somatostatin inhibits gastric acid secretion more effectively than pantoprazole in patients with...
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ORIGINAL ARTICLE
Somatostatin inhibits gastric acid secretion more effectively thanpantoprazole in patients with peptic ulcer bleeding: A prospective,randomized, placebo-controlled trial
ALEC AVGERINOS1,2, SPIROS SGOUROS1, NIKOS VIAZIS1, JOHN
VLACHOGIANNAKOS1, KOSTIS PAPAXOINIS1, CHRISTINA BERGELE1,
PANTELIS SKLAVOS1 & SOTIRIS A. RAPTIS2
1Second Department of Gastroenterology, Evangelismos Hospital, Athens, Greece, and 2Second Department of Medicine
Propaedeutic Research Unit, Attiko University Hospital, Athens, Greece
AbstractObjective. Gastric acid inhibition is beneficial in the management of peptic ulcer bleeding (PUB). The aim of this double-blind study was to test whether somatostatin (SST) increases intragastric pH in PUB as compared with pantoprazole (PAN)and placebo (PLA). Material and methods. Eligible patients were randomized to receive SST (500 mg/h�/250 mg bolus),or PAN (8 mg/h�/80 mg bolus) or PLA (normal saline) i.v., for 24 h. All patients underwent gastric pH monitoring duringthe infusion of the trial drugs. Results. The three groups (SST, n�/14; PAN, n�/14; PLA, n�/15) were comparable forage, gender, aetiology of PUB and laboratory data at admission. Mean (9/SE) baseline pH levels in the fundus increasedduring the administration of the trial drugs (SST: 1.949/0.18 to 6.139/0.37, p B/0.0001; PAN: 1.939/0.16 to 5.659/0.37,p B/0.0001; PLA: 1.869/0.12 to 2.109/0.15, p�/0.0917). During the first 12 h of infusion, the mean (9/SE) percentage timespent above pH 4.0 and 5.4 was higher with SST versus PAN (84.4%9/4.8 versus 55.1%9/8.3, p�/0.0049 and 74.2%9/6.5versus 47.1%9/8.3, p�/0.0163, respectively) and there was a trend favouring the SST group regarding the time spent abovepH 6.0 and 6.8 (65.7%9/6.4 versus 43.3%9/8.2, p�/0.0669 and 49.2%9/7.7 versus 28.49/6.6, p�/0.0738, respective-ly). Conclusions. In PUB, both SST and PAN inhibit gastric acid secretion as compared with placebo. However, duringthe first 12 h of the infusion, SST was more effective than PAN in maintaining high intragastric pH. These results mayprovide a rationale for the administration of SST in PUB.
Key Words: Gastric acid inhibition, pantoprazole, peptic ulcer bleeding, somatostatin
Introduction
Peptic ulceration is the most important cause of non-
variceal upper gastrointestinal bleeding (NVUGIB)
and accounts for more than 65% of all cases that
present with haematemesis and or melaena [1,2].
Bleeding from ulcers ceases spontaneously in about
80% of patients. In the remaining 20%, bleeding will
continue or recur and therefore active treatment will
be required. The vast majority of patients with peptic
ulcer bleeding (PUB) will survive the index bleeding
episode. However, a subgroup of these patients does
not fare as well, accounting for an overall mortality
rate of 6�/7%. Unfortunately, this figure has re-
mained relatively stable for the past four decades,
despite improved medical and surgical treatments,
the development of diagnostic and therapeutic en-
doscopy, and the availability of intensive care units.
Therefore, further medical therapy to support and
maintain haemostasis would be beneficial. Data
from in vitro studies have shown that platelet
aggregation, the initial step of haemostasis, proceeds
optimally at neutral pH. In a slightly acidic environ-
ment, platelet aggregation is already impaired and is
virtually abolished at pH values B/6. In acidic gastric
juice, pepsinogen is activated to pepsin and can
readily digest freshly formed blood clots within
minutes. Furthermore, plasmin-mediated fibrinoly-
sis is increased and might thus impair reinforcement
Correspondence: Alec Avgerinos, 2nd Department of Gastroenterology, Evangelismos Hospital, 10 Kaplanon Street, GR-10680, Athens, Greece. Tel: �/30
694 5197 126. Fax: �/30 210 7233 671. E-mail: [email protected]
Scandinavian Journal of Gastroenterology, 2005; 40: 515�/522
(Received 13 July 2004; accepted 29 October 2004)
ISSN 0036-5521 print/ISSN 1502-7708 online # 2005 Taylor & Francis
DOI: 10.1080/00365520510015458
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of the initial platelet clot by a fibrin clot. This might
be important, as rebleeding of ulcers may be caused
by early dissolution of the clot [3�/7]. Therefore,
therapy with potent anti-secretory drugs, such as
proton-pump inhibitors (PPIs), makes considerable
sense in the rationale for thrombus stabilization to
control PUB [2,8�/12]. It has been shown that
administering 8 mg/h of omeprazole after a bolus
injection may produce consistently high intragastric
pH values and reduce the rate of recurrent bleeding
after endoscopic treatment of PUB [13,14]. How-
ever, there has been recent evidence suggesting that
the administration of PPIs alone is not helpful in the
management of patients with PUB and high-risk
endoscopic stigmata [8,15,16].
