Intensive Care Med (2023) 49:334–336
https://doi.org/10.1007/s00134-022-06959-9
LASTING LEGACY IN INTENSIVE CARE MEDICINE
Prevention of upper gastrointestinal
bleeding in critical illness
Mette Krag1,3, Waleed Alhazzani4,5 and Morten Hylander Møller2*
© 2023 Springer-Verlag GmbH Germany, part of Springer Nature
Critically ill patients in the intensive care unit (ICU)
are at risk of developing stress ulcers [1]. To prevent
stress ulcers and gastrointestinal (GI) bleeding, clini-
cians prescribe pharmacologic prophylaxis (i.e. stress
ulcer prophylaxis, SUP) to patients with risk factors [2].
Historically, antacids and later sucralfate were the pre-
ferred agents, but with histamine-2-receptor antagonists
(H2RAs) and proton pump inhibitors (PPIs), the oppor-
tunity for intravenous administration became available
and today, the vast majority of prescribed SUP is H2RA
and PPI [1].
The pathophysiology behind stress ulcers is not com-
pletely understood, but it has been hypothesised that
stress ulcerations are caused by decreased mucosal
blood flow, ischaemia and reperfusion injury [3]. Endo-
scopic studies of critically ill patients have showed
visible mucosal damage in up to 90% of patients after
three days of admission [4]. Although most erosions
are superficial and asymptomatic, in some cases, they
may cause clinically important haemorrhage or perfo-
ration [3].
Heterogeneous populations, varying definitions of
GI bleeding, and difficulties in diagnosing stress ulcers
make it difficult to estimate the prevalence, but a recent
trial randomising ICU patients at high risk of bleeding
showed an incidence of 4% in ICU patients not receiv-
ing SUP, and 2.5% in patients receiving pantoprazole [5].
*Correspondence: Mortenhylander@gmail.com
2
Department of Intensive Care, Rigshospitalet, University of Copenhagen,
Copenhagen, Denmark
Full author information is available at the end of the article
Importantly, data suggest that stress ulceration is the sole
source of GI bleeding in only 50% of the patients, sug-
gesting that sources of GI bleeding not prevented by SUP
are frequent [6].
Risk factors for upper GI bleeding
Historically, mechanical ventilation and coagulopa-
thy were widely accepted as the main risk factors for GI
bleeding in critically ill patients [7]. However, a recent
post hoc analysis of the SUP-ICU trial did not show an
association between mechanical ventilation and risk of
bleeding [8]. In this analysis, severity of illness, use of
circulatory support and renal replacement therapy were
associated with higher risk of bleeding. Furthermore, a
systematic review of 8 studies (116,497 patients) found
coagulopathy, shock and liver disease to be associated
with increased risk of GI bleeding but not mechanical
ventilation [9]. Of note, the limitations included the ret-
rospective design for some studies and heterogeneity.
Gastric protection
Historically, sucralfate was used as SUP, but nowadays
the majority of clinicians prefer using H2RA or PPI
[10]. PPIs are more frequently used than H2RAs in most
countries, with pantoprazole being most commonly
used [1].
Although some studies suggests that enteral nutrition
is associated with a lower risk of GI bleeding [6], there is
lack of high-certainty evidence. Therefore, the preventive
effect of enteral nutrition remains unclear. Despite this,
many clinicians take enteral nutrition into account when
prescribing or discontinuing SUP [10].

Clinical effectiveness of SUP
SUP versus placebo
The SUP-ICU trial assessed the desirable and undesirable
effects of pantoprazole versus placebo in 3350 acutely
admitted, adult ICU patients with risk factors for GI
bleeding [5]. In this trial, the median duration of treat-
ment was four days. The trial found a reduction in the
risk of GI bleeding in patients allocated to pantoprazole
(number needed to treat 59), but no effect on mortality
or the other secondary outcomes. An updated systematic
review of 41 clinical trials with 6790 patients [11] and
a Bayesian network meta-analysis 47 trials and 39,569
patients [12] yielded congruent results.
