9/20/2012 1 Stress Ulcer Prophylaxis Rob Wills, Pharm.D., BCPS Clinical Manager of Pharmacy PGY1 Residency Program Director St. Luke’s Boise-Meridian Medical Centers Disclosure Statement • No conflict of interest Objectives • Who should be receiving stress ulcer prophylaxis in your institution? – Pathophysiology – Risk Factors • What medications are best to use to prevent stress ulcers? – The great debate: PPI’s vs. H2RA’s vs. sucralfate • What are the complications of providing stress ulcer prophylaxis? – Strategies for gaining back the control
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9/20/2012
1
Stress Ulcer Prophylaxis
Rob Wills, Pharm.D., BCPS
Clinical Manager of Pharmacy
PGY1 Residency Program Director
St. Luke’s Boise-Meridian Medical Centers
Disclosure Statement
• No conflict of interest
Objectives
• Who should be receiving stress ulcer prophylaxis in your
institution?
– Pathophysiology
– Risk Factors
• What medications are best to use to prevent stress ulcers?
– The great debate: PPI’s vs. H2RA’s vs. sucralfate
• What are the complications of providing stress ulcer prophylaxis?
– Strategies for gaining back the control
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Objectives
• Who should be receiving stress ulcer prophylaxis in your
institution?
– Pathophysiology
– Risk Factors
• What medications are best to use to prevent stress ulcers?
– The great debate: PPI’s vs. H2RA’s vs. sucralfate
• What are the complications of providing stress ulcer prophylaxis?
– Strategies for gaining back the control
The Guidelines
• Last updated 1999
• What’s missing?
• Are they still relevant?
ASHP Therapeutic Guidelines on SUP. AJHP.1999;56(4):347-379.
History
1800’s
Erosions & Gastric Ulcers have been known
to develop
1800’s
Erosions & Gastric Ulcers have been known
to develop
1970’s
Gastric Acid linked as possible cause of stress
ulcer development
1970’s
Gastric Acid linked as possible cause of stress
ulcer development
1980’s
Incidence of stress-ulcer related bleeding was
found to be decreased by increasing gastric pH
1980’s
Incidence of stress-ulcer related bleeding was
found to be decreased by increasing gastric pH
ASHP Therapeutic Guidelines on SUP. AJHP.1999;56(4):347-379.Schuster DP. Crit Care Med. 1993;21:4-6.Schuster DP, et al. Am J Med. 1984;76:623-630.Sesler JM. ACCN. 2007;18(2):119-128.
Illustration of the difference between an erosion and an ulcer. An erosion is a mucosal break that does not penetrate themuscularismucosae, whereas an ulcer does penetrate the muscularismucosae. Reprinted with permission from Weinstein.39
Figure Legend:
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Where is this occurring?
• SRMD typically occur in
the acid-producing
areas of stomach
– Upper body
– Fundus
Accessed from www.webmd.com 8-2012
Risk of Bleeding
• Table 2 from 1999
ASHP Guidelines
– Diverse endpoints
– What’s it all mean?
ASHP Therapeutic Guidelines on SUP. AJHP.1999;56(4):347-379.
Definitions
• Clinically Important
Bleeding
• Guaiac-positive stool
• Nasogastric (NG) aspirate
• Frank hematemesis or
melena without an
accompanied decrease in
hemoglobin level, BP or a
need for transfusionASHP Therapeutic Guidelines on SUP. AJHP.1999;56(4):347-379.Schuster DP. Crit Care Med. 1993;21:4-6.Schuster DP, et al. Am J Med. 1984;76:623-630.Sesler JM. ACCN. 2007;18(2):119-128.
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Classification of GI Bleeding
Outcome Measure of
GI Bleeding
Definition Incidence
Endoscopic Evidence Endoscopic evidence of gastroduodenal SRMD lesions
Present in 74 to 100% of
ICU patients
Occult Guaiac-positive stools or nasogastric aspirate
Present in 15 to 50% of ICU
patients
Overt OR
Clinically evident
Hematemesis, gross blood or coffee grounds material in nasogastric tube aspirate, hematochezia or melena
Present in less than 5 to
25% of ICU patients
Clinically Significant Gastroduondenal bleeding associated with clinically important complications- Hemodynamic compromise- Need for blood transfusion- Need for surgery
Present in less than 5% of
ICU patients
Table 1
Naylor DF. Clinical Applications of Stress Ulcer Prophylaxis. Soc of Crit Care Med. 2012 conference.Cook et al. NEJM.1994;330:377-381.
