Implementation of a Guideline to

Decrease Use of Acid-Suppressing

Medications in the NICU
Asimenia Angelidou, MD, PhD,​a,​b Katherine Bell, MD,​b,​c Munish Gupta, MD, MMSc,​b,​d
Kristen Tropea Leeman, MD,​a,​b Anne Hansen, MD, MPHa,​b

BACKGROUND AND OBJECTIVES: Acid-suppressing medications are used extensively

in term and preterm newborns despite limited efficacy data and increasing
evidence for potential harm. We sought to reduce nonindicated use of proton
pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) in
our level III/IV NICU by developing and implementing a guideline for their
use. Our specific aim was to reduce prescriptions among infants <1 month
corrected age from a baseline of 7.5 to 4 per month by December 2016.
METHODS: Our outcome measures were number of nonindicated PPI/H2RA
abstract
aDivisionof Newborn Medicine, Boston Children’s Hospital,
Boston, Massachusetts; dDepartment of Neonatology, Beth
Israel Deaconess Medical Center, Boston, Massachusetts;
bDepartment of Pediatrics, Harvard Medical School,
Harvard University, Boston, Massachusetts; and
cDepartment of Pediatric Newborn Medicine, Brigham and

Women's Hospital, Boston, Massachusetts

prescriptions per month, total (indicated and nonindicated) prescriptions
per month and percent of patient days with PPI/H2RA therapy. We also Drs Angelidou and Bell assisted with study design,
performed data collection and analysis, and
tracked potential complications associated with PPIs/H2RAs as secondary
drafted the manuscript; Dr Gupta performed data
outcomes and gastrointestinal bleed as a balancing measure. Interventions analysis and reviewed and revised the manuscript;
and plan-do-study-act cycles included implementation of the initial Dr Tropea Leeman assisted with study design
guideline, guideline revision based on staff feedback, and staff education. and reviewed and revised the manuscript; Dr
Hansen conceptualized and designed the study
By using statistical process control charts and interrupted time series and reviewed and revised the manuscript; and
analysis, we compared outcomes over an 8-month baseline period and 2 all authors approved the final manuscript as
postimplementation periods spanning 19 months. submitted.
DOI: https://​doi.​org/​10.​1542/​peds.​2017-​1715
RESULTS: Nonindicated prescription of PPIs/H2RAs decreased from mean
7.5 per month to 0 (P = .001). Concurrently, total PPI/H2RA prescriptions Accepted for publication Aug 21, 2017

decreased from mean 11.5 per month to 2.5 (P = .002). Rates of the Address correspondence to Asimenia Angelidou, MD
PhD, Division of Newborn Medicine, Department of
balancing measure and potentially related complications remained stable Medicine, Boston Children’s Hospital, 300 Longwood
over time. Ave, Enders 9, Boston, MA 02115. E-mail: asimenia.
angelidou@childrens.harvard.edu
CONCLUSIONS: Implementation of an evidence-based guideline in our unit led to
a significant decrease in nonindicated use of acid-suppressing medications PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online,
1098-4275).
and reduced the burden of exposure to PPIs/H2RAs. This intervention could
Copyright © 2017 by the American Academy of
feasibly be implemented in other similar inpatient settings. Pediatrics
FINANCIAL DISCLOSURE: The authors have
indicated they have no financial relationships
relevant to this article to disclose.
Proton pump inhibitors (PPIs) and interhospital variation in prescription
histamine-2 receptor antagonists rates.‍1,​2‍ FUNDING: Supported by the Quality Improvement
and Patient Safety trainee grant provided to Drs Bell
(H2RAs) are some of the most Mounting evidence of adverse effects and Angelidou by the Program for Patient Safety
frequently prescribed medications from acid-suppressing medications‍3–‍‍ 6‍ and Quality and the Office of Graduate Medical
in the NICU. Despite limited safety has raised concerns about their risk- Education at Boston Children’s Hospital.
and efficacy data in neonates, almost benefit profile in infants. Recent
one quarter of NICU patients receive guidelines recommend against routine To cite: Angelidou A, Bell K, Gupta M, et al.
acid-suppressing medications, usage of PPIs/H2RAs in both term and Implementation of a Guideline to Decrease Use
of Acid-Suppressing Medications in the NICU.
with the majority continued after preterm infants,​7 and the American
Pediatrics. 2017;140(6):e20171715
discharge, although there is significant Academy of Pediatrics “Choosing

