Stress-related mucosal disease in the critically ill patient

Nature Reviews Gastroenterology and Hepatology

Volumn 12, Issue 2, 2015, Pages 98-107

  Bardou, Marc ^a   Quenot, Jean Pierre ^a   Barkun, Alan ^b  

^a DIJON UNIVERSITY HOSPITAL   (France)

^b MONTREAL GENERAL HOSPITAL   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

CIMETIDINE; OMEPRAZOLE; PLACEBO; PROTON PUMP INHIBITOR; RANITIDINE; SUCRALFATE; VITAMIN K GROUP;

ARTIFICIAL VENTILATION; CASE CONTROL STUDY; CLOSTRIDIUM DIFFICILE INFECTION; COHORT ANALYSIS; COST EFFECTIVENESS ANALYSIS; CRITICALLY ILL PATIENT; ENDOSCOPY; ENTERIC FEEDING; GASTROENTEROLOGIST; HEMATEMESIS; HOSPITAL INFECTION; HUMAN; INTENSIVE CARE UNIT; MORTALITY; MUCOSAL DISEASE; MULTIPLE ORGAN FAILURE; OBSERVATIONAL STUDY; PATHOPHYSIOLOGY; PEPTIC ULCER BLEEDING; PNEUMONIA; PREVALENCE; PRIORITY JOURNAL; PSEUDOMONAS AERUGINOSA; RANDOMIZED CONTROLLED TRIAL (TOPIC); RESPIRATORY FAILURE; RETROSPECTIVE STUDY; REVIEW; RISK BENEFIT ANALYSIS; RISK REDUCTION; STAPHYLOCOCCUS AUREUS; STOMACH ACID SECRETION; STRESS; STRESS RELATED MUCOSAL DISEASE; TREND STUDY; UPPER GASTROINTESTINAL BLEEDING; COMPLICATION; CRITICAL ILLNESS; PEPTIC ULCER HEMORRHAGE; PHYSIOLOGICAL STRESS; PROCEDURES; RISK FACTOR; STOMACH ULCER;

CRITICAL ILLNESS; ENTERAL NUTRITION; HUMANS; PEPTIC ULCER HEMORRHAGE; PROTON PUMP INHIBITORS; RISK FACTORS; STOMACH ULCER; STRESS, PHYSIOLOGICAL;

EID: 84926093575     PISSN: 17595045     EISSN: 17595053     Source Type: Journal    
DOI: 10.1038/nrgastro.2014.235     Document Type: Review

References (127)

1. Marik, P. E., Vasu, T., Hirani, A. & Pachinburavan, M. Stress ulcer prophylaxis in the new millennium: a systematic review and meta?analysis. Crit. Care Med. 38, 2222-2228 (2010).
2. Laine, L., Takeuchi, K. & Tarnawski, A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology 135, 41-60 (2008).
3. Laine, L. et al. Lower gastrointestinal events in a double?blind trial of the cyclo?oxygenase?2 selective inhibitor etoricoxib and the traditional nonsteroidal anti?inflammatory drug diclofenac. Gastroenterology 135, 1517-1525 (2008).
4. Cook, D. J. et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N. Engl. J. Med. 330, 377-381 (1994).
5. Reintam Blaser, A. et al. Gastrointestinal symptoms during the first week of intensive care are associated with poor outcome: a prospective multicentre study. Intensive Care Med. 39, 899-909 (2013).
6. Buendgens, L. 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 29, 696.e11-696.e15 (2014).
7. Spirt, M. J. Stress?related mucosal disease: risk factors and prophylactic therapy. Clin. Ther. 26, 197-213 (2004).
8. Stollman, N. & Metz, D. C. Pathophysiology and prophylaxis of stress ulcer in intensive care unit patients. J. Crit. Care 20, 35-45 (2005).
