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Nausea & Vomiting - Harrison's Principles of Internal Medicine (22nd Ed, 2025)
Chapter 48: Nausea, Vomiting, and Indigestion
DEFINITIONS
| Term | Definition |
|---|---|
| Nausea | The subjective feeling of a need to vomit |
| Vomiting (Emesis) | Oral expulsion of GI contents via gut and thoracoabdominal wall contractions - involuntary |
| Regurgitation | Effortless passage of gastric contents into the mouth (no contraction) |
| Rumination | Repeated regurgitation of food residue - volitional |
MECHANISMS
Brainstem Coordination of Vomiting
- Coordinated by brainstem nuclei:
- Nucleus tractus solitarius
- Dorsal vagal and phrenic nuclei
- Medullary respiratory nuclei
- Nuclei controlling pharyngeal, facial, and tongue movements
- Neurotransmitters involved: NK1, 5-HT1, endocannabinoids, vasopressin
Nausea - Cortical Component
- Requires cognitive and emotional input
- Involves: insula, anterior cingulate cortex, amygdala (on functional brain imaging)
- Associated with autonomic responses: diaphoresis, pallor, altered heart rate
Somatic/Visceral Muscle Response During Emesis
- Inspiratory thoracic and abdominal wall muscles contract
- Raises intrathoracic and intraabdominal pressures
- Propulsive gastroduodenal motility replaced by retrograde contractions
Sites of Emetic Stimuli
| Site | Stimulus | Pathway |
|---|---|---|
| Cerebral cortex | Unpleasant thoughts/smells | CNS direct |
| Labyrinthine | Motion sickness, inner ear disorders | Vestibular pathways |
| Gastric/visceral afferents | Gastric irritants, cisplatin | Vagal afferents |
| Non-gastric afferents | Bowel obstruction, mesenteric ischemia | Peripheral |
| Area postrema (CTZ) | Bloodborne - drugs, toxins, uremia, ketoacidosis | Chemoreceptor trigger zone |
Neurotransmitter-Receptor Specificity (Key for Drug Targets)
| Receptor | Location | Relevance |
|---|---|---|
| M1, H1 | Vestibular system | Motion sickness |
| 5-HT3 | Vagal afferents | Chemotherapy-induced N&V |
| 5-HT3, M1, H1, D2 | Area postrema (CTZ) | Drug/toxin-induced N&V |
| NK1 | CNS (cortex + brainstem) | Nausea + vomiting (both) |
| CB1 | Cerebral cortex + brainstem | Cannabinoid pathway |
DIFFERENTIAL DIAGNOSIS
Intraperitoneal Causes
- Obstruction: Ulcers/malignancy (gastric outlet), adhesions, volvulus, intussusception, Crohn's disease
- Enteric infections: Bacterial, viral gastroenteritis
- Inflammatory: Cholecystitis, pancreatitis, appendicitis, hepatitis
- Motility disorders: Gastroparesis, intestinal pseudo-obstruction, functional dyspepsia
Extraperitoneal Causes
- CNS: Migraine, increased intracranial pressure, CNS tumors, meningitis, seizures
- Labyrinthine: Vestibular neuritis, Meniere's disease, motion sickness
- Cardiac: Inferior MI (vagal response)
- Metabolic/Endocrine: Pregnancy, uremia, diabetic ketoacidosis, Addison's disease, hyperthyroidism, hypercalcemia, hyponatremia
Medications and Toxins
- Opioids, NSAIDs, antibiotics, chemotherapy (especially cisplatin)
- Digoxin, colchicine
- Radiation therapy
- Alcohol, tobacco
Functional Causes
- Cyclic vomiting syndrome (CVS)
- Cannabinoid hyperemesis syndrome (CHS)
- Functional nausea/vomiting (part of DGBI spectrum)
CLINICAL APPROACH / HISTORY
Timing and pattern:
- Acute onset (<1 week): infection, drug, obstruction, MI
- Chronic/recurrent: gastroparesis, functional, CNS, metabolic
Relation to meals:
- Immediately postprandial: psychogenic, gastric outlet obstruction
- 1-4 hours after meals: gastroparesis, gastric obstruction
- Vomiting undigested food hours after eating: gastroparesis or pyloric obstruction
Character of vomitus:
- Bilious: distal to pylorus (rules out pyloric obstruction)
- Feculent: small bowel obstruction or gastrocolic fistula
- Blood: Mallory-Weiss tear, peptic ulcer, malignancy
Associated symptoms:
- Abdominal pain, fever, jaundice, weight loss
- Vertigo/tinnitus (labyrinthine cause)
- Headache/visual changes (CNS cause)
- Amenorrhea (pregnancy)
INVESTIGATIONS
| Test | Indication |
|---|---|
| Blood count | Bleeding, infection |
| Electrolytes, BUN, Cr | Metabolic cause, dehydration |
| Thyroid function, calcium | Metabolic screening |
| Liver/pancreatic enzymes | Hepatobiliary cause |
| Serum B-hCG | Pregnancy |
| Urine ketones/glucose | DKA |
| Upper endoscopy | Structural/mucosal disease |
