Nausea and Vomiting (Emesis)

• Introduction to emesis
  • Nausea
  • Retching
  • Vomiting
• Symptoms of emesis
• Causes of nausea and vomiting
• Mechanisms of emesis
  • Central nervous system control
    • Chemoreceptor trigger zone (CTZ)
    • Integrative trigger zone
  • Afferent pathways
  • Efferent pathways
• Stimuli for vomiting
  • Pain, sight, smell, taste, emotion
  • Motion sickness
  • Opioid medications
  • Cancer therapy
  • Hormonal changes during pregnancy
  • Post-operative nausea and vomiting (PONV)
  • Toxins
  • Throat/stomach
• Consequences of vomiting
• Management and treatment of nausea and vomiting
  • Antiemetic medications
  • Dietary management of nausea

Introduction to emesis

Vomiting can also be referred to as emesis, and consists of the following stages:

Nausea
Nausea is an unpleasant sensation of wanting to vomit, and is often associated with cold sweat, pallor, salivation, loss of gastric tone, duodenal contraction, and the reflux of intestinal contents into the stomach. Nausea generally precedes vomiting, but can occur by itself. The system that brings about the loss of gastric tone, of gastric relaxation, is the efferent part of the long loop intestinal reflex that relaxes the gut during food intake.

Retching
Retching is a strong involuntary effort to vomit, and usually follows nausea. During retching, the abdominal muscles, chest wall and diaphragm all contract without any expulsion of gastric contents.

Vomiting
Vomiting is the forceful expulsion of the contents of the gastrointestinal system out through the mouth. From an evolutionary perspective, it is thought to have evolved as a defense mechanism of the body, serving a protective function to rid the body of noxious substances that have been ingested, rather than allowing them to be retained and absorbed by the intestine.
Contrary to popular belief, the stomach itself does not actively expel its contents during vomiting. The stomach, oesophagus, and their relevant sphincters are all in fact relaxed during vomiting. Most of the force that expels the contents arises from the contraction of the diaphragm, which is the major respiratory muscle, and the abdominal muscles, which are the muscles involved in active expiration.

Symptoms of emesis

The symptoms of emesis include:

• Profuse salivation;
• Sweating;
• Elevated heart rate;
• Pallor;
• Nausea; and
• Retching movements.

Causes of nausea and vomiting

The following table highlights the major and most common causes of nausea and vomiting:

Irritation of the stomach and duodenum	Indigestion; Allergies; Bowel obstructions; Gallstones; Liver problems; Pancreatitis.
Infectious causes	Viral labyrinthitis; Viral gastroenteritis; Influenza; Whooping cough; Food poisoning.
Endocrine causes	Pregnancy.
Labyrinth causes	Motion sickness; Meniere’s disease.
Increased intracranial pressure	Haemorrhage. Vomiting following a head injury is considered dangerous as it indicates swelling or bleeding within the cranial cavity; Meningitis; Lesions in parts of the brain.
Changes in body chemicals	High blood sugar levels in diabetics; Higher than normal blood calcium levels.
Drug/treatment induced	Cancer chemotherapy; Opiates (e.g. morphine, codeine); Digoxin; Immunotherapy; Nicotine; Antibiotics; Radiotherapy; Alcohol excess.
Reflex	Severe pain.
Post-operative	Anaesthetics; Analgesics.
Central nervous system (CNS)	Anticipation; Migraine; Bulimia nervosa; Psychogenic stimuli (e.g. nauseating sights and odours, high levels of stress and anxiety).
Tactile/touch stimulation	Stimulation of the back of the throat. In some people, this can even include the presence of a tongue depressor or dental instrument.

Mechanisms of emesis

The mechanisms of emesis can be divided into three components:

1. Afferent inputs go to the central nervous system (CNS), relaying the signals of emetic stimuli;
2. These signals are received, recognised, and centrally processed. They then form integrated emetic efferent signals coming from the CNS;
3. These motor and chemical efferent pathways relay signals that lead to the coordinated respiratory, gastrointestinal and abdominal muscle expulsive actions of vomiting.

Central nervous system control
There are two medullary centres of vomiting in the brain known as the sensory “chemoreceptor trigger zone (CTZ)” and the integrative centre.

Chemoreceptor trigger zone (CTZ)
The CTZ is located in the medulla of the brain. It has a defensive blood-brain barrier for detecting circulating toxins in the blood and cerebrospinal fluid (CSF), and is sensitive to a number of circulating emetic agents, including morphine, intravenous copper sulphate, and certain circulating metabolic emetic agents associated with uraemia, infections and radiation. When activated, the CTZ does not initiate vomiting itself, but relays stimuli to the integrative vomiting centre which produces the actual act of emesis.