9. Masson, S. C., Mabasa, V. H., Malyuk, D. L. & Perrott, J. L. Validity evidence for FASTHUGMAIDENS, a mnemonic for identifying drugrelated problems in the intensive care unit. Can. J. Hosp. Pharm. 66, 157-162 (2013).
10. Barkun, A. N., Bardou, M., Pham, C. Q. & Martel, M. Proton pump inhibitors vs. histamine 2 receptor antagonists for stressrelated mucosal bleeding prophylaxis in critically ill patients: a meta?analysis. Am. J. Gastroenterol. 107, 507-520 (2012).
11. Leontiadis, G. I. et al. Systematic reviews of the clinical effectiveness and cost?effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding. Health Technol. Assess. 11, 1-164 (2007).
12. Alhazzani, W., Alenezi, F., Jaeschke, R. Z., Moayyedi, P. & Cook, D. J. Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and meta?analysis. Crit. Care Med. 41, 693-705 (2013).
13. Lin, P. C., Chang, C. H., Hsu, P. I., Tseng, P. L. & Huang, Y. B. The efficacy and safety of proton pump inhibitors vs histamine?2 receptor antagonists for stress ulcer bleeding prophylaxis among critical care patients: a meta?analysis. Crit. Care Med. 38, 1197-1205 (2010).
14. Peura, D. A. & Johnson, L. F. Cimetidine for prevention and treatment of gastroduodenal mucosal lesions in patients in an intensive care unit. Ann. Intern. Med. 103, 173-177 (1985).
15. Skillman, J. J. & Silen, W. Acute gastroduodenal "stress" ulceration: barrier disruption of varied pathogenesis? Gastroenterology 59, 478-482 (1970).
16. Zandstra, D. F. & Stoutenbeek, C. P. The virtual absence of stress?ulceration related bleeding in ICU patients receiving prolonged mechanical ventilation without any prophylaxis. A prospective cohort study. Intensive Care Med. 20, 335-340 (1994).
17. Duerksen, D. R. Stress?related mucosal disease in critically ill patients. Best Pract. Res. Clin. Gastroenterol. 17, 327-344 (2003).
18. Alhazzani, W., Alshahrani, M., Moayyedi, P. & Jaeschke, R. Stress ulcer prophylaxis in critically ill patients: review of the evidence. Pol. Arch. Med. Wewn. 122, 107-114 (2012).
19. Zimmerman, J. E., Kramer, A. A. & Knaus, W. A. Changes in hospital mortality for United States intensive care unit admissions from 1988 to 2012. Crit. Care 17, R81 (2013).
20. Cook, D. et al. Risk factors for clinically important upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. Crit. Care Med. 27, 2812-2817 (1999).
21. Schuster, D. P., Rowley, H., Feinstein, S., McGue, M. K. & Zuckerman, G. R. Prospective evaluation of the risk of upper gastrointestinal bleeding after admission to a medical intensive care unit. Am. J. Med. 76, 623-630 (1984).
22. Beejay, U. & Wolfe, M. M. Acute gastrointestinal bleeding in the intensive care unit. The gastroenterologist's perspective. Gastroenterol. Clin. North Am. 29, 309-336 (2000).
23. Steinberg, K. P. Stress?related mucosal disease in the critically ill patient: risk factors and strategies to prevent stress?related bleeding in the intensive care unit. Crit. Care Med. 30, 362-364 (2002).
24. Daley, R. J., Rebuck, J. A., Welage, L. S. & Rogers, F. B. Prevention of stress ulceration: current trends in critical care. Crit. Care Med. 32, 2008-2013 (2004).
25. Quenot, J. P. et al. Bedside adherence to clinical practice guidelines in the intensive care unit: the TECLA study. Intensive Care Med. 34, 1393-1400 (2008).
26. Quenot, J. P., Thiery, N. & Barbar, S. When should stress ulcer prophylaxis be used in the ICU? Curr. Opin. Crit. Care 15, 139-143 (2009).
