Vomiting follows stimulation of the vomiting centre in the medulla of the brain. This may be via the chemoreceptor trigger zone, which is sensitive to many drugs and to certain metabolic disturbances, or from actions on other areas such as the vestibular apparatus of the ear (in motion sickness), the cerebral cortex (in psychogenic vomiting), and multiple peripheral receptors. In adults vomiting is almost invariably preceded by a sensation of nausea.
In situations where it can be anticipated, such as motion sickness, surgery, and cancer therapy, antiemetic drugs are given prophylactically, but if this fails they may need to be given therapeutically. Vomiting of unknown origin should ideally not be treated until the underlying cause has been found. If vomiting is prolonged, dehydration, hypokalaemia, and alkalosis may occur and replacement of fluid and electrolytes may be necessary, especially in young children and the elderly.
Nausea and vomiting are common adverse effects of cancer chemotherapy and for many patients represent a major drawback to treatment. Once experienced, anticipatory vomiting may occur at the sight of medical staff or a needle and mis problem may be severe enough in some cases to hinder or prevent further treatment.
Antineoplastic or cytotoxic tings may induce vomiting by bom a central action on the chemoreceptor trigger zone and a peripheral action on the gastrointestinal tract. The cerebral cortex is probably responsible for anticipatory vomiting. Mechanisms involving 5-HT3-receptors are important in the pamogenesis of acute cisplatin-associated vomiting, whereas different mechanisms are probably involved in delayed emesis.
The emetic potential of antineoplastics varies in terms of severity and incidence. A risk classification system, based on the proportion of patients who experience emesis in the absence of effective antiemetic prophylaxis, has been developed. Although mere are slight variations in published lists, examples of risk for some common drugs include:
- high (more than 90% frequency of emesis) and can be very severe with chlormemine, cisplatin, high-dose cyclophosphamide, dacarbazine, dactinomycin, and streptozocin
- moderate (30 to 90% frequency of emesis) with carboplatin, more modest doses of cyclophosphamide, doxorubicin, epirubicin, irinotecan, high-dose methotrexate, and oxaliplatin
- low (10 to 30% frequency of emesis) with etoposide, fluorouracil, lower doses of methotrexate, andtaxanes
- minimal (less than 10% frequency of emesis) with bleomycin, oral chlorambucil, fludarabine, oral methotrexate, rituximab, and vinca alkaloids
Emetogenicity may depend to some extent on the dose, route, and schedule of chemotherapy. Some combination therapy has resulted in a higher incidence of vomiting than would be expected from the constituents. The onset and duration of vomiting also varies from drug to ting. For cisplatin the onset may be between 4 and 8 hours after a dose, while the duration may be up to 48 hours or occasionally even longer a persistent feeling of nausea, and sometimes vomiting, lasting for several days may also occur.
After chlormethine, vomiting may begin within a half to 2 hours, whereas after cyclophosphamide mere may be a latent interval of 9 to 18 hours, but in bom cases vomiting is generally less prolonged man with cisplatin. Acute emesis (mat occurring within 24 hours of chemotherapy) has generally been easier to control than delayed emesis (mat occurring more man 24 hours after chemotherapy) or anticipatory emesis. In patients whose regimens are given over several days delayed emesis from the initial doses may overlap with acute emesis from later doses.
Cancer chemotherapy: Management
Guidelines for the management of nausea and vomiting associated with chemotherapy have been produced. It is important mat effective antiemetic prophylaxis is given from the first course of chemotherapy, to avoid subsequent problems with anticipatory vomiting. With the antiemetic drugs now available it should be possible to control acute emesis delayed emesis has proved more resistant but new treatments are becoming available. Drugs used in antiemetic regimens have included:
- dopamine antagonists such as metoclopramide, dom-peridone, and some phenomiazines such as prochlorperazine
- corticosteroids such as dexamethasone
- 5-HT3 antagonists such as ondansetron
- neurokinin-1 (NK-1) receptor antagonists such as aprepitant
- cannabinoids such as nabilone
- benzodiazepines such as lorazepam
- antihistamines such as diphenhydramine
The choice depends on the emetogenicity of the cancer chemotherapy regimen, as well as factors such as the age of the patient.
