Alkaline
Gastroesophageal
By Richard A. Malthaner,
Reflux in Infants
Kurt D. Newman,
and Children
Robert Parry, Lynn F. Duffy, and Judson
G. Randolph
Washington, DC l The incidence of alkaline gastroesophageal reflux (GER) was examined in 111 consecutive children referred for evaluation of GER during a l-year period. The results of 24-hour pH monitoring studies and the medical records were retrospectively evaluated. Acid reflux was defined as occurring whenever the pH was less than 4 and alkaline reflux was defined whenever the pH was greater than 7. The percentage of time that reflux occurred, the number of reflux episodes, the number of episodes greater than 5 minutes, and the longest episode were all recorded. Based on these data, four categories of patients were identified as compared with normal values as determined by Pellegrini et al. When using criteria based on the percentage of time that reflux occurred, the largest group of children with GER was found to reflux acid (50%). However, 27 children (24%) had combined acid and alkaline reflux. Eighteen (16%) had predominantly alkaline reflux. Previously, these 16 children would have been considered as having a low likelihood of reflux by pH criteria. Endoscopic examination showed that pathological evidence of esophagitis occurred in four of the children with pure alkaline reflux. This review shows that symptomatic GER in infants and children may be due to acid or alkaline secretions or a mixture of both. A previously unrecognized cohort exists of children who demonstrate primarily alkaline reflux. These patients need to be recognized and may benefit from a therapeutic program specifically designed to control alkaline reflux. Copyright o 1991 by W.B. Saunders Company INDEX WORDS:
Gastroesophageal
reflux, alkaline, pediatric.
T
HE RETROGRADE MOVEMENT of gastroduodenal contents into the esophagus (GER) is common in infants and can result in serious morbidity and mortality.‘” Early studies by Carre indicated that without therapy, 60% of infants were symptom-free by 18 months of age, but that 30%. had persistent symptoms, with 5% developing strictures and another 5% dying of pneumonia or inanition.4.5 Advances in diagnosis and treatment have led to a decrease in the morbidity rate and an increase in the survival rate for children with severe reflux. Intraesophageal pH monitoring has become a main-
From the Departments of Surgery and Gastroenterology, Children S National Medical Center, George Washington University, Washington, DC. Presented at the Jens G. Rosenkrantz Resident Competition at the 42nd Annual Meeting of the Surgical Section of the American Academy of Pediattics, Boston, Massachusetts, October 6-7, 1990. Address reprint requests to Kurt Newman, MD, Department of Surgery, Children’s National Medical Center, Ill Michigan Ave, NW Washington, DC 20010. Copyright o 1991 by WB. Saunders Company 0022-3468/91/2608-0019$03.00/O 986
stay of the diagnosis of pediatric patients suspected of having GER.6 Most studies in children have focused on acid reflux. Alkaline esophageal reflux has not been recognized in children, although this entity has been shown in adults.7 Bile has been detected in 87% of adult patients with esophagitis, and in animal experiments, the alkaline mixture of bile and pancreatic secretions has been shown to cause severe esophagitis.8-1’ In order to assess the contribution of alkaline reflux to esophageal injury in infants and children, an investigation has been performed to determine the incidence of alkaline GER in a pediatric population.
MATERIALS
AND METHODS
Twenty-four-hour intraluminal esophageal pH monitoring studies were retrospectively evaluated in 128 consecutive children referred for symptoms of GER at our institution in 1988. Standard pH electrodes (Beckman Zeromatic IV pH meter, Irvine, CA; or Biosearch Ambi-24, Somerville, NJ) were placed in the distal esophagus of each child and the position was verified radiographitally. The measurements were recorded on a strip chart recorder. All antireflux medications were discontinued at least 24 hours prior to the study and patients were maintained in their natural position during the study. Nonthickened feedings were given and these time points were recorded. All reflux episodes occurring during feedings were eliminated. If the feedings were not recorded, the patient was excluded from the study. Each tracing was manually read by counting the number of reflux episodes and measuring the duration of each episode in minutes. Acid reflux was considered to occur whenever the pH was less than 4. The percentage of time that the esophagus was exposed to acid during the 24-hour period was calculated (number of minutes pH < 4 divided by the total time for study). In addition, the number of acid reflux episodes per hour (number of times pH < 4 divided by the number of hours of study), the number of acid reflux episodes greater than 5 min/h (number of times pH 7 divided by the total time for the study), the number of 5-minute alkaline episodes per hour (number of times pH > 7 divided by the number of hours of study), and the duration of the longest single episode of pH greater than 7 during the 24-hour period were recorded. For comparison, normal values for alkaline reflux were taken from measurements obtained from 15 asymptomatic adult volunteers originally studied and defined by Pellegrini et al.’ The mean of each parameter plus 2 SD defined the upper limit of normal. Fiberoptic upper endoscopy, upper gastrointestinal barium studies, and radionuclide “milk scans” were performed as clinically indicated. The medical records were reviewed for clinical correlation and follow-up. The official radiology and pathology reports Journal ofPediatric Surgery, Vol26, No 8 (August), 1991: pp 986-991
ALKALINE GASTROESOPHAGEAL
REFLUX
reviewed to determine the presence or absence of reflux and esophagitis. Results are expressed as the mean f SEM. Differences in means were evaluated for significance using the paired Student’s t test. Differences were considered significant if P < .05.
were
RESULTS
One hundred twenty-eight children had pH monitor recordings during a 1Zmonth period. Seventeen children were eliminated because the feeding episodes were not recorded, leaving 111 patients for evaluation.
NOll Refluxers
n=
15
n=
15
Acid
Combined
Refluxers n = 48
Refluxers n = 30
Alkaline Refluxers n=
18
Fig 2. Number of episodes per hour of esophageal pH 7 in children (*P < .Ol).
