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Supplement: Arginine Metabolism: Enzymology, Nutrition, and Clinical Significance

Enteral and Parenteral Arginine Supplementation to Improve Medical Outcomes in Hospitalized Patients¹

Laboratories for Surgical Metabolism and Nutrition, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

² To whom correspondence should be addressed. E-mail: dwilmore{at}partners.org.

	ABSTRACT

TOP ABSTRACT LITERATURE CITED

 
The amino acid L-arginine has been administered as a single supplement to humans in an effort to improve the outcome of seriously ill patients. In normal individuals, markers of collagen biosynthesis have increased with daily oral doses ranging from 14 to 24.8 g of free arginine for 14 d. No clinical evidence of improved wound healing has been reported in the few patient studies performed to date. Administration of enteral, but not intravenous, arginine has been associated with markers of improved immune function in normal individuals and in some, but not all, patient groups studied. A single study in premature infants suggested that supplementation of L-arginine (261 mg · kg^–1 · d^–1) administered by both the parenteral and enteral routes decreased the incidence of necrotizing enterocolitis. A single study demonstrated that oral arginine administration in conjunction with conventional chemotherapy for active tuberculosis to HIV– but not HIV+ individuals enhanced treatment responses. In both these area, larger multicenter investigations are needed. For a difference to be a difference it has to make a difference. Supplementation of only L-arginine does not to date universally show benefit, nor does it show harm. At this time there is no rationale for the routine supplementation of arginine alone to enhance recovery from serious illness. Because of the potential for harm, this amino acid should only be administered to critically ill patients in large doses under carefully monitored study conditions.

KEY WORDS: • arginine • parenteral nutrition

Arginine is a nonessential amino acid that is important in protein synthesis and plays a key role in the intermediate metabolism of nitrogen by participating in the urea cycle. Arginine can be synthesized by the body and hence dietary arginine is not essential to nitrogen economy in normal adults (1) or necessary for normal growth in children (2). However, plasma concentrations may be largely determined by nutrient supply, because synthetic machinery does not adequately compensate in response to low levels of arginine intake (3,4). In addition to its role in protein synthesis and nitrogen disposal, arginine serves as a precursor to glutamine, proline, and putrescine (via ornithine), with the latter compound participating in the synthesis of polyamines. However, the functional role that has attracted the greatest interest to physicians caring for the critically ill is the contribution of arginine in the synthesis of nitric oxide (NO). In the past 2 decades it was found that nitric oxide plays an integral role in the regulatory function of the immune system and in governing the vascular response to sepsis; henceforth, investigators have directed their efforts toward manipulating this function in an effort to enhance host responses to infection and inflammation. Administering L-arginine is one important strategy being investigated to improve the care of this patient group.

Is arginine a conditionally essential amino acid?

In young rats, cats, and dogs, arginine has been shown to be an essential nutrient and elimination of this substance from the diet can limit optimal growth (5,6). This is not the case for humans under normal circumstances. However, there may be some situations where arginine can be thought of as a conditionally essential amino acid. For example, Heird and associates (7) described 3 premature infants who received an imbalanced intravenous feeding solution composed of crystalline amino acids, free of arginine, at a dose of 2.5 g · kg^–1 · d^–1. Hyperammonemia occurred but resolved with the administration of parenteral arginine. In another study, Batshaw and associates reported that 50% of premature infants weighing <2,500 g had elevated ammonia levels within the first 2 months of life when compared to infants weighing >2,500 g (8). When arginine and ornithine levels were compared in 2 groups of matched infants, with one group having normal ammonia levels and the other group having elevated levels, the arginine concentrations were significant lower in the hyperammonemic group. When oral arginine supplements were provided, ammonia levels fell about 25% when compared to an untreated group.

