Nausea and Vomiting

Mark Feldman, MD
 Case Report
• seorang wanita tua berumur 29 tahun
G1/P0/Ab0 komplain Mual, muntah
berulang, lebih buruk di pagi hari tapi
kadang di akhir hari, dan gagal menambah
berat badan. Dia berada di minggu ke 13
kehamilannya. Sejarah medisnya yang lalu
adalah negatif kecuali gangguan obsesif-
kompulsif
• Apa diagnosis dari wanita tersebut?
 Terminology
• Nausea: from the Latin naus ( a ship); Sensasi
yang sangat tidak menyenangkan bahwa seseorang
bisa segera muntah
• Retching: aktivitas otot abdomen dan torax ,
sering sukarela, menyebabkan inspirasi paksa
terhadap mulut tertutup dan glotis tanpa
pengeluaran lambung dari isi lambung ("heave
kering")
• Muntah: kontraksi otot otot perut, toraks
dan GI (kelenturan) yang mengarah ke
pengusiran isi perut secara kuat dari mulut
 Terminology, cont’d
• Regurgitasi: kembalinya isi esophagus atau
gaster ke dalam mulut yang tidak terkait
dengan kontraksi otot mual atau tidak
disengaja.
• Ruminasi: makanan yang dimuntahkan pada
masa postprandial, dikunyah kembali dan
kemudian ditelan kembali.
 VOMITING
PATHWAYS

Ipecac syrup
 Inter-subject variability in
emesis threshold in humans
• 18 sukarelawan sehat menerima dosis yang sama
dari agonis opiat / dopamin, apomorphine
• Dosis apo disesuaikan dengan berat badan (0,03
mg / kg s.q.)
• Tanggapan di antara relawan bersifat heterogen:
• 16 melaporkan mual dalam waktu 6 ± 2 menit setelah
injeksi
• 14 mengalami muntah 8 ± 2 menit setelah injeksi; 2
lainnya yang melaporkan mual tidak muntah
• 2 tidak melaporkan mual atau mengalami muntah
Cannon,Best,Batson,and Feldman. Behavior Research & Therapy 21:669-73,1983
 Etiologi umum mual dan
muntah
• Gangguan jalur GI
– toxins, infections,
obstruction, inflammation,
motility disorders
• Non-GI infections
– liver, CNS, renal,
pneumonia, others
• Kehamilan
• Peradangan Viseral
– pancreas, GB, peritoneum
• Iskemia miokardial
infark
• Other CNS disorders
– migraine, neoplasm, bleed
• Gangguan vestibular
• Metabolic/endocrine
– DKA, uremia, adrenal
insufficiency, hyper- or
hypothyroidism, hyper- or
hypoparathyroidism
• Keracunan Alkohol
• Psychogenic
• Paparan Radiasi
• Medications
Nausea/vomiting as component of CC
on teaching service at PHD (75 cases)
GI DISEASES (n= 30 )

Gastroduodenal 6
PUD (2), FD, DG, GOO,food
poisoning
Intestinal diseases 8
SBO(2), LBO, pseudo-
obstruction, gastroenteritis(2),
diverticulitis (2)
Pancreatitis 6
Biliary disease 5
cholecystitis (3), cholangitis (2)
Hepatic disease 5
hepatitis (3), liver masses,
ischemia vs. hepatitis
Nausea/vomiting as component of CC
on teaching service at PHD (75 cases)
OTHERS (n=45)
Metabolic 11 CNS disease 13
DKA(6), hypergylcemia, hypo- CVA/TIA (4), meningitis (4),
glycemia, hypercalcemia, hypo- seizure (2), primary tumor,
natremia (3) brain metastases, toxo/HIV
Toxic 5 Renal causes 8
alcohol, CO, digoxin, lithium, uremia (4), UTI ± stones (2),
ethylene glycol acute renal failure, renal infarct
Miscellaneous 4 Cardiac 4
Malaria, pneumonia, bulimia,
diabetic foot ulcer with osteo cocaine-induced (2), USA, afib
 Petunjuk untuk muntah
psikogenik
• Biasanya perempuan dan seringkali muda
• Mungkin menyangkal atau meminimalkan
mual
• Jarang terjadi di depan umum atau di depan
orang lain
• Ada gangguan makan, penyalahgunaan obat
pencahar, penyalahgunaan diuretik umum
• Gangguan psikologis umum terjadi
• Komplikasi muntah mungkin ada
 Muntah surreptitious: kapan
mencurigainya?
• Penurunan berat badan yang tidak dapat dijelaskan
• Ada gangguan makan atau kondisi psikologis lainnya
• Peluntikan pencahar dan / atau diuretik yang ada
• Gangguan elektrolit dan / atau asam basa konsisten dengan
muntah, termasuk nefropati hipokalemik
• Komplikasi emetik (dengan penolakan muntah)
 Pengobatan yang sering
dilakukan untuk mual dan
muntah
• Cancer chemotherapy • Metformin
– e.g. cisplatin
• Anti-parkinsonians
• Analgesics – e.g., bromcryptine, L-DOPA
– e.g. opiates, NSAIDs
• Anti-convulsants
• Anti-arrythmics – e.g., phenytoin, carbamazepine
– e.g., digoxin, quinidine
• Anti-hypertensives
• Antibiotics
– e.g., erythromycin
• Theophylline
• Oral contraceptives • Anesthetic agents
 Penyebab mual dan muntah
yang kurang dikenal
• Cepat menurunkan berat
badan / body gips (SMA
syndrome)
• Infeksi esophagitis
• esp. jika
immunocompromised
• Penarikan opiat
• Sediaan herbal
• Kehamilan
• mual kehamilan dini
• hiperemesis gravidarum
• Sindrom AFLP / HELLP
 Komplikasi muntah
• Orang dewasa gizi: penurunan berat badan;
anak-anak: gagal untuk mendapatkan
• Cutaneous (petechia, purpura)
• Orophayngeal (gigi, sakit tenggorokan)
• Esophagitis / hematoma esofagus
• GE Junctional: M-W air mata; pecah
(Boorhaave)
• Metabolik: elektrolit, asam basa, air
• Ginjal: azotemia prerenal; ATN; nefropati
hipokalemia
 Post-emetic purpura
(“mask phenomenom)

