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Nausea,Vomiting, and Indigestion

Chapter 48 | Part 2 – Cardinal Manifestations & Presentation · Part 2 – Cardinal Manifestations & Presentation · Chapter 48

Key Clinical Points

  1. Nausea requires cognitive/emotional input (cerebral cortex; insula, anterior cingulate cortex, amygdala) and is associated with autonomic responses; vomiting is a brainstem-coordinated motor response.
  2. Functional dyspepsia is defined as bothersome postprardial fullness, early satiety, or epigastric pain/burning with onset ≥6 months in the absence of an organic cause.
  3. Alarm features (weight loss, dysphagia, bleeding, etc.) mandate upper endoscopy regardless of age.
  4. Metoclopramide can cause irreversible movement disorders (tardive dyskinesia); use with caution in elderly patients.
  5. Cannabinoid Hyperemesis Syndrome (CHS) resolves with discontinuation of cannabis for ≥6 months.
  6. Cyclic Vomiting Syndrome (CVS) is associated with migraines, autonomic dysfunction, and menstrual cycling.
  7. Gastroparesis is diagnosed via gastric scintigraphy or 13C-labeled breath test showing delayed emptying.
  8. PPI therapy is first-line for GERD; confirm H. pylori eradication 4–6 weeks after therapy.
  9. QTc prolongation is a risk with 5-HT antagonists, NK antagonists, and domperidone; ECG surveillance is advised.
  10. In pregnancy, antihistamines (meclizine) and antidopaminergics (prochlorperazine) have limited efficacy; ginger and pyridoxine are alternatives.

DEFINITION & OVERVIEW

Nausea and vomiting are cardinal manifestations of diseases affecting the gastrointestinal tract, central nervous system, and other organ systems. Indigestion encompasses complaints including nausea, vomiting, heartburn, regurgitation, and dyspepsia.

Definitions

• Nausea: The feeling of a need to vomit. • Vomiting (Emesis): The oral expulsion of gastrointestinal contents resulting from gut and thoracoabdominal wall contractions. • Regurgitation: The effortless passage of gastric contents into the mouth (contrasted with emesis). • Rumination: The repeated regurgitation of food residue (exhibits volitional control). • Indigestion: Broadly encompasses complaints including nausea, vomiting, heartburn, regurgitation, and dyspepsia. • Dyspepsia: Symptoms that are thought to originate in the gastroduodenal region. • Gastroparesis-like symptoms (GPLS): A syndrome indistinguishable from gastroparesis but with normal gastric emptying. • Cyclic Vomiting Syndrome (CVS): Presents with discrete episodes of relentless vomiting; prevalence 1.4%; associated with migraines, autonomic dysfunction, and menstrual cycling. • Cannabinoid Hyperemesis Syndrome (CHS): Presents with cyclical vomiting in individuals with long-standing (>1 year) use of large quantities of cannabis at least 4 days weekly; resolves with discontinuation for ≥6 months. • Rumination Syndrome: Often misdiagnosed as refractory vomiting; vomiting occurring minutes after eating characterizes this condition. • Chronic Nausea Vomiting Syndrome (CNVS): Defined as bothersome nausea and/or one or more vomiting episodes at least weekly.

Dysphagia Overview

• Significance: Cardinal symptom of several malignancies; must be evaluated. • Malignancy Mechanism: Most commonly due to intraluminal obstruction (esophageal or proximal gastric cancer, metastatic deposits) and less commonly due to extrinsic compression (lymphoma, lung cancer) or paraneoplastic syndromes. • Oropharyngeal Dysphagia: Most commonly results from functional deficits caused by neurologic disorders. • Esophageal Dysphagia: Primarily a localized pathology; exceptions include skin diseases (scleroderma, pemphigoid, lichen planus, epidermolysis bullosa). • Eosinophilic Esophagitis: Important cause of dysphagia; treatable via dietary elimination, PPI, swallowed topically acting glucocorticoids, and biologic therapies targeting cytokines involved in type 2 inflammation.

