Stressed Out: Evaluating the Need for Stress Ulcer Prophylaxis in the ICU Josh Arnold, PharmD PGY1 Pharmacy Resident Pharmacy Grand Rounds November 8, 2016 2016 MFMER slide-1
Objectives Identify the significance and potential mechanisms of stress ulcer development in critically ill patients Discuss evidence for the use of stress ulcer prophylaxis in specific patient populations Describe the implications and potential adverse effects associated with the use of stress ulcer prophylaxis 2016 MFMER slide-2
Significance and mechanisms Populations Implications and adverse effects 2016 MFMER slide-3
Epidemiology Incidence Stress ulcers are present in the majority of critically ill patients Within 24 hours of ICU admission, >75% of patients demonstrate evidence of mucosal damage Approximately 5-25% will have bleeding ~1-4% will have clinically significant bleeding Complications Severe ulceration and bleeding can: Lengthen ICU stay by up to 8 days Increase mortality as much as 4-fold ICU: intensive care unit Cook DJ, et al. Crit Care. 2001;5:368-75 Fennerty MB. Crit Care Med. 2002;30(6 Suppl):S351-5. Laine L, et al. Gastroenterology. 2008;135(1):41-60. 2016 MFMER slide-4
Which of the following is a potential mechanism of stress ulcer development in the critically ill patient? A. Increased gastrointestinal motility B. Decreased splanchnic blood flow C. Increased bicarbonate secretion D. Decreased duration of mechanical ventilation 2016 MFMER slide-5
Increased Catecholamines Increased Vasoconstriction Decreased Cardiac Output Hypovolemia Proinflammatory Cytokine Release Splanchnic Hypoperfusion Reduced HCO 3 Secretion Reduced Mucosal Blood Flow Decreased GI Motility Acid Back- Diffusion Mucosal Vulnerability Stollman N, et al. J Crit Care. 2005;20(1):35-45. 2016 MFMER slide-6
Additional factors Mechanical ventilation Promotes RAAS activity and catecholamine release High PEEP decrease venous return and reduces preload Medications Opiates and sedatives can decrease gut motility and impair venous return Systemic hemodynamic changes due to vasopressor therapy Glucocorticoids and NSAIDS Coagulopathy Impaired ability to terminate active bleeding PEEP: positive end-expiratory pressure RAAS: renin-angiotensin-aldosterone system Coagulopathy: platelets <50,000; INR >1.5; PTT >2x control value Buendgens L, et al. World J Crit Care Med. 2016;5(1):57-64. Stollman N, et al. J Crit Care. 2005;20(1):35-45. 2016 MFMER slide-7
Significance and mechanisms Populations Implications and adverse effects 2016 MFMER slide-8
In what populations do you recommend the use of stress ulcer prophylaxis? A. Patients meeting guideline recommendations B. Patients I believe are high-risk C. All ICU patients D. I ask a crystal ball 2016 MFMER slide-9
Cook et al. (1994) Prospective, multicenter, cohort study Primary endpoint: clinically important GI bleeding 2252 patients, 674 received SUP 71.8% H 2 RA; 0.3% omeprazole 33 patients met primary endpoint (1.5%) Independent Risk Factors Odds Ratio Significance Mechanical ventilation >48 hrs 15.6 p < 0.001 Coagulopathy 4.3 p < 0.001 1.6% patients diagnosed with sepsis 48.5% primary diagnosis of cardiovascular surgery Mortality 9.7% SUP: stress ulcer prophylaxis GI: gastrointestinal Cook DJ, et al. N Engl J Med. 1994;330(6):377-81. 2016 MFMER slide-10
