Gastric Electrical Stimulation has an Immediate Antiemetic Effect in ...

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IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 53, NO. 6, JUNE 2006

Gastric Electrical Stimulation has an Immediate Antiemetic Effect in Patients With Gastroparesis Babajide O. Familoni*, Thomas L. Abell, Sudhir K. Bhaskar, Guy R. Voeller, and Stephanie R. Blair

Abstract—Background: Electrical stimulation has been successfully employed to treat diseases involving electro-pathology in the heart, skeletal muscles, and the brain, but not in the GI tract. Aim: This study examined the clinical feasibility and efficacy of GES in treating patients with severe gastroparesis. Methods: Nausea, vomiting, GEA, and liquid and solid gastric emptying were monitored in eleven patients with refractory gastroparesis at baseline and after one week of continuous electrical stimulation administered at 12 cycles/min. Eight patients were subsequently implanted with permanent stimulation devices. Follow-up studies were conducted after 1, 3, 6, and 12 mo. of stimulation. Results: After one week of stimulation, patients’ quantified symptoms of nausea and vomiting decreased significantly, and liquid emptying and GEA improved. This improvement was maintained over time in the patients who continued to receive stimulation. Emptying of solids showed progressive improvement that became significant after 3 mo. The three patients who did not receive stimulation after the trial period showed significantly higher symptoms at 12 mo. Conclusion: This paper demonstrates that GES at a frequency of 12 cycles/min has an immediate antiemetic effect, followed by an improvement in disordered gastric emptying. Index Terms—Electrical stimulation, gastric electrical activity, gastric emptying, gastroparesis, nausea, pacing, percutaneous gastrostomy, vomiting.

DTPA ECA GEA

NOMENCLATURE Diethylenetriamine pentaacetic acid. Electrical control activity. Gastric electrical activity.

GES PEG IPG

Gastric electrical stimulation. Percutaneous gastrostomy. Implantable pulse generator.

I. INTRODUCTION EFRACTORY gastroparesis and its associated symptomatology have a profound physical, psychological, and socioeconomic effect on sufferers and their families. The inci-

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Manuscript received December 6, 2004; revised October 29, 2005. This work was supported in part by Bakken Research Center, Medtronic, Maastricht, The Netherlands under a Research Grant. Asterisk indicates corresponding author. *B. O. Familoni was with the Department of Electrical Engineering, The University of Memphis, Memphis, TN 38152 USA. He is now with the Savannah State University, Savannah, GA 31404 USA (e-mail: [email protected]). T. L. Abell was with the Division of Gastroenterology, The University of Tennessee-Memphis, Memphis, TN 38103 USA. He is now with the University of Mississippi Medical Center, Jackson, MS 39216 USA. S. K. Bhaskar and S. R. Blair are with the Division of Gastroenterology, The University of Tennessee-Memphis, Memphis, TN 38103 USA. G. R. Voeller is with the Department of Surgery, The University of TennesseeMemphis, Memphis, TN 38103 USA. Digital Object Identifier 10.1109/TBME.2006.873395

dence of this disease is conservatively estimated from referral center data to include an addition of close to 50 new patients per million of the general population [1], [2]. In these several millions with the disease, gastroparesis is either of idiopathic origin or developed secondary to other conditions such as diabetic gastropathy and gastrointestinal surgery. More than 50% of this population report significant symptoms of bloating, nausea, vomiting, abdominal pain, and other symptoms [1], [3]. In these patients, stomach and/or small bowel motility becomes disordered, slows considerably, or ceases. Because of such gut dysmotility, there is decreased nutrient uptake and the patient becomes malnourished and underweight [4], [5]. Initial medical therapy for these patients often includes prokinetic drug therapy combined with antiemetic agents [3]. In severe cases, percutaneous jejunostomy tubes may be placed to deliver nutrients, often with PEG tubes to evacuate undigested stomach contents. GES offers hope as a treatment alternative for delayed gastric emptying and associated nausea, and vomiting that are refractory to other therapies. The stomach is emptied by tonic and phasic propulsive contractions controlled by GEA in conjunction with myogenic and neurohormonal factors at the organ level [6], [7]. Because of this control function, the rhythmic component of the GEA is sometimes called the ECA.The rationale for electrical stimulation therapy is that if this control mechanism falters, it may be artificially reinstated by supplying an appropriately configured electrical stimulus. To date, experimental trials with electrical stimulation in the stomach have had limited clinical success or significance. Its potential has been widely recognized for a while [8]–[22], but its efficacy has remained unproven until recently [18], [22], [23]. In general, intramuscular electrical stimulation offers the best chance of delivering the supraliminal stimulus required to activate the tissue. In the stomach, implantation of serosal electrodes requires laparotomy, which often cannot be justified when a given patient’s predisposition to respond to GES is unproven. In this paper, we report an evaluation of temporary GES for treating patients with gastroparesis. Patients responding to temporary GES may then be considered for permanent implantation of a gastric stimulator. II. PATIENTS Eleven patients (mean age 36.50 3.39 years, range 18 to 47 years) including two males and nine females were enrolled in the study. Two of these patients had diabetic gastroparesis and nine had idiopathic gastroparesis. (Table I). Gastroparesis in the patients was confirmed by history of delayed radionuclide liquid and/or solid gastric emptying, history of otherwise unexplained nausea, vomiting, abdominal pain, weight loss,

