Murray & Pindoria-2014

Nutrition support for bone marrow transplant patients

(Review)

Murray SM, Pindoria S

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2009, Issue 1

http://www.thecochranelibrary.com

Nutrition support for bone marrow transplant patients (Review)

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 1 Mean duration (+/-SD) of time in

hospital (e.g. admission to discharge or from day ’0’ to discharge).. . . . . . . . . . . . . . . . 37

Analysis 1.2. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 2 Mean(+/-SD) number of days patients

had some degree of mucositis from start to end of study.. . . . . . . . . . . . . . . . . . . . 38

Analysis 1.3. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 3 Number of patients who developed

line infections from start to end of study.. . . . . . . . . . . . . . . . . . . . . . . . . 39

Analysis 1.4. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 4 Difference in mean % change in body

weight from start to end of the study between the trial groups.. . . . . . . . . . . . . . . . . . 40

Analysis 1.5. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 5 Mean duration (+/-SD) that nutritional

intervention is given as PN.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Analysis 1.6. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 6 Number of patients who developed >

grade 2 graft versus host disease (GVHD).. . . . . . . . . . . . . . . . . . . . . . . . . 42

Analysis 1.7. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 7 Number of days(+/-SD) to achieve

normal neutrophil level (>0.5 X 10/9/l) after day 0 of BMT.. . . . . . . . . . . . . . . . . . 43

Analysis 1.8. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 8 Actual numbers of patients who have

completed the study and survived to the 100th day post BMT.. . . . . . . . . . . . . . . . . . 44

Analysis 1.9. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 9 Actual number of patients who have

completed the study and survived beyond day 100 post BMT.. . . . . . . . . . . . . . . . . . 45

Analysis 1.10. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 10 Number with positive blood

cultures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Analysis 2.1. Comparison 2 PN + glutamine versus standard PN, Outcome 1 Mean duration(+/-SD) of time in hospital

(e.g. admission to discharge or from day 0 to discharge home).. . . . . . . . . . . . . . . . . . 46

Analysis 2.2. Comparison 2 PN + glutamine versus standard PN, Outcome 2 Mean(+/-SD) cumulative mucositis score. 47

Analysis 2.3. Comparison 2 PN + glutamine versus standard PN, Outcome 3 Number of patients who developed line

infections from start to end of study.. . . . . . . . . . . . . . . . . . . . . . . . . . . 48

Analysis 2.4. Comparison 2 PN + glutamine versus standard PN, Outcome 4 Difference in mean % change in body weight

from start to end of the study between the trial groups.. . . . . . . . . . . . . . . . . . . . 49

Analysis 2.5. Comparison 2 PN + glutamine versus standard PN, Outcome 5 Mean duration (+/-SD) that nutritional

intervention is given.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Analysis 2.6. Comparison 2 PN + glutamine versus standard PN, Outcome 6 Number of patients who developed >/=grade

2 graft versus host disease (GVHD).. . . . . . . . . . . . . . . . . . . . . . . . . . . 51

Analysis 2.7. Comparison 2 PN + glutamine versus standard PN, Outcome 7 Number of days(+/-SD) to achieve normal

neutrophil level (>0.5 X 10/9/l) after day 0 of BMT.. . . . . . . . . . . . . . . . . . . . . 52

Analysis 2.8. Comparison 2 PN + glutamine versus standard PN, Outcome 8 Actual numbers of patients who have

completed the study and survived to the 100th day post BMT.. . . . . . . . . . . . . . . . . . 53

Analysis 2.9. Comparison 2 PN + glutamine versus standard PN, Outcome 9 Number of patients with positive blood

cultures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

iNutrition support for bone marrow transplant patients (Review)


Analysis 3.1. Comparison 3 PN vs IV hydration, Outcome 1 Mean duration (+/-SD) of time in hospital (e.g. from discharge

admission to discharge or day 0 to discharge).. . . . . . . . . . . . . . . . . . . . . . . 55

Analysis 3.2. Comparison 3 PN vs IV hydration, Outcome 2 Mean(+/-SD) number of days patients had some degree of

mucositis from start to end of study.. . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Analysis 3.3. Comparison 3 PN vs IV hydration, Outcome 3 Number of patients who developed line infections from start

to end of study.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Analysis 3.4. Comparison 3 PN vs IV hydration, Outcome 4 Difference in mean % change in body weight from start to

end of the study between the trial groups.. . . . . . . . . . . . . . . . . . . . . . . . . 58

Analysis 3.5. Comparison 3 PN vs IV hydration, Outcome 5 Mean duration (+/-SD) that nutritional intervention is

given.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Analysis 3.6. Comparison 3 PN vs IV hydration, Outcome 6 Number of patients who developed > grade 2 graft versus host

disease (GVHD).. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

Analysis 3.7. Comparison 3 PN vs IV hydration, Outcome 7 Number of days(+/-SD) to achieve normal neutrophil level

(>0.5 X 10/9/l) after day 0 of BMT.. . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Analysis 3.8. Comparison 3 PN vs IV hydration, Outcome 8 Actual numbers of patients who have completed the study

and survived to the 100th day post BMT.. . . . . . . . . . . . . . . . . . . . . . . . . 62

Analysis 3.9. Comparison 3 PN vs IV hydration, Outcome 9 Actual number of patients who survived to day 200 post

BMT.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Analysis 3.10. Comparison 3 PN vs IV hydration, Outcome 10 Mean % change in albumin. . . . . . . . . . 64

Analysis 4.1. Comparison 4 PN vs enteral feeding studies, Outcome 1 Mean duration (+/-SD) of time in hospital (e.g. from

admission to discharge or day 0 to discharge).. . . . . . . . . . . . . . . . . . . . . . . 65

Analysis 4.2. Comparison 4 PN vs enteral feeding studies, Outcome 2 Mean(+/-SD) number of days patients had some

degree of mucositis from start to end of study.. . . . . . . . . . . . . . . . . . . . . . . 66

Analysis 4.3. Comparison 4 PN vs enteral feeding studies, Outcome 3 Number of patients who developed line infections

from start to end of study.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Analysis 4.4. Comparison 4 PN vs enteral feeding studies, Outcome 4 Difference in mean % change in body weight from

start to end of the study between the trial groups.. . . . . . . . . . . . . . . . . . . . . . 68

Analysis 4.5. Comparison 4 PN vs enteral feeding studies, Outcome 5 Mean duration (+/-SD) that nutritional intervention

is given.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

Analysis 4.6. Comparison 4 PN vs enteral feeding studies, Outcome 6 Number of patients who developed > grade 2 graft

versus host disease (GVHD).. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Analysis 4.7. Comparison 4 PN vs enteral feeding studies, Outcome 7 Number of days(+/-SD) to achieve normal neutrophil

level (>0.5 X 10/9/l) after day 0 of BMT.. . . . . . . . . . . . . . . . . . . . . . . . . 71

Analysis 4.8. Comparison 4 PN vs enteral feeding studies, Outcome 8 Actual numbers of patients who have completed the

study and survived to the 100th day post BMT.. . . . . . . . . . . . . . . . . . . . . . . 72

Analysis 4.9. Comparison 4 PN vs enteral feeding studies, Outcome 9 Actual number of patients who have completed the

study and survived beyond day 200 post BMT.. . . . . . . . . . . . . . . . . . . . . . . 73

Analysis 5.1. Comparison 5 Oral eicosapentaenoic acid supplementation versus nil, Outcome 1 Numbers not developing

graft versus host disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

74ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

75APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

76FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiNutrition support for bone marrow transplant patients (Review)


[Intervention Review]

Nutrition support for bone marrow transplant patients

Susan M Murray1, Sima Pindoria2

1Royal College of Physicians, London, UK. 2Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, London,

UK

Contact address: Susan M Murray, Royal College of Physicians, London, UK. [email protected].

Editorial group: Cochrane Pain, Palliative and Supportive Care Group.

Publication status and date: Edited (no change to conclusions), published in Issue 5, 2014.

Review content assessed as up-to-date: 30 April 2008.

Citation: Murray SM, Pindoria S. Nutrition support for bone marrow transplant patients. Cochrane Database of Systematic Reviews

2009, Issue 1. Art. No.: CD002920. DOI: 10.1002/14651858.CD002920.pub3.


A B S T R A C T

Background

This is an update of the original Cochrane review published in Issue 2, 2002. Bone marrow transplantation involves administration of

toxic chemotherapy and infusion of marrow cells. After treatment, patients can develop poor appetite, mucositis and gastrointestinal

failure, leading to malnutrition. To prevent this, parenteral nutrition (PN) support is often first choice but is associated with increased

risk of infection. Enteral nutrition (EN) is an alternative, as is addition of substrates.

Objectives

To determine efficacy of EN or PN support for patients receiving bone marrow transplant.

Search methods

Search of The Cochrane Library, MEDLINE, EMBASE and CINAHL in November 2000 and subsequently June 2006.

Selection criteria

RCTs that compared one form of nutrition support with another, or control, for bone marrow transplant patients.

Data collection and analysis

Twenty nine studies were identified. Data were collected on participants’ characteristics; adverse effects; neutropaenia; % change in

body weight; graft versus host disease; and survival.

Main results

In two studies (82 participants) glutamine mouthwash reduced number of days patients were neutropenic (6.82 days, 95%CI (1.67

to 11.98) P = 0.009) compared with placebo. Three studies reported (103 participants) that patients receiving PN with glutamine had

reduced hospital stay, 6.62 d (95%CI 3.47 to 9.77, P = 0.00004) compared with patients receiving standard PN. However, in the

update a further study was added (147 participants) which altered the pooled results: duration in hospital may be increased for those

who receive PN with additional glutamine - 0.22 days (95%CI (1.29 to 1.72). Two other studies reported that (73 participants) patients

receiving PN plus glutamine had reduced incidence of positive blood cultures (OR 0.23, 95%CI 0.08 to 0.65, P = 0.006) compared to

those receiving standard PN. However, a study from the update (113 participants in total) showed the odds of having a positive blood

culture have increased but are still less likely if the patient receives PN with glutamine compared to standard PN (OR 0.46, 95%CI

0.20 to 1.04). When patients were given PN versus IV hydration, (25 participants) patients receiving PN had a higher incidence of

line infections (OR 21.23, 95%CI 4.15 to 108.73, P = 0.0002) compared to those receiving standard IV fluids. The update identified

1Nutrition support for bone marrow transplant patients (Review)


mailto:[email protected]

one study which recognised that (55 participants) those who received IV were likely to spend less time in hospital, 3.30 days (95%CI

-0.38 to 6.98, P = 0.08), although this result was not significant. As reported in the original review there remains no evaluable data to

properly compare PN with EN.

Authors’ conclusions

In this update an additional study that compared PN and Glutamine versus standard PN showed that the certain benefits of parenteral

nutrition with added glutamine compared to standard PN for reducing hospital stay are no longer definite. When PN with glutamine

is compared with standard PN, patients may not leave hospital earlier, but do have reduced incidence of positive blood cultures, than

those receiving standard PN. Where possible use of intravenous fluids and oral diet should be considered as a preference to parenteral

nutrition, however, in the event of a patient suffering severe gastrointestinal failure even with a trial of enteral feeding, PN with the

addition of glutamine could be considered.

P L A I N L A N G U A G E S U M M A R Y

Nutritional support for patients who have had a bone marrow transplant

Bone marrow transplant patients can experience prolonged poor appetite with vomiting and diarrhoea. Malnutrition is a consequence.

To prevent this, patients can receive nutritious fluids orally or via a nasogastric tube, or intravenously as parenteral nutrition. The

benefits of either route are unclear. Studies were found that compared these interventions but missing data prevents proper assessment

of the benefits. However, the limited data available indicates that when patients undergo bone marrow transplantation and are given

intravenous fluids and are encouraged to have an oral diet they are less likely to experience infections and are more likely to go home

earlier than if they are given standard parenteral nutrition routinely. In the event that patients nutritional intake is inadequate because

of an inadequate oral intake or because they are unable to tolerate tube feeding and are given parenteral nutrition with added glutamine

they are likely to have less infections but may not necessarily leave hospital earlier.

B A C K G R O U N D

Patients receiving bone marrow transplantation (BMT) for malig-

nant and non malignant diseases are prone to varying degrees of

gastrointestinal failure. The main symptoms are prolonged vomit-

ing, diarrhoea and at worst but rarely, intestinal obstruction. The

cause of gastrointestinal failure is unclear but BMT patients in

addition to receiving chemotherapy, which is toxic to the gut and

destroys the host’s marrow cells, receive either donor marrow cells

(allogeneic) or their own marrow cells (autologous). The receipt

of marrow increases the potential complication of graft versus host

disease and infection which can magnify the difficulties in the

nutritional management of these patients. Many patients experi-

ence a significant reduction in appetite and therefore calorie intake

within a few days of admission to hospital which is frequently as-

sociated with a significant decrease in body weight. Consequently

optimum delivery of nutrition support often becomes essential

early on in the course of treatment for a BMT.

Traditionally, parenteral nutrition (PN), which is the adminis-

tration of intravenous nutrition given to bypass the alimentary

canal when it is not functioning adequately, has been given as

the first option of nutrition support to BMT patients (Weisdorf

1984; Herrmann 1993). This is in preference to enteral nutrition

(EN) which is the delivery of oral or tube feeding via any route

connected to the gastrointestinal tract. The reasons for this are

probably because routine insertion of long lines has enabled PN

to be delivered relatively effortlessly and also because there was a

belief that enteral feeding is an unacceptable form of ’force feed-

ing’ (Rickard 1980) and may not be well tolerated. The advan-

tages of either of these types of nutrition support in BMT patients

are not clear but PN is associated with more complications e.g.

increased line infections and reduction in gut mucosal integrity

(Kudsk 1994) which may lead to longer hospitalisation. There are

some reports from prospective studies, on the successes of enteral

feeding in these types of patients (Papadopoulou 1997). Several

authors would now argue that enteral feeding should always be

considered as the first option of nutrition support for these patients

(Mercadante 1998a; Iestra 1999). However, there have been few

attempts from prospective randomised controlled trials to prove

the benefits of enteral or parenteral nutrition support for BMT

patients.



