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Gastric Electrical Stimulation and the “Eye of the Beholder”
Editorial Gastric Electrical Stimulation and the “Eye of the Beholder”
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aring for patients with diabetes mellitus and gastroparesis can be challenging for gastroenterologists. In the worst scenarios, frequent vomiting leads to dehydration, electrolyte abnormalities, kidney malfunction, abdominal wall pain from retching, frequent visits to the emergency room for intravenous fluids, and multiple hospitalizations.1 Pureed food, jejunostomy tubes, and enteral feeding or total parenteral nutrition may be required to maintain weight.2 Unexpected fluctuations in glucose levels in these patients make accurate insulin dosing very difficult. As the number of people with diabetes increases, more patients will develop severe gastroparesis and more will suffer the increased mortality and morbidity related to gastroparesis.3 From a gastrokinetic drug treatment approach for gastroparesis symptoms, the gastroenterologist’s armamentarium is limited to 3: metoclopramide, erythromycin, or domperidone (which requires Food and Drug Administration approval). If drugs fail to reduce symptoms associated with gastroparesis, then what? Ghrelin agonists appear promising,4 but clinical trials for diabetic gastroparesis are in the research studies phase. Where does gastric electrical stimulation (GES) therapy “fit in”? An understanding of the electrical activities of the stomach is helpful in appreciating the potential for electrical approaches such as GES for the treatment of gastric neuromuscular disorders. Normal gastric emptying requires normal gastric electrical rhythms, termed slow waves, to coordinate the peristaltic contractions that triturate and empty ingested foods.5,6 Slow waves are the pacemaker waves of the stomach and are generated by specialized cells within the gastric wall, the interstitial cells of Cajal (ICCs).7 Slow waves travel from the pacemaker region in the proximal corpus along the greater curvature of the stomach to the distal antrum at 3 cycles per minute (cpm).5,6 The gastric ICCs are diminished in murine diabetes and in human diabetes.8 When the ICCs are reduced, the normal 3-cpm slow wave activity is reduced and gastric dysrhythmias such as tachygastrias emerge.9 Patients with gastric dysrhythmias also had poorer symptom outcome with GES treatment compared with patients with normal 3-cpm electrogastrogram (EGG) rhythm. Histologic studies indicate the ICCs and enteric neurons are reduced in number and are damaged in patients with diabetes mellitus and gastroparesis, whereas the smooth muscle appears normal.10 GES provides low-amplitude, brief bursts of electrical current at 12 cpm, a modulating (not a pacemaking) stimulation.11 Gastric pacemaker devices, on the other hand, require a higher current that is applied near the normal 3-cpm pacemaker frequency.12 An excellent review of these aspects of gastric electrical therapies has been published recently.13 In this issue of Clinical Gastroenterology and Hepatology, McCallum et al14 report their multicenter experience with GES therapy in 55 symptomatic patients with severe, drug-refractory diabetic gastroparesis. Almost 20% of the patients needed enteral or parental nutritional support. Subjects received GES therapy for 6 weeks beginning immediately after the device was implanted. After 6 weeks of GES, half of the group was ran-
domly assigned to continue with the GES “on” and the other half to GES “off ” for 3 months. Then the groups were crossed over with the GES on group crossing over to GES off and the GES off group crossing over to GES on for another 3-month, double-blind treatment period. There was no wash-out period of time. Subjects then received open-label GES for 4.5 months, thus concluding the 12-month study. Vomiting frequency was reduced significantly during the 6 weeks of GES treatment that began immediately after implantation compared with baseline; but there was no difference in vomiting frequency with GES on or GES off during the two 3-month, placebo-controlled study periods. Thus, GES did not achieve the primary end point of the study. Thirty-five patients finished the 12-month study and vomiting frequency improved significantly compared with baseline. This study epitomizes a conundrum that accompanies many important clinical and scientific studies. The problem is this: the take-home message from scientific studies may be very different depending on the eye of the beholder. From a scientific viewpoint the primary objective was not met. This is a negative study. Do the results indicate that the