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FAMILONI et al.: GES HAS AN IMMEDIATE ANTIEMETIC EFFECT IN PATIENTS WITH GASTROPARESIS

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TABLE I SCORES OF NAUSEA (NX) AND VOMITING (VX) FREQUENCY/DAY AS A FUNCTION OF STIMULATION TIME IN PATIENTS WITH OR WITHOUT IMPLANTED GASTRIC STIMULATOR. SCORES FOR THE LAST SEVEN DAYS BEFORE THE 1, 3, 6, AND 12-MO. VISITS WERE ENTERED AS THE SCORES FOR THOSE PERIODS. PATIENTS ARE CLASSIFIED AS IDIOPATHIC (I) OR DIABETIC (D). THE IDIOPATHIC PATIENTS ARE FURTHER CLASSIFIED AS HAVING MYOPATHIES (M) OR NEUROPATHY (N). THE MEAN SCORE AND STANDARD ERROR WERE COMPUTED AS A FUNCTION OF TIME

early satiety, and/or anorexia, and no evidence of mechanical obstruction. All of the patients had failed available medical therapy including bethanecol, cisapride, erythromycin, and metoclopramide and/or domperidone, and had been implanted with PEG (for gastric decompression) and/or jejunostomy feeding tubes to supplement nutrition. III. METHODS The protocol was approved by the Food and Drug Administration as an Investigational Device Exemption in 1995 (NoG940 061) and by the University of Tennessee, Memphis’ Institutional Review Board, and all patients signed informed consent forms. Frequencies of nausea and of vomiting, a composite symptom intensity score, and quality of life were monitored by self-administered, standardized questionnaires at baseline [24], [25]. Baseline liquid and solid gastric emptying tests were administered for liquids with a mixture of milk and Ensure labeled DTPA, and for solids with Egg Beeters labeled with with [26]–[28]. The GES study was conducted in two phases as described later. A. Phase I Phase I was a two-week screening study to determine if a given patient responded to electrical stimulation. Patients were

prepared for standard endoscopy by intravenous injections using fentanyl, phenergan and/or Versed (midazolam), after oral lidocaine spray. The electrodes employed in Phase I were modified fetal scalp spiral electrodes, FES1000 (Graphic Controls Corporation). Each electrode was a stainless steel helix cemented into a base and housed in a removable, rigid, tubular jacket for ease of insertion and placement. Two or three pairs of the electrodes were inserted one at a time through the PEG opening, guided, and secured into the gastric antral mucosa by monitoring its progress with the aid of the endoscopic picture. The electrodes were anchored approximately 1 cm apart by screwing them into the mucosa on the greater curvature. (Fig. 1). The leads were brought out through the PEG opening and connected outside the body to the terminals of an Itrell II model 7424 (Medtronic, Inc., Minneapolis, MN) IPG. The Itrell II’s sealed titanium casing contains a long-life battery and electronics to control the stimulation. The amplitude, width, on time, off time, and repetition frequency of the pulse delivered by the IPG are programmable by telemetry using a Medtronic 7432 Console programmer (Medtronic, Inc., Minneapolis, MN). The other electrode pairs were connected to a Sensomedic dynograph to record GEA at endoscopy for 15 min before the pulse generator was switched on (designated as the baseline GEA). Recordings were continued with stimulation for another 15 min in the procedure room. After endoscopy, recordings of

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scores weekly on provided forms and also to report for solid and liquid emptying tests at 1, 3, 6, and 12 mo. following surgery. Data for the last 7 days prior to these clinic visits were designated as the scores for the 1, 3, 6, and 12-mo. periods. Symptoms scores were repeated after 12 mo. in the three patients who did not receive permanent devices. The sixth month check-up was configured as follows. The patients had solid and liquid gastric emptying tests with their stimulators in its normally ON mode. After the emptying test, their stimulators were programmed into the OFF mode, and they were scheduled for a repeat emptying test in 5 to 7 days. During that period, patients could request to have their stimulator turned back on before the second emptying test if their distress level became unbearable. After the second emptying test, the stimulators were reprogrammed back into the ON mode. C. Data Analysis Fig. 1. Photograph taken at endoscopic implantation of fetal spiral electrodes used for transmucosal electrical stimulation of the stomach. The electrodes were mounted in a plastic molding and attached to the connecting leads.

