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Parenteral Glutamine Supplementation Does Not Reduce the Risk of Mortality or Late-Onset Sepsis in Extremely Low Birth Weight Infants

Brenda B. Poindexter, MD^*, Richard A. Ehrenkranz, MD, Barbara J. Stoll, MD, Linda L. Wright, MD^||, W. Kenneth Poole, PhD^¶, William Oh, MD^#, Charles R. Bauer, MD^**, Lu-Ann Papile, MD, Jon E. Tyson, MD, MPH, Waldemar A. Carlo, MD^||||, Abbot R. Laptook, MD^¶¶, Vivek Narendran, MD, MRCP^##, David K. Stevenson, MD^***, Avroy A. Fanaroff, MB, BCh, Sheldon B. Korones, MD, Seetha Shankaran, MD^||||||, Neil N. Finer, MD^¶¶¶, James A. Lemons, MD^* and for the National Institute of Child Health and Human Development Neonatal Research Network

^* Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
^|| National Institute of Child Health and Human Development, Bethesda, Maryland
^¶ Research Triangle Institute, Research Triangle Park, North Carolina
^# Department of Pediatrics, Brown University, Providence, Rhode Island
^** Department of Pediatrics, University of Miami, Miami, Florida
Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, New Mexico
Center for Clinical Research and Evidence Based Medicine, University of Texas Health Science Center at Houston Medical School, Houston, Texas
^|||| Department of Pediatrics, University of Alabama, Birmingham, Alabama
^¶¶ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas
^## Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio
^*** Division of Neonatology, Stanford University Medical Center, Palo Alto, California
Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio
The Newborn Center, University of Tennessee, Memphis, Tennessee
^|||||| Division of Neonatology and Perinatal Medicine, Wayne State University, Detroit, Michigan
^¶¶¶ University of California at San Diego Medical Center, University of California, San Diego, California

ABSTRACT

Background. Glutamine is one of the most abundant amino acids in both plasma and human milk, yet it is not included in standard intravenous amino acid solutions. Previous studies have suggested that parenteral nutrition (PN) supplemented with glutamine may reduce sepsis and mortality in critically ill adults. Whether glutamine supplementation would provide a similar benefit to extremely low birth weight (ELBW) infants is not known.

Methods. We performed a multicenter, randomized, double-masked, clinical trial to assess the safety and efficacy of early PN supplemented with glutamine in decreasing the risk of death or late-onset sepsis in ELBW infants. Infants 401 to 1000 g were randomized within 72 hours of birth to receive either TrophAmine (control) or an isonitrogenous study amino acid solution with 20% glutamine whenever they received PN up to 120 days of age, death, or discharge from the hospital. The primary outcome was death or late-onset sepsis.

Results. Of the 721 infants who were assigned to glutamine supplementation, 370 (51%) died or developed late-onset sepsis, as compared with 343 of the 712 infants (48%) assigned to control (relative risk: 1.07; 95% confidence interval: 0.97–1.17). Glutamine had no effect on tolerance of enteral feeds, necrotizing enterocolitis, or growth. No significant adverse events were observed with glutamine supplementation.

Conclusions. Parenteral glutamine supplementation as studied did not decrease mortality or the incidence of late-onset sepsis in ELBW infants. Consequently, although no harm was demonstrated, routine use of parenteral glutamine supplementation cannot be recommended in this population.

Key Words: glutamine • parenteral nutrition • extremely low birth weight infants • randomized clinical trial

Abbreviations: PN, parenteral nutrition • ELBW, extremely low birth weight • RR, relative risk • CI, confidence interval

Although glutamine is the most abundant amino acid in both plasma and human milk,¹ it is not included in standard intravenous amino acid solutions because of its limited stability in solution and the assumption that it is a nonessential amino acid. Previous studies in animals and critically ill adults have suggested that parenteral nutrition (PN) supplemented with glutamine reduces the risk of sepsis and mortality.^2,3 However, it is unclear whether parenteral glutamine supplementation would provide a similar benefit to premature infants.

We conducted a multicenter, randomized, double-masked clinical trial to determine the efficacy and safety of parenteral glutamine supplementation in extremely low birth weight (ELBW) infants (birth weight 1000 g). Our primary hypothesis was that parenteral glutamine supplementation would decrease the risk of death or late-onset sepsis.

