What SUP?.... With Stress Ulcer

Prophylaxis

Alabama Society of Health System

Pharmacists

June 5, 2020

Presented by: Charles E. DuRant, Jr., Pharm.D.

https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=2ahUKEwjX6OTOhZrmAhWkmOAKHc_RBzYQjRx6BAgBEAQ&url=%2Furl%3Fsa%3Di%26rct%3Dj%26q%3D%26esrc%3Ds%26source%3Dimages%26cd%3D%26ved%3D%26url%3Dhttp%253A%252F%252Fwww.patientcareonline.com%252Fgastrointestinal-disorders%252Fdoes-stress-cause-ulcers-round-ii%26psig%3DAOvVaw3aFObjDkzbtbbUGMD98Bqg%26ust%3D1575481722715023&psig=AOvVaw3aFObjDkzbtbbUGMD98Bqg&ust=1575481722715023https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=2ahUKEwiS9quLhZrmAhXEY98KHXKdA1IQjRx6BAgBEAQ&url=https%3A%2F%2Fcriticalcare.news%2Fstory%2Fefficacy-and-safety-of-stress-ulcer-prophylaxis-in-critically-ill-patients%2F&psig=AOvVaw3aFObjDkzbtbbUGMD98Bqg&ust=1575481722715023

Disclosure

• The author of this presentation has no financial or personal interests to disclose

Objectives

Technicians• Describe the pathophysiology of an acute stress ulcer

• Review the pharmacology of H2-antagonists, proton pump inhibitors, and sucralfate

• Discuss side-effects and concerns associated with agents for stress ulcer prophylaxis

Pharmacists• Discuss clinical indications for stress ulcer prophylaxis and review

recommended pharmacologic treatment options

• Examine the guidelines and medical evidence on stress ulcer prophylaxis

• Review when to initiate and when to discontinue stress ulcer prophylaxis

Questions to Consider

• What is the importance of Stress Ulcer Prophylaxis (SUP)?

• Are the published guidelines still relevant?

• Are PPI’s for SUP considered controversial?

• Are the risks of SUP greater than the benefits?

• In whom and when is SUP important?

• What do a couple of the more recent studies on SUP tell us?

• Is SUP being used properly in your facility?

What is a

stress

ulcer?

Image adapted from N Engl J Med 2018;378:2506-16

Pathophysiology

Critically ill patients have a compromised network of defenses

• Increase in catecholamines, vasoconstriction and systemic inflammation & decrease in cardiac output →→→ Leads to splanchnic hypoperfusion

• As blood flow is diverted to major organs ischemia, it induces reperfusion and a low gastric intramuscular pH.

• Reduce bicarbonate secretion, decreased musical blood flow and GI motility, & increased acid secretion →→→ breaks down the mucosa defense/ barrier in the gut

• Low pH and lack of muscoalbarrier →→→ stress ulcers formation

What are Stress Ulcers?

Gastric Antral Erosions Pyloric Ulcer with Adherent Clot

Self-Assessment Question #1

True or False – Stress ulcers primarily form in critically ill patients as result of an over-production of acid in the stomach?

• False – while acid production certainly contributes, a reduction in the gastric lining protective measures has more to do with the development of stress ulcers

Definitions and Incidence• Mucosal or sub-mucosal ulceration - Endoscopically documented

gastroduodenal mucuosal or submucosal erosions or ulcerations; 75-100% incidence among selected critically ill patients; generally asymptomatic

• Occult Bleeding - Gastric or fecal samples w/ guaiac-positive testing for blood; approx. 15-50% in critically ill patients

• Overt Bleeding – Hematemesis, frank blood or coffee-grounds in nasogastric aspirate, or melena – historically around 5% in critically ill patients; approximately 0.3% among general med-surg patients

• Clinically Important Bleeding – Approximately 3% in critically ill; defined as Overt bleeding in addition to one or more of the following: • Spontaneous ↓ in BP; orthostatic ↑ in Pulse, ↓ in Hgb of > 2g/dL over 24hr;

transfusion > 2 units PRBCs w/i 24hr after start of bleeding; or invasive interventions (i.e. therapeutic endoscopy or vasopressor initiation or increase)

N Engl J Med 2018;378:2506-16

Acute illness

Shock

Respiratory failure

Head trauma

Thermal injury

Drugs:

Anticoagulants

Antiplatelet agents

NSAIDs

Chronic conditions:

Coagulopathy

Renal dysfunction liver disease

Helicobacter pylori

Devices:

Mechanical ventilation

Renal-replacement therapy

extracorporeal life support

Risk for Upper Gastrointestinal

Bleeding

Pharmacotherapy for Stress Ulcer Prophylaxis

PROTON PUMP

INHIBITORS

HISTAMINE 2 RECEPTOR

ANTAGONISTS

CRYOPROTECTIVE

AGENTS

Pharmacology

• H2-Antagonists

• Ranitidine (Zantac)

• Famotidine (Pepcid)

• Cimetidine (Tagamet)

• Proton Pump Inhibitors

• Pantoprazole (Protonix)

• Omeprazole (Prilosec)

• Esomeprazole (Nexium)

• Sucralfate

Histamine 2 Receptor Antagonist

Mechanism of Action: Competitive inhibition of histamine at H2 receptors

of the gastric parietal cells, which inhibits

gastric acid secretion

Adverse Effects: Headache, dizziness,

fatigue, tolerance, CNS confusion

Medications:

Famotidine (most commonly used)

Ranitidine

Cimetidine

Nizatidine

Dosing: H2RAs

Famotidine Oral, Nasogastric tube, IV → 20 mg twice a dayContinuous infusion: 1.7mg/hr

Ranitidine Oral or Nasogastric tube → 150 mg twice a day IV → 50 mg every 6-8 hrsContinuous infusion: 6.25mg/hr

Cimetidine Oral, Nasogastric tube, IV → 300mg four times a day Continuous infusion: 50mg/hr

Nizatidine Dosing for this indication has not been established

Proton Pump Inhibitors

Mechanism of Action:

• Suppresses gastric basal and stimulated acid secretion by inhibiting the parietal cell H+/K+ ATP pump

Adverse Effects:

headaches, nausea , vomiting, diarrhea, fractures, and possible association with nosocomial infections such as pneumonia & CDI infections

Medications:Pantoprazole→Most commonly used

Omeprazole

Lansoprazole

Rabeprazole

Esomeprazole

Dexlansoprazole

Dosing: Proton Pump InhibitorsPantoprazole

• Oral or Nasogastric tube → 40 mg once daily

• IV → 40mg loading dose, followed by 20 mg once daily

Omeprazole

• Oral or Nasogastric tube → 40 mg once daily

• IV → 40mg loading dose, followed by 20 mg once daily

Lansoprazole

• Oral or Nasogastric tube → 30 mg once daily

Rabeprazole, Esomeprazole, Dexlansoprazole: Dosing for this indication has not been established

Cyprotective Agents: Sucralfate

Mucosal coating

agent

Mechanism of Action: Forms

a complex by binding with

positively charged proteins in

exudates, forming a viscous

paste-like, adhesive

substance. This selectively

forms a protective coating

that acts locally to protect the

gastric lining against peptic

acid, pepsin, and bile salts.

Adverse Effects:

constipation

Dosing:

Oral or Nasogastric tube:

1 gram four times daily

Pharmacology: SucralfateAdapted from: https://www.picmonic.com/learn/sucralfate-carafate_2084

Self-Assessment Question #2

Which of the following side effects is most commonly associatedwith sucralfate?

A. Diarrhea

B. Insomnia

C. Constipation

D. Psychosis

E. Headache

Answer: C - Constipation is the most commonly reported side effect associated with sucralfate with an incidence of around 2%

Guidelines on Stress Ulcer Prophylaxis

Guidelines published on SUP

• ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis (1998)

• EAST: Practice Management Guidelines for Stress Ulcer Prophylaxis (2008)

• DASAIM/DSIT: Guidelines for Stress Ulcer Prophylaxis in the ICU (2014)

• Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock (2016)

What was happening in 1998? The year the ASHP Guidelines were published: 1998

January 26 – President Clinton becomes embroiled in the Lewinsky scandal

March 27 – The Food and Drug Administration approves Viagra for use as a treatment for erectile dysfunction, the first pill to be approved for this condition in the United States.

June 14 – The Chicago Bulls win their 6th NBA title in 8 years when they beat the Utah Jazz, 87–86 in Game 6. This is also Michael Jordan's last game as a Bull, clinching the game in the final seconds on a fadeaway jumper.

July 24 - Saving Private Ryan premieres in movie theaters.

