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REVIEW

CURRENT
OPINION Prevention of gastrointestinal bleeding in critically
ill patients
Hasan M. Al-Dorzi and Yaseen M. Arabi

Purpose of review
This review focuses on the current literature on the epidemiology and prevention of stress-induced clinically
important gastrointestinal bleeding in ICU patients.
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Recent findings
The incidence of stress-induced clinically important gastrointestinal bleeding in critically ill patients seems to
be decreasing. Observational studies and an exploratory randomized controlled trial suggest that early
enteral nutrition may be effective in preventing gastrointestinal bleeding in patients who are not at high
risk. Recent systemic reviews and meta-analyses indicate that proton pump inhibitors and H2 receptor
antagonists are more effective than placebo in preventing clinically important gastrointestinal bleeding,
especially in high-risk and very high-risk patients, but do not reduce mortality. Although observational data
suggested an association of proton pump inhibitors and H2 receptor antagonists with Clostridium difficile
infection and pneumonia, this association was not confirmed in randomized controlled trials.
Summary
The incidence of stress-induced clinically important gastrointestinal bleeding in critically ill patients seems to
have decreased over time. Even though stress ulcer prophylaxis in critically ill patients has been a research
focus for decades, many questions remain unanswered, such as which groups of patients are likely to
benefit and what pharmacologic agent is associated with the best benefit-to-harm ratio.
Keywords
enteral nutrition, gastrointestinal bleeding, histamine 2 receptor antagonists, intensive care, proton pump
inhibitor, stress ulcer prophylaxis

INTRODUCTION as the presence of overt gastrointestinal bleeding

Critically ill patients are at risk for developing stress-
induced gastrointestinal bleeding. Reduced blood
flow, ischemia, and reperfusion injury of the
mucosa might contribute to the development of
esophageal, gastric, and duodenal erosions and
ulcers. Several studies have demonstrated that
stress-induced gastrointestinal bleeding in critically
ill patients is associated with increased morbidity
with one of the following four features in the
absence of other causes: a spontaneous drop of
systolic blood pressure or diastolic blood pressure
at least 20 mmHg within 24 h of overt gastrointesti-
nal bleeding, an orthostatic increase in pulse rate of
20 beats/minute and a decrease in SBP of at least
10 mmHg, a decrease in hemoglobin of at least 2 g/dl
in 24 h, and transfusion of at least 2 units of packed
&

and mortality. In this review, we summarize the
recent literature mostly published in the last
18 months (2019–2020) on stress-induced gastroin-
testinal bleeding and its prevention in critically
ill patients.
DEFINITIONS
Overt gastrointestinal bleeding is defined as having
any of the following: hematemesis, gross blood or
‘coffee ground’ material in a nasogastric aspirate,
&
hematochezia, or melena [1 ]. Clinically important
upper gastrointestinal bleeding is generally defined
red blood cells within 24 h of bleeding [1 ].
College of Medicine, King Saud Bin Abdulaziz University for Health
Sciences, King Abdullah International Medical Research Center, and
Intensive Care Department, King Abdulaziz Medical City, Riyadh, Saudi
Arabia
Correspondence to Yaseen M. Arabi, MD, FCCP, FCCM, College of
Medicine, King Saud Bin Abdulaziz University for Health Sciences, King
Abdullah International Medical Research Center, and Intensive Care
Department, King Abdulaziz Medical City, ICU2, Mail Code 1425, PO
Box 22490, Riyadh 11426, Saudi Arabia. Tel: +966 118011111 x18855
; e-mail: arabi@ngha.med.sa
Curr Opin Crit Care 2021, 26:000–000
DOI:10.1097/MCC.0000000000000803

