IN THE NAME OF GOD

1. IN THE NAME OF GOD Nausea, Vomiting

2. Nausea: feeling of a need to vomit • Vomiting (emesis): oral expulsion of gastrointestinal contents due to contractions of gut and thoracoabdominal wall musculature • Vomiting is contrasted with regurgitation, the effortless passage of gastric contents into the mouth • Rumination: repeated regurgitation of food residue, which may be rechewed and reswallowed • In contrast to emesis, these phenomena may exhibit volitional control

3. MECHANISMS • Vomiting is coordinated by the brainstem and is effected by responses in the gut, pharynx, and somatic musculature • Mechanisms underlying nausea are poorly understood but likely involve the cerebral cortex(supported by functional brain imaging studies), as nausea requires conscious perception

4. Coordination of Emesis(Brainstem nuclei) • Including the nucleus tractussolitarius; dorsal vagal and phrenic nuclei; medullary nuclei regulating respiration; and nuclei that control pharyngeal, facial, and tongue movements • NeurokininNK1, serotonin 5-HT3, vasopressin • Somatic and visceral muscles(Inspiratory thoracic and abdominal wall muscles) contract, producing high intrathoracic and intraabdominal pressures that evacuate the stomach, gastric cardia herniates above the diaphragm, larynx moves upward

5. Coordination of Emesis Brainstem nuclei • Distally migrating gut contractions are normally regulated by an electrical phenomenon, the slow wave, which cycles at 3 cycles/min in the stomach and 11 cycles/ min in the duodenum • During emesis, the slow wave is abolished and is replaced by orally propagating spikes that evoke retrograde contractions that assist in expulsion of gut contents.

6. Emetic stimuli • act at several sites • Unpleasant thoughts or smells originates in the brain(cortex) • cranial nerves mediate vomiting after gag reflex • Motion sickness and inner ear disorders act on the labyrinthine system…. stimulate vestibular muscarinic M1 and histaminergic H1 receptors

7. Emetic stimuli • Gastric irritants and cytotoxic agents like cisplatin stimulate gastroduodenal vagal afferent nerves • Nongastric afferents are activated by intestinal and colonic obstruction and mesenteric ischemia • The area postrema(medulla nuclei) responds to bloodborne stimuli (emetogenic drugs, bacterial toxins, uremia, hypoxia, ketoacidosis) and is termed the chemoreceptor trigger zone.

8. Neurotransmitters mediating vomiting are selective for different sites • Vagal afferent stimuli activate serotonin 5-HT3 receptors • The area postrema is served by nerves acting on 5-HT3, M1, H1, and dopamine D2 subtypes • Cannabinoid CB1 pathways may participate in the cerebral cortex • Optimal pharmacologic therapy of vomiting requires understanding of these pathways.

9. DDx

10. APPROACH TO THE PATIENT • HISTORY AND PHYSICAL EXAMINATION • The history helps define the etiology…..Drugs, toxins, and infections often cause acute symptoms, established illnesses evoke chronic complaints • Gastroparesis and pyloric obstruction elicit vomiting within an hour of eating • Emesisfrom intestinal blockage occurs later • Vomiting within minutes of meal …. Rumination syndrome • With severe gastric emptying delays, the vomitus may contain food residue ingested hours or days before

11. APPROACH TO THE PATIENT • Hematemesis raises suspicion of an ulcer, malignancy, or Mallory-Weiss tear • Feculent emesis is noted with distal intestinal or colonic obstruction • Bilious vomiting excludes gastric obstruction, whereas emesis of undigested food is consistent with a Zenker’s diverticulum or achalasia • Vomiting can relieve abdominal pain from a bowel obstruction, but has no effect in pancreatitis or cholecystitis • Profound weight loss raises concern about malignancy or obstruction

12. Fevers suggest inflammation • An intracranial source is considered if there are headaches or visual field changes • Vertigo or tinnitus indicates labyrinthine disease • The physical examination complements the history….Orthostatic hypotension and reduced skin turgor indicate intravascular fluid loss • Pulmonary abnormalities raise concern for aspiration of vomitus • Abdominal auscultation may reveal absent bowel sounds with ileus

