A randomized trial of glutamine and antioxidants in critically ill patients.
Heyland Daren,Muscedere John,Wischmeyer Paul E,Cook Deborah,Jones Gwynne,Albert Martin,Elke Gunnar,Berger Mette M,Day Andrew G,
The New England journal of medicine
BACKGROUND:Critically ill patients have considerable oxidative stress. Glutamine and antioxidant supplementation may offer therapeutic benefit, although current data are conflicting. METHODS:In this blinded 2-by-2 factorial trial, we randomly assigned 1223 critically ill adults in 40 intensive care units (ICUs) in Canada, the United States, and Europe who had multiorgan failure and were receiving mechanical ventilation to receive supplements of glutamine, antioxidants, both, or placebo. Supplements were started within 24 hours after admission to the ICU and were provided both intravenously and enterally. The primary outcome was 28-day mortality. Because of the interim-analysis plan, a P value of less than 0.044 at the final analysis was considered to indicate statistical significance. RESULTS:There was a trend toward increased mortality at 28 days among patients who received glutamine as compared with those who did not receive glutamine (32.4% vs. 27.2%; adjusted odds ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.64; P=0.05). In-hospital mortality and mortality at 6 months were significantly higher among those who received glutamine than among those who did not. Glutamine had no effect on rates of organ failure or infectious complications. Antioxidants had no effect on 28-day mortality (30.8%, vs. 28.8% with no antioxidants; adjusted odds ratio, 1.09; 95% CI, 0.86 to 1.40; P=0.48) or any other secondary end point. There were no differences among the groups with respect to serious adverse events (P=0.83). CONCLUSIONS:Early provision of glutamine or antioxidants did not improve clinical outcomes, and glutamine was associated with an increase in mortality among critically ill patients with multiorgan failure. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00133978.).
10.1056/NEJMoa1212722
Trial of the route of early nutritional support in critically ill adults.
Harvey Sheila E,Parrott Francesca,Harrison David A,Bear Danielle E,Segaran Ella,Beale Richard,Bellingan Geoff,Leonard Richard,Mythen Michael G,Rowan Kathryn M,
The New England journal of medicine
BACKGROUND:Uncertainty exists about the most effective route for delivery of early nutritional support in critically ill adults. We hypothesized that delivery through the parenteral route is superior to that through the enteral route. METHODS:We conducted a pragmatic, randomized trial involving adults with an unplanned admission to one of 33 English intensive care units. We randomly assigned patients who could be fed through either the parenteral or the enteral route to a delivery route, with nutritional support initiated within 36 hours after admission and continued for up to 5 days. The primary outcome was all-cause mortality at 30 days. RESULTS:We enrolled 2400 patients; 2388 (99.5%) were included in the analysis (1191 in the parenteral group and 1197 in the enteral group). By 30 days, 393 of 1188 patients (33.1%) in the parenteral group and 409 of 1195 patients (34.2%) in the enteral group had died (relative risk in parenteral group, 0.97; 95% confidence interval, 0.86 to 1.08; P=0.57). There were significant reductions in the parenteral group, as compared with the enteral group, in rates of hypoglycemia (44 patients [3.7%] vs. 74 patients [6.2%]; P=0.006) and vomiting (100 patients [8.4%] vs. 194 patients [16.2%]; P<0.001). There were no significant differences between the parenteral group and the enteral group in the mean number of treated infectious complications (0.22 vs. 0.21; P=0.72), 90-day mortality (442 of 1184 patients [37.3%] vs. 464 of 1188 patients [39.1%], P=0.40), in rates of 14 other secondary outcomes, or in rates of adverse events. Caloric intake was similar in the two groups, with the target intake not achieved in most patients. CONCLUSIONS:We found no significant difference in 30-day mortality associated with the route of delivery of early nutritional support in critically ill adults. (Funded by the United Kingdom National Institute for Health Research; CALORIES Current Controlled Trials number, ISRCTN17386141.).