For prophylaxis of acute emesis associated with highly emetogenic chemotherapy, a 5-HT3 antagonist with dexamemasone and aprepitant (or fosaprepitant) is recommended. At equipotent doses, dolasetron, granisetron, ondansetron, and tropisetron are effective and equally safe. Palonosetron, which has a prolonged action, may also be used. High-dose metoclopramide was formerly used, but frequently caused extrapyramidal adverse effects, particularly in patients under 30 years of age diphenhydramine was used to reduce these effects
For prophylaxis of acute emesis associated with moderately emetogenic chemotherapy, dexamemasone with a 5-HT3 antagonist is suggested. Aprepitant (or fosaprepitant) may be added for patients given an anthracycline and cyclophosphamide or other chemotherapy tings of moderate emetic risk
Dexamemasone alone may be used for prophylaxis with chemotherapy of low emetic risk, alternatives include prochlorperazine or metoclopramide. No routine prophylactic antiemetic needs to be given for chemotherapy of minimal emetic risk, however, asneeded or prophylactic use of dexamethasone, a phenomiazine, or metoclopramide is common, particularly for patients with poor emetic control during previous therapy
Lorazepam may be used for its amnestic, sedative, and anxiolytic effects as an adjunct to antiemetics when anticipatory emesis is a problem
Good control of acute emesis is important in preventing delayed emesis. In addition, for prophylaxis of delayed emesis from highly emetogenic chemotherapy, a combination of dexamethasone with aprepitant may be used. After moderately emetogenic chemotherapy, prophylaxis with a single ting such as dexamethasone, a 5-HT3 antagonist, or metoclopramide (with or without diphenhydramine) may be sufficient. Aprepitant or dexamethasone alone has been suggested for patients given an anthracycline with cyclophosphamide.
Cannabinoids such as dronabinol and nabilone have been used for chemotherapy-induced nausea and vomiting, usually as second-line drugs. Although they have some advantages because of their effects on mood, their use is limited by adverse effects.
If breakthrough emesis occurs, management is often difficult. The general principle of treatment is to add an additional antiemetic from a different class multiple concurrent drugs, perhaps in alternating schedules or by alternating routes may need to be considered. Since oral dosage may not be feasible because of ongoing vomiting, treatment is often given by the rectal or intravenous routes. More intensive prophylactic treatment should be considered in subsequent courses.
Motion sickness has been described as a normal reaction to stimuli that occur during passive transportation and to which the individual is not adapted. The term embraces all forms of travel sickness including sea sickness, car sickness, train sickness, and air sickness. It is a type of vertigo in which autonomic symptoms predominate, therefore signs and symptoms include pallor, sweating, increased salivation, yawning, malaise, and hyperventilation.
Motion sickness: Management
The aim is to prevent motion sickness and antiemetics are more effective if given prophylactically before nausea and vomiting has developed. The principal tings used are the antimusearinie hyoseine and some of the centrally acting antihistamines. In some countries dexamfetamine has been tried, although its adverse effects and the risk of abuse make it an unlikely choice. Antiemetic drugs not effective against motion sickness include metoclopramide, domperidone, chlorpromazine, and 5-HT3 antagonists. Ginger has been tried. Evidence for the value of wrist acupressure is equivocal.
For short-term protection against motion sickness hyoseine hydrobromide has been shown to be effective. It can be taken by mourn about 30 minutes before a journey followed by further doses every 6 hours if necessary. Transdermal hyoseine has a longer duration of action, but the patches need to be applied to the skin several hours before travelling.
There is little good evidence comparing the effectiveness of antihistamines with hyoseine against motion sickness, but they are often better tolerated. They are usually given by mouth and include cinnarizine, cyclizine, dimenhydrinate, meclozine, and promethazine all have similar efficacy, but differ in onset and duration of action and in the extent of adverse effects such as drowsiness. Their antimusearinie properties may contribute to their effects. Non-sedating antihistamines (e.g. astemizole and terfenadine) penetrate poorly into the CNS and do not appear to be effective against motion sickness.
Once motion sickness has developed, gastric motility is inhibited and oral antiemetics are unlikely to be effective. Where intramuscular injection is feasible, promethazine appears to be the most effective treatment. If exposure is likely to be prolonged, transdermal hyoseine may be useful, but will not provide benefit for some hours.
