Nausea and Vomiting in the ED-

A mechanistic approach with Evidence

Palliative Medicine Workshop for UBC Emergency Medicine Residents

Susanne Moadebi PharmD July 29th, 2015 HOPE Centre

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Outline n  List common mechanisms which cause nausea and vomiting

n  Classify antiemetic agents based on major neurotransmitters and receptor targets

n  Review current literature on antiemetic use in the emergency department

n  Outline general symptom and treatment principles for Malignant Bowel Obstruction

n  Outline risk factors for QTc prolongation with antiemetic agents

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ABC of palliative careNausea, vomiting, and intestinal obstruction

Mary J Baines

Nausea and vomiting

Nausea, vomiting, and retching are common and distressingcomplaints: surveys have found that 50-60% of patients withadvanced cancer suffer from one or more of these. Thesesymptoms are more common in patients under 65 years old, inwomen, and in those with cancer of the stomach or breast.

Assessment

An understanding of the emetic process and the mainneurotransmitters involved is helpful in assessing and treatingpatients who are vomiting because antiemetic drugs arepredominately neurotransmitter blocking agents. They areeffective at different receptor sites and therefore treat differentcauses of vomiting.

As well as the specific causes of vomiting resulting directlyor indirectly from advanced malignancy, patients may developunrelated conditions such as gastroenteritis or gall bladderdisease. In most cases the cause of vomiting is multifactorial, butit is helpful in planning treatment to list all contributing factors.

The causes of vomiting can usually be determined from acareful history and clinical examination. Note should be takenof the volume, content, and timing of vomits. A biochemicalprofile may be needed, but other investigations are ofteninappropriate.

Management

Nausea can be treated with oral drugs, but alternative routes areneeded for patients with severe vomiting. It must beremembered, however, that persistent nausea may decreasegastric emptying, with a resultant decrease in drug absorption.An antiemetic injection is suitable to control a single episode,but with a persistent problem it is preferable to give drugs bysubcutaneous infusion using an infusion device such as a pocketsized syringe driver. Antiemetics, in suppository or tablet form,can also be given rectally, but buccal administration ofantiemetics is poorly tolerated.

Non-drug methods are important; these include avoidanceof food smells or unpleasant odours, diversion, and relaxation.Some patients report benefit from acupuncture or acupressurebands.

Specific cause of vomitingIn a few patients, a specific cause of vomiting can be identifiedand treated successfully. However, most patients haveirreversible and multiple causes of vomiting and requiretreatment with antiemetics and other measures.

Opioid induced vomiting—About 30% of patients who receivemorphine feel nauseated during the first week of treatment.Metoclopramide should be given prophylactically to cover thisperiod. Haloperidol is an alternative.

Cytotoxic chemotherapy—The use of ondansetron, granisetron,or tropisetron—the 5-HT3 receptor antagonists—has greatlyimproved the control of emesis, even with cisplatin. This effect isenhanced by combining the antiemetic with dexamethasone.High dose metoclopramide and dexamethasone is a lesseffective but cheaper alternative. Lorazepam is used to reduceanticipatory anxiety and nausea.

Common causes of vomiting in patients with advanced

cancer

x DrugsEspecially opioids andchemotherapy

x Gastric causesGastritis or ulcerationFunctional gastric stasis due toexternal pressureCarcinoma of stomachGastroduodenal obstruction

x Constipationx Intestinal obstruction

x Biochemical causesRenal failureHypercalcaemiaInfectionTumour toxins

x Raised intracranial pressurex Vestibular disturbancex Abdominal or pelvic

radiotherapyx Anxietyx Cough induced

Reversible causes of vomiting

Cause of vomiting Treatment

Hypercalcaemia Rehydration and bisphosphonates

Infection Antibiotics

Raised intracranialpressure

Dexamethasone

Gastric irritation orulceration

Stop non-steroidal anti-inflammatory drugGive omeprazole or H2 receptor antagonist

Constipation Rectal measures and laxatives

Anxiety Explanation and reassurance, possibly alsoanxiolytic drugs

Brain

Cerebral cortexBiochemical

upset

Anxiety

Drugs (includingchemotherapy)

Motionsickness

Vagalafferents

Serotonin receptors5-HT35-HT4Dopamine receptorCholinergic muscarinic receptorHistamine receptorγ-aminobutyric acid receptor

Chemoreceptor trigger zone(area postrema + solitary tractnucleus)

Vestibular system

Pressure receptors

Raised intracranialpressure

Gut

Vomiting centre(s)

Emesis

Functional gastric stasis

Hepatomegaly

Intestinal obstruction

Radiotherapy

Chemotherapy

The emetic process—pathways of emesis and the neurotransmitters involved

Clinical review

1148 BMJ VOLUME 315 1 NOVEMBER 1997

Drug D2 H1 M1 5HT3 5HT4 Scopolamine HBr Promethazine

Ondansetron

Prochlorperazine

Chlorpromazine

Metoclopramide

Haloperidol

Domperidone

Olanzapine

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What about giving dimenhydrinate for opioid induced NV? n  Mixed mechanisms and advanced cancer respond better to

dopamine blockers than antihistamines

n  Prospective studies comparing one regimen with another are lacking.

n  Metoclopramide or domperidone are first-line agents because they improve GI motility and act on the CTZ

n  Consider ondansetron

n  Consider olanzapine in refractory cases

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Metoclopramide vs placebo

Henzi et al. Br J Anaesth. 1999 Nov;83(5):761-71

Study Design

Systematic review

N=66 studies (3260 patients) randomized comparisons of metoclopramide with placebo in surgical patients. oral, i.m., intranasal or i.v. metoclopramide in children and adults.

Primary Endpoint

Early PONV (within 6 h after operation), late PONV (48 h) and adverse effects.

Results In adults, the best documented regimen was 10 mg i.v. NNT to prevent early vomiting = 9.1 (95%CI 5.5-27) and NNT to prevent late vomiting = 10 (6-41), In children, the best documented regimen was 0.25 mg kg-1 i.v. The NNT to prevent early vomiting was 5.8 (3.9-11). There was no significant late anti-vomiting effect

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Malignant Bowel Obstruction

n  Metoclopramide

n  Haloperidol (5–15 mg/day)

n  Methotrimeprazine (50–150 mg/day)

n  Hyoscine butylbromide (Buscopan®)

(60-120mg/day)

n  Octreotide (200 - 900 mcg/day)

n  Steriods

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Take home points 1)  VOMIT acronym

2)  Better to use metoclopramide consider D2 antagonism which may offset decreased persistalsis caused by the opioids

3)  For palliative/frail patients with constipation add an osmotic laxative (e.g PEG 3350) Don’t use docusate insufficient evidence to support its use. Use octreotide for malignant bowel obstruction

4)  Common drugs known to prolong QTc include domperidone, olanzapine, ondansetron and methadone

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Questions?

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