Prevention of GI bleeding in the ICU

Waleed Th.AletrebyICU Registrar

King Saud Medical CityRiyadh, KSA

Stress Ulcers• Also known as Stress Related Mucosal disease.• Encompasses 2 types:1. 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.

2.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.

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.

PATHOPHYSIOLOGY

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.

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.

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.

Critical illness

Decrease CO

Hypovolemiacatecholamines

vasoconstriction Proinflammatorycytokines

Splanchnic hypoperfusion

Dec HCO3Dec Mucosal

Blood flowDec motility

AcidBack diffusion

Acute Stress Ulcer

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

Risk Factors• In a landmark, prospective, multicenter cohort

investigation (N=2252),

• 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:

• 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.

Risk factors: Major• Mechanical ventilation for more than 48 hours.

• Coagulopathy platelet count of <50,000mm3INR>1.5PTT of >2 times the control

• Recent GI ulcers/bleeding Within 12 months.

Risk factors: Minor (2 or more)

• Sepsis or septic shock.• ICU admission > 1 week.• Burn >35%• Head and spinal trauma.• Multi-organ failure.• High dose corticosteroids: Methylprednisolone ≥ 40 mg/day Hydrocortisone ≥ 250 mg/day

Prognosis• Overt GI bleeding due to stress ulceration is

associated with increased mortality.

So, What to do ?

PREVENTION

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.

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. 2004;49:906-913.

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.

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; 23:313.

• Cook D, et al.Canadian Critical Care Trials Group. Crit Care Med 1999;27:2812.

• 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.

• 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.

Pharmacological prevention

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).

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.

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.

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)

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.

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.

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.

Proton pump inhibitors• PPIs (particularly Omeprazole) delay clearence of:

warfarin, diazepam, phenytoin, digoxin, theophylline, and carbamazepine.

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.

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. 1999;27:98-103.)

Which agent to choose ?

Comparative studies

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.

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.

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.

Level 2• Aluminum containing compounds should not be

used in patients on dialysis.

• Prophylaxis should continue during mechanical ventilation or intensive care unit stay.

Level 3

• Enteral feeding alone may be insufficient stress ulcer prophylaxis.

• Prophylaxis should continue until able to tolerate enteral nutrition.