10.1056/NEJMoa1409860
Energy-Dense versus Routine Enteral Nutrition in the Critically Ill.
,Chapman Marianne,Peake Sandra L,Bellomo Rinaldo,Davies Andrew,Deane Adam,Horowitz Michael,Hurford Sally,Lange Kylie,Little Lorraine,Mackle Diane,O’Connor Stephanie,Presneill Jeffrey,Ridley Emma,Williams Patricia,Young Paul
The New England journal of medicine
BACKGROUND:The effect of delivering nutrition at different calorie levels during critical illness is uncertain, and patients typically receive less than the recommended amount. METHODS:We conducted a multicenter, double-blind, randomized trial, involving adults undergoing mechanical ventilation in 46 Australian and New Zealand intensive care units (ICUs), to evaluate energy-dense (1.5 kcal per milliliter) as compared with routine (1.0 kcal per milliliter) enteral nutrition at a dose of 1 ml per kilogram of ideal body weight per hour, commencing at or within 12 hours of the initiation of nutrition support and continuing for up to 28 days while the patient was in the ICU. The primary outcome was all-cause mortality within 90 days. RESULTS:There were 3957 patients included in the modified intention-to-treat analysis (1971 in the 1.5-kcal group and 1986 in the 1.0-kcal group). The volume of enteral nutrition delivered during the trial was similar in the two groups; however, patients in the 1.5-kcal group received a mean (±SD) of 1863±478 kcal per day as compared with 1262±313 kcal per day in the 1.0-kcal group (mean difference, 601 kcal per day; 95% confidence interval [CI], 576 to 626). By day 90, a total of 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 had died (relative risk, 1.05; 95% CI, 0.94 to 1.16; P=0.41). The results were similar in seven predefined subgroups. Higher calorie delivery did not affect survival time, receipt of organ support, number of days alive and out of the ICU and hospital or free of organ support, or the incidence of infective complications or adverse events. CONCLUSIONS:In patients undergoing mechanical ventilation, the rate of survival at 90 days associated with the use of an energy-dense formulation for enteral delivery of nutrition was not higher than that with routine enteral nutrition. (Funded by National Health and Medical Research Institute of Australia and the Health Research Council of New Zealand; TARGET ClinicalTrials.gov number, NCT02306746 .).
10.1056/NEJMoa1811687
Impact of the route of nutrition on gut mucosa in ventilated adults with shock: an ancillary of the NUTRIREA-2 trial.
Piton Gaël,Le Gouge Amélie,Brulé Noelle,Cypriani Benoit,Lacherade Jean-Claude,Nseir Saad,Mira Jean-Paul,Mercier Emmanuelle,Sirodot Michel,Rigaud Jean-Philippe,Malaquin Stéphanie,Soum Edouard,Djibre Michel,Gaudry Stéphane,Thévenin Didier,Reignier Jean
Intensive care medicine
PURPOSE:The effects of the route of nutrition on the gut mucosa of patients with shock are unclear. Plasma citrulline concentration is a marker of enterocyte mass, and plasma intestinal fatty acid binding protein (I-FABP) concentration is a marker of enterocyte damage. We aimed to study the effect of the route of nutrition on plasma citrulline concentration measured at day 3 of nutrition. MATERIALS AND METHODS:Ancillary study of the NUTRIREA-2 trial. Ventilated adults with shock were randomly assigned to receive enteral or parenteral nutrition. Enterocyte biomarkers were measured at baseline, day 3, and day 8 of nutrition. RESULT:A total of 165 patients from 13 French ICUs were included in the study: 85 patients in the enteral group and 80 patients in the parenteral group. At baseline, plasma citrulline was low without difference between groups (12.2 µmol L vs 13.3 µmol L). At day 3, plasma citrulline concentration was higher in the enteral group than in the parenteral group (18.7 µmol L vs 15.3 µmol L, p = 0.01). Plasma I-FABP concentration was increased at baseline, without difference between groups (245 pg mL vs 244 pg mL). Plasma I-FABP concentration was higher in the enteral group than in the parenteral group at day 3 and day 8 (158 pg mL vs 50 pg mL, p = 0.005 and 225 pg mL vs 50 pg mL, p = 0.03). CONCLUSION:Plasma citrulline concentration was higher after 3 days of enteral nutrition than after 3 days of parenteral nutrition. This result raises the question of the possibility that enteral nutrition is associated with a more rapid restoration of enterocyte mass than parenteral nutrition.
