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Gastroparesis: Pathophysiology and management

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1 Gastroparesis: Pathophysiology and management
Normal colonic transit time: 5-59 hours. Normal small bowel transit time: hours Normal gastric transit time: 1-5 hours Preceptor: Dr. Govind Makharia Speaker: Dr. Moka Praneeth

2 Gastroparesis-Overview
Definition Epidemiology Pathophysiology Clinical Manifestations Diagnosis Treatment

3 Definition The diagnosis of gastroparesis is based on the combination of symptoms of gastroparesis, absence of gastric outlet obstruction or ulceration (documneted on UGIE or Barium swallow), and documentation of delay in gastric emptying. Michael Camilleri et al. Clinical Guideline: Management of Gastroparesis. Am J Gastroenterol 2013

4 Gastroparesis in Olmsted County, 1996–2006
Incidence The age-adjusted prevalence of definite gastroparesis per 100,000 person was 9.6 (95% CI, 1.8–17.4) for men and 37.8 (95% CI, 23.2–52.4) for women. Incidence & prevalence of gastroparesis in India: ? A. Definite gastroparesis B. Definite+probable gastroparesis C. Definite+probable+possible gastroparesis. Definite gastroparesis: delayed gastric emptying by standard scintigraphy and symptoms of nausea and/or vomiting, postprandial fullness, early satiety, bloating, or epigastric pain for more than 3 months, Probable gastroparesis: symptoms as above plus food retention on endoscopy or an upper GI study, but no scintigraphy had been performed, Possible gastroparesis: typical symptoms alone or delayed gastric emptying by scintigraphy in the absence of GI symptoms. aIncidence per 100,000 person-years, age-adjusted to the population structure of 2000 U.S. whites. bIncidence per 100,000 person-years, age-and gender-adjusted to the population structure of 2000 U.S. whites. Jung HK et al. J Neurogastroenterol Motil. 2010

5 Gastroparesis: Etiology
Mean age of onset: 34 years. 82%- females Kendall and McCallum. Gastroenterology 1993. Soykan et al. Dig Dis Sci 1998.

6 The motor function of the gut is controlled at three main levels: extrinsic neural control (vagal and sympathetic); intrinsic neural control; and excitability of smooth muscle cells controlled by transmitters. Gastric emptying entails interaction among smooth muscle, enteric and extrinsic autonomic nerves, and the interstitial cells of Cajal (ICC)

7 Electrophysiologic basis of gastric peristaltic waves
The plateau and action potentials occur during circular muscle contractions. Peristaltic waves originate in the pacemaker area. The frequency (3 cycles per minute [cpm]) and propagation velocity (approximately 14 mm/second) of the gastric peristaltic waves are controlled by the slow wave, which leads the contraction from the proximal corpus to the distal antrum, as shown at electrodes A through D. The solid black linesand arrowsindicate the circumferential and distal propagation of the peristaltic wave, which forms a ring contraction (small arrow), indicating a moving peristaltic contraction. Peristaltic contractions occur three times per minute, the frequency of the gastric slow wave. The increased myoelectrical activity of the plateau potentials and action potentials linked with the slow wave results in increased amplitude of the EGG signal (thick black lines). The fundus does not participate in the gastric peristaltic contractions.

8 Gastric neuromuscular work after ingestion of a solid meal
To receive the ingested solid foods and accommodate the volume of food without increasing intragastric pressure, the fundic smooth muscle relaxes (receptive relaxation). The fundus then contracts to empty the ingested food into the corpus and antrum for trituration and emptying. Recurrent corpus-antral peristaltic waves mill the solids into chyme, which is composed of 1- to 2-mm solid particles suspended in gastric juice. Antral peristaltic waves, indicated by the ring-like indentation in the antrum, empty 2 to 4 mL of the chyme through the pylorus and into the duodenal bulb at the slow wave frequency of three peristaltic contractions per minute. Antropyloroduodenal coordination indicates efficient emptying of chyme through the pylorus, which modulates flow of the chyme by varying sphincter resistance. Contractions in the duodenum also provide resistance to emptying.

9 Normal gastric emptying
The proximal stomach serves as the reservoir of food, and the distal stomach as the grinder Solids are initially retained in the stomach and undergo churning while antral contractions propel particles toward the closed pylorus. Food particles are emptied once they have been broken down to approximately 2 mm in diameter

10 Gastric neuromuscular disorders

11 Diabetic gastroparesis-pathophysiology
Traditionally considered to be Neuropathic. Gastric acid output reduced, Vagus nerve dysfunction reduces pyloric relaxation and thereby prohibits passage of foods. Vagus nerve histology shows myelin degeneration. However, some patients have gastroparesis without evidence of generalized autonomic neuropathy. Non-neuropathic Decreased Interstitial Cells of Cajal (ICCs) Hyperglycemia Blunts antral contraction in healthy humans In diabetics, hyperglycemia delays gastric emptying that improves with euglycemia.The major functionality of nNOS is control of the muscle tone of the lower esophageal sphincter, the pylorus, the sphincter of Oddi, and the anus. Additionally, it modulates the accommodative reflex of the fundus and the peristaltic reflex of the small intestine.