Downloaded from www.aappublications.org/news by guest on July 23, 2019

PEDIATRICS Volume 140, number 6, December 2017:e20171715 Quality Report
Wisely” campaign recently identified
usage in preterm infants as 1 of the
top 5 unnecessary treatments in
newborn medicine.‍8
Acid-suppressing medications are
most commonly prescribed in the
NICU for gastroesophageal reflux
(GER), apnea and bradycardia,
bronchopulmonary dysplasia, airway
anomalies, and bowel anomalies.‍1,​2‍
The lack of high quality evidence
in infants prevents consensus
regarding use for airway anomalies‍9,​10
‍ Our team performed a literature
and bowel anomalies such as
esophageal atresia,​7,​11
‍ which remain
controversial. However, evidence
clearly demonstrates no benefit from
acid suppression for GER in term
or preterm infants‍12–15
‍‍ or apnea in
premature infants.‍16–‍‍‍‍ 22
‍ More than 650 infants are admitted
Although benefits of acid suppression
in infancy seem increasingly unlikely,
adverse effects from PPI/H2RA
treatment are now well documented.
Reduced gastric acidity, alteration of
the gut microbiome and interference
with neutrophil function result in
increased risk of gastrointestinal
infections in term infants‍3 and
necrotizing enterocolitis in preterm
infants.‍4,​5,​
‍ 23
‍ Treatment increases
rates of community-acquired
pneumonia even in healthy infants
in the outpatient setting23 and is
associated with ventilator-associated
pneumonia in the PICU‍24 and late-
onset sepsis in the NICU.‍25 Gastric pH
changes impede calcium absorption
with potentially harmful effects on
bone development and increased risk
of fractures.‍6 Adverse effects are of
particular concern for neonates and
premature infants, whose relative
liver immaturity may result in
delayed drug metabolism.‍6
Because of these concerns, we
assembled a quality improvement
team to measure and reduce the
nonindicated use of PPIs/H2RAs in
our NICU. We sought to develop a
guideline for prescription of acid-
suppressing medications to foster
change in prescribing behavior and
reduce practice variation.‍26
Downloaded from www.aappublications.org/news by guest on July 23, 2019
2 Angelidou et al
In addition to guideline development,
we sought to use quality
improvement methods to implement
the guideline and ensure adherence.
The specific aim of our project was to
reduce the number of nonindicated
PPI/H2RA prescriptions among
infants <1 month corrected age from
a baseline of 7.5 to 4 per month by
December 2016.
Methods
Setting
The Boston Children’s Hospital
NICU is an academic tertiary and
quaternary referral center serving
infants ≤6 months old with complex
medical or surgical conditions.
each year through the emergency
department or transferred from
other hospitals. More than 80% of
these infants are <1 month corrected
age at admission. All infants are
cared for by a multidisciplinary team,
including neonatologists, neonatal
fellows, neonatal nurse practitioners,
and NICU-dedicated nutritionists
and pharmacists. The team caring
for infants with surgical diagnoses
additionally includes pediatric
surgeons, pediatric surgical fellows,
and surgical critical care fellows.
Before this project, there were no
guidelines regarding the use of acid-
suppressing medications in our NICU,
and prescription of these medications
was per clinician discretion.
Medication prescriptions are written
by the neonatal fellow, surgical
critical care fellow, or neonatal nurse
practitioner in our unit.
Intervention
We assembled an interdisciplinary
team of physicians specializing in
neonatology (fellows and attending
physicians, including the NICU
medical director), pediatric surgery,
and pediatric gastroenterology; NICU
nurses; and neonatal pharmacists.
Our team analyzed key drivers (‍Fig 1)
and developed interventions to
minimize nonindicated use of
acid-suppressing medications.
Interventions fell into 3 categories:
(1) establishing evidence-based
criteria for PPI/H2RA prescription
and implementing them as a clinical
practice guideline, (2) educating staff,
and (3) encouraging staff buy-in and
guideline uptake. ‍Figure 2 shows a
timeline of the interventions.
Guideline Development
review and agreed on the following
evidence-based indications for
prescribing a PPI/H2RA to infants
<1 month corrected age: (1) lack
of integrity of the gastric lining,​‍27
(2) esophageal atresia,​‍7 (3)
otolaryngologic surgery or vocal
cord edema and erythema with
airway compromise,​‍9 (4) short bowel
syndrome or presence of ostomy
(due to association with gastric acid
hypersecretion‍28), and (5) systemic
steroid therapy.27,​29‍ Prescription
for these conditions was considered
justifiable but not mandatory.
Although many of these indications
are controversial, there was not
enough evidence to confidently
exclude benefit from PPI/H2RA use
in these conditions; therefore, use
based on clinician judgment and
local expert consensus was
considered reasonable. Conditions
specifically not supported by
the guideline included nil per os
(NPO) status, feeding intolerance,
uncomplicated GER, and apnea and
bradycardia.‍12,​13,​
‍ 16,​
‍ 17
In February 2016, we received
feedback from clinical staff that a
small subset of patients warranted
a trial of acid-suppressing
medication therapy for conditions
not prespecified by the guideline;
generally, these were difficult
clinical cases (eg, patients
considered for surgical intervention
because of feeding problems) in
which distinguishing between
uncomplicated GER and symptomatic
GER disease (GERD) was challenging.
FIGURE 1
Key driver diagram. MD, doctor of medicine; NP, nurse practitioner; RN, registered nurse.
We do not routinely use pH or
impedance probes to diagnose GERD
because of their invasive nature and
lack of correlation with objective
esophagitis,​‍30 nor do we routinely
use a reflux symptom index score.
We revised the guidelines to include
a medication trial for indications not
specified by our original guideline;
clinicians wishing to initiate a trial
of therapy were then considered
compliant if they documented
the goal and length of the trial
(up to 7 days based on H2RA/PPI
pharmacokinetics), and objective
criteria for deciding whether
treatment was effective.
We excluded patients with