Integrative vomiting centre
The integrative vomiting centre coordinates activities of the nearby neural structures to produce a complex patterned response, resulting in the processing and action of the vomiting reflex. The centre is located in the medulla. The motor component of the vomiting centre is controlled by both somatic and autonomic systems, meaning that both voluntary and involuntary systems are involved in the process. Their inputs are coordinated by the vomiting centre.
Somatic efferent pathways control respiratory and abdominal musculature, and visceral efferent components mediating changes in gastric tone and motility, while salivation, pallor and sweating are autonomic epiphenomena. The autonomic nervous system is not essential for the mechanical act of vomiting, but the activation of efferent nerves of the abdominal organs in the emetic process is proportional to the duration and intensity of the nausea that accompanies the process.

Afferent pathways
The vomiting centre is predominantly activated by three different mechanisms:

1. By nervous impulses from the stomach, intestinal tract, and other portions of the body, resulting in a reflexive activation;
2. By stimulation from the higher brain centres;
3. By the chemoreceptor trigger zone (CTZ) sending impulses.

Afferent impulses may also arise from other sites, such as unpleasant sights and odours, as well as severe parietal pain. The most common afferent pathways are in the viscera, or abdominal organs. Vomiting can be provoked by occlusion of the coronary vessels, distension of the intestine, and irritation of the gastrointestinal mucosa. In the gastrointestinal tract, mechanoreceptors in the intestinal wall are activated by abnormal contractions, distension or physical damage. Potentially harmful chemical stimuli can also activate chemoreceptors located in the intestinal wall. These receptors then release information to the vomiting centre.

Efferent pathways
The neural pathways involved in the motor act of vomiting are associated mainly with the phrenic nerve to the diaphragm, the spinal nerves to the abdominal and intercostal muscles, efferent visceral autonomic fibres to the gut, and the viscera efferent fibres to parts of the voluntary muscles of the pharynx and larynx. The vomiting reflex is mediated by both the autonomic and somatic systems, and consists of two phases:

1. Prodomal phase (pre-ejection): Relaxation of gastric muscles followed by small intestinal retrograde peristalsis;
2. Ejection phase: Comprises of retching and vomiting including expulsion of gastric contents.

Stimuli for vomiting

Pain, sight, smell, taste, emotion
The experience of these sensations leads to information sent to the higher centres in the brain, and then information relayed to the vomiting centre and CTZ via chemicals that transmit information to the brain, hence the name ‘neurotransmitters‘. The one that is most commonly responsible is acetylcholine, or Ach. Neurotransmitters stimulate and activate the vomiting reflex through the afferent pathways previously described.

Motion sickness
Motion sickness is due to labyrinth stimulation. The labyrinth is a part of the inner ear involved in balance and perception of movement. Labyrinth stimulation leads to impulses passing along the vestibular nerve to the central nervous system, where it activates the CTZ to produce emesis. Neurotransmitters such as histamine or Ach are also released to the CTZ, which itself can releases chemicals such as dopamine and serotonin (5HT) that go on to stimulate the vomiting centre, which releases Ach, which then leads to the feelings of nausea and actions of vomiting.

Opioid medications
Opioids such as codeine, morphine, pethidine, fentanyl, methadone, oxycodon, and tramadol can cause nausea and vomiting through a number of different possible mechanisms such as stimulation of CTZ, increased vestibular sensitivity, gastric stasis, or impaired intestinal motility and constipation.

Cancer therapy
Chemotherapy
Cytotoxic drugs cause stimulation of 5-HT3-receptors peripherally and possibly centrally on the CTZ. This in turn will cause the release of the aforementioned chemical transmitters dopamine and 5HT, which trigger the vomiting centre and cause the release of Ach, thereby leading to induction of nausea and vomiting. Chemotherapy-induced nausea and vomiting can affect the quality of life and result in dehydration, weight loss and malnutrition.
There are three types of emesis following cytotoxic chemotherapy:

1. Acute emesis: symptoms occurring within the first 24 hours after chemotherapy;
2. Delayed emesis: symptoms occurring after 24-48 hours after last dose of chemotherapy;
3. Anticipatory emesis: a conditioned response in patients who have developed significant chemotherapy-induced nausea and vomiting during previous cycle of therapy.