PPI versus H2RA
Several RCTs and systematic reviews compared PPI and
H2RA. The publication of the cluster cross-over ran-
domised registry-based PEPTIC trial (26,982 patients)
comparing PPI versus H2RA in patients with a median
time in ICU of three days, substantially improved the
precision of the results [13]. The authors reported fewer
patients with clinically important GI bleeding in patients
receiving PPIs, with no difference in mortality between
groups. The aforementioned network meta-analysis
found that H2RA reduced GI bleeding without affect-
ing mortality compared to placebo, but PPI was superior
in reducing GI bleeding compared to H2RA (number
needed to treat 130) [12].
Safety of SUP
Mortality
As previously outlined, the SUP-ICU trial and the PEP-
TIC trial found no difference in mortality when compar-
ing PPI to placebo and PPI to H2RA, respectively. Of
note, a pre-planned subgroup analysis in the SUP-ICU
trial and a post hoc subgroup analysis in the PEPTIC trial
indicated excess mortality among the most severely ill
patients allocated to PPI [5, 13]. Since the findings derive
from subgroup analyses, it could be a chance finding and
should be interpreted with caution. The ongoing REVISE
trial (NCT 03374800) will help confirm or refute these
observations.
Nosocomial pneumonia
Acid suppressants increase the gastric pH, which can
lead to bacterial overgrowth in the stomach. Hence, acid
suppressants have been linked with the development of
ventilator-associated pneumonia [3]. However, RCTs and
335
systematic reviews have not been able to confirm this [5,
11, 12].
Clostridium difficile infection
Gastric acidity may confer a protective effect against
bacteria, treatment with acid suppressants may alter the
microbiome and is hypothesised to increase the risk of
enteric infections including Clostridium difficile infec-
tion [3]. The SUP-ICU trial (PPI vs. placebo) and the
PEPTIC trial (PPI vs. H2RA) both reported data on
Clostridium difficile infection and found that Clostridium
difficile infection was very rare (< 1.5%), with no differ-
ence between the intervention groups.
Cardiovascular complications
Observational studies associated PPI with cardiovascu-
lar events in non-ICU patients [14]. Researchers hypoth-
esised that the interaction between clopidogrel and PPIs
may reduce the effectiveness of clopidogrel and increase
the risk of adverse cardiac events [14]. However, the
results of the SUP-ICU trial showed no increase in car-
diovascular events with PPI therapy [5].
SUP in the future
Pharmacological SUP has been widely and somewhat
uncritically used in critically ill patients, but research
findings from recent years may have changed this.
Results from large trials suggest that SUP reduces the
risk of GI bleeding without any definitive increase in
harm. This suggests that SUP might be better reserved
for critically ill patients at high risk of GI bleeding and
may be stopped once the risk factors are absent, includ-
ing when the clinical condition improves. On the other
hand, GI bleeding is rare, the reduction in GI bleeding
was not coupled with improvement in other patient-
important outcomes, its widespread use can be associ-
ated with resource use and costs [15], and it is unclear
if the severely ill ICU patients could be harmed by SUP
[5, 13].
Take‑home messages
Although the topic of SUP has been extensively studied,
high-quality studies may help shed light on some areas
of uncertainty including (1) identification of the target
population for SUP, (2) evaluation of the role of non-
pharmacological protection, (3) evaluation of the desir-
able and undesirable effects of pharmacological gastric
protection with H2RA vs. placebo, and (4) evaluation
336
Fig. 1 Knowledge gaps in gastric protection in critical illness
of the safety of SUP in the most severely ill patients
(Fig. 1).
Author details
1
Department of Intensive Care, Holbæk Hospital, Holbæk, Denmark. 2 Depart-
ment of Intensive Care, Rigshospitalet, University of Copenhagen, Copenha-
gen, Denmark. 3 Department of Clinical Medicine, University of Copenhagen,
Copenhagen, Denmark. 4 Department of Medicine, McMaster University,
Hamilton, ON, Canada. 5 Department of Critical Care, Prince Sultan Military
Medical City, The General Directorate of Armed Forces Health Services, Riyadh,
Saudi Arabia.
Declarations
Conflicts of interest
MHM and MK sponsored and coordinated the SUP-ICU trial (NCT02467621).
WA was the primary investigator of the REVISE Pilot trial (NCT02290327) and a
co-investigator on the REVISE Trial (NCT03374800).
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
Received: 28 October 2022 Accepted: 10 December 2022
Published: 4 January 2023
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