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,**,
,3
*
Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, Canada T6G 2P5;
The Research Institute, The Hospital for Sick Children, Toronto, ON, Canada; and
**
Departments of Paediatrics and
Nutritional Sciences, University of Toronto, Toronto, ON, Canada M5G 1X8
3To whom correspondence should be addressed: E-mail: ron.ball{at}ualberta.ca.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • amino acid requirements • leucine • indicator amino acid oxidation • piglets • total parenteral nutrition
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). The primary objective of TPN lies in the maintenance or improvement of the nutritional and metabolic status of patients who can not be adequately nourished by oral or enteral feeding for a long period of time (2
).
Low-birth-weight (LBW) infants constitute a majority of the patients who often can not tolerate enteral feedings due to a variety of factors including short bowel syndrome, gastrointestinal surgery, chronic severe diarrhea, immature bowel function and respiratory diseases (3
,4
). Thus, TPN regimens are continuously being refined to meet the infant’s need for growth and development without placing too much stress on their immature biochemical and physiological systems. An "optimal" profile for neonatal TPN that provides amino acids in a combination maximizing protein accretion and growth, and minimizing amino acid degradation has not been established (5
,6
).
Experiments designed to determine amino acid requirements or kinetics are currently being planned in infants, but prolonged dietary treatments that are deficient in indispensable and conditionally indispensable amino acids could endanger them (3
). The piglet model developed by our group (6
) to study amino acid kinetics and requirements during TPN is more practical, allows serial blood measurements and the requirements for threonine (7
), lysine (8
), phenylalanine (9
), tyrosine (10
), methionine (11
) and tryptophan (12
) have been determined to date using the Indicator Amino Acid Oxidation (IAAO) method.
The branched-chain amino acids (BCAA), isoleucine, leucine and valine, appear to be metabolized predominantly by extrahepatic tissues (13
). Hence, BCAA research interest has focused largely on muscle metabolism, although there have been reports of splanchnic uptake of BCAA in humans (14
–16
). Recently, in both pigs (17
,18
) and dogs (19
), studies have shown splanchnic metabolism of leucine. The BCAA also exhibit antagonism in which excessive intakes of leucine in young growing rats fed a protein-restricted diet antagonize the utilization of the other two BCAA (20
). Thus, maintaining an appropriate ratio among the BCAA is very important.
TPN feeding by-passes the gut; thus the parenteral requirement of many amino acids differs from the enteral requirement (5
). We showed in previous experiments using the IAAO technique that the parenteral amino acid requirements are lower than the enteral requirements for threonine, lysine and phenylalanine. (7
–9
). In the present study, our hypothesis was that the parenteral and enteral requirements for total BCAA in neonatal piglets would differ. A lower parenteral requirement for total BCAA would indicate uptake of BCAA by the splanchnic tissues during first-pass intestinal metabolism.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The Animal Care Committee of the University of Alberta approved all procedures used in this experiment. Male Yorkshire piglets (n = 32), weighing 
1.5 kg and 1–2 d old, were transferred to the Metabolic Research Facility at the University of Alberta. The piglets were weighed and anesthetized for the surgical implantation of catheters (Ed-Art, Don Mills, Canada). During surgery, anesthesia was maintained with 0.8% halothane. Venous catheters were placed following modified procedures of Wykes et al. (6
) and Rombeau et al. (21
) for gastric catheters. The surgical procedures were described recently by Bertolo et al. (7
). After surgery, the piglets were fitted with adjustable cotton jackets, which prevent tangling and occluding of the catheters. The laboratory conditions and piglet housing were described previously (6
).
Diet treatment.
The compositions of the elemental and complete diets were based on the initial formulation by Wykes et al. (6
), with modifications. Diet was infused (continuous, 24 h) using infusion pumps via a tether-swivel system (Alice King Chatham Medical Arts, Los Angeles, CA) intravenously (Experiment 1, parenteral BCAA requirement) or intragastrically (Experiment 2, enteral BCAA requirement). At full infusion rate [272 mL/(kg · d)], the complete diet provided 1.1 MJ available energy/(kg · d) and 14.6, 27.4 and 9.4 g amino acids, glucose and fat/(kg body weight · d), respectively. The base amino acid profile of the diet was as described previously (7
) and the addition of the BCAA to make the test diets is described below. After surgery, all piglets were administered the complete diet intravenously, at 50% of the full rate for 6 h and then at 75% overnight, counting the day of surgery as d 0. On d 1, in Experiment 1, the diet was infused at the full rate intravenously. In Experiment 2, the piglets were switched to 50% of full rate intragastric feeding on d 1; the intragastric infusion rate was increased to the full rate by d 2 (and the intravenous feeding was discontinued) and maintained until d 5.
