OSHP 4-18 - Villanueva · stress ulcers in the ICU? A) GI hypoperfusion B) Anemia C) Infection D) Hypersecretory state 3 Pre rAssessment Which of the following have been identified

Updates in stress ulcer prophylaxis: Ispharmacological prophylaxis still

indicated?Ruben D Villanueva, PharmD, BCCCP, BCPS

Assistant professorOU HSC College of Pharmacy

Trauma Critical CareOU Medical Center

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Objectives

• Describe the pathophysiology of stress ulcers in thecritically ill

• Compare and contrast current stress ulcer prophylaxisguidelines

• Summarize recent stress ulcer prophylaxis literature

• Determine a critically ill patient’s continued need forstress ulcer prophylaxis

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Pre Assessment

Which of the following is the underlyingpathophysiologic process for the development ofstress ulcers in the ICU?

A) GI hypoperfusionB) AnemiaC) InfectionD) Hypersecretory state

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Pre Assessment

Which of the following have been identified asindependent risk factors for clinically significant GIbleeding in critically ill patients?

A) SepsisB) Organ transplantC) Vasoactive medicationsD) Renal replacement therapy

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Pre Assessment

Enteral nutrition would likely be sufficient for stressulcer prophylaxis in which of the following scenarios?

A) Mechanically ventilated patient receiving continuousrenal replacement therapy with an INR of 2

B) Mechanically ventilated TBI patient withoutintracranial hypertension

C) Mechanically ventilated patient with chronic liver andkidney disease, COPD, and receiving corticosteroids

D) Mechanically ventilated patient without significantPMH, an INR of 1.9 and on norepinephrine

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BACKGROUND &PATHOPHYSIOLOGY

Updates in Stress Ulcer Prophylaxis

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BackgroundStress related mucosal disease/damage• Represents a continuum

– Asymptomatic superficial lesions to clinicallysignificant GI bleeding (GIB)

• Two types– Stress related injury– Stress ulcers

• EXCLUDES variceal bleeding

Plummer, M. P., Blaser, A. R., & Deane, A. M. (2014). Stress ulceration: prevalence, pathology, and association with adverse outcomes. Critical Care, 18(213), 1 7.Fennerty, M. B. (2002). Pathophysiology of the upper gastrointestinal tract in the critically ill patient: Rationale for the therapeutic benefits of acid suppression. Crit Care Med, 30, S351 S355.

Stress related mucosal bleedingOccult Guaiac+ stool or gastric aspirateOvert (OB) Hematemesis, hematochezia, melena

Clinically important (CIB) Overt PLUS 1: hemodynamic changes,need for transfusion, or Hgb >2g/dL

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Background

• Asymptomatic erosions (± occult bleeding)– Present in 74 – 100% of critically ill patients within72hr of admission to the ICU based on endoscopy

• Rates of overt and clinically significant bleedingdepend on how they are defined– 2001 review suggested overt bleedingmay occur in

25% of ICU patients without pharmacologic SUP– Overall incidence of clinically significant GI bleedingin patients without pharmacologic SUP reported at 3– 4% (0.6 – 5%)

Mutlu, G. M., Mutlu, E. A., & Factor, P. (2001). GI Complications in Patients Receiving Mechanical Ventilation. CHEST, 119, 1222 1241.Bardou, M., Quenot, J. P., & Barkun, A. (2015). Stress related mucosal disease in the critically ill patient. Nat Rev Gastroenterol Hepatol, 12, 98 107.Plummer, M. P., Blaser, A. R., & Deane, A. M. (2014). Stress ulceration: prevalence, pathology, and association with adverse outcomes. Critical Care, 18(213), 1 7.

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Background

• Mortality varies by population– Combined data from 2 large studies (N = 1666) ofmechanically ventilated (MV) patients

• Attributable mortality of clinically important bleeding– Absolute risk: 20 – 30%– Relative risk (vs no CIB): 1 – 4

– Recent data reported 55.6% 90d mortality w/CIB

Cook, D. J., Griffith, L., Walter, S. D., Guyatt, G., O'Meade, M., Heyland, D., . . . Tryba, M. (2001). The attributable mortality and length ofintesive care unit stay of clinically important gastrointestinal bleeding in critically ill patients. Critical Care, 5(6), 368 375.Krag, M., Perner, A., Wetterslev, J., Wise, M. P., Borthwick, M., Bendel, S., . . . Moller, M. H. (2015). Prevalence and outcome ofgastrointestinal bleeding and use of acid suppressantsina cutely ill adult intensive care patients. Intensive Care Med, 41, 833 845.

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Vasoconstric on

Bardou, M., Quenot, J. P., & Barkun, A. (2015). Stress related mucosal disease in the critically ill patient. Nat Rev Gastroenterol Hepatol, 12, 98 107.Buendgens, L., Koch, A., & Tacke, F. (2016). Prevention of stress ulcer bleeding at the intensives care unit: Risks and benefits of stress ulcer prophylaxis.World J Crit Care Med, 5(1), 57 64.

