Introduction
Nausea
Nausea is described as the sensations that are felt immediately before vomiting.
Vomiting (Emesis)
Vomiting is a physical event that results in the speedy, forceful evacuation of stomach contents up to and out of the mouth. This is triggered by afferent impulses to the vomiting center located in the brain medulla from the chemoreceptor trigger zone, pharynx, gastrointestinal (GI) tract (through vagal afferent fibers), and the cerebral cortex. This may or may not be preceded by nausea. Retching, or repetitive active contraction of the abdominal muscles, occurs between nausea and vomiting. Retching is without the discharge of gastric contents from the mouth.
It is of prime importance to differentiate vomiting from other physical phenomena: Regurgitation is a passive phenomenon during which esophageal contents flow into the mouth. Rumination is a passive phenomenon during which recently ingested food is regurgitated effortlessly into the mouth, whereupon it is rechewed and reswallowed or spat out.
Epidemiology
Population studies show that more than half of adults experience at least one episode of nausea, and over 30% report at least one episode of vomiting within a year, with women reporting nausea more frequently than men. Similar findings have been reported in other epidemiological studies, and racial differences have also been observed, with White and African-American individuals reporting lower rates of nausea than Asian and Asian-American populations.
Etiology
Nausea and vomiting may result from various underlying conditions. Abdominal causes include mechanical obstruction (eg gastric outlet obstruction), motility disorders (eg gastroparesis), and other gastrointestinal conditions such as Crohn disease or acute hepatitis. These may also be triggered by medications (eg aspirin or antibiotics), infectious agents (viral or bacterial), metabolic or endocrine disorders (eg diabetes mellitus or pregnancy), and neurologic conditions (eg demyelinating disorders, labyrinthine disturbances, or seizures). Additionally, nausea and vomiting commonly occur in specific clinical contexts, including the postoperative period and as adverse effects of chemotherapy or radiation therapy.
Other causes of nausea and vomiting are: Migraine; vertigo; advanced cancer; prolonged starvation; congestive heart failure (nausea and vomiting results from passive congestion of the liver and gut); acute myocardial infarction (MI); hypercalcemia; raised intracranial pressure; cannabinoid hyperemesis syndrome; chronic nausea and vomiting syndrome (a combination of chronic idiopathic nausea and functional vomiting), and cyclic vomiting syndrome.
Cyclic vomiting syndrome is intermittent acute nausea and vomiting episodes of <1 week duration with asymptomatic periods in between. This is associated with migraine headaches, motion sickness, stress, and atopy. This is more common among children and young adults.
Pathophysiology
The coordination of vomiting is controlled by the emetic (vomiting) center located in the medulla. When stimulated, this center activates neural pathways that initiate the sequence of vomiting. The process occurs in three stages. First, nausea develops due to cortical activation, accompanied by relaxation of the stomach and inhibition of gastric and intestinal peristalsis. Second, retching occurs, characterized by spasmodic contractions of the diaphragm and intercostal muscles with closure of the glottis. Finally, vomiting takes place when somatic and visceral responses act together, leading to strong contractions of the diaphragm and abdominal muscles, relaxation of the lower esophageal sphincter, and reverse peristalsis that propels intestinal contents into the stomach and then out through the mouth.
Classification
DISORDERS OF GUT MOTILITY
Gastroparesis
Nausea & Vomiting_Disease Background 1
Functional disorders of gut motility give rise to nausea because of the inability to clear food and secretions. Gastroparesis may be part of the following conditions: Postvagotomy and postgastric drainage surgery patients; pancreatic malignancy; systemic diseases (eg diabetes mellitus [DM], systemic lupus erythematous [SLE] and other connective tissue diseases); and idiopathic gastroparesis. The dysfunction is documented by tests of gastric motor function. Clinicians should be careful not to quickly assume that confirmed gastroparesis is the primary cause in itself of a patient’s symptoms. Consider gastric electrical stimulation or peroral endoscopic pyloromyotomy for refractory vomiting due to gastroparesis.
Other Conditions Associated with Disorders of Gut Motility
Other conditions that may result in gut dysmotility are chronic intestinal pseudo-obstruction, Roux-en-Y syndrome, and functional dyspepsia.
INFECTIOUS CAUSES OF NAUSEA AND VOMITING
Several infections, most of which have systemic and GI tract involvement, may cause nausea and vomiting.
