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Stress Ulcer Prophylaxis in the ICU – Adult/Pediatric/Neonatal - Inpatient

Stress Ulcer Prophylaxis in the ICU – Adult/Pediatric/Neonatal - Inpatient - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Medications


1
Stress Ulcer Prophylaxis in the Intensive Care Unit –
Adult/Pediatric/Neonatal – Inpatient
Clinical Practice Guideline
Note: Active Table of Contents – Click to follow link
EXECUTIVE SUMMARY ........................................................................................................... 3
SCOPE ...................................................................................................................................... 4
METHODOLOGY ...................................................................................................................... 4
DEFINITIONS ............................................................................................................................ 5
INTRODUCTION ....................................................................................................................... 5
RECOMMENDATIONS – ADULT ICU PATIENTS .................................................................... 8
RECOMMENDATIONS – PEDIATRIC ICU PATIENTS ............................................................10
RECOMMENDATIONS – NEONATAL ICU PATIENTS ............................................................10
RECOMMENDATIONS – ADULT, PEDIATRIC, AND NEONATAL ICU PATIENTS ................12
UW HEALTH IMPLEMENTATION ............................................................................................13
APPENDIX A ............................................................................................................................14
REFERENCES .........................................................................................................................15
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Contact for Content:
Name: Jeff Fish, PharmD, Clinical Pharmacist
Phone Number: 263-1290
Email Address: jtfish@uwhealth.org

Contact for Changes:
Name: Philip Trapskin, PharmD, Drug Policy Program
Phone Number: 265-0341
Email Address: ptrapskin@uwhealth.org

Guideline Author(s):
Updated by:
Chris Viesselmann, PharmD – Pharmacy
Glynis Kinney, PharmD – Pharmacy
Jeff Fish, PharmD – Pharmacy
Matt Willenborg, PharmD – Pharmacy

Coordinating Team Members:
Carin Bouchard, PharmD – Drug Policy Program

Review Individuals/Bodies:
Pierre Kory, MD – Critical Care
Ann O’Rourke, MD – Critical Care
Josh Medow, MD, MS – Neurocritical Care
Lee Faucher, MD – Burn
Angela Gibson, MD – Trauma, Burn
Jon Ketzler, MD – Anesthesiology
Jagan Ramamoorthy, MD – Anesthesiology
Matthew Anderson, MD – Critical Care
Sushant Srinivasan, MD – Pediatrics (PICU)
Matthew Harer, MD – Pediatrics (NICU)
Jamie Limjoco, MD, MS – Pediatrics (NICU)
Jenna Potter, NP – Critical Care
Erin Billmeyer, NP – Critical Care
Heather Templin, NP – Critical Care
Anna Krupp, NP – Critical Care
Carin Bouchard, PharmD – Drug Policy Program
Martha Starzewski, PharmD – Pharmacy
Monica Bogenschutz, PharmD – Pharmacy

Committee Approvals/Dates:
Pharmacy and Therapeutics Committee June 2011, September 2017

Release Date: October 2017 | Next Review Date: July 2019




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Executive Summary
Guideline Overview
The purpose of this guideline is to provide a framework for appropriate use and prescribing of acid-
suppressive agents for adult, pediatric and neonatal patients in intensive care units for stress ulcer
prophylaxis.

Key Revisions (2016 Periodic Review)
1. Change scope of focus to the intensive care unit (ICU)
2. Removal of multitrauma as an indicator of stress ulcer prophylaxis in adults
3. Removal of GCS ≤ 10, inability to obey commands, dual antiplatelet therapy and therapeutic
anticoagulation as reasonable indications for stress ulcer prophylaxis in adults
4. Removal of acute renal failure, hepatic/renal transplantation, hepatic failure or 2 of the following risk
factors (sepsis, ICU stay > 1 week, occult bleeding ≥ 6 days, use of high dose corticosteroids) as
indications where stress ulcer prophylaxis may be considered in adults
5. Histamine receptor blockers are now recommended as the preferred agent for stress ulcer
prophylaxis in adults over proton pump inhibitors
6. Change qualification of thermal injury percentage (≥ 20%) required for stress ulcer prophylaxis in both
adults and pediatrics
7. Recommendations for stress ulcer prophylaxis inclusion criteria for pediatric patients with non-
invasive positive pressure ventilation was added
8. Histamine receptor blockers are now recommended as the preferred agent for stress ulcer
prophylaxis in pediatric thermal injuries over proton pump inhibitors
9. Recommendation for the use of stress ulcer prophylaxis in neonates was removed
10. Recommendations were added to consider discontinuation of stress ulcer prophylaxis when patients
tolerate enteral nutrition, even if other risk factors are present
11. Recommendations were added to consider discontinuation of stress ulcer prophylaxis in traumatic
brain injury patients 2 weeks after injury if other complicating factors are absent

