Control of Nocturnal Gastric Acidity: A Role for Low Dose Bedtime Ranitidine to Supplement Daily...

Control of Nocturnal Gastric AcidityA Role for Low Dose Bedtime Ranitidine to Supplement

Daily Omeprazole

MALCOLM ROBINSON, MD,* SHEILA RODRIGUEZ-STANLEY, PhD,*ARTHUR A. CIOCIOLA, PhD,† JONATHAN FILINTO, BS,* SATTAR ZUBAIDI, MD,*

PHILIP B. MINER, Jr., MD,* and JERRY D. GARDNER, MD‡

In some patients, proton pump inhibitors do not abolish nocturnal gastric acidity andadditional evening antisecretory medication may be required. In 16 subjects with chronicheartburn, 24-hr gastric and esophageal pH were measured at baseline and again after sixdays of 20 mg omeprazole alone at 08:00 hr followed by placebo, 75 mg ranitidine, or 20 mgomeprazole at 22:00 hr. Integrated acidity was calculated from the cumulative, time-weightedmean acid concentrations (derived from pH values for each second). Baseline integratedgastric acidity increased progressively over 24 hr, whereas integrated esophageal acidityincreased only until 22:00 hr. Morning omeprazole nearly abolished 24-hr esophageal acidityand significantly decreased overall gastric acidity but did not abolish nocturnal gastric acidity.Adding evening ranitidine or omeprazole nearly eliminated the nocturnal increase in gastricacidity. Integrated acidity was more sensitive than time pH � 4 in assessing gastric andesophageal acidity as well as their inhibition by omeprazole and ranitidine. In conclusion,integrated acidity provides novel information regarding the synergy of omeprazole plusranitidine. Adding low-dose ranitidine helps control nocturnal gastric acidity that can occurwith conventional omeprazole administration. Although the heartburn patients in the presentstudy had nocturnal gastric acidity without accompanying nocturnal esophageal acid reflux,other patients who do have nocturnal esophageal reflux might profit from addition of bedtimeranitidine or another gastric antisecretory agent.

KEY WORDS: gastric secretion; heartburn; GERD; PPI’s; H2-RAs; integrated acidity.

Continuous esophageal pH recording has been usedto document gastroesophageal reflux, explore thepathophysiology of gastroesophageal reflux disease

(GERD) and assess various gastric antisecretory andprokinetic agents (1–6). Gastric pH studies have pro-vided classical data that establish the efficacy of gas-tric antisecretory drugs (3–6). Most studies of gastricor esophageal pH have involved healthy volunteers orpatients with severe GERD, including erosive esoph-agitis (1–6). On the other hand, the most commonuse of antisecretory medication for prevention orrelief of heartburn is by subjects without erosiveesophagitis (6). Common heartburn leads to self-medication with over-the-counter (OTC) antacids orhistamine H2-receptor antagonists (H2-RAs). Heart-burn sufferers who self-medicate were selected for thepresent study to better understand gastric antisecre-

Manuscript received August 20, 2000; revised manuscript re-ceived June 29, 2001; accepted August 3, 2001.

From the *Oklahoma Foundation for Digestive Research, Uni-versity of Oklahoma, Health Sciences Center, Oklahoma City,Oklahoma; †Pfizer Consumer Healthcare, Morris Plains, New Jer-sey; and ‡Science for Organizations, Inc., Chatham, New Jersey.

This work was supported by a grant from Warner-Lambert to theOklahoma Foundation for Digestive Research and a consultingagreement between Science for Organizations, Inc. and Warner-Lambert.

Address for reprint requests: Dr. Jerry D. Gardner, Science forOrganizations, Inc., 156 Terrace Drive, Chatham, New Jersey07928.

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265Digestive Diseases and Sciences, Vol. 47, No. 2 (February 2002)0163-2116/02/0200-0265/0 © 2002 Plenum Publishing Corporation

tory pharmacology in this important clinical popula-tion.