EPIDEMIOLOGY

• Population Prevalence: ◦ Nausea alone at least weekly: 1.9% of population. ◦ Nausea plus vomiting: 1.1% of population. ◦ Cyclic Vomiting Syndrome (CVS): 1.4% prevalence. ◦ Gastroesophageal Reflux Disease (GERD): Heartburn and regurgitation have 70% sensitivity and specificity; prevalence is 18–28%. ◦ Functional Dyspepsia: Cause of symptoms in 70–80% of dyspeptic patients; population prevalence 7.2%. ◦ Postoperative Emesis: Occurs after 25% of surgeries. ◦ Nausea in Pregnancy: Affects 70% of women in the first trimester. • Risk Factors: ◦ Modifiable: Medications (opioids, NSAIDs, chemotherapy), toxins (ethanol), diet (FODMAPs, gluten), lifestyle (smoking, caffeine). ◦ Non-modifiable: Age (>60 years), gender (pregnancy), genetic factors (predisposition to reflux and dyspepsia), comorbidities (diabetes, Parkinson's disease, scleroderma).

ETIOLOGY & PATHOPHYSIOLOGY

• Mechanisms of Vomiting: ◦ Coordination: Brainstem-mediated; involves gut, pharynx, and somatic musculature. ◦ Nausea Mechanisms: Requires cognitive/emotional input (cerebral cortex); associated with autonomic responses (diaphoresis, pallor). Functional imaging shows activation in the insula, anterior cingulate cortex, and amygdala. ◦ Brainstem Nuclei: Nucleus tractus solitarius; dorsal vagal and phrenic nuclei; medullary nuclei regulating respiration; pharyngeal, facial, and tongue control. ◦ Neurotransmitters: Neurokinin (NK), serotonin (5-HT), endocannabinoid, and vasopressin pathways. ◦ Muscle Response: Somatic/visceral muscles respond stereotypically; propulsive gastroduodenal motor activity is replaced by orally propagating retrograde contractions. ◦ Emesis Activators: ◦ Brain: Thoughts or smells → Central origin. ◦ Labyrinthine: Motion sickness/inner ear disorders → Muscarinic M and Histaminergic H receptors. ◦ Vagal Afferents: Gastric irritants/cytotoxic agents (e.g., cisplatin) → 5-HT receptors. ◦ Non-gastric Afferents: Bowel obstruction or mesenteric ischemia. ◦ Area Postrema (Chemoreceptor Trigger Zone): Bloodborne stimuli (emetogenic drugs, toxins, uremia, ketoacidosis) → 5-HT, M, H, and Dopamine D receptors. ◦ CNS Pathways: NK1 receptors mediate both nausea and vomiting; Cannabinoid CB pathways in cerebral cortex/brainstem. • Pathophysiology of Indigestion: ◦ Gastroesophageal Reflux: Result of reduced LES tone (scleroderma, pregnancy), frequent TLESRs, reduced esophageal motility or saliva production, increased intra-gastric pressure (obesity), or large hiatal hernias. ◦ Gastric Motor Dysfunction: Delayed gastric emptying in ~30% of functional dyspeptics; rapid gastric emptying in 5%; impaired fundus relaxation (accommodation) in ~40% leads to bloating and early satiety. ◦ Visceral Afferent Hypersensitivity: ◦ 30% of patients have lower tolerance for gastric/duodenal distention. ◦ Others show hypersensitivity to chemical stimuli (capsaicin, acid, lipid). ◦ Immune Activation: Increased duodenal epithelial permeability; increased eosinophils and mast cells (noted in 20% with post-viral onset). ◦ Microbiome: Altered duodenal bacteria correlate with severity; FODMAPs/gluten increase inflammation. • Pathophysiology of Dysphagia: ◦ Oropharyngeal: Functional deficits from neurologic disorders (CVA, myasthenia gravis, polymyositis, Parkinson's disease, ALS). ◦ Esophageal: Structural causes (Schatzki's ring, GERD, eosinophilic esophagitis) or motility issues (achalasia, esophageal spasm).

