January 2018 E-Journal Club
We do not run any training programs in December or January, as everyone takes time to celebrate the holidays and get settled into a new year. We did hold our monthly Journal Club in January, however, to discuss a recent article that we had been anxious to review.
Allingstrup MJ, Kondrup J, Wiis J, et al. Early goal-directed nutrition versus standard of care in adult intensive care patients: the single-centre, randomised, outcome assessor-blinded EAT-ICU trial. Intensive Care Med. 2017;43(11):1637-1647.
This was single center, randomized unblinded study in adult ICU patients to assess the effect of early supplemental PN to meet full individualized nutrition goals based on indirect calorimetry and urine nitrogen excretion compared to the standard of practice of estimated nutrition needs, modest protein goals and slow enteral feeding progression. The early goal-directed nutrition (EGDN) group had energy expenditure measured by indirect calorimetry every other day, and received at least 1.5 gm protein/kg (or greater based on daily 24-hr urinary urea excretion). The standard of care group goals were 25 kcal/kg/day, 1.2 gm protein/kg, and PN was not provided until day 7 if EN goals were not reached. Enteral nutrition was initiated within 24 h of randomization and gradually increased over the following days “as tolerated by the patient”.
In both groups gastric residuals were checked every 4-6 hours and feeding rates were reduced if residuals were between 150-500 mls. Carbohydrate provision was decreased if insulin requirement was greater than 5 units/hr X 12 hours and protein provision was decreased by 0.2 g/kg/day if plasma urea exceeded 56 mg/dl (20 mmol/l).
All patients in the EGDN group received parenteral nutrition from the first day of the study and the goal was to provide 100% of measured energy/protein requirements from the first full study day and throughout the entire ICU stay to a maximum of 90 days.
The primary outcome of the study was physical quality of life at 6 months, as assessed by the physical component summary score of the Medical Outcomes Study 36-item short form health survey version 2. Patients who had died at 6 months were given the lowest possible PCS score (zero). The questionnaire survey was performed as a phone interview by research personnel who were blinded to the respondents study group. The investigators determined that they would require at least 200 patients to show a 15% relative reduction in the primary outcome.
Secondary outcomes included 28-day, 90-day and 6-month mortality, mental component summary (MCS) score of SF-36 at 6 months, length of
stay in ICU and in hospital among 6 months survivors, percentage of days alive and without renal replacement therapy (RRT), mechanical ventilation, or inotropic/vasopressor support during the first 90 days, acute use of RRT and new organ failure, serious adverse reactions, nosocomial infections from 48 h after inclusion until ICU discharge, accumulated energy and protein balance, insulin dose and rates of severe hyper and hypoglycemia.
The investigators also analyzed data by the stratification variable of hematologic malignancy and two preplanned subgroups of: (1) with and without plasma urea greater than 20 mmol/l or use of any form of RRT at baseline and (2) Simplified Acute Physiology Score (SAPS) II above the median of all included patients.
Inclusion and Exclusion Criteria:
Patients 18 years of age or older within 24 h of any ICU admission for inclusion if they were (1) acutely admitted to the ICU; (2) had an expected length of stay in the ICU of more than 3 days; (3) were mechanically ventilated via a cuffed endotracheal or tracheotomy tube; (4) had a central venous catheter and (5) were expected to read and understand Danish.
Patients with a BMI equal to or below 17 and those who appeared malnourished, Burns > 10% surface area, hepatic failure or severe hepatic dysfunction, traumatic brain injury, DKA or hyperosmolar non-ketotic acidosis, hyperlipidemia, hemodynamic instability or death imminent.
Investigators screened 586 patients and randomized 203 patients, with 2 early deaths and 2 patients withdrawing consent, so ultimately data from 199 patients was analyzed. Baseline characteristics were similar between the groups, with 48% medical ICU patients and 48% emergency surgery patients.
The investigators reported that measured energy expenditure was “different” from estimated energy needs (no statistics or p-value provided). However, mean measured REE was only 194 kcals/day greater than that estimated by 25 kcal/kg. The actual delivery of calories and protein were very different between the groups. The EGDN group received an average of 1877 kcal/day (1567–2254) compared to the standard care group which received an average of 1061 kcal/day (745–1470). Protein delivery in the EGDN group was 1.47 gm/kg/day (1.13–1.69) compared to the standard group which received only 0.50 gm/kg/day (0.29–0.69).
The EGDN group had a greater cumulative energy and protein balance at day 3 and 7 and over the course of the ICU stay as compared to the standard of care group. More patients in the EGDN group experienced at least one episode of hyperglycaemia, and the cumulative dose of insulin administered was higher in the EGDN group as compared to the standard of care group.
