Gut 1996; 38: 649-654

PAPERS

Relation between oesophageal acid exposure andhealing of oesophagitis with omeprazole inpatients with severe reflux oesophagitis

R H Holloway, J Dent, F Narielvala, AM Mackinnon

AbstractBackground/aims-Reducing oesophagealacid exposure by suppressing acid secre-tion with omeprazole is highly effective inhealing reflux oesophagitis. Some patientswith severe oesophagitis, fail to heal andwhether this results from inadequate acidsuppression or other factors is unclear.The aim of this study, was to investigatethe relation between oesophageal acidexposure and healing in patients withsevere reflux oesophagitis treated withomeprazole.Methods-Sixty one patients with grade3 or 4 ulcerative oesophagitis weretreated for eight weeks with omeprazole20 mg every morning. Those patientsunhealed at eight weeks were treatedwith 40 mg every morning for a furthereight weeks. Endoscopy and 24 houroesophageal pH monitoring were per-formed before treatment and at the endof each treatment phase while receivingtreatment.Results-Thirty per cent of patients failedto heal with the 20 mg dose. Unhealedpatients had greater total 24 houroesophageal acid exposure before treat-ment, and while receiving treatment alsohad greater acid exposure and a smallerreduction in acid exposure than didpatients who healed. Forty seven per centofthe unhealed patients also failed to healwith the 40 mg dose. These patients hadsimilar levels of acid exposure beforetreatment to those who healed, but hadgreater acid exposure while receivingtreatment, particularly at night whensupine.Conclusions-Patients with severe ulcera-tive oesophagitis who are refractory toomeprazole have greater oesophageal acidexposure while receiving treatment thanresponding patients. This is due to areduced responsiveness to acid suppres-sion, and is likely to be an importantfactor underlying the failure of theoesophagitis to heal.(Gut 1996; 38: 649-654)

Keywords: gastro-oesophageal reflux, pH monitoring,gastric acid secretion, oesophagus.

The duration of oesophageal acid exposure isthe most important factor determining theseverity of reflux symptoms1 and the degree ofoesophagitis2 3. Sustained high level acid sup-pression with the potent acid pump inhibitor,omeprazole, has proved an extremely effectivetreatment for reflux oesophagitis. Completehealing has been reported in 70% to 90% ofpatients4-10 even in patients who were refrac-tory to H2 receptor antagonistsll-14. Healingrates, however, in the most severely affectedpatients with endoscopic grades 3 and 4 aresubstantially less, only 58%, with doses up to40 mg per day6. The reasons for this failure arenot clear. A direct relation exists between heal-ing rate and the degree of acid suppressionover 24 hours'5, and inadequate acid suppres-sion appears to be an important factor under-lying the failure to heal with H2 receptorantagonists.5 16 A recent study'7 in patientswith severe reflux oesophagitis that was refrac-tory to omeprazole showed that such patientshad persistent pathological reflux, particularlyat night. However, the relation betweenoesophageal acid exposure and healing ofoesophagitis with omeprazole has not been for-mally studied in a prospective manner. Theaim of this study, therefore, was to investigatethe relation between oesophageal acid expo-sure and healing of oesophagitis with omepra-zole in patients with severe oesophagitis.

Methods

PatientsSixty one outpatients (49 M, 12 F age range23-86 years, mean 63) with severe refluxoesophagitis, endoscopic grade 3 or 46 wererecruited at three Adelaide university teachinghospitals: Royal Adelaide Hospital (22patients), Repatriation General Hospital(21 patients), and Flinders Medical Centre (17patients). Patients were excluded if aged under18 years. Other reasons for exclusion were pre-vious oesophageal gastric or duodenal surgeryexcept for simple closure of a perforation ordilatation, presence of strictures (other thanmild) requiring dilatation, oesophagitis due tosystemic disease, infection, intubation or othermechanical trauma, caustic or other bums,irradiation or physical deformity, concurrentgastric or duodenal ulcer or oesophageal

