Pediatric Critical Care Medicine

Gastric Acid Suppressant Prophylaxis in

Pediatric Intensive Care
Current Practice as Reflected in a Large Administrative Database
Andrew T. Costarino, MD; Dingwei Dai, PhD; Rui Feng, PhD; Chris Feudtner,
MD, PhD, MPH; James P. Guevara, MD, MPH
Disclosures
Pediatr Crit Care Med. 2015;16(7):605-612.

Abstract and Introduction

Abstract
Objectives: Stress-related gastrointestinal bleeding may occur in PICU patients.
Raising gastric pH with acid suppressant medications is the accepted treatment.
We describe the use of histamine 2 receptor blockers and proton pump inhibitors
and associated factors among a national sample of PICU patients.

Design: Retrospective cohort analysis using Pediatric Health Information System

clinically detailed administrative database.

Setting: Forty-two children's hospitals throughout the United States.

Patients: All hospitalizations for all patients 20 years old or younger, admitted
directly to a PICU, from January 1, 2007, through December 31, 2011.

Interventions: None.

Measurements and Main Results: The exposure of interest was treatment with
a histamine 2 receptor blocker, proton pump inhibitor, or both on the first day of
PICU admission. Demographics, principal and additional diagnoses, and
procedure codes were assessed. For each hospitalization, principal diagnosis,
coagulation disorder, head trauma, spinal trauma, severe burns, sepsis,
gastrointestinal hemorrhage, mechanical ventilation, blood product transfusion,
and 10 complex chronic conditions were identified. The frequency of principal
diagnoses was determined to identify the most prevalent PICU diseases. Acid
suppressant use was categorized as high or low. Three hundred and thirty-six
thousand ten inpatient hospitalizations were sampled. Histamine 2 receptor

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blocker or proton pump inhibitor was used in 60.0%, with histamine 2 receptor
blocker alone in 70.4%, proton pump inhibitor alone in 17.8%, and both agents in
11.8%. Use increased over the sample years 2007 through 2011. Gastrointestinal
bleeding occurred in 1.32% of hospitalizations with transfusion needed in 0.1%.
Among most prevalent diagnoses, histamine 2 receptor blocker and proton pump
inhibitor use ranged from 33% to 87%. Sepsis, coagulopathy, and mechanical
ventilation identified higher use. Use of histamine 2 receptor blocker or proton
pump inhibitor among hospitals varied considerably ranging from 28% to 87%.

Conclusions: Histamine 2 receptor blocker and proton pump inhibitor are

prescribed in most PICU patients, but significant variation exists across health
conditions and hospitals. Institutional preferences likely influence variation.
Gastrointestinal hemorrhage is infrequent in the current era. Study data
limitations prevent examination of associations between medication use and
patient outcomes.

Introduction
Stress-related upper gastrointestinal bleeding in critically ill patients results
when cytoprotective epithelial mucus and bicarbonate are compromised by
mucosal ischemia, allowing injury from locally secreted acid.[13] Management has
focused on raising gastric pH, and as a result, histamine 2 receptor blockers (H2)
and proton pump inhibitors (PPIs) are commonly used in adult intensive
care.[1,2,4,5] Even as estimates of the prevalence of stress-related gastrointestinal
bleeding in PICU populations have ranged widely,[59] acid suppressant
medications have increasingly been used in PICU practice.[914]Gastric acid is an
important component of host defense and is also necessary for nutrient
absorption. Acid suppression has increasingly been found to be associated with
infection and other complications.[1522] Recent improvements in resuscitation,
respiratory support techniques, and other aspects of care may have reduced the
prevalence of stress-related gastrointestinal hemorrhage.[4,9,12,1922] Thus, an
epidemiologic surveillance review of current practice of acid suppressant use in
hospitalized children in a PICU setting is timely. We specifically aimed to describe
current use of medications for stress-related gastrointestinal bleeding prophylaxis
in relation to risk factors, geography and hospital variation, as well as assessing
temporal trends.

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Materials and Methods
Study Population and Setting
This study used the Pediatric Health Information System (PHIS)
database.[23] The PHIS database is maintained by the Children's Hospital
Association (Kansas City, KS) and contains resource utilization data, including
detailed pharmacy information, from 42 freestanding children's hospitals
representing most major U.S. metropolitan areas and approximately 70% of
freestanding pediatric acute care hospital admissions in the United States. Our
study included hospitalized children 20 years old or younger, discharged from
participating hospitals between January 1, 2007, and December 31, 2011, who
were admitted to the PICU on the first hospital day. We excluded patients
transferred into the PICU from other hospital locations. The institutional review
board at The Children's Hospital of Philadelphia deemed this study of de-
identified data to not constitute human subjects research.

