Can a relationship be shown between persistent delayed gastric emptying and prevision of resistance to treatment and/or recurrence in patients treated for gastro-esophageal reflux?
C. Scarpignato (Nantes, Parma),
I. Pelosini (Parma), J.P. Galmiche (Nantes)
How is gastric emptying related to gastroesophageal reflux disease?
There is now increasing evidence to suggest that gastroesophageal reflux disease (GERD) is a multifactorial disorder  with the following factors contributing to its pathogenesis:
1) the barrier to reflux provided by the lower esophageal sphincter (LES),
2) the ability of the esophagus to clear refluxed material,
3) the role played by the stomach in terms of gastric secretion, volume, distention and emptying,
4) the potential of refluxed material to damage the esophagus,
5) the intrinsic resistance of the esophageal mucosa to damage (Figure 1).
Gastric volume is the major determinant of the amount of fluid that can be refluxed: an increased gastric volume increases the likelihood of gastroesophageal reflux. Gastric volume is in its turn determined by the rate of gastric emptying, basal secretory states, duodenogastric reflux and the degree of gastric distention.
On theoretical grounds, a delayed emptying rate can be followed by an increased number and duration of gastroesophageal reflux episodes. As a consequence of the increased intragastric volume, there will be indeed an increase of gastroesophageal pressure gradient, an increase of the number of spontaneous LES relaxations and, finally, a stimulation of acid secretion with subsequent increase of the gastric content available for reflux. Furthermore, delayed clearance of bile acids and pancreatic secretions, which pass intermittently across the pylorus, may permit these toxic agents to reflux into the esophagus and to cause esophageal mucosal damage.
Figure 1. Major factors involved in the pathogenesis of GERD. (From  with permission.)
If delayed gastric emptying plays a role in the pathogenesis of the disease, it may relate to gastric distention. Already in 1980, Pettersson et al.  argued that gastric distention causes a change in gastric wall tension in the region of the LES. Later on, Samelson et al.  used a sphincter model to show that the distal end of the sphincter is stretched open before the remainder of the sphincter is affected. Delayed gastric emptying of food may act to distend the stomach and thus the LES and permit more frequent episodes of reflux to occur. A further factor may be the prolongation of post-prandial state. This is particularly important since it has been observed that GER episodes occur more frequently after meals . Inasmuch as delay in gastric emptying prolongs the post-prandial state, it may also prolong this tendency to increased reflux events.
Besides gastric distention, additional mechanisms are involved in the genesis of post-prandial GER. These include food-induced gastric secretion and the reduction of LES pressure by some meal components  and by the released peptides, especially CCK. Decrease of LES pressure, however, is responsible for only a minor proportion of reflux episodes and the post-prandial increase in gastroesophageal reflux largely results from an increase in transient LES relaxations (TLESRs) [6, 7]. In this connection, Holloway et al.  clearly showed that - although gastric distention does not affect basal LES pressure - it resulted in a significant threefold increase in the rate of TLESRs which was more marked in reflux patients, who, in addition, presented a greater proportion of complete relaxations than did normal subjects. A correlation between the number of post-prandial TLESRs and the amount of material retained in the proximal stomach has been demonstrated .
Is there a derangement of gastrointestinal motility in GERD?
It is well known to every clinician that some patients with reflux esophagitis complain of vomiting [10, 11], a symptom suggesting subclinical or overt gastric retention . More than 15 years ago DeMeester et al.  were among the first to suggest that symptomatic post-prandial gastroesophageal reflux may originate from gastric stasis. This hypothesis was supported by the finding of Behar and Ramsby  who showed that with reflux esophagitis patients have an antral motor activity which is significantly lower in comparison with that of healthy subjects. Thor and Fürstenberg  10 years later demonstrated in the small bowel of GERD patients a deranged motility pattern with an increased time interval between activity fronts of migrating motor complexes (MMCs) and a decreased frequency of contractions and subsequently Testoni et al.  showed that among patients with esophagitis 72.7% of them have less than 2 (cut-off value of healthy controls) antral MMCs during 4 h manometric monitoring of the antro-duodenal region.
