What are the boundaries between physiologic and pathologic reflux in relation to age in infancy?

S.R. Orenstein (Pittsburgh)

To determine the boundaries between physiologic and pathologic reflux requires a definition of "physiologic" or "normal". Several meanings of this term are possible. The first is purely quantitative, a proportion (for example, 95%) of all individuals are considered to fall within this definition of normal and the "tail(s)" of the distribution are considered abnormal. The other meaning is a qualitative one, which connotes that no harm results.

It is evident that reflux which is quantitatively normal may be qualitatively abnormal: if, for example, the refluxate is aspirated, or if the refluxate triggers harmful bronchospasm. Similarly, reflux which is abnormal in a strictly quantitative sense may, nevertheless, produce no harmful effects and thus be considered qualitatively physiologic. This paper will address both meanings, and explore whether there are age-related boundaries between physiologic and pathologic reflux.

Reflux quantification

Methods of quantifying reflux in children range from the very nontechnical (simple observation for regurgitation), to very technical (barium fluoroscopy, gastroesophageal scintigraphy and pH probe).

Observation for regurgitation was earliest method of documenting reflux and still has a role in identifying reflux in infants, although it is clear that such regurgitant reflux represents at most only "the tip of the iceberg" of reflux episodes and that regurgitant reflux may even result from different mechanisms than nonregurgitant reflux [1]. Data from our Infant Gastroesophageal Reflux Questionnaire (©Susan Orenstein, 1992) indicate that parents report that about 70% of infants referred for evaluation for reflux disease (and a similar proportion of them who are subsequently shown to have reflux disease) will have regurgitation as "a problem" [2], in contrast to about 20% of infants seen in a well baby clinic (unpublished data). Specifically, the parents of the infants with reflux report that about 80% of them regurgitate at least once a day and at least 5 ml per episode, whereas only 40% of nonreferred, well infants do so. It can be seen that there is both significantly more regurgitation in infants with reflux disease and a great deal of overlap between them and normal infants. After a year of age, regurgitation is infrequent in children with reflux disease as well as in normals.

Fluoroscopic barium gastroesophagography has been used for several decades to document the occurrence of gastroesophageal reflux episodes. Without using provocative maneuvers, fluoroscopy demonstrates reflux episodes more often and higher in the esophagus in children with reflux disease than in those without

symptoms of reflux disease, although, again, there is overlap between normals and reflux patients. The reflux episodes also decrease in frequency and height in the esophagus during aging in normals. A retrospective study of 470 children delineated the upper range of normal for the number of episodes seen in 5 min of fluoroscopy: younger than 6 weeks, three episodes; 7 weeks-1 year, two episodes; 1-6 years, one episode; and over 6 years, less than one episode [3]. This study also crudely quantified the volume of refluxate, by distinguishing reflux that reached the level of the clavicles from reflux that did not. Of the reflux episodes in each age group of asymptomatic children, the proportion which reached the clavicles decreased with age: 86% of episodes in normal infants younger than 6 weeks old reached the clavicles, whereas only 20% of the episodes in the normal teenagers did.

Scintigraphic gastroesophagography was introduced for evaluation of reflux less than 2 decades ago [4,5]. Scintigraphic monitoring, like fluoroscopic monitoring, documents reflux in the postprandial period. In contrast to fluoroscopy, however, the monitoring can be done during an entire postprandial hour without prohibitive radiation exposure and the "meal" is a physiological meal, rather than barium. Theoretically, one could quantify frequency, actual volume and duration of reflux episodes, but I am aware of no published data quantifying reflux scintigraphically in relation to age in normal children. One could roughly estimate the normal limits of scintigraphic reflux in relation to age from pH probe-measured postprandial reflux following an acid meal [6], but 24-h pH probe values for asymptomatic normal infants and children are only known using milk formula feedings [7,8], which hide postprandial reflux from detection by the pH probe.

Figure 1) [7,8,10]. The total daily duration of esophageal acidification is a product of the frequency of episodes and their (mean) duration. Two other measures related to total esophageal acid exposure which are often scored on pH probes are the number of episodes longer than 5 min and the duration of the longest episode. Finally, the pH probe's ability to quantify the degree of acidity and the capabilities of computerized scoring systems have led investigators to measure the "area under the curve", a product of the degree of acidity and the duration of exposure [11-14].

Predicting qualitative abnormalities

Only the pH probe measures have been evaluated in detail for their ability to predict qualitative abnormalities (disease) due to gastroesophageal reflux. Several scores have been published which have been mathematically derived to select those patients with reflux disease [15,16], but these derived scores have the disadvantage of obscuring the primary data [17,18]. In contrast, several different simpler scores have been

Figure 1. .Physiologic reflux: range of normal values (mean ± 2SD) in children of various ages (n = 285) and in adults (n = 15). Top panel depicts frequency of reflux episodes; bottom panel depicts total duration of esophageal acidification throughout the day, during normal activities and diet [8,10]. Figure previously published [9].

shown to correlate with different manifestations of reflux disease.

Thus the reflux index (the percentage of the day with esophageal pH < 4) is greater in those with esophagitis than in those without esophagitis. In both children [19] and adults [20], all controls without esophagitis have a reflux index below 10%, whereas one half to two-thirds of those with esophagitis have a reflux index greater than 10%; this cutoff does not appear to vary much with age. Another study in adults found by Receiver-Operating-Characteristic analysis that the optimal cutoff was slightly lower, 7% with a sensitivity and specificity of 89 and 93%, although half of the "patients" were endoscopically normal (histology was not reported) [21].

The area under pH 4 curve (AUC), which correlates with the reflux index [11,14], is also greater in patients with esophagitis than in those without. Extrapolating from data presented graphically [14], it seems that one can calculate that a cutoff value of 20 min-units-below-four (e.g., 20 min of pH 3, or 10 min of pH 2) per hour of monitoring is a good predictor of histologic esophagitis. I have calculated its sensitivity as 93%, its specificity as 88%, its positive predictive value as 84% and its negative predictive value as 95% for the children presented. Other investigators have identified

a corresponding value of 32 per day (i.e., 1.3 per hour) to predict reflux disease in general [12]. The 15-fold difference may reflect the insensitivity of esophageal histology from grasp biopsies for identifying children with problematic reflux and the nonspecificity of a reflux index of 4%, the gold standards used by the two groups of investigators. There are no data, however, to assess whether this cutoff value varies with age. For both the AUC and the reflux index, one might expect that the lifetime duration of acid exposure might play a role in the genesis of esophagitis; thus it may be that esophagitis in very young children requires a greater degree or duration of daily acid exposure, because of the necessarily limited lifetime duration of exposure. The mean duration of reflux during sleep is a score which has been correlated with respiratory complications of reflux by several investigators [22-24]. A value of about 4 min has been found to be a useful threshold; again, this value has not been evaluated in relationship to age.

Conclusion

Infants manifest more reflux than adults when evaluated by any of several methods, including simple observation for regurgitation, fluoroscopic monitoring and pH probe monitoring. However, pH probe studies of normal infants and adults clearly show that this decrease in acid gastroesophageal reflux during infancy is much less than one might anticipate from the decrease in observable regurgitation during this period of maturation.

The decrease in some manifestations of reflux disease (such as malnutrition or apnea) during development is unlikely to be due to simple reduction in reflux quantity, but rather to be due to other developmental changes (such as suppression of regurgitation or of abnormal respiratory reflexes). Similarly, the increase in other manifestations of reflux disease (such as esophagitis, Barrett's esophagus, or stricture) is likely to be due to a cumulative increase in lifetime esophageal exposure to injurious material.

References

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2. Orenstein SR, Cohn JF, Shalaby TM, Kartan R. Reliability and validity of an infant gastroesophageal reflux questionnaire. Clin Pediatr 1993;32:472-484.

3. Cleveland RH, Kushner DC, Schwartz AN. Gastroesophageal reflux in children: results of a standardized fluoroscopic approach. Am J Roentgenol 1983:141:53-56.

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5. Heyman S, Kirkpatrick JA, Winter HS, Treves S. An improved radionuclide method for the diagnosis of gastroesophageal reflux and aspiration in children (milk scan). Radiology 1979;131:479-482.