GastrointestinalMedicine, RoyalAdelaide HospitalR H HollowayJ Dent

GastroenterologyUnits RepatriationHospital, AdelaideF Narielvala

Flinders MedicalCentre, Adelaide,South AustraliaAM Mackinnon

Accepted for publication20 November 1995

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varices, ongoing upper gastrointestinalhaemorrhage, other serious illness (cardiac,renal or hepatic disease, or evidence of malig-nancy), treatment with an investigational drugwithin four weeks of the initial endoscopy or

use of any antisecretory or prokinetic agentafter the initial endoscopy, and alcoholism,drug misuse or other conditions considered tointerfere with patient compliance. No pregnantor lactating women were included in the study.Use of analgesics and non-steroidal anti-inflammatory agents was noted but patientsusing them were not excluded. Mild strictureswere dilated before entry at the discretion ofthe endoscopist. The study was approved bythe human ethics committees at each of thethree participating hospitals and each patientgave their written informed consent.

Study designThe study was of open design. Ambulatoryoesophageal pH monitoring was performedwithin one week of the initial endoscopy. Aminimum washout period of two days forpatients treated with H2 antagonists or fivedays for patients treated with omeprazole was

allowed before the pH monitoring. Patientswere then treated with omeprazole 20 mgdaily for eight weeks. Endoscopy and pHmonitoring were repeated during the lastweek while receiving treatment. Patientswhose oesophagitis had healed as evidencedby complete resolution of all macroscopicerosions or ulceration left the study at thispoint. Those patients with persistent erosionsor ulceration were treated with omeprazole40 mg daily for eight weeks and endoscopyand pH monitoring repeated during the lastweek as before.

EndoscopyUpper gastrointestinal endoscopy (OlympusGIF XQ10 or Pentax FG34JH) was performedby an experienced observer not more than 10days before starting treatment. When theendoscopy was performed at the end of a treat-ment phase, the endoscopist was blinded to theresults of the pH monitoring. The severity andextent of macroscopic oesophageal ulcerationor erosion was scored as follows6: grade 0, no

mucosal abnormalities; grade 1, no macro-

scopic erosions but erythema, hyperaemia or

mucosal friability; grade 2, superficial erosionsinvolving <10% of the mucosal surface of thedistal 5 cm of oesophageal squamous mucosa;grade 3, superficial erosions or ulcerationinvolving 10%/o-50% of the mucosal surface ofthe distal 5 cm of the oesophageal squamousmucosa; grade 4, deep peptic ulceration any-where in the oesophagus or confluent erosionof >50% of the mucosal surface of the distal 5cm of the oesophageal squamous mucosa.

Only patients with unequivocal severe erosivepeptic oesophagitis of grade 3 or 4 were

entered into the study. Patients with refluxdisease characterised by columnar metaplasiaor benign stricture without macroscopicmucosal erosion were not entered.

OesophagealpH monitoringTwenty four hour ambulatory oesophageal pHmonitoring was performed using an antimonypH electrode (Synectics) positioned 5 cmabove the manometrically determined loweroesophageal sphincter and connected to aportable digital recorder (SynecticsDigitrapper Mark II 6100). Patients wererequested to avoid drinking coffee, cordials,and fruit juices during the recording period.Omeprazole treatment was continued butpatients were not allowed to take any antacid.

Clinical and laboratory assessmentSymptoms were assessed by interview at entryand at four weekly intervals during the study.Heartburn, (day and night scored separately),regurgitation and dysphagia were graded as: 0- none, 1 - mild, not interfering with usualactivity; 2 - moderate, interfering with usualactivity; and 3 - severe, incapacitating and pre-venting usual activity. Patients were specifi-cally questioned about the occurrence ofadverse events or symptoms. Compliance,assessed at each visit by capsule counts, wasjudged to be adequate only if at least 75% ofthe capsules had been consumed. Bloodsamples were taken for haematological andbiochemical testing.

Data analysisThe pH data were analysed by computer(Synectics, Esophogram) for the durationpH<4 and the number of reflux episodes. Acidclearance time was calculated by dividing theduration pH<4 by the number of refluxepisodes. Values were determined separately forthe total 24 hours, and upright, supine, andthree hour postprandial periods. Data for healedand unhealed patients were compared using theMann-Whitney U test and are expressed in thetext as median (interquartile range).

