1. Prophylaxis in the Intensive Care Unit Dr. Mohammad Aljawadi PharmD, Msc, PhD PHCL 478 Clinical Pharmacy Department College of Pharmacy King Saud University APRIL 2015 1

2. Learning Objectives To Identify patients in need of prophylaxis in the intensive care To understand the pathophysiology of stress ulcer To understand the role of different SUP modalities and their place of therapy To be able to choose the right SUP for the right patients based on understanding both patient and drug related variables 2

3. Prophylaxis VTE Prophylaxis Surgical Prophylaxis Stress Ulcer Prophylaxis 3

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5. VTE Prophylaxis Discussed in details in PHCL 477 5

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7. Surgical Prophylaxis Goal:To prevent surgical site infections (SSIs) The American Society of Health-System Pharmacists (ASHP) Infectious Diseases Society of America (IDSA) The Surgical Infection Society (SIS) Society of Healthcare Epidemiology of America (SHEA) 7 Guidelines for antimicrobial prophylaxis in surgery

8. Choice of Antimicrobial agents Possible microorganisms ▫ Most common  S. aureus and coagulase negative staphylococci ▫ Heart, kidney, or liver transplants and intra-abdominal procedures  Gram-negative rods and enterococci plus normal skin flora. 8 Cefazolin, cefoxitin, cefotetan, or cefuroxime.

9. Choice of Antimicrobial Agents MRSA colonization: ▫ Risk factors:  Male sex, age greater than 60 years, diabetes, and low income women  Risk of SSIs increase by 2- to 14-fold ▫ Prophylactic approach  Preoperative Vancomycin  Mupirocin intranasaly for MRSA decolonization 5 days before surgery  Chlorhexidine baths 9

10. When to give and when to stop? Give: ▫ 1 Hour (60 mins) before the procedure ▫ Vancomcyin  IV infusion  120 mins Stop: ▫ 24 hours after the procedure  To reduce the incidence of super-infection and resistance 10

11. Special Considerations Obese patients > 120 Kg needs higher dose Hypersensitivity to cephalosporins Hypotension and red-neck syndrome with vancomycin 11 http://journal.frontiersin.org/article/10.3389/fpubh.2014.00217/full

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13. Background: Definitions and Incidence Stress-related mucosal damage (SRMD) ▫ Case series of patients who developed duodenal ulceration following extensive burns Gastrointestinal bleeding: ▫ Occult bleeding (Incidence: 13% to 50%) ▫ Overt bleeding (Incidence: up to 30%) ▫ CIGIB (Incidence: 0.3% to 4%)  Mortality due to CIGIB is 48.5% compared to 9.1% among non-bleeders (RR= 2.9, 95%CI =1.6 to 5.5)  ICU length of stay is 4 to 8 days longer 13

14. Stress Ulcer-related Bleeding Clinically-Important Gastrointestinal Bleeding (0.3% to 4%) Overt Bleeding (Up to 30%) Occult Bleeding (13% to 50%) Stress-related mucosal damage (97%-100%) 14

15. Stress Ulcer Mucosal Damage Source: http://gastrointestinalatlas.com/English/Stomach/Gastritis/gastritis.html http://gastrointestinalatlas.com/English/Stomach/Gastritis/gastritis.html Peptic Ulcer Disease Source: http://www.practicalhospital.com/stomach-diseases/peptic-ulcer-disease 15

16. Background: Risk Factors MajorMinor ( 2 or more) Mechanical Ventilation > 48 hrs. Coagulopathy ▫ Platelet count less than 50,000, international normalized ratio (INR) greater than 1.5, or activated partial thromboplastin time (aPTT) more than 2 times control Head Injuries Major Burns Sepsis Multiple Trauma Injury Renal Failure Hepatic Failure Corticosteroid Therapy > 250 mg of hydrocortisone or equivalent daily ICU stay of > 1 week Partial Hepatectomy Transplantation History of Gastric Ulcer or bleeding a year prior to admission Occult or overt bleeding for ≥ 6 days 16