congenital diaphragmatic hernia or
receiving extracorporeal membrane
Downloaded from www.aappublications.org/news by guest on July 23, 2019
PEDIATRICS Volume 140, number 6, December 2017
oxygenation because they are
cohorted in a different unit in our
hospital.
Staff Education
Before guideline implementation, our
team spent 2 months familiarizing
NICU staff with the guideline and
addressing misconceptions about
PPI/H2RA use. A team member
provided in-person education
at monthly staff meetings for
physicians, nurse practitioners, and
nurses. We posted a 1-page guideline
summary in several locations in
the NICU, particularly near the
computers used to order medications
and in the rounding workroom. After
revision of the guideline in February
2016, we spent an additional 2
months reeducating staff, including
rotating attending physicians, by
using similar methods (‍Fig 2).
Encouraging Staff Buy-In and Uptake
We sent monthly reminder e-mails
summarizing the guideline to the
on-service physicians and nurse
practitioners. A project team member
visited the unit daily on weekdays
during the first month after
implementation to answer questions
and subsequently team members
were available by e-mail. By using the
plan-do-study-act (PDSA) method,​‍31
we assessed the success of our
implementation process by reviewing
outcome data every 2 months and
made rapid cycle changes as needed
to support uptake and adherence
(‍Fig 2). Changes included: (1)
recruiting our NICU nutritionists
3
FIGURE 2
Project timeline. CL, center line; LCL, lower control limit; RN, registered nurse; UCL, upper control limit.
(who help clinicians write parenteral
nutrition [PN] orders) to assess
need for H2RA inclusion in PN on
the basis of guideline criteria, (2)
adding a notation to the nurses’
daily rounding sheet to ensure the
indication for the medication was
discussed on rounds, (3) providing
an incentive of free lunch for the unit
staff each week that they achieved
100% adherence to the guideline,
and (4) assigning a dedicated staff
member to collect data daily on
rounds, enabling real-time data
tracking and feedback.
Data Collection and Measures
We performed a retrospective
chart review from February to
September 2014 to obtain adequate
data to assess the baseline rate and
indications for acid-suppressing
medication prescription. We
then prospectively collected data
for 19 months after guideline
implementation, ending when the
project had met its goal consistently
for 6 months. We obtained census
and demographic data from the
Children’s Hospitals Neonatal
Database. We identified all infants
Downloaded from www.aappublications.org/news by guest on July 23, 2019
4 Angelidou et al
<1 month corrected age who
were prescribed acid-suppressing
medications (at least 1 dose enterally
or intravenously, including in PN)
from electronic prescription data,
and tracked the number of PPI/H2RA
prescriptions (both indicated and
nonindicated) and the duration of
therapy.
The primary outcome measure
was the number of prescriptions
each month that did not meet
guideline criteria (ie, nonindicated
prescriptions). Secondary outcomes
included the total number of
(indicated and nonindicated) PPI/
H2RA prescriptions each month, and
the ratio of patient days on which a
PPI/H2RA was administered to total
patient days each month for infants
admitted at <1 month corrected age
as a measure of overall burden of
exposure.
In each period, we categorized
the reasons for nonindicated
prescriptions (by using chart review
from the daily progress notes at the
time of prescription) for analysis
with Pareto charts. After guideline
implementation, we requested that
clinicians complete a paper form
(Supplemental Fig 8) documenting
the indication for new prescriptions.
Starting in July 2016, a dedicated
staff member completed the form
during daily rounds.
The completion rate for paper-
tracking forms served as our process
measure.
Additional outcome measures
were complications that have been
associated with acid-suppressing
medication use, including sepsis
(defined as positive blood, urine, or
cerebrospinal fluid culture results
or clinical diagnosis resulting in
treatment with antibiotics for at
least 7 days), ventilator-associated
pneumonia or tracheitis, necrotizing
enterocolitis (Bell stage >1), and
fracture (confirmed by radiograph).
We also tracked gastrointestinal
bleeding as an outcome that might
indicate harm from withholding
acid-suppressing medication. We
retrieved this information from
the Children’s Hospitals Neonatal
Database and daily International
Classification of Diseases, Ninth
Revision billing codes.
TABLE 1 Characteristics of Infants <1 Month Corrected Age Admitted to the NICU During Each Period of the Project
Characteristica Period 1b Period 2 Period 3 P
N = 370 N = 401 N = 293
Admissions per month, median number 46.5 (35–52) 42 (34–59) 48 (39–64) .44
(range)
Boys, n (%) 217 (58.7) 230 (57.4) 185 (63.1) .29
Gestational age at birth, median week 37 (23–42) 37 (23–41) 38 (22–42) .22
(range)
  <30 59 (16%) 48 (15%) 40 (14%) .12
  30–<37 119 (32%) 99 (25%) 81 (28%)
 ≥37 192 (52%) 244 (61%) 172 (59%)
Birth weightc, median gram (range) 2767 (500–5330) 2865 (430–5449) 2910 (560–4820) .37
  <1500 71 (19%) 65 (16%) 43 (15%) .35
  1500–2499 94 (26%) 86 (21%) 65 (22%)
 ≥2500 203 (55%) 233 (58%) 180 (61%)
Postmenstrual age at admission, 39 (24–43) 39 (23–43) 39 (24–43) .94
median week (range)
  <30 27 (7%) 29 (7%) 23 (8%) .69
  30–<37 82 (22%) 75 (19%) 53 (18%)
  37–<44 261 (71%) 297 (74%) 217 (74%)
Postnatal age on admission, median 3 (0–132) 4 (0–126) 3 (0–118) .44
day (range)
Length of stay, median day (range) 5 (0–126) 5 (0–170) 4 (0–64) .55
Surgical diagnoses, n (%) 133 (35.9) 131 (32.7) 65 (22.1) <.001
a Data are displayed as median (range) for nonparametric continuous data, compared by a Kruskal-Wallis test and N (%) for categorical data, compared by a χ2 test.
b Period 1: baseline before guideline implementation (February 1–October 30, 2014); period 2: postimplementation (May 1, 2015–January 31, 2016); period 3: postimplementation (June
1–November 30, 2016).
c Birth weight data were missing for 2 infants in period 1, 17 in period 2, and 5 in period 3.