Two authors, Lipman 1991b and Klein 1994, have previously, in-

dependently, reviewed the efficacy of nutrition support in cancer

patients. Both authors examined controlled trials of various forms

of nutrition support in a variety of patients receiving therapy for

cancer and BMT. They reported that nutrition support did not

appear to consistently improve nutritional parameters and was

not clinically effective in improving other important outcomes

for cancer patients. However, there was some evidence from two

randomised controlled trials (RCTs) (Szeluga 1987 and Weisdorf

1987) that BMT patients, survival rate improved when given PN

but infection rates and costs were higher for those receiving PN

compared to those receiving EN. Both of these reviews have been

assessed by peer reviewers from the Centre for Reviews and Dis-

semination, York, UK, (reviews on The Cochrane Library). They

commented that, whilst the conclusions of these reviews may re-

flect the benefits of nutrition support for patients receiving treat-

ment for cancer, they were unable to determine the completeness

of the reviews because they did not satisfy the methodological cri-

teria that has been proposed for scientific overviews.

Since then, and in the last decade, there has been increasing inter-

est in the addition of glutamine to both enteral and parenteral so-

lutions. Glutamine is considered to be a non-essential amino acid

which may become an essential amino acid for the catabolic sick

patient. It may also have an affect on preventing gut atrophy and

also enhance immune function (Sax 1992), both of which are po-

tentially debilitating problems for BMT patients. As a result there

have been an increasing number of controlled and uncontrolled

trials reporting the benefits of glutamine in BMT patients.

Since the treatment for BMT patients differs significantly from

cancer patients because of the receipt of marrow cells, this review

(unlike Lipman 1991b and Klein 1994) has focused specifically

on BMT patients. The aim is to assess the effectiveness of any type

of feeding regime that has been compared in patients receiving

BMT.

O B J E C T I V E S

To determine the efficacy of any form of enteral or parenteral nu-

trition support given to patients receiving bone marrow transplan-

tation. Efficacy will be considered in terms of time in hospital,

complications, change in nutritional status e.g. change in body

weight, and survival.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Any randomised (strict format of patient allocation to experimen-

tal group e.g. centralised randomisation) or quasi randomised (e.g.

alternate patient admissions) controlled trial.

Types of participants

Participants of all ages receiving any type of bone marrow trans-

plant.

Types of interventions

RCTs comparing one type or mode of nutrition support (enteral

or parenteral) with another or with an intravenous solution of

glucose/saline. Where enteral nutrition (EN) is the delivery of any

substance of nutritional value in solid or liquid form (and can

include usual food intake) that passes any part of the digestive tract,

regardless of the method of delivery e.g. orally or via a tube (e.g.

nasogastric, gastrostomy, jejunostomy). Parenteral nutrition (PN)

is the administration of nutritional liquids containing a minimum

of glucose and amino acids which is administered through the

central or peripheral venous system and therefore bypasses the

gastrointestinal tract.

Types of outcome measures

Defined outcome measures considered most important are listed

below.

Primary outcomes

• Hospital duration e.g. mean duration admission to

discharge or from day 0 to discharge home.

• Mucositis - mean number of days patient groups had some

degree of mucositis from start to end of study.

• GVHD - number of patients who developed > grade 2 graft

versus host disease (GVHD).

• Nutritional status -difference in mean % change in body

weight from start to end of study between the trial groups.

• Duration of nutritional intervention/time to resume

adequate oral intake.

• Neutropaenia mean number of days to achieve normal

neutrophil level after day of BMT, day 0.

• Line infection - number of patients who developed line

infections from start to the end of the study.

• Number with positive blood cultures.

• Survival to 100 day - actual numbers who have completed

study surviving to the 100th day post-BMT.

• Survival beyond 100 days - actual numbers who have

completed study surviving beyond day 100 or two year survival.



Secondary outcomes

• Vomiting - mean number of days patients had >/= than 3

vomits/day from start to end of study.

• Diarrhoea - mean number of days patients had >/= 3 bowel

motions /day from start to end of study.

• Veno Occlusive Disease - number of patients who developed

veno occlusive disease (VOD) actual number/per group.

• Liver function disturbances - number of patients who had

an abnormal bilirubin level from the start of study to end of

study.

• Hepatomegaly - number of patients who developed

hepatomegaly from start to end of study.

• Albumin - mean change in albumin from start to end of

study between the trial groups.

• Pre-Albumin - mean change in pre-albumin from start to

end of study between the trial groups.

• Engraftment - mean duration for each group to achieve

engraftment, post-BMT (from day 0).

Search methods for identification of studies

Studies were identified by searching The Cochrane Library (Issue

4, 2000, subsequent search Issue 2, 2006), MEDLINE (1966 to

2000, subsequent search June 2006), EMBASE (1988 to 2000,

subsequent search June 2006) and CINAHL (1982 to 2000, sub-

sequent search June 2006). An example of the search strategy used

and adapted for all databases searched can be seen in Appendix 1.

Reference lists of identified trials and conference proceedings were

also searched for relevant studies.

A search strategy (with no randomised controlled trial (RCT)

filter) was designed for identifying trials from the following

databases: The Cochrane Library, MEDLINE, EMBASE and

CINAHL.

Hand searching included nutrition and bone marrow transplant

conference proceedings, reference lists of papers found through

electronic searching, and consultation with experts.

Data collection and analysis

Study selection

Studies identified by the computerised search were scanned by

the lead review author and all apparently relevant studies were

retrieved. These were assessed independently by the lead review

author (SM) and co-author (SP) for inclusion or exclusion in the

review according to the pre-specified inclusion criteria. A data ex-

traction form was designed and used to record data on partici-

pants, interventions and outcomes as described in the ’Criteria

for considering studies for this review’ section above. Differences

between review authors’ extracted results were resolved by discus-

sion.

Correspondence with authors

Many of the authors of included studies either did not report all

of the desired outcomes of interest or presented them in a format

unsuitable for meta-analysis. Where it was possible to locate the

authors of the main studies, a standard letter requesting further

information was sent.

Statistical methods

Outcomes measured as continuous data (time in hospital, change

in nutritional status) were analysed using means and mean dif-

ferences with their corresponding standard deviations and stan-

dard errors, and reported with 95% confidence intervals (CIs).

Dichotomous data were analysed using odds ratios and reported

with 95% CIs. Where meta-analyses were possible, summary es-

timates of measures of relevant outcomes with 95% CIs were re-

ported using a fixed-effect model.

Statistical heterogeneity was tested using a Chi square test. Where

the P value was less than or equal to 0.05 this indicated significant

heterogeneity, and If this is the case a random effects model will

be used to derive a summary statistic with 95% CIs.

It was planned to investigate clinical heterogeneity by performing

analyses on the following sub-groups: adults versus children (0 to

18 years); disease type; transplant type. However, insufficient data

were available.

Similarly, there were insufficient data to:

• assess the effect of the type of allocation concealment;

• assess the effect of loss to follow-up;

• calculate a ’number needed to treat to benefit’ (NNT).

R E S U L T S

Description of studies

In the first review thirty five studies were identified of which 11

were excluded. Two review authors extracted data from 24 studies

which fulfilled all the inclusion criteria; 16 were allocated to four

interventions: oral glutamine versus placebo; PN and glutamine

versus standard PN; PN versus IV hydration; PN versus EN. Eight

other studies compared a variety of other interventions that could

not be grouped. The details of trials in each group are listed below.

For the update of this review 17 studies were identified, 12 were

excluded and five were included. Three of the five included studies

were allocated to either oral glutamine versus placebo (1); PN and

glutamine versus standard PN (1); PN versus IV hydration (1).



Two other studies were separate interventions and could not be

grouped.

Consequently in this review there are 29 included studies -19 stud-

ies have been allocated to four main types of nutritional interven-

tions and ten studies remain ungrouped since they individually

assess other types of interventions.

Data were collected on participants’ characteristics; adverse effects;

neutropaenia; % change in body weight; graft versus host disease;

and survival.

Oral glutamine versus placebo

Following the original review when there were four studies, one

further study Aquino 2005 was identified in the update. The five

trials (Aquino 2005; Coghlin Dickson 2000; Jebb 1995; Schloerb

1999) compare oral glutamine versus placebo and include 463

participants. In one trial by Schloerb 1999, participants failing to

take the oral supplement were given either PN with glutamine

or standard PN according to which group the participants were

originally randomised. Despite this, the results of this study were

allocated to this group because the original allocation was to oral

glutamine or placebo.

Parenteral nutrition with glutamine versus standard

parenteral nutrition

In the original review there were seven publications of trials com-

paring PN with glutamine versus standard PN. Four of these were

duplicate reports of one original study by Ziegler 1992. They were

MacBurney 1994; Scheltinga 1991; Ziegler 1998; Young 1993.

Data from studies by Ziegler 1992; Brown 1998; Schloerb 1993

were used. For the update of this review another study Pytlik 2002

was found and merged with the data from the three studies previ-

ously mentioned, totaling 148 participants.

Standard parenteral nutrition versus intravenous

hydration

Two trials involving a total of 166 participants were identified in

the first review (Lough 1990; Weisdorf 1987). A further study

Roberts 2003a was identified in the update and has been merged

with these studies. The total number of participants in this group

of studies is 221.

Parenteral nutrition versus enteral nutrition

In the first review one full report and two abstracts (Cope 1997;

Szeluga 1987; Young 1997), including a total of 144 participants,

were identified. During the update of this review one other study

comparing PN versus EN (Hopman 2003) was found but the

outcome data could not be used since it appeared that some of

the outcome data was obtained from participants who were not

randomised into the study.

The other eight trials identified in the first review (Aldamiz 1996;

Charuhas 1997; Jimenez 1999; Lenssen 1987; Lenssen 1998;

Malhotra 1996; Mulder 1989; Muscaritoli 1998) and two others in

the update (Santos 2001; Takatsuka 2002) compared a miscellany

of nutritional interventions, and could not be allocated to the

above groups.

Risk of bias in included studies

Three aspects of study methodology were addressed:

• allocation concealment (Mulrow 1997);

• blinding (although this was not considered to be a real

threat to biasing the results since the main outcomes were

considered to be objective measures);

• loss to follow up.

The details of these can be viewed in Additional Table 1.

Effects of interventions

Although five additional studies were added to the update of this

review many of the outcomes in these studies could not be in-

cluded in the data analysis since they were either presented in het-

erogenous units or were not relevant to the objectives of this re-

view.

The results of the four main groups of comparisons of nutrition

support are listed below.

Oral glutamine versus oral placebo

For a number of the main outcomes adequate data were provided

by Jebb 1995 and Schloerb 1999 only.

The use of an oral placebo mouth wash, resulted in a significant

reduction in days to achieve a normal neutrophil level (6.82 days,

95% CI (1.67 to 11.98) P = 0.009) compared to an oral glutamine

mouth wash.

The results for hospital duration, change in body weight, duration

of nutritional intervention, numbers with positive blood cultures

were not significant and also remained not significant when the

additional data retrieved in the update of this review from Aquino

2005 for survival at 100 days was added.

PN and glutamine versus standard PN

In the first review data was provided by either two or all three au-

thors on all the main outcomes of interest except line infections.

For the update, outcome data from the study reported by Pytlik

2002 for hospital duration, mean cumulative mucositis score, du-

ration that nutritional intervention (PN) was given and numbers

of participants with positive blood cultures were added. In the

first review one of the most significant outcomes was that, for par-

ticipants receiving glutamine enriched PN, hospital duration was



reduced by 6.62 days (weighted mean difference) with 95% CI

-9.77 to 3.47, P = 0.00004. However, with the addition of the

data from Pytlik 2002 it appears that the possibility that PN with

added glutamine could reduce hospital admission is no longer ap-

parent since the pooled result suggests that participants given PN

with Glutamine (although not significant) have an increase of 0.22

days in hospital with 95% CI -1.29 to 1.72, P = 0.78 compared

with participants given standard PN. Despite the additional data

added in from Pytlik 2002 the likelihood of these participants de-

veloping positive blood cultures remains less compared to those

on standard PN, although this is not significant. The odds ratio is

0.46 with a 95% CI 0.20 to 1.04, P = 0.06.

For the first review and with this update no significant difference

was found in the treatment affect for either PN and glutamine or

standard PN for severity of mucositis, change in body weight, dura-

tion parenteral nutrition required, incidence of > grade 2 GVHD,

duration of neutropaenia and survival at 100 days.

PN versus IV hydration

Like the first review Lough 1990; Weisdorf 1987 and now Roberts

2003a considered a number of similar outcomes, however a num-

ber of the outcomes within these studies are expressed in a variety

of different units that has not always made it possible to pool all the

outcomes of interest into a meta-analysis. In the first review Lough

1990 provided data on a number of outcomes of interest, some

showing significant differences between the PN and IV hydration

group. His data showed that the odds of having a line infection

when given PN compared to IV hydration were 21.23 than for

participants receiving IV hydration (95% CI 4.15 to 108.73, P

= 0.0002). Also, the mean percentage change in albumin for the

IV hydration group showed surprisingly significant increases in

albumin concentrations compared to the PN group and this was

also found with in the study by Roberts 2003a. (The pooled mean

difference was -3.72 (95% CI -5.96 to -1.49), P = 0.001). Lough

1990 also indicated that for percentage change in body weight

PN was more beneficial than IV hydration for preventing weight

loss and this was also identified in the study by Roberts 2003a.

