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Zentilin P, Iiritano E, Dulbecco P, Bilardi C, Savarino E, De Conca S, et al. Normal values of 24-h ambulatory intraluminal impedance combined with pH-metry in subjects eating a Mediterranean diet. Dig Liver Dis. 2006;38:226–32
Normal values of 24-h ambulatory intraluminal impedance combined with pH-metry in subjects eating a Mediterranean dietP. Zentilina, E. Iiritanoa, P. Dulbeccoa, C. Bilardia, E. Savarinoa, S. De Concaa, A. Parodia, S. Reglionia, S. Vignerib, V. Savarinoa,∗ a Department of Internal Medicine and Medical Speciality, University of the Studies of Genoa, Viale Benedetto XV, n. 6, 16132 Genoa, Italy b Department of Clinical Medicine and Emerging Pathology, Palermo, Italy ∗ Corresponding author. Tel.: +39 010 3538956; fax: +39 010 3538956. E-mail address: vsavarin@unige.it (V. Savarino). Abstract Background and aims. Multichannel intraluminal impedance combined with pH-metry is a novel technique for studying gastrooesophageal reflux. As refluxes are particularly frequent after meals, we carried out this study in order to assess the impact of a Mediterranean diet on normal values of impedancemetry. Methods. Twenty-five Italian healthy subjects (13 men, median age 29 years, range 22–67 years) without reflux symptoms were recruited for this study. They underwent oesophageal 24-h impedance + pH-metry. A Mediterranean diet was given to all subjects on the day of examination and its total energy intake was 9668.5 kJ (2300 kcal). Results. A total of 1518 refluxes were recorded during 24 h with more upright than recumbent episodes (median 15 versus 0; p < 0.01). The median total acid exposure time was 0.5% (range 0–4.2%). Acid and weakly acidic refluxes were equally reported (49% versus 51%). Weakly acidic episodes were more frequent than acid ones during 1-h postprandial periods (68% versus 32%; p < 0.0001). Liquid-only and mixed refluxes reached the proximal oesophagus (15 cm above lower oesophageal sphincter) in 42.6% of cases. Median acid clearing time was longer than median bolus clearing time (28 s versus 12 s; p < 0.01). Conclusions. This study provides normal values of pH-impedancemetry in Italian people eating a Mediterranean diet and are suitable for comparative pathophysiological investigations on reflux patients who have dietary habits similar to those of our country. © 2006 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Gastro-oesophageal reflux; 24-h ambulatory pH-impedance 1. Introduction Multichannel intraluminal impedance (MII) combined with pH-metry is a new interesting technique for the study of gastro-oesophageal reflux disease (GORD). This examination can be performed in ambulatory conditions and throughout the entire 24-h period, just like the traditional oesophageal pH monitoring. With respect to the latter method, the measurement of impedance allows us to know the physical properties of refluxate, that is if reflux episodes are composed by gas, liquid or mixed (gas + liquid) material [1–3]. Moreover, the combination of pH-metry with impedance has the relevant advantage to distinguish acid from weakly acidic reflux events, thus contributing to overcome the most important limitation of pH monitoring alone, which is not able to detect reflux events different from the acid ones [4,5]. Finally, the use of catheters with multiple impedance electrode pairs gives us an additional useful information, in that we know the antegrade or retrograde direction of the bolus along the oesophagus and, in case of the latter event, we can immediately observe how much proximally the refluxate migrates [6,7]. Two recent papers have also shown that measurements obtained with electrical impedance are highly reproducible during both the postprandial period [8] and the circadian cycle [9]. As with all the new techniques with potential widespread applicability in both research and clinical practice, the assessment of normal values is of paramount importance in order to define what is ‘GORD’ and ‘not GORD’. So far, few studies in this field have been published. Two of them were mainly performed in healthy U.S. subjects [10,11] and, although volunteers had presumably common dietary habits, important differences in normal values were observed. In fact, Shay et al. [10] found that acid refluxwas two-fold more frequent than weakly acidic reflux in their 60 healthy volunteers, while Balaji et al. [11] observed that the majority of 24-h reflux events (59%) were non-conventional acid refluxes in their 17 normal subjects. Moreover, reflux reached the proximal oesophagus in 34% of episodes of the former and in 11% of the latter study. A third investigation by Zerbib et al. [9] provides normal values from French and Belgian healthy subjects and they are partially at variance with those of U.S. studies in terms of median number of reflux events and number of acid and weakly acidic refluxes. We believe that one