Original Guidelines - AJHP 1999 Recommended SUP use in high risk patients With coagulopathies Requiring mechanical ventilation for >48 hours With history of GI ulceration or bleed within 1 year Special populations Patients with 2 of the following Sepsis ICU stay >1 week Occult bleeding lasting 6 days High-dose steroids SUP: stress ulcer prophylaxis GI: gastrointestinal ASHP Board of Directors. Am J Health Syst Pharm. 1999;56(4):347-79. 2016 MFMER slide-11
Original Guidelines Number needed to treat Low risk patients: >900 High risk patients: 30 Limitations Little data on use of PPI therapy Low strength of evidence Outdated GCS: glasgow coma score BSA: body surface area PPI: proton-pump inhibitor ASHP Board of Directors. Am J Health Syst Pharm. 1999;56(4):347-79. Cash BD. Crit Care Med. 2002;30(6 Suppl):S373-8. 2016 MFMER slide-12
What has changed? The 2000s Mechanical ventilation >48 hrs Acute renal insufficiency Sepsis syndrome History of gastrointestinal bleeding Severe head or spinal cord injury Anticoagulation Major surgery (>4 hrs) Renal replacement therapy Coagulopathy Acute hepatic failure High-dose corticosteroids Thermal injury involving >35% BSA Low intragastric ph Hypotension Acute lung injury Number of comorbidities BSA: body surface area Quenot JP, et al. Curr Opin Crit Care. 2009;15(2):139-43. 2016 MFMER slide-13
Do all our patients really need stress ulcer prophylaxis? 2016 MFMER slide-14
Krag et al. (2015) Prospective, observational, international, 7-day cohort study Primary outcome: clinically important gastrointestinal bleeding during ICU stay Secondary outcomes: overt GI bleeding in ICU; 90 day mortality Total of 1,034 patients, with 27 patients developing clinically important GI bleed GI: gastrointestinal Krag M, et al. Intensive Care Med. 2015;41(5):833-45. 2016 MFMER slide-15
Krag et al. (2015) 73% of patients received acid suppressant therapy during ICU stay 59% of patients with clinically important GI bleeding received SUP prior to bleed 90-day mortality Overall: 26.2% Without clinically important GI bleed: 25.4% With clinically important GI bleed: 55.6% Independent Risk Factors OR (95% CI) Adj* OR (95% CI) Overt GI bleeding 1.70 (0.70-4.10) 1.17 (0.43-3.21) Clinically important GI bleeding 3.72 (1.72-8.04) 1.70 (0.68-4.28) SUP: stress ulcer prophylaxis GI: gastrointestinal *adjusted for: age, gender, comorbidites, SOFA score, mechanical ventilation, coagulopathy, etc Krag M, et al. Intensive Care Med. 2015;41(5):833-45. 2016 MFMER slide-16
When do patients bleed? Number of Patients with clinically important bleeds 9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Duration of ICU stay (days) Krag M, et al. Intensive Care Med. 2015;41(5):833-45. 2016 MFMER slide-17
What risks exist? Independent Baseline Risk Factors Adj Odds Ratio (95% CI) for clinically important GI bleed 3 co-existing diseases 8.9 (2.7-28.8) Co-existing liver disease 7.6 (3.3-17.6) Renal replacement therapy 6.9 (2.7-17.5) Co-existing coagulopathy 5.2 (2.3-11.8) Acute coagulopathy 4.2 (1.7-10.2) Use of SUP on ICU day 1 3.6 (1.3-10.2) Higher organ failure score 1.4 (1.2-1.5) Mechanical ventilation on ICU day 1 1.3 (0.6-3.1) Coagulopathy: platelets <50,000 mm and/or INR >1.5 either during current hospitalization or on ICU admission Krag M, et al. Intensive Care Med. 2015;41(5):833-45. 2016 MFMER slide-18
Summary Found the incidence of clinically important GI bleeding was low at 2.6% Surprising results: Mechanical ventilation was not associated with increased risk of GI bleeding The use of stress ulcer prophylaxis on ICU day 1 was associated with an increased risk of GI bleeding Influx of new data poses the question Is stress ulcer prophylaxis benefitting our patients? 2016 MFMER slide-19