Thus, it appears that some premature infants may demonstrate a requirement for dietary arginine, and this may be a case of the amino acid becoming conditionally essential. Data from studies performed in both adult and pediatric patients who have sustained severe thermal injury suggest that arginine may become essential following severe injury. Yu et.al. (9,10) measured arginine kinetics in these patient groups using stable isotope tracer techniques and determined that there was little net de novo arginine synthesis, suggesting that influx of arginine was largely, if not totally, from the preformed arginine derived from proteolysis or from feeding formulas. Thus, the body does not increase the production of arginine following severe injury in order to meet the presumed increased demands.

However, in other conditions in adult humans where arginine has been administered in an attempt to enhance recovery, little evidence is available to suggest that a deficiency state exists. Rather, excessive dietary supplementation of arginine is provided to obtain a pharmacological effect from this amino acid, not to correct a nutrient deficient state.

How much arginine is enough?

Dietary arginine probably amounts to 2–6 g/ day, depending on the level of protein intake, because arginine concentration in egg, muscle, and liver protein is 5% of total protein (11). A variety of studies have been performed providing oral arginine supplements. Although low dose supplements in the range of 3–4 g/d have been studied (12), most investigators have given 9 or more g/d. For example, Barbul (13–15) performed 3 studies in normal volunteers giving 14, 17, and 24.8 g arginine/d for up to 2 wk with no major reported side effects. Beaumier and associates (16) gave 39.3 g/d for 6 d to normal volunteers. Other studies reported diabetic patients who received 9 g/d for up to a month (17) and investigations were carried out in subjects with HIV infection who received 19.6 g arginine/d for 14 d (18). Thus, it appears that large doses (>10 g/d) are necessary to determine specific effects and administration of this quantity has not been associated with reported side effects or toxicities.

Intravenous administration of arginine commonly occurs. Most amino acid solutions designed for parenteral nutrition contain about 8–11 g arginine/100 g amino acids (19). Thus, a 70 kg individual requiring 1.5 g amino acids · kg^–1 · d^–1 would receive 10 g arginine/d. In one study (20), L-arginine was infused alone at a dose of 20 g/d for 7 d. Parenteral arginine is administered as a constant infusion that may not stimulate the hormonal responses observed following an intravenous bolus infusion or the administration of a large oral dose of arginine. Specialized amino acid solutions are available for patients in renal and hepatic failure but arginine is generally omitted from such mixtures or the concentration of this amino acid is greatly reduced.

Clinical utility—wound healing

In a variety of laboratory studies, supplemental arginine administration has enhanced wound healing in animals, particularly rodents. In 1990 Barbul and associates (13) reported the effects of administration of supplemental arginine on collagen deposition and immune function in healthy volunteers. All individuals had small polytetraflouroethylene catheters inserted subcutaneously into the right deltoid region to be harvested later and assessed for collagen ingrowth and biosynthesis. The subjects were randomized into 3 groups; the first received 30 g arginine hydrochloride/24 h (which contained 24.8 g free arginine), the second received 30 g arginine aspartate (17 g free arginine) daily, and the third received placebo. The supplement volunteers consumed an oral diet ad libitum for 2 wk, at which point the catheters were removed and the contents analyzed for hydroxyproline content, which was used as an index of synthesis of new collagen. Arginine supplementation enhanced the amount of hydroxyproline in the catheters with the placebo group having 10.1 ± 2.32 nmol/cm graft vs. 17.57 ± 2.16 in the arginine asparate group and 23.85 ± 2.16 in the arginine hydrochloride group (P < 0.02 for both arginine groups vs. placebo, data presented as means ± SEM). Simultaneously, lymphocyte mitogenesis increased in both supplemented groups in response to standard stimuli.

In a similar study (14), investigators from the same laboratory studied the effect of arginine administration on wound healing in healthy elderly individuals (>65 y of age). Thirty individuals received 30 g arginine aspartate (containing 17 g free arginine) and 9 subjects served as controls and received placebo. After 2 weeks of supplementation, the hydroxyproline content in the subcutaneous catheters in the supplemented group was about 50% greater than in the placebo controls. Arginine administration did not influence the DNA content in the catheters or the rate of epithelialization of the skin defect. In addition to improved mitogesis, serum insulin-like growth factor-1 was elevated in the group receiving arginine.