September 4 – Google, Inc. is founded in Menlo Park, California, by Stanford University Ph.D. candidates Larry Page and Sergey Brin.[6]

https://en.wikipedia.org/wiki/Food_and_Drug_Administrationhttps://en.wikipedia.org/wiki/Viagrahttps://en.wikipedia.org/wiki/Erectile_dysfunctionhttps://en.wikipedia.org/wiki/Chicago_Bullshttps://en.wikipedia.org/wiki/National_Basketball_Associationhttps://en.wikipedia.org/wiki/Utah_Jazzhttps://en.wikipedia.org/wiki/Michael_Jordanhttps://en.wikipedia.org/wiki/The_Shot_(1998_NBA_Finals)https://en.wikipedia.org/wiki/Saving_Private_Ryanhttps://en.wikipedia.org/wiki/Googlehttps://en.wikipedia.org/wiki/Menlo_Park,_Californiahttps://en.wikipedia.org/wiki/Stanford_Universityhttps://en.wikipedia.org/wiki/Larry_Pagehttps://en.wikipedia.org/wiki/Sergey_Brinhttps://en.wikipedia.org/wiki/1998_in_the_United_States#cite_note-6

ASHP Therapeutic Guidelines on Stress

Ulcer Prophylaxis: November 14, 1998

Major Indications:• Mechanical Ventilation >48hrs• Coagulopathy

• INR >1.5• Platelet count: < 50• PTT: > 2x baseline

Minor Indications: Any 2 of the following:• Sepsis, • ICU stay >7 days, • occult bleeding lasting >6 days, • High daily dose steroid that

exceeds: Hydrocortisone 250mg, Methylprednisolone 50mg, Prednisone 50mg, Dexamethasone 10mg

May be Considered Indications: • Glascow Coma Score 35% of total

body surface• Major trauma with an injury

severity score of >16, • Hepatic failure• Spinal cord injury• History of GI bleed or ulceration

within last year • Major surgery lasting > 4 hrs

Special Considerations: • Partial hepatectomy, • Poly-trauma w/ISS 16 , • Transplants, • Hepatic failure

EAST: Practice Management Guidelines for Stress Ulcer Prophylaxis: 2008

Indication:Level 1 Recommendation: SUP is recommended for all patients with :

• Mechanical ventilation• Coagulopathy• Traumatic brain injury• Major brain injury

Level 2 Recommendation: SUP recommended for all ICU patients with

• Multi-trauma• Sepsis• Acute renal failure

Level 3 Recommendation:

SUP recommended for all ICU patients with:

• ISS > 15 • Requirement of high dose

steroids

Duration:

Level 2: Continue until extubated or out of ICU

Level 3: Continue until tolerating enteral nutrition

Treatment:Level 1 Recommendation: No difference between H2-antagonists, cytoprotective agents, and some PPIs

Level 2 Recommendations Aluminium-containing compounds should not be used in patients on dialysis

Level 3 Recommendations: Enteral feeding alone may be insufficient for SUP

Danish Guideline for Stress Ulcer Prophylaxis in the Intensive Care Unit (January 26, 2014)

Consensus Recommendations of Danish Experts based on published literatureSUP vs. Placebo in the ICU?

• SUP vs. Placebo/No Prophylaxis - No firm evidence for benefit or harm of SUP as compared to placebo or no prophylaxis

PPI vs. H2RA?

• Suggest using PPIs when SUP is indicated in adult critically ill patients in the ICU

SUP and Enteral Nutrition?

• Insufficient evidence to make any recommendation

SUP in ICU Subpopulations: Trauma, Burn, Septic, and Cardiothoracic Patients?

• Insufficient evidence to make any recommendation

Summary:Recommend not using SUP routinely for critically ill patients in the ICU outside of the context of randomized clinical trials; however if SUP is considered clinically indicated…use a PPI.