Viral Infections
Viral gastroenteritis, which may be caused by rotaviruses, adenoviruses, noroviruses, and other agents, may cause nausea and vomiting.
Bacterial Infections
Bacterial infections may result in the production of toxins, which may act on the vomiting center in the brainstem. Causative toxin-producing organisms include Salmonella sp, Staphylococcus aureus, Clostridium perfringens, and Bacillus cereus. Systemic infections may also give rise to nausea and vomiting (eg meningitis, hepatitis).
MOTION SICKNESS
Nausea & Vomiting_Disease Background 2
Motion sickness is a labyrinthine system-related disorder brought about by chronic repetitive movements, which stimulate afferent neural pathways and lead to activation of the brain stem nuclei, which set off the GI and somatic aspects of vomiting. Autonomic stimulation gives rise to pallor, salivation, and diaphoresis. Other diseases that affect the labyrinthine system and produce nausea and vomiting are Meniere’s disease, viral labyrinthitis, and labyrinthine tumors.
NAUSEA AND VOMITING OF PREGNANCY AND HYPEREMESIS GRAVIDARUM
Nausea and Vomiting of Pregnancy
Nausea and vomiting of pregnancy are common conditions that affect about ¾ of pregnant women. Approximately 50-80% of women may have nausea only. These may occur at all times of the day (not just in the morning). Symptoms usually begin 4-7 weeks after the last menstrual period and cease by 12 weeks in most women. Increased incidence is noted in the following situations: Previous pregnancy with nausea and vomiting; nulliparity; young maternal age; obesity; family history of hyperemesis gravidarum; increased placental mass (eg molar or multiple pregnancies); and history of motion sickness or migraine. These are self-limiting in most patients, and usually resolve without complications as pregnancy proceeds.
Nausea & Vomiting_Disease Background 3
Hyperemesis Gravidarum
Hyperemesis gravidarum represents the most severe form of nausea and vomiting of pregnancy that can lead to dehydration and limitation of daily activities. This is the most common reason for hospital admission during the first part of pregnancy; it usually begins before 16-22 weeks of gestation. A diagnosis of exclusion based on typical signs and symptoms and the absence of other causes that may explain the clinical presentation.
The criteria for diagnosis of hyperemesis gravidarum are as follows: Persistent vomiting not related to other causes; evidence of weight loss, usually ≥5% of prepregnancy weight; evidence of starvation, ie ketonuria; and abnormalities of electrolyte levels, thyroid and liver may also be present. Hyperemesis gravidarum may lead to significant complications, including the following: Rupture of the esophagus; acute tubular necrosis; Wernicke’s encephalopathy secondary to thiamine deficiency; hyperthyroxinemia with low TSH levels; and depression. Rates of recurrence vary from 15-81% in future pregnancies.
Please see Nausea and
Vomiting in Pregnancy
disease management chart for further information.
POSTOPERATIVE NAUSEA AND VOMITING (PONV)
Risk Factors for Postoperative Nausea and Vomiting
The presence of certain risk factors is predictive of a patient’s likelihood of experiencing postoperative nausea and vomiting and should be used to assess a patient's risk and to guide management. Patient factors are female gender, young age, non-smoker, history of motion sickness, previous episode of PONV, and postoperative opioid use. Surgical factors are craniotomy, laparoscopy, laparotomy, major breast surgery, otolaryngological procedures, plastic surgery, strabismus surgery, bariatric surgery, gynecological surgery, and cholecystectomy. Anesthetic risk factors include general versus regional anesthesia; duration of anesthesia; the use of volatile anesthetics and nitrous oxide; and postoperative opioids.
Postoperative Nausea and Vomiting Risk Score
The Apfel simplified risk score uses four risk factors: Female gender, history of postoperative nausea and vomiting and/or motion sickness, non-smoking status, and postoperative opioid use. Each risk factor is scored with 1 point. The emesis potential of 0, 1, 2, 3, and 4 risk factors is approximately 10%, 20%, 40%, 60%, and 80%, respectively. Risk categories may be classified as low (0-1 risk factor), medium (2 risk factors), or high (≥3 risk factors).
