GASTROPARESIS Arnold Wald, M.D., AGA-F University of Wisconsin School of Medicine & Public Health, Madison, WI

MAIN FUNCTIONS OF STOMACH I. PROXIMAL Functions: Accommodation Storage of ingested food Regulation of intragastric pressure Tonic movement of chyme Motor Pattern: Tonic activity DISTAL Functions: Grinding of food Emptying to duodenum Motor Pattern: Phasic activity

Motility of the Antral Pump Is Initiated by a Dominant Pacemaker in the Mid-corpus Pacemaker potentials determine contractile parameters Fundus Contractile parameters Max frequency (3/min) Propagation velocity Propagation direction Pacemaker region Pacemaker potential Motility of the Antral Pump Is Initiated by a Dominant Pacemaker in the Mid-Corpus Gastric action potentials determine the duration and strength of the phasic contractions of the antral pump. They are initiated by a dominant pacemaker located in the corpus distal to the midregion. After they are started at the pacemaker site, the action potentials propagate rapidly around the gastric circumference and trigger a ring-like contraction. The action potentials and associated ring-like contraction then travel more slowly toward the gastroduodenal junction. Electrical syncytial properties of the gastric musculature account for the propagation of the action potentials from the pacemaker site to the gastroduodenal junction. The pacemaker region in humans generates action potentials and associated antral contractions at a frequency of 3 per minute. The gastric action potential is about 5 seconds long and has a rising (depolarization) phase, a plateau phase, and a falling (repolarization) phase. Szurszewski JH. Electrophysiological basis of gastrointestinal motility. In: Johnson LR, Alpers DH, Christensen J, Jacobson ED, Walsh JH, eds. Physiology of the Gastrointestinal Tract. New York: Raven Press; 198:383-422. Pylorus Antrum Corpus The antral pump is formed by the mid and distal corpus, antrum, and pylorus B3 B87 3

% Meal remaining in stomach Onset and Rate of Gastric Emptying Varies With the Composition of the Meal Emptying phase Lag phase 100 Solid meal 75 % Meal remaining in stomach 50 Semisolid meal Onset and Rate of Gastric Emptying Varies With the Composition of the Meal Liquids empty faster than solids when a mixed meal is in the stomach. If an experimental meal that consists of solid particles of various sizes that are suspended in water is instilled in the stomach, emptying of the particles lags behind emptying of the liquid. With digestible particles (eg, chunks of liver), the lag phase reflects the time that is required for the grinding action of the antral pump to reduce the particle size. Meyer, JH. Motility of the stomach and gastroduodenal junction. In: Johnson LR, ed. Physiology of the Gastrointestinal Tract. 2nd ed. New York: Raven Press; 1987:613-629. 25 Liquid meal 20 40 60 80 100 Time after meal (min) B4 4

Gastric emptying – evolving concepts Relationship with symptoms unclear NOT nausea, vomiting or pain Accelerating gastric emptying does not necessarily improve symptoms Symptomatic improvement including weight gain is possible without improving gastric emptying Gastroparesis is frequently overdiagnosed on the basis of outdated emptying tests

Causes of Gastroparesis Idiopathic 36% Diabetic 29% Upper GI surgery 13% Parkinson’s 8% Collagen tissue disorder 5% Intestinal pseudo-obstruction 4% Miscellaneous (Incl eating disorders) 6% Soykan et al, DDS 1998; 43:2398-2404

Drugs that delay gastric emptying (Partial listing) β Agonists Anticholinergics Tricyclic agents Phenothiazines Dopamine agonists Opiates Proton pump inhibitors Miscellaneous Dexfenfluramine Antihistamines Lithium Tetrahydrocannabinol Tobacco

Workup for suspected gastroparesis UGI Series: Excludes mechanical obstruction Retention of barium w/o obstruction is diagnostic Endoscopy: Bezoar without obstruction highly suggestive Gastric Emptying: Solids more sensitive than liquids

Normal values for low fat, egg white GES Lower normal limit Upper normal limit Time for gastric retention* for gastric retention** 0.5 hr. 70% 1.0 hr. 30% 90% 2.0 hr. 60% 4.0 hr. 10% * Lower value suggests rapid emptying ** Higher values suggest delayed emptying Am J Gastroenterol 2008

Which of the following would you recommend: 2. A 30 y.o. woman with a one year history of type II diabetes mellitus presents with nausea and early satiety. Her blood sugars have been erratic and her last HBAIC was 9.2. Endoscopy was normal and a gastric emptying test showed 20% retention of the meal at 4 hours (normal < 10%). Which of the following would you recommend: a) Metoclopramide b) Rigorous control of blood sugars c) Erythromycin d) Botulinum toxin injection of the pylorus