the electrical activity were made daily throughout this phase of the study. GEA data recorded during stimulation were designated as the stimulation-driven GEA. The pulse generator and leads were housed in a small pouch strapped around the patient’s waist. Stimulation via the pulse generator was performed continuously in all patients for 7 to 14 days postimplantation. Based on results from previous studies, we elected a pacing signal higher than the physiologic signal in frequency [21], [22]. The pacing current was pulse-shaped with and an amplitude of 5 mA delivered at a pulse width of 330 a frequency of 12 cycles/min. Frequency of nausea and of vomiting were scored daily and solid and liquid gastric emptying tests were repeated about the 7th day with the IPG still in the ON mode. An electrocardiogram (EKG) was recorded with the pulse generator on for 5 min and off for 5 min. The electrodes were removed at a subsequent endoscopy. B. Phase II Eligibility for Phase II of the protocol was contingent on positive response to treatment in Phase I: patients who demonstrated and 60% improvement in better than 35% improvement in is the time that symptoms qualified for Phase II of the study. it took for 50% of the test meal to clear the stomach. In Phase II, permanent intramuscular electrodes were implanted into the gastric serosa at laparotomy. One pair of SP4300 intramuscular platinum electrodes (Medtronic, Inc. Minneapolis, MN) were implanted subserosally into the greater curvature of the antral wall about 6 cm from the pylorus. The electrodes were connected to the IPG located in a subcutaneous pouch in the lower abdomen. An EKG was recorded with the IPG on for 5 min and off for 5 min. After surgery, the patients were allowed to have food by mouth as tolerated. Patients’ stimulators were programmed as described above, and switched on before they were released from the hospital. They were instructed to record their symptom

Electrical signals were recorded on the dynograph with a lower-end cut-off frequency of 0.017 Hz (1 cycle/min) and a higher-end cut-off frequency of 30 Hz (1800 cycles/min). They were simultaneously recorded in digital format on a 7-channel TEAC RD-17 tape recorder (Montebello, CA) at a sampling frequency of 75 Hz. The recorded signals were visually scored for regularity in the ECA period, presence of other abnormalities, and frequency and amplitudes of the ECA. We defined tachygastria as an ECA rate higher than 3.5 cycles/min and gastric electrical dysrhythmia as a beat-to-beat variability greater than 10% in the period of the activity [34]. Frequency of nausea and vomiting and a composite symptom intensity score were monitored daily in Phase I and weekly in Phase II. Nausea and vomiting were scored as number of episodes/day, and the composite intensity score measured the intensity of all symptoms on a scale of 0 to 60. The gastric emptying test in our Laboratory is identical to that previously described by Abell, Camilleri et al. [26]–[29]. It consisted of scintigraphic scatter counts from the liquid and solid meals described previously in the Methods’ section. The percentage of isotope left in the stomach after correcting for background scatter, crossover, and decay, was computed and plotted as a function of time [28]. Liquid and solid gastric emptying were quantified by determining the percentage of the meal left in the stomach at 60 (%60) and 120 min (%120), respectively, and by the number of minutes that it took to empty 50% of the stomach . Based on values obtained in controls by Abell content et al. [28] and Elashoff et al. [29], solid gastric emptying is is greater than 142 min or %120 considered delayed if is greater than 65%. Liquid emptying is considered delayed if is greater than 59 min, or %60 is greater than 50%. All variables were tested to see if they were normally distributed by computing Shapiro-Wilk statistics for each variable on a VAX mainframe computer. Parametric analysis was employed for normally distributed data. These analyzes included descriptive statistics expressed as the mean the standard error. Means were compared using student’s T-tests, and a multiple repeated measures design was employed to identify significant changes in gastric emptying and symptoms over the course of the study.


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Fig. 2. Intrinsic GEA recorded in a patient shows tachygastria at a frequency of 4.46 cycles/min before stimulation. Electrical stimulation at 12 cycles/min applied at the “IPG on” mark resulted in normal GEA at 2.7 cycles/min. There is also an artifact at the onset of stimulation.

Fig. 3(a). Baseline uncoupled gastric electrical abnormality in a patient with 4 pairs of serosal electrodes. The three most proximal electrodes (E1, E2, and E3) recorded GEA at 8.01 cycles/min, while the electrode at the terminal antrum, E4 recorded a normal 2.62 cycles/min.

Fig. 3(b). With postoperative GES at 12 cycles/min delivered at electrode E1, electrical uncoupling was resolved. All channels displayed activity at a normal 2.39 cycles/min.