The weighted mean difference for percentage change in weight

in the first review was 2.76 (95% CI 1.26 to 4.26, P = 0.0003)

and with the additional data from Roberts 2003A the weighted

mean difference was 2.81 (95%CI 1.34 to -4.29). There was no

significant difference in survival at 200 days post BMT. Lough

1990 showed that the odds of surviving this long post BMT were

2.10 (95%CI 0.48 to 9.18, P = 0.3) favouring PN over IV hydra-

tion (29 participants). Roberts 2003a provided data on survival at

two years post BMT and five years post BMT but this could not

be merged with the survival data provided by Lough 1990 since

it was estimated at different time points. The data from Roberts

2003a showed that the probability of survival at two years was

higher for the participants who received PN, 74%, compared to

57% for those who were in the group randomised to receive oral

diet and or intravenous hydration. However at 5 years post BMT

the probability of survival in either the PN or the oral diet/IV

hydration group was the same at 38%.

PN versus EN

For the update of this review one other RCT (Hopman 2003) was

found but could not be included since the outcome data included

data from participants who were not originally randomised into

the study. No further studies were included for this part. There-

fore the findings reported in the first review remain that for the

three studies originally reported, a number of outcomes of inter-

est were presented but none of the data could be utilised. Data

provided by Szeluga 1987 on change in body weight indicated

that participants receiving parenteral nutrition were more likely

to gain weight with this form of nutrition support. However, the

crossover of participants from one group to another during the

study provided uncertainty on the clarity of the data presented

in the paper. Young 1997 presented similar data as median and

ranges, which could not be utilised but also favoured parenteral

nutrition for maintaining body weight, although the results were

not significant. All three authors (Cope 1997, Szeluga 1987 and

Young 1997) reported measuring hospital duration but the data

were inadequate for analysis.

Cope 1997 and Young 1997 both suggested that length of hos-

pitalisation was significantly shorter in the enteral feeding group,

whilst Szeluga 1987 implied that there was no significant differ-

ence between either group.

Since all the other included studies could not be grouped and had

low power, no comprehensive assessment of the results could be

made. If future randomised controlled trials of studies of these

interventions are performed, it may then be possible to group some

of the outcomes.

D I S C U S S I O N

This review had wider inclusion criteria than those on nutrition

support and cancer by Lipman 1991b and Klein 1994, but in-

cluded only BMT patients. The identification of 24 RCTs in the

first review and now a further five in the update of this review

suggests there is a keen interest in identifying the best mode of

nutrition support for BMT patients.

In the first review we reported that for oral glutamine versus oral

placebo trials, data from two out of four studies only could be

used. This reduced the pooled sample size significantly. Most of

the results were inconclusive for the outcomes of interest. One of

the authors of a trial with no usable data (Coghlin Dickson 2000)

concluded that the benefits of oral glutamine were inconclusive

and that further trials are required. In the first review we suggested

that since the studies of Coghlin Dickson 2000 and Anderson



1998 included 251 participants, it would have been beneficial if the

missing data from these studies could be retrieved to increase the

pooled sample size and improve the reliability of detecting a true

affect of the intervention, before further studies are performed. For

the update of this review one further study by Aquino 2005 which

included children (whose mean age ranged from 9-10 years) has

been added to this group of studies and whilst there is interesting

data provided most of this could not be pooled with the exception

of one outcome - survival to the 100th day. For this it appears

that the children who received the placebo were more likely to

survive to the 100th day post BMT than those who received the

intervention but this result and the overall pooled result is not

significant.

In the first review for the PN and glutamine versus standard PN

trials, we commented on the positive effect that PN with Glu-

tamine had on reducing the incidence of positive blood cultures

and hospital duration. However the addition of data in the sec-

ond review from Pytlik 2002, with 40 additional participants now

suggests that participants given PN with Glutamine may actually

have an increased hospital duration compared to those given stan-

dard PN, although it must be emphasised that this is not signifi-

cant. However the likelihood that patients will have more positive

blood cultures if they are not given PN with Glutamine remains

consistent but the data for this is also not significant. It would

now seem that the benefits of giving BMT patients who need PN

(because of an inadequate oral intake), PN with Glutamine is not

clear.

For the studies that compared parenteral nutrition versus intra-

venous hydration and following the update of this review the ben-

efits of PN remain unclear because of insufficient data. The addi-

tion of data from Roberts 2003a showed further that patients given

PN are less likely to experience a large decrease in body weight and

hence their nutritional status is perhaps better maintained. Data

on the incidence of line infections remain the same as presented

in the study by Lough 1990 who showed that there was a higher

incidence of line infections associated with parenteral nutrition

compared to the intravenous hydration group, and reminds us that

parenteral nutrition should be administered with caution when

there is evidence of poor tolerance of enteral feed and prolonged

gastrointestinal failure.

In the first review we reported that the results from the parenteral

nutrition versus enteral nutrition trials were inconclusive due to

inadequate data. For the update of this review we identified a

further trial that compared the benefits of PN versus EN, however,

this was excluded because there was not a proper intention to

treat analysis. The authors of these studies have hinted that enteral

nutrition when compared to PN may have an affect on reducing

hospital duration which could have important benefits to patients

as well as cost saving advantages, suggesting the need for a large

randomised controlled trial to compare parenteral nutrition versus

enteral nutrition.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Readers of the original review are advised to re-read this update as

the conclusions have changed.

• Routine use of parenteral nutrition and glutamine for bone

marrow patients predicted to have prolonged gastrointestinal

failure, could be considered.

• Caution in the routine use of PN is still required because of

the increased risk of line infection

• Where possible use of intravenous fluids and oral diet

should be considered as a preference to parenteral nutrition,

however, in the event of a patient suffering severe gastrointestinal

failure even with a trial of enteral feeding, PN with the addition

of glutamine could be considered.

Implications for research

For this update 17 more studies were identified in June 2006

and five studies were included. Consequently there are now 29

included studies -19 studies are allocated to four main sub reviews

and ten studies remain ungrouped. To conclude:

• The benefits of oral glutamine mouth washes compared to

oral placebo remain unclear and further studies or the provision

of complete data from the studies already performed are required.

• The benefits of glutamine in PN compared to standard PN

are now not certain.

• For patients who receive PN and glutamine there no longer

appears to be a reduction in hospital stay, but they may have a

reduced incidence of positive blood cultures.

• The benefits of enteral nutrition in preference to PN are

still not clear, reflecting an urgent need for a good quality

prospective RCTs in this area.

A C K N O W L E D G E M E N T S

• Systematic Reviews Training Unit at the Institute of Child

Health, London for providing Susan Murray with funding to

undertake training in systematic reviews.



• Professor PR Schloerb and Dr CH Poynton kindly

provided unpublished data for this review.

• I acknowledge Peter Katz input in updating the search

strategy for the updated review who is sadly now deceased.

R E F E R E N C E S

References to studies included in this review

Aldamiz 1996 {published data only}

Aldamiz EL, Bachiller MP, Ariz MC, Gimenez A, Barcia

MJ, Marin M. Continuous versus cyclic parenteral nutrition

during bone marrow transplantation: Assessment and

follow-up. Clinical Nutrition 1996;15(6):333–6.

Anderson 1998 {published data only}

Anderson PM, Ramsay NK, Shu XO, Rydholm N,

Rogosheske J, Nicklow R, et al.Effect of low-dose oral

glutamine on painful stomatitis during bone marrow

transplantation. Bone Marrow Transplant 1998;22(4):

339–44. [: 1]

Aquino 2005 {published data only}∗ VM Aquino, AR Harvey, JH Garvin, KT Godder, ML

Nieder, RH Adams, et al.A double blind randomized

placebo-controlled study of oral glutamine in the prevention

of mucositis in children undergoing hematopoietic stem cell

transplantation: a pediatric blood and marrow transplant

consortium study. Bone Marrow Transplantation 2005;36:

611–6.

Brown 1998 {published data only}

Brown SA, Goringe A, Fegan C, Davies SV, Giddings J,

Whittaker JA, et al.Parenteral glutamine protects hepatic

function during bone marrow transplantation. Bone

Marrow Transplant 1998;22(3):281–4.

Charuhas 1997 {published data only}

Charuhas PM, Fosberg KL, Bruemmer B, Aker SN,

Leisenring W, Seidel K, Sullivan KM. A double-blind

randomized trial comparing outpatient parenteral nutrition

with intravenous hydration: effect on resumption of oral

intake after marrow transplantation. Journal of Parenteral

and Enteral Nutrition 1997;21(3):157–61.

Coghlin Dickson 2000 {published data only}

Coghlin Dickson T, Wong RM, Negrin RS, Shizuru

JA, Johnston LJ, Hu WW, et al.Effect of oral glutamine

supplementation during bone marrow transplantation.

Journal of Parenteral and Enteral Nutrition 2000;24(2):61–6.

Cope 1997 {published data only}

Cope FO. Prophylactic enteral support to BMT patients

reduces length of hospital stay, improves GI integrity and

nutritional status, and reduces intake requirements required

for positive outcome. Procedures of the Annual Meeting of

the American Society for Clinical Oncology. 1997.

Jebb 1995 {published data only}

Jebb SA, Marcus R, Elia M. A pilot study of oral glutamine

supplementation in patients receiving bone marrow

transplants. Clinical Nutrition 1995;14(3):162–5.

Jimenez 1999 {published data only}

Jimenez JF, Ortiz LC, Garcia GJ, Garnacho MJ, Rodriguez

FJ, Espigado TI. Prospective, comparative study of different

amino acid and lipid solutions in the parenteral nutrition

of patients subjected to a bone marrow transplantation.

Nutricion Hospitalaria 1999;14(2):57–66.

Lenssen 1987 {published data only}

Lenssen P, Cheney CL, Aker SN, Cunningham BA,

Darbinian J, Gauvreau JM, Barale KV. Intravenous

branched chain amino acid trial in marrow transplant

recipients. Journal of Parenteral and Enteral Nutrition 1987;

11(2):112–8.

Lenssen 1998 {published data only}

Lenssen P, Bruemmer BA, Bowden RA, Gooley T, Aker

SN, Mattson D. Intravenous lipid dose and incidence of

bacteremia and fungemia in patients undergoing bone

marrow transplantation. American Journal of Clinical

Nutrition 1998;67(5):927–33.

Lough 1990 {published data only}

Lough M, Watkins R, Campbell M, Carr K, Burnett

A, Shenkin A. Parenteral nutrition in bone marrow

transplantation. Clinical Nutrition 1990;9(2):97–101.

MacBurney 1994 {published data only}

MacBurney M, Young LS, Ziegler TR, Wilmore DW. A

cost-evaluation of glutamine-supplemented parenteral

nutrition in adult bone marrow transplant patients. Journal

of American Dietetics Association 1994;94(11):1263–6.

Malhotra 1996 {published and unpublished data}

Malhotra D, DeMeo D, Kruger A, Rooney D, Holmes

E, Poe L, et al.Oral elemental nutrition improves

gastrointestinal integrity in patients undergoing bone

marrow transplantation. Proceedings of Asco Vol. 1996;

Vol. 15:450. [: 13]

Mulder 1989 {published data only}

Mulder PO, Bouman JG, Gietema JA, Van Rijsbergen H,

Mulder NH, Van der Geest S, et al.Hyperalimentation in

autologous bone marrow transplantation for solid tumors.

Comparison of total parenteral versus partial parenteral plus

enteral nutrition. Cancer 1989;64(10):2045–52.

Muscaritoli 1998 {published data only}

Muscaritoli M, Conversano L, Torelli GF, Arcese W,

Capria S, Cangiano C, et al.Clinical and metabolic effects



of different parenteral nutrition regimens in patients

undergoing allogeneic bone marrow transplantation.

Transplantation 1998;66(5):610–6.

Pytlik 2002 {published data only}

Pytlik R, Benes P, Patorkova M, Chocenska E, Gregora E,

Prochazka B, et al.Standardised parenteral alanyl-glutamine

dipeptide supplementation is not beneficial in autologous

transplant patients: a randomized, double-blind, placebo

controlled study. Bone Marrow Transplantation 2002;30:

953–961.

Roberts 2003a {published data only}∗ Roberts S, Miller J, Pineiro L, Jennings L. Total parenteral

nutrition vs oral diet in autologous hematopoietic cell

transplant recipients. Bone Marrow Transplantation 2003;

32:715–21.

Santos 2001 {published data only}∗ Santos P, Lourenco R, Camilo ME, Oliveira AG, Figueira

I, Pereira ME, et al.Parenteral nutrition and cyclosporine:

do lipids make a difference? A prospective randomised cross

over trial. Clinical Nutrition 2001;20(1):31–36.

Scheltinga 1991 {published data only}

Scheltinga MR, Young LS, Benfell K, Bye RL, Ziegler TR,

Santos AA, et al.Glutamine-enriched intravenous feedings

attenuate extracellular fluid expansion after a standard stress.

Annals of Surgery 1991;214(4):385–95.

Schloerb 1993 {published data only}

Schloerb PR, Amare M. Total parenteral nutrition with

glutamine in bone marrow transplantation and other clinical

applications (a randomized double-blind study). Journal of

Parenteral and Enteral Nutrition 1993;17(5):407–13.

Schloerb 1999 {published data only}

Schloerb PR, Skikne BS. Oral and parenteral glutamine in

bone marrow transplantation: a randomized, double-blind

study. Journal of Parenteral and Enteral Nutrition 1999;23

(3):117–22.

Szeluga 1987 {published data only}

Szeluga DJ, Stuart RK, Brookmeyer R, Utermohlen

V, Santos GW. Nutritional support of bone marrow

transplant recipients: a prospective, randomized clinical

trial comparing total parenteral nutrition to an enteral

feeding program. Cancer Research 1987;47(12):3309–16.

Takatsuka 2002 {published data only}∗ Takatsuka H, Takemoto Y, Iwata N, Suehiro A, Hamano

T, Okamoto T, Kanamaru A. Oral eicosapentaenoic acid

for complications of bone marrow transplantation. Bone

Marrow Transplantation 2001;28:769–74.