Approaches to Decrease Baseline Postoperative Nausea and Vomiting Risk
To decrease baseline postoperative nausea and vomiting risk, minimize intraoperative and postoperative opioids by using multimodal analgesic regimens. Preferentially use of regional anesthesia (eg spinal or epidural anesthesia) over general anesthesia and the use of Propofol for anesthesia induction and maintenance may be done. Avoid nitrous oxide in surgeries lasting >1 hour and volatile anesthetics. Use Sugammadex rather than Neostigmine in reversing neuromuscular blockade. Hydrate patients adequately.
CHEMOTHERAPY- AND RADIATION-RELATED NAUSEA AND VOMITING
Nausea & Vomiting_Disease Background 4
Incidence of Chemotherapy-Related Nausea and Vomiting
About 70-80% of cancer patients receiving chemotherapy experience nausea and vomiting. The incidence and severity of nausea and vomiting following chemotherapy are influenced by the following factors: Chemotherapeutic agents used; dosage of chemotherapeutic agents; schedule and route of administration; radiation therapy target; and individual patient propensities (eg female gender, younger age, previous chemotherapy-related nausea and vomiting, history of alcohol use, motion sickness or morning sickness during pregnancy, and presence of anxiety).
Effects of Chemotherapy-Related Nausea and Vomiting
The following are the effects of chemotherapy-related nausea and vomiting: Poor compliance or withdrawal from chemotherapy; malnutrition, anorexia, dehydration, or metabolic imbalances; decreased level of functioning and mental status; esophageal tears; and wound dehiscence.
Classification of Chemotherapy-Related Nausea and Vomiting
Acute-onset Nausea and Vomiting
Acute-onset nausea and vomiting occur within a few minutes to several hours after chemotherapy administration. This usually peaks after 5-6 hours and resolves within 24 hours.
Delayed-onset Nausea and Vomiting
Delayed-onset nausea and vomiting arise >24 hours after chemotherapy administration. This commonly occurs with highly emetogenic agents such as: Cisplatin, Carboplatin, Cyclophosphamide and/or anthracyclines.
Anticipatory Nausea and Vomiting
Anticipatory nausea and vomiting are a conditioned response that occurs before patients receive their next chemotherapy treatment. This usually occurs when patients have had a previous unpleasant experience with chemotherapy. Younger patients are more prone to anticipatory nausea and vomiting because they have poorer emesis control, and they usually receive more aggressive chemotherapy regimens.
Breakthrough Nausea and Vomiting
Breakthrough nausea and vomiting occur within 5 days of the end of chemotherapy. This is nausea and vomiting that arises in spite of preventive treatment and/or needs rescue with antiemetic therapy.
Refractory Nausea and Vomiting
Refractory nausea and vomiting are symptoms that occur during subsequent chemotherapy sessions when antiemetic prophylaxis and/or rescue have failed during previous treatment sessions.
Classification of Chemotherapeutic Agents According to Emetogenic Potential1
The type of antiemetic treatment regimen that a patient needs depends on the emetogenic potential of the chemotherapeutic agents that a patient is receiving. The risk of nausea and vomiting for chemotherapeutic agents with high emetic risk lasts for about 3 days and with moderate emetic risk 2 days after the final dose of chemotherapy.
High (Emetic Risk >90%)
Intravenous (IV) agents with high emetic risk are: Anthracycline/Cyclophosphamide combination, Carboplatin (AUC ≥4), Carmustine (>0.25 g/m2), Cisplatin, Cyclophosphamide (>1.5 g/m2), Dacarbazine, Datopotamab deruxtecan-dlnk, Doxorubicin (≥0.06 g/m2), Epirubicin (>0.09 g/m2), Fam-trastuzumab deruxtecan-nxki, Ifosfamide (≥2 g/m2 per dose), Mechlorethamine, Melphalan (≥0.14 g/m2), Sacituzumab govitecan-hziy, Streptozocin, and Zolbetuximab-clzb.
Moderate (Emetic Risk Between >30-90%)
Intravenous agents with moderate emetic risk are: Aldesleukin (>12-15 million IU/m2), Amifostine (>0.3 g/m2), Bendamustine, Busulfan, Carboplatin (AUC <4), Carmustine (≤0.25 g/m2), Clofarabine, Cyclophosphamide (≤1.5 g/m2), Cytarabine (>0.2 g/m2), Dactinomycin, Daunorubicin, Dinutuximab, Doxorubicin (<0.06 g/m2), dual-drug liposomal encapsulation of Cytarabine and Daunorubicin, Epirubicin (≤0.09 g/m2), Idarubicin, Ifosfamide (<2 g/m2 per dose), Irinotecan, Liposomal Irinotecan, Lurbinectedin, Melphalan (<0.14 g/m2), Methotrexate (≥0.25 g/m2), Mirvetuximab soravtansine-gynx, Naxitamab-gqgk, Oxaliplatin, Romidepsin, Temozolomide, and Trabectedin.