Surviving Sepsis Campaign:

International Guidelines for

Management of Sepsis and

Septic Shock: 2016

• Sepsis/septic shock PLUS risk factors

• Strongest clinical predictors of GIB risk MV > 48 hrs and coagulopathy

• Preexisting liver disease, need for RRT, and higher organ failure scores were independent predictors of GIB risk

• Recommends against SUP in patients without risk factors

• Suggest EITHER PPI or H2RB for SUP

Guidelines on Stress Ulcer ProphylaxisASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis 1998

EAST: Practice Management Guidelines for Stress Ulcer Prophylaxis: 2008

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016

Indications for SUP

Major Indications:• Mechanical Ventilation >48hrs• Coagulopathy Minor Indications: Any 2 of the following:• Sepsis, • ICU stay >7 days, • occult bleeding lasting >6 days, • High dose steroid that have a daily dose that

exceeds o Hydrocortisone 250mg,o Methylprednisolone 50mgo Prednisone 50mgo Dexamethasone 10mg

Special Indications: • Glascow Coma Score 35% of total body surface• Major trauma with an injury severity score of

>16, • Hepatic failure• spinal cord injury• History of GI bleed or ulceration within last

year • Major surgery lasting > 4 hrs

May be Considered: Partial hepatectomy, Polytrauma w/ISS 16, Transplants, Hepatic failure

Level 1: Patients who are recommended for stress ulcer prophylaxis:• Mechanical ventilation• Coagulopathy• Traumatic brain injury• Major brain injury

Level 2: For all ICU patients with• Multi-trauma• Sepsis• Acute renal failure

Level 3: • ISS > 15 • Requirement of high dose steroids ( >250mgs

hydrocortisone or equic per day)

Duration:Level II Continue until extubated or out of ICU

Level IIIContinue until tolerating EN

• Sepsis/septic shock PLUS risk factors • Strongest clinical predictors of GIB risk MV > 48 hrs and

coagulopathy• Preexisting liver disease, need for RRT, and higher organ

failure scores were independent predictors of GIB risk • Recommends against SUP in patients without risk

factors • Either PPI or H2RB appropriate for SUP

Danish Consensus Guidelines on SUP in the ICU (2014)• No firm evidence for benefit or harm of SUP compared to

placebo/no prophylaxis• Suggest using a PPI when SUP is indicated in adult

critically ill patients in the ICU• Insufficient evidence that enteral nutrition helps • SUP in ICU Sub-populations: Trauma, Septic, and

Cardiothoracic Patients – insufficient evidence of benefit.

PPIs vs. H2RAs

Which is better? • Meta analysis data have demonstrated proton

pump inhibitors to be more effective in critically ill patients for reducing CIGIB compared to an H2RB.1

• Other studies have suggest H2RB’s are associated with significantly lower CIGIB.2

• Additional large scale clinical trials are needed to determine the comparative efficacy of PPIs vs. H2RAs in stress ulcer prophylaxis

• More data is needed comparing the treatment impact of both treatments on mortality and length of stay

1-Crit Care Med 2013; 41:693-705

2-CHEST 2018; 154:557-566

Is SUP

Appropriate? Main Reasons for Overuse of PPIs in SUP

• Use low-risk patients and in non-intensive care units

• Use in patients on steroid therapy alone

• Use in anticoagulant treatment without risk factors of GI injury

• Overtreatment of functional dyspepsia

• Wrong diagnosis of acid-related disorders

Eur J Intern Med 2017; 37:19-24

Accepted Uses of PPIs

Conditions Supporting long-term PPI Use According to AGA/ACG

✓ Maintenance of symptom control in GERD✓ Maintenance of healing of erosive esophagitis✓ Barrett’s esophagus✓ NSAID users at increased risk✓ Antiplatelet agent users with increased risk✓ Pathological hypersecretory conditions (i.e. ZES)

Accepted Indications for PPI Use (FDA in USA and NICE in UK)✓ Healing and maintenance of of erosive

esophagitis✓ GERD (including NERD, esphophageal strictures,

and Barrett’s esophagus)✓ Treatment of H. pylori infection in combination

w/ ABX✓ Short-term treatment of H. pylori-negative

peptic ulcer and maintenance of healed ulcer✓ NSAID-induced dyspepsia

✓ Healing of NSAID associated gastric ulcer✓ Risk reduction of NSAID associated gastric ulcer✓ Pathologic hypersecretory conditions (i.e.

Zollinger-Ellison Syndrome = ZES)✓ Critically ill patients on prolonged mechanical

ventilation✓ Short-term treatment with regular review of

patients with functional dyspepsia

When to discontinue SUP

1

As the number of risk factors diminish as a patient progresses, the need for SUP does as well.

2

In most clinical trials, SUP was discontinued when evidence of clinical bleeding and extubationwas gone.

3

Studies also discontinued SUP when the patients were discharged from the intensive care.

4

It is reasonable to presume that SUP can be stopped once the risk factors are resolved.