27. Frandah, W., Colmer?Hamood, J., Nugent, K. & Raj, R. Patterns of use of prophylaxis for stress?related mucosal disease in patients admitted to the intensive care unit. J. Intensive Care Med. 29, 96-103 (2014).
28. deFoneska, A. & Kaunitz, J. D. Gastroduodenal mucosal defense. Curr. Opin. Gastroenterol. 26, 604-610 (2010).
29. Ferrer?Ferrer, M. et al. Polymorphisms in genes coding for HSP?70 are associated with gastric cancer and duodenal ulcer in a population at high risk of gastric cancer in Costa Rica. Arch. Med. Res. 44, 467-474 (2013).
30. Tahara, T. et al. Role of heat?shock protein (HSP) 70-72 genotype in peptic ulcer in Japanese population. Hepatogastroenterology 59, 426-429 (2012).
31. Takahashi, T. et al. Correlation of heat shock protein expression to gender difference in development of stress?induced gastric mucosal injury in rats. J. Clin. Biochem. Nutr. 47, 64-73 (2010).
32. Hawkey, C. J. & Rampton, D. S. Prostaglandins and the gastrointestinal mucosa: are they important in its function, disease, or treatment? Gastroenterology 89, 1162-1188 (1985).
33. Flemstrom, G. & Turnberg, L. A. Gastroduodenal defence mechanisms. Clin. Gastroenterol. 13, 327-354 (1984).
34. Phillipson, M., Atuma, C., Henriksnas, J. & Holm, L. The importance of mucus layers and bicarbonate transport in preservation of gastric juxtamucosal pH. Am. J. Physiol. Gastrointest. Liver Physiol. 282, 211-219 (2002).
35. Flynn, R. et al. Stress ulceration and gastric mucosal cell kinetics: the influence of prophylaxis against acute stress ulceration. J. Surg. Res. 55, 188-192 (1993).
36. Robert, A. Cytoprotection of the gastrointestinal mucosa. Adv. Intern. Med. 28, 325-337 (1983).
37. Fennerty, M. B. Pathophysiology of the upper gastrointestinal tract in the critically ill patient: rationale for the therapeutic benefits of acid suppression. Crit. Care Med. 30 (Suppl.), 351-355 (2002).
38. MacLaren, R., Reynolds, P. M. & Allen, R. R. Histamine?2 receptor antagonists vs proton pump inhibitors on gastrointestinal tract hemorrhage and infectious complications in the intensive care unit. JAMA Intern. Med. 174, 564-574 (2014).
39. Chierego, M., Verdant, C. & De Backer, D. Microcirculatory alterations in critically ill patients. Minerva Anestesiol. 72, 199-205 (2006).
40. Bailey, R. W. et al. The fundamental hemodynamic mechanism underlying gastric "stress ulceration" in cardiogenic shock. Ann. Surg. 205, 597-612 (1987).
41. Yasue, N. & Guth, P. H. Role of exogenous acid and retransfusion in hemorrhagic shock?induced gastric lesions in the rat. Gastroenterology 94, 1135-1143 (1988).
42. Cook, D. J. et al. The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients. Crit. Care 5, 368-375 (2001).
43. Mutlu, G. M., Mutlu, E. A. & Factor, P. GI complications in patients receiving mechanical ventilation. Chest 119, 1222-1241 (2001).
44. Martindale, R. G. Contemporary strategies for the prevention of stress?related mucosal bleeding. Am. J. Health Syst. Pharm. 62 (Suppl. 2), 11-17 (2005).
45. Perry, M. A., Wadhwa, S., Parks, D. A., Pickard, W. & Granger, D. N. Role of oxygen radicals in ischemia?induced lesions in the cat stomach. Gastroenterology 90, 362-367 (1986).
46. Stupak, D. P., Abdelsayed, G. G. & Soloway, G. N. Motility disorders of the upper gastrointestinal tract in the intensive care unit: pathophysiology and contemporary management. J. Clin. Gastroenterol. 46, 449-456 (2012).