Weisdorf 1987 {published data only}

Weisdorf SA, Lysne J, Wind D, Haake RJ, Sharp HL,

Goldman A, et al.Positive effect of prophylactic total

parenteral nutrition on long-term outcome of bone marrow

transplantation. Transplantation 1987;43(6):833–8.

Young 1993 {published data only}

Young LS, Bye R, Scheltinga M, Ziegler TR, Jacobs DO,

Wilmore DW. Patients receiving glutamine-supplemented

intravenous feedings report an improvement in mood.

Journal of Parenteral and Enteral Nutrition 1993;17(5):

422–7.

Young 1997 {published and unpublished data}

Young M, Stanford J, Walker DJ, Frost G. Preliminary report

of the efficacy of nasogastric feeding in allogeneic adult bone

marrow transplant patients. Original Communications of

the Nutrition Society Original Communications of the

Nutrition Society 1997. [: 24]

Ziegler 1992 {published data only}

Ziegler TR, Young LS, Benfell K, Scheltinga M, Hortos K,

Bye R, et al.Clinical and metabolic efficacy of glutamine-

supplemented parenteral nutrition after bone marrow

transplantation. A randomized, double-blind, controlled

study. Annals of Internal Medicine 1992;116(10):821–8.


Ziegler TR, Bye RL, Persinger RL, Young LS, Antin JH,

Wilmore DW. Effects of glutamine supplementation on

circulating lymphocytes after bone marrow transplantation:

a pilot study. American Journal of Medical Sciences 1998;315

(1):4–10.

References to studies excluded from this review

Clemens 1997 {published data only}

Clemens MR, Waladkhani AR, Bublitz K, Ehninger G,

Gey KF. Supplementation with antioxidants prior to bone

marrow transplantation. Wien Klin Wochenschr 1997;109

(19):771–6.

Cohen 1996 {published data only}

Cohen D. Nutrition management of gastrointestinal graft-

versus-host disease following bone marrow transplantation.

Support Line 1996;5:13–5.

Duggan 2004 {published data only}

Duggan C, Stark A, Auestad N, Collier S, Fulhan J,

Gura K, et al.Glutamine Supplementation in Infants with

Gastrointestinal Disease: A randomized placebo controlled

pilot trial. Nutrition 2004;20:752–6.

Ford 1992 {published data only}

Ford EG. Clinical comparison of tolerance to elemental

or polymeric enteral feedings in the postoperative patient.

Journal of the American College of Nutrition 1992;11(1):

11–6.

Hopman 2003 {published data only}

Hopman G, Pena E, le Cessie S, van Weel MH, Vossen

JMJJ, Mearin ML. Tube feeding and Bone Marrow

Transplantation. Medical and Paediatric Oncology 2003;40

(6):375–9.

Klein 1994 {published data only}

Klein S, Koretz RL. Nutrition support in patients with

cancer: what do the data really show?. Nutrition in Clinical

Practice 1994;9(3):91–100.

Lipman 1991a {published data only}

Lipman TO. Grains or veins: Is enteral nutrition really

better than parenteral nutrition? A look at the evidence.

Journal of Parenteral and Enteral Nutrition 1998;60(22/3):

167–82.



Mercadante 1998a {published data only}

Mercadante S. Parenteral versus enteral nutrition in cancer

patients: Indications and practice. Supportive Care in

Cancer 1998;6(2):85–93.

Mobrahan 1992 {published data only}

Mobrahan S. Glutamine: A conditionally essential nutrient

or another nutritional puzzle. Nutrition Reviews 1992;50

(11):331–3.

Piccirillo 2002 {published data only}

Piccirillo N, S De Matteis L, Laurenti P, Chiusolo F, Sora

S, Rutella S, et al.Glutmine enriched parenteral nutrition

after autologous peripheral blood stem cell transplantation:

effects on immune reconstitution and mucositis. Bone

Marrow Transplantation 2002;29:Suppl S 21.

Piccirillo 2004 {published data only}

N Piccirillo, S De Matteis, F Sora, L Laurenti, P Chiusolo,

G Leone, S Sica. Glutamine parenteral supplementation in

stem cell transplant. Bone Marrow Transplantation 2004.

Poznarova 2003 {published data only}

Poznarova A, Horacek J, Zac P, Kmonicek M, Maly J. A

randomised double blind comparative study of parenteral

nutritional support with or without glutamine in autologous

stem cell transplantation for hematologic malignancies.

Bone Marrow Transplantation. 2003; Vol. 31 (Suppl 1):

S219–20.

Pytilik 2002a {published data only}

Pytilik R, Benes P, Gregora E, Pajorkova M, Chocenska

E, Prochazka B, et al.No role for parenteral glutamine

supplementation in autologous stem cell transplant

patients: results of a triple blinded study. Bone Marrow

Transplantation. 2002; Vol. 29 (Suppl2):S20.

Pytilik 2002b {published data only}

Pytilik R, Benes P, Patorkova M, Chocenska E, Gregora E,

Prochazka B, et al.Standardised Parenteral alanyl glutamine

dipeptide supplementation is not beneficial in autologous

transplant patients: a randomised, double blind, placebo

controlled study.. Bone Marrow Transplantation 2002;30

(12):953–61.

Ramsay 1981 {published data only}

Ramsay N. Prevention of graft versus host disease (GVHD)

in bone marrow transplantation (BMT) recipients: A

randomized study. Procedures of the American Association

of Cancer Research. 1981.

Reiffers 1996 {published data only}

Reiffers J. Allogeneic vs autologous stem cell transplantation

vs chemotherapy in patients with acute myeloid leukemia

in first remission: the BGMT 87 study. Leukemia 1996;10

(12):1874–82.

Sax 1992 {published data only}

Sax HC. Clinical and metabolic efficacy of glutamine-

supplemented parenteral nutrition after bone marrow

transplantation. A randomized, double-blind, controlled

study. Journal of Parenteral and Enteral Nutrition 1992;16

(6):589–90.

Schied 2004 {published data only}

Schied C, Hermann K, Kremer G, Holsing A, Heck G,

Fuchs M, et al.Randomized, double blind, controlled study

of glycl-glutamine-dipeptide in the parenteral nutrition

of patients with acute leukaemia undergoing intensive

chemotherapy. Nutrition 2004;20:249–54.

Souba 1993 {published data only}

Souba WW. Total parenteral nutrition with glutamine in

bone marrow transplantation and other clinical applications.

Journal of Parenteral and Enteral Nutrition 1993;17(5):403.

Stern 2000 {published data only}

Jean M Stern, Barbara Bruemmer, Carol M Moinpour,

Keith Sullivan, Polly Lennssen, Saundra Aker. lmpact of a

randomised, controlled trial of liberal versus conservative

hospital discharge criteria on energy, protein and fluid

intake in patients who received marrow transplants. Journal

of the American Dietetic Association 2000;100:1015–22.

Takatsuka 2001 {published data only}

Takatsuka H, Takemoto Y, Iwata N, Suehiro A, Hamano

T, Kanamaru A, et al.Oral Eicosapentaenoic acid for

complications of bone marrow transplantation. Bone

Marrow Transplantation 2001;28(8):769–74.


Thomas R Ziegler. Glutamine Supplementation in Cancer

Patients Receiving Bone Marrow Transplantation and High

Dose Chemotherapy. The Journal of Nutrition September

2001;131(9S):2578S–84S.


Ziegler TR. Glutamine supplementation in bone marrow

transplantation. British Journal of Nutrition 2002;87, Suppl

1:S9–15.

Additional references

Herrmann 1993

Herrmann VM, Petruska PJ. Nutrition support in bone

marrow transplant recipients. Nutritional Clinical Practice

1993;8(1):19–27.

Iestra 1999

Iestra JA, Fibbe WE, Zwinderman AH, Romijn JA,

Kromhout D. Parenteral nutrition following intensive

cytotoxic therapy: an exploratory study on the need for

parenteral nutrition after various treatment approaches

for haematological malignancies. Bone Marrow Transplant

1999;23(9):933–9.

Kudsk 1994

Kudsk KA. Gut mucosal nutritional support- enteral

nutrition as primary therapy after multiple system trauma.

Gut 1994;suppl 1:S52–4.

Lipman 1991b

Lipman T. Clinical trials of nutrition support in cancer,

parenteral and enteral therapy. Haematology/Oncology

Clinics of North America 1991;5(1):91–101.



Mulrow 1997

Mulrow CD, Oxman AD, editors. Cochrane Reviewer’s

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1997.

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PJ, Booth IW. Enteral nutrition after bone marrow

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Rickard 1980

Rickard KA. Effectiveness of enteral and parenteral nutrition

in the nutritional management of children with Wilm’s

tumour. Clinical Nutrition 1980;33:2622–9.

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Paediatric Gastroenterology and Nutrition 1984;3:95–100.∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Aldamiz 1996

Methods Randomised controlled trial

Method of randomisation is not clear.

Participants 24 recruited

BMT type 6 Allogeneic and 18 Autologous BMT patients.

Disease type not specified

Age mean(+/-SD) years:

Continuous PN = 37(+/-9.3)

Cyclical PN = 35.4(+/- 11.1)

Interventions 12 Continuous PN

12 Cyclical PN

Start criteria: Day +1 after BMT

Stop criteria: not clear.

Outcomes Hospital duration

Change in body weight

Graft versus host disease

Duration of PN

Duration neutropaenia

Notes There were no losses to follow up.

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - Unclear

Anderson 1998

Methods Randomised controlled trial.

Method of randomisation is truly random (computer generated random number list.)


BMT type: 106 Allogeneic/87 Autologous

Disease type: Haem malignancy 106

Haem disorders 8

Solid tumour 62

Inherited disorders 17

Age (yrs) - mean (range)

Oral Glutamine = 29 (1-62)

Oral Placebo = 27 (1-62)



Anderson 1998 (Continued)

Interventions Randomisation:

98 -Oral mouth rinse glutamine or 1 g/m2, x4/day.

95 - Oral mouth rinse glycine 1g/m2, x4/day

Start criteria: 7 days before BMT

Stop criteria: 28 days after BMT

Outcomes Mucositis


Survival at day 28 and day 100.

Notes Follow up:195 recruited, 2 withdrew

98 - Glutamine group ( 2 did not participate)

95 - Control

Risk of bias


Allocation concealment (selection bias) Low risk A - Adequate

Aquino 2005


Method of randomisation was via a random permutation table at a central pharmacy

Participants 120 CHILDREN recruited

BMT type: 106 Allogeneic: 54

Autologous: 66

Disease type: Haem malignancy 64

Solid tumour:48

Haem abnormalities: 10

Age (yrs) - mean

Oral Glutamine =8.9yr

Oral Glycine = 10.5

Interventions Oral glutamine v Oral glycine 2g/m2 (max 4g/day) dissolved in 500 ml solution adminis-

tered twice daily

Outcomes % of doses taken

Hospital days (?units)

Mucositis score

Toxicities

IV narcotic use (days)

PN use (days)

Episodes of bacteraemia

Toxities (including mortality)



Aquino 2005 (Continued)

Notes The study was described as a double blind randomised controlled trial. Method of ran-

domisation was clear but there was no mention on whether the assessors were blind to the

treatment allocation. There were no apparent losses to follow up

Risk of bias



Brown 1998


Method of randomisation is truly random


BMT type: 7 Allogeneic/ 27 Autologous

Disease type: 34 Haem malignancy

Age- years, median (range)

Glutamine = 41(19-62)

Control = 32 (16-55)


18 PN + Glutamine (50 g glutamine/day)

16 to Standard PN (no glutamine)

Start criteria: day -7 before BMT

Stop criteria: on day discharge.

Outcomes Change in body weight


Survival

Notes Follow up :34 recruited, 8 withdrew.

18- Glutamine group

( four withdrew)

16- Control group ( four withdrew)

Risk of bias





Charuhas 1997



Participants 265 BMT (Out patients) recruited


Disease type: 241 Haem malignancy,

2 Haem disorders

12 solid tumour

3 Inherited disorders

Age (range) years:

PN group = 2.7 - 64.2 yrs

IV hydration = 2.1 - 63.1 yrs.


128 PN

130 IV Hydration

Start criteria: at discharge

Stop criteria: oral intake >85% energy requirements, for 3 consecutive days

Outcomes Hospital readmission

Time to resume oral intake


GVHD

Survival to day 150 (post BMT)

Notes

Risk of bias



Coghlin Dickson 2000






Age (range) years:

Glutamine group:17-58 yrs

Control: 21-59 yrs


29 Oral Glutamine (10 g x 3 doses/day).

29 Placebo (Sucrose, 10 g x 3/day).



Coghlin Dickson 2000 (Continued)


Mucositis

Duration of PN

Engraftment

Survival at 2 years


Risk of bias



Cope 1997




BMT type: not specified

Disease type: not specified

Age - not specified


23 EN

40 PN

Start/Stop criteria:not stated.


Mucositis

Change in nutritional status

Notes Loss to follow up is not clear.

Risk of bias





Jebb 1995




BMT type: 24 Autologous


Age range not specified.


12 Oral mouth rinse glutamine, 4g x 4/d.

12 Oral mouth rinse polycal, 4g x 4/d.

Start criteria: day +1 after BMT until Stop criteria: mucositis resolved or discharge


Mucositis

Duration of PN

Duration of neutropaenia

Notes Follow up: 24 recruited, 8 withdrew.

12- Oral glutamine group ( four withdrew)

12- Control group ( four withdrew)

.

Risk of bias



Jimenez 1999



Participants 62 BMT patients.


19 - 22.5% BCAA* + 20%LCT

26 - 45% BCAA* + 20%LCT*

17- 45% BCAA*+ 20%MCT*/ LCT*


Duration of Mucositis

Duration of PN

Lipid metabolism

Nutritional assessment parameters.

