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Clinical response to gastric electrical stimulation in patients with postsurgical gastroparesis
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3:49 –54
Clinical Response to Gastric Electrical Stimulation in Patients With Postsurgical Gastroparesis RICHARD MCCALLUM,* ZHIYUE LIN,* PAUL WETZEL,* IRENE SAROSIEK,* and JAMESON FORSTER‡ Departments of *Medicine and ‡Surgery, University of Kansas Medical Center, Kansas City, Kansas
Background & Aims: The aim of this study was to report the long-term clinical response to high-frequency gastric electrical stimulation (GES) in 16 patients with postsurgical gastroparesis who failed standard medical therapy. Methods: Clinical data collected at baseline and after 6 and 12 months of GES included (1) severity and frequency of 6 upper gastrointestinal (GI) symptoms by using a 5-point symptom interview questionnaire and total symptom score, (2) health-related quality of life including physical composite score and mental composite score, (3) 4-hour standardized gastric emptying of a solid meal by scintigraphy, and (4) nutritional status. Results: The severity and frequency of all 6 upper GI symptoms, total symptom score, physical composite score, and mental composite score were significantly improved after 6 months and sustained at 12 months (P < .05). All patients had delayed gastric emptying at baseline. Gastric emptying was not significantly faster at 12 months, although 3 normalized. At implantation, 7 of 16 patients required nutritional support with a feeding jejunostomy tube; after GES, 4 were able to discontinue jejunal feeding. The mean number of hospitalization days was significantly reduced by a mean 25 days compared with the prior year. One patient had the device removed after 12 months because of infection around the pulse generator. Conclusions: Long-term GES significantly improved upper GI symptoms, quality of life, the nutritional status, and hospitalization requirements of patients with postsurgical gastroparesis. Although vagal nerve damage or disruption was part of the underlying pathophysiology, GES therapy was still effective and is a potential treatment option for the long-term management of postsurgical gastroparesis. A controlled clinical trial of GES for PSG patients (who are refractory to medical therapy) is indicated given these encouraging results.
upper gastrointestinal (GI) surgery.1–3 The incidence increases to as high as 50% in those with chronic gastric outlet obstruction before surgery.4,5 Other surgeries that are associated with delayed gastric emptying (GE) include Billroth I and II antral resections, Roux-en-Y gastrojejunostomy, fundoplication, esophagectomy with colon or gastric pull-up, and pylorus-preserving Whipple procedure.6 Associated symptoms include nausea, vomiting, early satiety, abdominal pain, and weight loss. Severe gastroparesis might result in recurrent hospitalizations, malnutrition, and significant mortality.1,7 Symptomatic management of PSG includes dietary manipulation and the combination of prokinetic and antiemetic agents.3,8,9 However, only metoclopramide and erythromycin are commercially available in the United States, and both have side effects that make them intolerable for more than 40% of patients.10 Without an antrum, medical therapies are less successful, and medications might not be reliably absorbed because of bezoar formation.6,11 In severe cases, patients might be placed on a liquid caloric diet. For patients who fail these therapies, surgical interventions are often contemplated.11 These include tube gastrostomy for gastric decompression and jejunostomy for enteral feedings. Total gastrectomy is reserved for intractable vomiting and weight loss after all other options have failed. This is usually in the patient after partial gastric resection with either a Billroth I or II with or without a Roux-en-Y reconstruction. Recently, gastric electrical stimulation (GES) has been investigated as a new approach for treatment of medically refractory gastroparesis.12,13 Several studies have shown that GES by an implantable device with high-frequency
ostsurgical gastroparesis (PSG), identified as a chronic form of gastric atony in the absence of mechanical obstruction that results from disruption of the normal mechanisms that govern gastric motility, develops in up to 10% of patients who undergo vagotomy (either deliberate or inadvertent) as part of their
Abbreviations used in this paper: GE, gastric emptying; GES, gastric electrical stimulation; HQOL, health-related quality of life; MCS, mental composite score; PCS, physical composite score; PSG, postsurgical gastroparesis; TPN, total parenteral nutrition. © 2005 by the American Gastroenterological Association 1542-3565/05/$30.00 PII: 10.1053/S1542-3565(04)00605-6
P
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(12 cycles/min) and low-energy stimulation parameters (330 s and 5 mA) produced a significant and sustained improvement in symptoms and nutritional status in most patients with intractable symptomatic gastroparesis.14 –18 On the basis of the WAVESS data,16 the US Food and Drug Administration approved GES with high frequency and low energy parameters (ENTERRA Therapy System; Medtronic, Minneapolis, MN) in March 2000 under a Humanitarian Device Exemption for symptomatic relief in patients with diabetic and idiopathic gastroparesis, but not for postsurgical etiologies.19 There are only 2 preliminary reports of GES therapy in patients with PSG.20,21 However, these 2 studies are performed in a small group of PSG patients with various durations of GES therapy, thus underpowering the statistical analysis of the clinical effects of GES. In this present report, we analyzed the clinical response after 12 months of GES therapy in patients with PSG, including symptoms, health-related quality of life (HQOL), nutritional status, and GE.
Methods Patients There were 16 patients (15 women and 1 man; mean age, 46 years; range, 21– 66 years) who underwent GES implantation for documented refractory PSG between 2000 and 2003 at the University of Kansas Medical Center, Kansas City, Kansas. The key inclusion criteria were (1) documented diagnosis of gastroparesis for more than 1 year and refractoriness to antiemetics and prokinetics; (2) more than 7 emetic episodes per week; (3) in the setting of fundoplication where patients can not vomit then chronic daily nausea was the criterion; and (4) delayed GE (gastric retention greater than 60% at 2 hours and greater than 10% at 4 hours) based on a 4-hour standardized radionuclide solid meal.22 Patients were excluded if they had organic obstruction or pseudo-obstruction, primary eating or swallowing disorders, chemical dependency, positive pregnancy test result, or psychogenic vomiting. The study protocol was approved by the Human Subjects Committee at University of Kansas Medical Center, and written consent forms were obtained from all subjects before the study.
Study Protocol This study consisted of (1) a baseline (the 4-week period before surgery) evaluation of medical history and upper GI symptoms, GE test, HQOL, assessment of nutritional status, pregnancy testing, and blood chemistries to determine the qualification for enrollment; (2) surgical placement of the GES system by laparotomy as previously described if the stomach is intact15,16 or position of the 2 electrodes in the muscularis propria of the greater curvature at 2 and 3 cm proximal to the gastric anastomosis in the case of antrectomy; (3) removal of any parenteral nutrition, gastric decompression
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devices, or gastrically placed jejunal feeding tubes and (4) in cases of malnutrition placement of a feeding jejunostomy tube if not already in place; and (5) follow-up at 6 and 12 months after implantation to repeat baseline measurements. In addition, adverse events, including hospitalizations, were monitored throughout the follow-up period. The detailed descriptions of the GES system and surgical and stimulation techniques have been published previously.15,16
Assessment of Symptoms Each patient completed a Symptoms Interview Form at baseline and at 6- and 12-month follow-up visits. This form assessed the symptoms of gastroparesis occurring during the last 2 weeks before the interview for severity and frequency of vomiting, nausea, early satiety, bloating, postprandial fullness, and epigastric pain. The severity of each symptom was graded by the patients as 0, absent; 1, mild (not influencing the usual activities); 2, moderate (diverting from, but not urging modifications of, usual activities); 3, severe (influencing usual activities, severely enough to urge modifications); and 4, extremely severe (requiring bed rest). Also the frequency of each symptom was graded as 0, absent; 1, rare (1/wk); 2, occasional (2–3/wk); 3, frequent (4 – 6/wk); and 4, extremely frequent (ⱖ7/wk). The sum of the severity ratings of the 6 symptom subscores comprised the overall total symptom score (TSS) for severity, and the sum of the frequency ratings of the 6 symptom subscores comprised the overall TSS for frequency.