Slow gastric emptying was frequent in women with type 2 diabetes with hyperglycemia and normalized after diabetic control J Diabetes & Complications, 2013

2. A 23 y.o. woman developed a viral illness associated with fever, myalgias, nausea, vomiting and diarrhea. Although most of her symptoms resolved over 2 weeks, she continued to have nausea, occasional retentive vomiting, early satiety and a 10 lb. weight loss. Endoscopy showed a modest amount of retained food in the stomach and a gastric retention of a test meal consisting of egg whites, toast and jam at 4 hours was 35% (normal <10%). Which of the following would you recommend first? a) Metoclopramide b) Botulinum toxin injection (pylorus) c) Erythromycin d) Gastric stimulator

Management of Gastroparesis Dietary Modifications Small frequent (6/day) meals Reduced fat (<40 gm/day) Soup, crackers, noodles, pasta, potatoes, rice, cheese Reduced fiber  helps avoid bezoar Liquid caloric supplementation

Prokinetic Agents Motilides: erythromycin ACh-esterase inhibitors: pyridostigmine Motilides: erythromycin Antidopamine agents: domperidone* Antidopamine/serotonin agents: metoclopramide Serotonin agents: tegaserod*, prucalopride* *Not available in USA

ERYTHROMYCIN Motilin agonist No antiemetic effect Stimulates antral contractions (IV >> PO) Stimulates MMC Dose: 125-250 mg bid/tid (PO) 3 mg/kg q 8 hours (IV)

Metoclopramide Central/peripheral D2 antagonist and 5 HT agonist Increases antral contractions Decreases fundal relaxation Improves antroduodenal coordination Dose: 5-20 mg qid (PO, IV, SQ, SL)

Metoclopramide * Boxed Warning for chronic use issued by FDA* 30% of patients experience side effects 10% have neurologic side effects Parkinson-type syndrome Tardive dyskinesia Hyperprolactinemia * Boxed Warning for chronic use issued by FDA*

Domperidone Peripheral D2 antagonist Increases antral contractions Decreases fundal relaxation Improves antroduodenal coordination Dose: 10-30 mg qid (PO) Limited availability in USA

Efficacy of Domperidone in Diabetic Gastroparesis □ Improved symptoms in 64% □ Improved gastric emptying in 60% □ Reduced hospital admission in 67% □ 28 trials (19 double arm); 1016 patients Sugumar A et al, CGH 2008

Effects of Botulinum Toxin on GE and GI Symptoms Within Group Between Group P Botox P Placebo Improved % 37.5 56.3 0.29 GCSI score -6.8 + 9.2 0.01 -10.1 + 12.7 0.42 GVAS score -190 + 228 -176 + 256 0.02 0.88 % Gastric retention 2 hr -16.3 + 22.9 -10.8 + 20.6 0.08 0.52 % Gastric retention 4 hr -13.3 + 18.0 -3.6 + 25.5 0.62 0.27 Friedenberg FK, et al. Am J Gastro 2008

3. A 28 y.o. man with IDDM is referred for chronic and recurrent nausea and vomiting. He reports 3-4 episodes yearly for the past 5 years with frequent ED visits or hospitalizations lasting 3-4 days. Between episodes, he feels well and has lost no weight. During these episodes, he finds great relief when taking hot showers. The most appropriate intervention for this patient is: a) Domperidone 20 mg AC meals b) Nortriptyline in doses up to 100mg hs c) Discontinue smoking marijuana d) Strict control of blood sugars; metoclopramide 10 mg SQ during episodes

Cyclic Vomiting Syndrome Recurrent and stereotypical episodes of severe nausea and vomiting separated by symptom free intervals - Gastric emptying rapid or normal - Maintenance of weight

Cannabinoid Hyperemesis - Cyclic vomiting syndrome - Compulsive hot water bathing - Poor response to TCAs

Cyclic Vomiting in Adults (Non-Cannabinoid) Association with migraine headaches Psychological disorders (anxiety/depression) Absence of compulsive hot water bathing Often responds to TCAs

References 1. Hasler WL. Gastroparesis: pathogenesis, diagnosis and management. Nat Rev Gastroenterol Hepatol 2011;8:438-53.   2. Choung RS et al. Cyclic vomiting syndrome and functional vomiting in adults. Neurogastroenterol Motil 2011;24:20-26