Catecholamines Shock or hypotension Hypovolemia

Cardiac output Proinflammatorycytokine release

Splanchnic and mucosalhypoperfusion

HCO3secretion

Mucosalblood flow

Acute Stress ulcer

Gastric Acid

Critical Illness

Mucosal vulnerability

GI Mo lity Protec vefactors, i.e HSP, TFF

Acid backdiffusion

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RISK FACTORSUpdates in Stress Ulcer Prophylaxis

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Risk FactorsCook et al., 1994† Simons et al., 1995‡ Cook et al., 1999†

Design MC Pro Obs (N = 2252) Retro. (N = 33,637) MC Pro. RCT (N = 1077)

Patients

60±15 years17.4% on MV48.5% CV surgeryTBI <2.5%

Poly traumaNo breakdown ofpatient characteristics*EXCLUDED burns*

Age ~60 years100% on MV~60% medical~22% emerg. surgery

Intervent.Encouraged withholding SUPEXCEPT certain populations30% on SUP

N/ARanitidine: 50mg IV q8hr

Sucral: 1gm PT q6hr

GIBDefinitions

CIB†: OB plus 1 within 24hr of onset of bleeding (absent other causes): SBP by20mmHg, SBP by 10mmHg or HR by 20bpm on si ng up; Hgb >2mg/dL plustx; tx after which the Hgb did not rise by number units tx’d minus 2mg/dLSevere stress ulcer/CIB‡: perforation or bleeding requiring >2 units tx’d

Outcomes

Mortality (%) 9 vs. 48.5 Mortality w/GIB (%) 25 ICU mort. (%) 19 vs. 36.7

GIB: 14±12d after admitOB: 4.4%o 95%CI 3.6 – 5.6%CIB: 1.5%o 95%CI 1 – 2.1%

GIB: 51% 14d p injuryo 40% on H2RAo 25% diet/gastric ENOB: 0.17%CIB: 0.05%

GIB: median 3d (2 – 6d)OB : 4.7% (3.4 – 6)CIB: 2.6% (1.6 – 3.6)

MC = multicenter, Pro = prospective, Obs = observational, Retro = restrospecitve, RCT = randomized controlled trialMV = mechanical ventliation, CV = cardiovascular, TBI = traumatic brain injuryGIB = gastrointestinal bleeding, OB = overt bleeding CIB = clinically important bleeding, tx = transfusion*Certain populations = TBI, burns w/BSA >30%, peptic ulcer disease/gastritis, recent GIB, organ transplant

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Cook et al., 1994* Simons et al., 1995** Cook et al., 1999*RiskFactorCIB*GIB**

Univariate (OR)HOTN: 25.5Sepsis: 7.3Liver fx: 6.5Renal fx: 4.6Steroids: 3.7Organ txp: 3.6Anticoagulation tx: 3.3EN 3.8

Independent (OR)MV >48hr: 15.6Coagulopathy : 4.3

***31/33 CIBs had MVor coagulopathy******22/33 CIBs w/BOTHMV andcoagulopathy******2/1405 CIBs withneither MV orcoagulopathy ***

Univariate (RR)TS<13: 2.8AIS head 3: 4.8>2 Organ fxs: 49.4ARDS: 30.1Renal Fx: 45.5Liver fx: 51Coagulopathy: 26.3Pneumonia 20.4Other infx: 23.3

Independent (OR)SCI: 2ISS 16: 12.6Age >55: 2.5

***ALL CIB had either SCIor ISS 16***

Univariate (RR)Plt <50k 2.58 (1.19 – 5.57)Max Scr 1.19 (1.06 – 1.35)Max MOD 1.11 (1.01 – 1.21)Renal MOD 1.46 (1.14 – 1.87)Hep MOD 1.37 (1.04 – 1.77)EN 0.35 (0.16 – 0.76)H2RA 0.4 (0.18 – 0.89)

Independent (RR)Max Scr 1.16 (1.02 – 1.32)EN 0.3 (0.13 – 0.67)H2RA 0.39 (0.17 – 0.83)

OR = odds ratio, RR = relative risk, txp = transplant, AC anticoagulant, tx = treatment, TS = truama score, AIS = abbreviated injury severityscore, fx = failure, SCI = spinal cord, ISS = injury severity score, MOD = multi organ dysfunction score, EN = enteral nutrition 13

Risk Factors: 2000sAll (N = 1034) CIB (N = 1007) +CIB (N = 27) P

Age, median (IQR) 63 (48 – 74) 64 (48 – 75) 58 (51 – 70) 0.324

SOFA, median (IQR) 6 (4 – 8 ) 6 (4 8) 10 (7 – 14) <0.001

Coagulop. at admission, % 12.4 11.7 37 <0.001

Comorbidities, %

0 48.5 4.9 18.5 0.002

1 30.8 30.6 37 0.474

2 14.8 14.6 22.2 0.271

3 4.4 4.1 18.5 0.005

>3 1.5 1.5 3.7 0.347

Mechanical vent. at admit, % 52.6 52.3 63 0.275

Circ. support at admit, % 45.4 44.7 70.3 0.009

RRT at admit, % 6.8 6.1 33.3 <0.001

90d Mortality, % 26.2 25.4 55.6CIB = clinically important bleeding SOFA = sequential organ failure assessment, Coagulop = coagulopathy, Circ support =circulatory support (i.e. vasoactive infusions), RRT = renal replacement therapy

Krag, M., Perner, A., Wetterslev, J., Wise, M. P., Borthwick, M., Bendel, S., . . . Moller, M. H. (2015). Prevalence and outcome of gastrointestinal bleeding anduse of acid suppressantsina cutely ill adult intensive care patients. Intensive Care Med, 41, 833 845.