Conversely from the antral one, motor function of the corpus-fundus region of the stomach has received little attention in relation to the pathophysiology of GERD. It is this region of the stomach, adjacent to the LES, that is involved in the accommodation of a meal and control of intragastric pressure . Smooth-muscle fibers forming the LES belong to the third muscular layer of the gastric wall . It seems reasonable to suppose that the occurrence of reflux of gastric contents into the esophagus requires a gastroesophageal luminal pressure gradient at the moment of reflux. In theory, therefore, a disturbance in the control of intragastric pressure may play a role in the pathogenesis of GERD. In this connection, Hartley et al.  showed that patients with GERD exhibit lower intragastric pressures in response to fundic distention compared with healthy controls. Since expulsion of liquid chyme from the stomach is largely dependent on the gastroduodenal pressure gradient , an abnormally low intragastric pressure during distention would be expected to delay gastric emptying of liquids.
What is the gastric emptying pattern in GERD?
All the above findings clearly indicate that the motility disorder in GERD is not always confined to esophagus but may also involve the stomach and small bowel. A derangement of gastric emptying of both solids and liquids should therefore be expected from the observed alterations of gastric (both antral and fundic) and intestinal motility. Studies concerning gastric emptying in GERD (for review see ), however, have provided conflicting results. Many reasons can account for discrepancies in findings [21, 22], the most striking one being a different methodological (i.e. different techniques of measuring gastric emptying and different kinds of test meal) and statistical (different methods of testing for significance between groups in gastric emptying studies) approach. In addition, criteria for selection of patient and control populations were also different in the different investigations. In particular, patients had a different gravity of the disease (with or without esophagitis), the range of control values was often wide, controls were not often age and sex matched and the influence of associated diseases (especially dyspepsia) [21, 23] was never taken into account. Patients with reflux symptoms are indeed not a homogeneous population and other digestive disorders can mimic GERD . Last but not least, when doing this kind of investigation one should keep in mind that motor derangement can be intermittent.
Although vomiting and other dyspeptic symptoms are suggestive of gastric stasis, their predictive value for the presence of documented gastric stasis is very poor . Scintigraphic studies (or other validated methods for measurement of gastric emptying) are therefore the only reliable way of evaluating the frequency of gastric stasis in GERD [20, 26]. Of 20 studies including 670 patients, in which objective evaluation of gastric emptying was performed, 14 concluded that a significant delay in gastric emptying was present in GERD patients. Amongst 10 investigations, which studied simultaneously gastric emptying of both solids and liquids, three found no delay in gastric emptying, four that stasis was present for liquids and solids, two that stasis was present for solids only and one that stasis occurred with liquids only . The frequency of delayed gastric emptying in patients with GERD, available from 16 studies, is given in Table I. Gastric stasis was found in about 40% of patients and affected solids a little more than liquids.
In most published studies, no clear correlation was found between the presence and intensity of gastric stasis and the presence and severity of reflux , or between LES pressure and the intensity of stasis . However, Micali et al.  were able to show a significant correlation between the degree of esophageal damage and the emptying half-time (Figure 2): the greater the severity of esophageal lesions, the slower the emptying rate.Accordingly, Maddern et al.  found a higher incidence of esophagitis in reflux patients with delayed gastric emptying and Collins et al.  reported a marked delay of emptying rate of both solids and liquids in patients with erosive esophagitis. These results therefore suggest not only that reflux esophagitis is accompanied by delayed gastric emptying, but also that impairement of gastric motor functions correlates with the severity of the disease. In line with this hypothesis, Corinaldesi et al. [32, 33] found that patients with severe esophagitis present gastric emptying of liquids which is significantly delayed when compared to both healthy controls and grade I-II esophagitis. In their population, however, both disease groups presented a similar delay in gastric emptying of solids when compared to controls.
