EAL

ONC: Hematopoietic Cell Transplant (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

to test whether if the administration of lipids to bone marrow transplant patients (autologous or allogeneic) resulted in more bacterial or fungal infections

Inclusion Criteria:

Patients diagnosed with a malignancy who were having either allogeneic or autologous marrow transplant at the Fred Hutchinson Cancer Research Center in Seattle, WA, USA
Signed informed consent

Exclusion Criteria:

Not the patient's first transplant
Allergy to lipid emulsions
Hypertriglyceridemia
Already has or being treated for a culture-proven infection
Histioincompatible with their donor
had a dose of 100 g lipid in the prior month

No age restrictions

Description of Study Protocol:

Recruitment: 512 patients undergoing marrow transplant for hematologic malignancy were recruited and enrolled in this study at Fred Hutchinson Cancer Center.

Design: Patients were randomly assigned on the 3rd day of conditioning to receive either the low dose lipid TPN (6-8% total energy needs as lipids) or the standard dose (25-30%.) Patients were stratified for conditions that might impact the incidence of infection (GVHD prophylaxis, total body irradiation as part of the conditioning regimen, prescribed pentoxifylline or fluconazole, IV immunoglobulin or recombinant growth factors.)

Blinding used: Not indicated

Intervention:

Low dose TPN- 6-8% total energy needs as lipids

Standard dose TPN- 25-30% total energy needs as lipids

Daily energy requirements were calculated at 1.5 x BEE for adults (1.6x BEE for kids). Oral intake allowed; low bacterial diet in laminar air flow rooms and regular diet in standard reverse isolation rooms. Oral and parenteral intake were calculated daily to provide 1.5 x BEE.

TPN started when oral intake fell below BEE. Lipids continued until oral intake exceeded 10 kcal/kg for two consecutive days. Dextrose and amino acid continued at the discretion of the medical team.

Lipids were infused over 12 hours for both groups. Serum glucose was maintained at less than 200 mg/dL by adding insulin to the dextrose/amino acid solution with sliding scale as needed.

Statistical Analysis:

Intent-to-treat analysis was only used for primary endpoint and rate of subsequent blood infections in patients who were found to have an infection within 24 hours of randomization.
Log-rank test for association between hazard of infection and lipid group (excluded early discharge, death or treatment failure) and association between lipid group and engraftment, GVHD, relapse and death (excluded for patients who died before engraftment, GVHD or relapse)
Cox regression for multivariate failure data used to assess association of lipid group and blood infections for those with multiple blood infections
Significance for final analysis set at 0.0475 (<0.0025 for interim analysis)

Data Collection Summary:

Timing of Measurements:

Primary endpoint - time to 1st bacteremia or fungemia by 30 days posttransplant or discharge, whichever comes first

Secondary endpoints -

time to first bacteremia/fungemia by 60 days posttransplant
time to first infection at any site by 30 and 60 days posttransplant
rate of subsequent infections after initial infection

Serum glucose and caloric intake measured daily

Essential fatty acids were checked on day 20 and day 40

Dependent Variables

Bacteremia or fungemia- one or more positive blood cultures
Other sites of infection - cellulitis; pneumonia; esophagitis; infection of liver, kidneys, spleen, or brain; infection of CNS, peritoneal or pleural cavities, urinary tract infection; or infection of central venous catheter.

Independent Variables

Low dose TPN- 6-8% lipids

Control Variables

Standard dose TPN- 25-30% lipids

Description of Actual Data Sample:

Initial N: 512 patients

Standard group- 253 patients (153 male/100 female)

Low dose group- 259 patients (142 male/117 female)

Attrition (final N): 474

Standard group - 236 (13 lost to infection within 24 hours and 4 to treatment failure)

Low dose group- 238 (17 lost to infection within 24 hours and 4 to treatment failure)

Age:

Standard group - Median 35 years (range 0.5-65)

Low dose group - Median 35 years (range 0.4-67)

Ethnicity: not disclosed

Other relevant demographics:

No differences for age, sex, type of transplant (autologous or allogeneic or unrelated donor), diagnosis (hematologic malignancies), laminar air flow isolation, or treatment protocols.

Anthropometrics (e.g., were groups same or different on important measures)

Location: Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Summary of Results:

Lipid group and time to first blood infection within 30 days of transplant

Intent to treat analysis: no association (P=0.98), 63 in each group had an infection
Excluding those with infection within 24 hours of lipids: no association (P=0.95), 55 in standard dose, 54 in low dose
Mean time to first infection: 13.3 +/- 8.7 days for standard dose, 14.1+/- 7.6 days for low dose group

Lipid group and time to bacterial of fungal infection within 30 days of tranplant

No association (p=0.94), 7 in SD and 8 in LD

Lipid group and time to first infection within 60 days of transplant

NS for time to first infection (P=0.58)
NS for first infection at any site (P=0.77)

Effect of lipid group to rate of multiple infections NS (P=0.36)

Effect of serum glucose

the time to first bacteremia/fungemia was adjusted and analyzed based of levels of serum glucose and did not show any effect

Engraftment

SD- 224 patients (93%) and LD- 227 patients (94%) experienced engraftment
No association between lipid group and time to engraftment (P=0.20); SD was 23 +/- 8.5 days, LD 22.3 +/-6.7 days

GVHD

149 (77%) SD and 148 (75%) LD developed acute GVHD (grades II-IV) of those undergoing allogeneic transplants
No association between lipid groups and time to GVHD (P=0.30)

Time to relapse

At 15O days post-transplant, no difference between groups (P=0.82); 25 patients in SD and 27 patients in LD

Survival

At 60 days posttransplant, no difference between groups (P=0.55); 32 SD and 37 LD
At 150 days posttransplant, no significant difference again (P=0.48); 79 SD and 72 LD

Author Conclusion:

This study had a large enough sample size to detect meaningful differences between groups if they existed.
The lower dose group did not experienced higher levels of serum glucose, but there was 3 treatment failures due to inability to meet energy needs from glucose, suggesting that some marrow transplants may need more than 6-8% lipid calories.
Low dose lipids did not have any impact on incidence of infections in BMT patients. As a result, clinicians should feel comfortable adjusting nutrition support regimens (more CHO or more lipids) without concern for infection risk.

Funding Source:

Government:

NIH

Reviewer Comments:

Study did include pediatric patients (% of overall patients unknown)

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	No
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		???
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	???
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	???
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	Yes
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	Yes
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	???