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GI bleeding definitions and outcomes

Overt bleeding (OB) 1 of the following: hematemesis, coffee groundemesis, melena, hematochezia, bloody NG aspirate

Clinically important bleeding (CIB) OB plus 1 of the following within 24hr of OB in theabsence of other causes: BP 20 mmHg, startof/increase of vasopressor 20 %, Hgb 2 g/dl, tx2 units RBCs during bleeding episode

Acid suppression therapy at admit, % 37.4

PPI, % 55

H2RA, % 17

Median time to GIB, days (IQR) 3 (2 – 6)

21/27 7d of ICU stay

OB (49/1034), % (95%CI) 4.7 (3.4 6)

CIB (27/1034), % (95%CI) 2.6 (1.6 – 3.6)

***27/27 receiving SUP at time of bleed***

90d Mortality and CIB, % 55.6

OR 3.72( 1.72 – 8.04)

aOR 1.70 (0.68 – 4.28)Krag, M., Perner, A., Wetterslev, J., Wise, M. P., Borthwick, M., Bendel, S., . . . Moller, M. H. (2015). Prevalence and outcome of gastrointestinal bleeding and use of acid suppressantsina cutely ill adult intensive care patients. Intensive Care Med, 41, 833 845.

Risk Factors: 2000s

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Risk Factors: 2000sRisk Factor Overt GI Bleeding (aOR) CIB (aOR)

SOFA score 1.25 (1.14–1.38) 1.37 (1.22–1.55)

Chronic liver disease* 4.51 (2.30–8.86) 7.64 (3.32–17.57)

Coagulopathy* 2.64 (1.29–5.42) 4.22 (1.74–10.23)

Comorbidities

1 2.51 (1.15–5.46) 3.03 (1.00–9.25)

2 2.80 (1.17–6.67) 3.22 (0.94–11.06)

3 4.24 (1.31–13.72) 9.29 (2.34–36.94)

>3 6.66 (1.22–36.42) 8.88 (2.74–28.80)

Circulatory support at admit 2.39 (1.28–4.46) 2.31 (0.99–5.40)

RRT at admit* 7.35 (3.47–15.56) 6.89 (2.72–17.48)

Coagulopathy. at admit* 4.06 (2.16–7.63) 5.21 (2.29–11.83)

Anticoagulation at admit 2.25 (1.04–4.87) 1.77 (0.61–5.16)

Acid suppressive tx at admit 2.95 (1.44–6.06) 3.61 (1.28–10.20*Previously identified risk factors for CIB

Krag, M., Perner, A., Wetterslev, J., Wise, M. P., Borthwick, M., Bendel, S., . . . Moller, M. H. (2015). Prevalence and outcome of gastrointestinal bleeding and use of acidsuppressantsina cutely ill adult intensive care patients. Intensive Care Med, 41, 833 845.

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Risk Factors: Enteral Nutrition

• Protective effects of EN– Increased splanchnic blood flow– EN formulations are typically alkaline

• Independent predictor of lower rates of CIB inMV patients on SUP: 0.3 (0.13 – 0.67)

Cook, D., Heyland, D., Griffith, L., Cook, R., Marshall, J. C., & Pagliarello, J. (1999). Rik factors for clinically important upper gastrointestinal bleeding in patientsrequiring mechanical ventilation. Crit Care Med, 27(12), 2812 2817.Hurt, R. T., Frazier, T. H., McClave, S. A., Crittenden, N. E., Kulisek, C., Saad, M., & Franklin, G. A. (2012). Stress Ulcer Prophylaxis in Intensive Care Unit Patients andthe Role of Enteral Nutrition. J Parenter Enteral Nutr, 36(6), 721 731.

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Risk Factors: Summary

• Several risk factors for CIB have been identified– 1990s data

• Consistent univariate risk factors– Multi organ failure, liver failure, renal failure, coagulopathy

• Independent risk factors– MV >48hr, coagulopathy, SCI, ISS 16, maximum Scr

– 2015 data• Independent risk factors

– High organ failure scores (SOFA), chronic liver disease,coagulopathy, 3 comorbidities, renal failure

• Enteral nutrition may serve as a protective factor– Effects on GI blood flow and pH– Negative risk factor in a PRCT of pharmacological SUP

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GUIDELINESUpdates in Stress Ulcer Prophylaxis

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ASHP 1999 EAST 2008 SSC 2016Indicationso MV >48hr or coagulopathy (C)o GIB or GI ulcer in past year (D)o TBI w/GCS 10 (B)o >35% BSA burns (B)o 2 of following (D):

o Sepsis, ICU >7d, occultbleeding >6d, >250mg HCequivalents

MAY BE indicatedo Partial hepatectomy (C)o Poly trauma w/ISS 16 (D)o Transplants (D)o Hepatic failure (D)o SCI (D)

Indications (level I)o MVo Coagulopathyo TBIo Major burnIndications (level II)o Polytraumao Sepsiso Acute renal failureIndications (level III)o ISS >15o >250mg HC equivalentso Select populations no ppx is

neededLevel IIContinue until extubated or outof ICULevel IIIContinue until tolerating EN

Indications(strong rec, low quality):o Sepsis/septic shock

PLUS risk factorso Mentioned “strongest

clinical predictors ofGIB risk” MV >48hrand coagulopathy

o “…preexisting liverdisease, need for RRT,and higher organfailure scores wereindependentpredictors of GIB risk”

Recommend against SUPin those w/o risk factors(BPS)

Choice should be institution specificInsufficient data for PPI

Level INo difference b/w H2RA,cytoprotectants, and some PPIsLevel IIIEnteral feeding alone may beinsufficient

Either H2RA or PPI (weakrec, low quality)

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PROSPECTIVE AND RETROSPECTIVEUpdates in Stress Ulcer Prophylaxis: Recent Publications

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Recent Publications

Sasbuchi, Y., Matsui, H., Lefor, A. K., Fushimi, K., & Yasunaga, H. (2016). Risks and Benefits of Stress Ulcer Prophylaxis for Patients with Severe Sepsis. Crit Care Med, 44, e464 e469.

