Critically evaluate the role of proton pump inhibitors to prevent upper gastrointestinal bleeding in ICU patients.

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College answer


Rationale
Upper GI bleeding can occur due to stress ulceration in critically ill patients; risk of clinically significant bleeding estimated at around 1.5% in ventilated patients taking stress ulcer prophylaxis, historically up to 15% in those without prophylaxis.

Major risk factors for GI bleeding appear to be duration of mechanical ventilation and presence of a coagulopathy, also use of steroids, past history of peptic ulcer disease [Cook NEJM 1994]
Enteral nutrition may be preventative [Marik Crit Care Med 2010]

Many studies have shown a reduction in GI bleeding with the use of prophylaxis
PPIs are very effective at treating stress ulcer-related bleeding and are the most potent medications available to prevent GI bleeding in ICU patients [Barkun AN et al Gastroenterol 2012 Apr; 107(4)] Cook et al 2013, Int Care Med 2018).

Disadvantages
Side effects of use of PPI may include increase risk of VAP, C. Difficile infection, acute interstitial nephritis, and cost (included unintended long-term use). They may have an immunosuppressive effect.

Evidence
SUP-ICU [NEJM 2018] demonstrated that PPI use compared to placebo resulted in a reduced rate of clinically important GI bleeding (2.5% vs 4.2%], NNT = 59. No difference in mortality.
PEPTIC (JAMA 2020) demonstrated that in ventilated ICU patients, PPIs were more effective at reducing GI bleeding than H2RBs. No effect on mortality, ICU LOS or C Difficile infection rate. The study had a high crossover rate.
In a subset of cardiac surgical patients, the GI bleeding rate was very low, and mortality was increased with allocation to PPI group.

REVISE trial currently underway will provide an update on the beneficial effect of PPI compared to placebo for stress ulcer prophylaxis in ICU patients.

Overall, there is a clear need to define high-risk critically ill patient sub-group that is likely to benefit from stress ulcer prophylaxis, accounting for those that receive enteral nutrition. In light of PEPTIC, it is unlikely that PPIs offer a mortality benefit over H2RBs.

Summary: (candidates should justify their own practice; there is not currently a clear “correct” answer for this and so this serves as an example only):
In my practice, I would only use stress ulcer prophylaxis in ICU patients who are at high risk of GI bleeding (mechanically ventilated >48 hours and either: coagulopathy; shock/MODS/high illness severity; or high dose corticosteroids)
I would use H2RB as my standard prophylaxis medication
 
I would use PPI as treatment for any patients with signs of GI bleeding
I would assess the ongoing need for prophylaxis daily and cease when patient is no longer high risk, including when enteral nutrition is commenced.
I would routinely cease stress ulcer prophylaxis prior to discharge to the wards

Good answers contained the following points:
The rationale for using them. Advantages (cheap, widely available) Potential disadvantages
A summary of the evidence. The key points would be that they do appear to lower the incidence of GI bleeding, but do not seem to reduce mortality (and some suggestion that mortality might be increased in particular populations). A grasp of what the evidence suggests was sufficient, although detailed knowledge of recent studies was awarded marks.
A summary statement.
 

Discussion

Rationale

  • Gastrointestinal bleeding in the critically ill patient may be due to a variety of causes; these include bleeding from stress ulceration, oesophageal varices, and colonic polyps.
  • Given that in the ICU GI bleeding is combined with a series of other major organ dysfunction syndromes, it tends to have a catastrophic mortality rate
  • It is therefore important to be able to protect at-risk patients from this complication.

Advantages

  • Decreased risk of gastrointestinal bleeding
  • Decreased exposure to blood products, and the attendant risks thereof

Disadvantages

  • Decreased gastric acidity, thus increased risk of non-sterile aspiration
  • Increased risk of gastrointestinal bacterial overgrowth and translocation
  • Increased risk of Clostridium difficile infections
  • Possibly an increase in the risk of VAP

Evidence for the routine use of ulcer prophylaxis

  • A recent meta-analysis suggests that the quality and quantity of the evidence is still poor, but on the weight of the available evidence there is neither a mortality improvement nor any increase in the risk of nosocomial pneumonia.
  • There appears to be no benefit for stress ulcer prophylaxis in patients who are tolerating enteral feeding, and in these patients stress ulcer prophylaxis is not needed.
  • There is insufficient evidence to recommend the mandatory use of stress ulcer prophylaxis in any specific patient group 
  • Obviously, correcting coagulopathy (and not triggering any new coagulopathy, nor disabling the platelets with NSAIDs) is a good way to prevent catastrophic bleeding in the ICU.
  • SUP-ICU (Krag et al, 2018) did not find any mortality benefit, but there was a reduction in clinically significant UGI bleeding events. Having said this, even in the control group, the risk of this bleeding was only 4.4%.

Evidence to support one drug class over another

  • Contemporary meta-analsysis suggests some benefit from the use of PPIs.  
  • Pro-PPI studies include a big 2016 meta-analysis by Alshamsi et al, which revealed them to be more effective at preventing clinically significant episodes of bleeding.
  • However, it must be pointed out that many of the studies which met inclusion criteria didn't even specify what they meant by "bleeding". When other meta-analysis authors selected studies limited to ones with a low risk of bias, the results they arrived at were not significant (Barletta et al, 2016).

Summary

PPIs are indicated in at-risk patient in ICU who are intolerant of enteral feeding, and who are otherwise at risk of gastrointestinal bleeding. Further research is required to discriminated between different classes of drugs in terms of efficacy, and to identify the at-risk population.

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.

Lucas, Charles E., et al. "Natural history and surgical dilemma of stress gastric bleeding." Archives of surgery 102.4 (1971): 266-273.

Hastings, Paul R., et al. "Antacid titration in the prevention of acute gastrointestinal bleeding: A controlled, randomized trial in 100 critically ill patients." New England Journal of Medicine298.19 (1978): 1041-1045.

Krag, Mette, et al. "Stress ulcer prophylaxis with a proton pump inhibitor versus placebo in critically ill patients (SUP-ICU trial): study protocol for a randomised controlled trial." Trials17.1 (2016): 205.

Krag, Mette, et al. "Pantoprazole in patients at risk for gastrointestinal bleeding in the ICU." New England Journal of Medicine 379.23 (2018): 2199-2208.