In a patient with persistent nausea and vomiting but no evidence of obstruction on imaging, what are the next management steps?

Management of Persistent Nausea and Vomiting Without Obstruction

Initiate dopamine receptor antagonists as first-line therapy, titrating to maximum benefit and tolerance, then add agents from different drug classes sequentially if symptoms persist after 4 weeks. 1, 2, 3

Initial Diagnostic Workup

Before escalating antiemetic therapy, obtain targeted laboratory studies to identify treatable causes:

• Complete blood count, comprehensive metabolic panel (including calcium), liver function tests, lipase, and urinalysis to exclude metabolic derangements, hypercalcemia, hypothyroidism, and Addison's disease 2
• Urine pregnancy test in all women of reproductive age—hyperemesis gravidarum is the most common endocrine cause of persistent vomiting in this demographic and occurs in 0.35–2% of pregnancies 2
• Urine drug screen with specific attention to cannabis use history—Cannabis Hyperemesis Syndrome requires 6 months of cessation or 3 typical cycle lengths without vomiting for definitive diagnosis 2
• Correct electrolyte abnormalities immediately, particularly hypokalemia, hypomagnesemia, hypochloremia, and metabolic alkalosis, which are common after prolonged vomiting 2
• Administer thiamine 100 mg IV before glucose-containing fluids to prevent Wernicke's encephalopathy in patients with prolonged vomiting 2

Imaging and Endoscopy

• Perform one-time esophagogastroduodenoscopy (EGD) or upper GI imaging to exclude obstructive lesions, gastroparesis, or gastritis 2
• Avoid repeated endoscopy or imaging studies unless new symptoms develop 2

Stepwise Pharmacologic Algorithm

First-Line Therapy (Days 1–28)

Start with dopamine receptor antagonists, administered around-the-clock rather than PRN 1, 2:

• Metoclopramide 10–20 mg IV/PO every 6–8 hours—particularly effective for gastroparesis and gastric stasis, as it promotes gastric emptying 1, 2, 3
• Prochlorperazine 10 mg IV/PO every 6–8 hours as an alternative first-line dopamine antagonist 1, 2, 3
• Haloperidol 0.5–2 mg IV/PO every 4–6 hours when additional anti-dopaminergic effect is needed 1, 2, 3

Monitor for extrapyramidal symptoms (particularly in young males) and treat with diphenhydramine 50 mg IV if they develop 2, 3

Second-Line Therapy (If Symptoms Persist After 4 Weeks)

Add a 5-HT3 receptor antagonist from a different drug class rather than replacing the dopamine antagonist 1, 2, 3:

• Ondansetron 4–8 mg IV/PO every 8 hours (maximum 16 mg per dose) 1, 2, 4
• Sublingual ondansetron tablets may improve absorption in actively vomiting patients 3
• Monitor for QTc prolongation, especially when combined with other QT-prolonging agents 2, 4

Consider adding adjunctive agents targeting different receptor pathways 1, 2:

• Anticholinergic agents (e.g., scopolamine) 1
• Antihistamines (e.g., meclizine) 1
• Lorazepam 0.5–1 mg PO/IV every 4–6 hours if anxiety contributes to nausea 1, 2

Third-Line Therapy (If Symptoms Persist After 48–72 Hours of Second-Line Therapy)

Add corticosteroids and consider olanzapine 1, 2, 3:

• Dexamethasone 4–10 mg IV/PO twice daily for severe or central-nervous-system-related nausea 1, 2, 5
• Olanzapine (dosing per guidelines) if not already tried 1, 2

Fourth-Line Therapy (Refractory Symptoms)

For intractable vomiting, consider continuous IV/subcutaneous infusion of antiemetics 1, 3:

• Multiple concurrent agents in alternating schedules may be necessary 1, 2
• Dronabinol 2.5–7.5 mg PO every 4 hours as needed—FDA-approved cannabinoid for refractory nausea unresponsive to conventional antiemetics 2, 3

Route of Administration Considerations

The oral route is often not feasible due to ongoing vomiting; use alternative routes 1, 2, 3:

• Rectal suppositories (promethazine, prochlorperazine) 3
• Sublingual formulations (ondansetron, alprazolam) 3
• Intravenous or intramuscular administration when other routes fail 1, 4

Supportive Care and Fluid Management

• Administer isotonic IV fluids (lactated Ringer's or normal saline) for moderate-to-severe dehydration, altered mental status, or inability to tolerate oral intake 2
• Oral rehydration solution (ORS) is first-line for mild-to-moderate dehydration when the patient can tolerate oral intake 2
• Ensure adequate fluid intake of at least 1.5 L/day and recommend small, frequent meals 2

Treatment of Specific Underlying Causes

• For gastroparesis or gastritis: Continue metoclopramide and add proton pump inhibitor or H2 receptor antagonist 2, 3
• For hypercalcemia: Correct metabolic abnormalities and treat dehydration 2
• For medication-induced vomiting: Discontinue non-essential constipating or emetogenic medications 1, 3

Critical Pitfalls to Avoid

• Never use metoclopramide or other prokinetic antiemetics in suspected mechanical bowel obstruction—this can mask progressive ileus and gastric distention 2, 3, 4
• Do not replace one antiemetic with another; instead, add agents from different drug classes to target different neuroreceptors involved in the emetic response 1, 2, 3
• Avoid repeated endoscopy or imaging unless new symptoms develop 2
• Do not stigmatize patients with cannabis use—offer abortive and prophylactic therapy even with ongoing use, as treatments can still be effective 2
• Prevention is far easier than treating established vomiting—administer antiemetics on a scheduled basis rather than PRN 1, 2

Reassessment and Follow-Up

Before the next intervention cycle, reassess for non-pharmacologic causes 1:

• Brain metastases 1, 3
• Electrolyte abnormalities 1, 2
• Tumor infiltration of the bowel or other gastrointestinal abnormality 1
• Other comorbidities 1

If a cyclic pattern of vomiting emerges, consider cyclic vomiting syndrome and initiate prophylactic amitriptyline 50 mg nightly 2