Patient Characteristics
Sixty-three children (57%) were less than 1 year of age, and eight (7%) patients were older than 10 years, the oldest being 15. There were 59 boys (53%) and 52 girls (47%). Sixty-four of the children (58%) had at least one associated illness, which included cerebral palsy/mental retardation (21%), seizures (17%), hydrocephalus (13%), cardiac anomalies (13%), prematurity (11%) bronchopulmonary dysplasia (6%) asthma (6%), hypothyroidism (3%) ureteral-vesical reflw (3%) Charge syndrome (2%), spina bifida (2%) Down’s syndrome (2%) and previous closedhead injuries (2%). Twenty-Four HourpH Esophageal Monitoring Studies
On the basis of the percentage of time that the esophageal pH was either less than 4 or greater than 7 (percent criteria), the children were divided into four groups: (1) those without acid or alkaline reflux (nonrefluxers); (2) those with acid reflux (acid refluxers); (3) those with combined acid and alkaline reflux (combined refluxers); and (4) those with alkaline reflux (alkaline refluxers). Based on this criterion, 10 children (9%) had no reflux, 56 (50%) had acid reflux, 27 (24%) had combined acid-alkaline reflux, and 18 (16%) had alkaline reflux (Fig 1).
*
251
J-
“Normals’
Tz5
I
*
When compared with normal adult values as defined by Pellegrini and investigators,’ children defined as nonrefluxers had an esophageal pH less than 4 (2.1% -t 0.4%) or greater than 7 (0.4% 4 0.1%) that was not significantly different than normals (1.5% ‘_ 0.4% and 0.4% AZ0.2%, respectively). The acid refluxers had an esophageal pH less than 4 for 20.7% f 2.5% of the time; this was significantly higher than the 1.5% + 0.4% observed in normals (P < .Ol). The percentage of time the pH was greater than 7 did not significantly differ from normal (0.5 + 0.1 v 0.4 + 0.2). Children defined as combined acid-alkaline refluxers had both acid (12.3% ‘- 1.7%) and alkaline (13.3% f 2.7%) reflux that was significantly higher than normal. The percentage of time the pH was greater than 7 for the alkaline refluxers (16.6% 2 4.3%) was also significantly higher than normal. All of the alkaline refluxers had minimal acid reflux (1.8% + 0.3%) that was similar to normals. This categorization of children into four groups persisted regardless of which criterion was used to define GER. When the number of reflux episodes per hour was analyzed, four similar groups of children were noted (Fig 2). This was also true for the number of reflux episodes greater than 5 min/h (Fig 3) and for the longest single reflux episode (Fig 4). When all four criteria were applied, 5 of 18 children categorized as alkaline refluxers by percent criteria also had significant acid reflex. However, 13 children had pure alkaline reflux by all four categories. These 13 patients would have been previously considered as having no GER when acid criteria alone were used. Radiological Studies
‘Normals’
” = 15
NWl
Refluxers n = 10
Acid Refl”XtE n = 56
Combined Refluxers n = 27
Alkaline Refhxers n-
18
Fig 1. Percent time of esophageal pH 7 in children (“P < .Ol). Normal values were derived from Pellegrini et al.7
Sixteen of the 18 children with diagnosed by pH study had upper (UGI) barium x-rays of which 11 reflux. Ten of the 18 children with
alkaline reflux gastrointestinal (69%) showed pH-probe diag-
MALTHANER
988
I
2-
nuclear milk scan showed severe reflux, and a UGI series showed mild reflux. Upper endoscopy showed mild esophagitis (Fig 5). The boy was treated with nasogastric tube feeds without antireflux medication. On subsequent follow-up, he continues on nasogastric tube feeds and persists in choking when fed orally. Retrospective analysis of the pH study showed alkaline reflux.
-2
: 2 B a r.
*
Ia t
1 --
Case 2
-- 1
0 .a z
A l-year-old girl with severe cardiac anomalies initially required a gastrostomy for persistent vomiting and failure to thrive. The child subsequently developed repeated episodes of aspiration pneumonia. A pH study was interpreted as normal, but a UGI showed severe reflux. She underwent a Nissen and gastrostomy. Presently, she is doing well on oral feedings and has had no further pneumonias. Retrospective review of the pH study showed alkaline reflux.
*
*
.z
1
l
z :’
0
n ‘Normals’
n=
15
i
0
NOfl
Acid
Combined
Alkaline
Refluxers
Refluxers
Refluxers
Refluxers
” = 45
n = 21
n = 24
n = 21
Fig 3. Number of reflux episodes of esophageal pH < 4 or > 7 that are greater than 5 min/h in children (*P < .Ol).
nosed alkaline reflux had nuclear “milk scans” which 8 (80%) showed reflux. Seventeen of these patients had either UGI, “milk scan,” or both, and (76%) of these studies confirmed the presence GER.
of 18 13 of
Endoscopy
Endoscopy was performed on 8 of the 18 children defined as alkaline refluxers by percent criteria. Four patients (50%) had microscopic evidence of esophagitis. The other four children had normal endoscopies. CASE REPORTS The following illustrative case reports are examples of children with alkaline reflux when defined by percent time the pH is greater than 7, who would have been classified as having no reflux by traditional acid criteria.
Case I A 1%year-old boy with hydrocephalus, cerebral palsy, mental retardation, and Hirschsprung’s disease, who had had a previous endorectal pull-through procedure, was referred for evaluation of vomiting and failure to thrive. The pH study was interpreted as having no acid reflux using pH criteria as defined by Euler.” A
‘Normals’
n = 15
Non
Acid
Combined
Alkaline
Refluxers
Refluxers
Refluxers
Refluxers
n=3
n = 16
n = 55
n = 37
Fig 4. Longest episode of esophageal (‘P < IN).