Propensity Matched Japanese Database Cohort Study

Design Case control

Database Japanese diagnosis procedure combination database

PatientsCases: severe sepsis (sepsis + 1 organ dysfunction)

Exposure: SUP (PPI or H2RA within 2 days of admission)

Outcomes, % SUP (N = 16,651) Control (N = 16,651) P value

GIB* 0.5 0.6 0.208

30d Mortality 16.4 16.9 0.249

CDI 1.4 1.3 0.588

HAP 3.9 3.3 0.012

Significant subgroup interactions for 30d mortality, %** Pvalue PintxICU admission within 2d 15.7 19.6 0.002 0.004

MV within 2d† 20.5 23.1 0.005 0.010

Vasoactive meds w/n 2d 17.6 19.6 0.002 0.002

2 organ failures† 23.6 26.2 0.012 0.041*Requiring endoscopic hemostasis within 30d of admission, **No other subgroup interactions noted†Previously iden ed risk factorsCDI = Clostridium difficile infection, HAP = hospital acquired pneumonia

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Recent Publications• Design

– International, multicenter, randomized, blinded, placebocontrolled

• Interventions– IV pantoprazole 40mg daily while on MV or until GIB vs.placebo (PBO)

• Decision to continue PPI after extubation at physician discretion

Alhazzani, W., Guyatt, G., Alshahrani, M., Deane, A. M., Marshall, J. C., Hall, R., . . . Cook, D. (2017). Witholding Pantoprazole for Stress Ulcer Prophylaxis in Critically Ill Patients: APilot Randomized Clinical Trial and Meta Analysis. Crit Care Med, 45, 1121 1129.

Outcomes and Inclusion/Exclusion Criteria

GIB outcome definition (CIB)OB PLUS 1 within 24 hours in the absence of another cause:SBP/DBP 20 mm Hg, orthosta c HR 20bpm or SBP

10mmHg, Hgb 2g/dL within 24 hours, tx 2 units PRBCs

Inclusion Expected mechanical ventilation (MV) >48hr

Exclusion

MV 72hr prior to randomization, use of PPI due to active bleedor risk of bleeding, dual an platelet therapy prior torandomization, palliative care, 2 “daily dose equivalents” of ppxH2RA or PPI

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Recent PublicationsCharacteristics PPI (N = 49) PBO (N = 42)Age, median (IQR) 61.8 (48.4 – 73.5) 55.3 (42.4 – 65.6)

Admission type, %

Medical 79.6 73.8

Surgical 4.1 11.9

Trauma 16.3 14.3

APACHE II, median (IQR) 21 (17 – 26) 21.5 (14 – 27)

Comorbidities, %

Respiratory failure 10.2 7.1

All others 8% (CHF, ESRD, Immunocompromised)

Medications within 3d of randomization, %

ASA 22.4 19

PPx UFH 16.3 14.3

PPx LMWH 24.5 26.2

Alhazzani, W., Guyatt, G., Alshahrani, M., Deane, A. M., Marshall, J. C., Hall, R., . . . Cook, D. (2017). Witholding Pantoprazole for Stress Ulcer Prophylaxis in Critically Ill Patients:A Pilot Randomized Clinical Trial and Meta Analysis. Crit Care Med, 45, 1121 1129.

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Recent Publications

Alhazzani, W., Guyatt, G., Alshahrani, M., Deane, A. M., Marshall, J. C., Hall, R., . . . Cook, D. (2017). Withholding Pantoprazole for Stress Ulcer Prophylaxis inCritically Ill Patients: A Pilot Randomized Clinical Trial and Meta Analysis. Crit Care Med, 45, 1121 1129.

Patient Characteristics relevant to SUP

Characteristic PPI (N = 49) PBO (N = 42)Study day 1, %

Mechanical ventilation 100 100

Vasoactive meds 44.9 57.1

Intermittent hemodialysis 0 2.4

Continuous renal replacement 4.1 7.1

Lowest Hgb, mean (SD) 9.86 (2.22) 10.4 (2.21)

Highest INR, mean (SD) 1.43 (0.5) 1.32 (0.4)

Lowest platelet count, mean (SD) 183.4 (81) 197.3 (111.2)

H2RA b/f randomization, % 4.1 7.1

PPI b/f randomization, % 30.6 33.3

Duration of mech vent, median (IQR) 9 (5 – 17) 6.5 (4 – 14)

Median days of treatment, N (IQR) 5 (3 – 15) 5 (2 – 11)*89% receiving EN during initial 72hr of admission

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Recent Publications

Alhazzani, W., Guyatt, G., Alshahrani, M., Deane, A. M., Marshall, J. C., Hall, R., . . . Cook, D. (2017). Witholding Pantoprazole for Stress Ulcer Prophylaxis inCritically Ill Patients: A Pilot Randomized Clinical Trial and Meta Analysis. Crit Care Med, 45, 1121 1129.

