Greet Hermans1, Michael P Casaer2, Beatrix Clerckx2, Fabian Güiza3, Tine Vanhullebusch3, Sarah Derde3, Philippe Meersseman1, Inge Derese3, Dieter Mesotten2, Pieter J Wouters2, Sophie Van Cromphaut2, Yves Debaveye2, Rik Gosselink4, Jan Gunst2, Alexander Wilmer5, Greet Van den Berghe6, Ilse Vanhorebeek3. 1. Medical Intensive-Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium; Laboratory of Intensive-Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. 2. Department of Intensive Care Medicine, University Hospitals Leuven, Leuven, Belgium; Laboratory of Intensive-Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. 3. Laboratory of Intensive-Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. 4. Department of Rehabilitation Sciences, KU Leuven, Leuven, Belgium. 5. Medical Intensive-Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium. 6. Department of Intensive Care Medicine, University Hospitals Leuven, Leuven, Belgium; Laboratory of Intensive-Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. Electronic address: greet.vandenberghe@med.kuleuven.be.
Abstract
BACKGROUND:Patients who are critically ill can develop so-called intensive-care unit acquired weakness, which delays rehabilitation. Reduced muscle mass, quality, or both might have a role. The Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) trial (registered with ClinicalTrials.gov, number NCT00512122) showed that tolerating macronutrient deficit for 1 week in intensive-care units (late parenteral nutrition [PN]) accelerated recovery compared with early PN. The role of weakness was unclear. Our aim was to assess whether late PN and early PN differentially affect muscle weakness and autophagic quality control of myofibres. METHODS: In this prospectively planned subanalysis of the EPaNIC trial, weakness (MRC sum score) was assessed in 600 awake, cooperative patients. Skeletal muscle biopsies, harvested from 122 patients 8 days after randomisation and from 20 matched healthy controls, were studied for autophagy and atrophy. We determined the significance of differences with Mann-Whitney U, Median, Kruskal-Wallis, or χ(2) (exact) tests, as appropriate. FINDINGS: With late PN, 105 (34%) of 305 patients had weakness on first assessment (median day 9 post-randomisation) compared with 127 (43%) of 295 patients given early PN (absolute difference -9%, 95% CI -16 to -1; p=0·030). Weakness recovered faster with late PN than with early PN (p=0·021). Myofibre cross-sectional area was less and density was lower in critically ill patients than in healthy controls, similarly with early PN and late PN. The LC3 (microtubule-associated protein light chain 3) II to LC3I ratio, related to autophagosome formation, was higher in patients given late PN than early PN (p=0·026), reaching values almost double those in the healthy control group (p=0·0016), and coinciding with less ubiquitin staining (p=0·019). A higher LC3II to LC3I ratio was independently associated with less weakness (p=0·047). Expression of mRNA encoding contractile myofibrillary proteins was lower and E3-ligase expression higher in muscle biopsies from patients than in control participants (p≤0·0006), but was unaffected by nutrition. INTERPRETATION: Tolerating a substantial macronutrient deficit early during critical illness did not affect muscle wasting, but allowed more efficient activation of autophagic quality control of myofibres and reduced weakness. FUNDING: UZ Leuven, Research Foundation-Flanders, the Flemish Government, and the European Research Council.
RCT Entities:
BACKGROUND:Patients who are critically ill can develop so-called intensive-care unit acquired weakness, which delays rehabilitation. Reduced muscle mass, quality, or both might have a role. The Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically IllPatients (EPaNIC) trial (registered with ClinicalTrials.gov, number NCT00512122) showed that tolerating macronutrient deficit for 1 week in intensive-care units (late parenteral nutrition [PN]) accelerated recovery compared with early PN. The role of weakness was unclear. Our aim was to assess whether late PN and early PN differentially affect muscle weakness and autophagic quality control of myofibres. METHODS: In this prospectively planned subanalysis of the EPaNIC trial, weakness (MRC sum score) was assessed in 600 awake, cooperative patients. Skeletal muscle biopsies, harvested from 122 patients 8 days after randomisation and from 20 matched healthy controls, were studied for autophagy and atrophy. We determined the significance of differences with Mann-Whitney U, Median, Kruskal-Wallis, or χ(2) (exact) tests, as appropriate. FINDINGS: With late PN, 105 (34%) of 305 patients had weakness on first assessment (median day 9 post-randomisation) compared with 127 (43%) of 295 patients given early PN (absolute difference -9%, 95% CI -16 to -1; p=0·030). Weakness recovered faster with late PN than with early PN (p=0·021). Myofibre cross-sectional area was less and density was lower in critically illpatients than in healthy controls, similarly with early PN and late PN. The LC3 (microtubule-associated protein light chain 3) II to LC3I ratio, related to autophagosome formation, was higher in patients given late PN than early PN (p=0·026), reaching values almost double those in the healthy control group (p=0·0016), and coinciding with less ubiquitin staining (p=0·019). A higher LC3II to LC3I ratio was independently associated with less weakness (p=0·047). Expression of mRNA encoding contractile myofibrillary proteins was lower and E3-ligase expression higher in muscle biopsies from patients than in control participants (p≤0·0006), but was unaffected by nutrition. INTERPRETATION: Tolerating a substantial macronutrient deficit early during critical illness did not affect muscle wasting, but allowed more efficient activation of autophagic quality control of myofibres and reduced weakness. FUNDING: UZ Leuven, Research Foundation-Flanders, the Flemish Government, and the European Research Council.