1. Stress Ulcer Prophylaxis “As Clear as Mud”
Keith M. Olsen, Pharm.D, FCCP, FCCM
Dean and Professor
College of Pharmacy
University of Arkansas for Medical Sciences
Little Rock, AR

2. Disclosures
I am the Vice-Chancellor for the American College of Critical Care Medicine (ACCM) and therefore have knowledge on guidelines published and not published by the Society of Critical Care Medicine
I am one of the developers of Zegerid© (omeprazole/sodium bicarbonate)
I have published research on stress-ulcer prophylaxis and acid-suppressive therapy in the intensive care unit

3. Objectives
At completion of this seminar on stress ulcer prophylaxis (SUP), the pharmacist will able to:
Identify patients likely to benefit from acid suppression.
Identify patients who may benefit from SUP.
Describe the relationship between acid suppressive drugs and adverse events.
List the consequences of inappropriate SUP.

4. ICU Indications For Acid Suppression
Upper gastrointestinal (non-variceal) bleeding
Stress related mucosal damage

5. RCT Comparison of IV Cimetidine & Omeprazole in Bleeding Peptic Ulcers
All patients had active bleeding or non bleeding visible vessel (NBVV) and received endoscopic therapy (not applied equally)
% Rebleeding
N=240
% of Time pH > 6
P=.004
84.4%
P<.001
21.7%
53.5%
5.8%
Omeprazole 80 mg IV bolus mg/h
Cimetidine 300 mg IV bolus + 50mg/h
Lin HJ, et al. Arch Int Med. 1998;158:54.

6. Rebleeding Rates With PPIs vs. H2RAs: Meta-analysis
Total 0.40 [95% CI: 0.27–0.59]
0.1
0.2 1 5 10
Favors H2RA OR
(95% CI Fixed)
Comparison of 11 clinical trials
Favors PPI
PPIs show a more consistent reduction in rebleeding rates
* Meta-analysis combines odds ratios (OR) of individual studies in global OR (Peto method)
Gisbert JP, et al. Aliment Pharmacol Ther. 2001;15:917–926.

7. JAMA Int Med 2014

9. Guidelines for Stress Ulcer Prophylaxis in Adult Critically Ill Patients
Henry Cohen, PharmD, MSc, Robert MacLaren, PharmD, MPH,
Robert G. Martindale, MD, PhD, Lena M. Napolitano, MD,
Douglas F. Naylor Jr., MD, Jill A. Rebuck, PharmD, H. David Reines, MD,
Richard H. Savel, MD, Anne S. Pohlman, RN, MSN, Joseph F. Dasta, MSc
Crit Care Med 2015; in review
H2RAs
PPIs or H2RAs

10. Pathophysiology of Stress Ulcers
Critical Illness
Hypovolemia
Increased catecholamines
Increased vasoconstriction
 Cardiac output
Proinflammatory cytokine release
Splanchnic hypoperfusion
Reduced HCO3 secretion
Reduced mucosal blood flow
Decreased GI motility
Acid back-diffusion
Acute Stress Ulcer
Adapted from Mutlu GM, et al. Chest. 2001;119:1222–1241.
Adapted from Silen W. Hosp Pract. 1980;15:93–100.

11. Stress Ulcer Prophylaxis Ideal Pharmacologic Agent
Effective
Safe
Minimal interactions
Diverse administration options
Economically justified

12. “We are what we repeatedly do
“We are what we repeatedly do. Excellence, therefore, is not an act, but a habit” Aristotle

13. Acid Suppressive Drug Use in US and Canadian Hospitals - 2013%
2003
1998
J Crit Care 2013;29:

14. Gastric Acid Suppression in the ICU%
# of Patients
Study Day
Crit Care Med 2005;33:760-5

15. Proton Pump Inhibitor Gastric Acid Suppression: Oral vs IV
Olsen KM, Devlin J Alimen Pcol Ther 2011

16. Medical ICU Case Mix Heterogeneous vs. Homogeneous
Gastric Acid
Tube Feedings
Sepsis
AKI
GI Blood
Flow
HOMOGENEOUS
Mechanical
Ventilation
Trauma
Surgery
Hypotension
Atherosclerotic
Vascular Disease
Age

17. Pathophysiology of Stress Ulcers
Critical Illness
Hypovolemia
Increased catecholamines
Increased vasoconstriction
 Cardiac output
Proinflammatory cytokine release
Splanchnic hypoperfusion
Reduced HCO3 secretion
Reduced mucosal blood flow
Decreased GI motility
Acid back-diffusion
Acute Stress Ulcer
Adapted from Mutlu GM, et al. Chest. 2001;119:1222–1241.
Adapted from Silen W. Hosp Pract. 1980;15:93–100.

