Original Communication

European Journal of Clinical Nutrition (2003) 57, 31–36. doi:10.1038/sj.ejcn.1601517

Oral glutamine in paediatric oncology patients: a dose finding study

E Ward2,*,, S Picton1,*,, U Reid1,, D Thomas1,, C Gardener1,, M Smith3,, M Henderson3,, V Holden4,, S Kinsey1, I Lewis1 and V Allgar5,

  1. 1Yorkshire Regional Centre for Paediatric Oncology and Haematology, Leeds, UK
  2. 2Dietetic Department, St James's University Hospital, Leeds, UK
  3. 3Chemical Pathology Department, St James's University Hospital, Leeds, UK
  4. 4Pharmacy Department, St James's University Hospital, Leeds, UK
  5. 5Research and Development Department, St James's University Hospital, Leeds, UK

Correspondence: E Ward, Paediatric Dietician, Dietetic Department, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK. E-mail: paediatric_dietitian.sjuh@leedsth.nhs.uk

*Guarantor: S Picton and E Ward.

Contributors: EW initiated this study. The study design was developed in discussions involving the first 10 investigators. EW, UR, DT, CG and MS conducted the study. Data analysis was done by VA. All investigators were involved in discussions on data interpretation. The paper was written by EW and SP with contribution from MH.

Received 13 July 2001; Revised 12 April 2002; Accepted 18 April 2002.

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Abstract

Objective: The purpose of this study was to determine the most appropriate dose of oral glutamine to use in a further clinical study in paediatric oncology patients.

Design: This was a phase I, pharmokinetic study.

Setting: The study was carried out at The Yorkshire Regional Centre for Paediatric Oncology and Haematology, St James's University Hospital, Leeds, UK.

Subjects: Thirteen patients undergoing treatment for paediatric malignancy participated in this study. All 13 completed the study.

Interventions: The most appropriate dose was determined by patient acceptability and by plasma glutamine and ammonia levels measured at timed intervals after ingestion of a single glutamine dose.

Results: Doses of 0.35, 0.5 and 0.65 g/kg were well tolerated with no untoward plasma glutamine and ammonia levels. One patient was recruited to a higher dose of 0.75 g/kg, but the plasma glutamine and ammonia levels peaked at 2601 and 155 micromol/l, respectively. The ammonia level was greater than the acceptable upper limit. It was difficult to disperse the glutamine adequately at this dose, resulting in the suspension being found to be unpalatable and therefore no further patients were recruited at this dose.

Conclusion: It was concluded that 0.65 g/kg is a safe dose of glutamine to use in a clinical study in paediatric oncology patients.

Sponsorship: Scientific Hospital Supplies UK Ltd provided the L-glutamine and financial help for the biochemical analysis.

Keywords:

mucositis, glutamine, ammonia, child, oncology

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Introduction

Glutamine is a major fuel and important nitrogen source for enterocytes and plays a key role in maintaining mucosal cell integrity and gut barrier function (van Acker et al, 1999; Rhoads, 1999; Buchman, 1996; Hall et al, 1996; Gardiner et al, 1995; Lacey & Wilmore, 1990; Miller, 1999).

Many chemotherapy drugs, in particular anthracyclines, actinomycin and high-dose methotrexate, result in both structural and functional injuries to the gastrointestinal tract (Sweetenham et al, 1989; Lind, 1995) resulting in mucositis severe enough to prevent an adequate oral intake. It is therefore frequently necessary to support the patient with parenteral nutrition which is associated with a decreased enzyme activity and an increased intestinal permeability, potentially leading to an increased risk of bacteraemia and endotoxaemia (Guedon et al, 1986; Buchman et al, 1995).

Although animal data on the effects of glutamine supplementation are fairly extensive (Fox et al, 1987, 1988, 1989; Burke et al, 1989; Jacobs et al, 1987; Wang et al, 1988) clinical studies are still quite limited (Smith, 1997). However, no toxic effects of glutamine given either parenterally or enterally have been demonstrated (Ziegler et al, 1992; van Zaanen et al, 1994; Skubitz & Anderson, 1996). Glutamine added to parenteral nutrition has been shown to help prevent intestinal atrophy and to maintain gut integrity (Tremel et al, 1994; van der Hulst et al, 1993). Studies in adult oncology patients have shown that glutamine given orally is well tolerated (Skubitz & Anderson, 1996; Jebb et al, 1995; Schloerb & Skikne, 1999). In one such study a significant decrease in the severity of chemotherapy induced stomatitis was seen using a 'swish and swallow' technique (Skubitz & Anderson, 1996). Doses of glutamine given to adult patients vary from 0.2 to 0.57 g glutamine/kg/day (Ziegler et al, 1992; Skubitz & Anderson, 1996; Jebb et al, 1995; Schloerb & Skikne, 1999). There is only one published study of oral glutamine involving paediatric oncology patients (Anderson et al, 1998). In this randomized double-blind cross-over study 16 children were given a much smaller dose of 2 g/m2 glutamine or placebo twice daily for 14 days. There was a significant reduction in the duration and severity of chemotherapy-associated stomatitis. This study also demonstrated that glutamine is well tolerated at this dose (Anderson et al, 1998).