Assessment of Health-Related Quality of Life HQOL was assessed by using the previously validated SF-36 Health Status Survey (acute) questionnaire.23 Two summary scores were derived from the 8 subscores of the SF-36 questionnaire and reported as the physical composite score (PCS) and the mental composite score (MCS). PCS and MCS are norm-based measures for which the mean ⫾ standard deviation for the general US population is 50 ⫾ 10.24
Measurement of Gastric Emptying GE scintigraphy was performed in the morning after an overnight fast as previously described22 with prokinetics stopped for at least 3 days. This standardized method for GE consists of a scrambled egg substitute (120 g of Free Cholesterol & Fat Free Egg; Sunny Fresh Foods, Inc, Monticello, MN) (60 kcal) labeled with 99m Tc sulfur-colloid (1 mCi), 2 slices of whole wheat bread (120 kcal), 30 g jelly (75 kcal), and 120 mL of water.22 The meal has a total caloric value of 255 kcal (nutritional composition: 72% carbohydrate, 24% protein, 2% fat, and 2% fiber). Anterior and posterior images of the stomach were taken immediately after eating and then hourly for 4 hours. Gastric retention of gamma counts was calculated by the Department of Nuclear Medicine by using geometric and decay correction. Delayed GE was defined as the percentage of gastric retention equal to or greater than 60% at 2 hours and equal to or greater than 10% at 4 hours or both.22
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Table 1. Patient Demographics and Baseline Measures 1 y before GES Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Age (y)
Sex
BMI (kg/m2)
Years of gastroparesis
Gastric retention at 4 hr (%)
Days in hospital
Weight loss (lb)
66 60 64 31 45 46 57 21 37 49 34 27 36 53 58 49 46 ⫾ 3
F F F M F F F F F F F F F F F F
25.2 18.0 17.2 30.8 23.5 33.2 20.4 14.0 33.8 31.8 21.3 22.7 28.2 18.0 25.9 18.6 23.9 ⫾ 1.6
2 4 33 3 10 4 1.5 3.5 1.5 2 1 1.5 3.5 15 2 1.5 5.6 ⫾ 2.0
35 88 22 56 32 33 43 34 57 28 N/A (vomited) 75 78 93 52 75 52.0 (34.0–75.0)
0 16 0 30 50 0 16 7 40 0 100 0 200 30 0 0 31 ⫾ 13
35 30 30 30 20 0 40 14 40 50 48 40 60 30 0 0 30 ⫾ 4
Nutritional support
J-tube J-tube TPN J-tube
TPN J-tube J-tube J-tube
NOTE. GE results (% retention) are reported as median and interquartile range. All other measures are reported as means ⫾ standard errors. BMI, body mass index; J-tube, jejunostomy tube; N/A, not available; TPN, total parenteral nutrition.
Statistical Analysis The symptom subscores, TSS, PCS, MCS, body weight, and hospitalization days, reported as means ⫾ standard error, at baseline and at 6 and 12 months of GES were compared by analysis of variance and paired t test analysis. The Wilcoxon signed rank test was used for paired comparison of GE. Results of GE are reported as median and interquartile range. Statistical significance was assigned for P value ⬍.05.
Results Baseline Demographics The mean duration of gastroparetic symptoms was 5.6 years (range, 1–33 years). On average the patients had lost 13.6 kg (range, 0 –27.2 kg) and were hospitalized for a mean of 31 days (range, 0 –200 days) in the year before the GES. Six patients were enterally supplemented through a variety of feeding tubes, and 2 were receiving total parenteral nutrition (TPN). Fifteen patients had delayed solid GE at baseline (Table 1). The remaining patient could not complete the GE study because of vomiting, but she was included in this study on the basis of her clinical history and prior abnormal GE results from an outside medical center. The specific surgical procedures that preceded their symptoms and documented gastroparesis in these 16 PSG patients are as follows: Nissen fundoplication (5), vagotomy and pyloroplasty (3), Billroth I and vagotomy (2), Billroth II and vagotomy (2), cholecystectomy (1), spinal surgery (2), and esophagectomy with colonic interposition (2).
Upper Gastrointestinal Symptoms The results of upper GI symptoms are summarized in Table 2. In comparison with baseline, all 6 mean symptom severity subscores (vomiting, nausea, early satiety, bloating, postprandial fullness, and epigastric pain) decreased ⬎50% at 6 months of GES. The mean severity of nausea and epigastric pain also decreased ⬎50% at 12 months compared to baseline. Both total symptom severity and frequency were significantly reduced at 6 months of GES and sustained at 12 months compared to the initial baseline (P ⬍ .05). In reviewing the Symptom Interview Form at 12 months of follow-up, 10 patients (63%) had a ⬎50% decrease in TSS. Health-Related Quality of Life At baseline, mean PCS and MCS scores (28.6 and 39.7, respectively; Table 2) were substantially below the US norm (50 ⫾ 10),23 and both scores significantly improved at 6 and 12 months (P ⬍ .05). The majority of the improvement was observed within the first 6 months. Specifically, the MCS increased to 49.1 at 6 months, approaching normal. Hospitalizations Hospitalizations for gastroparesis symptoms averaged 31 ⫾ 13 days (range, 0 –200 days) for the year before receiving GES therapy. This average significantly decreased to 6 ⫾ 2 days (range, 0 –29 days) (P ⬍ .05)
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Table 2. Summary of Results of Upper GI Symptom Severity and Frequency, HQOL, and GE at Baseline, 6 and 12 Months After Receiving GES Therapy Severity score (0–4)
Baseline (n ⫽ 16)
6 mo of GES (n ⫽ 16)
12 mo (n ⫽ 16)
Vomiting Nausea Early satiety Bloating Postprandial fullness Epigastric pain TSS of severity (0–24) Frequency score (0–4) Vomiting Nausea Early satiety Bloating Postprandial fullness Epigastric pain TSS of frequency (0–24) HQOL PCS MCS Gastric retention (%) At 2 hours (range) At 4 hours (range)
2.0 ⫾ 0.5 3.4 ⫾ 0.2 2.9 ⫾ 0.2 3.1 ⫾ 0.2 2.9 ⫾ 0.2 2.6 ⫾ 0.3 17.1 ⫾ 0.7 Baseline (n ⫽ 16) 2.1 ⫾ 0.5 3.9 ⫾ 0.1 3.7 ⫾ 0.2 3.4 ⫾ 0.2 3.5 ⫾ 0.2 2.7 ⫾ 0.4 19.2 ⫾ 0.7 Baseline (n ⫽ 16) 28.6 ⫾ 2.1 39.7 ⫾ 3.1 Baseline (n ⫽ 15) 81.0 (70.0–92.0) 52.0 (34.0–75.0)
0.5 ⫾ 0.2a 1.4 ⫾ 0.3a 1.3 ⫾ 0.3a 1.3 ⫾ 0.3a 1.3 ⫾ 0.4a 1.1 ⫾ 0.3a 6.9 ⫾ 1.3a 6 mo of GES (n ⫽ 16) 0.6 ⫾ 0.3a 1.8 ⫾ 0.3a 1.3 ⫾ 0.3a 1.6 ⫾ 0.4a 1.8 ⫾ 0.4a 1.1 ⫾ 0.3a 7.9 ⫾ 1.3a 6 mo of GES (n ⫽ 16) 40.2 ⫾ 1.9a 49.1 ⫾ 3.6a 6 mo (n ⫽ 12) 67.0 (51.0–87.0) 34.0 (25.0–65.0)
1.1 ⫾ 0.3a 1.4 ⫾ 0.2a 1.7 ⫾ 0.4a 1.6 ⫾ 0.4a 1.6 ⫾ 0.3a 0.8 ⫾ 0.3a 8.6 ⫾ 1.5a 12 mo (n ⫽ 16) 1.2 ⫾ 0.3a 1.8 ⫾ 0.3a 2.2 ⫾ 0.4a 1.7 ⫾ 0.4a 1.8 ⫾ 0.4a 1.3 ⫾ 0.4a 9.8 ⫾ 1.5a 12 mo (n ⫽ 15) 37.7 ⫾ 2.7a 49.6 ⫾ 3.2a 12 mo (n ⫽ 13) 66.0 (51.0–90.0) 40.0 (19.0–73.0)
aP
⬍ .05 compared to baseline.