Outcome Measure of
GI Bleeding
Definition Incidence
Clinically Important Gastrointestinal bleeding with- Spontaneous decrease in systolic blood
pressure of more than 20 mmHg within 24 hours of the first GI episode
- Orthostatic increase in heart rate of 20
beats/minute and a decrease in systolic blood pressure of 10 mmHg when the patient assumes an upright position
- Decrease in hemoglobin concentration of at least 2 g/dL and transfusion of 2 units of packed red blood cells within 24 hours after
bleeding, or- Failure of the hemoglobin concentration to
increase after transfusion by at least the number of transfused units minus 2 g/dL
Present in 0.1 to 4%
of ICU patients
Table 1 cont
Naylor DF. Clinical Applications of Stress Ulcer Prophylaxis. Soc of Crit Care Med. 2012 conference.
Cook et al. NEJM.1994;330:377-381.
Epidemiology
• GI Ulceration
– 75% to 100% occur within 24 hours of ICU
admission
• Overt bleeding < 25%
• Clinically significant bleeding < 6%
– Rates are decreasing
Cook DJ, NEJM. 1994;330:377-81
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Outcomes
• Morbidity
• Increases length of ICU stay from 4 to 8 days, or even 11 days longer stay
• Mortality
– 50% - 75% of patients with clinically significant bleed
– ~ 12% directly attributable to the bleed
• Cost of bleed
– $7000 in 1999
Cook et al. NEJM.1994;330:377-381.Sesler JM. ACCN. 2007;18(2):119-128.
Proposed mechanisms for development of stressulceration. SRMD results from the complex interaction of multiplesystems. The specific relationships depicted remain somewhatspeculative. Reprinted with permission from Bresalier.44
Figure Legend:
GI Complications in Patients Receiving Mechanical Ventilation*
Proposed mechanisms for the development of GI complications during MV. MV can contribute to the pathogenesis of GI problems in much the same way as critical illness by affectingsplanchnicblood flow and leading to increased release ofproinflammatorymediators. SIRS = systemic inflammatory response syndrome; TNF-α = tumor necrosis factor-α.
Figure Legend:
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Critical Illness
Splanchnic Hypoperfusion
Reduced
HCO3 Secretion
Reduced
Mucosal Blood
Flow
Decreased
GI Motility
Acid Back
Diffusion
Decreased Cardiac
Output
Increased
Catecholamines
HypovolemiaProinflammatory
Cytokine Release
Acute Stress Ulcer
Increased
Vasoconstriction
Mutlu GM, Mutlu EA, Factor P. GI complications in patients receiving mechanical ventilation. Chest. 2001;119:1222-1241.
Risk factors for SRMD
• Respiratory failure requiring
mechanical ventilation ≥ 48 hrs
• Coagulopathy (INR > 1.5 or
platelet count < 50,000 mm3
• Acute renal insufficiency
• Acute hepatic failure
• Sepsis syndrome
• Hypotension
• Severe head or spinal cord injury
• Anticoagulation
• History of gastrointestinal
bleeding
• Low intragastric pH
• Thermal injury involving more
than 35% of the BSA
• Major surgery lasting > 4 hrs
• High dose corticosteroids
• Enteral feedings
Cook et al. NEJM.1994;330:377-381.Sesler JM. ACCN. 2007;18(2):119-128.
Ranitidine IV 50 mg Q6 to 8 hrs Reduce dose to 50 mg Q24
hr
PO 150 mg PO BID Reduce dose to 150 mg Q24
hr
Famotidine PO
NG & IV
20 mg Q12h Reduce dose to 20 mg daily
Dosing
ASHP Therapeutic Guidelines on SUP. AJHP.1999;56(4):347-379.Lexi-comp Online. Accessed 8-2012Sesler JM. ACCN. 2007;18(2):119-128.
Medication Route Dose
Proton Pump Inhibitors
Esomeprazole PO
NG & IV
40 mg daily
Lansoprazole PO
NG & IV
15 or 30 mg daily
Omeprazole PO
NG
20 to 40 mg daily
Pantoprazole PO
NG & IV
40 mg daily
Dosing
ASHP Therapeutic Guidelines on SUP. AJHP.1999;56(4):347-379.Lexi-comp Online. Accessed 8-2012Sesler JM. ACCN. 2007;18(2):119-128.
