Clinical Studies with Arginine in Patients at Risk of Sepsis and Septic Complications

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The first clinical study to demonstrate a benefit from supplemental dietary arginine in surgical patients was performed in 30 patients undergoing major operations for gastrointestinal malignancy (Daly et al., 1988). Patients were commenced on enteral feeding post-operatively and were randomized to receive either arginine (25 g day-1) or isonitrogenous glycine (43 g day-1) for 7 days. Arginine supplementation resulted in elevated plasma arginine and ornithine levels and was associated with an enhanced response of peripheral-blood lymphocytes to mitogens by day 7 and with an increased number of circulating CD4+ cells. Only the arginine-supplemented group achieved a positive nitrogen balance, which was attained by day 6 (Fig. 5.5). However, there was no difference in clinical outcome between the two groups.

CD4 (T-helper cell) expression



■ Arginine


. Glycine



T lymphocyte activation (Con A)

TD c

100 80 6040 20 0


- Arginine


- Glycine



Nitrogen balance s

Post-op days

Fig. 5.5. Some immunological and metabolic effects of supplemental arginine in patients undergoing surgery for upper gastrointestinal malignancy (adapted from Reynolds et al., 1990). Con A, concanavalin A.

At this time, two other dietary factors were emerging as playing an important role in modulating host defence - namely nucleotides and n-3 fatty acids. In mice fed nucleotide-free diets, supplemental RNA or uracil is required to restore cellular immunity, anti-fungal resistance, anti-bacterial resistance and, the bactericidal activity of macrophages (Van Buren et al., 1994). n-3 fatty acid supplementation, in clinical and laboratory studies, has been associated with improved survival after burn injury, reduced post-injury infectious complications and diminished immunosuppression secondary to transfusion (Daly et al., 1992). The proposed mechanisms of omega-3 fatty acid-induced improvements in immune function are related to an alteration of prostaglandin synthesis pathways from 2-series to 3-series prostaglandins (see Calder and Field, Chapter 4, this volume).

A study was therefore performed to examine the effect of enteral nutrition with supplemental arginine, RNA and n-3 fatty acids on immunological, metabolic and clinical outcome in patients after surgery (Daly et al., 1992). Eighty-five patients requiring operations for upper gastrointestinal malignancies were randomized to receive a supplemental diet (IMPACT®, Sandoz Nutrition, Minneapolis, Minnesota, USA) or a standard enteral diet. Patients receiving the supplemental diet had a significantly greater nitrogen balance over the course of the study. Lymphocyte mito-genesis was reduced in both groups in the immediate post-operative period but returned to normal levels only in the supplemented group, by post-operative day 7. Infectious and wound complications occurred less commonly in the supplemented than in the control group (11% vs. 37%; P = 0.02) and mean length of hospital stay was significantly shorter in the supplemented group. A subsequent study (Daly et al., 1995) used the same feeding protocol in 60 patients requiring surgery with or without adjuvant radiation/chemotherapy for upper gastrointestinal malignancy. Patients receiving the supplemental diet had fewer wound and infectious complications (10% vs. 43%; P < 0.05), and shorter length of hospital stay (16 vs. 22 days; P < 0.05) than patients receiving the standard enteral diet.

Since then, an increasing number of studies have been performed comparing immunonutrition (using one of the two formulas outlined in Table 5.1) to standard enteral feeding regimes in critically ill patients. In one of the largest such studies, a multicentre, prospective randomized trial compared early enteral nutrition by IMPACT® with standard enteral nutrition in 296 patients in intensive care units (Bower et al., 1995). While mortality rates and infectious complications were the same in the treatment groups, subgroup analysis showed two interesting results. First, the mean length of hospital stay of septic patients was significantly reduced (P < 0.05). Second, in the 100 patients who were able to complete the total planned intake of the enteral diet within the first 7 days, there was a significant reduction in infectious complications (0.54 ± 0.78 vs. 0.94 ± 0.87) between the supplemented and control groups.