during the first year of GES, and 8 patients (50%) required no hospital admissions. Gastric Emptying Although both 2- and 4-hour median gastric retention at 6 and 12 months was numerically less than that at baseline, they were not statistically different (Table 2). Of the 13 patients who completed the GE test at 12 months, 3 (23%) did normalize their GE, whereas all others remained delayed including 4 patients (31%) whose gastric retention actually worsened. Of the 3 patients with no GE results at 12 months, one did not finish because of vomiting 1 hour after eating test meal, one was too sick to undergo the test, and one was interviewed by telephone. Nutritional Status At implantation, 7 of 16 patients required nutritional support in the form of a feeding jejunostomy tube. Of these 7 patients, 4 were able to discontinue the jejunal feeding at 2, 4, 6, and 11 months after GES, and 3 still required supplemental feeding at 12 months. Average body weight increased by more than 3 kg at 6 months and continued at 12 months (60.8 ⫾ 4.7 kg vs 64.2 ⫾ 4.5 kg vs 64.5 ⫾ 4.3 kg, respectively; P ⬍ .05 compared to baseline). Adverse Events Related to Gastric Electrical Stimulation Therapy One patient had the device removed after 12 months because of infection in the pocket of the pulse
generator. One patient had the implanted GES system replaced at 23 months postoperatively as a result of her involvement in an accident because the electrodes were detached from the gastric muscle by the trauma. Her symptoms reappeared 7 days after the accident, and the load impedance was found to be increased and exceed the upper limit. The abdominal x-ray showed dislodgment of the proximal lead from its original location in the gastric smooth muscle. On re-exploration, there was confirmation that one of the leads had become detached. The device and electrodes were replaced, and her symptoms improved very soon after replacement of the GES system, and the load impedance returned to normal.
Discussion The patients in this study had a variety of surgical procedures. However, the outcome was documented PSG, characterized by delayed GE and postprandial nausea and vomiting. Although the operations differed, all had undergone a procedure that involved either a known vagotomy or the potential for accidental injury to the vagus verve. They all had failed to respond to prokinetic agents, and ultimately they had a GES system implanted and received high frequency GES for at least 1 year. Previous studies have investigated the efficacy of high frequency GES in improvement of upper GI symptoms and quality of life in patients with severe gastroparesis as a result of diabetes or with idiopathic etiology.14 –18 There are only 2 preliminary publications reporting the
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results of GES in patients with PSG.20,21 The first only included 5 PSG patients followed for up to 6 months, and there was no statistical analysis included in that study.20 The second reported our initial experience with 12 PSG patients with various follow-up times (3 months–1 year).21 Therefore, the present study is the first to investigate the effects of high frequency GES in a relatively large group of patients with PSG for more than a 12-month period. Our results showed that long-term GES improved the upper GI symptoms and HQOL as well as nutritional support and the need for hospitalizations. These results are consistent with previous studies on the effects of GES in patients with diabetic or idiopathic gastroparesis.14 –18 The mean gastric retention measured by a standardized 4-hour scintigraphy of a solid meal was not significantly reduced at 6 or 12 months. The 4-hour gastric retention at 6 and 12 months was still 4 times normal value, ie, markedly delayed. This observation is in agreement with previous reports,16,18 indicating no association between changes in symptoms and GE in patients with gastroparesis treated with high frequency GES. Individually, only 23% of patients evaluated at 12 months of GES had their 2- or 4-hour gastric retention reduced to a normal value. In contrast, McCallum et al.25 showed that low frequency and high energy GES for a period of 1–3 months significantly improved GE and returned the majority of patients with gastroparesis (67%) to normal, as well as reversing gastric dysrhythmia with enhancement of the gastric slow waves. The major difference between these 2 studies was the stimulation parameters used. This suggests in the future that different stimulation parameters will be needed to reverse dysmotility in PSG. The mechanisms by which the upper GI symptoms in PSG patients were improved with GES remain to be elucidated. Short-pulse GES, similar to the parameters used in this study, was evaluated in a canine model by using vasopressin to induce gastric dysrhythmias and vomiting in both intact and vagotomized dogs.26 Shortpulse stimulation produced a significant reduction in vomiting in intact animals but not in those with acute vagotomy. This observation might suggest that the antiemetic effect of short-pulse stimulation was vagally mediated. The results of this present study and earlier clinical observations,17,20,25 however, indicate that GES is also effective in relieving symptoms in patients with PSG, including those with vagotomy, suggesting that the effects of GES might not be solely vagally mediated. Diabetic patients with gastroparesis have benefited symptomatically from GES therapy in a double-blind
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trial16 utilizing GES in the same parameters as our trial, as well as in another study utilizing different parameters (low frequency and high energy) in which stimulation of gastric smooth muscle also improved GE.25 The advanced diabetic patients treated in both of these reports frequently had accompanying vagal dysfunction. This provides further evidence that GES is still effective even without normal vagal nerve innervation or function. This study was not placebo controlled, so we cannot rule out that the impressive response observed after GES might represent a placebo response. In diabetic and idiopathic patients, a double-blind study did show that 1-month GES resulted in significantly better symptom improvement than 1-month sham,16 and further reports indicated that this symptomatic response to GES is sustained in the majority of initial responders.17,18 Also in the present study our patients had failed all medical therapy, and the ability of GES therapy to induce a sustained clinical improvement and quality of life for more than 12 months exceeds any placebo expectations or possibilities. In our initial study of high frequency GES in patients with gastroparesis, we performed serosal recordings of gastric electrical activity and concluded that high frequency GES did not normalize dysrhythmias while still achieving symptom reduction.27 Mechanisms other than motor stimulation have been proposed to explain the reductions in nausea and vomiting and include adrenergic and cholinergic functions,28 fundic relaxation,29 GI hormones,30 and afferent brain stem pathways.31 It would have to be hypothesized in our patients that the afferent pathways to the brain are explained by regrowth of the vagal nerve fibers or the development of collaterals, or that afferent signals are ascending via the sympathetic nervous system. In conclusion, long-term GES significantly improved the severity and frequency of upper GI symptoms, quality of life, and nutritional and hospitalization status of patients with postsurgical gastroparesis refractory to medical therapy. Although vagal nerve damage was part of the underlying pathophysiology in these patients, GES therapy was still effective and is a potential treatment for the long-term management of postsurgical gastroparesis. A controlled clinical trial of GES for PSG patients (who are refractory to medical therapy) is indicated given these encouraging results.
