What are the potential adverse effects of glutamine (glutamine) supplementation in pediatric patients?

Adverse Effects of Glutamine in Children

Glutamine supplementation should not be routinely used in infants and children up to age 2 years, and is not recommended for children with septic shock or sepsis-associated organ dysfunction, as current evidence shows no clinical benefit and raises concerns about potential adverse effects including elevated ammonia levels and neurological risks. 1

Guideline-Based Recommendations Against Routine Use

Infants and Young Children (≤2 years)

• The ESPGHAN/ESPEN/ESPR/CSPEN guidelines provide a strong recommendation (Grade A, Level 1++) against additional glutamine supplementation in infants and children up to age 2 years. 1
• Systematic reviews demonstrate no evidence from randomized trials supporting routine glutamine use in infants for reducing sepsis, mortality, or improving growth outcomes. 1
• Ten days of glutamine supplementation in very-low-birth-weight infants resulted in higher plasma glutamine levels, but ammonia levels were not increased in this short-term study—however, longer-term safety data are lacking. 1

Critically Ill Children with Sepsis

• The Surviving Sepsis Campaign 2020 guidelines suggest against glutamine supplementation in children with septic shock or sepsis-associated organ dysfunction (weak recommendation, low quality evidence). 1
• This recommendation applies regardless of the route of administration (enteral or parenteral). 1

Documented and Theoretical Adverse Effects

Neurological Concerns

• Glutamine is metabolized to glutamate and ammonia, both of which have known neurological effects, making psychological and behavioral monitoring especially important. 2
• High protein intake has been shown to result in neurological damage in preterm infants, and individual amino acids cause various adverse effects with neurological manifestations being most frequently observed. 2
• Safety studies have not fully evaluated chronic consumption by healthy subjects across all pediatric age groups. 2

Metabolic Effects

• While one small study showed glutamine supplementation (10.8 mg/kg/day) decreased liver enzymes and ammonia concentrations in some infants receiving parenteral nutrition, this was a short-term study and anecdotal evidence only suggests potential benefits for elevated liver enzymes. 1
• The concern remains that glutamine metabolism produces ammonia, which could theoretically accumulate with prolonged supplementation. 2

Gastrointestinal Disease

• In young infants with severe gastrointestinal disease, meta-analysis of two trials (100 infants total) found no statistically significant difference in death risk or invasive infection rates with glutamine supplementation. 3
• Available data are insufficient to determine whether glutamine has important benefits for young infants with severe gastrointestinal disease. 3

Limited Evidence of Safety in Specific Populations

Potential Benefits in Select Contexts (Not Routine Use)

• In children undergoing hematopoietic stem cell transplant, one small case-control study (41 patients) showed glutamine reduced fever duration and sinusoidal obstruction syndrome incidence, with a trend toward reduced severe mucositis. 4
• In children with solid tumors receiving chemotherapy, oral glutamine (4 g/m²/day for 5 days) showed improvements in some nutritional and immunological parameters in a small study (21 children). 5
• However, these specialized oncology contexts do not support routine use, and the studies were too small to establish definitive safety profiles. 4, 5

Older Children with Sickle Cell Disease

• L-glutamine (Endari) may reduce pain events in children ≥5 years with sickle cell disease, though the mechanism is poorly understood and may involve reducing oxidative stress. 1
• This represents a specific FDA-approved indication, not routine supplementation. 1

Critical Safety Gaps

• The literature review on glutamine supplementation in pediatric patients reveals conflicting studies, partly due to different effects of enteral versus parenteral administration, with insufficient evidence overall. 6
• Methodological issues have been noted in multiple studies, and further mechanistic data along with large randomized controlled trials are needed in select populations. 6
• Only four studies have specifically addressed glutamine safety, concluding it is safe in adults and preterm infants, but chronic consumption safety data across all pediatric age groups remain inadequate. 2

Clinical Pitfalls to Avoid

• Do not use glutamine supplementation routinely in critically ill children, as guidelines explicitly recommend against this practice. 1
• Avoid glutamine in infants and children under 2 years outside of specific parenteral nutrition formulations where it may already be included. 1
• Be aware that while acute toxicity appears low in short-term studies, neurological monitoring may be warranted given glutamine's metabolism to neurotoxic compounds. 2
• Recognize that specialized uses (HSCT, chemotherapy, sickle cell disease ≥5 years) require medical supervision and do not translate to general pediatric supplementation. 1, 4, 5