IV. RESULTS The Shapiro-Wilk statistics confirmed that all of the variables were normally distributed at the 0.01 level. A. Phase I Prestimulation intrinsic GEA was recorded in the patients at a mean frequency of 3.52 0.29 cycles/min and an amplitude of 0.89 0.19 mV. The ECA was normal in three patients and abnormal in eight. Of the eight patients with abnormal ECA, six patients exhibited prolonged dysrhythmia up to 15 min, one patient had tachygastria, and one patient had a mixture of tachygastria and dysrhythmia. Electrical stimulation normalized ECA in the patients. The ECA with stimulation was recorded at a frequency of 3.09 0.12 cycles/min and an amplitude of 0.85

0.14 mV . (Fig. 2). Baseline abnormalities in GEA as shown in Fig. 3(a) were normalized by electrical stimulation both in its frequency [Fig. 3(b)] and its coupling [Fig. 3(c)]. 2.25 episodes of At baseline, patients experienced 8.45 nausea and 9.82 2.78 episodes of vomiting per day. During approximately 7 days of electrical stimulation (Phase I), as indicated in Table I, patients tolerated food by mouth better, and their quantified symptoms of nausea and vomiting reduced sigepisodes of nausea/day nificantly to 0.55 0.31 episodes of vomiting per day. The and 0.09 0.09 composite symptom intensity score also decreased from a baseline value of 49.80 3.97 to 19.30 6.39 units with stimulation. There was no significant improvement in solid phase gastric emptying. Percentage of liquid meal not emptied at 60 min reduced from 66.67 6.21% at baseline to 54.89

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Fig. 3(c). Coupling and aborad propagation is evident from the dashed lines inserted with the time scale expanded.

TABLE II EFFECT OF GES ON EMPTYING AND SYMPTOMS (MEAN ERROR) AS A FUNCTION OF TIME. THE MEANS ARE COMPARED TO THE BASELINE SCORE WITH THE LEVEL OF SIGNIFICANCE OF THE DIFFERENCE IN MEANS INDICATED IN PARENTHESES

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7.03% . (Table II). No adverse effects of the electrical stimulus were observed on the EKG. Symptom scores were quantified in seven of the eleven patients 2–5 days after the electrodes were explanted at the end of Phase I. Six of these seven patients monitored became symptomatic again within hours of removing the electrodes from their stomach. The average scores for nausea, vomiting, and composite intensity score for all 7 patients increased to 7.86 2.91 episodes/day, 4.53 2.70 episodes/day, and 43.75 6.01, respectively. In Fig. 4, symptom scores for nausea and vomiting are expressed in episodes/week and displayed on the same set of axes as the composite intensity scores. While these scores were 0.79, 0.19, not significantly different from baseline values ( and 0.17, respectively), they were significantly higher than those , 0.05, and 0.01, respectively). during stimulation (

B. Phase II Eight of the eleven patients screened in Phase I were implanted with permanent stimulation devices for Phase II. In these eight patients, measurements were repeated at the 1, 3, 6, and 12-mo. marks. In the group of three patients who did not receive a permanent device, measurements of symptoms were repeated at 12 mo.. Patients who received permanent stimulation tolerated food by mouth better and were able to switch from enteral or parenteral nutrition. Quantified symptoms of nausea and vomiting maintained the improvement seen in the temporary stimulation phase (Phase I). By the twelfth month, these patients experienced only 1.07 0.48 episodes of nausea and 0.54 0.37 episodes of vomiting per day, and a symptom intensity of


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Fig. 4. Bar chart comparing symptom scores (nausea, vomiting, and intensity in units/week) in seven patients at the baseline to scores during one week of electrical stimulation and after stimulation was discontinued. The difference in means between baseline and pacing scores (p < 0:009) and between pacing and after-pacing scores (p < 0:05) were statistically significant. The difference between baseline and after-pacing scores were not significant (p = 0:17).

25.57 7.34 . (Table I). Solid %120 and liquid %60 in these patients improved gradually over time. These improvements became statistically significant after the 3-mo. checkup and solid and liquid emptying were normal by 6 mo. (Table II). Seven patients in the stimulation group had their stimulators switched off for up to one week following the sixth month evaluation. Three of the patients were so distressed that their stimulators were reprogrammed back into the ON mode (at their request) before a second gastric emptying test could be performed. In the remaining 4 patients, solid %120 increased 7.63% (with the stimulator ON) significantly from 46.50 17.00% (with the stimulator OFF), . to 70.00 Three patients made a total of 6 unscheduled hospital visits for reasons of increased symptoms. In all cases, it was confirmed with the console programmer that their stimulators were in the OFF mode. Vomiting frequency in the patients experiencing these random switch offs averaged 3.61 episodes/day during the switch-off period compared with 0.49 episodes/day at periods when the IPG was confirmed ON with the console programmer. As in Phase I, no harmful effects of the stimulus were observed on the EKG. Patients who did not receive permanent stimulation experienced 6.71 2.17 episodes of nausea per day and 6.52 2.24 episodes of vomiting per day, after 12 mo.. These symptom scores were significantly higher than their scores after one week and , respectively). of stimulation ( V. DISCUSSION In 1963, Bilgutay et al. reported the first commercially available device for electrically stimulating the gastrointestinal tract as a treatment for gut dysmotility, the Peristart [8]. Subsequent studies by Berger et al. [9] and Quast et al. [10] reported no beneficial effects of the device. In the 70s, groups in Canada and the United States were successful in entraining the electrical activity of canine stomach with stimulation [11]–[14]. Electrical stimulation as a possible treatment for gastric motor dysfunction is recently experiencing a renaissance, but its clinical efficacy has remained elusive and unproven. For GES to become a useful alternative therapy for refractory gastroparesis, the stimulus must entrain the control activity, elicit highly organized response activity and contractions, and thus improve gastric emptying, relieve symptoms attributed to gastroparesis (nausea, vomiting, pain, etc.), and improve the patient’s quality of life.