References 1. Eckhauser FE, Conrad M, Knol JA, et al. Safety and long-term durability of completion gastrectomy in 81 patients with postsurgical gastroparesis syndrome. Am Surg 1998;64:711–716. 2. Azproz F, Malagelada J-R. Gastric tone measured by an electronic barostat in heath and postsurgical gastroparesis. Gastroenterology 1987;82:934 –943.
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3. Kendall BJ, McCallum RW. Gastroparesis and the current use of prokinetic drugs. Gastroenterologist 1993;1:107–114. 4. Polepalle C, Valenzuela G, McCallum RW. Predicting gastric stasis after surgery for peptic ulcer. Am J Gastroenterol 1989;84:A112. 5. McCallum RW, Polepalle SC, Schirmer B. Completion gastrectomy for refractory gastroparesis following surgery for peptic ulcer disease: long-term follow-up with subjective and objective parameters. Dig Dis Sci 1991;36:1556 –1561. 6. McCallum RW, George SJ: Review: gastroparesis. Clinical Perspectives in Gastroenterology 2001;4:147–154. 7. McElhinney C, Sarosiek I, Lin Z, et al. Comparison of hospitalizations, medications, and quality of life in patients receiving gastric electrical stimulation (GES) therapy for severe gastroparesis (abstract). Gastroenterology 2002;122:A-82. 8. Rabine JC, Barnett JL. Management of the patients with gastroparesis. J Clin Gastroenterol 2001;32:11–18. 9. Camilleri M. Appraisal of medium- and long-term treatment of gastroparesis and chronic intestinal dysmotility. Am J Gastroenterol 1994;89:1769 –1774. 10. Sturm A, Holtmann G, Goebell H, et al. Prokinetics in patients with gastroparesis: a systematic analysis. Digestion 1999;60: 422– 427. 11. Jones MP, Maganti K. A systematic review of surgical therapy for gastroparesis. Am J Gastroenterol 2003;98:2122–2129. 12. Lin ZY, Forster J, Sarosiek I, et al. Review article: treatment of gastroparesis with electrical stimulation. Dig Dis Sic 2003;48: 837– 848. 13. Bortolotti M. The “electrical way” to cure gastroparesis. Am J Gastroenterol 2002;97:1874 –1883. 14. Familoni BO, Abell TL, Nemoto D, et al. Electrical stimulation at a frequency higher than basal rate in human stomach. Dig Dis Sci 1997;42:885– 891. 15. Forster J, Sarosiek I, Delcore R, et al. Gastric pacing is a new surgical treatment for gastroparesis. Am J Surg 2001;182: 676 – 681. 16. Abell T, McCallum RW, Hocking M, et al. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003;125:421– 428. 17. Abell TL, Cutsem EV, Abrahamsson H, et al. Gastric electrical stimulation in intractable symptomatic gastroparesis. Digestion 2002;66:204 –212. 18. Lin Z, Forster J, Sarosiek I, et al. Treatment of diabetic gastroparesis by high-frequency gastric electrical stimulation. Diabetes Care 2004;27:1071–1076. 19. US Food and Drug Administration. H990014-Enterra Therapy System (formerly named Gastric Electrical Stimulation (GES) system). Issued March 31, 2000. Available at: http://www.fda.gov/ cdrh/ode/H990014sum.html. 20. Luo J, Abell TL, Eaton P, et al. Gastric electrical stimulation improves both GI symptoms and gastric emptying in patients with “postsurgical” gastroparesis. Gastroenterology 1999;116:A1332.
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21. Forster J, Lin ZY, Sarosiek I, et al. Clinical response to long-term gastric electrical stimulation in patients with post-surgical gastroparesis. Gastroenterology 2004;126:A-807. 22. Tougas G, Eaker EY, Abell TL, et al. Assessment of gastric emptying using a low fat meal: establishment of international control values. Am J Gastroenterol 2000;95:1456 –1462. 23. Ware JE Jr. SF-36 Health Survey: manual and interpretation guide. Boston, MA: The Health Institute, New England Medical Center, 1993. 24. Ware JE, Kosinski M, Keller SD. SF-36 Physical and Mental Health Summary Scales: a user’s manual. Boston, MA: Health Assessment Lab, 1994. 25. McCallum RW, Chen JDZ, Lin ZY, et al. Gastric pacing improves emptying and symptoms in patients with gastroparesis. Gastroenterology 1998;114:456 – 461. 26. Chen JDZ, Qian L, Ouyang H, et al. Gastric electrical stimulation with short pulses reduces vomiting but not dysrhythmias in dogs. Gastroenterology 2003;124:401– 409. 27. Lin ZY, Forster J, Sarosiek I, et al. Effect of high-frequency electrical stimulation on gastric myoelectric activity in gastroparetic patients. Neurogastroenterol Motil 2004;16:205–212. 28. Luo J, Rashed H, Eaton P, et al. Long-term treatment of gastric electrical stimulation is associated with autonomic and enteric nervous system changes (abstract). Dig Dis Sci 2000;45:1244. 29. Tack J, Coulie B, Van Cutsem E, et al. The influence of gastric electrical stimulation on proximal gastric motor and sensory function in severe idiopathic gastroparesis (abstract). Gastroenterology 1999;116:G4733. 30. Al-Jubiri A, Luo J, Rashed H, et al. Gastric electrical stimulation is associated with increased pancreatic synthetic function when compared to normals and medical controls (abstract). Gastroenterology 2001;120:A647. 31. Tougas G, Huizinga JD. Gastric pacing as a treatment for intractable gastroparesis: shocking news? Gastroenterology 1998;114: 598 – 601.
Address requests for reprints to: Richard W. McCallum, MD, Department of Medicine, Mail stop: 1058, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160. e-mail: [email protected]; fax: (913)-588-3856. Portions of the study were presented in abstract format at the American Gastroenterological Association meeting in 2004. The authors would like to acknowledge the following individuals for their contributions: Sara Durham, Suzanne Denton, and Katherine Roeser as well as faculty, fellows, and nursing staff in the Division of Gastroenterology, Janet Kelly, RN, the operating room staff, and surgical residents. We also wish to acknowledge Dr Twillman in psychology and pain management and the faculty and staff of the Nuclear Medicine Department. We also thank Warren Starkebaum, PhD, at Medtronic as well as the Medtronic Gastroenterology Group.
