant can be accumulative after repeated administration. Maropitant should be avoided in cases where GI obstruction or perforation are suspected or identified. Some patients can experience pain on subcutaneous (SC) administration, which is believed to be as a result of the free drug rather than the bound drug in the injectable solution. As more drug is bound at lower temperatures, injection pain can be reduced by storing the product in the fridge and injecting from a chilled bottle (Narishetty et al, 2009). Dosing can be reduced in patients with hepatic insufficiency. Maropitant has cardiac calcium and potassium channel-blocking effects, and although this effect is typically considered to be clinically insignificant, close monitoring of cardiac rhythm in patients with an arrhythmia is recommended
- Administration: SC, IV, or per os (PO) (oral). Maropitant is rapidly absorbed so works quickly.
Metoclopramide
- Metoclopramide has both antiemetic and GI stimulatory properties, and can be used in cases of GI stasis, nausea and vomiting. The exact pharmacokinetics are unknown; however, it seems to act centrally by antagonising dopamine (DA2) and serotonin (5-HT3) at the chemoreceptor trigger zone. The prokinetic stimulatory effect is increasing the release of acetylcholine in the smooth muscle of the stomach and small intestines (Trepanier, 2010)
- Indications and rationale: metoclopramide is most commonly administered to manage vomiting, ileus/delayed gastric emptying, regurgitation secondary to the previous or gastroesophageal reflux. Management of the described may result in the patient feeling less nausea, although metoclopramide itself does not appear to do much to treat the feeling of nausea directly (Kolahian and Jarolmasjed, 2010)
- Contraindications and considerations: metoclopramide is contraindicated in cases where GI obstruction or perforation is suspected or identified. It should also not be used in patients with GI haemorrhage, epilepsy or phaeochromocytoma (may induce hypertensive crisis). It is less effective in cats as they have fewer dopamine receptors than dogs in the chemoreceptor trigger zone. The most commonly reported adverse reactions seen are changes in mentation or behaviour. Metoclopramide has been reported to interact with the following medications: cholinergic drugs enhance metoclopramide's GI effects, atropine antagonises metoclopramide's GI effects; central nervous system depressants (including anaesthetics, opioids and sedatives) may enhance depressant effects. It may be beneficial to half the dose in patients with altered renal function (Trepanier, 2018)
- Administration: metoclopramide can be given PO, SC or IV (bolus vs constant rate infusion (CRI)). In the hospitalised patient, it is often preferred to administer via a CRI to ensure reliable administration and absorption, and it may prevent the peaks and troughs of bolus therapy (Figure 3).
Mirtazapine
- Mirtazapine is a tricyclic antidepressant medication which antagonises 5HT3, H1 and alpha2 receptors. When alpha2 receptors are antagonised, they interfere with the negative feedback loop, leading to an increase in circulating noradrenaline. It is this noradrenaline increase that acts on other receptors to increase appetite. Antagonism of the 5HT3 receptors leads to antiemetic and anti-nausea properties
- Indications and rationale: the most common use for mirtazapine in veterinary medicine is to stimulate appetite; however, it could be considered in cases of vomiting or nausea. It has also been shown to improve gastric tone and gastric emptying in dogs (Yin et al, 2014)
- Contraindications and considerations: sedation is a common side effect; however, some cats may demonstrate frenzied behaviour such as vocalisation and restlessness. Hypotension has been associated with mirtazapine administration and thought to be secondary to the alpha2 effects. Mirtazapine should be used with caution when administered concurrently with serotonergic effects because of the risk of serotonin syndrome. A lower dose should be administered to patients with reduced glomerular filtration rate and possibly also those with liver disease
- Administration: PO or transdermal. Daily dosing in cats without liver or kidney disease may be appropriate, while every-other-day dosing may be more suitable for those with decreased liver or kidney function (Quimby et al, 2011; Fitzpatrick et al, 2018). Once or twice daily dosing in dogs is appropriate (Giorgi and Yun, 2012).
Ondansetron
- Ondansetron is an antiemetic used in cases with vomiting and nausea. It is a serotonin (5-HT3) receptor antagonist and so works both centrally and peripherally. It has been used in human medicine to control nausea and vomiting associated with chemotherapy
- Indications and rationale: ondansetron is indicated to manage vomiting and nausea (Kenward et al, 2017). It has no effect on GI motility
- Contraindications and considerations: it is suggested that ondansetron be used with caution in patients with reduced liver function. Some literature states it should also be used with caution in cats. It should not be administered to patients with GI obstruction or perforation. A documented incompatibility is with tramadol; when given concurrently, tramadol's effectiveness is reduced so higher doses may be required. High doses may result in cardiac potassium channel blockade; therefore, monitoring of cardiac rhythm in patients with an arrhythmia or antiarrhythmia medication is recommended
- Administration: IV or PO. If given IV, there are two protocols that can be adopted: either a loading dose followed by infusion or intermittent bolus doses. The typically poor oral bioavailability and inter-individual variation of oral bioavailability results is unpredictable beneficial responses when administered orally (Quimby et al, 2014; Baek et al, 2015).
