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O R I G I N A L A R T I C L E jgh_5900 1236..1243

Comparison of p.o. or i.v. proton pump inhibitors on 72-h

intragastric pH in bleeding peptic ulcerGul Javid, Showkat Ali Zargar, Riyaz-u-saif., Bashir Ahmad Khan, Ghulam Nabi Yatoo,

Altaf Hussain Shah, Ghulam Mohammad Gulzar, Jaswinder Singh Sodhi and Mushtaq Ahmad Khan

Department of Gastroenterology, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India

Abstract

Background and Aims: After successful endoscopic hemostasis in bleeding peptic ulcer,

addition of proton pump inhibitors reduce the rate of recurrent bleeding by maintaining

intragastric pH at neutral level. The aim of the present study was to evaluate the effect of

various proton pump inhibitors given through different routes on intragastric pH over 72 h

after endoscopic hemostasis in bleeding peptic ulcer.

Methods: Ninety consecutive patients who had successful endoscopic therapy of bleeding

peptic ulcer underwent 72-h continuous ambulatory intragastric pH study, were randomly

assigned to receive p.o. omeprazole 80 mg bolus followed by 40 mg every 12 h for 72 h or

i.v. 80 mg omeprazole followed by infusion 8 mg/h for 72 h. Oral pantoprazole 80 mg

bolus followed by 80 mg every 12 h for 72 h or i.v. 80 mg pantoprazole followed by

infusion of 8 mg/h for 72 h. Oral rabeprazole 80 mg bolus followed by 40 mg every 12 h

for 72 h or i.v. 80 mg rabeprazole followed by infusion 8 mg/h for 72 h. Five patients

received no treatment after successful endoscopic therapy and underwent 72-h pH study.

Results: Mean 72-h intragastric pH for p.o. omeprazole was 6.56 versus 6.93 for ome-

prazole infusion (P = 0.48). Mean 72-h intragastric pH for p.o. pantoprazole was 6.34

versus 6.32 for pantoprazole infusion (P = 0.62). Mean 72-h intragastric pH for rabeprazole

p.o. was 6.11 versus 6.18 rabeprazole i.v. (P = 0.55). Mean 72-h pH for the no proton pump

inhibitor group was 2.04.

Conclusion: There was no significant difference among various proton pump inhibitorsgiven through different routes on raising intragastric pH above 6 for 72 h after successful

endoscopic hemostasis in bleeding peptic ulcer.

Key words

72-h intragastric pH, bleeding peptic ulcer,

endoscopic therapy, proton pump inhibitors.

Accepted for publication 27 February 2009.

Correspondence

Dr Gul Javid, Department of

Gastroenterology, Gulistan Manzil, Amira

Kadal Srinagar Kashmir India 190001.

Email:[email protected]

Introduction

Acute gastro duodenal ulcer bleeding remains a therapeutic chal-

lenge with significant morbidity and mortality. Endoscopic

therapy using various modalities significantly reduces re-bleeding,

need for surgery and mortality in patients with peptic ulcer bleed-

ing.1 Endoscopic therapy achieves successful hemostasis in more

than 90% of patients, and re-bleeding occurs in 10–30% of

patients.2–4 Re-bleeding has an important impact on prognosis.5,6

Addition of proton pump inhibitors (PPI) after successful endo-

scopic therapy reduces the risk of further re-bleeding.7–9 Gastric

acidity may play an important role in pathogenesis of recurrent

bleeding. A high gastric pH may help stabilize the clot by avoiding

pepsinogen activation.10,11

The first major defense against uncontrolled hemorrhage aside

from transient vasoconstriction which follows vascular injury is

the formation of a platelet plug. A platelet plug alone can secure

adequate hemostasis for several hours (except in lesions of major

vessels), but thereafter the plug disintegrates unless it has been

reinforced by a fibrin clot.12 Significant disorder at almost any

level of coagulation cascade can thus lead to hemorrhagic tenden-

cies. The physiology of hemostasis demands a pH value near 7. A

pH of less than 2 is responsible for pepsin activity. Pepsin activity

is inversely inactivated and denatured at pH 7. A pH of more than

4 is necessary for clot lysis prevention and a pH of more than 6 is

necessary for hemostasis.13 Pharmacologically, PPI can quickly

achieve an optimal intragastric pH condition in support of the

physiological cascade of hemostasis.14

Previously, effects of PPI on intragastric pH have been investi-

gated in single comparator studies15,16 and cross-over study.17 In a

meta-analysis on PPI and outcome of endoscopic hemostasis in

bleeding peptic ulcers, the authors concluded that in bleeding

peptic ulcer patients who have undergone successful endoscopic

therapy, the benefit of PPI as adjuvant to endotherapy is indepen-

dent of route and dose of administration of PPI.18 We performed a

randomized trial in order to compare the effect of high p.o. doses

and continuous infusion of PPI on intragastric pH over 72 h after

endoscopic therapy.