Clinical Response to Gastric Electrical Stimulation in Patients With Postsurgical Gastroparesis RICHARD MCCALLUM,* ZHIYUE LIN,* PAUL WETZEL,* IRENE SAROSIEK,* and JAMESON FORSTER‡ Departments of *Medicine and ‡Surgery, University of Kansas Medical Center, Kansas City, Kansas
Background & Aims: The aim of this study was to report the long-term clinical response to high-frequency gastric electrical stimulation (GES) in 16 patients with postsurgical gastroparesis who failed standard medical therapy. Methods: Clinical data collected at baseline and after 6 and 12 months of GES included (1) severity and frequency of 6 upper gastrointestinal (GI) symptoms by using a 5-point symptom interview questionnaire and total symptom score, (2) health-related quality of life including physical composite score and mental composite score, (3) 4-hour standardized gastric emptying of a solid meal by scintigraphy, and (4) nutritional status. Results: The severity and frequency of all 6 upper GI symptoms, total symptom score, physical composite score, and mental composite score were significantly improved after 6 months and sustained at 12 months (P < .05). All patients had delayed gastric emptying at baseline. Gastric emptying was not significantly faster at 12 months, although 3 normalized. At implantation, 7 of 16 patients required nutritional support with a feeding jejunostomy tube; after GES, 4 were able to discontinue jejunal feeding. The mean number of hospitalization days was significantly reduced by a mean 25 days compared with the prior year. One patient had the device removed after 12 months because of infection around the pulse generator. Conclusions: Long-term GES significantly improved upper GI symptoms, quality of life, the nutritional status, and hospitalization requirements of patients with postsurgical gastroparesis. Although vagal nerve damage or disruption was part of the underlying pathophysiology, GES therapy was still effective and is a potential treatment option for the long-term management of postsurgical gastroparesis. A controlled clinical trial of GES for PSG patients (who are refractory to medical therapy) is indicated given these encouraging results.
upper gastrointestinal (GI) surgery.1–3 The incidence increases to as high as 50% in those with chronic gastric outlet obstruction before surgery.4,5 Other surgeries that are associated with delayed gastric emptying (GE) include Billroth I and II antral resections, Roux-en-Y gastrojejunostomy, fundoplication, esophagectomy with colon or gastric pull-up, and pylorus-preserving Whipple procedure.6 Associated symptoms include nausea, vomiting, early satiety, abdominal pain, and weight loss. Severe gastroparesis might result in recurrent hospitalizations, malnutrition, and significant mortality.1,7 Symptomatic management of PSG includes dietary manipulation and the combination of prokinetic and antiemetic agents.3,8,9 However, only metoclopramide and erythromycin are commercially available in the United States, and both have side effects that make them intolerable for more than 40% of patients.10 Without an antrum, medical therapies are less successful, and medications might not be reliably absorbed because of bezoar formation.6,11 In severe cases, patients might be placed on a liquid caloric diet. For patients who fail these therapies, surgical interventions are often contemplated.11 These include tube gastrostomy for gastric decompression and jejunostomy for enteral feedings. Total gastrectomy is reserved for intractable vomiting and weight loss after all other options have failed. This is usually in the patient after partial gastric resection with either a Billroth I or II with or without a Roux-en-Y reconstruction. Recently, gastric electrical stimulation (GES) has been investigated as a new approach for treatment of medically refractory gastroparesis.12,13 Several studies have shown that GES by an implantable device with high-frequency
ostsurgical gastroparesis (PSG), identified as a chronic form of gastric atony in the absence of mechanical obstruction that results from disruption of the normal mechanisms that govern gastric motility, develops in up to 10% of patients who undergo vagotomy (either deliberate or inadvertent) as part of their
Abbreviations used in this paper: GE, gastric emptying; GES, gastric electrical stimulation; HQOL, health-related quality of life; MCS, mental composite score; PCS, physical composite score; PSG, postsurgical gastroparesis; TPN, total parenteral nutrition. © 2005 by the American Gastroenterological Association 1542-3565/05/$30.00 PII: 10.1053/S1542-3565(04)00605-6
P
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(12 cycles/min) and low-energy stimulation parameters (330 s and 5 mA) produced a significant and sustained improvement in symptoms and nutritional status in most patients with intractable symptomatic gastroparesis.14 –18 On the basis of the WAVESS data,16 the US Food and Drug Administration approved GES with high frequency and low energy parameters (ENTERRA Therapy System; Medtronic, Minneapolis, MN) in March 2000 under a Humanitarian Device Exemption for symptomatic relief in patients with diabetic and idiopathic gastroparesis, but not for postsurgical etiologies.19 There are only 2 preliminary reports of GES therapy in patients with PSG.20,21 However, these 2 studies are performed in a small group of PSG patients with various durations of GES therapy, thus underpowering the statistical analysis of the clinical effects of GES. In this present report, we analyzed the clinical response after 12 months of GES therapy in patients with PSG, including symptoms, health-related quality of life (HQOL), nutritional status, and GE.
Methods Patients There were 16 patients (15 women and 1 man; mean age, 46 years; range, 21– 66 years) who underwent GES implantation for documented refractory PSG between 2000 and 2003 at the University of Kansas Medical Center, Kansas City, Kansas. The key inclusion criteria were (1) documented diagnosis of gastroparesis for more than 1 year and refractoriness to antiemetics and prokinetics; (2) more than 7 emetic episodes per week; (3) in the setting of fundoplication where patients can not vomit then chronic daily nausea was the criterion; and (4) delayed GE (gastric retention greater than 60% at 2 hours and greater than 10% at 4 hours) based on a 4-hour standardized radionuclide solid meal.22 Patients were excluded if they had organic obstruction or pseudo-obstruction, primary eating or swallowing disorders, chemical dependency, positive pregnancy test result, or psychogenic vomiting. The study protocol was approved by the Human Subjects Committee at University of Kansas Medical Center, and written consent forms were obtained from all subjects before the study.
Study Protocol This study consisted of (1) a baseline (the 4-week period before surgery) evaluation of medical history and upper GI symptoms, GE test, HQOL, assessment of nutritional status, pregnancy testing, and blood chemistries to determine the qualification for enrollment; (2) surgical placement of the GES system by laparotomy as previously described if the stomach is intact15,16 or position of the 2 electrodes in the muscularis propria of the greater curvature at 2 and 3 cm proximal to the gastric anastomosis in the case of antrectomy; (3) removal of any parenteral nutrition, gastric decompression
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devices, or gastrically placed jejunal feeding tubes and (4) in cases of malnutrition placement of a feeding jejunostomy tube if not already in place; and (5) follow-up at 6 and 12 months after implantation to repeat baseline measurements. In addition, adverse events, including hospitalizations, were monitored throughout the follow-up period. The detailed descriptions of the GES system and surgical and stimulation techniques have been published previously.15,16
Assessment of Symptoms Each patient completed a Symptoms Interview Form at baseline and at 6- and 12-month follow-up visits. This form assessed the symptoms of gastroparesis occurring during the last 2 weeks before the interview for severity and frequency of vomiting, nausea, early satiety, bloating, postprandial fullness, and epigastric pain. The severity of each symptom was graded by the patients as 0, absent; 1, mild (not influencing the usual activities); 2, moderate (diverting from, but not urging modifications of, usual activities); 3, severe (influencing usual activities, severely enough to urge modifications); and 4, extremely severe (requiring bed rest). Also the frequency of each symptom was graded as 0, absent; 1, rare (1/wk); 2, occasional (2–3/wk); 3, frequent (4 – 6/wk); and 4, extremely frequent (ⱖ7/wk). The sum of the severity ratings of the 6 symptom subscores comprised the overall total symptom score (TSS) for severity, and the sum of the frequency ratings of the 6 symptom subscores comprised the overall TSS for frequency.
