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

Background.Critically ill patients develop 'intensive care unit-acquired weakness', which delays rehabilitation.Reduced muscle mass and/or quality could play a role.The EPaNIC-trial showed that tolerating macronutrient deficit for one week in ICU (late-PN) accelerated recovery compared with early parenteral nutrition (early-PN) to prevent such deficit.The role of weakness herein was unclear.We hypothesised that late-PN may allow better autophagic quality control in myofibers whereby less weakness could occur.Methods.In this prospectively planned subanalysis of the EPaNIC-RCT, weakness 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 atrophy and autophagy.Findings.With late-PN, 105 (34%) patients had weakness on first evaluation (median day 9 post-randomisation) compared with 127 (43%) early-PN patients (absolute difference -9 (-16 to -1 95% CI)%, p=0•030).Weakness recovered faster with late-PN than with early-PN (p=0•021).Myofiber size and density were lower in patients than controls, similarly with early-PN and late-PN.Messenger-RNA encoding contractile myofibrillary proteins were lower and E3-ligases higher in muscle from patients than controls (p<0•0010), again unaffected by nutrition.In contrast, the LC3-II/LC3-I ratio, reflecting autophagosome formation, was higher in late-PN than in early-PN patients (p=0•026), reaching values almost double those of controls (p=0•0016), and coinciding with less ubiquitin staining (p=0•019).A higher LC3-II/LC3-I ratio was independently associated with less weakness (0•047).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 myofibers and reduced weakness.