Key Practice Recommendations
Recommendations – Adult ICU Patients

1. Appropriate indications for the use of pharmacologic stress ulcer prophylaxis in adults
2. Inappropriate indications for the use of pharmacologic stress ulcer prophylaxis in adults
3. PPIs and H2RAs are considered appropriate for stress ulcer prophylaxis in adults, and sucralfate is
an alternative agent for adults unable to tolerate H2RAs or PPIs

Recommendations – Pediatric ICU Patients

4. Appropriate indications for the use of pharmacologic stress ulcer prophylaxis in pediatric patients
5. Inappropriate indications for the use of pharmacologic stress ulcer prophylaxis in pediatric patients
6. PPIs and H2RAs are considered appropriate for stress ulcer prophylaxis in pediatrics
7. Sucralfate is not recommended for pediatric patients

Recommendations – Neonatal ICU Patients

8. The use of stress ulcer prophylaxis in neonates is not recommended
9. The use of proton pump inhibitor is not approved for use in infants < 1 year of age and sucralfate in
neonates is not recommended and may be harmful
10. Inappropriate indications for the use of pharmacologic stress ulcer prophylaxis in neonates

Recommendations – Adult, Pediatric, and Neonatal ICU Patients
11. Recommended duration of stress ulcer prophylaxis for all patients


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Companion Documents
1. Prevention of Ventilator Associated Events (VAE) – Adult – Inpatient Clinical Practice Guideline
2. Clostridium difficile Infection: Prevention, Diagnosis and Treatment – Adult/Pediatric –
Inpatient/Ambulatory/Emergency Department Clinical Practice Guideline
3. Renal Function-Based Dose Adjustments - Adult -Inpatient/Ambulatory Clinical Practice Guideline
Scope
Disease/Condition(s):
Stress ulcer prophylaxis in the intensive care unit.

This guideline does not address the following conditions and patient populations due to either direct
indication for acid suppression therapy or ulcer formation due to non-stress related mechanisms:
- active treatment of gastric ulcers, GI bleeding, or hypersecretory disorders
- acid suppression treatment following total gastrectomy or other bariatric procedures
- prevention of gastrointestinal bleeding in patients with high risk medications (e.g. nonsteroidal
antiinflammatory drugs, anticoagulants, antiplatelet agents, or steroids) when no other risk factors
for stress ulcers are present
- Solid organ transplant recipients
- Stress ulcer prophylaxis outside of the ICU

Clinical Speciality:
Critical Care – adult, pediatric and neonatal

Intended Users:
Critical Care Physicians, Advanced Practice Providers, Clinical Pharmacists and Registered Nurses

Objective(s):
To provide an evidenced based guideline to assist clinicians in identifying critically ill patients requiring
stress ulcer prophylaxis, in selecting appropriate pharmacologic agents for stress ulcer prophylaxis and to
minimize inappropriate use of stress ulcer prophylaxis

Target Population:
Adult, pediatric, and neonatal intensive care patients at risk for stress ulcers

Interventions and Practices Considered:
ξ Pharmacologic prophylaxis of stress ulcers

Major Outcomes Considered:
ξ Preventing stress ulcers
ξ Reducing inappropriate prescribing
ξ Reducing adverse event related to inappropriate stress ulcer prophylaxis

Methodology
Methods Used to Collect/Select the Evidence:
The UW Health Guidelines for Stress Ulcer Prophylaxis in Adults and Pediatrics was updated with a
literature search using MEDLINE and Cochrane databases, and an evaluation of referenced literature.
Searches were extended to reviews and studies conducted in humans and published in English.
Reference lists of relevant studies were also reviewed.

Methods Used to Formulate the Recommendations:
The workgroup members agreed to adopt recommendations developed by external organizations and/or
arrived at a consensus through discussion of the literature and expert experience. All recommendations
endorsed or developed by the guideline workgroup were reviewed and approved by other stakeholders or
committees (as appropriate).

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Methods Used to Assess the Quality of the Evidence/Strength of the Recommendations:
Recommendations developed by external organizations maintained the evidence grade assigned within
the original source document and were adopted for use at UW Health.

Internally developed recommendations, or those adopted from external sources without an assigned
evidence grade, were evaluated by the guideline workgroup using an algorithm adapted from the Grading
of Recommendations Assessment, Development and Evaluation (GRADE) methodology (see Figure 1 in
Appendix A).

Rating Scheme for the Strength of the Evidence/Recommendations:
See Appendix A for the rating scheme(s) used within this document.