of the major reasons for the above discrepancies was the different meal composition adopted in the three studies, because it is well known that the majority of reflux events occur in postprandial periods, particularly in healthy subjects [12,13]. Zerbib et al. [9] and Shay et al. [10] encouraged the volunteers to eat their usual daily meals, but dietary habits partially differ between European and American populations and the daily caloric intake was not mentioned in both studies, whereas Balaji et al. [11] gave a refluxogenic meal consisting of a hamburger, fries and milkshake, even though how many times during the 24 h this kind of food was given is not reported. So, we think that there is need for a better definition of normal values in relation to a more precise characterisation of the meal composition, its energy content and timing, which can differ from country to country around the world. Therefore, we carried out this study in a group of Italian healthy volunteers, who ate a well-characterised diet, in order to assess whether our normal values obtained with MII-pH technology differ from those already published in normal people from other countries. 2. Subjects and methods Twenty-five Italian healthy volunteers without symptoms of GORD and other gastro-enterological or systemic diseases were recruited for this study. Subjects with previous oesophageal and gastric surgery were excluded. Their demographic and manometric characteristics are reported in Table 1. Each subject provided informed consent to the investigation, which was approved by our local Ethics Committee. 2.1. Study equipment A 2.1mm diameter catheter (Sandhill Scientific, Denver, CO, USA) which comprised one antimony pH sensor between the second and the third impedance rings and six electrode pairs measuring intraluminal impedance positioned at 3, 5, 7, 9, 15 and 17 cmabove the lower oesophageal sphincter (LOS). An ambulatory recorder stored the signals taken at 50 samples per second from both the six impedance rings and the pH channel during the whole 24-h period (SleuthTM, Sandhill Scientific). 2.2. Study protocol Ambulatory impedance studies were performed in each subject as outpatient after an overnight fast and a standard manometric evaluation to exclude important motility disorders was also done. The MII-pH catheter was positioned in order to have the pH sensor at 5 cm above the upper limit of LOS, as defined on the basis of the manometric study. The pH sensor was calibrated with buffers at pH 4.0 and 7.0 and an external reference electrode was attached to the anterior chest. Every MII-pH probe was used once only and we did not observe any malfunctioning of them. Each subject ate three standard meals during the examination (breakfast at 8.00 a.m., lunch at noon and dinner at 6.00 p.m.) and their composition was as follows: breakfast included 11.2 g protein, 13.2 g fat, 54.3 g carbohydrate; lunch consisted of 52.3 g protein, 33.3 g fat, 136.6 g carbohydrate and 400 ml non-sparkling water; dinner consisted of 30.4 g protein, 35.8 g fat, 107 g carbohydrate and 500 ml non-sparkling water. At breakfast, subjects ate milk and bread, at lunch and dinner pasta or rice, white meat or beef and fish or low-fat cheese, bread, vegetables and fruits. The total daily energy intake was 9668.5 kJ, corresponding to 2300 kcal (32% were supplied by fat, 16% by proteins and 52% by carbohydrates). Subjects were provided with a list of beverages with a pH< 5.0 units to be avoided between meals because they could interfere with interpretation of MII-pH data. Subjects were also asked to maintain their normal daily activities and their usual sleep schedule. Event markers on the ambulatory monitoring device recorded meal times and posture changes. Data recording was concluded after 24 h, when subjects returned to our hospital service. 2.3. Test interpretation Mean study duration was 23.26 h. A retrograde 50% fall in impedance from the baseline in the two distal impedance sites signified the presence of liquid-only reflux. Gas-only reflux was defined as an increase in impedance >3000 in any two consecutive impedance rings with one site having an absolute value >7000. When a fall in impedance to <50% of resting impedance (liquid) was preceded or followed by an abrupt rise in impedance (gas), it was defined to be a mixed refluxate. The chemical characteristics of the refluxate were defined in accordance with the criteria proposed in a recent international workshop [14]. Changes in pH measurements occurring simultaneously with at least 50% falls in impedance were classified as follows: (a) acid reflux: a pH fall to <4.0 from a pre-event pH > 4.0 units lasting for >5 s. (b) Superimposed acid reflux: liquid reflux monitored by impedance electrodes while oesophageal pH is still <4.0 units, i.e. pH in the distal oesophagus has not returned to >4.0 units after an acid reflux. (c) Weakly acidic reflux: pH nadir is ≥4.0 