ET AL
pH ~4 or >7 in children
DISCUSSION
The management of GER is a significant clinical problem in children. Evaluation is often confused by conflicting tests and studies. A history of effortless regurgitation or aspiration is suggestive. Diagnostic studies including a barium meal, gastric scintigraphy, esophagoscopy, esophageal manometry, and esophageal pH monitoring are supportive of the diagnosis of GER. Meyers et al has shown that 24-hour esophageal pH monitoring is the “gold standard” in children and closely parallels clinical findings.” A variety of pH study methods are popular, including those of Euler et a1,13Sondhemier,14 and Jolley et al.” Each method has advantages and disadvantages and most centers now use several parameters to interpret pH recordings, but all are based on acid criteria. In adults, the 24-hour intraluminal esophageal pH monitor has been shown to be the most accurate test for evaluating GER.16 In normal adults, 96% of the time the pH varies between 4 and 7 at the lower end of the esophagus.” Because the frequency of “physiological” alkaline reflux in normal children is
Fig 5. Biopsy of esophagus in a patient with alkaline reflux. Specimen shows inflammatory cells and eosinophils consistent with esophagitis (original magnification x400).
ALKALINE
GASTROESOPHAGEAL
REFLUX
989
not known, we used values for alkaline reflux that had been determined in adults for the statistical comparison of pediatric alkaline GER. Data presented here show that alkaline GER occurred in a group of pediatric patients referred for evaluation of GER. Using 24-hour pH monitoring to define reflux, four groups were identified: nonrefluxers, predominantly acid refluxers, combined acidalkaline refluxers, and predominately alkaline refluxers. As expected, the largest cohort of children with GER were pure acid refluxers (50%). However, 24% of children had combined acid and alkaline reflux. In fact, 13 children (12%) had consistently “pure” alkaline reflux regardless of which criterion was used and would have been previously considered normal using acid criteria. The pH in the lower esophagus is affected by many variables. Precise pH probes and accurate daily calibration are mandatory to ensure reliable measurements. The bicarbonate concentration of saliva transiently increases when stimulated by food and this may increase the pH above 7.” For this reason, pH changes that occurred during feeding were excluded from analysis. Other causes of an alkaline esophagus include bacterial infection of the mouth or an obstructed distal esophagus, which promotes an overgrowth of bacteria. Medications that decrease gastric acidity also contribute to alkaline reflux. All antireflux medications were routinely discontinued prior to pH study; in fact, 12 of the 18 alkaline refluxers were not taking any gastric-acid-reducing drugs. Exposure of the esophageal lumen to a pH greater than 7 implies the presence of duodenal juice in the esophagus. Conjugated bile acids have been detected in the esophagus of adult patients with esophagitis.’ Rode et al observed duodenal GER in 44% of 36 neonates determined by postprandial bile stained vomiting and UGI studies and he believed that this form of the phrenopyloric syndrome was due to a motility disturbance.” Alkaline reflux gastritis and esophagitis result from
mucosal injury by duodenal contents. Esophagitis has been observed in the absence of peptic acid secretion after total gastrectomy, atrophic gastritis, and achlorhydria associated with pernicious anemia.” Severe tissue destruction can result from exposure of the esophagus to duodenal enzymes both in animal modand in humans.7JZa A recent investigation has els l&11.21 also shown that the dysplastic changes observed with Barrett’s epithelium may result from the reflux of alkaline duodenal juice into the esophagus.14 However, the exact agent responsible for esophagitis is unknown. Bile, trypsin, pepsin, and lysolecithin have all been implicated. In the presence of acid, pepsin and conjugated bile salts produce the greatest injury. In an alkaline environment, trypsin and deconjugated bile salts are more damaging.2’~24,25 In four of our alkaline reflux children, esophageal injury was detected by microscopic examination of endoscopic biopsies. This suggests that alkaline esophageal reflux may be damaging to the esophageal mucosa in pediatric patients. The therapy for alkaline reflux is unclear. In adults, medical therapy for alkaline reflux using antacids, H, antagonists, bile salt absorbants, sucralfate, prostaglandins, and metoclopramide has been unrewarding. Additionally, patients who fail standard medical therapy for reflux may do so because of a lack of efficacy against alkaline components. Clearly, further studies are required to assess the contribution of alkaline reflux to GER and to elucidate effective treatment. This retrospective review has shown that a substantial percentage (24%) of children with GER have combined acid and alkaline reflux and that another 16% have alkaline GER without acid reflux. The children with alkaline GER had severe symptomatic GER and some had biopsy-proven esophagitis; yet they would have been classified as nonrefluxers by standard pH criteria. These patients need to be recognized and may benefit from a therapeutic program specifically designed to control alkaline reflux.
