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Barletta et al

7.

systematic review and meta-analysis evaluated randomized controlled trials comparing pharmacologic
SUP with placebo where at least 50% of enrolled
patients received enteral nutrition.28 Clinically important bleeding was reported in 4 trials which included
725 patients and no difference was noted with SUP
(RR [95% CI] = 0.63 [0.29-1.37]). One randomized
controlled exploratory study evaluated 102 patients
who received enteral nutrition plus pantoprazole versus enteral nutrition plus placebo.27 No difference in
the incidence of CIB was noted (1.8% vs 2.1% for the
treatment and placebo groups, respectively). In the
SUP-ICU trial, a large majority of patients were
receiving enteral nutrition. In fact, the percentage of
patients receiving enteral nutrition on days 1, 2, and 3
postenrollment was 57%, 75%, and 81%, respectively. Thus, the benefits observed were likely recognized in addition to that provided by enteral nutrition.
Further research is required to delineate the role of
enteral nutrition in preventing CIB or if SUP can
safely be discontinued when patients are tolerating
enteral feeds as tolerance may signify the reversal of
gastrointestinal ischemia.
Risk factors for CIB are poorly defined. The 2 most
commonly quoted risk factors for CIB are mechanical
ventilation exceeding 48 hours and coagulopathy.
These parameters result from a landmark study of 2252
ICU patients that evaluated risk factors after physicians
were encouraged to withhold prophylaxis unless
patients had head injury, burns >30% BSA, transplant,
or recently a peptic ulcer or gastrointestinal bleed ultimately resulting in 674 patients who received prophylaxis and 1578 who did not.16 The univariate analyses
showed that respiratory failure, coagulopathy, hypotension, sepsis, hepatic failure, renal failure, enteral nutrition,
glucocorticoid
administration,
organ
transplantation, and anticoagulant therapy were all
associated with CIB. Only mechanical ventilation and
coagulopathy were significantly associated with CIB
after multivariate regression analyses (although the
presence of hypotension resulted in a P value of .08).
The majority of patients enrolled had either the primary
diagnosis of cardiovascular disease or cardiovascular
surgery representing 54.8% of the study cohort. Few
patients had central nervous system injury (4%), sepsis
(1.6%), head injury (1.2%), or multiple trauma (0.8%).
Therefore, the results of this study must be taken into
context given the population evaluated and the exclusion of patients with potential risk factors. Moreover,
this study was conducted 25 years ago when practices
were substantially different (eg, lack of noninvasive
ventilation, lack of revascularization procedures for
coronary emergencies, etc). It is not surprising that
additional risk assessments have shown some of the
same risk factors as this landmark trial but also a variety of additional parameters that include nutritional

failure, multiple trauma, spinal cord injury, head injury,
thermal injury, acute kidney injury, need for renal
replacement therapy, liver disease, use of anticoagulants, and the number of comorbid disease states.6,29-32
When assessed as a whole, the risk factors that are frequently quoted are generally delineated into parameters
that represent mucosal ischemia (respiratory failure,
need for mechanical ventilation, multiple trauma,
shock/hypotension, nutritional failure, solid organ
transplant), increased bleeding risk (acute or chronic
kidney injury, need for renal replacement therapy, acute
or chronic liver disease, use of anticoagulants), or
heightened gastric acid production or reduced production of protective substances (spinal cord injury, head
injury or other intracranial processes, thermal injury,
history of gastrointestinal injury, use of corticosteroids). Unfortunately, all these parameters are common
across critically ill patients, so definitively delineating
risk factors to guide the selection of patients who
should receive SUP is challenging. Moreover, studies
often focus on medical or surgical patients, so applying
findings to a heterogeneous critically ill population is
problematic. A recent systematic review found acid
suppression provided significant reductions in CIB
over placebo in neurosurgical patients but not in surgery/trauma or medical ICU patients with risk factors.14
This same systematic review, however, found no benefit of SUP in studies conducted after the practice of
early goal directed therapy. This further reinforces the
concept that therapies have evolved over the past 25
years to the extent that information from the 1990s may
no longer apply. Ultimately, risk factors are numerous
and the lack of definition of risk means that most critically ill patients will receive SUP. Another concern
related to risk is the use of acid suppression prior to
admission to the ICU. These patients were excluded
from the SUP-ICU trial. Typical practice is to continue
outpatient acid suppression therapy during hospitalization irrespective of risk for CIB.

Questions the SUP-ICU Trial Does Not
Address
Although the SUP-ICU trial provides insight on numerous
dilemmas surrounding SUP, it is important to address the
issues that it does not address. First is whether these results
would also apply to H2RAs. As there was no H2RA arm in
the SUP-ICU trial, it remains unknown if their overall effect
(ie, the balance between bleeding and infectious complications) would be similar to that recognized with PPIs. H2RAs
inhibit the secretion of histamine-stimulated acid and limit
the extent of reperfusion injury by mediating inflammation
(perhaps more so than PPIs).9 Data examining CIB rates
between H2RAs and PPIs though are conflicting as a recent
network meta-analysis suggests CIB rates may be lower with
PPIs22 while observational studies report CIB rates that are
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