device does not work? Or did flaws in the study design doom GES and the primary outcome measure? For example, the cross-over study design has been abandoned in most drug trials because of the potential for carry-over effects of the active drug into the placebo portion of the drug protocol. In this device study, the GES on period of therapy during the first 3-month period of stimulation may have had carry-over effects into the GES off treatment during the second 3-month period. Also, the carry-over effects of GES in the first 6 weeks when vomiting frequency was reduced certainly affected the first double-blind treatment phase. Hopefully, these flaws will be avoided in future study designs. What about the viewpoint of the patient with diabetic gastroparesis? From the viewpoint of the patient with severe gastroparesis symptoms, this study offers hope. That is, the average weekly vomiting episodes did decrease 57% after 6 weeks of therapy, an effect also present at the end of 12 months. Although vomiting frequency is only one of the symptoms associated with gastroparesis, it is an important one. If the subject is not vomiting, then food and medications can be ingested and absorbed. Other symptoms associated with gastroparesis and gastric emptying improved at 1 year. Thus, this article provides hope because some patients did obtain relief. What does this study mean from the viewpoint of the gastroenterologist who is trained in scientific methods and who also is responsible for care for diabetic patients with gastroparesis and irremediable symptoms? The study failed to achieve statistical significance for reducing vomiting in the doubleblind portion of the trial; but, as discussed earlier, some portion of patients was helped by GES. Weekly vomiting frequency was decreased significantly in patients with diabetic gastroparesis compared with idiopathic gastroparesis during an 8-week, double-blind GES treatment period.11 Thus, the beneficial effects of GES for patients with diabetic gastroparesis seem to be a consistent finding. So what should gastroenterologists do? I believe that gastroenterologists should develop a neurogastroenterology portion CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2010;8:908 –909
November 2010
of their practice to take care of patients with gastric neuromuscular disorders such as diabetic gastroparesis. A rational approach to these patients follows 4 steps: diagnosis, diet, drugs, and device. Diagnosis means a credible diagnosis of gastroparesis should be established based on a 4-hour, solid-phase, gastric-emptying study15 or wireless motility capsule study.16 An EGG study confirms the presence of gastric dysrhythmia or normal 3-cpm EGG pattern. A normal 3-cpm EGG rhythm reflects the presence of ICCs and predicts better GES outcomes.9 If the EGG shows a high-amplitude, 3-cpm signal, then gastric outlet obstruction should be considered.17 Another reversible cause of gastroparesis, chronic mesenteric ischemia, should be excluded.18 Patients should understand that their diet is crucial. Proper gastroparesis diet counseling should be provided.2,6 Patients must try to match the foods they select to eat (carbohydrates and proteins vs fats and indigestible fibers) with a basic understanding of their stomach’s impaired ability to mix and empty solid foods. Many postprandial symptoms improve with this dietary information and basic insights about stomach muscle function. Continued efforts to reduce hyperglycemia episodes are needed because hyperglycemia causes gastric dysrhythmias19 and reduces effectiveness of prokinetic drugs such as erythromycin.20 A step-wise approach to the available prokinetic drugs should be tried including a trial of domperidone.21 If these drugs fail to help symptoms and if weight loss develops, then device therapy with GES should be considered. Neurogastroenterologists should work with surgeons who have interests in stomach physiology and in GES, much like cardiologists interact with cardiothoracic surgeons in the collaborative management of patients with complex cardiac electrophysiologic abnormalities. In summary, this is a study whose beauty truly lies in the eyes of the beholder. Gastroenterologists and statisticians recognize the study failed to reach the primary end point. Patients recognize that GES provided relief for a number of these participants who had noxious, unremitting symptoms associated with gastroparesis. In my opinion, gastroenterologists should initiate and coordinate GES treatment (after documenting gastroparesis, excluding reversible causes of gastroparesis and exhausting diet and drugs) for their patients with irremediable symptoms and diabetic gastroparesis.