REFERENCES 1. Herbst JJ: Gastro-oesophageal reflux. J Pediatr 98:859-870, 1981 2. Gastro-oesophageal reflux in children. Lancet 1:144-145, 1982 (editorial) 3. Boix-Ochoa J: Gastroesophageal reflux, in Welch KJ, Randolph JG, Ravitch MM, et al (eds): Pediatric Surgery (ed 4). Chicago, IL, Year Book, 1986, pp 712-720 4. Carre JJ: The natural history of the partial thoracic stomach (“hiatal hernia”) in children. Arch Dis Child 34:344-348, 1959 5. Carre JJ, Astley R: The fate of the partial thoracic stomach (“hiatus hernia”) in children. Arch Dis Child 35:484-486, 1960
6. Boyle JT: Gastroesophageal reflux in the pediatric patient. Gastroenterol Clin North Am 18:315-337, 1989 7. Pellegrini CA, DeMeester TR, Wernly JA, et al: Alkaline gastroesophageal reflux. Am J Surg 135177-184, 1978 8. Gotley DC, Morgan AP, Cooper MJ: Bile acid concentrations in the refluxate of patients with reflux oesophagitis. Br J Surg 75587-590, 1988 9. Cross FS, Wangensteen OH: Role of bile and pancreatic juice in production of esophageal erosions and anemia. Proc Sot Exp Biol Med 77~862~866,195l 10. Lambert R: Relative importance of biliary and pancreatic
990
MALTHANER
secretions in the genesis of esophagitis in rats. Am .I Dig Dis 7:1026-1033, 1962 11. Moffat RC, Berkas EM: Bile esophagitis. Arch Surg 91:963966,1965 12. Meyers WF, Roberts CC, Johnson DG, et al: Value of tests for evaluation of gastroesophageal reflux in children. J Pediatr Surg 20:515-520,1985 13. Euler AR, Byrne WJ: Twenty-four hour esophageal intraluminal pH probe testing: A comparative analysis. Gastroenterology 80:957-961,198l 14. Sondheimer JM: Continuous monitoring of distal esophageal pH: A diagnostic test for gastroesophageal reflux in infants. J Pediatr 96:804-807,198O 15. Jolley SG, Johnson DG, Herbst JJ, et al: The significance of gastroesophageal reflux patterns in children. J Pediatr Surg 16:859865,198l 16. DeMeester TR, Johnson LF: The evaluation of objective measurements of gastroesophageal reflux and their contribution to patient management. Surg Clin North Am 56:39-53, 1976 17. Attwood SE, DeMeester TR, Bremner CG, et al: Alkaline gastroesophageal reflux: Implications in the development of complications in Barrett’s columnar-lined lower esophagus. Surgery 106:764-770,1989
ET AL
18. Davenport HD: The Physiology of the Digestive Tract. Chicago, IL, Year Book Medical, 1971, p 85 19. Rode H, Cywes S, Davies MRQ: The phreno-pyloric syndrome in symptomatic gastroesophageal reflux. J Pediatr Surg 17:152-157,1982 20. Palmer ER: Subacute erosive (“peptic”) esophagitis associated with achlorhydria. N Engl J Med 262:927-929,196O 21. Lilliemoe KD, Johnson LF, Harmon JW: Alkaline esophagitis: A comparison of the ability of components of gastroduodenal contents to injure the rabbit esophagus. Gastroenterology 85:621628,1983 22. Kivilaakso E, Fromm D, Silen W: Effect of bile salts and related compounds on isolated esophageal mucosa. Surgery 87:280285,198O 23. Bachir GS, Collis JL: Effect of perfusion of bile salts solutions into the esophagus of hiatal hernia patients and controls. Thorax 31:271-277,1976 24. Salo JA, Kivilaakso E: Role of bile salts and trypsin in the pathogenesis of experimental alkaline esophagitis. Surgery 93:525532,1983 25. Harmon JW, Johnson LF, Maydonovitch CL: Effects of acid and bile salts on the rabbit esophageal mucosa. Dig Dis Sci 26:65-77, 1981
Discussion S.G. Jolley (Las Vegas, NV): The authors have tried to reproduce in children the data from DeMeester’s group suggesting a significant incidence of alkaline GER in adults. They’ve used similar methods for the performance and interpretation of the esophageal pH recording and have arrived at a similar conclusionthat alkaline GER is a significant problem in children with GER symptoms. I take issue with their conclusions. There are more likely explanations than alkaline GER for their false-negative results. First, frequent postprandial reflux is normal in childien, and this is not controlled for in patients receiving a variable number of feedings. Second, the observation that reflux episodes occur much more frequently during awake periods than during sleep periods in normal children was not accounted for by the JohnsonDeMeester method. Third, the buffering effect of milk or formula on gastric acid obscures acid reffux episodes in many children during the 2-hour postprandial period. When you account for the factors mentioned, virtually all children with symptoms caused by GER can be identified and separated from normal children with the pH score derived from greater than 2 hour postcibal periods. To date, I’ve performed over 1,500 pH recordings in about 1,000 infants and children. Even though I’ve looked, I have not been able to identify an episode of alkaline GER in a child who did not have an intermittent duodenal obstruction, a previous partial gastrectomy, or a gastric drainage procedure. In my experi-
ence, an esophageal pH greater than 7 has been caused by (1) increased salivation prior to feedings, following acid reflux episodes, and on awakening from sleep, (2) movement artifact, (3) antimony esophageal pH electrodes that may not be H+ selective and tend to read up to 1.0 pH unit higher than actual value, or (4) any malfunction in the esophageal pH electrode. I have three questions for the authors. First, can you document that the episodes of esophageal pH greater than 7 were in fact due to refluxed duodenal contents? Second, what type of esophageal pH electrode did you use and what length of time above pH 7 was necessary to call it a reflux episode? Third, we perform a barium swallow with an UGI series in all children with GER symptoms to exclude anatomic lesions in these areas. How can you be sure that the children with “alkaline reflux” didn’t have malrotation of the midgut? R. Foglia (St Louis, MO): I have three questions. First, was the population with the alkaline reflux different in terms of age than your patients that had the more conventional acid reflux? Second, how do you account for the combined patients with acid and alkaline reflux; if there was reflux back from the duodenum, was there less acid in those patients? Third, were they hyposecretors, and to confirm this did you look to see whether there was any bile in the stomach? W. Toyama (Marshfield, WI): I’d like to ask one question. You said that approximately 50 of these
ALKALINE
GASTROESOPHAGEAL
REFLUX
children had other illnesses that might account for this type of disorder. Could you describe this further. R.A. Malthaner (response): Our study is a retrospective study and contrary to Dr Jolley’s data there were numerous episodes where the pH did in fact go above 7. In these episodes, we specifically eliminated those that were associated with feedings for at least half an hour after the feeding. We did not feel that the increase in pH was due to bicarbonate secretion as such. The patients that had barium studies did not have any anatomic abnormalities that could have accounted for the alkaline reflux. Conditions that are known to cause an increase in pH such as esophageal stricture or infections in the oral mucosa ‘were not present. The pH probes used were antimony probes and that is the standard at our hospital. The other
991
illnesses were mainly neurological in origin, such as cerebral palsy, mental retardation, and seizure disorders. The other children had cardiac anomalies. There was only one child who had a tracheoesophageal fistula. In terms of the age differences in the groups, they were not significantly different. In the children that had combined acid and alkaline reflux, we postulate episodes of reflux of acid into the esophagus and at other times episodes of reflux of alkaline secretions into the esophagus. These are not necessarily related in time and were not related to the feeds. We did not evaluate bile in the stomach or esophagus, although determining the source of alkaline reflux is important. This is a retrospective study and we are planning a prospective study to look at these questions.
