Stress Ulceration in ICU: Overview plus Meta-Analysis

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Stress Ulceration in ICUOverview plus
Meta-Analysis

• James Nott CT1 ACCS

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Aims

• Epidemiology and Definition
• Pathophysiology of Stress ulcers
• Clinical presentation
• Risk factors
• Prophylaxis agents available mechanisms
• Meta-Analysis
• PPIs vs H2RA for stress ulcer prophylaxis in
  critically ill patients.

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Epidemiology / Definition

• Common
• 1.5 8.5 GI bleeding in all ICU patients
• 15 - 25 of ICU patients not on prophylaxis
• 75 mucosal abnormalities of ICU patients lt72hrs
  (major burn/cranial trauma)
• Ulcer
• Lesion of mucosal membrane accompanied by oedema
  and necrosis of surrounding tissue
• Loci
• Stress ulcers - Fundus (Proximal)
• Peptic ulcers - antrum (Distal) / proximal
  duodenum
• Presentation range
• Asymptomatic Acute haemorrhage
  depending on depth of ulcer

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Pathophysiology

• Imbalance mucosal protection vs gastric pH
• Multi-factorial
• 
  

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Clinical Presentation

• Range depends on depth of ulcer
• Superficial Asymptomatic
• Deep Haemorrhage (Haematemesis /Melena)

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Who is at risk?

• Intubated gt48hrs OR 15.6 (3) Cook. DJ et
  al 94
• Coagulopathy OR 4.3
• Additional risks identified
• SHOCK
  Everyone!
• Sepsis
• Hepatic and Renal failure
• Multiple trauma
• Burns of gt35 BSA
• Glucocorticoid therapy

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Prophylaxis Pharmacological / Enteral feeding

• Pharmacological mechanisms
• 1) Block acid secretion
• Competitive H2 antagonists (Ranitidine)
• Proton pump inhibitors (Omeprazole)
• 2) Neutralise stomach acid contents
• Antacids (Gaviscon) Bicarbonate neutralises pH

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Prophylaxis cont...

• 3) Protecting stomach mucosa nil buffering
• Sucraflate - polysaccharide Aluminium hydroxide
  
• 4) Prostaglandin analogues
• Misoprostol inhibit parietal cells to generate
  cAMP, thus reduce stomach acid secretion

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What are the common S/Es of pharmacological
agents?

• Nosocomial pneumonia (HAP/VAP)
• ? pH Less hostile environment for bacteria
• Not so with Sucralfate (not affects pH)
• Ways to reduce risk (Preventing aspiration)
• - Patient position semirecumbant not supine
• - Mouth care Chlorhexidine mouthwash/gel
• - Subglotic drainage
• - ? Residual gastric monitoring

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Meta-analysis Critical Care Medicine March 2013

• Aim
• Determine efficacy and safety of proton pump
  inhibitors verses H2 receptor antagonists for the
  prevention of upper GI bleeding in ICU
• Methodology
• Search strategy
• MEDLINE (1948-March 2012)
• EMBASE (1980-March 2012) Two
  researchers independently
• ACPJC (1991-March 2012)
  extracted data
• Cochrane (central) database
• CINHAL.
• Any disagreements resolved by discussion or
  consensus

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Eligibility Criteria

• Types of study
• - Randomised Control Trials (RCTs)
• Population
• - ICU Adults (Medical and Surgical included)
• Intervention
• - Control H2RA InterventionPPIs
• - para-enteral/enteral
• - regardless of dose, frequency and duration

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Outcomes

• Primary outcomes
• - clinically important GI bleed (?Meaning Hb
  drop/instability)
• - overt upper GI bleeding
• (coffee ground emesis, melena, fresh blood PR
  from UGI )
• Secondary outcomes
• Nosocomial pneumonia (VAP/HAP)
• All-cause mortality
• ICU length of stay
• C. Diff infection

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Quality Assessment (Cochrane Risk of Bias
Tool)

• All trials assessed for risk, depending on
  domains
• Low risk low in ALL domains
• Unclear risk is unclear in gt1 domain
• High risk is high in gt1 domain
• Domains
• Sequence Generation
• Allocation concealment
• Blinding
• Incomplete outcome data
• Selective reporting bias
• Free of other bias
• Plus Overall risk of bias
  

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Which studies were included?
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Statistical Analysis

• Data analysed using RevMan 5.1 model.
• Pooled
• Dichotomous outcomes - RR 95 CI
• Continuous outcomes Mean
• Methods of assessing heterogeneity (? Bias)
• Subgroup analysis Size,
• Eggers test /funnel plot to assess publication
  bias

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Results Primary Outcomes

• Primary objectives
• 1) Clinically important bleeding (12 Trials
  n1614)
• Significantly lower RR with PPIs vs H2RA
• (RR 0.36 95 CI 0.19-0.68 p0.002)

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Results Primary outcomes

• 2) Overt Bleeding ( 14 Trials n 1720)
• Significantly lower RR with PPIs vs H2RA
• (RR 0.35 95CI 0.21-0.59 plt0.0001)

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Results Secondary outcomes

• 1) Nosocomial Pneumonia ( 8 Trials, n 1100)
• No significant difference RR 1.06 95 CI
  (0.73-1.52) p0.76

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Results Secondary outcomes

• 2) Mortality ( 8 Trials n 1196)
• No significant difference RR 1.01 95 CI
  (0.83-1.24) p0.91

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Results Secondary outcomes

• 3) ICU Length of stay ( 5 Trials n555)
• No significant difference CI (-2.20-1.13) p53
• 4) Clostridium difficile infection
• No trials reported on C. Difficile infection

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Findings

• Significantly ? risk of both 10 outcomes with
  PPIs
• - Clinically important GI bleeding RR 0.36
  (0.19-0.68)
• - Overt UGI bleeding RR 0.35 (0.21-0.59)
• No significant ? risk of 20 outcomes with PPIs
  vs H2RA
• Nosocomial pneumonia RR 1.06 (0.73-1.52)
• ICU mortality RR 1.01 (0.83-1.24)
• ICU length of stay RR 0.54 (-2.20-1.13)

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Limitations Risk of Bias

• Primary outcomes (14 Trials)
• Low risk of bias 3
  Inflates benefit of PPIs
• Unclear 5
• High risk of bias 6 (lack of blinding)
• Publication bias (Funnel plot)
• Larger trials (y axis) are more reliable
  closer to mean RR (x axis)

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Limitations Cont....

• Definitions varied (Pneumonia)
• No randomisation of nutritional strategies
• Age of studies (1948) ? relevance to todays
• Accepts - PPIs may lower risk of GI bleeding
• Welcomes further research
• - Effect of early nutrition
• - Cost-benefit analysis
• - C. Diff infection

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Should we change current practice at QA?

• NO!
• Meta-analysis does not show significant evidence
  that PPIs are better than H2RAs.
• Rantidine is cheap and as effective as PPIs for
  ulcer prophylaxis, so why change?
• Establish enteral nutrition important no
  statistical evidence.

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• Thank you, any questions!?!

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References

• Cook.DJ, Stress ulcer prophylaxis. Best evidence
  synthesis Scand J Gastroenterol Supple 1995
  21048
• Stollman. N, Pathophysiology and prophylaxis of
  stress ulceration in ICU, Journal of critical
  care, vol 20, March 2005
• 3) Cook. DJ et al, risk factors for
  gastrointestinal bleeding in critical ill
  patients, Canadian Critical Care Trials Group. N
  Engl J Med 1994 330377
• 5) Marik P.E et al, Stress ulceration prophylaxis
  in the new millennium, meta-analysis. Critical
  Care Med 2010 382222