Which Agent is Better?
• H2RA’s vs. Antacids
• H2RA’s vs. Sucralfate
• H2RA’s vs. PPI’s
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Medication Mode of ActionOther Protective
Mechanisms
Comments/
Complications
AntacidsDirect neutralization of gastric acid in a dose-dependent fashion Gastric pH is kept > 3.5–4.0
Binds to bile acids (Al+3 based) Increases local PG production improved mucosal blood flow increased mucus/HCO3 production Stimulates epithelial regeneration
Increased nursing costs Hypermagnesemia (Mg+2 based) Hypophosphotemia (Al+3 based) Constipation (Al+3 based) Diarrhea (Mg+2 based) Interferes with absorption of certain drugs (eg, tetracycline, quinolones)
H2-BlockersIncrease gastric pH by blocking H2-receptors
No beneficial cytoprotective effects
Continuous provides better pH control compared to intermittent, but is not more effective as a preventive therapy Interstitial nephritis Confusion (especially elderly) Thrombocytopenia Hypotension, sinus bradycardia (rapid IV infusion) P450-mediated effects (particularly cimetidine)
Proton pump inhibitors
Inhibits parietal cell H+-K+-adenosine triphosphatase and blocks the final step of H+ ion production
No beneficial cytoprotective effects Diarrhea P450-mediated effects
Sucralfate
Aluminum sucrose sulfate Does not affect the luminal pH Acts via coating and protection of gastric mucosa
Increases local PG production Stimulates mucus/HCO3 production (independently of PG) Stimulates epidermal growth factor
Antibacterial effects Costs less than IV H2-blockers Constipation Interferes with absorption of certain drugs (eg, tetracycline, quinolones)
Prostaglandin analogsAntisecretory and cytoprotective effects on the gastric mucosa
Inhibits acid secretion at high doses Diarrhea Abdominal pain
PirenzepineAnticholinergic Inhibits acid secretion via M1 muscarinic receptors
Increases local PG production Stimulates mucus/HCO3 production Improves mucosal blood flow (2 and 3 can occur independently of PG)
Association between current use of proton pump inhibitors (PPIs) and community-acquired pneumonia, according to the timing of first PPI prescription. ORs indicates odds ratios.
Figure Legend:
Proton-Pump Inhibitor Use and the Risk for
Community-Acquired Pneumonia
Ann Intern Med. 2008;149(6):391-398.
Odds Ratios for Community-Acquired Pneumonia Associated with Exposure to Proton-Pump Inhibitors and Histamine-2–Receptor Antagonists among New Recipients of Each Drug*
Figure Legend:
Ann Intern Med. 2008;149(6):391-398.
Odds Ratios for Community-Acquired Pneumonia Associated with Proton-Pump Inhibitor Exposure with Expanded Case–Control Matching Criteria
Figure Legend:
Proton-Pump Inhibitor Use and the Risk for
Community-Acquired Pneumonia
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Risk of Community-Acquired Pneumonia and Use of Gastric Acid–Suppressive Drugs
Howell et al. Arch Intern Med. 2010;170(9):784-790.
Howell et al. Arch Intern Med. 2010;170(9):784-790.
Original Article
Host and Pathogen Factors for Clostridium difficile
Infection and Colonization
• In this prospective cohort study of patients admitted to hospitals in Quebec and Ontario, 2.8% of patients had Clostridium difficile infection and 3.0% had asymptomatic C. difficile colonization during hospitalization.
N Engl J MedVolume 365(18):1693-1703
November 3, 2011
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Loo VG et al. N Engl J Med 2011;365:1693-1703
Odds Ratios for Health Care–Associated Clostridium difficile Infection and Colonization According to Various Patient and Pathogen Characteristics.
Loo VG et al. N Engl J Med 2011;365:1693-1703
Odds Ratios for Health Care–Associated Clostridium difficile Infection among Study Patients Who Had Positive Cultures for C. difficile, According to Various Patient and Pathogen
Characteristics and Type of Analysis.