Continuous pH data are usually displayed as graphsof pH vs time or, in the case of gastric pH, as graphsdisplaying percentages of the recording period withpH above or below a particular value. Even thoughconventional pH recordings generate as many as 900measurements per hour, nearly all analyses reducesuch data to single values for number of esophagealrefluxes or intervals with pH above or below a partic-ular value (eg, pH � 4). Measuring time at pH belowa particular value is only an approximation of esoph-ageal acid exposure. For example, it will not distin-guish between 3 hr of exposure to a pH of 1.1 and 3hr of exposure to pH 3.9. The pathological conse-quences of these seemingly identical acid exposuresmight differ dramatically. In the present study, dataare presented from simultaneous 24-hr esophagealand gastric pH recordings in patients with symptom-atic GERD. These data permit calculation of inte-grated esophageal and gastric acidity and quantifyacidity over time.

Despite the effectiveness of proton pump inhibitors(PPIs) for reducing gastric and esophageal acidity,many GERD patients treated with a single dose ofomeprazole may have poorly controlled esophagealacid exposure and/or symptoms, and multiple dailydoses are often administered (5–12). Others (7–11)have demonstrated that nocturnal acid breakthrough,defined as gastric pH � 4 for more than 60 minduring the night, occurs in normal volunteers andpatients receiving omeprazole 20 mg twice a day orlansoprazole 30 mg twice a day. This nocturnal acidbreakthrough has correlated with gastroesophagealreflux in some patients with GERD (9) and can bereduced by a bedtime dose of ranitidine (150 or 300mg) (7). Since patients being treated with a PPI oncedaily in the morning can experience a nocturnal in-crease in gastric acidity, it seemed possible that anOTC dose of ranitidine (75 mg) might be suitable forcontrol of nocturnal gastric acidity in such patients. Ifso, a low dose of ranitidine at bedtime might providecost effective adjunctive therapy for symptom controland/or healing in some patients.

MATERIALS AND METHODS

This study was approved by and conducted in compliancewith good clinical practices as supervised by the WesternInstitutional Review Board, Olympia, WA. All subjectsenrolled in this study gave written informed consent.

Subjects. Subjects were 9 men and 7 women who expe-rienced heartburn �3 times/week for at least six months.

Subjects were not tested for H. pylori infection. Subjectswere excluded if they had been treated with a histamineH2-RA, sucralfate, a prostaglandin analog, a PPI, or bis-muth subsalicylate within seven days or with any investiga-tional drug within 30 days prior to study entry. Subjectswere also excluded if they had esophageal stricture, gastriculcer, or duodenal ulcer on upper gastrointestinal endos-copy within one year prior to study entry; previous gastric oresophageal surgery; pyloric stenosis; or had been treated forcancer other than basal cell skin cancer.

Study Design. The study was conducted at the OklahomaFoundation for Digestive Research on the campus of theUniversity of Oklahoma Health Sciences Center. It was asingle-blind, three-way crossover evaluation of the effects ofsix days of treatment with 20 mg omeprazole given beforebreakfast at 08:00 hr followed by placebo, 75 mg ranitidine,or 20 mg omeprazole given at 22:00–23:00 hr on 24-hrgastric and esophageal pH.

Gastric and esophageal pH were measured at baselineand then after six days of one of the active treatments.Three to five days elapsed between the baseline evaluationand the first active treatment. Subjects then underwent a 7to 10-day washout period between each active treatment.

Subjects fasted from approximately 22:00 hr the eveningbefore until the beginning of pH recording, usually at 08:00hr the following morning. Standardized meals were ingestedduring the pH recording periods. Breakfast was provided athours 09:00–09:30 hr, lunch at 13:00–14:00 hr and dinner at18:00–19:00 hr. Smoking and ingestion of food or liquidsbetween meals were prohibited during the pH recordingperiods. Gastric antisecretory medications other than studymedications were prohibited for the duration of the study.Antacids were permitted as needed for relief of symptomsthroughout the study, except during the pH recording pe-riods.

Gastric and esophageal pH data were collected using anambulatory, semidisposable, dual-channel pH recordingsystem (Medtronic Synectics) with antimony electrodes.[Acid concentrations measured with semidisposable record-ing systems are approximately 50% of those measured withdisposable systems (unpublished findings).] One electrodewas placed in the stomach 10 cm below and the second wasplaced in the esophagus 5 cm above the manometricallydefined upper border of the lower esophageal sphincter.Electrodes were calibrated to pH 1 and 7 using solutionscomposed of pH 1.07, 59 mM KNO3, 27 mM KCl, and pH7.01, 16.5 mM Tris buffer, 40 mM KNO3, 96 mM KCl. Datawere collected using a portable data storage unit (Digitrap-per, Medtronic Synectics). Recordings began at 08:00 hrand continued for 24 hr. Values for intragastric and intra-esophageal pH were recorded every 4 sec. Data were trans-ferred from the portable data storage unit and processed inDOS mode using software designed for pH recordings(Polygram for Windows, Version 2.04, Medtronic Synec-tics). The software adjusts all pH values for the differencebetween the temperature at which the electrodes werecalibrated (25°C) and the recording temperature (37°C).

Although we refer to the current measurements as acidconcentration, the pH electrode actually measures hydro-gen ion activity. Others have documented the extent towhich hydrogen ion concentration can differ from hydrogenion activity, particularly in the presence of other ions, and

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266 Digestive Diseases and Sciences, Vol. 47, No. 2 (February 2002)

have developed methods to adjust hydrogen ion activity tohydrogen ion concentration (13, 14). We have calibratedthe electrodes to pH 1 and 7 using polyelectrolyte solutionsprovided by the manufacturer, which results in measuredhydrogen ion activity more closely approximating the hy-drogen ion concentration. We have not adjusted the mea-sured hydrogen ion activity.

Analytical Procedures. Polygram software calculates val-ues for conventional parameters of esophageal and gastricpH recordings, ie, number of esophageal refluxes, percent-age of the recording period of esophageal pH � 4, andpercentage of the recording period of gastric pH � 4.

Polygram software also takes the individual pH valuesthat are recorded every 4 sec and fills in the same value forthe other 3 sec, resulting in one value for every second ofthe recording period for each electrode. These pH data for1-sec intervals were used to calculate integrated acidity.

Dual-channel recordings from baseline and each activetreatment period were analyzed from each of 16 subjects(64 records). Recordings from one subject were omittedbecause of noncompliance.

Integrated gastric and esophageal acidity were calculatedfor each second of the recording period as follows: (1) Acidconcentration (mM) � 1000 � 10�pH; (2) acidity (mmol/hr/liter) � (acid in mM at time t � acid in mM at timet�1)/2 � (t � t�1); (3) values for acidity were summedcumulatively for every second; (4) integrated acidity isexpressed as mM � time, ie, mmol.hr/liter; and (5) in thepresent study, values for integrated acidity were analyzedfor each hour of the 24-hr recording period.

This calculation of integrated acidity has been referred toas mean weighted acidity by others (15). Values for inte-grated acidity at any given time indicate the cumulativeintegrated acidity up to that point in time. Mean acidconcentration for each hour was calculated as integratedacidity at time t minus integrated acidity at time t�1. Theresulting value represents the mean acid concentration forthe hour indicated.

Values are displayed in relation to a 24-hr clock with08:00 hr as the beginning of the recording period.

Statistical Analyses. Statistical analyses were performedusing Microsoft Excel 97 or GraphPad for InStat version3.01 for Windows software. Previously (16), we found thatvalues from different subjects for integrated gastric andesophageal acidity as well as for time of gastric and esoph-

ageal pH � 4 are not normally distributed; therefore,median values are presented in the present paper. Resultsfor baseline and the three active treatments were analyzedusing nonparametric repeated measures ANOVA andDunn’s multiple comparisons test (nonparametric). Thetime course of action of a particular active treatment wasevaluated using the Wilcoxon matched pairs test to com-pare values with the particular active treatment to valuesmeasured at the same time without that particular activetreatment. We are aware of the shortcomings of unadjustedP values obtained from multiple comparisons, even whenthe comparisons may be highly correlated; however, thevalues that are referred to as significantly different shouldbe considered in terms of the pattern that emerges fromthese exploratory statistical analyses.

Table 1 summarizes results for conventional parametersfrom 24-hr pH recordings at baseline and after six days ofeach active treatment. Each active treatment significantlydecreased the number of esophageal reflux episodes, thepercentage of the recording period that of the esophagealpH � 4, and the percentage of the recording period of thegastric pH � 4. For all parameters, results with 20 mgomeprazole at 08:00 hr followed by placebo at 22:00–23:00hr were not significantly different from those with 20 mgomeprazole at 08:00 hr followed by 75 mg ranitidine or 20mg omeprazole at 22:00–23:00 hr.