Recognition of Potential Health Care Disparities:
None noted
Definitions
Stress ulcers: erosions that may develop in acid and pepsin secreting mucosa of the stomach within
hours to days in critically ill patients, and commonly occur in multiple sites.1

Clinically important bleeding: for the purpose of these guidelines, was defined as gastroduodenal
bleeding associated with hemodynamic compromise, need for blood transfusion, or requirement for
surgery.2

Neonates: patients from birth to 28 days of age3

Pediatrics: patients from 29 days of age to 18 years of age3

Adults: patients 19 years of age or older3
Introduction
Background
Theories for causes of stress ulcer formation include gastric hypoperfusion, acid over secretion,
underproduction of gastric mucus, and Helicobacter pylori infection.2 The incidence of stress ulceration is
estimated to be 5-25% in ICU patients.2,4,5 However, clinically significant GI bleeding has been shown to
occur in only 1-6% of these patients at most, although the definitions of clinically significant bleeding
varied widely between studies (many of which were published 15-20 years ago or more).2,4,5 In patients
who develop clinically significant GI bleeding, approximately half of these patients develop bleeding within
the first 48 hours of their ICU stay.6 Mortality in critically ill patients who experience clinically significant
bleeding has been estimated at 48.5% compared to 9.1% for those without significant bleeding in a study
from 1994.7 Furthermore, clinically significant bleeding is associated with an estimated excess ICU length
of stay of 4-8 days in a 2001 study.8 Despite these early estimates, there have been many changes to the
care of critically ill patients over the past several decades, and therefore it is likely that the incidence of GI
bleeding as well as the outcomes in patients who bleed may have also changed significantly.6

Stress ulcer prophylaxis (SUP) using pharmacologic agents has since become standard therapy to
prevent stress ulcer formation and bleeding in intensive care units. It is recommended by international
guidelines for critically ill patients at risk of stress ulcers, and has also become increasingly common in
general medicine patients, although not recommended in this population.2,9,10

Indications for SUP
SUP is not necessary for all ICU patients, and is often prescribed inappropraitely.9 In a study of 2,252
adults (651 receiving SUP, 1,568 not receiving SUP), 33 (1.5%) had clinically significant bleeding (10
having received SUP, 23 not receiving SUP).7 The independent risk factors for bleeding in this study were
respiratory failure requiring mechanical ventilation for more than 48 hours (odds ratio 15.6, p<0.001), and
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6
coagulopathy in patients not receiving exogenous anticoagulation (odds ratio 4.3, p<0.001). The risk of
clinically significant bleeding in the population of patients without these risk factors was 0.1% (2 out of
1405 patients). Smaller studies have suggested several additional risk factors for stress ulcers in the
critically ill, including burns, organ transplantation, spinal cord injuries, hepatic failure, multiple trauma,
history of GI bleed, sepsis, extended ICU stays, occult bleeding, and corticosteroid use, although the
clinical relevance of these risk factors has not been thoroughly defined in the literature.2,11-13 With respect
to corticosteroid use, a 2013 systematic review of 3 meta-analyses indicated that peptic ulceration in the
setting of concomitant corticosteroid therapy was rare, with a reported incidence of 0.4-1.8%.14

While the use of SUP is associated with approximately a 2-fold decrease in the risk of clinically important
bleeding compared to no prophylaxis, 15 no study or analysis to date has shown a benefit to mortality or
reduction in ICU length of stay associated with SUP therapy. It should also be noted that prophylaxis only
reduces and does not eliminate the risk of bleeding.

The impact enteral nutrition has on the need for SUP is not clearly defined. A systematic review and
meta-analysis of 17 randomized controlled studies conducted from 1980 to 2004 (1836 patients) was
conducted to evaluate the benefit and risks of SUP to prevent clinically significant GI bleeding in ICU
patients receiving histamine 2 receptor antagonists (H2RAs) compared to placebo when patients received
enteral nutrition.16 No publication bias was seen on funnel plots. Only 3 of the included trials provided
enteral nutrition to patients studied (262 patients). In the overall population, SUP was associated with a
reduction in clinically significant GI bleeding (OR 0.47; 95% CI 0.29-0.76; p<0.002; I2=44%), but not an
increased risk of hospital acquired pneumonia (OR 1.53; 95% CI 0.89-2.61; p=0.12; I2=41%). In the
subgroup of patients receiving enteral nutrition, SUP did not affect the incidence of clinically significant GI
bleeding (OR 1.26; 95% CI 0.43-3.7) but was associated with increased risk of hospital acquired
pneumonia (OR 2.81; 95% CI 1.2-6.56; p=0.02; I2=0%). No difference in mortality was shown between
H2RA and placebo in the overall population, but was higher in the subgroup that received SUP and
enteral nutrition (OR 1.89; 95% CI 1.04-3.44; p=0.04).