Test diets.
On d 5, the piglets were randomly assigned to receive one of the 9 test diets (Experiment 1) or 7 test diets (Experiment 2), containing graded levels of BCAA. The test levels of total BCAA ranged from deficient to excess on the basis of the NRC requirements for swine (22
) for piglets weighing between 1 and 5 kg. The test levels were [Experiment 1: 0.2, 0.5, 0.8, 1.1, 1.4, 2.0, 2.6, 3.2 or 3.8 g/(kg · d); Experiment 2: 0.2, 0.8, 1.4, 2.0, 2.6, 3.2 or 3.8 g/(kg · d)]. The ratio among the three BCAA was the same in all test diets, (1:1.8:1.2, isoleucine/leucine/valine) based on NRC recommendations (22
). At the completion of d 6 oxidation, the piglets were returned to the complete diet for 24 h. At 2100 h on d 7, the piglets were randomly assigned to another test diet level. This method was used to decrease the minimum number of piglets required per study, by conducting two oxidations per piglet (d 6 and 8). We verified that this procedure does not alter oxidation rate on d 8 when corrected for background radioactivity (Brunton, Pencharz, Ball et al., unpublished data).
Tracer infusion, sample collection and analytical procedures.
Details of the infusion protocol and 14CO2 and blood collection were described previously (9
). Briefly, on d 6 and 8, the piglets were transferred to plexiglas boxes, 16–18 h after the start of the test diet infusion. A 30-min period was allowed for the piglets to acclimatize and the CO2 to equilibrate in the chamber; then phenylalanine flux and oxidation were determined by a primed [186 kBq (5 µCi)/kg], constant infusion [130 kBq (3.5 µCi)/(kg · h)] of a tracer solution containing 92.5 MBq (2.5 mCi)/L of L-[1-14C]phenylalanine (American Radiolabeled Chemicals, St. Louis, MO). Air was drawn from the boxes by a pump and the total amount of 14CO2 expired was trapped in a series of gas washing bottles containing CO2 absorber (ethanolamine/ethylene glycol monomethylether, 1:2, v/v). Blood samples (1.5 mL) were drawn at time 0 and every 0.5 h during the 4-h study. The blood samples were centrifuged (3000 x g for 5 min), and plasma collected and stored at -80°C until analysis of phenylalanine specific radioactivity (SRA) and amino acid concentrations. On d 8, a 5-h study was conducted; h 1 was used for collection of background enrichment before the primed, constant infusion. Immediately upon completion of the oxidation study on d 8, the piglets were injected with a lethal dose (750 mg) of sodium pentobarbital through the venous sampling line.
The rate of expiration of 14CO2 was determined by liquid scintillation counting of radioactivity in the CO2 absorber. The plasma concentrations of amino acids and the SRA of plasma phenylalanine were analyzed by reverse-phase HPLC; collection and liquid scintillation counting of radioactive fractions were described previously (9
). Phenylalanine intake, flux, balance, the percentage of dose oxidized, oxidation, nonoxidative disposal and release from protein breakdown were calculated as described previously (9
).
Statistical analyses.
Each experiment was a fully randomized design with the test diet levels as the main treatment effect. Differences among test diet intakes within each experiment were determined by one-way ANOVA using the PROC GLM procedure (SAS/STAT version 8.1, SAS institute, Cary, NC). When the F-test was significant, differences among test diet intakes were assessed using Tukey’s multiple comparisons procedure. The mean requirements for the BCAA in parenterally and enterally fed piglets were determined by breakpoint analysis using a combined two-phase linear regression crossover model, modified from Ball and Bayley (23
) and Seber (24
). Regression variables included the amino acid intake as independent variable and phenylalanine oxidation [the percentage of dose] as the dependent variable. The upper limit of the 95% confidence interval (CI) of the breakpoint was estimated for each parameter to determine a safe level of intake.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Experiment 1: parenteral BCAA requirement.