Assessment of Health-Related Quality of Life HQOL was assessed by using the previously validated SF-36 Health Status Survey (acute) questionnaire.23 Two summary scores were derived from the 8 subscores of the SF-36 questionnaire and reported as the physical composite score (PCS) and the mental composite score (MCS). PCS and MCS are norm-based measures for which the mean ⫾ standard deviation for the general US population is 50 ⫾ 10.24
Measurement of Gastric Emptying GE scintigraphy was performed in the morning after an overnight fast as previously described22 with prokinetics stopped for at least 3 days. This standardized method for GE consists of a scrambled egg substitute (120 g of Free Cholesterol & Fat Free Egg; Sunny Fresh Foods, Inc, Monticello, MN) (60 kcal) labeled with 99m Tc sulfur-colloid (1 mCi), 2 slices of whole wheat bread (120 kcal), 30 g jelly (75 kcal), and 120 mL of water.22 The meal has a total caloric value of 255 kcal (nutritional composition: 72% carbohydrate, 24% protein, 2% fat, and 2% fiber). Anterior and posterior images of the stomach were taken immediately after eating and then hourly for 4 hours. Gastric retention of gamma counts was calculated by the Department of Nuclear Medicine by using geometric and decay correction. Delayed GE was defined as the percentage of gastric retention equal to or greater than 60% at 2 hours and equal to or greater than 10% at 4 hours or both.22
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Table 1. Patient Demographics and Baseline Measures 1 y before GES Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Age (y)
Sex
BMI (kg/m2)
Years of gastroparesis
Gastric retention at 4 hr (%)
Days in hospital
Weight loss (lb)
66 60 64 31 45 46 57 21 37 49 34 27 36 53 58 49 46 ⫾ 3
F F F M F F F F F F F F F F F F
25.2 18.0 17.2 30.8 23.5 33.2 20.4 14.0 33.8 31.8 21.3 22.7 28.2 18.0 25.9 18.6 23.9 ⫾ 1.6
2 4 33 3 10 4 1.5 3.5 1.5 2 1 1.5 3.5 15 2 1.5 5.6 ⫾ 2.0
35 88 22 56 32 33 43 34 57 28 N/A (vomited) 75 78 93 52 75 52.0 (34.0–75.0)
0 16 0 30 50 0 16 7 40 0 100 0 200 30 0 0 31 ⫾ 13
35 30 30 30 20 0 40 14 40 50 48 40 60 30 0 0 30 ⫾ 4
Nutritional support
J-tube J-tube TPN J-tube
TPN J-tube J-tube J-tube
NOTE. GE results (% retention) are reported as median and interquartile range. All other measures are reported as means ⫾ standard errors. BMI, body mass index; J-tube, jejunostomy tube; N/A, not available; TPN, total parenteral nutrition.
Statistical Analysis The symptom subscores, TSS, PCS, MCS, body weight, and hospitalization days, reported as means ⫾ standard error, at baseline and at 6 and 12 months of GES were compared by analysis of variance and paired t test analysis. The Wilcoxon signed rank test was used for paired comparison of GE. Results of GE are reported as median and interquartile range. Statistical significance was assigned for P value ⬍.05.
Results Baseline Demographics The mean duration of gastroparetic symptoms was 5.6 years (range, 1–33 years). On average the patients had lost 13.6 kg (range, 0 –27.2 kg) and were hospitalized for a mean of 31 days (range, 0 –200 days) in the year before the GES. Six patients were enterally supplemented through a variety of feeding tubes, and 2 were receiving total parenteral nutrition (TPN). Fifteen patients had delayed solid GE at baseline (Table 1). The remaining patient could not complete the GE study because of vomiting, but she was included in this study on the basis of her clinical history and prior abnormal GE results from an outside medical center. The specific surgical procedures that preceded their symptoms and documented gastroparesis in these 16 PSG patients are as follows: Nissen fundoplication (5), vagotomy and pyloroplasty (3), Billroth I and vagotomy (2), Billroth II and vagotomy (2), cholecystectomy (1), spinal surgery (2), and esophagectomy with colonic interposition (2).
Upper Gastrointestinal Symptoms The results of upper GI symptoms are summarized in Table 2. In comparison with baseline, all 6 mean symptom severity subscores (vomiting, nausea, early satiety, bloating, postprandial fullness, and epigastric pain) decreased ⬎50% at 6 months of GES. The mean severity of nausea and epigastric pain also decreased ⬎50% at 12 months compared to baseline. Both total symptom severity and frequency were significantly reduced at 6 months of GES and sustained at 12 months compared to the initial baseline (P ⬍ .05). In reviewing the Symptom Interview Form at 12 months of follow-up, 10 patients (63%) had a ⬎50% decrease in TSS. Health-Related Quality of Life At baseline, mean PCS and MCS scores (28.6 and 39.7, respectively; Table 2) were substantially below the US norm (50 ⫾ 10),23 and both scores significantly improved at 6 and 12 months (P ⬍ .05). The majority of the improvement was observed within the first 6 months. Specifically, the MCS increased to 49.1 at 6 months, approaching normal. Hospitalizations Hospitalizations for gastroparesis symptoms averaged 31 ⫾ 13 days (range, 0 –200 days) for the year before receiving GES therapy. This average significantly decreased to 6 ⫾ 2 days (range, 0 –29 days) (P ⬍ .05)
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Table 2. Summary of Results of Upper GI Symptom Severity and Frequency, HQOL, and GE at Baseline, 6 and 12 Months After Receiving GES Therapy Severity score (0–4)
Baseline (n ⫽ 16)
6 mo of GES (n ⫽ 16)
12 mo (n ⫽ 16)
Vomiting Nausea Early satiety Bloating Postprandial fullness Epigastric pain TSS of severity (0–24) Frequency score (0–4) Vomiting Nausea Early satiety Bloating Postprandial fullness Epigastric pain TSS of frequency (0–24) HQOL PCS MCS Gastric retention (%) At 2 hours (range) At 4 hours (range)
2.0 ⫾ 0.5 3.4 ⫾ 0.2 2.9 ⫾ 0.2 3.1 ⫾ 0.2 2.9 ⫾ 0.2 2.6 ⫾ 0.3 17.1 ⫾ 0.7 Baseline (n ⫽ 16) 2.1 ⫾ 0.5 3.9 ⫾ 0.1 3.7 ⫾ 0.2 3.4 ⫾ 0.2 3.5 ⫾ 0.2 2.7 ⫾ 0.4 19.2 ⫾ 0.7 Baseline (n ⫽ 16) 28.6 ⫾ 2.1 39.7 ⫾ 3.1 Baseline (n ⫽ 15) 81.0 (70.0–92.0) 52.0 (34.0–75.0)
0.5 ⫾ 0.2a 1.4 ⫾ 0.3a 1.3 ⫾ 0.3a 1.3 ⫾ 0.3a 1.3 ⫾ 0.4a 1.1 ⫾ 0.3a 6.9 ⫾ 1.3a 6 mo of GES (n ⫽ 16) 0.6 ⫾ 0.3a 1.8 ⫾ 0.3a 1.3 ⫾ 0.3a 1.6 ⫾ 0.4a 1.8 ⫾ 0.4a 1.1 ⫾ 0.3a 7.9 ⫾ 1.3a 6 mo of GES (n ⫽ 16) 40.2 ⫾ 1.9a 49.1 ⫾ 3.6a 6 mo (n ⫽ 12) 67.0 (51.0–87.0) 34.0 (25.0–65.0)
1.1 ⫾ 0.3a 1.4 ⫾ 0.2a 1.7 ⫾ 0.4a 1.6 ⫾ 0.4a 1.6 ⫾ 0.3a 0.8 ⫾ 0.3a 8.6 ⫾ 1.5a 12 mo (n ⫽ 16) 1.2 ⫾ 0.3a 1.8 ⫾ 0.3a 2.2 ⫾ 0.4a 1.7 ⫾ 0.4a 1.8 ⫾ 0.4a 1.3 ⫾ 0.4a 9.8 ⫾ 1.5a 12 mo (n ⫽ 15) 37.7 ⫾ 2.7a 49.6 ⫾ 3.2a 12 mo (n ⫽ 13) 66.0 (51.0–90.0) 40.0 (19.0–73.0)
aP
⬍ .05 compared to baseline.
