Nutrition during the acute phase of critical illness: discussions on NUTRIREA-3

We congratulate Jean Reignier and colleagues1Reignier J Plantefeve G Mira JP et al.Low versus standard calorie and protein feeding in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3).Lancet Respir Med. 2023; (published online March 20.)https://doi.org/10.1016/S2213-2600(23)00092-9Summary Full Text Full Text PDF Scopus (2) Google Scholar for completing the NUTRIREA-3 trial, wherein mechanically ventilated, critically ill patients receiving vasoactive therapy for shock within 24 h of intubation were randomly assigned to receive either low or standard feeding (6 vs 25 kcal/kg per day and 0·2–0·4 vs 1·0–1·3 g of protein/kg per day, respectively). The authors concluded that an early low energy and protein intake was associated with faster recovery and fewer complications. We respectfully suggest that the conclusion should be revised to reflect the findings that an early high energy and protein intake in patients with shock is harmful and not that "restriction was superior to standard" intake. In the NUTRIREA-3 trial, patients received high-dose norepinephrine (median 0·5 μg/kg per min), and were provided with early high energy and protein that contradicts international clinical practice guidelines.2McClave SA Taylor BE Martindale RG et al.Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.).JPEN J Parenter Enteral Nutr. 2016; 40: 159-211Crossref PubMed Google Scholar, 3Singer P Blaser AR Berger MM et al.ESPEN guideline on clinical nutrition in the intensive care unit.Clin Nutr. 2019; 38: 48-79Summary Full Text Full Text PDF PubMed Scopus (1183) Google Scholar The authors state that they "compared with the standard calorie and protein intakes recommended in current guidelines". Although the energy and protein goals are correct, the authors overlooked the associated recommendation to deliver nutrition progressively over a week. In NUTRIREA-3 (as with NUTRIREA-24Reignier J Boisrame-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: 133-143Summary Full Text Full Text PDF PubMed Scopus (288) Google Scholar) there was an immediate full nutrition delivery, which is warned against in the guidelines since such practice is known to be deleterious. Furthermore, the investigators have overlooked the results of NUTRIREA-2, which showed that early high energy intake via enteral nutrition increased the risk of bowel ischaemia, which is an outcome replicated in NUTRIREA-3. The harm of an early high energy intake might also be attributed to the significantly higher incidence of hypophosphataemia, because a previous study showed higher 60-day mortality in this population even when electrolytes were adequately replenished.5Doig GS Simpson F Heighes PT et al.Restricted versus continued standard caloric intake during the management of refeeding syndrome in critically ill adults: a randomised, parallel-group, multicentre, single-blind controlled trial.Lancet Respir Med. 2015; 3: 943-952Summary Full Text Full Text PDF PubMed Google Scholar Notably, NUTRIREA-3 can be compared with the TARGET trial,6Chapman M Peake SL Bellomo R et al.Energy-dense versus routine enteral nutrition in the critically ill.N Engl J Med. 2018; 379: 1823-1834Crossref PubMed Scopus (175) Google Scholar which did not show harm when a higher energy dose than that in NUTRIREA-3 was administered during the first 2 days of admission to an intensive care unit. Notably, the energy dose for the lower nutrition group in TARGET was similar to that of the standard treatment in NUTRIREA-3 (table). The potential reasons for the absence of harm in TARGET could be that the mortality risk of the patients in TARGET was lower than those in NUTRIREA-3, and if low energy and protein were indeed beneficial (as posited by NUTRIREA-3), then TARGET might have represented a trial comparing two harmful interventions. These uncertainties might be resolved through a network meta-analysis, because there exist enough trials with varying caloric doses.TableComparison of patient characteristics and nutrition interventions between the TARGET and NUTRIREA-3 trialsTARGET (N=3957)NUTRIREA-3 (N=3036)Higher energy group (n=1971)Lower energy group (n=1986)Higher energy group (n=1515)Lower energy group (n=1521)Patient characteristicsAge57·2 (16·6)57·5 (16·5)66 (13)66 (13)Medical diagnosis at admission1443 (73·2%)1435 (72·3%)1258 (83·0%)1253 (82·4%)BMI29·2 (7·2)29·3 (7·9)27·0 (23·0–31·5)26·7 (23·0–31·1)Sequential organ failure assessmentNRNR10 (8–13)10 (8–13)Acute physiology and chronic health evaluation II22·0 (8·3)22·1 (8·5)NRNRSimplified acute physiology score IINRNR61 (48–74)60 (48–74)Patients with vasoactive drugs1235 (62·7%)1253 (63·1%)1486 (98·1%)1481 (97·4%)Norepineprine dose, μg/kg per minNRNR0·50 (0·25–1·00)0·50 (0·25–0·99)Patients with renal replacement therapy172 (8·7%)177 (8·9%)183 (12·1%)161 (10·6%)90-day mortality in the control group505/1966 (25·7%)..648 (42·8%)..InterventionsStart time, hIntensive care unit admission to starting trial nutrition: 15·8 (7·7–26·3)Intensive care unit admission to starting trial nutrition: 15·9 (7·9–28·3)Intubation to feeding: 17·0 (10·8–21·8)Intubation to feeding: 16·7 (10·6–21·6)Duration of intervention, days6 (3–11), continuing for up to 28 days6 (3–11), continuing for up to 28 daysUp to 7 daysUp to 7 daysEnergy receivedKcal per day (trial nutrition)1863 (478)1262 (313)NRNRKcal/kg per day (trial nutrition)29·1 (6·2)19·6 (4·0)19·9 (15·3–22·6)5·1 (4·0–5·9)Protein receivedg per day69·6 (17·8)69·4 (17·2)NRNRg/kg per day1·09 (0·22)1·08 (0·23)0·9 (0·7–1·0)0·2 (0·2–0·3)Fluids, LVolume of trial nutrition similar between groupsVolume of trial nutrition similar between groups17·2 (9·7–23·4)11·1 (6·1–16·4)Enteral nutrition routeAll patientsAll patients846 (55·8%)932 (61·3%)Supplemental parenteral nutrition route109 (5·5%)85/1985 (4·3%)296 (19·5%)208 (13·7%)Data shown as mean (SD), %, or median (IQR). NR=not reported. Open table in a new tab Data shown as mean (SD), %, or median (IQR). NR=not reported. Overall, we acknowledge the importance and efforts of identifying the optimal energy and protein doses for critically ill patients; however, the lessons learned from previous studies require careful consideration. We declare no competing interests. Low versus standard calorie and protein feeding in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3)Compared with standard calorie and protein targets, early calorie and protein restriction did not decrease mortality but was associated with faster recovery and fewer complications. Full-Text PDF