Somatostatin (SST), significantly reduces splan-
chnic blood flow in patients with variceal and
NVUGIB [17,18] and is an invaluable tool in the
control of UGIB in patients with cirrhosis with
portal hypertension [19�/24]. Its administration in
PUB may therefore prove to be a valuable option.
However, there is a lack of direct proof of an effect of
SST on gastric acid secretion in patients with PUB.
The aim of this study was to test the hypothesis that
SST may reduce gastric acidity in PUB, as compared
with pantoprazole (PAN) and placebo (PLA).
Material and methods
Patient selection
Patients with melaena and/or haematemesis who
were admitted to our centres between March 2002
and June 2003 were recruited if they met
the following criteria: age �/18 years; admission
within 24 h of the initial signs of bleeding; endo-
scopic signs of stages IIc and III PUB according to
the classification of Forrest et al. [25]; and written
informed consent to participate in the study, from
the patient or next of kin. We excluded patients if
they had: previously been included in the trial;
received antisecretory or vasoactive drugs for the
bleeding episode; been treated with antisecretory
drugs (PPIs, anti-H2 receptor antagonists) during
the week before the bleeding episode; documented
signs of hypovolaemia related to the current bleeding
episode; previous upper gastrointestinal surgery;
received anticoagulant therapy (vitamin K antago-
nists or heparin including low molecular weight
(LMW) heparins); deficient haemostasis (platelets
B/40�/109/l, international normalized ratio of the
prothrombin time �/1 �/5, or activated partial throm-
boplastin time �/40 s); known pernicious anaemia or
achylia; known gastric malignancy; known liver
cirrhosis or portal hypertension; a history of lacta-
tion, pregnancy or pregnancy potential (unless using
an effective means of contraception); known allergy
to SST or its analogues and/or PPIs; terminal-stage
illness in which endoscopy is contraindicated; renal
failure (creatinine ]/2 mg/dl); and finally, if after
emergency endoscopy, the mean 1-h gastric pH
was ]/4. Hypovolaemia was defined as systolic blood
pressure B/90 mmHg and heart rate �/100 bpm,
or orthostatic changes in systolic blood pressure
(decrease of �/20 mmHg) or in heart rate (increase
�/20 bpm) or signs of hypoperfusion (such as cold
extremities, sweating, peripheral cyanosis) or occur-
rence of symptoms of hypovolaemia defined as
fatigue and/or dizziness, sweating, malaise or faint-
ing between the first signs of bleeding and randomi-
zation.
pH monitoring
At the end of the emergency gastroscopy, the gastric
content was endoscopically removed as far as possi-
ble. In all eligible patients, pH monitoring was
performed, as reported previously [26], within 1 h
after endoscopy. Intragastric pH was measured via a
nasogastric probe using a single crystal antimony pH
catheter (Zinetics; Medtronic-Synetics, Skorlunde,
Denmark) connected to a portable data logger
(Digitrapper pH 400; Medtronic-Synetics, Skor-
lunde, Denmark). The pH catheter was inserted
transnasally into the stomach, under fluoroscopic
control, 15 cm below the cardia. The pH was
recorded every 4 s during the study period, from
two points in the stomach at 5 cm (fundus) and
15 cm (body) below the cardia. Initially, pH was
recorded for 1 h. Only patients with a mean 1-h
intragastric pH B/4 (baseline value), from any point
of the stomach, were randomized, and pH monitor-
ing was continued for a further period of 24 h.
During the pH recording period, patients received
nil by mouth.
Randomization and treatment
Patients were randomized by using the envelope
draw method, to receive 500 mg/h SST (UCB SA,
Belgium) or 8 mg/h PAN (Altana Pharma AG,
Konstanz, Germany) or normal saline given intrave-
nously (i.v.) as PLA, continuously for 24 h. Rando-
mization was carried out within 30 min after the end
of the baseline pH monitoring. In addition, all
patients received one bolus i.v. injection of 250 mg
SST or 80 mg PAN or 10 ml PLA, immediately after
the start of the continuous infusion of the trial drug.
In order to achieve the double-blind design of
the study, for each group of patients, we used
identical medications prepared in identical syringes
(i.e. the same shape, colour and consistency) and
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administered in 500 ml normal saline �/ this was
maintained throughout the 24-h study period. Con-
sequently, neither the patient nor the physician was
aware of the treatment type received by the patients.
The study was carried out in accordance with the
principles of the Declaration of Helsinki. Prior to
implementation, the protocol was approved by the
ethics committees of our centres. Plasma and blood
replacement, as well as other concomitant medica-
tions (vitamins, etc.) were initiated and continued
as standard supportive therapy. Blood products
(packed red cells, plasma expanders or fresh frozen
plasma) were administered in patients showing one
of the following clinical signs of bleeding: haema-
temesis; haemodynamic instability �/ a rise in pulse
rate of at least 20 bpm with a drop in systolic blood
pressure of at least of 20 mmHg; haemoglobin level
B/9 g/dl; haematocrit B/30%. During the 24-h study
period, heart rate, blood pressure, haemoglobin and
blood glucose were recorded every 6 h. The quan-
tities of blood products transfused were continuously
monitored for 72 h from randomization. Patients
received antisecretory drugs at the discretion of the
attendant physician after the end of the 24-h study
period. Patients were contacted 30 days after the
PUB episode in order to assess their final outcome.
Criteria of assessment
The primary end-point was to assess the number of
subjects who ‘‘succeeded’’ in maintaining a mean
intragastric pH of �/4 in the fundus, during the 24-h
drug infusion period. We based the analysis of our
data only on the pH values obtained from the
fundus, since available evidence [26] suggests that
the fundus is the optimal location to evaluate the
presence of gastric acid and that the pH values
obtained from this area are highly reproducible.
The secondary end-points were to evaluate: a) the
percentage of time spent above thresholds of pH 4.0,
5.4, 6.0 and 6.8 at 0�/12 h and 0�/24 h, during the
drug infusion period. The time spent above thresh-
olds was calculated as follows:
b) The effect of acid suppression on the following
variables: rebleeding and mortality during the fol-
low-up period (up to 30 days after randomization);
amount of blood products transfused during 72 h
from randomization; the need for surgery; duration
of hospital stay; and the healing of the ulcer at
30 days. c) Treatment safety, which was assessed by
the adverse effects reported by the patients or
recorded by the attending physicians. All adverse
events were coded according to the World Health
Organization dictionary. For each adverse event, the
causal relationship with the study drug and the
severity of the event were noted.
Sample size and power calculation
The number of patients needed was computed under
the assumption that the mean 24-h gastric pH of the
study population is 2.5 with an SD of 2.5. The
significance level was set at 5% and the power level
at 80%. It was found that 63 patients were needed in
order to show that SST, when administered during a
24-h infusion period, could increase the mean 24-h
gastric pH from 2.5 to 4.5, as compared with
placebo. Taking into account a 10% withdrawal
rate, this means that at least 69 patients needed to
be randomized in the study. The study was termi-
nated after 43 patients had been entered, since an
interim analysis performed at that time showed a
clear discrepancy between the groups regarding the
proportion of patients who ‘‘succeeded’’ in main-
taining a mean pH �/4.
Statistical analysis
All analyses of the effects of treatment regimens were
carried out using the intention-to-treat principle,
which implies that the analyses included all rando-
mized patients throughout the available follow-up
period. The level of significance was set at 5%. The
proportion of patients who ‘‘succeeded’’ in main-
taining a mean pH �/4 was analysed by logistic and
exact logistic regression. The actual mean 24-h pH
values were analysed by ANCOVA models. The two-
sided paired t-tests were used to analyse the changes
from baseline. ANCOVA models were also used to
examine the time spent above pH 4.0, 5.4, 6.0 and
6.8. For the logistic regression and ANCOVA
models and: 1) all p-values of the three pairwise
comparisons between treatment groups were Bon-
ferroni corrected, 2) treatment group and the prog-
nostic factors haemoglobin, blood urea nitrogen,
creatinine at screening and age, gender, Helicobacter
Time spent�n of recordings above threshold in the recordings period � 100%
n of valid recordings in the recording period
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pylori infection, endoscopic signs of bleeding accord-
ing to the Forrest classification and ulcer type were
entered as predictors. For the exact logistic regres-
sion, only treatment was used as a predictor. Since
there was a lack of variability in the outcome for
some treatment groups, the normal logistic regres-
sion did not converge and is not fully reliable.
Therefore, treatment groups are also analysed using
exact logistic regression, which does not suffer from
such lack of variability. Owing to computational
vastness, no other variables could be added in this
exact analysis.
Results
Patients
A total of 186 patients with signs of PUB were
screened during the study period. Of the 186
screened patients, 143 were excluded for the follow-
ing reasons: 64 (44.7%) had treatment with anti-
secretory or vasoactive drugs; 16 (11.2%) refused to
give consent; 19 (13.3%) had haemodynamic in-
stability; 10 (7%) had previous UGI surgery; 9
(6.3%) had baseline pH levels ]/4; 6 (4.2%) showed
recent stigmata of PUB such as visible vessels or an
adherent clot and, finally, 19 (13.3%) were excluded
for other reasons (4 malignancies, 6 on anticoagu-
lants, 5 terminal-stage illness, 2 renal failure and
2 liver cirrhosis). Of the remaining 43 patients who
were randomized, 14 patients received SST, 14
received PAN and 15 received PLA. The three
groups were comparable with respect to age, gender,
aetiology of PUB, baseline haemoglobin levels,
blood urea nitrogen, serum creatinine, H. pylori
infection and endoscopic signs of bleeding at admis-
sion (Table I). The mean time (9/SE) between the
first clinical signs of bleeding and randomization was
9.4 h 9/1.76, 9.3 h9/1.95 and 7.4 h9/1.44 for the
SST, PAN and PLA groups, respectively. All 43
patients received the trial drug as scheduled, during
the 24-h pH recording period. However, in one of
these patients (PAN group) the pH recording was
interrupted for 7 consecutive hours, because the
patient was feeling uncomfortable and the pH
catheter had to be removed. Another patient (SST
group) was found to have cirrhosis.
Primary end-point
During the 24-h recording period, the proportion of
patients who ‘‘succeeded’’ in maintaining a mean pH
�/4 was higher (p B/0.0001) in the SST (13/14
patients, 92.9%) and PAN (12/14 patients, 85.7%)
groups as compared with the PLA group (0%). The
results from the exact logistic regression analysis
showed a significant difference (p B/0.0001) between
the active treatments and placebo, illustrating that
SST and PAN have an effect on the response rate.
The pH values, from all patients with peptic ulcers in
both sites of the stomach, before (baseline values�/
1 h mean pH value) and during the infusion of the
drugs, are presented in Table II. As shown, the mean
pH values increased significantly (p B/0 �/0001) dur-
ing the trial drug infusion period versus baseline,
from both sites of the stomach, except for the
placebo group in the fundus (p�/0.0917) and in
the body (p�/0.0306). Despite this increase in pH in
the body versus baseline values in the placebo group,
no subject in this group had a mean pH value �/4.0
during the 24-h study period from any point of the
stomach. The difference in the mean 24-h pH
measurements between the three groups was sig-
nificant (p B/0 �/0001). The mean (9/SE) gastric pH
Table I. Clinical and laboratory data (mean 9/SE) at randomization.
Somatostatin
(n�/14)
Pantoprazole
(n�/14)
Placebo
(n�/15)
Age (years) 45.19/2.8 53.29/4.9 50.59/3.4
Gender (male/female) 13/1 11/3 13/2
Gastric/duodenal ulcer* 5/9 7/7 7/8
Haemoglobin (g/dl) 11.39/0.44 11.59/0.39 11.39/0.39
Blood urea nitrogen (mmol/l) 18.29/1.53 19.69/2.19 17.29/1.28
Creatinine (mmol/l) 929/3.46 92.99/3.03 90.19/3.05
Helicobacter pylori (no. patients) 10 8 10
Forrest IIc/III 12/2 12/2 13/2
*Transpyloric ulcers (one patient in the pantoprazole and one in the placebo group) were considered as gastric ulcers.
Table II. Mean (9/SE) pH values in both sites of the stomach
before (baseline values�/1 h mean pH) and during drug infusion
in patients with peptic ulcer bleeding.
Site Baseline 0�/24 h p -value*
Somatostatin Fundus 1.949/0.18 6.139/0.37 B/0.0001
(n�/14) Body 2.059/0.18 6.179/0.41 B/0.0001
Pantoprazole Fundus 1.939/0.16 5.659/0.37 B/0.0001
(n�/14) Body 2.399/0.25 6.279/0.45 B/0.0001
Placebo Fundus 1.869/0.12 2.109/0.15 0.0917
(n�/15) Body 2.029/0.15 2.429/0.21 0.0306
*Changes versus baseline values, two-sided paired t -test.
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in the fundus increased in the same way in patients
with gastric ulcers (SST: 1.79/0.07 to 5.939/0.9,
p�/0.0094; PAN: 1.859/0.30 to 4.849/0.59, p�/
0.0029; PLA: 2.029/0.17 to 2.329/0.25, p�/
0.2107) and duodenal ulcers (SST: 2.249/0.27 to
6.259/0.33, p B/0. �/0001; PAN: 2.019/0.11 to 6.459/
0.19, p B/0.0001; PLA: 1.729/0.16 to 1.919/0.14,
p�/0.3187).
The gastric pH profile in the fundus of the three
groups during the 24-h infusion period is presented
in Figure 1. As shown, the mean pH in the SST and
PAN groups is always higher than placebo (SST
versus PLA: p B/0.0001, except for the time period
1�/2 h, where p�/0.0074; PAN versus PLA: p B/
0.0001, except for the time period 0�/4 h, where
p�/0.0855, and 0�/3 h, where p�/0.3758, and there
was no difference for the first 2 h). The only
independent variable related to the gastric pH was
the type of drug given (ANCOVA, pB/0.0001).
Secondary end-points
Time spent above pH thresholds. The mean (9/SE)
percentages of time spent above pH 4.0, 5.4, 6.0 and
6.8 are presented in Table III. The time spent above
pH thresholds of 4.0 and 5.4 during the first 12 h of
the infusion period was higher in the SST group as
compared with the PAN group (p�/0.0049, p�/
0.0163, respectively) and there was a trend (p�/
0.0669 and p�/0.0738) favouring the SST group
regarding the time spent above pH 6.0 and 6.8,
Figure 1. Mean (9/SE) 24 h gastric profile in the fundus of patients bleeding from peptic ulcer during the infusion of the trial drugs. The
starting-point (time 0) represents the baseline values before administration of the trial drug. Notice the comparatively steep slope of the SST
line in the segment corresponding to the first 4 h. A similar, but less pronounced effect, can be seen in the PAN line in the 0 to 12-h period,
after which the behaviour is comparable (SST versus PAN: p�/0.0173 for the time period 0�/12 h, p�/0.6468 for the time period 0�/24 h).
Abbreviations: SST�/somatostatin; PAN�/pantoprazole; PLA�/placebo.
Table III. Mean (9/SE) percentage of time spent above pH thresholds in the fundus during the specified infusion periods of somatostatin
(SST), pantoprazole (PAN) and placebo (PLA).
p -value*
pH thresholds
Time period
(h)
Somatostatin
(n�/14)
Pantoprazole
(n�/14)
Placebo
(n�/15)
SST versus
PLA
PAN versus
PLA
SST versus
PAN
�/4.0 0�/12 84.49/4.8 55.19/8.3 7.19/2.7 B/0.0001 B/0.0001 0.0049
0�/24 82.69/6.3 70.19/7.2 89/2.5 B/0.0001 B/0.0001 0.2347
�/5.4 0�/12 74.29/6.5 47.19/8.3 2.29/0.8 B/0.0001 0.0001 0.0163
0�/24 72.59/6.9 61.99/7.8 49/1.7 B/0.0001 B/0.0001 0.4745
�/6.0 0�/12 65.79/6.4 43.39/8.2 1.59/0.7 B/0.0001 0.0002 0.0669
0�/24 64.19/6.9 57.39/7.9 39/1.4 B/0.0001 B/0.0001 1.0000
�/6.8 0�/12 49.29/7.7 28.49/6.6 19/0.5 B/0.0001 0.0059 0.0738
0�/24 47.99/7.5 42.89/6.6 1.99/0.9 B/0.0001 B/0.0001 1.0000
*Pairwise comparisons of treatments.
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respectively. The type of drug given was the only
independent variable related to the percentage of
time spent above pH thresholds (ANCOVA, p B/
0.0001) for the 0 to 24-h period.
Other outcome variables
Only one patient re-bled (third day after randomiza-
tion) during the follow-up period. This patient was
found to have a malignant ulcer and was operated
on. At the 30-day follow-up, all patients were alive
and ulcer healing was achieved in all but 4 patients
(1 with duodenal ulcer in the SST group, 1 with
gastric ulcer in the PAN group and in 2 with
duodenal ulcer in the PLA group). The transfusion
requirements during the 72-h study period were
similar in all groups (SST: 2 units, PAN: 1 unit and
PLA: 2 units). The mean (9/SE) hospital duration
was 3.42 days 9/0.47 in the SST group, 5.57 days 9/
1.8 in the PAN group and 3.4 days 9/0.49 in the
PLA group. In the PAN group, hospital stay was
reduced to 3.84 days 9/0.55 when a patient with
gastric cancer who was operated on was excluded
from the analysis.
Adverse events
No serious adverse events were reported during the
infusion period. Seventeen patients developed mild
clinically relevant adverse events, but most of the
patients recovered after the end of the infusion
period. Hyperglycaemia was the most frequently
reported adverse event. The occurrence of hypergly-
caemia was related to the treatment group (p�/
0.0013). This significance was due to the higher
prevalence of hyperglycaemia in SST patients than
in other patients (SST: 10, PAN: 2 and PLA: 2).
