February 2018 E-Journal Club
We generally do not host training programs in February, due to the fickle uncertainties of the weather. This year was no exception, since we varied from frozen solid to unseasonably warm with little or no notice recently. Our journal club for February is the largest randomized study of early enteral nutrition in the adult ICU to date. I suspect that we will be discussing and considering the results of this study for some time to come.
Reignier J, Boisramé-Helms J, Brisard L, et al. Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2). Lancet. 2018; 391(10116):133-143.
This was multi-center (44 ICUs), randomized unblinded study in 2410 adult ICU patients to assess the effect of early enteral nutrition (EN) compared to early parenteral nutrition (PN) in critically ill, mechanically ventilated, vasopressor dependent patients. Nutrition support was started as soon as possible after randomization, and was initiated in all patients no later than 24 hours after intubation.
The parenteral nutrition group received exclusive PN for the first 72 hours, then after the patient met study criteria for hemodynamic stability (normolactemia and no vasopressor support X 24 hours), the PN was held and EN was started at the goal flow rate. If the patient continued to have hyperlactemia or vasopressor requirement, PN was continued X 7 days, then EN was initiated (if there were no contraindications outside hemodynamic status).
The enteral group received exclusive EN for the first 7 days, and patients with persistent EN intolerance could receive PN only on day 8 of the study. EN was started polymeric formulas at goal flow rates, gastric residuals were not checked and feeding was not held for “minor regurgitation”.
Nutrition support for both groups was based on 20-25 kcals/kg of actual weight X 7 days, then on 25-30 kcals/kg actual weight from day 8 to extubation.
The primary outcome of the study was day 28 all-cause mortality. Secondary outcomes included Sequential Organ Failure Assessment (SOFA) score, bodyweight, amounts of calories and proteins delivered, vomiting, prokinetic medications, stool, blood glucose, insulin treatment, blood lactic acid, bilirubin, alanine aminotransferase, and aspartate aminotransferase, antiulcer prophylaxis, anti-infectious treatments, prone position, dialysis during the intervention period, day 90 mortality, ICU mortality, hospital mortality, ICU stay length, acute care hospital stay length, days without life support, ICU acquired infections, and non-infectious complications.
The investigators determined that they would need to enroll 2854 patients for a 5% decrease in 28-day mortality in the EN group.
Inclusion and Exclusion Criteria:
Patients 18 years of age or older who were expected to require more than 48 h of invasive mechanical ventilation, vasoactive therapy (adrenaline,
dobutamine, or noradrenaline) via a central venous catheter for shock and planned to start on nutrition support within 24 h after endotracheal intubation (or within 24 h after ICU admission if intubation occurred before ICU admission).Exclusion criteria:
Mechanical ventilation started more than 24 h earlier; gastrointestinal surgery within the past month; history of gastrectomy, esophagectomy, duodeno-pancreatectomy, bypass surgery, gastric banding, or short bowel syndrome; feeding gastrostomy or jejunostomy; pre-existing long-term home enteral or parenteral nutrition; active gastrointestinal bleeding; treatment limitation decisions; adult under legal guardianship; pregnancy; breastfeeding; current inclusion in a randomized trial designed to compare enteral nutrition to parenteral nutrition; contraindication to parenteral nutrition (known hypersensitivity to egg or soybean proteins or to another component, inborn error in amino acid metabolism, or severe familial dyslipidaemia affecting triglyceride levels).
Investigators screened 10,855 patients (!) and randomized 2410 patients (22% of those screened). There were 59 patients (26 PN, 33 EN) who were either off vasoactive medications by randomization or on mechanical ventilation > 24 hours, and 9 who were lost to follow up by day 28, but all 2410 randomized patients were included in the primary outcome analysis (intention to treat). At the second planned interim analysis, after 1202 EN patients and 1208 PN patients had been enrolled, the study was prematurely terminated for futility (No significant difference in 28-day mortality was likely with full enrollment).
There was no significant difference in the primary study outcome of 28-day mortality [443 (37%) EN patients and 422 (35%) PN patients]. There were also no significant differences between the groups in the other clinical outcomes such as mortality at 90 days or in the ICU or hospital, ICU length of stay, hospital length of stay, infections, pneumonia, bacteremia, days without mechanical ventilation or dialysis or vasopressor support.
Median time from intubation to the start of nutrition support was approx 16 hours in both groups. The PN group had a significantly increased calorie and protein delivery compared to the EN group (19.6 kcal/kg, 0.8 gm protein/kg PN compared to 17.8 kcals/kg, 0.7 gm protein/kg EN).
