Aliment Pharmacol Ther 2005; 21: 29–34.

doi: 10.1111/j.1365-2036.2004.02298.x

An evaluation of the antireflux properties of sodium alginate by means of combined multichannel intraluminal impedance and pH-metry P. ZENTILIN*, P. DULBECCO*, E. SAV ARINO*, A. PAROD I*, E. IIRITANO*, C. BILAR DI*, S. REGLIONI*, S. VIGN ERI  & V. SAVARINO* *Dipartimento di Medicina Interna e Specialita` Mediche, Universita` di Genoa, Genoa, Italy;  Dipartimento di Medicina Clinica e Patologie Emergenti, University of Palermo, Palermo, Italy Accepted for publication 4 October 2004

SUMMARY

Background: Alginate-based preparations act as mechanical antireflux barrier, which can reduce both acid and non-acid reflux events and limit the proximal migration of oesophageal refluxate. Aim: To evaluate all the above features with a novel technique, multichannel electrical impedance and pH-metry. Methods: Ten reflux patients underwent stationary impedancemetry and pH-metry after eating a refluxogenic meal. They were studied 1 h in basal conditions and 1 h after taking 10 mL of Gaviscon Advance. In both sessions, measurements were obtained in right lateral and supine decubitus.

INTRODUCTION

Alginate-based formulations are used worldwide for the symptomatic treatment of gastro-oesophageal reflux disease (GERD) with successful results.1, 2 They have also proven efficacy in the therapy of GERD in infants.3, 4 These drugs appear to act by a unique mechanism, which differs from that of traditional antacids. In the presence of gastric acid, alginates precipitate forming a gel. They also contain sodium bicarbonate, that, in the acid milieu of the stomach, is rapidly converted to Correspondence to: Prof. V. Savarino, Cattedra di Gastroenterologia, Dipartimento di Medicina Interna e Specialita` Mediche, Universita` degli Studi di Genova, Viale Benedetto xv, n. 6, 16132 Genova, Italy. E-mail: [email protected] Ó 2005 Blackwell Publishing Ltd

Results: Alginate preparation was able to decrease significantly (P < 0.05) the number of acid reflux events and the percentage time pH < 4.0 compared with baseline. There was no effect of the drug on nonacid refluxes. Gaviscon Advance was also significantly effective (P < 0.05) in reducing the height of proximal migration of reflux events compared with baseline in both decubitus positions. Conclusions: Our findings explain how Gaviscon Advance controls acid reflux episodes, limits the proximal migration of refluxed material and thereby decreases symptoms in clinical practice.

carbon dioxide which becomes entrapped within the gel precipitate and forms a foam floating as a raft on the surface of gastric contents.5 So, alginate preparations act by means of a physical mechanism, which does not rely on absorption into the systemic circulation. As to the mode of action proposed to explain the antireflux effect of these agents, several studies have shown that the alginate-based raft remains in the upper part of the stomach as a physical barrier capable of preventing reflux episodes6, 7 or moves into the oesophagus in place or ahead of gastric contents during reflux events.8 In recent years, a new alginate preparation (Gaviscon Advance) has been introduced in the market. It has a higher alginate content/unit volume than the traditional 29