Nausea and vomiting are common in terminal illness, and may be prolonged. Causes may include gastric irritation or stasis, bowel obstruction, renal failure, hypercalcaemia, raised intracranial pressure, infection, or the effects of tings or radiation anxiety, cough, and pain may exacerbate the condition.
Palliative care: Management
Management will depend on the cause of the nausea and vomiting. The evidence base for many antiemetics in terminal care is poor it is perhaps best for metoclopramide, but evidence for many common and apparently effective interventions, such as haloperidol, cyclizine, and levomepromazine, is conflicting. However, guidelines have been developed, either empirically or based on considerations of the likely causes. Recommendations include:
- any correctable causes should be managed appropriately, and treatment for exacerbating conditions (such as anxiety) given
- an appropriate antiemetic should be given immediately, and repeated as often as necessary. If nausea is continuous or vomiting frequent, subcutaneous injection or continuous subcutaneous infusion may be preferred to the oral route. The usual initial choice for palliative care in the UK is between metoclopramide (preferred if the cause is gastric stasis, gastritis, or functional bowel obstruction), haloperidol (favoured in ting-induced vomiting, hypercalcaemia, and renal failure), and cyclizine (raised intracranial pressure, motion sickness, organic bowel obstruction)
- if treatment fails an alternative ting may be considered, or combination therapy may be necessary (prokinetics such as metoclopramide should not be combined with antimusearinie tings as their actions are antagonistic). Dexamethasone (usually added to the regimen), or levomepromazine or olanzapine (broad-spectrum antiemetics these are usually substituted for the previous regimen) are useful where first-line tings fail. Olanzapine is usually used if levomepromazine is too sedative. Other phenothiazines, notably prochlorperazine, and the phenothiazine antihistamine promethazine, are sometimes still used, but chlorpromazine is less effective man levomepromazine where a broad-spectrum drug is required. The role of 5-HT3 antagonists is limited but they may be useful in nausea and vomiting secondary to chemotherapy (above) or radiotherapy (below), or sometimes in bowel obstruction or renal failure
- if mere is colic or a need to reduce secretions, hyoseine butylbromide should be given, alone or with cyclizine. If mis is inadequate in patients with obstruction, octreotide may be helpful.
Non-drug measures may include appropriate diet and avoidance of unpleasant odours, adequate hydration, and regular mouth care. Acupressure and acupuncture may provide some benefit.
Postoperative nausea and vomiting
Postoperative nausea and vomiting (PONV) is a common and distressing adverse effect of anaesthesia and surgery it is seen in some 20 to 30% of patients undergoing surgery under general anaesthesia, and is perceived by patients as a problem comparable to postoperative pain.
Risk factors for PONV include a history of motion sickness or previous postoperative nausea and vomiting, female sex, not smoking, use of opioids during or after surgery, use of volatile inhaled anaesthetics or nitrous oxide, and prolonged surgery. It is widely considered mat certain types of surgery carry an increased risk, but mis is now being questioned. A study comparing various predictive models found mat none was perfect, but that a simplified model based on history, sex, smoking status, and opioid use was as effective as more complex methods.
Postoperative nausea and vomiting: Management
Prediction of risk is of value since much of the management of postoperative nausea and vomiting focuses on prevention. It is generally agreed that prophylaxis should be reserved for patients at moderate to high risk. In these, various strategies may be adopted to reduce risk where possible, including the use of regional anaesthesia or total intravenous anaesthesia with propofol, avoidance of nitrous oxide, minimal use of opioids, adequate hydration (especially with colloids), and possibly the use of intraoperative supplemental oxygen (although not all studies found this of benefit). Avoidance of high-dose neostigmine (limiting the dose to a maximum of 2.5 mg in adults) has also been suggested.
There is evidence that some nonpharmacological interventions, such as acupuncture of the P6 point, may also be effective, especially for nausea. Many types of drugs have been tried as prophylactic antiemetics. These include the 5-HT3 antagonists, phenomiazines such as prochlorperazine, butyrophenones such as droperidol, antihistamines such as promethazine, cyclizine, or dimenhydrinate, and some other tings such as dexamethasone and hyoseine. A large and well-designed multicentre study (the IMPACT trial) has shown mat ondansetron, droperidol, and dexamemasone are of similar efficacy it also confirmed that avoidance of volatile anaesthetics and nitrous oxide was of as much benefit in preventing PONV as use of a prophylactic antiemetic. The evidence suggests that other 5-HT3 antagonists are of similar efficacy to ondansetron.
