Prevention of GI bleeding in ICU

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Prevention of GI bleeding in the ICU

• Waleed Th.Aletreby
• ICU Registrar
• King Saud Medical City
• Riyadh KSA

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Stress Ulcers

• Also known as Stress Related Mucosal disease.
• Encompasses 2 types
• Stress related injury which is diffuse
  superficial mucosal damage that cause oozing of
  blood from superficial capillary beds. In the
  fundus and body of stomach antrum duodenum or
  distal esophagus.
• Discrete stress ulcers which are deep focal
  lesions that penetrate the submucosa most often
  in the body and fundal parts of the stomach. And
  cause massive hemorrhage or rarely perforation.

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Epidemiology

• Within 24 hrs of ICU admission 75 to 100 of
  critically ill patients have some endoscopic
  evidence of gastroduodenal lesions.
• Overt GI bleeding range from 1.5 to 8.5 among
  all ICU patients.
• And as high as 15 among patients who do not
  receive stress ulcer prophylaxis.
• Clinically significant bleeding (hemodynamic
  compromise need for blood transfusion need for
  surgery) occurs in approximately 2 to 6 of ICU
  patients.

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Pathophysiology
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Normally

• The integrity of the gastric mucosa is maintained
  by the microcirculation and the mucus layer.
• which nourishes the mucosa and eliminates
  hydrogen ions oxygen radicals and other
  potentially toxic substances.
• The mucus layer protects the epithelial mucosal
  surface from hydrogen ions (including acid) and
  other potentially harmful substances.
• It traps bicarbonate ions secreted by the mucosa
  to neutralize hydrogen ions.

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Normally

• At normal levels nitric oxide synthase enhances
  gastric mucosal integrity by maintaining blood
  flow and perfusion in the gastric mucosa.
• The buffering effect of bicarbonate and the mucus
  layer keep pH neutral even though the pH in the
  gastric lumen is often between 1.5 and 2.0.

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In critically ill patients

• The major factors of SRMD recognized include
  reduced blood flow mucosal ischemia
  hypoperfusion and reperfusion injury.
• Gastric hypoperfusion causes the release of
  nitric oxide production of oxygen radicals and
  reduction of prostaglandin synthesis.
• Additionally upper GIT motility is slowed
  leading to prolonged exposure of the poorly
  defended mucosa to gastric acid.

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Critical illness
Hypovolemia
catecholamines
Decrease CO
Proinflammatory cytokines
vasoconstriction
Splanchnic hypoperfusion
Dec HCO3
Dec Mucosal Blood flow
Dec motility
Acid Back diffusion
Acute Stress Ulcer
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Risk Factors

• Deborah J. Cook
• Professor Department of Medicine
• Clinical Epidemiology Biostatistics
• Joint Member Dept of Clinical Epidemiology
  Biostatistics
• Academic Chair Critical Care Medicine McMaster
  University
• Co-Chair Critical Research Interest Group

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Risk Factors

• In a landmark prospective multicenter cohort
  investigation (N2252)
• Cook et al. studied the risk factors for stress
  ulceration in the ICU and the incidence of
  clinically important GIT bleeding.
• Clinically important bleeding was defined as
  overt bleeding complicated by one of the
  following within 24 hours after the onset of
  bleeding

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• Spontaneous decrease in SBP of 20 mm Hg or more.
• Increase in heart rate more than 20 beats per
  minute.
• Decrease in SBP more than 10 mm Hg on sitting up.
• Decrease in hemoglobin level more than 2 g/dL and
  subsequent transfusion of blood after which
  hemoglobin levels do not increase by a value
  defined as the number of units transfused minus 2.

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Risk factors Major

• Mechanical ventilation for more than 48 hours.
• Coagulopathy
• platelet count of lt50000mm3
• INRgt1.5
• PTT of gt2 times the control
• Recent GI ulcers/bleeding Within 12 months.

