Archives of Disease in Childhood 1993; 69: 655-659

Omeprazole and high dose ranitidine in thetreatment of refractory reflux oesophagitis

S Cucchiara, R Minella, C Iervolino, M T Franco, A Campanozzi, M Franceschi,F D'Armiento, S Auricchio

2nd School ofMedicine, UniversityofNaples, Italy,Department ofPaediatricsS CucchiaraR MinellaC IervolinoMT FrancoA CampanozziS Auricchio

Department ofPathologyF D'Armiento

Schering Plough,MilanM Franceschi

Correspondence to:Dr Salvatore Cucchiara,Department of Paediatrics,GI Endoscopy and MotilityUnit, Facolta di Medicina,University of Naples'Federico H', Via S Pansini5, 80131 Napoli, Italy.Accepted 28 July 1993

AbstractThirty two consecutive patients (age range6 months-13*4 years) with severe refluxoesophagitis were randomised to a thera-peutic trial for eight weeks during whichthey received either standard doses ofomeprazole (40 mg/day/1*73 m2 surfacearea) or high doses of ranitidine (20mg/kg/day). Twenty five patients com-pleted the trial (12 on omeprazole, 13 onranitidine). At entry and at the end of thetrial patients underwent symptomaticscore assessment, endoscopic and histo-logical evaluation of the oesophagus, andsimultaneous oesophageal and gastric pHmeasurement; results are given as median(range). Both therapeutic regimens wereeffective in decreasing clinical score(omeprazole before 24-0 (15-33), after 9-0(0-18); ranitidine before 19 5 (12-33), after9-0 (6-12)), in improving the histologicaldegree ofoesophagitis (omeprazole before8-0 (6-10), after 2-0 (0-60); ranitidinebefore 8-0 (8-10), after 2-0 (2-6)), and inreducing oesophageal acid exposure,measured as minutes of reflux at 24 hourpH monitoring (omeprazole before 129*4(84-217), after 44-6 (0.16-128); ranitidinebefore 207-3 (66-306), after 58-4 (32-128))as well as intragastric acidity, measuredas median intragastric pH (omeprazolebefore 2-1 (1.0-3.0), after 5S1 (2.2-7.4);ranitidine before 1*9 (1.6-4), after 3-4(2-3-5.3)). Serum gastrin concentrationwas >150 ng/l in four patients on omepra-zole and in three patients on ranitidine.It is concluded that in children withrefractory reflux oesophagitis high dosesof ranitidine are comparable withomeprazole for the healing ofoesophagitisand relief of symptoms; both drugsresulted in efficacious reduction of intra-gastric acidity and intraoesophageal acidexposure.(Arch Dis Child 1993; 69: 655-659)

Gastro-oesophageal reflux (GOR) disease is acomplex disorder with several pathogeneticcomponents.1 2 Motility abnormalities such aslower oesophageal sphincter incompetence,defective oesophageal clearance, and delayedgastric emptying play a major part in the occur-rence of reflux; however, gastric acid is crucialfor the development and severity of oeso-phagitis, as well as for the clinical sequelae ofthe disease.3 The role of gastric acid secretionin the pathogenesis of GOR disease is

emphasised by the fact that improved healingrates of oesophagitis are obtained through apowerful and sustained inhibition of gastricacid secretion induced by omeprazole, a sub-stituted benzimidazole that inhibits theH+/K+ATPase enzyme of the gastric parietalcells.47 Omeprazole has also resulted inmucosal healing in most patients with severeoesophagitis resistant to long term and/or highdose treatment with H2 receptor antagonists.89

It is generally agreed that GOR disease inchildhood exhibits a more benign clinicalcourse after medical treatment compared withadults.'0 Nevertheless, severe reflux disease iscommon in children and can be responsible forsignificant morbidity and life threateningevents'l; furthermore, surgery is not uncom-monly performed in children with persistent orintractable GOR disease.'2

In this study we have compared omeprazolewith ranitidine given at high doses in childrenwith GOR disease resistant to traditional anti-secretory treatment associated with pro-kinetics. We wished to evaluate the clinicalefficacy and the effect on oesophagitis and onboth oesophageal and gastric acidity of the twotherapeutic regimens.