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MCC 270207
Gastrointestinal system
KEY POINTS
 Although the rate of clinically important gastrointestinal
bleeding has decreased in critically ill patients, there is
still a need for risk assessment to determine who would
benefit from stress ulcer prophylaxis.
 Early enteral nutrition with no pharmacologic stress
ulcer prophylaxis may be enough to prevent
gastrointestinal bleeding in low-risk and moderate-risk
critically ill patients.
 The recent evidence indicates that proton pump
inhibitors and H2 receptor antagonists are more
effective than placebo in preventing gastrointestinal
bleeding, especially in high and very high-risk patients;
however, they may increase the risk of pneumonia.
 Additional trials are needed to determine which agent
for stress ulcer prophylaxis has the best benefit-to-
harm ratio.
EPIDEMIOLOGY OF GASTROINTESTINAL
BLEEDING IN CRITICALLY ILL PATIENTS
Stress ulcers in critically ill patients have been rec-
ognized for decades. Recent studies have shown
different rates of gastrointestinal bleeding in criti-
cally ill patients, likely because of differences in ICU
population and gastrointestinal bleeding definition.
Using the Nationwide Inpatient Sample database,
the incidence of gastrointestinal bleeding was 5.4%
among 119 684 patients with septic shock in the
United States, with stable incidence over 10 years
(2003–2012) [2]. A meta-analysis of 35 studies
(16 659 ICU patients treated with corticosteroids
versus placebo) found that overt gastrointestinal
bleeding occurred in 2.1% [3]. A multicenter retro-
spective cohort study using the Philips eICU
Research Institute data repository [70 093 ICU
patients in the United States with at least one risk
factor for gastrointestinal bleeding and receiving
either proton pump inhibitors (PPIs) or H2 receptor
antagonists (H2RAs)], clinically significant gastroin-
testinal bleeding occurred in 0.6% [4]. Another
multicenter, retrospective study of 1416 neurocrit-
ical care patients in China demonstrated that the
overall incidence rate of stress-induced upper gas-
trointestinal bleeding within 14 days from cerebral
lesion onset was 12.9% [95% confidence interval
(CI) 11.2–14.7%] [5]. The rate of clinically impor-
tant gastrointestinal bleeding was low (0.76%) [5].
RISK FACTORS FOR GASTROINTESTINAL
BLEEDING IN CRITICALLY ILL PATIENTS
Gastrointestinal bleeding risk factors have been
evaluated by several studies. A systemic review of
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four studies (74 456 patients) found that acute kid-
ney injury (relative effect 2.38; 95% CI 1.07–5.28)
and male gender (relative effect 1.24; 95% CI 1.03–
1.50) were associated with clinically important gas-
&
trointestinal bleeding [1 ]. After excluding the study
that had high-bias risk, coagulopathy (relative effect
4.76; 95% CI 2.62–8.63), shock (relative effect 2.60;
95% CI 1.25–5.42), and chronic liver disease (rela-
tive effect 7.64; 95% CI 3.32–17.58) were associated
with clinically important gastrointestinal bleeding
&
[1 ]. The association between mechanical ventila-
tion and clinically important gastrointestinal bleed-
ing was uncertain (relative effect 1.93, 95% CI 0.57–
&
6.50, very low certainty) [1 ]. A systematic review
and meta-analysis (35 studies, 16 659 patients) to
compare the rate of overt gastrointestinal bleeding
in critically ill patients receiving corticosteroids
versus placebo found that corticosteroid therapy
was not associated with overt gastrointestinal bleed-
ing (risk ratio 1.08; 95% CI 0.88–1.33; P ¼ 0.46;
I2 ¼ 0%) [3]. One observational study evaluated 40
consecutive ICU patients receiving epinephrine
infusion in whom a stress ulcer was later diagnosed
by an upper gastrointestinal endoscopy performed
within 24 h of clinically important gastrointestinal
bleeding [6]. The study found that the doses of
epinephrine (odds ratio for a log10 increase of epi-
nephrine dose 0.22; 95% CI 0.12–0.38) and enteral
nutrition (odds ratio for a log10 increase of kcal/day
0.55; 95% CI 0.41–0.72) had a significant protective
effect on the occurrence of stress ulcer [6]. Renal
replacement therapy increased the risk of stress ulcer
in the model [6]. This study suggested that improve-
ment in the overall hemodynamic status could
counterbalance the potential harmful effects of epi-
nephrine infusion on the splanchnic circulation in
patients with shock.
PREVENTION OF GASTROINTESTINAL
BLEEDING IN CRITICALLY ILL PATIENTS
Enteral nutrition
Earlier studies about gastrointestinal bleeding and
stress ulcer prophylaxis (SUP) were performed in the
1980s and early 1990s when delayed initiation of
enteral nutrition was a common practice. In addi-
tion, general ICU management has changed in the
last two decades. Enteral nutrition probably reduces
the risk of stress-induced gastrointestinal bleeding,
likely by maintaining the gastrointestinal barrier
function and stimulating blood flow. In a mice
model of indomethacin-induced ulcers, there was
a significant, dose-dependent decrease in the num-
ber and area of gastric lesions in mice given enteral
nutrition compared with control mice given
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MCC 270207
purified water [7]. There was no significant differ-
ence between the two groups of mice which received
different enteral formulae [7]. Using a Japanese
database (2010–2018) and propensity score match-
ing, a retrospective study of 50 663 ICU adult
patients with at least one risk factor for gastrointes-