doi:10.1111/j.1440-1746.2009.05900.x

1236 Journal of Gastroenterology and Hepatology 24 (2009) 1236–1243 © 2009 The Authors

Journal compilation © 2009 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd

mailto:[email protected]

mailto:[email protected]



Methods

Study population

This study was conducted in the Department of Gastroenterology,

Sher-i-Kashmir Institute of Medical Sciences, from May 2004 to

January 2007 and was approved by the Postgraduate ClinicalResearch and Ethical Committee of Medicine. All consecutive

patients above 18 years of age with proven peptic ulcer (gastric or

duodenal) bleeding were included in this study.

After the documentation of gastrointestinal bleeding, patients

were resuscitated. All patients admitted to this hospital with a

history of peptic ulcer bleeding (i.e. hematemesis and/or melena)

or who bled while in hospital, underwent emergency endoscopy as

soon as possible, always within 12 h of bleeding or immediately

after resuscitation in patients with massive bleeding or shock. The

possibility of endoscopic therapy was discussed with the patient

and/or their relatives and written informed consent was obtained

before the endoscopy. Endoscopic therapy was given if endoscopy

showed a peptic ulcer in the stomach or duodenum with active

bleeding (spurting hemorrhage, oozing hemorrhage) or stigmata of recent hemorrhage (a non-bleeding visible vessel). Assessment of

presence of those stigmata was made after adherent clots and

debris of the ulcer base had been vigorously washed away.19 Initial

hemostasis was defined as no visible hemorrhage lasting for 5 min

after endoscopy therapy. Patients who achieved hemostasis with

endoscopic therapy (witnessed by endoscopy) were eligible for

entry into the study.

Method of endoscopic treatment

Endoscopic hemostasis was achieved using a combination of heat

probe preceded by epinephrine injection. Epinephrine (1 : 10 000diluted in normal saline) was injected in aliquots of 0.5–1 mL into

and around the bleeding area. After injection therapy, heater probe

thermocoagulation was given to the ulcer using an Olympus heater

probe unit with 2.8-mm probe (Olympus USE-2; Olympus, Tokyo

Japan). The energy output of the heater probe was set at 25 J and

coaptive pulses (minimum of three) were applied until cavitation

and adequate coagulation was obtained. The bleeding site was

observed for 5 min and challenged with maximum water irrigation

for 10 s. If any further bleeding occurred, the above procedure was

repeated.20 The endoscope used in the study was a fibro-optic

endoscope, FG-29V (Pentax, Tokyo, Japan).

Exclusion criteria

Patients were excluded if they: were under 18 years of age; unable

or unwilling to give written informed consent; pregnant or lactat-

ing; taking anticoagulants; had more than one possible source of

bleeding; had severe coagulopathy (prothrombin time 30% less

than normal) or platelet count less than 50 000/mm 3;2 had previous

acid reducing surgeries (vagotomy, gastric resection); were mori-

bund because of terminal cancer or severe comorbid illness; or had

bleeding gastric cancer. Patients who did not obtain initial hemo-

stasis with endoscopic therapy or re-bled within 3 days were also

excluded.

pH monitoring

Eligible patients after successful endoscopic hemostasis under

went 72-h intragastric pH metery using a pH electrode connected

to a data recorder (Proxima Light 2; Mentova, Italy). The patients

were enrolled after written informed consent was obtained and

received treatment protocol as described. The electrode was posi-tioned in the gastric body under fluoroscopic guidance and con-

tinuously recorded pH at 6-s intervals.

Randomization and pharmacological treatment

Immediately after endoscopic control of bleeding and successful

placing probe of the pH monitor in the corpus of the stomach

(fluoroscopically documented), eligible patients were randomly

assigned to receive different PPI (pantoprazole, omeprazole and

rabeprazole) through different routes (p.o. and infusion). No other

treatment in the form of antacid, H2-receptor antagonist or others

was given.

In the omeprazole group (Dr Reddy’s Laboratories, Hyderabad,

India), patients were randomly assigned to receive omeprazole

either as an i.v. bolus of 80 mg followed by continuous infusion of

8 mg/h for 72 h, or 80 mg p.o. bolus followed by 40 mg after every

12 h for 72 h and i.v. saline.

