CONTENTS
- Rapid Reference 🚀
- Differential diagnosis of nausea and vomiting
- Evaluation
- Construction of an antiemetic regimen
- Podcast
- Questions & discussion
- Pitfalls
medications which may cause nausea
- Chemotherapy.
- Analgesics:
- Aspirin.
- NSAIDs.
- Opioids.
- Antibiotics:
- Erythromycin.
- Sulfonamides.
- Acyclovir.
- Cardiovascular:
- Antiarrhythmics.
- Antihypertensives (beta-blockers, calcium channel blockers).
- Digoxin.
- Diuretics.
- Endocrine:
- Oral contraception.
- Oral antidiabetic agents.
- Neurology:
- Anticonvulsants.
- Parkinson's disease medications (dopaminergic).
- Anesthetic agents.
gastrointestinal
- Obstruction (e.g., intestinal obstruction, gastric outlet obstruction).
- Hypomotility (e.g., gastroparesis, ileus).
- Acute gastroenteritis.
- Pancreatitis.
- Mesenteric ischemia.
- Appendicitis, cholecystitis.
- Constipation.
central nervous system
- Ear and labyrinthine disorders (often associated with vertigo):
- Vestibular neuronitis.
- Meniere's disease.
- Otitis media.
- Intracranial pressure elevation.
- Migraine.
- Cyclic vomiting syndrome, cannabinoid hyperemesis syndrome.
other organ system / metabolic
- Pregnancy (hyperemesis gravidarum; generally within the first nine weeks of pregnancy).
- Uremia.
- Fulminant hepatic failure.
- Ketoacidosis (e.g., diabetic ketoacidosis).
- Hypercalcemia.
- Hyperthyroidism.
- Addison's disease.
- Myocardial ischemia (anginal equivalent).
History and physical examination are the highest yield investigations. In many cases, these may reveal the etiology without additional evaluation. For patients in whom initial investigation is unrevealing, the following studies may be considered (with an evaluation tailored to the patient).
physical examination
- Neurologic examination
- If concern for elevated intracranial pressure, assess this using optic nerve ultrasonography.
- Abdominal examination, ideally using ultrasonography
- i) Gastric ultrasonography may estimate size and contents of the stomach.
- ii) Small bowel peristalsis may be assessed, to evaluate for obstruction.
- Measurement of gastric residual volume (for intubated patients with a gastric tube)
laboratory studies
- Chemistries (including Ca/Mg/Phos)
- Liver function tests
- Lipase, if clinical concern for pancreatitis
- Cortisol level, if adrenal insufficiency is suspected
- TSH, if hyperthyroidism is suspected
- Pregnancy testing, as appropriate
imaging studies
- Abdominal X-ray may be considered, to evaluate for obstruction or ileus.
- Neuroimaging, if history and physical examination suggest elevated intracranial pressure.
isopropyl alcohol pads
- Sniffing isopropyl alcohol pads has been demonstrated to be effective in some studies.(29523018) Aromatherapy is doubtless the safest medical intervention for treatment of nausea/vomiting. Thus, it may be reasonable to add this as a co-intervention with a front-line parenteral antiemetic.
- May be utilized while awaiting medications to come from pharmacy.
initial considerations
- [1] Significant QT prolongation: options include
- Olanzapine.
- Palonosetron.
- Dimenhydrinate, meclizine.
- Benzodiazepine.
- Haloperidol/droperidol: these do increase QT interval slightly, but the amount of increase is minimal at emetic doses. (32346211)
- [2] Parkinson's disease or extrapyramidal side-effects from medications is a relative contraindication to agents that block the D2 dopamine receptors..
situations where a specific agent(s) might be preferred
- Vestibular etiologies:
- Pathophysiology involves H1 histamine and M1 muscarinic acetylcholine receptors.
- Anticholinergic agents.
- Antihistamine agents.
- Alternative: dopamine antagonists. (32346211)
- Gastroenteritis:
- Dopamine antagonists (e.g., metoclopramide, prochlorperazine).
- Serotonin antagonists. (32346211)
- Gastroparesis:
- 1st line is often metoclopramide.
- 2nd line is often haloperidol/droperidol.
- Alternative: olanzapine.
- Migraine-associated:
- Opioid-induced:
- Postoperative n/v:
- Pregnancy:
- Chemotherapy-induced:
- Serotonin antagonists.
- Neurokinin-1 antagonists.
- Dopamine antagonists (e.g., butyrophenones, olanzapine).
- Benzodiazepines.
- Less effective: antihistamines, metoclopramide, prochlorperazine. (32346211)
- Radiation-induced:
- Serotonin antagonists.