18. Clinical Trials: H2RAs vs. PPIs
Conrad et al. Crit Care Med 2005
MC, R, DB, phase 3, non-inferiority trial
Adult ICU patients (n=359)
MV ≥ 48h + one additional risk factor
Omeprazole + NaHCO3 PT 40 mg q6-8h x 2 doses, then q24h (n=178)
Cimetidine 300 mg IV x 1, then 50mg/h infusion (n=181)
Non-inferiority margin < 5%
*Non-inferior; *^p<0.05; ^p>0.05
Admitted to ICU for at least 72 hours, cimetidine only SUP FDA approved at that time; no longer available.
Conrad S, et al Crit Care Med 2005;33:760-5

19. Clinical Trials: H2RAs vs. PPIs
SC, R, partial-blinding, placebo- controlled trial
Adult ICU trauma or surgery patients (n=287)
MV > 48h or with coagulopathy
Omeprazole 40 mg IV daily
Famotidine 40mg IV q12h
Sucralfate 1gm NG q6h
Placebo
Mean gastric pH ≥ 4 in all groups, including placebo
p>0.05 for all
comparisons
Admitted to ICU for at least 72 hours, cimetidine only SUP FDA approved at that time; no longer available.
Kantorova Hepatogastroenterology 2004;51:757-61

20. RCTs: PPIs vs. H2RA 14 randomized controlled trials (RCTs)
Wide differences in study design
Many non-inferiority trials
Different risk factors
Different definitions of bleeding and significant bleeding

21. Other Comparative RCTs
Author
Design
Study Population N
1o Outcome
Powell et al
Thor Surg 1993
SC, PC, OL
Post-CABG 41
Δ Gastric pH/Volume of gastric secretions
Levy et al
Dig Dis Sci 1997
SC, OL
? Mixed ICU w/ ≥1 RF 67
Clinically Important Bleeding
(Overt + ↓ Hgb w/HD instability or PRBC)
Hata, et al
Circ J 2005
CT-ICU, ASA/Warfarin
210
Hematemesis
Somberg, et al
J Trauma 2008
MC, OL
Trauma (77%)
202
% Time Gastric pH ≥ 4
Solouki, et al
Tannaffos 2009
SC, DB
? Mixed ICU, MV≥ 48h
129
Clinical Important Bleeding
(overt + HD instability or PRBC)
Liu, et al
J Neurosurg 2013
ICH s/p OR
165
Overt GI Bleed ± PRBC
DN = double blind; HD = hemodynamic; ICH = Intracerebral hemorrhage; MC = multicenter;
OL = open label; PB = partial blinding; PC = placebo controlled; RF = risk factor; SC = single center
CT = cardio thoracic surgery
Three other RCT not published in English language (total N=166)

22. Meta-Analyses Pongprasobchai et al. 2009 Lin, et al 2010
3 RCT, n=569
Clinically important bleed = OR 0.42 (0.2,0.91)
No difference in nosocomial pneumonia
Pongprasobchai et al. 2009
7 RCT (2 as abstracts only), n=936
Upper GI bleed – Risk difference (-0.09, 0.01); I2=66%
No difference in nosocomial pneumonia or ICU mortality
Lin, et al 2010
13 RCT (5 as abstracts only). N=1587
Clinically significant bleeding – OR 0.3 (0.17, 0.54); I2=0%
No difference in pneumonia, ICU length of stay, ICU mortality
Barkun, et al
J Med Assoc Thai 2009;92;632; Crit Care Med 2010;38:1197; Am J Gastroenterol 2012;107:

23. Types of studies included Randomized, Parallel Control
Crit Care Med 2013;41:693
Characteristic
Criteria
Types of studies included
Randomized, Parallel Control
Study population
Adult patients, Medical or surgical ICU
Intervention
Any PPI therapy
Control
Any H2RA therapy
Primary outcome
GI bleed (clinically important vs. overt)
Secondary outcome
Pneumonia, ICU-mortality, ICU LOS, C. difficile
Methodologic quality
Cochrane risk of bias tool
Analysis
Random effect model, a prior subgroup analysis, statistical heterogeneity with I2 statistic
14 randomized controlled trials (n=1720)

