Gastroparesis or Cyclic Vomiting: Does it Matter for Treatment?

Transcription

1 Gastroparesis or Cyclic Vomiting: Does it Matter for Treatment? Brian E. Lacy, MD, PhD, FACG Professor of Medicine Geisel School of Medicine at Dartmouth Chief, Section of Gastroenterology & Hepatology Director, GI Motility Laboratory Dartmouth-Hitchcock Medical Center Lebanon, NH Case Study - I 23-year-old man is referred to you with complaints of nausea and bilious emesis x 3 days, occurring 4-5 times per hour. Unable to take in any liquids or solids. Onset 3 years ago; unable to identify any precipitating event. ER visits every 6-8 weeks. Several admissions; left AMA twice. Treated with IV fluids, ondansetron, benadryl, omeprazole, lorazepam. Epigastric pain is present during these episodes No other GI symptoms Weight has remained stable Page 1 of 19

2 Case Study - II Allergies none Medications: gabapentin PMH: migraine headaches; last 3 months ago PSH: appendectomy as a child Social: graduated from college, lives with parents Family history: bipolar disease, alcohol addiction Habits: Occasional marijuana. No ETOH PE: Elevated BP on all ED visits, otherwise normal PE Case Study - III Urine toxicology screen: (+) cannabinoids on one occasion Labs: Metabolic alkalosis, anion gap of 23, otherwise normal CBC, BMP, lipase EKG: normal KUB: normal Psych consult placed for psychogenic vomiting Page 2 of 19

3 Case Study - IV What is the most likely diagnosis? A) Gastroparesis (idiopathic) B) Pheochromocytoma C) Cyclic vomiting syndrome D) Hyperemesis cannabis syndrome E) Functional dyspepsia F) Psychogenic vomiting G) Other Case Study: Key Question Based on your diagnosis, what treatment options are available and how do they differ? Page 3 of 19

4 Cyclic Vomiting Syndrome First described in France in 1806 (Heberden) 1 st English description in 9 children (Dr. Gee fitful or recurrent vomiting ) CVS - first used clinically in First reported in adults in Prevalence: Pediatrics ~ 0.1%; School age children ~ 2% Adults unclear 1 Smith C, J Pediatr 1973; 10: SCobie BA. Med J Aust 1983; 1: Cyclic Vomiting Syndrome Median age of onset: 5 yrs in children; 35 yrs in adults Average time to diagnose: 2.7 yrs in children; 8 yrs in adults Men and women similarly affected Natural History chronic in most; migraines Risk factors: poor sleep, stress, headaches, menstrual cycle, ANS dysfunction, hyperesthesia, fatigue, foods (chocolate, cheese) Prakash & Clouse, AJG 1999; 94: ; Abell TL et al; Mayo Clin Proc 1988; 63: Page 4 of 19

5 CVS: Symptoms Discrete, recurrent, stereotypical episodes of nausea and vomiting; explosive; self-limited average duration = 3-6 days Separated by symptom-free intervals days ( interepisodes ) Generally a short prodromal period (1-2 hrs) Vomiting >4 episodes/hour (mean = 12) Mid-epigastric pain is present in nearly all Pts Associated symptoms: anorexia, pallor, lethargy Rapid resolution of Sx like a lightswitch The 4 Phases of CVS Inter-episodic; Prodrome; Emetic phase; Recovery phase Page 5 of 19

6 CVS: Putative Pathophysiology Arterial vasospasm Smooth muscle spasm Central process Severe hyperesthesia Mitochondrial dysfunction ANS dysfunction Concomitant anxiety/depression ACTH/cortisol/CRF variations CVS: Differential Diagnosis Acute gastroenteritis/food poisoning Gastroparesis Hyperemesis cannabis syndrome Medications (prescribed/otc/illicit) Ischemia/MAL syndrome/sma syndrome Cholecystitis/Pancreatitis Malrotation/intermittent SBO/volvulus Psychological Migraine headaches/cns causes Endocrine disorders (e.g., Addison s; pheochromo.) AIP/hereditary angioedema/cip Acute hydronephrosis with UPJ obstruction Page 6 of 19

7 CVS: Diagnosis KUB Laboratory studies (CBC, CMP, Ca+, Mg+, phosphorous, lipase, CRP, TSH, tox screen) Urinalysis with toxicology screen EGD RUQ US SBFT Consider: CT Angiogram of A/P MRI of brain Specialized laboratory studies porphyria, pheo. CVS: Treatment Acute: iv fluids, antiemetics, anxiolytics Chronic Cyproheptadine Propranolol TCAs Sumatriptan Anticonvulsants (topiramate, levetiracetam) Ketorolac L-carnitine Prokinetic agents Page 7 of 19

8 Cyproheptadine: 1 st Line Tx 1 st generation anti-histamine (cyproheptadine) 5-HT 2a receptor antagonist Calcium channel blocker Dosing: 4 mg p.o. t.i.d. Peak plasma levels: 3 hrs; t ½ = 8 hrs Side effects: sedation (12%), weight gain (10%), anticholinergic CYPROHEPTADINE Madani et al, J PEDS 2013 Page 8 of 19

