Table 7.

Therapeutic strategies for ICU-related weakness

Level of Evidence	Presumed Target	Presumed Target at Cellular/Molecular Level
Direct evidence for benefit
Tight glycemic control	Nerve	Improved microcirculation (E) (183, 393, 781)
		Improved mitochondrial function (E) (735)
		Attenuated loss of nerve fibers (E) (603)
Withholding parenteral nutrition during first week in ICU	Muscle	Improved autophagic muscle quality control (A) (300)
Indirect evidence for benefit
Sedation sparing protocol	Muscle	Prevention of disuse atrophy caused by decreased protein synthesis, anabolic resistance, and increased protein degradation by the ubiquitin proteasome system (C, D) (81, 260)
Early limb mobilization	Muscle	Autophagy (C, D) (294, 689)
Potential evidence for harm: limit use unless evidence-based benefit
Corticosteroids	Muscle	Promoting atrophy by decreased protein synthesis and increased proteolysis by the ubiquitin proteasome and lysosomal system (A, B) (154, 616, 617, 703)
Neuromuscular blocking agents	NMJ	Prolonged neuromuscular blockade (A) (265)
	Muscle	Denervation atrophy (D)
Theoretical benefit
Careful electrolyte management (Na+, K+, P, Mg2+, Ca2+)	Nerve	Nerve membrane excitability (E)
	NMJ	Neuromuscular transmission (E)
	Muscle	Muscle membrane excitability (E); excitation-contraction coupling (E)
Ventilator weaning protocol	Muscle	Avoiding fatigue (E) (387)
Electrical muscle stimulation	Muscle	Prevention of atrophy by suppression of ubiquitin proteasome system and calpain and increased anabolic pathways by induction of growth factors (A, C, D) (73, 171, 467, 664, 765)
		Autophagy (E)

The level of available evidence is graded as follows: A) human data from critically ill patients; B) experimental data from ICU models; C) human data from noncritically ill or healthy volunteers; D) experimental data from other animal models, including immobilization/denervation; E) hypothesis.