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

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

Positional Cloning Reveals Strain-Dependent Expression of <em>Trim16</em> to Alter Susceptibility to Bleomycin-Induced Pulmonary Fibrosis in Mice

<div><p>Pulmonary fibrosis is a disease of significant morbidity, with no effective therapeutics and an as yet incompletely defined genetic basis. The chemotherapeutic agent bleomycin induces pulmonary fibrosis in susceptible C57BL/6J mice but not in mice of the C3H/HeJ strain, and this differential strain response has been used in prior studies to map bleomycin-induced pulmonary fibrosis susceptibility loci named <em>Blmpf1</em> and <em>Blmpf2</em>. In this study we isolated the quantitative trait gene underlying <em>Blmpf2</em> initially by histologically phenotyping the bleomycin-induced lung disease of sublines of congenic mice to reduce the linkage region to 13 genes. Of these genes, <em>Trim16</em> was identified to have strain-dependent expression in the lung, which we determined was due to sequence variation in the promoter. Over-expression of <em>Trim16</em> by plasmid injection increased pulmonary fibrosis, and bronchoalveolar lavage levels of both interleukin 12/23-p40 and neutrophils, in bleomycin treated B6.C3H-<em>Blmpf2</em> subcongenic mice compared to subcongenic mice treated with bleomycin only, which follows the C57BL/6J versus C3H/HeJ strain difference in these traits. In summary we demonstrate that genetic variation in <em>Trim16</em> leads to its strain-dependent expression, which alters susceptibility to bleomycin-induced pulmonary fibrosis in mice.</p> </div

Positional cloning reveals strain-dependent expression of Trim16 to alter susceptibility to bleomycin-induced pulmonary fibrosis in mice.

Pulmonary fibrosis is a disease of significant morbidity, with no effective therapeutics and an as yet incompletely defined genetic basis. The chemotherapeutic agent bleomycin induces pulmonary fibrosis in susceptible C57BL/6J mice but not in mice of the C3H/HeJ strain, and this differential strain response has been used in prior studies to map bleomycin-induced pulmonary fibrosis susceptibility loci named Blmpf1 and Blmpf2. In this study we isolated the quantitative trait gene underlying Blmpf2 initially by histologically phenotyping the bleomycin-induced lung disease of sublines of congenic mice to reduce the linkage region to 13 genes. Of these genes, Trim16 was identified to have strain-dependent expression in the lung, which we determined was due to sequence variation in the promoter. Over-expression of Trim16 by plasmid injection increased pulmonary fibrosis, and bronchoalveolar lavage levels of both interleukin 12/23-p40 and neutrophils, in bleomycin treated B6.C3H-Blmpf2 subcongenic mice compared to subcongenic mice treated with bleomycin only, which follows the C57BL/6J versus C3H/HeJ strain difference in these traits. In summary we demonstrate that genetic variation in Trim16 leads to its strain-dependent expression, which alters susceptibility to bleomycin-induced pulmonary fibrosis in mice

Pulmonary expression of reduced region <i>Blmpf2</i> genes.

<p>Real-time quantitative PCR of genes mapping to the reduced <i>Blmpf2</i> region prior to (day 0: non-treated) and following bleomycin treatment (day 42) in the lungs of B6 and C3H mice. Gene expression was normalized to the Ataxin10 reference gene and is presented relative to the level in untreated C3H mice. Mean ±SEM of 5 per group. * indicates a significant difference in expression in lungs of bleomycin-treated mice relative to untreated controls, p<0.05; ^# indicates a significant difference in expression by strain, p<0.05.</p

B6 and C3H <i>Trim16</i> promoter sequence variation alters transcription.

<p>B6/C3H sequence differences in the putative promoter region of <i>Trim16</i> (* indicates novel to Sanger, MGI). Allele specific promoter sequence alters the expression of a luciferase reporter vector transfected into the RAW 264.7 macrophage cell line.</p

Bleomycin-induced lung phenotype of <i>Blmpf2</i> subcongenic mice.

