What data is there to support discontinuing stress ulcer prophylaxis when a patient is on tube feeds?

Comment by InpharmD Researcher

Meta-analyses investigating the effectiveness of stress ulcer prophylaxis in reducing clinically-relevant bleeding in patients receiving enteral nutrition have yielded mixed results. Generally, these patients are critically ill or admitted to the intensive care unit (ICU). While some have found no benefit to this type of prophylaxis, a meta-analysis that included a broader range of clinical studies has suggested the need for further investigation to confirm or refute the absence of benefit.

Background

A 2018 meta-analysis investigates the effect of pharmacologic stress ulcer prophylaxis (SUP) for stress-related gastrointestinal (GI) bleeds in patients on enteral tube feeds within the intensive care unit (ICU). Included studies used either proton pump inhibitors (PPIs) or histamine 2 receptor antagonists (H2RAs). From a total of 7 included studies (N= 889), no statistically significant difference in GI bleed was found between pharmacologic SUP and placebo group (risk ratio [RR] 0.80; 95% confidence interval [CI] 0.49 to 1.31; p= 0.37). There was no effect found on overall mortality, Clostridium difficile infection, length of stay in the ICU, or duration of mechanical ventilation. There was an increased risk of hospitalization-acquired pneumonia in those receiving SUP (RR 1.53; 95% CI 1.04 to 2.27; p= 0.03). Based on these results, pharmacologic SUP did not appear to be beneficial, although the included studies were characterized by a small sample size with different outcome definitions of GI bleeding. The presentation of patients also varied among ICU patients. [1]

A 2019 meta-analysis observing PPI and H2RA SUP in critically ill adults performed a sub-analysis investigating its efficacy in patients receiving enteral nutrition. A trial sequential analysis (TSA), which determines the current evidence is strong enough to form a conclusion, is performed along with the meta-analysis due to sparse data and increased risk of random errors. While the initial results suggest that SUP in patients receiving enteral nutrition can decrease the risk of clinically important GI bleed (RR  0.61; 95% CI 0.44 to 0.85; TSA-adjusted CI: 0.16 to 2.38) and overt GI bleed (RR 0.64; 95% CI 0.42 to 0.96; TSA-adjusted CI 0.12 to 3.35), the benefits are not apparent in the TSA-adjusted analysis. Therefore, the authors conclude that there is no benefit with SUP to reduce GI bleed in critically-ill patients. [2]

Partly in response to previous studies challenging the role of pharmacologic SUP, A 2019 meta-analysis assessed the use of PPI or H2RA SUP in adult, critically ill patients. Their strategy included all randomized controlled studies (RCTs) that compared SUP to either placebo, control, no therapy, or enteral nutrition alone. From a total of 34 included studies (N= 3,220), SUP was associated with a significant decrease in clinically important bleeding (risk ratio [RR] 0.53; 95% CI 0.37 to 0.76; p<0.001), overt bleeding (RR 0.55; 95% CI 0.39 to 0.76; p= 0.0003), and any bleeding (RR 0.54; 95% CI 0.41 to 0.71; p<0.00001). TSA was also performed for this meta-analysis which still supported these findings. Seven of the trials (n= 960) permitted the use of enteral nutrition. Subgroup analysis of these patients still observed a reduction of clinically important bleeding rates (RR 0.57; p= 0.05). The majority of studies were deemed to have a high risk of bias. Based on these results, the authors suggest not to abandon the use of SUP until higher-quality studies can determine if there is a lack of benefit. [3]

References:

[1] Huang HB, Jiang W, Wang CY, Qin HY, Du B. Stress ulcer prophylaxis in intensive care unit patients receiving enteral nutrition: a systematic review and meta-analysis. Crit Care. 2018;22(1):20. Published 2018 Jan 28. doi:10.1186/s13054-017-1937-1
[2] Zhou X, Fang H, Xu J, et al. Stress ulcer prophylaxis with proton pump inhibitors or histamine 2 receptor antagonists in critically ill adults - a meta-analysis of randomized controlled trials with trial sequential analysis. BMC Gastroenterol. 2019;19(1):193. Published 2019 Nov 21. doi:10.1186/s12876-019-1105-y
[3] Reynolds PM, MacLaren R. Re-evaluating the Utility of Stress Ulcer Prophylaxis in the Critically Ill Patient: A Clinical Scenario-Based Meta-Analysis. Pharmacotherapy. 2019;39(3):408-420. doi:10.1002/phar.2172
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What data is there to support discontinuing stress ulcer prophylaxis when a patient is on tube feeds?

Level of evidence

A - Multiple high-quality studies with consistent results  Read more→


Please see Tables 1-2 for your response.

 

Enteral nutrition as stress ulcer prophylaxis in critically ill patients: A randomized controlled exploratory study

Design

Prospective, double-blind, randomized, placebo-controlled, exploratory study

N= 124

Objective

 To investigate whether early enteral nutrition alone may be sufficient prophylaxis against stress-related gastrointestinal (GI) bleeding in mechanically ventilated patients

Study Groups

Treatment (n= 55)

Placebo (n= 47)

Inclusion Criteria

 Age 18 years or older, admitted to the intensive care unit (ICU), expected to need mechanical ventilation for > 48 hours

Exclusion Criteria

 GI bleed prior to study enrollment, admission to ICU with a primary diagnosis of burn injury, closed head injury or increased intracranial pressure, partial or complete gastrectomy, pregnancy/lactation

Methods

Patients were randomized to receive either the treatment group, where enteral nutrition and pantoprazole 40 mg intravenous (IV) daily dose was administered, or the placebo group, where patients received enteral nutrition and normal saline. All patients received the same enteral nutrition formula dosed based on caloric requirements of 25-30 kcal/kg/day.