tinal bleeding found that the mortality of the group
who received enteral nutrition with SUP
(N ¼ 46 048) was similar to that of the group who
received enteral nutrition alone (25.6 versus 25%,
&
respectively; odds ratio 1.03; 95% CI 0.94–1.14) [8 ].
Additionally, there was no difference in the need for
endoscopic hemostasis for gastrointestinal bleeding
& &
and in Clostridium difficile infection [8 ]. However,
the rate of hospital-acquired pneumonia was signif-
icantly higher in the SUP group than the control
&
group (10 versus 8.4%) [8 ]. Another retrospective,
single-center cohort study evaluated 167 patients
with risk factors for gastrointestinal bleeding and
showed no difference in gastrointestinal bleeding,
perforation, or ulceration in the 147 patients who
had SUP and enteral nutrition compared with those
who had enteral therapy only (14.3 versus 5%,
P ¼ 0.48) [9].
In a double-blind placebo-controlled random-
ized trial, 102 mechanically ventilated patients in
the medical ICU who were on early enteral nutrition
using a volume-based feeding protocol were ran-
domized to intravenous pantoprazole or placebo.
The study found no between-group difference in
the incidence of clinically significant gastrointesti-
nal bleeding (1.8 and 2.1%, respectively; P ¼ 0.99)
but this exploratory small study was not powered to
&
detect small differences [10 ].
Pharmacological stress ulcer prophylaxis
SUP (with PPIs, H2RAs, or sucralfate) is frequently
used in critically ill patients even when risk factors
for gastrointestinal bleeding are absent [11]. How-
ever, there have been multiple studies in the last two
decades that questioned the effectiveness of SUP in
preventing gastrointestinal bleeding and reducing
mortality among critically ill patients and raised
concerns about potential side effects. In the Euro-
pean, multicenter, blinded Stress Ulcer Prophylaxis
in the Intensive Care Unit (SUP-ICU) trial, 3298
critically ill patients at risk for gastrointestinal bleed-
ing were randomized to receive 40 mg of intrave-
nous pantoprazole or placebo daily during the ICU
stay and found no difference in the primary out-
come of 90-day mortality (relative risk 1.02; 95% CI
0.91–1.13; P ¼ 0.76). There was no significant dif-
ference in a composite of clinically important
gastrointestinal bleeding, pneumonia, C. difficile
infection, or myocardial ischemia (relative risk
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Prevention of gastrointestinal bleeding Al-Dorzi and Arabi
&
0.96; 95% CI 0.83–1.11) [12 ]. However, clinically
important gastrointestinal bleeding occurred less
frequently with pantoprazole (relative risk 0.58;
&
95% CI 0.40–0.86) [12 ].
A 1-year follow-up of 3261 patients enrolled in
the SUP-ICU trial demonstrated no difference in 1-
year mortality (relative risk 1.01; 95% CI 0.92–1.10)
[13]. A post hoc analysis of 1140 patients with high
disease severity (SAPS II > 53) enrolled in the SUP-
ICU trial, showed that pantoprazole was associated
with increased 90-day mortality (relative risk 1.13;
&
95% CI 1.00–1.29) [14 ], which was also demon-
strated in further post hoc analysis using Bayesian
hierarchical logistic regression models [15 ,16].
These observations are important but are limited
by methodological concerns that included missing
SAPS II data, baseline imbalances, and between-
group differences in withdrawals or lost-to-follow-
&
up [14 ].
A preplanned sub-study of the SUP-ICU trial
assessed the effect of pantoprazole versus placebo
on gastrointestinal bleeding in ICU patients receiv-
ing renal replacement therapy [17]. Clinically
important gastrointestinal bleeding occurred in
7.8% of patients receiving renal replacement ther-
apy at baseline (95% CI 4.5–11.1%) and 9.2% of
those who received renal replacement therapy at
any time in ICU (95% CI 6.8–11.6%) [17]. Panto-
prazole versus placebo did not reduce gastrointesti-
nal bleeding incidence and was not associated with
difference in 90-day mortality or infectious adverse
events in this population [17].
In a cluster crossover randomized clinical trial
(PEPTIC trial), 26 982 patients requiring invasive
mechanical ventilation within 24 h of ICU admis-
sion were randomized by site at 50 ICUs in five
countries to a PPI strategy or an H2RA strategy for
&&
SUP [18 ]. Hospital mortality was not different
between patients who were allocated to PPI and
H2RA strategy (risk ratio 1.05; 95% CI 1.00–1.10,
P ¼ 0.054) [18 ]. One limitation of the study was the
&&
considerable crossover of treatments (4.1% of
patients randomized to PPI received H2RAs and
20.1% of patients randomized to H2RA received
&&
PPIs) [18 ]. Nevertheless, these findings reiterate
the concerns of higher mortality with PPI at least
in certain groups of critically ill patients [16].
Three recent systematic reviews assessed SUP in
ICU patients. A Cochrane review of randomized
controlled trials and quasi-randomized controlled
trials in ICU patients admitted for longer than 48 h
found that any intervention (H2RAs, PPIs, antacids,
sucralfate, prostaglandin analogs, or anticholiner-
gics) compared with placebo/no prophylaxis to
reduce the risk of clinically important gastrointesti-
nal bleeding rate (risk ratio 0.47; 95% CI 0.39–0.57;
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Gastrointestinal system
moderate certainty of evidence), such that any inter-
vention reduced the gastrointestinal bleeding rate
by 10% (95% CI 12.0–7%) from 188 with placebo/no