Even though all subjects in the present study had impor-tant heartburn, Table 1 illustrates that, a majority hadvalues for the percent time esophageal pH � 4 that werebelow the conventional cutoff values of 4–6% that defineabnormal esophageal acid exposure (1, 6). Of the 15 sub-jects in the present study, seven had values above 4%, andfour had values above 6%. These results are consistent withfindings of others (6) that approximately half of subjectswith symptomatic GERD have values for the percent timeesophageal pH � 4 that are below 4–6%.

Figure 1 (left) illustrates results for mean gastric acidconcentration over each hour of the 24-hr recording period.At baseline, mean gastric acid concentration showed peri-odic fluctuations produced by ingestion of meals that buff-ered the intragastric contents. There was a prominent noc-turnal increase in mean gastric acid concentration over theperiod from 22:00 to 04:00 hr. After six days of treatmentwith 20 mg omeprazole at 08:00 hr and nocturnal placebo,the mean gastric acid concentration was decreased during

TABLE 1. VALUES FOR CONVENTIONAL PARAMETERS FROM24-HOUR PH RECORDINGS*

TreatmentReflux

episodes (N)Time Esophageal pH

� 4 (%)Time Gastric pH

� 4 (%)

Control 84 (69–190) 3.9 (2.3–7.6) 91 (88–94)Om-Pl 34 (13–55) 0.8 (0.3–1.6) 57 (34–73)Om-Ran 30 (6–61) 0.8 (0.1–1.9) 38 (16–44)Om-Om 32 (9–54) 0.7 (0.1–1.2) 24 (12–40)

*Results are medians (interquartile range) from 15 subjects at baseline (control) andafter six days of treatment with the agents indicated. Pl, placebo; Om, omeprazole20 mg; Ran, ranitidine 75 mg. The agent indicated first was given at 08:00 hr, andthe agent indicated second was given at 22:00–23:00 hr. Values with each activetreatment were significantly different from control (P � 0.01). No active treatmentgave results that were significantly different from those with any other activetreatment.

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267Digestive Diseases and Sciences, Vol. 47, No. 2 (February 2002)

the day and evening hours, whereas the nocturnal increasein acid concentration persisted (Figure 1 left). After 24:00hr, the mean gastric acid concentration with omeprazole-placebo did not differ significantly from that at baseline at01:00–06:00 hr except at 03:00 hr (P � 0.026), which mayhave differed significantly simply because of the multiplecomparisons (Figure 1 left). After six days of treatment with20 mg omeprazole at 08:00 hr plus nocturnal 75 mg raniti-dine or nocturnal 20 mg omeprazole, the mean gastric acidconcentration was reduced throughout the 24-hr period andacid concentrations during the nocturnal peak (01:00–05:00 hr) were significantly lower than corresponding base-line concentrations (P � 0.01). Results for gastric acidconcentration with omeprazole–ranitidine were not signifi-cantly different from those with omeprazole–omeprazole.Thus, nocturnal ranitidine and nocturnal omeprazole weresimilarly effective in reducing the nocturnal increase inintegrated gastric acidity that occurred after midnight insubjects taking a single morning dose of omeprazole.

Figure 1 (right) gives results for integrated gastric acidityfor each hour of the 24-hr recording period. At baseline,integrated gastric acidity increased progressively over thecourse of the 24-hr period. With each active treatment,24-hr integrated gastric acidity was significantly lower (P �0.01) than at baseline.