In pediatric populations, the rate of clinically significant bleeding was 1.6% in a cohort of 1006 patients in
a pediatric intensive care unit, and was associated with several risk factors including respiratory failure,
coagulopathy, and mortality score.17 However, studies regarding morbidity and mortality related to
clinically significant gastrointestinal bleeding has not been well studied in children, and specific indications
for SUP in pediatrics and neonates are poorly defined.18

A systematic review of 8 randomized controlled trials was conducted to evaluate the efficacy of stress
ulcer prophylaxis treatments for the prevention of gastrointestinal bleeding in critically ill children.18 Two
studies had high risk of bias, and the remaining six studies had unclear risk of bias. A meta-analysis of
two trials (300 patients) revealed that stress ulcer prophylaxis (omeprazole, ranitidine, sucralfate, and
almagate) was associated with a reduced incidence of gastrointestinal bleeding compared with no
prophylaxis (RR 0.41; 95% CI 0.19-0.91; I2=12%), but significance was lost when a third trial comparing
prophylaxis to placebo was included in the analysis (N=340 patients total; RR 0.69; 95% CI 0.41-1.17;
I
2=63%). There were no significant differences in rates of nosocomial pneumonia (2 trials) or mortality (1
trial) between groups. Additionally, no differences in incidences of bleeding, mortality, or nosocomial
pneumonia were found between omeprazole, ranitidine, famotidine, sucralfate, or almagate in the studies.
Publication bias was not assessed as outcomes were pooled for no greater than three studies; however
the methodological quality of the studies was noted to be poor.

A prospective, single-center, randomized controlled trial in a pediatric intensive care unit of 165 patients
with risk factors for gastrointestinal hemorrhage was conducted to investigate the impact of almagate,
ranitidine, and sucralfate prophylaxis on the incidence of gastrointestinal hemorrhage.19 Patients
admitted to the pediatric intensive care unit with shock, acute cardiac, respiratory, hepatic, or renal failure,
sepsis, coagulopathy, neurologic dysfunction, multi-trauma, severe acidosis, or major surgery were
included in the study, but excluded if they experienced nasal or pharyngeal bleeding. Patients were
randomized into 4 groups (N=35 patients each) to receive almagate, ranitidine, sucralfate, or no
prophylaxis (control), respectively. For the outcome of important gastrointestinal bleeding, any
prophylaxis (5.7%; 6/105 patients) was superior to no prophylaxis (20%; 7/35 patients; p<0.05), however
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7
there were no significant differences between individual treatment groups (almagate group: 5.7%; 2/35
patients, ranitidine group: 8.5%; 3/35 patients, sucralfate group: 2.8%; 1/35 patients). There was a trend
toward significantly higher mean gastric pH in the almagate group (pH 6.1) and the ranitidine group (pH
4.8) compared to the sucralfate group (pH 3.5), but all were significantly increased compared to control
(pH 2.4; p>0.001). No difference in mortality between groups was observed, and no nosocomial
pneumonia was identified over the course of the study. This trial was limited by the unblinded nature of
the study and by the small number of patients included.

Another prospective, single-center, randomized controlled trial of 160 patients requiring mechanical
ventilation upon admission to the pediatric intensive care unit to investigate the incidence of ventilator-
associated pneumonia in patients receiving stress ulcer prophylaxis.20 Patients were randomized to
receive sucralfate (N=38), ranitidine (N=42), omeprazole (N=38), or no prophylaxis (N=42). For the
primary outcome of ventilator-associated pneumonia, there were no significant differences between
sucralfate (42%; 17/38 patients), ranitidine (48%; 20/42 patients), omeprazole (45%; 17/38 patients), or
control groups (41%; 17/42 patients; p=0.963). There were no significant differences in the outcomes of
mortality or gastrointestinal bleeding between groups. This trial was limited by the unblinded nature of the
study and by the small number of patients included.

Choice of Agent for SUP
The specific agent for SUP has also not been clearly identified. A systematic review and meta-analysis of
14 prospective randomized controlled trials (1720 patients) was conducted to compare H2RAs to PPIs for
the prevention of gastrointestinal bleeding in critically ill patients.5 PPI therapy was associated with less
clinically significant bleeding (1.2%; 12/1019 patients) compared to H2RA therapy (6.4%; 38/595 patients;
RR 0.36; 95% CI 0.19-0.68; p=0.002; I2=0%). There were no differences in rates of nosocomial
pneumonia, ICU length of stay, or ICU mortality between groups. The definition of clinically significant
bleeding differed between authors. Likely publication bias was noted on funnel plot. Risk of bias varied
among the trials in the analysis, with only 3 trials at an overall low risk of bias. Significance between
treatment groups for prevention of gastrointestinal bleeding was lost when trials with high or unclear risk
of bias were excluded from the analysis.