CLINICAL FEATURES

• Nausea and Vomiting Symptoms: ◦ Pancreatitis/Cholecystitis/Appendicitis → Vomiting from visceral irritation/ileus. ◦ Bilious vomiting → Excludes gastric obstruction. ◦ Undigested food emesis → Zenker's diverticulum or achalasia. ◦ Weight loss → Concern for malignancy or ischemia. ◦ Hot baths/showers → Associated with CHS and CVS. ◦ Headache/Visual changes → Suggest intracranial source. ◦ Vertigo/Tinnitus → Suggest labyrinthine disease. ◦ Hematemesis → Suspect ulcer, malignancy, or Mallory-Weiss tear. ◦ Feculent emesis → Distal intestinal or colonic obstruction. ◦ Intense episodic emesis with intervals → CVS or CHS. • Indigestion Symptoms: ◦ GERD: Heartburn/regurgitation (70% sensitivity/specificity). ◦ Functional Dyspepsia: Postprandial fullness, early satiety, or epigastric pain/burning (≥6 months duration). ◦ Postprandial Distress Syndrome (PDS): Meal-induced fullness and early satiety (prevalence 6.1%). ◦ Epigastric Pain Syndrome (EPS): Epigastric pain/burning (prevalence 2.4%). ◦ Atypical GERD: Pharyngitis, asthma, cough, bronchitis, hoarseness, chest pain. ◦ Biliary colic: Acute episodes of RUQ or epigastric pain. • Dysphagia Symptoms: ◦ Oropharyngeal: Severe in chronic neurologic disorders. ◦ Esophageal: Difficulty due to obstruction or motility issues. ◦ Skin disease: Mucocutaneous changes (scleroderma, pemphigoid, lichen planus). • Alarm Features (Table 48-3): 1. Odynophagia or dysphagia 2. Unexplained weight loss 3. Recurrent vomiting 4. Occult or gross gastrointestinal bleeding 5. Jaundice 6. Palpable mass or adenopathy 7. Family history of gastroesophageal malignancy.

DIFFERENTIAL DIAGNOSIS

• Nausea and Vomiting (Table 48-1): ◦ Intraperitoneal: Pyloric/Small-bowel/Colonic obstruction, SMA syndrome, Enteric infections (Viral, Bacterial), Inflammatory diseases (Cholecystitis, Pancreatitis, Appendicitis, Hepatitis), Altered sensorimotor function (Gastroparesis, IBD, CVS, CHS, Rumination, Mesenteric insufficiency, Celiac artery stenosis, Median arcuate ligament syndrome, Biliary colic, Abdominal irradiation). ◦ Extraperitoneal: Cardiopulmonary disease, Cardiomyopathy, Myocardial infarction, Labyrinthine disease, Motion sickness, Labyrinthitis, Malignancy, Intracerebral disorders, Hemorrhage, Abscess, Hydrocephalus, Psychiatric illness (Anorexia/Bulimia, Depression), Postoperative vomiting. ◦ Medications/Metabolic: Chemotherapy, Opioids, Analgesics, GLP-1 agonists, Oral hypoglycemics, Parkinson's/Restless legs therapies, Antidepressants, Smoking cessation agents, Antibiotics, Cardiac antiarrhythmics/antihypertensives, Oral contraceptives, Endocrine/metabolic disease, Pregnancy, Uremia, Ketoacidosis, Thyroid/parathyroid disease, Adrenal insufficiency, Toxins (Liver failure, Ethanol). • Indigestion: ◦ GERD ◦ Functional Dyspepsia ◦ Ulcer Disease (H. pylori, NSAIDs) ◦ Malignancy (Esophageal adenocarcinoma, Squamous cell carcinoma) ◦ Other: Eosinophilic esophagitis, pill esophagitis, biliary colic, intestinal lactase deficiency, SIBO, celiac disease, nonceloric gluten sensitivity, pancreatic disease, hepatocellular carcinoma, Ménétrier's disease, infiltrative diseases (sarcoidosis, mastocytosis), mesenteric ischemia, thyroid/parathyroid disease, abdominal wall strain, CHF, tuberculosis. • Dysphagia: ◦ Malignancies (Intraluminal obstruction, Extrinsic compression). ◦ Structural: Schatzki's ring, GERD, eosinophilic esophagitis. ◦ Motility: Achalisia, esophageal spasm. ◦ Neurologic: Myasthenia gravis, polymyositis, Parkinson's disease, ALS. ◦ Skin Disease: Scleroderma, pemphigoid, lichen planus, epidermolysis bullosa.