In a more recent study (15), arginine (14 g) was administered with a mixture of other substances (B-hydroxy-B-methylbutyrate and glutamine) in a blinded study in elderly volunteers. Similar endpoints were followed and the normal subjects that received the specialized mixture demonstrated increased rates of collagen deposition. It was not determined which substance was the active component in the mixture.

Associated with these wound-healing studies in normal volunteers, a variety of endpoints have been monitored to evaluate safety associated with arginine administration (21,22). The protocols did not provide for neutral observers to follow a detailed assessment protocol to determine complications and toxicities associated with arginine administration. However, the investigators reported few side effects and/or associated complications with the arginine doses administrated. Initially, gastrointestinal disturbances were noted, but these resolved by administering the amino acid in divided doses throughout the day.

In summary, administering arginine to normal volunteers for 2 wk improved collagen synthesis, as determined by a surrogate marker of collagen deposition in a plastic tube implanted in the subcutaneous tissue. This finding was observed in both middle aged and elderly individuals; the latter group is known to have prolonged rates of wound healing. However, while these studies are encouraging, there is no data that demonstrate that supplemental arginine actually improves healing of wounds sustained following an injury or operation and thus enhances clinical outcome in patients. These clinical studies are necessary to conclude that arginine should be utilized for this indication.

Arginine in tube feedings

In addition to using arginine as an oral supplement, this amino acid has been administered to seriously ill patients via a feeding tube along with other dietary constituents. One of the first studies utilizing this approach was reported by Daly et al. (23), who determined the effect of arginine on the immune and metabolic responses in 30 patients with cancer of their upper gastrointestinal tract who underwent surgical resection. In the postoperative period, patients received tube feedings supplemented with either L-arginine (25 g/d) or L-glycine (43 g, which served as an isonitrogenous control). Over the 7 d of study, nitrogen balance was similar in the 2 groups but T-lymphocyte activation increased significantly in the arginine group at day 4 and 7 postoperatively, when compared with the glycine group. However, respiratory, infectious, and gastrointestinal complications were comparable in the 2 small groups of patients (Table 1). These same findings were rereported in a subsequent publication (24) that appeared 2 years later in the critical care literature.

Studying critically ill patients, Preiser and associates (27) focused their investigations in individuals receiving long-term enteral tube feedings. Of the 37 patients who completed the 7-d study, 20 received a formula enriched with free arginine (6.3 g/L) and 17 received an isocaloric and isonitrogenous arginine-free control solution. Blood and urine was obtained to determine the effects of arginine supplementation on nitric oxide production and amino acid concentrations.

The plasma concentrations of arginine and ornithine increased significantly in the arginine-supplemented group (from 55 ± 9 mmol/L to 102 ± 9 and from 57 ± 7 to 135 ± 11, respectively, mean ± SEM) and no alterations in these concentrations were detected in the patients who received the control formula. There were no differences between groups in either nitric oxide production or plasma phenylanlanine concentration (the latter used as an index of protein catabolism).

Several conclusions can be made from these studies of arginine supplemented enteral feedings. First, glycine was used in several studies as a control for arginine administration. Glycine has both metabolic and immunological effects and when administered in the large doses reported (e.g., 43 g/d) this substance should not be considered an inert control. This design flaw makes these studies extremely difficult to interpret because no true control data are available for comparison of the arginine effects. Secondly, no studies using arginine as a single supplement reported improved outcome, although increases in in vitro immunological functions were observed in studies in normal volunteers and in some, but not all, studies in patients. Lastly, a carefully performed metabolic study showed that enterally administered arginine was absorbed and appeared to be metabolized mainly to ornithine.