prophylaxis to 88 per 1000 patients [19]. There was
no significant association between nosocomial
pneumonia and each of H2RAs (risk ratio 1.12;
95% CI 0.85–1.48), PPI (risk ratio 1.24; 95% CI
0.77–1.98) and sucralfate (risk ratio 1.33; 95% CI
0.86–2.04) compared with placebo/no prophylaxis
[19]. PPIs were more effective in preventing clini-
cally important upper gastrointestinal bleeding in
ICU patients compared with H2RAs (risk ratio 2.90;
95% CI 1.83–4.58; 18 studies; 1636 participants
from 13 randomized controlled trials; low certainty
of evidence) [19]. Nosocomial pneumonia incidence
was similar in the H2RAs and PPI groups (risk ratio
1.02; 95% CI 0.77–1.35; low certainty of evidence).
Another systematic review of 42 trials that random-
ized 6899 ICU patients (three had overall low risk of
bias) found that SUP did not affect all-cause mortal-
ity (relative risk 1.03; 95% CI 0.94–1.14; trial
sequential analysis-adjusted CI 0.94–1.14), but
was associated with a lower risk of any gastrointes-
tinal bleeding as compared with placebo/no prophy-
laxis (relative risk 0.60; 95% CI 0.47–0.77; trial
sequential analysis-adjusted CI 0.36–1.00) [20].
The conventional meta-analysis indicated that clin-
ically important gastrointestinal bleeding was
reduced with SUP (relative risk 0.63; 95% CI 0.48–
0.81), but the trial sequential analysis-adjusted CI
was 0.35–1.13 indicating lack of firm evidence [20].
The association between SUP and C. difficile enteri-
tis, myocardial ischemia, and health-related quality
of life were inconclusive because of sparse data [20].
A systematic review and network meta-analysis of
randomized controlled trials that compared SUP
with PPIs, H2RAs, or sucralfate versus one another
or placebo or no prophylaxis in adult critically ill
patients found 72 eligible trials (12 660 patients)
[21]. For patients at highest risk (> 8%) or high risk
(4–8%) of gastrointestinal bleeding, both PPIs and
H2RAs reduced clinically important gastrointestinal
bleeding compared with placebo or no prophylaxis
(odds ratio for PPIs, 0.61; 95% CI 0.42–0.89 and for
H2RAs, 0.46; 95% CI 0.27–0.79) [21]. Both PPIs and
H2RAs may increase the risk of pneumonia com-
pared with no prophylaxis (odds ratio for PPIs, 1.39;
95% CI 0.98–2.10, and odds ratio for H2RAs 1.26;
95% CI 0.89–1.85) [21]. There was no evidence for
any association of SUP with mortality, C. difficile
infection, length of intensive care stay, length of
hospital stay, or duration of mechanical ventilation
[21]. After the PEPTIC trial, the systemic review was
updated (literature search up to February 2020) and
included 74 trials and showed similar findings
&&
[22 ]. The systematic review found that PPIs (risk
4 www.co-criticalcare.com
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ratio 1.03; 95% credible interval 0.93–1.14) and
H2RAs (risk ratio 0.98; 95% credible interval,
0.89–1.08) probably had little or no impact on
mortality compared with no prophylaxis (moderate
certainty) and the analysis did not completely
&&
exclude an increase in mortality with PPIs [22 ].
Although both PPIs (risk ratio 0.46, credible interval,
0.29–0.66) and H2RAs (risk ratio 0.67, 95% credible
interval, 0.48–0.94) probably reduced clinically
important gastrointestinal bleeding, the magnitude
of reduction was probably greater in PPIs than
H2RAs (risk ratio for PPIs compared with H2RAs,
&&
0.69; 95% credible interval, 0.45–0.93) [22 ]. This
reduction seems to be important in higher but not
&&
lower bleeding risk patients [22 ].
Triggered by the SUP-ICU trial, an international
guideline panel that included patients, clinicians,
and methodologists produced SUP recommenda-
tions in critically ill patients using the GRADE
&
approach [23 ]. The panel issued a weak recommen-
dation for using SUP in critically ill patients at high
risk (>4%) for clinically important gastrointestinal
bleeding, and a weak recommendation for not using
SUP in critically ill patients at lower risk (4%) for
&
clinically important bleeding (Fig. 1) [23 ]. The
panel issued a weak recommendation favoring PPIs
rather than H2RAs and a strong recommendation
&
against using sucralfate (Fig. 1) [23 ].
Quality improvement projects are required to
improve SUP practices in the ICU and to prevent
gastrointestinal bleeding. A before–after study
found that adding a new H2RA medication to the
order set significantly increased the number of
patients prescribed an H2RA for SUP (0 versus
20%, P < 0.001), but with no change in the inci-
dence of gastrointestinal bleeding [24]. Another
before–after quality improvement study in five Aus-
tralian ICUs found that the proportion of hospital
survivors inappropriately continued on SUP after
ICU discharge decreased from 42.4 to 7.7% (odds
ratio 8.83; 95% CI 4.47–17.45) and the number of C.
difficile-associated disease from 10 patients to one
[25]. The extrapolated direct and indirect savings to
all Australian ICUs from the reduced prescription of
PPI were estimated at AUD$2.08 and AUD$16.59 -
million/year, respectively [25].
FUTURE STUDIES
A preplanned exploratory substudy of the SUP-ICU
trial will describe differences in therapeutic and
diagnostic procedures used in patients with clini-
cally important gastrointestinal bleeding according
to early versus late bleeding and 90-day vital status
[26]. The Re-evaluating the Inhibition of Stress Ero-
sions (REVISE) trial, an international multicenter
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Prevention of gastrointestinal bleeding Al-Dorzi and Arabi

