Pyloroplasty improves long-term gastric emptying in rats undergoing fundoplication

Pyloroplasty Improves Long-Term Gastric Emptying in Rats Undergoing Fundoplication By Joaquim Bustorff-Silva, Eric W. Fonkalsrud, Carlos A. Perez, Carl Hoh, Helen E. Raybould, and James B. Atkinson Los Angeles, California

Background: Conflicting reports exist regarding the permanence of improved gastric emptying (GE) after fundoplication for gastroesophageal reflux in children. Methods: Changes in gastric volume (GV) and GE of a radiolabeled mixed meal induced by a Nissen fundoplication (NF) were compared with those with a NF plus pyloroplasty (NF ⫹ P). GE was measured preoperatively, 15 and 30 days postoperation, in 24 Sprague-Dawley rats; 12 had NF alone, and 12 had NF ⫹ P. Results were expressed as percent gastric retention at 90 minutes (GR90). GV was measured at the same time periods in 20 additional rats. Results: NF rats had enhanced GE with reduction of preoperative GR90 from 37.6% to 23.7% at 15 days (P ⬍ .05); however, at 30 days the GR90 increased to 34.3%. NF ⫹ P rats had

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ISSEN FUNDOPLICATION (NF) is the most commonly used operation for the treatment of gastroesophageal reflux disease in children in the United States.1 Despite the success of the NF in controlling reflux, occasional patients may experience postoperative symptoms of early satiety, bloating, retching, and even recurrent reflux. Although clinical reports suggest that these complications, in several patients, may be related to a delay in gastric emptying (DGE),2,3 the performance of a concomitant gastric drainage procedure for such patients at the time of NF remains controversial. Previously reported clinical and experimental data have shown that a NF produces an acceleration of gastric emptying (GE).4,5 The improvement in GE is believed to be associated with changes in the degree of gastric relaxation and compliance, which, in turn, may be a cause of postoperative dyspeptic symptoms.6 Recent studies from our laboratory have found that the mechanism by which a NF increases GE is by elevating gastric pressure and reducing gastric compliance.7 The NF has been shown to produce only a transient improvement in GE. The current study was undertaken to determine if performing a pyloroplasty (P) together with NF (NF ⫹ P) would enhance GE more permanently than NF alone, and if postoperative gastric distension is less with NF ⫹ P compared with NF alone.

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enhanced GE with reduction in GR90 from 37.2% to 20.8% at 15 days (P ⬍ .05), which persisted at 30 days (20.4%). Mean GV decreased from (1.36 mL/100 g body weight) preoperation to 0.86 at 15 days (P ⬍ .05) at 15 days in the NF group, and returned to 1.29 at 30 days. Mean GV decreased from 1.36 to 0.91 at 15 days in the NF ⫹ P rats and persisted at 0.90 at 30 days.

Conclusion: In the rat model, NF enhances GE transiently, whereas NF ⫹ P produces long-term enhancement of GE. J Pediatr Surg 35:1087-1090. Copyright r 2000 by W.B. Saunders Company. INDEX WORDS: Gastric emptying, pyloroplasty, Nissen fundoplication, gastroesophageal reflux.

MATERIALS AND METHODS Forty-four male Sprague-Dawley rats, weighing between 280 g and 300 g were kept in a controlled environment with temperature and humidity control and with 12-hour light-dark cycles. The rats were housed in separate cages and allowed standard rat chow throughout the experiment. Before any procedures, the rats were placed in wire-bottom cages and fasted for 24 hours for solids. Water was withdrawn immediately before the tests. During the days that preceded the GE tests, the rats were trained to remain in special lucite restrainers for periods of up to 3 hours, 3 or 4 times a week. During this period they were allowed water and food ad libitum. Twenty-four rats were included in the GE studies. After the initial measurement of GE, the rats were assigned randomly to either a Nissen fundoplication (NF group), or NF plus Heineke-Mikulicz pyloroplasty (NF ⫹ P group). Gastric emptying studies were repeated 15 and 30 days after the operations. Gastric volume (GV) was evaluated using a different set of 20 rats. Six animals were used to measure preoperative GV. Twenty-four rats

