It is not known whether postsurgery systemic inflammation and plasma amino acid abnormalities are still present during rehabilitation of individuals after elective hip arthroplasty (EHA). Sixty subjects (36 females; age
Elective hip arthroplasty (EHA) is a surgical technique used for patients with damaged hip joints after degenerative osteoarthritis or an injury. One and half million EHA operations are carried out all over the world each year [
EHA and post-EHA rehab allow patients to regain physical ability and improve their quality of life. However, a number of factors may hinder both the duration and outcome of rehabilitation, including preoperative functional state, postoperative anemia, and any infection or metabolic alterations. Among the latter, the possible persistence of inflammation and alterations of plasma amino acids [
Here, we have formulated two hypotheses. Firstly, rehab subjects after EHA could have alterations of circulating amino acids from persistent inflammation. To test this hypothesis, we measured plasma amino acid levels and inflammation markers. Secondly, this study investigated whether the administration of essential amino acids (EAAs) could enhance the recovery of hip-joint dysfunction of the operated hip and correct/limit plasma amino acid alterations. The rationale for this choice was based on the fact that these substrates are well-known to enhance body and muscle protein synthesis (hence tissue accrual) [
The ultimate purpose of this study was to stimulate further research on the topic and to provide added recommendations for rehabilitation management.
Sixty-eight subjects at
On the second day after admission, patients underwent the following procedures.
Routine variables, including serum total protein (g/dL) and protein electrophoresis. C-reactive protein (CRP) as a marker of systemic inflammation (using an immune-turbidimetric method. Normal value is <0.8 mg/dL). Plasma amino acids: the concentration of free amino acids in the plasma was measured using an AminoQuant II amino acid analyzer, based on the HP 1090 HPLC system, with fully automated precolumn derivatization. Both orthopthalaldehyde (OPA) and 9-fluorenyl-methyl-chloroformate (FMOC) reaction chemistries were used, according to the manufacturer’s protocol. Measurements were made by injecting 1
Nutritional analysis on the amount of food actually ingested was used to calculate actual ingested calories and macronutrients [
Patients were then assigned to the treatment or placebo according to a randomized allocation procedure established before patient admission to our rehabilitation department. A randomization list was generated using SAS statistical software, A and B being the identifiers of the blinded treatment. The list was made available to both the physiatrist (E. B.) and the hospital pharmacist. The physiatrist allocated patients sequentially to treatment A or B according to the randomization list. The author of the article (A. R.) who interpreted all the results and the physiatrist (S. C) who evaluated the clinical-functional state (HHS) were blinded to the patient allocation. The treatment consisted of 14-d EAA supplementation. Eight g/d (2 packages) of EAAs (Aminotrophic, Professional Dietetics, Milan, Italy) or a placebo (maltodextrin) was supplied. One package (4 g) of EAAs contained the essential leucine (1.250 g), lysine (0.65 g), isoleucine (0.625 g), valine (0.625 g), threonine (0.35 g), phenylalanine (0.1 g), methionine (0.05 g), and tryptophan (0.02 g) as well as cysteine (0.15 g), tyrosine (0.03 g), and histidine (0.15 g). The 14-day treatment was dictated by the rehabilitation center policy, which permitted patients to stay for a maximum of 20 days.
With regard to the placebo, we decided not to use isonitrogenous nonessential amino acids as, under physiological conditions, these amino acids are inferior to essential amino acids in boosting protein synthesis or limiting protein breakdown. The use of maltodextrin as a placebo would have been a more appropriate choice since this carbohydrate, like essential amino acids [
Passive mobilization of hip movements in triple flexion (hip, knee, and ankle). Stretching the adductor and flexor muscles of the operated limb. Hip extension using isotonic contraction of the gluteus. Isotonic contraction of the quadriceps muscles against a resistance of 1 kg. Assisted gait training with the use of walking sticks and training for the stairs. Maintenance of cardiorespiratory capacity.