DIAGNOSTIC APPROACH

  1. Dysphagia Evaluation:
  2. Suspected Oral/Pharyngeal → Fluoroscopic Swallow Study (swallow therapist).
  3. Suspected Esophageal → Upper Endoscopy (most useful; allows biopsy and visualization).
  4. Suspected Motility Disorder → Esophageal Manometry (if endoscopy is non-explanatory).
  5. Structural/Complex Issues → Barium Radiography (adjunctive for subtle strictures, prior surgery, diverticula, paraesophageal herniation).
  6. Nausea and Vomiting Evaluation:
  7. Electrolyte Replacement → if hypokalemia or metabolic alkalosis.
  8. Imaging/Labs:
  9. Blood count (exclude anemia from bleeding).
  10. Pancreatic/Liver biochemistries (suspected biliary disease).
  11. Endocrine/Rheumatologic/Paraneoplastic serologies.
  12. Abdominal Radiography → identify air-fluid levels (obstruction) or dilated loops (ileus).
  13. CT/MRI → define bowel wall thickening, inflammation, or intracranial disease.
  14. Ultrasound → for biliary etiologies.
  15. Specialized Testing:
  16. Gastric Scintigraphy or 13C-labeled breath test → diagnose gastroparesis.
  17. Intestinal Scintigraphy/Radiography → intestinal pseudoobstruction.
  18. Small-intestinal Manometry → differentiate neuropathic vs. myopathic pseudoobstruction.
  19. Esophageal pH Monitoring → diagnose GERD.
  20. Impedance Planimetry → detect reduced pyloric distensibility.
  21. Indigestion Evaluation:
  22. H. pylori Status → Fecal antigen or urea breath test (initial step).
  23. Confirmation of Eradication → 4–6 weeks after therapy.
  24. Upper Endoscopy → if patient is >60, has alarm symptoms, or fails medical therapy.
  25. Metabolic Screening → Thyroid chemistry, Calcium levels, Serologies (celiac).
  26. Specialized Testing:
  27. Gastric Emptying Test → if PDS symptoms persist despite treatment.
  28. Breath Testing after Carbohydrate → detect lactase deficiency or SIBO.