Low (Emetic Risk Between 10-30%)
Intravenous agents with low emetic risk are: Ado-trastuzumab emtansine, Aldesleukin (≤12 million IU/m2), Amifostine (≤0.3 g/m2), Amivantamab-vmjw, Arsenic trioxide, Axicabtagene ciloleucel, Azacitidine, Belinostat, Brentuximab vedotin, Brexucabtagene autoleucel, Cabazitaxel, Carfilzomib, Ciltacabtagene autoleucel, Copanlisib, Cytarabine (0.1-0.2 g/m2), Docetaxel, Elranatamab-bcmm, Enfortumab vedotin-ejfv, Epcoritamab-bysp, Eribulin, Etoposide, 5-Fluorouracil, Floxuridine, Gemcitabine, Gemtuzumab ozogamicin, Idecabtagene vicleucel, Inotuzumab ozogamicin, Isatuximab-irfc, Ixabepilone, Lifileucel, Lisocabtagene maraleucel, Liposomal Doxorubicin, Loncastuximab tesirine-lpyl, Methotrexate (>0.05-<0.25 g/m2), Mitomycin, Mitomycin pyelocalyceal solution, Mitoxantrone, Mogamulizumab-kpkc, Mosunetuzumab-axgb, Necitumumab, Omacetaxine, Paclitaxel, Paclitaxel-albumin, Pemetrexed, Pentostatin, Polatuzumab vedotin-piig, Pralatrexate, Tafasitamab-cxix, Tagraxofusp-erzs, Talimogene laherparepvec, Tebentafusp-tebn, Thiotepa, Tisagenlecleucel, Tisotumab vedotin-tftv, Topotecan, and Ziv-aflibercept.
Minimal (Emetic Risk <10%)
Intravenous agents with minimal emetic risk are: Alemtuzumab, Asparaginase, Atezolizumab, Atezolizumab and Hyaluronidase-tqjs, Avelumab, Betibeglogene autotemcel, Bevacizumab, Bleomycin, Blinatumomab, Bortezomib, Cemiplimab-rwlc, Cetuximab, Cladribine, Cytarabine (<0.1 g/m2), Daratumumab, Daratumumab and Hyaluronidase-fihj, Decitabine, Degarelix, Dexrazoxane, Dostarlimab-gxly, Durvalumab, Elotuzumab, Fludarabine, Fulvestrant, Glofitamab-gxbm, Goserelin, Histrelin, Imetelstat, Ipilimumab, Lanreotide, Leuprolide, Lovotibeglogene autotemcel, Liposomal Vincristine, Luspatercept-aamt, Margetuximab-cmkb, Methotrexate (≤0.05 g/m2), Nelarabine, Nivolumab, Nivolumab and Hyaluronidase-nvhy, Nivolumab/Relatlimab-rmbw, Obinutuzumab, Ofatumumab, Panitumumab, Pembrolizumab, Pertuzumab, Pertuzumab/Trastuzumab and Hyaluronidase-zzxf, Ramucirumab, Retifanlimabdlwr, Rituximab, Rituximab and Hyaluronidase, Siltuximab, Sirolimus-albumin, Talquetamab-tgvs, Tarlatamabdlle, Teclistamab-cqyv, Temsirolimus, Tislelizumab-jsgr, Toripalimab-tpzi, Trastuzumab, Trastuzumab and Hyaluronidase-oysk, Tremelimumab-actl, Triptorelin, Valrubicin, Vinblastine, Vincristine, and Vinorelbine.
Oral Antineoplastic Agents with Moderate to High Emetic Risk (≥30%)
Oral antineoplastic agents with moderate to high emetic risk are: Azacitidine, Busulfan (≥0.004 g/day), Ceritinib, Cyclophosphamide (≥0.1 g/m2/day), Fedratinib, Lomustine (single day), Midostaurin, Mitotane, Selinexor, Temozolomide (>0.075 g/m2/day), and Temozolomide (≤0.075 g/m2/day) with concurrent radiation therapy.