Notes (Original paper in Spanish)



Jimenez 1999 (Continued)

Risk of bias



Lenssen 1987


Method of randomisation is truly random.

Participants 40 recruited.

BMT type: 40 Allogeneic


Age median(range) years:

23%BCAA*, PN = 28.5 (18-48)

45% BCAA*, PN = 28.5 (18-49)


20 - 23%BCAA* (PN)

20 - 45% BCAA*(PN)

Start criteria: pre BMT (day not specified)

Stop criteria: oral protein >10g/day.

Outcomes Graft versus host disease


20 - 23%BCAA* (PN) (9 withdrew.)

20 - 45% BCAA*(PN) (12 withdrew.)

Risk of bias



Lenssen 1998




BMT type: 419 Allogeneic/ 93 Autologous Disease type: 512 Haem malignancy

Age mean + (range) years:

Standard PN Lipid group = 35 (0.5-65)

PN+ low dose lipid group = 35 (0.4 -67).



Lenssen 1998 (Continued)


253 Standard PN Lipid

259 Low dose PN Lipid

Start criteria: oral energy intake < basal requirements

Stop criteria: oral energy intake >10kcals/kg/day.

Outcomes Graft versus host disease.

Death by day 60 and day 150 post BMT.


253 Standard PN (20 withdrew)

259 Low dose PN Lipid

(23 withdrew)

Risk of bias



Lough 1990




BMT type: 17 Allogeneic/12 Autologous


Age range (14-44 yrs)


14 PN

15 IV Hydration.

Start criteria: day+1 after BMT until Stop criteria: 15 days after BMT?

Outcomes Change in body weight

Notes Follow up: 29 randomised,

14 PN (4 excluded from analysis).

15 IV (none excluded)

Risk of bias





MacBurney 1994






Age range: not specified


22 PN+ Glutamine (0.57 g/kg/day

21 Standard PN (no glutamine)

Start criteria: day+1 after BMT

Stop criteria: oral intake > 50% energy requirements for 3 days


Survival

Notes Small sub report from Ziegler’s 1992 study.

Cost is the main outcome reported.

Risk of bias



Malhotra 1996




BMT type: not specified


Age range: not specified


Elemental diet

Normal ad lib diet.

Start criteria - 72 hours pre high dose therapy.

Stop criteria: not stated.

Outcomes Mucositis

Nausea

Diarrhoea

Sugar absorption tests for gastro-duodenal permeability, small bowel absorption and small

bowel permeability



Malhotra 1996 (Continued)

Notes Abstract report only.

Risk of bias



Mulder 1989




BMT type: 22 Autologous

Disease type: 22 solid tumour

Age (range) years:

PN group = 28- 54 yrs

EN group = 21- 56 yrs.


11 PN

11 PN+EN

Start criteria:day + 4 after BMT

Stop criteria: leukocyte count > 1x 109.



Survival


Risk of bias



Muscaritoli 1998






Age mean(range) years:



Muscaritoli 1998 (Continued)

Glucose based PN = 30.5 (15-47)

Lipid based PN = 29.1 (16-44)


35 PN Glucose

31 PN Lipid

Start criteria - day +1 after BMT.

Stop criteria - day + 16 after BMT.


Change in body weight.


Survival

Notes Follow up : 66 recruited, 6 withdrew.

35 PN Glucose (4 withdrew)

31 PN Lipid (2 withdrew)

Risk of bias



Pytlik 2002

Methods Randomised controlled trial method of randomisation is clear and apart from the hospital

pharmacists all other personnel were blind to the treatment allocation


BMT type:

Autologous -40

Disease type: Haem malignancy -32

Solid tumour - 4

Other inherited conditions -4

Age range (mean +/-sd):

Intervention: (PN and Glutamine)

49 +/- 12

Control: Placebo

42+/-14


PN + glutamine - n=21

PN + placebo - n =19

Start criteria: administered from day +1 to day +14 or to discharge



Pytlik 2002 (Continued)

Outcomes Mean days of Diarrhoea (>3 stools per day)

Mean oral energy intake

Mean days in hospital post transplantation

Mean days with severe mucositis

Days of PN

Notes For most of the outcomes it did not appear that there was loss to follow up

Risk of bias



Roberts 2003a


Method of randomisation is unclear as is the level of allocation concealment

Participants 55 recruited:

BMT type: Autologous -55

Disease type: Solid tumours (Breast cancer):55

Mean Age:

PN group:41.6 yrs

Oral diet group:45.6


PN:27

Oral diet:28

(also given IV fluids)

PN started day -1 were also allowed ad lib oral diet.

Outcomes Nutritional status including:

% decrease in body weight

Nos with +ve blood cultures

No. days on antibiotics

Liver function

Change in mood disturbance

% probability of survival at 2 and 5 years.

Notes

Risk of bias





Santos 2001

Methods Randomised cross over controlled trial.

Method of randomisation is truly random although the extent of blinding of the participants

and the investigators is unclear

Participants 10 recruited:

BMT type: 10 allogeneic transplant patients

Disease type: all had haematological malignancies

Mean age: 36.7 years (sd 12.0).


Group 1: PN with lipid for 4 days and then PN without lipids for 4 days.

Intervention group 2: PN without lipids for 4 days and then PN with lipids for 4 days.

The composition of the PN lipid solution was given as 0.8 g/kg/d of 50:50 mixture of

medium and long chain triglycerides

Outcomes Levels of cyclosporin in blood samples.

Notes The authors reported that cyclosporin A pharmokinetics were not influenced by varying

types of lipid enriched PN admixtures

Risk of bias



Scheltinga 1991






Age( years)- mean(SEM)

PN + Glutamine - 36+/-3

Standard PN - 33+/-3


10 PN+Glutamine (0.57g/kg/day)






Duration of PN



Scheltinga 1991 (Continued)


Small sub report from Ziegler’s 1992 study.

Risk of bias



Schloerb 1993






3 Solid tumour

Age (years) - mean (range)

PN + Glutamine 35.6(19-55)

Standard PN - 37.6 (19-55)


16 PN+ Glutamine (2830 mg glutamine/100 ml)


Start criteria - unclear

Stop criteria - oral intake >50% energy requirements.


Mucositis


Duration of PN


Neutropaenia

Positive blood cultures


Risk of bias





Schloerb 1999




BMT type:19 Allogeneic/ 47 Autologous Disease type: 43 Haem malignancy

23 Solid tumour

Age: all > 17 yrs.


35 Oral Glutamine,10g x 3 /day.

33 Oral/PN Glycine, 10g x 3/day.

Start criteria: unclear.

Stop criteria: oral intake >50% energy requirement.


Mucositis


Survival

Duration of PN


Risk of bias



Szeluga 1987



Participants 65 recruited. 61 participated.



16 other miscellany of disorders.

Age (years)

PN = 21 > 19 yrs, 10 < 19 yrs.

EN group = 21 > 19 yrs, 9 < 19 yrs.


31PN

30 EN

(4 withdrew)

Start criteria: day before BMT

Stop criteria: 28 days after BMT



Szeluga 1987 (Continued)


Duration of PN


Neutropaenia


Survival

Notes 65 recruited.

61 participated, 4 withdrew. 57 could be evaluated at day 28.

27 PN group (4 treatment failures).

30 EN group. (7 received PN).

Although 7 failed enteral feeds and received PN their outcomes were included in the EN

group analysis.

However 2 from the PN group were crossed at some stage into the EN group and were

included in the EN group analysis . Consequently numbers for each outcome presented

are unclear and none can be used

Risk of bias



Takatsuka 2002




BMT type: Allogeneic - 17

Disease type - haematological malignancy - 17

Age: < 17yrs - 1

>/= 17yrs - 16


8 - eicosapentaenoic acid(EPA) from day -21 to day 180 post BMT

9 - received nil

Outcomes Numbers developing GVHD - graft versus host disease

Notes

Risk of bias





Weisdorf 1987




BMT type:104 Allogeneic/ 32 Autologous

Disease type:118 Haem malignancy

8 Solid tumour

3 Inherited disorder

5 Haem abnormalities

1 other malignancy

2 unaccounted

Age - years, mean (+/-SD) for

PN group = 20 (+/- 12.9)

IV hydration = 18.3 (+/- 12.9)


71 PN

66 IV Hydration.

Start criteria: 7 days before BMT.

Stop criteria: 4 weeks post BMT.



Survival

Notes Difficulty extracting data from paper.

There were no apparent losses to follow up.

Risk of bias



Young 1993






Age (yrs) (mean (range):

PN + Glutamine = 36 (20-49)

Standard PN = 30 (22-44)


13 PN + Glutamine (0.57g glutamine/kg/day)

10 Standard PN



Young 1993 (Continued)

Start criteria : Day + 1 after BMT.

Stop criteria : oral intake >50% energy requirements.


Duration of PN


Small report from

Ziegler’s 1992 study.

Main outcome reported is mood.

Risk of bias



Young 1997




BMT type:20 Allogeneic


Age: not specified

Allogeneic BMT patients.

Age - not specified


10 PN

10 EN

Start criteria: weight loss >10% nutritional requirements inadequate.

Stop criteria:not stated.

Outcomes Duration of feeding (PN/EN



10 PN

10 EN ( 5 withdrew)

Abstract version only.

Risk of bias




Young 1997 (Continued)


Ziegler 1992






Age (years) - mean (range)

PN + Glutamine - 32.1(20-48)

Standard PN - 35.5(20-49)


24 PN+ Glutamine (0.57g/kg/day)

21 Standard PN ( no glutamine).




Duration of PN

Mucositis

Neutropaenia


Positive blood cultures

Survival

Notes Follow up: 45 recruited.

24 PN + Glutamine - 2 were not followed up for hospital duration but were for all other

outcomes reported.

21 Standard PN - (1 withdrew)

Note a number of studies are sub reports of this main study and they will not be included

in the analysis

Risk of bias





Ziegler 1998






Age (years) - mean (+/- SE)

PN + Glutamine - 36 (+/- 3

Standard PN - 35 (+/-3)


9 PN+ Glutamine (0.57 g/kg/day)

11 Standard PN ( no glutamine).

Start criteria - day+1 after BMT

Stop criteria - not stated

Outcomes Duration of PN

Neutropaenia

Clinical infection


Small report from Ziegler’s main 1992 study.

Main outcome reported effect on circulating lymphocytes.

Risk of bias



Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Clemens 1997 This is not a randomised controlled trial.

Cohen 1996 This is not a report of a randomised controlled trial but single case report

Duggan 2004 These patients were not bone marrow transplant patients they were infants with gastrointestinal disease

Ford 1992 The study does not include bone marrow transplant patients.

Hopman 2003 This study compared enteral nutrition versus parenteral nutrition however the investigators combined data of

patients who were randomised into the study with patients who were not randomised into the study. Conse-

quently the data from the randomised patients was merged with the data from the non randomised patients

preventing the data of the randomised patients to be evaluated



(Continued)

Klein 1994 This is not a report of a randomised controlled trial.

Lipman 1991a This is not a report of a randomised controlled trial but a report of a review of clinical trials of nutrition support

in Cancer patients

Mercadante 1998a This is not a report of a randomised controlled trial but a report on the benefits of enteral nutrition versus

parenteral nutrition for oncology patients

Mobrahan 1992 This is not a report of a randomised controlled trial but instead a report on the potential benefits of glutamine

for Bone Marrow Transplant patients

Piccirillo 2002 The data was presented in abstract form however it was not possible to adequately evaluate this study report

Piccirillo 2004 The data was presented in abstract form and was not evaluable

Poznarova 2003 The data was presented in abstract form and was not evaluable

Pytilik 2002a The data was presented in abstract form and was not evaluable

Pytilik 2002b The data was presented in abstract form and was not evaluable

Ramsay 1981 This randomised controlled trial did not use any form or type of nutrition support as its intervention

Reiffers 1996 This randomised controlled trial did not use any form or type of nutrition support as its intervention

Sax 1992 This is not a report of a randomised controlled trial but a comment report of a randomised controlled trial

(Ziegler 1992) that compared glutamine supplemented PN with standard PN

Schied 2004 This randomised controlled study which compared standard PN with PN and glutamine was conducted on

patients receiving intensive chemotherapy but they did not undergo bone marrow transplantation within this

study. This study is excluded because it did not meet the population inclusion criteria

Souba 1993 This is not a report of a randomised controlled trial but a comment report of other randomised controlled trials

that have compared glutamine supplemented PN with standard PN

Stern 2000 The intervention was related to early versus delayed discharge home and did not meet the inclusion criteria

Takatsuka 2001 This study is excluded since data from the same study published a year later is being included within this review

Ziegler 2001 This was not a randomised controlled trial but a review paper

Ziegler 2002 This was not a randomised controlled trial but a review paper



D A T A A N D A N A L Y S E S

Comparison 1. Oral glutamine versus oral placebo studies

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Mean duration (+/-SD) of time

in hospital (e.g. admission to

discharge or from day ’0’ to

discharge).

5 453 Mean Difference (IV, Fixed, 95% CI) -2.39 [-6.11, 1.34]

2 Mean(+/-SD) number of days

patients had some degree of

mucositis from start to end of

study.

5 335 Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0]

3 Number of patients who

developed line infections from

start to end of study.

5 335 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.0 [0.0, 0.0]

4 Difference in mean % change in

body weight from start to end

of the study between the trial

groups.

5 327 Mean Difference (IV, Fixed, 95% CI) 5.73 [-7.09, 18.55]

5 Mean duration (+/-SD) that

nutritional intervention is

given as PN.



developed > grade 2 graft versus

host disease (GVHD).


7 Number of days(+/-SD) to

achieve normal neutrophil level

(>0.5 X 10/9/l) after day 0 of

BMT.


8 Actual numbers of patients who

have completed the study and

survived to the 100th day post

BMT.


9 Actual number of patients who


survived beyond day 100 post

BMT.