13. High-pitched rushes suggest bowel obstruction, whereas a succussion splash upon abrupt lateral movement of the patient is found with gastroparesis or pyloric obstruction • Tenderness or involuntary guarding raises suspicion of inflammation, whereas fecal blood suggests mucosal injury from ulcer, ischemia, or tumor. • Neurologic disease presents with papilledema, visual field loss, or focal neural abnormalities • Neoplasm is suggested by palpation of masses or adenopathy.

14. DIAGNOSTIC TESTING • For intractable symptoms or an elusive diagnosis, selected screening tests can direct clinical care • Electrolyte replacement(hypokalemia or metabolic alkalosis) • Iron-deficiency anemia mandates a search for mucosal injury • Pancreaticobiliary disease is indicated by abnormal pancreatic or liver biochemistries, whereas endocrinologic, rheumatologic, or paraneoplastic etiologies are suggested by hormone or serologic abnormalities

15. If bowel obstruction is suspected, supine and upright abdominal radiographs may show intestinal air-fluid levels with reduced colonic air • Ileus is characterized by diffusely dilated air-filled bowel loops • Anatomic studies may be indicated if initial testing is nondiagnostic. • Upper endoscopy detects ulcers, malignancy, and retained gastric food residue in gastroparesis • Small-bowel barium radiography or computed tomography (CT) diagnoses partial bowel obstruction.

16. Colonoscopy or contrast enema radiography detects colonic obstruction • Ultrasound or CT defines intraperitonealinflammation; CT and magnetic resonance imaging (MRI) enterographyprovide superior definition of inflammation in Crohn’sdisease • CTor MRI of the head can delineate intracranial disease • Mesentericangiography, CT, or MRI is useful for suspected ischemia • Gastrointestinal motility testing may detect an underlying motor disorder when anatomic abnormalities are absent • Gastroparesis…. gastric scintigraphy(emptying of a radiolabeled meal is measured), Isotopic breath tests and wireless motility capsule

17. Intestinal pseudoobstruction…. abnormal barium transit and luminal dilation on small-bowel contrast radiography • Delayed small-bowel transit also may be detected by wireless capsule techniques • Combined ambulatory esophageal pH/impedance testing and high-resolution manometry can facilitate diagnosis of rumination syndrome

18. TREATMENT Nausea and Vomiting • GENERAL PRINCIPLES • Therapy of vomiting is tailored to correcting remediable abnormalities if possible • Hospitalizationis considered for severe dehydration, especially if oral fluid replenishment cannot be sustained • Once oral intake is tolerated, nutrients are restarted with low-fat liquids, because lipids delay gastric emptying • Foods high in indigestible residue are avoided because these prolong gastric retention. • Controlling blood glucose in poorly controlled diabetics can reduce hospitalizations in gastroparesis

20. ANTIEMETIC MEDICATIONS • The most commonly act on central nervous system sites • Antihistamines like dimenhydrinateand meclizine and anticholinergiclike scopolamine act on labyrinthine pathways to treat motion sickness and inner ear disorders. • Dopamine D2 antagonists treat emesis evoked by area postremastimuli and are used for medication, toxic, and metabolic etiologies • Dopamine antagonists cross the blood-brain barrier and cause anxiety, movement disorders, and hyperprolactinemic effects (galactorrhea, sexual dysfunction).

21. 5-HT3 antagonists such as ondansetron and granisetroncan prevent postoperative vomiting, radiation therapy–induced symptoms, and cancer chemotherapy– induced emesis, but also are used for other causes of emesis with limited evidence for efficacy • Tricyclic antidepressant agents provide symptomatic benefit in patients with chronic idiopathic nausea and functional vomiting as well as in long-standing diabetic patients with nausea and vomiting • Other antidepressants such as mirtazapine and olanzapine also may exhibit antiemetic effects.