47. Haglund, U. Stress ulcers. Scand. J. Gastroenterol. Suppl. 175, 27-33 (1990).
48. Itoh, M. & Guth, P. H. Role of oxygen?derived free radicals in hemorrhagic shock?induced gastric lesions in the rat. Gastroenterology 88, 1162-1167 (1985).
49. Smith, P., O'Brien, P., Fromm, D. & Silen, W. Secretory state of gastric mucosa and resistance to injury by exogenous acid. Am. J. Surg. 133, 81-85 (1977).
50. Marrone, G. C. & Silen, W. Pathogenesis, diagnosis and treatment of acute gastric mucosal lesions. Clin. Gastroenterol. 13, 635-650 (1984).
51. Dzienis, H., Gronbech, J. E., Varhaug, J. E., Lekven, J. & Svanes, K. Regional blood flow and acid secretion associated with damage and restitution of the gastric surface epithelium in cats. Eur. Surg. Res. 19, 98-112 (1987).
52. Durham, R. M. & Shapiro, M. J. Stress gastritis revisited. Surg. Clin. North Am. 71, 791-810 (1991).
53. Synnerstad, I., Johansson, M., Nylander, O. & Holm, L. Intraluminal acid and gastric mucosal integrity: the importance of blood?borne bicarbonate. Am. J. Physiol. Gastrointest. Liver Physiol. 280, 121-129 (2001).
54. Szabo, S. Mechanisms of gastric mucosal injury and protection. J. Clin. Gastroenterol. 13 (Suppl. 2), 21-34 (1991).
55. Miller, T. A. Mechanisms of stress?related mucosal damage. Am. J. Med. 83, 8-14 (1987).
56. Goldin, G. F. & Peura, D. A. Stress?related mucosal damage. What to do or not to do. Gastrointest. Endosc. Clin. N. Am. 6, 505-526 (1996).
57. Samloff, I. M. Peptic ulcer: the many proteinases of aggression. Gastroenterology 96, 586-595 (1989).
58. Schiessel, R., Feil, W. & Wenzl, E. Mechanisms of stress ulceration and implications for treatment. Gastroenterol. Clin. North Am. 19, 101-120 (1990).
59. Krag, M., Perner, A., Wetterslev, J., Wise, M. P. & Hylander Moller, M. Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients. A systematic review of randomised clinical trials with meta?analysis and trial sequential analysis. Intensive Care Med. 40, 11-22 (2014).
60. Kotlyanskaya, A., Luka, B. & Mukherji, R. A comparison of lansoprazole disintegrating tablet, lansoprazole suspension or ranitidine for stress ulcer prophylaxis in critically ill patients [abstract 194]. Crit. Care Med. 7 (2008).
61. Drasar, B. S., Shiner, M. & McLeod, G. M. Studies on the intestinal flora. I. The bacterial flora of the gastrointestinal tract in healthy and achlorhydric persons. Gastroenterology 56, 71-79 (1969).
62. Thorens, J. et al. Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study. Gut 39, 54-59 (1996).
63. Wang, K. et al. The effect of H2?receptor antagonist and proton pump inhibitor on microbial proliferation in the stomach. Hepatogastroenterology 51, 1540-1543 (2004).
64. Zedtwitz?Liebenstein, K. et al. Omeprazole treatment diminishes intra? and extracellular neutrophil reactive oxygen production and bactericidal activity. Crit. Care Med. 30, 1118-1122 (2002).
65. Giuliano, C., Wilhelm, S. M. & Kale?Pradhan, P. B. Are proton pump inhibitors associated with the development of community?acquired pneumonia? A meta?analysis. Expert Rev. Clin. Pharmacol. 5, 337-344 (2012).
66. Filion, K. B. et al. Proton pump inhibitors and the risk of hospitalisation for community?acquired pneumonia: replicated cohort studies with metaanalysis. Gut 63, 552-558 (2014).
