Journal of Critical Care (2008) 23, 416421

Histamine 2 receptor antagonists vs intravenous proton

pump inhibitors in a pediatric intensive care unit:
A comparison of gastric pH
Nancy M. Tofil MD a,, Kim W. Benner PharmD b ,
M. Paige Fuller PharmD c , Margaret K. Winkler MD a
a
Division of Critical Care, Department of Pediatrics, University of Alabama at Birmingham,
Birmingham, Al 35233, USA
b
Samford University McWhorter School of Pharmacy, Birmingham, Al 35233, USA
c
Vanderbilt Children's Hospital, Nashville, TN, USA

Keywords:
Abstract
Stress ulcer prophylaxis;
Purpose: The aim of this study was to assess gastric pH in critically ill pediatric patients receiving
Children;
intravenous stress ulcer medication.
Gastric pH;
Materials and Methods: A prospective study was done in 48 patients with a gastric tube in place who
Proton pump inhibitor;
were receiving either ranitidine or a proton pump inhibitor and no enteral nutrition. Daily peak and
Histamine 2 receptor
trough gastric pHs were measured.
antagonists
Results: The median age was 7 years 5 months (range, 1 month to 19 years), the median weight was
31 kg (range, 3-130 kg), and the median pediatric risk of mortality 2 (PRISM2) score was 12.5 (range,
0-31). All patients were intubated and 8 received dialysis. The average trough pH was 4.4 1.6 in the
ranitidine group, 4.9 1.8 in the once daily proton pump inhibitor group, and 5.0 1.2 in the twice daily
proton pump inhibitor group (P = .16). The average peak pH was 5.3 1.8 in the ranitidine group, 5.9
1.6 in the once daily proton pump inhibitor group, and 6.0 1.0 in the twice daily proton pump inhibitor
group (P = .06). Three (10%) of 28 trough pH measurements in the twice daily proton pump inhibitor
group were more acidic than 4 vs 24 (40%) of 60 in the ranitidine group, and 22 (40%) of 56 in the once
daily proton pump inhibitor group (P = .02). One (4%) of 27 peak pH measurements in the twice daily
proton pump inhibitor group were more acidic than 4 vs 13 (20%) of 61 in the ranitidine group, and
9 (16%) of 56 in the once daily proton pump inhibitor group (P = .12). Three patients (6%; 95%
confidence interval, 0.51%-16%) developed upper gastrointestinal bleeding, and 4 patients (8%; 95%
confidence interval, 0%-13%) developed ventilator-acquired pneumonia.
Conclusions: Many critically ill pediatric patients receiving stress ulcer prophylaxis have a trough or
peak gastric pH more acidic than 4.
2008 Elsevier Inc. All rights reserved.

Work was done at University of Alabama at Birmingham in the pediatric intensive care unit at the Children's Hospital of Alabama.
Corresponding author.
E-mail address: ntofil@peds.uab.edu (N.M. Tofil).

0883-9441/$ see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcrc.2007.10.038
H2RAs vs intravenous PPIs in a PICU
1. Introduction
Stress ulcers are common in critically ill patients. By
endoscopic examination, gastric ulcers are seen in almost all
critically ill patients [1]. However, most studies evaluate for
upper gastrointestinal bleeding (UGIB) as a clinically
important outcome resulting from ulceration. Cook et al [2]
prospectively evaluated more than 2200 adult patients in
intensive care unit (ICU) and found the incidence of
clinically significant UGIB to be 1.5%. The most important
risk factors for adults identified in this study were
mechanical ventilation and coagulopathy. In critically ill
children, the rate of clinically significant UGIB is similar at
1.6% to 5.3% [3,4]. Risk factors for children include a
pediatric risk of mortality 2 (PRISM2) score greater than 10
[5], respiratory failure, or coagulopathy. Both of these studies
similarly defined clinically significant UGIB as overt
bleeding (defined as hematemesis, gross blood or coffee
grounds in a nasogastric aspirate, hematochezia, or melana)
complicated by one of the following within 24 hours of
bleeding (in the absence of other causes): a spontaneous
decrease of more than 20 mm Hg in the systolic blood
pressure, an increase of more than 20 beats per minute in the
heart rate, or a decrease in the hemoglobin of more than 2 g/
dL. Although the aforementioned trials are large, prospective
analyses using histamine 2 receptor antagonists (H2RAs),
they predated the use of proton pump inhibitors (PPIs) for
ulcer prophylaxis. In a landmark study by Cook et al [6], it
was shown that by raising gastric pH, H2RAs can reduce the
risk of clinically significant bleeding by approximately 50%.