22. GASTROINTESTINAL MOTOR STIMULANTS • Drugs that stimulate gastric emptying are used for gastroparesis • Metoclopramide, a combined 5-HT4 agonist and D2 antagonist, is effective in gastroparesis, but antidopaminergicside effects, such as dystonias and mood and sleep disturbances, limit use in ∼25% of cases • Erythromycinincreases gastroduodenalmotility by action on receptors for motilin, an endogenous stimulant of fasting motor activity • Intravenous erythromycin is useful for inpatients with refractory gastroparesis, but oral forms have some utility • Domperidone, a D2 antagonist, exhibits prokinetic and antiemetic effects but does not cross into most brain regions; thus, anxiety and dystonic reactions are rare

23. The main side effects of domperidone relate to induction of hyperprolactinemiavia effects on pituitary regions served by a porous blood-brain barrier • Refractory motility disorders pose significant challenges • Intestinal pseudoobstruction may respond to the somatostatinanalogue octreotide, which induces propagative small-intestinal motor complexes • Acetylcholinesterase inhibitors such as pyridostigmineare also observed to benefit some patients with small-bowel dysmotility • .

24. Pyloric injections of botulinum toxin are reported in uncontrolled studies to reduce gastroparesis symptoms, but small controlled trials observe benefits no greater than sham treatments • Surgical pyloroplasty has improved symptoms in case series • Placing a feeding jejunostomyreduces hospitalizations and improves overall health in some patients with drug-refractory gastroparesis

25. Postvagotomygastroparesis may improve with near-total gastric resection; similar operations are now being tried for other gastroparesis etiologies • Implanted gastric electrical stimulators may reduce symptoms, enhance nutrition, improve quality of life, and decrease health care expenditures in medication-refractory gastroparesis, but small controlled trials do not report convincing benefits.

26. SAFETY CONSIDERATIONS • Safety concerns about selected antiemetics have been emphasized. • Centrally acting antidopaminergics, especially metoclopramide, can cause irreversible movement disorders such as tardive dyskinesia, particularly in older patients • This complication should be carefully explained and documented in the medical record • Some agents with antiemetic properties includingdomperidone, erythromycin, tricyclics, and 5-HT3 antagonists can induce dangerous cardiac rhythm disturbances, especially in those with QTc interval prolongation on electrocardiography (ECG) • Surveillance ECG testing has been advocated for some of these agents

27. SELECTED CLINICAL SETTINGS • Some cancer chemotherapies are intensely emetogenic • Combining a 5-HT3 antagonist, an NK1 antagonist, and a glucocorticoid provides significant control of both acute and delayed vomiting after highly emetogenicchemotherapy • Unlike other drugs in the same class, the 5-HT3 antagonist palonosetronexhibits efficacy at preventing delayed chemotherapy-induced vomiting.

28. Benzodiazepines such as lorazepam can reduce anticipatory nausea and vomiting • Miscellaneous therapies with benefit in chemotherapy induced emesis include cannabinoids, olanzapine, and alternative therapies like ginger • Most antiemetic regimens produce greater reductions in vomiting than in nausea

29. Clinicians should exercise caution in managing pregnant patients with nausea • Studies of the teratogenic effects of antiemetic agents provide conflicting results • Few controlled trials have been performed in nausea of pregnancy • Antihistamines such as meclizine and doxylamine, antidopaminergics such as prochlorperazine, and antiserotonergics such as ondansetron demonstrate limited efficacy • Some obstetricians offer alternative therapies such as pyridoxine, acupressure, or ginger

30. Managing cyclic vomiting syndrome is a challenge • Prophylaxis with tricyclic antidepressants, cyproheptadine, or β-adrenoceptorantagonists can reduce the severity and frequency of attacks. • Intravenous 5-HT3 antagonists combined with the sedating effects of a benzodiazepine like lorazepam are a mainstay of treatment of acute flares • Small studies report benefits with antimigraine agents, including the 5-HT1 agonist sumatriptan, as well as selected anticonvulsants such as zonisamide and levetiracetam.