In the pantoprazole group (Sun Pharmaceutical Industries,

Mumbai, India), patients were randomly assigned to receive pan-

toprazole either as an i.v. bolus of 80 mg followed by 8 mg/h

infusion for 72 h, or 80 mg p.o. bolus followed by 80 mg after

every 12 h for 72 h and i.v. saline.

In the rabeprazole group (Cadila Pharmaceutical, Ahmedabad,

India), patients were randomly assigned to receive rabeprazole

either as an i.v. bolus of 80 mg followed by 8 mg/kg continuous

infusion for 72 h, or 80 mg p.o. bolus followed by 40 mg after

every 12 h for 72 h and i.v. saline. Patients in all groups wereallowed to take clear liquids only.

Randomization was carried out in the endoscopy laboratory by

opening an opaque sealed numbered envelope by the senior endo-

scopy technologist. Treatment assignments were made based on

random numbers derived from a table of random numbers in

blocks of four. Patients and the attending physicians taking care of

the patient were blinded to the nature of treatment. The treatment

code was known only to the senior endoscopy technologist and

pharmacist.

We also studied 72-h intragastric pH in five patients who had

successful endoscopic hemostasis and did not receive any PPI

except i.v. saline thus acted as control group. After 72 h, patients

who were Helicobacter pylori-infected received triple therapy and

p.o. PPI daily for 8 weeks and patients who were not H. pylori-

infected received daily PPI for 8 weeks irrespective of treatment

protocol. Three out of five patients in no PPI group were H.

pylori-infected and received triple therapy and p.o. PPI for

8 weeks; those who were not H. pylori-infected received p.o. PPI

for 8 weeks.

Clinical monitoring

Patients were observed for re-bleeding in a high-care facility of the

gastroenterology ward. Every patient was serially monitored for

vital signs, hemoglobin concentration, need for blood transfusion,

G Javid et al. i.v. vs p.o. PPI in bleeding peptic ulcer

1237Journal of Gastroenterology and Hepatology 24 (2009) 1236–1243 © 2009 The Authors




need for surgery and length of hospital stay. Demographic fea-

tures, comorbid illness, ulcer size, initial hemoglobin level, use of

non-steroidal anti inflammatory drugs (NSAIDs) and H. pylori

status as determined by enzyme-linked immunosorbent assay

(ELISA) were recorded. Re-bleeding was defined by fresh hemate-

mesis, melena or both, with either shock (systolic blood pressure

of 100 mmHg or a pulse rate of 100 b.p.m., accompanied bycold sweats, pallor and oliguria); or a fall in hemoglobin of 2 g/dL

or more over a 24-h period after initial stabilization of vital signs.

Patients meeting these criteria were excluded from our study and

underwent emergency endoscopy within 4 h to confirm the diag-

nosis of re-bleeding. Re-bleeding was managed in both groups

with repeat endoscopic therapy as before or by surgery as

necessary.

The pH monitor was also continuously checked to see the posi-

tion of the electrode and was subsequently manipulated under

fluoroscope if needed. The primary end-point was to see the time

for which intragastric pH remained above 6 over 72 h with various

PPI when given through different routes.

Statistical analysis

The primary comparison was between the mean 72-h intragastric

pH with p.o. PPI and that with PPI infusion. If the difference

between these two measurements was less than 10% of the mean

pH with PPI infusion, then the two group forms were considered

therapeutically equivalent, provided the minimum pH achieved

with p.o. PPI was more than 6. For that reason, it was estimated

that 43 evaluable patients would be required to provide 95% over

all power to detect a difference of 10% between the p.o. PPI group

and PPI infusion group, assuming the variance to be 0.16 and the

significance level (type 1 error) to be 0.05. The trial was designed

to randomize 45 patients in each group so that 15 patients each

would receive omeprazole, pantoprazole or rabeprazole p.o., or byinfusion.

Statistical analysis was performed on an intention-to-treat basis.

All data were expressed as the mean standard deviation. Quan-

titative data between different treatment groups were compared

using the Student’s t -test and Mann–Whitney U -test. Categorical

data were compared with Pearson’s test and Fisher’s exact test. 21

The 95% confidence intervals (CI) associated with proportions

were calculated. A two-tailed P-value < 0.05 was considered sig-

nificant. Statistical analysis was carried out with SPSS for

Windows (ver. 11.5; SPSS, Chicago, IL, USA).

Results

During the study period, 326 patients with peptic ulcer bleeding

were seen. The prevalence of various types of stigmata of recent

hemorrhage were as follows: 45 (13.80%) active bleeders (spurt-

ing and oozing); 78 (23.90%) non-bleeding visible vessel; 54

(16.56%) adherent clot or flat red spot; and 149 (45.70%) clean

base. Of these, 123 patients who revealed active bleeding (45

patients) or non-bleeding visible vessel (78 patients) underwent

emergency endoscopic therapy. Initial endoscopic hemostasis was

obtained in 119 (96.74%) patients. Endoscopic treatment was

unsuccessful in four patients due to torrential bleeding that

obscured the bleeding area and prevented adequate endoscopic

treatment; these patients were treated by emergency surgery. Thus,

119 patients were taken for our study; of them, seven patients

refused to give consent for pH monitoring, and in six patients there

was difficulty in placing the pH probe because of deformed nasal

septa or previous surgery in the nose. Re-bleeding occurred in

eight patients during 72-h pH monitoring who required second

endoscopy or surgery as necessary and eight patient refused 72-h

pH monitoring after giving initial consent. The remaining 90patients underwent randomization to receive omeprazole, panto-

prazole and rabeprazole either in p.o. or infusion form in higher

doses. Five patients were taken for 72-h intragastric pH study, who

received endoscopic therapy but no PPI and i.v. saline thus acted as

the control group.

Omeprazole was given either as 80 mg p.o. bolus followed by

40 mg p.o. every 12 h for 72 h and i.v. saline or 80 mg i.v. bolus

followed by 8 mg/h infusion for 72 h. A total of 15 patients were

included in each group. Pantoprazole was given either as 80 mg

p.o. bolus followed by 80 mg p.o. every 12 h for 72 h and i.v.

saline or 80 mg i.v. bolus followed by 8 mg/h infusion for 72 h. A

total of 15 patients were included in each group. Rabeprazole was

given either 80 mg i.v. bolus followed by 8 mg/h infusion for 72 hor 80 mg p.o. bolus followed by 40 mg p.o. every 12 h for 72 h and

i.v. saline. A total of 15 patients were included in each group. The

groups were well matched with respect to the patient and endo-

scopic features (Table 1).

The mean 72-h intragastric pH in the omeprazole group when

given through the p.o. route was 6.56 0.99 (standard error of

mean [SEM], 0.11) versus 6.93 0.96 (SEM, 0.10) when given as

infusion with a statistically insignificant difference between the

two groups of P = 0.48. The median 72-h intragastric pH with p.o.

omeprazole was 6.76 versus 7.14 for omeprazole infusion. The

minimum pH for omeprazole p.o. was 0.96 versus 1.12 for ome-

prazole infusion group. The maximum pH for omeprazole p.o. and

for omeprazole infusion was 7.26 and 7.54, respectively. The 25th

and 75th percentile of 72-h intragastric pH with p.o. omeprazolewas 6.60 and 6.94 versus 6.90 and 7.28, respectively with ome-

prazole infusion. The 95% CI for mean 72-h intragastric pH with

p.o. omeprazole was 6.33–6.79 versus 6.71–7.15 with omeprazole

infusion. There was no statistically significant difference between

the two groups.

The mean 72-h intragastric pH in the pantoprazole group when

given through the p.o. route was 6.34 0.90 (SEM, 0.10) versus

6.32 0.81 (SEM, 0.09) when given as infusion with no statisti-

cally significant difference between the two groups (P = 0.62).

The median 72-h intragastric pH with pantoprazole p.o. was 6.52

versus 6.48 with pantoprazole infusion. The minimum pH for

pantoprazole p.o. was 1.22 versus 1.54 for the pantoprazole infu-

sion group. The maximum pH for pantoprazole p.o. was 6.84

versus 6.88 for the pantoprazole infusion group. The 25th and 75th

percentile of 72-h intragastric pH with pantoprazole p.o. was 6.38

and 6.68 versus 6.32 and 6.64, respectively, with pantoprazole

infusion. The 95% CI for the mean with pantoprazole p.o. was

6.13–6.55 versus 6.12–6.50 with pantoprazole infusion. There was

no statistically significant difference between the two groups.

The mean 72-h intragastric pH in the rabeprazole group, when

given through the p.o. route was 6.11 0.86 (SEM, 0.99) versus

6.18 0.83 (SEM, 0.09) with rabeprazole infusion with no statis-

tically significant difference between the two groups P = 0.55. The

minimum pH for p.o. rabeprazole was 1.44 versus 1.56 with

rabeprazole infusion. The maximum pH for p.o. rabeprazole was

i.v. vs p.o. PPI in bleeding peptic ulcer G Javid et al.