67. Eom, C. S. et al. Use of acid?suppressive drugs and risk of pneumonia: a systematic review and meta?analysis. CMAJ 183, 310-319 (2011).
68. Dial, S., Delaney, J. A., Barkun, A. N. & Suissa, S. Use of gastric acid?suppressive agents and the risk of community?acquired Clostridium difficileassociated disease. JAMA 294, 2989-2995 (2005).
69. Tleyjeh, I. M. et al. Association between proton pump inhibitor therapy and Clostridium difficile infection: a contemporary systematic review and meta?analysis. PLoS ONE 7, e50836 (2012).
70. Shivashankar, R. et al. Clinical factors associated with development of severecomplicated Clostridium difficile infection. Clin. Gastroenterol. Hepatol. 11, 1466-1471 (2013).
71. Janarthanan, S., Ditah, I., Adler, D. G. & Ehrinpreis, M. N. Clostridium difficile?associated diarrhea and proton pump inhibitor therapy: a meta?analysis. Am. J. Gastroenterol. 107, 1001-1010 (2012).
72. Kwok, C. S. et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta?analysis. Am. J. Gastroenterol. 107, 1011-1019 (2012).
73. Pant, C., Madonia, P. & Minocha, A. Does PPI therapy predispose to Clostridium difficile infection? Nat. Rev. Gastroenterol. Hepatol. 6, 555-557 (2009).
74. Khorvash, F., Abbasi, S., Meidani, M., Dehdashti, F. & Ataei, B. The comparison between proton pump inhibitors and sucralfate in incidence of ventilator associated pneumonia in critically ill patients. Adv. Biomed. Res. 3, 52 (2014).
75. Vincent, J. L. et al. The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. JAMA 274, 639-644 (1995).
76. Lewis, S. C., Li, L., Murphy, M. V., Klompas, M. & Epicenters, C. D. C. P. Risk factors for ventilator?associated events: a case?control multivariable analysis. Crit. Care Med. 42, 1839-1848 (2014).
77. Barletta, J. F., El?Ibiary, S. Y., Davis, L. E., Nguyen, B. & Raney, C. R. Proton pump inhibitors and the risk for hospital?acquired Clostridium difficile infection. Mayo Clin. Proc. 88, 1085-1090 (2013).
78. Eastwood, G. M. et al. Opinions and practice of stress ulcer prophylaxis in Australian and New Zealand intensive care units. Crit. Care Resusc. 16, 170-174 (2014).
79. Barletta, J. F. et al. Pharmacoepidemiology of stress ulcer prophylaxis in the United States and Canada. J. Crit. Care (2014).
80. Murphy, C. E. et al. Frequency of inappropriate continuation of acid suppressive therapy after discharge in patients who began therapy in the surgical intensive care unit. Pharmacotherapy 28, 968-976 (2008).
81. Farrell, C. P., Mercogliano, G. & Kuntz, C. L. Overuse of stress ulcer prophylaxis in the critical care setting and beyond. J. Crit. Care 25, 214-220 (2010).
82. MacLaren, R., Jarvis, C. L. & Fish, D. N. Use of enteral nutrition for stress ulcer prophylaxis. Ann. Pharmacother. 35, 1614-1623 (2001).
83. Hurt, R. T. et al. Stress prophylaxis in intensive care unit patients and the role of enteral nutrition. J. Parenter. Enteral. Nutr. 36, 721-731 (2012).
84. Ruiz?Santana, S. et al. Stress?induced gastroduodenal lesions and total parenteral nutrition in critically ill patients: frequency, complications, and the value of prophylactic treatment. A prospective, randomized study. Crit. Care Med. 19, 887-891 (1991).
85. Osman, D., Djibre, M., Da Silva, D. & Goulenok, C. Management by the intensivist of gastrointestinal bleeding in adults and children. Ann. Intensive Care 2, 46 (2012).