POP-UP 2016 Primary Objective Evaluate if prophylactic PPI administration is overtly beneficial or harmful Design Single-center, prospective, randomized, double-blind, parallel-group study Inclusion Criteria Anticipate mechanical ventilation >24 hours and receive enteral nutrition within 48 hrs Exclusion Criteria Use of acid-suppressive therapy prior to admission; admission with GI bleeding, history of PUD, receiving >100mg daily of prednisolone, recent GI or cardiac surgery PPI; proton pump inhibitor PUD: peptic ulcer disease Selvanderan SP, et al. Crit Care Med. 2016;44(10):1842-50. 2016 MFMER slide-20
Baseline characteristics Characteristics Placebo (n=108) Pantoprazole (n=106) Age (yr) 52 (±17) 52 (±18) APACHE III score 66 (±28) 66 (±26) End-stage renal failure 0 (0%) 1 (0.9%) Non-operative 68 (63%) 70 (66%) Post-operative 31 (29%) 27 (25%) ICU diagnosis Placebo (n=108) Pantoprazole (n=106) Trauma 32 (30%) 31 (29%) Neurologic 26 (24%) 35 (33%) Respiratory/CV/Sepsis 41 (38%) 31 (29%) Unless specified, data are mean (SD) Selvanderan SP, et al. Crit Care Med. 2016;44(10):1842-50. 2016 MFMER slide-21
Outcomes Major Outcomes Placebo (n=108) Pantoprazole (n=106) Clinically significant GI bleeding 0 (0%) 0 (0%) Infective ventilator-associated complication 1 (0.9%) 2 (1.9%) Positive C. difficile infection 0 (0%) 1 (0.9%) Additional Outcomes Placebo (n=108) Pantoprazole (n=106) Significance Length of stay (days) in the ICU 7 (4-14) 6 (3-11) p = 0.16 Ventilator-free days 21 (4-25) 21 (0-25) p = 0.69 90-day mortality 25 (23.1%) 30 (28.3%) p = 0.33 Selvanderan SP, et al. Crit Care Med. 2016;44(10):1842-50. 2016 MFMER slide-22
Strengths Prospective, randomized, double-blind trial Compared standard of care to placebo Only included mechanically ventilated patients Low risk of selection bias Therefore, stress ulcer prophylaxis offers no benefit compared to placebo right? 2016 MFMER slide-23
Limitations Insufficient sample size Low incidence of GI bleed Excluded 87% of patients recruited Unique characteristics of included patients Early implementation of other therapies Shorter duration of mechanical ventilation 2016 MFMER slide-24
Significance and mechanisms Populations Implications and adverse effects 2016 MFMER slide-25
Incorrect use of stress ulcer prophylaxis Rafinazari et al. (2016) Design Results Conclusion Prospective, single center 200 randomly selected ICU patients over 9 months with stay >72 hrs 160 (80%) received SUP 44.4% did not have an indication* 6.3% did not receive SUP although indicated 38.5% of patients did not receive appropriate SUP on ICU admission 81.2% were continued on inappropriate SUP upon transfer from ICU *per ASHP guidelines SUP: stress ulcer prophylaxis Rafinazari N, et al. J Res Pharm Pract. 2016;5(3):186-92. Buendgens L, et al. World J Crit Care Med. 2016;5(1):57-64. 2016 MFMER slide-26
Continued use after ICU stay Wohlt et al. (2007) 394 patients met eligibility criteria 357 patients prescribed SUP 80% continued SUP on transfer from ICU 60% of SUP continuation was inappropriate 24.4% discharged with inappropriate prescription Unnecessary cost of $13,973 SUP: stress ulcer prophylaxis Wohlt, et al. Ann Pharmacother. 2007;41(10):1611-6. 2016 MFMER slide-27