6.78 versus 6.78 with rabeprazole infusion. The 25th and 75th

percentile pH with rabeprazole p.o. was 6.16 and 6.44 versus 6.26

and 6.58, respectively, with the rabeprazole infusion group. The

95% CI for the mean with rabeprazole p.o. was 5.91–6.30 versus

5.99–6.37 with rabeprazole infusion. There was no statistically

significant difference between the two groups (Table 2).

The mean pH on day 1 with omeprazole p.o. was 6.63 versus

6.61 with omeprazole infusion. The mean pH on day 2 with ome-

prazole p.o. was 6.82 versus 6.92 with omeprazole infusion. The

mean pH on day 3 with omeprazole p.o. was 6.72 versus 6.92 with

omeprazole infusion. The median time to reach a gastric pH of 6 or

above was 60 min. (range, 50–140 min) after an initial p.o. bolus

Table 1 Demographic characteristics of patients of p.o. and infusion group of PPI*

Oral group n = 45 Infusion group n = 45

Omeprazole Pantoprazole Rabeprazole Omeprazole Pantoprazole Rabeprazole

n = 15 n = 15 n = 15 n = 15 n = 15 n = 15

No. of patients 15 15 15 15 15 15

Mean age (years) 35.6 7 35 15.8 35.6 11.7 35.8 10 35 15.8 33.4 10.8

Age range (years) 28–45 18–60 22–50 22–50 18–60 22–50

Presentation

Hemetemesis 7 6 8 6 5 7

Melena 12 13 14 13 13 14

Both 7 6 7 6 6 6

Shock at presentation 1 1 0 0 0 1

Mean Hb at presentation

(g/dL) range

9.2 2.1 (5–13) 9.5 2.1 (6–12) 9.1 2.1 (6–13) 9.1 2.1 (6–13) 9.3 2.2 (5–13) 9.5 2.1 (6–12)

Comorbid illness 0 0 0 0 0 0

H. pylori † infected 10 9 10 9 10 8

NSAID intake 2 1 1 1 2 1

Stigmata of bleeding

Spurting 4 3 2 3 3 2

Oozing 3 4 3 4 2 4

Non-bleeding vessel 8 8 10 8 10 9

Mean ulcer size (cm) 1.4 07 1.4 07 1.4 07 1.2 0.8 1.2 0.8 1.2 0.8

Mean dose of epinephrine

(mL)

11.6 11.6 11.5 11.5 11.5 11.6

No. of heater probe pulses

used (mean)

4 4 4 4 4 4

*No statistical significant difference between the two groups. †Helicobacter pylori. NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump

inhibitors.

Table 2 Effects of various PPI when given in p.o. or infusion form on 72-h intragastric pH*

Oral group n = 45 Infusion group n = 45

Omeprazole Pantoprazole Rabeprazole Omeprazole Pantoprazole Rabeprazole

n = 15 n = 15 n = 15 n = 15 n = 15 n = 15

Mean 6.56 6.34 6.11 6.93 6.32 6.18

Median 6.76 6.52 6.32 7.14 6.48 6.42

Standard deviation 0.99 0.90 0.86 0.96 0.81 0.83

SEM 0.11 0.10 0.99 0.10 0.09 0.09

Minimum 0.96 1.22 1.44 1.12 1.54 1.56

Maximum 7.26 6.84 6.78 7.54 6.88 6.78

Percentiles

25 6.60 6.38 6.16 6.90 6.32 6.26

50 6.76 6.52 6.32 7.14 6.48 6.42

75 6.94 6.68 6.44 7.28 6.64 6.58

95% CI for Mean 6.33- 6.79 6.13–6.55 5.91–6.30 6.71–7.15 6.12–6.50 5.99–6.37

*P -value for: omeprazole p.o. vs omeprazole infusion (P = 0.48); omeprazole infusion vs pantoprazole infusion (P = 0.15); pantoprazole p.o. vs

pantoprazole infusion (P = 0.62); omeprazole infusion vs rabeprazole infusion (P = 0.09); rabeprazole p.o. v s rabeprazole infusion (P = 0.55); panto-

prazole infusion vs rabeprazole infusion (P = 0.73). This shows there is statistically no difference between PPI when given p.o.ly or as infusion. CI,

confidence interval; PPI, proton pump inhibitors; SEM, standard error of the mean.






of omeprazole and persisted above 6 for approximately 98% of thetime in the first 24 h and 100% of the time in the next 2 days of

72-h pH monitoring. The median time to reach intragastric pH of

6 or above was 45 min (range, 35–125 min) after the initial i.v.

bolus of omeprazole infusion and persisted above 6 for approxi-

mately 98% of the time in the first 24 h and 100% of the time in the

next 2 days of 72-h pH monitoring (Fig. 1).