86. Madsen, K. R. et al. Guideline for stress ulcer prophylaxis in the intensive care unit. Dan. Med. J. 61, C4811 (2014).
87. Barkun, A. N. et al. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann. Intern. Med. 152, 101-113 (2010).
88. Laine, L. & Jensen, D. M. Management of patients with ulcer bleeding. Am. J. Gastroenterol. 107, 345-360 (2012).
89. Lu, Y., Loffroy, R., Lau, J. Y. & Barkun, A. Multidisciplinary management strategies for acute non?variceal upper gastrointestinal bleeding. Br. J. Surg. 101, 34-50 (2014).
90. Opio, C. K. & Garcia?Tsao, G. Managing varices: drugs, bands, and shunts. Gastroenterol. Clin. North Am. 40, 561-579 (2011).
91. Myburgh, J. A. et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N. Engl. J. Med. 367, 1901-1911 (2012).
92. Perner, A. et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N. Engl. J. Med. 367, 124-134 (2012).
93. Jairath, V. et al. Red cell transfusion for the management of upper gastrointestinal haemorrhage. Cochrane Database of Systematic Reviews, Issue 9 Art. No.: CD006613. http://dx.doi.org/10.1002/14651858.CD006613. pub3.
94. Villanueva, C. et al. Transfusion strategies for acute upper gastrointestinal bleeding. N. Engl. J. Med. 368, 11-21 (2013).
95. Hebert, P. C. & Carson, J. L. Transfusion threshold of 7 g per deciliter-the new normal. N. Engl. J. Med. 371, 1459-1461 (2014).
96. Dellinger, R. P. et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012. Crit. Care Med. 41, 580-637 (2013).
97. Palamidessi, N., Sinert, R., Falzon, L. & Zehtabchi, S. Nasogastric aspiration and lavage in emergency department patients with hematochezia or melena without hematemesis. Acad. Emerg. Med. 17, 126-132 (2010).
98. Razzaghi, A. & Barkun, A. N. Platelet transfusion threshold in patients with upper gastrointestinal bleeding: a systematic review. J. Clin. Gastroenterol. 46, 482-486 (2012).
99. Gralnek, I. M., Barkun, A. N. & Bardou, M. Management of acute bleeding from a peptic ulcer. N. Engl. J. Med. 359, 928-937 (2008).
100. Rockall, T. A., Logan, R. F., Devlin, H. B. & Northfield, T. C. Risk assessment after acute upper gastrointestinal haemorrhage. Gut 38, 316-321 (1996).
101. Barkun, A. N., Bardou, M., Martel, M., Gralnek, I. M. & Sung, J. J. Prokinetics in acute upper GI bleeding: a meta?analysis. Gastrointest. Endosc. 72, 1138-1145 (2010).
102. Sreedharan, A. et al. Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding. Cochrane Database Systematic Reviews, Issue 7 Art. No.: CD005415. http://dx.doi.org/10.1002/14651858.CD005415.pub3.
103. Barkun, A. N. Should every patient with suspected upper GI bleeding receive a proton pump inhibitor while awaiting endoscopy? Gastrointest. Endosc. 67, 1064-1066 (2008).
104. Lau, J. Y. et al. Omeprazole before endoscopy in patients with gastrointestinal bleeding. N. Engl. J. Med. 356, 1631-1640 (2007).
105. Lim, L. G. et al. Urgent endoscopy is associated with lower mortality in high?risk but not low?risk nonvariceal upper gastrointestinal bleeding. Endoscopy 43, 300-306 (2011).
106. Rockey, D. C. Lower gastrointestinal bleeding. Gastroenterology 130, 165-171 (2006).
107. Barkun, A. New topical hemostatic powders in endoscopy. Gastroenterol. Hepatol. (N.Y.) 9, 744-746 (2013).
108. Sung, J. J. et al. Continuation of low?dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Ann. Intern. Med. 152, 1-9 (2010).