Outcome PPI (N = 49) PBO (N = 42) RR (95%CI)Any GIB, % 8.2 7.1 1.14 (0.27 – 4.82)

Minor UGIB, % 2 2.4 0.86 (0.06 – 13.29)

Clinically important GIB, % 6.1 4.8 1.29 (0.23 – 7.33)

GIB requiring intervention, % 6.1 4.8 1.29 (0.23 – 7.33)

Incident CDI, % 4.1 2.4 1.71 (0.16 – 18.24)

VAP, % 20.4 14.3 1.43 (0.57 – 3.60)

ICU mortality, % 22.4 23.8 (p = 1)

Hospital Mortality, % 34.7 31 (p = 0.824)

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Prospective/Retrospective: Summary• Retrospective data: severe sepsis/septic shock

– NO association between H2RA/PPI SUP and reduction in GIB requiringendoscopic hemostasis

– Subgroups whomay benefit• Mechanical ventilation• Multi organ failure

• Recent placebo controlled data:– PPI SUP DOES NOT appear to significantly reduce clinically important GI

bleeds in a MV population• Caveats

– Minimal co morbidities– Not on dual antiplatelet therapy– No renal failure– No coagulopathy– Early enteral nutrition (within 72hr of ICU admission)

– Numerically higher rates of CDI and VAP– No difference in mortality

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ENTERAL NUTRITIONUpdates in Stress Ulcer Prophylaxis: Recent Publications

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– Single center, randomized, blinded, placebo controlled

• Interventions– IV pantoprazole 40mg daily until extubation or 14d vs.placebo (PBO)


Primary outcome: clinicallyimportant GI bleeding(OB = overt bleeding)

OB PLUS 1: MAP 20 mm Hg within 24 hours in the absence ofanother cause, Hgb 2g/dL within 24 hours, or need forendoscopy or surgery to achieve hemostasis

Inclusion Expected MV >24hr and ENTERNAL NUTRITION (EN) within 48hr

Exclusion

AST prior to admit, admitted w/GIB, hx PUD, >100mgprednisolone equivalents, upper GI or cardiac surgery duringcurrent hospitalization, Jehovah’s Witness, could not receivestudy drug within 36hr of MV, palliative care, readmitted to ICU

Selvanderan, S. P., Summers, M. J., Finnis, M. E., Plummer, M. P., Abdelhamid, Y. A., Anderson, M. B., . . . Deane, A. M. (2016). Pantoprazole or Placebo for Stress UlcerProphylaxis (POP UP): Randomized Double Blind Exploratory Study. Crit Care Med, 44, 1842 1850.

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Recent PublicationsCharacteristic PBO (N = 108) Pantoprazole (N = 106)

Age (yr), mean (SD) 52 (17) 52 (18)

APACHE III, mean (SD) 66 (28) 66 (26)

IV/PO Steroids, % 14 8

Vasoactive infusions, % 53 49

Max vasoactive dose(mcg/min), median (IQR)

10 (6 – 18) 10 (5 – 21)

Primary ICU diagnostic group (N; nonoperative/operative)

Trauma 32 (20/12) 31 (18/13)

Neuro 26 (18/8) 35 (27/8)

Respiratory 24 (14/10) 19 (15/4)

Cardiovascular 14( 13/1) 9 (7/2)

Source of ICU admission, %

Operating theatre 49 45

Emerg Dept 33 30

General ward 11 16


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Recent PublicationsPatient Characteristics relevant to SUP

PBO Pantoprazole P value

Hemostatic dysfunction, % 32 37 0.50INR >1.5 19 23 0.46

PTT >40s 25 20 0.36

Plt <100,000 17 19 0.78

Steroids, % 22 16 0.25

Enteral nutrition

Number who received, % 87 83 0.41

Time from MV to initiation, hr 16 (95%CI 10 – 25) 16 (95%CI 8 – 22) 0.37

Volume/day, ml (95%CI) 798 (697 898) 844 (729 958) 0.55

EN intolerance, % 39 32 0.30

Time from start of MV to 1st dose, hr 17 (16 – 19) 16 (15 – 18) 0.44

Median number of doses, days (IQR) 3 (2 – 7) 3 (1 – 7) 0.58EN intolerance defined as gastric residuals >250ml at least once on any day


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Outcome PBO (N = 108) Pantoprazole (N = 106) P value

Overt bleeding, % 5.6 (95%CI 2.1 – 11.7) 2.8 (95%CI 0.6 – 8) 0.5

Clinically significantbleeding, N 0 (upper 97.5%CI 3.36) 0 (upper 97.5% 3.42)

IVAC or PNA, % 0.9 (95%CI 0.02 – 5.1) 1.9 (95%CI 0.2 – 5.1)

C. difficile, N 0 (upper 97.5%CI 3.4) 1 (95%CI 0.02 – 5.1)

90 day mortality, % 23.1 (95%CI 15.6 – 32.2) 28.3 (95%CI 20 – 37.9) 0.88IVAC = infective ventilator associated complications

Recent Publications


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– Two site, prospective, randomized, blinded,controlled

• Interventions– Placebo/EN vs 40mg IV pantoprazole daily/EN

El Kersh, K., Jalil, B., McClave, S. A., Cavallazzi, R., Guardiola, J., Guilkey, K., . . . Saad, M. (2018). Enteral nutrition as stress ulcer prophylaxis in critically ill patients: A randomizedcontrolled exploratory study. Journal of Critical Care, 43, 108 113.