KENNETH L. KOCH, MD Section on Gastroenterology Wake Forest University School of Medicine Winston-Salem, North Carolina References 1. Koch KL. Diabetic gastropathy: gastric neuromuscular dysfunction in diabetes mellitus. A review of symptoms, pathophysiology, and treatment. Dig Dis Sci 1999;44:1061–1075. 2. Parrish CR. Nutrition concerns for the patient with gastroparesis. Curr Gastroenterol Rep 2007;9:295–302. 3. Hye-Keung Jung, Choung RS, Locke RG 3rd, et al. The incidence prevalence and outcomes of patients with gastroparesis in Olmstead County Minnesota, from 1996 –2006. Gastroenterology 2009;136:1225–1233. 4. Ejskjaer N, Vestergaard ET, Hellstrom PM, et al. Ghrelin receptor
GASTRIC ELECTRICAL STIMULATION
5.
6.
7.
8.
9.
10. 11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
909
agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis. Aliment Pharmacol Ther 2009;29:1179 –1187. Hinder RA, Kelley KA. Human gastric pacesetter potential: sight of origin, spread, and response to gastric transection and proximal vagotomy. Am J Surg 1997;133:29 –33. Koch KL. Gastric neuromuscular function and neuromuscular disorders. In: Feldman M, Friedman LS, Brandt LJ, eds. Gastrointestinal and liver diseases. Philadelphia: Saunders, 2010:789 – 815. Sanders KM, Koh SD, Ward SM. Interstitial cells of Cajal as pacemakers in the gastrointestinal tract. Ann Rev Physiol 2006; 68:307–343. He CL, Soffer EE, Ferris CD, et al. Loss of interstitial cells of Cajal and inhibitory innervation in insulin-dependent diabetes. Gastroenterology 2001;121:427– 434. Lin Z, Sarosiek I, Forster J, et al. Association of the status of interstitial cells of Cajal and electrogastrogram parameters, gastric emptying and symptoms in patients with gastroparesis. Neurogastroenterol Motil 2010;22:56 – 61. Lurken MS, Kashyap P, Parkman HP, et al. The pathological basis of gastroparesis. Gastroenterology 2008;134:A536. Abell T, Hocking M, McCallum R, et al. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003;125:421– 428. McCallum RW, Chen JD, Lin Z, et al. Gastric pacing improves emptying and symptoms in patients with gastroparesis. Gastroenterology 1998;114:456 – 461. Hasler WL. Methods of gastric electrical stimulation and pacing: a review of their benefits and mechanisms of action in gastroparesis and obesity. Neurogastroenterol Motil 2009;21:229 –243. McCallum RW, Snape W, Brody F, et al. Gastric electrical stimulation with Enterra therapy improves symptoms from diabetic gastroparesis in a prospective study. Clin Gastroenterol Hepatol 2010;8:947–954. 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. Kuo B, McCallum RW, Koch KL, et al. Comparison of gastric emptying of a non-digestible capsule to a radio-labeled meal in healthy and gastroparetic subjects. Aliment Pharmacol Ther 2008;27:186 –196. Brzana RJ, Bingaman S, Koch KL. Gastric myoelectrical activity in patients with gastric outlet obstruction and idiopathic gastroparesis. Am J Gastroenterol 1998;93:1083–1089. Liberski SM, Koch KL, Atnip RG, et al. Ischemic gastroparesis: resolution after revascularization. Gastroenterology 1990;99: 252–257. Jebbink RJA, Samsom M, Bruijs PP, et al. Hyperglycemia induces abnormalities of gastric myoelectrical activity in patients with type 1 diabetes mellitus. Gastroenterology 1994;107:1390 –1397. Rayner CK, Su YC, Doran SM, et al. The stimulation of antral motility by erythromycin is attenuated by hyperglycemia. Am J Gastroenterol 2000;95:2233–2241. Koch KL, Stern RM, Stewart WR, et al. Gastric emptying and gastric myoelectrical activity in patients with symptomatic diabetic gastroparesis: effects of long-term domperidone treatment. Am J Gastroenterol 1989;84:1069 –1075.
Conflicts of interest The author discloses the following: Dr Koch is on the scientific advisory board of Smartpill Corp and a 3CPM Co shareholder. doi:10.1016/j.cgh.2010.07.010
C
aring for patients with diabetes mellitus and gastroparesis can be challenging for gastroenterologists. In the worst scenarios, frequent vomiting leads to dehydration, electrolyte abnormalities, kidney malfunction, abdominal wall pain from retching, frequent visits to the emergency room for intravenous fluids, and multiple hospitalizations.1 Pureed food, jejunostomy tubes, and enteral feeding or total parenteral nutrition may be required to maintain weight.2 Unexpected fluctuations in glucose levels in these patients make accurate insulin dosing very difficult. As the number of people with diabetes increases, more patients will develop severe gastroparesis and more will suffer the increased mortality and morbidity related to gastroparesis.3 From a gastrokinetic drug treatment approach for gastroparesis symptoms, the gastroenterologist’s armamentarium is limited to 3: metoclopramide, erythromycin, or domperidone (which requires Food and Drug Administration approval). If drugs fail to reduce symptoms associated with gastroparesis, then what? Ghrelin agonists appear promising,4 but clinical trials for diabetic gastroparesis are in the research studies phase. Where does gastric electrical stimulation (GES) therapy “fit in”? An understanding of the electrical activities of the stomach is helpful in appreciating the potential for electrical approaches such as GES for the treatment of gastric neuromuscular disorders. Normal gastric emptying requires normal gastric electrical rhythms, termed slow waves, to coordinate the peristaltic contractions that triturate and empty ingested foods.5,6 Slow waves are the pacemaker waves of the stomach and are generated by specialized cells within the gastric wall, the interstitial cells of Cajal (ICCs).7 Slow waves travel from the pacemaker region in the proximal corpus along the greater curvature of the stomach to the distal antrum at 3 cycles per minute (cpm).5,6 The gastric ICCs are diminished in murine diabetes and in human diabetes.8 When the ICCs are reduced, the normal 3-cpm slow wave activity is reduced and gastric dysrhythmias such as tachygastrias emerge.9 Patients with gastric dysrhythmias also had poorer symptom outcome with GES treatment compared with patients with normal 3-cpm electrogastrogram (EGG) rhythm. Histologic studies indicate the ICCs and enteric neurons are reduced in number and are damaged in patients with diabetes mellitus and gastroparesis, whereas the smooth muscle appears normal.10 GES provides low-amplitude, brief bursts of electrical current at 12 cpm, a modulating (not a pacemaking) stimulation.11 Gastric pacemaker devices, on the other hand, require a higher current that is applied near the normal 3-cpm pacemaker frequency.12 An excellent review of these aspects of gastric electrical therapies has been published recently.13 In this issue of Clinical Gastroenterology and Hepatology, McCallum et al14 report their multicenter experience with GES therapy in 55 symptomatic patients with severe, drug-refractory diabetic gastroparesis. Almost 20% of the patients needed enteral or parental nutritional support. Subjects received GES therapy for 6 weeks beginning immediately after the device was implanted. After 6 weeks of GES, half of the group was ran-
domly assigned to continue with the GES “on” and the other half to GES “off ” for 3 months. Then the groups were crossed over with the GES on group crossing over to GES off and the GES off group crossing over to GES on for another 3-month, double-blind treatment period. There was no wash-out period of time. Subjects then received open-label GES for 4.5 months, thus concluding the 12-month study. Vomiting frequency was reduced significantly during the 6 weeks of GES treatment that began immediately after implantation compared with baseline; but there was no difference in vomiting frequency with GES on or GES off during the two 3-month, placebo-controlled study periods. Thus, GES did not achieve the primary end point of the study. Thirty-five patients finished the 12-month study and vomiting frequency improved significantly compared with baseline. This study epitomizes a conundrum that accompanies many important clinical and scientific studies. The problem is this: the take-home message from scientific studies may be very different depending on the eye of the beholder. From a scientific viewpoint the primary objective was not met. This is a negative study. Do the results indicate that the device does not work? Or did