Measurements
Patient hospitalizations were defined as "Exposed" if the H2 or PPI
medication was administered on the first hospital day; otherwise, they were
categorized as "Unexposed," even if patients were prescribed acid suppression
after the first day. These definitions were used in order to capture prophylaxis use
of these medications rather than treatment. Several health conditions with
possible associations with acid suppression therapy were identified based
on International Classification of Diseases, 9th Revision(ICD-9) codes and
procedure codes and included the presence or absence of: 1) a coagulation
disorder, 2) head trauma, 3) spinal trauma, 4) severe burns, 5) sepsis, and 6)
mechanical ventilation on the first hospital day ( Appendix 1, Supplemental Digital
Content 1, http://links.lww.com/PCC/A160). Additionally, principal and additional
ICD-9 designations and procedure codes were used to identify, for each
hospitalization, the presence or absence of gastrointestinal hemorrhage and
blood product transfusion (Appendix 1, Supplemental Digital Content
1, http://links.lww.com/PCC/A160). Complex chronic conditions (CCCs) were
defined as medical conditions that can be reasonably expected to last at least 12
months and that involved either several different organ systems or one organ
system severely enough to require specialty pediatric care and probably some
period of hospitalization in a tertiary care center. Each of 10 CCCs was identified
by the recently published classification scheme based on ICD-9 diagnosis and
procedure codes.[24]

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Data Analysis
Exposure groups were compared for patient-level differences in
demographics, diagnoses, and treatment-related variables listed above using chi-
square test; p values less than 0.05 were considered significant. In addition, we
examined for secular and hospital-level differences in exposure based on yearly
trends from 2007 through 2011, geographic U.S. census region, and participating
hospital identifier.

Differences in principal diagnosis (ICD-9) between the unexposed and the

exposed categories were used to identify the conditions leading to PICU
admission that are most, and least, associated with the use of these medications.
The frequency of each principal ICD-9 diagnosis was determined. The top 10
most prevalent PICU diagnoses represented approximately 22% of all
hospitalizations in the sample. For hospitalizations associated with each of these
most prevalent PICU diagnoses, the proportion receiving first day acid
suppressants was compared to that of the total study sample. Using this analysis,
we classified some principal ICD-9 diagnoses as "high use" and others as "low
use" for acid suppression prophylaxis. The "high use" label was assigned if the
exposed proportion of encounters with a diagnosis was greater than the mean
exposure proportion of the total sample of all PICU patients and "low use" if the
percent exposed was less than the mean exposure proportion.

A multivariate, mixed-effect logistic regression model was developed to

determine the joint effects of factors for medication exposure. The demographic,
diagnosis, and treatment variables having significant marginal associations with
exposure at the 0.05 level by chi-square test were initially included. The variation
from 42 hospitals was incorporated as a random effect and other covariates as
fixed effects in the model.[25] Because the selected risk factors might be
correlated, a backward model selection was then used to eliminate some
variables that contribute insignificantly (using likelihood ratio test) given other
variables in the multivariate model. The risk estimate in the final model was
reported. All data management and statistical analyses were performed with SAS
9.3 (SAS Institute, Cary, NS) and Stata 13.1 (StataCorp, College Station, TX).

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Results
The sample included 336,010 inpatient hospitalizations that commenced
with admission to the PICU, representing 1,686,770 PICU and 3,030,810 total
hospital days. A similar number of records met database query inclusion criteria
in each of the five sample calendar years, thus, each year, 2007 through 2011,
comprised approximately 20% of the sample. The population characteristics of
the exposed and unexposed groups are listed in Table 1. Small but statistically
significant differences were noted for age, primarily due to a small increase in the
proportion of infants in the exposed group. The exposed stayed in the hospital
longer, were more likely to need mechanical ventilation, were less often
discharged to home, and had a higher mortality than the unexposed group,
reflecting greater severity of illness.

Gastric acid suppressant medication, prescribed on the first day of PICU

hospitalization, was common, occurring in 60.0% (95% CI, 59.860.14) of
hospitalizations. Among those receiving treatment, H2 were used more frequently
(70.4%) than the PPI (17.8%), and both types of agents were used in 11.8% of
cases. Length of treatment with these medications averaged 5.3 11.3 days,
which accounted for 78.4% and 45.0% of PICU and hospital days, respectively.
The majority of patients receiving H2 blockers were treated with ranitidine
(84.4%) while 15.6% received famitodine. The most common PPI was
lansoprazole (43.1%). Other agents in this class included pantoprazole (34.4%),
esomeprazole (16.5%), omeprozole (6.1%), and rabeprazole (0.01%). The
fraction of patients treated with acid suppressants gradually increased over the
cohort years (p < 0.001). This trend use was significant for 1) any use of these
medications, z = 34.10, p < 0.001; 2) H2 use, z = 14.26, p < 0.001; 3) PPI
use, z = 33.12, p < 0.001; and 4) exposure to both medications, z = 15.11, p <
0.001. Nonparametric test for trend over ordered groups. This trend of increasing
use was most apparent for increasing use of PPI[26](Fig. 1).