The mean pH on day 1 with pantoprazole p.o. was 6.36 versus

6.61 with pantoprazole infusion and on day 2 mean pH with

pantoprazole p.o. was 6.58 versus 6.71 with pantoprazole infusion.

The mean pH for day 3 with p.o. pantoprazole was 6.60 versus

6.77 with pantoprazole infusion. The median time to reach a

gastric pH of 6 or above was 52 min (range, 44–135 min) after the

initial p.o. bolus of pantoprazole and persists above 6 for approxi-

mately 97% of the time in the first 24 h and 100% of the time in the

next 2 days of 72 h. The median time to reach a gastric pH above

6 was 45 min (range, 30–118 min) after the initial i.v. bolus of

pantoprazole and persisted above 6 for 98% of the time in the first

24 h and 100% of the time in the next 2 days of 72-h pH monitor-

ing (Fig. 2).

The mean pH on day 1 with rabeprazole p.o. was 6.16 versus

5.73 with rabeprazole infusion. The mean pH on day 2 with

rabeprazole p.o. was 6.29 versus 6.82 with rabeprazole infusions

and for day 3 were 6.35 versus 6.79, respectively. The median time

to reach a gastric pH of 6 or above was 58 min (range,

48–130 min) after the initial p.o. bolus of rabeprazole and per-

sisted above 6 for 96% of the time in the first 24 h and 100% of thetime in the next 2 days of 72-h pH monitoring. The median time to

reach a gastric pH of 6 or above was 42 min (range, 35–115 min)

after the initial i.v. bolus of rabeprazole and persisted above 6 for

approximately 97% of the time in the first 24 h and remained

above 6 for 100% of the time in the next 2 days of 72-h pH

monitoring (Fig. 3).

Subgroup analysis

The mean 72-h intragastric pH with omeprazole infusion was 6.93

versus 6.32 pantoprazole infusion, there was no significant statis-

tical difference between the two groups (P = 0.15). The mean 72-h

intragastric pH for pantoprazole infusion was 6.32 versus 6.18

with rabeprazole infusion which was statistically insignificant

(P = 0.73). The mean 72-h intragastric pH for omeprazole infusion

was 6.93 versus 6.18 for rabeprazole infusion and the difference

was statistically insignificant (P = 0.09). The comparison of intra-

gastric pH for 72 h of different PPI when given through the i.v.

route and with no PPI is shown in Figure 4, and the difference

between the PPI group and no PPI group was statistically signifi-

cant (P < 0.05). The mean 72-h intragastric pH with omeprazole

p.o. was 6.56 versus 6.34 with pantoprazole p.o. and the difference

was statistically insignificant (P = 0.61). The mean 72-h intragas-

tric pH with pantoprazole p.o. was 6.34 versus 6.11 with rabepra-

zole p.o. and the difference was statistically insignificant

(P = 0.57). The mean 72-h intragastric pH with omeprazole p.o.

was 6.56 versus 6.11 with rabeprazole p.o. the difference wasstatistically insignificant (P = 0.29). The comparison of intragas-

tric pH for 72 h of different PPI when given through the p.o. route

and with no PPI is shown in Figure 5 and the difference between

the PPI group and no PPI group was statistically significant

(P < 0.05).

No PPI group

Five patients after successful endoscopic hemostasis of bleeding

peptic ulcer underwent 72-h intragastric pH monitoring, and these

patients received only normal saline for 72 h. The mean pH was

0

1

2

3

4

5

6

7

8

1 4 7 10 13 16 19 2 2 2 5 2 8 3 1 3 4 3 7 4 0 4 3 4 6 4 9 5 2 5 5 5 8 6 1 6 4 67 70

Time in h

pH

Figure 1 Graph showing effect of administration of omeprazole

through different routes on 72-h intragastric pH. Mean pH (omepra-

zole p.o.); — Mean pH (omeprazole infusion).

0

1

2

3

4

5

6

7

8

1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64 67 70

Time in h

pH

Figure 2 Graph showing effect of administration of pantoprazole

through different routes on 72-h intragastric pH. — Mean pH (pantopra-

zole p.o.); Mean pH (pantoprazole infusion).

0

1

2

3

4

5

6

7

8

1 4 7 101316192225283134374043464952555861646770

Time in Hours

pH

Figure 3 Graph showing effect of administration of rabeprazole

through different routes on 72-h intragastric pH. — Mean pH (Rabepra-

zole Oral); Mean pH (Rabeprazole Infusion).