12 NOS – impaired expression
Gastric myenteric plexus of spontaneously diabetic biobreeding /Worcester (BB/W) rats was studied NANC relaxation in gastric muscle preparations in response to transmural stimulation obtained from diabetic BB/W rats was significantly impaired frequency-dependent NANC relaxation in response to transmural stimulation was markedly antagonized by N(G)-nitro-L-arginine-methyl ester, indicating mediation by the neuronal release of NO Takahashi T et al. Gastroenterology Nov

13 NOS – impaired expression
The number of NOS-immunoreactive cells in the gastric myenteric plexus and the NOS activity were significantly reduced in diabetic BB/W rats. Northern blot analysis showed that the density of NOS messenger RNA bands at 9.5 kilobases was significantly reduced in the gastric tissues of diabetic BB/W rats. NOS expression in duodenum, ileum, and colon of diabetic animals was not statistically different from controls. Decreased expression of NOS in antrum may contribute to altered gastric emptying observed in diabetics. Similar results were obtained in Streptozocin-diabetic rats. Takahashi T et al. Gastroenterology Nov

14 Watkins CC et al. J Clin Invest. 2000
nNOS protein expression in the pyloric myenteric neurons is depleted in diabetic mice: reversal by insulin treatment. (a) Immunohistochemical analysis of nNOS protein expression. nNOS is present in wild-type but not nNOS–/– pyloric myenteric neurons whereas nNOS expression is lost in both NOD diabetic mice. Insulin treatment (1 week) reverses the expression. In situ hybridization analysis of nNOS expression. nNOS mRNA expression is present in wild-type and depleted in nNOS–/– pyloric myenteric neurons whereas nNOS mRNA expression is significantly decreased in diabetic mice.. Loss of fundal relaxation in nNOS–/– or diabetic mice would be expected to accelerate gastric emptying, whereas loss of pyloric or duodenal relaxation may delay gastric emptying. In both nNOS–/– and diabetic mice, the loss of nNOS is associated with delayed gastric emptying consistent with a major physiological effect on pyloric function. This conclusion is supported by our findings of more pronounced depletion of nNOS in the pylorus compared with the fundus and antrum and with the anatomic changes observed in these animals. Insulin restores gastric emptying in this study. Watkins CC et al. J Clin Invest. 2000

15 Patterns of Gastric Emptying in Healthy People and in Patients with Diabetic Gastroparesis
Non-nutrient liquids empty rapidly; the rate is fastest when there is a large volume. If there are increased calories in the liquid phase of the meal, emptying is relatively constant over time, with a maximum rate of 200 kcal/hour. Thus, solids empty during two phases over 3 to 4 hours: an initial lag period (during which retention occurs), followed by a phase of relatively constant emptying.

16 Idiopathic gastroparesis/IG – intact vagal function
13 normal subjects, 9 patients of DG, 10 patients of IG, 5 patients of postsurgical gastroparesis There were significantly decreased fasting levels of pancreatic polypeptide and ghrelin in the diabetic (79±26pg/ml) and postsurgical gastroparesis groups (51±11 pg/ml) compared to the normal subjects (315±76 pg/ml) and the idiopathic gastroparesis group (161±53 pg/ml). Gaddipati KV et al. Dig Dis Sci. 2006

17 IG – intact vagal function
Sham feeding was characterized by an increase in pancreatic polypeptide levels in normal controls and patients with idiopathic gastroparesis, with no change in diabetic and postsurgical gastroparesis. Meal ingestion resulted in an increase in pancreatic polypeptide concentration in the normal subjects groups and idiopathic gastroparesis group. Gaddipati KV et al. Dig Dis Sci. 2006

18 IG & DG-cellular changes
Full-thickness gastric body biopsy specimens were obtained from 40 patients with gastroparesis (20 diabetic) and matched controls. Sections were stained for H&E and trichrome and immunolabeled with antibodies against PGP 9.5, nNOS, VIP, substance P, and tyrosine hydroxylase to quantify nerves, S100β for glia, Kit for ICCs, CD45 and CD68 for immune cells, and smoothelin for smooth muscle cells. Grover M et al. Gastroenterology May

19 IG vs DG-cellular changes
Histologic abnormalities were found in 83% of patients. The most common defects were loss of ICC with remaining ICC showing injury, an abnormal immune infiltrate containing macrophages, and decreased nerve fibers. On light microscopy, no significant differences were found between DG and IG with the exception of nNOS expression, which was decreased in more patients with IG (40%) compared with DG patients (20%) by visual grading. ICC were greatly reduced in the distal stomach in diabetic mice manifesting delayed gastric emptying, impaired electrical pacemaking, and reduced motor neurotransmission. Grover M et al. Gastroenterology May