Figure 2 illustrates values for gastric acidity during thenocturnal period from 22:00 to 08:00 hr with differenttreatments. During the period 24:00 to 06:00 hr, the meangastric acid concentration with 20 mg omeprazole at 08:00hr followed by 75 mg ranitidine or 20 mg omeprazole at22:00 hr was significantly lower than with 20 mg omeprazoleat 08:00 hr and placebo at 22:00 hr (Figure 2 left). Valuesfor integrated gastric acidity with 20 mg omeprazole at

08:00 hr followed by 75 mg ranitidine or 20 mg omeprazoleat 22:00 hr were significantly lower than with 20 mg ome-prazole at 08:00 hr and placebo at 22:00 hr from 22:00 to08:00 hr (Figure 2 middle). (Since integrated acidity iscumulative, a significant decrease over one period of timewill be reflected in all subsequent time periods.) Figure 2(right) illustrates values from each subject for integratedgastric acidity during the nocturnal period with morningomeprazole followed by nocturnal placebo or nocturnalranitidine. All values with nocturnal ranitidine were 100mmol/hr/liter or less whereas those with nocturnal placebowere as high as 450 mmol/hr/liter. The ranitidine-induceddecrease in nocturnal gastric acidity also tended to begreater in subjects who had relatively high values withnocturnal placebo (Figure 2 right).

Figure 3 left illustrates that at baseline, mean esophagealacid concentration was increased during the day andevening, but not at night, even though there was a majornocturnal increase in gastric acidity (compare Figure 3 leftto Figure 1 left). There was little or no esophageal acidexposure after six days of each active treatment (P � 0.01compared to control).

As illustrated in Figure 3 (right) the pattern for inte-grated esophageal acidity differed from that for integratedgastric acidity (Figure 1 right) in that at baseline, integratedesophageal acidity increased progressively from 10:00 hrthrough 22:00 hr but did not change appreciably thereafter.With each active treatment 24-hr integrated esophagealacidity was significantly lower (P � 0.01) than at baseline,and there were no significant differences among the differ-ent active treatments.

In a previous study (16), we found that subjects withGERD can be classified into two groups based on their

Fig 1. Mean gastric acid concentration and integrated gastric acidity at baseline (control) and after six days of treatment with the agentsindicated. Results given are medians from 15 subjects. Pl, placebo; Om, omeprazole 20 mg; Ran; ranitidine 75 mg. The agent indicatedfirst was given at 08:00 hr, and the agent indicated second was given at 22:00–23:00 hr. The arrows at the top of the left panel indicatethe times of the meals.

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pattern of integrated esophageal acidity. One group hada monophasic pattern of integrated esophageal acidityand 50% of maximal esophageal acidity occurred by17:00 hr with little or no nocturnal esophageal acid

exposure. The other group had a biphasic pattern, and50% of maximal esophageal acidity did not occur until01:00 hr. Subjects with a biphasic pattern had substantialnocturnal esophageal acidity. Each subject in the present

Fig 2. Nocturnal mean gastric acid concentration and nocturnal integrated gastric acidity at baseline (control) and after six days oftreatment with the agents indicated. Pl, placebo; Om, omeprazole 20 mg; Ran, ranitidine 75 mg. The agent indicated first was given at08:00 hr, and the agent indicated second was given at 22:00–23:00 hr. Values in the left and middle panels are medians from 15 subjects.In the left panel, the crosses at the top of the panel indicate times at which values with Om-Ran and Om-Om are significantly lower thanvalues with Om-Pl (P � 0.05). In the right panel, values for integrated acidity are for 22:00–08:00 hr, and the solid diagonal line is theidentity line for values with Om-Pl. Each point represents a pair of values for one subject and the vertical distance from the solid linerepresents the magnitude of the difference between the pair of values. Points below the solid line indicate that integrated gastric acidityis less with Om-Ran than with Om-Pl, and values above the solid line indicate the opposite. In the right panel, values with Om-Ran aresignificantly lower than those with Om-Pl (P � 0.0024).

Fig 3. Mean esophageal acid concentration and integrated esophageal acidity at baseline (control) and after six days of treatment with theagents indicated. Results given are medians from 15 subjects. Pl, placebo; Om, omeprazole 20 mg; Ran, ranitidine 75 mg. The agentindicated first was given at 08:00 hr, and the agent indicated second was given at 22:00–23:00 hr. The arrows at the top of the left panelindicate the times of the meals.

INTEGRATED ACIDITY


study had a monophasic pattern for integrated esopha-geal acidity. Baseline integrated esophageal acidity was50% of maximal at 18:40 � 00:30 hr (mean � SEM, N �15).