5

In ASHP guidelines SUP is not recommended in non-ICU patients, medical, surgical patients and patients with fewer than 2 risk factors

Consequences of unnecessary acid suppression:

• Infection- Acid suppression may impair the destruction of ingested microorganisms, resulting in overgrowth of bacteria • Overuse of PPIs → increase risk of infections such as Clostridium

difficile and community acquired pneumonia

• Bone fractures- PPIs lower gastric acidity, and can inhibit intestinal calcium absorption. Thus, PPIs may directly inhibit bone resorption by osteoclasts.

• Drug Interactions: (i.e. Reduction in clopidogrel efficacy- Competitive inhibition of CYP2C19, which is necessary to metabolize clopidogrel

• Unnecessary cost- Overprescribing cost patients and hospitals for unnecessary therapy

Arch Intern Med 2010;170:784-90Aliment Pharmacol Ther. 2011;34;1269-81

Crit Care Med 2010;38:2222-8Am J Gastroenterol; 2007:2047-56

Pantoprazole vs. Placebo in High Risk ICU Patients• SUP-ICU Trial Group

• Multicenter, blinded, randomized parallel-group placebo-controlled.

• N=3298

• 1:1 assignment • 1645 Pantoprazole; 1653 Placebo

• Patients had at least one risk factor for CIGIB: • shock, anticoagulation, renal replacment

therapy, mechanical ventilation (expected to last >24hrs), liver disease, or coagulopathy

NEJM 2018;379:2199-208

Pantoprazole vs. Placebo in High Risk ICU PatientsPrimary Outcome

• Mortality at 90 days

Secondary• Composite endpoint

• Clinically important GI Bleeding• New-onset pneumonia• C. difficile infection• Acute myocardial infarction

Results• 510 of 1642 (31.1%) Pantoprazole patients

had died at 90 days• 499 of 1640 (30.4%) in the placebo group

had died at 90 days. • 2.5% of Pantoprazole patients had CIGIB• 4.2% of placebo patients had CIGIB• Other secondary outcomes were similar

NEJM 2018;379:2199-208

PEPTIC STUDY

Rationale: • Data suggests PPIs reduce bleeding risk and are prescribed more frequently, but many clinicians prescribe H2RBs.• Previous meta-analysis concluded that PPIs might be more effective than H2RBs in preventing GI bleeding, however

data is limited and there are still questions regarding the robustness of the data.• Uncertainty as to which class of agents to use is a decision that affects an estimated 2.5 million critically ill patients

per year in developed high-income countries alone. • The relative difference in SUP drugs on mortality rates are unknown.

JAMA 2020; 323: 616-626

PEPTIC Study: Pantoprazole vs. H2RBs in the ICUKey Points: Question: What is the comparative effect on in hospital mortality of using PPIs vs. H2RBs for SUP among adults requiring mechanical ventilation in ICU.Trial Design:International open-label, Cluster Crossover, registry-embeded randomized clinical trialSetting: 50 ICUs in 5 countries between Aug 2016 – Jan 2019Patients: N=26,982 pts

JAMA 2020;323(7):616-626

PEPTIC Study: Pantoprazole vs. H2RBs in the ICUIntervention: • ICU pts requiring mechanical

ventilation were randomized by site to a PPI strategy or an H2RB strategy for SUP

Primary Outcome• All-cause Mortality at 90 days

during index hospitalization

Secondary• Clinically important UGI Bleeding• C. difficile infection• ICU and Hospital LOS

JAMA 2020;323(7):616-626

PEPTIC Study: Pantoprazole vs. H2RBs in the ICUResultsPrimary Outcome

• Mortality• 18.3% In-hospital Mortality rate for patients at

sites randomized to PPIs• 17.5% in-hospital Mortality for patients at sites

randomized to H2RB

Secondary Outcome

• Clinically Significant Upper GI Bleeding • 172 of 13,434 pts (1.3%) in the PPI group vs. • 239 of 13,392 pts (1.8%) in the H2RB group

• Clostridioides difficile infection diagnosis• 40 of 13,436 pts (0.30% in the PPI group vs.• 57 of 13,392 pts (0.43%) in the H2RB group