Primary outcome: overt (OB)or clinically significant (CIB) GIbleeding

OB: coffee ground NG aspirate or emesis, bloody secretions inNG tube or hematemesis, melena or hematocheziaCIB*: 3 point Hct within a 24 hour period + signs of OB, or byan unexplained 6 point Hct it in a 48 hour period

Inclusion Expected MV >24hr and NO contraindications to EN within first24hr of admission

Exclusion GIB prior to study enrollment, admitted with burn injury, TBI orintracranial pressure, hx of partial/complete gastrectomy

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Recent Publications

El Kersh, K., Jalil, B., McClave, S. A., Cavallazzi, R., Guardiola, J., Guilkey, K., . . . Saad, M. (2018). Enteral nutrition as stress ulcer prophylaxis in critically ill patients: Arandomized controlled exploratory study. Journal of Critical Care, 43, 108 113.

Characteristic PPI (N = 55) PBO (N = 47)Median age, (IQR) 62 (49.5 – 68) 58 (40.5 – 66.5)Median SOFA score, (IQR) 7 (6 – 10) 7 (6 – 10)CHF, % 13 26CKD, % 13 9DM, % 25 36Other Comorbidities, % 80 81Admission dx, %

Neuro 20 19Pulmonary 51 53

Sepsis 18 11Other (%) 24 17

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Recent Publications

El Kersh, K., Jalil, B., McClave, S. A., Cavallazzi, R., Guardiola, J., Guilkey, K., . . . Saad, M. (2018). Enteral nutrition as stress ulcer prophylaxis in critically illpatients: A randomized controlled exploratory study. Journal of Critical Care, 43, 108 113.

Characteristic PPI (N = 55) PBO (N = 47)

Pre study meds within 1 week, %

NSAIDs 84 83

Corticosteroids 95 98

PPI 82 78

H2RA 95 91

Daily EN volume (ml), median (IQR) 699 (539.5) 715.5 (434 – 1081.9)

Total EN volume given (ml), median (IQR) 2540 (880 5493) 2914 (868 – 4236.5)

%Goal EN delivered, median (IQR) 55 (36.6 – 66.4) 64.4 (40.2 – 69.4)

Pressor during study, % 55 40

Hemostatic dysfx at anytime, % 45 47

Median Scr (mg/dL), median (IQR) 1 ( 0.8 – 1.8) 0.9 (0.8 – 1.4)

Duration of MV (d), median (IQR) 4 (2.2 – 7) 5 (3 – 8)

Median number of doses PPI/PBO 3 (2 – 7) 3 (2 – 6)35

Recent Publications

Characteristic PPI (N = 55) PBO (N = 47) P valueOvert GIB, % 1.82 2.13 0.99CIB GIB, % 1.82 2.13 0.99Incident CDI, % 1.82 6.38 0.33CIB: 3 point Hct within a 24 hour period + signs of overt GI bleeding, or by an 6 point Hct it in a 48 hourperiod

El Kersh, K., Jalil, B., McClave, S. A., Cavallazzi, R., Guardiola, J., Guilkey, K., . . . Saad, M. (2018). Enteral nutrition as stress ulcer prophylaxis in critically illpatients: A randomized controlled exploratory study. Journal of Critical Care, 43, 108 113.

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Palm, N., Mckinzie, B., Ferguson, P. L., Chapman, E., Dorlon, M., Eriksson, E. A., . . . Fakhry, S. M. (2016). Pharmacologic Stress Gastropathy Prophylaxis May NotBe Necessary in At Risk Surgical Trauma ICU Patients Tolerating Enteral Nutrition. Journal of Intensive Care Medicine, 1 6.

Retrospective review of STICU patients receiving ENPatients (N = 200); >95% trauma) Excluded primary coagulopathy , continued

SUP throughout ICU stay, or intolerant of EN

Median age 42yr (IQR 29 – 55)

TBI (%) 73.5

ISS 16 – 25, % (severe) 40.6

ISS >26 – 75, % (profound) 38

NSAIDS, % 31

Median time to EN (d) 1 (IQR 1 – 2)

Gastric FT location, % 94

Median duration of SUP (d) 3 (IQR 3 – 5; 96.5% H2RA)

Median duration of MV (d) 14 (IQR 10 – 20)

Median duration of MV w/o SUP (d) 10 (IQR 4 – 15)

Median ICU LOS (d) 15 (11 – 21)

Clinically important GIB, % (95%CI) 0.5 (0 – 1.48)

TBI (N = 147) 0.68 (0 – 2) *ONLY GIB NOTED*

VAP/1000 days 1

CDI/1000 days 0.2

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SR and MA of ICU Patients Receiving Enteral NutritionMethods RCTs of patients receiving pharmacological SUP vs PBO or no SUP

Studies (N = 7)

2 from 2017, 2 from 2016, 2 from 1990s, 1 from 1980s4 studies w/PPIs, 3 w/H2RAs, 1 w/sucralfate ; 4/7 used PBO, 3 noppx3 reported clinically significant GIB, 6 reported overt GIB