10 Number with positive blood

cultures




Comparison 2. PN + glutamine versus standard PN


studies

No. of


1 Mean duration(+/-SD) of time

in hospital (e.g. admission to

discharge or from day 0 to

discharge home).


2 Mean(+/-SD) cumulative

mucositis score









groups.




given.



developed >/=grade 2 graft

versus host disease (GVHD).





BMT.





BMT.


9 Number of patients with positive

blood cultures


Comparison 3. PN vs IV hydration


studies

No. of


1 Mean duration (+/-SD) of time

in hospital (e.g. from discharge

admission to discharge or day 0

to discharge).





study.











groups.




given.









BMT.





BMT.



survived to day 200 post BMT.


10 Mean % change in albumin 3 217 Mean Difference (IV, Fixed, 95% CI) -3.72 [-5.96, -1.49]

Comparison 4. PN vs enteral feeding studies


studies

No. of


1 Mean duration (+/-SD) of

time in hospital (e.g. from

admission to discharge or day 0

to discharge).





study.









groups.




given.











BMT.





BMT.




survived beyond day 200 post

BMT.


Comparison 5. Oral eicosapentaenoic acid supplementation versus nil


studies

No. of


1 Numbers not developing graft

versus host disease

1 17 Odds Ratio (M-H, Fixed, 95% CI) 12.09 [0.52, 280.40]



Analysis 1.1. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 1 Mean duration (+/-SD)

of time in hospital (e.g. admission to discharge or from day ’0’ to discharge)..

Review: Nutrition support for bone marrow transplant patients

Comparison: 1 Oral glutamine versus oral placebo studies

Outcome: 1 Mean duration (+/-SD) of time in hospital (e.g. admission to discharge or from day ’0’ to discharge).

Study or subgroup Oral Glutamine PlaceboMean

DifferenceMean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Anderson 1998 98 0 (0) 95 0 (0) 0.0 [ 0.0, 0.0 ]

Aquino 2005 57 0 (0) 63 0 (0) 0.0 [ 0.0, 0.0 ]

Coghlin Dickson 2000 29 0 (0) 29 0 (0) 0.0 [ 0.0, 0.0 ]

Jebb 1995 8 25.6 (2.2) 8 28.3 (5.5) -2.70 [ -6.80, 1.40 ]

Schloerb 1999 35 30.71 (15.19) 31 31.65 (20.69) -0.94 [ -9.79, 7.91 ]

Total (95% CI) 227 226 -2.39 [ -6.11, 1.34 ]

Heterogeneity: Chi2 = 0.12, df = 1 (P = 0.72); I2 =0.0%

Test for overall effect: Z = 1.26 (P = 0.21)

Test for subgroup differences: Not applicable

-10 -5 0 5 10

Oral Glutamine Placebo



Analysis 1.2. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 2 Mean(+/-SD) number of

days patients had some degree of mucositis from start to end of study..



Outcome: 2 Mean(+/-SD) number of days patients had some degree of mucositis from start to end of study.

Study or subgroup Oral glutamine PlaceboMean

DifferenceMean

Difference


Anderson 1998 98 0 (0) 95 0 (0) 0.0 [ 0.0, 0.0 ]

Aquino 2005 1 0 (0) 1 0 (0) 0.0 [ 0.0, 0.0 ]

Coghlin Dickson 2000 29 0 (0) 29 0 (0) 0.0 [ 0.0, 0.0 ]

Jebb 1995 8 0 (0) 8 0 (0) 0.0 [ 0.0, 0.0 ]

Schloerb 1999 35 0 (0) 31 0 (0) 0.0 [ 0.0, 0.0 ]

Total (95% CI) 171 164 0.0 [ 0.0, 0.0 ]

Heterogeneity: Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0%

Test for overall effect: Z = 0.0 (P < 0.00001)


-10 -5 0 5 10




Analysis 1.3. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 3 Number of patients

who developed line infections from start to end of study..



Outcome: 3 Number of patients who developed line infections from start to end of study.

Study or subgroup Oral Glutamine PlaceboPeto

Odds RatioPeto

Odds Ratio

n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI

Anderson 1998 0/98 0/95 0.0 [ 0.0, 0.0 ]

Aquino 2005 0/1 0/1 0.0 [ 0.0, 0.0 ]

Coghlin Dickson 2000 0/29 0/29 0.0 [ 0.0, 0.0 ]

Jebb 1995 0/8 0/8 0.0 [ 0.0, 0.0 ]

Schloerb 1999 0/35 0/31 0.0 [ 0.0, 0.0 ]

Total (95% CI) 171 164 0.0 [ 0.0, 0.0 ]

Total events: 0 (Oral Glutamine), 0 (Placebo)




0.1 0.2 0.5 1 2 5 10




Analysis 1.4. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 4 Difference in mean %

change in body weight from start to end of the study between the trial groups..



Outcome: 4 Difference in mean % change in body weight from start to end of the study between the trial groups.


DifferenceMean

Difference


Anderson 1998 98 0 (0) 95 0 (0) 0.0 [ 0.0, 0.0 ]

Aquino 2005 1 0 (0) 1 0 (0) 0.0 [ 0.0, 0.0 ]

Coghlin Dickson 2000 29 0 (0) 29 0 (0) 0.0 [ 0.0, 0.0 ]

Jebb 1995 8 0 (0) 8 0 (0) 0.0 [ 0.0, 0.0 ]

Schloerb 1999 32 0.06 (27.1) 26 -5.67 (22.7) 5.73 [ -7.09, 18.55 ]

Total (95% CI) 168 159 5.73 [ -7.09, 18.55 ]




-10 -5 0 5 10

Placebo Oral Glutamine



Analysis 1.5. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 5 Mean duration (+/-SD)

that nutritional intervention is given as PN..



Outcome: 5 Mean duration (+/-SD) that nutritional intervention is given as PN.


DifferenceMean

Difference


Aldamiz 1996 1 0 (0) 1 0 (0) 0.0 [ 0.0, 0.0 ]

Anderson 1998 98 0 (0) 95 0 (0) 0.0 [ 0.0, 0.0 ]

Aquino 2005 57 0 (0) 63 0 (0) 0.0 [ 0.0, 0.0 ]

Coghlin Dickson 2000 29 0 (0) 29 0 (0) 0.0 [ 0.0, 0.0 ]

Jebb 1995 8 11.3 (5) 8 6.6 (4.2) 4.70 [ 0.18, 9.22 ]

Schloerb 1999 35 8.89 (5.06) 31 17.55 (14.13) -8.66 [ -13.91, -3.41 ]

Total (95% CI) 228 227 -1.00 [ -4.42, 2.43 ]

Heterogeneity: Chi2 = 14.28, df = 1 (P = 0.00016); I2 =93%



-10 -5 0 5 10




Analysis 1.6. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 6 Number of patients

who developed > grade 2 graft versus host disease (GVHD)..



Outcome: 6 Number of patients who developed > grade 2 graft versus host disease (GVHD).


Odds RatioPeto

Odds Ratio


Anderson 1998 0/98 0/95 0.0 [ 0.0, 0.0 ]

Aquino 2005 0/1 0/1 0.0 [ 0.0, 0.0 ]

Coghlin Dickson 2000 0/29 0/29 0.0 [ 0.0, 0.0 ]

Jebb 1995 0/8 0/8 0.0 [ 0.0, 0.0 ]

Schloerb 1999 0/35 0/31 0.0 [ 0.0, 0.0 ]

Total (95% CI) 171 164 0.0 [ 0.0, 0.0 ]





0.1 0.2 0.5 1 2 5 10




Analysis 1.7. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 7 Number of days(+/-SD)

to achieve normal neutrophil level (>0.5 X 10/9/l) after day 0 of BMT..



Outcome: 7 Number of days(+/-SD) to achieve normal neutrophil level (>0.5 X 10/9/l) after day 0 of BMT.


DifferenceMean

Difference


Anderson 1998 98 0 (0) 95 0 (0) 0.0 [ 0.0, 0.0 ]

Aquino 2005 1 0 (0) 1 0 (0) 0.0 [ 0.0, 0.0 ]

Coghlin Dickson 2000 29 0 (0) 29 0 (0) 0.0 [ 0.0, 0.0 ]

Jebb 1995 8 28.4 (11.5) 8 25.4 (11.7) 3.00 [ -8.37, 14.37 ]

Schloerb 1999 35 19.26 (16.3) 31 11.45 (5.88) 7.81 [ 2.03, 13.59 ]

Total (95% CI) 171 164 6.82 [ 1.67, 11.98 ]




-10 -5 0 5 10




Analysis 1.8. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 8 Actual numbers of

patients who have completed the study and survived to the 100th day post BMT..



Outcome: 8 Actual numbers of patients who have completed the study and survived to the 100th day post BMT.


Odds RatioPeto

Odds Ratio


Anderson 1998 86/98 77/95 1.66 [ 0.76, 3.61 ]

Aquino 2005 51/57 57/63 0.90 [ 0.27, 2.94 ]

Coghlin Dickson 2000 0/29 0/29 0.0 [ 0.0, 0.0 ]

Jebb 1995 0/8 0/8 0.0 [ 0.0, 0.0 ]

Schloerb 1999 19/35 12/31 1.85 [ 0.71, 4.84 ]

Total (95% CI) 227 226 1.51 [ 0.88, 2.60 ]





0.1 0.2 0.5 1 2 5 10

Placebo Oral Glutamine



Analysis 1.9. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 9 Actual number of

patients who have completed the study and survived beyond day 100 post BMT..



Outcome: 9 Actual number of patients who have completed the study and survived beyond day 100 post BMT.


Odds RatioPeto

Odds Ratio


Anderson 1998 0/98 0/95 0.0 [ 0.0, 0.0 ]

Aquino 2005 0/57 0/63 0.0 [ 0.0, 0.0 ]

Coghlin Dickson 2000 0/29 0/29 0.0 [ 0.0, 0.0 ]

Jebb 1995 0/8 0/8 0.0 [ 0.0, 0.0 ]

Schloerb 1999 0/35 0/31 0.0 [ 0.0, 0.0 ]

Total (95% CI) 227 226 0.0 [ 0.0, 0.0 ]





0.1 0.2 0.5 1 2 5 10




Analysis 1.10. Comparison 1 Oral glutamine versus oral placebo studies, Outcome 10 Number with

positive blood cultures.



Outcome: 10 Number with positive blood cultures

Study or subgroup Treatment ControlPeto

Odds Ratio WeightPeto

Odds Ratio


Schloerb 1999 9/35 7/31 100.0 % 1.18 [ 0.39, 3.62 ]

Total (95% CI) 35 31 100.0 % 1.18 [ 0.39, 3.62 ]

Total events: 9 (Treatment), 7 (Control)

Heterogeneity: not applicable



0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Analysis 2.1. Comparison 2 PN + glutamine versus standard PN, Outcome 1 Mean duration(+/-SD) of time

in hospital (e.g. admission to discharge or from day 0 to discharge home)..


Comparison: 2 PN + glutamine versus standard PN

Outcome: 1 Mean duration(+/-SD) of time in hospital (e.g. admission to discharge or from day 0 to discharge home).

Study or subgroup PN + Glutamine Standard PNMean

Difference WeightMean

Difference


Brown 1998 16 28.25 (6.93) 16 37.44 (25.37) 1.4 % -9.19 [ -22.08, 3.70 ]

Pytlik 2002 21 13.5 (3.1) 19 11.27 (2.4) 77.2 % 2.23 [ 0.52, 3.94 ]

Schloerb 1993 16 26.9 (5.2) 13 32.7 (7.57) 9.6 % -5.80 [ -10.64, -0.96 ]

Ziegler 1992 22 29 (4.69) 20 36 (8.94) 11.8 % -7.00 [ -11.38, -2.62 ]

Total (95% CI) 75 68 100.0 % 0.22 [ -1.29, 1.72 ]




-10 -5 0 5 10

PN + Glutamine Standard PN



Analysis 2.2. Comparison 2 PN + glutamine versus standard PN, Outcome 2 Mean(+/-SD) cumulative

mucositis score.



Outcome: 2 Mean(+/-SD) cumulative mucositis score


DifferenceMean

Difference


Brown 1998 18 0 (0) 16 0 (0) 0.0 [ 0.0, 0.0 ]

Pytlik 2002 21 13.5 (2.3) 19 12.6 (1.5) 0.90 [ -0.29, 2.09 ]

Schloerb 1993 16 0.7 (0.8) 13 0.9 (0.72) -0.20 [ -0.75, 0.35 ]

Ziegler 1992 24 2.1 (1.96) 20 2.2 (2.23) -0.10 [ -1.35, 1.15 ]

Total (95% CI) 79 68 -0.02 [ -0.48, 0.45 ]




-10 -5 0 5 10




Analysis 2.3. Comparison 2 PN + glutamine versus standard PN, Outcome 3 Number of patients who

developed line infections from start to end of study..




Study or subgroup PN + Glutamine Standard PNPeto

Odds RatioPeto

Odds Ratio


Brown 1998 0/18 0/16 0.0 [ 0.0, 0.0 ]

Pytlik 2002 0/1 0/1 0.0 [ 0.0, 0.0 ]

Schloerb 1993 0/16 0/13 0.0 [ 0.0, 0.0 ]

Ziegler 1992 0/24 0/21 0.0 [ 0.0, 0.0 ]

Total (95% CI) 59 51 0.0 [ 0.0, 0.0 ]

Total events: 0 (PN + Glutamine), 0 (Standard PN)




0.1 0.2 0.5 1 2 5 10




Analysis 2.4. Comparison 2 PN + glutamine versus standard PN, Outcome 4 Difference in mean % change

in body weight from start to end of the study between the trial groups..





