James Nott CT1 ACCS
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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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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 <72hrs (major burn/cranial
trauma)
Ulcer:
‘Lesion of mucosal membrane accompanied by oedema and necrosis of
surrounding tissue’
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Loci:
Stress ulcers - Fundus (Proximal)
Peptic ulcers - antrum (Distal) / proximal duodenum
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Presentation range:
Asymptomatic – Acute haemorrhage depending on depth of ulcer
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Imbalance: mucosal protection vs gastric pH
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Multi-factorial:
Range depends on depth of ulcer
Superficial: Asymptomatic
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Deep: Haemorrhage (Haematemesis /Melena)
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Intubated >48hrs OR 15.6
Coagulopathy OR 4.3
Additional risks identified:
SHOCK
Everyone!
Sepsis
Hepatic and Renal failure
Multiple trauma
Burns of >35% BSA
Glucocorticoid therapy
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(3) Cook. DJ et al ’94
Pharmacological mechanisms:
1) Block acid secretion
 Competitive H2 antagonists (Ranitidine)
 Proton pump inhibitors (Omeprazole)
2) Neutralise stomach acid contents
Antacids (Gaviscon) – Bicarbonate neutralises pH
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
Nosocomial pneumonia (HAP/VAP)
↑ pH – Less hostile environment for bacteria
Not so with Sucralfate (not affects pH)
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Ways to reduce risk: (Preventing aspiration)
- Patient position – semirecumbant not supine
- Mouth care – Chlorhexidine mouthwash/gel
- Subglotic drainage
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- ? Residual gastric monitoring
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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)
independently
ACPJC (1991-March 2012)
Cochrane (central) database
CINHAL.
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Two researchers
extracted data
Any disagreements resolved by discussion or consensus
Types of study:
- Randomised Control Trials (RCTs)
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Population:
- ICU Adults (Medical and Surgical included)
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Intervention:
- Control= H2RA Intervention=PPIs
- para-enteral/enteral
- regardless of dose, frequency and duration
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Primary outcomes:
- clinically important GI bleed (?Meaning Hb
drop/instability)
- overt upper GI bleeding
(coffee ground emesis, melena, fresh blood PR from
UGI )
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Secondary outcomes:
Nosocomial pneumonia (VAP/HAP)
All-cause mortality
ICU length of stay
C. Diff infection
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All trials assessed for risk, depending on domains:
Low = risk low in ALL domains
Unclear =risk is unclear in >1 domain
High = risk is high in >1 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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Data analysed using RevMan 5.1 model.
 Pooled:
Dichotomous outcomes - RR
95% CI
Continuous outcomes – Mean
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Methods of assessing heterogeneity (? Bias):
Subgroup analysis – Size,
Egger’s test /funnel plot to assess publication
bias
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Primary objectives:
1) Clinically important bleeding (12 Trials
n=1614)
Significantly lower RR with PPIs vs H2RA:
(RR 0.36 95% CI 0.19-0.68 p=0.002)
2) Overt Bleeding ( 14 Trials n= 1720)
Significantly lower RR with PPIs vs H2RA:
(RR 0.35; 95%CI 0.21-0.59 p<0.0001)
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1) Nosocomial Pneumonia ( 8 Trials, n= 1100)
No significant difference: RR 1.06 95% CI (0.731.52) p=0.76
2) Mortality ( 8 Trials n= 1196)
No significant difference: RR 1.01 95% CI (0.831.24) p=0.91
3) ICU Length of stay ( 5 Trials n=555)
No significant difference :CI (-2.20-1.13) p=53
4) Clostridium difficile infection
No trials reported on C. Difficile infection
‘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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Primary outcomes (14 Trials):
Low risk of bias – 3
Unclear – 5
High risk of bias – 6 (lack of blinding)
Inflates benefit of PPIs
Publication bias (Funnel plot):
Larger trials (y axis) are more reliable – closer to mean RR (x axis)
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Inverted funnel shape
Clinically important bleeding
Overt bleeding outcome
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Definitions varied (Pneumonia)
No randomisation of nutritional strategies
Age of studies (1948) – ? relevance to today’s
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Accepts - ‘PPIs may lower risk of GI bleeding’
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Welcomes further research:
- Effect of early nutrition
- Cost-benefit analysis
- C. Diff infection
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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.
Thank you, any questions!?!
Cook.DJ, Stress ulcer prophylaxis. Best evidence
synthesis Scand J Gastroenterol Supple 1995;
210:48
2)
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; 330:377
5) Marik P.E et al, Stress ulceration prophylaxis in
the new millennium, meta-analysis. Critical Care
Med 2010; 38:2222
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