Data were collected and managed
by using Research Electronic Data
Capture tools.‍32
Statistical Analysis
We used statistical process control
charts to analyze changes in the
outcome measures over time.‍31
We used c-charts for the primary
outcome measure of number of
nonindicated and total prescriptions
of PPIs/H2RAs because an infant
could have >1 prescription during
his or her hospitalization and the
number of infants admitted each
month was relatively constant. We
used a p-chart for the secondary
outcome measure of ratio of PPI/
H2RA days to total patient days.
Because there were significant
differences in each outcome between
periods, we identified process
changes between each period and
analyzed the control charts with
those process changes. Changes in
median values of outcomes in each
period were compared by Kruskal-
Wallis test, and proportions were
compared by χ2 test.
We then validated our findings
from the control charts by using
interrupted time series (ITS)
analysis, which can distinguish
change in outcome occurring because
of an intervention from change that
would have been expected on the
basis of the trend occurring during
the previous time period. To assess
differences between periods, we
calculated differences between the
average level in each period while
controlling for the trend in the
baseline period.
We used QI Macros for Excel version
2015.10 (KnowWare International
Inc, Denver, CO) to create and
analyze control charts. All other
analyses were performed by using
IBM SPSS Statistics version 22.0
(IBM Corporation) and SAS software
version 9.4 (SAS Institute Inc, Cary,
NC).
Ethics
This project was identified by
the Boston Children’s Hospital
Institutional Review Board as a
quality improvement project and
therefore exempt from review.
Results
Demographic data for infants
admitted to the NICU at <1 month
corrected age were similar in each
period, with the exception of fewer
surgical diagnoses in period 3
(‍Table 1).
For the primary outcome measure
of number of nonindicated
prescriptions per month, c-chart
analysis showed a significant
decrease in each postimplementation
period, from 7.5 in the baseline
period to 2.5 in period 2 and 0
in period 3 (‍Fig 3). Statistical
comparison of the medians in the
3 periods (‍Table 2) confirmed
significant differences. ITS analysis
(‍Table 3) confirmed the significant
reduction in nonindicated
prescriptions in each period,
revealing that after taking into
account the trend toward increasing
prescription of PPIs/H2RAs over
time during the baseline period,

Downloaded from www.aappublications.org/news by guest on July 23, 2019

PEDIATRICS Volume 140, number 6, December 2017 5
TABLE 2 Process and Outcome Measure Results
Measurea Period 1 Period 2 Period 3 P
Process measure
  No. PPI/H2RA prescriptions with completed — 19 (37.3%) 17 (77.2%) <.001
paper-tracking form, N (percentage of PPI/H2RA
prescriptions)b
Outcome measures
  No. nonindicated prescriptions per month, median 7.5 (4–11) 2 (0–8) 0 (0–2) .001
(range)
  Total no. prescriptions per month, median (range) 11.5 (7–16) 8 (4–12) 2.5 (2–8) .002
  Patient days with PPIs/H2RAs over total patient days 42.8% (41.3–44.3) 32.9% (31.6–34.3) 20.2% (19.9–21.5) <.001
per month, percentage (95% CI)
  Proportion of infants <1 mo corrected age who 18.1% (14.2–22.1) 15.7% (12.1–19.3) 14.3% (10.3–18.4) .40
developed infection, percentage (95% CI)
CI, confidence interval; —, not applicable.
a Data are displayed as median (range) for integer data, compared by a Kruskal-Wallis test and percentage (95% CI) or N (percentage) for proportion data, compared by a χ2 test.
b Process measure was only calculated for mo after implementation of the paper-tracking form in July 2015.