MANAGEMENT & TREATMENT

  1. General Principles:
  2. Address underlying causes (e.g., H. pylori, GERD, obstruction).
  3. Provide hydration and electrolyte replacement for vomiting.
  4. Antiemetic Medications (Table 48-2):
  5. Antihistaminergic: Dimenhydrinate, meclizine → Motion sickness, inner ear disease.
  6. Anticholinergic: Scopolamine → Motion sickness, inner ear disease.
  7. Antidopaminergic: Prochlorperazine, thiethylperazine, haloperidl → Medication/toxin/metabolic induced emesis, chemotherapy, CHS.
  8. 5-HT antagonist: Ondansetron, granisetron → Chemotherapy, radiation, postoperative, opioid-induced nausea/vomiting.
  9. Cannabinoids: Tetrahydrocannabinol, cannabidiol → Chemotherapy induced emesis, gastroparesis.
  10. Tricyclic antidepressant: Amitriptyline, nortriptyline → CNVS, CVS, gastroparesis.
  11. Other antidepressant/atypical antipsychotic: Mirtazapine, olanzapine → Functional dyspepsia, chemotherapy, gastroparesis.
  12. Neuropathic modulator: Gabapentin → Chemotherapy induced emesis.
  13. NK receptor antagonists: Aprepitant, fosaprepitant, netupitant, rolapit → Chemotherapy induced emesis.
  14. 5-HT agonist and antidopaminergic: Metoclopramide.
  15. Motilin agonist: Erythromycin.
  16. Peripheral antidopaminergic: Domperidone.
  17. Pure 5-HT agonist: Prucalopride.
  18. Somatostatin analogue: Octreotide.
  19. Acetylcholinesterase inhibitor: Pyridostigmine.
  20. Special Settings:
  21. Benzodiazepines (Lorazepam) → Anticipatory nausea/vomiting, CVS.
  22. 5-HT agonist (Buspirone, tandospirone) → Functional dyspepsia.
  23. Glucocorticoids (Methylprednisolone, dexamethasone) → Chemotherapy induced emesis.
  24. Anticonvulsants (Topiramate, zonisamide, levetiracetam) → CVS.
  25. Antimigraine agents (Sumatriptan) → CVS.
  26. Topical analgesic (Capsaicin cream) → CHS.
  27. Specific Condition Management:
  28. Gastroparesis: Use of prokinetics or nutritional support; monitor for aspiration risk.
  29. GERD: PPI therapy is first-line.
  30. CVS/CHS: Discontinue offending agents (cannabis) and use specific medications (anticonvulsants, sumatriptan, capsaicin).

Dysphagia Management

• Nutritional Support: Nasogastric tube or gastrostomy tube for severe cases. - Note: These do not protect against aspiration of saliva or refluxed contents.

COMPLICATIONS & PROGNOSIS

• Gastroparesis: Risk of malnutrition and aspiration; 20% of patients report pain over nausea/vomiting. • Malignancy Risk: High suspicion in patients with alarm features (weight loss, dysphagia, bleeding) or those >60 years old with undiagnosed dyspepsia. • Safety Considerations: - Metoclopramide: Risk of irreversible movement disorders (tardive dyskinesia). - 5-HT/NK Antagonists & Domperidone: Risk of QTc prolongation; requires ECG monitoring.

SPECIAL POPULATIONS

• Pregnancy: - Nausea affects 70% in first trimester. - Treatment: Meclizine, prochlorperazine (limited efficacy), ginger, or pyridoxine. • Elderly: - Use caution with metoclopramide due to movement disorder risk. - Age >60 is a trigger for endoscopy in undiagnosed dyspepsia.

KEY PEARLS & CLINICAL TRAPS

• Diagnostic Clues: - Bilious vomiting → No gastric obstruction. - Undigested food → Zenker's or achalasia. - Feculent emesis → Distal obstruction. - Motion sickness/Tinnitus → Labyrinthine disease. • Exclusion Criteria: - Rule out malignancy in any patient with alarm features (Table 3). - Rule out mechanical obstruction before assuming functional disorders. • Safety Traps: - Avoid metoclopramide in elderly if possible due to tardive dyskinesia. - Monitor QTc when using domperidone or NK antagonists.