Patients and methodsThirty two consecutive patients (age range 6months-13 4 years; 16 boys and 16 girls)were enrolled in this study. These patientshad previously received a diagnosis ofGOR oesophagitis, based on 24 hour intra-oesophageal pH monitoring and endoscopywith histology of the oesophageal mucosa. Allhad been unresponsive to an antireflux treat-ment including combined administration ofranitidine (8 mg/kg/day, given in two doses)and cisapride (0-8 mg/kg/day, given in threedoses) for eight weeks. Unresponsiveness wasdefined as persistence of GOR symptoms andoesophagitis as detected by endoscopy andhistology. None of the patients entering intothe study had received combined treatment ofcisapride and ranitidine for a period longerthan eight weeks.

Before enrolment in the study, patientsunderwent symptomatic assessment, 24hour intraoesophageal and intragastric pHmeasurement, and endoscopy of the oesopha-gus with biopsy. Patients were randomised toan eight week therapeutic trial of eitheromeprazole (40 mg/day/1 73 m2 surface area)given each morning or high doses of ranitidine(20 mg/kg/day) morning and evening. Oeso-phageal strictures, systemic extraintestinal

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Table 1 Scoring system for symptoms ofGOR disease

Symptoms Points

Vomiting and/or regurgitation 0 Absent (that is < 1)(No of days/week) 3 1

6 2-<59 >5

Recurrent pneumonia and/or 0 Noneasthma (No of episodes/2 6 1monthsX6) 12 2

18 3Anorexia or early satiety(%)* 0 >75-100

3 >50-756 >25-509 <25

Pyrosis, chest pain, irritability 0 Absent (that is < 1)(No of days/week) 3 1-3

6 >3-<79 >7

*Inability to finish a normal size meal, expressed as percentageof calories taken with meals in comparison with daily calorierequirement (over the week preceding the symptom evalua-tion).

diseases, and neurological disorders were

excluded in all patients. Treatment was startedwithin three days of the baseline endoscopyand pH study, which were performed by one ofthe authors who was unaware of the drugassignment and clinical follow up.Symptoms were quantified at baseline and at

the end of the trial by grading, on a weeklybasis, GOR symptoms using a scale 0-3-6-9(table 1). For this purpose, parents were

instructed to record, on a diary card, frequencyand severity of GOR symptoms. A physicalexamination was performed at each study visit.Blood and urine samples were collected atthe entry and at the end of the trial.Haematological and biochemical analysisincluded complete blood cell count, erythro-cyte sedimentation rate, serum creatinine,bilirubin, alkaline phosphatase, aspartateaminotransferase, alanine aminotransferase,serum electrolytes, and urinalysis. Fastingserum gastrin concentrations were obtained atbaseline and at the end of the treatment.Twenty four hour combined measurement

of intraoesophageal and intragastric pH was

performed with two flexible pH glass elec-trodes (Ingold M 1-5, Urdorf, Switzerland)passed through the naso-oesophageal routeand positioned in the distal oesophagus and inthe gastric corpus, respectively. The tip of theoesophageal electrode was located at the 87%of the distance between nares and loweroesophageal sphincter as determined accord-ing to Strobel's formula in patients under theage of 1 year.'3 In subjects older than 1 year or

over 1 metre in height the tip of the electrodewas positioned fluoroscopically so that it laidover the third vertebral body above thediaphragm throughout the respiratory cycle.'4The tip of the intragastric electrode was

located in the gastric corpus under fluoroscopyand was checked again the following day, at theend of the test. A silver/silver chloride refer-ence electrode was applied to the chest skin.The measuring electrodes were carefully cali-brated at the beginning and at the end of eachstudy using commercially available standardbuffer solutions (pH 4 0 and pH 7-0,Beckman); drift of the electrodes wereaccepted if less than 0-2 pH units. GOR wasdefined whenever the distal oesophageal pH

dropped to less than 4-0 for at least 20 seconds.The electrodes were connected with a portablebattery operated recorder (Proxima 'Light',Synectics, Milan); data recorded were trans-ferred to an IBM personal computer andanalysed by Esophogram software 5-4(Synectics, Milan).The following intraoesophageal and intra-

gastric pH parameters were measured: the timethe oesophageal pH was <4 0 (oesophagealexposure acid time); intragastric median pH;intragastric hydrogen activities (mMol/1) thatwere converted from the pH values using a