A meta-analysis of 8 randomized controlled trials and 5 abstracts (1587 patients combined) was also
conducted to compare the efficacy of H2RAs to PPIs for the prevention of stress-related gastrointestinal
bleeding in critically ill patients.21 PPI therapy was associated with less clinically significant bleeding
(1.3%; 13/967 patients) compared to H2RA therapy (6.6%; 41/620 patients; OR 0.30; 95% CI 0.17-0.54),
and no heterogeneity was detected (p=0.93; I2=0%). There were no significant differences in rates of
nosocomial pneumonia or mortality between groups. No publication bias was detected on funnel plot, but
the definition of clinically significant bleeding differed between authors, which limits the robustness of the
results. Furthermore, the authors noted that many of the studies included in the analysis were of poor
methodological quality, and significant heterogeneity (p=0.03; I2=46%) was noted in a sensitivity analysis
using risk difference rather than odds ratio for the primary outcome. However, the overall conclusion in
the sensitivity analysis remained significant in favor of PPIs over H2RAs for the prevention of
gastrointestinal bleeding (risk difference -0.026; 95% CI -0.049 to -0.003).

A meta-analysis of 7 randomized controlled trials (936 patients) published prior to June 2008 was
conducted to compare H2RAs to PPIs for the prevention of gastrointestinal bleeding in critically ill
patients.22 The difference in the risk of gastrointestinal bleeding for PPI therapy compared to H2RAs was
-0.04 (95% CI -0.09 to 0.01; p=0.08), however significant heterogeneity was noted across the studies
included in the analysis (p=0.08; I2=66%). When a single trial from 1997(67 patients) that showed a
significant benefit of PPI therapy over H2RA therapy for the reduction of bleeding events (risk difference -
0.25; 95% CI -0.43 to -0.08) was removed from the analysis, the difference in risk among the remaining
trials was -0.02 (95% CI -0.05 to 0.01; p=0.19), and the heterogeneity was reduced (I2=26%). There were
no significant differences in rates of nosocomial pneumonia or mortality between groups. Likely
publication bias was also revealed on a funnel plot, indicating possible flawed estimates due to poor study
quality and methodology or minimal publication of studies with opposing results.

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In contrast to the previously discussed meta-analyses of prospective trials, a recently published
pharmacoepidemiologic cohort study of 35,312 patients receiving mechanical ventilation for 24 hours or
longer across 71 hospitals was conducted to compare H2RAs to PPIs for the prevention of
gastrointestinal bleeding as well as the risk of nosocomial pneumonia and Clostridium difficile infections.23
PPI therapy, compared to H2RA therapy, was associated with increased rates of clinically significant
bleeding (5.9%; 1287/21873 patients vs. 2.1%; 276/13439 patients, respectively; p<0.001), nosocomial
pneumonia (38.6%; 8435/21873 patients vs. 27%; 3630/13439 patients, respectively; p<0.001), and
Clostridium difficile infection (3.8%; 835/21873 patients vs. 2.2%; 294/13439 patients, respectively;
p<0.001). Data presented in this study is from a database collected prior to January 2009, and baseline
patient characteristics varied between groups.

A multicenter, blinded, placebo-controlled randomized controlled trial of 1200 patients compared
sucralfate with ranitidine for the prevention of gastrointestinal bleeding in patients requiring mechanical
ventilation.24 Ranitidine was associated with a lower rate of clinically significant bleeding (1.7%; 10/596
patients) compared to sucralfate (3.8%; 23/604 patients; RR 0.44; 95% CI 0.21-0.92; p=0.02). There
were no significant differences in the rates of nosocomial pneumonia or mortality.
No studies have been published demonstrating outcome superiority of PPIs over sucralfate for stress
ulcer prophylaxis.25

Risks of SUP
The use of acid suppressive therapies for SUP is not benign, and increases gastric pH allowing for
bacterial overgrowth in the GI tract which may lead to infection.23 In fact, SUP has been associated with
both an increased risk of developing hospital-acquired pneumonia and Clostridium difficile-associated
diarrhea.26-28 In a prospective, single-center cohort study in non-intensive care unit inpatients revealed an
increased risk of hospital-acquired pneumonia in the patients exposed to either PPI or H2RA therapy with
an adjusted OR of 1.3 (95% CI 1.1-1.4) compared to no acid-suppressive therapy.27 This risk remained
significant only in the group exposed to PPIs (OR 1.3; 95% CI 1.1-1.4) and was not significant in the
group exposed to H2RAs (OR 1.2; 95% CI 0.98-1.4).27 Furthermore, pantoprazole was shown to have an
increased risk of nosocomial pneumonia when compared directly with ranitidine in a retrospective
analysis of a cardiothoracic surgery database, with pantoprazole being identified as an independent risk
factor for nosocomial pneumonia (OR 2.7; 95% CI 1.1-6.7; p=0.0034).26 A retrospective case-control
study also revealed an association between PPI therapy and Clostridium difficile associated diarrhea (OR
3.6; 95% CI 1.7-8.3; p<0.001), whereas H2RA therapy did not show a significant association.28 Finally,
the risk of nosocomial Clostridium difficile infection has been shown to increase with increasing level of
acid suppression in a cohort study of hospitalized patients, where the level of acid suppression was
defined as no acid suppression, H2RA therapy, PPI daily, and PPI more frequently than daily (listed from
lowest level to highest level of acid suppression).29 Thus, acid suppressive therapies should only be used
in patients at risk of developing gastric stress ulcers.

