With regard to gastric ulceration in the ICU:
a)    List five risk factors for developing stress related gastric ulceration in ICU patients.
(20% marks)
b)    Discuss briefly strategies for prevention of gastrointestinal bleeding resulting from stress ulcers among ICU patients. Include in your answer the available evidence for these. (80% marks)

[Click here to toggle visibility of the answers]

College answer

a)

Risk factors 

  1. Coagulopathy, 
  2. Mechanical ventilation for >48 hours
  3. Renal failure
  4. Traumatic brain injury, spinal cord injury, or burn injury
  5. History of GI ulceration or bleeding within the past year
  6. Shock 
  7. An intensive care unit (ICU) stay more than one week, 
  8. Occult GI bleeding for six or more days 
  9. Glucocorticoid therapy.

b)

Strategies for prevention of GI bleeding resulting from stress ulcers among ICU patients. 

  • Prevent gastric ischemia
    • Treat underlying problem responsible for gut Ischemia.
    • Supportive ICU care
  • Reduce gastric acid injury
    • Decrease acid production (H2 Antagonist and PPI)
      • Advantages
        • Decreased risk of gastrointestinal bleeding
        • Decreased exposure to blood products, and associated risk related to transfusion
      • Disadvantages
        • Decreased gastric acidity, thus increased risk of non-sterile aspiration and development of nosocomial pneumonia.
        • Increased risk of gastrointestinal bacterial overgrowth and translocation
        • Increased risk of Clostridium difficile infections

H2 blockers: 

Inhibits histamine stimulated acid secretion and are better than placebo, antacid or sucralfate as stress ulcer prophylaxis. No evidence they are superior than PPI.

Tolerance, requires dose adjustment in renal failure; rarely causes thrombocytopenia. 

Proton pump inhibitors: 

Pantoprazole and omeprazole do seem to have some benefit in protecting patients from stress ulceration. In critically ill patients, proton pump inhibitors seem to be more effective than histamine 2 receptor antagonists in preventing clinically important and overt upper gastrointestinal bleeding. No clear evidence that one PPI is better than the other.

Meta-analysis of 13 RCTs; n = 1587 patients (H2 blockers versus PPI) Found less GI bleeding among those who received a PPI (1.3 versus 6.6 percent, odds ratio 0.30, 95% CI 0.17-0.54) no difference in mortality or the incidence of nosocomial pneumonia.  (Detail not required)

 Side effects include: Interstitial nephritis Clostridium difficile enterocolitis, GI upset and headaches. Long-term use associated with fractures, hypomagnesemia hypocalcemia.

Enteral feeding 

Observational studies data suggest that enteral nutrition may be adequate substitute for pharmacologic stress ulcer prophylaxis in ICU patients, however controlled trials are necessary for confirmation.  There appears to be no benefit for stress ulcer prophylaxis in patients who are tolerating enteral feeding, and in these patients stress ulcer prophylaxis may not be needed. However, it is still unclear if enteral feeding is alone sufficient in protection of stress ulcers in high risk patients. 

Examiners Comments:

 Generally, poorly answered. Superficial knowledge of pharmacology and evidence base. 

Discussion

a) 

According to Cook et al (1994), independent risk factors for stress ulceration are:

  • Respiratory failure with mechanical ventilation for >48 hrs
  • Coagulopathy or anticoagulant use
  • Hypotension, shock states of any sort
  • Liver failure
  • Renal failure
  • Fasting state (no enteral feeding)
  • Steroid use (especially dexamethasone)

b)

To "include in your answer the available evidence for these", this answer to Question 1 from the first paper of 2003 was updated with contemporary data.

  • Antacids - These were the mainstay of ulcer prophylaxis in the 1980s (see Gonzalez et al, 1985). They were given hourly, and required hourly gastric pH measurement to titrate (the usual goal was to aim for a gastric pH of > 5.0). The available agents tend to have nasty metallic ions eg. magnesium, aluminium, sodium. Also, one might develop some metabolic alkalosis, or worse yet a bowel obstruction.
  • Sucralfate - an aluminium salt of sucrose octasulphate - coats ulcers and increases mucus production, but does absolutely nothing for gastric pH. This may be an advantage, as the low pH can continue killing pathogenic organisms, while the mucosa is protected by a thick coat of nicely viscous mucus. Again, constipation is a major side-effect. Sucralfate can form a bezoar, clogging the gastric outlet, and it can prevent the absorption of nutrients by binding to the components of enteral feeds. It is also thought to have a tendency to absorb or adsorb useful medications. The popularity of sucralfate decreased in the late 1990s when a trial compared it unfavorably to ranitidine (Cook et al, 1998); in fact ranitidine was twice as good.
  • H2-receptor antagonists like ranitidine became popular in the wake of trials which favourable compared them to antacids and sucralfate. Unfortunately these drugs have a tendency towards tachyphylaxis after the first day of therapy. Their use has been largely superceded by PPIs; however their one major remaining advantage is cost. Wikipedia lists the wholesale price of one tablet as 0.01$ (US), making it attractive in the developing world
  • Proton pump inhibitors eg. pantoprazole and omeprazole became available in the nineties and have subsequently superceded the H2 receptor antagonists. The college answer refers to a meta-analysis -if you can call that "refers", as they do not give a proper reference. That meta-analysis is Barkun et al (2012). A more recent publication (Alshamsi et al, 2016) included 19 trials (2117 patients) and found that overall there was a reduction in the risk of clinically significant bleeding when compared to H2 receptor antagonists, but with a NNT of 37. There was no mortality benefit. Also, thus far nobody can tell which patients are at sufficiently high risk to benefit from them. Fortunately, detail not required.
  • Enteral nutrition buffers gastric pH and suppresses stress-induced vagal stimulation, while proving trophic and circulatory benefits to the gut mucosa, but is occasionally impractical (i.e. not always can you feed them). Furthermore, these benefits were demonstrated mainly in animal studies and retrospective audits (MacLaren, 2001). A more recent prospective RCT (El-Kersh, 2018) found no difference, but only 2 patients had GI bleeding in each group. Ultimately, the benefit of enteral nutrution as stress ulcer prophylaxis has been extrapolated from the finding that it is usually safe to withold PPIs from patients who are tolerating enteral nutrition, i.e. with no additional GI bleeding risk (Alhazzani et al, 2017).