there were on average 7.9 fewer TABLE 3 ITS Analysis of Outcomes

prescriptions per month in period Nonindicated Total PPI/H2RA Patient Days per
2 than expected and 12.8 fewer per Prescriptions Prescriptions Total Patient Days
month in period 3. As a sensitivity Baseline trend (slope) 0.3 (P = .04) −0.03 (P = .26) 0.1 (P = .87)
analysis, we also performed Level change from period 1 to −7.9 (P < .001) −3.4 (P = .21) −12.8 (P = .08)
control charts and ITS analysis period 2
for the number of nonindicated Level change from period 1 to −12.8 (P < .001) −7.5 (P = .11) −26.3 (P = .04)
prescriptions if medication trial period 3
prescriptions were classified as
nonindicated, and the significant
reduction in each period remained
(data not shown).
Concurrent with the decrease in
nonindicated prescriptions, the total
number of PPI/H2RA prescriptions
per month also decreased from
11.6 at baseline to 3.7 in the final
period (‍Fig 4). In addition, the
ratio of PPI/H2RA patient days to
total patient days (which reflects
the overall burden of exposure
to acid-suppressing medications)
decreased to less than half the
baseline value (20.2% vs 44.7%, P <
.001) (‍Fig 5). Statistical comparison
of the median values in each period
confirmed significant decreases
between periods (‍Table 2). With
our ITS analysis, we confirmed the
significant reduction in patient
days of medication exposure but
the reduction in total number of
prescriptions did not reach statistical
significance (‍Table 3).
FIGURE 3
The Pareto chart showed that C-chart of nonindicated prescriptions of acid-suppressing medications among infants <1 month
corrected age. Triangles with a dashed line represent the number of nonindicated prescriptions
before guideline implementation,
under the original guideline definitions (ie, the number of infants started on a trial of acid-
acid-suppressing medications were suppressing medications for indications not specifically covered by the guideline). CL, center line;
commonly prescribed to infants LCL, lower control limit; UCL, upper control limit.

Downloaded from www.aappublications.org/news by guest on July 23, 2019

6 Angelidou et al

FIGURE 4
C-chart of total number of new prescriptions of acid-suppressing medications, both indicated and
nonindicated, among infants <1 month corrected age. Numbers shown are the center line for each
period. CL, center line; LCL, lower control limit; UCL, upper control limit.
with surgical diagnoses while
NPO, particularly through routine
inclusion of H2RAs in PN (‍Fig 6).
After our first PDSA cycle that
was focused on PN, we eliminated
routine use of H2RAs and virtually
eliminated nonindicated H2RA use in
PN, which was sustained throughout
the entire project (Supplemental
Fig 7). Infants with gastroschisis
were also routinely prescribed acid
suppression during the baseline
period, which we eliminated
completely (‍Fig 6). Improvements in
prescriptions for GER and apnea and
bradycardia were slower but finally
decreased in period 3 after additional
PDSA cycles introducing staff
incentives for guideline adherence
and real-time data collection on
rounds.
There was a significant increase in
paper-tracking form completion in
period 3 (‍Table 2), which served as
our process measure. None of the
nonindicated prescriptions had a
paper-tracking form filled out.
Downloaded from www.aappublications.org/news by guest on July 23, 2019
PEDIATRICS Volume 140, number 6, December 2017
Complications associated with PPI/
H2RA use were variable during each
period, but showed no significant
change over time (‍Table 2). The most
common occurrence was infection,
with an incidence of 14% to 18%.
No infants developed necrotizing
enterocolitis or fracture during or
after treatment with PPIs/H2RAs.
There were no cases of our balancing
measure, gastrointestinal bleeding.
Discussion
Implementation of an evidence-
based guideline for use of acid-
suppressing medications resulted in
a significant decrease in prescription
of these medications in our tertiary
and quaternary NICU, particularly
for conditions not supported by
the guideline. We also showed a
significant reduction in the exposure
of infants <1 month corrected age to
acid-suppressing medication, both in
terms of number of prescriptions and
percentage of patient days on which
acid suppression was administered,
after guideline implementation.
Nonindicated uses among surgical
patients (gastroschisis and routine
inclusion in PN for NPO infants)
declined quickly after guideline
implementation, suggesting that
education alone was enough to
change practice. Inclusion of a
pediatric surgeon on the project
team likely improved buy-in
and uptake among the surgical
providers. Improvements for
medical diagnoses such as reflux
and apnea and bradycardia were
slower despite broad support from
physicians, including the medical
director of our NICU. This may have
been, in part, because of lack of
guideline awareness among some
rotating attending physicians, and
adherence improved after guideline
dissemination among this group.
After guideline launch, we used
several PDSA cycles to improve
guideline adherence. Interventions
such as including acid-suppressing
medications on the nurses’ rounding
sheet had limited impact, whereas
the introduction of staff incentives
had notable impact, which remained
even after discontinuation of the
incentives, indicating sustained
change. Real-time data collection
was key to the project’s success
by allowing us to provide the staff
incentives and give timely feedback
to providers, and because the process
of daily data collection likely also
increased staff awareness of the
guideline. We noted anecdotally
a marked improvement in
documentation of the indication for
PPI/H2RA prescription throughout
the postimplementation periods,
suggesting increased staff awareness
of the guideline and thoughtfulness
about indications for use.
Responding to staff feedback and
revising the guideline to include a
trial of medication use for difficult
cases was also instrumental in
achieving 100% adherence to the
guideline. The decision of staff to
7