The PN group had significantly a lower frequency of hypoglycemia (n=13 PN, n= 29 EN) and a higher frequency of blood lactate normalization (n= 743 EN, n= 797 PN) compared to the EN group. The incidence of vomiting, diarrhea and colonic pseudo-obstruction were significantly greater in the EN, compared to the PN group. The EN group also has significantly greater incidence of bowel ischemia, compared to the PN group (19 EN, 5 PN).
“….the enteral route is not clinically superior over the parenteral route for early nutritional support with a normocaloric target in critically ill patients treated with mechanical ventilation and vasopressor support for shock. Our data indicate an increased risk of gastrointestinal complications with early isocaloric enteral nutrition compared to parenteral nutrition in these patients.”
This study is of the largest ever randomized investigation into the effects of early EN in critically ill adults. Considering that the current ASPEN guidelines for early EN are based on 936 total patients in all of the studies from 1979 to 2012 added together, the results and evaluation of this study have substantial implications for the future practice of adult critical care nutrition support. This study was notable for successfully initiating EN in an expeditious manner, which is one of the limitations of several of the older studies. Also notable, is the fact that this study provided meaningful amounts of nutrition in a timely manner by starting EN at goal flow rates and by not conservatively advancing feeding rates over several hours or days, and not monitoring gastric contents. However, it is possible that the aggressive provision of full feeding may be one of the more contentious portions of the study protocol, because of the increase in in ischemic bowel cases in the EN group. The results of this study suggest that there are no benefits of early EN in critically ill adults, or at least that providing goal rate EN to patients that are not completely hemodynamically stable has negative effects that outweigh any potential benefit of early EN.
Ischemic bowel generally occurs infrequently, so it is very difficult to study, even in larger randomized investigations. However, the results of this study suggest that very early EN at full volumes without monitoring gastric residuals may be a risk factor for ischemic bowel, especially in those patients that have not been fully resuscitated or not hemodynamically stable. We did discuss that the aggressive EN feeding protocol also resulted in a significant increase in emesis in the EN group, but did not result in a significant difference in pneumonia incidence between the groups. However, it is notable that both groups actually had a relatively high incidence of emesis, and to remember that the early PN group was started on EN after day 3, with 25% of the total calories provision from the PN group came from EN.
This is now the third study of short-term, reduced calorie PN that did not show a significant increase in infectious complications compared to EN.(1,2) Unfortunately, there will be a temptation for some people to suggest more global statements like “PN does not increase risk of infection”. It will be important to remember that all of the available studies provided PN for 1 week or less, in contrast to the real world where there is a temptation to leave patients on PN for longer periods of time.
The final consideration (also mentioned in the editorial) is that it is really too bad that there was not a group of unfed patients in this study to examine if there is any benefit or risk of very early EN or PN relative to no nutrition support. The inherent limitations of our data, and the risks of professional hubris in assuming that early nutrition support is beneficial have been noted, with great persistence, for more than 25 years. (3-4) With evidence accumulating that early EN or early full calories may not have benefit, and an interest in autogaphy as a potentially essential component of later anabolism, there is at last a recognition that we need to randomize critically ill adults to early versus no (0, none, nada) nutrition support.
Our Take Home Message(s)
- Providing early, full EN to patients with marginal hemodynamic stability did not provide outcome benefits and appeared to increase the risk of ischemic bowel, emesis and diarrhea.
- Short-term, hypocaloric PN appears reasonably safe.
- There is a need for research to find out when we should begin nutrition support in critically ill adults for optimal outcomes.
- 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.
- 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.
- Koretz RL. Nutritional supplementation in the ICU. How critical is nutrition for the critically ill? Am J Respir Crit Care Med. 1995 Feb;151(2 Pt 1):570-3.
- Koretz RL. The calorie conundrum. JPEN J Parenter Enteral Nutr. 2002 May-Jun;26(3):182-3.
Other News on the UVAHS GI Nutrition Website: (www.ginutrition.virginia.edu):
Latest PG Article: Amyloid: A Wolf in Sheep’s Clothing
- March 20: Celiac Disease by Carol Rees Parrish, MS, RD
- Upcoming Topics: Nutrition Management of GI Fistulas, Issues with Jejunal Feeding
Joe Krenitsky MS, RDN PS – Please feel free to forward on to friends and colleagues.