An issue exposed by this study is the sparsity of information on the mechanism of action of GES. The optimum frequency for achieving this goal is currently controversial [18], [21]–[23]. Until recently, researchers have mainly employed frequencies similar to that of the native ECA to stimulate the stomach with inconclusive results [11]–[19]. A number of reports [21], [22] and the current study now suggest that higher frequencies than the basal rhythm may have greater efficacy in GES. Familoni et al. found that although electrical stimulation at both 5 cycles/min and 20 cycles/min entrained gastric ECA in a canine model, motility elicited by the higher frequency stimulus (20 cycles/min) was significantly higher [21]. In Abell et al. [23], the present study, and a previous case report [22], stimulation at 12 cycles/min, (approximately four times the intrinsic rate) regularized gastric ECA, ameliorated nausea and vomiting in patients within hours, and improved motility over time. Although they did not report human studies, Mintchev et al. demonstrated that stimulation in canine stomach with sequential bipolar pulses at a frequency of 50 Hz produced artificial contractions and promoted expulsion of pellets [37]. A similar efficacy of higher frequency electrical stimulation was recently reported in successfully treating Parkinson’s disease. Our findings in this series of patients include an antiemetic benefit of GES. The mechanism of action may involve electrical activation and entrainment of the tissue at the injection site. As depicted in Fig. 2, our current results suggest that abnormal GEA [Fig. 3(a)] may be normalized [Fig. 3(b)] immediately by an appropriately configured electrical stimulus. Transmucosal recording of GEA as these have been validated by comparison with serosal recordings in previous studies [35], [36]. The entrainment may then be coupled to, and spread to adjacent tissue bundles. [Fig. 3(c)]. Although electrical excitation of gastric muscle requires a supraliminal signal, it is not merely a question of injecting a large enough amount of energy. The configuration of the stimulus is very important. At stimulation frequencies close to the intrinsic rate, direct and selective myogenic activation may be the dominant mode of accomplishing this. This is supported by data showing that stimulation signals close to the intrinsic rate are still effective in activating canine gastric tissue in spite of atropine or vagotomy [13], [15]. As the frequency of the stimulating signal increases, the electrical time constant of the vagal and intramural nerves become comparable to the

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period of the injected signal. This greatly increases the chances of preferential neural activation, which then leads to the release of acetylcholine, resulting in pharmacological excitation of the muscle. This is supported by studies reported by Cook et al. [30]. Mintchev et al.’s report concluded that their high frequency pulses activated the cholinergic nerve in dogs [37]. Follow-up studies for instance may examine the effectiveness of stimulation in animal models with and without the action of neuro-toxins and autonomic function blockade. Still, it is not clear how this translates into symptom reduction. We believe that follow-up studies must also examine the efficacy of GES and determine its mechanism of action. In studies where symptom measurement cannot be instrumented otherwise, they are generally self-reported by the patients. There is always the possibility of exaggerated scores, especially at baseline. In this study, patients’ histories of nausea, vomiting, abdominal pain, bloating, and early satiety were well documented, dating back several years. The measurement instruments have also been validated in a similar cohort of patients [24], [25]. Future studies might be designed with a longer run-in period during which symptoms are scored prospectively. The recurrence of GI symptoms in the seven patients in-between Phases I and II, the inadvertent switch offs in three patients, recurrence of symptoms and delayed gastric emptying at the 6-mo OFF evaluation, and the natural progression of symptoms in the group of three patients who did not receive permanent stimulation, provide evidence to counter a possible placebo effect and problems with self-reporting of symptoms. In the three patients who did not receive permanent stimulation, baseline symptom scores (in episodes/day) were not significantly different from those of the group receiving permanent stimuversus 9.63 3.55, ; lators ( versus 10.38 2.81, ). Their natural history (at 12 mo.) confirmed that patients in the control group were more symptomatic than the patients who continued versus 0.54 to receive stimulation ( 0.37, ; versus 1.07 0.45, ). The inadvertent and spontaneous switch offs in 3 patients were not planned, but in effect provided randomized data. In all cases, these switch offs were only discovered after the patients presented with greatly increased gastrointestinal symptoms. The first indication that a device has accidentally turned off is usually a patient calling in to complain. In the clinic, we then interrogate the stimulator with a Medtronic 7432 Console Programmer to determine its setting. We hypothesize that these spontaneous switch offs were accomplished by exposure to large electromagnetic fields of unknown origin, since the stimulator is toggled on and off via transcutaneous electromagnetic pulses. Possible sources include high tension power lines, large magnets such as those in loud speakers, and security devices at airports or departmental stores. Future experimental designs with these devices could include a method for logging when the device is ON and when it is not. The effect of electrical stimulation on nausea and vomiting was immediate. This is in agreement with the previous report by Abell et al. [23]. In addition, we also found an immediate improvement in the patient’s liquid emptying. The effect on solid