10.1007/s00134-019-05649-3
Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2).
Reignier Jean,Boisramé-Helms Julie,Brisard Laurent,Lascarrou Jean-Baptiste,Ait Hssain Ali,Anguel Nadia,Argaud Laurent,Asehnoune Karim,Asfar Pierre,Bellec Frédéric,Botoc Vlad,Bretagnol Anne,Bui Hoang-Nam,Canet Emmanuel,Da Silva Daniel,Darmon Michael,Das Vincent,Devaquet Jérôme,Djibre Michel,Ganster Frédérique,Garrouste-Orgeas Maité,Gaudry Stéphane,Gontier Olivier,Guérin Claude,Guidet Bertrand,Guitton Christophe,Herbrecht Jean-Etienne,Lacherade Jean-Claude,Letocart Philippe,Martino Frédéric,Maxime Virginie,Mercier Emmanuelle,Mira Jean-Paul,Nseir Saad,Piton Gael,Quenot Jean-Pierre,Richecoeur Jack,Rigaud Jean-Philippe,Robert René,Rolin Nathalie,Schwebel Carole,Sirodot Michel,Tinturier François,Thévenin Didier,Giraudeau Bruno,Le Gouge Amélie, ,
Lancet (London, England)
BACKGROUND:Whether the route of early feeding affects outcomes of patients with severe critical illnesses is controversial. We hypothesised that outcomes were better with early first-line enteral nutrition than with early first-line parenteral nutrition. METHODS:In this randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2 trial) done at 44 French intensive-care units (ICUs), adults (18 years or older) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned (1:1) to either parenteral nutrition or enteral nutrition, both targeting normocaloric goals (20-25 kcal/kg per day), within 24 h after intubation. Randomisation was stratified by centre using permutation blocks of variable sizes. Given that route of nutrition cannot be masked, blinding of the physicians and nurses was not feasible. Patients receiving parenteral nutrition could be switched to enteral nutrition after at least 72 h in the event of shock resolution (no vasopressor support for 24 consecutive hours and arterial lactate <2 mmol/L). The primary endpoint was mortality on day 28 after randomisation in the intention-to-treat-population. This study is registered with ClinicalTrials.gov, number NCT01802099. FINDINGS:After the second interim analysis, the independent Data Safety and Monitoring Board deemed that completing patient enrolment was unlikely to significantly change the results of the trial and recommended stopping patient recruitment. Between March 22, 2013, and June 30, 2015, 2410 patients were enrolled and randomly assigned; 1202 to the enteral group and 1208 to the parenteral group. By day 28, 443 (37%) of 1202 patients in the enteral group and 422 (35%) of 1208 patients in the parenteral group had died (absolute difference estimate 2·0%; [95% CI -1·9 to 5·8]; p=0·33). Cumulative incidence of patients with ICU-acquired infections did not differ between the enteral group (173 [14%]) and the parenteral group (194 [16%]; hazard ratio [HR] 0·89 [95% CI 0·72-1·09]; p=0·25). Compared with the parenteral group, the enteral group had higher cumulative incidences of patients with vomiting (406 [34%] vs 246 [20%]; HR 1·89 [1·62-2·20]; p<0·0001), diarrhoea (432 [36%] vs 393 [33%]; 1·20 [1·05-1·37]; p=0·009), bowel ischaemia (19 [2%] vs five [<1%]; 3·84 [1·43-10·3]; p=0·007), and acute colonic pseudo-obstruction (11 [1%] vs three [<1%]; 3·7 [1·03-13·2; p=0·04). INTERPRETATION:In critically ill adults with shock, early isocaloric enteral nutrition did not reduce mortality or the risk of secondary infections but was associated with a greater risk of digestive complications compared with early isocaloric parenteral nutrition. FUNDING:La Roche-sur-Yon Departmental Hospital and French Ministry of Health.
10.1016/S0140-6736(17)32146-3
Factors associated with acute mesenteric ischemia among critically ill ventilated patients with shock: a post hoc analysis of the NUTRIREA2 trial.
Intensive care medicine
PURPOSE:Acute mesenteric ischemia (AMI) is a rare, but life-threatening condition occurring among critically ill patients. Several factors have been associated with AMI, but the causal link is debated, most studies being retrospective. Among these factors, enteral nutrition (EN) could be associated with AMI, in particular among patients with shock. We aimed to study the factors independently associated with AMI in a post hoc analysis of the NUTRIREA-2 trial including 2410 critically ill ventilated patients with shock, randomly assigned to receive EN or parenteral nutrition (PN). METHODS:Post hoc analysis of the NUTRIREA-2 trial was conducted. Ventilated adults with shock were randomly assigned to receive EN or PN. AMI was assessed by computed tomography, endoscopy, or laparotomy. Factors associated with AMI were studied by univariate and multivariate analysis. RESULTS:2410 patients from 44 French intensive care units (ICUs) were included in the study: 1202 patients in the enteral group and 1208 patients in the parenteral group. The median age was 67 [58-76] years, with 67% men, a SAPS II score of 59 [46-74], and a medical cause for ICU admission in 92.7%. AMI was diagnosed among 24 (1%) patients, mainly by computed tomography (79%) or endoscopy (38%). The mechanism of AMI was non-occlusive mesenteric ischemia (n = 12), occlusive (n = 4), and indeterminate (n = 8). The median duration between inclusion in the trial and AMI diagnosis was 4 [1-11] days. Patients with AMI were older, had a higher SAPS II score at ICU admission, had higher plasma lactate, creatinine, and ASAT concentrations and lower hemoglobin concentration, had more frequently EN, dobutamine, and CVVHDF at inclusion, developed more frequently bacteremia during ICU stay, and had higher 28-day and 90-day mortality rates compared with patients without AMI. By multivariate analysis, AMI was independently associated with EN, dobutamine use, SAPS II score ≥ 62 and hemoglobin concentration ≤ 10.9 g/dL. CONCLUSION:Among critically ill ventilated patients with shock, EN, dobutamine use, SAPS II score ≥ 62 and hemoglobin ≤ 10.9 g/dL were independently associated with AMI. Among critically ill ventilated patients requiring vasopressors, EN should be delayed or introduced cautiously in case of low cardiac output requiring dobutamine and/or in case of multiple organ failure with high SAPS II score.
10.1007/s00134-022-06637-w
Nutrition dose in the early acute phase of critical illness: Finding the sweet spot and heeding the lessons from the NUTRIREA trials.
JPEN. Journal of parenteral and enteral nutrition
The landmark NUTRIREA-2 and NUTRIREA-3 trials compared the route and dose of nutrition, respectively, in critically ill patients with circulatory shock. The results of both trials support a "less-is-more" paradigm shift in the early acute phase of critical illness. In this review, the authors outline and appraise the results of the NUTRIREA-2 and NUTRIREA-3 trials, introduce the concept of identifying the "sweet spot" for nutrition dose based on severity of illness/nutrition risk and nutrition dose, and identify the unintended consequences of delivering full-dose nutrition in sicker critically ill patients during the early acute phase of critical illness.
10.1002/jpen.2539