FIGURE 5
P-chart of burden of acid-suppressing medication exposure among infants <1 month corrected age,
expressed as percentage of patient days on which infants received acid-suppressing medications.
Numbers shown are the center line for each period. CL, center line; LCL, lower control limit; UCL,
upper control limit.
prescribe PPIs/H2RAs in these trial
cases was largely claimed to be a
“last resort” before more invasive
treatments (such as postpyloric
feeds) were pursued. We were
reassured that providers did not
use the trial as an excuse for liberal
prescription because the burden of
PPI/H2RA exposure continued to
decrease in period 3. Over a 6-month
period, there were only 3 cases of
the trial being used, all for possible
GERD: 1 of the patients had the rare
diagnosis of diaphragmatic flutter
and was treated long-term because
of symptomatic improvement
during the trial, whereas the other 2
were discharged 1 and 3 days after
medication initiation (1 of whom
was available for follow-up, and
medication was discontinued because
of ineffectiveness).
Downloaded from www.aappublications.org/news by guest on July 23, 2019
8 Angelidou et al
Despite the significant reduction in
use of acid-suppressing medications,
we did not detect any decrease
in the incidence of potentially
associated adverse events, including
infection, necrotizing enterocolitis, or
fractures. Necrotizing enterocolitis
and fracture were such rare events
that conclusions are limited.
Infections, on the other hand, are
relatively common in the NICU but
are multifactorial events unlikely
to be solely attributable to acid-
suppressing medications.
Our project has some limitations.
This intervention may not be
generalizable to NICUs that care
for a different patient mix (for
example, nonsurgical cases or
primarily inborn infants) or in which
rates of PPI/H2RA use are already
low; although, the baseline rate of
acid-suppressing medication use
and indications for prescription in
our unit were remarkably similar
to other published series including
units with widely varying patient
populations.‍1,​2‍ Development of
any guideline for acid-suppressing
medications in neonates is limited
by the poor quality of available
efficacy data, and it could be argued
that there are no indications for
PPI/H2RA use in the NICU that are
supported by high-quality evidence.
Nevertheless, even with the inclusion
of some controversial indications
in our guideline, we were able to
significantly impact prescription
rates. The decline in total
prescriptions paralleling the decline
in nonindicated prescriptions is
reassuring in that prescribers did not
simply reclassify prescriptions from
nonindicated to indicated conditions.
In addition, although we did not see
any increase in potential adverse
events, continued monitoring is
needed to ensure decreased PPI/
H2RA use is not associated with
adverse events over time. Finally,
although this guideline was
successful in the inpatient setting,
recent evidence shows the majority
of infants receiving acid-suppressing
medications after NICU discharge
were started on the medication as
outpatients.‍3,​33
‍ Given the known risks
of PPI/H2RA use in outpatient infant
populations,​3 addressing outpatient
prescription via establishment
of similar guidelines would be an
important next step but was beyond
the scope of our project.
Conclusions
Given the mounting evidence for
potential adverse effects, acid-
suppressing medications should
only be prescribed to neonates
after careful consideration.
Implementation of an evidence-
based guideline in our tertiary and
quaternary NICU accompanied
by leadership involvement, staff
 the Pharmacy Department at
Boston Children’s Hospital for
providing pharmacy-derived data
for medication administration;
Susan Maher, Jackie Paquette, and
Mark Moline for their assistance
with abstraction of data from the
Children’s Hospitals Neonatal
Database; Allison Cox for assisting
with real-time data tracking; Ashley
Park for administrative assistance;
and Radhika Kamalia from the
Department of Medicine Quality
Improvement Department and
Patrice Melvin from the Program
for Patient Safety and Quality for
their assistance with statistical
analysis.

FIGURE 6
Pareto chart of diagnoses for nonindicated prescriptions of acid-suppressing medication in each
period. Some infants had >1 diagnosis associated with their prescription. Period 1: baseline before
Abbreviations
guideline implementation (February 1, 2014, to September 20, 2014); period 2: postimplementation GER: gastroesophageal reflux
(May 1, 2015, to January 31, 2016); period 3: postimplementation (June 1, 2016, to November 30,
GERD: gastroesophageal reflux
2016).
disease
H2RA: histamine-2 receptor
incentives, and real-time data settings providing inpatient care to
antagonist
tracking led to excellent adherence sick newborns.
ITS: interrupted time series
that directly correlated with a
NPO: nil per os
substantial decrease in overall
Acknowledgments PDSA: plan-do-study-act
burden of exposure to PPI/H2RAs
PN: parenteral nutrition
in our unit. This guideline could be We thank Brenda Dodson, Jenny
PPI: proton pump inhibitor
feasibly implemented in other similar Kim, and Esther Chang from