phase gastric emptying was not statistically significant until several weeks later. A similar latency was observed in a previous case study [22]. To explain this, we postulate that gastric tissue may exhibit a “disuse memory.” That is, it takes some time before gastric antral tissue returns to normal mechanical activity levels after a period of inactivity. Similar observations have been noted in physical therapy and in the treatment of visceral muscles with electrical stimulation. Mortimer et al. reported that metabolic and histochemical changes begin to appear in muscle fibers only after several weeks of electrical stimulation. After such persistent electrical exercise, they reported a substantial increase in muscle twitch duration, capillary density, and fatigue resistance [31]. Part of the hindrance to clinical research into GES is the ethical dilemma of chronically implanting stimulators and electrodes in patients in whom the efficacy of the treatment modality is unproven. In this study, we developed a method for screening patients with preexisting PEGs for a therapeutic trial of GES. Placement of transmucosal electrodes as described here carries a small risk of bleeding and infection at the implantation site, i.e., the usual risks associated with standard endoscopy. In patients without a PEG, similar temporary stimulation can be achieved by placing electrodes at laparoscopy [36] and analytical method can be used to a limited extent [38]. VI. CONCLUSION These preliminary results suggest that continuous GES at 12 cycles/min has an immediate and enduring antiemetic effect in patients with drug refractory gastroparesis. An effect on liquid gastric emptying appears within a week, but its effect on solid phase emptying may be delayed for up to 6 mo. The study indicates the need for randomized, controlled follow-up studies to establish the efficacy of GES in gastroparesis. ACKNOWLEDGMENT This study was conducted as part of the Gastric ElectroMechanical Stimulation (GEMS) group’s multi center study and some of the data has already been published as part of that study in Digestion (vol. 66, pp. 204-212, 2002). REFERENCES [1] National Institute of Diabetes and Digestive and Kidney Diseases, Diabetes in America, 2nd Ed. 1995, NIH publication # 95-1468. [2] I. Soykan, B. Sivri, I. Sarosiek, and B. Kiernan et al., “Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis,” Digestive Dis. Sci., vol. 43, pp. 2398–2404, 1998. [3] Y. W. Kang and C. H. Kim, “Gastroparesis: diagnostic and therapeutic strategies,” Digestive Dis. Sci., vol. 10, pp. 181–189, 1992. [4] K. L. Koch, R. G. Atnip, and R. M. Stern, “Gastric emptying and gastric myoelectrical activity in patients with diabetic gastroparesis: effect of long-term domperidone treatment,” Am. J. Gastroenterol., vol. 84, no. 9, pp. 1069–1075, 1989. [5] W. G. Thompson, Gut Reactions: Understanding Symptoms of the Digestive Tract. New York: Plenum, 1990, p. 177. [6] C. F. Code, J. H. Szurszewski, K. A. Kelly, and I. B. Smith, “A concept of control of gastrointestinal motility,” in Handbook of Physiology: Alimentary Canal. Washington, DC: Am. Physiological Soc., vol. 5, sec. 6. [7] J. H. Szurszewski, “Electrical basis of gastrointestinal motility,” in Physiology of the Gastrointestinal Tract, L. R. Johnson, Ed. New York: Raven, 1981, p. 1435.