Arginine in the treatment of active tuberculosis

In a randomized double-blind study, adults with smear-positive tuberculosis were randomized to receive arginine or placebo in addition to conventional chemotherapy for 4 wk (28). The primary endpoints were conversion of sputum to negative status, weight gain, and improvement of symptoms. Biochemical endpoints were also monitored. A significant positive clinical response was noted in the HIV– patients who received the arginine supplement but not in the HIV+ supplemented patients. The authors conclude that this effect is likely mediated by the increased production of nitric oxide, which is known to be involved in the host defense against tuberculosis.

Arginine for the prevention of necrotizing enterocolitis in the premature infant

A significant number of premature infants develop inflammation of the intestinal tract, referred to as necrotizing enterocolitis (NEC), early in life. It has already been noted that many premature infants have low levels of arginine, and subsequent studies have associated low arginine plasma concentrations with NEC (29,30). To determine whether supplementation of arginine could reduce NEC in premature infants, Amin and associates studied 152 premature infants weighing <1250 g (31). The infants were prospectively randomized into 2 groups, one received arginine (1.5 mmol · kg^–1 · d^–1 equilivent to 261 mg · kg^–1 · d^–1) and the other a low arginine diet. The arginine was initially added to the parenteral feedings but when enteral feeds reached 40% of the infant’s requirement the arginine was given by the enteral route.

The patients were well matched on entry to the study and otherwise received comparable care. NEC developed in 5 infants receiving arginine and in 21 infants receiving placebo (P < 0.001). Arginine concentrations increased in the study group, but no other differences occurred between the 2 groups when comparing nutrient intake or plasma amino acid concentrations. Other complications were similar between the 2 groups, and this included the number of days required on a ventilator, the incidence of interventricular hemorrhage, and the occurrence of sepsis (Table 3).

Arginine supplementation in intravenous formulas

As previously noted, arginine is present in most balanced intravenous formulas, and represents about 10% of the amino acids infused; patients on average will receive about 10 g of arginine/d. Few long-term studies have been performed supplementing intravenous diets with arginine above these levels. Short-term studies have infused L-arginine at rates ranging between 0.5 and 0.525 g · kg^–1 · 30 min^–1, and investigators (33) have examined responses to these infusions in infants with persistent pulmonary hypertension and adults with salt sensitive and essential hypertension, to name a few of the many protocols reported in the literature.

Two investigations examined the effects of arginine supplementation in designing intravenous amino acid solutions. In a classic study by Vinners, Furst, and associates (34), the nutritive effects of nonessential amino acids were studied in normal individuals. These investigators found that arginine had the highest nutritive value of all nonessential amino acids tested, although it competed with lysine for renal excretion (a topic which will be discussed later). These investigators concluded that arginine should be included in balanced solutions to prevent hyperammonemia, and they recommended an infusion of 6 g/d.

In a more recent study, Berard et al. (35) infused a standard balanced amino acid solution to critically ill patients and then altered the solution composition based on variations in the plasma aminogram. The investigators found that variations in arginine concentrations after the initial 3 d of infusion of a balanced amino acid formula were always associated with abnormal variations in lysine concentrations. The data demonstrated that the excessive infusion of lysine impaired arginine metabolism and that by reducing the lysine supply the concentration of arginine would be normalized.

Three other arginine infusion studies deserve mention. Sigal et al. (20) infused 20 g of arginine hydrochloride daily (given with no other amino acids) into postoperative surgical patients for 7 d and compared the outcome to a matched group of patients receiving a balanced amino acid formula (Travasol; Baxter). The plasma arginine and ornithine levels rose in the arginine infusion group from 49 ± 16 to 228 ± 50 and from 31 ± 16 to 191 ± 76, respectively (mean ± SD), and did not change significantly in the controls. Nitrogen balance was similar in the 2 groups over the 7-day study period. Lymphocyte proliferation fell in both groups and there were no differences in immune responses between groups. Thus, when arginine was infused without adequate calories or other amino acids, no enhancement of mitogen-stimulated lymphocyte proliferation was observed.