2.05, and median pH was 2.20 (SEM, 0.06). The 25th and 75th

percentile of 72-h intragastric pH without any PPI therapy was

1.65 and 2.35 with a mean 95% CI was 1.92–2.17 (Table 3). The

pH never raised above 4 in these patients and when this pH was

compared with the other PPI group the difference was statistically

significant P < 0.05.

Outcome

There was no statistically significant difference between hospital

stay, re-bleeding, surgery and need of transfusion in patients

among different groups (Table 4). Five patients who did not

receive any PPI for 72 h after endoscopic therapy did not have

re-bleeding or surgery.

Discussion

The result of this study demonstrates that i.v. and high p.o. doses of

various PPI are equal in their ability to suppress gastric acid

secretion in patients of bleeding peptic ulcer treated with

endoscopic therapy. There was no difference in intragastric pH for

72 h with various PPI (omeprazole, pantoprazole and rabeprazole)

when given through different routes (p.o./infusion). But when the

PPI group was compared with the non-PPI group there was a

statistically significant difference in 72-h intragastric pH. The pH

remained more than 6 for most of the time with PPI and it remained

less than 4 most of the time with the non-PPI group. Regarding the

outcome of patients there was no statistical significance.

The pharmacotherapy of bleeding peptic ulcer after successful

endoscopic therapy is directed at attempting to keep the intragas-

tric pH above the protolytic range of pepsin to stabilize the clotting

process. Fresten et al.22 conducted a study to compare 24-h intra-

gastric pH effects of lansoprazole 30 mg administered nasogastri-

cally with pantoprazole 40 mg administered i.v. Healthy adults

were enrolled in an open-label two-way cross-over single-centre

study. Lansoprazole produced a significantly higher mean 24-h

intragastric pH value in relation to pantoprazole on day 1 (3.05 vs

2.76, P < 0.001) and on day 5 (3.65 vs 3.45, P = 0.024).

Figure 4 Graph showing effect of administration of various proton

pump inhibitors (PPI) in infusion form on 72-h intragastric pH and in

non-PPI group. - - - MEAN pH (Omeprazole Infusion); — MEAN pH

(Rabeprazole infusion); MEAN pH (Pantoprazole infusion).

Figure 5 Graph showing effect of administration of various proton

pump inhibitors (PPI) in p.o. form on 72-h intragastric pH and in non-PPI

group. Mean pH (Rabeprazole Oral); — MEAN pH (Pantoprazole Oral);

- - - MEAN pH (Omeprazole Rabeprazole Oral).

Table 3 Study of 72-h intragastric pH study of five patients in non-PPI

group

Mean 2.05

Median 2.20

Standard deviation 0.55

SEM 0.06Minimum 1.15

Maximum 3.45

Percentiles

25 1.65

50 2.20

75 2.35

95% CI (mean) 1.92–2.17

CI, confidence interval; PPI, proton pump inhibitors; SEM, standard error

of the mean.

Table 4 Outcome of patients with bleeding peptic ulcer according to

treatment received after successful endoscopic hemostasis

Omeprazole p.o. Omeprazole infusion

Blood transfusion (units) 4 3

Hospital stay (days) 3.5 3.5

Surgery† 1 0

Re-bleeding† 2 1

Death 0 0

Pantoprazole p.o. Pantoprazole infusion

Blood transfusion (units) 3 3

Hospital stay (in days) 3.7 3.5

Surgery† 1 l

Re-bleeding† 1 1

Death 0 0

Rabeprazole p.o. Rabeprazole infusion

Blood transfusion (units) 3 2Hospital stay (days) 3.5 3.7

Surgery† 0 l

Re-bleeding† 1 2

Death 0 0

†These patients were excluded from 72-h pH study.






Philips et al.17 conducted a five-way cross-over study to eva-

luate and compare 24-h intragastric pH following standard doses

of esomeprazole, lansoprazole, omeprazole, pantoprazole and

rabeprazole, administered once daily in 34 H. pylori-negative

patients aged 18–60 years with significant gastro-esophageal

reflux disease. This randomized open-label comparative five-way

cross-over study evaluated 24-h intragastric pH profile. On day 5,intragastric pH was maintained for a mean of 14.0 h with esome-

prazole, 12.1 h with rabeprazole, 11.8 h with omeprazole, 11.5 h

with lansoprazole and 10.1 h with pantoprazole (P 0.001).

Esomeprazole at the standard dose of 40 mg once daily provided

more effective control of gastric acidity at steady state than stan-

dard doses of lansoprazole, omeprazole, pantoprazole and rabepra-

zole (P < 0.05). We conducted a 72-h intragastric pH study on i.v.

pantoprazole and found that the median time to reach a gastric pH

of 6 was 45 min (range, 29–118) after the initial bolus of panto-

prazole infusion and persisted approximately 5.6–7.1 for the

remaining 72 h.9 Oral and i.v. dosage of pantoprazole have been

found to be equivalent in their ability to suppress gastric acid

secretion in patients with gastro-esophageal reflux disease.