but <7.0 units during reflux. (d) Weakly alkaline reflux: no acid is present as intraoesophageal pH increases to ≥7.0 or remains ≥7.0 units during reflux. Gastro-oesophageal reflux detected only by the pH sensor was defined as pH-only reflux. Fig. 1 shows an example of acid, weakly acidic and weakly alkaline reflux events, according to the above-mentioned criteria. Fig. 1. Combined pH-impedance recordings showing examples of the three types of reflux. Vertical bars on impedance channels indicate the beginning and the end of bolus reflux. Horizontal bars on the pH channel show pH values. (a) Weakly acidic reflux, (b) weakly alkaline reflux and (c) acid reflux. Bolus exposure time was defined as the time from liquid bolus entry (50% fall in impedance from the baseline) to liquid bolus clearance (impedance increase to the value denoting liquid reflux entry for ≥5 s). Acid exposure time was classically defined as total time pH was <4.0 units divided by the time monitored. Extent of reflux migration was calculated for the liquid component in both liquid-only and mixed gas–liquid reflux events. Distal reflux was confined to 5 cm above the LOS, while reflux was defined intermediate if the refluxate had reached 9 cm and proximal if it had reached 15 cm above the LOS. 2.4. Data analysis Data analysis was performed via Bioview software (Sandhill Scientific), but manual analysis by two investigators was reserved for the following variables: median bolus clearing time (upright, recumbent, total), number of gas, liquid and mixed refluxes (upright, recumbent, total), number of acid and weakly acidic refluxes (upright, recumbent, total), number of postprandial reflux events with their physical and chemical characteristics. Statistical analysis was performed by means of the non-parametric Wilcoxon signed rank test because experimental data were not normally distributed. The 95th percentile was calculated. Chi-square test was used to compare median bolus and acid exposure times and percentages of acid versus weakly acidic reflux. Meal times were excluded from analysis, while the three 1-h and 2-h postprandial periods were also analysed separately from the total 24-h data. p values <0.05 were considered significant. 3. Results
The examination was well tolerated by all subjects and we did not observe any important technical failure. A total of 1518 reflux episodes were registered in our 25 healthy volunteers with a median number of 16 events per subject (95th percentile 48). All reflux events, both acid and weakly acidic, were much higher in upright than in recumbent position, with a median number of 15 (95th percentile 45) and 0 (95th percentile 4), respectively (p < 0.01). The rate of acid and weakly acidic episodes over 24 h is almost identical (49% versus 51%). Thus, about half of reflux events would have been missed by standard pH-based monitoring. Superimposed acid reflux was extremely rare, in that it was found in only 1.5% of cases. The analysis of the proportion of acid and weakly acidic reflux events in the three 2-h postprandial periods shows that weakly acidic reflux events are predominant (68%) during the first postprandial hour, while the acid ones become more numerous (61%) during the second hour after meals. This can be attributable to the fact that reflux of food itself or food mixed with gastric acid secretions prevails in earlier postprandial periods. Table 2 reports gastro-oesophageal reflux events detected over 24 h, in upright and recumbent positions. By excluding postprandial periods, acid refluxes prevailed over weakly acidic and weakly alkaline refluxes during total time and in upright position. The physical characteristics of gastrooesophageal reflux events are reported in Table 3. It appears that mixed refluxes were predominant over liquid-only and gas-only refluxes, considering both total time and upright position. Table 4 reports the exposure of oesophageal mucosa to reflux volume detected by impedance. It emerges that the median bolus clearance timewas 12 s and the median number of reflux events reaching 15 cm above the LOS was 17. The parameters of acid gastro-oesophageal reflux are reported in Table 5, where it can be seen that the median total acid exposure time throughout the whole 24-h period was 0.5% (range 0–4.2%; 95th percentile 4.0%). Moreover, the mean acid clearing time was 28 s and this value is much longer (p < 0.01) than the previously reported acid bolus clearance time (12 s). Finally, Table 6 shows the comparison of pH and impedance variables between men and women in our study. The total number of acid reflux events was significantly higher in males than in females (28 versus 11, p < 0.01); moreover, a more prolonged acid clearing time (p < 0.01), a higher number of liquid refluxes (p < 0.01) and a more proximal migration of refluxate (p < 0.01) were also observed in men. By excluding superimposed acid reflux events, median acid