during the first year of GES, and 8 patients (50%) required no hospital admissions. Gastric Emptying Although both 2- and 4-hour median gastric retention at 6 and 12 months was numerically less than that at baseline, they were not statistically different (Table 2). Of the 13 patients who completed the GE test at 12 months, 3 (23%) did normalize their GE, whereas all others remained delayed including 4 patients (31%) whose gastric retention actually worsened. Of the 3 patients with no GE results at 12 months, one did not finish because of vomiting 1 hour after eating test meal, one was too sick to undergo the test, and one was interviewed by telephone. Nutritional Status At implantation, 7 of 16 patients required nutritional support in the form of a feeding jejunostomy tube. Of these 7 patients, 4 were able to discontinue the jejunal feeding at 2, 4, 6, and 11 months after GES, and 3 still required supplemental feeding at 12 months. Average body weight increased by more than 3 kg at 6 months and continued at 12 months (60.8 ⫾ 4.7 kg vs 64.2 ⫾ 4.5 kg vs 64.5 ⫾ 4.3 kg, respectively; P ⬍ .05 compared to baseline). Adverse Events Related to Gastric Electrical Stimulation Therapy One patient had the device removed after 12 months because of infection in the pocket of the pulse
generator. One patient had the implanted GES system replaced at 23 months postoperatively as a result of her involvement in an accident because the electrodes were detached from the gastric muscle by the trauma. Her symptoms reappeared 7 days after the accident, and the load impedance was found to be increased and exceed the upper limit. The abdominal x-ray showed dislodgment of the proximal lead from its original location in the gastric smooth muscle. On re-exploration, there was confirmation that one of the leads had become detached. The device and electrodes were replaced, and her symptoms improved very soon after replacement of the GES system, and the load impedance returned to normal.
Discussion The patients in this study had a variety of surgical procedures. However, the outcome was documented PSG, characterized by delayed GE and postprandial nausea and vomiting. Although the operations differed, all had undergone a procedure that involved either a known vagotomy or the potential for accidental injury to the vagus verve. They all had failed to respond to prokinetic agents, and ultimately they had a GES system implanted and received high frequency GES for at least 1 year. Previous studies have investigated the efficacy of high frequency GES in improvement of upper GI symptoms and quality of life in patients with severe gastroparesis as a result of diabetes or with idiopathic etiology.14 –18 There are only 2 preliminary publications reporting the
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results of GES in patients with PSG.20,21 The first only included 5 PSG patients followed for up to 6 months, and there was no statistical analysis included in that study.20 The second reported our initial experience with 12 PSG patients with various follow-up times (3 months–1 year).21 Therefore, the present study is the first to investigate the effects of high frequency GES in a relatively large group of patients with PSG for more than a 12-month period. Our results showed that long-term GES improved the upper GI symptoms and HQOL as well as nutritional support and the need for hospitalizations. These results are consistent with previous studies on the effects of GES in patients with diabetic or idiopathic gastroparesis.14 –18 The mean gastric retention measured by a standardized 4-hour scintigraphy of a solid meal was not significantly reduced at 6 or 12 months. The 4-hour gastric retention at 6 and 12 months was still 4 times normal value, ie, markedly delayed. This observation is in agreement with previous reports,16,18 indicating no association between changes in symptoms and GE in patients with gastroparesis treated with high frequency GES. Individually, only 23% of patients evaluated at 12 months of GES had their 2- or 4-hour gastric retention reduced to a normal value. In contrast, McCallum et al.25 showed that low frequency and high energy GES for a period of 1–3 months significantly improved GE and returned the majority of patients with gastroparesis (67%) to normal, as well as reversing gastric dysrhythmia with enhancement of the gastric slow waves. The major difference between these 2 studies was the stimulation parameters used. This suggests in the future that different stimulation parameters will be needed to reverse dysmotility in PSG. The mechanisms by which the upper GI symptoms in PSG patients were improved with GES remain to be elucidated. Short-pulse GES, similar to the parameters used in this study, was evaluated in a canine model by using vasopressin to induce gastric dysrhythmias and vomiting in both intact and vagotomized dogs.26 Shortpulse stimulation produced a significant reduction in vomiting in intact animals but not in those with acute vagotomy. This observation might suggest that the antiemetic effect of short-pulse stimulation was vagally mediated. The results of this present study and earlier clinical observations,17,20,25 however, indicate that GES is also effective in relieving symptoms in patients with PSG, including those with vagotomy, suggesting that the effects of GES might not be solely vagally mediated. Diabetic patients with gastroparesis have benefited symptomatically from GES therapy in a double-blind
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trial16 utilizing GES in the same parameters as our trial, as well as in another study utilizing different parameters (low frequency and high energy) in which stimulation of gastric smooth muscle also improved GE.25 The advanced diabetic patients treated in both of these reports frequently had accompanying vagal dysfunction. This provides further evidence that GES is still effective even without normal vagal nerve innervation or function. This study was not placebo controlled, so we cannot rule out that the impressive response observed after GES might represent a placebo response. In diabetic and idiopathic patients, a double-blind study did show that 1-month GES resulted in significantly better symptom improvement than 1-month sham,16 and further reports indicated that this symptomatic response to GES is sustained in the majority of initial responders.17,18 Also in the present study our patients had failed all medical therapy, and the ability of GES therapy to induce a sustained clinical improvement and quality of life for more than 12 months exceeds any placebo expectations or possibilities. In our initial study of high frequency GES in patients with gastroparesis, we performed serosal recordings of gastric electrical activity and concluded that high frequency GES did not normalize dysrhythmias while still achieving symptom reduction.27 Mechanisms other than motor stimulation have been proposed to explain the reductions in nausea and vomiting and include adrenergic and cholinergic functions,28 fundic relaxation,29 GI hormones,30 and afferent brain stem pathways.31 It would have to be hypothesized in our patients that the afferent pathways to the brain are explained by regrowth of the vagal nerve fibers or the development of collaterals, or that afferent signals are ascending via the sympathetic nervous system. In conclusion, long-term GES significantly improved the severity and frequency of upper GI symptoms, quality of life, and nutritional and hospitalization status of patients with postsurgical gastroparesis refractory to medical therapy. Although vagal nerve damage was part of the underlying pathophysiology in these patients, GES therapy was still effective and is a potential treatment for the long-term management of postsurgical gastroparesis. A controlled clinical trial of GES for PSG patients (who are refractory to medical therapy) is indicated given these encouraging results.