DifferenceMean

Difference


Brown 1998 16 -6.85 (1.74) 15 -7.45 (2.54) 0.60 [ -0.94, 2.14 ]

Pytlik 2002 1 0 (0) 1 0 (0) 0.0 [ 0.0, 0.0 ]

Schloerb 1993 16 -0.61 (1.17) 13 0.56 (2.46) -1.17 [ -2.62, 0.28 ]

Ziegler 1992 24 0 (0) 21 0 (0) 0.0 [ 0.0, 0.0 ]

Total (95% CI) 57 50 -0.34 [ -1.40, 0.72 ]




-10 -5 0 5 10

Standard PN PN + Glut



Analysis 2.5. Comparison 2 PN + glutamine versus standard PN, Outcome 5 Mean duration (+/-SD) that

nutritional intervention is given..



Outcome: 5 Mean duration (+/-SD) that nutritional intervention is given.


Difference WeightMean

Difference


Brown 1998 18 23.22 (10.22) 16 18.81 (11.72) 7.1 % 4.41 [ -3.02, 11.84 ]

Pytlik 2002 21 3.5 (4.2) 19 2.8 (3.5) 69.3 % 0.70 [ -1.69, 3.09 ]

Schloerb 1993 16 30 (20) 13 31 (10.82) 3.0 % -1.00 [ -12.43, 10.43 ]

Ziegler 1992 24 26 (9.8) 20 28 (4.47) 20.6 % -2.00 [ -6.38, 2.38 ]

Total (95% CI) 79 68 100.0 % 0.36 [ -1.63, 2.35 ]




-10 -5 0 5 10




Analysis 2.6. Comparison 2 PN + glutamine versus standard PN, Outcome 6 Number of patients who

developed >/=grade 2 graft versus host disease (GVHD)..



Outcome: 6 Number of patients who developed >/=grade 2 graft versus host disease (GVHD).


Odds RatioPeto

Odds Ratio


Brown 1998 0/18 3/16 0.10 [ 0.01, 1.08 ]

Pytlik 2002 0/1 0/1 0.0 [ 0.0, 0.0 ]

Schloerb 1993 0/16 0/13 0.0 [ 0.0, 0.0 ]

Ziegler 1992 6/24 5/20 1.00 [ 0.26, 3.88 ]

Total (95% CI) 59 50 0.57 [ 0.18, 1.83 ]





0.1 0.2 0.5 1 2 5 10




Analysis 2.7. Comparison 2 PN + glutamine versus standard PN, Outcome 7 Number of days(+/-SD) to

achieve normal neutrophil level (>0.5 X 10/9/l) after day 0 of BMT..





DifferenceMean

Difference


Brown 1998 17 14.88 (5.33) 14 17.36 (7.74) -2.48 [ -7.26, 2.30 ]

Pytlik 2002 1 0 (0) 1 0 (0) 0.0 [ 0.0, 0.0 ]

Schloerb 1993 16 14 (8) 13 15 (6.85) -1.00 [ -6.41, 4.41 ]

Ziegler 1992 24 20 (4.9) 20 18 (4.47) 2.00 [ -0.77, 4.77 ]

Total (95% CI) 58 48 0.57 [ -1.63, 2.76 ]




-10 -5 0 5 10




Analysis 2.8. Comparison 2 PN + glutamine versus standard PN, Outcome 8 Actual numbers of patients

who have completed the study and survived to the 100th day post BMT..





Odds RatioPeto

Odds Ratio


Brown 1998 17/18 15/16 1.13 [ 0.07, 18.94 ]

Pytlik 2002 0/1 0/1 0.0 [ 0.0, 0.0 ]

Schloerb 1993 0/16 0/13 0.0 [ 0.0, 0.0 ]

Ziegler 1992 20/24 18/20 0.58 [ 0.10, 3.18 ]

Total (95% CI) 59 50 0.69 [ 0.16, 2.97 ]





0.1 0.2 0.5 1 2 5 10




Analysis 2.9. Comparison 2 PN + glutamine versus standard PN, Outcome 9 Number of patients with

positive blood cultures.



Outcome: 9 Number of patients with positive blood cultures


Odds RatioPeto

Odds Ratio


Brown 1998 0/18 0/16 0.0 [ 0.0, 0.0 ]

Pytlik 2002 8/21 6/19 1.32 [ 0.37, 4.78 ]

Schloerb 1993 11/16 11/13 0.43 [ 0.08, 2.33 ]

Ziegler 1992 14/24 19/20 0.15 [ 0.04, 0.57 ]

Total (95% CI) 79 68 0.46 [ 0.20, 1.04 ]





0.1 0.2 0.5 1 2 5 10

Favours PN+Glutamine Favours Standard PN



Analysis 3.1. Comparison 3 PN vs IV hydration, Outcome 1 Mean duration (+/-SD) of time in hospital (e.g.

from discharge admission to discharge or day 0 to discharge)..


Comparison: 3 PN vs IV hydration

Outcome: 1 Mean duration (+/-SD) of time in hospital (e.g. from discharge admission to discharge or day 0 to discharge).

Study or subgroup Parenteral nutrition Intravenous hydratnMean

DifferenceMean

Difference


Lough 1990 14 0 (0) 15 0 (0) 0.0 [ 0.0, 0.0 ]

Roberts 2003a 27 28.7 (8.8) 28 25.4 (4.3) 3.30 [ -0.38, 6.98 ]

Weisdorf 1987 71 0 (0) 66 0 (0) 0.0 [ 0.0, 0.0 ]

Total (95% CI) 112 109 3.30 [ -0.38, 6.98 ]




-10 -5 0 5 10

Favours PN Favours IV



Analysis 3.2. Comparison 3 PN vs IV hydration, Outcome 2 Mean(+/-SD) number of days patients had some

degree of mucositis from start to end of study..




Study or subgroup Parenteral nutrition Intravenous HydratnMean

DifferenceMean

Difference


Lough 1990 14 0 (0) 15 0 (0) 0.0 [ 0.0, 0.0 ]

Roberts 2003a 27 0 (0) 28 0 (0) 0.0 [ 0.0, 0.0 ]

Weisdorf 1987 71 0 (0) 66 0 (0) 0.0 [ 0.0, 0.0 ]

Total (95% CI) 112 109 0.0 [ 0.0, 0.0 ]




-10 -5 0 5 10




Analysis 3.3. Comparison 3 PN vs IV hydration, Outcome 3 Number of patients who developed line

infections from start to end of study..




Study or subgroup Parenteral nutrition Intravenous hydratnPeto

Odds RatioPeto

Odds Ratio


Lough 1990 8/10 1/15 21.23 [ 4.15, 108.73 ]

Roberts 2003a 0/27 0/28 0.0 [ 0.0, 0.0 ]

Weisdorf 1987 0/71 0/66 0.0 [ 0.0, 0.0 ]

Total (95% CI) 108 109 21.23 [ 4.15, 108.73 ]

Total events: 8 (Parenteral nutrition), 1 (Intravenous hydratn)




0.1 0.2 0.5 1 2 5 10




Analysis 3.4. Comparison 3 PN vs IV hydration, Outcome 4 Difference in mean % change in body weight

from start to end of the study between the trial groups..





DifferenceMean

Difference


Lough 1990 10 -4.42 (2.3) 15 -7.18 (0.9) 2.76 [ 1.26, 4.26 ]

Roberts 2003a 27 -2 (13.8) 28 -6.5 (17.7) 4.50 [ -3.87, 12.87 ]

Weisdorf 1987 71 0 (0) 66 0 (0) 0.0 [ 0.0, 0.0 ]

Total (95% CI) 108 109 2.81 [ 1.34, 4.29 ]




-10 -5 0 5 10

Favours IV Favours PN



Analysis 3.5. Comparison 3 PN vs IV hydration, Outcome 5 Mean duration (+/-SD) that nutritional

intervention is given..




Study or subgroup Parenteral nutrition Intravenous HydratnMean

DifferenceMean

Difference


Lough 1990 14 10 (4) 15 0 (0) 0.0 [ 0.0, 0.0 ]

Roberts 2003a 27 17.5 (7.4) 28 5.3 (5.9) 12.20 [ 8.66, 15.74 ]

Weisdorf 1987 71 0 (0) 66 0 (0) 0.0 [ 0.0, 0.0 ]

Total (95% CI) 112 109 12.20 [ 8.66, 15.74 ]




-10 -5 0 5 10




Analysis 3.6. Comparison 3 PN vs IV hydration, Outcome 6 Number of patients who developed > grade 2

graft versus host disease (GVHD)..




Study or subgroup Parenteral nutrition Intravenous HydratnPeto

Odds RatioPeto

Odds Ratio


Lough 1990 0/14 0/15 0.0 [ 0.0, 0.0 ]

Roberts 2003a 0/27 0/28 0.0 [ 0.0, 0.0 ]

Weisdorf 1987 0/71 0/66 0.0 [ 0.0, 0.0 ]

Total (95% CI) 112 109 0.0 [ 0.0, 0.0 ]

Total events: 0 (Parenteral nutrition), 0 (Intravenous Hydratn)




0.1 0.2 0.5 1 2 5 10




Analysis 3.7. Comparison 3 PN vs IV hydration, Outcome 7 Number of days(+/-SD) to achieve normal

neutrophil level (>0.5 X 10/9/l) after day 0 of BMT..





DifferenceMean

Difference


Lough 1990 14 0 (0) 15 0 (0) 0.0 [ 0.0, 0.0 ]

Roberts 2003a 27 0 (0) 28 0 (0) 0.0 [ 0.0, 0.0 ]

Weisdorf 1987 71 0 (0) 66 0 (0) 0.0 [ 0.0, 0.0 ]

Total (95% CI) 112 109 0.0 [ 0.0, 0.0 ]




-10 -5 0 5 10




Analysis 3.8. Comparison 3 PN vs IV hydration, Outcome 8 Actual numbers of patients who have

completed the study and survived to the 100th day post BMT..





Odds RatioPeto

Odds Ratio


Lough 1990 0/14 0/15 0.0 [ 0.0, 0.0 ]

Roberts 2003a 0/27 0/28 0.0 [ 0.0, 0.0 ]

Weisdorf 1987 0/71 0/66 0.0 [ 0.0, 0.0 ]

Total (95% CI) 112 109 0.0 [ 0.0, 0.0 ]





0.1 0.2 0.5 1 2 5 10




Analysis 3.9. Comparison 3 PN vs IV hydration, Outcome 9 Actual number of patients who survived to day

200 post BMT..



Outcome: 9 Actual number of patients who survived to day 200 post BMT.


Odds RatioPeto

Odds Ratio


Lough 1990 10/14 8/15 2.10 [ 0.48, 9.18 ]

Roberts 2003a 0/27 0/28 0.0 [ 0.0, 0.0 ]

Weisdorf 1987 0/71 0/66 0.0 [ 0.0, 0.0 ]

Total (95% CI) 112 109 2.10 [ 0.48, 9.18 ]





0.1 0.2 0.5 1 2 5 10




Analysis 3.10. Comparison 3 PN vs IV hydration, Outcome 10 Mean % change in albumin.



Outcome: 10 Mean % change in albumin

Study or subgroup PN Intravenous hydratioMean

DifferenceMean

Difference


Lough 1990 10 -1.24 (5.3) 15 4.69 (4.4) -5.93 [ -9.90, -1.96 ]

Roberts 2003a 27 12.9 (6) 28 15.6 (4) -2.70 [ -5.41, 0.01 ]

Weisdorf 1987 71 0 (0) 66 0 (0) 0.0 [ 0.0, 0.0 ]

Total (95% CI) 108 109 -3.72 [ -5.96, -1.49 ]




-10 -5 0 5 10




Analysis 4.1. Comparison 4 PN vs enteral feeding studies, Outcome 1 Mean duration (+/-SD) of time in

hospital (e.g. from admission to discharge or day 0 to discharge)..


Comparison: 4 PN vs enteral feeding studies

Outcome: 1 Mean duration (+/-SD) of time in hospital (e.g. from admission to discharge or day 0 to discharge).

Study or subgroup Enteral ParenteralMean

DifferenceMean

Difference


Cope 1997 23 0 (0) 40 0 (0) 0.0 [ 0.0, 0.0 ]

Szeluga 1987 30 0 (0) 31 0 (0) 0.0 [ 0.0, 0.0 ]

Young 1997 10 0 (0) 10 0 (0) 0.0 [ 0.0, 0.0 ]

Total (95% CI) 63 81 0.0 [ 0.0, 0.0 ]




-10 -5 0 5 10

Favours Enteral Favours Parenteral



Analysis 4.2. Comparison 4 PN vs enteral feeding studies, Outcome 2 Mean(+/-SD) number of days patients

had some degree of mucositis from start to end of study..





DifferenceMean

Difference


Cope 1997 23 0 (0) 40 0 (0) 0.0 [ 0.0, 0.0 ]

Szeluga 1987 30 0 (0) 31 0 (0) 0.0 [ 0.0, 0.0 ]

Young 1997 10 0 (0) 10 0 (0) 0.0 [ 0.0, 0.0 ]

Total (95% CI) 63 81 0.0 [ 0.0, 0.0 ]




-10 -5 0 5 10

Favours enteral Favours parenteral



Analysis 4.3. Comparison 4 PN vs enteral feeding studies, Outcome 3 Number of patients who developed

line infections from start to end of study..




Study or subgroup Enteral ParenteralPeto

Odds RatioPeto

Odds Ratio


Cope 1997 0/23 0/40 0.0 [ 0.0, 0.0 ]

Szeluga 1987 0/30 0/31 0.0 [ 0.0, 0.0 ]

Young 1997 0/10 0/10 0.0 [ 0.0, 0.0 ]

Total (95% CI) 63 81 0.0 [ 0.0, 0.0 ]

Total events: 0 (Enteral), 0 (Parenteral)




0.1 0.2 0.5 1 2 5 10

Favours Enteral Favours Parenteral



Analysis 4.4. Comparison 4 PN vs enteral feeding studies, Outcome 4 Difference in mean % change in body

weight from start to end of the study between the trial groups..