- Dopamine antagonists.
- Dexamethasone.
- Multifactorial or unknown etiology:
- Haloperidol was shown to be equivalent to etiology-guided therapies in one study, suggesting that haloperidol may have broad efficacy across different etiologies. (33443705)
initial therapy ineffective
- If a single antiemetic agent is ineffective, then a second agent may be added to it (ideally targeting a different receptor).
![](https://i0.wp.com/emcrit.org/wp-content/uploads/2020/08/image523.jpg?resize=400%2C313&ssl=1)
general comments
- Ondansetron is a fairly safe and broad-spectrum antiemetic. Unlike many other antiemetic agents, there are no sedative or extrapyramidal side effects.
- Ondansetron is often used as front-line therapy for management of nausea/vomiting.
dosing
- 8 mg PO/IV q8hr PRN, ⚠️ infuse or slowly push each dose over 15 minutes.
- Oral disintegrating tablet (ODT) may be useful in patients unable to swallow (8 mg ODT q8hr PRN).
- Renal impairment: No adjustment
- Significant liver dysfunction (Child class C cirrhosis): max 8 mg per 24 hours.
- More: 📚 MedScape monograph on ondansetron
cautions & contraindications
- Contraindication: QT prolongation or high risk of Torsade de Pointes (e.g., untreated hypokalemia).
- Ondansetron can prolong QT interval and cause Torsade de Pointes. (29259513)
- Among commonly utilized antiemetics, ondansetron might carry a relatively higher risk of Torsade de Pointes than other agents. In contrast, there is widespread concern regarding haloperidol or droperidol, but the risk of Torsade de Pointes is probably minimal at the tiny doses of droperidol or haloperidol which are used to treat nausea.
- Although ondansetron might be riskier than some other antiemetics, the absolute risk of arrhythmia remains low. Ondansetron is one of the most widely utilized medications, yet relatively few reports exist of its causing Torsade de Pointes.(24314899) Interestingly, many of these events occurred within 1-2 minutes of rapidly pushing ondansetron – an unnecessarily risky practice which should probably be avoided (figure above).
- The most common side effects are mild headache (1/36 patients) and constipation (1/23 patients).
palonosetron
- Palonosetron is a second-generation 5HT3 antagonist, with the following advantages compared to ondansetron:
- Absence of QT prolongation (perhaps the greatest advantage).(26111957)
- Longer half-life (~40 hours).
- Superior efficacy compared to ondansetron (especially the 8-mg dosing of ondansetron).
- 0.25 mg palonosetron IV is a commonly used dose for prevention of chemotherapy-induced nausea and vomiting.(26345982)
- There are no real contraindications to palonosetron (aside from a history of anaphylaxis to the drug).
- The main drawback is cost and availability. Palonosetron is a bit more expensive than ondansetron (a single 0.25 mg dose costs $130 according to goodrx.com). However, improved efficacy and reduced need to redose palonosetron can render it cost-effective. (17532704)
- More: 📚 MedScape monograph on palonosetron
general comments
- Prochlorperazine (COMPAZINE) is more selective for D2 receptors. This comes with advantages and disadvantages:
- Advantage: Less sedation than other phenothiazines.
- Disadvantage: Higher rate of extrapyramidal side effects (e.g., akathisia, dystonia).
- Prochlorperazine is available over the counter in the United States, implying a reasonable safety profile.
- Promethazine (PHENERGAN)
- Disadvantage: Can cause tissue damage if extravasation, so generally shouldn't be given intravenously.
- Chlorpromazine (THORAZINE)
- It is not typically used for treatment of nausea/vomiting. However, chlorpromazine is overall quite similar to promethazine.
- Chlorpromazine could be considered as an alternative to promethazine, especially if intravenous administration is required.
dosing
- Prochlorperazine (COMPAZINE)
- 5-10 mg IV q4-6 hours PRN (max 40 mg total daily).
- More: 📚 MedScape monograph on prochlorperazine
- Chlorpromazine (THORAZINE)
- 25 mg IM/IV q4-8 hours PRN.
- More: 📚 MedScape monograph on chlorpromazine
- Promethazine (PHENERGAN)
- 12.5-25 mg PO/IM q4-6hr PRN (max 25 mg/dose, max 100 mg/day).
- 25 mg per rectum q12 hours PRN.
- IV administration is avoided, since severe tissue damage can occur.(25841474)
- More: 📚 MedScape monograph on promethazine
cautions & contraindications
- General contraindications to these agents:
- Parkinson's disease
- Somnolence, with a risk of respiratory suppression
- Chlorpromazine (THORAZINE): May cause neutropenia, so it's contraindicated in leukopenia.
