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Arterio-venous differences in amino acids, glucose, lactate and fatty acids in burn patients; effect of ornithine alpha-ketoglutarate
CLINICAL
NUTRITION
(1986) 5: 22 l-226
Arteri .o-Venous Differences in Amino Acids, Glucose, Lactate and Fatty Acids in Burn Patients; Effect of Ornithine Alpha-Ketoglutarate L. Cynober*, F. Blonde*, N. Liorettt, J. Giboudeau*. Laboratoire de Biochimie A*, Service des Briilist, Saint Antoine, 75571 Paris Cedex 12, France (Reprint requests to L.C.)
C. Coudray-Lucas*,
Dkpartement
d’Anesthtsiologie$,
Saizy Rt$ H6pital
and
Saint Antoine,
184 rue du Fg
ABSTRACT The study concerns two groups of seven burn patients matched for age, weight and total burn surface. Both groups received conventional enteral nutrition, while one was given a 10 g/day alpha-ketoglutarate ornithine (OKG) supplement. Femoral venous and arterial blood was taken from day 2 to day 13 post-burn in order to determine levels of amino acids, nonesterified fatty acids (NEFA), glucose and lactate. In the control group large negative arterio-venous differences ( 1’j A-V) were observed in amino acid and lactate levels whereas they were significantly lower with regard to Hyp, Gly, Lys and Ala in the OKG-treated group. AA-V was near zero for glucose and NEFA in both groups. These results support the view that OKG-therapy limits the output of amino acids in the leg and that glucose and NEFA do not constitute the main fuel in muscle.
(TBSA) ranging from 16.531”,, were studied from day 2 to day 13 post-burn. Seven were used as controls, the remaining seven received OKG’. The two groups were well matched for TBSA, age, weight and height. Clinical data are given in Table 1. All patients were stable following injury except one (in the treated group) who developed acute renal failure on day 13 and one patient (in the control group) who developed septicemia on day 11. Both were subsequently removed from the protocol. All clinical research was conducted in accordance with the principles for human experimentation as defined in the Helsinki declaration. All patients received the same continuous enteral nutrition consisting of milk and Realmentyl “? as reported previously [7,8]. In addition, OKG-treated subjects received 10 g of OKG enterally every day from day 2, before nutrition commenced. On the days the patients were studied, the enteral nutrition of every subject was interrupted at 6a.m. Arterial and venous femoral blood samples were taken at 9a.m. Samples were taken on days 2 (basal), 4, 7, 10 and 13 post-burn and immediately centrifuged (except for blood lactate determinations). Plasma and serum were stored at - 20°C until analysis. Plasma amino acids were measured by gas chromatography as previously described [9]. For this test,
INTRODUCTION In recent years, ornithine alpha-ketoglutarate (OKG) has been shown to be a useful adjuvant of enteral and parenteral nutrition, improving the nitrogen balance and reducing urea nitrogen losses in surgical, trauma, septic and burned patients [l+. This has been attributed either to a decrease in catabolism [l] or an increase in protein anabolism [3,4]. Although modifications of free amino acid patterns in muscle induced by OKG therapy have been explored in surgical patients [l], to our knowledge there have been no reports concerning arterio-venous amino acid differences ([L A-VIAA) in traumatised patients. The only studies available concern healthy subjects in whom small variations in muscle amino acid flux were observed [5]. However, the flux of substrates in health and disease probably differ in their sensitivity to exogenous supplementation in metabolic intermediates such as ornithine and alpha-ketoglutarate [6]. We therefore measured arterial and venous amino acids (together with glucose, lactate and non-esterified fatty acids-NEFA) in two groups of burn patients, one of which received OKG. In addition, results obtained for nitrogen balance and 3-methylhistidine excretion are given to help in interpreting the data.
PATIENTS Fourteen
AND METHODS burn
patients
with total burn
surface
I Omicetil”, Laboratoires France. 2Laboratoires Sopharga,
areas 221
Logeais,
Issy Les Moulineaux,
Paris, France.
222
ARTERIO-VENOUS
Table 1
Clinical
DIFFERENCES
IN AMINO
data relative to subjects
ACIDS,
GLUCOSE,
LACTATE
AND
FATTY
ACIDS
IN BURN
studied Full
Burn patients Control 1 2 3 4 5 6 7 mean *SD Treated 1 2 3 4 5 6 7 mean *SD
PATIENTS
Sex
Age
Height (m)
Weight (kg)
M F M M F M F
46 30 33 15 19 30 35 29 f 10
1.68 1.71 1.75 1.70 1.64 1.71 1.62 1.68 kO.04
67 58 66 51.5 54 80 55.5 61 +9
M M M
36 26 50
1.60 1.81 1.75
63 66.5 75.5
F M M M
41 45 50 27 39 f- 10
1.58 1.66 1.70 1.63 i .67 j~O.08
60 61 69 58.5 65 f6
TBSA (“U)
Complications
thickness BSA(” II)
20.5 20 16.5 20 21 20 29 21
Hospitalisation (days)
12 3 0 0 0 0 0
94 31 25 42 21 12 40 37 +26
22 18 19
0 6 0
16 40 16
30 31 21 22.5 23 &5
0 10 10 0
f4
11 dead (D21) 46 14 23 * 15
History
alcoholic
and associated trauma
diahorrea (D21)
R.F. heroin addict alcoholic septicemia (D 11)
psychotic fracture hand
of the
blast, ARF (D13) alcoholic viral hepatitis
TBSA: Total burn surface area ARF: Acute renal failure. R.F.: Respiratory failure. samples were deproteinised with sulfosalicylic acid prior to storage at -20°C. Twenty-four h urines were collected for the determination of 3-methylhistidine by ion-exchange chromatography as previously described [lo] and for urea and creatinine excretion measurements. Serum NEFA plasma glucose, blood lactate and urine creatinine and urea were routinely measured. Nitrogen balance was estimated from nitrogen intake and urinary urea loss plus estimated cutaneous and fecal losses. Student’s t-test was used for statistical comparisons between control and treated burn patient values.
(p < 0.02), glycine, alanine and lysine (p < 0.05) (Fig. 3). After day 4, with the improvement in AA-V in the control group, there were no statistical differences between the two series (data not shown). There was no difference between the two groups in [AA-V] lactate [AA-V] glucose and [AA-V] NEFA (data not shown). Finally, nitrogen balance was significantly (p < 0.05) less negative at day 13 in the OKG-treated group but there was no difference in 3-methylhistidine excretion (Table 2).
DISCUSSION RESULTS In the untreated (control) group, femoral [AA-V] AA were negative at day 4, except for methionine. They gradually returned to zero at day 10, except for alanine and lysine (Fig. 1). On the contrary, the nitrogen balance remained negative throughout the study (Fig. 1). [AA-V] lactate was negative at day 4 and then returned to zero. No evidence for glucose or NEFA uptake (i.e., positive [AA-V]) was found (Fig. 2). In OKG-treated burn subjects, the [A A-V]AA was markedly less negative than in the control group at day 4 significant differences in hydroxyproline with
Numerous reports have dealt with plasma and serum amino acid variations after burn injury [4,1 l-161. In general, in the first week following injury a decrease in neoglucogenic amino acids [4,8,11-16) and an increase in tyrosine and phenylalanine [4,8,10-151 are found, whereas branched chain amino acids remain stable [4,8,11-131 or are reduced [14-161. Our results (not shown) for venous amino acid concentrations are in accord with this general pattern which is also found in most hypercatabolic situations [ 17,181. However, variations in [ A A-V] AA after burn injury are poorly documented: a study by Aulick and Wilmore [19] suffers from several methodological problems: 1) The range of
CLINICAL
223
NUTRITION
HYP ASP + ASN ;;i ;L$~ORN THR LEU PRO VAL GLY GLU +GLN
LYS
z a n
ALA
-15
I
I
I
I
I
2
4
7
10
13
-
jours Fig. 1 Time related variations in arterio-venous differences in amino acid levels (0) and nitrogen balance ( n ) in seven burn patients not receiving OKG. Each curve refers to individual amino acids: 1) alanine, 2) lysine, 3) glutamate + glutamine, 4) glycine, 5) valine, 6) leucine, 7) proline, 8) threonine, 9) tyrosine, 10) phenylalanine, 11) serine, 12) isoleucine, 13) ornithine, 14) aspartate + asparagine 15) hydroxyproline, 16) methionine. The position of each amino acid to the left of the vertical axis represents the largest negative arterio-venous difference for the amino acid concerned.
ARTERIO-VENOUS
DIFFERENCES
IN AMINO
ACIDS,
GLUCOSE,
LACTATE
Table 2
Days postburn 2 4 7 10 13
AND
FATTY
ACIDS
IN BURN
PATIENTS
Nitrogen balance and 3-merhylhisridine Nitrogen balance
excretion
Control (g’dayireaced
3-methylhistidine (~~mol/mmol creatinine) Control Treated
- 15.5 f 5.1 - 12.4 * 3.8 ~ 14.3 f 3.6 -11.3 & 1.6 -9.2 f 3.6 - 10.4 f 5.4 -7.8 f 2.9
37.0 f 5.7 37.3 It 3.4 40.5 f 5.6 43.3 + 10.7 29.7 f 3.2 32.4 LIZ 1.5 37.0 f 1.4
-7.6
+ 2.0
+2.0 f 1.7*
35.9 +
1.9 27.5 + 3.5
lp < 0.05 between control and OKG treated patients. Results are expressed as mean * SEM. a
4
7
13
10
DAYS
Time-related variations in arterio-venous differences in lactate ( n ), glucose (0) and NEFA (A) levels in the control group. Data are given as mean + SEM. burn surface area was wide (12-74”,,) and the subjects probably did not all show the same degree of response to trauma. 2) A single measurement was made and took place between the 7th and 21st day post-burn, with the result that the subjects were not all in the same post-
GLY
VAL
MET
THR
SER
ASP
burn metabolic phase [20]. 3) The number of amino acids studied was limited (alanine, glycine, proline, serine, threonine, methionine, leucine, valine, phenylalanine). For these reasons, comparisons with our own results are difficult. Care must be taken in interpreting our data however, as for technical reasons, leg blood flow was not measured. Nevertheless, as Iapichino er al., have stated [21], [AA-V] AA reflect the amino acid balance in
i ASN
PHE
Fig. 3 Arterio-venous differences in amino acids 4 days after injury. Results are given as mean f SEM
1_1control W OKG-treated lp < 0.05 l*p < 0.02
LEU
iLE
GLU
i GLN
PRO
LYS
HYP
TYR
CLINICAL
the leg and can be interpreted qualitatively in patients not suffering from shock, which is the case in this study.
Furthermore, it is interesting to note that leg blood flow in burn injury is six times higher than in healthy subjects but constant from one burn patient to another. [ 191 In the control group, nitrogen balance remained negative until day 13 although [AA-V] AA had returned to equilibrium by that time as had 3-methylhistidine excretion. This suggests that extra-muscular protein catabolism is involved after day 7 and/or that protein intake is qualitatively unsuitable and that administered nitrogen is not retained by the organism. No evidence for NEFA uptake was found and glucose captation was rather low. This might suggest that other fuels such as ketone bodies are used by the unaffected leg of the burn patient, a hypothesis confirmed by data from the literature [22,23]. The most marked difference between the control and the OKG-treated group is the decrease in muscle amino acid release observed in the treated group on day 4. This observation depends of course on there being no major difference in leg blood flow between the two groups. This is probably so since all the subjects were comparable in terms of the extent of the trauma (no difference between the two groups in cortisol and glucagon plasma levels-data not shown-and similar burn surface areas). However, it is impossible to exclude differences in leg blood flow from one patient to another. Nitrogen balance was less negative after day 4 in the OKG-treated group, significantly at day 13. These data suggest that OKG either limits protein catabolism or increases protein anabolism. The second hypothesis would appear more likely since OKG was not found in this study to affect 3-methylhistidine urinary output, It is interesting to note that in surgical patients OKG has been found to decrease 3-methylhistidine excretion [I]. However, in septic and polytrauma patients, it has been found that OKG had an anabolic action [3]. As it is well known that extent of modifications in protein anabolism and catabolism varies differently according to the extent of the trauma, it is possible that OKG has a preferential action on protein catabolism after surgery and on protein anabolism after burn injury, sepsis and polytrauma. It is unlikely that the action of OKG results from the difference in nitrogen intake between the two groups: OKG provides 1.35 g nitrogen per day i.e., the difference in nitrogen intake between the two groups was only 3”,, at day 13. The mechanism by which OKG exerts its anabolic action remains obscure. We have demonstrated elsewhere [24], that OKG has no action on insulinemia or hGH plasma levels in burn injury although this mechanism has previously been suggested [ 1,3]. Other possibilities involve polyamine synthesis from ornithine [25] or branched chain keto acid (BCKA) synthesis by
NUTRITION
225
transaminase pathways, alpha-ketoglutarate promoting the formation of BCKA from branched-chain amino acids with the release of glutamate [2h]. REFERENCES
Ill Leander
U, Furst P, Vesterberg K, Vinnars E 1985 Nitrogen sparing effect of Ornicetil in the immediate post-operative state. I-Clinical biochemistry and nitrogen balance. Clinical Nutrition 4: 43-51 121 Nicolas F, Rodineau P 1982 Essai controle croise de I’alpha-cetoglutarate d’ornithine en alimentation enterale. Ouest Medical 35: 71 l-71 3 131 Demarcq J M, Delbas M, Trochu G, Crignon J J 1984 Effets de l’alpha-cetoglutarate d’ornithine sur I’etat nutritionnel des malades de reanimation. Cahier\ d’Anesthesiologie 32: 3-6 [41 Cynober L, Saizy R, Nguyen Dinh F, Lioret N, Giboudeau J 1984 Effect of enterally administered ornithine alpha-ketoglutarate on plasma and urinary amino acid levels after burn injury. Journal of ‘Trauma 24: 590-596 bl Eriksson L S, Reihner E, Wahren J 1985 Infusion of ornithine-alpha-ketoglutarate in healthy subjects: effects on protein metabolism. Clinical Nutrition ,4: 77-76 161 Cynober L, Giboudeau J, Saizy R 1986 Correspondence. Clintcal Nutrition 4: 255-256 enterale 171 Baux S, Saizy R, Aubert P 1979 L’alimentation chew le brule. Annales de Chirurgie Plastique 21: 67-70 181 Cynuber L, Nguyen Dinh F, Blonde F, Saizy R. Giboudeau J 1982 Plasma and urinary amino acid pattern in severe burn patients-Evolution throughout the healmg period. American Journal of Clinical Nutrition 36: 416425 [91 Cynober L, Blonde F, Nguyen Dinh I;, Gerbet I>. Giboudeau J 1983 Mesure des acides amines plasmatiques et urinaires par chromatographie en phase gazeuse chez des sujets sains; variations en fonction de l’ige et du sexe. Annales de Biologie Clinique 41: 33-38 C, Ziegler F, Giboudeau J [lOI Cynober L, Coudray-Lucas 1985 High performance ion-exchange chromatography of amino acids in biological fluids using chromakon SOO-performance of the apparatus. Journal of Automated Chemistry 7: 301-203 Cynober L, Nguyen Dinh F, Saizy R, Blonde I, [Ill Giboudeau J 1983 Plasma amino acid levels in the first few days after burn injury and their predictive value. Intensive Care Medicine 9: 325-331 M, Saizy R, 1121 Aussel C, Cynober L, Lioret N, Dubreuil Giboudeau J 1984 Plasma amino acid pattern in burn subjects: influence of septicemia. Clinical Nutrition 3: 237-239 C, Cynober L, Lioret N, Saizy R, Baux [I31 Coudray-Lucas S, Giboudeau J 1985 Origins of hyperphenylalaninemia in burn patients. Clinical Nutrition 4: 179-183 [I41 Snelling C F T, Woolf L I, Groves A C, Moore J P, Duff J H 1982 Amino acid metabolism in patients with severe burns. Surgery 91: 474-481 J W, Watanabe C, MacMillan [I51 Stinnett J D, Alexander B G, Fischer I E, Morris M I, Trocki 0. Miskell I’. Edwards L, James J 1982 Plasma and skeletal amino acids following severe burn injury in patients and experimental animals. Annals of Surgery 195: 75-89 [I’51 Chang X S, Yang C C, Hsu W S, Hsu W T, Shih T S 1984 Changes of serum amino acids in severely burned patients. Burns 10: 109-l 15
226
ARTERIO-VENOUS
DIFFERENCES
IN AMINO
ACIDS,
GLUCOSE,
[ 171 Roth E, Funovics J, Muhlbacher F, Sporn I’, Mauritz W 1983 Metabolic parameters as predictors of outcome in critically ill. New Aspects of Clinical Nutrition, Karger, Ed. Basel, pp 97-l 13 [ 181 Gelfand R A, De Fronzo R A, Gusberg R 1983 Metabolic alterations associated with major injury or infection. New Aspects of Clinical Nutrition, Karger Ed, Basel, pp 21 l-239 [19] Aulick L H, Wilmore D W 1979 Increased peripheral amino acid release following burn injury. Surgery 85: 560-565 [20] Batstone G F, Alberti K G, Hinks L, Smythe I’, Laing J E, Ward C M, Ely D W, Bloom S R 1975 Metabolic studies in subjects following thermal injury. Burns 2: 207-225 [21] Iapichino G, Radrizzani D, Bonetti G, Colombo A, Damia G, Della Torre P, Ferro A, Leoni L, Ronzoni G, Scherini A 1985 Parenteral Nutrition of injured patients: effect of manipulation of amino acid infusion (increasing branched-chain while decreasing aromatic and sulphurated amino acids). Clinical Nutrition 4: 121-128 Submission date: 28 March
LACTATE
AND
FATTY
ACIDS
IN BURN
PATIENTS
[22] Ryan M T 1976 Metabolic adaptations for energy production during trauma and sepsis. Surgical Clinics of North America 56: 1073-1090 ]231 Abbott W C, Schiller W R, Long C L, Birkhahn R H, Blackemore W S 1985 The effect of major thermal injury on plasma ketone body levels. Journal of Parenteral and Enteral Nutrition 91: 153-158 M, Lioret N, Cynober L, Aussel C, [241 Vaubourdolle Coudray-Lucas C, Saizy R, Giboudeau J 1985 Influence of enterally administered ornithine r ketoglutarate on hormonal patterns in burn patients. 1st Congress of the European Burns Association, Groningen, The Netherlands WI Grill0 M A 1985 Metabolism and function of polyamines. International Journal of Biochemistry 17: 943-948 WI Aussel C, Cynober L, Lioret N, Dubreuil M, Saizy R, Giboudeau J 1985 Branched-chain keto acid plasma concentrations following burn injury. Effects of enteral feeding supplemented with ornithine ketoglutarate. 4th World Congress Intensive Critical Care Medicine. Jerusalem, Israel
1986. Accepted after revision: 21 June 1986
NUTRITION
(1986) 5: 22 l-226
Arteri .o-Venous Differences in Amino Acids, Glucose, Lactate and Fatty Acids in Burn Patients; Effect of Ornithine Alpha-Ketoglutarate L. Cynober*, F. Blonde*, N. Liorettt, J. Giboudeau*. Laboratoire de Biochimie A*, Service des Briilist, Saint Antoine, 75571 Paris Cedex 12, France (Reprint requests to L.C.)
C. Coudray-Lucas*,
Dkpartement
d’Anesthtsiologie$,
Saizy Rt$ H6pital
and
Saint Antoine,
184 rue du Fg
ABSTRACT The study concerns two groups of seven burn patients matched for age, weight and total burn surface. Both groups received conventional enteral nutrition, while one was given a 10 g/day alpha-ketoglutarate ornithine (OKG) supplement. Femoral venous and arterial blood was taken from day 2 to day 13 post-burn in order to determine levels of amino acids, nonesterified fatty acids (NEFA), glucose and lactate. In the control group large negative arterio-venous differences ( 1’j A-V) were observed in amino acid and lactate levels whereas they were significantly lower with regard to Hyp, Gly, Lys and Ala in the OKG-treated group. AA-V was near zero for glucose and NEFA in both groups. These results support the view that OKG-therapy limits the output of amino acids in the leg and that glucose and NEFA do not constitute the main fuel in muscle.
(TBSA) ranging from 16.531”,, were studied from day 2 to day 13 post-burn. Seven were used as controls, the remaining seven received OKG’. The two groups were well matched for TBSA, age, weight and height. Clinical data are given in Table 1. All patients were stable following injury except one (in the treated group) who developed acute renal failure on day 13 and one patient (in the control group) who developed septicemia on day 11. Both were subsequently removed from the protocol. All clinical research was conducted in accordance with the principles for human experimentation as defined in the Helsinki declaration. All patients received the same continuous enteral nutrition consisting of milk and Realmentyl “? as reported previously [7,8]. In addition, OKG-treated subjects received 10 g of OKG enterally every day from day 2, before nutrition commenced. On the days the patients were studied, the enteral nutrition of every subject was interrupted at 6a.m. Arterial and venous femoral blood samples were taken at 9a.m. Samples were taken on days 2 (basal), 4, 7, 10 and 13 post-burn and immediately centrifuged (except for blood lactate determinations). Plasma and serum were stored at - 20°C until analysis. Plasma amino acids were measured by gas chromatography as previously described [9]. For this test,
INTRODUCTION In recent years, ornithine alpha-ketoglutarate (OKG) has been shown to be a useful adjuvant of enteral and parenteral nutrition, improving the nitrogen balance and reducing urea nitrogen losses in surgical, trauma, septic and burned patients [l+. This has been attributed either to a decrease in catabolism [l] or an increase in protein anabolism [3,4]. Although modifications of free amino acid patterns in muscle induced by OKG therapy have been explored in surgical patients [l], to our knowledge there have been no reports concerning arterio-venous amino acid differences ([L A-VIAA) in traumatised patients. The only studies available concern healthy subjects in whom small variations in muscle amino acid flux were observed [5]. However, the flux of substrates in health and disease probably differ in their sensitivity to exogenous supplementation in metabolic intermediates such as ornithine and alpha-ketoglutarate [6]. We therefore measured arterial and venous amino acids (together with glucose, lactate and non-esterified fatty acids-NEFA) in two groups of burn patients, one of which received OKG. In addition, results obtained for nitrogen balance and 3-methylhistidine excretion are given to help in interpreting the data.
PATIENTS Fourteen
AND METHODS burn
patients
with total burn
surface
I Omicetil”, Laboratoires France. 2Laboratoires Sopharga,
areas 221
Logeais,
Issy Les Moulineaux,
Paris, France.
222
ARTERIO-VENOUS
Table 1
Clinical
DIFFERENCES
IN AMINO
data relative to subjects
ACIDS,
GLUCOSE,
LACTATE
AND
FATTY
ACIDS
IN BURN
studied Full
Burn patients Control 1 2 3 4 5 6 7 mean *SD Treated 1 2 3 4 5 6 7 mean *SD
PATIENTS
Sex
Age
Height (m)
Weight (kg)
M F M M F M F
46 30 33 15 19 30 35 29 f 10
1.68 1.71 1.75 1.70 1.64 1.71 1.62 1.68 kO.04
67 58 66 51.5 54 80 55.5 61 +9
M M M
36 26 50
1.60 1.81 1.75
63 66.5 75.5
F M M M
41 45 50 27 39 f- 10
1.58 1.66 1.70 1.63 i .67 j~O.08
60 61 69 58.5 65 f6
TBSA (“U)
Complications
thickness BSA(” II)
20.5 20 16.5 20 21 20 29 21
Hospitalisation (days)
12 3 0 0 0 0 0
94 31 25 42 21 12 40 37 +26
22 18 19
0 6 0
16 40 16
30 31 21 22.5 23 &5
0 10 10 0
f4
11 dead (D21) 46 14 23 * 15
History
alcoholic
and associated trauma
diahorrea (D21)
R.F. heroin addict alcoholic septicemia (D 11)
psychotic fracture hand
of the
blast, ARF (D13) alcoholic viral hepatitis
TBSA: Total burn surface area ARF: Acute renal failure. R.F.: Respiratory failure. samples were deproteinised with sulfosalicylic acid prior to storage at -20°C. Twenty-four h urines were collected for the determination of 3-methylhistidine by ion-exchange chromatography as previously described [lo] and for urea and creatinine excretion measurements. Serum NEFA plasma glucose, blood lactate and urine creatinine and urea were routinely measured. Nitrogen balance was estimated from nitrogen intake and urinary urea loss plus estimated cutaneous and fecal losses. Student’s t-test was used for statistical comparisons between control and treated burn patient values.
(p < 0.02), glycine, alanine and lysine (p < 0.05) (Fig. 3). After day 4, with the improvement in AA-V in the control group, there were no statistical differences between the two series (data not shown). There was no difference between the two groups in [AA-V] lactate [AA-V] glucose and [AA-V] NEFA (data not shown). Finally, nitrogen balance was significantly (p < 0.05) less negative at day 13 in the OKG-treated group but there was no difference in 3-methylhistidine excretion (Table 2).
DISCUSSION RESULTS In the untreated (control) group, femoral [AA-V] AA were negative at day 4, except for methionine. They gradually returned to zero at day 10, except for alanine and lysine (Fig. 1). On the contrary, the nitrogen balance remained negative throughout the study (Fig. 1). [AA-V] lactate was negative at day 4 and then returned to zero. No evidence for glucose or NEFA uptake (i.e., positive [AA-V]) was found (Fig. 2). In OKG-treated burn subjects, the [A A-V]AA was markedly less negative than in the control group at day 4 significant differences in hydroxyproline with
Numerous reports have dealt with plasma and serum amino acid variations after burn injury [4,1 l-161. In general, in the first week following injury a decrease in neoglucogenic amino acids [4,8,11-16) and an increase in tyrosine and phenylalanine [4,8,10-151 are found, whereas branched chain amino acids remain stable [4,8,11-131 or are reduced [14-161. Our results (not shown) for venous amino acid concentrations are in accord with this general pattern which is also found in most hypercatabolic situations [ 17,181. However, variations in [ A A-V] AA after burn injury are poorly documented: a study by Aulick and Wilmore [19] suffers from several methodological problems: 1) The range of
CLINICAL
223
NUTRITION
HYP ASP + ASN ;;i ;L$~ORN THR LEU PRO VAL GLY GLU +GLN
LYS
z a n
ALA
-15
I
I
I
I
I
2
4
7
10
13
-
jours Fig. 1 Time related variations in arterio-venous differences in amino acid levels (0) and nitrogen balance ( n ) in seven burn patients not receiving OKG. Each curve refers to individual amino acids: 1) alanine, 2) lysine, 3) glutamate + glutamine, 4) glycine, 5) valine, 6) leucine, 7) proline, 8) threonine, 9) tyrosine, 10) phenylalanine, 11) serine, 12) isoleucine, 13) ornithine, 14) aspartate + asparagine 15) hydroxyproline, 16) methionine. The position of each amino acid to the left of the vertical axis represents the largest negative arterio-venous difference for the amino acid concerned.
ARTERIO-VENOUS
DIFFERENCES
IN AMINO
ACIDS,
GLUCOSE,
LACTATE
Table 2
Days postburn 2 4 7 10 13
AND
FATTY
ACIDS
IN BURN
PATIENTS
Nitrogen balance and 3-merhylhisridine Nitrogen balance
excretion
Control (g’dayireaced
3-methylhistidine (~~mol/mmol creatinine) Control Treated
- 15.5 f 5.1 - 12.4 * 3.8 ~ 14.3 f 3.6 -11.3 & 1.6 -9.2 f 3.6 - 10.4 f 5.4 -7.8 f 2.9
37.0 f 5.7 37.3 It 3.4 40.5 f 5.6 43.3 + 10.7 29.7 f 3.2 32.4 LIZ 1.5 37.0 f 1.4
-7.6
+ 2.0
+2.0 f 1.7*
35.9 +
1.9 27.5 + 3.5
lp < 0.05 between control and OKG treated patients. Results are expressed as mean * SEM. a
4
7
13
10
DAYS
Time-related variations in arterio-venous differences in lactate ( n ), glucose (0) and NEFA (A) levels in the control group. Data are given as mean + SEM. burn surface area was wide (12-74”,,) and the subjects probably did not all show the same degree of response to trauma. 2) A single measurement was made and took place between the 7th and 21st day post-burn, with the result that the subjects were not all in the same post-
GLY
VAL
MET
THR
SER
ASP
burn metabolic phase [20]. 3) The number of amino acids studied was limited (alanine, glycine, proline, serine, threonine, methionine, leucine, valine, phenylalanine). For these reasons, comparisons with our own results are difficult. Care must be taken in interpreting our data however, as for technical reasons, leg blood flow was not measured. Nevertheless, as Iapichino er al., have stated [21], [AA-V] AA reflect the amino acid balance in
i ASN
PHE
Fig. 3 Arterio-venous differences in amino acids 4 days after injury. Results are given as mean f SEM
1_1control W OKG-treated lp < 0.05 l*p < 0.02
LEU
iLE
GLU
i GLN
PRO
LYS
HYP
TYR
CLINICAL
the leg and can be interpreted qualitatively in patients not suffering from shock, which is the case in this study.
Furthermore, it is interesting to note that leg blood flow in burn injury is six times higher than in healthy subjects but constant from one burn patient to another. [ 191 In the control group, nitrogen balance remained negative until day 13 although [AA-V] AA had returned to equilibrium by that time as had 3-methylhistidine excretion. This suggests that extra-muscular protein catabolism is involved after day 7 and/or that protein intake is qualitatively unsuitable and that administered nitrogen is not retained by the organism. No evidence for NEFA uptake was found and glucose captation was rather low. This might suggest that other fuels such as ketone bodies are used by the unaffected leg of the burn patient, a hypothesis confirmed by data from the literature [22,23]. The most marked difference between the control and the OKG-treated group is the decrease in muscle amino acid release observed in the treated group on day 4. This observation depends of course on there being no major difference in leg blood flow between the two groups. This is probably so since all the subjects were comparable in terms of the extent of the trauma (no difference between the two groups in cortisol and glucagon plasma levels-data not shown-and similar burn surface areas). However, it is impossible to exclude differences in leg blood flow from one patient to another. Nitrogen balance was less negative after day 4 in the OKG-treated group, significantly at day 13. These data suggest that OKG either limits protein catabolism or increases protein anabolism. The second hypothesis would appear more likely since OKG was not found in this study to affect 3-methylhistidine urinary output, It is interesting to note that in surgical patients OKG has been found to decrease 3-methylhistidine excretion [I]. However, in septic and polytrauma patients, it has been found that OKG had an anabolic action [3]. As it is well known that extent of modifications in protein anabolism and catabolism varies differently according to the extent of the trauma, it is possible that OKG has a preferential action on protein catabolism after surgery and on protein anabolism after burn injury, sepsis and polytrauma. It is unlikely that the action of OKG results from the difference in nitrogen intake between the two groups: OKG provides 1.35 g nitrogen per day i.e., the difference in nitrogen intake between the two groups was only 3”,, at day 13. The mechanism by which OKG exerts its anabolic action remains obscure. We have demonstrated elsewhere [24], that OKG has no action on insulinemia or hGH plasma levels in burn injury although this mechanism has previously been suggested [ 1,3]. Other possibilities involve polyamine synthesis from ornithine [25] or branched chain keto acid (BCKA) synthesis by
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1986. Accepted after revision: 21 June 1986