DifferenceMean

Difference


Cope 1997 23 0 (0) 40 0 (0) 0.0 [ 0.0, 0.0 ]

Szeluga 1987 30 0 (0) 31 0 (0) 0.0 [ 0.0, 0.0 ]

Young 1997 10 0 (0) 10 0 (0) 0.0 [ 0.0, 0.0 ]

Total (95% CI) 63 81 0.0 [ 0.0, 0.0 ]




-10 -5 0 5 10

Favours Parenteral Favours enteral



Analysis 4.5. Comparison 4 PN vs enteral feeding studies, Outcome 5 Mean duration (+/-SD) that

nutritional intervention is given..





DifferenceMean

Difference


Cope 1997 23 0 (0) 40 0 (0) 0.0 [ 0.0, 0.0 ]

Szeluga 1987 30 0 (0) 31 0 (0) 0.0 [ 0.0, 0.0 ]

Young 1997 10 0 (0) 10 0 (0) 0.0 [ 0.0, 0.0 ]

Total (95% CI) 63 81 0.0 [ 0.0, 0.0 ]




-10 -5 0 5 10




Analysis 4.6. Comparison 4 PN vs enteral feeding studies, Outcome 6 Number of patients who developed >

grade 2 graft versus host disease (GVHD)..





Odds RatioPeto

Odds Ratio


Cope 1997 0/23 0/40 0.0 [ 0.0, 0.0 ]

Szeluga 1987 0/30 0/31 0.0 [ 0.0, 0.0 ]

Young 1997 0/10 0/10 0.0 [ 0.0, 0.0 ]

Total (95% CI) 63 81 0.0 [ 0.0, 0.0 ]





0.1 0.2 0.5 1 2 5 10




Analysis 4.7. Comparison 4 PN vs enteral feeding studies, Outcome 7 Number of days(+/-SD) to achieve

normal neutrophil level (>0.5 X 10/9/l) after day 0 of BMT..





DifferenceMean

Difference


Cope 1997 23 0 (0) 40 0 (0) 0.0 [ 0.0, 0.0 ]

Szeluga 1987 30 0 (0) 31 0 (0) 0.0 [ 0.0, 0.0 ]

Young 1997 10 0 (0) 10 0 (0) 0.0 [ 0.0, 0.0 ]

Total (95% CI) 63 81 0.0 [ 0.0, 0.0 ]




-10 -5 0 5 10




Analysis 4.8. Comparison 4 PN vs enteral feeding studies, Outcome 8 Actual numbers of patients who have

completed the study and survived to the 100th day post BMT..





Odds RatioPeto

Odds Ratio


Cope 1997 0/23 0/40 0.0 [ 0.0, 0.0 ]

Szeluga 1987 0/30 0/31 0.0 [ 0.0, 0.0 ]

Young 1997 0/10 0/10 0.0 [ 0.0, 0.0 ]

Total (95% CI) 63 81 0.0 [ 0.0, 0.0 ]





0.1 0.2 0.5 1 2 5 10




Analysis 4.9. Comparison 4 PN vs enteral feeding studies, Outcome 9 Actual number of patients who have

completed the study and survived beyond day 200 post BMT..



Outcome: 9 Actual number of patients who have completed the study and survived beyond day 200 post BMT.


Odds RatioPeto

Odds Ratio


Cope 1997 0/23 0/40 0.0 [ 0.0, 0.0 ]

Szeluga 1987 0/30 0/31 0.0 [ 0.0, 0.0 ]

Young 1997 0/10 0/10 0.0 [ 0.0, 0.0 ]

Total (95% CI) 63 81 0.0 [ 0.0, 0.0 ]





0.1 0.2 0.5 1 2 5 10


Analysis 5.1. Comparison 5 Oral eicosapentaenoic acid supplementation versus nil, Outcome 1 Numbers

not developing graft versus host disease.


Comparison: 5 Oral eicosapentaenoic acid supplementation versus nil

Outcome: 1 Numbers not developing graft versus host disease

Study or subgroup Treatment Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Takatsuka 2002 3/8 0/9 100.0 % 12.09 [ 0.52, 280.40 ]

Total (95% CI) 8 9 100.0 % 12.09 [ 0.52, 280.40 ]

Total events: 3 (Treatment), 0 (Control)

Heterogeneity: not applicable



0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control



A D D I T I O N A L T A B L E S

Table 1. Summary table - Quality of studies assessed

Study ID Randomisation Allocation con-

ceal

Double blind Participants

masked

Clinicians

masked

Assessors

masked

Anderson 1998 Truly random Adequate Yes Yes Yes Yes

Jebb 1995 Unclear Unclear Yes Yes Yes Yes

Schloerb 1999 Truly random Adequate Yes Yes Yes Yes

Coghlin

Dickson 2000

Unclear Unclear Yes Yes Unclear Unclear

Brown 1998 Truly random Adequate Yes Yes Yes Yes

Schloerb 1993 Truly random Adequate Yes Yes Yes Yes

Ziegler 1992 Unclear Adequate Yes Yes Yes Uncertain

Lough 1990 Truly random Adequate No No No No

Weisdorf 1987 Unclear Unclear No Uncertain Uncertain Uncertain

Szeluga 1987 Unclear Unclear No Uncertain Uncertain Uncertain

Young 1997 Unclear Unclear No Uncertain Uncertain Uncertain

Cope 1997 Unclear Unclear No Uncertain Uncertain Uncertain

Macburney

1994

Unclear Unclear Yes Yes Yes Yes

Scheltinga 1991 Unclear Unclear Yes Yes Yes Uncertain

Young 1993 Unclear Unclear Yes Yes Yes Yes

Ziegler 1998 Unclear Unclear Yes Uncertain Uncertain Uncertain

Charhuas 1997 Unclear Unclear Yes Yes Yes Yes

Mulder 1989 Unclear Unclear No Uncertain Uncertain Uncertain

Lenssen 1998 Unclear Unclear Uncertain Uncertain Uncertain Uncertain



Table 1. Summary table - Quality of studies assessed (Continued)

Aldamiz 1996 Unclear Unclear Uncertain Uncertain Uncertain Uncertain

Lenssen 1987 Truly random Adequate Yes Yes Yes Yes

Jimenez 1999

Malhotra 1996 Unclear Unclear Uncertain Uncertain Uncertain Uncertain

Muscaritoli

1998

Unclear Unclear No No No Uncertain

Takatsuka 2002 Unclear Unclear No Uncertain Uncertain Uncertain

Roberts 2003a Unclear Unclear No No No Uncertain

Pytilik 2002 Truly random Adequate Yes Yes Yes Yes

Santos 2001 Truly random Adequate Uncertain Uncertain Uncertain Uncertain

Aquino 2005 Truly random Adequate Yes Unclear Unclear Unclear

A P P E N D I C E S

Appendix 1. Example search strategy

#1 explode “Nutrition”/ all subheadings

#2 explode “Nutrition-Assessment”/ all subheadings

#3 explode “Feeding-Methods”/ all subheadings

#4 “Intubation,-Gastrointestinal”/ all subheadings

#5 “Gastrostomy”/ all subheadings

#6 “Eating”/ all subheadings

#7 explode “Foods,-Specialized”/ all subheadings

#8 explode “Food”/ all subheadings

#9 explode “Feeding-Behavior”/ all subheadings

#10 explode “Appetite”/ all subheadings

#11 “Jejunostomy”/ all subheadings

#12 “Glutamine”/ all subheadings

#13 glutamin*

#14 nutrition*

#15 food*

#16 feed*

#17 nasogastr*

#18 nasojejun*

#19 nasoduoden*

#20 gastrostom*



#21 gastrojejunostom*

#22 naso near duoden*

#23 naso near1 gastr*

#24 jejun*

#25 bolus*

#26 intub*

#27 appetite*

#28 parenteral*

#29 calor*

#30 intake*

#31 sip*

#32 oral*

#33 diet*

#34 intraven*

#35 enteral*

#36 tube*

#37 supplement*

#38 fortif*

#39 formula*

#40 eat*

#41 hydrolysate*

#42 novel* substrate*

#43 elemental

#44 PN in TI,TO,CM,AB

#45 EN in TI,TO,CM,AB

#46 TPN in TI,TO,CM,AB

#47 NG in TI,TO,CM,AB

#48 PEG in TI,TO,CM,AB

#49 “Bone-Marrow-Transplantation”/ all subheadings

#50 bone marrow near transplan*

#51 Peripheral blast stem cell transplan*

#52 BMT*

#53 MATCH* SIB* DON*

#54 MATCH* UNREL* DON*

#56 PBSCT*

#57 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 # or #14 or #15 or #16 or #17 or #18 or #19 or #

20 or #21 or #22 or #23 or #24 or #5 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38

or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48

#58 #49 or #50 or #51 or #52 or #53 or #54 or #55 or #56

#59 #57 and #58

F E E D B A C K



Including the study by Pytlik 2002, 2 October 2013

Summary

With regard to the analysis ’Parenteral nutrition with glutamine versus standard parenteral nutrition’ I would respectfully ask the authors

to consider the appropriateness of including the study by Pytlik 2002. The intervention group received daily GLN supplementation

from day +1 to day +14 of transplant regardless of their need for PN. In fact the intervention group received PN for just 3.5 days on

average. Hence this study was not of glutamine supplemented PN.If there is a benefit of GLN it is likely to be in those patients requiring

nutritional support as per the other studies originally included (Ziegler and Schloerb). Subsequent studies have shown a benefit in

allogeneic but not autologous transplant patients - if this review were to be updated it would be very useful to see meta-analysis per

transplant type“

Name: Julie Beckerson

Affiliation: Imperial College Healthcare NHS Trust

Role: Haematology Dietitian

Reply

The inclusion criteria for this review were: Study type- Randomised Controlled Trial, Patient type - receiving any type of bone marrow

transplant, and the Type of Intervention- must compare one form of enteral or parenteral nutrition with another mode of nutrition

support or IV fluid. There was no minimum or maximum duration specified for receiving the intervention.

With the Pytilik 2002 study, the intervention group received daily GLN supplementation from day +1 to day +14 of transplant

regardless of their need for PN. The intervention group received PN for just 3.5 days on average.

The duration for receiving the PN with or without GLN (albeit for an average of 3.5 days ) was not a reason for excluding this study.

The hypothesis being that we do not know the optimum duration for receiving the intervention. This remains an included study.

In a future update a meta-analysis for the different types of transplants would be worthy to investigate.

Contributors

Susan Murray, Royal College of Physicians.

W H A T ’ S N E W

Last assessed as up-to-date: 30 April 2008.

Date Event Description

4 April 2014 Amended This review has been withdrawn. Please see Published notes.



H I S T O R Y

Protocol first published: Issue 1, 2001

Review first published: Issue 2, 2002

Date Event Description

4 April 2014 Feedback has been incorporated Feedback added regarding a query about the appro-

priateness of the Pytilik 2002 study for inclusion. See

Feedback.

12 November 2008 Amended Contact details updated

13 August 2008 Amended This review update should have been put up for publi-

cation in Issue 3, 2008 but unfortunately due to tech-

nical error did not make it

14 May 2008 Amended Converted to new review format.

30 April 2008 New citation required and conclusions have changed This review is made up of four small sub reviews. For

the update of this review 17 potential studies were

identified in the re-run of the search which was con-

ducted in June 2006. Five of the 17 studies were in-

cluded, three of which were grouped within three other

reviews which are included in this review that is:

Oral Glutamine versus placebo (one study Aquino

2005 (n = 120 children)), Parenteral nutrition (PN)

with Glutamine versus standard PN (one study Pytilik

2002 (n = 40)) and Parenteral nutrition versus Intra-

venous hydration (one study Roberts 2003 (n = 55))

. The two other studies were not pooled but added to

the eight other heterogenous studies identified in the

original review

The addition of data from the studies by Aquino 2005

and Roberts 2003 does not affect the results or conclu-

sions of the sub reviews that they were part of. How-

ever, for the sub review that compared PN with addi-

tional glutamine versus standard PN, following further

analysis with the additional data from Pytilik 2002 the

pooled result for hospital duration did not show the

same benefit to patients who received the interven-

tion PN with Glutamine in that, hospital duration no

longer seemed to be reduced for patients who received

the intervention. However, the likelihood that these

patients will have less infections remains the same. In

the original review of this material we proposed that

for patients who were unable to have an adequate oral

diet and who had gastrointestinal failure resulting in

the need for PN, PN with added glutamine should be



(Continued)

considered. We would now alter this to say that giv-

ing patients PN with additional glutamine could be of

benefit but also further research on this is required to

further confirm this.

Previous readers of this review would benefit from

reading this updated review

C O N T R I B U T I O N S O F A U T H O R S

SM & SP both worked on the protocol, review and the update with SM primarily writing up the revisions to the text for the update.

D E C L A R A T I O N S O F I N T E R E S T

None known

N O T E S

This review is now out of date although it is correct as of the date of publication [Issue 4, 2008]. The original author team is unable

to complete the update, hence the decision to withdraw.

We are seeking new authors to develop a new protocol which would serve to update the existing review and incorporate the latest

evidence into a new Cochrane Review. However, we would suggest that the current topic is too broad and would therefore recommend

reassessing the title prior to registration. Please contact PaPaS if you are interested: http://papas.cochrane.org/contact-us.

I N D E X T E R M SMedical Subject Headings (MeSH)

∗Enteral Nutrition; ∗Parenteral Nutrition; Bone Marrow Transplantation [∗adverse effects]; Fluid Therapy [methods]; Glutamine

[administration & dosage]; Length of Stay; Malnutrition [etiology; ∗prevention & control]; Randomized Controlled Trials as Topic

MeSH check words

Humans



http://papas.cochrane.org/contact-us





Documents

Murray & Pindoria-2014