6. Orenstein SR, Klein HA, Rosenthal MS. Scintigraphic images for quantifying pediatric gastroesophageal reflux: a study of simultaneous scintigraphy and pH probe using multiplexed data and acid feedings. J Nucl Med 1993:34:1228-1234.

7. Vandenplas Y, Govaerts H, Helven R, Sacre L. Gastroesophageal reflux, as measured by 24-h pH monitoring, in 509 healthy infants screened for risk of sudden infant death syndrome. Pediatrics 1991 ;88:834-840.

8. Vandenplas Y, Sacre SL. Continuous 24-h esophageal pH monitoring in 285 asymptomatic infants 0-15 months old. J Pediatr Gastroenterol Nutr 1987:6:220-224.

9. Orenstein SR. Gastroesophageal reflux. In: Stockman J. Winter R (eds) Current Problems in Pediatrics. Chicago: Mosby Year Book Medical Publishers, 1991:193-241.

10. Johnson LF, DeMeester TR. Twenty-four-hour pH monitoring of the distal esophagus: a quantitative measure of gastroesophageal reflux. Am J Gastroenterol 1974:62:325-332.

11. Stoker D, Williams J, Colin-Jones D. Use of the area under the curve to assess the esophageal pH test. Gastroenterology 1991 ;100(5,Pt2):A 169.

12. Tovar J, Izquierdo M, Eizaguirre I. The area under pH curve: a single-figure parameter representative of esophageal acid exposure. J Pediatr Surg 1991:26:163-167.

13. Izquierdo M, Tovar J, Eizaguirre I. L'exposition acide oesophagienne en un seul chiffre: la surface sous la courbe de pH. Chir Pediatr 1989:30:1-5.

14. Vandenplas Y, Franckx CA, Pipeleers MM, Derde MP, Sacre SL. Area under pH 4: advantages of a new parameter in the interpretation of esophageal pH monitoring data in infants. J Pediatr Gastroenterol Nutr 1989:9:34-39.

15. Jolley SG, Johnson DG, Herbst JJ, Pena A, Gamier R. An assessment of gastroesophageal reflux in children by extended monitoring of the distal esophagus. Surgery 1978;84:16-23.

16. Euler AR, Byrne WJ. Twenty-four-hour esophageal intraluminal pH probe testing: a comparative analysis. Gastroenterology 1981:80:957-961.

17. Grill BB. Twenty-four-hour esophageal pH monitoring: what's the score? J Pediatr Gastroenterol Nutr 1992:14:249-251.

18. Friesen CA, Hayes R, Hodge C, Roberts CC. Comparison of methods of assessing 24-h intraesophageal pH recordings in children. J Pediatr Gastroenterol Nutr 1992:14:252-255.

19. Baer M, Maki M, Nurminen J, Turjanmaa V, Pukander J, Vesikari T. Esophagitis and findings of long-term esophageal pH recording in children with repeated lower respiratory tract symptoms. J Pediatr Gastroenterol Nutr 1986:5:187-190.

20. Schlesinger PK, Donahue PE, Schmid B, Layden T. Limitations of 24-h intraesophageal pH monitoring in the hospital setting. Gastroenterology 1985:89:797-804.

21. Schindlbeck NE, Heinrich CH, Konig A, Dendorfer A, Pace F, Muller-Lissner SA. Optimal thresholds, sensitivity, and specificity of long-term pH-metry for the detection of gastroesophageal reflux disease. Gastroenterology 1987:93:85-90.

22. Johnson DG, Jolley SG, Herbst JJ, Cordell LJ. Surgical selection of infants with gastroesophageal reflux. J Pediatr Surg 1981:16(4, suppl l):587-594.

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G.H. Willital (Münster)

What are the diagnostic procedures for gastroesophageal reflux in children?