| Abdominal X-ray/CT | Obstruction, ileus |
| Ultrasound/MRI | Pancreaticobiliary disease |
| Gastric emptying scintigraphy | Suspected gastroparesis (4-hour nuclear study is gold standard) |
| Breath tests | Lactase deficiency, SIBO, carbohydrate intolerance |
| Serology (anti-TTG) | Celiac disease |
TREATMENT OF NAUSEA AND VOMITING
General Measures
- Correct fluid and electrolyte deficits (IV fluids if needed)
- NPO or clear liquids initially; advance diet as tolerated
- Identify and remove the offending cause
Antiemetic Drug Classes
| Drug Class | Examples | Mechanism | Primary Use |
|---|---|---|---|
| Phenothiazines | Prochlorperazine, promethazine | D2 block (CTZ) + H1/M1 | General N&V |
| Butyrophenones | Haloperidol, droperidol | D2 block (CTZ) | Refractory N&V |
| Metoclopramide | - | D2 block + prokinetic (5-HT4 agonist) | Gastroparesis, CINV |
| Domperidone | - | D2 block (peripheral) | Gastroparesis |
| 5-HT3 antagonists | Ondansetron, granisetron, palonosetron | 5-HT3 block (vagal afferents + CTZ) | CINV, post-op N&V |
| NK1 antagonists | Aprepitant, fosaprepitant | NK1 block (CNS) | CINV (delayed phase) |
| Corticosteroids | Dexamethasone | Unclear | CINV (adjunct) |
| Antihistamines | Dimenhydrinate, meclizine, diphenhydramine | H1 + M1 block | Motion sickness, vestibular N&V |
| Anticholinergics | Scopolamine (patch) | M1 block | Motion sickness |
| Benzodiazepines | Lorazepam | CNS | Anticipatory CINV, anxiety |
| Cannabinoids | Dronabinol, nabilone | CB1 agonist | CINV (refractory) |
| Olanzapine | - | Multi-receptor (D2, H1, 5-HT2) | CINV, refractory N&V |
Chemotherapy-Induced Nausea and Vomiting (CINV)
- Acute CINV (0-24h): 5-HT3 antagonist + NK1 antagonist + dexamethasone
- Delayed CINV (>24h): NK1 antagonist (aprepitant) + dexamethasone ± metoclopramide
- Highly emetogenic regimens (e.g., cisplatin): triple therapy (5-HT3 + NK1 + dex) + olanzapine (quadruple therapy)
- Anticipatory CINV: Lorazepam; best prevented by good control in prior cycles
Gastroparesis
- Dietary modification: small, frequent, low-fat, low-fiber meals; avoid carbonated drinks
- Prokinetics: Metoclopramide (first-line, but risk of tardive dyskinesia with long-term use), domperidone, erythromycin (motilin agonist)
- Refractory: gastric electrical stimulation (Enterra device)
Cyclic Vomiting Syndrome (CVS)
- Prophylaxis: tricyclic antidepressants (amitriptyline), topiramate, cyproheptadine (children)
- Acute attack: sumatriptan, ondansetron, benzodiazepines, IV fluids
Cannabinoid Hyperemesis Syndrome (CHS)
- Classic triad: chronic cannabis use, cyclic vomiting, compulsive hot bathing
- Treatment: cessation of cannabis; topical capsaicin to abdomen (depletes substance P); haloperidol in acute setting
Motion Sickness
- Scopolamine patch (most effective, applied behind ear 4h prior)
- Antihistamines: meclizine, dimenhydrinate
- Avoid reading; focus on horizon
KEY TABLES FROM HARRISON
Table 48-1 (Causes of Nausea and Vomiting) categories:
- Intraperitoneal - obstructive, inflammatory, motility, functional
- Extraperitoneal - CNS, cardiac, metabolic/endocrine
- Medications and toxins
- Postoperative
- Pregnancy-related
IMPORTANT HIGH-YIELD POINTS
- Area postrema = CTZ - responds to bloodborne emetogenic stimuli; outside blood-brain barrier; targeted by D2 blockers and 5-HT3 antagonists
- NK1 receptors mediate both nausea AND vomiting centrally - NK1 antagonists (aprepitant) are critical for delayed CINV
- 5-HT3 receptors on vagal afferents are the primary trigger for chemotherapy/radiation N&V
- Metoclopramide crosses BBB - risk of tardive dyskinesia; domperidone does not cross BBB
- Gastroparesis gold standard = 4-hour gastric emptying scintigraphy (solid meal, 10% retained at 4h = diagnostic)
- Vomiting vs. regurgitation vs. rumination: Only vomiting is truly involuntary; regurgitation and rumination have volitional control
- Feculent vomitus = distal bowel obstruction or gastrocolic fistula
- Morning vomiting with no nausea preceding it = classic CNS (increased ICP) - projectile, effortless
- CHS: Hot compulsive bathing is pathognomonic; topical capsaicin works acutely
Source: Harrison's Principles of Internal Medicine, 22nd Edition (2025, McGraw Hill Medical), Chapter 48: Nausea, Vomiting, and Indigestion
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