24. Clinically Important BleedingND ND
At 64% reduction one would say it is a done deal, but lets look closer. 4 studies did not have definitions and the levy study provided 19% and this study was questionable at it was the only study to show significance. 5 trials were not incuded because risk was at 0 There is a risk difference and when this is re ND ND
NNT = 78
Risk Difference (00.54, 0.001)
Test for heterogeneity: I2 = 52%
A= only available as abstract; ND = no definition provided for clinically important bleed
NNT = number needed to treat
Crit Care Med 2013;41:693

25. Influence of Risk of Bias
When you take all favor ppi but difficult to find reason however the relative risk was 0.36 with PPIs compared to H2RA; however the an a priori subgroup analysis revealed these findings were driven by trials with a high or unclear risk of bias. Limiting the analysis to to RCTs that were low risk of bias showed no significant difference
Crit Care Med 2013;41:693

26. Secondary Outcomes Analysis
Cumulative Result
(PPI vs.. H2RA)
Relative Risk (95% CI)
Nosocomial pneumonia
(8 trials, n=1100)
10.5% vs. 10.5%
1.06 ( )
ICU mortality
(8 trials, n=1196)
17.5% vs. 21.2%
1.10 (0.83 – 1.13)*
ICU length of stay
(5 trials, n=555) __
-054 (-2.20 – 1.13)
C. Difficile infection
(0 trials, n=0) NA
*Results reported as mean difference
Crit Care Med 2013;41:693

27. One More Meta-Analysis
Intensive Care Med 2014;40:11-20
20 trials included; H2RA (20 trials) and PPI (two trials)
Conventional MA revealed a reduction in bleeding with SUP
Sequential trial analysis indicated No Significance
Like all other MA, no mortality benefit

28. Raises the question, “Is acid suppression necessary in critically ill patients”?

29. Observational Studies
- 35,312 Adult patients
requiring MV > 24h
- 686 Adult patients with
severe sepsis and MV >48h
Caution with interpreting observational studies because of method flaws. But they can be used for hypothesis generating.
% GIB
JAMA Intern Med 2014;174:564, Ann Pharmacother 2014;48:1276

30. Withholding Pantoprazole for Stress Ulcer Prophylaxis in Critically Ill Patients: A Pilot Randomized Clinical Trial and Meta-Analysis
Patient Criteria
Interventions/Outcomes
> 18 years of age
Invasive MV anticipated for > 48 hours or at least 72 hours prior to randomization
No active GI bleed or increased risk of bleeding
2 antiplatelet drugs
Palliative care or decision to withdraw life support
Pregnancy
Receipt of > two DDE of prophylaxis with H2RA or PPI
Primary: withholding SUP
Randomized, blinded, placebo controlled
Clinical Outcomes
Clinically important GI bleed
Ventilator associated pneumonia (VAP)
C. difficile infection
ICU mortalitry
ICU length of stay
Hospital length of stay
Crit Care Med 2017;45:

31. Baseline Patient Characteristics
Variable
Pantoprazole, n=49
Placebo, n=42
Age
61.8 ( )
55.3 ( )
APACHE II
21 (17-26)
21.5 (14-27)
Mechanical ventilation
100%
Crit Care Med 2017;45:

32. Pantoprazole vs. Placebo in SUP Among Mechanically Ventilated Patients
Crit Care Med 2017;45:

33. Clinically Important Gastrointestinal Bleeding
Meta-Analysis
Clinically Important Gastrointestinal Bleeding
Crit Care Med 2017;45:

35. Consequences of Overuse
Clostridium difficile exists in two forms
Acid-sensitive vegetative form
Acid-resistant spore form
Vegetative form typically destroyed in acid environment
Altering gastric acidity may predispose patient to acquiring enteric infections
Over 30 trials have evaluated PPIs and C. difficile; 2 retrospective trials in the ICU; no RCTs
Over 30 papers evaluating; majority say they increase risk. None use SUP. Two retrospective trials have looked at the ICU

36. Antibiotic Exposure Within 90 Days Timing of Most Recent PPI Exposure
PPIs and Risk of Community-Acquired C. difficile–Associated Disease (CDAD)
Antibiotic Exposure Within 90 Days
Adjusted OR for CDAD
95% CI
Antibiotics
3.1
PPI
2.9
H2RA
2.0
1Association between medications and CDAD based on clinical diagnosis and/or toxin positive
Cases = 1233 vs Controls = 12,330
Timing of Most Recent PPI Exposure
Adjusted OR for CDAD
95% CI
≤ 90 days
0.9
days
0.7
days
2Association between outpatient PPI use and hospitalization for CDAD
Cases = 1389 vs Controls = 12,303
1Dial S, et al. JAMA. 2005;294:
2Lowe DO, et al. Clin Infect Dis. 2006;43:

37. C. difficile Risk in MICU
Retrospective cohort of patients admitted to medical ICU (> 24 hours)
CDAD positive definition
Diarrhea > 24 hours and
C difficile toxin A and B (ICU day 2 up to 2 months post–discharge)
Variable
Crude HR (95% CI)
Adjusted HR (95% CI)
PPI
1.02 ( )
0.90 ( )
H2RA
0.95 ( )
0.78 ( )
Clindamycin
1.95 ( )
2.06 ( )
Macrolide
2.24 (
1.85 ( )
Infect Control Hosp Epidemiol 2007;28:1305

38. C. difficile Risk & PPIs in MICU
Retrospective cohort of patients admitted to medical ICU (> 24 hours)
N=1770 total; n=134 were C. difficile +
C difficile toxin A and B (48 h after ICU admission – 30 days)
87.8% PPI use
83.6% ≥ 1 antibiotic
Variable
HR (95% CI)
PPI
1.11 ( )
Prior room occupant with C. difficile
2.35 ( )
Infect Control Hosp Epidemiol 2011;32:201

39. Odds ratio for C. difficile–associated disease
PPIs and Risk of Community-Acquired CDAD
317 cases of community-acquired C. difficile–associated disease treated with oral vancomycin and 3167 controls
Exposure within 90 days
Odds ratio for C. difficile–associated disease
95% CI
Antibiotic
8.2
6.1 – 11.0
PPI
3.5
2.3 – 5.2
Questions remain:
Epidemiologic studies have limitations
C. difficile–associated disease involves a complex interaction between host, pathogen, and environment
Dial S, et al. CMAJ. 2006;175:
Cunningham R. CMAJ. 2006;175:

40. Stress Ulcer Prophylaxis & Pneumonia: Meta-analyses of Critical Care Studies
Study
No. Trials Included
Adjusted OR (95% OR CI)
Krag (Inten Care Med 2014)
N=7 RCTs
PPI/H2RA vs PLC
1.16 ( )
Alhazzani (Crit Care Med 2013)
N=8 RCTs
PPI vs. H2RA
1.06 ( )
Barkun (Am J Gastro 2012)
1.05 ( )
Marik (Crit Care Med 2010)
H2RA vs. control
1.26 ( )
Huang (crit Care 2010)
H2RA vs. Sucralfate
1.32 ( )
Lin (Crit Care Med 2010)
N=6 RCTS
RR=0.00 ( )
Messori (BMJ 2000)
N=3 RCTs
Ranitidine vs. PLC
0.98 ( )
Cook (JAMA 1996(
H2RA vs. PLC
1.25 ( )
Cook (JAMA 1996)
N=11RCTs
0.78 ( )

41. Meta-Analysis: Pneumonia Proton Pump Inhibitors vs. Placebo
Crit Care Med 2017;45:

42. Efficacy and Safety Take Home Messages
Prevention of clinical important GI bleeds
Prevalence of CI-GIB is low
Majority of RCTs demonstrate no difference
Results of meta-analyses dependent on statistical analysis
No improvement in mortality
Treatment effect in favor of PPIs diminishes with high quality (i.e., low risk of bias) RCTs

43. Efficacy and Safety Take Home Messages
Consistent findings of no statistical difference regarding nosocomial pneumonia, ICU length of stay, and ICU mortality
Observational data suggest a relationship between PPI use and C. difficile infection
No comparative data from RCTs support C. difficile associated infection
Until then, either option can be justified for SUP, although randomized trials suggest no prophylaxis is required
However, time has come that pharmacist with physicians can start limiting SUP to only the most severely ill
In the ICU, less is often more

44. In randomized controlled trials of SUP, which of the following statements is true?
PPIs decrease mortality
H2RAs increase mortality
Neither PPIs or H2RAs decrease mortality
Both PPIs and H2RAs have no impact on mortality

45. The primary cause of stress ulcers in medical ICU patients is:
Decreased bicarbonate secretion
Splanchic hypoperfusion
Hypersecretion of acid in the stomach
Release of IL-6 into the gastric mucosa
Splanchnic

46. Which of the following statements are true regarding the impact of PPIs on C. difficile infection in the ICU?
Previous occupant of the room with C. difficile significantly increases the incidence
Antibiotics generally have a lower incidence of C. difficile compared to PPIs
PPIs have a significant impact on toxin A but not toxin B in C. difficile infection
Prior exposure to an H2RA is generally required before a PPI can induce C. difficile infection