20 IG vs DG- Ultrastructural differences
Tissue was collected from anterior aspect of stomach, midway between GC and LC where the gastroepiploic vessels meet, at ~ 9 cm proximal to pylorus, from 20 DG, 20 IG and 20 patients undergoing gastric bypass for obesity 4 tissue strips for each patient 1 mm × 10 mm long and containing the muscularis propria plus a small portion of the tunica submucosa, were immediately cut after the full thickness biopsy was obtained and processed for electron microscopy The NIDDK GpCRC J Cell Mol Med July

21 IG vs DG- Ultrastructural differences
ICC were affected in both diabetic and idiopathic gastroparesis. 19/20 DG patients had a thickened basal lamina around smooth muscle cells and nerves. In contrast, tissues from 18/20 patients with IG did not have the thickened basal lamina around smooth muscle cells and nerves but had more intense fibrosis than those from DG Nerve damage was much more prominent in IG with both nerve cell bodies and nerve fibers affected to a greater degree. Unlike in DG, glial cells were also abnormal in IG neuronal cell body, nerve fibers and glial cells were markedly altered in idiopathic gastroparesis, while only nerve ending abnormalities were seen in the diabetic patients. Smooth muscle cell abnormalities were not commonly seen in diabetic and idiopathic gastroparesis and gap junctions were maintained in all patients studied. However, contractile activity of the muscle coat may still be compromised because the smooth muscle cells were encased in a less elastic stroma. residual ICC were rarely in contact with each other and smooth muscle cells and never to nerve endings. This is in sharp contrast to what is seen in control tissues. The NIDDK GpCRC J Cell Mol Med July

22 Clinical Manifestations
Nausea % Vomiting % Bloating 75% Early Satiety % Abdominal pain % Rule out rumination syndrome Pain- burning, vague or crampy, localised, nocturnal and exacerbated by meals. Rumination syndrome - daily, early postprandial, effortless regurgitation of food, which typically occurs with each meal for months. Nausea, vomiting, early satiety, and postprandial fullness correlate better with delayed gastric emptying than upper abdominal pain and bloating. Differentiation: CVS, cannabinoid use. Soykan et al. Dig Dis Sci Nov; 43(11):

23 Dyspepsia & gastric emptying
In a meta analysis of 17 studies involving 868 dyspeptic patients and 397 controls, significant delay of solid gastric emptying was present in 40% of patients of FD1 Severity of delay does not correlate with symptoms Rapid gastric emptying, rather than delayed gastric emptying, might provoke functional dyspepsia.2 Other GI motor abnormalities, altered visceral sensation and psychosocial factors should be considered in evaluating patients of dyspepsia. 1. Perri F et al. Am J Gastroenterol 1993. 2. Kusano M et al. J Gastroenterol Hepatol Apr

24 Gastroparesis: a proposed classification
Grade 1: Mild gastroparesis Symptoms relatively easily controlled Able to maintain weight and nutrition on a regular diet or minor dietary modifications Grade 2: Compensated gastroparesis Moderate symptoms with partial control with pharmacological agents Able to maintain nutrition with dietary and lifestyle adjustments Rare hospital admissions Grade 3: Gastroparesis with gastric failure Refractory symptoms despite medical therapy Inability to maintain nutrition via oral route Frequent emergency room visits or hospitalizations Abell et al. Neurogastroenterol Motil (2006) 18, 263–283

25 Diabetic Gastroparesis (DG)
Prevalence of delayed emptying in longstanding Type-1 and 2 Diabetics: 27-58% and 30% respectively Diabetic gastroparesis typically develops after DM has been established for ≥10 years, and patients with type 1 diabetes might have triopathy the community prevalence was estimated to be ~ 5 % among type 1 diabetics, 1 % among type 2 diabetics, and 0.2 % of controls in Olmsted County, Minnesota.

26 DG-natural history 20 patients (6 men and 14 women) of diabetes mellitus (16 with type-1 DM, 4 with Type-2 DM) No differences in mean gastric emptying of the solid component (retention at 100 minutes at baseline: 56% +/- 19% vs. follow-up: 51% +/- 21%, P = 0.23) or the liquid component (time for 50% to empty at baseline: 33 +/- 11 minutes vs. follow-up: 31 +/- 12 minutes, P = 0.71) during follow-up Jones KL et al. Am J Med 2002