Within 2 days before patient discharge, all procedures except for nutritional intake were repeated. The local ethics scientific committee approved the protocol (# 118 in the Maugeri Foundation Scientific Annals 2011, page 432) after the subjects gave their informed consent.
Descriptive statistics were carried out for all recorded variables, reporting mean and standard deviations for quantitative variables and distribution frequencies for qualitative variables. Chi-squared test was used for categorical variables. Wilcoxon signed rank test was used to compare the difference in HHS of the entire patient population between admission to and discharge from rehabilitation institute. Paired Student’s
Repeated measures analysis of variance tested the over time changes in plasma amino acids of the randomized subgroups. Kruskal-Wallis test was used to compare the over time gains of HHS in randomized EAA and placebo subgroups. Statistical significance was set at
Table
Demographic, anthropometric variables, nutritional intakes, biohumoral variables, and clinical-functional test of the entire patient population at admission to our rehab institute.
Admission | Discharge |
| |
---|---|---|---|
Age (yrs) | 66.58 ± 8.37 | — | n.s. |
M/F | 24/36 | — | n.s. |
Body weight (kg) | 74.5 ± 14.5 | 73.9 ± 14.5 | n.s. |
Body mass index (BMI) kg/m2 | 26.6 ± 4.1 | 26.5 ± 4.05 | n.s. |
Time from index event (days) | 17.05 ± 1.12 | 34 ± 2.0 | n.s. |
Length of stay (days) | 16.9 ± 1.0 | — | n.s. |
|
|||
Energy (kcal) | 2123 ± 325 | — | n.s. |
kcal/kg | 28.5 ± 2.7 | — | n.s. |
Carbohydrates (g/kg) | 3.9 ± 0.6 | — | n.s. |
Proteins (g/kg) | 1.01 ± 0.3 | — | n.s. |
Lipids (g/kg) | 1.01 ± 0.35 | — | n.s. |
|
|||
Glucose (mg/dL; n.v. |
84.6 ± 14.8 | 83.4 ± 12 | n.s. |
Urea (mg/dL; n.v. |
35.1 ± 8.8 | 34.6 ± 7.7 | n.s. |
Creatinine (mg/dL; n.v. |
0.74 ± 0.09 | 0.76 ± 0.12 | n.s. |
Erythrocyte sedimentation rate (mm/1 hr; n.v. |
47.9 ± 25.9 | 40.4 ± 24.9 | n.s. |
C-reactive protein (mg/dL; n.v. |
20.4 ± 19.6 | 8.21 ± 11.1 | n.s. |
Hemoglobin (g/dL; n.v. |
10.4 ± 1.09 | 11.3 ± 1.09 | <0.02 |
Iron ( |
40.4 ± 19 | 48.5 ± 17.7 | n.s. |
Ferritin (ng/mL; n.v. |
257.4 ± 201.8 | 235 ± 182 | n.s. |
Transferrin (mg/dL; n.v. |
203 ± 32 | 209 ± 30.6 | n.s. |
Albumin (g/dL; n.v. |
3.55 ± 0.37 | 3.79 ± 0.33 | n.s. |
Total protein (g/dL; n.v. |
6.24 ± 0.50 | 6.49 ± 0.47 | n.s. |
|
6.96 ± 1.28 | 5.49 ± 0.71 | n.s. |
|
12.45 ± 2.2 | 11.33 ± 2.06 | n.s. |
|
|||
Harris hip score | 40.78 ± 2.70 | 73.15 ± 7.52 | <0.0001 |
Data are expressed as mean ± standard deviation.