On the other hand, PPIs act at the final pathway of the proton
pump within the gastric parietal cells by irreversibly binding
to the proton pump and are more effective in raising gastric
pH than H2RAs [7]. In contrast to H2RAs, PPIs are not
associated with the development of tolerance [8].
Recently, Levy et al [9] prospectively randomized 67
adult patients in ICU who are at high risk for UGIB to either
ranitidine or omeprazole prophylaxis and found the rate of
clinically significant bleeding in the ranitidine group to be
31% vs only 6% in the omeprazole group, P b .05. In
pediatric patients, Yildizdas et al [10] prospectively
randomized 160 patients in pediatric ICU (PICU) to
sucralfate, ranitidine, omeprazole, or no stress ulcer
prophylaxis and found no difference between the rates of
UGIB or ventilator-acquired pneumonia (VAP).
Within the last few years, intravenous PPIs have become
available. This route of delivery can be advantageous in
critically ill patients of whom uncertainty exists concerning
enteral absorption of medications. Although published
recommendations for pediatric dosing of intravenous
H2RAs and PPIs exist for patients with erosive esophagitis
and gastroesophageal reflux, these doses may not be
appropriate for stress ulcer prophylaxis in the critically ill
pediatric patient [11,12]. There are many studies evaluating
the incidence, risk factors, and outcomes of stress ulcers in
adults, but less pediatric information is known. Furthermore,
417
no previous studies have compared the efficacy of
intravenous PPIs and H2RAs to appropriately raise gastric
pH in a broad range of critically ill children. Therefore, this
study was designed to compare the efficacy of intravenous
PPIs vs H2RAs in raising gastric pH.
2. Methods and materials
2.1. Patients
We prospectively enrolled patients in PICU for an 18-
month period from February 2004 to August 2005.
Eligibility criteria were a nasogastric or oral-gastric tube in
place, administration of either intravenous H2RAs or
intravenous PPIs for stress ulcer prophylaxis, and availability
of parents for consent. Exclusion criteria were enteral
feedings, presence of a UGIB at the time of PICU admission,
or previous enrollment in this study.
2.2. Methods
This study was approved by the institutional review board
of the University of Alabama at Birmingham, Ala. The
choice, dose, and frequency of stress ulcer prophylactic
medications were left to the discretion of the clinical care
team. All patients on an H2RA were on ranitidine, commonly
dosed at 1 mg/kg per dose every 8 hours (maximum dose, 50
mg). After approximately 9 months of our study, our hospital
changed the intravenous PPI on formulary from pantopra-
zole, commonly dosed at 1 mg/kg per dose every 12 to 24
hours (maximum dose, 40 mg), to lansoprazole, commonly
dosed at 1 mg/kg per dose every 12 to 24 hours (maximum
dose, 30 mg). Gastric pH was measured by the bedside nurse
or a study investigator 2 hours after dosing (peak pH) and
just before the next dose (trough pH) as part of our study
protocol. The trough level was obtained just before the dose
to record the lowest gastric pH value in each patient. A peak
and trough pHs were obtained once daily on each patient,
regardless of the number of doses of a H2RA or PPI given.
Before each pH measurement, proper position of the gastric
tube was confirmed by auscultation of insufflated air and by
reviewing daily routine roentgenograms. One to 3 mm of
gastric contents were removed from the gastric tube with a
syringe and placed on pH paper (Fisher Scientific, Fair
Lawn, NJ). A colorimetric scale was used to determine the
gastric pH with a range from 1 to 11 with an increment of 0.5
pH units. Goal pH was a gastric pH more alkaline than 4
[7,13]. This goal was determined a priori by the research
team after critical review of the available literature. The
clinical care team was notified of pH values more acidic than
4. The patient's gastric pH, the time of collection, and
collectors' initials were recorded. Patient complications were
also recorded, including UGIB and VAP. For study purposes,
a UGIB was defined as clinically significant if bleeding was
418 N.M. Tofil et al.

associated with hemodynamic changes (hypotension, tachy- 21 days). Although all study patients were intubated, this was
cardia) or a drop in hemoglobin greater than 2 g/dL within 24 not a requirement for enrollment. In addition, 8 patients
hours not attributable to other causes. Upper gastrointestinal received continuous renal replacement therapy, and 2
bleeding was defined as overt if the patient had grossly patients received extracorporeal membrane oxygenation.