27 DG-natural history Mean blood glucose (17.0 +/- 5.6 mmol/L vs /- 4.9 mmol/L, P = 0.007) and HbA(1c) (8.4% +/- 2.3% vs. 7.6% +/- 1.3%, P = 0.03) levels were lower at follow-up. There was no difference in symptom score (baseline: 3.9 +/- 2.7 vs. follow-up: 4.2 +/- 4.0, P = 0.78). There was evidence of autonomic neuropathy in 7 patients (35%) at baseline and 16 (80%) at follow-up. In patients with diabetes mellitus, any marked changes in either gastric emptying or upper gastrointestinal symptoms were not observed during a 12-year period. Diabetic gastroparesis is not a rapidly progressive disorder. Parasympathetic function was evaluated by the variation (R-R interval) in the heart rate during deep breathing and the immediate heart rate response to standing (“30:15”). Sympathetic function was assessed by the fall in systolic blood pressure in response to standing. The result of each test was scored as 0 (normal), 1 (borderline), or 2 (abnormal). Jones KL et al. Am J Med 2002

28 DG-natural history Between , 86 patients of DM underwent assessment Solid gastric emptying percentage of retention at 100 min) was delayed in 48 (56%) patients and liquid emptying (50% emptying time) was delayed in 24 (28%) patients. At follow-up in 1998, 62 patients were known to be alive, 21 had died, and 3 were lost to follow-up. Kong MF et al. Diabetes Care 1999

29 DG-natural history In the group who had died, duration of diabetes (P = 0.048), score for autonomic neuropathy (P = 0.046), and esophageal transit (P = 0.032) were greater than in those patients who were alive, but there were no differences in gastric emptying between the two groups. Of the 83 patients who could be followed up, 32 of the 45 patients (71%) with delayed solid emptying and 18 of the 24 patients (75%) with delay in liquid emptying were alive Gastroparesis was not associated with a poor prognosis In IG, Symptoms may resolve over several years. Normal pH response after sham feedings Kong MF et al. Diabetes Care 1999

30 IG vs DG - Differences Out of 416 patients, 254 patients of IG, 137 with DG and 25 with other causes More likely to be female (89% vs 71%-T1 vs 76%-T2), Caucasians (90% vs 77% vs 76%) Mean Age at enrollment: T2DM (53 ± 11) > IG (41 ± 14) > T1 DM (39 ± 11 years) Obesity in: T2 DM (71%) vs 28% (T1DM) vs IG (26%) The NIDDK GpCRC. Clin Gastroenterol Hepatol. 2011

31 IG vs DG - Differences Nausea and vomitings are the most common symptoms prompting evaluation for DG Abdominal pain was more often a symptom prompting evaluation for IG (76% IG, 60% T1DM, 70% T2DM; p=0.01). Patients with IG have more early satiety and abdominal pain compared with patients with DG who have more severe retching. The NIDDK GpCRC. Clin Gastroenterol Hepatol. 2011

32 IG vs DG - Differences 20% having chronic but stable symptoms, 33% having chronic but worsening symptoms, 33% having chronic symptoms with periodic exacerbation, and 10% having a cyclic pattern. Patients with T1DM were more likely to have grade 3 gastroparesis severity (29% IG, 49% T1DM, 39% T2DM) and had greater frequency of hospitalisations due to dehydration The NIDDK GpCRC. Clin Gastroenterol Hepatol. 2011

33 IG vs DG - Differences The symptoms with highest severity at enrollment were stomach fullness and postprandial fullness for IG, nausea for T1DM, and stomach fullness for T2DM. DG had more severe retching and T1DM had more severe vomiting than IG Severity of postprandial fullness and upper abdominal pain in: IG > DG Severity of stomach fullness in: IG > DG. The NIDDK GpCRC. Clin Gastroenterol Hepatol. 2011

34 IG vs DG - Differences Gastric retention in: T1 DM (47 ± 27% at 4 hours) > T2 DM (33 ± 24) > IG (28 ± 19) IG had an increase in endometriosis and migraine headaches, whereas T2DM had an increase in coronary artery disease. An acute onset of symptoms was reported in approximately half of the patients in each of the IG, T1DM, and T2DM. An initial prodrome was present at the start of symptoms in a minority, approximately 15% of cases, without significant differences among the three groups. Patients with T1DM were more likely than IG to be treated with gastric electric stimulation. There was a slight increase in feelings of hopelessness as assessed by BDI and a slight increase in the trait anxiety score in T1DM patients compared to IG. The NIDDK GpCRC. Clin Gastroenterol Hepatol. 2011

35 Evaluation Clinical Evaluation Evaluate Volume Status
Abdominal distention, Succussion splash Clues to other etiologies Malar rash, sclerodactyly Cachexia, lymphadenopathy Lab Electrolytes Protein/albumin Glucose Thyroid/parathyroid If suspected, autoantibodies for scleroderma, SLE, polymyositis

36 Gastric emptying scintigraphy
Medications that affect gastric emptying should be stopped at least 48 h before diagnostic testing; test started aft er blood glucose is < mg / dl.