Results

Pre-treatmentSixty patients entered the study of which 59received medication; one patient withdrew

TABLE I Clinical and endoscopic data at entry into thestudy

Omeprazole Omeprazole(20 mg) (40 mg)

Number entered 60 17Male:female 48:12 16:1Mean age (range) (y) 63 (23-86) 65 (23-84)Symptom duration<1 Year 6 21-5 Years 16 6

>5 Years 37 9Cigarette smokers 9 2Recent NSAID use 9 1Recent aspirin use 15 4Recent H2 receptor antagonists 26 10Oesophagitis at entryGrade 3 44 12Grade 4 15 5Columnar mucosa 39 8Deep ulcer 5 3Stricture 6 2

NSAID, non-steroidal anti-inflammatory drug.

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Relation between oesophageal acid exposure and healing of oesophagitis with omeprazole in patients with severe reflux oesophagitis

Healedo Unhealed

o(74.5)

0

00

a0

0

00

I o..Botem0

Before treatment

0

80

A O0

OmeprazoleFigure 1: Effect ofomeprazole 20 mg every morning ontotal 24 hour oesophageal acid exposure. Each pointrepresents data for an individual patient. The horizontalbars show median values. **p<0.01 v healed.

before receiving medication. Four patientswere withdrawn from the study. Reasons forwithdrawal were: nausea that occurred within24 hours of starting omeprazole (one patient),failure to comply (one patient), loss to followup (three patients) thus leaving 55 patientsavailable for analysis. Table I summarises thedemographic, clinical and endoscopic data on

entry into the trial.Pre-treatment total 24 hour oesophageal acid

exposure in the patients who did not heal withomeprazole 20 mg was significantly greaterthan that in the patients who healed (Fig 1).Ten of 17 (59%) unhealed patients hadreceived H2 antagonists before the study com-

pared with 16 of 38 (42%) patients who healed.Total 24 hour acid exposure in the unhealedpatients who had taken H2 antagonists (28.8%,22.6-34.2%) was significantly greater than inthose who had not taken H2 antagonists(17.0%, 11-1-19.8%, p<003). Previous use ofH2 antagonists, however, did not alfect acidexposure in the patients who healed (19.8%,14-6-19*8% v 20-2%, 16.5-20*2%)0.Values for pre-treatment upright, supine,

and postprandial acid exposure, however, were

similar in the two groups (Table II). Pre-treat-ment acid clearance times were also similar inthe two groups (healed: 1P7 min, 0.6-3.0 min;unhealed: 3v5 min, 2v6-5*1 min).

For patients who remained unhealed on 20mg omeprazole and subsequently received the40 mg dose, pre-treatment total, upright,supine, and postprandial oesophageal acidexposures were similar in those who eventuallyhealed and those who remained unhealed(Table III, Fig 2). Oesophageal acid clearancetime before treatment was also similar in thehealed patients (3.1 min, 2.6-6.2 min) to thatin the unhealed patients (3.9 min, 3.5-5.9min).

Phase 1: omeprazole 20 mgSeventeen patients failed to heal theiroesophagitis after eight weeks' treatment withomeprazole 20 mg every morning. Total 24hour oesophageal acid exposure while receivingtreatment was significantly greater in thosepatients who failed to heal than in those whohealed (Fig 1), and significantly fewer unhealedpatients fell within the normal range of <55% (4of 17 patients v 27 of 38 patients, p<0005).The mean percentage fall in total acid exposurewith treatment in the unhealed patients (45%)was significantly less than that in the healedpatients (82%), p<002). Unhealed patientsalso had greater levels of upright, supine, andpostprandial reflux during treatment than didthose who healed (Table II).Most patients (47 of 55) were rendered

symptom free after eight weeks of treatment.The prevalence of complete symptom relief inthe patients who did not heal (15 of 17patients) was similar to that in those whohealed (32 of 38 patients). The use of hista-mine H2 receptor antagonists before entry intothe trial (healed - 42%, unhealed - 58%), non-steroidal anti-inflammatory agents (healed -

45%, unhealed - 290/o), and smoking (healed -

four of 38, unhealed - one of 16) were not sta-tistically different in the two groups.