flaws in the study design doom GES and the primary outcome measure? For example, the cross-over study design has been abandoned in most drug trials because of the potential for carry-over effects of the active drug into the placebo portion of the drug protocol. In this device study, the GES on period of therapy during the first 3-month period of stimulation may have had carry-over effects into the GES off treatment during the second 3-month period. Also, the carry-over effects of GES in the first 6 weeks when vomiting frequency was reduced certainly affected the first double-blind treatment phase. Hopefully, these flaws will be avoided in future study designs. What about the viewpoint of the patient with diabetic gastroparesis? From the viewpoint of the patient with severe gastroparesis symptoms, this study offers hope. That is, the average weekly vomiting episodes did decrease 57% after 6 weeks of therapy, an effect also present at the end of 12 months. Although vomiting frequency is only one of the symptoms associated with gastroparesis, it is an important one. If the subject is not vomiting, then food and medications can be ingested and absorbed. Other symptoms associated with gastroparesis and gastric emptying improved at 1 year. Thus, this article provides hope because some patients did obtain relief. What does this study mean from the viewpoint of the gastroenterologist who is trained in scientific methods and who also is responsible for care for diabetic patients with gastroparesis and irremediable symptoms? The study failed to achieve statistical significance for reducing vomiting in the doubleblind portion of the trial; but, as discussed earlier, some portion of patients was helped by GES. Weekly vomiting frequency was decreased significantly in patients with diabetic gastroparesis compared with idiopathic gastroparesis during an 8-week, double-blind GES treatment period.11 Thus, the beneficial effects of GES for patients with diabetic gastroparesis seem to be a consistent finding. So what should gastroenterologists do? I believe that gastroenterologists should develop a neurogastroenterology portion CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2010;8:908 –909
November 2010
of their practice to take care of patients with gastric neuromuscular disorders such as diabetic gastroparesis. A rational approach to these patients follows 4 steps: diagnosis, diet, drugs, and device. Diagnosis means a credible diagnosis of gastroparesis should be established based on a 4-hour, solid-phase, gastric-emptying study15 or wireless motility capsule study.16 An EGG study confirms the presence of gastric dysrhythmia or normal 3-cpm EGG pattern. A normal 3-cpm EGG rhythm reflects the presence of ICCs and predicts better GES outcomes.9 If the EGG shows a high-amplitude, 3-cpm signal, then gastric outlet obstruction should be considered.17 Another reversible cause of gastroparesis, chronic mesenteric ischemia, should be excluded.18 Patients should understand that their diet is crucial. Proper gastroparesis diet counseling should be provided.2,6 Patients must try to match the foods they select to eat (carbohydrates and proteins vs fats and indigestible fibers) with a basic understanding of their stomach’s impaired ability to mix and empty solid foods. Many postprandial symptoms improve with this dietary information and basic insights about stomach muscle function. Continued efforts to reduce hyperglycemia episodes are needed because hyperglycemia causes gastric dysrhythmias19 and reduces effectiveness of prokinetic drugs such as erythromycin.20 A step-wise approach to the available prokinetic drugs should be tried including a trial of domperidone.21 If these drugs fail to help symptoms and if weight loss develops, then device therapy with GES should be considered. Neurogastroenterologists should work with surgeons who have interests in stomach physiology and in GES, much like cardiologists interact with cardiothoracic surgeons in the collaborative management of patients with complex cardiac electrophysiologic abnormalities. In summary, this is a study whose beauty truly lies in the eyes of the beholder. Gastroenterologists and statisticians recognize the study failed to reach the primary end point. Patients recognize that GES provided relief for a number of these participants who had noxious, unremitting symptoms associated with gastroparesis. In my opinion, gastroenterologists should initiate and coordinate GES treatment (after documenting gastroparesis, excluding reversible causes of gastroparesis and exhausting diet and drugs) for their patients with irremediable symptoms and diabetic gastroparesis.