Statistical analysis: paired
All patients had systemic inflammation as indicated by elevated serum CRP, which was more than 25 times higher than the normal maximal value. The erythrosedimentation rate (ESR) and the positive reactants of inflammatory response (serum alpha 1 and alpha 2 globulin concentrations) were above normal, whereas negative proteins (albumin and transferrin) were normal. All patients had mild anemia (Table
Functionally, the patients had severe reduction of hip function as indicated by their HHS test (
Plasma amino acid levels can be seen in Table
Venous plasma concentration (
Healthy subjects ( |
Patients ( |
||
---|---|---|---|
Admission | Discharge ( |
||
Aspartate | 19 ± 9 | 21.9 ± 11.6 | 16 ± 9 |
Glutamate | 95 ± 63 | 154 ± 93 | 128.6 ± 32 |
Asparagine | 23 ± 9 | 19.7 ± 9.2 |
19.1 ± 11.2 |
Serine | 111 ± 31 | 65.8 ± 33 |
50.8 ± 15.2 |
Glutamine | 483 ± 100 | 99.4 ± 32 |
120.5 ± 28 |
Histidine | 62 ± 12 | 68.6 ± 35.6 | 66.5 ± 24 |
Glycine | 227 ± 80 | 143 ± 107 |
122 ± 23.5 |
Threonine | 118 ± 32 | 198 ± 104 | 173.7 ± 62.9 |
Citrulline | 8.5 ± 2.1 | 19.6 ± 9.4 | 22.3 ± 9.7 |
3-Methylhistidine | 3.24 ± 0.87 | 4.86 ± 2.5 | 6.4 ± 4.1 |
Alanine | 385 ± 92 | 307 ± 82 | 298 ± 89 |
Arginine | 62 ± 20 | 138 ± 60 |
160 ± 81.40 |
Tyrosine | 65 ± 14 | 47 ± 16 |
48.7 ± 16.7 |
Cysteine | — | 48 ± 28.5 | 50 ± 16.8 |
Valine | 249 ± 58 | 202 ± 74 | 203 ± 69 |
Methionine | 21.5 ± 5.2 | 24.8 ± 15.7 | 18.1 ± 10 |
Tryptophan | 70 ± 33 | 70.3 ± 33 | 59 ± 28 |
Phenylalanine | 70 ± 30 | 51.20 ± 20 | 50.5 ± 20 |
Isoleucine | 68 ± 16 | 63.6 ± 26 | 61 ± 21 |
Leucine | 128 ± 28 | 105 ± 49 | 102 ± 35.8 |
Lysine | 180 ± 36 | 107 ± 57 |
96 ± 21 |
Total AAs | 2493.5 ± 652.4 | 1960 ± 890.5 |
1872 ± 628.3 |
Total EAAs | 904.5 ± 238 | 822 ± 379 | 821.5 ± 268 |
Data are expressed as mean ± standard deviation.
Statistical analysis:
(a) unpaired
(b) paired
Demographic, anthropometric variables, nutritional intakes, biohumoral variables, and clinical-functional test of the admitted patients after randomization.
Placebo | EAAs |
| |
---|---|---|---|
Age (yrs) |
65.6 ± 9.50 | 67.9 ± 7.3 | 0.2 |
M/F |
10/20 | 14/16 | 0.3 |
Body weight (kg) |
73.0 ± 12.2 | 75.9 ± 15.9 | 0.3 |
Body mass index (BMI) |
27.5 ± 3.9 | 29.8 ± 4.2 | 0.07 |
Time from index event (days) |
16.0 ± 1.1 | 17.9 ± 1.2 | <0.05 |
Length of stay (days) |
15.2 ± 1.2 | 17 ± 0.8 | <0.08 |
|
|||
Energy (kcal) | 1980 ± 285 | 2210 ± 441 | 0.3 |
kcal/kg | 27.1 ± 2.1 | 29.1 ± 4.33 | 0.5 |
Carbohydrates (g/kg) | 3.7 ± 0.4 | 4.1 ± 0.8 | 0.8 |
Proteins (g/kg) | 1.1 ± 0.4 | 0.9 ± 0.2 | 0.6 |
Lipids (g/kg) | 0.95 ± 0.25 | 1.15 ± 0.40 | 0.8 |
|
|||
Glucose (mg/dL; n.v. |
82.2 ± 16.5 | 87.0 ± 15.5 | 0.6 |
Urea (mg/dL; n.v. |