37 Patient Preparation NPO at least 3 hours prior to the procedure
No smoking for 3 hours prior to the procedure Ensure that diabetics receive orange juice 4-12 hrs before examination Briefly explain to the patient: The oral administration of the radiotracer Positioning and immobilization during the imaging Tobacco smoking delays gastric emptying

38 Procedure Time 1.5 hrs liquid, up to 3-4 hrs solid
Baseline solid Study: Prepare one or two eggs/chicken liver/idli (in AIIMS) and mixed in radiotracer Stir and scramble Or prepare choice of gastronomic vehicle with radiotracer Administer to patient PO with ml of water. Encourage patient to eat quickly The Technetium (Tc)-99m sulfur colloid radiolabeled meal consisted of the equivalent of two large eggs, two slices of bread and jam with water. Emptying of fats is slow as compared to emptying of proteins or carbohydrates. Incomplete meal ingestion can lead to values suggesting more rapid emptying. Vomiting a portion of the ingested meal after the initial baseline image may lead to lower subsequent estimated gastric retention values, so that GE appears faster than it was. extending measurements out to 4 h increases the detection rate of delayed emptying.

39 Procedure (cont) Patient Supine
Place patient in supine position. Acquisition should be started as quickly as possible after ingestion of food Position camera anterior or LAO Instruct patient to remain motionless during imaging Obtain Patient images every 5 minutes up to 30 minutes, then every 15 minutes thereafter, allowing the patient to ambulate between images Or preset dynamic images for minutes. Patient remain motionless under camera Supine is good for checking esophageal reflux

40 Procedure (cont) Patient standing
Position patient standing or sitting, one image facing camera. Optional :one image with back to camera Obtain immediate images, then every 10 minutes Standing, sitting, then standing uses normal movement and gravity to aid realism in study

41 Procedure Liquid Study
Baseline Liquid Study Add 500 uci of 99mTc-DPA TO 120 ml, of water or orange juice Administer to patient PO, encourage patient to drink quickly. Images same as solid study, although only imaged for 1.5 hours Liquid GE tests are generally not clinically useful, because normal emptying of liquids is frequently maintained despite very severe gastroparesis for solids (41). Meals currently used for measuring GE consist of a variety of foods, including chicken liver, eggs, egg whites, oatmeal, or pancakes.

42 Normal Results Liquid (e.g., radiolabeled water or orange juice ) t1/2 (50%) at minutes ) or 80% in 1 hour Solid (Type and size of meals and population varies): t1/2 (50%) movement out the stomach within a lower limit of 32 minutes to an upper limit of 120 min with and adult mean of 90 min. Delayed GE (gastric retention) was determined to be >90% at 1 h, >60% at 2 h and>10% gastric retention at 4 h. Terminate study before 60 min if gastric emptying becomes > 95% <30% retention at 1 h (50) is indicative of rapid GE. For rapid GE, currently, the 1-h GE value is recommended.

43 Wireless motility capsule
Medications that alter gastric pH and gastric emptying should be discontinued ≥ 3-7 days before the WMC test. WMC has been FDA approved for evaluation of suspected gastroparesis and of colonic transit in the setting of chronic constipation.

44 A schematic representation of the patient procedure for performing a wireless motility capsule study. The WMC should not be administered to patients with a history of gastric bezoar, swallowing disorders, dysphagia to food or pills for any reason, suspected strictures or fistulae along the gastrointestinal tract, physiologic gastrointestinal obstruction, gastrointestinal surgery within the previous 3 months, Crohn's disease, diverticulitis, or an implanted or portal electromechanical medical device (eg, a cardiac pacemaker or infusion pump). The WMC is ingested immediately following ingestion of a standardized 260-kcal nutrient bar (SmartBar, which consists of 17% protein, 66% carbohydrate, 2% fat, and 3% fiber) and 50 mL of water. In order to avoid the potential effects of exercise on transit measurement, the patient is instructed to avoid strenuous or vigorous exercise during the testing period. Farmer A D et al. United European Gastroenterology Journal 2013;

45 The external appearance of the wireless motility capsule (a), which records pH, temperature, and pressure in real time as it traverses the GI tract in comparison to a wireless endoscopy capsule (b). A small (6" × 4" × 1.5") lightweight external data recorder containing a rechargeable battery is attached to a specially designed belt worn around the patient’s waist, and the patient is instructed to keep the data receiver within 5 feet of his or her body during the testing period (3–5 days). The patient is instructed regarding how to manually record activities such as meals, sleep, and bowel movements by pushing an event button on the data receiver. the WMC is not dissimilar to the WCE in that it is constructed of polyurethane and contains a battery that provides power to the capsule for at least 5 days.10 The WMC contains a high-frequency transmitter that broadcasts data in real time to an external receiver. The WMC has dimensions of 26.8 mm × 11.7 mm (vis-à-vis the wireless capsule endoscopy (WCE; PillCam; Given Imaging, Israel) measuring 26 × 11 mm). In contrast to the WMC, the WCE encompasses a miniature, encapsulated video camera designed to image the entire small bowel, taking approximately 50,000–60,000 digital images per study. Farmer A D et al. United European Gastroenterology Journal 2013;

46 A sample motility graph showing data from a wireless motility capsule
A sample motility graph showing data from a wireless motility capsule. Temperature, pH, and pressure measurements can be used to calculate gastric emptying, small bowel transit, colonic transit, and whole gut transit times, as well as other motility information. Immediately following ingestion of the WMC, there is an abrupt rise in recorded temperature from ambient temperature to normal body temperature (approximately 36°C). The WMC’s exit from the stomach is defined by an abrupt rise in pH (≥2 pH units), which corresponds to the capsule’s passage from the acidic environment of the stomach to the more alkaline environment of the proximal duodenum. the WMC, representing a nondigestible solid, has been shown to empty with return of phase 3 of the migrating motor complex, which occurs upon complete emptying of solid food from the stomach. Passage into the cecum is defined by a sustained (>10 minutes in duration) pH drop of at least 1 pH unit, which occurs as the WMC leaves the alkaline environment of the terminal ileum and enters the more acidic environment of the cecum. If the pH drop in the ileocecal junction is not evident, abrupt changes in pressure wave frequency or amplitude may provide supportive evidence of the transition from the small bowel to the colon. 75% of patients with a GET over 12 hours had a number of gastric contractions below the fifth percentile of normal, compared to 8% of patients with a GET less than 12 hours. When adding together WMC contractile activity by measuring areas under pressure curves, constipated patients with normal colonic transit (<59 hours) or mildly to moderately delayed transit (59–100 hours) exhibited contractility that was 33–50% higher than in healthy controls. This increase was most prominent in patients with constipation-predominant irritable bowel syndrome. In contrast, a preliminary evaluation of a cohort enriched with severely constipated patients found that profound delays in colonic transit (>100 hours) were associated with significantly reduced contractile activity. the WMC’s manufacturer defined rapid transit as a CTT less than 5 hours and delayed colonic transit as a CTT greater than 59 hours. In a postmarketing analysis of nearly 6,000 shipped capsules, there have been 20 reports of prolonged capsule retention (5 in the stomach, 2 in the small intestine, and 13 in the colon), which corresponds to a retention rate of 0.33%. An upper endoscopy was required for extraction of the 5 capsules that were retained in the stomach. Of the remaining 15 cases, only 1 capsule required drug intervention; the other 14 capsules passed spontaneously. There were no obstructions requiring surgical intervention.

47 Comparison of the various techniques, currently utilized, indicating their relative advantageous and disadvantageous features. Comparison of the various techniques, currently utilized, indicating their relative advantageous and disadvantageous features. Validation studies are extensive for scintigraphy. Results of breath test are unreliable in the presence of malabsorption, liver failure, pancreatic or pulmonary disorders. Farmer A D et al. United European Gastroenterology Journal 2013;

48 Clinical impact The association of delayed emptying with specific symptoms is relatively weak Gastric emptying tests do not yield a high diagnostic specificity With few exceptions, most studies have failed to demonstrate a correlation between the severity of delayed emptying and response to prokinetics An initial treatment approach should be required before performing gastric emptying test In refractory patients or in those with symptoms that impair nutritional status or the ability to function normally, assessment of gastric emptying may play a pivotal role Tack J et al. Best Pract Res Clin Gastroenterol. 2009

49 GERD-Gastric emptying study
Gastroparesis can be associated with and may aggravate GERD. Evaluation for the presence of gastroparesis should be considered in patients with GERD that is refractory to acid-suppressive treatment. Michael Camilleri et al. Clinical Guideline: Management of Gastroparesis. Am J Gastroenterol 2013

50 Treatment algorithm Pramlintide and GLP-1 analogs may delay gastric emptying in diabetics. Cessation of these treatments and use of alternative approaches should be considered before initiation of therapy for gastroparesis.

51

52 Dietary/Non-medical Poor evidence - Multiple small meals
Liquid instead of solid meals Low fat, Reduce indigestible fiber Discontinue medications that slow emptying if possible

53 Nutrition If oral intake is insuffi cient, then enteral alimentation by jejunostomy tube feeding should be pursued (after a trial of nasoenteric tube feeding). Indications for enteral nutrition include : unintentional loss of 10 % or more of the usual body weight during a period of 3 – 6 months repeated hospitalizations for refractory symptoms. Michael Camilleri et al. Clinical Guideline: Management of Gastroparesis. Am J Gastroenterol 2013

54 Antiemetics No evidence from controlled trials Phenothiazines
Prochlorperazine (Stemetil) Promethazine (Phenergan) Serotonin 5-HT3 antagonists Ondansetron (Zofran) Muscarinic antagonisits Butylscopolamine (Buscopan)

55 Prokinetics-algorithm
Metoclopramide (Maxalon) Only FDA approved drug for gastroparesis Erythromycin Domperidone (Motilium/Vomidon) Not FDA approved in US Cisapride (Prepulsid) Removed from market 2000 Cardiac toxicity

56 Pasricha et al. J Neurogastroenterol Motil, Vol.19

57 Endoscopic Therapy Venting PEG Botox injection – Pylorus
Pyloric Balloon Dilation (No published evidence) Temporary placement of stimulation leads in stomach to predict response to more permanent stimulator

58 Intrapyloric injection of Botox
23 patients (5 males, 19 idiopathic) underwent 2 UGIEs with 4 week interval Injection of saline (in 11 as first injection) or botox 4×25 U (in 12 patients) in a cross-over RCT Before the start of the study and 4 weeks after each treatment, they underwent a solid and liquid gastric emptying breath test with measurement of meal-related symptom scores, and filled out the GCSI GCSI is based on three subscales: post-prandial fullness/early satiety (4 items- stomach fullness, not able to finish a normal size meal, feeling excessively full after meals, loss of appetite); nausea/vomiting (3 items- nausea , rectching, vomitings), and bloating (2 items- bloating, stomach or belly visibly larger). Arts J et al. Aliment Pharmacol Ther. 2007

59 Intrapyloric injection of Botox
Significant improvement in emptying and GCSI was seen after initial injection of saline or botox. No further improvement occurred after the second injection No significant difference in improvements of solid t(1/2) and liquid t(1/2), meal-related symptom scores or GCSI In a cohort of predominantly idiopathic gastroparesis patients, botox is not superior to placebo in improving either symptoms or the rate of gastric emptying. although there is a need for further study in patients with documented “ pylorospasm. ” Arts J et al. Aliment Pharmacol Ther. 2007

60 Surgical Gastrostomy for venting and jejunostomy for feeding
Completion gastrectomy in markedly symptomatic PSG Pyloroplasty (± jejunal feeding tube placement) Subtotal gastrectomy + Roux-Y reconstruction for gastric atony due to PSG) Gastric Electrical Stimulation Cost prohibitive especially for TPN

61 Gastric Electric Stimulation
Gastric Neurostimulation (Enterra)  High Frequency (~ 4 x Slow Wave Freq) Low Energy with short pulse 12 bpm Frequency Gastric Pacing: Pacing is an application of an electrical stimulus that activates contraction of gastric smooth muscle, entraining at that rate of intrinsic slow wave by a low frequency high energy long pulse stimulation. Pacing needs implantation of too large and heavy batteries. Neurostimulation activates a nausea and vomiting control mechanism utilising a high frequency low energy short pulse stimulation to achieve symptomatic relief. Miniaturisation and implantation is possible with neurostimulation. 3 bpm  Low Frequency (~ Slow Wave Freq) High Energy with long pulse Energy

62 Mechanisms of action of gastric electrical stimulation
Unknown Gastric emptying not consistently improved Gastric dysrhythmias not normalised Increased gastric accommodation Increased vagal afferent activity Increased thalamic activity McCallum RW et al. Neurogastroenterol Motil 2013

63 Enterra therapy: Humanitarian device exemption
Enterra therapy was granted approval as a Humanitarian Use Device (HUD) to be used in patients with refractory diabetic or idiopathic gastroparesis, restricted to institutions where Institutional review board approval has been obtained FDA 2000

64 Enterra therapy CE mark Indication
Enterra therapy is indicated for the treatment of patients with chronic intractable (drug refractory) nausea and vomitings secondary to gastroparesis GES improves nausea and vomitings more than abdominal pain.

65 Copyright © 2014 American Medical Association. All rights reserved.
From: Gastric Electrical Stimulation:  An Alternative Surgical Therapy for Patients With Gastroparesis Arch Surg. 2005;140(9): doi: /archsurg Figure Legend: Diagrammatic representation of the laparoscopic placement technique showing trocar placement, lead placement in the stomach wall, and position of the subcutaneous pocket for the neurostimulator. Date of download: 1/30/2014 Copyright © 2014 American Medical Association. All rights reserved.

66 GES improves nausea an vomitings more than abdominal pain.

67 GES for the Treatment of Gastroparesis: A Meta-Analysis
13 papers Total Symptom Severity Score Requirement for Enteral or Parenteral Nutritional Support Vomiting Symptom Severity Score Change in Weight (kg) Nausea Symptom Severity Score Of 13 included studies, 12 lacked controls and only one was blinded and randomized. Following GES, patients reported improvements in total symptom severity score (3/13 studies, mean difference 6.52 ; P = 0.01), vomiting severity score, nausea severity score (4/13), SF-36 physical composite score (4/13), SF-36 mental composite score (4/13), requirement for enteral or parenteral nutrition (8/13), and 4-h gastric emptying (5/13, 12.7%). Weight gain did not reach significance (3/13, 3.68 kg [CI: -0.23, 7.58]; P = 0.07). The device removal or reimplantation rate was 8.3%. O’Grady G, et al. World J Surg 2009; 33:

68 GES for the Treatment of Gastroparesis: A Meta-Analysis
Complications 8.3 % (22/265 patients, 10/13 studies) Infection 8 Skin erosion 6 Pain at site 4 Gastric perforation 2 Device migration 1 Volvulus 1 O’Grady G, et al. World J Surg 2009; 33:

69 GES for the Treatment of Gastroparesis: A Meta-Analysis
A meta-analysis of 10 studies (n = 601) using high-frequency GES to treat patients with gastroparesis from January 1995 to January 2011 GES significantly improved both TSS (P < ) and gastric retention at 2 h (P = 0.003) and 4 h (P < ) in patients with diabetic gastroparesis (DG), while gastric retention at 2 h (P = 0.18) in idiopathic gastroparesis (IG) patients, and gastric retention at 4 h (P = 0.23) in postsurgical gastroparesis (PSG) patients, did not reach significance. High-frequency GES is an effective and safe method for treating refractory gastroparesis. DG patients seem the most responsive to GES, both subjectively and objectively, while the IG and PSG subgroups are less responsive and need further research. Chu H et al. J Gastroenterol Hepatol. 2012

70 Glucose Control in Diabetic gastroparesis Patients
HbA1c Reduction at 6 and 12 months vs. Baseline Baseline 8.6% Baseline 9.4% Baseline 9.8% At 6 mths At 12 mths 8.5% 8.4% 6.5% Forster et al: Further experience with gastric stimulation to treat drug refractory gastroparesis. Am J Surgery 2003; 186(6): Lin et al: Treatment of Diabetic Gastroparesis by High-Frequency Gastric Electrical Stimulation. Diabetes Care 2004; 27(5), Van Der Voort et al: Gastric Electrical Stimulation Results in Improved Metabolic Control in Diabetic Patients Suffering From Gastroparesis. Exp Clin Endocrinol Diabetes 2005; 113:38-42

71 Nutritional Support Lin et al: Treatment of Diabetic Gastroparesis by High-Frequency Gastric Electrical Stimulation. Diabetes Care 2004; 27(5),

72 Conclusion More studies on gastroparesis are warranted in India
WMC is as good and has advantages compared to gastric emptying scintigraphy, the gold standard GES is a good choice for refractory gastroparesis Treatment options are likely to improve after the pathophysiology of gastroparesis is better understood.

73 Thank you

74 WAVESS*: Study Design Multicenter double blind crossover
March 14-15, 1997 WAVESS*: Study Design Multicenter double blind crossover ON Random Baseline 1/2 Implant 1/2 OFF Phase I Phase II 1 2 6 12 Months N= Patients 17 diabetic 16 idiopathic * Worldwide Anti-Vomiting Electrical Stimulation Study Study Initiation Meeting USA, Washington 13

75 Gastric Electrical Stimulation
Enterra System (Medtronic)

76 The History of Gastric Stimulation
1972: Kelly and Laforce at Mayo Clinic induced antegrade and retrograde conduction of slow waves in canines with gastric stimulation. 1988: McCallum et al at University of Virginia showed increased gastric emptying in canines with vagotomy 1997: Familoni et al reported improved peristalsis in canines with GES 1998: The WAVESS study group demonstrated the feasibility of GES, leading to Enterra therapy.

77 The History of Gastric Stimulation
1963 – Bilgutay et al.: Gastric stimulation was practiced for the treatment of postoperative ileus.

78 Surgery Laparoscopy - 3 Ports
Left upper quadrant port becomes stimulator pocket Length of stay: 2-3 days Evaluate neurostimulator parameters before discharge

79 Lead Location Greater curvature Leads placed 10cm from pylorus
Utilize measuring tape or 10cm suture length Leads 1cm apart

80 One centimeter electrode length in stomach wall
Lead Placement Proximal anchoring point utilizing winged/trumpet anchor One centimeter electrode length in stomach wall

81 Lead Fixation Disc sutured to stomach wall 1-2 sutures
Lead suture wire clipped to disc 1-2 clips

82 Switch on and interrogation
Device is initiated remotely A system check is performed and impedance is checked Power setting is programmed and rechecked on discharge

83 Comparison of methods used to assess gastric emptying
Parkman et al. Neurogastroenterol Motil Feb

84 Gastroparesis: Pathophysiology
Excessive relaxation Poor antro-pyloro-duodenal synchronisation Antral hypomotility Abnormal duodenal motility


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