109. de Aquino Lima, J. P. & Brophy, J. M. Conflicting evidence: what's a clinician to do? Ann. Intern. Med. 153, 413-415 (2010).
110. Heyland, D. et al. Enteral nutrition in the critically ill patient: a prospective survey. Crit. Care Med. 23, 1055-1060 (1995).
111. Schupp, K. N., Schrand, L. M. & Mutnick, A. H. A cost?effectiveness analysis of stress ulcer prophylaxis. Ann. Pharmacother. 37, 631-635 (2003).
112. Barletta, J. F. & Sclar, D. A. Use of proton pump inhibitors for the provision of stress ulcer prophylaxis: clinical and economic consequences. Pharmacoeconomics 32, 5-13 (2014).
113. MacLaren, R. & Campbell, J. Cost?effectiveness of histamine receptor?2 antagonist versus proton pump inhibitor for stress ulcer prophylaxis in critically ill patients. Crit. Care Med. 42, 809-815 (2014).
114. Freedberg, D. E. & Abrams, J. A. Does confounding explain the association between PPIs and Clostridium difficile?related diarrhea? Am. J. Gastroenterol. 108, 278-279 (2013).
115. Barkun, A. N., Adam, V., Martel, M. & Bardou, M. Cost?effectiveness analysis: stress ulcer bleeding prophylaxis with proton pump inhibitors, H2 receptor antagonists. Value Health 16, 14-22 (2013).
116. ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis. ASHP Commission on Therapeutics and approved by the ASHP Board of Directors on November 14 1998. Am. J. Health. Syst. Pharm. 56, 347-379 (1999).
117. Guillamondegui, O. D. et al. Practice management guidelines for stress ulcer prophylaxis [online], https://www.east.org/resources/treatmentguidelines/stress?ulcer?prophylaxis (2008).
118. Heidelbaugh, J. J. & Inadomi, J. M. Magnitude and economic impact of inappropriate use of stress ulcer prophylaxis in non?ICU hospitalized patients. Am. J. Gastroenterol. 101, 2200-2205 (2006).
119. Thomas, L. et al. Longitudinal analysis of the costs associated with inpatient initiation and subsequent outpatient continuation of proton pump inhibitor therapy for stress ulcer prophylaxis in a large managed care organization. J. Manag. Care Pharm. 16, 122-129 (2010).
120. Devlin, J. W., Claire, K. S., Dulchavsky, S. A. & Tyburski, J. G. Impact of trauma stress ulcer prophylaxis guidelines on drug cost and frequency of major gastrointestinal bleeding. Pharmacotherapy 19, 452-460 (1999).
121. Pitimana?aree, S. et al. Implementation of a clinical practice guideline for stress ulcer prophylaxis increases appropriateness and decreases cost of care. Intensive Care Med. 24, 217-223 (1998).
122. Barkun, A. N. et al. Effectiveness of disseminating consensus management recommendations for ulcer bleeding: a cluster randomized trial. CMAJ 185, 156-166 (2013).
123. Filbin, M. R. et al. The microcirculation is preserved in emergency department low?acuity sepsis patients without hypotension. Acad. Emerg. Med. 21, 154-162 (2014).
124. Shapiro, N. I. & Angus, D. C. A review of therapeutic attempts to recruit the microcirculation in patients with sepsis. Minerva Anestesiol. 80, 225-235 (2014).
125. Karakaya, K. et al. Mitigation of indomethacininduced gastric mucosal lesions by a potent specific type V phosphodiesterase inhibitor. World J. Gastroenterol. 15, 5091-5096 (2009).
126. Taldone, T., Ochiana, S. O., Patel, P. D. & Chiosis, G. Selective targeting of the stress chaperome as a therapeutic strategy. Trends Pharmacol. Sci. (2014).
127. Bulger, J. et al. Choosing wisely in adult hospital medicine: five opportunities for improved healthcare value. J. Hosp. Med. 8, 486-492 (2013).