Patients (N = 889)

4 mixed ICUs, 3 MICUs; mean age 50 – 60s, 2 studies 20 – 40s4 studies 100% receiving EN, all studies >50%5 studies 100% on MV, 1 >60%, 1 20 – 30%Duration of MV ranged from 4 – 21d

GIB (RR) 0.8 (0.49 – 1.31), I2 = 8%

Overt GIB (N = 589) 0.79 (0.44 – 1.39), I2 = 24%

Clinically sig. (N = 725) 0.63 (0.29 – 1.37), I2 = 25%

Subgroups No significant differences noted (PPI/H2RA/Sucral, year published,sample size >100, blinded/unblinded,MICU/mixed, route)

CDI (N = 407) 0.89 (0.29 – 1.39), I2 = 0%

HAP (N = 407) 1.53 (1.04 – 2.27), I2 = 0%

VAP (N = 425) 1.24 (0.72 – 2.15), I2 = 0%

Mortality (N = 861) 1.21 (0.94 – 1.56), I2 = 0%

Huang, H. B., Jiang, W., Wang, C. Y., Qin, H. Y., & Du, B. (2018). Stress ulcer prophylaxis in intensive care unit patients receiving enteral nutrition: a systematicreview and meta analysis. Critical Care, 22(20), 1 9

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Enteral Nutrition: Summary• PPI SUP appears to offer NO benefit in reducing CIB ifMV

patients tolerating early enteral nutrition (i.e. 24hr)– PENDING < 100mg prednisolone equivalents– NO upper GI/cardiac surgery, burns, renal failure,

multiple/significant comorbidities

• PPI SUP and CDI/VAP– Does not appear to be a significant increase when used short term

• Coagulopathy?– 30 – 47% included in prospective data sets

• Hepatic dysfunction?– Case by case basis

• TBI?– Case by case basis

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META ANALYSESUpdates in Stress Ulcer Prophylaxis: Recent Publications

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Liu, B., Liu, S., Yin, A., & Siddiqi, J. (2015). Risks and benefits of stress ulcer prophylaxis in adult neurocritical patients: a systematic review and meta analysis ofrandomized controlled trials. Critical Care, 19(409), 1 13.

Systematic Review and Meta analysis: SUP vs No SUP/PBODesign RCTS including neurocritical care patients

Studies(N = 8)

1 from 1980s, 4 from 1990s, 1 from 2000s, 2 after 20107/8 in ICU setting, 1 perioperative6 used H2RAs, 1 used both H2RAs and PPIsPlacebo used in 7 trials, 1 used no ppx**No trialsmet the criteria of adequate random sequence generation,allocation concealment, and blinding**

PatientsN = 829 (288 TBI, 440 intracerebral hemorrhage; remainder emergency NES)Mean ages ranged from 29.6yr – 61yrMean GCS 5 – 9.8 across 6 studies

Outcome Upper GIB as defined in each individual studyONLY 1 evaluated CIB, remainder OVERT

UGIB(N = 8, 829 pts)

11% vs. 33%RR 0.31 (0.2 – 0.47); I2 45% (p = 0.09)

Mortality(N = 5, 381 pts)

23% vs. 30%RR 0.70 (0.5 – 0.98); I2 0% (p = 0.62)

Recent Publications

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Systematic Review and Meta analysis of PPIs vs H2RAs

Methods RCTs of comparison studies

Studies(N = 19, 2117 patients)

6 Abstracts10 IV PPI, 8 PO PPI10 high risk of bias, 3 low risk; 6 unclear9 inadequately blinded***None evaluated enteral nutrition status***

Overt GIBPPI vs H2RA(N = 17, 1897 pts)

4 PRIOR to 2000, 4 AFTER 2010 (2/4 ABSTRACT)0.48 (0.34 – 0.66), I2 = 3%

CI GIBPPI vs H2RA(N = 14, 1679 pts)

4 PRIOR to 2000, 3 AFTER 2010 (2/3 ABSTRACT)5 WITHOUT clearly defined GIB, 2 OVERT only; others w/various defs.

RR 0.39 (0.21 – 0.71), I2 = 0%

PNA(N = 13, 1571 pts) RR 1.12 (0.86 – 1.46), I2 = 2%

Mortality(N = 11, 1487) RR 1.05 (0.87 – 1.27), I2 = 0%

Alshamsi, F., Belley Cote, E., Cook, D., Almenawar, S., Alqahtani, Z., Perri, D., . . . Alhazzani, W. (2016). Efficacy and safety of proton pump inhibitors for stressulcer prophylaxis in critically ill patients: a systematic review and meta analysis of randomized trials. Critical Care, 20(120), 1 12.

Recent Publications

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Waleed, A., Alshamsi, F., Belley Cote, E., Heel Ansdel, D., Brignnardello Petersen, R., Alquraini, M., . . . Guyatt, G. (2018). Efficacy and safety of stress ulcer prophylaxis incritically ill patients: a network meta analysis of randomized trials. Intensive Care Med, 44, 1 11.