23

Pantoflickova et al.24 conducted a cross-over study on 18 H.

pylori-negative subjects. Twenty-four hour intragastric pH moni-

toring was performed on day of treatment (once daily for rabepra-

zole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg, omeprazole

20 mg, omeprazole multiple unit pellet system [MUPS] tablets

20 mg or placebo). The intragastric pH (3.4) and time at pH of

more than 4 during the 24-h post-dose (8 h) were significantly

greater with rabeprazole than with lansoprazole, pantoprazole,

omeprazole capsule, omeprazole MUPS or placebo (P 0.04 for

rabeprazole vs others).

Observations of therapeutic and physiological variability among

the five different PPI continue to arise as our experience with these

agents increases. Theories behind these observations include dif-

ferences in parietal cell mass among different populations andcytochrome P450 polymorphism resulting in different PPI phar-

macokinetic profiles among individual patients. PPI therapy for

ulcer bleeding has been more efficacious in Asia than else-

where.25,26 Most pH studies have been on volunteers or cross-over

studies or in small groups; this is a first randomized trial to study

72-h pH in various PPI after successful endoscopic therapy in

patients of peptic ulcer bleed. Katz and colleagues 27 reported the

results of their evaluation of gastric acid suppression achieved with

five available PPI at a standard recommended dose for erosive

esophagitis, and found that healing was better with esomeprazole

than other PPI. However, all of the PPI resulted in a pH value of

more than 4 for at least 8–10 h. The acid suppressive efficacy of

rabeprazole 20 mg has been shown to be similar to that of ome-

prazole,28,29 as is the case with omeprazole and esomeprazole.30 We

used high p.o. and i.v. forms of three PPI (omeprazole, pantopra-

zole, rabeprazole); as in these three PPI, both p.o. and i.v. forms

are available, and only recently has esomeprazole i.v. become

available; this why we could compare only these three PPI.

We used high doses of PPI as it has been shown that a rapid

increase of intragastric pH above 6 can be reliably achieved only

by continuous infusion with a large initial bolus dose of PPI.31 In

bleeding peptic ulcer patients, the risk of ulcer re-bleeding is

highest during first 3 days and most re-bleed in the first 24 h;32 this

was the rationale of choosing a high-dose treatment period of

3 days with PPI. The treatment regime was aimed at elevating and

maintaining the intragastric pH at a level 6 or higher and thereby

promoting hemostasis. In our study, intragastric pH for 72 h with

omeprazole when given in different routes (infusion vs p.o.)

showed that intragastric pH raised to above 4 within 1 h in both

groups and remained above 6 for more than 98% of the time for the

remaining 72 h. Almost the same results were obtained with the

pantoprazole and rabeprazole groups of drugs on intragastric pHwhen given through different routes. There was no significant

statistical difference on intragastric pH with group of drugs (ome-

prazole, rabeprazole and pantoprazole) when given in different

routes (p.o. vs infusion; P > 0.05). The median pH remained above

6 in all forms of drugs for more than 98% of the time in the first

day and 100% of the time in the second and third days.

We excluded patients with re-bleeding or continuous bleed as

presence of blood would interfere with the study of pH. There

were eight patients who re-bled and were evenly distributed in

each group. We studied other outcome parameters like number of

blood transfusions, hospital stay, surgery, re-bleed and deaths.

There was no statistical significance in outcome.

In conclusion, our results demonstrated that high doses of dif-ferent groups of PPI (omeprazole, rabeprazole, pantoprazole)

when given in different forms (p.o. or infusion) after successful

endoscopic therapy achieved an intragastric pH of 6 and above

within 1 h of administration and maintained a pH of more than 6

for more than 98% of the time. There was an insignificant differ-

ence among various PPI on 72-h intragastric pH, however, there

was a significant difference between the PPI group and non-PPI

group. Thus, we conclude that a high dose of PPI maintains intra-

gastric pH above 6 regardless of route of administration.

Acknowledgments

The authors thank Mr Nazir Ahmad Patoo, chief pharmacist, andhis staff; Mr Ghulam Nabi Dar, technical officer of the endoscopic

unit; Mr Ghulam Mustafa, technical officer of the motility labora-

tory, and his staff for assistance in this study. We also thank

Mr Gulzar Ahmad and Mr Nazir Ahmad for their secretarial

assistance.

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