 Delayed emesis as well as acute emesis is a particular problem with high-dose of cisplatin and other agents such as doxorubicin. However, in up to 75% of patients, this can be prevented or alleviated by using correct anti-nausea and anti-vomiting drugs, known as anti-emetics.
Generally, for management of chemotherapy-induced nausea and vomiting a combination of anti-emetic drugs is used. For instance, dopamine antagonists, such as metoclopramide (Maxolon), and serotonin antagonists, such as palonosetron (Aloxi) and granisetron (Kytril), are used together with a corticosteroid, such as dexamethasone, to match the strengths of chemotherapy agents.
In up to 75% of patients, this can be completely prevented by using correct anti-nausea and anti-vomiting drugs, known as anti-emetics. Nausea and vomiting are particular problems with some agents such as doxorubicin and others that contain platinum. Usually a combination of anti-emetic drugs is used. For example, metoclopramide and serotonin antagonists are used in combination with a steroid to match the strengths of chemotherapy agents.
Radiotherapy
Whether radiation therapy causes nausea and vomiting depends on the part of the body being treated, the amount of radiation given, and how often the treatment is given.
When the area of the body being treated includes a large part of the abdomen, specifically, the small intestine (or small bowel), there is a greater chance of nausea and vomiting occurring. About 50% of the people with cancer who receive standard doses (180 to 200 centiGray) of radiation to their abdomen will have nausea and vomiting. These symptoms can occur 1 to 2 hours after treatment and can last for several hours.
Of those being treated with total body radiation therapy, used in bone marrow transplants, about 60% to 90% will develop nausea and vomiting if not given medicines to prevent nausea and vomiting. These people may also receive high doses of chemotherapy to prepare for the transplant.
The combination of radiation therapy and chemotherapy increases the chance of nausea and vomiting. People who receive one large dose of radiation therapy have a greater chance of nausea and vomiting than those who receive radiation therapy in smaller doses.

Hormonal changes during pregnancy
Symptoms of nausea and vomiting are common during the first trimester of the stages of pregnancy. The exact mechanisms of pregnancy-induced nausea and vomiting still is not clear, however it is thought that elevated level of pregnancy hormones can play a role in inducing nausea and vomiting. Adequate hydration should be advised. Dietary modification such as small, frequent, high-carbohydrate, low-fat meals may help.

For more information, see Nausea and Vomiting in Pregnancy.

Post-operative nausea and vomiting (PONV)
PONV is a result of several potential factors such as:

• The types of anaesthetic agents used such as inhaled gases and/or medications, such as morphine;
• The type and the site of operation such as operations around the ear and inner ear, eyes, mouth and some abdominal surgery;
• The age of the patient; for instance young adults and the elderly are more susceptible to PONV;
• The gender of the patient; females are more susceptible to PONV;
• Patients with co-existing conditions such as those who are overweight and/or obese, diabetic, pregnant or suffering from hypothyroidism.

It is evident that some surgeries due to the above factors may trigger the release of 5HT from enterochromaffin-like cells in the visceral mucosa and initiate the emesis reflex and its accompanying feeling of nausea. Some risk factors that can predispose you to getting nausea and vomiting following a surgical procedure:

• Age: Younger patients and the elderly are more at risk of having post-operative nausea and vomiting;
• Gender: Women tend to suffer more than men do.
• Nutrition: People who are overweight or obese have a much higher risk of getting nausea and vomiting after a surgery. It is a condition that patients must fast before surgery, as contents in the stomach puts you at a much higher risk of vomiting after a surgery or at least feeling nauseous;
• Past history: If you have previously had nausea and vomiting after a surgical procedure and/or you suffer from motion sickness makes you more susceptible to getting nausea and vomiting after an operation;
• Cancer therapy: Patients undergoing chemotherapy and radiotherapy are more likely to suffer as well;
• Anaesthetic and surgical factors: Sometimes certain types of anaesthetic agents (such as inhaled gases) and medications (such as morphine) can lead to nausea and vomiting. Some surgical factors such as operations around the ear and inner ear, eyes, mouth and some abdominal surgery increase the risk of you getting nausea and vomiting afterwards.

All steps will be taken by the anaesthetists and doctors caring for you to prevent post-operative nausea and vomiting, however, in some instances, it can not be prevented and they will give you medications to ease the discomfort.

Toxins
The ingested toxin substances such as alcohol can induce life-saving physiological response to these circulating foreign particles. The CTZ is relatively permeable, enabling the circulating substance or mediators to act directly on this centre. Activation of this centre is followed by release of the aforementioned chemical transmitters dopamine and 5HT, which trigger the vomiting centre and cause the release of Ach, thereby leading to induction of nausea and vomiting.

Throat/stomach
Stimulation of parts of the throat and/or stomach can lead to nerve and chemical transmitter release of information to an area of the spinal cord and brain (known as the nucleus of the solitary tract), which goes on to trigger the vomiting centre and the cascaded of nausea and vomiting through Ach release.

Consequences of vomiting

Severe and prolonged vomiting can cause the following harmful consequences:

• Dehydration, which can be lethal, especially in children;
• Protracted vomiting may result in starvation, malnutrition and vitamin deficiency;
• Severe post-operative vomiting can increase bleeding, aspiration pneumonia, and induce the re-opening of surgical wounds as a result of involuntary muscle contractions associated with vomiting;
• Metabolic alkalosis.