Phase 2: omeprazole 40 mgSixteen of 17 patients who failed to heal withomeprazole 20 mg received eight weeks treat-ment with omeprazole 40 mg every morning;one patient withdrew at week 8 for social rea-sons. Two other patients refused to undergofurther pH monitoring leaving 14 patientsavailable for analysis. Eight of 15 patients whounderwent endoscopy healed their oesophagi-tis with the larger dose. All patients who healed

TABLE II Oesophageal acid exposure with omeprazole 20 mg every morning

Oesophageal acid exposure

Pre-treatment Omeprazole 20 mg

Patient Total Upright Supine Postprandial Total Upright Supine Postprandialgroup (%() (V.) (/o) (%) (%/) (%) (%) (%/)Healed 16.0 14-5 13-7 18-9 1-8 1-3 0-6 0-2

(84-20.3) (9-3-21-9) (5.5-22.2) (13-7-28-3) (0-2-6-1) (04-3-4) (0-70) (0-2.1)Unhealed 21.3* 23-3 15-3 27-7 9-1t 7.2* 17.1* 1.7*

(16-2-28-8) (106-26-3) (84-43 9) (140-34.4) (66-17.5) (14-14.0) (0.5-23 8) (0-5-12-4)

Median (interquartile range), *p<0 03, tp<0-01, v healed.

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TABLE Ill Oesophageal acid exposure with omeprazole 40 mg every morning

Oesophageal acid exposure

Pre-treatment Omeprazole (20 mg) Omeprazole (40 mg)

Patient Total Upright Supine Postprandial Total Upright Supine Postprandial Total Upright Supine Postprandialgroup (%.) (V.) (V.) (%) (%) (Vo) (%) (Vo) (Go) (Go) (0) (Go)

Healed 20-8 25-3 13-7 29-8 7-7 7-4 3-2 4-2 1-3 0.3 2-0 0-2(19-2-24-8) (19-2-26-8) (6.3-34 8) (24-7-34 6) (46-11.0) (30-15-9) (0-3-10.7) (0.7-14-2) (0 1-3.4) (0-1-08) (0 1-49) (0-0 4)

Unhealed 28-4 20-2 439 26-3 17-5 2-3 24.9t 1-7 181t 9.1* 33-0t 7-4(194-34.2) (10.9-25.3) (22.2-50.3) (18-8-31-9) (11.6-19.7) (1-5-12-1) (223-47 6) (0 6-11 6) (15-9-19.9) (4 8-10.2) (31 8-39 8) (1 7-16.1)

Median (interquartile range), *p<0.05, tp<0 005 v healed.

and four of six unhealed patients were ren-dered asymptomatic; two unhealed patientshad residual mild heartburn (grade 1).

During treatment total oesophageal acidexposure was significantly greater in thosepatients who failed to heal than in those whohealed (Fig 2), and all unhealed patients hadacid exposures above 50/o (range 10.3-21.8%)compared with only one of eight healedpatients. Upright acid exposure was similar inthe healed and unhealed patients while receiv-ing 20 mg omeprazole but was significantlygreater in the unhealed patients with the 40 mgdose (Table III). Supine acid exposure, how-ever, was significantly greater in the unhealedpatients during treatment with both the 20 mgdose and 40 mg dose. Postprandial acid expo-sure was similar in the healed and unhealedpatients with both the 20 mg and 40 mg doses.

DiscussionIn this study we evaluated prospectively therelation between oesophageal acid exposureand healing of oesophagitis in patients withsevere reflux oesophagitis treated with omepra-zole. Our data show that failure of oesophagitisto heal is associated with a higher level ofoesophageal acid exposure before treatment,and higher levels of acid exposure while receiv-ing omeprazole because of a smaller reductionin acid exposure, particularly at night. Thesefindings are consistent with the hypothesis thatfailure of oesophagitis to heal with omeprazoleis due to inadequate acid suppression.