METHODS

Study Infants
Inclusion criteria were a birth weight of 401 to 1000 g and the presence of intravenous access. To facilitate early initiation of PN, we enrolled all infants within 72 hours after birth. We excluded infants with major congenital anomalies, those with congenital nonbacterial infection, those thought to have a terminal illness (as indicated by a pH <6.80 or the presence of hypoxia with bradycardia for >2 hours), and those for whom a decision had been made not to provide full support. The study was conducted at 15 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network (see Appendix 1) between October 1999 and August 2001. The institutional review board at each center approved the study protocol, and written, informed consent was obtained from a parent of each infant.

Intervention
Infants in the control group received TrophAmine (B Braun, Irvine, CA) as their intravenous amino acid solution, and infants in the glutamine group received an isonitrogenous study amino acid solution with 20% glutamine, which consisted of TrophAmine and nonpyrogenic L-glutamine powder (Ajinomoto, Raleigh, NC). A US Food and Drug Administration-approved drug manufacturer compounded the study amino acid solution under controlled, clean-room conditions (Central Admixture Pharmacy Services, Inc, Irvine, CA). Before beginning the study, both Central Admixture Pharmacy Services and the laboratory at Indiana University School of Medicine documented sterility and stability of the glutamine-enriched amino acid solution to 17 weeks. The hospital pharmacist labeled all bags of PN with the final amino acid concentration. Research nurses recorded the volume of PN that the infant received on a daily basis, thereby permitting calculation of actual amino acid intake. The glutamine-enriched solution was visually indistinguishable from standard PN; consequently, caregivers were masked to the treatment group. A standard dose of cysteine hydrochloride (40 mg/g amino acid; 120 mg/kg per day maximum)^4,5 was added to the final compounded bag of PN in both groups.

Although the study protocol specified guidelines for the use of PN, including early initiation and rapid advancement of amino acid intake to 3 to 3.5 g/kg per day, the neonatologist caring for the infant determined the appropriateness of and final prescription for the total PN and made all decisions related to the introduction and advancement of enteral feeds. Infants received study PN and were followed until they were discharged from the hospital, died, or reached 120 days of age, whichever came first.

Outcomes
The primary outcome was the composite of death or late-onset sepsis (positive blood or cerebrospinal fluid culture for bacteria or fungi obtained after 72 hours of age in the presence of compatible clinical signs of septicemia). Secondary outcomes included the number of episodes of late-onset sepsis, incidence of proven necrotizing enterocolitis,⁶ days on the ventilator, length of hospital stay, tolerance of enteral feeds (full enteral feeds were defined as receiving 110 kcal/kg per day enterally), feeding intolerance (defined by the need to hold enteral feeds 24 hours), total duration of PN, and growth. To monitor safety, we also recorded laboratory values from routine PN monitoring when obtained. In addition, plasma amino acid and ammonia concentrations were obtained and centrally analyzed in the first 10 infants enrolled at each center before initiation of study PN and again after receiving study PN for 10 days.⁷ Research nurses collected all study data using defined criteria and standardized study forms; all data were subsequently transmitted electronically to the central data-coordinating center.

Statistical Analysis
The study was designed to identify a 20% relative reduction in mortality or late-onset sepsis with 80% power and a 2-tailed type I error of 0.05. Assuming a 35% incidence of death or late-onset sepsis among 1000-g birth weight infants,⁸ we calculated that 690 infants per group would be required.

Data were analyzed by using SAS software (SAS Institute Inc, Cary, NC). The analysis of the differences in baseline characteristics used the Wilcoxon rank sum test for continuous variables and Fisher’s exact or ² tests for categorical variables. The 2 groups were compared according to the intention to treat. Primary outcome measures were adjusted for center and birth weight stratum.

An independent data monitoring committee used the Lan-DeMets procedure⁹ with an O’Brien-Fleming spending function¹⁰ to assess efficacy. Two interim analyses were performed at the predetermined intervals of 25% and 50% of targeted enrollment.

RESULTS

Study Infants and Intervention
The numbers of infants who were screened and randomized are shown in Fig 1. A total of 1433 infants were randomized; the baseline characteristics of the infants in the 2 groups were similar (Table 1). Timing and characteristics of PN administration are shown in Table 2. Parenteral amino acid intake over the first 14 days of the study and the day of life of first receipt of a minimum of 3 g/kg per day of intravenous amino acids were similar between the 2 groups.

