The Journal of Nutrition Vol. 128 No. 3 March 1998, pp. 563-569

A Randomized Controlled Trial of the Influence of the Mode of Enteral Ornithine -Ketoglutarate Administration in Burn Patients^1,2,3

Jean-Pascal De Bandt^{*, 4}, Colette Coudray-Lucas^*, Nicole Lioret, Soo Kyung Lim^*, Robert Saizy, Jacqueline Giboudeau^*, and Luc Cynober^{*, 5}

^* Laboratoire de Biochimie A and  Service des Brûlés, Hôpital Saint Antoine, 75571 Paris Cedex 12, France

	ABSTRACT

Abstract Introduction Methods Results Discussion References

To investigate appropriate mode and daily dose of enteral ornithine -ketoglutarate (OKG) administration, 54 burn patients (total burn surface area: 20-50%) were included in a randomized controlled trial and assigned to receive either a supplement of OKG (10, 20 or 30 g/d) as bolus or continuous infusion, or a continuous infusion of an isonitrogenous amount of a soy protein mixture (Protil-1: 10, 20 or 30 g/d) in addition to their enteral diet. The influence of these treatments on clinical outcome and biological indices was evaluated. OKG administration significantly improved nitrogen balance and reduced 3-methylhistidine and hydroxyproline urinary elimination. This was associated with a gradual rise in plasma glutamine over time. Given as a bolus, OKG significantly improved wound healing, assessed both clinically [day of last graft: (mean ± SEM) OKG bolus 23.7 ± 2.1 d versus Protil-1, 39.9 ± 9.9 d; P < 0.05] and by hydroxyproline excretion, and biological markers of nitrogen metabolism, and tended to reduce duration of enteral nutrition (P = 0.12). The higher catabolic status in the patients administered 20 g OKG/d at the onset of the study, despite randomization, precludes any definite conclusion (concerning the dose-effect relationship). However, based on 3-methylhistidine elimination, our data indicate a benefit of 30 g OKG/d administration over 10 g/d. This study further supports OKG supplementation in burn patients. In addition, this is the first trial based on objective data that favors bolus over continuous infusion of OKG in critically ill patients.

	INTRODUCTION

Abstract Introduction Methods Results Discussion References

Burn injury, which is associated with accelerated metabolic rates, increased nitrogen loss, lean body mass loss and abnormalities in lipid and carbohydrate metabolism, is considered to be a major cause of hypercatabolism. Artificial nutrition designed to meet the increased metabolic demands thus represents an integral component of burn patient therapy. Although enteral nutrition with conventional polymeric diets commonly is used in these patients, there is a need for qualitative improvement of the nutritional support (Gilpin et al. 1993).

In this respect, clinical trials in acute situations including burn, trauma, sepsis and surgical patients have demonstrated a beneficial effect of supplementation of the nutritional sup-port with ornithine -ketoglutarate (OKG)⁶ on nitrogen homeostasis (Cynober et al. 1984 and 1987, Donati et al. 1993, Hammarqvist et al. 1990, Jeevanandam 1993, Leander et al. 1985, Le Bever et al. 1993, Mertes et al. 1988, Vaubourdolle et al. 1987, Wernerman et al. 1989 and 1990). The metabolic properties of OKG are multiple (Cynober 1995); -ketoglutarate and ornithine are precursors of glutamate and glutamine, the latter playing a major role in the regulation of protein metabolism. Ornithine also is used for the synthesis of arginine, proline and polyamines, which are involved in cell proliferation and/or wound repair (Grillo 1985, Kirk and Barbul 1990). Finally -ketoglutarate acts as a nitrogen scavenger. These unique metabolic properties result mainly from a specific interaction between ornithine and -ketoglutarate (Cynober et al. 1986, Le Boucher et al. 1997).

In burn patients, OKG supplementation (10-20 g/d) has been shown to reduce protein catabolism (Cynober et al. 1984, 1987, Le Bever et al. 1993) and improve nitrogen balance (Cynober et al. 1986 and 1987, Donati et al. 1993), glucose tolerance (Vaubourdolle et al. 1987), nutritional status (Cynober et al. 1986 and 1987, Donati et al. 1993, Le Bever et al. 1993) and wound healing (Donati et al. 1993, Le Bever et al. 1993). In addition, experimental studies in burned rats have demonstrated that OKG promotes the replenishment of the depleted tissue glutamine pools, reduces muscle protein catabolism and stimulates protein synthesis in the liver and intestine (Le Boucher et al. 1995, Vaubourdolle et al. 1991, Ziegler et al. 1991).

In these trials, OKG was supplied either as boluses or via continuous infusion, and the doses used ranged between 10 and 20 g/d. However, there are no objective data to guide the choice of mode and dose of administration. Studies in experimental models (Ziegler et al. 1991), healthy subjects (Payne-James et al. 1989) and burn patients (Le Bricon et al. 1997) have demonstrated variations in OKG metabolic effects according to the dose and/or the mode of OKG administration; the synthesis of the key OKG metabolites is determined largely by the rate of OKG administration. To date, there is no information on the importance of this issue in critically ill patients in terms of clinical end-points and nutritional status. At a time of heightened interest in the possible pharmacological properties of key nutrients, it is desirable to assess the influence of dose and mode of administration of drugs such as OKG on the efficiency of the nutritional support. The present study was performed to determine the most efficient pattern of OKG therapy, i.e., the optimal mode (bolus or continuous infusion) and dose (10, 20 or 30 g/d) of administration, as judged by clinical, nutritional and biological variables.

	PATIENTS AND METHODS

Abstract Introduction Methods Results Discussion References

Patients.  Fifty-four burn patients, admitted for thermal injury (TBSA: total burn surface area: 20-50%) in the intensive care burn unit of the Hôpital Saint Antoine, were prospectively studied for 21 d after injury. Exclusion criteria were as follows: admission 24 h after burn injury, renal or hepatic failure, age <15 or >60 y, no enteral nutritional support. The procedures followed in this study complied with the Helsinki Declaration of 1975 as revised in 1983, and informed consent was obtained from all patients.

The patients were resuscitated parenterally and then alimented enterally. Enteral nutrition was started with Osmolite (Abbott, Rungis, France) for 24-48 h after burn injury, after which all the patients received the same gastric continuous enteral nutrition infusion, which consisted of a commercial polymeric diet (Dripsol 81, Promedica Diététique, Paris, France), via a nasal tube. The amino acid composition of the diet is given in Table 1. The diet contained 19.1% protein, 11.04% fat and 63.1% carbohydrate. Individual nutritional requirements were evaluated on the basis of body weight using the Harris-Benedict formula. Energy was increased gradually from 2.2 to an average of 14.6 MJ/d by d 8 postburn. Nitrogen supplied by the diet increased in parallel to reach 26 g/d on d 8. 

The diet was supplemented with OKG (Cetornan, Laboratoires Jacques Logeais, Issy-les-Moulineaux, France) (10, 20 or 30 g/d) or an isonitrogenous amount of a soy protein mixture (Protil-1, Jacquemaire, Villefranche-sur-Saône, France). Patients were allocated consecutively to nine treatment groups according to a randomization table. The nine treatment groups were defined according to mode and dose of nitrogen supplement administration: 10 g OKG/d as a single bolus (administered at 0900 h); 20 g OKG/d as two boluses (10 g each, administered at 0900 and 2100 h); 30 g OKG/d as three boluses (10 g each, administered at 0900, 1700 and 0100 h); 10, 20 or 30 g OKG/d mixed with daily nutrition; 10, 20 or 30 g Protil-1/d mixed with daily nutrition. Supplements were administered from d 2 after injury. For bolus administration, 10 g OKG was dissolved in 200 mL water and administered directly through the enteral tube.

From the 54 patients randomized, only 48 actually were studied because six patients were excluded: one for intestinal hemorrhage on d 4, one for cardiac arrest on d 5, one who died on d 5 from respiratory failure, 1 who died on d 10 from acute renal failure on d 6, and 2 because the enteral diet (Dripsol 81) was no longer commercially available at the time of their inclusion.

A summary of the characteristics of the different groups is given in Table 2. Severity was expressed as TBSA and as unit burn standard (UBS: TBSA + 3 × full thickness burn surface area). TBSA was assessed first on admission and confirmed 48-72 h later.

Clinical follow-up.  In addition to standard clinical assessment, the following indices also were studied: evolution of body weight, tolerance of the enteral diet (diarrhea, vomiting, temporary arrest of enteral nutrition), number and length of septic episodes, day of last graft, duration of enteral nutrition and of hospital stay and mortality.

Sample handling.  Enteral nutrition was stopped every day for all patients at 0600 h and blood samples were collected at 0900 h, after which nutrition was resumed. Venous blood samples and daily urine specimen were collected on d 2, 4, 7, 10, 13 and 21 after injury.

Heparinized blood samples were centrifuged rapidly, and plasma was used directly for the measurement of glucose and after deproteinization with sulfosalicylic acid (50 g/L) for amino acid determination.

Urine samples were used directly for the measurement of total nitrogen and hydroxyproline and after deproteinization with sulfosalicylic acid for the measurement of 3-methylhistidine (3MH).

When biological determinations were delayed, samples were stored at 20°C.

Analytical methods.  Glucose was measured by the routine glucose-oxidase method adapted on an Astra 8 analyzer (Beckman, Palo Alto, CA).

Amino acids and 3MH were measured on a System 6300 analyzer (Beckman) by ion-exchange chromatography with post-column ninhydrin derivatization for detection. Glucosaminic acid and amino-ethylcysteine were used as internal standard for plasma amino acid analysis, and amino-guanidino-propionic acid for 3MH determination

Total urinary nitrogen was measured by chemoluminescence on an Antek 9950 analyser (Antek, Houston, TX).

Hydroxyproline in urine was determined after acid hydrolysis (16 h, 110°C) by the reaction with p-dimethylaminobenzaldehyde after oxidation by chloramine-T (Hypronosticon, Organon Teknika, Fresnes, France).

Calculations.  Nitrogen balance was calculated as follows: urinary nitrogen loss was measured (total urinary nitrogen) on d 2, 4, 7, 10, 13 and 21. Extra-urinary nitrogen losses were estimated to be 10% of nitrogen intake (Konstantinides 1992).

Areas under curves (AUC) were calculated by the trapezoidal method (Houin 1990) for 3MH and hydroxyproline urinary elimination and for nitrogen balance.

All results are expressed as means ± SEM. Statistical analysis was performed on PCSM software (Deltasoft, Grenoble, France). Given the expected variations among patients and the limited number of patients per group studied (6), preselected comparisons were carried out as OKG versus Protil to evaluate the efficiency of OKG therapy, OKG Bolus versus OKG continuous infusion versus Protil-1 to evaluate the importance of the mode of OKG administration and 10 g OKG versus 20 g OKG versus 30 g OKG to evaluate the importance of the dose of administered OKG. Qualitative parameters were compared by the chi-square test. For quantitative parameters, nonparametric Mann-Whitney and Kruskal-Wallis tests were used for the comparison between two or several groups respectively (Schwartz 1996). Analysis of variance for repeated measurement (AVRM) was used to assess the influence of the treatment on the evolution of biological parameters throughout the study period. The level of significance was set at 0.05.

	RESULTS

Abstract Introduction Methods Results Discussion References

No differences were found among the nine groups in evolution of body weight, tolerance of the enteral diet, number and length of septic episodes and mortality for a given dose or mode of administration of the nitrogen supplement (Table 2).

Global effects of OKG.  To assess the overall effects of OKG, data were pooled irrespective of dose and mode of administration. OKG and Protil-1 groups were matched for demographic variables and nutritional support. Dietary intakes of the two groups until d 9 postburn are given in Table 3.

In the OKG-treated group, the evolution of nitrogen balance was significantly different from the other groups throughout the study period (AVRM: P = 0.015) (Fig. 1A). In parallel, 3MH excretion was lower in OKG-treated patients (on d 10: OKG: 383.5 ± 28.4 µmol/d vs. Protil-1: 544.7 ± 61.8 µmol/d; P < 0.05), (Fig. 1B). This was accompanied by a significant reduction in hydroxyproline urinary elimination (AUC_d2-d13: OKG: 12,735 ± 1432 µmol vs. Protil-1: 19,522 ± 2805 µmol/d; P < 0.05) (Fig. 1B).

View larger version (22K): [in this window] [in a new window]   Fig 1. Influence of ornithine -ketoglutarate (OKG) or an isonitrogenous (Protil-1) supplementation of the enteral diet on the evolution of nitrogen balance (A), daily urinary excretion of 3-methylhistidine (3MH) and hydroxyproline (B) and plasma glutamine and ornithine (C) in burn patients throughout the study period (d 2-d 21 after burn). Data were pooled according to the supplement, irrespective of dose (10, 20 or 30 g/d) and mode (continuous infusion or separated boluses) of administration; in the control group (Protil-1), the supplement was delivered only as continuous infusion. Venous blood samples and daily urine specimens were collected on d 2, 4, 7, 10, 13 and 21 after injury. Values are presented as a function of the day after burn injury and expressed as means ± SEM. *P < 0.05 OKG vs. Protil-1.

Plasma amino acids displayed a gradual and significant increase (P < 0.01 on d 10 and 13) in plasma ornithine and glutamine levels after OKG administration (Fig. 1C).

Influence of the mode of OKG administration.  To evaluate the effect of the mode of OKG administration, data were pooled regardless of the dose of the nitrogen supplement as OKG bolus, OKG continuous infusion and Protil-1 groups. The three groups were matched for demographics, severity of burn injury (UBS) and nutritional support.

The duration of enteral nutrition and the length of hospital stay tended to be lower in the OKG bolus group (P = 0.12) (Table 4). However, wound healing by the day of last graft was significantly shorter in the OKG bolus groups versus OKG continuous infusion and versus Protil-1 (Table 4).

Glucose tolerance pertaining to variations in glycemia was improved significantly by OKG bolus (AVRM: P < 0.05 OKG bolus vs. OKG continuous infusion and vs. Protil-1) (data not shown).

Although the evolution of nitrogen balance was significantly different between the OKG Bolus and Protil-1 groups (AVRM: P = 0.01) (Fig. 2A), cumulative nitrogen balance, calculated as AUC, only tended to differ (AUC_d2-d13: OKG bolus: 17.7 ± 15.8 vs. OKG continuous infusion: 47.7 ± 20.3 vs. Protil-1: 62.8 ± 20.5 g N; P = 0.10). On day 10, 3MH elimination was decreased significantly in the OKG bolus group (Fig. 2B). In addition, OKG as bolus or continuous infusion decreased hydroxyproline urinary excretion (AUC_d2-d13: OKG Bolus: 11,701 ± 2,828 vs. OKG Continuous infusion: 13,510 ± 1,836 vs. Protil-1: 19,522 ± 2,805 µmol; P  0.03 vs. Protil-1) (Fig. 2B).

View larger version (27K): [in this window] [in a new window]   Fig 2. Influence of the mode of administration, either separated boluses or continuous infusion, of OKG on nitrogen homeostasis and protein catabolism in burn patients. Data were pooled irrespective of supplement daily dose (10, 20 or 30 g/d) according to the mode of OKG administration either bolus (OKG Bolus) or continuous infusion (OKG continuous infusion); in the control group (Protil-1), the supplement was delivered only as continuous infusion. Nitrogen balance (A), daily urinary excretion of 3-methylhistidine (3MH) and hydroxyproline (B) and plasma glutamine and ornithine (C) were evaluated throughout the study period (d 2-21 after burn) from venous blood samples and daily urine specimens collected on d 2, 4, 7, 10, 13 and 21 after injury. Values, presented as a function of the day after burn injury, are expressed as means ± SEM. *P < 0.05 OKG bolus vs. Protil-1; +P < 0.05 OKG bolus vs. OKG continuous infusion.

View larger version (29K): [in this window] [in a new window]   Fig 3. Influence of the dose of enterally administered ornithine -ketoglutarate (OKG; 10, 20 or 30 g/d) on nitrogen homeostasis and protein catabolism in burn patients. Data were pooled irrespective of mode of administration (bolus or continuous infusion) according to the daily dose of OKG (10, 20 or 30 g/d). Nitrogen balance (A) and daily urinary excretion of hydroxyproline (B) and 3-methylhistidine (3MH) were evaluated throughout the study period (d 2-d 21 after burn) from daily urine specimens collected on days 2, 4, 7, 10, 13 and 21 after injury. Values, presented as a function of the day after burn injury, are expressed as means ± SEM. *P < 0.05 OKG 30 g/d vs. OKG 10 g/d; **P < 0.05 OKG 20 g/d vs. OKG 10 g/d; +P < 0.05 OKG 30 g/d vs. OKG 20 g/d.

OKG increased plasma glutamine concentration throughout the study period in the bolus group (AVRM: P = 0.01 vs Protil-1) (Fig. 2C). A significant increase in plasma ornithine was observed after day 7 in the bolus group and to a lesser extent in the continuous infusion group (Fig. 2C).

Analysis of the influence of the mode of administration at each of the three levels of OKG supplementation showed no significant difference for the 10 g/d and 20 g/d groups. For the 30 g/d supplement groups, the duration of enteral nutrition was significantly shorter in the bolus group (27.2 ± 3.3 d in the 30 g bolus group vs. 43.0 ± 5.1 d in the 30 g OKG continuous infusion group vs. 51.3 ± 28.2 d in the 30 g Protil-1 group; P < 0.05), and bolus administration decreased the urinary elimination of 3MH and hydroxyproline and increased plasma glutamine and ornithine concentrations (Table 5).

Influence of the dose of OKG.  To evaluate the effect of the dose of OKG, data were pooled according to dose: 10, 20 or 30 g OKG/d, regardless of the mode of OKG administration. The three groups were matched for demographics and severity of burn injury (UBS).

There was no difference among the three Protil-1 treated groups, indicating the absence of effect of supplemental nitrogen on clinical and biological variables (data not shown).

For the patients receiving 30 g OKG/d, there was a significant reduction in 3MH urinary elimination compared with the 10 and 20 g OKG/d-treated patients (AUC_d2-d13: OKG 30 g: 3311 ± 356 vs. OKG 20 g: 5440 ± 896 vs. OKG 10 g: 4555 ± 298 µmol; P  0.01 vs. OKG 30 g) (Fig. 3). Hydroxyproline urinary elimination, similar in the 10 g/d and 30 g/d groups, was significantly greater in the 20 g OKG/d group (AUC_d2-d13: OKG 30 g: 9758 ± 1011 vs. OKG 20 g: 17,599 ± 2857 vs. OKG 10 g: 9720 ± 1366 µmol; P  0.01 vs. OKG 20 g). It must be noted that, despite the randomization, the 20 g OKG/d group demonstrated a poorer nitrogen balance at the onset of the study, and this was accompanied by higher rate of urinary elimination of hydroxyproline and 3MH on the following days (Fig. 3). This probably could explain the lack of significant difference among groups when the mode of administration and the dose were taken into account simultaneously.

	DISCUSSION

Abstract Introduction Methods Results Discussion References

As previously demonstrated in different studies (Cynober et al. 1984 and 1987, Donati et al. 1993), our data indicate a positive effect of OKG administration on nitrogen metabolism as shown by the improvement in nitrogen balance regardless of the dose and mode of OKG administration. We also observed in OKG-treated burn patients a decrease in the elimination of 3MH, a marker of myofibrillar protein catabolism (Grecos et al. 1984), in agreement with the study of Le Bever et al. (1993). Thus it may be suggested that OKG decreases muscle proteolysis as already shown in burned rats (Vaubourdolle et al. 1991). The extent of OKG metabolism is demonstrated by the rise in plasma ornithinemia related to OKG administration that became apparent only from day 10 after burn injury, i.e., at the end of the most catabolic phase as previously observed (Cynober et al. 1984). Concomitantly OKG led to a dramatic improvement in plasma glutamine level; this increase in glutamine availability, consistent with the known ability of OKG to generate glutamine (Cynober 1993, Hammarqvist et al. 1990, Le Boucher et al. 1995, Vaubourdolle et al. 1991), is likely to be involved in the improvement in nitrogen metabolism, given the role of glutamine as a regulator of peripheral protein catabolism (Millward et al. 1989). This effect on protein metabolism is supported further by the reduction in the urinary elimination of hydroxyproline, a marker of collagen turnover (Grant and Prockop 1972), which may be associated with OKG-induced improvement in wound healing demonstrated here as in other studies (Donati et al. 1993, Le Bever et al. 1993).

We must emphasize that the tolerance to enteral nutrition was satisfactory and not different among groups. This is of particular interest because large doses of OKG (>10 g/d) given as bolus induce diarrhea, which precludes its use under that mode (Cynober 1991). The design of our study, i.e., fractionation into several separate 10-g boluses, enabled us to increase dosage without adverse side effects.

Our data favor bolus administration over continuous infusion. It has been suggested that in both experimental models (Le Boucher et al. 1997) and healthy volunteers (Cynober et al. 1990) the appearance of OKG metabolites, i.e., glutamine, ornithine, arginine and polyamines, depends on a specific interaction between -ketoglutarate and ornithine metabolism. In fact, KG and ornithine can be interconverted through glutamate semi-aldehyde and glutamate, and these reactions are nearly in equilibrium and fully reversible (Cynober 1993). When KG or ornithine is administered alone, they are catabolized in different pathways; the simultaneous administration of these two compounds, through the saturation of certain metabolic pathways, may shift KG and ornithine metabolism toward glutamine, arginine and polyamine synthesis (Cynober 1993). For this interaction to occur, sufficiently large amounts of these two molecules must be present. This may be the case when OKG is administered as a bolus but not for a small dosage of OKG delivered in continuous infusion (Cynober 1993, Le Bricon et al. 1997, Payne-James et al. 1989). The consequences of this interaction after bolus administration are shown in our study not only by the improvement in biological markers of protein turnover but also by the reduction in the time for wound healing and, for the 30 g OKG/d dose, by the reduction in the duration of enteral nutrition. In addition, it is noteworthy that OKG bolus administration improves glucose tolerance as reported previously (Vaubourdolle et al. 1987). This suggests that the bolus mode enables the endocrine stimulatory effect of ornithine (Cynober et al. 1990) to appear.

Results are not so clear concerning the dose-effect relationship. Two reasons for this can be offered. First, despite the large size of the burn population studied, the small number of patients in each group hampered statistical analysis because of large interindividual variations. Second, despite the randomization, patients receiving 20 g OKG/d demonstrated a more negative nitrogen balance on day 2 after injury; this suggests that these patients were in a more catabolic state. This was indicated further by the higher 3MH and hydroxyproline urinary elimination on day 10 after injury in this group. Still, the decrease in 3MH elimination in the 30 g OKG/d group compared with the 10 g OKG/d group suggests a possible dose-effect relationship. This point deserves further study.

In conclusion, it is clear from our findings that bolus administration of OKG, which enables the generation of key anabolic compounds, is to be preferred over continuous infusion to promote nitrogen economy and improve tissue healing in burn patients. In these very catabolic patients, a 10 g daily OKG supplement may not be optimal; more studies are needed to define the exact dosage required.

	FOOTNOTES

Manuscript received 29 October 1996. Initial reviews completed 16 December 1996. Revision accepted 18 May 1997.

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