Drug selection in the hospitalised patient
The postoperative hospitalised patient
Maropitant may decrease the time to eating following surgery in dogs and decreased postoperative vomiting, but the effect of maropitant on opioid-induced nausea is less clear (Ramsey et al, 2014; Swallow et al, 2017). If an opioid premedication is used, pre-medication with acepromazine, if suitable for that patient, or use of metoclopramide can be considered in the postoperative period (Claude et al, 2014; Koh et al, 2014; Lorenzutti et al, 2017).
Patient hospitalised with vomiting and ileus
Attempts should be made to try to understand the cause of vomiting and ileus. This would include ensuring electrolytes are within normal limits and there is no evidence of kidney or liver injury. Abdominal radiographs and ultrasound can be performed to determine if there is evidence of a GI obstruction or inflammation of any of the abdominal viscera. Any primary disease process, electrolyte abnormality and abdominal pain should be managed. As vomiting increases the risk of aspiration pneumonia, maropitant would be indicated, and prokinetic-antiemetics such as metoclopramide or mirtazapine can be added if the patient's symptoms persist. Ondansetron may be suitable if the patient's nausea continues but close patient monitoring is recommended owing to the increased potential of serotonin syndrome if multiple drugs that act via 5HT3 are prescribed.
The patient hospitalised for chemotherapy-associated gastrointestinal upset and nausea
Although maropitant has been demonstrated to decrease chemotherapy-associated vomiting, it has not reliably decreased chemotherapy-associated nausea (Vail et al, 2007; Rau et al, 2010; Kenward et al, 2017). Therefore, if nausea is the main concern, ondansetron may be an appropriate treatment option (Topal et al, 2005; Kenward et al, 2017).
Non-antiemetic drug support
In addition to pharmacological support, there are a number of other avenues to consider in the patient's treatment plan in order to help minimise these GI signs:
- Early mobilisation will encourage GI movement, lymphatic and blood flow
- Appropriate pain management is a necessity in any critically ill patient with the go-to analgesic option often being opioids. However, it has been well documented that opioids have an effect on GI motility. A multimodal approach is preferred to allow lower dosages of several medications and therefore fewer side effects of each
- Appropriate fluid resuscitation: Achieving the correct fluid balance for the patient is a challenge as inadequate fluid therapy leads to reduced organ perfusion, but overzealous fluid therapy can lead to GI oedema. The patient's fluid plan should be regularly reassessed and adjusted as necessary.
- Early enteral nutrition is important in any critically ill patient in order to aid their recovery while hospitalised. It will aid in GI blood flow, minimising the risk of GI bacterial translocation, stimulated GI motility and normal GI physiology
- Administration of future IV chemotherapeutics following a period of patient starvation may be considered as vincristine-associated nausea is lessened by short period of starvation in dogs (Duckett et al, 2021)
- Acupuncture has been shown to decrease morphine-associated and lidocaine-associated nausea (Koh et al, 2014; St James et al, 2019). This therapeutic modality could be used as part of a multimodal treatment programme of nausea.
Conclusion
While the true incidence of nausea, vomiting, ileus and regurgitation is not known for hospitalised cats and dogs, if these symptoms are left untreated, patient welfare is affected and risk of complications increase, leading to a longer and possibly more expensive hospitalisation, and often a more guarded prognosis. Registered and student veterinary nurses play an important role in identifying patients that demonstrate the signs associated with these symptoms. They can liaise with the veterinary surgeon to ensure that the most suitable pharmacological agent is added to the treatment plan, safely administer the medication and closely monitor patients for any adverse drug effects, as well as consider incorporating appropriate non-pharmacological interventions into the patient care plan.
KEY POINTS
- Nausea, vomiting and gastric dysmotility are commonly experienced symptoms in hospitalised patients.
- There is currently no validated nausea scale for veterinary patients making this a challenging clinical sign to observe.
- Vomiting and regurgitation should be differentiated so the patient can be appropriately managed.
- There are a range of different drugs that may be helpful in managing nausea and vomiting depending on the likely underlying cause.
- Patients with nausea and vomiting should also have an appropriate fluid therapy plan, analgesia and nutritional plan.