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Prophylaxis in the Intensive Care Unit

Dr. Mohammad Aljawadi PharmD, Msc, PhDPHCL 478

Clinical Pharmacy DepartmentCollege of Pharmacy King Saud University

APRIL 2015

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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

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Prophylaxis•VTE Prophylaxis•Surgical Prophylaxis•Stress Ulcer Prophylaxis

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VTE Prophylaxis

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VTE Prophylaxis•Discussed in details in PHCL 477

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Surgical Prophylaxis

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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)

Guidelines for antimicrobial prophylaxis in surgery

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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.

Cefazolin, cefoxitin, cefotetan, or cefuroxime.

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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

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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

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Special Considerations•Obese patients > 120 Kg needs higher dose•Hypersensitivity to cephalosporins•Hypotension and red-neck syndrome with

vancomycin

http://journal.frontiersin.org/article/10.3389/fpubh.2014.00217/full

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Surgical Prophylaxis

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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

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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%)

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Stress Ulcer Mucosal DamageSource:

http://gastrointestinalatlas.com/English/Stomach/Gastritis/gastritis.html

Peptic Ulcer DiseaseSource:

http://www.practicalhospital.com/stomach-diseases/peptic-ulcer-disease

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Background: Risk FactorsMajor Minor ( 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

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Stress Ulcer Risk factors based on Current Guidelines

Risk factors of gastrointestinal bleeding due to stress ulcer Source Major Mechanical Ventilation > 48 hrs. ASHP & EAST Coagulopathy ASHP & EAST Major Head Injuries ASHP & EAST Major Burns (>35% of BSA) ASHP & EASTMinor Sepsis ASHP & EAST Multiple Trauma Injury ASHP & EAST Corticosteroid Therapy > 250 mg of hydrocortisone or equivalent daily ASHP & EAST Spinal cord injuries or Head injuries ASHP Renal Failure ASHP Hepatic Failure ASHP Partial Hepatectomy ASHP Transplantation ASHP History of Gastric Ulcer or bleeding a year prior to admission ASHP ICU stay of > 1 week ASHP Occult or overt bleeding for ≥ 6 days ASHPASHP: American Society of Health System Pharmacists; EAST: Eastern Association for the Surgery of

Trauma; BSA: Body Surface Area, ICU: Intensive Care Unit

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Natural Defense Mechanism

Gastric Acidand Pepsin

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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

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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

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Sequence of Events to Stress Ulcer Splanchnic hypo-perfusion and ischemia of gastric microcirculation / Low Gastric Motility

Reduction in nutrient absorption and impairment in oxygen delivery.

Mucus and Bicarbonate production decreases

Mucosal acid-buffering capacity deteriorates

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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.

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.

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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

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Site of Action for GAMAS

Why PPIs is More Potent?

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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.

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Published Studies Stress Ulcer Prophylaxis-related:Gastrointestinal Bleeding Nosocomial PneumoniaClostridium Difficile-Associated Diseases

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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

Ref: (Cook D.J, 1996)

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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

Ref: (Cook D.J, 1996)

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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

Ref: (Cook D.J, 1996)

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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)

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Meta-analyses that compared PPIs to H2Bs:

Reference Number 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.

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Summary of literature: CIGIB•Only one RCT and a series of meta-analyses favored

PPIs over H2Bs.

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Published Studies Stress Ulcer Prophylaxis-related:Gastrointestinal Bleeding Nosocomial PneumoniaClostridium Difficile-Associated Diseases

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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

Ref: (Cook D.J, 1996)

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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).

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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)

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Meta-analyses that compared PPIs to H2Bs:

Reference Number 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.

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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.

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Published Studies Stress Ulcer Prophylaxis-related:Gastrointestinal Bleeding Nosocomial PneumoniaClostridium Difficile-Associated Diseases

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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, I2= 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, I2= 87%

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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.

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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%

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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

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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.

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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.

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H2Bs:

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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)

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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)

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GAMAS Overutilization

2008 2009 2010 2011 2012 Total0

102030405060708090

100PPIs, H2Bs, Sucralfate or Antacids PPIs, H2Bs or Sucralfate

Year

Per

cent

age

• 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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Overall 2008 (n=78,838)

2009 (n=122,548)

2010 (n=137,386)

2011 (n=153,137)

2012 (n=80,610)

0

10

20

30

40

50

60

70

80

90

100

46.6 45.84 45.91 47.88 46.59 46.22

39.81 40.67 41.15 39.37 39.36 38.54

3.58 3.19 3.2 3.44 3.81 4.33

10.01 10.3 9.75 9.3 10.24 10.91

Percentages of Stress Ulcer Prophylaxis Use by Indication between 2008 and 2012 (N=572,519)

Did not Use and did not have an indication (Appropiate)

Did not use and had an indica-tion (Underutilization)

Used and did not have an indica-tion (Overutilization)

Used and had an indication (Appropiate)

Perc

enta

ge

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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]

Multivariable logistic regression:

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Take home message

Stop SUP when risk factors are resolved or

patients discharged from the ICU

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

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Questions