View larger version (28K): [in this window] [in a new window]   Fig. 1. ELBW infants (401–1000 g) screened and randomly assigned to the glutamine and standard PN groups.

DISCUSSION

This is the first large, randomized, double-masked, multicenter trial of parenteral glutamine in ELBW infants. Previous data in critically ill adults and animal models suggest that glutamine may have an important role in reducing the risk of death and infection by enhancing immune function and gut integrity. Thus, glutamine supplementation is an attractive potential therapy for extremely premature infants who undergo extreme increases in metabolic demand and are at high risk for infection and feeding complications in the neonatal period. Clinical use of parenteral glutamine has been limited to date because of problems with solubility. In this trial, we overcame problems associated with glutamine instability in PN and increased plasma glutamine concentrations in extremely preterm infants without apparent biochemical risk, but we were unable to demonstrate a reduction in the risk of death or late-onset sepsis. Thus, routine use of parenteral glutamine as administered in this study in ELBW infants cannot be recommended.

Glutamine has several unique properties that suggest an important role in immunity, metabolism, and intestinal function. It is the most abundant amino acid in human plasma and milk,¹ and, in utero, is taken up by the developing mammalian fetus in greater quantity than any other amino acid.¹¹ Although glutamine is not an essential amino acid, there is growing evidence that the capacity to adequately increase de novo glutamine synthesis may be challenged during stress and critical illness.¹² In addition, glutamine is consumed as a primary substrate in large quantity by replicating cells including lymphocytes, fibroblasts, enterocytes, and tumor cells.^13–15 These properties provide strong rationale for the studies of glutamine supplementation in critically ill adults and animal models, many of which have demonstrated improved survival and decreased infection.^2,3,16,17 Furthermore, in both human and animal investigations, glutamine has been found to enhance gut integrity, improve gut immune function, and decrease bacterial translocation.

Placental supply of glutamine is terminated abruptly by preterm birth, and glutamine is not present in currently available amino acid solutions. One previous study in premature infants, although limited by a small sample size, suggested shorter time to reach full enteral feedings, fewer days on PN, and a tendency toward shorter length of hospital stay in a <800-g birth weight cohort of infants who received parenteral glutamine supplementation.¹⁸ In addition, a small trial of enteral glutamine supplementation in premature infants demonstrated a decreased incidence of sepsis and improved tolerance of enteral feedings.¹⁹

We designed a trial of early parenteral glutamine rather than a trial of enteral glutamine for several reasons. Our previous research indicated that extremely preterm infants are at the highest risk for death and late-onset sepsis in the first month of life.^8,20 A parenteral route ensured early and constant provision of glutamine to our extremely premature patients, who depended on the parenteral route of nutrition for an average of 30 days after birth. Parenteral glutamine also allowed us to avoid the confounding that would have resulted from practice variability associated with enteral feedings and the high concentration of glutamine in human milk.

Given the overwhelming evidence that early provision of intravenous amino acids can limit catabolism in extremely premature infants,^21,22 our goal was early, aggressive delivery of intravenous amino acids. Although this trial resulted in earlier amino acid delivery at most of the participating centers, infants in both groups, on average, did not receive 3 g/kg per day of amino acids until 10 days of age. By this point in time, most also were receiving small volumes of enteral feeds; therefore, it is possible that we did not consistently deliver a sufficient dose of glutamine to demonstrate an effect in this high-risk group. Conversely, plasma glutamine concentrations increased significantly in infants in the glutamine group and were comparable to healthy, breastfed, term infants²³ and to the level achieved in a previous clinical trial of glutamine supplementation in premature infants.¹⁸ Because PN was continued for the first month of life in the vast majority of infants, it is unlikely that the duration of supplementation is responsible for the negative results.

Given the near-linear relationship between nitrogen intake and nitrogen retention, the study amino acid solution was designed to be isonitrogenous with TrophAmine. Consequently, the substitution of 20% of the standard amino acids with glutamine may have unmasked other limitations in the currently available solutions. Although there was no difference in the plasma concentration of total essential amino acids between the groups, infants in the glutamine group had a significantly greater decrease in plasma tyrosine (widely considered to be conditionally essential in premature infants) in response to study PN than did the control group.⁷ However, there was no change in whole-body protein synthesis or turnover in a subset of infants,²⁴ and there was no difference in weight at 36 weeks’ postmenstrual age between the groups, suggesting that overall amino acid supply was not limited by the substitution with 20% glutamine in the study amino acid solution.

Although we hypothesized that the infants who received parenteral glutamine would require fewer days on PN because of enhanced gut integrity and decreased bacterial translocation through the gut, the trend in the current study was that the infants who received glutamine actually required more days of PN support. In contrast to adults, it is possible that an enteral intervention is necessary to enhance gut integrity in premature infants. This concept is supported by the protective effect of breast milk against necrotizing enterocolitis.²⁵ However, Vaughn et al²⁶ recently completed a randomized trial of enteral glutamine supplementation in 649 infants with birth weights between 500 and 1250 g and found no reduction in nosocomial sepsis in the infants who received glutamine.

The obvious question is: Why are our findings in contrast to previous studies, particularly the large, randomized, clinical trials in bone marrow transplant recipients and critically ill adults? We chose to enroll extremely premature infants, because this population is at significant risk of mortality and morbidity from late-onset sepsis.⁸ However, the organisms responsible for sepsis in neonates are different from those in adults. It is possible also that deficiencies in the immune system predisposing premature neonates to sepsis may not be amenable to a nutritional intervention such as glutamine supplementation.

Developmental differences between adults and immature neonates also may have contributed to the different outcome in our population. The pathophysiology of illness and the ability to compensate for glutamine deficiency may be different in these groups. The amino acid solutions used in the current study supplied glutamate (as did the clinical trials in adults). To the extent that glutamate is converted to glutamine, these patients may not have been truly glutamine deficient, particularly because PN was initiated so early. This would be in contrast to the studies in adults, in which the subjects were nutritionally depleted and catabolic. In addition, our study design was a preventative measure, whereas the majority of the adult trials enrolled critically ill subjects.

Although parenteral glutamine supplementation seems to be well tolerated in extremely premature neonates, we cannot advocate its routine use currently, given the lack of clinical efficacy in this randomized, clinical trial. Future studies are needed to determine whether glutamine supplementation may be of benefit to other subsets of critically ill neonates.

ACKNOWLEDGMENTS

This work was supported by cooperative agreements with the National Institute of Child Health and Human Development (U10 HD27856 [Dr Lemons], U10 HD27871 [Dr Ehrenkranz], U10 HD27851 [Dr Stoll], U10 HD36790 [Dr Poole], U10 HD27904 [Dr Oh], U10 HD21397 [Dr Bauer], U10 HD27881 [Dr Papile], U10 HD21373 [Dr Tyson], U10 HD34216 [Dr Carlo], U10 HD40689 [Dr Laptook], U10 HD27853 [Dr Donovan], U10 HD27880 [Dr Stevenson], U10 HD21364 [Dr Fanaroff], U10 HD21415 [Dr Korones], U10 HD21385 [Dr Shankaran], and U10 HD40461 [Dr Finer]) and General Clinical Research Centers grants M01 RR00750 (Indiana University), M01 RR 06022 (Yale University), M01 RR 00997 (University of New Mexico), M01 RR08084 (University of Cincinnati), and M01 RR00070 (Stanford University).

We are indebted to Drs Gordon Avery, Mary D’Alton, John Fletcher, Christine Gleason, Maureen Maguire, Carol Redmond, Charlotte Catz, and William Heird for their contribution as members of the data and safety monitoring committee; to Lisa Wrage for assistance with the statistical analyses; and to our medical and nursing colleagues and the infants and their parents, who participated in the study.

FOOTNOTES

Received for publication May 15, 2003; Accepted Jul 23, 2003.

Reprint requests to (B.B.P.) Riley Hospital for Children, 699 West Dr, RR 208, Indianapolis, IN 46202-5210. E-mail: bpoindex{at}iupui.edu

This work was presented in part at the Pediatric Academic Societies’ Annual Meeting, Baltimore, MD, May 5, 2002.

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This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via ISI Web of Science (30) Citing Articles via Google Scholar Google Scholar Articles by Poindexter, B. B. Search for Related Content PubMed PubMed Citation Articles by Poindexter, B. B. Related Collections Nutrition & Metabolism Related AAP Red Book topics: Yersinia enterocolitica and...

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