Muscle Strength, Functional Mobility, and PROMs
Patients in both groups reported significant declines from baseline functional status at 2 weeks postoperatively (p < 0.05 for all); functional measures and patient-reported outcome measures (PROMs) did not change significantly from baseline to 6 weeks postoperatively after correction for multiple tests. Secondary analyses focused on quadriceps and hamstrings strength, functional mobility, and PROMs demonstrated no significant treatment effects in these measures at 2 or 6 weeks postoperatively (Table IV).
Physical Activity and Caloric Intake
The placebo and EAA groups did not significantly differ in terms of average energy expended preoperatively (319.71 ± 56.97 compared with 408.15 ± 45.37 kcal/day; p = 0.24) or at 2 and 6 weeks postoperatively after adjusting for baseline values. Energy intake was moderate at baseline, averaging 1,731 and 1,949 kcal/day in the placebo and EAA groups, respectively. In both groups, caloric intake, protein intake, fat intake, and carbohydrate intake declined significantly from baseline to 2 weeks postoperatively (p < 0.05 for all), but not from baseline to 6 weeks postoperatively (p > 0.05 for all). Nutritional measures did not significantly differ between the 2 groups (p > 0.05 for all).
Compliance and Safety
Patients reported taking 99% of the EAA doses and 96% of the placebo doses. No study-related adverse events were reported. Patients who withdrew did so for non-study-related health reasons. Non-study-related adverse events did not significantly differ between the groups at the midpoint or at the end of the study according to O’Brien-Fleming-adjusted alpha thresholds. The groups did not significantly differ in terms of any of the 15 liver and kidney function or homocysteine tests (Table V). NMR analysis of 8 randomly selected EAA supplement vials revealed the following target and measured amounts: histidine (target, 2.2 g; measured, 2.94 ± 0.15 g), isoleucine (target, 2.0 g; measured, 1.97 ± 0.08 g), leucine (target, 3.6 g; measured, 3.07 ± 0.13 g), lysine (target, 3.2 g; measured, 2.64 ± 0.14 g), methionine (target, 0.6 g; measured, 0.63 ± 0.03 g), phenylalanine (target, 3.2 g; measured, 2.9 ± 0.0 g), threonine (target, 2.8 g; measured, 3.3 ± 0.10 g), and valine (target, 2.4 g; measured, 2.96 ± 0.24 g).
The present study confirms our proof-of-principle findings from 2013 showing preservation of muscle following TKA in older adults receiving EAA treatment compared with those receiving placebo9. That study showed that twice-daily ingestion of 20 g of EAA for 1 week before through 6 weeks after TKA had muscle-sparing effects in the quadriceps and hamstrings on the involved and contralateral sides at 6 weeks postoperatively. In the present study, the EAA group lost <5% in quadriceps and hamstrings muscle volume at 6 weeks across both legs, replicating the previous study. Specifically, the patients who received EAA treatment lost an average 4.9% in muscle volume in the present study, compared with 4.6% in the previous study. Among patients who received placebo treatment, however, those in the current study lost less muscle overall (10.1%) than those in the previous study (13.6%). As a result, the difference in atrophy rates between the 2 treatment groups in the present study was less (5% difference) than that in the previous study (9% difference). Despite the differences between the studies, the results favoring EAA supplementation are promising.
The present study, unlike the previous study, did not demonstrate significant differences in functional mobility or strength outcomes between treatment groups. Given that the results related to muscle atrophy and functional mobility were more similar between the 2 treatment groups in the present study than in the previous study, the lack of significant between-group differences in functional mobility measures might be expected. Measures of functional mobility are less reliable than physiological measures such as muscle volume; idiosyncratic patient factors (e.g., common cold) may have introduced noise into the functional results, making functional differences harder to detect, but would not have affected muscle volume results. The present study was designed primarily to detect differences in highly reliable physiological measures and may have lacked statistical power to detect functional measures. However, the absence of replication with these measures is not necessarily a contradiction. The likelihood of conflicting results at the p = 0.05 level from 2 studies with power of 0.80 is “32% or about 1 chance in 3.”20
Differences in results between the 2 studies may reflect differences in hospital protocols. Postoperative recovery expectations were higher for all patients in the present study, including those in the placebo group, than for those in the previous study. Between studies, the participating hospitals implemented a fast-track program, which has been associated with reduced pain21, earlier achievement of 90° of flexion, reduced reliance on walking aids22, and lower rates of subsequent joint manipulation23. The recent standardized hospital program with earlier hospital discharge may have decreased differences between conditions on functional outcomes during the weeks immediately following surgery.