Evidence for some of the older drugs is less extensive, although benefit has often been shown in individual studies. Systematic reviews have confirmed the benefit of prophylaxis with dimenhydrinate and transdermal hyoseine but have suggested mat metoclopramide, which has been widely used, is in fact of little value in preventing postoperative nausea and vomiting, perhaps because the doses used are too low. However, another systematic review included metoclopramide in a list of tings mat reliably prevented PONV compared with placebo other drugs listed were cyclizine, dexamemasone, dolasetron, droperidol, granisetron, ondansetron, and tropisetron. Gingerroothas also been suggested, but again does not seem to be effective in mis context, although there is some evidence of benefit for intramuscular ephedrine. Clonidine has also been reported to produce benefit, possibly secondary to reduced sympathetic tone and lower use of inhalation anaesthetics and opioids.
Neurokinin-1 antagonists such as aprepitant may also be effective. In patients at moderate risk of postoperative nausea and vomiting, therefore, in addition to risk reduction, use of a single prophylactic antiemetic may be considered: this might be a 5-HT3 antagonist, droperidol (although concerns about effects on QT interval have restricted its availability), or dexamethasone or perhaps transdermal hyoscine, dimenhydrinate, or another drug such as promethazine or a heterocyclic phenomiazine (prochlorperazine or perphenazine). In patients at higher risk, or in whom nausea and vomiting would be particularly problematic, a combination of antiemetics from different classes should be given, since the IMPACT study has shown that the effects of such interventions are additive.
If postoperative nausea and vomiting develops, treatment will depend on whether prophylaxis was given. In patients who have received no prophylaxis, or only dexamemasone, a small dose of a 5-HT3 antagonist has been recommended. If PONV occurs within 6 hours of surgery despite antiemetic prophylaxis, additional doses of the same drug convey no further benefit, and treatment with tings from another class is recommended. Beyond mis time any suitable drug may be used, but dexamemasone and transdermal hyoscine are not recommended for treatment because of their slow onset of action.
Nausea and vomiting or ‘morning sickness’ is common in the first trimester of pregnancy, but is generally mild and does not require ting therapy. Dietary modification such as eating small frequent carbohydrate meals is widely thought to be helpful. A systematic review has suggested that pyridoxine, which has been shown to be of benefit, should be tried first if ting therapy is required. Benefit has also been reported with ginger root, but evidence of benefit from stimulation of the P6 acupuncture point is ambiguous. A number of antihistamines such as buclizine, dimenhydrinate, hydroxyzine, meclozine, promethazine, and thiethylperazine have also been tried, and appear to be more effective than placebo, but mere are obvious concerns about potential effects on the fetus (see Pregnancy, under Precautions for Antihistamines). Although no real evidence of a teratogenic effect exists, therapy has tended to be reserved for severe cases, and short-term use.
Persistent vomiting and severe nausea may progress to hyperemesis gravidarum if adequate hydration cannot be maintained the condition occurs in up to 1% of pregnancies. Management of hyperemesis includes hospitalisa-tion for intravenous fluid and electrolyte replacement, and this is usually sufficient. Routine thiamine supplementation, by mourn if tolerated, otherwise parenterally, has been recommended to reduce the risk of Wernicke’s, although mere is some dissent from mis view. If hyperemesis fails to respond to rehydration, antiemetics should be used options include domperidone, phenomiazines, and antihistamines. It has been suggested mat hyperemesis unresponsive to conventional therapy may respond to oral prednisolone or intravenous hydrocortisone. There have also been anecdotal reports of ondansetron being used successfully in life-threatening hyperemesis gravidarum unresponsive to conventional treatment, although a double-blind pilot study found it to be no more effective than promethazine. A systematic review found no evidence of benefit for any intervention in hyperemesis gravidarum.
The risk of emesis with radiotherapy varies with the treatment given, particularly the area of the body irradiated. However, emetic risk, and recommendations for use of antiemetics, are less clearly defined than in the situation of chemotherapy-induced nausea and vomiting. Use of a prophylactic 5-HT3 antagonist is usually recommended in patients receiving radiation to the upper abdomen. Dexamemasone may be added for those receiving total body irradiation. For radiotherapy of minimal emetogenic potential, treatment on an asneeded only basis has been suggested.