Revisiting Stress Ulcer Prophylaxis NAHLA IRTIZA ISMAIL

HOSPITAL MELAKA

A spectrum….

Superfical lesion

Asymptomatic

Occult GI bleeding

Anaemia

Overt GI bleeding

+ Anaemia

Clinically Significant GI

bleeding +

Transfusion

Peura D: Stress-related mucosal damage. Clin Ther 1986, 8(A):14–23

Incidence Within 12 -24 hours of admission in 50-70% of ICU patients

Mucosal damage evidenced via endoscopy

75-100% 1

Clinically evident bleeding 5-25% 1

Overt Bleeding 1-3% 2,3

1. Mutlu GM et al. Chest 2001, 119:1222–1241 2. Bardou, M. et al. Nat. Rev. Gastroenterol. Hepatol. 12, 98–107 (2015) 3. Krag M et al. ntensive Care Med (2015) 41:833–845.

MORBIDITY

Increases length of stay in the ICU (48 days)

MORTALITY

50-70% in patients with clinically significant bleed

Not new….

• ‘Lethal stress ulceration’ in patients with:

• Respiratory failure

• Hypotension

• Sepsis (Skillman and Silen)

• ‘Stress related ulcerative syndrome’ (Lucas et al)

70s

• Stress gastritis/ stress-induced gastritis

• Stress-related erosive syndrome

• Stress ulcer syndrome

• Stress related mucosal disease

NOW

Pathophysiology

Stollman N & Metz DC. 2005 Mar;20(1):35-45

Risk Factors

A prospective multicentre cohort studies N = 2252 APACHE II : 21 + 9 (moderate to severe illness) End points :

• Overt bleeding • Clinically important GI

bleeding.

OVERT BLEEDING

•Hematemesis

•Gross blood or ‘coffee grounds’ material in the NG tube

•Hematochezia

•melaena

CLINICALLY IMPORTANT BLEEDING

Overt bleeding complicated by one of the following within 24 hours after the onset: • a spontaneous decrease of > than 20

mmHg in SBP

• An increase in > than 20 bpm heart rate

• A decrease of Hb > than 2 g/dl and transfusion of 2 units of blood

Risk factors •Mechanical ventilation > 48 hours

•Coagulopathy (thrombocytopenia PLT < 50,0000, INR > 1.5, PTT > 2 x control)

•Hepatic failure

•Renal failure

•Sepsis

•Shock

•Multiorgan failure

•Burn

•Severe head injury

•History of peptic ulcer disease or GI bleeding

•Organ transplantation

•Antiplatelet, anticoagulants, fibrinolytics, corticosteroids

Agents for Stress Ulcer prophylaxis (SUP)

Antacids

Sucralfate

Histamine 2 Receptor Antagonist (H2RA)

Proton Pump Inhibitor (PPI)

Sucralfate

•Sulfated polysaccharide complexed with Aluminium Hydroxide

•Adhere to epithelial cells forming a physical barrier.

•Protects the gastric mucosa from the effects of acid and pepsin.

Limitations:

•Can impair the absorption of enteral feeds and co-administered oral medication

•Constipation

•Bezoar formation

•Aluminium toxicity

PREVIOUS

•Inferior to H2RAs to reduce clinically significant bleeding1

NOW

•rarely used as a first-line therapy

1.Cook D et al. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. N Engl J Med 1998; 338:791.

H2RA & PPI

Sascha Kopic, and John P. Geibel Physiol Rev 2013;93:189-268

Parietal cell

H2RA •competitively inhibit histamine binding to its G-protein coupled receptor a reduction in acid production overall decrease in gastric secretions.

•IV and oral formalation

•Examples : oCimetidine

oRanitidine

oFamotidine

oNizatidine

Limitation: •Tachyphylaxis can occur rapidly.

•Rebound hypersecretion after discontinuation

•diarrhoea and constipation

•headache, drowsiness, confusion and fatigue

•muscular pain

•neutropenia, agranulocytosis, and thrombocytopenia.

•bradycardia, tachycardia, and hypotension

•Hepatitis (cimetidine and ranitidine)

•Drug interaction via inhibition of CYP450 decrease clearance of drugs o theophylline, lignocaine, erythromycin, warfarin

o less with Ranitidine

PPI •Prodrug

•PPIs inactivate the H+/K+ ATPase enzyme at the secretory surface of the parietal cell inhibits the secretion of H+ ions increases the intragastric pH.