Reference Tables

TABLE 48-1 Causes of Nausea and Vomiting INTRAPERITONEAL Obstructing disorders

Harrison's 22e, p.297

INTRAPERITONEAL EXTRAPERITONEAL MEDICATIONS/
METABOLIC DISORDERS
Obstructing disorders
Pyloric obstruction
Small-bowel
obstruction
Colonic obstruction
Superior mesenteric
artery syndrome
Enteric infections
Viral
Bacterial
Inflammatory diseases
Cholecystitis
Pancreatitis
Appendicitis
Hepatitis
Altered sensorimotor
function
Gastroparesis
Intestinal
pseudoobstruction
Gastroesophageal
reflux
Chronic nausea
vomiting syndrome
(CNVS)
Gastroparesis-like
symptoms (GPLS)
Cyclic vomiting
syndrome (CVS)
Cannabinoid
hyperemesis syndrome
(CHS)
Rumination syndrome
Mesenteric insufficiency
Celiac artery stenosis
Median arcuate
ligament syndrome
Biliary colic
Abdominal irradiation		 Cardiopulmonary
disease
Cardiomyopathy
Myocardial infarction
Labyrinthine disease
Motion sickness
Labyrinthitis
Malignancy
Intracerebral disorders
Malignancy
Hemorrhage
Abscess
Hydrocephalus
Psychiatric illness
Anorexia and bulimia
nervosa
Depression
Postoperative vomiting		 Drugs
Cancer chemotherapy
Opioids
Analgesics
Glucagon-like
peptide-1 (GLP-1)
receptor agonists
Oral hypoglycemics
Parkinson’s disease/
restless legs therapies
Antidepressants
Smoking cessation
agents
Antibiotics
Cardiac
antiarrhythmics/
antihypertensives
Oral contraceptives
Endocrine/metabolic
disease
Pregnancy
Uremia
Ketoacidosis
Thyroid and
parathyroid disease
Adrenal insufficiency
Toxins
Liver failure
Ethanol

TABLE 48-2 Treatment of Nausea and Vomiting TREATMENT Antiemetic agents

Harrison's 22e, p.299

TREATMENT MECHANISM EXAMPLES CLINICAL INDICATIONS
Antiemetic agents Antihistaminergic Dimenhydrinate, meclizine Motion sickness, inner ear disease
Anticholinergic Scopolamine Motion sickness, inner ear disease
Antidopaminergic Prochlorperazine, thiethylperazine,
haloperidol		 Medication-, toxin-, or metabolic-induced emesis,
chemotherapy-induced emesis,? cannabinoid hyperemesis
syndrome
5-HT antagonist
3		 Ondansetron, granisetron Chemotherapy- and radiation-induced emesis, postoperative
emesis, opioid-induced nausea and vomiting
Cannabinoids Tetrahydrocannabinol, cannabidiol Chemotherapy-induced emesis, gastroparesis
Tricyclic antidepressant Amitriptyline, nortriptyline Chronic nausea vomiting syndrome, cyclic vomiting
syndrome,? gastroparesis
Other antidepressant/atypical
antipsychotic		 Mirtazapine, olanzapine Functional dyspepsia, chemotherapy-induced emesis,?
gastroparesis
Neuropathic modulator Gabapentin Chemotherapy-induced emesis
Neurokinin (NK) receptor antagonists
1		 Aprepitant, fosaprepitant, netupitant,
rolapitant		 Chemotherapy-induced emesis
5-HT agonist and antidopaminergic
4		 Metoclopramide
Motilin agonist Erythromycin
Peripheral antidopaminergic Domperidone
Pure 5-HT agonist
4		 Prucalopride
Somatostatin analogue Octreotide
Acetylcholinesterase inhibitor Pyridostigmine
Special settings Benzodiazepines Lorazepam Anticipatory nausea and vomiting with chemotherapy, cyclic
vomiting syndrome
5-HT agonist
1A		 Buspirone, tandospirone Functional dyspepsia
Glucocorticoids Methylprednisolone, dexamethasone Chemotherapy-induced emesis
Anticonvulsants Topiramate, zonisamide, levetiracetam Cyclic vomiting syndrome
Antimigraine agents Sumatriptan Cyclic vomiting syndrome
Topical analgesic Capsaicin cream Cannabinoid hyperemesis syndrome

TABLE 48-3 Alarm Symptoms in Gastroesophageal Reflux Disease Odynophagia or dysphagia Unexplained weight loss Recurrent…

Harrison's 22e, p.301

  • Odynophagia or dysphagia
  • Unexplained weight loss
  • Recurrent vomiting
  • Occult or gross gastrointestinal bleeding
  • Jaundice
  • Palpable mass or adenopathy
  • Family history of gastroesophageal malignancy