- All of these agents can prolong the QT interval (even prochlorperazine). (16860311, 32468935)
general comments 💊
- Metoclopramide may be generally conceptualized as a combination of haloperidol plus a little ondansetron and some pro-kinetic activity (see receptor table above).
- Many antiemetics have both anti-D2 activity plus anticholinergic activity (e.g., olanzapine, prochlorperazine, promethazine). This intrinsic anticholinergic activity may reduce the rate of extrapyramidal symptoms caused by D2 antagonism (because anticholinergics can be used to treat extrapyramidal symptoms!). Agents with anti D2 activity that lack anticholinergic activity may tend to have the highest rate of extrapyramidal symptoms (e.g., haloperidol, droperidol, and metoclopramide).
- Metoclopramide's pattern of predominant D2 antagonism suggests that it will be an effective antiemetic, but it will also cause extrapyramidal side effects. Alternatively, if metoclopramide is dosed low enough to avoid any potential extrapyramidal side effects, then it will cease to work as an antiemetic (more on this below).
- Strengths
- Pro-kinetic properties may be beneficial for patients with gastroparesis.
- Lack of anticholinergic or antihistamine effects make metoclopramide non-sedating.
- May be useful for pregnancy-induced nausea/vomiting. (32468935)
dosing
- Dosing for nausea:
- Background on dosing: Traditionally, 10 mg IV q4-6 hours PRN has often been used. However, this may be too low of a dose to have a substantial effect. An RCT evaluating the prevention of postoperative nausea and vomiting found no efficacy from 10 mg metoclopramide, with increasing efficacy at 25-mg or 50-mg doses (figure below).(16861255) Historically, doses as high as 200 mg q4hr have been used, but these doses were associated with higher rates of extrapyramidal effects.(25841470) Doses of 1-2 mg/kg are currently recommended for prevention of chemotherapy-related emesis.
- One reasonable approach might be:
- 20 mg or 25 mg IV q4-6hrs PRN
- Slow intravenous infusion over 15 minutes reduces side effects (akathisia) without affecting efficacy.
- Dosing for gastroparesis: 10 mg IV q6hr-q8hr.
- Renal adjustment:
- GFR 10-40 ml: Dose-reduce by 50%.
- GFR <10 ml/min: Dose reduce by 75%.
- Severe liver failure: Dose reduce by 50%. (34816707)
cautions & contraindications
- Contraindications:
- [1] Parkinson's disease or prior adverse reaction to antipsychotics (e.g., dystonia, neuroleptic malignant syndrome, or tardive dyskinesia).
- [2] Seizure disorder.
- [3] QT prolongation.
- Side effects:
- Antipyramidal side-effects (e.g., tardive dyskinesia, akathisia, dyskinesia, dystonia). These are rare with 10-mg dosing and associated mostly with chronic use or higher doses.
glucocorticoids
- These are not used as front-line agents, but can be useful in combination with other agents (e.g., ondansetron). They require ~4-5 hours to take effect, making them a poor choice for a patient with active emesis. (25841470)
- Glucocorticoids have been investigated primarily for prevention of chemotherapy-induced nausea/vomiting. The evidentiary basis supporting their use in other situations is poor. (33443705)
- The mechanism of action is unknown.
- The most commonly investigated agent appears to be dexamethasone at doses of ~8 mg.
antihistamines
- Their benefit seems restricted mostly to nausea/vomiting due to vestibular abnormality and postoperative emesis.
- Antihistamines may be useful in patients with Parkinson's disease, who are at increased risk of extrapyramidal symptoms due to most other classes of antiemetics.
- Use of antihistamines in the ICU is limited by their promotion of delirium.
dronabinol
- Dronabinol is not generally used as an antiemetic in critical illness, but could be considered as a palliative measure in patients with malignancy.
- Side effects include sedation, tachycardia, dry mouth, and visual hallucinations.
- More: 📚 MedScape monograph on dronabinol
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- If the patient doesn't respond to one antiemetic, switching to a different agent may not work (especially to a different agent with a similar mechanism of action). Rather, it may be more effective to add a second agent that acts at a different receptor.(25841474)
- Avoid rapid IV pushes of antiemetic agents, as this may increase the risk of side effects (especially QT prolongation with ondansetron, or extrapyramidal side effects with D2 receptor antagonists).
- Avoid D2 receptor antagonists in patients with Parkinson's disease.
- Be extremely cautious about the intravenous use of promethazine (or perhaps avoid this entirely). Extravasation or inadvertent intra-arterial administration of promethazine can cause tissue necrosis.