Recommendations – Adult ICU Patients
1. Appropriate indications for the use of pharmacologic stress ulcer prophylaxis in adults
1.1. SUP is recommended in the following situations:
1.1.1. Mechanical ventilation for more than 48 hours2,7,30 (UW Health Strong Recommendation,
High Quality of Evidence)
1.1.2. Coagulopathy (platelet count < 50,000/µL, INR > 1.5, or PTT > 2 times the control value
while not on exogenous anticoagulation)2,7,30 (UW Health Strong Recommendation, High
Quality of Evidence)
1.1.3. Acute traumatic brain injury (with Glasgow coma score ≤10 or inability to obey simple
commands)2,30 (UW Health Strong Recommendation, Moderate Quality of Evidence)
1.1.4. Acute spinal cord injury 2,31 (UW Health Strong Recommendation, Low Quality of
Evidence)
1.1.5. Major thermal injury (≥20% of total body surface area)2,30,32 (UW Health Strong
Recommendation, Moderate Quality of Evidence)

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1.2. SUP may be considered in the following situations:
1.2.1. History of GI ulceration or bleeding within 12 months before admission to the ICU2 (UW
Health Weak/Conditional Recommendation, Very Low Quality of Evidence)
1.2.2. Partial hepatectomy in the ICU2,31,32 (UW Health Weak/Conditional Recommendation,
Low Quality of Evidence)

1.3. Discontinuation of SUP may be considered in patients tolerating enteral nutrition despite the
persistent presence of indications for SUP prophylaxis6,16 (UW Health Weak/Conditional
Recommendation, Low Quality of Evidence)

Table 1. Adult indications for stress ulcer prophylaxis in the ICU
Recommended prophylaxis Consider prophylaxis
ξ Mechanical ventilation for more than 48
hours
ξ Coagulopathy while not on exogenous
anticoagulation
o platelets < 50,000/µL
o INR > 1.5
o PTT > 2 times the control value
ξ Acute traumatic brain injury with Glasgow
coma score ≤10 or inability to obey simple
commands
ξ Acute spinal cord injury
ξ Major thermal injury (≥20% of total body
surface area)
ξ History of GI ulceration or bleeding within
12 months before admission
ξ Partial hepatectomy in the ICU


2. Inappropriate indications for the use of pharmacologic stress ulcer prophylaxis in adults
2.1. Continuation of SUP beyond when indications no longer exist2,9 (UW Health Strong
Recommendation, Low Quality of Evidence)
2.2. Therapeutic anticoagulant therapy without additional risk factors9 (UW Health Strong
Recommendation, Moderate Quality of Evidence)
2.3. Short-term high dose corticosteroid therapy without additional risk factors33 (UW Health Strong
Recommendation, Moderate Quality of Evidence)
2.4. During the temporary period when patients are NPO after surgery or procedures with no
additional risk factors (UW Health Strong Recommendation, Low Quality of Evidence)