Gastroesophageal
By Richard A. Malthaner,
Reflux in Infants
Kurt D. Newman,
and Children
Robert Parry, Lynn F. Duffy, and Judson
G. Randolph
Washington, DC l The incidence of alkaline gastroesophageal reflux (GER) was examined in 111 consecutive children referred for evaluation of GER during a l-year period. The results of 24-hour pH monitoring studies and the medical records were retrospectively evaluated. Acid reflux was defined as occurring whenever the pH was less than 4 and alkaline reflux was defined whenever the pH was greater than 7. The percentage of time that reflux occurred, the number of reflux episodes, the number of episodes greater than 5 minutes, and the longest episode were all recorded. Based on these data, four categories of patients were identified as compared with normal values as determined by Pellegrini et al. When using criteria based on the percentage of time that reflux occurred, the largest group of children with GER was found to reflux acid (50%). However, 27 children (24%) had combined acid and alkaline reflux. Eighteen (16%) had predominantly alkaline reflux. Previously, these 16 children would have been considered as having a low likelihood of reflux by pH criteria. Endoscopic examination showed that pathological evidence of esophagitis occurred in four of the children with pure alkaline reflux. This review shows that symptomatic GER in infants and children may be due to acid or alkaline secretions or a mixture of both. A previously unrecognized cohort exists of children who demonstrate primarily alkaline reflux. These patients need to be recognized and may benefit from a therapeutic program specifically designed to control alkaline reflux. Copyright o 1991 by W.B. Saunders Company INDEX WORDS:
Gastroesophageal
reflux, alkaline, pediatric.
T
HE RETROGRADE MOVEMENT of gastroduodenal contents into the esophagus (GER) is common in infants and can result in serious morbidity and mortality.‘” Early studies by Carre indicated that without therapy, 60% of infants were symptom-free by 18 months of age, but that 30%. had persistent symptoms, with 5% developing strictures and another 5% dying of pneumonia or inanition.4.5 Advances in diagnosis and treatment have led to a decrease in the morbidity rate and an increase in the survival rate for children with severe reflux. Intraesophageal pH monitoring has become a main-
From the Departments of Surgery and Gastroenterology, Children S National Medical Center, George Washington University, Washington, DC. Presented at the Jens G. Rosenkrantz Resident Competition at the 42nd Annual Meeting of the Surgical Section of the American Academy of Pediattics, Boston, Massachusetts, October 6-7, 1990. Address reprint requests to Kurt Newman, MD, Department of Surgery, Children’s National Medical Center, Ill Michigan Ave, NW Washington, DC 20010. Copyright o 1991 by WB. Saunders Company 0022-3468/91/2608-0019$03.00/O 986
stay of the diagnosis of pediatric patients suspected of having GER.6 Most studies in children have focused on acid reflux. Alkaline esophageal reflux has not been recognized in children, although this entity has been shown in adults.7 Bile has been detected in 87% of adult patients with esophagitis, and in animal experiments, the alkaline mixture of bile and pancreatic secretions has been shown to cause severe esophagitis.8-1’ In order to assess the contribution of alkaline reflux to esophageal injury in infants and children, an investigation has been performed to determine the incidence of alkaline GER in a pediatric population.
MATERIALS
AND METHODS
Twenty-four-hour intraluminal esophageal pH monitoring studies were retrospectively evaluated in 128 consecutive children referred for symptoms of GER at our institution in 1988. Standard pH electrodes (Beckman Zeromatic IV pH meter, Irvine, CA; or Biosearch Ambi-24, Somerville, NJ) were placed in the distal esophagus of each child and the position was verified radiographitally. The measurements were recorded on a strip chart recorder. All antireflux medications were discontinued at least 24 hours prior to the study and patients were maintained in their natural position during the study. Nonthickened feedings were given and these time points were recorded. All reflux episodes occurring during feedings were eliminated. If the feedings were not recorded, the patient was excluded from the study. Each tracing was manually read by counting the number of reflux episodes and measuring the duration of each episode in minutes. Acid reflux was considered to occur whenever the pH was less than 4. The percentage of time that the esophagus was exposed to acid during the 24-hour period was calculated (number of minutes pH < 4 divided by the total time for study). In addition, the number of acid reflux episodes per hour (number of times pH < 4 divided by the number of hours of study), the number of acid reflux episodes greater than 5 min/h (number of times pH 7 divided by the total time for the study), the number of 5-minute alkaline episodes per hour (number of times pH > 7 divided by the number of hours of study), and the duration of the longest single episode of pH greater than 7 during the 24-hour period were recorded. For comparison, normal values for alkaline reflux were taken from measurements obtained from 15 asymptomatic adult volunteers originally studied and defined by Pellegrini et al.’ The mean of each parameter plus 2 SD defined the upper limit of normal. Fiberoptic upper endoscopy, upper gastrointestinal barium studies, and radionuclide “milk scans” were performed as clinically indicated. The medical records were reviewed for clinical correlation and follow-up. The official radiology and pathology reports Journal ofPediatric Surgery, Vol26, No 8 (August), 1991: pp 986-991
ALKALINE GASTROESOPHAGEAL
REFLUX
reviewed to determine the presence or absence of reflux and esophagitis. Results are expressed as the mean f SEM. Differences in means were evaluated for significance using the paired Student’s t test. Differences were considered significant if P < .05.
were
RESULTS
One hundred twenty-eight children had pH monitor recordings during a 1Zmonth period. Seventeen children were eliminated because the feeding episodes were not recorded, leaving 111 patients for evaluation.
NOll Refluxers
n=
15
n=
15
Acid
Combined
Refluxers n = 48
Refluxers n = 30
Alkaline Refluxers n=
18
Fig 2. Number of episodes per hour of esophageal pH 7 in children (*P < .Ol).