In a somewhat similar study, Song and associates (36) monitored immune responses in patients with colorectal cancer undergoing resection. In the group receiving 20 g arginine supplemented in their parenteral nutrition, immune responses were improved compared to the nonsupplemented group. No outcome differences were noted.

In the third study (37), arginine and glutamate were added to standard nutritional solutions in an attempt to provide glutamine precursors. The amount of arginine present in the study solution was about 50% greater than that present in the control. Plasma concentrations of arginine increased in the supplemented group and there was a significant relation between concentrations of arginine and glutamine (r = 0.45, P < 0.01). This association was not found in the patients receiving the control solutions. During the study the incidence of infection increased from 7/20 to 8/20 in the group receiving the standard solution and from 3/17 to 8/17 in the patients receiving the enriched formula. The 28-d mortality was 6/17 in the control group and 8/20 in the arginine-enriched formula group.

In conclusion, a variety of infusion studies using supplemental arginine were performed but the outcome in seriously ill hospitalized patients was not altered.

The safety of arginine

Supplemental arginine has been provided in a variety of clinical situations, including administration to patients with cancer. Some animal studies suggest that arginine administration will reduce tumor growth. However this approach is controversial. In a human study, patients with breast cancer received either a standard diet or a diet containing supplemental arginine (30 g/d) for 3 d before operation (38). At the time of surgery, the rate of protein synthesis within the tumor was determined using stable isotope techniques and tumor tissue was stained to determine the presence of the activation antigen Ki67. The median rate of tumor protein synthesis was 10%/d in the control patients and 25.6% in patients receiving arginine supplements (P < 0.005). The rates of protein synthesis correlated with the Ki67 expression, confirming that tumor cells, rather than cellular infiltrate, accounted for the changes observed.

As a result of this and other data, one recent review (33) stated, "long-term data regarding the impact of arginine supplementation on mortality are not available. It has been suggested that this is probably a result of persistent concern about the possible promotion of tumor growth in some cases."

In work previously mentioned, Vinners and co-workers (34) examined the effect of arginine infusion along with other amino acids in normal individuals. With infusion of arginine at varying doses there was increased urinary excretion of the amino acid lysine. This occurred because arginine competed with lysine for tubular reabsorption and thus augmented the renal excretion of this particular amino acid. The infusion of about 10 g of arginine/d provoked the excretion of about 10% of the amount of lysine administered. Administration of large doses of arginine should not occur over the long term without consideration that imbalances of other amino acids may occur.

Finally, it is important to mention that immunomodulatory enteral diets containing arginine (about 12 g/L) and other supplements "may be associated with excess mortality in some subgroups of critically ill patients" (39). Those who have reviewed these data "hypothesize that systemic inflammation might be undesirably intensified by immune-enhancing nutrients like arginine in critically ill patients" and they recommend that patients with the inflammatory response syndrome should not receive immune-enhancing substrates (40). The data have recently been reviewed by a professional group who concluded that there was insufficient data to recommend that these enteral formulas containing agrinine and other immunoactive substances be administered to critically ill patients in intensive care units (41). Until more carefully executed studies are published, a strong clinical recommendation cannot be made at this time for delivering arginine-supplemented diets to seriously ill patients. Such immunomodulatory diets should only be administered to critically ill patients under carefully controlled circumstances with a process in place to objectively monitor toxicities and outcome.

	FOOTNOTES

 
¹ Prepared for the conference "Symposium on Arginine" held April 5–6, 2004 in Bermuda. The conference was sponsored in part by an educational grant from Ajinomoto USA, Inc. Conference proceedings are published as a supplement to The Journal of Nutrition. Guest Editors for the supplement were Sidney M. Morris, Jr., Joseph Loscalzo, Dennis Bier, and Wiley W. Souba.

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