3. Selection of agent for SUP
3.1. Both proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs) are considered
appropriate for stress ulcer prophylaxis in adults. There is conflicting evidence in the literature
with regards to which agent is superior.5,10,21-23 Limited data exists about the incidence of hospital
acquired infections associated with these agents.22,23,26-29 (UW Health Weak/Conditional
Recommendation, Moderate Quality of Evidence
3.1.1. Stress ulcer prophylaxis with an H2RA may be considered as preferred over prophylaxis
with a PPI due to the concern for hospital acquired infections. (UW Health
Weak/Conditional Recommendation, Very Low Quality of Evidence)
3.1.2. See Table 2 for dosing recommendations. (UW Health Strong Recommendation, Low
Quality of Evidence)
3.2. Sucralfate is an alternative agent for adults unable to tolerate H2RAs (UW Health Strong
Recommendation, High Quality of Evidence) or PPIs24,25 (UW Health Strong
Recommendation, Low Quality of Evidence)
3.3. Sucralfate may bind several drugs (e.g., digoxin, warfarin, phenytoin, quinolones, etc.) if
administered concomitantly. Sucralfate should be administered one hour before or two hours
after such interacting medications. Sucralfate must be administered into the stomach to be
effective as a protective agent. Administration through a post-pyloric or jejunal feeding tube is of
no benefit.
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3.4. An enteral route is preferred for both PPIs and H2RAs when feasible. (UW Health Strong
Recommendation, Low Quality of Evidence)
Recommendations – Pediatric ICU Patients
4. Appropriate indications for the use of pharmacologic stress ulcer prophylaxis in pediatric patients
4.1. SUP is recommended in patients with at least two of the following risk factors (UW Health
Strong Recommendation, Moderate Quality of Evidence):
4.1.1. Mechanical ventilation > 48 hours34
4.1.2. Organ failure34:
4.1.2.1. Respiratory failure (peak inspiratory pressure > 25 cm H2O).
4.1.2.1.1. There is no data for or against use of SUP in non-invasive positive
pressure ventilation (NIPPV); however, it would be reasonable to use the same
guideline regarding peak inspiratory pressures in intubated patients (UW Health
Strong Recommendation, Low Quality of Evidence)
4.1.2.2. Renal failure (serum creatinine ≥2 times the upper limit of normal for age, or two-fold
increase in baseline serum creatinine)
4.1.2.3. Neurologic failure (Glasgow coma score ≤11, or acute mental status change with a
decrease in Glasgow coma score ≥3 from baseline)
4.1.2.4. Hepatic failure (total bilirubin ≥4 mg/dL or serum alanine transaminase ≥2 times the
upper limit of normal for age)
4.1.3. Coagulopathy (platelet count <100,000/µL or PT, aPTT, or thrombin time >20% of control
value)2,17,34-36
4.1.4. Pediatric Risk of Mortality Score37 ≥102,17,34,35
4.1.5. Shock (hypotensive for age and poor peripheral perfusion or acidosis)18,38
4.1.6. Surgery time ≥3 hours18,38
4.1.7. Multi-trauma (trauma to at least two systems)18,38
4.1.8. Pneumonia18,35
4.1.9. SUP is recommended in patients with thermal injury (≥20% total body surface area)2,39 (UW
Health Weak/Conditional Recommendation, Very Low Quality of Evidence)

5. Inappropriate indications for the use of pharmacologic stress ulcer prophylaxis in pediatric patients
5.1. Continuation of SUP in patients when risk factors are no longer present 2 (UW Health Strong
Recommendation, Low Quality of Evidence)
5.2. There is no evidence of benefit for the use of SUP for pediatric patients on short-term high dose
corticosteroid therapy for acute respiratory illness without additional risk factors (UW Health
Strong Recommendation, Low Quality of Evidence).

6. PPIs and H2RAs are considered appropriate for stress ulcer prophylaxis in children.2,18 See Table 2
for dosing recommendations. (UW Health Weak/Conditional Recommendation, Moderate Quality
of Evidence)
6.1. H2RAs may be considered as preferred over PPIs for stress ulcer prophylaxis in children with
thermal injuries (UW Health Weak/Conditional Recommendation, Very Low Quality of
Evidence)

7. Sucralfate is not recommended for pediatric patients.18-20 (UW Health Strong Recommendation,
Moderate Quality of Evidence)
Recommendations – Neonatal ICU Patients
8. Appropriate indications for the use of pharmacologic stress ulcer prophylaxis in neonates
8.1. Very little evidence is available for stress ulcer prophylaxis in neonates. One small, randomized
controlled trial found mechanical ventilation as a significant risk factor for upper gastrointestinal
bleeding. This study also noted abnormal mode of delivery or hypotension may increase risk of
stress induced lesions. However, the study noted the majority of lesions noted were not
clinically significant40
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8.2. There is a lack of evidence to support use of SUP in neonates (UW Health Strong
Recommendation, Low Quality of Evidence)

9. Inappropriate indications for the use of pharmacologic stress ulcer prophylaxis
9.1. Continuation of SUP beyond when high-risk situations no longer exist2 (UW Health Strong
Recommendation, Low Quality of Evidence)
9.2. When the risk of SUP outweighs the benefit based on clinical judgment (UW Health Strong
Recommendation, Low Quality of Evidence)
9.2.1. Potential risks of SUP in neonates:41
9.2.1.1. Hypergastrinemia
9.2.1.2. Enterochromaffin-like cell hyperplasia
9.2.1.3. Carcinoid formation
9.2.1.4. Vitamin B12 deficiency
9.2.1.5. Hypomagnesemia
9.2.1.6. Necrotizing enterocolitis
9.2.1.7. Osteoporosis
9.2.1.8. Atrophic gastritis
9.2.1.9. Infection

10. If SUP is chosen, H2RAs may be considered as PPIs have not been approved for use in infants
younger than 1 year of age.3,42 (UW Health Weak/Conditional Recommendation, Low Quality of
Evidence)

11. The use of sucralfate in neonates is not recommended and may be harmful due to the risk of bezoar
formation, particularly in neonates with gastrointestinal motility disorders, and aluminum toxicity in
neonates with renal impairment.2 (UW Health Strong Recommendation, Low Quality of
Evidence)