Despite these substantial differences in nutrition provision, there was no significant difference in the primary outcome of physical quality of life score at 6 months, nor a difference in any of the secondary outcomes, nor in any of the preplanned subgroups or when the data was stratified by hematologic malignancy.
“….we observed no difference between the two groups in physical quality of life at 6 months or in mortality, rates of organ failures, serious adverse reactions or nosocomial infections in the ICU, length of ICU or hospital stay, or days alive without life support at 90 days.”
This study did a remarkable job of rapidly meeting nutrition goals, and avoided potential overfeeding by obtaining early, and frequent indirect calorimetry measurements. Additionally, the study did not focus only on calories, it also provided adequate protein. Although the study was not double-blind, the researchers did at least have concealed allocation into groups, and investigators who collected data on the primary outcome and those who diagnosed nosocomial infections were reportedly blinded to the study groups.
One of the limiting factors of this study is the fact that due to mortality, only 51 patients in EGDN and 53 in standard group were able to complete surveys for the primary outcome, which was about ½ of that calculated as needed for statistical power. This study was certainly too small to robustly investigate outcomes such as mortality in a mixed (medical and surgical) ICU population. However, consider the fairly large number of secondary outcomes, it is perhaps surprising that nothing was statistically different between the groups, even if by chance alone.
It is notable, that although the EGDN received early PN, there was no increased incidence of infectious complications in the EGDN group. One potential reason for the lack of infectious complications was the short duration of therapy, since time on mechanical ventilation was only 5-6 days, and time in the ICU was only 7-8 days, and the modest number of patients in the study. It is also noteworthy that the lipid emulsion used for PN provided a mixed fatty acid profile (not primarily omega-6 fatty acids as used in older studies of PN). Importantly, unlike many past PN studies, the researchers took pains to avoid overfeeding calories. Providing excessive calories may have contributed to the infectious complications of older PN studies, as well as more recent studies of early supplemental PN. A recent study of short-term, hypocaloric PN with 2388 patients was also notable for no difference in infectious complications compared to hypocaloric EN.(1)
There were several other interesting findings that we discussed in our journal club. One of these was that despite the large difference in the actual protein provision received by the two groups (1.47gm/kg EGDN compared to 0.5 gm/kg in standard care), there was no significant difference in the requirement for renal replacement therapy, and no clinically relevant difference in plasma urea between the 2 groups (37.8 mg/dl in EGDN versus 25.2 mg/dl standard therapy). Although the number of patients who required renal replacement were modest, this study is still valuable because there are virtually no other randomized studies of protein load and renal replacement outcomes in adult ICU patients.
Another tidbit that our group found interesting is the miniscule difference (<100 kcals/day) in calories recommended by indirect calorimetry and 25 kcals/kg. Considering the lack of difference in nutrition recommended by indirect calorimetry and the lack of difference in clinical outcomes from modest differences in calorie provision in this and other studies (2-4), it is long past due to stop referring to indirect calorimetry as a “gold standard” for how to nourish critically ill adult patients.
Our group also mentioned that it is valuable to consider who this study may not apply to, such as severely malnourished patients. Although this study did not used a validated nutrition assessment tool, they did exclude severely malnourished patients, as well as those with burn injury. Although the best current data does not support rapidly providing full calorie and protein needs with PN in most adult ICU patients, it would be wise to consider that there may be specific populations who may benefit from early full nutrition.
Our Take Home Message(s)
- Providing early, full calorie and protein goals with supplemental parenteral nutrition did not improve clinical outcomes or long-term quality of life in adult ICU patients.
- There is a need for adequately large randomized studies to investigate the optimal timing and amounts of nutrition for critically ill patients.
- Harvey SE, Parrott F, Harrison DA, et al. Trial of the Route of Early Nutritional Support in Critically Ill Adults. N Engl J Med. 2014;371(18):1673-1684.
- Arabi YM, Aldawood AS, Haddad SH, et al. Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults. N Engl J Med. 2015; 372(25):2398-2408.
- 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.
- Arabi YM, Tamim HM, Dhar GS, et al. Permissive underfeeding and intensive insulin therapy in critically ill patients: a randomized controlled trial. Am J Clin Nutr. 2011;93(3):569-77.
Other News on the UVAHS GI Nutrition Website: (www.ginutrition.virginia.edu):
Latest PG Article: Moo-ove Over, Cow’s Milk: The Rise of Plant-Based Dairy Alternatives
- February 8: Nutrition in Acute Kidney Injury by Joe Krenitsky, MS, RD
- March 21: Celiac Disease by Carol Rees Parrish, MS, RD
Joe Krenitsky MS, RDN
PS – Please feel free to forward on to friends and colleagues.