Therapeutic Advances in Gastroenterology Review

Ther Adv Gastroenterol

A clinical guide to using intravenous (2010) 3(1) 11—22
DOI: 10.1177/
proton-pump inhibitors in reflux and 1756283X09352095
! The Author(s), 2010.

peptic ulcers Reprints and permissions:

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Sandy H. Pang and David Y. Graham

Abstract: Intravenous (IV) proton-pump inhibitors (PPIs) are potent gastric acid suppressing
agents, and their use is popular in clinical practice. Both IV and oral PPIs have similarly short
half-lives, and their effects on acid secretion are similar, thus their dosing and dosage intervals
appear to be interchangeable. The possible exception is when sustained high pHs are required
to promote clot stabilization in bleeding peptic ulcers. Continuous infusion appears to be the
only form of administration that reliably achieves these high target pHs. IV PPI is indicated in
the treatment of high-risk peptic ulcers, complicated gastroesophageal reflux, stress-induced
ulcer prophylaxis, Zollinger—Ellison syndrome, and whenever it is impossible or impractical to
give oral therapy. The widespread use of PPIs has been controversial. IV PPIs have been linked
to the development of nosocomial pneumonia in the intensive care setting and to spontaneous
bacterial peritonitis in cirrhotic patients. This review discusses the use of IV PPI in different
clinical scenarios, its controversies, and issues of appropriate use.

Keywords: proton-pump inhibitor (PPI), H2-receptor antagonist, acid secretion, peptic ulcer,
gastroesophageal reflux disease, stress ulcer, bleeding ulcer, gastrointestinal hemorrhage,
Zollinger-Ellison syndrome

Introduction These factors often come into play in critically ill Correspondence to:
David Y. Graham, MD
The introduction of the first proton-pump patients, who may require IV PPIs either to treat Department of Medicine,
inhibitor (PPI), omeprazole, in 1989, marked acid-secreting disorders, or as prophylaxis against Michael E. DeBakey
Veterans Affairs Medical
the end of a search for effective control of acid stress-related mucosal injury. IV PPI plays a syner- Center and Baylor College
secretion. Omeprazole was followed by lansopra- gistic role in the treatment of bleeding peptic ulcers of Medicine, Houston, TX,
USA
zole (1995), pantoprazole (1997), rabeprazole requiring endoscopic hemostasis, although its cost- [email protected]
(1999), and the S-enantiomer of omeprazole, effectiveness requires further study. Sandy H. Pang, MB BS
esomeprazole (2001). PPIs are available in intra- FRACP
Institute of Digestive
venous (IV) and oral forms (enteric-coated The widespread use of IV PPI has caused con- Disease, Chinese
delayed release, microencapsulated beads in a troversy, including concern over its association University of Hong Kong,
Shatin, Hong Kong SAR,
capsule or suspension, and unprotected drug with respiratory complications in the critically China
with sodium bicarbonate). ill, and with spontaneous bacterial peritonitis
(SBP) in cirrhotic patients. IV PPIs have been
Currently, IV PPI is approved by the US Food and reported to be commonly used inappropriately
Drug Administration (FDA) for treating patients which, if true, represent a misuse of healthcare
who are unable to tolerate oral medications due resources. This article reviews the current evi-
to complicated erosive esophagitis, and in patients dence for the use of IV PPIs in peptic ulcer dis-
with Zollinger—Ellison syndrome (ZES) with ease and gastroesophageal reflux disease
pathological hypersecretory states. In real life prac- (GERD), including the controversies, and also
tices, the use of IV PPI is much more widespread. addresses issues surrounding appropriate use.
The decision to administer IV PPI depends on sev-
eral factors such as the ability of the patient to Pharmacology — overview
swallow, gastric motility, intestinal transport and PPIs are substituted benzimidazoles that cova-
permeability, and cytochrome p450 activity. lently bind to the H+/K+ ATPase enzyme,