Loo VG et al. N Engl J Med 2011;365:1693-1703
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Times to Health Care–Associated Clostridium difficile Infection and Colonization during Hospitalization.
Loo VG et al. N Engl J Med 2011;365:1693-1703
Proposed Mechanism
• Higher pH allows for opportunistic infections to survive
– Gatric Acid suppression has been associated with increased
colonization even into the typically sterile upper GI tract altering GI
flora
• H2RA’s and PPI’s found to increase patient risk
– PPI’s possibly more so due to increased acid suppression
• Question about c diff?
– Transmission via acid resistant spores
– Instead the vegetative form is able to survive
Dial et al. JAMA. 2005;23:2989-2995.
Risk of Recurrent C. difficile• 1166 patients
– Metronidazole or
Vancomycin treated CDI
– 527 (45.2%) received PPI’s
– Similar antibiotic exposure
in both groups
• Results
– 42% increased risk of
recurrence
Linsky et al. Arch Intern Med. 2010;170(9):772-778.
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Proton Pump Inhibitors and Risk for Recurrent Clostridium
Recurrence-free survival in those exposed vs unexposed to proton pump inhibitors (PPIs) during treatment for incident Clostridium difficile infection. Time to recurrence started from the incident toxin finding or the start of antibiotic treatment (≤3 days after the diagnosis).
Figure Legend:
Risk of C.diff Talking Points
• H2RA are less likely to be associated with C.
difficile infection
• Recent PPI exposure may lead to an increased
risk of C. difficile infection and recurrent
infection
Naylor DF. Clinical Applications of Stress Ulcer Prophylaxis. Soc of Crit Care Med. 2012 conference.
When Do We Stop?
• Patients should be
reassessed daily
• Once the indication is
removed the med
should be discontinued
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652 ICU Admissions
652 ICU Admissions
248 patients initiated on Stress Ulcer
Prophylaxis in ICU
215/248 (84%) transferred from ICU
on SUP
24% Discharged from hospital on SUP
without appropriate indication
523 ICU Admissions
523 ICU Admissions
357 patients received SUP in ICU
316/357 (89%) were transferred out of ICU
on SUP
24% Discharged from hospital on SUP with
no indication
Sent home with souvenir?
Wohlt et al. Ann of
Pharmacotherapy.
2007;41:1611-1616.
Murphy et al.
Pharmacotherapy.
2008;28:968-766.
What can we do?
• Start with education
– Hatch et al. 2010
• Looked at educational
intervention to reduce
non-indicated prescribing
of gastric acid
suppressants for SUP
Hatch JB, et al. Ann of
Pharmacotherapy.
2010;44:1565-71.
Pharmacist Intervention
1. Dosing card with
indications
2. Pharmacist interaction
during multidisciplinary
rounds
3. Medication
reconciliation by RPh at
discharge
Hatch JB, et al. Ann of
Pharmacotherapy.
2010;44:1565-71.
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Results
356 patients included in study
356 patients included in study
158 (44%) were using acid-
suppressing meds prior to admission
Compared to 25.6% in Wohlt’s
study
308 received SUP while in ICU
308 received SUP while in ICU
11% had no identifiable indication
259 continued upon transfer out of the ICU
259 continued upon transfer out of the ICU
84 (24%) had no clear indication
Improvement of 50.7% from
previous study
After dischargeAfter discharge
197 continued acid-suppression
therapy
31 (8.7%) not having a clear
indication
64.3% reduction
Hatch JB, et al. Ann of
Pharmacotherapy.
2010;44:1565-71.
Wohlt et al. Ann of
Pharmacotherapy.
2007;41:1611-1616.
Applying this to your practice
H2RA’s are the preferred agent for initial prevention of GI hemorrhage resulting from Stress Related Mucosal Disease in patients that are at risk
PPI’s should be reserved for patients unable to tolerate H2RA’s
PPI therapy should be given enterally or via intermittent intravenous administration
Antacids and sucralfate are not recommended for prevention of SRMD
Enteral nutrition should not be used alone as prophylaxis
Naylor DF, Rebuck JA, Maclaren R, et al. Clinical Applications of Stress Ulcer Prophylaxis. 2012. SCCM Annual Conference.
Questions
• Who should be receiving stress ulcer
prophylaxis in your institution?
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Only those with clear indications
• Drug therapy is recommended for any One of the following