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Risk factors Minor (2 or more)

• Sepsis or septic shock.
• ICU admission gt 1 week.
• Burn gt35
• Head and spinal trauma.
• Multi-organ failure.
• High dose corticosteroids
• Methylprednisolone 40 mg/day
• Hydrocortisone 250 mg/day

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Prognosis

• Overt GI bleeding due to stress ulceration is
  associated with increased mortality.

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So What to do

• PREVENTION

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Non Pharmacological

• High risk patients should be aggressively
  monitored and treated.
• Frequently assessed for signs of
  hypoperfusion(blood pressure skin color and
  warmth and mental status).
• Laboratory investigations (hemoglobin hematocrit
  WBC and serum electrolyte levels).
• Local irritants (NSAID or aspirin) should be
  avoided.
• Restrict the use of vasopressors when possible
  because they worsen ischemia of the GIT.

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Non Pharmacological

• Peripheral oxygen saturation levels are not an
  indication of gastromucosal perfusion.
• In one study critically ill patients with sepsis
  who required mechanical ventilation had
  approximately 50 less blood flow in the upper
  GIT than controls. Both groups however had
  normal peripheral oxygen saturation.
• Spirt MJ Guth PH Randall G Leung FW.
  Gastroduodenal perfusion and mortality in
  mechanical ventilation-dependent patients with
  systemic inflammatory response syndrome. Dig Dis
  Sci. 200449906-913.

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Non Pharmacological

• Gastric tonometry the measurement of the carbon
  dioxide level inside the stomach in order to
  assess the degree of blood flow to the stomach
  and bowel.

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Enteral nutrition

• Enteral feedings initiated within 12 hours of
  trauma were as effective as H2RA.
• The risk of clinically important gastric bleeding
  was reduced in patients receiving enteral
  feedings.
• Raff T et al.Burns 1997 23313.
• Cook D et al.Canadian Critical Care Trials
  Group. Crit Care Med 1999272812.

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• Surgical Critical Care and Medical Critical Care
  Services at Orlando Regional Medical Center
  recommend considering discontinuing prophylaxis
  therapy in all patients when full enteral feeding
  is tolerated except for mechanically ventilated
  patients.
• A meta-analysis published in 2010 included 17
  randomized controlled trials that enrolled a
  total of 1836 patients (Marik P et al) showed
  that Stress ulcer prophylaxis did not decrease
  the risk for GI bleeding in the patients that
  were fed enterally.

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• The gastroprotective effect of enteral feedings
  is an area of continued debate.
• Overall studies in which the effects of enteral
  nutrition on gastric bleeding risk were evaluated
  have had numerous shortcomings.
• Including inadequate statistical power
  concurrent use of pharmacological prophylaxis
  lack of a consistent enteral nutrition regimen
  and variable definitions of bleeding.

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Pharmacological prevention
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1) Histamine2 Receptor Agonists

• Act by decreasing gastric acid secretion through
  reversible competitive inhibition of histamine
  stimulated acid secretion and are effective in
  reducing basal acid production.
• cimetidine ranitidine famotidine nizatidine.
• Significantly lower rates of clinically important
  GIT bleeding among patients who received
  ranitidine than among patients who received
  sucralfate (cook et al 1998).

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Histamine2 Receptor Agonists

• They can be given orally via NGT or
  intravenously and well tolerated.
• Continuous IV infusion is more effective than
  bolus IV at controlling gastric pH but not in
  preventingclinically significant GI bleeding.
• Incidence of thrombocytopenia is rare.
• Ranitidine 50mg IV Q8h 150mg PO Q12h.

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Histamine2 Receptor Agonists

• Gastrin and acetylcholine provide alternative
  pathways to the stimulation of acid secretion
  acid suppression with H2RA is incomplete.
• Dosing can be difficult because of the nonlinear
  kinetics and short duration of action.
• Tolerance develops with H2RA as early as 72 hours
  after administration.
• Decrease clearance of warfarin theophylline
  phenytoin lidocaine and clarithromycin (mainly
  cimetidine). Ranitidine interactions though less
  frequent can occur with nifedipine and
  cyclosporine.