EAA supplement compounding practices changed between the studies, which may have affected treatment outcomes. The EAA mixing and dispensing practices used in the present study resulted in inconsistent amino acid compositions across all vials. Most notably, the leucine concentration fell consistently short of the 3.6 g/vial target by an average 0.53 g. Murphy et al. recently reported that free-living older men who ingested 5 g of leucine with each meal for 3 days while on either a low or high-protein diet had elevated basal and post-exercise muscle protein synthesis rates compared with the same individuals on the same diets (low or high-protein) without supplemental leucine24. Subjects on low and high-protein diets supplemented with 5 grams of leucine per meal did not differ from one another24. This finding suggests that under-representation of leucine content in the EAA group may have negatively influenced outcomes. Variations in EAA composition may help to explain why the present study did not demonstrate, as the previous study did, that patients receiving EAA had significantly greater improvements on functional mobility tests than those receiving placebo9.
Despite EAA supplement variability, EAA treatment significantly attenuated muscle atrophy, consistent with the findings of our previous report9. Increasing evidence supports defined protocols for EAA supplement dosing regimens. Supplement ingestion 1 hour after physical therapy was a design feature of both our previous study9 and the current investigation because, in an earlier study, we found that ingestion of similar amounts of EAA 1 hour after exercise enhanced muscle protein synthesis response and mTORC1 (mammalian target of rapamycin complex 1) signaling10. Enhanced muscle protein synthesis response to exercise with protein or EAA ingestion has been shown in several laboratories25 - 28. In addition, Jordan et al.29, in a study of older individuals on an isocaloric, isonitrogenous diet (with physical activity levels controlled for), showed that nitrogen balance increased 57% when protein was consumed immediately after daily exercise as opposed to at rest earlier in the day.
To our knowledge, there are no PROMs for functional status of the knee that can be used to detect minimum clinically important differences in the acute postoperative period (2 and 6 weeks after TKA); our study demonstrated no difference in KOOS or VR-12 scores between treatment groups at 6 weeks after surgery. Future work is needed to assess differences in patient-reported quality-of-life and knee-specific outcomes at 3 and 6 months after TKA for participants ingesting placebo versus EAA.
Energy intake in the present study was moderate, in line with other studies of older healthy adults23 and older patient populations10 , 24. While reduced energy intake across treatment conditions was found at 2 weeks after TKA in both our 2013 study9 and the current study, both the absolute amount of energy intake and the change from baseline differed. The mean kcal/day at 2 weeks after TKA were about 400 lower in our 2013 study than in the current study in both the placebo group (1,396 compared with 1,731) and the EAA group (1,546 compared with 1,949). Differences in energy intake in the immediate post-acute period may have contributed to differences in outcomes between the 2 studies.
The present study had several limitations. Analyses were limited to the acute postoperative period because previous research has shown that significant muscle loss occurs within the first 2 weeks after surgery9. Future research should explore muscle volume and functional outcomes across longer follow-up periods, ideally 2 years or longer. The retention rate of 63.9%—after accounting for the withdrawal of participants deemed ineligible after randomization—was lower than anticipated. Participants withdrew for personal reasons related to health, supplement compliance, and lack of time. Dropout rates did not differ between the groups, and baseline characteristics were not significantly different between dropouts and completers. Medications used to promote recovery after TKA, such as muscle relaxants, could have influenced results, but it is important to note that the proportion of muscle relaxant users did not differ between the groups, and muscle relaxants did not significantly interact with treatment group to predict outcomes. Finally, the inconsistent EAA composition across all vials is a limitation that could have affected results.
The present findings extend our understanding of the potential beneficial effects of EAA use in patients managed with TKA. Future studies designed to identify mechanisms of action, durability of effect, and longer dosing regimens are needed. Our results suggest that EAA supplementation is potentially effective for helping older adult patients to recover from TKA surgery.
The authors are grateful to Michelle Bremer and Anthony Paluso for study coordination; to Chelsey Policar, Katie Kowalski, Amanda Morris, Katia Krane, Eli Edwards, and Callie Porter for data collection; to Dr. Fred Sabb, Dr. Jolinda Smith, and Scott Watrous for MRI technical assistance; to Dr. Timothy Burnett for assistance with MIPAV; to Dr. Thomas Metz and Nancy Isern of the Pacific Northwest National Laboratory, Richland, Washington, for EAA analyses; to Dr. Lewis E. Kazis, ScD, Director, Center for the Assessment of Pharmaceutical Practices, Boston University School of Public Health, for permission to use the VR-12 health survey in this and ongoing trials at Slocum.
Investigation performed at the Department of Human Physiology, University of Oregon, Eugene; Oregon Research Institute, Eugene; Slocum Research and Education Foundation, Eugene; Oregon Health & Science University, Portland; and Slocum Center for Orthopedics and Sports Medicine, Eugene, Oregon.
Disclosure: The study was funded by the National Institute on Aging (AG046401), which did not play a role in the investigation. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A46).
Disclaimer: The content of this manuscript is solely the responsibility of the authors and does not represent the official views of the funders.
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© 2018 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Journal of Bone and Joint Surgery, Incorporated.