Defining the Value of Analgesia for Total Knee Arthroplasty Using Time-Driven Activity-Based Costing: A Novel Approach to Clinical Practice Transformation.

OBJECTIVE: To compare the relative value of 3 analgesic pathways for total knee arthroplasty (TKA). PATIENTS AND METHODS: Time-driven activity-based costing analyses were performed on 3 common analgesic pathways for patients undergoing TKA: periarticular infiltration (PAI) only, PAI and single-injection adductor canal blockade (SACB), and PAI and continuous adductor canal blockade (CACB). Additionally, adult patients who underwent elective primary TKA from November 1, 2017, to May 1, 2018, were retrospectively identified to analyze analgesic (pain score, opiate use) and hospital outcomes (distance walked, length of stay) after TKA based on analgesic pathway. RESULTS: There was no difference in patient demographic characteristics, specifically complexity (American Society of Anesthesiologists score) or preoperative opiate use, between groups. Compared with PAI, total cost (labor and material) was 1.4-times greater for PAI plus SACB and 2.3-times greater for PAI plus CACB. The addition of SACB to PAI resulted in lower average and maximum pain scores and opiate use on the day of operation compared with PAI alone. Average and maximum pain scores and opiate use between SACB and CACB were not significantly different. Walking distance and hospital length of stay were not significantly different between groups. CONCLUSION: Perioperative care teams should consider the cost and relative value of pain management when selecting the optimal analgesic strategy for TKA. Despite slightly higher relative cost, the combination of SACB with PAI may offer short-term analgesic benefit compared with PAI alone, which could enhance its relative value in TKA.

Mitochondrial therapy improves limb perfusion and myopathy following hindlimb ischemia.

Critical limb ischemia is a devastating manifestation of peripheral arterial disease with no effective strategies for improving morbidity and mortality outcomes. We tested the hypothesis that cellular mitochondrial function is a key component of limb pathology and that improving mitochondrial function represents a novel paradigm for therapy. BALB/c mice were treated with a therapeutic mitochondrial-targeting peptide (MTP-131) and subjected to limb ischemia (HLI). Compared to vehicle control, MTP-131 rescued limb muscle capillary density and blood flow (64.7±11% of contralateral vs. 39.9±4%), and improved muscle regeneration. MTP-131 also increased electron transport system flux across all conditions at HLI day-7. In vitro, primary muscle cells exposed to experimental ischemia demonstrated markedly reduced (~75%) cellular respiration, which was rescued by MTP-131 during a recovery period. Compared to muscle cells, endothelial cell (HUVEC) respiration was inherently protected from ischemia (~30% reduction), but was also enhanced by MTP-131. These findings demonstrate an important link between ischemic tissue bioenergetics and limb blood flow and indicate that the mitochondria may be a pharmaceutical target for therapeutic intervention during critical limb ischemia.

Exercise-induced protection against reperfusion arrhythmia involves stabilization of mitochondrial energetics.

Mitochondria influence cardiac electrophysiology through energy- and redox-sensitive ion channels in the sarcolemma, with the collapse of energetics believed to be centrally involved in arrhythmogenesis. This study was conducted to determine if preservation of mitochondrial membrane potential (ΔΨm) contributes to the antiarrhythmic effect of exercise. We utilized perfused hearts, isolated myocytes, and isolated mitochondria exposed to metabolic challenge to determine the effects of exercise on cardiac mitochondria. Hearts from sedentary (Sed) and exercised (Ex; 10 days of treadmill running) Sprague-Dawley rats were perfused on a two-photon microscope stage for simultaneous measurement of ΔΨm and ECG. After ischemia-reperfusion, the collapse of ΔΨm was commensurate with the onset of arrhythmia. Exercise preserved ΔΨm and decreased the incidence of fibrillation/tachycardia (P < 0.05). Our findings in intact hearts were corroborated in isolated myocytes exposed to in vitro hypoxia-reoxygenation, with Ex rats demonstrating enhanced redox control and sustained ΔΨm during reoxygenation. Finally, we induced anoxia-reoxygenation in isolated mitochondria using high-resolution respirometry with simultaneous measurement of respiration and H2O2 Mitochondria from Ex rats sustained respiration with lower rates of H2O2 emission than Sed rats. Exercise helps sustain postischemic mitochondrial bioenergetics and redox homeostasis, which is associated with preserved ΔΨm and protection against reperfusion arrhythmia. The reduction of fatal ventricular arrhythmias through exercise-induced mitochondrial adaptations indicates that mitochondrial therapeutics may be an effective target for the treatment of heart disease.

Why Does Exercise "Trigger" Adaptive Protective Responses in the Heart?

Numerous epidemiological studies suggest that individuals who exercise have decreased cardiac morbidity and mortality. Pre-clinical studies in animal models also find clear cardioprotective phenotypes in animals that exercise, specifically characterized by lower myocardial infarction and arrhythmia. Despite the clear benefits, the underlying cellular and molecular mechanisms that are responsible for exercise preconditioning are not fully understood. In particular, the adaptive signaling events that occur during exercise to "trigger" cardioprotection represent emerging paradigms. In this review, we discuss recent studies that have identified several different factors that appear to initiate exercise preconditioning. We summarize the evidence for and against specific cellular factors in triggering exercise adaptations and identify areas for future study.