•Examples : oOmeprazole

oPantoprazole

oLansoprazole

oEsomeprazole

•In contrast to H2RA the use of PPIs is not associated with the development of tolerance

•No renal adjustment required

Limitations •GI : diarrhoea, nausea, vomiting and abdominal pain

•Acute interstitial nephritis (rash, fever, arthralgias, oliguria AKI)

•Hypomagnesemia with chronic use

•Headaches

Potential complication of SUP : • Gastric acid is important in natural host defense.

• Intragastric pH < 4 is optimal for bactericidal action

• Administration of PPI and H2RA suppress gastric acid production raises the intragastric pH.

o increase colonization of the stomach with pathogenic organisms. Aspiration Pneumonia

o Survival of acid resistant spores of C. Difficile Clostridium difficile infection

H2RA vs PPIs

Year Guidelines/Studies Findings/Remarks

1999 American Society of Health System Pharmacists (ASHSP)

Before PPI era

2008 Eastern Association for the Surgery of Trauma guidelines

No difference in efficacy between H2RA and PPI

2010 Lin et al. 1 Not in favour of PPIs over H2RA for bleeding and mortality

2012 Surviving Sepsis Campaign Guidelines Favour the use of PPI over H2RA

1. Lin, P. C.. Et al. The efficacy and safety of proton pump inhibitors vs histamine-2 receptor antagonists for stress ulcer bleeding prophylaxis among critical care patients: a meta-analysis. Crit. Care Med. 38, 1197–1205 (2010)

H2RA vs PPIs

Year Guidelines/Studies Findings/Remarks

2012 Alhazzani et al. 1 PPIs more effective than H2RA at reducing clinically important and overt GI bleeding without increasing the risk of mortality and pneumonia

2012 Barkun et al 2 PPI significantly decreased the incidence of bleeding compared with H2RAs. No differences for the development of nosocomial pneumonia, duration of ICU stay, and mortality.

2014 MacLaren et al.3 Proton pump inhibitors are associated with greater risks of GI bleeding, pneumonia, and CDI than H2RAs in mechanically ventilated patients

1.Alhazzani et al. Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis. Critical care medicine 2013;41:693-705. 2. Barkun et al. Proton pump inhibitors vs histamine 2 receptor antagonists for stress-related mucoasal bleeding prophylaxis in critically ill patients: A meta-analysis.Am J Gastroenterol. 2012;107:507---20. 3. MacLaren et al. Histamine-2 Receptor Antagonists vs Proton Pump Inhibitors on Gastrointestinal Tract Hemorrhage and Infectious Complications in the Intensive Care Unit. JAMA Intern Med. 2014;174(4):564-574

Most recent

•Twenty trials (n = 1,971)

•No statistically significant difference in mortality or hospital-acquired pneumonia between SUP patients and the no prophylaxis/placebo patients.

•Conclusions: that both the quality and the quantity of evidence supporting the use of SUP in adult ICU patients is low. A large randomised clinical trials are warranted.

Choice of agents

H2RA ?

PPI?

No SUP ?

In our local context….

Abroad….

•recommend not using SUP routinely for adult critically ill patients in the ICU (1C).

•suggest using PPIs when stress ulcer prophylaxis is indicated in adult critically ill patients in the ICU (Grade 2C).

•Nutrition -There is insufficient evidence to make any recommendation.

Abroad….

Qs that I have during round

Should SUP be prescribed to all patients admitted to the ICU?

What medication should we use?

What at the risk factors?

Controversial

H2RA vs PPI

PPI if cannot tolerate H2RA

If cannot tolerate both sucralfate

Qs that I have during round

Enteral nutrition is adequate for prevention of SU?

Not adequate. BUT can consider oral instead of IV. $$$

IV (per vial), RM

Oral (per tab), RM

Ranitidine 0.42 0.16

Omeprazole 3.20 0.44

Pantoprazole 2.76 0.16

Esomeprazole 22.54 1.84

Qs that I have during round When should it be stopped?

Why it is important to stop?

When risk factors are absent. Thus assess daily. FASTHUG

Is the patient on pre-existing H2RA/PPI?

> 90% patients in ICU received SUP

> 86% SUP was continued outside

the ICU.

> 24.2% discharged out of hospital

with SUP.1

1. Murphy, C. E. et al. Frequency of inappropriate continuation of acid suppressive therapy after discharge in patients who began therapy in the surgical intensive care unit. Pharmacotherapy 28, 968–976 (2008).

This is the best thing that we can do now.

$$$

There are complications: Pneumonia/C.Diff diarrhoea.