Metabolic alkalosis
Metabolic alkalosis is a reduction in plasma concentrations of [H⁺] cause by a relative deficiency of noncarbonic acids. Under normal circumstances, Hydrochloric acid (HCl) is secreted into the lumen of the stomach during digestion. During this secretion, bicarbonate (HCO₃^–) is added. The HCO₃^– is usually neutralised by H⁺ as the gastric secretions are gradually reabsorbed. As a result, there is no net addition of HCO₃^– to plasma overall. Vomiting results in a loss of acidic gastric juices from the digestive tract, so that there is an abnormal loss of H⁺ from the body, and hence a loss of reabsorbed H⁺ to neutralise the extra HCO₃^– added to the plasma during gastric HCl secretion. This leads to an acid-base disturbance associated with an increase in HCO₃^– and a decrease in H⁺, hence the metabolic alkalosis.

Management and treatment of nausea and vomiting

1. Identify the pathway by which each cause triggers the vomiting reflex;
2. Identify the chemical transmitter involved in the identified pathway;
3. Choose a drug that is able to act as a preventer of this reflex pathway;
4. Appropriate drug delivery (e.g. as a tablet, as an injection). The route of administration depends on the state and condition of the patient. Drugs in rectal or parental form are necessary where oral medication is not tolerated or is contraindicated such as after major surgery;
5. Try to optimise the dose of the medication (usually start with the recommended dose).

If the underlying cause of the nausea and vomiting is unable to be identified, control of the symptoms should be established. It is also important to correct for electrolyte, fluid, and/or nutrient deficiencies.

Antiemetic medications
Dopamine antagonists
The members of this class of antiemetics are metoclopramide (Maxolon) and prochlorperazine (Stemitil). Metoclopramide has anti-dopamine action, which stimulates motility of the upper gut without stimulating the gastric, biliary or pancreatic secretions. Its exact mechanism is still unclear, however it is thought that metoclopramide may sensitize the tissues to the action of ACH. On the other hand, prochlorperazine has several activities such as anti-dopamine action, alpha-adrenoreceptor antagonism, weak anticholinergic, antihistamine and serotonin antagonism actions. Thereby its mechanisms of action give prochlorperazine strong antiemetic and antipsychotic properties.
Antihistamines
An example of this class of antiemetics is promethazine. Promethazine is a long acting antihistamine with sedative and anticholinergic properties that enhance the antiemetic activity.
5HT3 antagonists
5HT3 antagonists are mainly used to prevent or treat nausea and vomiting following cancer chemotherapy, radiotherapy or surgery. The members of this class of antiemetic are palonosetron (Aloxi), granisetron (Kytril), ondansetron, dolasetron and tropisetron. These medicines are potent antiemetic and highly selective antagonists of 5HT3 receptors. Because 5HT3 receptors are located peripherally on vagal nerve terminals and centrally in the CTZ, antagonism of this receptor is an effective method of preventing nausea and vomiting.
Anticholinergics
An example of this class of antiemetics is hyoscine, which is a belladonna alkaloid. Hyoscine has anti-spasmodic and anti-motility effect on the gut by inhibiting the activity of ACH.

Dietary management of nausea
Nausea with or without vomiting is a common side effect of surgery, chemotherapy, radiation therapy, and biological therapy. Nausea can prevent you from eating enough food and maintaining your nutritional intake and weight.
Dietary strategies to manage nausea include:

• Discuss anti nausea (antiemetic) medications with your doctor;
• Avoid eating 1–2 hours before your treatment if this makes nausea worse. Try to ‘catch up’ after treatment;
• Avoid foods that:
  • are fatty/greasy/fried;
  • are spicy or hot;
  • have strong odours.
• Eat small amounts more frequently and eat slowly;
• Eat before you get hungry, because hunger can make feelings of nausea stronger;
• Avoid eating in a room that is stuffy, too warm, or has cooking odors that might disagree with you;
• Sip cold clear fluids (e.g. cordial, flat gingerale, lemonade, diluted fruit juices, icy poles and jelly). This is particularly important if you are vomiting to prevent dehydration;
• Have foods and drinks at room temperature or cooler; hot foods may add to nausea;
• Rest after meals, because activity may slow digestion. It’s best to rest sitting up for about an hour after meals;
• Choose stomach-friendly foods, such as toast, crackers, yoghurt, creamed rice, oatmeal, boiled potatoes, rice, noodles, steamed/baked skinned chicken, canned peaches or other soft, bland fruits and vegetables, carbonated drinks that have gone flat;
• If vomiting persists after a day or two, contact your doctor or treatment centre. Contact them sooner if you feel very unwell.

Article kindly reviewed by:
The DAA WA Oncology Interest Group
and
Food4Health (Helen Baker Dietitian-APD)

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