34.7 ± 10.9 | 35.7 ± 8.1 | 0.2 |
Creatinine (mg/dL; n.v. |
0.73 ± 0.08 | 0.74 ± 0.09 | 0.2 |
Erythrocyte sedimentation rate (mm/1 hr; n.v. |
45.3 ± 24.2 | 49.4 ± 28 | 0.4 |
C-reactive protein (mg/dL; n.v. |
16.4 ± 11.7 | 20.5 ± 18.1 | 0.5 |
Hemoglobin (g/dL; n.v. |
10.4 ± 1.2 | 10.5 ± 0.96 | 0.1 |
Ferritin (ng/mL; n.v. |
206.7 ± 166 | 288 ± 212 | 0.3 |
Transferrin (mg/dL; n.v. |
215 ± 34 | 191 ± 29 | <0.04 |
Albumin (g/dL; n.v. |
3.62 ± 0 | 3.57 ± 0 | <0.07 |
Total protein (g/dL; n.v. |
6.37 ± 0.51 | 6.1 ± 0.38 | <0.04 |
|
6.7 ± 1.1 | 6.97 ± 1.38 | 0.1 |
|
11.9 ± 2.5 | 11.1 ± 2.4 | 0.1 |
|
|||
Harris hip score | 39.78 ± 4.89 | 41.8 ± 1.15 | 0.9 |
Data are expressed as mean ± standard deviation.
Statistical analysis:
(a)
(b)
(c)
The EAA group was different from the placebo one in the time from index event (
During rehab, the inflammation rate decreased similarly for both groups (CRP −
As can be seen from Table
Plasma amino acid levels (
Amino acid | Placebo ( |
EAAs ( |
Trend over time (interaction; |
||
---|---|---|---|---|---|
Admission | Discharge | Admission | Discharge ( |
||
Aspartate | 20.5 ± 8.2 | 14.3 ± 5.9 | 24.5 ± 16.7 | 11.1 ± 7.8 | =0.6 |
Glutamate | 177 ± 100 | 129.6 ± 19.6 | 143 ± 116 | 127.6 ± 45 | =0.8 |
Asparagine | 21.5 ± 10.6 | 20.5 ± 11.9 | 16.7 ± 6.6 | 17.7 ± 10.5 | =0.5 |
Serine | 72 ± 43 | 51.4 ± 20 | 64.5 ± 24 | 50.2 ± 10.3 | =0.9 |
Glutamine | 97 ± 33 | 124.3 ± 21 | 104.2 ± 31 | 128.4 ± 33 | =0.7 |
Histidine | 74.2 ± 33 | 72.6 ± 17 | 58.2 ± 40.1 | 64.0 ± 31.3 | =0.8 |
Glycine | 157 ± 125 | 121 ± 24.4 | 118 ± 60 | 130 ± 22.5 | =0.001 |
Threonine | 223 ± 96 | 177 ± 61.7 | 151.3 ± 110 | 170.3 ± 64 | =0.1 |
Citrulline | 20.5 ± 9.9 | 23.1 ± 10 | 19 ± 9.5 | 21.5 ± 9.4 | =0.6 |
3-Methylhistidine | 5.5 ± 2.9 | 8.3 ± 6.2 | 3.78 ± 1.22 | 4.5 ± 1.9 | =0.7 |
Alanine | 356 ± 195 | 312 ± 65 | 216 ± 119 | 284 ± 112 | =0.02 |
Arginine | 136 ± 67.7 | 200 ± 117 | 144.2 ± 51 | 119 ± 45 | =0.03 |
Tyrosine | 55.3 ± 27 | 49.3 ± 16.4 | 43.7 ± 14.9 | 48.0 ± 17 | =0.05 |
Cysteine | 55.1 ± 29.6 | 55.2 ± 19 | 34.4 ± 22.3 | 45.1 ± 14.5 | =0.05 |
Valine | 219 ± 71 | 214.5 ± 59 | 180.4 ± 77 | 193.1 ± 80 | =0.8 |
Methionine | 28.6 ± 16 | 19.7 ± 10.4 | 17.6 ± 14.4 | 16.5 ± 9.5 | =0.6 |
Tryptophan | 76.4 ± 28 | 62 ± 14.6 | 59 ± 40.4 | 56 ± 41.5 | =0.8 |
Phenylalanine | 54.4 ± 21 | 53.3 ± 16.6 | 45 ± 17 | 47.6 ± 24 | =0.9 |
Isoleucine | 66.5 ± 23 | 66.3 ± 20 | 62.1 ± 33 | 55.2 ± 21.8 | =0.8 |
Leucine | 113 ± 46 | 108 ± 36 | 98.1 ± 56 | 95.2 ± 36 | =0.9 |
Lysine | 109 ± 52 | 97 ± 26.6 | 95.1 ± 51 | 94.4 ± 15.5 | =0.8 |
Total AAs | 2137 ± 1004 | 1979 ± 603 | 1699 ± 913 | 1833 ± 658.5 | =0.02 |
Total EAAs | 890 ± 353 | 798 ± 247 | 709 ± 400 | 728 ± 293 | =0.05 |
EAAs = essential amino acids.