9 Propranolol TCAs Sumatriptan CVS: Next Line Therapy CVS: Treatment with anticonvulsants Levetiracetam 500 mg p.o. b.i.d. Headache, fatigue, dizziness Zonisamide mg q.d. Fatigue, dizziness Topiramate migraine Tx as well mg p.o. b.i.d. Depression, metabolic acidosis Page 9 of 19

10 CVS: Summary Frequently overlooked Commonly mistaken for Gastroparesis Clinical history is key Treatment is different than other FGIDs Much remains unknown Diet Medications Gastroparesis: Current therapeutic options Prokinetic agents Antiemetic agents CAM PEG / PEJ tubes Surgery Gastric stimulation Botulinum toxin injection of the pylorus TPN Page 10 of 19

11 Dietary Therapy & Gastroparesis Small frequent meals - 5 to 6 per day Low fat & low fiber Restore electrolytes & hydration Emphasize liquids (bouillon, sports drinks) Supplement diet with egg whites, protein powders, and nutritional drinks Control serum glucose Consider referral to a nutritionist Gastroparesis & Prokinetics Metoclopramide Domperidone Erythromycin Page 11 of 19

12 Metoclopramide A substituted benzamide derivative Chemical structure similar to procainamide Available since 1979 Increases ACh release from intrinsic neurons A dopamine D2-receptor antagonist Inhibits DA receptors centrally and peripherally Increases the amplitude of antral contractions Relaxes the pyloric sphincter FDA approved for diabetic GP Metoclopramide: Side Effects & Tardive Dyskinesia 30-40% of patients have side effects Anxiety, depression, insomnia, skin crawling, acute dystonic reaction, akathisia, Parkinsonism 37 cases of NMS; 8 deaths Black box warning (FDA ) TD - an extrapyramidal disorder characterized by irreversible involuntary movements Some reports state risk is as high as 15% Real risk: likely < 1% FDA: chronic use should be avoided Page 12 of 19

13 Domperidone A benzamidazole derivative Acts peripherally to block D2 receptors Increases local release of ACh Antiemetic activity is due to DA receptor blockade in the CTZ Side effects due to elevated prolactin levels PO form only; IV form may lead to arrhythmias Not FDA approved for treatment of GP Check EKG first; don t use if QT >450 ms in women, and 470 ms in men Domperidone: What s the data? 11 studies performed to date in Pts with GP 4 = open label; 1 single-blind Subjects: 3 to 287 Doses: 10 mg TID to 20 mg QID Study length: 4 weeks to 2 years Outcomes: Symptoms and/or gastric emptying Results: Symptoms improved in 36% - 94% Gastric emptying improved in 0 64% Similar or better than metoclopramide Page 13 of 19

14 Erythromycin A macrolide antibiotic Mimics the action of motilin Induces Phase III of the MMC Increases the amplitude of antral contractions and increases antro-duodenal coordination Ideal dose is 3 mg/kg Q 8 hrs Tachyphylaxis is common & expected Not FDA approved for gastroparesis Gastroparesis & Antiemetics Phenothiazines (compazine) Antihistamines (meclizine, diphenhydramine) Anticholinergics (scopolamine) DA antagonists (metoclopramide, domperidone) 5HT 3 antagonists (ondansetron, granisetron) Others: tigan, marinol, lorazepam, prednisone, aprepitant, haldol No controlled studies to support use in gastroparesis patients Page 14 of 19

15 TCAs & Idiopathic Gastroparesis 15 wk, R, DB, PC, multicenter trial Escalating dose of nortriptyline; max = 75 mg 130 Pts; mean age = 41 yrs; 89% women Primary endpoint: 50% decrease in GCSI score Results: No difference between the 2 groups Parkman et al, JAMA 2013; 310: Gastric Stimulation: Theoretical MOA Entrainment (pacing) of gastric slow waves can be achieved with low frequency/long duration pulses. But. Increases gastric emptying? No. Vagal nerve stimulation with modulation of CTZ and nausea and vomiting center. Very appealing PET study GES increases activity in thalamus But, why does it work in some patients with prior vagotomy? Page 15 of 19

16 Port Placement 3-4 Ports Typically utilize 5mm ports Upper right port becomes stimulator pocket Lead Fixation Page 16 of 19

17 Stimulator Pocket Abdominal pocket placement Utilize port placement site Leads pulled through port to site Snug fit Gastric stimulation FDA approved in 2000 as a HUD 14 studies published to date; only 1 = blinded 6 different publication groups total Study size: (most = 18-33) Most are mixed groups (DM and idiopathic) Page 17 of 19

18 Gastric Stimulation: Summary Improves nausea and vomiting in 50% of Pts 76% of Pts were able to stop TPN/PPN Some improvement in glycemic control Not helpful for pain or bloating Less helpful for those on narcotics More helpful in diabetics than non-diabetics Doesn t improve Gastric emptying time Doesn t change gastric electrical rhythm Appears to improve Patients quality-of-life CVS & GP: Summary Two challenging disorders Commonly confused CVS explosive episodes with normal interepisodes GP chronic, near daily symptoms Making the correct diagnosis matters Treatment differs Page 18 of 19

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