From the Departments of Surgery and Physiology, UCLA School of Medicine, Los Angeles, CA. Partially supported by grants NIH DK 41004 and CURE Digestive Diseases Center Grant DK 41301 (Dr Raybould), and grant #97/0927-2 from the Fundacao de Amparo a Pesquisa do Estado de Sao PauloFAPESP-SP (Dr Bustorff-Silva). Address reprint requests to Eric W. Fonkalsrud, MD, Department of Surgery, UCLA Medical Center, Los Angeles, CA 90095. Copyright r 2000 by W.B. Saunders Company 0022-3468/00/3507-0015$03.00/0 doi:10.1053/js.2000.7832

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were then chosen randomly to undergo a NF or NF ⫹ P. Six rats from each group were evaluated on the 15th, and the remaining six on the 30th postoperative day. NF was performed using sterile technique under general anesthesia using a combination of intraperitoneal ketamine and xylazine. A midline abdominal incision was made, and the stomach was exposed. The gastro-hepatic ligament was divided. The esophagus was isolated, and a retro-esophageal window was developed by blunt dissection. The upper gastric fundus was passed behind the esophagus and sutured to the anterior gastric wall, with two stitches of 5-0 silk. A floppy 1-cm long wrap was thus constructed. The abdominal wall was closed in layers. For rats undergoing pyloroplasty, an NF was performed as described above. The gastric antrum and pylorus were exposed and a 1-cm incision was made through the gastric antrum, pylorus, and onto the proximal duodenum extending through the mucosa. The incision was closed transversely in a single layer using interrupted 6-0 polypropylene stitches. Patency and water seal were ascertained by filling the stomach with saline and gently applying compression while observing the duodenum fill with fluid. The stomach was returned to the abdomen, and the laparotomy was closed in layers.

Gastric Emptying GE was measured in the rats after a 24-hour solid food fast. Water was offered until immediately before the experiment. The test meal consisted of 3 mL of egg white, containing 0.3 g protein, 0.03 g carbohydrate, and no fat. The total caloric content was 1.5 cal per meal. The meal was labeled with 350 mCi of technetium Tc 99–sulphur colloid. After labeling, the eggs were cooked for 2.5 minutes at 90°C to achieve a semisolid consistency. This resulted in 98% efficiency in labeling as measured with an in vitro test. The meal was placed into the distal esophagus of awake rats through a rigid orogastric tube connected to a syringe. Immediately after administration of the test meal, the rats were placed in a specially designed lucite restrainer and placed prone on a Siemens orbiter gamma camera equipped with a LEAP collimator. Scintigraphic images were obtained over 1-minute intervals every 7.5 minutes, beginning 1 minute after installation of the bolus, for a total examination time of 90 minutes. Thirteen images were produced for each subject. The stomach was manually drawn in every frame and the percentage of meal remaining in the stomach at each time was calculated by dividing the counts in the stomach on that specific frame by the counts in the stomach in the initial image (time ⫽ 0). These results were then normalized to permit construction of a GE curve for each rat at each study point. Results were expressed in terms of the percentage of meal remaining in the stomach after 90 minutes (GR90).

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pressure (IGP) corresponding to intragastric volumes of, respectively, 0.5, 1.0, and 1.5 mL/100 gm of body weight were registered. The stomach was then evacuated, allowed to rest for 30 minutes, and then the whole procedure repeated. This procedure was performed 3 times for each rat, and the results were expressed as an average of these 3 measurements. All animals were killed after the last measurement. A line plot of changes in pressure for increasing gastric volumes was constructed. A linear regression equation was plotted for each rat, and GV was calculated as the volume corresponding to an IGP of 10 mm Hg. Values of GR90 and GV are expressed in terms of mean ⫾ SEM. Values obtained at 15 and 30 postoperative days were compared against preoperative values using 1-way analysis of variance (ANOVA) for repeated measurements and Dunnet’s test for multiple comparisons against a control.