Critically ill patients

Risk of clinically Low risk Moderate risk High risk Very high risk
important GI (1-2%) (2-4%) (4-8%) (8-10%)
None of the following risk factors: Any of the following risk Coagulopathy (Platelets Mechanical ventilation
bleeding acute liver failure; use of steroids/ factors: mechanical <50 109/L, INR >1.5); use of without enteral nutrition;
immunosuppression; use of ventilation with enteral anticoagulants; cancer chronic liver disease
anticoagulants; cancer; male nutrition; shock; sepsis; 2 of the following factors:
gender acute kidney injury; male mechanical ventilation with
gender; use of steroids enteral nutrition; shock;
sepsis; acute kidney injury

Clinically important GI bleeding rate per 1000 patients (95% CI)

PPI versus no
prophylaxis[22] 6 fewer (9 fewer to 4 fewer) 16 fewer (21 fewer to 10 fewer) 32 fewer (43 fewer to 20 fewer) 49 fewer (64 fewer to 31 fewer)
H2RAs versus placebo[22]
4 fewer (6 fewer to 1 fewer) 10 fewer (fewer 16 to 2 fewer) 20 fewer (31 fewer to 4 fewer) 30 fewer (47 fewer to 5 fewer)

PPIs versus H2RAs[22]

3 fewer (7 fewer to 0) 6 fewer (17 fewer to 1 fewer) 13 fewer (34 fewer to 2 fewer) 18 fewer (50 fewer to 3 fewer)

Suggested approach No stress ulcer prophylaxis
Early enteral nutrition
Monitor the patient for the development of
additional risk factors for GI bleeding
increasing the risk to high.
No stress ulcer prophylaxis
Early enteral nutrition
Monitor the patient for the development
of additional risk factors for GI bleeding
increasing the risk to high.
Stress ulcer prophylaxis (PPI or
H2RAs)
Early enteral nutrition
PPI is more effective than H2RAs
in preventing GI bleeding.
Stress ulcer prophylaxis (PPI or
H2RAs)
Early enteral nutrition
PPI is more effective than H2RAs
in preventing GI bleeding.

Avoid inadvertent continuation of Avoid inadvertent continuation of

stress ulcer prophylaxis beyond ICU stress ulcer prophylaxis beyond
or when the risk factors cease to ICU or when the risk factors cease
exist. to exist.

FIGURE 1. The effect of stress ulcer prophylaxis on clinically important gastrointestinal bleeding in critically ill patients
according to the current evidence and a suggested approach [22 ,23 ]. && &

study that assesses SUP using pantoprazole versus Financial support and sponsorship
placebo in mechanically ventilated patients has None.
been enrolling patients [27].
Conflicts of interest
There are no conflicts of interest.
CONCLUSION
The rate of clinically important gastrointestinal
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