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 (Enlarge Image)

Figure 1.

The fraction of patient hospitalizations receiving treatment with acid suppressant medications on
the first PICU day is represented by study year. There was a significant trend of increasing use
over the study period. H2 = histamine 2 receptor blocker, PPI = proton pump inhibitor.

The 10 most frequent principal diagnoses associated with these PICU

hospitalizations are included inTable 2. Individually, each of these conditions
represents 13% of the study sample, but taken together they accounted for
approximately 22%. Among the groups with these prevalent diagnoses, the
proportion of patients receiving acid suppressants varied from 33% to 83%.
When diagnosis groups were compared to the total sample, the odds ratios for
acid suppressant treatment ranged from 0.32 (95% CI, 0.300.33) to 3.31 (95%
CI, 3.153.37) (Table 2). Using this analysis, and criteria noted above, the
proportion cut point for defining "high use" and "low use" principal diagnoses
were 60%. Classified as "high use" included 1) acute respiratory failure, 2)
asthma, 3) pneumonia, 4) tetralogy of Fallot, and 5) ventricular septal defect.
Alternatively, a designation of "low use" was assigned to: 1) diabetes mellitus
with ketoacidosis, 2) respiratory syncytial virus bronchiolitis, 3) status epilepticus,
4) craniofacial surgery, and 5) idiopathic scoliosis.

A CCC was present in over 56% of hospitalizations. Each of the 10 chronic

condition categories was positively associated with the use of first day acid
suppression. This was marked for the chronic diseases stemming from the
neonatal period (neonatal-CCC), for respiratory-CCC, gastrointestinal-CCC,
metabolic-CCC, and cardiovascular-CCC.

Several specific health conditions, which were not among the 10 most
prevalent but were identified from previous literature, treatment guidelines, and
clinical experience,[3,68,11,12,27,28] were examined for association with the use of
these medications. Sepsis (exposed proportion, 84.4%), mechanical ventilation

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on the first PICU day (83.74%), and coagulopathy (81.64%) were associated with
the use of prophylactic acid suppression medications as was spine trauma (76%)
and patients receiving surgery (66%). Suppressants were used less than average
in head trauma (54%) and burns (40.9%) (Table 3).

Gastrointestinal bleeding was recorded as a principal or additional

diagnosis in 4,444 hospitalizations, 1.32% (95% CI, 1.281.36) of this PICU
patient cohort. Hospitalizations with this diagnosis also receiving a transfusion
numbered 370, comprising 0.11% (95% CI, 0.100.12) of the sample. We
compared patients admitted for diagnoses associated with high use of acid
suppressant medications with those admitted for diagnoses associated with low
use. We observed that a significantly increased proportion of patients with the
high-use diagnoses had gastrointestinal bleeding (1.27% vs 0.3%; p < 0.001) and
gastrointestinal bleeding and a transfusion (0.11% vs 0.1%; p < 0.001).

We observed both hospital-level and regional-level differences in the use

of acid suppressants. Among the 42 PHI hospitals, the proportion of PICU
patients exposed to H2 and/or PPI varied from 28% to 87% (p < 0.001) (Fig. 2).
Similarly, patients receiving acid suppressant prophylaxis ranged from 52.4% in
the Midwest to 66.5% in the Northeast (p < 0.001).

Discussion
Observations of stress-related gastrointestinal bleeding and the impact of
H2 and PPIs on reducing gastric pH have established the practice of acid
prophylaxis in PICU populations since the 1990s.[68,12] Although the overall use of
acid suppressant medications in children has increased 10-fold in the last
decade,[13,15] current use of these medications for stress-ulcer prophylaxis in the
PICU populations is unknown. We examined current use of H2 and PPI in the
PICU population as reflected in a large administrative database of U.S. children's
hospitals. We limited our sample to direct admissions to the PICU and defined
exposure as receiving these medications on the first hospital day in order to focus
on prophylactic use of these agents. We observed that acid suppressants were
used in the majority of patients and were continued through most of the PICU
stay and half of the total hospitalization. While H2 were more frequently used,
increasingly, a PPI is prescribed. Increasing PPI use was associated with the
overall increase in prophylactic acid suppression over the study period. These
findings are similar to observations from surveys of adult practice in the United
States and United Kingdom.[30,31] Consistent with past observations of the risk of

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stress-related bleeding in children,[68]we did not find clinically important
differences in age, gender, and race between those exposed to the medications
and the unexposed.