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Therapeutic Advances in Gastroenterology 3 (1)

selectively and irreversibly inhibiting this final Helicobacter pylori, and decreased gastric parietal
step of acid secretion in a dose-dependent cell mass in Asians.
manner [Richardson et al. 1998]. PPIs are more
potent than histamine H2-receptor antagonists Use of intravenous PPI in peptic ulcer disease
(H2RAs), which only inhibit one of the pathways The use of IV PPI is perhaps best established in
involved in acid secretion. With prolonged the treatment of complicated peptic ulcer disease,
dosing, tolerance to the antisecretory effect of and has largely replaced the use of H2RA.
H2RAs develops [Merki and Wilder-Smith, A meta-analysis of 24 randomized controlled
1994]; this does not occur with PPIs. Thus, trials with 4373 patients, comparing IV or oral
PPIs have become the drug of choice when PPI with placebo or H2RA in bleeding peptic
potent inhibition of acid-secretion is required. ulcers, reported that PPI treatment in peptic
ulcer bleeding reduces rebleeding and surgery
Currently, three IV PPIs are available in the US compared with placebo or H2RA [Leontiadis
(esomeprazole, pantoprazole and lanzoprazole). et al. 2006]. All-cause mortality was not affected.
IV omeprazole is available in Europe and Asia.
IV PPIs should be administered through a dedi- Intragastric pH studies — oral versus intrave-
cated IV line, and flushed with compatible solu- nous PPI
tions pre- and post-administration [Package Endoscopic hemostasis plays a pivotal role in the
inserts (Prevacid, Protonix, Nexium), 2009]. treatment of bleeding peptic ulcers, and although
They should not be administered concomitantly this is successful >90% of the time, rebleeding
with other medications. Esomeprazole and still occurs within 72 h in up to 25% of cases
pantoprazole may be administered as a bolus [Laine and Peterson, 1994]. In vitro, an intragas-
(over 3 min and 2 min, respectively) or as an IV tric pH of >6 has been shown to promote clot
infusion (over 10—30 min and 15 min, respectively) stabilization by reducing pepsin-induced clot
[Protonix, Nexium (package insert), 2009]. lysis and increasing platelet aggregation [Barkun
Lansoprazole is approved for IV infusion over et al. 1999]. It follows that rapid achievement and
30 min only and requires administration through maintenance of an intragastric pH of >6 theoret-
a 1.2 mm pore size in-line filter to remove any pre- ically provide the optimal environment for peptic
cipitate that may form when the reconstituted drug ulcer healing and clot stabilization to occur.
product is mixed with IV solutions [Package insert
(Prevacid), 2009]. Esomeprazole and pantoprazole Several studies have looked at the efficacy of PPIs,
do not require a filter for administration. given in a combination of oral, IV bolus (defined
as administration with an IV push at regular inter-
PPIs are predominantly inactivated by the 2C19 vals) and high dose IV continuous infusion forms
and 3A isoform of the hepatic cytochrome p450 (usually preceded by an 80 mg bolus IV push, fol-
(CYP) mixed function oxidase system; the meta- lowed by an infusion at 8 mg/h), in achieving and
bolites are then eliminated in the urine and feces. maintaining this pH target goal of >6 [Javid et al.
The CYP2C19 gene located on chromosome 10 2009; Laine et al. 2008; Hartmann et al. 1998].
displays genetic polymorphism, with three Theoretically, high-dose IV continuous infusion
common inactivating mutations. Individuals should provide the most potent acid suppression.
with two mutant CYP2C19 alleles (poor meta- PPIs only inhibit stimulated parietal cells with
bolizers) metabolize PPIs more slowly than those active proton pumps and this is most successfully
with one mutant or two wild-type alleles (exten- and rapidly achieved by administering a bolus
sive metabolizers). Poor metabolizers may display dose intravenously (providing 100% bioavailabil-
a greater response to a standard dose of PPI com- ity theoretically); continuous infusion then pro-
pared with extensive metabolizers [Sugimoto vides a steady state of the drug to inactivate any
et al. 2006; Sagar et al. 2000]. The prevalence newly synthesized proton pumps, as well as any
of CYP2C19 mutations is more prevalent in newly recruited proton pumps on parietal cells
Asian populations (13—23%), compared with [Welage et al. 2003], which continue to be stimu-
European and North American white popula- lated by gastrin, histamine and food.
tions (3—5%) [Furuta et al. 2005, 1998]. This
results in a higher plasma level of PPI in However, this theoretical superiority has not been
Asians, and may in part explain the improved borne out as strongly in the medical literature
efficacies of PPI seen in this population, espe- as one may have expected. In one study, oral
cially considering the higher prevalence of and IV pantoprazole were equipotent in raising