17. Stress Ulcer Risk factors based on Current Guidelines Risk factors of gastrointestinal bleeding due to stress ulcerSource Major Mechanical Ventilation > 48 hrs.ASHP & EAST CoagulopathyASHP & EAST Major Head InjuriesASHP & EAST Major Burns (>35% of BSA)ASHP & EAST Minor SepsisASHP & EAST Multiple Trauma InjuryASHP & EAST Corticosteroid Therapy > 250 mg of hydrocortisone or equivalent dailyASHP & EAST Spinal cord injuries or Head injuriesASHP Renal FailureASHP Hepatic FailureASHP Partial HepatectomyASHP TransplantationASHP History of Gastric Ulcer or bleeding a year prior to admissionASHP ICU stay of > 1 weekASHP Occult or overt bleeding for ≥ 6 daysASHP ASHP: American Society of Health System Pharmacists; EAST: Eastern Association for the Surgery of Trauma; BSA: Body Surface Area, ICU: Intensive Care Unit 17

18. 18 Natural Defense Mechanism Gastric Acid and Pepsin

19. Natural Defense Mechanisms in the GI: A thick layer of mucus and bicarbonate Physical Barrier Splanchnic blood supply Sensory nerves Prostaglandins Continuous movements of the stomach 19

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21. Pathophysiology reduction in nutrient absorption, accompanied by impairment in oxygen delivery. mucus and bicarbonate production becomes diminished the mucosal acid-buffering capacity deteriorates gastric acid and pepsin 21

22. Sequence of Events to Stress Ulcer 22 Exposure to stressful events Splanchnic hypo-perfusion and ischemia of gastric microcirculation / Low Gastric Motility Reduction in nutrient absorption and impairment in oxygen delivery. Mucus and Bicarbonate production decreasesMucosal acid-buffering capacity deteriorates

23. Gastric Acid is crucial In animal models, under ischemic conditions alone, SRMD involved 4% of the stomach’s body and 3% of the antrum. In contrast, lesions involved 53% of the body and 45% of the antrum upon intra-gastric instillation. 23 Yasue N, Guth PH. Role of exogenous acid and retransfusion in hemorrhagic shock-induced gastric lesions in the rat. Gastroenterology. 1988;94(5 Pt 1):1135-1143. Leung FW, Itoh M, Hirabayashi K, Guth PH. Role of blood flow in gastric and duodenal mucosal injury in the rat. Gastroenterology. 1985;88(1 Pt 2):281-289. llation of gastric acid.

24. Prophylaxis Options: Main therapy: ▫ Gastric Acid Modifying Agents or Sucralfate (GAMAS)  Acid suppressants: ▫ Proton Pump inhibitors ▫ The most potent acid suppressants ▫ Histamine Type-2 Receptor Blockers  Sucralfate (local effect)  Antacids (acid neutralizing capacity) ▫ Enteral Nutrition 24

25. Site of Action for GAMAS 25 Why PPIs is More Potent?

26. The Role of Acid Suppressants Efficacy: ▫ Prevention of stress ulcer-related gastrointestinal bleeding Safety: ▫ Bacterial colonization in the gastric lumen  Nosocomial Pneumonia due to micro-aspiration  Clostridium difficile-associated diseases CIGIB, NP and CDAD are associated with increased ICU mortality and LOS. 26

27. Stress Ulcer Prophylaxis-related: Gastrointestinal Bleeding Nosocomial Pneumonia Clostridium Difficile-Associated Diseases 27

28. Gastrointestinal Bleeding: OR=0.58, 95%CI= (0.42-0.79), no. of RCTs=20 OR=0.44, 95%CI= (0.22-0.88), no. of RCTS=10 OR=1.15, 95%CI= (0.86-1.53), no. of RCTS=15 28 Ref: (Cook D.J, 1996)

29. Gastrointestinal Bleeding: OR=0.58, 95%CI= (0.42-0.79), no. of RCTs=20 OR=0.56, 95%CI= (0.37-0.84), no. of RCTS=16 OR=0.44, 95%CI= (0.22-0.88), no. of RCTS=10 OR=1.15, 95%CI= (0.86-1.53), no. of RCTS=15 29 Ref: (Cook D.J, 1996)

30. Gastrointestinal Bleeding: OR=0.58, 95%CI= (0.42-0.79), no. of RCTs=20 OR=0.56, 95%CI= (0.37-0.84), no. of RCTS=16 OR=0.44, 95%CI= (0.22-0.88), no. of RCTS=10 OR=1.15, 95%CI= (0.86-1.53), no. of RCTS=15 30 Ref: (Cook D.J, 1996)