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Liquid Gaviscon and, consequently, can be administered in lower dosage volume (5–10 mL compared with 10–20 mL) and this improves patient compliance.9 Moreover, the amount of sodium to be taken per dose is obviously reduced. Finally, Gaviscon Advance achieves an improved gastric retention as well as a superior gastric distribution compared with Liquid Gaviscon, with more remaining in the upper part of the stomach.10 Some studies8, 11–13 have shown the ability of Gaviscon Advance to diminish the reflux of acid into the oesophagus significantly, but it cannot be excluded that non-acid reflux episodes can also be controlled by the alginate-based raft-forming formulations. Moreover, the raft action as a mechanical reflux barrier may have the potential to reduce the proximal extent of refluxate along the oesophagus. The above possible advantages of Gaviscon Advance can now be easily assessed by means of combined multichannel intraluminal impedance (MII) and pH-metry.14, 15 This novel technique is able to overcome the most important limitation of traditional pH testing, i.e. the measurement of only acid reflux. In contrast, electrical impedance allows us to distinguish liquid from air refluxes and to differentiate between acid and non-acid liquid refluxes, depending on the concomitant changes in the intra-oesophageal pH.16, 17 Moreover, the impedance catheter contains multiple pairs of ring electrodes along the oesophagus, so that an exact assessment of the proximal extent of refluxed material can be achieved. Some investigations have already shown that this modern technique can be very useful in assessing the effectiveness of drugs or endoscopic devices proposed for the therapy of GERD, particularly if we want to know whether they can affect both acid and non-acid reflux or are able to reduce the proximal migration of the refluxate.18–20 In the present study, we decided to evaluate the effect of the antireflux barrier formed by Gaviscon Advance on both acid and non-acid reflux and on the height of proximal extent of reflux events along the oesophagus by means of a stationary apparatus combining impedancemetry with traditional pH testing (MII/pH).

PATIENTS AND METHODS

Patients Ten patients (six females and four males) with heartburn lasting for more than 6 months and occurring at

least three times weekly were included in this study. They had a mean age of 45.5 years (range 32–70). In fertile women, pregnancy was excluded by urine pregnancy analysis. No patient had previous oesophageal or gastric surgery or underwent concomitant therapies of any type. Patients treated with antisecretory or prokinetic drugs were asked to stop them at least 10 and 2 days, respectively, before the start of the trial. All patients underwent upper GI endoscopy no more than 1 month before the start of the study. Seven of them had non-erosive reflux disease and the other three had breaks in the oesophageal mucosa (two patients had grade A and one patient had grade B oesophagitis, according to Los Angeles classification). Hiatal hernia was detected in six patients. The study protocol was approved by our local Ethics Committee and was performed according to the Declaration of Helsinki. All patients gave written informed consent before the start of the trial. Methods Before undergoing stationary MII/pH, oesophageal manometry was performed in each patient in order to assess the pattern of body peristalsis of the organ and to determine lower oesophageal sphincter (LOS) location. Then, patients ingested a refluxogenic meal consisting of a continental breakfast (one cappuccino and two brioches containing cream, 350 kcal, 60% fat), 10 min before the MII/pH recording. Combined MII/pH measurements were obtained with a stationary apparatus (Sandhill Scientific Inc., Highlands Ranch, CO, USA). A 2.1-mm catheter with six pairs of ring electrodes set at 2 cm intervals was used. As impedance is measured between two adjacent electrodes, six measuring segments are available, four in the distal part of the oesophagus (at 2, 4, 6 and 8 cm from the electrode tip) and two in the proximal part of the organ (at 14 and 16 cm). A single pH antimony electrode is located between the second and third impedance ring electrodes. The probe was connected to a datalogger that continuously recorded pH and impedance measurements with a sampling rate of 50 Hz at each site. The MII/pH catheter was passed into the oesophagus transnasally and positioned with the pH electrode 5 cm above the upper margin of the LOS. After positioning the catheter, patients underwent 2-h periods of recording; one session was performed 1 h in basal conditions and another session 1 h after a Ó 2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 29–34

ALGINATE EFFECT ASSESSED BY IMPEDANCEMETRY

Data processing and statistical analysis All tracings were manually analysed by two investigators who calculated the number of acid (pH < 4.0 for at least 5 s) and non-acid reflux episodes (pH > 4.0 units) both in the 1 h basal conditions and in the 1-h period after taking the drug. A separate calculation for the two decubitus positions was also performed. Moreover, the proximal migration of reflux episodes was evaluated in the various periods of recording. Statistical analysis was performed with non-parametric tests, given the small number of patients studied. The median was used as central tendency parameter and the Wilcoxon signed rank test was adopted in order to compare the number of reflux episodes and the level of proximal extent of reflux events between basal and after-drug periods. The level of significance was set at P < 0.05. RESULTS