Duration

 Median length of hospital stay: 11 days

Outcome Measures

Primary: incidence of overt (coffee-ground aspirate in the nasogastric tube or coffee-ground emesis, bloody secretions in nasogastric tube or hematemesis, melena or hematochezia) or significant (a 3-point decrease in hematocrit within a 24-hour period with clinical signs of overt GI bleeding, or by an unexplained 6-point decrease in hematocrit in a 48-hour period) GI bleeding

Secondary: Incidence of clostridium difficult infection (CDI)

Baseline Characteristics

  

Treatment (n= 55)

Placebo (n= 47)

  

Age, years

 62 58  

Male

 30 28  
Body mass index, kg/m2

29.0

 29.0  
SAPS II score

41.0

 44.0  
SOFA score

7.0

 7.0  

Enteral feeding

Kcal/day delivered

Kcal/kg/day delivered

Daily volume received, mL

total volume delivered, mL

Percent of goal volume delivered

 

1,728

22

699

2,540

55%

 

1,728

22

715.5

2,914

64.38%

  

Results

Endpoint

Treatment (n= 55)

Placebo (n= 47)

p-value
Overt GI bleed

1 (1.82%)

1 (2.13%)

0.99

Significant GI bleed

1 (1.82%)

1 (2.13%)

0.99

Incidence of CDI

 1 (1.82%) 3 (6.38%) 0.33

Adverse Events

 N/A

Study Author Conclusions

 We found no benefit when pantoprazole is added to early enteral nutrition in mechanically ventilated critically ill patients. The routine prescription of acid-suppressive therapy in critically ill patients who tolerate early enteral nutrition warrants further evaluation.

InpharmD Researcher Critique

 Only medical ICU on mechanical ventilation was included. The use of antibiotics was not specific, which may have influenced the incidence of CDI.



References:

El-Kersh K, Jalil B, McClave SA, et al. Enteral nutrition as stress ulcer prophylaxis in critically ill patients: A randomized controlled exploratory study. J Crit Care. 2018;43:108-113. doi:10.1016/j.jcrc.2017.08.036

 

A Retrospective Cohort Analysis of the Use of Enteral Nutrition Plus Pharmacologic Prophylaxis or Enteral Nutrition Alone

Design

Retrospective, cohort study

N= 167

Objective

 To determine if enteral nutrition is similar to pharmacologic stress ulcer prophylaxis (SUP) with enteral nutrition (EN) for the reduction of gastrointestinal (GI) bleeding, perforation, or ulceration in intensive care unit (ICU) patients

Study Groups

SUP+EN (n= 147)

EN only (n= 20)

Inclusion Criteria

 Aged 18 years or older, received enteral nutrition and were either mechanically ventilated for > 48 hours, had admission INR > 1.5, platelet < 50,000/m3, experienced a GI bleed or ulceration in the past year

Exclusion Criteria

 Did not receive enteral nutrition

Methods

 Patient data from their electronic health record was collected for analysis.

Duration

 Until discharge or death

Outcome Measures

 Primary: clinically significant GI bleeding, perforation, and ulcer formation

Baseline Characteristics

  

SUP+EN (n= 147)

EN only (n= 20)

  

Age, years

 63.4 61.5  
Male 63

17

  

African-American race

 17 0  

Primary service

Medical ICU

Surgical ICU

Neuro ICU

Hospitalist

 

111

30

5

1

 

8

10

2

0

  

ICU length of stay, days

 8.2 9.55  

Hospital length of stay, days

 15.3 19.65  

Disposition

Home

Rehabilitation facility

Long-term acute care facility

Nursing home/skilled nursing facility

Death

 

48

8

11

41

39

 

6

1

3

5

5

  

Results

Endpoint

SUP+EN (n= 147)

EN only (n= 20)

p-Value

GI bleeding, perforation, or ulceration

21 (14.3%)

1 (5%)

0.4781

Pneumonia

62 (42.18%)

3 (15%)

0.0194

C. difficile infection

7 (4.76%)

0

> 0.999

Adverse Events

 N/A

Study Author Conclusions

 In this small cohort of patients, enteral nutrition alone is as effective as pharmacologic therapy in addition to enteral nutrition for the reduction of stress-related GI bleeding, perforation, and ulceration.

InpharmD Researcher Critique

 There was a wide disparity between patient populations in the SUP+EN versus EN alone group, which can influence the statistical power of the results. If one group has a significantly larger sample size than the other, it may skew the results toward that group and make it difficult to draw accurate conclusions about the treatment effect.



References:

Hamilton LA, Darby SH, Rowe AS. A Retrospective Cohort Analysis of the Use of Enteral Nutrition Plus Pharmacologic Prophylaxis or Enteral Nutrition Alone. Hosp Pharm. 2021;56(6):729-736. doi:10.1177/0018578720954159