E-Journal Club–January 2019

Greetings,

I am still getting caught-up with our recent journal clubs. We have had several Weekend Warrior programs and traineeships, in addition to our usual patient load that has kept us in motion. This month’s article is an important investigation into the effect of increasing initial calorie goals on outcomes in the adult ICU.

January Citation:

TARGET Investigators, for the ANZICS Clinical Trials Group, Chapman M, Peake SL, Bellomo R, et al. Energy-Dense versus Routine Enteral Nutrition in the Critically Ill. N Engl J Med. 2018;379(19):1823-1834.

Summary:

This was large multi-center, randomized, double-blind study of 3957 adult mixed ICU (medical, surgery, trauma, neuro, cardiovascular) patients, to investigate the effect of increased calorie provision on patient outcomes. Calories were increased in the experimental group by using a calorie dense (1.5 kcals/mL) formula.

Both groups received EN as soon as possible after randomization with a goal of reaching goal feeding rate within 48 hours. Target feeding was 1 ml formula/kg ideal weight/hour for both groups, with the standard group receiving a 1 kcal/mL formula and the increased calorie group receiving a 1.5 kcal/mL formula (i.e. standard group goal 24 kcals/kg versus experimental group goal of 36 kcals/kg). To minimize the risk of overfeeding, the maximum target rate was 100 ml per hour and catch-up feeding was not permitted. Blood glucose goals were ≤180 mg/dl (10 mmol/liter).

The primary study outcome was all-cause mortality within 90 days after randomization. Secondary outcomes included survival time (until day 90), 90-day cause-specific mortality, day 28 and in-hospital all-cause mortality, ICU-free and hospital-free days between randomization and day 28, the number of days free of organ support between randomization and day 28, percentage of patients receiving invasive ventilation, vasopressors, or new renal replacement therapy. Additional outcomes were the percentage of patients with positive blood cultures and the percentage receiving intravenous antimicrobial agents between randomization and day 28. Seven predefined subgroups were identified: age (≥65 or <65 years), diagnostic subgroups (trauma, sepsis, neurologic diagnosis, and treatment type [medical vs. surgical]), quintiles for the absolute risk of death based on the Australian and New Zealand Risk of Death Score and body-mass index.

Inclusion and Exclusion Criteria:

Inclusion criteria:

Adult patients receiving invasive mechanical ventilation, about to commence enteral nutrition, or had commenced enteral nutrition within the previous 12 hours and were expected to be receiving enteral nutrition in the ICU beyond the calendar day after randomization.

Exclusion criteria:

Received EN or PN > 12 hours, death deemed inevitable, underlying disease that makes survival to 90 days unlikely, ≥ 15% acute burns, previously enrolled in the study. Patients were also excluded if their treating clinician determined that the enteral nutrition formula or rate of delivery were clinically contraindicated (e.g. strict fluid restriction)

Major Results:

In total, 3997 patients underwent randomization (3 patients inadvertently underwent randomization twice), and 3957 patients were included in the modified intention-to-treat population (1971 in the 1.5-kcal group and 1986 in the 1.0-kcal group). There were no large differences in baseline characteristics between groups, with an average BMI of 29 in both groups.

The average volumes of enteral nutrition actually delivered was not significantly different between the groups (1242±318 ml per day in the 1.5-kcal group and 1262±313 ml per day in the 1.0-kcal group). Patients received the trial nutrition for a median of 6.0 days.

Patients in the 1.5-kcal group received significantly more calories: 1863±478 kcal/day as compared with 1262 ±313 kcal/day (mean difference, 47.6% more, 601 kcal/day difference; 95% CI, 576 to 626). Actual protein delivery was not significantly different between the groups (mean of 69.5 gm/day which was about 1.09 gm/kg ideal weight). The increased calorie group (1.5 kcal/mL) received 103±27% of the clinician-estimated requirements as compared with 69±18% in the 1.0 kcal/mL control group.

The primary outcome of day 90 mortality was not significantly different between groups: 523 of 1948 patients (26.8%) in the 1.5-kcal group and 505 of 1966 patients (25.7%) in the 1.0-kcal group died. There were no significant differences in any of the variables in the initial analysis or after adjustment for trial site and predefined baseline covariates. One or more adverse events occurred in 54 patients (2.7%) in the 1.5-kcal group and 51 patients (2.6%) in the 1.0-kcal group.