One patient in the SST group developed nausea
and three patients developed headache (PAN: 1,
PLA: 2).
Discussion
The proportion of patients who ‘‘succeeded’’ in
maintaining a mean gastric pH �/4 during the
infusion of the trial drugs was higher (p B/0.0001)
in the SST (13/14 patients, 92.9%) and PAN groups
(12/14 patients, 87.5%) as compared with PLA
(0%). These results confirm previous studies sug-
gesting that 8 mg/h omeprazole may effectively
neutralize intragastric pH in patients with PUB
[13,14]. However, during the first half of the
treatment, the time spent above pH 4.0 and 5.4
was higher with SST as compared with PAN (p�/
0.0049, p�/0.0163, respectively). The type of trial
drug given was the only independent variable related
to the gastric pH and the time spent above pH
thresholds for the 0 to 24-h period (p B/0.0001).
The above-mentioned assessment parameters
were chosen for the analysis of our data because in
several studies it is suggested that a reduction of
gastric acidity above these pH targets is critical to
secure haemostasis and control PUB [3�/7,27�/29].
Specifically: when gastric pH falls below 6.8, platelet
aggregation and blood coagulation become abnor-
mal; below pH 6.0, platelet desegregation takes
place; below 5.4, platelet aggregation and plasma
coagulation are virtually abolished; and below pH
4.0, fibrin clots are dissolved [3,6,7].
As shown, the three groups were comparable with
respect to clinical and laboratory data (Table I). The
mean age in the SST patients appears to be some-
what younger than those receiving PAN (45.19/2.8
versus 53.29/4.9, respectively; p�/0.3238). How-
ever, we believe that this difference has not influ-
enced the outcome of our patients since there is clear
evidence to suggest that gastric acid secretion is
unaffected by age [30].
For ethical and technical purposes, only patients
who usually have an uneventful recovery without any
kind of intervention were included (Forrest IIc, III)
[1,2]. As expected, the re-bleeding rate, transfusion
requirements, need for surgery, mortality and the
length of hospital stay were similar in all three
groups.
In most series concerning PUB, the initial rates
of haemostasis with endotherapy exceed 94%. At
the same time, the rates of recurrent bleeding are
substantial, especially in patients with severe coex-
isting conditions [1,31]. Therefore, the search for
medical therapy that will reduce the rates of recur-
rent bleeding and the need for surgery or endoscopic
treatment continues [1,11,32]. Perhaps the most
interesting finding from the published data regarding
medical treatment in PUB is the independent and
significant decrease in re-bleeding attributable to
PPI use that was noted in patients without high-risk
stigmata, most of whom did not undergo endoscopic
therapy [2,8,11]. In contrast, it has been shown that
omeprazole infusion alone is not helpful in prevent-
ing recurrent bleeding from ulcers with high-risk
stigmata, suggesting the use of other types of medical
therapy, i.e. vasoactive drugs, in this subgroup of
patients [8,15,16]. In fact, it has now become clear
that the early administration of SST, even as an
alternative to endoscopy, is helpful for the successful
management of UGIB in cirrhotic patients with
portal hypertension [24].
In this study we administered somatostatin at
a dose of 500 mcg/h. Although this is higher than
the 250 mcg/h dose used in everyday practice, we
chose to administer it because it appears to be more
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effective in reducing splanchnic blood flow. The
administration of 500 mcg SST as opposed to 250
mcg is more successful in reducing active bleeding at
endoscopy, making endotherapy easier to perform,
thus resulting in increased overall control of bleeding
and survival in cirrhotic patients with UGIB [21,22].
Peptic ulceration is the most frequent cause of
NVUGIB and is a life-threatening emergency. This
study shows that in PUB, both 500 mg/h SST and
8 mg/h PAN produce consistently high intragastric
pH values as compared with PLA. However, it is
evident that SST is more effective than PAN in
inhibiting gastric acid secretion during the first 12 h
of treatment. In such cases, SST, in addition to its
vasoactive effect, appears to act as a potent inhibitor
of gastric acid secretion, through the inhibition of
gastrin [27,33]. This additional advantage of SST
may be of importance for the early control of PUB.
Nevertheless, further studies are needed in order to
evaluate the efficacy and safety of different dose
schedules of SST treatment on the 24-h gastric pH
profile in patients with PUB. In view of the
mandatory role of gastric acid inhibition in promot-
ing haemostasis, our data may provide a rationale for
the administration of SST in PUB.
Acknowledgements
We thank Nirjhar Chatterjee for useful comments
and constructive criticism of the manuscript. Fund-
ing for the independent statistical analysis of the
study data was provided by UCB SA (Allee de la
Recherche 60, BE-1070 Brussels, Belgium).
References
[1] Laine L, Peterson WL. Bleeding peptic ulcer. N Engl J Med
1994;331:717�/27.
[2] Barkum A, Sandrine S, Enns R, Armstrong D, Gregor J,
Fedorak RNN, et al., and the RUGBE Investigators. The
Canadian registry of nonvariceal upper gastrointestinal
bleeding and endoscopy (RUGBE): endoscopic hemostasis
and proton pump inhibition are associated with improved
outcomes in a real-life setting. Am J Gastroenterol 2004;99:
1238�/46.
[3] Green FW Jr, Kaplan MM, Curtis LE, Levine PH. Effect of
acid and pepsin on blood coagulation and platelet aggrega-
tion. A possible contributor to prolonged gastroduodenal
mucosal hemorrhage. Gastroenterology 1978;74:38�/43.
[4] Vreeburg EM, Levi M, Rauws EAJ, Devender SJHV, Snel P,
Bartelsman JWFM, et al. Enhanced mucosal fibrinolytic
activity in gastroduodenal ulcer haemorrhage and the
beneficial effect of acid suppression. Aliment Pharmacol
Ther 2001;15:639�/46.
[5] Chalmhoff C, Creter D, Djaldetti M. The effect of pH on
platelet and coagulation factor activities. Am J Surg 1978;
136:257�/9.
[6] Patchett SE, Enright H, Afdhal N, O’Connell W, O’Dono-
ghue DP. Clot lysis by gastric juice: an in vivo study. Gut
1989;30:1704�/7.
[7] Patchett SE, O’Donoghue DPO. Pharmacological manipu-
lation of gastric juice: thromboelastographic assessment and
implications for treatment of gastrointestinal haemorrhage.
Gut 1995;36:358�/62.
[8] Khuroo MS, Yattoo GN, Javid G, Khan BA, Shah AA,
Gulzar GM, et al. A comparison of omeprazole and placebo
for bleeding peptic ulcer. N Engl J Med 1997;336:1054�/8.
[9] Schaffalitzky de Muckadell OB, Havelund T, Harling H,
Boesby S, Snel P, Vreeburg EM, et al. Effect of omeprazole
on the outcome of endoscopically treated bleeding peptic
ulcers: a randomized double-blind placebo-controlled multi-
center study. Scand J Gastroenterol 1997;32:320�/7.
[10] Barkun AN, Cockeram AW, Plourde V, Fedorak RN. Acid
suppression in non-variceal acute upper gastrointestinal
bleeding [review article]. Aliment Pharmacol Ther 1999;
13:1565�/84.
[11] Zed PJ, Loewen PS, Slavik RS, Marra CA. Meta-analysis of
proton pump inhibitors in treatment of bleeding peptic
ulcers. Ann Pharmacother 2001;35:1528�/34.
[12] Walt RP, Cotterell J, Mann SG, Freemantle NP, Langman
MJS. Continuous intravenous famotidine for haemorrhage
from peptic ulcer. Lancet 1992;340:1058�/62.
[13] Labenz J, Peitz U, Leusing C, Tillenburg B, Blum AL,
Borsch G. Efficacy of primed infusions with high dose
ranitidine and omeprazole to maintain high intragastric pH
in patients with peptic ulcer bleeding: a prospective rando-
mized controlled study. Gut 1997;40:36�/41.
[14] Lau JYW, Sung JJY, Lee KKC, Yung M-Y, Wong SKH, Wu
JCY, et al. Effect of intravenous omeprazole on recurrent
bleeding after endoscopic treatment of bleeding peptic
ulcers. N Engl J Med 2000;343:310�/6.
[15] Jensen DM, Kovacs TOG, Jutabha R, Machicado GA,
Gralnek IM, Savides TI, et al. Randomized trial of medical
or endoscopic therapy to prevent recurrent ulcer hemorrhage
in patients with adherent clots. Gastroenterology 2002;123:
407�/13.
[16] Sung JJW, Chan FKL, Lau JYW, Yung M-Y, Leung WK, Wu
JC, et al. The effect of endoscopic therapy in patients
receiving omeprazole for bleeding ulcers with nonbleeding
visible vessels or adherent clots. A randomized comparison.
Ann Intern Med 2003;139:237�/43.
[17] Sonnenberg GE, Keller U, Perruchoud A, Burckhardt D,
Gyr K. Effect of somatostatin on splanchnic hemodynamics
in patients with cirrhosis of the liver and in normal subjects.
Gastroenterology 1981;80:526�/32.
[18] Saruc M, Can M, Kucukmetin N, Tuzuoglu I, Tarhan S,
Goktan C, et al. Somatostatin infusion and hemodynamic
changes in patients with non-variceal upper gastrointestinal
bleeding: a pilot study. Med Sci Monit 2003;9:184�/7.
[19] Avgerinos A, Nevens F, Raptis S, Fevery J, and the ABOVE
Study Group. Early administration of somatostatin and
efficacy of sclerotherapy in acute oesophageal variceal
bleeds: The European Acute Bleeding Oesophageal Variceal
Episodes (ABOVE) randomized trial, Lancet 1997;350:
1495�/9.
[20] Avgerinos A. A role for somatostatin in upper gastrointest-
inal bleeding. Digestion 1998;59(Suppl 1):1�/22.
[21] Avgerinos A, Viazis N, Vlachogiannakos J, Poulianos G,
Armonis A, Manolakopoulos S, et al. Two different dose and
duration schedules of somatostatin-14 in the treatment of
patients with bleeding oesophageal varices. A non rando-
mised controlled study. J Hepatology 2000;32:171�/2.
[22] Mointinho E, Planas R, Banares R, Albillos A, Ruiz-Del-
Arbol L, Calvez C, et al. Variceal Bleeding Study Group.
Multicenter randomized controlled trial comparing different
schedules of treatment of somatostatin in the treatment of
acute variceal bleeding. J Hepatology 2001;35:712�/8.
Somatostatin and gastric acid inhibition 521
Scan
d J
Gas
troe
nter
ol D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y SU
NY
Sta
te U
nive
rsity
of
New
Yor
k at
Sto
ny B
rook
on
12/2
1/14
For
pers
onal
use
onl
y.
[23] Avgerinos A, Vlachogiannakos J, Viazis N, Raptis S. Clear-
ing the stomach before emergency endoscopy in cirrhotics
with acute upper gastrointestinal bleeding: a gastrokinetic or
a vasoactive drug? J Hepatology 2003;39:130�/1.
[24] D’Amico G, Pietrosi G, Tarantino I, Pagliaro L. Emergency
sclerotherapy versus vasoactive drugs for variceal bleeding in
cirrhosis: a Cochrane meta-analysis. Gastroenterology 2003;
124:1277�/91.
[25] Forrest JAH, Finlayson NDC, Shearman DCJ. Endoscopy
of upper gastrointestinal bleeding. Lancet 1974;2:394�/7.
[26] Fackler WK, Vaezi MF, Richter JE. Ambulatory gastric pH
monitoring: proper probe placement and normal values.
Aliment Pharmacol Ther 2001;15:1155�/62.
[27] Berstad A, Holm HA, Kittang E. Experience with antipeptic
agents. Scand J Gastroenterol 1979;14(Suppl 55):121�/3.
[28] Berstad A. Does profound acid inhibition improve haemos-
tasis in peptic ulcer bleeding? Scand J Gastroenterol 1997;
32:396�/8.
[29] Kaviani MJ, Hashemi MR, Kazemifar AR, Rootzitalab S,
Mostaghni AA, Merat S, et al. Effect of oral omeprazole in
reducing re-bleeding in bleeding peptic ulcers: a prospective,
double-blind, randomized, clinical trial. Aliment Pharmacol
Ther 2003;17:211�/6.
[30] Shih GL, Brensinger C, Katzka DA, Metz DC. Influence of
age and gender on gastric acid secretion as estimated by
integrated acidity in patients referred for 24-hour ambula-
tory pH monitoring. Am J Gastroenterol 2003;98:1713�/8.
[31] Gralnek IM, Jensen DM, Gornbein J, Kovacs TOG, Jutabha
R, Freeman ML, et al. Clinical and economic outcomes of
individuals with severe peptic ulcer haemorrhage and a non-
bleeding visible vessel: an analysis of two prospective clinical
trials. Am J Gastroenterol 1998;93:2047�/56.
[32] Imperiale TF, Birgisson S. Somatostatin or octreotide
compared with H2 antagonists and placebo in the manage-
ment of acute non-variceal upper gastrointestinal haemor-
rhage: a meta-analysis. Ann Intern Med 1997;127:1062�/71.
[33] Raptis S, Dollinger HC, von Berger L, Schlegel W, Schroder
KE, Pfeifer EF. Effects of somatostatin on gastric secretion
and gastrin release in man. Digestion 1975;13:15�/26.
522 A. Avgerinos et al.
Scan
d J
Gas
troe
nter
ol D
ownl
oade
d fr
om in
form
ahea
lthca
re.c
om b
y SU
NY
Sta
te U
nive
rsity
of
New
Yor
k at
Sto
ny B
rook
on
12/2
1/14
For
pers
onal
use
onl
y.