References

References

Oh's Intensive Care manual: Chapter 42  (pp. 487)  Acute  gastrointestinal  bleeding  by Joseph  JY  Sung

Cook, Deborah J., et al. "Risk factors for gastrointestinal bleeding in critically ill patients." New England Journal of Medicine 330.6 (1994): 377-381.

Marik, Paul E., et al. "Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis." Crit Care Med 38.11 (2010): 2222-2228.

Krag, Mette, et al. "Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients." Intensive care medicine 40.1 (2014): 11-22.

Madsen, Kristian Rørbæk, et al. "Guideline for Stress Ulcer Prophylaxis in the Intensive Care Unit." Danish medical journal 61.3 (2014): 1-4.

Plummer, Mark P., Annika Reintam Blaser, and Adam M. Deane. "Stress ulceration: prevalence, pathology and association with adverse outcomes."Critical Care 18.2 (2014): 213.

Yearsley, K. A., et al. "Proton pump inhibitor therapy is a risk factor for Clostridium difficile‐associated diarrhoea." Alimentary pharmacology & therapeutics 24.4 (2006): 613-619.

Steinberg, Kenneth P. "Stress-related mucosal disease in the critically ill patient: risk factors and strategies to prevent stress-related bleeding in the intensive care unit." Critical care medicine 30.6 (2002): S362-S364.

Buendgens, Lukas, Alexander Koch, and Frank Tacke. "Prevention of stress-related ulcer bleeding at the intensive care unit: Risks and benefits of stress ulcer prophylaxis." World journal of critical care medicine 5.1 (2016): 57.

Gonzalez, Edgar R., and Anthony R. Morkunas. "Prophylaxis of stress ulcers: Antacid titration vs. histamine2-receptor blockade." Drug intelligence & clinical pharmacy 19.11 (1985): 807-811.

Cook, Deborah, et al. "A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation." New England Journal of Medicine 338.12 (1998): 791-797.

Oh's Intensive Care manual: Chapter 42  (pp. 487)  Acute  gastrointestinal  bleeding  by Joseph  JY  Sung

Cook, Deborah J., et al. "Risk factors for gastrointestinal bleeding in critically ill patients." New England Journal of Medicine 330.6 (1994): 377-381.

Marik, Paul E., et al. "Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis." Crit Care Med 38.11 (2010): 2222-2228.

Krag, Mette, et al. "Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients." Intensive care medicine 40.1 (2014): 11-22.

Madsen, Kristian Rørbæk, et al. "Guideline for Stress Ulcer Prophylaxis in the Intensive Care Unit." Danish medical journal 61.3 (2014): 1-4.

Plummer, Mark P., Annika Reintam Blaser, and Adam M. Deane. "Stress ulceration: prevalence, pathology and association with adverse outcomes."Critical Care 18.2 (2014): 213.

Yearsley, K. A., et al. "Proton pump inhibitor therapy is a risk factor for Clostridium difficile‐associated diarrhoea." Alimentary pharmacology & therapeutics 24.4 (2006): 613-619.

Steinberg, Kenneth P. "Stress-related mucosal disease in the critically ill patient: risk factors and strategies to prevent stress-related bleeding in the intensive care unit." Critical care medicine 30.6 (2002): S362-S364.

Buendgens, Lukas, Alexander Koch, and Frank Tacke. "Prevention of stress-related ulcer bleeding at the intensive care unit: Risks and benefits of stress ulcer prophylaxis." World journal of critical care medicine 5.1 (2016): 57.

Gonzalez, Edgar R., and Anthony R. Morkunas. "Prophylaxis of stress ulcers: Antacid titration vs. histamine2-receptor blockade." Drug intelligence & clinical pharmacy 19.11 (1985): 807-811.

Cook, Deborah, et al. "A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation." New England Journal of Medicine 338.12 (1998): 791-797.

MacLaren, Robert, Catherine L. Jarvis, and Douglas N. Fish. "Use of enteral nutrition for stress ulcer prophylaxis." Annals of Pharmacotherapy 35.12 (2001): 1614-1623.

El-Kersh, Karim, et al. "Enteral nutrition as stress ulcer prophylaxis in critically ill patients: A randomized controlled exploratory study." Journal of critical care 43 (2018): 108-113.

Alhazzani, Waleed, et al. "Withholding pantoprazole for stress ulcer prophylaxis in critically ill patients: a pilot randomized clinical trial and meta-analysis." Critical care medicine 45.7 (2017): 1121-1129.

Barkun, Alan N., et al. "Proton pump inhibitors vs. histamine 2 receptor antagonists for stress-related mucosal bleeding prophylaxis in critically ill patients: a meta-analysis." The American journal of gastroenterology 107.4 (2012): 507.