bloody gastric aspirate or hematemesis. Ventilator-acquired Agents used for stress ulcer prophylaxis in the study
pneumonia was diagnosed if a chest roentgenogram obtained patients included ranitidine, pantoprazole, and lansopra-
48 hours or more after PICU admission showed a new and zole. The average dose of intravenous ranitidine used was
persistent infiltrate in combination with purulent tracheo- 1.05 0.24 mg/kg every 8 hours. Fourteen patients
bronchial secretions and recovery of an accepted nosocomial received pantoprazole as their PPI, and 12 patients
pathogen from tracheal aspiration. received lansoprazole. A post hoc analysis for peak pH
and trough pH was done for the 2 different PPI. There
2.3. Statistical analysis were no significant differences between pantoprazole and
lansoprazole; therefore, the 2 groups were rejoined. For
Descriptive statistics were used to summarize all once daily intravenous PPIs, the average dose was 1.06
continuous and categorical variables. Comparisons of gastric 0.22 mg/kg every 24 hours. For twice daily intravenous
pH between patient groups (H2RAs, once daily PPIs, and PPIs, the average dose was 1.02 0.13 mg/kg every
twice daily PPIs) and the type of pH measurement (trough 12 hours.
pH vs peak pH) were performed using analysis of variance Because the type and dose of stress ulcer medication was
and a Student t test. A post hoc analysis was analyzed left to the discretion of the clinical care team, some patients
evaluating the 2 different PPIs used in the study. All had a medication change during the course of the study.
statistical tests were 2-sided and were performed with a P Twenty-six patients began the study on a H2RA with 21
value of less than .05 indicating statistical significance using patients remaining on an H2RA for the duration of their
SPSS software (Version 11.5, SPSS, Chicago, Ill). enrollment, and 5 patients being changed to once daily PPIs.
Two of these 5 patients were changed to PPIs secondary to a
decreasing platelet count, 2 patients were changed to PPIs
secondary to low gastric pH, and 1 patient was changed to a
3. Results PPI secondary to renal insufficiency. In the study, 18 patients
started with once daily PPIs, with 14 patients remaining on
Forty-eight patients were enrolled for the 18-month study this regimen and 4 changing to twice daily PPIs. All 4 of
period. One patient was excluded from analysis because he these patients were changing medication because of low
received an enteral PPI. The median age was 7 years 5 gastric pH. Three patients started with twice daily PPIs and
months (range, 1 month to 19 years), and the median weight stayed on this regimen for the duration of the study. Before
was 31 kg (range, 3 to 130 kg). Thirty patients (63%) were hospitalization, 8 patients had already been prescribed
male, and the median PRISM2 score was 13 (range, 0 to 31). medication for gastroesophageal reflux symptoms: 5 patients
Primary patient diagnoses and demographics are listed in were on H2RAs and 3 patients were on PPIs.
Table 1. As noted, most patients had septic shock, respiratory Three (6%) of 48 patients (95% confidence interval, 0%-
failure, or neurologic failure. The median number of days 13%) in our study experienced UGIB. One patient (2%) had
each patient was enrolled in the study was 3 days (range, 1 to a clinically significant UGIB, and 2 patients (4%) experi-
enced overt UGIB. The patient with clinically significant
UGIB was an 11-year old with a brain tumor, ventriculitis,
Table 1 Patient diagnosis and demographics and shock. The patient was receiving once daily PPI for 8
Diagnosis n Median Median days with gastric pHs of 3.5 to 6, and study enrollment was
age (mo) weight (kg) terminated 4 days before the UGIB secondary to starting
Septic shock 14 86 (IQR, 30 (IQR, enteral feeds. However, the patient was continued on once
21148) 1141) daily PPI and had a normal prothrombin time and partial-
Respiratory failure 14 79 (IQR, 20 (IQR, thromboplastin time as well as a normal platelet count. The
19177) 1255) first patient with an overt UGIB was a 3-year old who
Neurologic failure a 13 144 (IQR, 46 (IQR, experienced a traumatic brain injury. On hospital day 5, the
74180) 3569) patient had a bloody gastric aspirate without hemodynamic
Hemolytic uremic 3 36 (range, 15 (range, changes and was on ranitidine with peak gastric pH of 6.0 to
syndrome 3059) 1319) 7.5 and trough gastric pH of 4.0 to 6.5. The second patient
Heart failure 2 50 (range, 14 (range, with an overt UGIB was a 4-year old with congenital heart
4555) 1017)
disease who had coffee-ground emesis from the nasogastric
Erosive esophagitis 1 94 46
a
tube without hemodynamic changes on postoperative day 9
Neurologic failure includes traumatic brain injury, cerebral from a Fontan procedure. The patient was on pantoprazole
vascular accident, encephalitis, and transverse myelitis.
once a day with peak pH of 5.5 and trough pH of 4.0 to 4.5.