RESULTS

The mean GE curves for the rats from the NF and NF ⫹ P groups are shown in Fig 1. Table 1 shows the mean ⫾ SEM of GR90 in the 2 groups. Rats from the NF group showed a significant improvement in GE at 15 days compared with preoperative values as noted by the decrease in GR90; however, by 30 days, GE returned to preoperative values as noted by the increase in GR90. In rats from the NF ⫹ P group an improvement in GE also was observed 15 days after the operation; however, this improvement persisted 30 days postoperation as noted by the continuing low GR90 measurement. None of the rats showed clinical evidence of dumping. Gastric volumes measured after progressive distension of the stomach to an IGP of 10 mm/Hg (dynamic gastric compliance) are shown in Fig 2. Fifteen days postoperation, the mean GV was reduced significantly in rats from both the NF and NF ⫹ P groups when compared with preoperative values. By the 30th postoperative day, however, GV returned to preoperative values in rats from the NF group, whereas in rats from the NF ⫹ P group, the GV remained at a low level, which was significantly lower than before the operation. DISCUSSION

Gastric Volume Measurements of GV were made under general anesthesia as described previously. A tracheotomy was constructed to secure a safe airway. An abdominal incision was performed using sterile technique, and the duodenum was exposed and suture ligated. Next, the distal esophagus was isolated and encircled with a 3-0 silk ligature. An 8Fr orogastric feeding tube with a side opening was passed into the stomach and confirmed by direct palpation. The suture in the distal esophagus was then tied, securing the tube in place to prevent reflux. The stomach was washed out with 5 aliquots of 3 mL saline. The feeding tube was then connected through a 3-way stopcock to an infusion pump (Harvard Apparatus, South Natick, MA), and also to a pressure transducer connected to a Hewlett-Packard pressure monitor, (model HP78353A), which measured pressure changes during infusion. Measurements were taken after 30 minutes of stabilization. Saline infusion was started at a rate of 1.5 mL/100 g/min, and continued in 20-second increments. Every 20 seconds (corresponding to an infusion volume of 0.5 mL/100 g) the infusion was interrupted, and the system was allowed to equilibrate for 1 minute. The intragastric

Delayed gastric emptying is recognized as a coexisting factor often complicating gastroesophageal reflux disease (GERD) in children but less common in adults. It has been reported to occur in from 15% to 50% of children with gastroesophageal reflux, with the frequency higher among children with neurological impairment.8 Sparse information is available concerning the actual pathophysiology of DGE in children with symptomatic reflux, although recent studies suggest that there may be a defect of global gastric motility rather than gastric outflow obstruction.9,10 It is believed that gastric retention may contribute to the occurrence of gastroesophageal reflux by distending the gastric fundus and increasing the number of transient lower esophageal sphincter relaxations. After fundoplication, persistent DGE is believed to cause gastric disten-

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Fig 1. Mean gastric emptying curves from rats in the NF and NF ⴙ P groups. Each curve represents the mean values from 6 animals. Each graph contains curves corresponding to the preoperative values, and those from 15 and 30 days postoperation. Two-way ANOVA, comparing the 3 different GE curves within each group shows that the curves from rats in the NF and NF ⴙ P groups were significantly different. (*P F .05, 15th postoperative day v preoperative). (*P F .05, 15th and 30th postoperative days v preoperative; 1-way ANOVA followed by Dunnet’s test).