<p>The mice were treated with bleomycin by mini-osmotic pump and euthanized 42 days later. The percentage of the lung with fibrosis was determined from image analysis of histological sections and the mean ± SEM of 10–19 bleomycin-treated mice for each subcongenic line, and for the parental strains, is given. * indicates a significant difference in fibrosis from B6 mice, p<0.05. Genotypes [C3H alleles (white box); B6 alleles (black box)] were determined with microsatellite and SNP markers; genotypes of line 6 are expanded at the bottom of the figure.</p

Measuring aortic diameter improves accuracy of esophageal Doppler in assessing fluid responsiveness

OBJECTIVE: Fluid responsiveness requires the accurate measurement of cardiac output that can be approached by aortic blood flow (ABF) as measured by esophageal Doppler monitoring (EDM). EDM devices may either include an echo-determination of aortic diameter or estimate aortic diameter from nomograms and thus consider it as constant. However, it is unclear if measuring aortic diameter increases the accuracy of EDM to identify fluid responsiveness. Aortic diameter varies with arterial pressure such that its measure could be essential for assessing the changes in ABF during acute circulatory failure. We attempted to demonstrate that measuring aortic diameter improved the accuracy of EDM to assess fluid responsiveness. DESIGN: Prospective study. SETTING: University hospital intensive care unit. PATIENTS: Seventy-six patients with acute circulatory failure in whom a fluid challenge was given. INTERVENTIONS: Rapid volume expansion (500 mL of NaCl 0.9%). MEASUREMENTS AND MAIN RESULTS: We measured aortic velocity and area by EDM before and after fluid loading and evaluated the effects of fluid challenge on ABF, either measured after fluid infusion (measured ABFafter) or estimated assuming an unchanging aortic area (estimated ABFafter). If measured ABFafter was used for assessing fluid response, it was increased above 15% compared with ABF at baseline in 41 patients (responders). Conversely, estimated ABF after increased above 15% from ABF at baseline in 27 patients only; that is, the effects of the challenge were underestimated in 14 patients. In these 14 patients, the relative change in mean arterial pressure during volume expansion was of greater magnitude than in patients who were classified as nonresponders by considering measured ABFafter. CONCLUSIONS: Monitoring the changes in aortic diameter improves the accuracy of EDM in assessing the hemodynamic effects of a fluid challenge, especially if it induces a large increase in arterial pressure. Estimating rather than measuring the aortic diameter may lead to underestimation of fluid responsiveness. Copyright © 2007 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins

Passive leg raising predicts fluid responsiveness in the critically ill

Objective: Passive leg raising (PLR) represents a "self-volume challenge" that could predict fluid response and might be useful when the respiratory variation of stroke volume cannot be used for that purpose. We hypothesized that the hemodynamic response to PLR predicts fluid responsiveness in mechanically ventilated patients. Design: Prospective study. Setting: Medical intensive care unit of a university hospital. Patients: We investigated 71 mechanically ventilated patients considered for volume expansion. Thirty-one patients had spontaneous breathing activity and/or arrhythmias. Interventions: We assessed hemodynamic status at baseline, after PLR, and after volume expansion (500 mL NaCl 0.9% infusion over 10 mins). Measurements and Main Results: We recorded aortic blood flow using esophageal Doppler and arterial pulse pressure. We calculated the respiratory variation of pulse pressure in patients without arrhythmias. In 37 patients (responders), aortic blood flow increased by ≥15% after fluid infusion. A PLR increase of aortic blood flow ≥10% predicted fluid responsiveness with a sensitivity of 97% and a specificity of 94%. A PLR increase of pulse pressure a 12% predicted volume responsiveness with significantly lower sensitivity (60%) and specificity (85%). In 30 patients without arrhythmias or spontaneous breathing, a respiratory variation in pulse pressure ≥12% was of similar predictive value as was PLR increases in aortic blood flow (sensitivity of 88% and specificity of 93%). In patients with spontaneous breathing activity, the specificity of respiratory variations in pulse pressure was poor (46%). Conclusions: The changes in aortic blood flow induced by PLR predict preload responsiveness in ventilated patients, whereas with arrhythmias and spontaneous breathing activity, respiratory variations of arterial pulse pressure poorly predict preload responsiveness. Copyright © 2006 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins