Proton pump inhibitors (PPIs) are more effective than H2 receptor antagonists (H2RAs) for preventing stress-related mucosal damage (SRMD) bleeding in critically ill patients. A meta-analysis of 13 studies found PPIs significantly reduced clinically significant upper GI bleeding compared to H2RAs, with an odds ratio of 0.39. PPIs did not increase the risk of nosocomial pneumonia or decrease mortality compared to H2RAs. While PPIs were better at preventing bleeding, they did not reduce the length of ICU stays compared to H2RAs. PPIs are the recommended option over H2RAs for SRMD bleeding prophylaxis in

1. Proton Pump Inhibitors
vs
H2 Receptor Antagonists
for Stress-Related Mucosal Bleeding
Prophylaxis in Critically ill patients

2. Problem of SRMB
In the intensive care admissions
Occult bleed- 15-50%
Overt bleed- 5-25%
Clinically significant UGIB- 1- 2.5%
Endoscopic evidence – 74- 100%
Morbidity increases – 4 times

3. Risk factors for SRMB
• Respiratory failure requiring mechanical ventilation for more than 48 hr
• Acute renal insufficiency
• Acute hepatic failure
• Severe head or spinal cord injury
• Burns involving more than 35% of the body surface area
• Major surgery (lasting more than 4 h)
• Anticoagulation
• Coagulopathy (INR > 1.5, aPTT > 2 or platelet count > 50 000 mm3)*
• Sepsis syndrome
• Hypotension
• Administration of high-dose corticosteroids (250 mg/d of steroids or
equivalent hydrocortisone)
• Enteral feedings

5. Due to this multifactorial etiology, the SRMD
lesions and their bleeding prevention,are
thought to be less critically dependent on
profound acid suppression than in the setting of
rebleeding prevention of peptic ulcers.
Hence the target pH in the prevention of SRMD
bleeding is a more modest intragastric pH of 4
(rather than the postulated 6 – 6.5 for
prevention of ulcer rebleeding and clot
stabilization in PUD)

6. What are the prevention options?
Sucralfate Enteral Feeding
H2RA and
PPI
Sucralfate-
(1) forms a protective barrier on the surface of
gastric mucosa;
(2) stimulates mucus and bicarbonate secretion;
(3) stimulates epidermal growth factor and renewal;
(4) improves mucosal blood flow and enhances
prostaglandin release

7. Though they have advantage of lesser risk of
nosocomial pneumonia due to absence of
gm –ve gastric colonisation as it does not alter
gastric pH,
Issues associated with their use like-
1) Clogging of NG tubes and bezoar formation
2) Constipation
3) Reports of aluminium toxicity
4) Effect on absorption of other oral drugs
have eventually led to their disuse

8. H2RA – most widely used as prophylaxis
(Year 2006 national survey of 2000 intensivists,
H2RAs were chosen 64% time, followed by PPIs
23.1%.)
-Lam NP et al Crit Care Med. 2006
(cimetidine,ranitidine, famotidine, and nizatidine)
They cause modest acid supression , are an
effective option in SRMB prevention and rebleed
prophylaxis.

9. But H2RA are not found to be effective in PUD
rebleeding prophylaxis.
Additionally problems like-
1) Early tolerance(72 hrs)
2) Drug interaction with use of cimetidine
have allowed PPIs to get past them in recent years
PPIs - Cause most potent acid supression
(lansoprazole,omeprazole, esomeprazole,
pantoprazole,rabeprazole)
They have an advantage of being useful in both settings
of SRMB prophylaxis and PUD ulcer rebleeding
prophylaxis.

10. But increased risk of
1) Nosocomial pneumonia
2) Clostridial difficile enterocolitis
3) Rebound hyperacidity after discontinuation
is a matter of concern in critical care setting.
Thus the superiority of PPI vs H2RA in SRMB
prevention prophylaxis is a matter of debate with
only few head to head trials or meta- analysis
available comparing them.

11. PPI vs. H2RA for
Stress-Related Mucosal
Bleeding Prophylaxis in
Critically ill Patients:
A Meta-Analysis
31st Jan 2012
Alan N. Barkun. MD, Marc Bardou. MD,
Myriam Martel , BSc, C.Q.D. Pham , PharmD

12. Methodology
Search strategy- Tailored literature searches from year
1980 to 2011 were conducted using OVID MEDLINE,
EMBASE, CENTRAL & ISI Web of knowledge 5.3.
Validity assessment
The eligibility and quality of the studies were assessed
independently by two investigators
(M.B. and C.Q.D.P.).
An independent third investigator A.N.B. arbitrated
disagreements
Conflict of interest- A. N Barkun is a consultant for
AstraZeneca and Takeda Canada.