Patient Characteristics
Sixty-three children (57%) were less than 1 year of age, and eight (7%) patients were older than 10 years, the oldest being 15. There were 59 boys (53%) and 52 girls (47%). Sixty-four of the children (58%) had at least one associated illness, which included cerebral palsy/mental retardation (21%), seizures (17%), hydrocephalus (13%), cardiac anomalies (13%), prematurity (11%) bronchopulmonary dysplasia (6%) asthma (6%), hypothyroidism (3%) ureteral-vesical reflw (3%) Charge syndrome (2%), spina bifida (2%) Down’s syndrome (2%) and previous closedhead injuries (2%). Twenty-Four HourpH Esophageal Monitoring Studies
On the basis of the percentage of time that the esophageal pH was either less than 4 or greater than 7 (percent criteria), the children were divided into four groups: (1) those without acid or alkaline reflux (nonrefluxers); (2) those with acid reflux (acid refluxers); (3) those with combined acid and alkaline reflux (combined refluxers); and (4) those with alkaline reflux (alkaline refluxers). Based on this criterion, 10 children (9%) had no reflux, 56 (50%) had acid reflux, 27 (24%) had combined acid-alkaline reflux, and 18 (16%) had alkaline reflux (Fig 1).
*
251
J-
“Normals’
Tz5
I
*
When compared with normal adult values as defined by Pellegrini and investigators,’ children defined as nonrefluxers had an esophageal pH less than 4 (2.1% -t 0.4%) or greater than 7 (0.4% 4 0.1%) that was not significantly different than normals (1.5% ‘_ 0.4% and 0.4% AZ0.2%, respectively). The acid refluxers had an esophageal pH less than 4 for 20.7% f 2.5% of the time; this was significantly higher than the 1.5% + 0.4% observed in normals (P < .Ol). The percentage of time the pH was greater than 7 did not significantly differ from normal (0.5 + 0.1 v 0.4 + 0.2). Children defined as combined acid-alkaline refluxers had both acid (12.3% ‘- 1.7%) and alkaline (13.3% f 2.7%) reflux that was significantly higher than normal. The percentage of time the pH was greater than 7 for the alkaline refluxers (16.6% 2 4.3%) was also significantly higher than normal. All of the alkaline refluxers had minimal acid reflux (1.8% + 0.3%) that was similar to normals. This categorization of children into four groups persisted regardless of which criterion was used to define GER. When the number of reflux episodes per hour was analyzed, four similar groups of children were noted (Fig 2). This was also true for the number of reflux episodes greater than 5 min/h (Fig 3) and for the longest single reflux episode (Fig 4). When all four criteria were applied, 5 of 18 children categorized as alkaline refluxers by percent criteria also had significant acid reflex. However, 13 children had pure alkaline reflux by all four categories. These 13 patients would have been previously considered as having no GER when acid criteria alone were used. Radiological Studies
‘Normals’
” = 15
NWl
Refluxers n = 10
Acid Refl”XtE n = 56
Combined Refluxers n = 27
Alkaline Refhxers n-
18
Fig 1. Percent time of esophageal pH 7 in children (“P < .Ol). Normal values were derived from Pellegrini et al.7
Sixteen of the 18 children with diagnosed by pH study had upper (UGI) barium x-rays of which 11 reflux. Ten of the 18 children with
alkaline reflux gastrointestinal (69%) showed pH-probe diag-
MALTHANER
988
I
2-
nuclear milk scan showed severe reflux, and a UGI series showed mild reflux. Upper endoscopy showed mild esophagitis (Fig 5). The boy was treated with nasogastric tube feeds without antireflux medication. On subsequent follow-up, he continues on nasogastric tube feeds and persists in choking when fed orally. Retrospective analysis of the pH study showed alkaline reflux.
-2
: 2 B a r.
*
Ia t
1 --
Case 2
-- 1
0 .a z
A l-year-old girl with severe cardiac anomalies initially required a gastrostomy for persistent vomiting and failure to thrive. The child subsequently developed repeated episodes of aspiration pneumonia. A pH study was interpreted as normal, but a UGI showed severe reflux. She underwent a Nissen and gastrostomy. Presently, she is doing well on oral feedings and has had no further pneumonias. Retrospective review of the pH study showed alkaline reflux.
*
*
.z
1
l
z :’
0
n ‘Normals’
n=
15
i
0
NOfl
Acid
Combined
Alkaline
Refluxers
Refluxers
Refluxers
Refluxers
” = 45
n = 21
n = 24
n = 21
Fig 3. Number of reflux episodes of esophageal pH < 4 or > 7 that are greater than 5 min/h in children (*P < .Ol).
nosed alkaline reflux had nuclear “milk scans” which 8 (80%) showed reflux. Seventeen of these patients had either UGI, “milk scan,” or both, and (76%) of these studies confirmed the presence GER.
of 18 13 of
Endoscopy
Endoscopy was performed on 8 of the 18 children defined as alkaline refluxers by percent criteria. Four patients (50%) had microscopic evidence of esophagitis. The other four children had normal endoscopies. CASE REPORTS The following illustrative case reports are examples of children with alkaline reflux when defined by percent time the pH is greater than 7, who would have been classified as having no reflux by traditional acid criteria.
Case I A 1%year-old boy with hydrocephalus, cerebral palsy, mental retardation, and Hirschsprung’s disease, who had had a previous endorectal pull-through procedure, was referred for evaluation of vomiting and failure to thrive. The pH study was interpreted as having no acid reflux using pH criteria as defined by Euler.” A
‘Normals’
n = 15
Non
Acid
Combined
Alkaline
Refluxers
Refluxers
Refluxers
Refluxers
n=3
n = 16
n = 55
n = 37
Fig 4. Longest episode of esophageal (‘P < IN).