Recently, the importance of gastric acid in host defense and nutrient

absorption has been better appreciated, raising concerns that widespread use of
these agents may contribute to infection and other complications. [16,18,21,22] Given
the limitations of the administrative database, we could not examine if any
association with sepsis and pneumonia was secondary to the use of these
agents. However, our observation that only a very small proportion of patients are
diagnosed with gastrointestinal hemorrhage is consistent with a reduction in the
prevalence of this complication in pediatric intensive care.

In this study, we found that prophylactic acid suppressants were used in a

broad and diverse group of diseases but in patients with several of the most
prevalent diagnoses use varied significantly from the population average. More
frequent prophylaxis use occurred in children with acute respiratory failure, in
asthma, when mechanical ventilation was needed, in patients needing surgery for
congenital heart disease, in those with sepsis, and in children with a
coagulopathy. The presence of a CCC was also associated with higher levels of
use. Again, these findings are consistent with past determinations of risk factors
for stress-related hemorrhage in adults and children.[5,6,27]

Alternatively, some of the common PICU conditions were associated with

less than average use of prophylaxis. These included children with diabetic
ketoacidosis and those receiving surgical management of craniofacial
abnormalities and surgery for scoliosis and those with status epilepticus. These
observations were surprising because past studies of critically ill children have
indicated that ketoacidosis, metabolic acidosis, prolonged surgery, and
neurologic failure are risk factors for gastrointestinal hemorrhage.[68] We were
similarly surprised, given past recommendations, that head trauma, severely
burned patients, and infants hospitalized in the PICU for treatment of viral
bronchiolitis had less than average use. For the burn patients, the small number
of hospitalizations may indicate that our sample does not reflect current practice.
CCCs, particularly those associated with respiratory disease and neonatal
disease, were associated with the use of these medications.

We observed dramatic regional-level and hospital-level associated

variation in acid suppressant prophylaxis. When adjusted for the hospital effect,
regional variation was less significant. Our multivariate explanatory model

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confirmed our observations of the importance of acute and chronic disease and
treating hospital in current practice relating acid suppressant use in the PICU.

As noted above, gastrointestinal bleeding, the primary condition for which

these medications are advocated, was recorded as a principal or additional
diagnosis in a very small number of patients. Furthermore, children diagnosed
with gastrointestinal hemorrhage who also received a transfusion included less
than one half of 1% of the sample. Our findings are in contrast to earlier studies
of the risk of bleeding in children[68,12] but consistent with more recent
observations in adults.[29,32] We did observe an increased prevalence of
gastrointestinal hemorrhage when we compared those with a principal diagnosis
associated with frequent prescription of prophylactic acid suppressants with those
with diagnoses associated with less frequent use of these medications. This
observation may indicate that the prescription of prophylactic acid suppressants
in PICU patients reflects clinical appreciation that some common diagnoses that
lead to PICU admission are more frequently associated with gastrointestinal
bleeding (i.e., residual confounding by indication). Nevertheless, our findings
suggest that clinically important gastrointestinal hemorrhage, in the most recent
era, is uncommon in the PICU population, even among patients with higher risk
disease processes.

Our study has several limitations that warrant discussion. By using ICD-9
coding to identify diseases and treatments, we may have underestimated the
prevalence of some health conditions. The PHIS dataset available for this study
does not include clinical variables such as vital signs, laboratory and imaging
studies or clinical scores, such as Glasgow coma score, therefore we could not
use stratification or other adjustment techniques to better understand out
findings. Similarly, information on prior home administration of acid suppressant
medications was unavailable. As with any observational study, treatment with
these agents was nonrandomized; therefore, indications for treatment and
severity of illness may have biased our observed associations. Additionally, the
timing of outcomes of interest to determine the sequence of events was not
impossible; therefore, an outcome event could have occurred prior to exposure
effect, invalidating any speculation regarding causality. As a result of these
limitations, we were not able to examine important outcomes, such as mortality,
length of stay, or infectious complications, in relation to acid suppressant
exposure in this cohort.

In conclusion, we examined recent prophylactic gastric acidsuppressant

medication use in a PICU population. We found that these medications are

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prescribed in most patients and are increasing over time, particularly the use of
PPI medications. Significant variation exists in the use of these medications that
is associated with acute and chronic diagnoses, treatment with mechanical
ventilation, and treatment hospital. Provider preference is a likely source for some
of the observed variation. Gastrointestinal hemorrhage is rare in the current era.
Limitations inherent in the study design prevent examination of causation of
outcomes with acid suppressant exposure. Future investigations seem warranted
to reexamine the value and adverse effects of these medications in PICU
patients.

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