Severity of oesophagitis as judged by endo-scopy before treatment is the most important

* (74.5)* Healed 40 mgo Unhealed 40 mg

0

0

(o-0-0

0

0

_ * A'-Before treatment Omeprazole Omeprazole

(20 mg) (40 mg)Figure 2: Effect of omeprazole 40 mg every morning on total 24 hour oesophageal acid

exposure. Each point represents data for an individual patient. The horizontal bars showmedian values. *p<0 005 v healed.

factor determining the response to treatmentwith acid suppressant drugs.4 6 7 18 19 Weselected patients with severe reflux oesopha-gitis as we have shown previously that suchpatients are more refractory to omeprazolethan patients with lesser degrees of oesopha-gitis.6 Most of the patients had provedrefractory to H2 receptor antagonists. Thehealing rate with the 20 mg dose in this study(69%) is comparable to that seen previously,6and illustrates the difficulty in treating patientswith severe oesophagitis even with potent acidsuppressants. In contrast with earlier studies,however, which reported similar healing rateswith 20 mg and 40 mg doses,6 8 doubling thedose of omeprazole from 20 mg to 40 mg inthis study was associated with healing of theoesophagitis in an additional 15% of thepatients. This increase in healing rate may havebeen a result of a longer duration of treatmentin the patients who received the 40 mg dose asthese patients had already received eightweeks' treatment with the 20 mg dose; in theprevious studies, patients received only eightweeks' treatment overall.The important finding from this study was

that failure of oesophagitis to heal was associ-ated with higher levels of acid exposure ontreatment. There are two main explanationsfor this finding. Firstly, patients that remainedunhealed on the 20 mg dose had higher levelsof acid exposure before treatment. Previousfindings on the relation between pre-treatmentoesophageal acid exposure and response toacid suppression have been conflicting. Somestudies have shown no relation.'6 20 21 A directrelation has been reported, however, inpatients refractory to H2 antagonists22 23 andmay be a consequence of more defectivegastro-oesophageal competence or moreseverely impaired oesophageal acid clearanceor both in the refractory patients. It has alsobeen suggested that higher pre-treatment acidexposure is related to gastric acid hyper-secretion.23

In this study, however, the higher pre-treat-ment acid exposure may have been related toprior use of H2 antagonists. Cessation of thesedrugs is associated with rebound gastric hyper-secretion.24 Pre-treatment acid exposure washigher only in patients who did not heal andwho had been taking H2 antagonists beforeentering the study; acid exposure was similar inhealed and unhealed patents who had nottaken H2 antagonists. Interestingly, previoususe of H2 antagonists did not affect pre-treat-ment acid exposure in patients who healedwith the 20 mg omeprazole dose suggesting

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that patients who did not heal may have differ-ent patterns of acid secretion. Despite the con-founding factor of H2 antagonists, however,differences in reflux patterns cannot accountfor the failure of patients to respond to thehigher dose of omeprazole as the pre-treatmentoesophageal acid exposure levels in thesepatients were no different from those in thepatients who healed with this dose.

Secondly, and more importantly, our datasuggest that failure of oesophagitis to heal isassociated with lower degrees of acid suppres-sion. Patients who did not heal with the 20 mgdose not only had higher levels of acid expo-sure while receiving treatment but also had asignificantly smaller reduction in acid expo-sure. Additionally, patients that remainedunhealed with the 40 mg dose had substan-tially higher levels of acid exposure on treat-ment despite similar pretreatment levels of acidexposure to those in patients who healed.Although we did not measure gastric acidsecretion, these findings are best explained by arelative refractoriness to acid suppression withomeprazole in a subgroup of patients withsevere oesophagitis. The reasons for this arenot clear. Possibilities include: gastric hyper-secretion, a decreased response of the parietalcell, perhaps related to increased drive for acidsecretion, poor absorption, and changedpharmacokinetics with increased metabolicrate or elimination.25 Whether or not refluxdisease in general2628 or that refractory to acidsuppressant treatment'8 23 29 is associated withacid hypersecretion is controversial. Patientswith duodenal ulcer exhibit substantial vari-ability in acid suppression with low (10 mg)doses of omeprazole, which becomes lessnoticeable with higher doses.30