Cutis, 1986
Mallory-Weiss tear with clot
 Two tears: one at 7 o’clock
opposite other tear at 1 o’clock
 Esophageal hematoma
secondary to forceful emesis

Lumen

mass

Digestive Diseases and Sciences 26: 1019, 1981

 Electrolyte and acid-base
disorders due to vomiting
Metabolic alkalosis
retention of HCO3- + volume- Typical SMA-6
contraction
Hypokalemia 13078283400.8
renal K+ losses + GI K+ loss + 
oral K+ intake
Hypochloremia
gastric chloride losses Pearl: Patients with uremia
Hyponatremia or Addison’s disease may
free water retention due to have normal or even high
volume contraction
serum K+ despite vomiting
Mual dan Muntah: Pertanyaan
Historis Utama
• Berapa lama?
• Hubungan dengan makanan?
• Isi dari muntahan?
• Gejala terkait
• nyeri di dada atau perut, demam, myalgia, diare,
vertigo, pusing, sakit kepala, gejala neurologis
fokal, penyakit kuning, penurunan berat badan
• Diabetes?
• Kapan menstruasi terakhir?
 Mual dan muntah : Temuan
Fisik utama
• Tanda vital BP dan tes kemiringan nadi
• Pemeriksaan kardiopulmoner
• Ujian perut Pemeriksaan rektal Pemeriksaan
neurologis termasuk pemeriksaan
fundoskopik (papilledema)
 Studi laboratorium: dipandu
oleh sejarah dan fisik
• Elektrolit, glukosa, BUN / kreatinin
• Kalsium, albumin, protein serum total
• CBC
• LFTs
• Tes kehamilan
• Urinalisis
• Serum lipase amilase
 Studi radiologi: dipandu oleh
sejarah dan fisik
• Plain abdominal films
• Abdominal sono or CT if pain is key feature
• Head CT or MRI if severe headache, papill-
edema, marked hypertension, altered mental
status, or focal neurological findings
• EGD or upper GI to separate GOO or high
duodenal obstruction from gastroparesis
• Radiopaque marker emptying studies or
radionuclide scintigraphy, esp. if diabetic
Chronic vomiting due to gastroparesis
associated with a gastric bezoar
Test meal: liquid, digestible
solid and indigestible solid
Radiopaque markers still in the
stomach 6 hours after meal in a
diabetic with nausea
 Markers in stomach 24 hours after
ingestion in patient with pseudo-
obstruction and small cell lung cancer
 ALGORITHMIC
APPROACH

or marker
 Pengobatan mual dan muntah
1. Mengobati komplikasi terlepas dari
penyebabnya
misalnya menggantikan garam, air,
kehilangan kalium
2. Identifikasi dan obati penyebabnya, bila
memungkinkan
3. Berikan gejala simtomatik sementara gejala
4. Gunakan tindakan pencegahan saat muntah
kemungkinan terjadi (mis., Kemoterapi
kanker, pemberian opiat parenteral)
 Obat dengan sifat antiemetik
dan mekanisme yang diketahui
• Antihistamines, e.g., meclizine (AntivertR)
– esp. for vestibular disorders
• Anticholinergics, e.g., scopolamine (Transderm ScopR,
DonnatalR)
– esp. for vestibular and GI disorders
• Dopamine antagonists, e.g.,metoclopramide (ReglanR) or
prochlorperazine (CompazineR)
– esp. for GI disorders
• Selective serotonin-3 (5HT3) RAs, e.g., odansetron,
granisetron, dolasetron
– esp. to prevent chemotherapy-induced nausea/vomiting
 Drugs with anti-emetic
properties (continued)
Multiple mechanisms of action:
• Promethazine (PhenerganR)
– dopamine antagonist
– H1 antihistamine
– anticholinergic
– CNS sedative
– prevention of opiate-induced nausea and vomiting
• Hydroxyzine (AtaraxR, VistarilR)
– H1 antihistamine
– anticholinergic
– CNS sedation
– prevention of opiate-induced nausea and vomiting
 Drugs with anti-emetic
properties (continued)
Uncertain mechanism of action:
• Trimethobenzamide (TiganR)
– Memblok emesis apomorphine-induced pada
anjing
– tidak menghalangi emesis dari p.o. CuSO4 pada
anjing
– mungkin bekerja di zona pemicu
kemoreseptor (CTZ) dari medula oblongata
• Bismuth subsalicylate (Pepto-BismolR)
 Adjunctive antiemetic agents
• Dexamethasone (DecadronR)
– bersama dengan antibiotik lain untuk
pencegahan kanker kemoterapi yang diinduksi
emesis
• Dronabinol (MarinolR)
– Untuk pencegahan kemoterapi kanker-diinduksi
emesis refrakter ke agen lainnya
– [juga untuk anoreksia dan penurunan berat
badan dalam AIDS]
 Summary
• Mual dan muntah adalah ciri dari banyak penyakit dan
gangguan GI dan non-GI.
• Terlepas dari penyebabnya, pengobatan mual dan muntah
pada awalnya harus fokus pada penggantian volume dan
defisit elektrolit. Nantinya, defisit nutrisi harus diatasi.
• Terlepas dari penyebabnya, mual dan muntah dapat
menyebabkan beberapa komplikasi GI dan non GI yang
mengancam jiwa.
• Penjelasan penyebabnya seringkali mungkin dilakukan,
dan pengobatan penyebabnya biasanya akan berhasil.
• Terapi simtomatik yang efektif untuk mual dan muntah
tersedia bila penyebabnya tidak jelas atau bila pengobatan
penyebab yang mendasari memerlukan waktu untuk
bekerja.
 Follow up on Case Report
• The patient was diagnosed with
hyperemesis gravidarum.
• Her TSH was undetectable, her free T4 and
serum T3 were markedly elevated.
• Her symptoms resolved in a few weeks,
without recurrence.
Goodwin et al. Transient hyperthyroidism and hyperemesis
gravidarum. Am J Obstet Gynecol 167: 648, 1992 and J.
Clin Endocrin Metab 75: 1333, 1992
 Management Of
Nausea and Vomiting
in Palliative Care
 Objectives

• review mechanisms/physiology of nausea and

vomiting

• review possible causes of nausea/vomiting in

palliative patients

• understand rationale behind selecting specific

antiemetics

• develop a systematic approach to managing nausea

and vomiting
 Definitions

• Nausea - an unpleasant feeling of the need to

vomit

• Vomiting - the expulsion of gastric contents

through the mouth, caused by forceful and
sustained contraction of the abdominal muscles
and diaphragm
INCIDENCE OF NAUSEA & VOMITING
IN TERMINAL CANCER PATIENTS

Nausea: 50 - 60 %

Vomiting: 30 %
 MECHANISM OF NAUSEA AND VOMITING

• Vomiting Centre (Central Pattern Generator) in reticular

formation of medulla

• activated by stimuli from:

– Chemoreceptor Trigger Zone (CTZ)
• in the area postrema, floor of the fourth ventricle, with
neural pathways projecting to the nucleus of the tractus
solitarius
• outside blood-brain barrier (fenestrated venules)
– Upper GI tract & pharynx
– Vestibular apparatus
– Higher cortical centres
 Cortex
• Sensory input
• Anxiety, memory
• Meningeal irritation • CTZ • drugs, metabolic
• Increased ICP
• dorsal vagal complex

GI

Vomiting Center Vestibular

VOMITING
• motion
• serotonin release from mucosal CENTRE
enterochromaffin cells (Central Pattern • CNS lesions
• obstruction • opioids
• stasis
Generator) • aggravates most
• inflammation nausea
 Muscarinic Serotonin
Neurokinin-1 Cannabinoid
Histamine Dopamine
Cortex
• Sensory input
• drugs,
• Anxiety, • CTZ metabolic
memory • dorsal vagal complex
• Meningeal
irritation
GI
• Increased ICP