standard table15; and the time the intragastricpH was less than 4 0 and 2-0. During the pHtest patients were provided with standardisedmeals for their age. The meals were adminis-tered at a predetermined time for each patient.No beverages with pH below 4 0 were givenand no food was allowed during the intervalsbetween meals. All the pH studies were startedat 8-00 am, after an overnight fast; all patientswere requested to stop drugs affectinggastrointestinal motility and reducing gastricacid secretion for at least one week before thepH study. The oesophageal and gastric pHstudies were performed at the beginning and atthe end of the trial; the final pH study was

done while patients were still receiving drugs.Endoscopy of the oesophagus was per-

formed with a paediatric fibreoptic endoscope(model GIFPQ20, Olympus, Torino) with a

bioptic channel having 2-8 mm diameter. Twobiopsy specimens were taken from the distaloesophageal mucosa, avoiding biopsies fromthe distal 20% of the oesophagus. Specimenswere examined for the following features: basalcell zone hyperplasia, elongation of the papil-lae, ingrowth of vessels in the papillae,presence of intraepithelial eosinophils and/orneutrophils, and findings of mucosal erosionsor ulcerations. Table 2 reports our scoring sys-

tem for the histological criteria of oesophagitis.Histological specimens were examined withthe aid of an ocular micrometer. Duringendoscopy oesophageal mucosa was observedfor the presence of friability, granularity,erosions, and ulcerations. The latter, whenpresent, were biopsied directly, even if locatedin the most distal oesophageal tract. Theendoscopy was performed at baseline andwithin 48 hours of finishing the trial.

Results are given as median (range) values.The non-parametric tests were used for stat-istical analysis. A p value less than 0 05 was

Table 2 Scoring system for histologicalfeatures of refluxoesophagitis

(A)

(B)(C)

(D)

(E)

Features

Elongation of papillae,* thickening of basal celllayert

A+ingrowth of vessels in the papillaeA,B+ 1-19 eosinophils and/or neutrophils on themost involved high power field

A,B+>20 eosinophils and/or neutrophils on themost involved high power field

Findings of mucosal erosions and/or ulcerations.Bleeding and slough of the mucosa

Points

2

46

8

10

*Papillae elongated if their height, relative to the thickness ofthe epithelium, was at least >50%.tBasal cell hyperplasia if its thickness, related to the entirethickness of the epithelium, was >25%.

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Table 3 Median (range) intraoesophageal and intragastricpH variables before and aftertreatment in the two groups

Omeprazole

Before treatmentTime of oesophageal pH <4-0 (min)Median intragastric pHIntragastric hydrogen activity (mmol/l)Time of intragastric pH <4 0 (min)Time of intragastric pH <2-0 (min)

After treatmentTime of oesophageal pH <4-0 (min)Median intragastric pHIntragastric hydrogen activity (mmol/l)Time of intragastric pH <4 0 (min)Time of intragastric pH <2-0 (min)

129-4 (84-217)2-1 (1-0-3-0)13-9 (1-2-100)

1301 (1065-1405)712 (272-1167)

44-6 (0-16-128)5-1 (22-7.4)*1 -4 (0 01-6-3)*

869 (483-1167)**290 (17-2-512)*

Ranitidine

207-3 (66-306)1-9 (1-6-4)

12-9 (0 1-25-12)1150 (1008-1388)807 (396-1036)

58-4 (32-128)**3-4 (2 3-5 3)**1-3 (0-01-5 0)*

851 (273-1127)**330 4 (17-2-535.6)*

*p<0.01, **p<0 05 v values before treatment.

considered as significant. The parents gaveinformed written consent and the protocol was

approved by the ethics committee of thefaculty.

ResultsOf the 32 patients originally recruited for thisstudy, 25 completed the trial and seven wereunable to complete the study, three on raniti-dine and four on omeprazole. Four of thesepatients were excluded as a result of non-

compliance with the protocol, two were lost tothe follow up, and one was withdrawn becauseof prolonged fever and upper respiratory infec-tions. Thirteen patients received high doses ofranitidine and 12 had omeprazole. The twogroups were comparable at baseline for severityof symptom score (omeprazole 24-0 (15-33);ranitidine 19-5 (12-33); not significant) andoesophagitis score (omeprazole 8-0 (6-10);ranitidine 8-0 (8-10); not significant).Endoscopy showed in eight patients on