Systematic Review and Meta analysis 2018 Comparing Pharmacological SUPDesign Network meta analysis of RCTs

Studies

Comparison studies of SUP pharmacotherapiesNo restrictions on dose/route57 eligible studies (18 PPI vs H2RA; 21 H2RA vs PBP; 18 H2RA vs Sucralf.)Risk of bias HIGH in 30 studies, low in 16***MAJORITY did not report on nutritional status***

CI GIB20/31 PRIOR to 2000, 4 AFTER 2010 (2/4 abstracts)GIB + 1: significant hemodynamic changes, need for 2unitstransfusion, signi cant Hgb, +endoscopic findings, need for surgery

H2RA vs PBO OR 0.64 (0.32 – 1.30), moderate

PPI vs PBO OR 0.24 (0.10 – 0.60), moderate

PPI vs H2RA OR 0.38 (0.20 – 0.73), moderate

Nosocomial PNA Per individual study definition

H2RA vs PBO 1.19 (0.80 – 1.78), moderate

PPI vs PBO 1.52 (0.95 – 2.42) moderate

PPI vs H2RA 1.27 (0.96 – 1.68), moderate

Mortality No significant differences (H2RA vs PPI, H2RA vs PBO, PPI vs PBO)

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Recent Publications

Alhazzani, W., Guyatt, G., Alshahrani, M., Deane, A. M., Marshall, J. C., Hall, R., . . . Cook, D. (2017). Withholding Pantoprazole for Stress Ulcer Prophylaxis inCritically Ill Patients: A Pilot Randomized Clinical Trial and Meta Analysis. Crit Care Med, 45, 1121 1129.

Systematic Review and Meta analysis: PPI SUP vs PBODesign RCTs of comparison studiesStudies N = 6; 1 from 1993, 1 from 2004, 1 from 2013, 3 from 2016

PatientsN = 7131 studied ICH, 1 studied CABG, 1 studied SICU; others mixed ICUpops.

Outcome Clinically important bleeding as defined in each studyVAP and CDI as defined in each study

GIB (CIB) N = 5 (1 from 1993, 1 from 2013, 3 from 2016)OR 0.96 (0.24 – 3.82); I2 = 0%, rated as low quality evidence

VAP OR 1.45 (0.84 – 2.50); I2 = 0%, rated as low quality evidenceCDI OR 2.10 (0.31 – 14.07); I2 = 0%, rated as low quality evidenceMortality OR 1.11 (0.76 – 1.61); I2 = 0%, rated as low quality evidence

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Meta Analyses: Summary• Neurocritical care patientsMAY benefit from H2RAs

– Reduction in overt bleeding– ?Mortality benefit– Based mainly on data PRIOR to 2000

• PNA/Mortality– No significant differences– Trends towards increased risk of PNA for PPIs vs PBO/H2RAs

• PPIs > H2RAs???– Majority of included studies PRIOR to 2000s– 50% data included after 2010 in abstract form

• PPI vs PBO– No significant benefit for reducing CIB when more recent data

included– No difference in PNA/CDI/Mortality

• Upper limit of 95%CI for CDI 14.5

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FINAL SUMMARY ANDRECOMMENDATIONS

Updates in Stress Ulcer Prophylaxis

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Final Summary• Critical illness places patients at increased risk forstress related mucosal disease

• Guidelines agree on some risk factors– Large studies consistently identify certain risk factors

• Renal failure, liver failure, multi organ failure, coagulopathy– Differences in independent risk factors

• Recent literature– Suggest not allMV patients require pharmacological SUP

• Enteral nutrition may suffice– Data very weak and outdated to support PPIs over H2RAs

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Final Recommendations for SUP: Mechanically Ventilated ICU Patients

Pharmacological SUP indicated

Coagulopathy*Renal failure/renal replacement therapy (RRT)Liver failureChronic liver diseaseMulti organ failureSevere burnsTBI*SCI

Pharmacological SUP NOT indicated

Tolerating EARLY enteral nutrition and NONE ofthe following:Dual antiplatelet therapy3 comorbidities (i.e. <3)>100mg prednisolone equivalentsUpper GI or cardiac surgeryRenal failure/RRT or hepatic failure

Case by case basisISS 16Coagulopathy*TBI*

***Consider stopping pharmacological SUP after extubation in MOST patients***

Post Assessment

Which of the following is the underlying physiologicprocess for the development of stress ulcers in theICU?

A) GI hypoperfusionB) AnemiaC) InfectionD) Hypersecretory state

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Post Assessment

Which of the following has been identified as anindependent risk factor for clinically significant GIbleeding in critically ill patients?

A) SepsisB) Organ transplantC) Vasoactive medicationsD) Renal replacement therapy

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Pre Assessment

Enteral nutrition would likely be sufficient for stressulcer prophylaxis in which of the following scenarios?

A) Mechanically ventilated patient receiving continuousrenal replacement therapy with an INR of 2.1

B) Mechanically ventilated TBI patient withoutintracranial hypertension

C) Mechanically ventilated patient with chronic liver andkidney disease, COPD, and receiving corticosteroids

D) Mechanically ventilated patient without significantPMH, an INR of 1.9, and on norepinephrine

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Updates in stress ulcer prophylaxis: Ispharmacological prophylaxis still

indicated?Ruben D Villanueva, PharmD, BCCCP, BCPS

Assistant professorOU HSC College of Pharmacy

Trauma Critical CareOU Medical Center

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Documents

OSHP 4-18 - Villanueva · stress ulcers in the ICU? A) GI hypoperfusion B) Anemia C) Infection D) Hypersecretory state 3 Pre rAssessment Which of the following have been identified