Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial.
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.


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
UZ Leuven, Research Foundation-Flanders, the Flemish Government, and the European Research Council.
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.
Greet
G
Hermans
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.
Michael P
MP
Casaer
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.
Beatrix
B
Clerckx
Laboratory of Intensive-Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Fabian
F
Güiza
Laboratory of Intensive-Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Tine
T
Vanhullebusch
Laboratory of Intensive-Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Sarah
S
Derde
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.
Philippe
P
Meersseman
Laboratory of Intensive-Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Inge
I
Derese
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.
Dieter
D
Mesotten
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.
Pieter J
PJ
Wouters
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.
Sophie
S
Van Cromphaut
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.
Yves
Y
Debaveye
Department of Rehabilitation Sciences, KU Leuven, Leuven, Belgium.
Rik
R
Gosselink
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.
Jan
J
Gunst
Medical Intensive-Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium.
Alexander
A
Wilmer
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.
Greet
G
Van den Berghe
Laboratory of Intensive-Care Medicine, Division of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Ilse
I
Vanhorebeek
D000199:Actins / Q000235:genetics; D000368:Aged; D001284:Atrophy; D001343:Autophagy; D024722:Cardiac Myosins / Q000235:genetics; D003422:Critical Care / Q000379:methods*; D002149:Energy Intake / Q000502:physiology*; D005260:Female; D006801:Humans; D007902:Length of Stay; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000473:pathology / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics; D018908:Muscle Weakness / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D018995:Myosin Heavy Chains / Q000235:genetics; D024507:Nonmuscle Myosin Type IIA / Q000235:genetics; D010288:Parenteral Nutrition / Q000379:methods*; D011446:Prospective Studies; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis; D012333:RNA, Messenger / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics; D013997:Time Factors; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000032:analysis; D044767:Ubiquitin-Protein Ligases / Q000032:analysis / Q000235:genetics
D000199:Actins; C477012:MAP1LC3A protein, human; C501641:MYH7 protein, human; D008869:Microtubule-Associated Proteins; D009124:Muscle Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases; D024722:Cardiac Myosins; D024507:Nonmuscle Myosin Type IIA; D018995:Myosin Heavy Chains