Elsevier

The Lancet

Volume 391, Issue 10116, 13–19 January 2018, Pages 133-143
The Lancet

Articles
Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2)

https://doi.org/10.1016/S0140-6736(17)32146-3Get rights and content

Summary

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.

Introduction

Acute critical illness requiring mechanical ventilation carries a risk of severe malnutrition, whose adverse effects include infections, muscle wasting, delayed recovery, and increased mortality.1 Nutritional support is therefore crucial. Guidelines recommend early enteral feeding supplying 20–25 kcal/kg per day during the acute phase of critical illness,2, 3 but rest on a low level of evidence. Whether timing, route, or dose of nutritional support affects the outcomes of critically ill patients remains unclear.4

Compared with parenteral nutrition, enteral nutrition was associated with improvements in gastrointestinal mucosa integrity, immune function, and tissue repair responses, which translated into decreases in nosocomial infections, hospital and intensive-care unit (ICU) stay lengths, and health-care costs.5, 6, 7, 8, 9, 10, 11 Early initiation of enteral nutrition (within 24–48 h after ICU admission) might enhance these beneficial effects and decrease mortality rates,3, 12, 13, 14, 15 but has been reported to induce gastrointestinal intolerance with vomiting in 30–70% of ICU patients, raising concerns about ventilator-associated pneumonia and undernutrition.16, 17, 18, 19, 20 Enteral nutrition was also associated with gut ischaemia in critically ill patients with shock.21, 22, 23, 24 Thus, whether enteral feeding has protective or deleterious effects on the gut remains controversial.21, 25 Meta-analyses provided conflicting results on the effect of feeding route on patient outcomes but included studies with heterogeneous designs, sample sizes, and illness severity.26, 27 Guidelines recommend postponing enteral nutrition in patients with shock until full resuscitation with haemodynamic stability is achieved.2, 3 Nevertheless, numerous studies suggest that mechanically ventilated ICU patients with haemodynamic instability might have better survival when early nutrition is given enterally rather than parenterally.12, 14, 23, 24, 28, 29, 30, 31, 32

Research in context

Evidence before this study

We searched PubMed without date or language restrictions for studies assessing enteral and parenteral nutritional support in critically ill patients. We also screened the reference lists in published guidelines, meta-analyses, and reviews. At the time our trial was designed, published studies including meta-analyses indicated reduced infectious complications and improved prognosis with enteral feeding compared to parenteral feeding. Observational studies suggested that factors associated with greater benefits from enteral nutrition might have worse critical illness severity and earlier compared with delayed enteral feeding. Recently, during the course of the NUTRIREA-2 study, the multicentre randomised CALORIES trial in an unselected population of critically ill patients was published. The results showed no differences in outcome or infectious complications between early enteral and early parenteral nutrition. A meta-analysis including the CALORIES trial and previous published studies found no difference in mortality; although early enteral nutrition was associated with shorter intensive-care unit (ICU) stay lengths and fewer infectious complications compared with early parenteral nutrition, subgroup analyses suggested that these effects might be limited to trials in which the energy intake was lower with enteral than with parenteral nutrition. The most recently published guidelines recommend early enteral feeding, at the early stage of critical illness. Thus, whether the route of early feeding influences outcomes of patients with severe critically illnesses remains controversial.

Added value of this study

The NUTRIREA-2 study is the second, large, randomised, controlled trial assessing the effect of the route of nutritional support in critically ill adults without contraindications to enteral or parenteral nutrition. By contrast with the CALORIES trial, NUTRIREA-2 focused on patients treated with invasive mechanical ventilation and vasopressor support for shock, because previous studies suggested that mechanically ventilated patients in ICU with haemodynamic instability might have better survival when early nutrition is given enterally rather than parenterally. In the NUTRIREA-2 trial, nutrition delivery was adapted according to a predetermined definition of the acute phase of critical illness. Furthermore, nutritional intakes were far closer to targets than in the CALORIES trial. The groups given early normocaloric enteral versus parenteral nutrition showed no significant differences in day 28 mortality; frequency of infectious complications; organ failure severity or duration; life support duration; ICU and hospital stay lengths; and ICU, hospital, or day 90 mortality. Compared with the parenteral route, the enteral route was associated with slightly lower calorie and protein intakes and with higher frequencies of hypoglycaemia. Proportions of patients with bowel ischaemia and colonic pseudo-obstruction were higher in the enteral group than in the parenteral group.

Implications of all the available evidence

The findings of NUTRIREA-2 are to some extent consistent with those of the CALORIES trial but not with those of meta-analyses suggesting benefits from the enteral route compared with the parenteral route. However, whereas the CALORIES trial also showed no outcome differences between feeding routes, NUTRIREA-2 raises concern about a rare but major complication of enteral feeding in patients with severe critical illness. Our data do not support a preference for early enteral compared with parenteral nutrition during the acute phase of critical illness in patients who have no contraindications to enteral or parenteral nutrition and who are receiving mechanical ventilation and vasopressor support for shock. Furthermore, our data suggest potential harmful effects on the gut of enteral nutrition with a normocaloric target.

We aimed to investigate whether early first-line enteral nutrition had beneficial clinical effects compared with early first-line parenteral nutrition, both targeting normocaloric goals, in patients requiring invasive mechanical ventilation and vasopressor support for shock.

Section snippets

Study design and participants

The NUTRIREA-2 trial was a randomised, controlled, multicentre, open-label, parallel-group study done in 44 French ICUs, including 28 (64%) in university hospitals.33

Adults (18 years or older) admitted to any of the participating ICUs were eligible if they were expected to require more than 48 h of invasive mechanical ventilation, concomitantly with vasoactive therapy (adrenaline, dobutamine, or noradrenaline) via a central venous catheter for shock and to be started on nutritional support

Results

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. The interim analyses are available in the appendix. Between March 22, 2013, and June 30, 2015, 2410 patients were randomised; 1202 to the enteral group and 1208 to the parenteral group (figure 1; appendix p 13). No patients were withdrawn, and all randomised

Discussion

Day 28 mortality did not differ significantly between groups given early normocaloric enteral versus parenteral nutrition during mechanical ventilation and vasoactive drug therapy for shock. Compared with the parenteral route, the enteral route was associated with slightly lower calorie and protein intakes and with higher frequencies of hypoglycaemia and adverse gastrointestinal events. The groups showed no significant differences for frequency of infectious complications; organ failure

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