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 SH Pang and DY Graham

intragastric pH, when administered at the same alone, or to endoscopic hemostasis first, followed
dose and intervals [Hartmann et al. 1998]. In by infusional IV omeprazole. Patients receiving
another intragastric pH study on 90 patients, the combination treatment had significantly
who had received endoscopic therapy for a bleed- lower rebleeding rates compared to those who
ing peptic ulcer, infusional IV was compared received infusional IV omeprazole alone (1.1%
against the oral forms of omeprazole, pantopra- versus 11.6%, p ¼ 0.009).
zole and rabeprazole [Javid et al. 2009]. All
groups achieved a mean 72 h intragastric pH of Although the use of IV PPI postendoscopic
>6, and there were no significant differences hemostasis has now become standard of care,
between the oral and infusional IV arms of each the above studies have limitations of being single
drug. Similar results were obtained with infu- center reports, consisting mainly of Southeast
sional IV and oral lansoprazole, although IV lan- Asians. The apparent efficacy of this approach
soprazole was more rapid in raising intragastric has been challenged by studies with inconsistent
pH initially [Laine et al. 2008]. conclusions in Western Europe and North
America [Jensen et al. 2006; Hasselgren et al.
The debate between infusional IV and oral PPI 1997; Schaffalitzky de Muckadell et al. 1997].
becomes more complicated when one wonders Moreover, mortality (probably the most impor-
whether achieving an intragastric pH of >6 is tant clinical outcome) has never been shown to
truly a key variable. Some intragastric pH studies be affected by the use of IV PPI. Racial differences
reported achieving a pH of >6 less than 30% of the in genetic polymorphisms of the CYP450 system,
time with infusional IV PPI [Metz et al. 2006]. The parietal cell mass and the prevalence of
solution to this could lie in the addition of a buffer- Helicobacter pylori have challenged the external
ing agent; for example, sodium bicarbonate, to a validity of the efficacy of high-dose infusional IV
PPI. Sodium bicarbonate has already been shown PPI. This controversy appears to have been laid to
independently to have the ability to raise intragas- rest with a recent randomized, double-blinded,
tric pH [Lin et al. 1998; Simmons et al. 1986]. This placebo-controlled trial by the Peptic Ulcer
combination should allow high intragastric pHs to Bleed Study Group, consisting of 767 patients
be easily and reliably achieved [Julapalli and (mainly Caucasians) from 16 countries [Sung
Graham, 2005]. However, no trials to date have et al. 2009]. This study reinforced the efficacy of
shown that upper gastrointestinal hemorrhage IV PPI infusion postendoscopic hemostasis (5.9%
(UGIH) patients have higher rebleeding rates if rebleeding within 72 hours in the IV esomeprazole
an intragastric pH of >6 is not continuously main- infusion bolus group versus 10.3% in the placebo
tained. It remains unclear whether this theoretical group; p ¼ 0.026). The difference remained sign-
goal is indeed clinically relevant. ficant at 7 and 30 days, suggesting that the benefits
of the drug is unlikely race-specific, and appears to
Post-endoscopic intravenous PPI be unequivocal, when compared to placebo.
IV PPI infusion, in combination with endoscopic
hemostasis, has been shown to achieve the lowest The conventional dosage of infusional IV PPI
rebleeding rates in ulcers with high risk bleeding (80 mg bolus followed by 8 mg/h for 72 h), used
stigmata [Zargar et al. 2006; Lau et al. 2000]. In a in several studies [Sung et al. 2009; Zargar et al.
landmark study by Lau et al. [2000], patients who 2006; Sung et al. 2003; Lau et al. 2000] and
underwent successful endoscopic hemostasis of endorsed by consensus statements [Barkun et al.
peptic ulcers with high risk stigmata, were subse- 2003; British Society of Gastroenterology
quently randomized to receive either 80 mg bolus Endoscopy Committee, 2002] have been chal-
of IV omeprazole followed by a continuous infu- lenged by studies which have found no difference
sion of 8 mg/h for 72 h, or a bolus followed by a between high dosage and low dosage IV PPI.
placebo infusion. Patients who received the high Andruilli et al. [2008] conducted a study across
dose PPI infusion had significantly lower rebleed- 11 Italian centers, and found no difference in
ing rates, when compared to those who received a in-hospital rebleeding and overall mortality rates,
placebo (6.7% versus 22.5%, p < 0.001). The in patients who were given the conventional high
importance of endoscopic hemostasis, in combi- dose PPI infusion, compared with those who had a
nation with high dose IV PPI, was reinforced in a standard dose of 40 mg IV daily for 72 h [Andriulli
study by Sung et al. [2003], in which patients with et al. 2008]. This study had a few limitations.
ulcers with nonbleeding visible vessels and clots Firstly, only inhospital rebleeding rates were
were randomized to infusional IV omeprazole reported as opposed to the more conventional

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Therapeutic Advances in Gastroenterology 3 (1)

28-day rebleeding rates. Patients who received the endoscopic therapy was lower in the omeprazole
lower PPI dose had shorter hospital stays; post- group compared with the placebo group (19.1%
discharge rebleeding episodes may have gone versus 28.4%, p ¼ 0.007), suggesting that high
undetected in this group. Other similar investiga- dose PPI infusion may hasten the resolution of
tions of PPI dosages have yielded conflicting results bleeding stigmata and the healing of the bleeding
[Bajaj et al. 2007; Lin et al. 2006; Udd et al. 2001]. lesions. Patients in the omeprazole group had
Large, prospective studies looking at hard clinical shorter hospital stays, but there were no differ-
outcomes such as rebleeding rates and mortality ences in 30-day rebleeding rates, need for sur-
are needed, before any recommendations can be gery, or 30-day mortality. This could possibly
made regarding the use of lower doses of IV PPI be attributed to the use of IV PPI infusion post-
in bleeding peptic ulcers. A prospective study by endoscopic hemostasis, which may have reduced
Sung et al. is currently underway to clinically com- the rates of the aforementioned clinical outcomes
pare infusional IV and oral PPI in the postendo- to such a point, that small differences could no
scopic hemostasis setting, the results of which will longer be detected even with their relatively large
hopefully further clarify the picture. sample size. Although high dose IV PPI in sta-
ble patients waiting for an EGD appears to accel-
Box 1. Summary of post-endoscopic intravenous PPI erate the healing of bleeding lesions and
in peptic ulcer disease. reduce the need for endoscopic therapy, it
 PPIs are superior to H2RAs in reducing should not replace early endoscopy and prompt
rebleeding and surgery in patients with bleed- resuscitation, which remain vital in preventing
ing peptic ulcers, but all cause mortality is not adverse outcomes in patients with UGIH.
affected.
 Infusional IV, bolus IV and oral PPI, when given
at the same dosage and intervals, are probably Box 2. Summary of pre-endoscopic IV PPI use.
equipotent in raising intragastric pH. Infusional
IV PPI likely achieves this fastest, although PPI  Pre-emptive infusional IV PPI in patients pre-
plus antacid (e.g. sodium bicarbonate) would senting with peptic ulcer bleeding may reduce
likely be even faster. the severity of bleeding stigmata and the need
 Clinically, infusional IV PPI (80 mg IV bolus fol- for endoscopic therapy.
lowed by 8 mg/h for 72 h), in combination with  This should not replace prompt resuscitation
endoscopic hemostasis provides the lowest and early EGD, especially in unstable patients.
rebleeding rates in high-risk peptic ulcers.
 IV bolus and oral PPI may be as efficacious as IV, intravenous; PPIs, proton-pump inhibitors; EGD,
infusional IV PPI, but more data is needed esophagogastroduodenoscopy
before this can be recommended.

PPIs, proton-pump inhibitors; H2RAs, H2-receptor Intravenous PPI in peptic ulcers with adherent
antagonists; IV, intravenous.
clots
The approach towards a clot is controversial. The
Pre-endoscopic intravenous PPI important factors to consider include the size of
The next logical question is whether IV PPI given the clot, the location of the lesion, the likelihood
pre-endoscopically in patients with bleeding of provoking massive bleeding, and the experi-
peptic ulcers would further improve patient out- ence of the endoscopist. Reports varied in their
comes. Daneshmend et al. [1992] first studied vigor in clot irrigation before declaring clots
the pre-endoscopic use of omeprazole (IV bolus adherent. Some use focal irrigation with a large
followed by intermittent IV and oral PPI) in 1992 thermal probe for up to 5 min; others use a
in 1147 patients with UGIH, and reported a sig- mechanical device such as a snare to ‘cheese-
nificant decrease in endoscopic signs of hemor- wire’ the clot. Some experienced endoscopists
rhage in patients who received omeprazole (33% advocate treating such lesions with the clot
omeprazole versus 45% placebo, p ¼ 0.0001) in situ by slipping a hemostatic device under the
[Daneshmend et al. 1992]. Similar findings clot, and treating the potential lesion blindly,
were reported in a study by Lau et al. in 2007, with or without pretreatment with epinephrine
which randomized 638 patients with UGIH to injection. The clot becomes attached to the
receiving either a high dose IV omeprazole infu- device and comes off when it is removed, and
sion or a placebo prior to receiving an esophago- any residual lesion is then treated. A meta-
gastroduodenoscopy (EGD) the following analysis of six studies involving 240 patients
morning [Lau et al. 2007]. The need for favored clot removal by focal irrigation or by

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 SH Pang and DY Graham

the ‘guillotine-snare’ technique, and treating the With regard to giving IV PPI pre-endoscopically,
underlying lesion endoscopically [Kahi et al. an analysis modeled on the results of the Lau
2005]. Whether a clot should be removed or et al. study concluded that the preemptive use
not remains controversial, especially when of infusional IV PPI is cost-effective, as it reduces
powerful PPIs are available. Laine et al. [1996] the cost of the endoscopic procedure and the
showed that after targeted irrigation for 5 min length of hospitalization [Tsoi et al. 2008]. The
with a 3.2 mm heater probe, only 8% of tightly drug-related costs are offset by the overall savings
adherent clots rebleed. This rate is likely to be in the management of UGIH. The same conclu-
even lower if infusional IV PPI were given. sion was reached in a similar study in a Canadian
setting [Enns et al. 2003], where the administra-
Box 3. Summary of IV PPI in peptic ulcers with tion of pre-emptive IV PPI is already common
adherent clots. practice. The overall savings will be made even
 The best approach for adherent clots remains more significant as the cost of IV PPI comes
unclear. down with the introduction of its generic forms.
 Factors such as the size of the clot, location of
the ulcer, likelihood of provoking massive
bleeding and the experience of the endoscopist Intravenous PPI in the prevention of stress-
should be taken into consideration. related mucosal injury
Stress, defined as a response to the severe
demands on the human body resulting in a dis-
Cost-effectiveness of intravenous PPI in ruption of homeostasis through physiological and
bleeding peptic ulcers psychological stimuli [Ali and Harty, 2009], has
In the postendoscopic hemostasis setting, the long been recognized to cause gastric mucosal
administration of IV PPI has been shown to be damage. The pathophysiology remains poorly
more cost-effective than giving oral PPI, which in understood, and is thought to include the disrup-
turn dominates over giving a placebo [Barkun tion of normal mucosal barrier defences due to
et al. 2004a; Barkun et al. 2004b]. Another hypoperfusion, ischemia and reperfusion, resul-
single center study compared the strategies of tant oxidative stress, and gastric microcirculatory
oral and IV PPI, in the context of performing disturbances [Ali and Harty, 2009]. The preva-
diagnostic or therapeutic endoscopies in patients lence of gastric lesions in critically ill patients is
requiring hospitalization with acute peptic ulcer estimated to be 75% to 100% in the first 1—3
bleeding, and reported high dose IV PPI with days of illness [Peura and Johnson, 1985; Czaja
therapeutic endoscopy to be the most cost-effec- et al. 1974]. It is estimated that up to 25% of
tive approach [Erstad, 2004]. This picture may patients in critical care will develop clinically
continue to evolve if oral or low-dose IV PPI can overt bleeding [Mutlu et al. 2001], defined as
be shown to be as efficacious as high-dose IV PPI hematemesis, melena, gross blood or ‘coffee
in preventing adverse outcomes. As the cost of IV grounds’ in the nasogastric tube. Clinically sig-
PPI decreases with the expiration of its patency nificant bleeding, defined as bleeding associated
and the introduction of generic formulations with hemodynamic instability or a drop in hemo-
both in oral and IV forms, it is likely that the globin requiring transfusion, occurs in 3—4% of
cost differences between oral and IV PPI will patients only [Mutlu et al. 2001].
become less significant. The main clinical
impact will be seen in a decrease in the length The strongest risk factors associated with stress-
of hospitalization associated with giving oral induced ulcer bleeding are respiratory failure
PPI postendoscopic hemostasis, or even avoiding (odds ratio [OR] 15.6) and coagulopathy (OR
hospitalization altogether in selected patients 4.3) [Cook et al. 1994]. Amongst patients with
who can be managed in an outpatient setting. one or both of these risk factors, 3.7% developed
Risk stratification tools such as the Blatchford clinically important bleeding. This was associated
[Stanley et al. 2009; Blatchford et al. 2000], with a mortality rate of 48.5%, compared to
Baylor rebleeding [Saeed et al. 1995] and the 9.1% in patients without gastrointestinal bleed-
Rockall scores [Rockall et al. 1996] may be valu- ing (p < 0.001). Other less significant risk factors
able in determining the risk of adverse outcomes include hypotension, sepsis, acute liver failure,
in patients with UGIH, and in turn help the deci- chronic renal failure, prolonged nasogastric tube
sion making process of which form, and what placement and alcoholism [Ellison et al. 1996;
dosage of PPI to use. Cook et al. 1994].