31. Randomized Controlled Trials that compared PPIs to H2Bs: Figure : Forrest Plot of Studies Comparing the Risk of Gastrointestinal Bleeding between Proton Pump Inhibitors and Histamine-2 Receptors Blockers in the Intensive Care Units (reprinted with permission of the authors: Al-Hazzani et al, 2013) 31

32. Meta-analyses that compared PPIs to H2Bs: ReferenceNumber of gastrointestinal bleeding episodes among the proton pump inhibitors (PPIs) group (%) Number of gastrointestinal bleeding episodes among Histamine-2 receptor blockers (H2Bs) group (%) Point of estimate and 95% confidence interval of the risk gastrointestinal bleeding comparing PPIs to H2Bs Pongprasobchai 2009 (n=569)10/282 (3.5%)23/287 (8.01%)OR: 0.42 (95%CI: 0.20 to 0.91) Zhou 2010 (n=771)10/449 (2.2%)22/322 (6.8%)OR: 0.45 (95%CI: 0.21 to 0.96) Lin PC 2010 (n=936)11/540 (2.04%)31/396 (7.8%)RD: -0.04 (95%CI: -0.09 to +0.01) Barkun AN 2012 (n=1,587)13/967 (1.3%)41/620 (6.6%)OR: 0.30 (95% CI: 0.17 to 0.54) Al-Hazzani 2013 (n=1,614)12/1019 (1.2%)38/595 (6.4%)RR: 0.36 (95% CI: 0.19 to 0.68) Table: Summary of the Meta-Analyses that Compared the Risk of Gastrointestinal Bleeding between Proton Pump Inhibitors and Histamine-2 Receptors Blockers in the Intensive Care Units OR: Odds Ratio, RD: Risk Difference, RR: Relative Risk, 95%CI: 95% Confidence Interval. 32

33. Summary of literature: CIGIB Only one RCT and a series of meta-analyses favored PPIs over H2Bs. 33

34. Stress Ulcer Prophylaxis-related: Gastrointestinal Bleeding Nosocomial Pneumonia Clostridium Difficile-Associated Diseases 34

35. Nosocomial Pneumonia: OR=0.78, 95%CI= (0.60-1.01), no. of RCTS=11 OR=1.27, 95%CI= (0.78-2), no. of RCTS=8 35 Ref: (Cook D.J, 1996)

36. Nosocomial Pneumonia: In another meta-analysis by Cook D.J. : ▫ Sucralfate vs. acid modifying drugs (Antacids+H2Bs)  OR=0.5, 95%CI: (0.2 to 0.79) A RCT: Sucralfate vs. Antacids vs. Ranitidine ▫ Early-onset NP: no difference ▫ Late-onset NP:  Ranitidine (n=80): 21%  Antacids (n=81): 16%  Sucralfate (n=83): 5% A meta-analysis that compared sucralfate to H2Bs: ▫ Ventilator-associated pneumonia was 32% higher among H2Bs patients. ▫ Late-onset NP was 4.36 times greater among the H2Bs (95%CI: 2.09 to 9.09). 36

37. Randomized Controlled Trials that compared PPIs to H2Bs: Figure : Forrest Plot of Studies Comparing the Risk of Nosocomial Pneumonia between Proton Pump Inhibitors and Histamine-2 Receptors Blockers in the Intensive Care Units (reprinted with permission of the authors: Al-Hazzani et al, 2013) 37

38. Meta-analyses that compared PPIs to H2Bs: ReferenceNumber of nosocomial pneumonia cases among the proton pump inhibitors (PPIs) group (%) Number of nosocomial pneumonia cases among Histamine-2 receptor blockers (H2Bs) group (%) Point of estimate and 95% confidence interval of the risk of nosocomial pneumonia comparing PPIs to H2Bs Pongprasobchai 2009 (n=569)29/282 (10.3%)29/287 (10.1%)OR: 1.02 (95%CI: 0.59 to 1.75) Zhou 2010 (n=771)45/449 (10.0%)32/322 (9.9%)OR: 1.03 (95%CI: 0.63 to 1.70) Lin PC 2010 (n=905)56/520 (10.8%)40/385 (10.4%)RD: 0 (95%CI: -0.04 to +0.05) Barkun AN 2012 (n=1,017)63/610 (10.3%)42/407 (10.3%)OR: 1.05 (95%CI: 0.69 to 1.62) Al-Hazzani 2013 (n=1,100) 66/626 (10.5%)50/474 (10.6%)RR: 1.06 (95%CI 0.73 to 1.52) Table: Summary of the Meta-Analyses that Compared the Risk of Nosocomial Pneumonia between Proton Pump Inhibitors and Histamine-2 Receptors Blockers in the Intensive Care Units OR: Odds Ratio, RD: Risk Difference, RR: Relative Risk, 95%CI: 95% Confidence Interval. 38

39. Summary It is unclear whether the lack of difference between PPIs and H2Bs is: ▫ Real ▫ Due to small sample size ▫ Due to the inability to differentiate early-onset from late-onset NP. 39

40. Stress Ulcer Prophylaxis-related: Gastrointestinal Bleeding Nosocomial Pneumonia Clostridium Difficile-Associated Diseases 40

41. The association between acid suppressants and CDAD: Meta-analysis (Tleyjah, 2012): ▫ 65% increase in the odds of developing CDAD with the use of PPIs compared to not receiving PPIs  OR: 1.65, 95% CI: 1.47 to 1.85, P< 0.0001, I 2 = 89.9%. Meta-analysis (Deshpande, 2012): ▫ PPIs was associated with higher odds of CDAD  OR: 2.15, 95% CI: 1.81 to 2.55, P< 0.0001, I 2 = 87% 41

42. The association between acid suppressants and CDAD: Medical ICU (March 2002-May 2004) ▫ A retrospective cohort study following an outbreak of CDAD ▫ N=827; (57% PPIs, 41% H2Bs, 22% neither) ▫ Adjusted HR did not show a significant association between acid suppressants and the risk of CDAD. 42

43. The association between acid suppressants and CDAD: The generalizability of this single ICU study is limited given: ▫ differences in practice between different ICU ▫ differences in patient populations ▫ unclear definition of exposure in this study ▫ lack of power to detect effect size difference less than 50% 43

44. 44 Summary of Literature: CDAD Studies in ICU settings are scarce ICU setting is a good setting for studying the association because of : ▫ higher incidence of CDAD in the ICU ▫ use SUP in ICU settings

45. Current practice: Antacids are not recommended and rarely used as SUP ▫ Antacids: Large and frequent dosing (30–60 mL every 1–4 hours), fluctuating gastric pH, electrolyte abnormalities (especially in patients with kidney disease), diarrhea, constipation, a propensity to clog enteral feeding tubes, and a requirement for gastric access. 45

46. Current Practice: Sucralfate is not recommended for preventing stress ulcers because of its inferiority compared to PPIs and H2Bs and it can clog enteral feeding tubes. 46

47. H2Bs: 47

48. PPIs: Pro-drugs Oral formulations are designed to dissolve at a pH > 5.6 ▫ Omeprazole 20 mg/day po or by tube (capsules)  Do not crush (delayed release)  Suspend in apple juice ▫ Esomeprazole Capsules 40 mg/day po  Do not crush (delayed release) ▫ Pantoprazole (Protonix)  Enteric-coated tablet 40 mg/day po  Crush and dissolve in 10 ml 4.2% sodium bicarbonate IV (ONLY for patients who CANNOT tolerate po/NG administration) 48

49. PPIs Adverse effects: ▫ Headache, diarrhea, constipation, abdominal pain, nausea No adjustment needed for renal or liver dysfunction Drug interactions: impaired conversion of clopidogrel to active form (e.g., omeprazole) 49

50. GAMAS Overutilization 50 Percentage of Patients who received SUP medications among patients who did not have stress ulcer risk factors, gastrointestinal diseases or gastrointestinal bleeding by year (Total=285,251)

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52. Factors Associated with GAMAS Overutilization: Mechanical Ventilation for less than 24 hours  OR:3.3; 99%CI: [2.3-4.4] Medications: ▫ Anticoagulants  OR:1.3; 99%CI[1.2,1.5] ▫ Antiplatelets:  OR:1.4; 99%CI[1.3,1.6] ▫ NSAIDs:  OR:1.8; 99%CI[1.6,1.9] 52 Multivariable logistic regression:

53. Take home message Stop SUP when risk factors are resolved or patients discharged from the ICU 53

54. New developments (FYI) PPIs may be associated with higher bleeding risk 54

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