Previously (16), we compared values for integrated acid-ity to corresponding values for percent time of pH below aparticular cutoff value calculated from the same pHrecords. With integrated esophageal acidity, the correlationincreased as the cutoff decreased from pH 6 to pH 3, andpercent time of esophageal pH � 3 gave the best correla-tion. Similarly, with integrated gastric acidity, the correla-tion increased as the cutoff decreased from pH 4 to pH 1,and percent time of gastric pH � 1 gave the best correla-tion.

Figure 4 illustrates values for percent time at pH � 4plotted as a function of corresponding values for 24-hrintegrated acidity calculated from the same records. Therewas a hyperbolic relationship between time of gastric pH �4 and integrated gastric acidity, and values for pH timereached a plateau at high values of integrated gastric acidity(Figure 4 left). Thus, as gastric acidity increased, measuringtime of gastric pH � 4 was progressively less able to detectthis increase, and values for pH time of over 90% wereassociated with values of integrated acidity that rangedfrom approximately 400 to nearly 1400 mmol/hr/liter. Therealso appeared to be a hyperbolic relationship between timeof esophageal pH � 4 and integrated esophageal acidity(Figure 4 right); however, the relationship is not as welldefined as it is for gastric acidity because of the limitednumber of values in the range of 6–12% for time of esoph-ageal pH � 4. Figure 4 (right) illustrates that, as occurredwith gastric acidity, values for time of esophageal pH � 4approached a plateau at high values of integrated esopha-geal acidity.

The hyperbolic relationships illustrated in Figure 4 sug-gest that time at pH � 4 will be less sensitive than inte-grated acidity in assessing the inhibitory effects of omepra-zole and ranitidine. Figure 5 illustrates that inhibition ofgastric acidity as well as esophageal acidity is significantlyhigher when assessed by integrated acidity than by time atpH � 4. Thus, not only is integrated acidity more sensitivethan time at pH � 4 in assessing gastric and esophagealacidity, but it is also more sensitive than time at pH � 4 inassessing the inhibitory effects of gastric antisecretoryagents.

DISCUSSION

In the present study, we calculated values for inte-grated gastric and integrated esophageal acidity from24-hr pH recordings performed in the conventionalmanner. These calculated values make it possible tofully quantify esophageal and gastric acidity overtime, in contrast to conventional parameters of per-cent time esophageal or gastric pH is less than aparticular value. For example, we found that as acid-ity increases, time at pH � 4 becomes progressivelyless able to measure this increase. Furthermore, timeat pH � 4 consistently underestimates the magnitudeof the effects of agents that decrease acidity. Calcu-lating integrated acidity also takes fuller advantage ofthe data available from continuous pH recordings.For example, data for integrated acidity make it pos-sible to determine the cumulative acid concentration

Fig 4. Time pH � 4 versus corresponding value for integrated acidity for the 24-hr recording period for all conditions (control as well asall active treatments) for all 15 subjects.

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over any particular time of interest and allow resultsfrom different patients to be combined over time.They also provide the opportunity to explore poten-tial relationships between esophageal acidity and gas-tric acidity and to quantify changes over time duringtreatment with a gastric antisecretory agent.

We found that the mean gastric acid concentrationfluctuated as a result of ingestion of meals. Followingthe evening meal, there was a particularly prominentincrease in gastric acidity during the nocturnal periodfrom 22:00 until 04:00 hr. Interestingly, all subjectswho participated in the present study showed amonophasic pattern of integrated esophageal acidity(16) in that they experienced increased esophagealacid exposure during the day and evening, but notduring the nocturnal period of increased gastric acid-ity.

Six days of treatment with a single morning dose of20 mg omeprazole significantly decreased integratedgastric acidity and integrated esophageal acidity overthe entire 24-hr period. This dose of omeprazole,however, did not eliminate the nocturnal increase inmean gastric acid concentration. Adding a nocturnaldose of 75 mg ranitidine or 20 mg omeprazole to themorning dose of 20 mg omeprazole nearly abolishedthe nocturnal increase in mean gastric acid concen-tration. Except for a 5-hr period in the morning

(09:00–13:00 hr), the effect on integrated gastric acid-ity of nocturnal 75 mg ranitidine, the currently avail-able OTC dose, was not significantly different fromthat of a second 20-mg dose of omeprazole, thecurrently available prescription dose.