• Hospital LOS – no significant between group differences

JAMA 2020;323(7):616-626

PEPTIC Study: Pantoprazole vs. H2RBs in the ICULimitations

• Predominately male patient population

• Open label, cluster

• 4.1% of patients in the PPI arm received at least 1 dose of a H2RB

• 20.1% of patients in the H2RB are received at least 1 PPI dose

• Potential for non-adherence bias as clinicians could over-ride the default SUP

• Patients given default SUP regardless of home medication regimen

JAMA 2020;323(7):616-626

What Should We do in Pharmacy About SUP? Question: Can Clinical Pharmacists impact Inappropriate SUP Use in hospitalized patients? Setting: 712 Bed Academic Medical Center in Arizona 12 month study conducted January 1, 2011 – January 31, 2012Population: N=1134 unique patients consisting of 16,415 patient days were evaluated. Design: Retrospective pre- & poststudy design before and after pharmacist led stress ulcer prophylaxis management program

In this facility prescriptive authority for SUP was granted to clinical pharmacists

Impact of a Clinical Pharmacist SUP Management program on

Inappropriate Use in Hospitalized patients

Am J Med 128:8, August 2015

Am J Med 128:8, August 2015

Self-Assessment Question #3

True or False – Pharmacy teams can have a positive impact on reducing unnecessary and inappropriate use of acid suppressive therapy?

• True – Absolutely- Pharmacists and Technicians can play a integral role in reducing and de-escalating unnecessary and inappropriate stress ulcer prophylaxis therapy.

Summary

• Critically ill patients are at risk of stress-related GI mucosal damage, ulceration, and bleeding

• Stress Ulcer Prophylaxis is an important consideration for patients in the ICU who are at risk for clinically important gastrointestinal bleeding

• SUP does not come without risk and this treatment should be routinely re-evaluated

• Providers should de-escalate SUP when patient risk factors moderate

• Pharmacists and technicians can play a key roles in assisting with re-evaluation and de-escalation of unnecessary SUP therapy

References:• Guillamondegui OD, Gunter OL Jr, Bonadies JA, et al. Stress ulcer prophy- laxis. Chicago: Eastern Association for the Surgery of Trauma, 2008

(http://www.east.org/education/practice-management -guidelines/stress-ulcer-prophylaxis).

• Madsen KR, Lorentzen K, Clausen N, et al. Guideline for stress ulcer prophylaxis in the intensive care unit. Dan Med J 2014;6:C4811

• Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017;43:304-77.

• MacLaren R, Reynolds PM, Allen RR. Histamine-2 receptor antagonists vs proton pump inhibitors on gastrointestinal tract hemorrhage and infectious complications in the intensive care unit. JAMA Intern Med 2014;174:564-74.

• Cook D, Guyatt G. Prophylaxis against upper gastrointestinal bleeding in hospitalized patients. N Engl J Med. 2018;378(26):2506–16.

• The PEPTIC Investigators: Effect of stress ulcer prophylaxis with proton pump inhibitors vs. histamine-2 receptor blockers on In-hospital mortality among ICU patients receiving invasive mechanical ventilation (The PEPTIC Randomized Clinical Trial). JAMA 2020;323:616-626.

• Krag M, Marker S, Perner A, and Wetterslev J et al. Pantoprazole in patients at risk for gastrointestinal bleeding in the ICU (SUP-ICU trial) NEJM 2018;378:2199-2208.

• Barletta JF, Sclar DA. Proton pump inhibitors increase the risk for hospital- acquired Clostridium difficile infection in critically ill patients. Crit Care 2014;18: 714.

• Buendgens L, Bruensing J, Matthes M, et al. Administration of proton pump inhibitors in critically ill medical patients is associated with increased risk of developing Clostridium difficile-associated diarrhea. J Crit Care 2014;29:696.e11-e15.

• Alshamsi, Fayez et al. “Efficacy and safety of proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis of randomized trials.” Critical care (London, England) vol. 20,1 120. 4 May. 2016, doi:10.1186/s13054-016-1305-6

• Alhazzani W, Alenezi F, Jaeschke RX et al. Proton Pump Inhibitors vs. Histamine 2 Receptor Antagonists for Stress Ulcer Prophylaxis in Critically Ill Patients: A systematic review and meta analysis Crit Care Med 2013; 41:693-705

• Buckley MS, Park AS, Anderson CS, et al. Impact of a clinical pharmacist stress ulcer prophylaxis management program on inappropriate use in hospitalized patients. Am J Med 2015;128:905-13.