omeprazole and in nine on high dose ranitidineerosions affecting the entire circumference ofthe distal oesophagus. In three patients on

omeprazole and in three on ranitidine therewere isolated rounded or linear erosions affect-ing the most distal oesophagus and not theentire circumference. In one patient onomeprazole and in one on ranitidine endoscopyshowed oerythema and friability with spon-taneous or contact bleeding. Intraoesophagealand intragastric pH variables were also similarin the two groups of patients (table 3). At theend of the trial both groups improved on theclinical score (omeprazole 9 0 (0-18), p<0-01;ranitidine 9-0 (6-12), p<0 01). Marked symp-tom relief (decrease of symptom score B60%)was observed in 10 patients on omeprazole andin nine patients on high doses of ranitidine.Both groups of patients had significantdecrease in histological score compared with

Table 4 Median (range) percentage of improvement of intraoesophageal and intragastricpH variables in the two groups

Time of oesophageal pH <4-0Time of intragastric pH <4-0Time of intragastric pH <2-0Median intragastric pHIntragastric hydrogen activities (mmol/l)

Omeprazole

61-9 (34-99)29-0 (16-4-62-8)61-5 (7-2-98 4)60-1 (9-3-81)97-9 (20 6-99-9)

Ranitidine

59-6 (2-83.4)**22-3 (2-1-72-8)**62-2 (0-35-95-6)**37-4 (0-56-7)*91-0 (0-98 7)**

*p<005 between omeprazole and ranitidine group.**No statistical difference between the two groups.

pretrial values (omeprazole 2-0 (0-6), p<0 01;ranitidine 2-0 (2-6), p<001). Healing ofoesophagitis (return to grade 0 or grade 2 ofhistological score) occurred in nine patients onomeprazole and in eight patients on high dosesof ranitidine.Endoscopy after the trial revealed isolated

small erosions affecting the distal oesophagusin three patients treated with omeprazole andin five patients on ranitidine; oerythema andoedema of distal oesophageal mucosa wereobserved in five patients on omeprazole and insix patients on ranitidine; oesophageal mucosaappeared normal in four patients treated withomeprazole and in two with ranitidine. Boththerapeutic regimens decreased markedlyoesophageal acid exposure time as well asintragastric acidity (table 3). Table 4 reportsthe percentage improvement of intra-oesophageal and intragastric pH variables inthe two treatment groups.Three patients on ranitidine and four on

omeprazole had fasting serum gastrin values> 150 ng/l at the end of the study. The highestreported serum gastrin concentration was 346ng/l for the omeprazole group and 482 ng/l forthe ranitidine group. No serious adverse eventsto require discontinuing treatment and noabnormalities in the laboratory results wereobserved.At the end of the trial drug treatment was

stopped; however, if symptoms reappeared,patients were treated with courses of cisaprideand ranitidine at conventional doses, asomeprazole or high dose ranitidine were notconsidered for long term treatment. At a sixmonth follow up after the end of the trial, sevenpatients previously treated with omeprazole andfive with high dose ranitidine were still sympto-matic and showed both abnormal oesopl.agealacid exposure at prolonged pH monitoring andoesophagitis at endoscopy (and histology); twoof them underwent antireflux surgery.

DiscussionThis study is the first controlled randomisedtrial comparing omeprazole with high doses ofranitidine in children with severe GOR disease,refractory to conventional treatment with H2blockers and prokinetics. Omeprazole inhibitsthe final step in acid production, that is theenzyme H+/K+ATPase in the parietal cells.16 Inseveral comparative studies in adults a clearsuperiority of omeprazole over standard dosesof H2 blockers in healing oesophagitis andimproving symptoms has been reported.17-22The efficacy of omeprazole in healing pepticoesophagitis is also evident when the drugis compared with high doses of H2 antag-onists.8 9 23 24 This has been attributed to amore complete and long lasting suppression ofgastric acid secretion induced by omeprazole ascompared with the currently available H2receptor blockers.'6 25 In our study the rate ofoesophagitis healing and symptom reliefinduced by omeprazole was comparable withthat observed with high dose ranitidine; further-more, both therapeutic regimens producedsimilar rates of decrease in oesophageal acid