Which of the following are potential adverse effects of acid-suppression therapy? A. Drug interactions B. Electrolyte abnormalities C. Clostridium difficile infection D. Nosocomial pneumonia E. All of the above 2016 MFMER slide-28
Clostridium difficile risk Meta-analyses 1-3 ~800,000 MacLaren et al. 35,312 n Population Findings Community, general & ICU Intubated >24 hours and SUP >48 hours Faleck et al. 18,134 ICU 3 days PPIs increase risk OR (CI): 1.29 (1.04-1.64) PPIs may have protective effect PPI: proton pump inhibitor 1. Kwok CS et al. Am J Gastroenterol 2012;107(7):1011-1019. 2. Janarthanan S et al. Am J Gastroenterol 2012;107(7):1001-1010. 3. Arriola V et al. Infect Control Hosp Epidemiol 2016 Sep 28; Epub ahead of print. MacLaren R et al. JAMA Intern Med 2014;174(4):564-574. Faleck DM et al. Am J Gastroenterol 30 Aug 2016; Advance online publication. 2016 MFMER slide-29
Pneumonia risk Alhazzani et al. 1,100 ICU MacLaren et al. 35,312 n Population Findings Intubated >24 hours and SUP >48 hours Alshamsi et al. 1,571 ICU No difference in PPI vs. H 2 RA PPI increased risk vs. H 2 RA No difference in PPI vs. H 2 RA PPI: proton pump inhibitor H2RA: H2 receptor antagonist Alhazzani W et al. Crit Care Med. 2013;41(3):693-705. MacLaren R et al. JAMA Intern Med 2014;174(4):564-574. Alshamsi F et al. Crit Care. 2016;20:120. 2016 MFMER slide-30
Future Direction Further larger RCT are needed evaluating: Specific risk factors for development of stressrelated mucosal damage Use of SUP compared to placebo in preventing clinically important GI bleed SUP-ICU trial ASHP is currently updating their guidelines, with plans for release in Spring 2017 RCT: randomized control trials SUP: stress ulcer prophylaxis GI: gastrointestinal Møller MH: SUP-ICU. Available at https://www.clinicaltrials.gov/ct2/show/nct02467621. 2016 MFMER slide-31
Recommendations Optimizing other therapies to prevent mucosal damage is highest priority Short-term use of SUP has a role in preventing clinically important gastrointestinal bleeding in high-risk populations Acute Duration of ICU stay Chronic Coagulopathy Mechanical ventilation Renal replacement therapy Septic shock Thermal injury >35% BSA Continuation of therapy 2016 MFMER slide-32
Stressed Out: Evaluating the Need for Stress Ulcer Prophylaxis in the ICU Josh Arnold, PharmD PGY1 Pharmacy Resident Pharmacy Grand Rounds November 8, 2016 2016 MFMER slide-33
PPI vs H 2 RA The use of PPI for SUP is associated with significantly lower rate of clinically important GI bleeding compared to H 2 RA Meta-analysis n Risk reduction (bleeding) Alhazzani et al 1720 Pongprasobchai et al 569 Alshamsi et al 2117 RR = 0.36 (95% CI, 0.19-0.67) OR = 0.42 (95% CI, 0.20-0.91) RR = 0.39 (95% CI, 0.21-0.71) Risk reduction (mortality) RR = 1.01 (95% CI, 0.83-1.24) n/a RR = 1.05 (95% CI, 0.87-1.27) PPI: proton pump inhibitor SUP: stress ulcer prophylaxis GI: gastrointestinal H 2 RA: histamine 2 receptor antagonist Pongprasobchai et al. J Med Assoc Thai. 2009;92:632 637. Alshamsi F et al. Crit Care. 2016;20:120. Alhazzani W et al. Crit Care Med. 2013;41(3):693-705. 2016 MFMER slide-34
PPI vs H 2 RA 120 % of time gastric ph >4 100 80 60 40 20 Omeprazole Ranitidine 0 Day 1 Day 2 Day 3 Fennerty MB. Crit Care Med. 2002;30(6 Suppl):S351-5. 2016 MFMER slide-35
Stressed Out: Evaluating the Need for Stress Ulcer Prophylaxis in the ICU Josh Arnold, PharmD PGY1 Pharmacy Resident Pharmacy Grand Rounds November 8, 2016 2016 MFMER slide-36