H2RAs vs intravenous PPIs in a PICU
Table 2 Average and standard deviation gastric pH and percentage of readings with pH greater than 4.0
Ranitidine
pH n pH
Trough pH 4.4 1.6 60
% trough pH N4 60% 36/60
Peak pH 5.3 1.8 61
% peak pH N4 80% 48/61
Trough pH was sampled just before the next dose of drug. Peak pH was sampled 2 hours after dosing. PPIsonce daily indicates PPIs dosed every 24 hours;
PPIstwice daily, PPIs dosed every 12 hours.
Four (8%) of 48 patients (95% confidence interval,
0.51%-16%) in the study developed VAP: 2 in the H2RA
group and 2 in the once daily PPI group. Forty patients (85%)
survived in the study. Of the 8 patients who died, 4 patients
had been terminated from the study before their death.
Reasons for study termination included removal of the
gastric tube for 27 patients (58%) (mostly associated with
extubation), enteral feeding initiation for 16 patients (34%),
and death for 4 patients (8%).
Table 2 depicts the average and SD values for trough
and peak gastric pH for the 3 groups and the percentage of
goal pH values defined as a pH value more alkaline than
4. A trend toward higher gastric pH in patients on twice
daily PPIs than either once daily PPIs or H2RAs was seen.
This trend was noted especially during the peak pH testing
point. When evaluating the data by categories of pH more
alkaline than 4 vs pH more acidic than 4.0, our results
show a statistically significant increase in achieving goal
gastric trough pH in patients on twice daily PPIs, and a
trend toward statistical significance during peak pH was
found. In this study, a large number of patients frequently
had a gastric pH more acidic than 4. We separately
analyzed all patients who stayed in the same groups
throughout the study. The average trough gastric pH was
4.8 1.7 for patients only on ranitidine, 5.6 1.7 for
patients only on once daily PPIs, and 5.6 0.9 for patients
only on twice daily PPIs (P = .057). The average peak
gastric pH was 5.5 1.6 for patients only on ranitidine,
6.2 1.2 for patients only on once daily PPIs, and 6.5
1.0 for patients only on twice daily PPIs (P = .016).
4. Discussion
Upper gastrointestinal bleeding is a rare but important
complication of pediatric serious illness making stress ulcer
prophylaxis a valuable pharmacotherapeutic intervention.
Stress ulcers can occur in these critically ill children, and
many children on stress ulcer prophylaxis have times when
their gastric pHs are more acidic than 4. Most direct
prophylactic therapies use drugs such as H2RAs and PPIs
to raise gastric pH in an attempt to minimize ulcer
formation. This prospective study demonstrates a trend
419
PPIsonce daily PPIstwice daily P
n pH n
4.9 1.8 56 5.0 1.2 28 .16
60% 34/56 90% 25/28 .02
5.9 1.6 56 6.0 1.0 27 .06
84% 47 96% 26/27 .06
toward higher gastric pH in patients on twice daily PPIs
than either once daily PPIs or H2RAs. This trend was noted
especially during the peak pH testing point. Although the
pathophysiology of ulcer development is complex and its
etiology can involve Helicobacter pylori and gastric
ischemia, one of the factors that can be manipulated is
gastric pH. Several studies involving intravenous ranitidine
and nasogastric omeprazole have also found variable
efficacy and inconsistent pH elevation in critically ill
children [13,14].
Studies in adult patients with UGIB show that intravenous
continuous infusions of PPIs can reliably raise and maintain
gastric pH at higher levels than intermittent dosing of PPIs
[15,16]. Although once daily dosing of a PPI is often
recommended and appears to be adequate in noncritically ill
patients, this dosing regimen may not be effective in
critically ill children [11,12]. Kaufman et al [17] studied
pediatric liver and small bowel transplantation patients and
found that enteral omeprazole was required as often as every
6 to 8 hours to maintain optimal gastric pH. Olsen et al [18]
concluded that twice daily omeprazole suspension in
critically ill pediatric transplant patients was more effective
than once daily dosing as measured by continuous pH
monitoring. Both of these studies were small and non-
randomized, with 22 and 11 patients, respectively. In the
current study with a larger sample size, we used intermittent
pH monitoring and produced similar findings.