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

References
1. Slaughter JL, Stenger MR, Reagan PB,
Jadcherla SR. Neonatal histamine-2
receptor antagonist and proton
pump inhibitor treatment at United
States children’s hospitals. J Pediatr.
2016;174:63–70.e3
2. Dhillon AS, Ewer AK. Diagnosis and
management of gastro-oesophageal
reflux in preterm infants in neonatal
intensive care units. Acta Paediatr.
2004;93(1):88–93
3. Canani RB, Cirillo P, Roggero P, et al;
Working Group on Intestinal Infections
of the Italian Society of Pediatric
Gastroenterology, Hepatology and
Nutrition (SIGENP). Therapy with
gastric acidity inhibitors increases
the risk of acute gastroenteritis and
community-acquired pneumonia in
children. Pediatrics. 2006;117(5).
Available at: www.​pediatrics.​org/​cgi/​
content/​full/​117/​5/​e817
4. Guillet R, Stoll BJ, Cotten CM, et al;
National Institute of Child Health
and Human Development Neonatal
Research Network. Association
of H2-blocker therapy and higher
incidence of necrotizing enterocolitis
in very low birth weight infants.
Pediatrics. 2006;117(2). Available at:
www.​pediatrics.​org/​cgi/​content/​full/​
117/​2/​e137
5. More K, Athalye-Jape G, Rao S, Patole
S. Association of inhibitors of gastric
acid secretion and higher incidence
of necrotizing enterocolitis in preterm
very low-birth-weight infants.
Am J Perinatol. 2013;30(10):849–856
6. Stark CM, Nylund CM. Side effects
and complications of proton pump
inhibitors: a pediatric perspective.
J Pediatr. 2016;168:16–22
7. Vandenplas Y, Rudolph CD, Di Lorenzo
C, et al; North American Society
for Pediatric Gastroenterology
Hepatology and Nutrition;
European Society for Pediatric
Gastroenterology Hepatology and
Nutrition. Pediatric gastroesophageal
reflux clinical practice guidelines:
joint recommendations of the North

Downloaded from www.aappublications.org/news by guest on July 23, 2019

PEDIATRICS Volume 140, number 6, December 2017 9
 American Society for Pediatric
Gastroenterology, Hepatology,
and Nutrition (NASPGHAN) and the
European Society for Pediatric
Gastroenterology, Hepatology, and
Nutrition (ESPGHAN). J Pediatr
Gastroenterol Nutr. 2009;49(4):498–547
8. Ho T, Dukhovny D, Zupancic JA,
Goldmann DA, Horbar JD, Pursley DM.
Choosing wisely in newborn medicine:
five opportunities to increase value.
Pediatrics. 2015;136(2). Available at:
www.​pediatrics.​org/​cgi/​content/​full/​
136/​2/​e482
9. Venkatesan NN, Pine HS, Underbrink
M. Laryngopharyngeal reflux disease
in children. Pediatr Clin North Am.
2013;60(4):865–878
10. Hagander L, Muszynska C,
Arnbjornsson E, Sandgren K.
Prophylactic treatment with proton
pump inhibitors in children operated
on for oesophageal atresia. Eur J
Pediatr Surg. 2012;22(2):139–142
11. Shawyer AC, D’Souza J, Pemberton
J, Flageole H. The management of
postoperative reflux in congenital
esophageal atresia-tracheoesophageal
fistula: a systematic review. Pediatr
Surg Int. 2014;30(10):987–996
12. Orenstein SR, Hassall E, Furmaga-
Jablonska W, Atkinson S, Raanan M.
Multicenter, double-blind, randomized,
placebo-controlled trial assessing the
efficacy and safety of proton pump
inhibitor lansoprazole in infants with
symptoms of gastroesophageal reflux
disease. J Pediatr. 2009;154(4):514–
520.e4
13. Omari TI, Haslam RR, Lundborg P,
Davidson GP. Effect of omeprazole on
acid gastroesophageal reflux and
gastric acidity in preterm infants with
pathological acid reflux. J Pediatr
Gastroenterol Nutr. 2007;44(1):41–44
14. Moore DJ, Tao BS, Lines DR, Hirte
C, Heddle ML, Davidson GP. Double-
blind placebo-controlled trial of
omeprazole in irritable infants with
gastroesophageal reflux. J Pediatr.
2003;143(2):219–223
15. Orenstein SR, Shalaby TM, Devandry
SN, et al. Famotidine for infant gastro-
oesophageal reflux: a multi-centre,
randomized, placebo-controlled,
Downloaded from www.aappublications.org/news by guest on July 23, 2019
10
withdrawal trial. Aliment Pharmacol
Ther. 2003;17(9):1097–1107
16. López-Alonso M, Moya MJ, Cabo JA,
et al. Twenty-four-hour esophageal
impedance-pH monitoring in
healthy preterm neonates: rate and
characteristics of acid, weakly acidic,
and weakly alkaline gastroesophageal
reflux. Pediatrics. 2006;118(2).
Available at: www.​pediatrics.​org/​cgi/​
content/​full/​118/​2/​e299
17. Finer NN, Higgins R, Kattwinkel J,
Martin RJ. Summary proceedings
from the apnea-of-prematurity group.
Pediatrics. 2006;117(3 pt 2):S47–S51
18. Poets CF. Gastroesophageal reflux: a
critical review of its role in preterm
infants. Pediatrics. 2004;113(2).
Available at: www.​pediatrics.​org/​cgi/​
content/​full/​113/​2/​e128
19. Peter CS, Sprodowski N, Bohnhorst
B, Silny J, Poets CF. Gastroesophageal
reflux and apnea of prematurity: no
temporal relationship. Pediatrics.
2002;109(1):8–11
20. Kimball AL, Carlton DP.
Gastroesophageal reflux medications
in the treatment of apnea in premature
infants. J Pediatr. 2001;138(3):355–360
21. Fuloria M, Hiatt D, Dillard RG, O’Shea
TM. Gastroesophageal reflux in very
low birth weight infants: association
with chronic lung disease and
outcomes through 1 year of age.
J Perinatol. 2000;20(4):235–239
22. Akinola E, Rosenkrantz TS,
Pappagallo M, McKay K, Hussain N.
Gastroesophageal reflux in infants <
32 weeks gestational age at birth: lack
of relationship to chronic lung disease.
Am J Perinatol. 2004;21(2):57–62
23. Canani RB, Terrin G. Gastric acidity
inhibitors and the risk of intestinal
infections. Curr Opin Gastroenterol.
2010;26(1):31–35
24. Elward AM, Warren DK, Fraser VJ.
Ventilator-associated pneumonia in
pediatric intensive care unit patients:
risk factors and outcomes. Pediatrics.
2002;109(5):758–764
25. Bianconi S, Gudavalli M, Sutija VG,
Lopez AL, Barillas-Arias L, Ron N.
Ranitidine and late-onset sepsis in the
neonatal intensive care unit. J Perinat
Med. 2007;35(2):147–150
26. Nuffield Institute for Health, University
of Leeds; Centre for Health Economics
and the NHS Centre for Reviews
and Dissemination, University of
York; Research Unit, Royal College
of Physicians. Implementing clinical
practice guidelines: can guidelines
be used to improve clinical practice?
Leeds, UK: University of Leeds; 1994.
Effective Health Care 8
27. López-Herce J, Dorao P, Elola P,
Delgado MA, Ruza F, Madero R; The
Gastrointestinal Hemorrhage Study
Group. Frequency and prophylaxis of
upper gastrointestinal hemorrhage
in critically ill children: a prospective
study comparing the efficacy of
almagate, ranitidine, and sucralfate.
Crit Care Med. 1992;20(8):1082–1089
28. Hyman PE, Everett SL, Harada T. Gastric
acid hypersecretion in short bowel
syndrome in infants: association
with extent of resection and enteral
feeding. J Pediatr Gastroenterol Nutr.
1986;5(2):191–197
29. Reveiz L, Guerrero-Lozano R, Camacho
A, Yara L, Mosquera PA. Stress ulcer,
gastritis, and gastrointestinal bleeding
prophylaxis in critically ill pediatric
patients: a systematic review. Pediatr
Crit Care Med. 2010;11(1):
124–132
30. Salvatore S, Hauser B, Vandemaele
K, Novario R, Vandenplas Y.
Gastroesophageal reflux disease in
infants: how much is predictable with
questionnaires, pH-metry, endoscopy
and histology? J Pediatr Gastroenterol
Nutr. 2005;40(2):210–215
31. Provost L, Murray S. The Health Care
Data Guide: Learning From Data for
Improvement. San Francisco, CA:
Jossey-Bass; 2011
32. Harris PA, Taylor R, Thielke R, Payne
J, Gonzalez N, Conde JG. Research
electronic data capture (REDCap)–a
metadata-driven methodology and
workflow process for providing
translational research informatics
support. J Biomed Inform.
2009;42(2):377–381
33. D’Agostino JA, Passarella M, Martin
AE, Lorch SA. Use of gastroesophageal
reflux medications in premature
infants after NICU discharge.
Pediatrics. 2016;138(6):e20161977
Angelidou et al
Implementation of a Guideline to Decrease Use of Acid-Suppressing Medications
in the NICU
Asimenia Angelidou, Katherine Bell, Munish Gupta, Kristen Tropea Leeman and
Anne Hansen
Pediatrics 2017;140;
DOI: 10.1542/peds.2017-1715 originally published online November 21, 2017;