Guide to emoji hyperlinks ![🔗](https://s.w.org/images/core/emoji/13.1.0/svg/1f517.svg)
= Link to online calculator.
= Link to Medscape monograph about a drug.
= Link to IBCC section about a drug.
= Link to IBCC section covering that topic.
= Link to FOAMed site with related information.
= Link to supplemental media.
References
- 16861255 Wallenborn J, Gelbrich G, Bulst D, et al. Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone: randomised double blind multicentre trial. BMJ. 2006;333(7563):324. doi:10.1136/bmj.38903.419549.80 [PubMed]
- 17532704 Tarricone R, Girolami F. Economic Evaluation of a New Antiemetic Drug – Palonosetron versus Ondansetron : Assessment of the Drug Price Ratio in Five European Countries. Clin Drug Investig. 2005;25(9):597-608. doi:10.2165/00044011-200525090-00005 [PubMed]
- 24314899 Freedman SB, Uleryk E, Rumantir M, Finkelstein Y. Ondansetron and the risk of cardiac arrhythmias: a systematic review and postmarketing analysis. Ann Emerg Med. 2014;64(1):19-25.e6. doi:10.1016/j.annemergmed.2013.10.026 [PubMed]
- 25841470 Smith HS, Smith JM, Smith AR. An overview of nausea/vomiting in palliative medicine. Ann Palliat Med. 2012;1(2):103-114. doi:10.3978/j.issn.2224-5820.2012.07.06 [PubMed]
- 25841474 Smith HS, Cox LR, Smith BR. Dopamine receptor antagonists. Ann Palliat Med. 2012;1(2):137-142. doi:10.3978/j.issn.2224-5820.2012.07.09 [PubMed]
- 26111957 Morganroth J, Flaharty KK, Parisi S, Moresino C. Effect of single doses of IV palonosetron, up to 2.25 mg, on the QTc interval duration: a double-blind, randomized, parallel group study in healthy volunteers. Support Care Cancer. 2016;24(2):621-627. doi:10.1007/s00520-015-2822-6 [PubMed]
- 26345982 Celio L, Niger M, Ricchini F, Agustoni F. Palonosetron in the prevention of chemotherapy-induced nausea and vomiting: an evidence-based review of safety, efficacy, and place in therapy. Core Evid. 2015;10:75-87. Published 2015 Aug 21. doi:10.2147/CE.S65555 [PubMed]
- 29259513 Lee DY, Trinh T, Roy SK. Torsades de Pointes after Ondansetron Infusion in 2 Patients. Tex Heart Inst J. 2017;44(5):366-369. Published 2017 Oct 1. doi:10.14503/THIJ-16-6040 [PubMed]
- 29523018 Hines S, Steels E, Chang A, Gibbons K. Aromatherapy for treatment of postoperative nausea and vomiting. Cochrane Database Syst Rev. 2012;(4):CD007598. Published 2012 Apr 18. doi:10.1002/14651858.CD007598.pub2 [PubMed]
- 31960161 Wickham RJ. Nausea and Vomiting: a Palliative Care Imperative. Curr Oncol Rep. 2020 Jan 20;22(1):1. doi: 10.1007/s11912-020-0871-6 [PubMed]
- 32346211 Athavale A, Athavale T, Roberts DM. Antiemetic drugs: what to prescribe and when. Aust Prescr. 2020 Apr;43(2):49-56. doi: 10.18773/austprescr.2020.011 [PubMed]
- 32468935 Dulay MS, Dulay JS. Antiemetics: types, actions and uses. Br J Hosp Med (Lond). 2020 May 2;81(5):1-8. doi: 10.12968/hmed.2020.0050 [PubMed]
- 32974072 Wickham RJ. Nausea and Vomiting Not Related to Cancer Therapy: Intractable Problem or Clinical Challenge? J Adv Pract Oncol. 2020 Jul;11(5):476-488. doi: 10.6004/jadpro.2020.11.5.4 [PubMed]
- 33443705 Hardy J, Davis MP. The Management of Nausea and Vomiting Not Related to Anticancer Therapy in Patients with Cancer. Curr Treat Options Oncol. 2021 Jan 14;22(2):17. doi: 10.1007/s11864-020-00813-0 [PubMed]
- 33471485 Heckroth M, Luckett RT, Moser C, Parajuli D, Abell TL. Nausea and Vomiting in 2021: A Comprehensive Update. J Clin Gastroenterol. 2021 Apr 1;55(4):279-299. doi: 10.1097/MCG.0000000000001485 [PubMed]