While oesophageal acid exposure was higheroverall in unhealed patients, the importantcomponent was a higher level of supine andtherefore nocturnal reflux. Indeed, the 40 mgdose had virtually no impact on supine refluxin the patients who failed to heal. These find-ings confirn previous reports of persistentlyincreased supine and nocturnal oesophagealacid exposure in patients with refluxoesophagitis resistant to omeprazole.5 17 Inpart this is probably a result of refractoriness ofnocturnal acid secretion. Omeprazole in dosesof 20 mg or greater virtually ablates daytimeacid secretion, whereas partial breakthroughoccurs at night.31-33 Whether nocturnal break-through is more noticeable in patients withrefractory reflux disease, however, awaitsspecific study. While persistence of nocturnaloesophageal acid exposure could also resultfrom more defective acid clearance, thishypothesis is not supported by our finding thatacid clearance times before treatment weresimilar in healed and unhealed patients forboth the 20 mg and 40 mg doses.

Oesophageal acid exposure was not the onlydeterminant of healing. Some patients healeddespite continuing high levels of acid exposure,and some patients failed to heal despite reduc-tion of acid exposure to below normal levels.Aspirin use has been implicated as a signifi-cant factor in the resistance of oesophagitis

treatment.34 As with other studies, however,6 8smoking or the use of non-steroidal anti-inflammatory drugs including aspirin did notaffect the rate ofhealing. Increased exposure tobile salts has been reported in patients withsevere reflux disease.35 Whether patients whoare refractory to omeprazole have greateroesophageal exposure to these agents, how-ever, remains to be determined.

In summary we have shown that failure ofsevere oesophagitis to heal with omeprazole isassociated with persistence of a high level ofoesophageal acid exposure that is most con-sistent with inadequate suppression of acidsecretion. The mechanisms underlying thisapparent refractoriness require further investi-gation. Our findings also underline the need inpatients with severe reflux disease to titrate thedose of omeprazole to achieve adequate acidsuppression, and that oesophageal pH moni-toring is a useful guide for this approach. Theapparent breakthrough of nocturnal acid secre-tion in refractory patients may be just relatedto dose. Whether or not night time comparedwith morning dosing,30 or dividing the single40 mg dose into twice daily 20 mg doses37would achieve better healing awaits furtherstudy.This study was supported by a project grant from the NHMRC.Omeprazole capsules and financial support were provided byAstra Pharmaceuticals Pty Ltd, Australia.The authors would like to thank their colleagues David

Hetzel, Peter Pritchard, and Richard Heddle for their invalu-able support, Marcus Tippett, Joylene Morcombe, and WendyFerguson for performing the pH monitoring studies and help inenrolling and caring for the patients. They also thank BronwynUnderwood and Katrina Perkins for their constant logisticalsupport.

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2 de Caestecker JS, Blackwell JN, Pryde A, Heading RC.Daytime gastro-oesophageal reflux is important inoesophagitis. Gut 1987; 28: 519-29.

3 Robertson D, Alersley JM, Shepherd H, Smith CL. Patternsof acid reflux in complicated oesophagitis. Gut 1987; 28:1484-8.

4 Havelund T, Laursen LS, Skoubo-Kristensen E, AndersenBN, Pedersen SA, Jensen KB, et al. Omeprazole andranitidine in treatment of reflux oesophagitis: doubleblind comparative trial. BMJ 1988; 296: 89-92.

5 Dehn TCB, Sheperd HA, Colin-Jones D, Kettlewell MGW,Carroll NJH. Double blind comparison of omeprazole(40mg od) versus cimetidine (400mg qd) in the treatmentof symptomatic erosive reflux oesophagitis, assessed endo-scopically, histologically and by 24 h pH monitoring. Gut1990; 31: 509-13.

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13 Lundell L, Rackman L, Ekstrom P, Enander LH, Fausa 0,Lind T, et al. Omeprazole of high-dose ranitidine in thetreatment of patients with refiux oesophagitis notresponding to "standard doses" of H2-receptor antago-nists. Aliment Pharmacol Ther 1990; 4: 145-55.

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