ET AL
pH ~4 or >7 in children
DISCUSSION
The management of GER is a significant clinical problem in children. Evaluation is often confused by conflicting tests and studies. A history of effortless regurgitation or aspiration is suggestive. Diagnostic studies including a barium meal, gastric scintigraphy, esophagoscopy, esophageal manometry, and esophageal pH monitoring are supportive of the diagnosis of GER. Meyers et al has shown that 24-hour esophageal pH monitoring is the “gold standard” in children and closely parallels clinical findings.” A variety of pH study methods are popular, including those of Euler et a1,13Sondhemier,14 and Jolley et al.” Each method has advantages and disadvantages and most centers now use several parameters to interpret pH recordings, but all are based on acid criteria. In adults, the 24-hour intraluminal esophageal pH monitor has been shown to be the most accurate test for evaluating GER.16 In normal adults, 96% of the time the pH varies between 4 and 7 at the lower end of the esophagus.” Because the frequency of “physiological” alkaline reflux in normal children is
Fig 5. Biopsy of esophagus in a patient with alkaline reflux. Specimen shows inflammatory cells and eosinophils consistent with esophagitis (original magnification x400).
ALKALINE
GASTROESOPHAGEAL
REFLUX
989
not known, we used values for alkaline reflux that had been determined in adults for the statistical comparison of pediatric alkaline GER. Data presented here show that alkaline GER occurred in a group of pediatric patients referred for evaluation of GER. Using 24-hour pH monitoring to define reflux, four groups were identified: nonrefluxers, predominantly acid refluxers, combined acidalkaline refluxers, and predominately alkaline refluxers. As expected, the largest cohort of children with GER were pure acid refluxers (50%). However, 24% of children had combined acid and alkaline reflux. In fact, 13 children (12%) had consistently “pure” alkaline reflux regardless of which criterion was used and would have been previously considered normal using acid criteria. The pH in the lower esophagus is affected by many variables. Precise pH probes and accurate daily calibration are mandatory to ensure reliable measurements. The bicarbonate concentration of saliva transiently increases when stimulated by food and this may increase the pH above 7.” For this reason, pH changes that occurred during feeding were excluded from analysis. Other causes of an alkaline esophagus include bacterial infection of the mouth or an obstructed distal esophagus, which promotes an overgrowth of bacteria. Medications that decrease gastric acidity also contribute to alkaline reflux. All antireflux medications were routinely discontinued prior to pH study; in fact, 12 of the 18 alkaline refluxers were not taking any gastric-acid-reducing drugs. Exposure of the esophageal lumen to a pH greater than 7 implies the presence of duodenal juice in the esophagus. Conjugated bile acids have been detected in the esophagus of adult patients with esophagitis.’ Rode et al observed duodenal GER in 44% of 36 neonates determined by postprandial bile stained vomiting and UGI studies and he believed that this form of the phrenopyloric syndrome was due to a motility disturbance.” Alkaline reflux gastritis and esophagitis result from
mucosal injury by duodenal contents. Esophagitis has been observed in the absence of peptic acid secretion after total gastrectomy, atrophic gastritis, and achlorhydria associated with pernicious anemia.” Severe tissue destruction can result from exposure of the esophagus to duodenal enzymes both in animal modand in humans.7JZa A recent investigation has els l&11.21 also shown that the dysplastic changes observed with Barrett’s epithelium may result from the reflux of alkaline duodenal juice into the esophagus.14 However, the exact agent responsible for esophagitis is unknown. Bile, trypsin, pepsin, and lysolecithin have all been implicated. In the presence of acid, pepsin and conjugated bile salts produce the greatest injury. In an alkaline environment, trypsin and deconjugated bile salts are more damaging.2’~24,25 In four of our alkaline reflux children, esophageal injury was detected by microscopic examination of endoscopic biopsies. This suggests that alkaline esophageal reflux may be damaging to the esophageal mucosa in pediatric patients. The therapy for alkaline reflux is unclear. In adults, medical therapy for alkaline reflux using antacids, H, antagonists, bile salt absorbants, sucralfate, prostaglandins, and metoclopramide has been unrewarding. Additionally, patients who fail standard medical therapy for reflux may do so because of a lack of efficacy against alkaline components. Clearly, further studies are required to assess the contribution of alkaline reflux to GER and to elucidate effective treatment. This retrospective review has shown that a substantial percentage (24%) of children with GER have combined acid and alkaline reflux and that another 16% have alkaline GER without acid reflux. The children with alkaline GER had severe symptomatic GER and some had biopsy-proven esophagitis; yet they would have been classified as nonrefluxers by standard pH criteria. These patients need to be recognized and may benefit from a therapeutic program specifically designed to control alkaline reflux.