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Therapeutic Advances in Gastroenterology 3 (1)

IV H2RA has long been established as efficacious patient significant dysphagia and odynophagia.
prophylaxis for stress induced mucosal injury in IV PPI therapy in these settings may be useful.
critically ill patients [Cook et al. 1998; Cook et al.
1991], and is the most widely used drug for this With regard to the potency in suppressing gastric
purpose [Quenot et al. 2009]. Continuous IV acid, there appears to be little difference between
H2RA is superior to intermittent bolus administra- oral and IV PPIs [Keating and Figgitt, 2004;
tion in maintaining intragastric pH at >4 [Siepler Kovacs et al. 2004; Metz et al. 2000]. The deci-
et al. 1989; Ostro et al. 1985]. IV PPI is probably sion to administer IV bolus PPI probably rests on
superior to IV H2RA because of its greater potency a patient’s ability to swallow oral PPIs. In a pilot
and lack of tolerance problems, but there is little study looking at the safety and efficacy of high-
evidence to support this in the critical care setting, dose infusional pantoprazole in the treatment of
apart from a few small trials with heterogeneous erosive esophagitis, patients with grade 4 esopha-
variables [Quenot et al. 2009]. A recent multicen- gitis were randomized to receiving either high
ter, randomized trial assessed the effects of inter- dose infusional or intermittent bolus IV panto-
mittent IV pantoprazole on intragastric pH in 200 prazole (40 mg daily for 72 h) [Cai et al. 2008].
patients in intensive care. The administration of Both groups were treated with oral pantoprazole
various doses of IV pantoprazole (40 mg every 12 40 mg daily for 4 days afterwards. Endoscopy on
or 24 h, and 80 mg every 8, 12 or 24 h) was com- day 6 to 8 showed complete or significant healing
pared with continuously infused cimetidine (30 mg of the esophagitis in the high dose infusional
bolus followed by 50 mg/h). The study found that, group, and partial or nil improvement in patients
on any day, 80 mg of IV pantoprazole given every in the oral PPI group. The difference was statis-
8 h or 12 h achieved the greatest percent time tically significant (p ¼ 0.015), suggesting that
where the intragastric pH was >4, but this was high-dose infusional PPI is the fastest way to
matched by 40 mg every 12 h on day 2 of the heal severe esophagitis, and that this is achievable
study [Somberg et al. 2008]. This suggests that in a matter of days. However, none of the patients
an initial 80 mg every 8 or 12 h for the first 24 h, in either group experienced any complications
followed by 40 mg every 12 h from the second day during the study. Whether this strategy is cost-
onwards, may obtain the best acid suppressing effective, and in what scenario this will be most
results. However, it is not clear if high-level acid clinically meaningful, requires further study.
suppression is truly required, and the benefits
must be weighed against the possible complications Box 5. Summary of IV PPI use in gastroesophageal
and side effects of administering IV PPI. reflux disease.
 IV and oral PPI appear to be equally efficacious
Box 4. Summary of IV PPI use in stress induced in suppressing gastric acid.
ulcer prophylaxis.  IV PPI is useful in patients who have severe
erosive esophagitis and are unable to tolerate
 Prophylaxis for stress-induced ulcers should oral therapy.
be reserved for patients with high risk factors;  Infusional IV PPI can heal erosive esophagitis
for example, respiratory failure and in a matter of days. Its clinical benefit over IV
coagulopathy. bolus PPI remains unknown.
 IV H2RA is commonly used although bolus IV
PPI is probably as efficacious. IV, intravenous; PPIs, proton-pump inhibitors.

