E-Journal Club – July 2021

Greetings!  Staffing changes, clinical responsibilities and the small matter of a worldwide pandemic have all contributed to a long gap without posting a summary of our journal club. We are starting to show some glimmers of normalcy here, and one of our goals is to get back on schedule with our journal clubs. We are hoping that some of our training programs will be able to restart in the future, even if for now, they are just online programs. Our current team members are pictured to the left.

July Citation:
Chapple LS, Summers MJ, Weinel LM R, et al. Effects of Standard vs Energy-Dense Formulae on Gastric Retention, Energy Delivery, and Glycemia in Critically Ill Patients. JPEN J Parenter Enteral Nutr. 2021; 45(4):710-719.

Summary:
This was a randomized, double-blind, crossover, non-inferiority study in adult, critically ill patients, which compared gastric emptying and carbohydrate absorption between a standard (1 kcal/mL) or energy-dense (2 kcal/mL) enteral formula. The study gave an isocaloric “test meal” of either 200 ml of a 1 kcal/mL formula (Nutrison) or 100 mL of a 2 kcal/mL formula (TwoCal) on alternating days after a 4-hour fast, and after checking/discarding any obtainable gastric residual. Each test meal contained 3-O-methyl-D-gluco-pyranose (3-OMG) H2O and Technetium-99M calcium phytate colloid to allow measurement of gastric retention and glucose absorption.

Gastric-emptying scintigraphic data and arterial 3-OMG were monitored at 15, 30, 45, 60, 90, 120, 150, 180, 210, and 240 minutes, and blood glucose concentrations were monitored using a portable glucometer. The primary endpoint of the study was the rate of gastric emptying of the test meals assessed as percentage gastric retention at 120 minutes using scintigraphy. The secondary endpoints included energy delivery to the small intestine (test meal percent emptied from stomach/100 × kcal in test meal), intestinal glucose absorption measured as area under the curve (AUC) of serum 3-OMG concentrations, and blood glucose concentrations (peak and AUC).

The investigators reported that a previous scintigraphic study of critically ill patients reported that the within-patient variability of gastric retention was estimated to be 42%. Therefore, they calculated that the present study would need 20 patients to have 80% power at 5% significance to determine non-inferiority of gastric retention with a non-inferiority margin of 24 percentage points.

Inclusion and Exclusion Criteria:
Inclusion criteria:
Adult mechanically ventilated patients, who were going to receive enteral nutrition (EN) via nasogastric tube and expected to remain ventilated ≥48 hours.

Exclusion criteria:
Pregnancy, receiving drugs known to affect gastric function, upper gastrointestinal surgery (esophageal, stomach, or duodenal), and lack of informed consent.

Major Results:
The study was stopped early due to difficulties with recruitment, including challenges in completing consecutive study days. The authors also reported that “paired data were not available in all participants because of technical difficulties with the γ-camera”. Fifteen patients had gastric-emptying data for the standard formula and 10 patients had gastric-emptying data for the energy-dense formula, with 10 patients who had gastric-emptying data available on both study days. In total the investigators reported that there were 18 total patients with some data from at least 1 study day.
The authors reported that primary outcome of percent gastric retention at 120 minutes crossed the predefined non-inferiority margin (standard, 17.0% ± 5.9% vs energy-dense, 32.5% ± 7.1%; mean difference, 12.7% [90% CI,0.8%–30.1%]; P = .085)

There was no significant difference in AUC for gastric retention, mean intestinal energy delivery to the intestine (via 3-OMG), or serum glucose at any time point.

Author’s Conclusions:
“…the use of energy-dense formulae does not increase the rate of emptying from the stomach, increase energy delivery to the small intestine, or improve glucose absorption or control. Accordingly, there appears to be no physiological or nutrition basis to support the prescription of energy-dense enteral formula on the sole premise of improving energy delivery…”

Evaluation:
One of the first things we noted about this study was that, with only 10 patients who received the calorie dense formula, the investigators were not able to enroll sufficient patients to achieve the goal of a true randomized, crossover study with the planned number of patients necessary for statistical power. Considering that these were critically ill patients, who could be expected to have as much as 42% difference in gastric empting between patients, it is not clear that there is anything clinically meaningful to be found in an average difference in gastric retention of 13% between a small bolus of formulas over 2 hours.

The authors state that the results of this study do not support the use of calorie dense formulas to improve calorie delivery to critically ill patients. However, there is a large study of nearly 4000 patients (TARGET study) which randomized patients to receive either a standard (1 kcal/mL) or calorie-dense (1.5 kcal/mL) formula, and showed that the calorie dense feeding group received an average of approximately 47% more calories (about 600 calories/day more) than the group receiving a standard formula. There was a 3.2% increase in regurgitation or emesis in the group receiving the calorie dense formula (18.9% calorie dense vs. 15.7% standard), and the 1.5-kcal group received significantly more promotility drugs. However, this statistical difference in vomiting did not result in any increase in pneumonia or other negative outcomes in the calorie dense group. We do know than most studies which have provided more enteral calories have done so at the cost of increased GI “issues” (usually increased emesis), even when the additional calories were not provided via the use of calorie dense formulas.

Although the TARGET study did not demonstrate an improvement in patient outcome from increased calorie delivery in the first week of critical illness, this does not negate the potential clinical benefits of using calorie dense formulas in patients with longer hospitalizations, recurrent surgical procedures, wounds, etc. who are having difficulty meeting their longer-term nutrition goals.

Some other points that we discussed included the fact that the calorie dense formula had 5% more fat calories, and had more than double the osmolality of the standard formula. We noted that other calorie dense (especially 1.5/mL) formulas often have a more modest fat content and osmolality. The authors do point out in the discussion section article that the calorie-dense formula contained casein, compared to the standard product being whey protein based, which also could have contributed to the modest numerical increase in gastric retention at 2 hours.

Our Take Home Message(s):
1. This underpowered, short term, scintigraphic data study does not provide sufficient evidence to counter the randomized data demonstrating that calorie-dense formulas can be used to safely increase calorie delivery for critically ill patients.
2. Be cautious if you see this study referenced as good data that calorie dense formulas may compromise gastric emptying or are not a practical way provide increased calories to critically ill patients.
3. It is reasonable to suspect that the acronym for 3-O-methyl-D-gluco-pyranose (3-OMG) was chosen before common texting acronyms became widely known.

References:

The TARGET Investigators, for the ANZICS Clinical Trials Group. Energy-Dense versus Routine Enteral Nutrition in the Critically Ill. N Engl J Med 2018; 379:1823-1834. DOI: 10.1056/NEJMoa1811687

Other News on the UVAHS GI Nutrition Website: (www.ginutrition.virginia.edu):

Latest PG Articles:
• July: Auto-Brewery Syndrome: A Schematic for Diagnosis and Appropriate Treatment
• June: Beyond the Banana Bag: Treating Nutritional Deficiencies of Alcohol Withdrawal Syndrome
• May: Vitamin D Replacement in Adults: Current Strategies in Clinical Management

Joe Krenitsky MS, RDN

PS – Please feel free to forward on to friends and colleagues.