Phenylalanine flux [232.7 µmol/(kg · h), pooled SEM: 38.4] and intake [111.4 µmol/(kg · h), pooled SEM: 4.2], did not differ (P > 0.05) across diet treatments, as expected and required by the IAAO technique. The lack of difference in flux indicates that the change in oxidation reflects a partitioning between oxidation and protein synthesis. BCAA intake significantly influenced phenylalanine oxidation expressed as a percentage of the dose oxidized (Fig. 1
). As the total BCAA intake increased from 0.2 to 1.1 g/(kg · d), phenylalanine oxidation declined (P < 0.05). Further increases in BCAA intake from 1.4 to 3.8 g/(kg · d) did not affect phenylalanine oxidation (P > 0.05, slope not different from zero).
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). The concentrations of glutamine, histidine, citrulline, threonine, arginine, tyrosine, tryptophan and lysine also decreased significantly with increases in BCAA intake (Table 1)
. BCAA intake affected the plasma phenylalanine concentration, which decreased from 262 to 114 µmol/L as BCAA intake increased from 0.2 to 1.4 g/(kg · d) (P < 0.05); no change in phenylalanine concentrations occurred with further increases in BCAA intake. Plasma concentration of isoleucine, leucine and valine were significantly affected by increases in BCAA intake (Fig. 2
and Table.1
).
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Phenylalanine flux (198.1 µmol/(kg · h), pooled SEM: 24.3) and intake (114.1 µmol/(kg · h), pooled SEM: 7.6) did not differ among the diet treatments, similar to Experiment 1, and as required by the IAAO technique. Phenylalanine oxidation was significantly influenced by BCAA intake expressed as a percentage of the dose oxidized (Fig. 3
). As the total BCAA intake increased from 0.2 to 2.6 g/(kg · d), phenylalanine oxidation decreased significantly (P < 0.05). Further increases in BCAA intake from 2.6 to 3.8 g/(kg · d), did not affect phenylalanine oxidation (P > 0.05, slope not different from zero).
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). Plasma concentrations of several amino acids (glutamate, glutamine, taurine, histidine, tyrosine, proline, ornithine and lysine) decreased as the supply of the limiting amino acids increased (Table 2)
. BCAA intake, as in Experiment 1, affected plasma phenylalanine concentration, which decreased from 134 to 84 µmol/L as BCAA intake increased from 0.2 to 2.6 g/(kg · d) (P < 0.05); no significant changes in plasma phenylalanine concentrations occurred with further increases in BCAA intake. The plasma concentrations of leucine remained low (50 µmol/L) (Fig. 4
), and did not vary with increases in BCAA intake from 0.2 to 2.0 g/(kg · d). As BCAA intake increased from 2.6 to 3.8 g/(kg · d), the concentration of leucine increased significantly (from 106 to 263 µmol/L, respectively). Plasma isoleucine and valine concentrations followed a markedly different pattern (Fig. 4)
than in Experiment 1 (Fig. 2)
beginning at the lowest BCAA intake of 0.2 g/(kg · d). Plasma isoleucine and valine concentrations increased significantly until the total BCAA intake was 2.0 g/(kg · d). With further increases in BCAA intake [2.6 to 3.8 g/(kg · d)], plasma isoleucine concentration tended to decrease (P = 0.07) and valine concentration remained high.
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, 3)
. The data partitioning was based on the model that produced the lowest combined sum of squares for error. The breakpoint estimate for phenylalanine oxidation as the percentage of dose in parenterally fed piglets was 1.53 g/(kg · d), 95% CI, 1.07–1.99 (Fig. 1)
. For enterally fed piglets, the breakpoint analysis yielded estimates of 2.64 g/(kg · d), 95% CI, 2.15–3.13(Fig. 3)
for phenylalanine oxidation as a percentage of dose. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). The requirements for several amino acids differ between parenteral and enteral feeding routes (7
,26
), and there is increasing evidence that currently available commercial amino acid solutions for nutritional support are inappropriate for maximizing nitrogen efficiency (5
). Estimation of the parenteral amino acid requirements from the requirements for oral feeding has several disadvantages because parenteral feeding by-passes the gut and results in lower total metabolic mass of the gut (3
,5
,7
). Thus, to provide a direct measurement of the parenteral BCAA requirement, in this study, piglets were supplied with an identical diet enterally and parenterally and the BCAA requirements were determined.
The mean parenteral BCAA requirement, as determined by the breakpoint of the two-phase regression crossover model, was 1.53 g/(kg · d) (Fig. 1)
, based on phenylalanine oxidation as a percentage of dose. The mean enteral requirement was estimated to be 2.64 g/(kg · d) (Fig. 3)
, based on phenylalanine oxidation as a percentage of dose. The safe level of BCAA intake, which would meet the needs of 95% of the population, or the upper 95% CI of the breakpoint estimate in parenteral feeding is 1.99 g/(kg · d); in enteral feeding, it is 3.13 g/(kg · d).
These results, suggesting that the small intestine uses BCAA to a large extent (44% of intake) are important because BCAA catabolism has been considered to be carried out mainly in extrahepatic tissues because of the higher activity of branched-chain amino transferase (BCAT), the first enzyme in the catabolic pathway of the BCAA, in skeletal muscle and the relatively lower activity of BCAT in the liver (27
). The IAAO method measures whole-body utilization of BCAA for protein synthesis; therefore, the results obtained include the metabolism and utilization of branched-chain 
ketoacids. Stoll et al. (17
) measured the appearance of amino acids in portal blood in 28-d-old piglets fed sow’s milk replacer continuously via catheters. They reported 57, 61 and 69% appearance of leucine, valine and isoleucine, respectively, in the portal blood, suggesting a portal drained visceral uptake of 43, 39 and 31%, respectively. Gelfand et al. (14
) observed one third of orally infused BCAA to be extracted by splanchnic tissues in adult humans and also suggested that the earlier observations (28
,29
) of BCAA selectively escaping the splanchnic bed after a protein meal led researchers to underemphasize the importance of splanchnic tissues in BCAA catabolism. These values (14
,17
) compare well with the 44% extraction of total BCAA found in the current study.
In both of the current experiments, BCAA were provided in the diets at a fixed ratio of 1:1.8:1.2 (isoleucine/leucine/valine) to remove the potential for antagonism among the BCAA, which could affect the requirements. To our knowledge, this is the first time such an approach has been used to determine BCAA requirements. The advantage of this approach is that it avoids the possible effects of antagonism on the requirements for the individual amino acids and simultaneously provides a test of whether the ratio of the BCAA is optimal.
In parenterally fed piglets, the plasma concentrations of BCAA remained low until the BCAA intake reached 1.5 g/(kg · d) (Fig. 2)
. The similarity in responses for the three BCAA when fed below the requirement suggests that the ratio used was close to optimal. All three BCAA concentrations continued to increase with increasing intakes of BCAA above requirement, but the different slope of the response for valine after BCAA intake of 1.5 g/(kg · d) suggests that it is being metabolized differently than leucine and isoleucine. An increasing rate of accumulation of valine in the plasma compared with leucine and isoleucine suggests a lower relative rate of catabolism once the valine requirement has been met. The BCAA share a common transport system into the cells, i.e., the Large Neutral Amino Acid carrier system or the L system (30
). Competition for uptake into the cells among the BCAA may play a role in the increased rate of accumulation of valine in plasma when BCAA are provided in a fixed ratio at levels higher than the total BCAA requirement.