IV, intravenous; H2RAs, H2-receptor antagonists; PPIs,

proton-pump inhibitors Intravenous PPI in the treatment of Zollinger-
Ellison syndrome
Intravenous PPI in gastroesophageal reflux A gastrinoma is a rare but important neuroendo-
disease crine tumor which generally originates in the
It is well established that PPI therapy is one of the proximal duodenum or pancreas. It can occur
most effective therapies available for healing ero- sporadically or in association with the multiple
sive esophagitis [Richter and Bochenek, 2000; endocrine neoplasia (MEN)-1 syndrome. ZES
Dekkers et al. 1999] Although it is uncommon is characterized by the uncontrolled secretion of
for this condition to cause death, when severe gastrin by the tumor, resulting in the hypersecre-
enough, it is associated with significant tion of gastric acid, profuse diarrhea, and severe
morbidity such as bleeding ulcers, strictures and refractory peptic ulcer disease. Its incidence
and malignancy. It can also occasionally cause a is estimated to be 0.1 to 3 per million in the US.

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 SH Pang and DY Graham

Potent gastric acid suppression is paramount in Adverse events associated with intravenous
the treatment algorithm of ZES, as complications PPI
arising from the hypersecretion of gastric acid There remains a concern that acid-suppression
and severe ulceration are responsible for signifi- increases the incidence of nosocomial pneumonia
cant morbidity and mortality. The ideal goal is to in ventilator-dependent patients. A meta-analysis
reduce the basal gastric acid output to <10 mEq/ has found that ranitidine is associated with
h for uncomplicated ZES, and <5 mEq/h for increased odds of nosocomial pneumonia com-
complicated ZES, such as that occurring in pared with sucralfate, which does not alter the
association with MEN-1, GERD, or after gas- intragastric pH [Messori et al. 2000]. In a large
trectomy [Maton, 1996]. cohort study, the use of acid-suppressive drugs
was associated with 30% increased odds for
Historically, high dose H2RA has been shown to developing hospital-acquired pneumonia
be effective in suppressing gastric acid secretion in [Herzig et al. 2009]. The use of pantoprazole in
ZES [Maton, 1996; Vinayek et al. 1993]. This has critically ill patients has been shown to be an
largely been replaced by PPI because of its greater independent risk factor for nosocomial pneumo-
potency and lack of development of tachyphylaxis. nia (OR 2.7; 95% CI, 1.1—6.7, p ¼ 0.034)
Oral PPI is safe and effective in maintaining the [Miano et al. 2009].
control of basal gastric acid output in ZES [Metz
et al. 2003]. IV PPI may play a role when patients The use of IV PPI is also common in
are unable to tolerate oral PPI, such as when they cirrhotic patients, especially in those with acute
have severe bleeding ulceration, pre-operatively, UGIH, where the source of bleeding is often
or during chemotherapy if they have metastatic unclear initially. PPIs are also often used to
disease. A bolus of 80 mg IV pantoprazole has prevent post-variceal banding ulcer formation.
been shown to be effective in acid control (defined A recent study found PPI use to be an indepen-
as <10 mEq/h) within 15—60 min of administra- dent risk factor for the development of SBP in
tion [Lew et al. 2000]. IV doses of 160 mg to cirrhotics (OR 4.31; CI 1.34—11.7) [Bajaj et al.
240 mg daily achieved 24-h acid control for 6 2009]. One hypothesis for this association is that
days, without any significant side effects. PPIs increase gut bacterial colonization, which
can possibly lead to small bowel bacterial over-
Patients entered this study in a hypersecretory
growth [Thorens et al. 1996]. Bacterial transloca-
state as the study required withholding the use
tion across the intestinal wall into the peritoneal
of oral PPI for 7 days. In real-life practices,
cavity is thought to play a role in the pathogenesis
patients are usually on a degree of acid suppres-
of SBP. Of more concern though, is the fact that
sion already from oral PPI therapy. A multicenter
47% of the patients receiving PPI in this study
study subsequently reported successful transition
had no documented indication for PPI treatment
of oral PPI therapy (omeprazole 20—200 mg daily
[Bajaj et al. 2009].
or lansoprazole 30—210 mg daily) to IV pantopra-
zole, without breakthrough gastric acid hyperse-
cretion [Metz et al. 2001]; 93% of patients in this Appropriate use of intravenous PPI
study achieved adequate acid control for 7 days There is increasing concern that IV PPI is being
(defined as <10 mEq/h or <5 mEq/h in patients prescribed inappropriately in the hospital and
with prior gastric reducing surgery) with 80 mg IV community setting. The use of IV PPI as prophy-
pantoprazole twice a day. One patient required a laxis against stress-related mucosal injury needs
dose escalation to IV 120 mg twice a day. to be judicious. Routine prophylaxis is not cost-
effective, and may subject patients to unnecessary
side effects. It should be reserved for patients
Box 6. Summary of IV PPI use intravenous ZES.
who are at higher risk of developing stress related
 IV PPI may be useful in the pre-operative ulcers. Acid-suppressive therapy is often inappro-
period or in patients who are unable to tolerate priately continued post ICU discharge, and even
oral therapy. Switching from oral to IV PPI is
safe.
beyond hospital discharge in the community
 The majority of patients require IV 160 mg [Wohlt et al. 2007; Gardner et al. 2006].
daily (80 mg b.d.). Some may require IV Physicians should review and discontinue the
240 mg daily. use of IV PPI when the risk factors responsible
for stress related mucosal injury are no longer
IV, intravenous; PPIs, proton-pump inhibitors.
present, and ensure that there is adequate