Data are reported as mean ± standard deviation.
Statistical analysis: repeated measures analysis of variance.
Trend over time: interaction differences in trends between groups.
All patients improved hip dysfunction (from baseline
Changes over time of clinical-functional test Harris hip score (HHS) in both placebo and EAA groups.
Placebo | EAAs |
|
|||
---|---|---|---|---|---|
Admission | Discharge | Admission | Discharge ( |
||
Harris hip score | 39.78 ± 4.89 | 70 ± 7.1 | 41.8 ± 1.15 | 76.37 ± 6.6 | 0.006 |
|
|||||
Pain | 18.7 ± 3.4 | 32.4 ± 6.2 | 20 ± 0 | 39.2 ± 5.59 | 0.01 |
Support | 1.73 ± 0.69 | 2.7 ± 0.45 | 1.93 ± 0.37 | 2.73 ± 0.45 | 0.7 |
Limp | 4.83 ± 0.91 | 8.5 ± 1.38 | 5 ± 0 | 8.72 ± 1.53 | 0.5 |
Distance | 1.93 ± 0.36 | 8 ± 0 | 2.1 ± 0.55 | 8 ± 0 | 0.8 |
Sitting | 3.13 ± 0.5 | 4.33 ± 0.96 | 3 ± 0 | 4.03 ± 1.01 | 0.7 |
Public transportation | 0 | 0.56 ± 0.5 | 0 | 0.58 ± 0.509 | 0.9 |
Stairs | 0 | 2 ± 0 | 0 | 2 ± 0 | — |
Shoe/socks | 1.86 ± 0.50 | 3.06 ± 1.01 | 2 ± 0 | 2.69 ± 0.97 | 0.3 |
Deformity | 4 ± 0 | 4 ± 0 | 4 ± 0 | 4 ± 0 | — |
ROM | 3.51 ± 0.35 | 4.43 ± 0.33 | 3.58 ± 0.387 | 4.44 ± 0.25 | 0.9 |
Statistical analysis: Kruskal-Wallis test.
Level of significance set at
Time courses of improvements of clinical-functional test in the two postsurgery subgroups. The plot shows the superiority of essential amino acids in enhancing hip function recovery.
This study shows that, in the rehabilitation phase of EHA, patients may have abnormal plasma levels of several amino acids that could be associated with systemic inflammation and may persist until the end of rehabilitation. While supplementation with EAAs may optimize post-EHA rehabilitation by enhancing the functional retrieval of hip-joint function, EAAs cannot correct amino acid abnormalities.
Inflammation is clearly a sequela of surgical trauma [
The reduced availability of these amino acids may, therefore, increase the risk of impaired and/or delayed wound repair and low quality of scar formation. The low glutamine level in patients combines with glycine and lysine in negatively influencing wound repair. Indeed, glutamine is an important fuel for fibroblast activities [
The coexistence of amino acid abnormalities with the patients’ normal protein intake indicates that the intake of protein (1 g/kg body weight) is not enough to correct alterations of amino acids. This raises the question of whether, in post-EHA, the observed altered amino acids could behave as semiessential amino acids.