Vomiting Center Vestibular

VOMITING
• serotonin release from mucosal CENTRE • motion
enterochromaffin cells (Central Pattern • CNS lesions
• obstruction
• stasis
Generator) • opioids
• inflammation • aggravates
most nausea
 RECEPTOR ANTAGONISM
Notes
D2 H1 AchM 5HT2 5HT3 5HT4 CB1 + 2 NK1
Metoclopramide +++ + ++
Domperidone ++++ +
Haloperidol ++++ +
Methotrimeprazine ++++ +++ ++ +++
CPZ ++++ ++ +
Olanzapine ++ + + +++ ++
Prochlorperazine ++ +
Dimenhydrinate + ++++ ++
Ondansetron ++++
Granisetron ++++
Scopolamine + + ++++
Dronabinol (++)* *Agonist

Nabilone (++)* *Agonist

Sativex (++)* *Agonist

Aprepitant +++
 NK1 Antagonists
(Aprepitant)
• not approved outside of chemotherapy-
induced emesis

• Substance P - induces vomiting; binds to

NK-1 receptors in the abdominal vagus,
the nucleus tractus solitarius, and the area
postrema

• NK1 antagonists inhibit action of

substance P in emetic pathways in both
 Cannabinoids In Nausea And Vomiting

 directly block emesis via agonism of CB1 receptors – in

the area postrema, nucleus solitarius tract, dorsal motor
nucleus in brainstem
 indirectly through a retrograde pathway to inhibit other
CNS neurotransmitters (serotonin, dopamine)
 may also have an effect at the enterochromaffin cells in
the GI tract
 In > 30 studies, THC and nabilone have been shown to
have a similar anti-emetic efficacy as the phenothiazines
PRINCIPLES OF TREATING NAUSEA & VOMITING

• Treat the cause, if possible and appropriate

• Environmental measures

• Antiemetic use:
– anticipate need if possible (preemptive)
– use adequate, regular doses
– aim at presumed receptor involved
– combinations if necessary
– anticipate need for non-oral routes
 Clinical Scenario Mechanism
Chemotherapy • 5HT3 released in gut
Sepsis; metabolic; renal • stimulation of CTZ
or hepatic failure
Opioid-Induced • constipation; decreased gut
motility
• stimulation of CTZ
• vestibular
Bowel obstruction • mechanical impasse
• stimulation of CTZ
• stimulation of gut stretch
receptors, peripheral
pathways
Radiation • stimulation of peripheral
pathways via 5HT3 released
from enterochromaffin cells
in gut
Brain tumor • raised ICP
• aggravated by movement
Motion-related • vestibular pathway
Typical Initial Treatment
Approach
5HT3 antagonists;
metoclopramide; haloperidol;
methotrimeprazine
laxatives (lactulose, PEG);
metoclopramide; haloperidol;
methotrimeprazine
dexamethasone; octreotide;
metoclopramide if incomplete
obst; haloperidol
5HT3 antagonists
dexamethasone;
dimenhydrinate
dimenhydrinate; scopolamine
 EXAMPLES OF ANTIEMETIC USE
Medication Examples
Class
Dopamine  metoclopramide 10 - 20 mg po/iv/sq/pr q4-8h
Antagonists  haloperidol 0.5 - 1 mg po/sq/iv q6-12h
 prochlorperazine 5 - 20 mg po/pr/iv q4-8h
 CPZ 25 - 50 mg po/pr/iv q6-8h
 olanzapine – start with 2.5 – 5 mg once/day
 methotrimeprazine 2.5 - 10 mg po/sl/sq/iv q4-8h
 domperidone 10 mg po q4-8h
Prokinetic  metoclopramide 10 - 20 mg po/iv/sq/pr/ q4-8h
 domperidone 10 mg po q4-8h
Antimuscarinic  scopolamine patch (Transderm-V®)
 EXAMPLES OF ANTIEMETIC USE ctd
Medication Examples
Class
H1 Antagonists  dimenhydrinate 25 - 100 mg po/iv/pr q4-8h
(sq may cause irritation, including necrosis)
 promethazine 25 mg po/iv q4-6h (Not sq)
 meclizine 25 mg po q6-12h
Serotonin  ondansetron 4 - 8 mg bid-tid po/sq/iv
Antagonists  granisetron 0.5 –1 mg po/sq/iv OD - bid
Cannabinoids  nabilone 1 – 2 mg po bid
 dronabinol 2.5 mg po bid, titrated up
Miscellaneous  dexamethasone 2 - 4 mg po/sq/iv OD-qid
 lorazepam 0.5 - 1 mg po/sl/iv q4-12h
 Non-Pharmacological Approaches

• Accupuncture

• Herbs
o Ginger
o Peppermint