Many patients in PICU have numerous risk factors for
UGIB. In our study, all patients were intubated for greater
than 48 hours, the median PRISM2 score was 13; 8 patients
were on continuous dialysis; and 2 patients received
extracorporeal membrane oxygenation. No patient was
receiving enteral nutrition during the study period to avoid
the confounding effect this may have on gastric pH. Our
study population was representative of common diagnoses
seen within the PICU; therefore, these data could be
reasonably extrapolated to similar pediatric patients. How-
ever, there were a relatively low number of patients with
cardiac diagnoses because in our institution many of these
patients are cared for in a separate cardiac ICU. This study
found similar rates of clinically significant bleeding as did
other studies [3,4,19].
Pediatric practitioners often rely on published guide-
lines for dosing medications. Published dosing ranges for
420
intravenous ranitidine are 2 to 4 mg/kg per 24 hours
divided every 6 to 8 hours with a maximum dose of 150
mg/d. Intravenous pantoprazole is recommended at 0.5 to
2 mg/kg per 24 hours divided every 12 to 24 hours
[11,12]. Our patients received an average daily dose of 3
mg/kg per 24 hours of ranitidine and 1 to 2 mg/kg per 24
hours of pantoprazole. Some of the lower gastric pH
readings in the H2RA group may have improved using 4
mg/kg per 24 hours. Harrison et al [14] reached a similar
conclusion in their study on gastric pH in critically ill
children on ranitidine.
The current study has some limitations. Gastric pH was
chosen as the measure of efficacy because UGIB is rare.
Thus, comparing the effectiveness of different drugs in
decreasing UGIB would require a prohibitive number of
patients. Although their mechanisms differ, both H2RAs
and PPIs are effective at decreasing the rate of stress
ulceration by raising gastric pH [3,20]. The pH technique
was performed by trained nurses with a colorimetric scale
and not with a pH meter. There is good correlation
between pH paper and pH meter measurements with some
positive bias of the pH paper compared to the pH meter
[21,22]. However, because the colorimetric measurements
involve comparison of colors to a reference scale, some
bias could have been introduced using this method.
Intermittent pH monitoring is not as effective as
continuous pH monitoring but is more assessable. Knowl-
edge of PPIs and H2RA pharmacodynamic properties is
important when choosing intermittent periods to measure
gastric pH. In children, both PPIs and H2RAs have a
time-to-peak plasma concentration of 1 to 4 hours
depending on the agent used [23,24]. In our institution,
pantoprazole and lansoprazole are the most commonly
used PPIs and have a time-to-peak plasma concentration
of 2 to 4 hours and 1.3 to 2.2 hours, respectively [23].
Lugo et al [24] studied the pharmacodynamics of
ranitidine in critically ill children and found that the
maximal inhibition of gastric acid, as defined by a
reduction in log [H+], occurred at 2.3 1.3 hours after
intravenous therapy. Periods for peak and trough measure-
ments were chosen based on pharmacokinetic data to most
appropriately monitor gastric pH [23,24]. However,
because we did not measure continuous gastric pH levels,
some important changes in gastric pH could have been
missed. This study was not a randomized trial, and stress
ulcer prophylactic medication choice and dosage were left
to the discretion of the clinical care team. Enrollment was
short because of the study design of ending participation
24 hours after starting enteral nutrition. Finally, the
decision to change stress ulcer medications was also at
the discretion of the attending physician. Eighty-one
percent of patients remained on the same medication
throughout the duration of the study. For the 5 patients
who changed from H2RAs to PPI, the first pH recordings
after the medication change could have resulted from a
combined effect of the 2 agents.
N.M. Tofil et al.
5. Conclusions
Although the risk of UGIB in critically ill patients is
low, the complications such as clinically significant UGIB
are important. One factor in the complex pathogenesis of
stress ulcer formation that clinicians can influence is the
gastric pH. Many patients in pediatric critical care on stress
ulcer prophylaxis within recommended dosage ranges do
not have a trough or a peak gastric pH more alkaline than
4. Twice daily intravenous PPIs appear to achieve a gastric
pH more alkaline than 4 more consistently than either
ranitidine or once daily intravenous PPIs. Additional
randomized trials are needed to further evaluate the use
of intravenous PPIs in critically ill pediatric patients to
prevent stress ulcer formation.
Acknowledgments
We gratefully thank all the nurses in the PICU who
assisted with this study. We also express our sincere
appreciation for the children and their families for participa-
tion in this research project.
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