In synthesis, rehabilitative patients after EHA may have an abnormal plasma amino acid profile, potentially increasing the risk for poor quality of wound repair.
After randomization, the two patient groups had different amounts of circulating transferrin and total proteins. Given the similarities for the other measured variables, these differences could be due to both different preoperative protein status and different postoperative metabolic response rates. This is suggested by both the time from index event and the trend to stay longer in acute setting observed in EAA patients.
The study shows that a supplementation with EAAs improved the levels of the circulating amino acids and enhanced hip function retrieval. The treatment with EAAs probably gave the patients a more balanced protein turnover. This is suggested by both the maintenance of branched chain amino acid (BCAA, leucine, isoleucine, and valine) concentrations and the improved concentration of glycine, threonine, and alanine, with normalization of arginine. This was not the case for controls.
However, the EAA treatment failed to normalize plasma glutamine. This would suggest that body requirements for this amino acid were higher than that provided both exogenously by diet and endogenously by essential BCAA metabolism [
Several mechanisms may explain the enhanced retrieval rate of hip-joint dysfunction associated with EAA supplementation. One mechanism is related to the effects of EAAs on wound repair. The phases of wound healing (i.e., inflammation, proliferation, and remodeling) require high EAA and semiessential glutamine and arginine [
Another mechanism underlying the beneficial effects of EAA on hip retrieval may be the potentiation of the increase of muscle mass and strength of the operated limb, damaged by factors including surgical stress, reduced or absent muscle contraction, being bed-ridden, unloading, and inflammation. In support of this, the 12-week administration of 7.5 g EAAs (very similar to the amount used here) to older women was shown to increase muscle mass (as measured by Dexa), while they failed to improve clinical outcomes such as knee extension and handgrip [
A further mechanism primed by EAAs to improve hip retrieval may be the attenuation of muscle weakness and soreness [
A preferential/prevalent use of supplemented EAAs in wound areas and regional muscles could also help explain the coexistence of plasma amino acid alterations and EAA’s failure to correct these alterations as well as better retrieval of hip-joint dysfunction.
The study has several limitations that need to be addressed in future investigations.
These results need to be confirmed in a larger sample size, which also takes into account the changes of these variables in relation to gender and patient body composition. This requires a well-planned powered study. Understanding the patients’ preoperative physical dysfunction rate would have strengthened the discussion. Pre- and postoperative assessment of muscle mass and strength could help us predict the gain in physical recovery better.
Notwithstanding these limitations, we believe this study can provide some useful suggestions for clinical practice.
The persistence of unmet metabolic alterations during the rehabilitation phase of EHA may predispose patients to a persistence of impairment and functional limitations at short- and long-term follow-up [
In conclusion, it could be useful to provide patients with a supplementation of EAAs, both during postexercise recovery to stimulate muscle protein synthesis [
This investigation would prompt us to look at two different research areas concerning changes in the dose and/or composition of the formula we used. For example, EAAs need to be tested at a dose higher than 8 g/d and/or for longer, to document whether plasma amino acid alterations may be corrected and functional recovery further enhanced. In addition, it could be clinically important to seek whether increasing the formula used here, that is, the amount of lysine and phenylalanine and adding the nonessential glycine, serine, asparagine, and glutamine, could further improve retrieval of postsurgery hip function. This could be particularly important for those patients who return home for full-hip function recovery and for subjects who, for any reason, do not have access to a post-EHA rehabilitation program.
This study shows that recovery of hip dysfunction after elective surgery of EHA may be enhanced by short-term supplemented essential amino acids which, however, fail to correct plasma amino acid alterations.
9-Fluorenyl-methyl-chloroformate
Body mass index
Body weight
Branched chain amino acids
C-reactive protein
Elective hip arthroplasty
Erythrosedimentation rate
Essential amino acids
Harris hip score
Insulin growth factor-1
Orthopthalaldehyde.
The authors declare that they have no competing interests.
The authors would like to thank Dr. Robert Coates (