As-needed (PRN) dosing may be initially appropriate on days of oral administration for certain anticancer agents such as: Abemaciclib, Adagrasib, Avapritinib, Binimetinib, Bosutinib (>0.4 g/day), Cabozantinib, Crizotinib, Dabrafenib, Elacestrant, Enasidenib, Encorafenib, Estramustine, Etoposide, Imatinib (>0.4 g/day), Lenvatinib (>0.012 g/day), Niraparib, Olaparib, Procarbazine, Rucaparib, Tovorafenib, and Trifluridine/Tipiracil.
Oral Antineoplastic Agents with Minimal to Low Emetic Risk (<30%)
Oral antineoplastic agents with minimal to low emetic risk are: Abiraterone, Acalabrutinib, Afatinib, Alectinib, Alpelisib, Anastrozole, Apalutamide, Asciminib, Axitinib, Belzutifan, Bexarotene, Bicalutamide, Bosutinib (≤0.4 g/day), Brigatinib, Busulfan (<0.004 g/day), Capecitabine, Capivasertib, Capmatinib, Chlorambucil, Cobimetinib, Cyclophosphamide (<0.1 g/m2/day), Dacomitinib, Darolutamide, Dasatinib, Decitabine and Cedazuridine, Duvelisib, Eflornithine, Entrectinib, Enzalutamide, Erdafitinib, Erlotinib, Everolimus, Exemestane, Fludarabine, Flutamide, Fruquintinib, Futibatinib, Gefitinib, Gilteritinib, Glasdegib, Hydroxyurea, Ibrutinib, Idelalisib, Imatinib (≤0.4 g/day), Ivosidenib, Ixazomib, Lapatinib, Larotrectinib, Lenalidomide, Lenvatinib (≤0.012 g/day), Letrozole, Lorlatinib, Megestrol, Melphalan, Mercaptopurine, Methotrexate, Momelotinib, Neratinib, Nilotinib, Nilutamide, Nirogacestat, Olutasidenib, Osimertinib, Pacritinib, Palbociclib, Pazopanib, Pemigatinib, Pexidartinib, Pirtobrutinib, Pomalidomide, Ponatinib, Pralsetinib, Quizartinib, Regorafenib, Relugolix, Repotrectinib, Ribociclib, Ripretinib, Ruxolitinib, Selpercatinib, Sonidegib, Sorafenib, Sotorasib, Sunitinib, Talazoparib tosylate, Tamoxifen, Tazemetostat, Temozolomide (≤0.075 g/m2/day), Tepotinib, Thalidomide, Thioguanine, Tivozanib, Topotecan, Toremifene, Trametinib, Tretinoin, Tucatinib, Vandetanib, Vemurafenib, Venetoclax, Vismodegib, Vorinostat, and Zanubrutinib.
1List of chemotherapeutic agents shown above is not exhaustive. Please refer to available guidelines from health authorities for the complete list.
Radiation-Induced Nausea and Vomiting
Whole-body radiation confers the highest emetic risk, whereas upper abdominal radiation is associated with a moderate emetic risk. The rapidly dividing cells of the intestinal tract are especially sensitive to radiation. The potential for postradiation nausea and vomiting is increased by higher total and daily fractional doses of radiation and a larger amount of irradiated tissue.
Classification of Radiotherapy Emetogenic Potential According to Irradiated Site
High (Emetic Risk >90%)
Total body irradiation has a high emetic risk.
Moderate (Emetic Risk Between 30-90%)
Craniospinal irradiation and irradiation in the upper abdomen have moderate emetic risk.
Low (Emetic Risk Between 10-30%)
Low emetic risk for irradiation in the cranium, head and neck, thorax, and pelvis.
Minimal (Emetic Risk <10%)
Minimal emetic risk for irradiation in the breast and extremities.
Classification of Radiopharmaceutical Anticancer Agents According to Emetogenic Potential
Moderate (Emetic Risk Between 30-90%)
Lutetium Lu-177 dotatate and Iobenguane iodine-131 have moderate emetic risk.
Low (Emetic Risk Between 10-30%)
Lutetium Lu-177 vipivotide tetraxetan has low emetic risk.
Minimal (Emetic Risk <10%)
Radium-223 dichloride, Sodium iodide I-131, Yttrium-90 ibritumomab tiuxetan, Strontium-89, and Yttrium-90 microspheres have minimal emetic risk.