The plasma concentrations of BCAA in enterally fed piglets (Fig. 4)
provided even more interesting results. Leucine followed the expected pattern; plasma concentrations of the limiting amino acid remained low until the requirement was reached, and then the limiting amino acid concentrations started to increase. On the contrary, the plasma concentrations of isoleucine and valine were high (118 and 220 µmol/L, respectively, Table. 2
), even when the supply of total BCAA in the diet was most deficient [0.2g/(kg · d)]. The concentrations of isoleucine and valine continued to increase with increasing supply of total BCAA, and valine concentrations appeared to reach a plateau once the total BCAA requirement was reached. The concentration of isoleucine showed a decreasing trend (P = 0.07), once the total BCAA requirement was reached. These responses could be partly a result of the presence of BCAA catabolizing enzymes in the gut of piglets. Although the enzymes have been shown to be present in the guts of rats and humans (31
), to our knowledge there are no comparable data for pigs. Similar patterns in plasma BCAA concentrations have been observed previously in pigs (32
) and in other species, i.e., human infants (33
), human adults (34
), rats (35
) and kittens (36
). In these experiments, all subjects were fed enterally and a dietary deficiency of leucine was concluded to cause elevated plasma concentrations of isoleucine and valine. In the current experiments, the previously described pattern was observed in enterally fed piglets (Fig. 4)
, but not in parenterally fed piglets (Fig. 2)
, although amino acid intakes were the same for both routes of feeding. We speculate that the differences in plasma amino acid pattern indicate that not only does the total requirement for BCAA differ between parenteral and enteral feeding, but that the optimum ratio of BCAA also differs between the routes of feeding. Thus, further experiments have to be conducted to determine the optimum ratio of the BCAA during both parenteral and enteral feeding.
The pattern of BCAA in the plasma of enterally fed piglets, compared with the parenterally fed piglets, clearly demonstrates that the gut has a high demand for leucine and a clear preference for leucine compared with isoleucine or valine. If the gut was using all three BCAA in the same proportion as the rest of the body, then the plasma amino acid pattern would have been similar for both routes of feeding. The observation in enterally fed piglets that valine and isoleucine increased in plasma whereas leucine remained low indicates that leucine is being extracted by the gut and therefore may be limiting protein synthesis in the rest of the body. Valine and isoleucine are not being used by the gut to the same extent and are being passed to the systemic circulation, but because protein synthesis is limited by leucine, these two amino acids increase in concentration in the plasma. When leucine is fed below the requirement, thus limiting protein synthesis, most of the other essential amino acids are higher in plasma than when leucine is fed above requirement (Table 2)
.
Yu et al. (37
) in a quantitative determination of leucine extraction by the splanchnic tissues in 20- to 25-kg dogs, suggested that 30–35% of total ingested leucine was metabolized by the gut tissues. Thus, it will be important to quantitate and determine the fate of the extracted leucine in neonatal piglets. This will provide important information regarding a potential role of BCAA in the development and metabolism of the intestine, especially in LBW infants.
Similar to the current study, the concentrations of valine in plasma in suckling piglets and human infants (Table 3
) were relatively higher than isoleucine and leucine. As discussed earlier, this increased accumulation may be due to competition for uptake of valine into cells once the total BCAA requirement has been met. The pattern of BCAA in human and sow’s milk (1:1.8:1 and 1:2.4:1.4, respectively, Ile/Leu/Val) closely resembles the pattern in the respective human fetal and piglet tissues (Table 3)
. Although this pattern may be appropriate in the case of orally fed piglets and human infants, the optimum ratio for parenteral solutions is unknown. Commercially available parenteral solutions have a wide variation in the ratio among the BCAA (5
), thus increasing the chances of either underfeeding or overfeeding any one amino acid. This could potentially be a cause for antagonism among the BCAA, thereby placing the neonate at risk. On the basis of the current observations of plasma BCAA patterns due to different routes of feeding, it is important that the appropriate ratio of BCAA for the neonate be determined both parenterally and enterally.
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FOOTNOTES |
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2 Supported by Alberta Pork, Alberta Agricultural Research Institute (AARI) and Canadian Institutes of Health Research (CIHR).
4 Abbreviations used: BCAA, branched-chain amino acids; BCAT, branched chain aminotransferase; CI, confidence interval; IAAO, indicator amino acid oxidation; LBW, low-birth-weight; SRA, specific radioactivity; TPN, total parenteral nutrition.
Manuscript received 13 May 2002. Initial review completed 8 June 2002. Revision accepted 5 July 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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4. Heird, W. C & Gomez, M. R. (1993) Parenteral nutrition. Tsang, R. C. Lucas, A. Uauy, R. Zlotkin, S. eds. Nutritional Needs of the Pre—Term Infant Scientific Basis and Practical Guidelines 1993:225-242 Caduceus Medical Publishers Pawling, NY .
5. Brunton, J. A., Ball, R. O. & Pencharz, P. B. (2000) Current total parenteral nutrition solutions for the neonate are inadequate. Curr. Opin. Clin. Nutr. Metab. Care 3:299-304.[Medline]
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