References 1. Eckhauser FE, Conrad M, Knol JA, et al. Safety and long-term durability of completion gastrectomy in 81 patients with postsurgical gastroparesis syndrome. Am Surg 1998;64:711–716. 2. Azproz F, Malagelada J-R. Gastric tone measured by an electronic barostat in heath and postsurgical gastroparesis. Gastroenterology 1987;82:934 –943.
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3. Kendall BJ, McCallum RW. Gastroparesis and the current use of prokinetic drugs. Gastroenterologist 1993;1:107–114. 4. Polepalle C, Valenzuela G, McCallum RW. Predicting gastric stasis after surgery for peptic ulcer. Am J Gastroenterol 1989;84:A112. 5. McCallum RW, Polepalle SC, Schirmer B. Completion gastrectomy for refractory gastroparesis following surgery for peptic ulcer disease: long-term follow-up with subjective and objective parameters. Dig Dis Sci 1991;36:1556 –1561. 6. McCallum RW, George SJ: Review: gastroparesis. Clinical Perspectives in Gastroenterology 2001;4:147–154. 7. McElhinney C, Sarosiek I, Lin Z, et al. Comparison of hospitalizations, medications, and quality of life in patients receiving gastric electrical stimulation (GES) therapy for severe gastroparesis (abstract). Gastroenterology 2002;122:A-82. 8. Rabine JC, Barnett JL. Management of the patients with gastroparesis. J Clin Gastroenterol 2001;32:11–18. 9. Camilleri M. Appraisal of medium- and long-term treatment of gastroparesis and chronic intestinal dysmotility. Am J Gastroenterol 1994;89:1769 –1774. 10. Sturm A, Holtmann G, Goebell H, et al. Prokinetics in patients with gastroparesis: a systematic analysis. Digestion 1999;60: 422– 427. 11. Jones MP, Maganti K. A systematic review of surgical therapy for gastroparesis. Am J Gastroenterol 2003;98:2122–2129. 12. Lin ZY, Forster J, Sarosiek I, et al. Review article: treatment of gastroparesis with electrical stimulation. Dig Dis Sic 2003;48: 837– 848. 13. Bortolotti M. The “electrical way” to cure gastroparesis. Am J Gastroenterol 2002;97:1874 –1883. 14. Familoni BO, Abell TL, Nemoto D, et al. Electrical stimulation at a frequency higher than basal rate in human stomach. Dig Dis Sci 1997;42:885– 891. 15. Forster J, Sarosiek I, Delcore R, et al. Gastric pacing is a new surgical treatment for gastroparesis. Am J Surg 2001;182: 676 – 681. 16. Abell T, McCallum RW, Hocking M, et al. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003;125:421– 428. 17. Abell TL, Cutsem EV, Abrahamsson H, et al. Gastric electrical stimulation in intractable symptomatic gastroparesis. Digestion 2002;66:204 –212. 18. Lin Z, Forster J, Sarosiek I, et al. Treatment of diabetic gastroparesis by high-frequency gastric electrical stimulation. Diabetes Care 2004;27:1071–1076. 19. US Food and Drug Administration. H990014-Enterra Therapy System (formerly named Gastric Electrical Stimulation (GES) system). Issued March 31, 2000. Available at: http://www.fda.gov/ cdrh/ode/H990014sum.html. 20. Luo J, Abell TL, Eaton P, et al. Gastric electrical stimulation improves both GI symptoms and gastric emptying in patients with “postsurgical” gastroparesis. Gastroenterology 1999;116:A1332.
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21. Forster J, Lin ZY, Sarosiek I, et al. Clinical response to long-term gastric electrical stimulation in patients with post-surgical gastroparesis. Gastroenterology 2004;126:A-807. 22. Tougas G, Eaker EY, Abell TL, et al. Assessment of gastric emptying using a low fat meal: establishment of international control values. Am J Gastroenterol 2000;95:1456 –1462. 23. Ware JE Jr. SF-36 Health Survey: manual and interpretation guide. Boston, MA: The Health Institute, New England Medical Center, 1993. 24. Ware JE, Kosinski M, Keller SD. SF-36 Physical and Mental Health Summary Scales: a user’s manual. Boston, MA: Health Assessment Lab, 1994. 25. McCallum RW, Chen JDZ, Lin ZY, et al. Gastric pacing improves emptying and symptoms in patients with gastroparesis. Gastroenterology 1998;114:456 – 461. 26. Chen JDZ, Qian L, Ouyang H, et al. Gastric electrical stimulation with short pulses reduces vomiting but not dysrhythmias in dogs. Gastroenterology 2003;124:401– 409. 27. Lin ZY, Forster J, Sarosiek I, et al. Effect of high-frequency electrical stimulation on gastric myoelectric activity in gastroparetic patients. Neurogastroenterol Motil 2004;16:205–212. 28. Luo J, Rashed H, Eaton P, et al. Long-term treatment of gastric electrical stimulation is associated with autonomic and enteric nervous system changes (abstract). Dig Dis Sci 2000;45:1244. 29. Tack J, Coulie B, Van Cutsem E, et al. The influence of gastric electrical stimulation on proximal gastric motor and sensory function in severe idiopathic gastroparesis (abstract). Gastroenterology 1999;116:G4733. 30. Al-Jubiri A, Luo J, Rashed H, et al. Gastric electrical stimulation is associated with increased pancreatic synthetic function when compared to normals and medical controls (abstract). Gastroenterology 2001;120:A647. 31. Tougas G, Huizinga JD. Gastric pacing as a treatment for intractable gastroparesis: shocking news? Gastroenterology 1998;114: 598 – 601.
Address requests for reprints to: Richard W. McCallum, MD, Department of Medicine, Mail stop: 1058, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160. e-mail: [email protected]; fax: (913)-588-3856. Portions of the study were presented in abstract format at the American Gastroenterological Association meeting in 2004. The authors would like to acknowledge the following individuals for their contributions: Sara Durham, Suzanne Denton, and Katherine Roeser as well as faculty, fellows, and nursing staff in the Division of Gastroenterology, Janet Kelly, RN, the operating room staff, and surgical residents. We also wish to acknowledge Dr Twillman in psychology and pain management and the faculty and staff of the Nuclear Medicine Department. We also thank Warren Starkebaum, PhD, at Medtronic as well as the Medtronic Gastroenterology Group.