In children the maximum tolerated dose of glutamine has not been determined. The aim of this study was to establish the most appropriate dose of glutamine which would then be used in a clinical study of efficacy during chemotherapy. The planned study would determine whether glutamine is effective in reducing the incidence and severity of mucositis in certain groups of at risk paediatric oncology patients.

The starting dose of glutamine chosen was 0.35 g/kg, which was within the range most commonly used in adult studies (Ziegler et al, 1992; Skubitz & Anderson, 1996; Jebb et al, 1995; Schloerb & Skikne, 1999).

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Materials and methods

Subjects

Thirteen patients undergoing treatment for paediatric malignancy participated in this initial dose-finding study. Informed consent was obtained from their parents and the study was approved by the local research ethics committee.

All patients were currently undergoing chemotherapy according to national agreed treatment protocols (MRC and UKCCSG) with the exception of one patient, who had just completed treatment for acute lymphoblastic leukaemia within the last month.

Glutamine administration

The patients were fasted for at least 2 h prior to taking the oral dose of glutamine during the morning of the test. The oral glutamine was administered as one oral dose mixed with sterile water at a maximum concentration of 10 g/100 ml water and a total volume of not more than 300 ml. This was flavoured with fruit squash (not fruit juice due to its acidity). As the glutamine did not dissolve completely at high concentration in water a 'swish and swallow' technique of the glutamine suspension was advised. Patient acceptability was recorded by the investigator. If the child already had a nasogastric tube in situ then the glutamine dose was given via the nasogastric tube. Whether taking orally or nasogastrically the dose was given over 15 min maximum. The initial dose of glutamine was 0.35 g/kg. The plan was for the dose escalation to take place in increments of 0.15 g/kg if three patients at each dose level had tolerated the glutamine. Glutamine tolerability was assessed by measurement of plasma glutamine and ammonia levels pre glutamine administration and at the following time intervals following glutamine ingestion: 15, 30, 45, 60, 90, 120, 240 and 360 min. If all three patients at each dose level found the suspension tolerable and had a plasma ammonia of less than 150 micromol/l, the following three patients would be given the next dose level. Dose escalation would cease if any two patients had high plasma ammonia levels or if the patients found the glutamine too unpalatable. If one of the first three patients in the 0.35 g/kg group had a high plasma ammonia level the dose of glutamine would be reduced by 0.15 g/kg increments.

Blood sampling and handling

All blood samples were taken by accessing the patient's central line. Due to the instability of glutamine in blood samples, the samples were deproteinized using 10% sulphosalicylic acid and equal volumes of solution containing norleucine and centrifuged immediately. The supernatant was frozen prior to analysis by automated ion exchange chromatography (Pharmacia biochrom 20). The ammonia samples were analysed immediately on the ward (Dic Kyoto Daiiche ammonia checker II model A.A. 4120).

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Results

Eleven of the 13 subjects drank the glutamine dose. Two patients had nasogastric tubes in situ and therefore the glutamine was given nasogastrically and the tubes were flushed well afterwards. Table 1 consists of a description of the patients and the dose of glutamine received. The glutamine was well tolerated by those subjects who took it orally up to the 0.65 g/kg dose level. There were similarly no problems with nasogastric administration. At the 0.5 g/kg dose level one subject vomited at the same time that his ammonia level peaked at 139 micromol/l. The ammonia level subsequently returned to its baseline level and he had no other symptoms. However as a precaution it was felt necessary to recruit a further three subjects to this dose level. Only one subject was included in the 0.75 g/kg dose level mainly due to problems with dispersing the glutamine in an acceptable oral volume. The patient did not tolerate the dose well because of the consistency. He vomited and both his plasma ammonia and glutamine levels continued to rise up to 120 min after taking the glutamine dose and the ammonia level reached above the maximum acceptable level of 150 micromol/l. The study was therefore closed. Table 2 shows the mean (plusminuss.e.m.) and range of the peak levels, time of the peak levels and the area under the curve (AUC) for the first three dose levels.



Figure 1 shows the mean (plusminuss.e.m.) plasma ammonia level at each dose level. As only one subject was included in the 0.75 g/kg dose there is no mean (plusminuss.e.m.) for this dose. Figure 2 shows the mean (plusminuss.e.m.) plasma glutamine level at each dose level. Similarly, as only one subject was included in the 0.75 g/kg dose, there is no mean (plusminuss.e.m.) for this dose.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Plasma Ammonia Levels (meanplusminuss.e.)

Full figure and legend (23K)

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Plasma Glutamine Level (meanplusminuss.e.)

Full figure and legend (27K)

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Discussion

The aim of the study was to establish the maximum tolerated dose of glutamine in children undergoing treatment with chemotherapy. Although ammonia derived from glutamine is excreted as ammonium via the kidneys or converted to urea in the liver with the liver also mopping up ammonia from both the systemic and portal circulations (Hall et al, 1996; Meijer et al, 1990; Bode & Souba, 1999), one concern was that hyperammonaemia might be an untoward complication, particularly in patients receiving chemotherapy due to the possibility of potential hepatorenal toxicity. It is difficult to define a safe upper limit for blood ammonia. There is a poor correlation between ammonia concentration and the severity of neurological symptoms in patients with Reye's syndrome, inborn errors of metabolism or severe liver disease. The limit of 150 micromol/l was chosen as an acceptable upper limit because premature infants, who are more vulnerable to toxins in general, commonly tolerate plasma ammonia levels up to this level without long-term ill effects (Green, 1988).

All the patients recruited to the study had liver function tests within normal range as defined by National Cancer Institute Common Toxicity Criteria.

The glutamine was well tolerated at the 0.35, 0.5 and the 0.65 g/kg with the plasma glutamine and ammonia comparing favourably with other studies of the safety and metabolic effects of glutamine (Ziegler et al, 1990, 1992). The subject who received the highest dose of 0.75 g/kg found the consistency unacceptable and he vomited at the time of the peak ammonia level. Both his ammonia and glutamine level only started to fall 120 min after taking the glutamine dose. This was prolonged compared with other studies of lower-dose glutamine in which the plasma glutamine level generally peaked at 30–45 min post administration of the oral test dose and then declined steadily to normal range within 90–120 min (Ziegler et al, 1990). The peak level of ammonia was also much higher than previously seen (Ziegler et al, 1990). It was not feasible to prove the dose-limiting toxicity in more patients because only one patient was recruited at the highest dose. However a combination of a high ammonia level for a prolonged period and the poor acceptability of the suspension resulted in the study being stopped.

The 11 subjects who drank the test doses found the actual taste of the solution acceptable. The main drawback was the 'grittiness' of the solution. Because of the poor solubility of glutamine it would have been necessary to add 150 ml of sterile water per 5 g of L-glutamine in order to dissolve it completely. This was the main drawback to the study as the doses were escalated because the volume of water would have been unacceptably great. Therefore the aim was not to dissolve the solution completely but to disperse it sufficiently so that after the solution had been swirled around in the cup prior to taking the last mouthful there would be no glutamine particles remaining in the cup once the dose had been swallowed. In order to achieve this the glutamine needed to be mixed in 100 ml of sterile water per 10 g of L-glutamine. This corresponds to the dilution used by Schloerb and Skikne (1999). The maximum acceptable volume of suspension was 300 ml in the larger patients taking the higher doses of glutamine. At the highest dose of 0.75 g/kg it was impossible to disperse the glutamine adequately in 300 ml and therefore the subject may not have actually receive the full dose. Hence the main reason for not recruiting any more subjects at this dose level was purely practical in that it was not possible to mix this dose adequately in 300 ml of water or less and guarantee that no glutamine particles would be left in the cup.

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Conclusion

It was therefore concluded that 0.65 g/kg of L-glutamine is a safe dose to be used in a clinical study and is acceptable in this group of subjects because it mixed adequately into a solution of 300 ml or less. The pharmokinetic results confirmed that this dose level was well tolerated with both the plasma ammonia and plasma glutamine levels peaking between 30 and 90 min and returning to normal levels by 360 min after the oral dose.

The aim of future studies is therefore to use 0.65 g/kg of glutamine/day in a clinical setting to determine whether or not it is effective in reducing the incidence and severity of mucositis of paediatric oncology patients when given alongside chemotherapy.

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Acknowledgements

We are grateful to SHS International for providing the L-glutamine and financial help for the biochemical analysis.

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