Comparing the same feeding formula with standard enteral nutrition, Braga et al. (1998) looked at 60 patients undergoing surgery for malignancy. While there was no demonstrable difference in the incidence of infectious complications between the two groups, the infectious complications occurring in the patients receiving the supplemental diet were assessed as being significantly less severe.

Kudsk et al. (1996) prospectively randomized 35 severely injured trauma patients to an enteral diet containing glutamine, arginine, n-3 fatty acids and

Table 5.1. Compositions of two enteral feeding formulae.

Content 1000 kcal-1

Component IMPACT® Immun-Aid®

Table 5.1. Compositions of two enteral feeding formulae.

Content 1000 kcal-1

Component IMPACT® Immun-Aid®

Protein (g)



Free arginine (g)



Free glutamine (g)



Other free amino acids (g)



Nucleic acids (g)



Total fat (g)



n-3 fatty acids (g)



Vitamins and minerals

Selectively enriched above

100% US RDA

RDA, recommended daily allowance.

RDA, recommended daily allowance.

nucleotides (Immun-Aid®, McGaw, Irvine, California, USA) or to an isonitroge-nous, isocaloric diet to investigate the effect on septic outcome. Significantly fewer major infectious complications developed in patients who received the supplemental diet than in the control group (6% vs. 41%; P = 0.02). Hospital stay was also significantly shorter.

One study to date has shown improvement in the mortality rate in patients receiving immunonutrition (Galban et al., 2000). This was a prospective, randomized, multicentre study of 176 septic patients in intensive care units: 89 patients received IMPACT®, while 87 patients received a standard high-protein enteral feed. The mortality rate was reduced in the treatment group compared with the control group (17 of 89 vs. 28 of 87; P < 0.05), and this was most marked in moderately ill patients with APACHE (Acute Physiological and Chronic Health Evaluation) II scores between 10 and 15 (1 of 26 vs. 8 of 29; P = 0.02). There was also a significant difference in the incidence of bacteraemia between the two groups (7 of 89 vs. 19 of 87; P = 0.01) and in the number of patients developing more than one nosocomial infection (5 of 89 vs. 17 of 87; P = 0.02).

In a prospective, randomized, double-blind trial Senkal et al. (1999) examined the effects of IMPACT® enteral nutrition compared with the standard enteral diet, when commenced 5 days pre-operatively in patients with upper gastrointestinal-tract malignancy. These authors used as end-points the incidence of postoperative infectious complications, the cost of treating these complications, and the overall cost-effectiveness of immunonutrition. One hundred and fifty-four patients were eligible for analysis. The number of patients developing infectious complications after day 3 was significantly reduced in the immunonutrition group (7 of 78 vs. 16 of 76; P = 0.04), as was the total number of complication events (14 vs. 27; P = 0.05). While the total number of patients developing complications (10 of 78 vs. 18 of 76) and the mean length of stay (22.2 ±4.1 days vs. 25.8 ± 3.8 days) in the treated group were decreased, these values did not reach statistical significance (P = 0.08 and P = 0.09, respectively). Despite higher product costs, the savings accrued by a substantially lower complication rate led to better cost-effectiveness in the group receiving immunonutrition.

Atkinson et al. (1998) performed a prospective, randomized, double-blind, controlled clinical trial in a heterogeneous group of critically ill patients in an intensive care unit. Infectious complications were not reported in this study, but, in the subgroup of patients (n = 101) who successfully achieved early enteral nutrition (> 2.5 l in the first 72 h), there was a significant reduction in the requirement for mechanical ventilation and in the length of hospital stay in the immunonutrition group.

In a meta-analysis of 12 studies containing 1482 critically ill patients, Beale et al. (1999) sought to address the clinical benefits derived from immunonutri-tion (IMPACT® or Immun-Aid®) over standard enteral feeds. This detailed analysis found that there was no overall effect on mortality. However, there were significant reductions in infection rate (P = 0.006), ventilator days (P = 0.04) and length of hospital stay (P = 0.0002) in the immunonutrition group. These benefits were found to be most impressive among surgical patients.

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