sion, which may, in turn, exert chronic stress on the gastroesophageal junction and thus increase the risk of wrap disruption and recurrent reflux.4-8 Previous clinical and experimental studies have shown that NF will increase IGP and decrease GV, which may enhance GE.5-11 The mechanisms involved may be explained by Laplace’s law, which states that a decrease in radius results in disproportionately less wall tension necessary to generate a greater intraluminal pressure. This mechanism of increased GE is transient and may occur at the expense of pressure disruption of the fundoplication. Additionally, a recent study using a proximal gastric barostat has shown that NF impairs the accommodation reflex of the gastric fundus6 resulting in increased emptying of liquids. The results of the current study show that NF transiently decreases GV while simultaneously increasing GE. Wilbur et al12 previously have shown that reducing the radius of the proximal stomach by fundectomy in dogs results in increasing the GE of liquids. Within 30

days after the operation, however, the GE returned to preoperative values, which was associated with the return of GV to the same levels measured before surgery. It is likely that reduced GV and compliance may have resulted in a chronic elevation of IGP, which, in turn, produced an increase in GE, but with gradual gastric distension. Further studies are in progress to determine the effects of NF alone and NF ⫹ P on GV and GE 60 days postoperation. Results from a recent clinical study suggest that children with DGE show transient improvement in GE after

Table 1. Gastric Emptying Measurements

GR90 (%) Mean ⫾ SEM

NF NF ⫹ P

Preoperative

15 Days Postoperatively

30 Days Postoperatively

37.6 ⫾ 3.5 37.2 ⫾ 6.6

23.7 ⫾ 3.7* 20.8 ⫾ 3.5*

34.3 ⫾ 5.7 20.4 ⫾ 4.1*†

NOTE. Mean ⫾ SEM of the percentage of isotope meal remaining in the stomach at 90 minutes (GR90) measured in rats from the NF and NF ⫹ P groups, before operation, and 15 days and 30 days postoperation (*P ⬍ .05 against preoperative values; 1-way ANOVA and Dunnet’s test; †P ⬍ .05 unpaired t test against NF group).

Fig 2. Gastric volume (GV) measured during intragastric instillation of increasing volumes of saline in rats from the NF and NF ⴙ P groups. GV was defined as the amount of saline necessary to achieve an intragastric pressure of 10 mm Hg. Each column represents a different study period. Results are expressed as mean ⴞ SEM. (*P F .05 against unoperated controls; 1-way ANOVA followed by Dunnet’s test).

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isolated NF, but have a higher risk of developing recurrent reflux than do patients who undergo an associated GE procedure.13 Jamieson et al14 studied patients 6 and 36 months after fundoplication and observed return of GE values to preoperative levels with some of the patients suffering from persistent dyspeptic symptoms. Because of the low incidence of recurrent reflux after NF in children, designing a well-controlled, randomized, long-term study to investigate the role of pyloroplasty in preventing recurrent reflux is difficult. Development of a prospective, randomized study to investigate pre- and postoperative GE in children undergoing NF with or without an associated GE procedure is limited further by costs and ethical issues. To our knowledge, within the limitations imposed by animal models, this is believed to be one of the first studies to investigate the effect on GE when combining a pyloroplasty with NF in animals. Data presented from the current study shows that adding a pyloroplasty to an NF produces a long-term improvement of GE with no late return to preoperative values. The observation that the GV remained low 30 days after the operation suggests that in the rats undergoing NF ⫹ P, facilitation of gastric outflow helped maintain IGP levels within normal range, which, in turn, prevented the progression of gastric distension and resulted in prolonged reduction in GV. There is increasing evidence that there may be an

association between elevated IGP and dyspeptic symptoms. Electrogastrographic studies have shown a correlation between altered gastric electric activity and persistent symptoms after NF.10 In normal subjects, it has been shown that an elevated IGP is perceived as a sensation of deep discomfort.15 Patients with functional gastrointestinal disorders are believed to often have even lower perception thresholds.16 A partial fundoplication, which does not decrease GV as much as the NF, and preserves the ability to burp, appears to be associated with low recurrence rates and a low incidence of the postfundoplication syndrome.17,18 Thus, in addition to correcting preoperative DGE, preventing the development of increased IGP also may help reduce the incidence of postoperative complications. The results of the current study in a normal rat model show that performing a NF produces anatomic changes in the stomach that temporarily increase GE and decrease GV and compliance. The ensuing elevation of IGP may cause chronic distension of the stomach with return to preoperative GE values. Combining a pyloroplasty with NF provides long-term enhancement of GE without producing gastric distension. These observations in the normal rat model show that a NF enhances GE transiently, whereas NF ⫹ P produces long-term enhancement of GE. It is unclear whether these observations may be related to the clinical setting.