The MII/pH examinations were well tolerated and resulted successfully in each patient. The median value of LOS pressure was normal (22.5 mmHg, range 4–42). Moreover, the median wave amplitude was normal (72.5 mmHg, range 50–180), but all patients showed manometric alterations of oesophageal peristalsis: variable amplitude of waves and multipeak waves, particularly in the distal part of the oesophagus. A total of 112 reflux events (84 acid and 28 non-acid events) were registered in basal conditions compared with 85 reflux events (26 acid and 59 non-acid events) after taking Gaviscon Advance. The difference between the number of basal and after-treatment acid refluxes was significant (P < 0.05), both in right lateral and supine decubitus positions. Figure 1 shows that the alginate preparation was able to reduce significantly (P < 0.05) the total percentage time elapsed below pH 4.0 units compared with basal values, when patients lay both in right lateral decubitus Ó 2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 29–34

18.0

% time at pH < 4 (median values)

single dose (10 mL) of Gaviscon Advance (Reckitt Benkiser Healthcare, Hull, UK). Studies were performed while patients lay in the right lateral decubitus position for 1/2 h and in supine decubitus position for another 1/2 h, both in basal conditions and after taking the alginate treatment. In particular, the right lateral decubitus was chosen because it has been shown to be associated with an increased oesophageal acid exposure.21, 22

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Basal After alginate intake

14.0 12.0 10.0 8.0 6.0 4.0

P < 0.05

P < 0 .05

2.0 0.0

Right lateral

Supine

Figure 1. Median oesophageal acid exposure in basal conditions and after alginate intake in the two decubitus positions.

and in supine decubitus positions. The reduction in the number of acid reflux events in each patient is shown in Figure 2 and it is evident that this effect occurred in all patients, but one. The effect of Gaviscon Advance on the number of nonacid reflux events was not significant, both in right lateral decubitus (median number 0.5 vs. 2, P < 0.10) and in supine decubitus positions (median number 1 vs. 1; P > 0.2). Rather surprisingly, the number of nonacid reflux events almost doubled after drug intake in five patients, as displayed in Figure 3. In the same patients, the number of acid reflux events was seen to diminish markedly, as displayed in Figure 2. Figure 4 shows that the alginate-based raft-forming preparation was able to reduce significantly the proximal migration level of all reflux events. This occurred when patients lay both in right lateral decubitus (median height 15 cm vs. 13 cm; P < 0.05) and in supine decubitus positions (median height 13.5 cm vs. 11.5 cm; P < 0.05). DISCUSSION

Our study shows that the effect of Gaviscon Advance on reflux events of a group of 10 patients with GERD is consistent, although it varies in relation to the type of acid and non-acid liquid refluxes. The alginate reduces substantially the number of acid refluxes and the percentage time spent below pH 4.0 units compared with basal values. In particular, the reduction in the number of acid reflux events would be expected because alginate antireflux agents act via a mechanical barrier action.13 This beneficial effect can be seen both in the right lateral and in supine decubitus positions for the

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No. acid reflux episodes

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Figure 2. Number of acid reflux episodes in basal conditions and after alginate intake in each patient studied.

No. non-acid reflux episodes

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total period of 1 h of our study and a recent investigation23 using a sophisticated technique, such as magnetic resonance imaging, has confirmed that the raft-forming alginate remains above the underlying meal for at least 60 min in all subjects evaluated. The good control of acid reflux observed confirms the results obtained in previous investigations performed with traditional pH-metry11–13 or with scintigraphic methods8, 24 and explains the proven effective and quick control of GERD symptomatology, in particular, heartburn, in both adults1, 2, 25 and infants.3, 4, 26, 27 A recent study by Poynard et al.28 on a very large sample of patients (n ¼ 1030) with grade I, II and III oesophagitis, according to Savary–Miller classification, has also

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Figure 3. Number of non-acid reflux episodes in basal conditions and after alginate intake in each patient studied.

shown the benefit of alginate in preventing symptomatic relapse over a period of 6 months of self-care treatment. No analogous action of alginate on non-acid reflux events was found in our study. Our data show that the median number of reflux events was not reduced in both decubitus positions and, it is noteworthy that it increased markedly in five patients after drug intake (see Figure 3). Conversely, the number of acid reflux episodes greatly diminished in all of them, as shown in Figure 2. This seems to confirm a previous observation by Vela et al.,18 who noted that omeprazole is very effective in abolishing acid refluxes, but the number of non-acid reflux events was seen to increase greatly after Ó 2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 29–34

ALGINATE EFFECT ASSESSED BY IMPEDANCEMETRY

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Proximal migration level (cm)

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Figure 4. Difference in median height of proximal migration of all reflux events between baseline and after alginate intake in the two decubitus positions.

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0.0

treatment with the proton pump inhibitor. It seems that the good control of acid unmasks non-acid reflux events and this phenomenon may have also occurred in our investigation. Non-acid reflux events detected by MII/ pH are very rarely alkaline refluxes17 and mainly consist of food itself or food contents mixed with gastric secretions.16 So, it is reasonable to think that the reduction in acid, independent of the way it is obtained, increases the number of non-acid material reflux. It is also possible that the transient increase in gastric pH determined by bicarbonate entrapped within the alginate gel29 or the reflux of the non-acid alginate itself into the oesophagus5 may favour this effect. The shift from acid to non-acid reflux events in the postprandial period is a new phenomenon, the observation of which has been allowed by the modern method we used in this study and further studies are required for a clearer picture. For the first time, the novel technique we have adopted in our study has permitted us to assess the ability of Gaviscon Advance to reduce the proximal migration of reflux material, independent of the position of the patient. This further advantage of the drug may be because of the fact that the raft acts as a cork in the LOS to prevent any gastric material from refluxing into the oesophagus30 or as a movable neutral sealant that temporarily occupies the oesophageal lumen when a gastric pressure wave pushes it up into the oesophagus.5 This beneficial effect can be of help in reducing not only typical, but also atypical symptoms, which are favoured by the migration of the refluxate up to the Ó 2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 29–34

Right lateral

Supine

mouth and then to the airways.31 In fact, in a previous investigation, Ramon et al.32 studied 104 asthmatic patients and 10 with intractable cough, who were treated with alginate combined with cimetidine. These authors observed an improvement in respiratory symptoms in 50% of cases and also seven of the 10 patients with chronic cough ameliorated by controlling gastrooesophageal reflux with the above-mentioned therapy. The accurate assessment of the height of oesophageal reflux with the single thin catheter used in MII/pH measurements certainly represents one of the most exciting future applications of MII/pH, in that this can improve our knowledge of the relationship between reflux events and atypical manifestations of GERD (hoarseness, chronic cough, asthma, etc.). In conclusion, our study confirms that Gaviscon Advance allows us to achieve a good control of acid reflux episodes and shows the ability of the drug to limit the proximal migration of reflux events. These findings explain its efficacy in relieving typical symptoms of GERD and the possible role of the drug in reducing atypical manifestations of GERD also. REFERENCES 1 Williams DL, Haigh GG, Redfern JN. The symptomatic treatment of heartburn and dyspepsia with Liquid GavisconÒ: a multicentre general practitioner study. J Int Med Res 1979; 7: 551–5. 2 Poynard T, Vernisse B, Agostini H for a Multicentre Group. Randomized, multicentre comparison of sodium alginate and cisapride in the symptomatic treatment of uncomplicated

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Ó 2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 21, 29–34