Table 2: Dosing recommendations for stress ulcer prophylaxis2
(UW Health Strong Recommendation, Low Quality of Evidence)
Adult Dosing
Medication Pantoprazole42 *Famotidine42 Sucralfate42
Parenteral Dose 40 mg IV once daily 20 mg IV every 12
hours
N/A
Enteral Dose 40 mg PO/NG once
daily
20 mg PO/NG twice
daily
1 g PO/NG four times
daily
Pediatric Dosing
Medication Pantoprazole43 *Famotidine2,43 Sucralfate2
Parenteral Dose

Do not exceed adult
doses listed above

1 mg/kg IV once daily 0.25 mg/kg/dose IV
every 12 hours
N/A
Enteral Dose

Do not exceed adult
doses listed above
1 mg/kg PO/NG once
daily
0.5 mg/kg/dose PO/NG
twice daily
Avoid use
Neonatal Dosing
Medication Pantoprazole43 *Famotidine2,43 Sucralfate2
Parenteral Dose

Do not exceed adult
doses listed above
0.5-1 mg/kg IV once
daily
0.5 mg/kg/dose IV per
day
N/A
Enteral Dose 0.5-1 mg/kg PO/NG 0.5 mg/kg/dose PO/NG Avoid use
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12

Do not exceed adult
doses listed above
once daily per day

*Refer to the UWHC Renal Dosing Guideline for famotidine dose recommendations in renal impairment
Recommendations – Adult, Pediatric, and Neonatal ICU Patients
12. Duration of Prophylaxis
12.1. Patients should be evaluated for the need of SUP:2,9,30 (UW Health Strong Recommendation,
Low Quality of Evidence)
12.1.1. On a daily basis
12.1.2. Upon transfer to a different level of care
12.1.3. Upon discharge from the hospital
12.1.4. When tolerating enteral feeding6,16
12.2. Stress ulcer prophylaxis may be discontinued once the original stressors are removed.2,9,30
Continuation of therapy after stress factors are eliminated exposes the patient to unnecessary
risks and increases the cost of therapy. (UW Health Strong Recommendation, Low Quality
of Evidence)
12.2.1. In adult patients with acute traumatic brain injury, discontinuation of SUP may be
considered at 2 weeks following the injury. A longer course of SUP therapy may be
indicated based on individual patient factors such as the presence of sympathetic storming
or neurological compromise. (UW Health Weak/Conditional Recommendation, Very Low
Quality of Evidence)
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13
UW Health Implementation
Potential Benefits:
Implementation of recommendations within this guideline provides a consistent approach to minimizing
the incidence of stress ulcer bleeding while avoiding adverse drug events from inappropriate use.

Potential Harms:
Patients receiving a medication for stress ulcer prophylaxis may be at higher risk of adverse drug events
such as pneumonia and Clostridium difficile infection. See section 9.2.1 for additional risks in neonatal
populations.

Qualifying Statements
There is currently a paucity of literature on many of the clinical indications for stress ulcer prophylaxis,
particularly in pediatric and neonatal populations, and several of the indications have been specifically
excluded from trials due to a presumed high risk of stress ulcer bleeding.

There are several studies and meta-analyses on the individual medications used for stress ulcer
prophylaxis, however the data from this literature is conflicting regarding the superiority of one agent over
another. Studies of the individual medications in pediatric and neonatal populations are particularly
limited.

As new data becomes available, recommendations may change.

Implementation Plan/Tools
1. Guideline will be housed on U-Connect in a dedicated folder for CPGs.
2. Release of the guideline will be advertised in the Physician/APP briefing newsletter.
3. Content and hyperlinks within clinical tools, documents, or Health Link related to the guideline
recommendation will be reviewed for consistency and modified as appropriate.

Disclaimer
CPGs are described to assist clinicians by providing a framework for the evaluation and treatment of
patients. This Clinical Practice Guideline outlines the preferred approach for most patients. It is not
intended to replace a clinician’s judgment or to establish a protocol for all patients. It is understood that
some patients will not fit the clinical condition contemplated by a guideline and that a guideline will rarely
establish the only appropriate approach to a problem.




















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14
Appendix A. Evidence Grading Scheme(s)

Figure 1. GRADE Methodology adapted by UW Health



GRADE Ranking of Evidence
High We are confident that the effect in the study reflects the actual effect.
Moderate We are quite confident that the effect in the study is close to the true effect, but it
is also possible it is substantially different.
Low The true effect may differ significantly from the estimate.
Very Low The true effect is likely to be substantially different from the estimated effect.

GRADE Ratings for Recommendations for or Against Practice
Strong The net benefit of the treatment is clear, patient values and circumstances
are unlikely to affect the decision.
Weak/conditional
Recommendation may be conditional upon patient values and
preferences, the resources available, or the setting in which the
intervention will be implemented.








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15
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