There was a significantly greater incidence of regurgitation or vomiting in the 1.5-kcal group (18.9% vs. 15.7%; relative risk, 1.20; 95% CI, 1.05 to 1.38), and the 1.5-kcal group received significantly more promotility drugs (47.4% vs. 39.6%; relative risk, 1.20; 95% CI, 1.11 to 1.29) and insulin.

The number of patients in the 1.5-kcal group who received insulin was 1093 (55.8%), as compared with 964 (49.0%) in the 1.0-kcal group (relative risk, 1.14; 95% CI, 1.07 to 1.21), and daily blood glucose levels were significantly higher in the 1.5-kcal group than in the 1.0-kcal group.

Author’s Conclusions:

“…increasing energy intake with the administration of energy-dense enteral nutrition did not affect survival among critically ill adults..”

Evaluation:

This study is remarkable for its high-quality methodology and an ample number of participants to study patient outcomes. Rarely at our journal clubs do we have so little to critique in terms of study quality.

This study adds to the body of literature from interventional studies which indicates (in sharp contrast to observational data) that modest (400-600 kcals/day), short-term (< 1 week) calorie deficits in the first week of the adult ICU do not result in negative clinical ramifications.^1-3 Also consistent from previous studies is the notion that feeding more calories results in more GI symptoms.

This study stands out from previous investigations, because the majority of patients in the higher calorie group actually met their full calorie goals. One distinct thing that we did learn from this study is that meeting calorie goals with a slow, steady increase in nutrition did not appear to be overtly harmful, which is in contrast to the data from volume-based based feeding, where patients who received full calories with volume-based feeding appeared to be harmed.⁴

One aspect of this study that we noted is that there was no attempt to subgroup by nutrition status, and there was no valid tool for nutrition assessment as part of the study. Undoubtable, someone without an accurate understand of malnutrition will comment that the patients in this study were not malnourished because the average BMI was 29 (making a million RDs cry out as one, in anger….). It is unclear that these results would necessarily apply to a severely malnourished population, or in very lean patients (only 2% of patients had a BMI < 18.8). Likewise, surgery/trauma patients were under-represented in this study, so it is not clear that these results would apply to patients with major or repeated surgical procedures.

Another aspect of this study that is worth considering is that both groups of patients received a very low protein provision of 1.09 gm/kg ideal weight, which means they received < 1 gm protein/kg of actual weight. We would generally try to optimize protein provision, especially in the setting of hypocaloric feeding. It is conceivable that patients who were receiving less calories might have had better outcomes than the full calorie group (remember they did have less hyperglycemia, less emesis) if they had received adequate protein. The group who received increased calories in this study would have likely had some degree of protein-sparing, and may have had better tolerance for what is essentially a protein restriction for a critically ill patient.

Our Take Home Message(s)

Meeting full calorie provision with an increased feeding goal and calorie-dense formulas does not improve patient outcome, and increases GI symptoms and hyperglycemia, compared to standard feedings.
The results of this study may not apply to very lean, severely malnourished or complicated surgical/trauma patients.
There is a need to study the effect of increased protein, reduced calorie feeding compared to standard feeding in the adult medical and surgery/trauma populations.

References:

Arabi YM, Aldawood AS, Haddad SH, et al. Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults. N Engl J Med.N Engl J Med. 2015;372(25):2398-2408
April Citation: Petros S, Horbach M, Seidel F, Weidhase L. Hypocaloric vs Normocaloric Nutrition in Critically Ill Patients: A Prospective Randomized Pilot Trial. JPEN. 2016;40(2):242-249.
The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Initial Trophic vs. Full Enteral Feeding in Patients with Acute Lung Injury: The EDEN Randomized Trial. 2012;307(8):795-803.
Braunschweig CA, Sheean PM, Peterson SJ, et al. Intensive Nutrition in Acute Lung Injury: A Clinical Trial (INTACT). JPEN J Parenter Enteral Nutr 2015 Jan;39(1):13-20.

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

Latest PG Article:

May: Enteral Nutrition Part IV: Hydration in the Enterally Fed Patient: It Isn’t Rocket Science

Upcoming Webinars:

May 23: Nutrition in Liver Disease—Joe Krenitsky, MS, RD

Joe Krenitsky MS, RDN

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