The diagnostic procedure to be undertaken in children suspected of gastroesophageal

reflux (GER) is a program of several points (Tables 1-3):

a. Family history: the most striking general symptoms in newborns and babies with GER are microaspirations with pulmonary distress syndrome at different intervals of time. Main clinical signs are recurrent atelectasis, recurrent pneumonia, and recurrent respiratory distress syndrome. One has to keep in mind that the lower esophageal sphincter (LES) has to undergo a maturation which takes between 1 and 1.5 years. This means that children may have, within this interval of time, a physiological reflux.

Table I. .Normal values for 24-h monitoring of intraesophageal pH in children

	Parameter	pH < 4 (% of time)	Reflux episodes (longest <12 min)
	Overall	<3.4%	#/d + 4(#>5'/day) < 50
	Fasting	<2.2%	1/h
	2-h postprandial	<10%	< 5/h

Table 2. .Classification of endoscopic findings in esophagitis according to Savary and Miller

	Stage	Endoscopic findings
	0	Symptoms of reflux without epithelial defects
	I	Few erosions
	II	Confluent but not circular erosions
	III	Circular erosions or ulcers
	IV	Peptic stricture

b. Measurement of pH, performed as a 24-h pH-metry in order to determine: length of reflux periods, frequency of reflux periods, deepest pH value during reflux episodes.

c. Manometry studies: these manometry studies are performed with double or triple tip catheter in order to record the pressure inside the abdomen, at the level of the LES and in the lower part of the esophagus. This enables the determination of the resting pressure inside the LES (between 15-25 mmHg in babies, toddlers and children). Furthermore, pressure upon the abdomen, and consecutively pressure inside the stomach, will not be registered in cases of a competent LES to the lower distal esophagus. This also can be registered by esophageal manometric studies.

d. Endoscopic investigations: they enable to determine whether alterations of the distal part of the esophagus can be recognized (edema, erosions, ulcers, scar formations, stenosis, classification of Savary and Miller). Furthermore, endoscopic investigations enable the determination of whether the esophagogastric junction is open or can be opened by air insufflation: if the sphincter is competent, air insufflation will cause no visible, spontaneous opening of the LES.

e. Scintigraphic investigations: they enable to determine scintigraphically the passage and the motility of the esophagus as well as the function of the LES and the function of the pylorus. One has to keep in mind that pylorus spasms are combined with a GER in about 15-18% of the cases.

Table 3. .Normal values for manometry of the lower esophageal sphincter (LES) in children

	Parameters	Normal	Pathological
	Pressure LES	10-20 mmHg	< 6 mmHg
	Abdominal length LES	2-4 cm	< 1 cm
	Total length LES	2.5-6 cm	< 2 cm

What is the indication for surgery in GER in children?

There is a physiological reflux in newborns and babies within the first year of life with an incompetent LES, reaching its normal activity within the 12 to 18 months after birth. The indication for reflux operation in children depends very much upon histology, pH-metry, endoscopy and esophageal manometry, especially if the reflux endoscopically demonstrates signs to be classified in the group of Savary and Miller type III and IV (i.e., alterations, bleeding, scar formations and stenosis), and is independent from age. In all other cases reflux below the age of 1-1.5 years should be treated conservatively.

In children not older than 1.5 to 2 years, if reflux occurs clinically and if manometric, endoscopic, and pH investigations demonstrate GER clearly, indication for surgery is also mandatory.

Which is the adequate operative procedure to treat GER in children?

There are four main surgical steps to be observed:

a. Intraoperative endoscopy of the esophagus, in order to determine the esophagogastric junction, is important to perform the retroesophageal hiatus plasty at the right level; this means not too low and not too high with regard to the gastroesophageal junction. The other point is that the endoscope lying inside the esophagus should be just the right size, in order to create the pathway through the diaphragm in an adequate diameter, not too wide and not too narrow. Therefore, intraoperative endoscopy is a very helpful method to perform the retroesophageal hiatus plasty adequately. The surgeon himself can see the light of the intraesophageal endoscope, so that this procedure can be performed with extreme precision by diaphanoscopy .

b. Fixation of the hiatus muscle to the esophagus at the right level, to be determined by intraoperative endoscopy.

c. Fixation of the fundus to the abdominal esophagus in order to create the angulation of His.

d. Fixation of the fundus of the stomach to the diaphragm in order to avoid recurrencies.