Gastric acidity seems to have received limited at-tention with respect to its potential role in esophagealacid exposure in patients with GERD, other thanobservations that inhibition of gastric acid secretiondecreases the duration of esophageal pH � 4 (8, 10,11). Hirschowitz has reported that basal and penta-gastrin-stimulated gastric acid secretion in patientswith esophagitis did not differ from values in patientswith unspecified medical conditions but who had noesophagitis (17–19). Others, however, have reportedincreased basal, peak, or maximal gastric acid secre-tion in patients with GERD compared to measure-ments in healthy subjects (20–22).

Integrated gastric acidity does not measure gastricacid secretion. Instead, integrated gastric acidity isthe cumulative gastric acid concentration integratedover time and underestimates gastric acid secretion,which is calculated from the amount of titratablegastric acid over time. Even if one determined intra-gastric volume, multiplying this volume by the acidconcentration measured by the pH electrode wouldstill underestimate gastric acid secretion, particularly

Fig 5. Inhibition of integrated acidity versus corresponding value for inhibition of time pH � 4 for all active treatments for all 15 subjects.The solid diagonal line is the identity line for inhibition of time pH � 4. Each point represents a pair of values for one subject and thevertical distance from the solid line represents the magnitude of the difference between the pair of values. Points above the solid lineindicate that inhibition is higher with integrated acidity than with time pH � 4, and values above the solid line indicate the opposite. Inboth panels, values for inhibition of integrated acidity are significantly higher than values for inhibition of time pH � 4 (P � 0.0001).

INTEGRATED ACIDITY


during meal ingestion. This occurs because followinga meal, gastric acid concentration decreases due tothe buffering effect of the ingested food, but gastricacid secretion increases as a result of meal-stimulatedacid secretion (23, 24). Even during the fasting state,integrated acidity will underestimate acid secretion,because there is a hyperbolic relationship betweenthe acid concentration in the fluid in the lumen of thestomach and the fluid secretory rate, and the acidconcentration becomes maximal and nearly constantat high fluid secretory rates (25). It is important tonote that the reported effects of gastric antisecretoryagents on gastric pH, even if the effect is assessed ina mathematically correct manner, underestimate an-tisecretory effects on gastric acid secretion. By thesame token, however, measuring the effects of anantisecretory agent on gastric acid secretion will over-estimate its effect on the intragastric acid concentra-tion. This may be important in estimating effects ofgastric antisecretory agents in GERD (3–7), particu-larly if GERD occurs in subjects with gastric acidhypersecretion, where the decrease in acid concentra-tion will not be commensurate with the decrease inthe volume of secreted fluid (25).

Others (1–5) have described nocturnal gastric acidbreakthrough (nocturnal gastric pH � 4 for at least 1hr) with 20 mg omeprazole or 30 mg lansoprazolegiven twice daily with breakfast and dinner and havereported that a third dose of a gastric antisecretoryagent may be necessary to eliminate this nocturnalincrease in gastric acidity. Nearly all published papershave measured only gastric pH, and the one paperthat measured esophageal pH (2) reported only theproportion of subjects who had at least one episode ofesophageal pH � 4 for at least 4 secs. The presentresults, however, illustrate that simultaneous mea-surements of integrated esophageal acidity and gas-tric acidity can quantify the extent to which esopha-geal acidity and gastric acidity increase during acidbreakthrough and identify subjects in whom this phe-nomenon might be important. A previous study (16)reported that integrated gastric acidity in subjectswith nocturnal esophageal acidity was similar to thatin subjects without nocturnal esophageal acidity, il-lustrating the importance of disturbed motility inGERD (26). In subjects in the present study, how-ever, there was little, if any nocturnal esophageal acidexposure even without omeprazole. In these particu-lar subjects, one would not expect nocturnal acidbreakthrough to be important in terms of theirGERD. In subjects with nocturnal esophageal expo-sure (ie, those with a biphasic pattern of integrated

esophageal acidity) (16), measurements of integratedesophageal and gastric acidity could quantify themagnitude of nocturnal reflux as well as the extent towhich nocturnal gastric acidity needs to be inhibitedto eliminate esophageal acid exposure.

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