How does delayed gastric emptying affect GER?
It seems therefore that reflux patients with delayed gastric emptying display a more severe esophageal mucosal damage. One reason could be the increased number and duration of gastroesophageal reflux episodes following gastric retention. Although some studies [28, 29, 34] failed to point out a relationship between gastric emptying and any of the studied parameters (e.g. LES pressure, pH-metric variables, acid secretion, etc.), we  were able to show that amongst GERD patients those with delayed gastric emptying spend a longer time at pH<4 than do patients whose emptying rate is normal (Figure 3). In patients with gastric motor derangement, a significant correlation was found between the emptying half-time and the reflux time (Figure 4). Similarly, in a group of patients submitted to antireflux surgery, those with delayed gastric emptying had an esophageal exposure to acid significantly higher than that of patients without gastric motor derangement  (Figure 5).
Figure 2. Correlation between emptying half-time and the degree of esophageal damage in 11 patients with symptomatic GERD. The line represents the least squares regression line
(y = 97.04 + 36.39x). (From  with permission.)
Figure 3. Post-prandial esophageal exposure to acid in healthy subjects and in patients with GERD. (From .)
Figure 4. Relationship
between emptying rate and esophageal exposure to acid in GERD patients responsive to medical treatment. (From .)
Figure 5. Esophageal exposure to acid in GERD patients resistant to medical treatment and submitted to antireflux surgery. (From .)
Do GERD patients resistant to medical treatment present more often with delayed gastric emptying?
Available data lead to the conclusion that patients with GERD may have either normal or abnormal gastric emptying, suggesting a delayed emptying rate not to be a critical factor in the pathogenesis of reflux disease. However, gastric motor derangement, when present, appears to be associated with (most probably favoring) the development of esophagitis. Delayed gastric emptying indeed will increase the volume of gastric contents available for reflux and, in conjunction with a delayed esophageal clearance, will strongly prolong the esophageal exposure to acid, thus resulting in development of mucosal damage. Whether the proportion of subjects with delayed emptying rate differs between patients resistant and responsive to medical treatment has not been investigated, as yet. To this end, we  have recently evaluated gastric emptying of solids and esophageal exposure to acid in two groups of GERD patients, resistant (n = 28) and responsive (n = 31) to medical therapy [high dose ranitidine (600 mg/day) or omeprazole (40 mg/day)], respectively. In both responsive and resistant patients esophageal exposure to acid was found to be dependent on emptying rate. However, delayed gastric emptying was more frequent in GERD patients unresponsive to medical treatment (Table II).
These results suggest that by increasing the intragastric volume available for reflux gastric retention can account for by resistance to medical therapy.
Although not a constant finding, the presence of a deranged gastric motility in patients with GERD has some important clinical implications. Based on data reviewed above, gastric emptying rate should be assessed in reflux patients with severe esophagitis or resistant to medical therapy. Moreover, these data further support the use of gastrokinetic compounds in the pharmacological treatment of GERD. These drugs, indeed, besides accelerating gastric emptying, also improve esophageal function by increasing LES pressure and the amplitude of primary peristaltic contractions (for review see [27, 38]). As a consequence, they reduce esophageal exposure to acid. This important pharmacological effect seems to be more pronounced in GERD patients whose emptying rate is delayed , most probably because - in this subgroup of patients - these drugs are able to correct both esophageal and gastric motor derangement. A recent study  actually showed that combining cisapride with omeprazole significantly increases its therapeutic efficacy in GERD patients with delayed gastric emptying while no benefit of added-on medication could be detected in those patients whose emptying rate fell within the normal range. Previous trials, performed in patients with unknown gastric emptying pattern, have shown that combining a prokinetic compound with an antisecretory drug gives in both short- [41-43] and long-term  management better results than those obtained with the antisecretory regimen alone. Selecting the appropriate patients (i.e. those with deranged gastric and/or esophageal motility) will most likely improve the effectiveness of added-on prokinetics.