KENNETH L. KOCH, MD Section on Gastroenterology Wake Forest University School of Medicine Winston-Salem, North Carolina References 1. Koch KL. Diabetic gastropathy: gastric neuromuscular dysfunction in diabetes mellitus. A review of symptoms, pathophysiology, and treatment. Dig Dis Sci 1999;44:1061–1075. 2. Parrish CR. Nutrition concerns for the patient with gastroparesis. Curr Gastroenterol Rep 2007;9:295–302. 3. Hye-Keung Jung, Choung RS, Locke RG 3rd, et al. The incidence prevalence and outcomes of patients with gastroparesis in Olmstead County Minnesota, from 1996 –2006. Gastroenterology 2009;136:1225–1233. 4. Ejskjaer N, Vestergaard ET, Hellstrom PM, et al. Ghrelin receptor
GASTRIC ELECTRICAL STIMULATION
5.
6.
7.
8.
9.
10. 11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
909
agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis. Aliment Pharmacol Ther 2009;29:1179 –1187. Hinder RA, Kelley KA. Human gastric pacesetter potential: sight of origin, spread, and response to gastric transection and proximal vagotomy. Am J Surg 1997;133:29 –33. Koch KL. Gastric neuromuscular function and neuromuscular disorders. In: Feldman M, Friedman LS, Brandt LJ, eds. Gastrointestinal and liver diseases. Philadelphia: Saunders, 2010:789 – 815. Sanders KM, Koh SD, Ward SM. Interstitial cells of Cajal as pacemakers in the gastrointestinal tract. Ann Rev Physiol 2006; 68:307–343. He CL, Soffer EE, Ferris CD, et al. Loss of interstitial cells of Cajal and inhibitory innervation in insulin-dependent diabetes. Gastroenterology 2001;121:427– 434. Lin Z, Sarosiek I, Forster J, et al. Association of the status of interstitial cells of Cajal and electrogastrogram parameters, gastric emptying and symptoms in patients with gastroparesis. Neurogastroenterol Motil 2010;22:56 – 61. Lurken MS, Kashyap P, Parkman HP, et al. The pathological basis of gastroparesis. Gastroenterology 2008;134:A536. Abell T, Hocking M, McCallum R, et al. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003;125:421– 428. McCallum RW, Chen JD, Lin Z, et al. Gastric pacing improves emptying and symptoms in patients with gastroparesis. Gastroenterology 1998;114:456 – 461. Hasler WL. Methods of gastric electrical stimulation and pacing: a review of their benefits and mechanisms of action in gastroparesis and obesity. Neurogastroenterol Motil 2009;21:229 –243. McCallum RW, Snape W, Brody F, et al. Gastric electrical stimulation with Enterra therapy improves symptoms from diabetic gastroparesis in a prospective study. Clin Gastroenterol Hepatol 2010;8:947–954. 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. Kuo B, McCallum RW, Koch KL, et al. Comparison of gastric emptying of a non-digestible capsule to a radio-labeled meal in healthy and gastroparetic subjects. Aliment Pharmacol Ther 2008;27:186 –196. Brzana RJ, Bingaman S, Koch KL. Gastric myoelectrical activity in patients with gastric outlet obstruction and idiopathic gastroparesis. Am J Gastroenterol 1998;93:1083–1089. Liberski SM, Koch KL, Atnip RG, et al. Ischemic gastroparesis: resolution after revascularization. Gastroenterology 1990;99: 252–257. Jebbink RJA, Samsom M, Bruijs PP, et al. Hyperglycemia induces abnormalities of gastric myoelectrical activity in patients with type 1 diabetes mellitus. Gastroenterology 1994;107:1390 –1397. Rayner CK, Su YC, Doran SM, et al. The stimulation of antral motility by erythromycin is attenuated by hyperglycemia. Am J Gastroenterol 2000;95:2233–2241. Koch KL, Stern RM, Stewart WR, et al. Gastric emptying and gastric myoelectrical activity in patients with symptomatic diabetic gastroparesis: effects of long-term domperidone treatment. Am J Gastroenterol 1989;84:1069 –1075.
Conflicts of interest The author discloses the following: Dr Koch is on the scientific advisory board of Smartpill Corp and a 3CPM Co shareholder. doi:10.1016/j.cgh.2010.07.010