[8] A. M. Bilgutay, R. Wingrove, W. O. Griffen, R. C. Bonnabeau, and C. W. Lillehei, “Gastrointestinal pacing: a new concept in the treatment of ileus,” Ann. Surg., vol. 158, pp. 338–347, 1963. [9] T. Berger, J. Kewenter, and N. G. Kock, “Response to gastrointestinal pacing: antral, duodenal and jejunal motility in control and postoperative patients,” Ann. Surg., vol. 164, no. 1, pp. 139–144, 1966. [10] D. C. Quast, A. C. Beall, and M. E. deBakey, “Clinical evaluation of the gastrointestinal pacer,” Surg. Gynecol. Obstet., vol. 120, p. 35, 1965. [11] K. A. Kelly and R. C. LaForce, “Pacing the canine stomach with electric stimulation,” Am. J. Physiol., vol. 222, no. 3, pp. 588–594, 1972. [12] K. A. Kelly, “Differential responses of the canine gastric corpus and antrum to electrical stimulation,” Am. J. Physiol., vol. 226, pp. 230–234, 1974. [13] S. K. Sarna and E. E. Daniel, “Electrical stimulation of gastric electrical control activity,” Am. J. Physiol., vol. 225, no. 1, pp. 125–131, 1973. [14] S. K. Sarna, K. L. Bowes, and E. E. Daniel, “Gastric pacemakers,” Gastroenterol, vol. 70, pp. 226–231, 1976. [15] B. E. Bellahsene, C. D. Lind, B. D. Schirmer, O. L. Updike, and R. W. McCallum, “Acceleration of gastric emptying with electrical stimulation in a canine model of gastroparesis,” Am. J. Physiol., vol. 262, pp. G826–G834, 1992. [16] T. L. Courtney, B. D. Schirmer, B. E. Bellahsene, O. L. Updike, and R. W. McCallum, “Gastric stimulation as a possible new therapy for patients with severe gastric stasis (abstr.),” Gastroenterol, vol. 100, p. A822, 1991. [17] M. P. Hocking, S. B. Vogel, and C. A. Sninsky, “Human gastric myoelectrical activity and gastric emptying following gastric surgery and with pacing,” Gastroenterol, vol. 103, pp. 1811–1816, 1992. [18] R. W. McCallum, J. D. Chen, Z. Lin, B. D. Schirmer, R. D. Williams, and R. A. Ross, “Gastric pacing improves emptying and symptoms in patients with gastroparesis,” Gastroenterology, vol. 114, pp. 456–461, 1998. [19] B. W. Miedema, M. G. Sarr, and K. A. Kelly, “Pacing the human stomach,” Surgery, vol. 111, pp. 143–150, 1992. [20] W. E. Waterfall, D. Miller, and D. N. Ghista, “Electrical stimulation of the human stomach,” Digestive Dis. Sci., vol. 30, p. 799, 1985, (Abstr.). [21] B. O. Familoni, T. L. Abell, D. Nemoto, G. Voeller, B. Johnson, A. Salem, and O. Gaber, “Efficacy of electrical stimulation at frequencies higher than the basal rate in canine stomach,” Digestive Dis. Sci., vol. 42, no. 5, pp. 892–897, 1997. [22] B. O. Familoni, T. L. Abell, G. R. Voeller, A. Salem, and O. Gaber, “Case report on electrical stimulation at a frequency higher than the basal rate in human stomach,” Digestive Dis. Sci., vol. 42, no. 5, pp. 885–891, May 1997. [23] Abell, Van Cutsem, Abrahamsson, Huizinga, Konturek, Galmiche, Voeller, Filez, Everts, Waterfall, Domschke, B. des Varannes, Familoni, Bourgeois, Janssens, and Tougais, “Gastric electrical stimulation in intractable gastroparesis,” Digestion, vol. 66, pp. 204–212, 2002. [24] T. L. Abell, T. F. Cutts, and T. Cooper, “Effect of cisapride therapy for severe dyspepsia on gastrointestinal symptoms and quality of life,” Scand. J. Gastroenterol., vol. 28, no. suppl. 195, pp. 60–64, 1993. [25] T. F. Cutts and T. L. Abell, “Quality of life measures in gastroenterology,” Motility, vol. 26, pp. 4–7, 1994. [26] T. L. Abell, M. Camilleri, V. S. Hench, and J.-R. Malagelada, “Gastric electromechanical function and gastric emptying in diabetic gastroparesis,” Eur. J. Gastroenterol. Hepatol., vol. 3, no. 2, pp. 163–167, 1991. [27] T. L. Abell, M. Camilleri, E. P. DiMagno, V. S. Hench, A. R. Zinsmeister, and J.-R. Malagelada, “Long-term efficacy of oral Cisapride in symptomatic upper gut dysmotility,” Digestive Dis. Sci., vol. 36, no. 5, pp. 616–620, 1991. [28] T. L. Abell, J. Malagelada, and A. R. Lucas et al., “Gastric electromechanical and neurohormonal function in anorexia nervosa,” Gastroenterology, vol. 93, pp. 958–965, 1987. [29] J. D. Elashoff, T. J. Reedy, and J. H. Meyer, “Analysis of gastric emptying data,” Gastroenterology, vol. 83, pp. 1306–1312, 1982. [30] M. A. Cook, K. Kowalewski, and E. E. Daniel, “Electrical and mechanical activity recorded from isolated, perfused canine stomach: the effects of some G.I. polypeptides,” in Proc. Int. Motility Symp., Banff, AB, Canada, 1973, pp. 233–242. [31] J. T. Mortimer, Motor Prostheses in Handbook of Physiology, Sec I.: The Nervous System. Volume II. Bethesda, MD: Am. Physiological Soc., 1981, pp. 155–187. [32] K. L. Koch, R. M. Stern, M. Vasey, J. Botti, G. W. Creasey, and A. Dwey, “Gastric dysrhythmia and nausea of pregnancy,” Digestive Dis. Sci., vol. 35, no. 8, pp. 961–968, 1990.