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2) Sucralfate

• Sucralfate is a sulfated polysaccharide complexed
  with aluminum hydroxide .
• It exerts its effects by coating and protecting
  the gastric mucosa without altering gastric acid
  secretion or significantly buffering acid.
• Administered orally or via NGT at a dose of 1
  gram four times per day.
• H2RA and sucralfate have comparable effectiveness
  for preventing stress ulcers at 10-25 and at
  15-40 respectively (Darlong V 2003 Kantorova
  I 2004)

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Sucralfate

• Since it does not inhibit or neutralize gastric
  acid it does not favor growth of gram-negative
  organisms in stomach or increase risk of
  nosocomial pneumonia.

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Sucralfate

• Sucralfate decreases the absorption of
  ciprofloxacin norfloxacin theophylline
  tetracycline phenytoin cimetidine ranitidine
  l-thyroxine ketoconazole and digoxin.
• Use of sucralfate should be avoided in patients
  with compromised renal function to avoid aluminum
  accumulation and poisoning.

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3) Proton pump inhibitors

• Block acid secretion by irreversibly binding to
  and inhibiting the hydrogen-potassium ATPase pump
  that resides on the luminal surface of the
  parietal cell membrane.
• omeprazole lansoprazole rabeprazole
  pantoprazole esomeprazole.
• They can be given orally via NGT or
  intravenously.
• Rapid onset of action linear kinetics longer
  duration of action and lack of observed
  tolerance.
• Not renally eliminated.
• Omeprazole 40 mg/24 hrs orally or NGT.

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Proton pump inhibitors

• PPIs (particularly Omeprazole) delay clearence
  of warfarin diazepam phenytoin digoxin
  theophylline and carbamazepine.

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4) Antacids

• Antacids neutralize gastric acid and protect the
  gastric mucosa.
• Administered every one to two hours at a dose of
  30 to 60 mL either orally or via nasogastric
  tube.
• Side effects include hypermagnesemia
  hypercalcemia hypophosphatemia constipation
  and diarrhea.
• Level 1 recommendation that antacids should not
  be used as stress ulcer prophylaxis.
• diarrhea flatulence headache nausea hepatic
  dysfunction electrolyte abnormalities
  constipation and altered drug absorption.

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5) Prostanoids

• Misoprostol inhibit gastric acid secretion by
  selectively reducing the ability of the parietal
  cell to generate cyclic AMP in response to
  histamine.
• Exert a cytoprotective effect by enhancing
  mucosal defense mechanisms.
• Rarely used in ICU due to the lack of data
  regarding their impact on clinically important
  outcomes.
• Found ineffective in stress ulcer prophylaxis by
  some authors (Lam NP National survey of stress
  ulcer prophylaxis.Crit Care Med. 19992798-103.)

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Which agent to choose

• Comparative studies

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Which agent to choose

• Agents that reduce the frequency of overt GI
  bleeding in ICU patients most effectively (H2
  blockers and PPIs) might be associated with more
  frequent nosocomial pneumonia.
• In contrast a less effective prophylactic agent
  ( sucralfate ) may be associated with fewer
  nosocomial pneumonias.
• Thus clinicians need to consider whether
  prevention of overt GI bleeding or minimizing the
  incidence of nosocomial pneumonia is of greater
  clinical importance.

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Which agent to choose

• Cost Choosing less expensive prophylactic
  agents or administering prophylaxis only to
  patients who are at high risk for stress
  ulceration can diminish the cost of stress ulcer
  prophylaxis.

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Level 1

• Prophylaxis is recommended for all high risk
  patients.
• There is no difference between H2 antagonists
  cytoprotective agents and some proton pump
  inhibitors.
• No recommendation regarding duration of
  prophylaxis.

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Level 2

• Aluminum containing compounds should not be used
  in patients on dialysis.
• Prophylaxis should continue during mechanical
  ventilation or intensive care unit stay.

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Level 3

• Enteral feeding alone may be insufficient stress
  ulcer prophylaxis.
• Prophylaxis should continue until able to
  tolerate enteral nutrition.

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