13. Inclusion criteria – RCTs of patients at risk for
bleeding in an ICU setting comparing PPIs
to H2RA were included.
Exclusion criteria – RCTs involving
- pediatric population ,
- comparing only different dosing regimens of the
same molecule and
- whose only outcomes were gastric pH
measurements were excluded.

14. Choice of outcomes
Primary outcome-
the rate of clinically significant upper gastro-
intestinal bleeding (UGIB)
Secondary outcome-
1) the occurrence of nosocomial pneumonia,
2) all-cause mortality, and
3) number of days in ICU.

15. Clinically significant UGIB
Overt bleeding (ie, hematemesis, gross blood or “coffee
grounds” material in NG aspirate, hematochezia,or melena)
complicated by one of the following within 24 hours after the
onset of bleeding:
1) Fall of > 20 mm Hg in systolic blood pressure;
2) Rise of > 20 beats per minute in the heart rate,
3) Fall of >10 mm Hg in the systolic blood pressure
measured on sitting up from supine position
4) Fall of more than 2 g/dL in the hemoglobin level and
subsequent blood transfusion, after which the
hemoglobin level did not increase by a value defined as
the number of units of blood transfused minus 2 g/dl
- Cook. MD et al N Engl J Med. 1994;330:

16. Statistical methods
For each outcome , effect size was calculated as
Odds ratio (OR) for the proportions
Weighted mean differences (WMD) for continuous
variables.
All statistical analyses were done using RevMan
Version 5.0.18 and R version 2.4.0 (R Foundation for
Statistical Computing,Vienna, Austria, 2008).

17. Included studies
From a total of 489 citations identified assessing
the outcome of upper GI bleed (1993-2010)-
only 13 studies
( 8 fully published articles + 5 abstracts )
involving 1,587 patients met the inclusion
criteria and hence included in meta- analysis

18. Primary outcome analysis
• With UGIB regardless of the definition for
the primary outcome analysis (significant +
non significant bleed)
A - 13
(n = 1587)
• Applying the definition of clinically
significant UGIB.
B - 6
(n= 951)
• Definition of clinically significant UGIB not
adhered with.
C - 7
(n=636)

19. (Treated- PPI, Controls – H2RA)
• OR = 0.30; 95% CI: 0.17– 0.54A
• OR = 0.39; 95 % CI: 0.19 – 0.77B
• OR = 0.17; 95 % CI: 0.06 – 0.52C

21. Inference
Prophylactic PPI administration significantly
decreased the incidence of
1) UGI bleeding overall
2) Clinically significant UGIB
3) Clinically non significant UGIB
as compared to H2RA

22. Secondary outcomes
A) Nosocomial pneumonia -
Nosocomial pneumonia was assessed in seven
studies ( n = 1,017 patients)
No significant associations were noted when
comparing its occurrence in PPI vs. H2RA-treated
patients
OR = 1.05; 95 % CI: 0.69 – 1.62

24. B) Mortality -
All-cause mortality was studied in eight trials
( n=1,260 )
No statistical differences were noted in mortality
OR = 1.19; 95% CI: 0.84 – 1.68

26. C) Days in ICU -
The total mean ICU stay in days was noted in
three studies (n= 339 )
This outcome was not significantly reduced
with the use of PPIs as compared to H2RAs
WMD = − 0.12 days; 95 % CI − 1.90 to 1.66

28. Rationalisation of the outcomes by authors
A) PPIs are superior to H2RA in reducing SRMD
related UGIB –
- PPI lead to more profound acid suppression and
since many SRMD lesions have been recently
found to be quite acid sensitive.
- PPI lead to pH dependent clot stabilisation and
reduce risk of rebleeding
- PPI exhibit some anti- inflammatory effect

29. B) PPIs do not appear to enhance the risk of
nosocomial pneumonia
Comparison was done with H2RA which itself
can increase the risk of nosocomial pneumonia
C) PPI do not reduce the mortality significantly
since very few patients actually die directly from
acute hemorrhagic complications but rather
from their underlying illnesses

30. D) PPI does not shorten ICU stay significantly
Again this outcome is dependent on multiple
variables and not only on SRMD related bleeding

31. Limitations of the metaanalysis
1) Impact on incidence of clostridium difficile
enterocolitis unadressed
2) Definition of clinically significant UGIB not
applicable in all studies included.
3) 2 trials were based on Asian populations whose
slow metabolisers trait if considered, may affect
the results. Author are not sure of significance of
this confounding factor.

32. Take home message
a) Use of PPI to prevent SRMD-related bleeding
is superior to prophylaxis with H2RA.
b) There is no increased risk of nosocomial
pneumonia with PPI.
c) PPIs don’t decrease overall mortality
d) Nor do they reduce the duration of ICU stay.
e) Don’t forget to discontinue prophylaxis when
patients begin an oral diet or are transferred
from the ICU (INR 60 / day)