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[33] R. M. Stern, K. L. Koch, W. R. Stewart, and I. M. Lindblad, “Spectral analysis of tachygastria recorded during motion sickness,” Gastroenterology, vol. 92, pp. 92–97, 1987. [34] B. O. Familoni, K. L. Bowes, Y. J. Kingma, and K. R. Cote, “Can transcutaneous recordings detect gastric electrical abnormalities,” Gut, vol. 32, no. 2, pp. 141–146, 1991. [35] J. W. Hamilton, B. E. Bellahsene, M. Reichelder, J. G. Webster, and B. P. Bass, “Human electrogastrograms: comparison of surface and mucosal recordings,” Digestive Dis. Sci., vol. 31, pp. 33–39, 1986. [36] B. O. Familoni, T. L. Abell, and G. Voeller, “Measurement of gastric and small bowel electrical activity at laparoscopy,” J. Laparoendoscopic Surg., vol. 4, no. 5, pp. 325–332, 1994. [37] M. P. Mintchev, C. P. Sanmiguel, M. Amaris, and K. L. Bowes, “Microprocessor-controlled movement of solid gastric content using sequential neural electrical stimulation,” Gastroenterology, vol. 118, pp. 258–263, 2000. [38] B. O. Familoni, Z. Gan, T. L. Abell, and G. Voeller, “Driving gastric electrical activity with electrical stimulation,” Ann. Biomed. Eng., vol. 33, no. 3, pp. 355–363, Mar. 2005.

Babajide O. Familoni (S’86–M’86–SM’97) received the B.Sc. degree (with Honors) from the University of Lagos, Nigeria, and the Ph.D. degree from the University of Alberta, Edmonton, AB, Canada, in 1986. He did a postdoctoral fellowship in gastrointestinal motility at the Department of Surgery in the University of Alberta Hospitals before joining the Department of Electrical Engineering at Memphis State University, Memphis, TN, in the fall of 1987. He became the Chair of that department in 1995. As Chair, he proposed and developed a Computer Engineering program, and changed the name to the department of Electrical & Computer Engineering. The program was visited and fully accredited by the Engineering Accreditation Commission of the Accreditation Board for Engineering and Technology (ABET) under his leadership in 2004. He left the University of Memphis in 2004 to join Savannah State University as the Dean of the College of Sciences & Technology. His research interests include GI motility, electrophysiology, control systems, and mathematical modeling. Dr. Familoni has won awards for his work in treating gastroparesis with electrical stimulation and holds two U.S. patents on devices and methods to do the same.

Thomas L. Abell received bachelors degrees from the University of South Dakota, Vermillion, and Yale University, New Haven, CT, and the M.D. degree from the University of South Dakota. He is a Professor of Medicine at the University of Mississippi Medical Center in Jackson, MS, and was at the University of Tennessee–Memphis, Memphis, until 2000. He is trained in Family Medicine, Behavioral Medicine, Internal Medicine, Gastroeneterology, and GI Motility Disorders. His work has focused, for the last 35 years, on the diagnosis and treatment of GI motility disorders, including intractable nausea and vomiting associated with gastroparesis. Most of the last 20 years has been devoted to the therapeutic roles of drugs, devices and behavior in GI motor disorders. His more recent work has focused on the development of endoscopic gastric electrical stimulation.

Sudhir K. Bhaskar is a graduate of University College of Medical Sciences, New Delhi, India He completed an internal medicine residency at the University of TennesseeMemphis and, subsequently, a fellowship in gastroenterology at the University of South Florida, Tampa, He is currently a practising gastroenterology in Orlando, FL. In addition, his interests include gastrointestinal motility disorders and liver disease. Dr. Bhaskar is board certified in internal medicine and gastroenterology. He is a member of the American Medical Association, the American College of Gastroenterology, and the American Gastroenterology Association.

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Guy R. Voeller received the M.D. degree from Tulane University School of Medicine, New Orleans, LA. He is currently a Professor of Surgery at University of Tennessee Health Science Center, Memphis. He was the Chief Resident in General Surgery at UTHSC, Memphis where he did a fellowship in Vascular Surgery. His special interests include Minimally Invasive Surgery and Endoscopic Surgery. He is listed as one of the “Best Doctors in America” and is a founding Member of the American Hernia Society. Dr. Voeller is board certified by the American Board of Surgery with additional qualifications in General Vascular Surgery. He is a Fellow of the Amer-


ican College of Surgeons, and a member of the American Hernia Society, the Society of American Gastrointestinal Endoscopic Surgeons, and the Society of Laparoendoscopic Surgeons. His awards and honors, include Alpha Omega Alpha National Medical Honor Society, finalist, “Health Care Hero” award, Medallion for Outstanding Performance from Department of Veterans Affairs, and a finalist and winner of “Health Care Hero” award.

Stephanie R. Blair is a registered nurse and the study coordinator.