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Therapeutic Advances in Gastroenterology 3 (1)

communication with the treating team upon a infusional, bolus IV and oral PPI, and their
patient’s transfer out of ICU, and also with the respective cost-effectiveness will likely be the
community medical care provider upon hospital focus of future studies in bleeding peptic ulcers.
discharge. The possible synergistic effects of buffering
agents in combination with PPIs may also be
A prospective study of two American commu- worth exploring. Using IV PPI appropriately
nity-based teaching hospitals reported no accept- will continue to be an issue in healthcare resource
able indication in 56% of patients who received management.
IV PPI during their hospitalization [Guda et al.
2004]. Of the patients who were started on PPIs Acknowledgements
for the first time, 81% were discharged with oral This material is based upon work supported in
PPI upon discharge. Another study looking at the part by the Institude of Digestive Diease, Chinese
use of IV PPI in UGIH and non-UGIH patients University of Hong Kong, and the Office of
has found that only 50% of UGIH patients Research and Development Medical Research
received IV PPI for an appropriate indication, Service Department of Veterans Affairs. Dr.
and that only 33% of non-UGIH patients were Graham is supported in part by Public Health
truly nil by mouth [Kaplan et al. 2005]. After Service grant DK56338 which funds the Texas
implementing multidisciplinary intervention, Medical Center Digestive Diseases Center and
including physician education, computerized R01 CA116845. The contents are solely the
dose template, pharmacists altering IV PPI responsibility of the authors and do not necessar-
orders in patients who were not nil by mouth, ily represent the official views of the VA or NIH.
and recommending a GI consult when a PPI
infusion is required, there was a significant abso- Conflict of interest statement
lute reduction in the degree of inappropriate pre- Dr Pang declares that there is no conflict of inter-
scription in the UGIH (26%; 95% CI 10—42%; est. In the last 2 years, Dr Graham has received
p < 0.0001) and in the non-UGIH (41%; 95% CI small amounts of grant support and/or free drugs
24—58%; p < 0.0001) subgroups. Increasing age or urea breath tests from Meretek and BioHit for
and a low mean daily dose were found to be pre- investigator initiated and completely investigator
dictors of inappropriate use, with a trend seen for controlled research. Dr Graham is a consultant
prescriptions written during evening shifts [Afif for Novartis in relation to vaccine development
et al. 2007]. for treatment or prevention of H. pylori infection.
He has received no payments in the last 2 years.
Box 7. Summary of IV PPI and adverse events.
Dr Graham is a also a paid consultant for Otsuka
 IV PPI has been associated with the develop- Pharmaceuticals and until July 2007 was a
ment of nosocomial pneumonia in critically ill member of the Board of Directors of Meretek,
patients. Diagnostics, the manufacturer of the 13C-urea
 PPI has also been linked to the development of
breath test. Meretek was absorbed into Otsuka
SBP in cirrhotics.
 IV PPI in these patients should be used judi- America in 2007. Dr Graham has received royal-
ciously, and their indications frequently ties on the Baylor College of Medicine patent
reviewed, as PPI is therapy is often inappropri- covering materials related to 13C-urea breath
ately continued. test. The patent will expire in October 2009 and
no more royalties will be received after that time.
IV, intravenous; PPIs, proton-pump inhibitors; SBP,
spontaneous bacterial peritonitis
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