Combination therapy with antisecretory drug and a prokinetic agent is reasonable for healing and maintenance in patients who have incomplete symptomatic improvement or mucosal healing with single drug therapy or special patients subgroups (e.g. patients whose predominant symptom is regurgitation, patients with predominant nocturnal symptoms, etc.). Combination therapy should anyway be limited to situations in which the added clinical benefit has been shown to justify the added cost .
9. Lundell L, Anvari M, Myers JC, Collins PH, Jamieson GG. The association between gastric distension and transient lower esophageal sphincter relaxations in patients with gastroesophageal reflux disease. Gastroenterology 1991;102:A478.
14. Thor K, Fürstenberg S. Deranged fasting motor activity in the duodenum and proximal small intestine in patients with reflux esophagitis. In: Siewert JR, Hölscher AH, eds. Diseases of the esophagus. Heidelberg: Springer-Verlag, 1988:1044-1046.
15. Testoni PA, Bagnolo F, Fanti L, Passaretti S, Tittobello A. Reflux esophagitis is often associated with impairment of interdigestive motility pattern of gastric antrum. Hepato-Gastroenterology 1989;36:A282.
24. Hogan WJ, Dodds WJ. Gastroesophageal reflux disease (reflux esophagitis). In: Sleisenger MH, Fordtran JD, eds. Gastrointestinal disease. Pathophysiology, diagnosis and treatment, 4th ed. Philadelphia: WB Saunders Co., 1989:594-619.
25. Jian R, Ducrotté F, Ruskoné A, Chaussade S, Rambaud JC, Modigliani R, Rain JD, Bernier JJ. Symptomatic, radionuclide and therapeutic assessment of chronic idiopatic dyspepsia. A double-blind placebo-controlled evaluation of cisapride. Dig Dis Sci 1989;34:657-664.
27. Heading RC, Baldi F, Holloway RH, Janssens J, Jian R, McCallum RW, Richter JE, Scarpignato C, Sontag SJ, Wienbeck M. Prokinetics in the treatment of gastro-oesophageal reflux disease. Eur J Gastroenterol Hepatol 1998;10:in press.
29. Bruley des Varannes S, Touchais JY, Weber J, Desechalliers JP, Sauger F, Denis P, Galmiche JP: sophagite de reflux: rôles respectifs des facteurs pathogéniques sophagiens et gastriques. Gastroenterol Clin Biol 1986;10:662-668.
31. Collins BJ, McFarland RJ, O'Hare MMT, Shaw C, Buchanan KD, Love AHG. Gastric emptying of a solid-liquid meal and gastrointestinal hormone responses in patients with erosive oesophagitis. Digestion 1986;33:61-68.
32. Corinaldesi R, Mattioli S, Stanghellini V, Pilotti V, Tosetti C, Felice V, Gozzetti G, Barbara L. Gastric acid secretion and emptying of solids and liquids in patients with severe reflux esophagitis. Gastroenterology 1989;96:A100.
38. Tytgat GNT, Janssens J, Reynolds JC, Wienbeck M. Update on the pathophysiology and management of gastro-oesophageal reflux disease: the role of prokinetic therapy. Eur J Gastroenterol Hepatol 1996;8:603-611.
41. Galmiche JP, Brandstatter G, Evreux M, Hentschel E, Kerstan E, Kratochvil P, Reichel W, Schutze K, Soule JC, Vitaux J. Combined therapy with cisapride and cimetidine in severe reflux oesophagitis: a double blind controlled trial. Gut 1988;29:675-681.
42. Wienbeck M and the Rampride Group II. Does motor stimulation by cisapride added to acid inhibition by H2-receptor blockade improve healing rates in patients with reflux esophagitis? Abstract Book, World Congress of Gastroenterology, Sidney 1990.
44. Vigneri S, Termini R, Leandro G, Badalamenti S, Pantalena M, Savarino V, Di Mario F, Battaglia G, Mela GS, Pilotto A, Plebani M, Davi G. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med 1995;333:1106-1110.