• Lilly, Craig M et al. “Comparative Effectiveness of Proton Pump Inhibitors vs Histamine Type 2 Receptor Blockers for Preventing Clinically Important Gastrointestinal Bleeding During Intensive Care: A Population-Based Study.” Chest vol. 154,3 (2018): 557-566. doi:10.1016/j.chest.2018.05.015

• Buendgens, Lukas et al. “Prevention of stress-related ulcer bleeding at the intensive care unit: Risks and benefits of stress ulcer prophylaxis.” World journal of critical care medicine vol. 5,1 57-64. 4 Feb. 2016, doi:10.5492/wjccm.v5.i1.57

• Chongnarungsin, Daych, et al. “Do All Hospitalized Patients Need Stress Ulcer Prophylaxis?” Cleveland Clinic Journal of Medicine, 12 Sept. 2017, https://www.mdedge.com/ccjm/article/96017/hospital-medicine/do-all-hospitalized-patients-need-stress-ulcer-prophylaxis/page/0/1.

References:• Buckley MS, Park AS, Anderson CS et al. Impact of a clinical pharmacist stress ulcer prophylaxis management program on inappropriate use

in hospitalized patients. Am J of Med 2015;128:905-319

• Savarino V, Dulbecco P, Nicola D, et al. The appropriate use of proton pump inhibitors (PPIs): need for reappraisal. Eur J Intern Med 2017; 37:19-24

• Pantoprazole [2019 December 2]. In: Lexi-Comp Online [AUHSOP Intranet]. Hudson, OH: Wolters Kluwer Clinical Drug Information [updated 2019, cited 2019 December 2]. [about p 20.]. Available from http://online.lexi.com/lco/action/home

• Omeprazole [2019 December 2]. In: Lexi-Comp Online [AUHSOP Intranet]. Hudson, OH: Wolters Kluwer Clinical Drug Information [updated 2019, cited 2019 November 2]. [about p 20.]. Available from http://online.lexi.com/lco/action/home

• Lansoprazole [2019 December 2]. In: Lexi-Comp Online [AUHSOP Intranet]. Hudson, OH: Wolters Kluwer Clinical Drug Information [updated 2019, cited 2019 November 2]. [about p 10.]. Available from http://online.lexi.com/lco/action/home

• Rabeprazole [2019 December 2]. In: Lexi-Comp Online [AUHSOP Intranet]. Hudson, OH: Wolters Kluwer Clinical Drug Information [updated 2019, cited 2019 November 1]. [about p 10.]. Available from http://online.lexi.com/lco/action/home

• Esomeprazole [2019 December 2]. In: Lexi-Comp Online [AUHSOP Intranet]. Hudson, OH: Wolters Kluwer Clinical Drug Information [updated 2019, cited 2019 November 19]. [about p 10.]. Available from http://online.lexi.com/lco/action/home

• Dexlansoprazole [2019 December 2]. In: Lexi-Comp Online [AUHSOP Intranet]. Hudson, OH: Wolters Kluwer Clinical Drug Information [updated 2019, cited 2019 November 30]. [about p 20.]. Available from http://online.lexi.com/lco/action/home

• Famotidine [2019 December 2]. In: Lexi-Comp Online [AUHSOP Intranet]. Hudson, OH: Wolters Kluwer Clinical Drug Information [updated 2019, cited 2019 November 28]. [about p 20.]. Available from http://online.lexi.com/lco/action/home

• Ranitidine [2019 December 2]. In: Lexi-Comp Online [AUHSOP Intranet]. Hudson, OH: Wolters Kluwer Clinical Drug Information [updated 2019, cited 2019 November 18]. [about p 20.]. Available from http://online.lexi.com/lco/action/home

• Cimetidine [2019 December 2]. In: Lexi-Comp Online [AUHSOP Intranet]. Hudson, OH: Wolters Kluwer Clinical Drug Information [updated 2019, cited 2019 November 18]. [about p 10.]. Available from http://online.lexi.com/lco/action/home

• Nizatidine [2019 December 2]. In: Lexi-Comp Online [AUHSOP Intranet]. Hudson, OH: Wolters Kluwer Clinical Drug Information [updated 2019, cited 2019 November 29]. [about p 10.]. Available from http://online.lexi.com/lco/action/home

• Sucralfate [2019 December 2]. In: Lexi-Comp Online [AUHSOP Intranet]. Hudson, OH: Wolters Kluwer Clinical Drug Information [updated 2019, cited 2019 November 29]. [about p 10.]. Available from http://online.lexi.com/lco/action/home

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