REFERENCES 1. Herbst JJ: Gastro-oesophageal reflux. J Pediatr 98:859-870, 1981 2. Gastro-oesophageal reflux in children. Lancet 1:144-145, 1982 (editorial) 3. Boix-Ochoa J: Gastroesophageal reflux, in Welch KJ, Randolph JG, Ravitch MM, et al (eds): Pediatric Surgery (ed 4). Chicago, IL, Year Book, 1986, pp 712-720 4. Carre JJ: The natural history of the partial thoracic stomach (“hiatal hernia”) in children. Arch Dis Child 34:344-348, 1959 5. Carre JJ, Astley R: The fate of the partial thoracic stomach (“hiatus hernia”) in children. Arch Dis Child 35:484-486, 1960
6. Boyle JT: Gastroesophageal reflux in the pediatric patient. Gastroenterol Clin North Am 18:315-337, 1989 7. Pellegrini CA, DeMeester TR, Wernly JA, et al: Alkaline gastroesophageal reflux. Am J Surg 135177-184, 1978 8. Gotley DC, Morgan AP, Cooper MJ: Bile acid concentrations in the refluxate of patients with reflux oesophagitis. Br J Surg 75587-590, 1988 9. Cross FS, Wangensteen OH: Role of bile and pancreatic juice in production of esophageal erosions and anemia. Proc Sot Exp Biol Med 77~862~866,195l 10. Lambert R: Relative importance of biliary and pancreatic
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secretions in the genesis of esophagitis in rats. Am .I Dig Dis 7:1026-1033, 1962 11. Moffat RC, Berkas EM: Bile esophagitis. Arch Surg 91:963966,1965 12. Meyers WF, Roberts CC, Johnson DG, et al: Value of tests for evaluation of gastroesophageal reflux in children. J Pediatr Surg 20:515-520,1985 13. Euler AR, Byrne WJ: Twenty-four hour esophageal intraluminal pH probe testing: A comparative analysis. Gastroenterology 80:957-961,198l 14. Sondheimer JM: Continuous monitoring of distal esophageal pH: A diagnostic test for gastroesophageal reflux in infants. J Pediatr 96:804-807,198O 15. Jolley SG, Johnson DG, Herbst JJ, et al: The significance of gastroesophageal reflux patterns in children. J Pediatr Surg 16:859865,198l 16. DeMeester TR, Johnson LF: The evaluation of objective measurements of gastroesophageal reflux and their contribution to patient management. Surg Clin North Am 56:39-53, 1976 17. Attwood SE, DeMeester TR, Bremner CG, et al: Alkaline gastroesophageal reflux: Implications in the development of complications in Barrett’s columnar-lined lower esophagus. Surgery 106:764-770,1989
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18. Davenport HD: The Physiology of the Digestive Tract. Chicago, IL, Year Book Medical, 1971, p 85 19. Rode H, Cywes S, Davies MRQ: The phreno-pyloric syndrome in symptomatic gastroesophageal reflux. J Pediatr Surg 17:152-157,1982 20. Palmer ER: Subacute erosive (“peptic”) esophagitis associated with achlorhydria. N Engl J Med 262:927-929,196O 21. Lilliemoe KD, Johnson LF, Harmon JW: Alkaline esophagitis: A comparison of the ability of components of gastroduodenal contents to injure the rabbit esophagus. Gastroenterology 85:621628,1983 22. Kivilaakso E, Fromm D, Silen W: Effect of bile salts and related compounds on isolated esophageal mucosa. Surgery 87:280285,198O 23. Bachir GS, Collis JL: Effect of perfusion of bile salts solutions into the esophagus of hiatal hernia patients and controls. Thorax 31:271-277,1976 24. Salo JA, Kivilaakso E: Role of bile salts and trypsin in the pathogenesis of experimental alkaline esophagitis. Surgery 93:525532,1983 25. Harmon JW, Johnson LF, Maydonovitch CL: Effects of acid and bile salts on the rabbit esophageal mucosa. Dig Dis Sci 26:65-77, 1981
Discussion S.G. Jolley (Las Vegas, NV): The authors have tried to reproduce in children the data from DeMeester’s group suggesting a significant incidence of alkaline GER in adults. They’ve used similar methods for the performance and interpretation of the esophageal pH recording and have arrived at a similar conclusionthat alkaline GER is a significant problem in children with GER symptoms. I take issue with their conclusions. There are more likely explanations than alkaline GER for their false-negative results. First, frequent postprandial reflux is normal in childien, and this is not controlled for in patients receiving a variable number of feedings. Second, the observation that reflux episodes occur much more frequently during awake periods than during sleep periods in normal children was not accounted for by the JohnsonDeMeester method. Third, the buffering effect of milk or formula on gastric acid obscures acid reffux episodes in many children during the 2-hour postprandial period. When you account for the factors mentioned, virtually all children with symptoms caused by GER can be identified and separated from normal children with the pH score derived from greater than 2 hour postcibal periods. To date, I’ve performed over 1,500 pH recordings in about 1,000 infants and children. Even though I’ve looked, I have not been able to identify an episode of alkaline GER in a child who did not have an intermittent duodenal obstruction, a previous partial gastrectomy, or a gastric drainage procedure. In my experi-
ence, an esophageal pH greater than 7 has been caused by (1) increased salivation prior to feedings, following acid reflux episodes, and on awakening from sleep, (2) movement artifact, (3) antimony esophageal pH electrodes that may not be H+ selective and tend to read up to 1.0 pH unit higher than actual value, or (4) any malfunction in the esophageal pH electrode. I have three questions for the authors. First, can you document that the episodes of esophageal pH greater than 7 were in fact due to refluxed duodenal contents? Second, what type of esophageal pH electrode did you use and what length of time above pH 7 was necessary to call it a reflux episode? Third, we perform a barium swallow with an UGI series in all children with GER symptoms to exclude anatomic lesions in these areas. How can you be sure that the children with “alkaline reflux” didn’t have malrotation of the midgut? R. Foglia (St Louis, MO): I have three questions. First, was the population with the alkaline reflux different in terms of age than your patients that had the more conventional acid reflux? Second, how do you account for the combined patients with acid and alkaline reflux; if there was reflux back from the duodenum, was there less acid in those patients? Third, were they hyposecretors, and to confirm this did you look to see whether there was any bile in the stomach? W. Toyama (Marshfield, WI): I’d like to ask one question. You said that approximately 50 of these
ALKALINE
GASTROESOPHAGEAL
REFLUX
children had other illnesses that might account for this type of disorder. Could you describe this further. R.A. Malthaner (response): Our study is a retrospective study and contrary to Dr Jolley’s data there were numerous episodes where the pH did in fact go above 7. In these episodes, we specifically eliminated those that were associated with feedings for at least half an hour after the feeding. We did not feel that the increase in pH was due to bicarbonate secretion as such. The patients that had barium studies did not have any anatomic abnormalities that could have accounted for the alkaline reflux. Conditions that are known to cause an increase in pH such as esophageal stricture or infections in the oral mucosa ‘were not present. The pH probes used were antimony probes and that is the standard at our hospital. The other
991
illnesses were mainly neurological in origin, such as cerebral palsy, mental retardation, and seizure disorders. The other children had cardiac anomalies. There was only one child who had a tracheoesophageal fistula. In terms of the age differences in the groups, they were not significantly different. In the children that had combined acid and alkaline reflux, we postulate episodes of reflux of acid into the esophagus and at other times episodes of reflux of alkaline secretions into the esophagus. These are not necessarily related in time and were not related to the feeds. We did not evaluate bile in the stomach or esophagus, although determining the source of alkaline reflux is important. This is a retrospective study and we are planning a prospective study to look at these questions.