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exposure and intragastric acidity. However,omeprazole was more effective than high doseranitidine in increasing intragastric median pH;this might be due to a less sustained acidsuppression by high dose ranitidine as comparedto omeprazole in individual cases, but a partiallack of efficacy of ranitidine cannot beexcluded.25 These results seem to confirm thecommon belief that refractoriness of GORdisease is mainly due to inadequate inhibition ofgastric acid secretion with the currently recom-mended doses ofH2 receptor blockers.26 On thispurpose, a recent report in paediatric patientssuggests that standard doses of H2 blockersmight not be adequate for effective suppressionof gastric acidity.27 Our results seem also to be atvariance with those reported in adults, in whoma clear superiority of omeprazole over high doseranitidine in improving symptoms and healingoesophagitis has been reported.'6 This could beexplained by the much higher dosage ofranitidine in this study than that used inprevious trials in adult patients.

While omeprazole has widely been used inadults with a severe degree of oesophagitis,experience with the drug in children is verylimited. In one report, three children withsevere reflux oesophagitis (two with centralnervous system disease), were successfullytreated by omeprazole.28 Recently, 15 childrenwith severe reflux disease, resistant to conven-tional treatment or high doses of ranitidine,were successfully treated with omeprazoleadministered for long term period (4-23months); in these patients the dose of the drugwas tailored on the basis of repeated 24 hourintraoesophageal pH monitoring.29We assessed intragastric acidity by con-

tinuous intraluminal pH measurement ofthe stomach.30 This technique is useful forpharmacological and physiological studies ofintragastric acidity in patients with uppergastrointestinal tract disease, provided thatvariables related to the method arestandardised, that is type and localisation ofthe electrode, timing of feedings, and intervalsbetween feeding.30 31 The method has pre-viously been validated and has been shown tobe as valid as gastric content sampling formeasurement of acidity of the stomach.32

Treatment aimed at intensively suppressinggastric acid secretion in children with refrac-tory oesophagitis might improve the long termcourse of the disease and avoid antirefluxsurgery. However, 12 of our patients weresymptomatic six months after the end of thetherapeutic trial with either omeprazole or highdose ranitidine and two needed antirefluxsurgery. Previous studies in adults have shownthat short term treatment with omeprazoledoes not reduce the relapse rate of thedisease.'6 33 This could be explained by returnof the intragastric pH to pretreatment values orby failure of omeprazole administered for ashort period to affect the motility abnormalitiesplaying a part in the occurrence of refluxevents, such as incompetence or transientrelaxation of lower oesophageal sphincterand/or delayed gastric emptying.' 2 Thetendency to recurrence of symptoms of almost

half of our patients after stopping drugs mightindicate the need for long term administrationof omeprazole or high dose ranitidine (andother drugs such as prokinetics) as mainte-nance treatment for the prevention of compli-cation and surgery.

Administration of omeprazole to humansresults in increased plasma gastrin concentra-tions because of marked suppression of gastricacidity.34 However, this increase is significantlylower than that occurring after completeanacidity of the stomach, such as in perniciousanaemia or in the experimental condition ofantrum exclusion.35 36 Furthermore, plasmagastrin concentrations after administration ofomeprazole are lower and less sustained thanthose detected in classical hypergastrinaemicconditions such as Zollinger-Ellison syn-drome.37 There is some concern about thehypergastrinaemia detected in patients treatedchronically with omeprazole, was long termstudies of toxicity in animals indicate thatenterochromoaffin-like cell carcinoids canarise in rats exposed life long to omeprazole.38Recent studies in man, however, indicate thatomeprazole, given at the recommended doses,does not affect gastric oxyntic endocrinecells.39

In conclusion, children with severe refluxoesophagitis resistant to previous treatmentwith conventional doses of ranitidine, consti-tute a group that can be successfully treatedwith high doses of ranitidine or with omepra-zole. Our study indicates that short termadministration of omeprazole and high doseranitidine are safe and effective. On the otherhand, as the relapse rate of the disease seems tobe unaffected by the drugs given for shortperiod, some patients would require long termtreatment. Data on long term administrationof these drugs in children are very limited.

This paper has been presented in abstract form at the XXVIAnnual Meeting of the European Society for PaediatricGastroenterology and Nutrition, Gothenburg, Sweden, 27June-I July 1993.

This paper is dedicated to Professor Salvatore Auricchio onhis sixtieth birthday.

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