The Possible Pathophysiological Outcomes and Mechanisms of Tourniquet-Induced Ischemia-Reperfusion Injury during Total Knee Arthroplasty

Table 1

Effects of TQ-induced I/R injury on localized skeletal muscles.

Study model/specimen/sample size/age	TQ pressure/ischemia time	Major findings (compared to baseline level)			Interpretation	References
		Clinical outcome	Mechanism
			Ischemia phase	Reperfusion phase
Cross-sectional study/vastus lateralis muscle biopsy//62–76 yr	≥300 mmHg, 32–52 min	↓ 12% of quadriceps muscle volume at 2 weeks after surgery	↔ eIF4G gene expression; ↓ phosphorylation of Akt at Ser^473 and 4E-BP1; ↑ phosphorylation of eEF2	↑ eIF4G gene expression; ↓ phosphorylation of Akt at Ser^473 and 4E-BP1; ↑ phosphorylation of eEF2	Cap-dependent translation initiation and elongation may be inhibited during skeletal muscle I/R	[9]
Randomized controlled trial/vastus medialis muscle biopsy//55–85 yr	380 mmHg, 60 min	N/A	↔ free, conjugated Ub; ↔ total Ub-protein ligase activity; ↑ proteasome-dependent and -independent peptidase activities	N/A	Upregulated proteasome-dependent and -independent peptidase activities suggested an increase in protein degradation at 60-minute ischemia time	[10]
Randomized controlled trial/vastus lateralis muscle biopsy//63–76 yr	Double SBP mmHg, 56–92 min	N/A	↑ all muscle-free amino acids, except glutamate; ↔ mitochondrial enzymes	↓ all muscle-free amino acids; ↔ mitochondrial enzymes	Degradation of free amino acids was more than synthesis during skeletal muscle ischemia; No mitochondrial dysfunction occurred at maximum ischemia and at 24 hours after reperfusion	[11]
Cross-sectional study/vastus lateralis muscle biopsy//60–78 yr	≥300 mmHg, 33–50 min	N/A	N/A	Upregulation of 72 genes including JAK-STAT, p53, JNK, NFκB, Akt, and MAPK	Genes related to cell stress pathways involved in reperfusion injury	[12]
Cross-sectional study/quadriceps muscle biopsy, venous blood//64–89 yr	300 mmHg	N/A	↑ positive ET-1-immunostaining cells; ↔ ET-1 mRNA expression; ↔ plasma ET-1	↑ positive ET-1-immunostaining cells; ↔ ET-1 mRNA expression; ↔ plasma ET-1	ET-1 is involved in skeletal muscle I/R	[13]
Cross-sectional study/quadriceps muscle biopsy//64–89 yr	300 mmHg	N/A	↔ nNOS, iNOS, and eNOS immunostaining in muscle fibers; ↑ nNOS mRNA expression; ↔ nNOS and eNOS protein expression; ↔ NOS activity	↑ nNOS and eNOS immunostaining in muscle fibers; ↑ nNOS mRNA expression; ↑ nNOS and eNOS protein expression; ↔ NOS activity	nNOS and eNOS were upregulated in postischemic muscle, but their activities were not altered	[14]
Randomized controlled trial/interstitial space fluid at gastrocnemius muscle//68 ± 8 yr	250 mmHg, 74 ± 4 min	N/A	↓ glucose; ↓ pyruvate; ↑ lactate; ↑ L/P ratio; ↑ glycerol	↓ glucose; ↑ pyruvate; ↑ lactate; ↔ L/P ratio; ↑ glycerol	Changes in the level of metabolic markers in the extracellular space suggested ischemic injury and persisted for up to 180 minutes after reperfusion	[20]
Randomized controlled trial/vastus medialis muscle biopsy//74 ± 3 yr	380 mmHg, 60 min	N/A	↔ mitochondrial enzymes	N/A	No effects on amount and function of mitochondria at 60-minute ischemia time	[18]

4E-BP1: eukaryotic initiation factor 4E-binding protein; eEF2: eukaryotic elongation factor 2; eIF4G: eukaryotic translation initiation factor 4 gamma; ET-1: endothelin 1; I/R: ischemia and reperfusion; JAK-STAT: Janus kinase/signal transducer and activator of transcription; JNK: c-Jun N-terminal kinase; L/P: lactate/pyruvate; MAPK: mitogen-activated protein kinase; mRNA: messenger ribonucleic acid; N/A: not available; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; NOS: nitric oxide synthase; SBP: systolic blood pressure; TQ: tourniquet; Ub: ubiquitin.