clearing times were significantly longer (p < 0.01) than median bolus clearing times. Fig. 2 shows the number of liquid-only and mixed reflux events which reached at various levels within the oesophagus as maximal extension. They were confined to the distal oesophagus in 3.3% of cases and reached the intermediate and the proximal oesophagus in 54.1% and 42.6% of cases, respectively. They were much more common in upright than in recumbent position (94%). Acid and weakly acidic refluxes were equally represented at 15 cm (p = 0.6); the number of liquid acid refluxes is higher than liquid weakly acidic and the mixed ones, both weakly acidic and acid (p < 0.02) (Fig. 2). Median bolus clearing time at 15 cmabove the LOS was about five-fold less than the total median bolus clearing time (2.6 s versus 12 s, p < 0.01), thus confirming that these episodes, reaching the proximal oesophagus, are cleared very quickly in healthy subjects. 4. Discussion This study is the first to characterise reflux events over the entire 24-h period in 25 Italian healthy volunteers studied with a novel technique, MII-pH test, and undergoing a typical Mediterranean diet, which differs from those adopted in other similar investigations. The upper level of 24-h oesophageal acid exposure we obtained was 4.2% and this corresponds to the normal values found by many authors using traditional 24-h pH monitoring [15,16]. This means that our population is representative of normal subjects commonly found in our and other countries. The median age of our population was 29 years and only three volunteers were over 50 years. Although young people were clearly predominant, the recent study by Zerbib et al. [9] did not show any influence of age in normal values of 24-h intraluminal impedance. As to the gender, the proportion of men and women was identical in our group of healthy volunteers, but we found that the number of acid refluxes was higher in males than in females and, in addition, they were mainly liquid and a higher number of refluxes reached the proximal oesophagus. Body mass index was similar in men and women in our study and therefore this parameter could not affect the above results. On the other hand, Zerbib et al. [9] also found an increased number of acid reflux events in males than in females and our similar findings support their suggestion that a separate analysis of impedance values in relation to gender should be taken into consideration in future pathophysiological studies. Our results show that about half of reflux events registered by MII-pH test are weakly acidic episodes, that would have not been detected using pH monitoring only. This is in contrast with data obtained by Zerbib et al. [9] and Shay et al. [10], who found that only one-third of total reflux events were weakly acidic. On the other hand, Balaji et al. [11] observed that the majority of reflux events were non-acid (59%), but this finding can be explained by the highly refluxogenic meal given to the subjects they studied. Although we do not know how many times it was given over the whole 24-h period and a separate analysis of postprandial periods was not done by these authors, it is reasonable to think that non-acid reflux events occurred mainly after meals. It is well known that the majority of reflux episodes registered in normal subjects take place in postprandial periods [12,13,17] because gastric distension favours the occurrence of transient inappropriate lower sphincter relaxations, which are the main mechanism determining reflux in healthy subjects [18,19]. In our study, weakly acidic reflux was recorded more frequently than acid reflux (68% versus 32%) during the first postprandial hour and so, we confirm data obtained by Sifrim et al. [12] and Shay et al. [10], who showed a significantly higher weakly acidic than acid reflux immediately after meals. Weakly acidic episodes prevail in these periods because they are represented by food itself or by food mixed with gastric secretions [20] and therefore their pH is generally higher than 4.0 units. For the above reasons, MII-pH has been shown to be more reliable than traditional pH monitoring in detecting all reflux events occurring after meals [1,7,12]. We found that liquid and mixed reflux events prevail in upright position and their proportions are very similar (30% versus 35%). A substantially equal distribution between liquid-only and mixed reflux events has also been reported in the study by Shay et al. (51% versus 49%, by excluding gas-only reflux from global analysis) and in the experience by Balaji et al. (35.4% versus 36.3%). If we look at the proximal extent of reflux events in normal subjects, 34% of them reached 15 cm in upright position in the study by Shay et al., 42.6% over 23 h in our study and only 11% in the paper by Balaji et al. The first two values are rather similar and confirm that reflux events can migrate proximally along the oesophagus also in healthy subjects. However, their duration is very short because the median bolus exposure time was 12 s in our study and 10.8 s in that by Shay et al. They were equally balanced between acid and weakly acidic reflux in our study, while acid reflux occurred more frequently in the study by Shay et al. The lower rate of proximal extent in the study by Balaji et al. is difficult to explain, but they had 58% of reflux reaching intermediate levels. Also in the study by Zerbib et al. [9], only 22% of reflux events reached 15 cm above the LOS and therefore this rate is lower than ours and that found by Shay et al. [10]. We did not find pH-only reflux, in contrast with the 2% rate reported by Shay et al. Also, Balaji et al. did not observe this kind of reflux detected by the pH sensor and not determining impedance changes above the LOS, but this can be due to the fact that subjects were asked not to drink acidic and carbonated beverages between meals. In fact, it has been shown that some pH-only reflux events can be attributed to the ingestion of acidic food with antegrade and not retrograde fall in impedance, which is the characteristics of all reflux events registered by MII-pH monitoring [3,14,21]. We detected a small number, only four, of weakly alkaline reflux episodes and they were also extremely rare in the studies by Shay et al. and Balaji et al. This confirms that alkaline reflux is an entity of poor physiological occurrence [4]. In the study by Zerbib et al. [9], on the contrary, the rate of weakly alkaline refluxeswas 10%, but these authors considered arbitrarily pH 6.5 instead of pH 7.0 as a limit between weakly alkaline and weakly acidic reflux events. The achievement of reliable normal values over 24 h is of paramount importance for this new technique, which has the potential of improving our pathophysiological knowledge of patients with erosive oesophagitis [12,20] as well as of those with NERD, whose subgroups with weakly acidic reflux and functional heartburn [22,23] can be better defined. Moreover, normal values of pH impedance monitoring can be useful in studies aimed at assessing the role of proximal reflux events in patients with suspected GORD associated with extraoesophageal symptoms [20] and evaluating the efficacy of medical, endoscopic and surgical therapies on both acid and non-acid reflux [24–26]. In conclusion, our normal values obtained with a standardised Mediterranean diet partially differ from those published in the same field. As meals play an important role in determining the rate of reflux events in both healthy subjects and GORD patients, it is likely that the different diets used in various studies are one of the most important reasons in explaining the divergent normal values found in them. If this is true, it should be realised that normal values achieved in some groups of subjects are not applicable to all populations studied around theworld and it is advisable that at least investigators of the same country establish their own parameters of normality. So, our normal values can be suitable for countries in which people have dietary habits similar to the Italian ones. Conflict of interest statement. None declared. References
Нормальные значения рН-импедансометрии у здоровых пациентов, находящихся на средиземноморской диете Аннотация на русском языке (М.М. Юрченко)
Известно, что гастроэзофагеальные рефлюксы особенно часто возникают после еды, поэтому было проведено исследование влияния средиземноморской диеты на нормальные значения рН-импедансометрии. Для исследования были набраны двадцать пять здоровых итальянцев (13 мужчин, средний возраст 29 лет, диапазон 22–67 лет) без симптомов рефлюкса. Они прошли 24-часовую эзофагеальную рН-импедансометрию. Всем испытуемым в день обследования была назначена средиземноморская диета, общее потребление энергии составило 9668,5 кДж (2300 Ккал). Всего было зарегистрировано 1518 рефлюксов в течение 24 часов, причем в вертикальном положении их было больше, чем в горизонтальном (медиана 15 против 0; p < 0,01). Медианное время воздействия кислоты составило 0,5% (диапазон 0–4,2%). Кислотные и слабокислые рефлюксы были зарегистрированы в равной степени (49% против 51%). Слабокислые эпизоды были более частыми, чем кислотные в течение одночасового постпрандиального периода (68% против 32%; p < 0,0001). Жидкостные и смешанные рефлюксы достигали проксимального отдела пищевода (на 15 см выше нижнего пищеводного сфинктера) в 42,6% случаев. Медианное время очищения от кислоты было больше, чем медианное время очищения от болюса (28 с против 12 с; p < 0,01). В данное исследовании получены нормальные значения pH-импедансометрии у итальянцев, придерживающихся средиземноморской диеты, что может быть использовано в сравнительных патофизиологических исследований у пациентов с гастроэзофагеальным рефлюксом, имеющих пищевые привычки, схожие с таковыми в Италии.
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