Updated Information &
Services
References
Subspecialty Collections
Permissions & Licensing
Reprints
including high resolution figures, can be found at:
http://pediatrics.aappublications.org/content/140/6/e20171715
This article cites 31 articles, 8 of which you can access for free at:
http://pediatrics.aappublications.org/content/140/6/e20171715#BIBL
This article, along with others on similar topics, appears in the
following collection(s):
Administration/Practice Management
http://www.aappublications.org/cgi/collection/administration:practice
_management_sub
Quality Improvement
http://www.aappublications.org/cgi/collection/quality_improvement_
sub
Fetus/Newborn Infant
http://www.aappublications.org/cgi/collection/fetus:newborn_infant_
sub
Information about reproducing this article in parts (figures, tables) or
in its entirety can be found online at:
http://www.aappublications.org/site/misc/Permissions.xhtml
Information about ordering reprints can be found online:
http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on July 23, 2019

Implementation of a Guideline to Decrease Use of Acid-Suppressing Medications
in the NICU
Asimenia Angelidou, Katherine Bell, Munish Gupta, Kristen Tropea Leeman and
Anne Hansen
Pediatrics 2017;140;
DOI: 10.1542/peds.2017-1715 originally published online November 21, 2017;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/140/6/e20171715

Data Supplement at:

http://pediatrics.aappublications.org/content/suppl/2017/11/18/peds.2017-1715.DCSupplemental

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since 1948. Pediatrics is owned, published, and trademarked by
the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2017 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
1073-0397.

Downloaded from www.aappublications.org/news by guest on July 23, 2019