REFERENCES 1. Fonkalsrud EW, Ashcraft KW, Coran AG, et al: Surgical treatment of gastroesophageal reflux in children: A combined hospital study of 7467 patients. Pediatrics 101:419-422, 1998 2. Hinder RA, Stein HJ, Bremner CG, et al: Relationship of a satisfactory outcome to normalization of delayed gastric emptying after Nissen fundoplication. Ann Surg 210:458-464, 1989 3. Jolley SG, Tunell WP, Leonard JC, et al: Gastric emptying in children with gastroesophageal reflux. II. The relationship to retching symptoms following antireflux surgery. J Pediatr Surg 22:927-930, 1987 4. Maddern GJ, Jamieson GG, Chatterton BE, et al: Is there an association between failed antireflux procedures and delayed gastric emptying? Ann Surg 202:162-165, 1985 5. Bustorff-Silva J, de Oliveira ER, Collares EF, et al: Effect of fundoplication on the gastric emptying of liquids. J Pediatr Surg 30:781-785, 1995 6. Wijnhoven BP, Salet GA, Roelofs JM, et al: Function of the proximal stomach after Nissen fundoplication. Br J Surg 85:267-271, 1998 7. Bustorff-Silva J, Perez CA, Fonkalsrud EW, et al: Gastric emptying following fundoplication is dependent on changes in gastric volume and compliance. J Pediatr Surg 34:1232-1235, 1999 8. Fonkalsrud EW, Ament ME: Gastroesophageal reflux in childhood. Curr Probl Surg 33:1-70, 1996 9. Cucchiara S, Salvia G, Borrelli O, et al: Gastric electrical dysrhythmias and delayed gastric emptying in gastroesophageal reflux disease. Am J Gastroenterol 92:1103-1108, 1997

10. Ravelli AM, Milla PJ: Vomiting and gastroesophageal motor activity in children with disorders of the central nervous system. J Pediatr Gastroenterol Nutr 26:56-63, 1998 11. Maddern GJ, Jamieson GG: Fundoplication enhances gastric emptying. Ann Surg 201:296-299, 1985 12. Wilbur BG, Kelly KA, Code CF: Effect of gastric fundectomy on canine gastric electrical and motor activity. Am J Physiol 226:14451449, 1974 13. Bustorff-Silva J, Fonkalsrud EW, Perez CA, et al: Gastric emptying procedures decrease the risk of postoperative recurrent reflux in children with delayed gastric emptying. J Pediatr Surg 34:79-83, 1999 14. Jamieson GG, Maddern GJ, Myers JC: Gastric emptying after fundoplication with and without proximal gastric vagotomy. Arch Surg 126:1414-1417, 1991 15. Holtmann G, Goebell H, Talley NJ: Gastrointestinal sensory function in functional dyspepsia. Gastroenterology 109:331-332, 1995 16. Lemann M, Dederding JP, Flourie B, et al: Abnormal perception of visceral pain in response to gastric distension in chronic idiopathic dyspepsia. The irritable stomach syndrome. Dig Dis Sci 36:1249-1254, 1991 17. Brown RA, Wynchank S, Rode H, et al: Is a gastric drainage procedure necessary at the time of antireflux surgery? J Pediatr Gastroenterol Nutr 25:377-380, 1997 18. Boix-Ochoa J: The physiologic approach to the management of gastric esophageal reflux. J Pediatr Surg 21:1032-1039, 1986